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Chemical Structure| 191732-72-6
Chemical Structure| 191732-72-6
Structure of 191732-72-6 * Storage: {[proInfo.prStorage]}
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Product Details of [ 191732-72-6 ]

CAS No. :191732-72-6 MDL No. :MFCD07772307
Formula : C13H13N3O3 Boiling Point : -
Linear Structure Formula :- InChI Key :GOTYRUGSSMKFNF-UHFFFAOYSA-N
M.W : 259.26 Pubchem ID :216326
Synonyms :
CC-5013

Calculated chemistry of [ 191732-72-6 ]

Physicochemical Properties

Num. heavy atoms : 19
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.31
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 74.93
TPSA : 92.5 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -8.24 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.06
Log Po/w (XLOGP3) : -0.5
Log Po/w (WLOGP) : -0.88
Log Po/w (MLOGP) : 0.14
Log Po/w (SILICOS-IT) : 0.61
Consensus Log Po/w : 0.09

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.3
Solubility : 13.0 mg/ml ; 0.0501 mol/l
Class : Very soluble
Log S (Ali) : -0.97
Solubility : 27.5 mg/ml ; 0.106 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.81
Solubility : 0.406 mg/ml ; 0.00157 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.33

Safety of [ 191732-72-6 ]

Signal Word:Danger Class:N/A
Precautionary Statements:P501-P202-P201-P280-P308+P313-P405 UN#:N/A
Hazard Statements:H360 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 191732-72-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 191732-72-6 ]

[ 191732-72-6 ] Synthesis Path-Downstream   1~84

  • 1
  • [ 827026-45-9 ]
  • [ 879126-98-4 ]
YieldReaction ConditionsOperation in experiment
98.2% With 5%-palladium/activated carbon; hydrogen; In ethanol; at 40℃; under 3000.3 Torr; 2) 0.4 g of 3-(4-nitro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dioneand 0.4 g of 5% palladium carbon were added to a solution of 15 ml of ethanol Kettle,Into the hydrogen (hydrogen pressure of 0.4MPa)In 40, C reduction reaction, the reaction was completed, filtered, the filtrate was concentrated under reduced pressure,Recrystallization of petroleum ether gave lenalidomide 21.6 g, yield 98.2%, HPLC purity 99.20%.
98% With sodium sulfide; ethanol; at 20℃; for 1h; Weigh 14.5g of 3- (7-nitro-3-oxo-1H-isoindol-2-yl) piperidine-2,6-dione prepared in step (6) and dissolve it in 200mL of absolute ethanol.Add 7.8g of reducing agent sodium sulfide,Reaction at room temperature for 1h,The ethanol was spin-dried to obtain 12.8 g of a white solid with a yield of 98%.
98% With sodium tetrahydroborate; ammonium chloride; In ethanol; water; at 90℃; for 1h; 116.4 g of 3- (4-nitro-1-oxoisoindololin-2-yl) piperidine-2,6-dione,A mixture of 88.7 g of sodium borohydride and 32.5 g of ammonium chloride was added to a mixed solution of 600 mL of water and 1.4 L of ethanol, and stirred at 90 C. for 1 hour.The mixture was then cooled to room temperature, filtered, and the resulting filtrate was evaporated in vacuo to a solid,It was redissolved in 500 mL of methanol, filtered through celite, and the filtrate was evaporated in vacuo to give the product.Light yellow solid, 103.6 g, yield 98%.
96.11% With palladium 10% on activated carbon; hydrogen; In ethanol; at 140℃; under 11251.1 Torr; for 0.00944444h;Green chemistry; Weigh the lenalidomide precursor nitro substance 300g add 7.5L of ethanol, stir well after adding 20 g of Pd-supported catalyst with 10% Pd / C activated carbon, mix thoroughly to form material I; Adjust the flow rate of the slurry pump so that the flow rate of the material I is 28.0 g / min, adjust the H2 gas flow meter flow rate of 300ml / min, the reaction temperature was 140 C, the molar ratio of nitrofen to H2 was 1: 3.5, the residence time of the reaction was 34s, the reaction pressure is 1.5MPa; The reaction solution was withdrawn from the outlet of the microchannel reactor and the solvent was distilled off under reduced pressure at 25 C. Then, 3 L of DMF was added and the mixture was stirred at room temperature for 30 minutes. Then, the supported catalyst was loaded with 10% Pd / C activated carbon catalyst of the water drop into the filtrate, about 30 minutes dripping finished, precipitation of a large number of solid, 5 C under the temperature stirring 1 hour, filtration, washing cake, 50 C vacuum drying for 12 hours, have lenalidomide 258.44g, the yield was 96.11% and the liquid purity was 99.4%.
96.0% With palladium 10% on activated carbon; hydrogen; In methanol; at 30 - 35℃; under 1500.15 - 2250.23 Torr; for 4h;Autoclave; Add 200 grams of methanol to a 500 ml stainless steel autoclave,21.8 g of 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione,1.0 g of 10% palladium on carbon catalyst,After replacing the nitrogen three times,Passing hydrogen,Keep the hydrogen pressure at 0.2-0.3 MPa,The reaction was carried out at 30-35 C for 4 hours.After replacing the nitrogen three times,Filtration removes palladium carbon,The filtrate is concentrated and evaporated to dryness.Recrystallized by adding 100 g of isopropyl alcohol.Obtained 18.7 grams of white solid to lenalidomide,The liquid phase purity is 99.7%,The product yield was 96.0%.
93.4% With palladium 10% on activated carbon; ammonium formate; In dimethyl sulfoxide; at 30 - 40℃; Compound II (<strong>[827026-45-9]3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindol-2-yl)piperidine-2,6-dione</strong>)(28.9 g, 0.1 mol), 10% palladium on carbon (10.0 g),Ammonium formate (15.8 g, 0.25 mol) was added to dimethyl sulfoxide (500 ml).Keep the temperature at 30~40 C, react for 7-8 h, filter hot,The filtrate was added to water (1500 ml), stirred and crystallized, and suction filtered.The filter cake is washed with water, and the filter cake is dried under vacuum at room temperature for 14 to 16 hours.Compound I (light yellow solid, 24.2 g),Mole yield: 93.4%.
92% With 5%-palladium/activated carbon; hydrogen; In ethanol; under 3040.2 Torr; for 1h; 3-(4-Nitro-1,3 dihydro-1-oxo-2-hydro-isoindol-2-yl)piperidine-2,6-dione 2.89 g (0.01 mol) was dissolved in 10 ml of ethanol.Add 5% palladium on carbon,4 atmospheres of hydrogen,Reaction 1h,The palladium carbon was removed by filtration, and the organic phase was evaporated to dryness to dryness, white product 2.38 g, yield 92%.
92.8% With palladium on activated charcoal; hydrogen; In ethanol; To step (2) the resulting 3-(4-nitro-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione (IV) (39.6 g, 9.5 mol) into the hydrogen, the catalyst palladium carbon (3.5 g) was added in the presence of an organic solvent ethanol solution (130 ml).a reduction reaction occurs, 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione (V) (34.65 g, 7.8 mol) the yield was 92.8%.
90% With iron; ammonium chloride; In ethanol; water; at 90℃; for 1.5h;Reflux; (V) (277.6 g, 0.96 mol) was slowly added to a solution of water (0.5 L) and ethanol (2.5 L), followed by slow addition of 3200 g of iron powder and continuous stirring to 90 C over 30 minutes. ) Was added to the system, refluxed for 1 h, concentrated, then 2 L of methanol was added, and the methanol solution containing lenalidomide (VI) was filtered, concentrated again, crystallized,224 g of the final compound lenalidomide (VI) was obtained in a yield of 90% and a purity of more than 99%.
90.3% With iron; acetic acid; In ethanol; water; at 65 - 75℃;Inert atmosphere; 550 mL of purified water, acetic acid (243 g, 4.0 mol), and 1.17 L of ethanol were added to a 3 L reaction kettle, and 78 g (0.27 mol, purity 99.84%, HPLC) of lenalidomide intermediate II and iron powder (114 g, 2.04) were stirred. mol (wherein the mass percentage of metallic chromium is about 0.1%) is added to the above reaction kettle and replaced with nitrogen twice.Heat to 65 C ~ 75 C and stir for 3 ~ 4 hours. Filter while hot.The filtrate was cooled to 15 C to 20 C and stirred for 1 to 2 hours. It was filtered and dried, washed with a mixed solution of 60 mL of ethanol and 40 mL of purified water, and washed with 80 mL of purified water to obtain a wet product. Add 550mL of purified water to the 3L reaction kettle, stir and add the wet product, add 123g of acetic acid and 390mL of ethanol, replace with nitrogen twice, add 8g of activated carbon, heat to 65 75 and stir for 1 ~ 2 hours, filter while hot The filtrate was cooled to 15 C to 20 C and stirred for 0.5 to 1 hour. It was filtered and dried, washed with a mixed solution of 1 L of ethanol and 0.66 L of purified water, and then 0.8 L of purified water, and dried under vacuum (55 C to 65 C, -0.01 MPa to -0.1 MPa) for 12 to 16 hours to obtain an off-white color. The solid was 63.2 g of lenalidomide I with a yield of 90.3% (total yield 79.4%, based on methyl 2-bromomethyl-3-nitrobenzoate). HPLC purity is 99.96%, maximum single impurity is 0.04%, total heavy metal residue is less than 10ppm, metal iron residue is 6ppm, metal chromium residue is <1ppm.
89% With ammonium formate;5% Pd(II)/C(eggshell); In methanol; at 20℃; for 2h; A mixture of 3-(4-nitro-l,3-dihydro-l-oxo-2H-isoindol-2-yl)-2,6- dioxopiperidine (7g), 5% Pd/C (1.4g) and ammonium formate (2.Ig) in methanol (35ml) was stirred completely at room temperature for 2 hours. Pd/C was filtered and the filtrate concentrated to dry under reduced pressure. Recrystallization from heated isopropanol and washing with water gave 5.6g of yellow crystal. yield: 89%. mp: 252.3 - 254.0C .1H-NMR: (300MHz, DMSO-dbeta )delta : 2.00 ~ 2.08(m, IH), 2.27 ~ 2.32(m, IH), 2.58 ~ 2.64(m, IH), 2.86 ~ 2.96(m, IH), 4.15(dd, 2H), 5.11(dd, 2H), 6.80(d, IH), 6.91(d, IH), 7.19(t, IH), 11.00 (s, IH). FAB(M+1): 260Element analysis: theoretical data: C 60.22%, H 5.05%, N 16.21% measured data: C 60.17%, H 5.21%, N 16.26% Preparation with the same method: (R)- 3-(4-amino-l-oxo-l,3-dihydro-2H-isoindol-2-yl) -2,6- dioxopiperidine; yield: 93%; purity99.41
85.6% With tin(ll) chloride; In ethanol; at 15 - 80℃; for 2h; 3-(4-Nitro-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione 197 g (0.68 mol) was added to a 2 L three-necked flask, 95% 950 ml of ethanol was stirred and heated for 15 min to 35 C, and 532 g of stannous chloride was added.The temperature is raised to 55 to 60 C and fully dissolved. Continue heating to 80 C for 2 h. Concentrate the reaction to dryness,Add 1.5 L of ethyl acetate to dissolve.A 2N aqueous solution of sodium hydroxide was added dropwise under ice cooling.The organic layer was separated and the aqueous layer was taken with ethyl acetate (EtOAc).The organic liquid was combined, washed with water and dried over anhydrous sodium sulfate.The solution was concentrated to dryness, washed with hot EtOAc EtOAc (EtOAc)150.9 g, yield 85.6%, purity 99.6% (HPLC).
84% With iron; ammonium chloride; In ethanol; water; at 60 - 80℃; for 4h; Example 2Preparation of lenalidomide (I)Ammonium chloride (95.6 g, 1.76 mol) is dissolved in water (580 mL). After that, 3- (4-nitro-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione (65.0 g, 0.22 mol) and ethanol (2,9 L) are added. The reaction mixture is heated to 60C and iron powder (49.0 g, 0.88 mol) is added with stirring. The reaction mixture is stirred at 80C for 4 hours, then filtered hot; the precipitate washed twice with hot ethanol-water mixture(50 mL water + 150 mL ethanol). The filtrate is evaporated, water (200 mL) is added to dry residue, and the mixture is stirred for 30 min. The precipitated product is filtered off and washed twice with water (50 mL). The raw product is boiled for 2.5 hours in a mixture of ethanol (900 mL) and water (600 mL), then activated charcoal (6 g) is added, and the mixture is boiled for 1 hour more. The hot mixture is filtered, the filtrate is allowed to crystallize at temperature 0-5C, and the precipitated product is filtered off. Obtained product is dried for 6 hours at 60C under 15-20 mbar pressure. Yield 47.6 g (84%), pale yellow substance, purity 99.8% (by HPLC).
84% With acetic acid; zinc; In methanol; N,N-dimethyl-formamide; at 65℃; for 0.25h;Inert atmosphere; 3-(4-nitro- i -oxo- i ,3-dihydro-2H-isoindol-2-yl)-2,6-piperidinedione (20 g, 69. i mmol) and zinc dust (i8.46 g, 277 mmol) were weighed to three necked iL flask equipped with magnetic stiffer, condenser and argon inlet. Methanol (460 mL) and N,N-dimethylformamide(i60 ml) were added. Resulting gray suspension was mixed with acetic acid (3i.i mL, 553 mmol, water content 0. iS% (v/v)) and mixture was heated to 65 C (bath). Once reaction reached internal reaction temperature 65 C, the mixture was stuffed for iS minutes.After iS minutes, the mixture was filtered hot into a clean three necked flask and resulting bluish clear solution was stuffed at 20-25 C. The suspension was spontaneouslycooled to 30 C over i h and then stirred at 20-25 C for next iO h.The suspension was stirred at -5C for 3 h, when it was filtered off and filter cake was washed with water (3 x 40 ml) and chilled methanol (2x30 ml) giving white powder of lenalidomide. The product was dried for 2 h (45 C, nitrogen stripping) giving lenalidomide Form A (15 g, 84 % yield, 100% HPLC purity) as a white powder.
83.6% With palladium 10% on activated carbon; hydrogen; In methanol; at 25℃; under 9000.9 Torr; for 10h; Add 3-(4-nitro-1,3-dihydro-1-oxo-2-hydro-isoindol-2-yl)piperidine-2,6-dione (2g) to a 500 mL hydrogenation reactor , 0.007mol),0.5 g 10% Pd / C, 200 mL of methanol, 1.2 MP hydrogen pressure, reaction at 25 C for 10 h, filtration, filter residue washed with 20 mL of methanol, the filtrate was concentrated to dryness under reduced pressure, washed with 50 mL of hot ethyl acetate for 30 min, filtered, filter cakeDrying to a pale yellow solid 1.5 g, a yield of 83.6%
80.4% With palladium 10% on activated carbon; hydrogen; In water; N,N-dimethyl-formamide; at 80℃; under 2250.23 - 6000.6 Torr;Green chemistry; Was added to the 2L hydrogenation vessel with a vacuum <strong>[827026-45-9]3-(4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione</strong>(I)10% palladium on charcoal (6 g), DMF (120 ml) and purified water (60 ml) the air was replaced with nitrogen and the nitrogen was replaced with hydrogen, hydrogen pressure maintained at 0.3 ~ 0.8Mpa, open the water bath heating, the reaction solution to maintain the temperature at 80 C stirring reaction, until the pressure of hydrogen is no longer down,The filtrate was distilled under reduced pressure to remove the DMF, the residue was stirred with water, cooled to 0 to 5 C, filtered, the cake was rinsed with methanol, and the filter cake was transferred to a vacuum oven at 45 to 55 C,To give a pale yellow solid, 53.8 g, yield: 80.4%.
80.1% With palladium 10% on activated carbon; hydrogen; at 30 - 40℃; Weigh 10.0g 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione, 400ml methanol,Under stirring, bubbling hydrogen gas under the liquid surface, adding 1.0g of 10% palladium carbon, stirring the reaction at a bath temperature of 30-40 degrees until TLC monitoring (methanol: dichloromethane = 1:20)After 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione reaction, suction filtration,When the filtrate is concentrated at 40 degrees to about 100ml (a quarter of the initial volume of the filtrate) solvent,Stop concentration, crystallize at -20 degrees for 1-3 hours, filter, wash the filter cake with 400ml of methanol, and drain to dry.40 degrees to give an off-white product was dried in vacuo lenalidomide i.e. 7.17 g of crude product, a yield of 80.1%,Purity: 98.1%, moisture content: 0.3%.
78% Example 2Preparation of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (I) (lenalidomide)3-(1-Oxo-4-nitro-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (100 g, 0.35 mol) was dissolved in an acetonitrile and methanol mixture (7000 ml, 1:1, v/v). A catalyst comprising a slurry of 10% Pd on charcoal (5.0 g) in methanol (25 ml) and having a moisture content of about 50% was added under a nitrogen atmosphere. The nitrogen gas was replaced with hydrogen gas and bubbled through the reaction mixture whilst stirring. The reaction mixture was maintained at 30-35 C. After one hour a second amount of the catalyst was added and the hydrogen bubbling continued until completion of the reaction after a total time of approximately 2-2.5 hours. Completion of the reaction was monitored by TLC. The catalyst was completely removed by filtration. The filtrate was concentrated by distillation at 45-50 C. temperature and 80-100 mmHg pressure and approximately two thirds of the solvent were removed. An equimolar amount of hydrogen chloride as an isopropanol solution was slowly added to the residual slurry. The mixture was then cooled to between about 5-10 C. and the resulting solid hydrochloride salt of lenalidomide was filtered, washed with methanol and dried.The filtered lenalidomide hydrochloride was resuspended in methanol (500 ml) and triethylamine (1.1 mole equivalent) was slowly added to the reaction mixture. The reaction mixture was cooled to 5-10 C. and the liberated lenalidomide was filtered, washed with methanol and dried.Yield: 70 g (78%)HPLC purity: 99.5% (by area normalisation)
75.8% With hydrogen;palladium 10% on activated carbon; In N,N-dimethyl-formamide; at 25 - 45℃; under 2206.72 - 2942.29 Torr;Parr shaker hydrogenator;Product distribution / selectivity; Example 3: Preparation of LenalidomideN,N-dimethylformamide (35 ml) was added to 3-(4-nitro-l-oxo-l,3-dihydro-2H- isoindol-2-yl)piperidine-2,6-dione (5 g) at 25C to 30C in a Parr shaker hydrogenator. 10% palladium-carbon (200 mg; 50% wet) was added to the reaction mixture and the hydrogen pressure was maintained at 3 to 4 kg/cm2 at 40C to 45C for 7 hours accompanied by shaking. The reaction mixture was filtered through a Celite bed and washed with N,N-dimethylformamide (10 ml). The filtrate was distilled and methanol (20 ml) was added to the solid obtained. The mixture was stirred for 14 hours at 25C to 30C, filtered, washed with methanol (10 ml) and dried under vacuum at 35C to 40C for 20 hours to obtain the title compound.Yield: 75.8%HPLC purity: 99.84%
75.8% With hydrogen;palladium 10% on activated carbon; In methanol; N,N-dimethyl-formamide; at 25 - 30℃; under 2585.81 - 3102.97 Torr;Parr shaker hydrogenator;Product distribution / selectivity; Example 4: Preparation of LenalidomideN,N-dimethylformamide (500 ml) was added to 3-(4-nitro-l-oxo-l,3-dihydro-2H- isoindol-2-yl)piperidine-2,6-dione (40 g) at 25C to 30C in a Parr shaker hydrogenator followed by the addition of methanol (500 ml). 10% palladium-carbon (4 g; 50% wet) was added to the reaction mixture and the hydrogen pressure was maintained at 50 to 60 psi at 20C to 25C for 3 hours accompanied by shaking. The reaction mixture was filtered through a Celite bed and washed with N,N-dimethylformamide (100 ml). The filtrate was distilled and n-propanol (200 ml) was added to the solid obtained. The mixture was stirred for 4 hours at 55C to 60C, filtered, washed with n-propanol (50 ml) and dried under vacuum at 45C to 50C to obtain the title compound.Yield: 75.8%
75% With iron; ammonium chloride; In ethanol; water; at 60 - 80℃; for 4h;Green chemistry; In a 4 l reactor, equipped with areflux condenser and a mechanical stirrer, a solution ofNH4Cl (95.6 g, 1.76 mol, 8 equiv) in H2O (580 ml) wasplaced, then nitro derivative 8a (65.0 g, 0.22 mol, 1 equiv)and EtOH (2.9 l) were added. The reaction mixture wasstirred at 350 rpm and heated up to 60C, after that ironpowder (24.5 g, 0.44 mol, 2 equiv) was added. Thesuspension was heated to 80C and stirred at thistemperature for 1 h, then another portion of iron powder(24.5 g, 0.44 mol, 2 equiv) was added and stirring wascontinued at 80C for 3 h. When the conversion wascomplete, the reaction mixture was filtered hot, the filtercake washed with hot EtOH-H2O mixture (3:1, 2×200 ml).The filtrate was evaporated to dryness, suspended in H2O(200 ml), and stirred for 30 min at room temperature. Theprecipitate was filtered off and washed with H2O (2×50 ml).The raw product was placed in a 2 l round-bottomed flask,EtOH-H2O mixture (3:2, 940 ml) was added, and thesuspension was refluxed with stirring for 1.5 h. Thenactivated charcoal (6 g) was added, the mixture refluxedwith stirring for another 1 h, filtered hot, the filtrate wasslowly cooled with stirring to 0-5C and stirred at thistemperature for 1 h. The precipitate was filtered off,washed with EtOH-H2O mixture (3:2, 100 ml), then withEtOH (100 ml), and dried in vacuum (15-20 mbar) at 60Cfor 6 h. Yield 36.8 g (82%), pale-yellow solid. The productwas recrystalized from EtOH-H2O mixture (3:2, 870 ml),thus obtaining pure lenalidomide (2) of pharmaceuticalgrade. Yield of pure product 33.9 g (75%; recrystallizationyield 92%), slightly yellow crystals, mp 265-267C (mp268-269C)20. HPLC purity 99.8%, content of eachindividual impurity is not higher than 0.03%. The productis semihydrate (polymorph form A)21. 1H NMR spectrum,delta, ppm (J, Hz): 1.19 (1H, dtd, J = 12.7, J = 5.3, J = 2.3) and1.46 (1H, qd, J = 13.3, J = 4.4, 4-CH2); 1.77 (1H, ddd, J = 17.2, J = 4.2, J = 2.2) and 2.08 (1H, ddd, J = 17.5,J = 13.6, J = 5.4, 5-CH2); 3.26 (1H, d, J = 17.0) and 3.36(1H, d, J = 17.0, 3-CH2 isoindole); 4.27 (1H, dd, J = 13.3,J = 5.1, 3-CH); 4.57 (2H, s, NH2); 5.96 (1H, d, J = 7.9, H-5isoindole); 6.08 (1H, d, J = 7.4, H-7 isoindole); 6.35 (1H, t,J = 7.6, H-6 isoindole); 10.16 (1H, s, NH). 13C NMRspectrum, delta, ppm: 22.8 (C-4); 31.2 (C-5); 45.5 (C-3isoindole); 51.5 (C-3); 110.4, 116.4, 125.6, 128.8, 132.3(C isoindole); 143.6 (C-4 isoindole); 168.9 (C=O); 171.2(C=O); 172.9 (C=O). Mass-spectrum, m/z (Irel, %): 261 (8),260 [M+H]+ (100).
29% With hydrogen;palladium 10% on activated carbon; In methanol; under 2362.74 Torr; for 42h; Preparation of Racemic Lenalidomide according toExample 16E of EP 0 925 294 BlA suspension of 28.9 g (0. 1 mol) rac-3-( 1 -oxo-4-nitroisoindoline-2- yl)piperidine-2 ,6-dione and 9g 10% Pd / C (0.09 eq. Pd) in 3 1 methanol (725 equiv. ) was hydrogenated under hydrogen pressure at 3. 15 bar (50 psi) for 42 h in a hydrogenation autoclave ( 10 1). Hydrogenation was extended to 42 h as hydrogenation was found to be incomplete after 5 h. The mixture was filtered on a Buchner filter under vacuum, and the solid on the filter rinsed with MeOH (250 ml). The light yellow colored filtrate was concentrated on a Rotavapor ( 1000 ml) flask to a residual volume of 150 ml. A light beige colored, crystalline solid with a melting point of 265 C was obtained (7.6 g, 29% ), which turned to light grey color on standing.Peak positions from XRPD obtained for rac-lenalidomide, which crystallized from MeOH when reaction solvent was evaporated, were matching to those from XRPD given in Figure 1 of WO 2005 / 023192 for lenalidomide anhydrous Form A.
3-(4-nitro-1 -oxo-1 ,3-dihydroisoindol-2-yl)-pipe?dine-2,6-dione (10 g), water (150 ml_), 10% palladium on carbon (0.5 g, 50% wet) and methanesulfonic acid (5.6 ml d:1.48) are charged into a conical flask and then transferred into an autoclave. Hydrogen gas (90 psi, 6.3 Kg/cm2) is applied to the suspension at 3O0C and stirred for 3 hours. The reaction mixture is filtered through a celite bed and the bed washed with water (50 ml_). The obtained filtrate is neutralized with 7% sodium bicarbonate solution (100 ml_) and stirred for 1 hour. The reaction suspension obtained is filtered and the solid dried at 500C under a vacuum of 600 mm Hg for 5-6 hours, to yield 7.2 g of lenalidomide. Purity by HPLC 99.93%.
3-(l-Oxo-4-nitro-l,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (100 g, 0.35 mol) was dissolved in an acetonitrile and methanol mixture (7000 ml, 1:1, v/v). A catalyst comprising a slurry of 10% Pd on charcoal (5.0 g) in methanol (25 ml) and having a moisture content of about 50% was added under a nitrogen atmosphere. The nitrogen gas was replaced with hydrogen gas and bubbled through the reaction mixture whilst stirring. The reaction mixture was maintained at 30-350C. After one hour a second amount of the catalyst was added and the hydrogen bubbling continued until completion of the reaction after a total time of approximately 2-2.5 hours. Completion of the reaction was monitored by TLC. The catalyst was completely removed by filtration. The filtrate was concentrated by distillation at 45-500C temperature and 80-100 mmHg pressure and approximately two thirds of the solvent were removed. An equimolar amount of hydrogen chloride as an isopropanol solution was slowly added to the residual slurry. The mixture was then cooled to between about 5-100C and the resulting solid hydrochloride salt of lenalidomide was filtered, washed with methanol and dried.The filtered lenalidomide hydrochloride was resuspended in methanol (500 ml) and triethylamine (1.1 mole equivalent) was slowly added to the reaction mixture. The reaction mixture was cooled to 5-100C and the liberated lenalidomide was filtered, washed with methanol and dried.Yield: 70 g (78%) HPLC purity: -99.5% (by area normalisation)
With hydrogen;palladium 10% on activated carbon; In N,N-dimethyl-formamide; under 2585.81 - 3102.97 Torr; for 3h;Product distribution / selectivity; Example 1 : Preparation of Form A of Lenalidomide:The l-oxo-2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline (40 g), N, N-dimethyl formamide (500 ml) and 50% wet 10% palladium-carbon (4 g) were charged in a hydrogenator. The hydrogen pressure was maintained in the hydrogenator at 50 psi to 60 psi for 3 hours. The reaction mixture was subsequently filtered through a Celite bed and washed with N, N-dimethylformamide (100 ml). The N, N-dimethylformamide was recovered from the filtrate under vacuum at 65 C to 70C to obtain a solid. Methyl acetate (200 ml) was added to the solid and the mixture was warmed to 45C to 50C. The reaction mixture was stirred for 4 hours at 45C to 50C, filtered, washed with methyl acetate (50 ml) and dried under vacuum at 45 C to 50C to obtain the title compound. Yield: 33.86 g
With hydrogen;palladium 10% on activated carbon; In N,N-dimethyl-formamide; under 2585.81 - 3102.97 Torr; for 4h; Example: Preparation of Form B of Lenalidomide:l-Oxo-2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline (100 g), N,N- dimethylformamide (125 ml) and 10% palladium-carbon (10 g) were charged in a hydrogenator. The hydrogen pressure was maintained in the hydrogenator at 50 psi to 60 psi for 4 hours. The reaction mixture was subsequently filtered through a Celite bed and washed with N,N-dimethylformamide (100 ml). Nu,Nu-dimethylformamide was recovered from the filtrate under vacuum (80C to 85C at about 30 mmHg) to obtain lenalidomide hemisolvate as a solid (N,N-dimethylformamide content: 12.35%). Water (1000 ml) was added to the above solid and the mixture was heated to 60C. The reaction mixture was stirred for 4 hours at 60C, filtered and dried under suction (45C to 50C at about 10 mmHg) to obtain the title compound having an XRPD pattern and FTIR pattern as depicted in Figure 1 and Figure 2, respectively.Yield: 80 gPurity (by HPLC): 100%Moisture content: 3.58% w/w
With hydrogen;palladium 10% on activated carbon; In N,N-dimethyl-formamide; at 60 - 65℃; for 6h; Preparation of Lenalidomide Technical grade materialInto a 5.0 L 4 necked RB flask, charged 100.0 g of 3-(4-nitro-l -oxo-l, 3 dihydro- isoindol-2-yl)-piperidine-2, 6-dione, 10.0 g of 10% Pd/C and 3200 ml of DMF under nitrogen atmosphere. Stirred the mass and raise the reaction mass temperature to 60 - 65C. Started the hydrogen gas bubbling into reaction mass at temperature 60 -65C for 6 hours. The progress of the reaction is monitored by TLC. Cooled the mass to temperature 25 to 30C. Filtered the catalyst Pd/C under plant vacuum in the presence of nitrogen atmosphere and wash with dimethylformamide; wet Pd/C is transferred into a polythene bag for recovery. Distilled off the above organic layer solvent completely under vacuum below 60C. Charged ethyl acetate 800 ml (lot-I) to the mass and stirred for 60 min. Filtered the solid and wash with 200 mL of ethyl acetate (Lot-II). Dried the above wet material in a at temperature 65-75C for 120-180 min. Dried Weight of the compound is 78. Og.
48 g 3-(4-Nitro-l -oxo-1 ,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione (200 gm), acetic acid and palladium carbon in hydrogenation were added and then applied hydrogen pressure. The reaction mass was stirred for 4 hours and filtered over celyte bed. The solvent was distilled off under vacuum at below 50C from the filtrate thus obtained to obtain a residual mass. To the residual mass was added water (750 ml) and stirred for 5 minutes. The contents were then cooled to 10C and the pH of the reaction mass was adjusted to 7.0 to 7.5 with ammonia. The reaction mass was stirred for 2 hours at 15C, filtered and then dried to obtain a solid. To the solid was added N-methylpyrrolidone (480 ml) at room temperature and then heated to 60C to obtain a solution. The solution was then cooled to 40C and then added ethanol (800 ml). The reaction mass was stirred for 1 hour at room temperature, filtered and dried to obtain a solid. To the solid was added toluene (180 ml) and then heated to 90 to 95C. The reaction mass was maintained for 1 hour at 90 to 95C and then cooled to room temperature. The reaction mass was stirred for 1 hour at room temperature and filtered. The solid obtained was dried under vacuum at 100C for 48 hours to obtain 48 gm of lenalidomide crystalline Form HI (Purity of High Performance Liquid Chromatography: 99.95%)
With palladium on activated charcoal; hydrogen; In methanol; under 7600.51 Torr; In the hydrogenation using methanol as solvent reduction synthesis experiment lenalidomide (the reaction is as follows, the reaction substrate 52.7g)
With palladium 10% on activated carbon; hydrogen; In tetrahydrofuran; A mixture of 3-(7-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1 equiv.) and palladium on activated carbon (10% wt) in THF is hydrogenated until the disappearance of the starting material. The mixture is filtered through Celite and concentrated to give lenalidomide.
6.9 g With palladium 10% on activated carbon; hydrogen; In methanol; under 2585.81 - 2844.39 Torr; for 0.583333h;Autoclave; <strong>[827026-45-9]3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione</strong>, (10 g) and 5 methanol (500 mL) was charged into a single necked round bottomed flask and the heterogeneous mass (slurry) was stirred for 15 min. To a clean 5 L autoclave, methanol. (2000 mL) and the slurry obtained above were charged with stirring. The reaction mass was degassed for 20 min using Nitrogen purging under stirring. 10% 6 Pd/C (50% wet, 2.0 g) was charged in to the reaction flask with 7 nitrogen purging and then Methanol (500 mL) was charged in to the autoclave. The reaction mixture was then degassed thrice with Hydrogen at 50-55 PSI. The reaction mixture was maintained at 50-55 PSI Hydrogen pressure for about 35 min and then the Hydrogen pressure was released. On completion of the reaction as confirmed by intermittent reaction monitoring by HPLC, the reaction mixture was filtered through celite bed and washed with Methanol (200 mL). The filtrate was concentrated at 55 C. under vacuum of 260-360 mm of 8 Hg till about only 200 mL vol. of reaction mixture is left. To this reaction mixture, isopropyl alcohol (200 mL) was added and again concentration of the reaction mixture was carried out under atmospheric pressure at 80 C. till about only 200 mL vol. of reaction mixture is left. The reaction mass was cooled to 40 C., filtered under vacuum with nitrogen blanket, washed with isopropyl alcohol (50 mL) and suck dried for 1 h. The solid material was further dried at 60 C. under vacuum (10-15 mm of Hg) for about 15 h, to obtain 9 Lenalidomide
With palladium 10% on activated carbon; ammonia; hydrogen; In 1-methyl-pyrrolidin-2-one; under 3102.97 Torr; for 12h;Large scale; 3-(4-nitro-1-oxoisoindolin-2-yl) piperidine-2,6-dione (IV) (2 kg, 6.91 mol) of example 4 was charged into 50 L Hydrogenation reactor. NH3 bubbled NMP (20 L) was charged. 10% Pd/C (100 g) was added and hydrogenation was carried for 12 hrs at hydrogen gas pressure of 60 psi. Progress of the reaction was monitored by HPLC. The catalyst was filtered through celite bed and bed was washed with NMP (2*2 L). The filtrate was concentrated at temperature 100 C. using high vacuum pump and the reaction mixture was cooled to room temperature. Acetone (60 mL) was added to the reaction mixture and stirred at reflux for one hour to obtain crude 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Lenalidomide). Quantity of the product obtained: 1.6 kg (crude) Nature: Gray color solid
480 g With palladium 10% on activated carbon; hydrogen; In N,N-dimethyl acetamide; at 25℃; under 4654.46 Torr; To a suspension of Formula-Il (50.0 g, 0.173 mol) in NN-Dimethyl acetamide (250 mL, 5.0 vol.), 10% Pd/C (5.0 g, 0.1% wlw) was added into a hydrogenator. The mass was stirredat 25±5C under H2 gas (90 psi) atmosphere. After completion of the reaction (Monitored through HPLC), the mass was filtered through celite, washed with NN -Dimethyl acetamide (100 mL, 2.0 vol). The resulting filtrate subjected for Charcoal (5.0 g, 0.1% w/w) treatment, filtered through celite bed at 55±5C, washed with NN -Dimethyl acetamide (100 mL, 2.0 vol) to obtain Formula-I as a solution in DMAc (480 g).
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; under 2068.65 Torr; for 16h; To a stirred solution of <strong>[827026-45-9]3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione</strong> (3.0 g, 10.37 mmol) in methanol (60 mL) was added 10 % Pd/C (0.7 g). The reaction was performed under hydrogen atmosphere (40 psi) at RT for 16 h. After completion of the reaction (monitored by TLC) the reaction mixture was filtered though celite. The filtrate was concentrated to afford title compound (2.4 g, 89 %) which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): d 10.98 (s, 1H), 7.18 (t, / = 8 Hz, 1H), 6.91 (d, J = 6.8 Hz, 1H), 6.79 (d, / = 7.2 Hz, 1H), 5.40 (s, 2H), 5.10 (dd, = 4.8 Hz, J2 = 13.2 Hz, 1H), 4.22-4.08 (m, 2H), 2.96-2.95 (m, 1H), 2.59-2.50 (m, 1H), 2.33-2.29 (m, 1H), 2.05-2.01 (m, 1H); LC-MS: m/z 260.1 (M+l)+ .

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  • 2
  • [ 24666-55-5 ]
  • [ 191732-72-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: H2, aq. HCl / 10 percent Pd/C / ethyl acetate / 2585.74 - 3102.89 Torr 2: Et3N / dimethylformamide / 80 °C 3: H2 / 10 percent Pd/C / methanol
Multi-step reaction with 3 steps 1: hydrogenchloride / dimethyl sulfoxide 2: triethylamine / acetonitrile / 3 h / Reflux 3: 5%-palladium/activated carbon; hydrogen / ethanol / 1 h / 3040.2 Torr
Multi-step reaction with 3 steps 1: hydrogen bromide; acetic acid / 1 h / 60 °C 2: triethylamine / acetonitrile / 10 h / 20 - 80 °C 3: tin(ll) chloride / ethanol / 2 h / 15 - 80 °C
  • 3
  • [ 79-04-9 ]
  • [ 191732-72-6 ]
  • [ 444287-87-0 ]
YieldReaction ConditionsOperation in experiment
93% In tetrahydrofuran for 1h; Reflux; 2-Chloro-/V-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)acetamide (XS01-101) To a solution of 3-(4-amino-l-oxoisoindolin-2-yl)piperidine-2,6-dione (500 mg, 1.93 mmol) in THF (20 mL) was added 2-chloroacetyl chloride (435 mg, 3.86 mmol), the mixture was heated to reflux for 1 h. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 mL) and filtered to give 2-chloro-A,-(2-(2,6-dioxopiperidin-3-yl)- 1 - oxoisoindolin-4-yl)acetamide (XS01-101) (600 mg, 93%) as a white solid. HPLC 98.9% UR = 7.98 min, CH3OH in 0.1% TFA water 5%~95% in 20 min); NMR (500 MHz, DMSO-ifc) d 11.02 (s, 1H), 10.19 (s, 1H), 7.82 (dd, 7 = 7.7, 1.3 Hz, 1H), 7.64-7.42 (m, 2H), 5.16 (dd, 7 = 13.3, 5.1 Hz, 1H), 4.46^1.28 (m, 4H), 2.92 (m, 1H), 2.68-2.57 (m, 1H), 2.43-2.28 (m, 1H), 2.10-1.96 (m, 1H); HPLC-MS (ESI+) m/z 336.1 (M+H)+. (See US2003/96841.)
4.64 g (92%) In tetrahydrofuran; diethyl ether N-[2-(2,6-dioxo(3-piperidyl))-1-oxoisoindolin-4-yl]-2-chloroacetamide I-44 N-[2-(2,6-dioxo(3-piperidyl))-1-oxoisoindolin-4-yl]-2-chloroacetamide I-44 To a stirred suspension of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3.89 g, 15.0 mmol) in THF (50 ml) was added chloroacetyl chloride (1.86 g, 16.5 mmol). The mixture was heated to reflux for 45 minutes. To the reaction mixture was added additional chloroacetyl chloride (0.15 g, 0.13 mmol). The reaction mixture was heated at reflux for an additional 30 minutes. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 4.64 g (92%) of product as an off-white solid: 1H NMR (DMSO-d6) δ11.04 (s, 1H), 10.22 (s, 1H), 7.82 (dd, J=1.6 and 7.2 Hz, 1H), 7.59-7.50 (m, 2H), 5.16 (dd, J=5.1 and 13.2 Hz, 1H), 4.46-4.30 (m, 4H), 3.00-2.85 (m, 1H), 2.65-2.58 (m, 1H), 2.44-2.28 (m, 1H), 2.06-2.01 (m, 1H).
With Cs2CO3 In acetonitrile at 20℃; for 5h; General procedure: To a mixture of lenalidomide 10 (2.59 g, 10 mmol, 1 equiv) inCH3CN was added Cs2CO3 (6.5 g, 20 mmol, 2 equiv), followed byappropriate chlorinated acylchloride (12 mmol, 1.2 equiv). Afterreacting at room temperature for 5 h, the mixture was filtered to removesalts and the filtrate was concentrated under reduced pressure to affordthe crude 11a-f without purification with yield 70-85%.
With Cs2CO3 In acetonitrile at 20℃; for 5h; General procedure: To a mixture of lenalidomide 10 (2.59 g, 10 mmol, 1 equiv) inCH3CN was added Cs2CO3 (6.5 g, 20 mmol, 2 equiv), followed byappropriate chlorinated acylchloride (12 mmol, 1.2 equiv). Afterreacting at room temperature for 5 h, the mixture was filtered to removesalts and the filtrate was concentrated under reduced pressure to affordthe crude 11a-f without purification with yield 70-85%.

  • 4
  • [ 191732-72-6 ]
  • [ 1061604-41-8 ]
YieldReaction ConditionsOperation in experiment
2.4% With hydrogenchloride; lithium hydroxide monohydrate; NaNO2
2.4% With hydrogenchloride; lithium hydroxide monohydrate; NaNO2 at 0 - 80℃; for 2.5h; 2 Example 2 3-(4-hydroxy-l-oxoisoindolin-2-yl)piperidine-2,6-dione[168] A 250mL-3N-RBF was charged with 3-(4-amino-l-oxoisoindolin-2- yl)piperidine-2,6-dione and H2O (10 vol) and cooled to 0-5 °C. NaNO2 (1.1 eq) and HCl (1.1 eq) were added, and the mixture was stirred for 30 minutess. The mixture was then heated to 75-80 0C for 2 hours. The mixture was cooled to room temperature, filtered and dried in vacuo (18 h, 35-40 °C). The crude product was purified by prep-HPLC (Conditions: Cl 8 Symmetry Column, 90:10 H2O: MeCN isocratic, 60 mL/min flow rate, product retention time -30 min) to give an off-white solid (240 mg, 2.4%, 99.5 HPLC AP); mp 296.39 °C; HPLC: Hypersil DBS C8 5m column, 250 x 4.6 mm, 35 °C; 99:1 to 85:15 Gradient CH3CNAO mM aq. KH2PO4 , 1.0 mL/min over 20 minutes; 7.60 min, 99.5% AP at 210/240 nm: 1H-NMR (DMSO-J6): 10.97 (IH, br s), 10.11 (IH, br s), 7.34 (IH, t), 7.17 (IH, d), 7.03 (IH, d), 5.09 (IH, dd), 4.25 (2H, dd), 2.97-2.85 (IH, m), 2.62-2.36 (2H, m), 2.03-1.96 (IH, m) ppm; 13C-NMR (DMSO-J15): 172.85, 171.04, 168.27, 152.55, 133.41,129.44, 127.94, 117.97, 113.71, 51.59, 45.09, 31.22, 22.42 ppm; LC-MS ES+ (M+ 1) 261 ; CHN-Analysis, calcd for C]3Hi2N2O4: C, 60.00%; H, 4.65%; N, 10.76%. Found: C, 59.54%; H, 4.88%; N, 10.48%.
Multi-step reaction with 3 steps 1.1: tert.-butylnitrite / acetonitrile / 4 h / 20 °C 2.1: sodium (meta)periodate / tetrahydrofuran; lithium hydroxide monohydrate / 2 h / 20 °C 2.2: 12 h / 20 °C 3.1: dihydrogen peroxide / dimethyl sulfoxide / 8 h / 20 °C / Inert atmosphere
1.5 g Stage #1: 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione With hydrogenchloride In lithium hydroxide monohydrate at 0℃; for 0.166667h; Stage #2: With NaNO2 In lithium hydroxide monohydrate at 20 - 70℃; for 3h; Step 1: 3-(4-hydroxy-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (2) Into a 250 mL single neck round bottom flask containing a well-stirred solution of 3-(4-amino-1- oxo-isoindolin-2-yl)piperidine-2,6-dione (1, 4 g, 15.43 mmol) in water (50 mL) was added concentrated HCl (aq 30%, 10 mL) at 0 °C. After 10 min, a solution of NaNO2 (1.60 g, 23.14 mmol) in water (10 mL) was added dropwise over 5 min. The reaction mixture was allowed to come to RT and then heated at 70 °C for 3 h. The reaction mixture was filtered to obtain a brown solid, which was purified by reverse phase column chromatography ( C18-column; Mobile phase A: 0.1% HCOOH in water and Mobile phase B: MeCN) to afford 3-(4-hydroxy-1-oxo-isoindolin- 2-yl)piperidine-2,6-dione (2, 1.5 g, 5.59 mmol) as a light brown solid. LCMS (ES+): m/z 261.1 [M + H] +
Multi-step reaction with 3 steps 1.1: tert.-butylnitrite / acetonitrile / 18 h / 20 °C 2.1: sodium (meta)periodate / tetrahydrofuran; lithium hydroxide monohydrate / 2 h / 20 °C 2.2: 18 h / 20 °C 3.1: dihydrogen peroxide / lithium hydroxide monohydrate; dimethyl sulfoxide / 18 h / 20 °C / Inert atmosphere

  • 5
  • [ 19171-18-7 ]
  • [ 879126-98-4 ]
YieldReaction ConditionsOperation in experiment
75% Example 1: Preparation of anhydrous lenalidomide according to the first aspect of the present invention from 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-nitro-isoindole.1,3-Dioxo-2-(2,6-dioxopiperidin-3-yl)-4-nitro-isoindole (10.0 g, 0.035 mol) was suspended in ethanol (120 ml) to which was added iron powder (9.6 g, 0.175 mol). Hydrochloric acid (18.5 ml) diluted with an equal volume of water was added to this mixture. The reaction mixture was heated to between about 65-7O0C and maintained at this temperature for between about 1 1/2-2 hours. The reaction mixture was cooled and filtered through a Celite pad and the resultant clear filtrate was concentrated. The pH of the filtrate was adjusted to between 7 to 8 with ammonia solution and the concentrated filtrate was further filtered through a Celite pad. The filtrate was again concentrated under reduced pressure. The product was finally dissolved in ethanol (50 ml) and heated at 45-5O0C until a clear solution was formed. The solution was cooled to about 5C and again filtered. The filtered solid was dried at 50-55C at reduced pressure for 3-4 hours until a constant weight of the product was obtained. The process resulted in 6.7 g (75% yield) of the novel anhydrous crystalline form of lenalidomide according to the present invention as an off-white to pale yellow powder.The chemical purity of the novel form of lenalidomide formed was found to be 99.6% as measured by HPLC. The water content, DSC and TGA analyses confirmed that the novel form was anhydrous, i.e. not a solvate or hydrate. The XRPD of the novel form showed that the novel form was free from other polymorphic forms.
75% 1,3-Dioxo-2-(2,6-dioxopiperidin-3-yl)-4-nitro-isoindole (10.0 g, 0.035 mol) was suspended in ethanol (120 ml) to which was added iron powder (9.6 g, 0.175 mol). Hydrochloric acid (18.5 ml) diluted with an equal volume of water was added to this mixture. The reaction mixture was heated to between about 65-70 C. and maintained at this temperature for between about 1½-2 hours. The reaction mixture was cooled and filtered through a Celite pad and the resultant clear filtrate was concentrated. The pH of the filtrate was adjusted to between 7 to 8 with ammonia solution and the concentrated filtrate was further filtered through a Celite pad. The filtrate was again concentrated under reduced pressure. The product was finally dissolved in ethanol (50 ml) and heated at 45-50 C. until a clear solution was formed. The solution was cooled to about 5 C. and again filtered. The filtered solid was dried at 50-55 C. at reduced pressure for 3-4 hours until a constant weight of the product was obtained. The process resulted in 6.7 g (75% yield) of the novel anhydrous crystalline form of lenalidomide according to the present invention as an off-white to pale yellow powder.The chemical purity of the novel form of lenalidomide formed was found to be 99.6% as measured by HPLC. The water content, DSC and TGA analyses confirmed that the novel form was anhydrous, i.e. not a solvate or hydrate. The XRPD of the novel form showed that the novel form was free from other polymorphic forms.
  • 6
  • [ 295357-66-3 ]
  • [ 191732-72-6 ]
YieldReaction ConditionsOperation in experiment
77.1% In N,N-dimethyl-formamide for 4h; Reflux; 1.5 (5) Preparation of 3- (7-amino-1-oxo-1,3-dihydroisoindol-2-yl) piperidine-2,6-dione 0.5 g of 3- (7-amino-1-oxo-1,3-dihydroisoindol-2-yl) pentanedioic acid, 2.5 mL of DMF,The reaction was heated to reflux for 4 hours with stirring. The reaction was concentrated under reduced pressure at 60 ° C and poured into ice water with rapid stirring. The mixture was filtered and the filter cake rinsed with isopropanol. The crude product was decolorized with activated carbon in isopropanol solution and recrystallized to give the title compound (0.36 g, yield 77.1%, purity 99.74%)
30% With urea In N,N-dimethyl-formamide Reflux; 11 A mixture of 3-(4-amino-l,3-dihydro-l-oxo-2H- isoindol-2-yl)-glutaric acid (5g) and urea (1.08g) in N, N-dimethylformamide (25ml) was stirred and heated under reflux for 3~4hours. The reaction mixture concentrated under reduced pressure at 60°C and then was added into ice water by being stirred rapidly. After filter, the cake was washed with isopropanol. The crude product was recrystallized from isopropanol and active carbon to give 1.4g of off-white target compound. Yield:30 % . mp: 252.1 ~ 254.3 °C1H-NMR: (300MHz, DMSO-dδ)δ: 2.03(m, 2H), 2.01 ~ 2.07(m, IH), 2.26 ~ 2.37(m, IH), 2.61 ~ 2.65(m, IH), 2.87 ~ 2.96(m, IH), 4.17(dd, 2H), 5.09(dd, IH), 5.36(s, 2H), 6.81(d, IH), 6.92(d, IH), 7.91(t, IH), 10.93(s, IH).1H-NMR: (300MHz, DMSO-dβ / D2O) δ: 2.02 ~ 2.05(m, IH), 2.32 ~ 2.36(m, IH), 2.60 ~ 2.65(m, IH), 2.83 ~ 2.88(m, IH), 4.17(dd, 2H), 5.04(dd, IH), 6.82(d, IH), 6.94(d, IH), 7.20(t, IH).FAB(M+1): 260Element analysis: theoretical data: C 60.22%, H 5.05%, N 16.21% measured data: C 60.30%, H 5.20%, N 16.18%
  • 7
  • [ 1198299-50-1 ]
  • [ 191732-72-6 ]
YieldReaction ConditionsOperation in experiment
85% With chloro-trimethyl-silane; sodium methylate; formamide In acetonitrile at 5 - 25℃; for 6h; 1-2 Example 2 Add 5g of 3-(4-amino-1,3-dihydro-1-oxo-2-hydro-isoindol-2-yl)-glutaric acid dimethyl ester to 25mlTo the acetonitrile, 0.35 g of trimethylchlorosilane and 7 g of formamide were added. Add 1.3 g of sodium methoxide below 5 ° C, and react for 3 hours after stirring.The temperature was raised to 25 ° C for 3 hours. The sodium methoxide was neutralized by adding acetic acid and stirred for 2 hours. After suction filtration, the acetonitrile is rinsed, rinsed with water, and dried.An off-white solid 3.6 g. Yield: 85% (purity: 99.84%).
48% With sodium amide In tetrahydrofuran at -40℃; for 3h; Inert atmosphere; 5 Under nitrogen in dry reaction flask was added sodium amide (30mmol 1.17g) (obtained by adding metallic sodium (690mg) into liquid ammonia (-40 °C, 300ml) and then adding catalytic amount of ferric nitrate). The solution of dimethyl 3-(4-amino-l,3-dihydro-l-oxo-2H-isoindol-2-yl)-glutarate (3g , lOmmol) in anhydrous tetrahydrofuran( 100ml) was added by droplet with the temperature maintaining at -40 °C and the mixture was stirred in heat preservation for 3 hours. ammonium chloride (5g) (ammonia spillover is allowed) and water (300ml) were added and the resulting mixture was filtered. The crude was recrystallized from isopropanol (15ml) to give target yield (1.22g).Yield 48 % . mp: 251.5°C ~ 252.5°C .1H-NMR: (500MHz, DMSO-dβ) δ: 2.02 ~ 2.04(m, IH), 2.27 ~ 2.34(m,IH), 2.60 ~ 2.63(m, IH), 2.88 ~ 2.95(m, IH), 4.16(dd, 2H), 5.10(dd, 2H), 6.80(d, IH), 6.92(d, IH), 7.19(t, IH), 10.19(s, IH)FAB(M+1): 260Element analysis: theoretical data: C 60.22%, H 5.05%, N 16.21% measured data: C 60.14%, H 5.16%, N 16.30% Test condition of HPLC: type and specification of column: phenomenex Luna 5u Cl 8250mmχ4.6mm; velocity: l .Oml/min; λ=230nm mobile phase : acetonitrile/0.1 %phosphate = 10/90 appearance time of target yield : 11.81 minutes purity of target yield: 99.29%
  • 8
  • [ 1198299-57-8 ]
  • [ 191732-72-6 ]
YieldReaction ConditionsOperation in experiment
72% Stage #1: 2-[4-(N-benzyloxycarbonyl)amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl]glutaramide In N,N-dimethyl-formamide at 160℃; Stage #2: With N,N-dimethyl-formamide In methanol at 30℃; for 2h; 9 3-[4-(N- benzyloxycarbonyl)amino-l ,3-dihydro-l -oxo-2H-isoindol-2-yl] -glutaramide(30g) was stirred with formamide (150ml) for 3~4 hours by slowly heating up to 160°C . The reaction mixture was cooled to 0°C and then mixed with water (750ml). After crystal growing for 1 hour, the resulting mixture was filtered and dried to give 21.6g of light yellow solid. The solution of this residue in methanol (325ml) was stirred with 5% Pd/C (0.3g) and formamide (22g) at 30 °C for 2 hours. Pd/C was filtered and the filtrate concentrated under reduced pressure to yield a yellow solid. Recrystallization and washing by isopropanol and active carbon gave 12.75g of light yellow solid. yield:72%. mp:251.1 ~ 252.4 °C .1H-NMR: (300MHz, DMSO-dβ) δ: 2.02(m, 2H), 2.01 ~ 2.06(m, IH), 2.25 ~ 2.39(m, IH), 2.59 ~ 2.64(m, IH), 2.83 ~ 2.94(m, IH), 4.16(dd, 2H), 5.08(dd, IH), 5.35(s, 2H), 6.80(d, IH), 6.93(d, IH), 7.90(t, IH), 10.91(s, IH). FAB(M+1): 260 Element analysis: theoretical data: C 60.22%, H 5.05%, N 16.21% measured data: C 60.27%, H 5.13%, N 16.26% Test condition of HPLC : type and specification of column: phenomenex Luna 5u Cl 8250mmχ4.6mm; velocity: l .Oml/min; λ=230nm mobile phase : acetonitrile/0.1 % phosphate = 10/90 appearance time of target yield: 11.77 minutes purity of target yield: 99.37%
  • 9
  • [ 1198299-71-6 ]
  • [ 191732-72-6 ]
YieldReaction ConditionsOperation in experiment
62% Stage #1: 4-[4-(N-benzyloxycarbonyl)amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl]isoglutamine With thionyl chloride In N,N-dimethyl-formamide at -20℃; Stage #2: With ammonium formate In methanol at 30℃; for 2h; 14 To a stirred mixture of 3-[4-(N- benzyloxycarbonyl)amino- 1,3-dihydro-l -oxo-2H-isoindol-2-yl]-isoglutamine (1Og) in DMF (30ml) was added thionyl chloride (5g) by droplet at -20°Cfor reaction in heat preservation for 2 ~ 3 hours. The resulting mixture was mixed in ice water stirred rapidly. Then the mixture was extracted with ethyl acetate (2 x 50ml) and dried over anhydrous sodium sulfate. Sodium sulfate was filtered and the filtrate concentrated to dryness under reduced pressure. The concentrate was mixed in methanol (100ml) and stirred with 5% Pd/C (Ig) and ammonium formate (7g) at 30°C for 2 hours. Pd/C was filtered and the filtrate concentrated to dryness. The concentrate was recrystallized from isopropanol and rinsed with water. Decompression drying gave 3.76g of target yield as a light yellow solid, yield: 62%. mp: 250.8 ~ 252.7°C .1H-NMR: (300MHz, DMSO-d6/D2O) δ: 2.04 ~ 2.10(m, IH), 2.34 ~ 2.39(m, IH), 2.61 ~ 2.67(m, IH), 2.87 ~ 2.9 l(m, IH), 4.18(dd,2H), 5.08(dd, 2H), 6.84(d, IH), 6.96(d, IH), 7.23(t, IH) FAB(M+1): 260 Element analysis: theoretical data: C 60.22%, H 5.05%, N 16.21% measured data: C 60.04%, H 5.31%, N 16.33% Test condition of HPLC: type and specification of column: phenomenex Luna 5u Cl 8250mmχ4.6mm; velocity: l .Oml/min; λ=230nm mobile phase : acetonitrile/0.1 %phosphate = 10/90 appearance time of target yield: 11.767 minutes purity of target yield: 99.69%.
  • 10
  • [ 191732-72-6 ]
  • (RS)-3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione sulfate [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% With sulfuric acid In acetic acid at 70℃; for 0.75h; 7 Preparation of Lenalidomide Sulfate (Form A)In a round bottom flask acetic acid (AcOH, 5 ml) was placed and 3-( l -oxo-4- amino-isoindoline-2-yl)piperidine-2,6-dione ( 1.0 g, 98.8 % pure) was added while stirring. Sulfuric acid (H2S04, 0. 1 ml, 96% ) was added. Immediately, a yellow coloured viscous oil was settled. After heating to 70 °C, a turbid solution was formed, while stirring and heating was continued for another 45 min. During that time, a crystalline solid precipitated. The suspension was filtered on a Buchner funnel, equipped with filter paper. The collected crystals were washed with 15 ml acetic acid and dried at 40 °C in vacuum drying cabinet at 100 mbar. The solids had a weight of 1 .16 g ( 100 % yield).
With sulfuric acid In methanol at 20℃; for 0.5h; 13 Example 13; To 100 mL of anhydrous methanol was added a compound represented by formula (II), in which Y represents H, (518 mg). A solution of 98% concentrated sulfuric acid (200 mg) in anhydrous methanol (100 mL) was added. The mixture was stirred for 30 mins at room temperature to make the system clear. After the mixture was subjected to rotary evaporation under reduced pressure to remove the solvent and a solid was obtained, anhydrous THF was added and the mixture was stirred for further 1 hour, and then filtered with pump. The filter cake was dried for 10 hours in vacuo. A sulfate of Compound (II), in which Y represents H, (2:1) was obtained.
  • 11
  • [ 191732-72-6 ]
  • (RS)-3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione sulfate/hydrogen sulfate [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% With sulfuric acid In water at 50℃; 9 Lenalidomide sulfate, obtained according to example 7 (0.25 g) was exactly weighed into a tared weighing bottle and this was placed into a hygrostat chamber over saturated C1 solution for equilibration (85% r.H. at 20°C) within 4 weeks. Within the first 16 hours the mass of the sample had grown by about 6-7 % (hygroscopicity) but during further exposure the mass of the substance was lowered again below 99 % from starting value (desolvation). DSC and XRPD had changed completely after this time. Example 9: Preparation of Lenalidomide sulfate /Hydrogen SulfateIn a round bottom flask 3 -( 1 -oxo-4-amino-isoindoline-2-yl)piperidine-2 , 6-dione ( 1 .0 g, 98.8 % pure) was placed. Water (5.2 ml) was added, and the mixture was heated to 50°C while stirring. Sulfuric acid (H2S04, 0. 1 ml, 96 % ) was added and a clear solution was obtained. The aqueous phase was concentrated to leave a viscous oil. THF (30 ml) was added and the crystal suspension, which had been formed, was decanted from the supernatant, slurried with two aliquots of THF ( 10 ml each) for 10 min. The washed solid was collected on a filter by vacuum filtration and dried at 40 °C in vacuum drying cabinet at 100 mbar. The solids had a weight of 1 . 10 g ( 100 % yield).
  • 12
  • [ 1243329-97-6 ]
  • [ 191732-72-6 ]
YieldReaction ConditionsOperation in experiment
82% With sodium hydrogencarbonate In water at 65 - 70℃; 3 Preparation of Lenalidomide BaseLenalidomide hydrochloride (345 g, 1 . 1 7 mol), obtained according to Example 2 , was charged to a 3 1 beaker and suspended in water ( 1500 ml). With stirring by a magnetic stirring bar, the suspension was heated to about 85°C. When most of the solid had dissolved, charcoal ( 10 g) was added in portions and stirring continued for 30 min at 80°C. The black suspension was filtered through a Buchner funnel into a preheated round bottom flask (3 1) under vacuum. The clear solution was kept at 70°C and 350 ml of a saturated NaHC03 sol. was added dropwise until pH 8. The measured inner temperature was 65°C .While stirring (50 rpm) the suspension was allowed to cool to RT overnight. The formed crystals were collected by filtration on a Buchner funnel and dried for 16 h at 40°C under vacuum ( 100 mbar). 258 g of lenalidomide base in the form of its hemihydrate (Form B according to WO 2005 / 023192 ) was obtained (98.9% pure, 82% from 314.77 g theory).
  • 13
  • (S)-3-(1-oxo-4-nitroisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
  • [ 191732-72-6 ]
YieldReaction ConditionsOperation in experiment
51% With palladium 10% on activated carbon; hydrogen In methanol for 5h; 6.1 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione A mixture of (S)-3-(1-oxo-4-nitroisoindolin-2-yl)piperidine-2,6-dione (1.0 g, 3.5 mmol) and 10% Pd/C (0.3 g) in methanol (600 mL) was hydrogenated in a Parr-Shaker apparatus at 50 psi of hydrogen for 5 hours. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The solid was slurried in hot ethyl acetate for 30 min, filtered and dried to afford 0.46 g (51%>) of the product as a white solid: mp 235.5-239°C; 1H NMR (DMSO-d6) δ 11.01 (s, 1H). 7.19(t, J=7.6 Hz, 1H). 6.90(d. J=7.3 Hz, 1H), 6.78(d, J=7.8 Hz, 1H), 5.42(s, 2H). 5.12(dd. J=5.1 and 13.1 Hz, 1H), 4.17(dd, J=17.0 and 28.8 Hz, 2H), 2.92-2.85(m, 1H). 2.64-2.49(m, 1H). 2.34-2.27(m, 1H), 2.06-1.99(m, 1H); 13C NMR (DMSO-d6) δ 172.85, 171.19, 168.84, 143.58, 132.22. 128.79, 125.56, 1 16.37, 1 10.39, 51.48, 45.49, 31.20, 22.74; HPLC. Waters Nova-Pak/C18, 3.9x150 mm, 4 micron, 1 mL/min, 240 nm, 10/90 CH3CN/0.1%H3P04(aq) 0.96 min(100%); Chiral analysis, Daicel Chiral Pak AD, 40/60 Hexane/IPA, 6.60 min(99.42%); Anal. Calcd for C13H13N3O3 : C, 60.23; H, 5.05; N, 16.21. Found : C, 59.96; H. 4.98; N, 15.84.
51% With palladium 10% on activated carbon; hydrogen In methanol for 5h; 6.1.5 6.1.5 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione A mixture of (S)-3-(1-oxo-4-nitroisoindolin-2-yl)piperidine-2,6-dione (1.0 g, 3.5 mmol) and 10% Pd/C (0.3 g) in methanol (600 mL) was hydrogenated in a Parr-Shaker apparatus at 50 psi of hydrogen for 5 hours. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The solid was slurried in hot ethyl acetate for 30 min, filtered and dried to afford 0.46 g (51%) of the product as a white solid: mp 235.5-239° C.; 1H NMR (DMSO-d6) δ 11.01 (s, 1H). 7.19 (t, J=7.6 Hz, 1H). 6.90 (d. J=7.3 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 5.42 (s, 2H). 5.12 (dd. J=5.1 and 13.1 Hz, 1H), 4.17 (dd, J=17.0 and 28.8 Hz, 2H), 2.92-2.85 (m, 1H). 2.64-2.49 (m, 1H). 2.34-2.27 (m, 1H), 2.06-1.99 (m, 1H); 13C NMR (DMSO-d6) δ 172.85, 171.19, 168.84, 143.58, 132.22. 128.79, 125.56, 1 16.37, 1 10.39, 51.48, 45.49, 31.20, 22.74; HPLC. Waters Nova-Pak/C18, 3.9*150 mm, 4 micron, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4 (aq) 0.96 min(100%); Chiral analysis, Daicel Chiral Pak AD, 40/60 Hexane/IPA, 6.60 min(99.42%); Anal. Calcd for C13H13N3O3: C, 60.23; H, 5.05; N, 16.21. Found: C, 59.96; H. 4.98; N, 15.84. 3-(4-Amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione may also be prepared by methods known in the art, for example, as provided in Drugs of the Future, 2003, 28(5): 425-431, the entirety of which is incorporated by reference.
51% With palladium 10% on activated carbon; hydrogen In methanol for 5h; 6.6.1 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione A mixture of (S)-3-(1-oxo-4-nitroisoindolin-2-yl)piperidine-2,6-dione (1.0 g, 3.5 mmol) and 10% Pd/C (0.3 g) in methanol (600 mL) was hydrogenated in a Parr-Shaker apparatus at 50 psi of hydrogen for 5 hours. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The solid was slurried in hot ethyl acetate for 30 min, filtered and dried to afford 0.46 g (51%) of the product as a white solid: mp 235.5-239° C.; 1H NMR (DMSO-d6) δ 11.01 (s, 1H). 7.19 (t, J=7.6 Hz, 1H). 6.90 (d. J=7.3 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 5.42 (s, 2H). 5.12 (dd. J=5.1 and 13.1 Hz, 1H), 4.17 (dd, J=17.0 and 28.8 Hz, 2H), 2.92-2.85 (m, 1H). 2.64-2.49 (m, 1H). 2.34-2.27 (m, 1H), 2.06-1.99 (m, 1H); 13C NMR (DMSO-d6) δ 172.85, 171.19, 168.84, 143.58, 132.22. 128.79, 125.56, 116.37, 110.39, 51.48, 45.49, 31.20, 22.74; HPLC. Waters Nova-Pak/C18, 3.9*150 mm, 4 micron, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4(aq) 0.96 min(100%); Chiral analysis, Daicel Chiral Pak AD, 40/60 Hexane/IPA, 6.60 min (99.42%); Anal. Calcd for C13H13N3O3: C, 60.23; H, 5.05; N, 16.21. Found: C, 59.96; H, 4.98; N, 15.84.
In methanol; hydrogen; ethyl acetate 6.5 6.1.5 6.1.5 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione A mixture of (S)-3-(1-oxo-4-nitroisoindolin-2-yl)piperidine-2,6-dione (1.0 g, 3.5 mmol) and 10% Pd/C (0.3 g) in methanol (600 mL) was hydrogenated in a Parr-Shaker apparatus at 50 psi of hydrogen for 5 hours. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The solid was slurried in hot ethyl acetate for 30 min, filtered and dried to afford 0.46 g (51%) of the product as a white solid: mp 235.5-239° C.; 1H NMR (DMSO-d6) δ 11.01 (s, 1H). 7.19 (t, J=7.6 Hz, 1H). 6.90 (d. J=7.3 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 5.42 (s, 2H). 5.12 (dd. J=5.1 and 13.1 Hz, 1H), 4.17 (dd, J=17.0 and 28.8 Hz, 2H), 2.92-2.85 (m, 1H). 2.64-2.49 (m, 1H). 2.34-2.27 (m, 1H), 2.06-1.99 (m, 1H); 13C NMR (DMSO-d6) δ 172.85, 171.19, 168.84, 143.58, 132.22. 128.79, 125.56, 1 16.37, 1 10.39, 51.48, 45.49, 31.20, 22.74; HPLC. Waters Nova-Pak/C18, 3.9*150 mm, 4 micron, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4(aq) 0.96 min(100%); Chiral analysis, Daicel Chiral Pak AD, 40/60 Hexane/IPA, 6.60 min(99.42%); Anal. Calcd for C13H13N3O3: C, 60.23; H, 5.05; N, 16.21. Found: C, 59.96; H. 4.98; N, 15.84. 3-(4-Amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione may also be prepared by methods known in the art, for example, as provided in Drugs of the Future, 2003, 28(5): 425-431, the entirety of which is incorporated by reference.

  • 14
  • [ 3303-84-2 ]
  • [ 191732-72-6 ]
  • [ 1407490-88-3 ]
YieldReaction ConditionsOperation in experiment
56.21% With pyridine; trichlorophosphate In acetonitrile at 20℃; for 2h; 5.1 Step 1: Preparation of (3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)-3-oxopropyl ) tert-butyl carbamate (5a) 3-(4-Amino-1-oxoisoindol-2-yl)piperidine-2,6-dione (0.3 g, 1.16 mmol),3-((tert-Butoxycarbonyl)amino)propanoic acid (0.26 g, 1.39 mmol)And pyridine (0.27 g, 3.47 mmol) was dissolved in 5 mL of acetonitrile.Slowly add dropwise phosphorus oxychloride (0.21 g, 1.39 mmol) in acetonitrile.After the reaction was completed at room temperature for 2 hours,The organic solvent was evaporated under reduced pressure, and water (20 mL)The organic layer was collected, dried over anhydrous sodium sulfate, and evaporated.Using dichloromethane / methanol (V / V = 100 / 1-30 / 1) to afford a yellow solid,The weight was 0.28 g, and the yield was 56.21%.
56% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 40℃; for 3.5h; 4.1.3. 8-Bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)octanamide (a5) General procedure: The mixture of lenalidomide (1.00g, 3.85 mmol), 8-bromooctanoic acid (1.03 g, 4.62 mmol), EDCI (0.88g, 4.62 mmol),DMAP (0.56g, 4.62 mmol) and DMF (20 mL) were stirred at 40 C inan oil bath for 3.5 h. The solvent was removed under reducedpressure. The residue was suspended with water and the aqueousphase was extracted with ethyl acetate. The organic phase waswashed with saturated salt water, dried with anhydrous sodiumsulfate. Ethyl acetate was removed under reduced pressure toobtain 0.97 g intermediate a5 as white solid.
48.18% With pyridine; trichlorophosphate In acetonitrile at 20℃; for 4h; Cooling with ice; 5.1 Step 1) Tert-butyl (3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3-propionyl) Carbamate (2a) lenalidomide (0.2g, 0.77mmol),3-((tert-butoxycarbonyl)amino)propionic acid (0.16 g, 0.85 mmol),Soluble in 2mL acetonitrile,Pyridine (0.18 g, 2.31 mmol) was added,Add 2ml of acetonitrile diluted phosphorus oxychloride in ice bath(0.14g, 0.92mmol),After the addition, remove the ice bath. After 4 hours at room temperature, add 20 mL of water.Extract with ethyl acetate, wash with saturated brine, collect the organic layer,Drying over anhydrous sodium sulfate and evaporation of the organic solvent under reduced pressureThe residue was purified by silica gel column chromatography.Elution with dichloromethane/methanol (V/V=100/1-40/1) gave a pale yellow solid,Weight 0.16g, yield 48.18%.
With HATU In N,N-dimethyl-formamide; acetonitrile at 20℃; for 18h; 5 Lenolidomide (0.5 mmol) is taken up in 5 mL of acetonitrile and 2 mL of DMF along with 3-((tert-butoxycarbonyl)amino)propanoic acid (0.5 mmol), HATU (0.55 mmol) and stirred at room temperature for 18 h. The reaction mixture is concentrated under reduced pressure and then diluted with EtOAC (20 mL). The organic layer is washed with water (4*5 mL), brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure. Purification by silica gel chromatography (95% CH2Cl2, 5% MeOH) affords tert-butyl (3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3-oxopropyl)carbamate. This material is then taken up in 10 mL of 4 N HCl in dioxane and allowed to stir at room temperature for 6 h. The reaction mixture is then concentrated under reduced pressure to afford the HCl salt of 3-amino-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propanamide.
With pyridine; trichlorophosphate In acetonitrile at 20℃; for 3h; 4.1.3. General procedure for the preparation of 35a-f General procedure: A mixture of 33a-f (0.85 mmol), lenalidomide (0.77 mmol), pyridine(2.31 mmol) and phosphorus oxychloride (0.93 mmol) in acetonitrile(10 mL) was stirred at room temperature for 3 h. After the reactionwas completed, the mixture was concentrated and then dilutedwith water (10 mL) and extracted with ethyl acetate (10 mL × 3). Thecombined organic layer was dried over anhydrous Na2SO4 and concentratedunder reduced pressure. The crude residue was purified byflash column chromatography (dichloromethane/methanol = 35:1) to give 34a-f (about 40% yield).

  • 15
  • [ 133-37-9 ]
  • [ 191732-72-6 ]
  • 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione-DL-tartaric acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
10 mg In n-heptane; 2,2,2-trifluoroethanol; water; ethyl acetate at 20℃; for 24h; 7 Example 7 - Preparation of a DL-Tartaric Acid Cocrystal of Lenalidomide Example 7 - Preparation of a DL-Tartaric Acid Cocrystal of Lenalidomide [00129] In a 4ml vial lOOmg of 3-(4-amino-l-oxo-l,3-dihydroisoindol-2-yl)piperidine-2,6- dione and 65 mg of DL-tartaric acid was taken and 3 ml of ethyl acetate: 2,2,2-trifhioro ethanol:heptanes:water (10: 10:20: 1) was added. It formed slurry at room temperature (RT). The slurry was stirred for approximately 24 hours, at which time approximately 3 to 10 mg of the solid present was isolated by vacuum filtration and air dried. XRPD data from this solid sample was examined and compared to XRPD data from known solid phases of 3-(4-amino-l-oxo-l,3- dihydroisoindol-2-yl)piperidine-2,6-dione and DL-tartaric acid in order to determine if, in addition to a novel solid phase, identified as the 3-(4-amino-l-oxo-l,3-dihydroisoindol-2- yl)piperidine-2,6-dione-DL-tartaric acid cocrystal, excess 3-(4-amino-l-oxo-l,3- dihydroisoindol-2-yl)piperidine-2,6-dione or DL-tartaric acid was present in the solid isolated from the reaction. Additional 3-(4-amino-l-oxo-l,3-dihydroisoindol-2-yl)piperidine-2,6-dione or DL-tartaric acid was added in 1 to 10 mg amounts to drive the product towards pure cocrystal. The process of isolating a 3 to 10 mg sample, obtaining and analyzing the XRPD data, and adding additional 3-(4-amino-l-oxo-l,3-dihydroisoindol-2-yl)piperidine-2,6-dione or DL-tartaric acid in 1 to 10 mg amounts and stirring for approximately 24 hours was repeated until the product obtained was only cocrystal based on XRPD data. The isolated solid was analyzed by XRPD, Raman spectroscopy, and 1H-NMR. The XRPD pattern of the material isolated at the end of the reaction is substantially the same as that shown in FIG 30. The Raman spectrum is substantially the same as that shown in FIG. 31. The 1H-NMR spectrum is substantially the same as that shown in FIGS. 32A, 32B, 32C, and 32D.
  • 16
  • [ 36070-80-1 ]
  • [ 879126-98-4 ]
  • 5-chloro-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pyrazine-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
33% With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; [00778] To a solution of lenalidomide (0.2g, 0.77 mmol) in DMF (4 mL) was added <strong>[36070-80-1]5-chloropyrazine-2-carboxylic acid</strong> (0.15g, 0.95 mmol), HATU, (0.29g, 0.77 mmol), and DIPEA (0.27mL, 1.54 mmol). The reaction was stirred at room temperature for 1 hr before it was quenched with saturated NH4C1 (5 mL). The mixture was extracted with EtOAc (10 mLx3), and the combined organic phase was dried over Na2SO4 and concentrated. Column chromatography gave 5-chloro-N-(2- (2,6-dioxopiperidin-3-yl)- 1 -oxoisoindolin-4-yl)pyrazine-2-carboxamide (0.1 g, 33%).
33% With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 10℃; for 1h; To a solution of lenalidomide (0.2g, 0.77 mmol) in DMF (4 mL) was added <strong>[36070-80-1]5-chloropyrazine-2-carboxylic acid</strong> (0.15g, 0.95 mmol), HATU, (0.29g, 0.77 mmol), and DIPEA (0.27mL, 1.54 mmol). The reaction was stirred at room temperature for 1 hr before it was quenched with saturated NH4C1 (5 mL). The mixture was extracted with EtOAc (10 mLx3), and the combined organic phase was dried over Na2S04 and concentrated. Column chromatography gave 5-chloro-N- (2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)pyrazine-2-carboxamide (0.1 g, 33%).
33% With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; [00782] SDC-TRAP-0 170[00783] 5- (4- (4-(3-(2,4-dihydroxy-5 -isopropylphenyl)-5-hydroxy-4H- 1 ,2,4-triazol- 4-yl)-2-fluorobenzyl)piperazin- 1 -yl)-N-(2-(2,6-dioxopiperidin-3-yl)- 1 -oxoisoindolin-4-yl)pyrazine-2-carboxamideNXCOOHHATU, DIPEA, DMF[00784] To a solution of lenalidomide (0.2g, 0.77 mmol) in DMF (4 mL) was added <strong>[36070-80-1]5-chloropyrazine-2-carboxylic acid</strong> (0.15g, 0.95 mmol), HATU, (0.29g, 0.77 mmol), and DIPEA (0.27mL, 1.54 mmol). The reaction was stuffed at room temperature for 1 hr before it was quenched with saturated NH4C1 (5 mL). The mixture was extracted with EtOAc (10 mLx3), and the combined organic phase was dried over Na2SO4 and concentrated. Column chromatography gave 5-chloro-N- (2-(2,6-dioxopiperidin-3-yl)- 1 -oxoisoindolin-4-yl)pyrazine-2-carboxamide (0.1 g, 33%).
  • 17
  • [ 7693-46-1 ]
  • [ 191732-72-6 ]
  • 4-nitrophenyl (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% In tetrahydrofuran for 2h; Reflux; 8.1 [00529] STEP-1: To a stuffed suspension of lenalidomide 1 (520mg, 2mmol) in dry THF (70 mL) was added 4-nitrophenyichioroformate (605mg, 3mmol). The reaction mixture was refluxed for 2h, concentrated to approximately 4OmL, and triturated with ethyl acetate to yield a white precipitate. The solid was collected by filtration and washed with ethyl acetate to give carbamate 2 (650mg, 77%).
77% In tetrahydrofuran for 2h; Reflux; 8.1 STEP-1: To a stirred suspension of lenalidomide 1 (520mg, 2mmol) in dry THF (70 mL) was added 4-nitrophenylchloroformate (605mg, 3mmol). The reaction mixture was refluxed for 2h, concentrated to approximately 40mL, and triturated with ethyl acetate to yield a white precipitate. The solid was collected by filtration and washed with ethyl acetate to give carbamate 2 (650mg, 77%).
77% In tetrahydrofuran for 2h; Reflux; 8.1 [00538] STEP-i: To a stirred suspension of lenalidomide 1 (520mg, 2mmol) in dry THF (70 mL) was added 4-nitrophenylchloroformate (605mg, 3mmol). The reaction mixture was refluxed for 2h, concentrated to approximately 40mL, and triturated with ethyl acetate to yield a white precipitate. The solid was collected by filtration and washed with ethyl acetate to give carbamate 2 (650mg, 77%).
74% In tetrahydrofuran at 80℃; for 4h; General procedures for the preparation of compounds 11a-11b. General procedure: To a solution of 5a or 5b(1.0 eq) in THF, 10 (1.5 eq) was added. The mixture was stirred at reflux for 4 h. After thereaction completed, the mixture was cooled to room temperature, filtered and washedwith THF to produce 11a_11b.4-Nitrophenyl (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)carbamate (11a)(yellow solid, yield 74%): 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 10.39 (s, 1H), 8.33(d, J = 9.0 Hz, 2H), 7.81 (dd, J = 6.5, 2.0 Hz, 1H), 7.63 - 7.48 (m, 4H), 5.16 (dd, J = 13.2, 5.0Hz, 1H), 4.49 (dd, J = 37.2, 17.7 Hz, 2H), 3.04 - 2.83 (m, 1H), 2.63 (d, J = 17.0 Hz, 1H), 2.46 -2.29 (m, 1H), 2.13 - 1.96 (m, 1H).
at 65℃; for 1h; [00793] A solution of lenalidomide (1.0 g, 3.86 mmol) and 4-nitrophenyl chloroformate (1.15 g, 5.70 mmol) was heated at 65 °C for 1 hr. The solution was allowed to cool to room temperature, then filtered. The solid was dried and used for the next step without further purification.
190 mg In tetrahydrofuran for 4h; Reflux; 3 To a solution of 3-(4-amino-l-oxoisoindolin-2-yl)piperidine-2,6-dione (200 mg, 0.77 mmol) in dry tetrahydrofuran (THF) (20 ml) was added 4-nitrophenyl carbonochloridate (233 mg, 1.16 mmol). The mixture was stirred at reflux for 4 hours. The mixture was concentrated to 5 mL and filtered to afford compound 10 as a solid (190 mg).

  • 18
  • [ 191732-72-6 ]
  • C13H13N3O3*(x)Br2Mg [ No CAS ]
YieldReaction ConditionsOperation in experiment
94% With magnesium bromide hexahydrate In methanol at 60℃; 13 Example 13. Solid Forms comprising lenalidomide and magnesium bromide A cocrystal comprising lenalidomide and magnesium bromide was also prepared using thestoichiometric flash evaporation method described in Example 5. Methanol was used as the solvent.In a scale up experiement, a solution of 66.1 mg (0.255 mmol) of lenalidomide and75.0 mg (0.257 mmol) of magnesium bromide hexahydrate in 75 mL of methanol wasconcentrated on a rotary evaporator at 60 °C. The flask containing the resulting solid was placed in an oven at 60 °C overnight. A few milliliters of diethyl ether were added to the flask, the solid was scraped from the walls with a spatula, and the mixture was transferred to a vial. The etherwas evaporated in a stream of dry air to give 105.8 mg (94% yield) of thelenalidomide/magnesium bromide cocrystal.
  • 19
  • [ 82413-63-6 ]
  • [ 879126-98-4 ]
  • (S)-3-(4-((4-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% At 30 C, A346A (119mg, 0.58mmol) and A308A (100mg, 0.39mmol) was dissolved in acetic acid (2.5mL) and dichloromethane (2.5mL) mixed solution was stirred for 1 hour, of NaBH(OAc)3 (246mg stirring, 1.16mmol), nitrogen for 18 hours. TLC showed the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure was added a saturated aqueous sodium bicarbonate solution (5mL) adjusted to pH 8, was added and extracted with DCM (25mL × 5), the organic phase was dried over anhydrous of Na2SO4 dried, filtered, and the filtrate was concentrated under reduced pressure, the residue was a mixed solution of ethyl acetate and petroleum ether (1/1) (25mL × 2) beating obtain 250mg crude product, prepared by Prep-HPLC to give a white solid product A346 (140mg, yield: 80%).
  • 20
  • [ 827026-43-7 ]
  • [ 191732-72-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: hydrogenchloride / water / 1 h / Reflux 2: palladium on activated charcoal; hydrogen / acetone / 2 °C 3: N,N-dimethyl-formamide / 4 h / Reflux
  • 21
  • [ 927-58-2 ]
  • [ 191732-72-6 ]
  • 4-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butanamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% In tetrahydrofuran at 20℃; for 2h; Intermediate 63 4-Bromo-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)butanamide To a solution of 3-(4-amino-l-oxoisoindolin-2-yl)piperidine-2,6-dione (from for example Astatech, 500 mg, 1.93 mmol) in THF (5 mL) was added 4-bromobutanoyl chloride (Aldrich) (0.223 mL, 1.929 mmol) and the mixture was stirred at room temperature for 2h. The solvent was removed in vacuo and the residue was triturated with ether, filtered, washed with ether and dried to give the title compound (700 mg, 1.715 mmol, 89 % yield). LCMS RT= 0.7 min,(M+H) 409.
  • 22
  • [ 3669-80-5 ]
  • [ 191732-72-6 ]
  • N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-11-hydroxyundecanamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
18% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; Intermediate 67 N-(2-(2,6-Dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-ll-hydroxyundecanamide To a solution of 11-hydroxyundecanoic acid (Aldrich) (0.5 g, 2.472 mmol) in DMF (5 mL) was added 3-(4-amino-l-oxoisoindolin-2-yl)piperidine-2,6-dione (0.641 g, 2.47 mmol) followed by HATU (1.222 g, 3.21 mmol) and DIPEA (1.727 mL, 9.89 mmol). The reaction mixture was stirred at room temeprature overnight. The solvent was removed and the residue was subjected to cromatography on 12g ISCO Combiflash column eluting with 0-10%MeOH:DCM to give the title compound (196 mg, 0.442 mmol, 18% yield). LCMS RT= 0.86 min,(M+H) 444
  • 23
  • [ 106-94-5 ]
  • [ 191732-72-6 ]
  • 3-(1-oxo-4-(propylamino)isoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
84% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 110℃; for 2h;
84% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 110℃; for 6h; 18 Example 18: Preparation of 3- (1-oxo-4- (propylamino) isoindololin-2-yl) piperidine-2,6-dione (3- (1-oxo-4- (propylamino ) isoindolin-2-yl) piperidine-2,6-dione; SIAIS1204083A) According to the method of scheme D, in the future lenalidomide (20 mg, 0.073 mmol, 1 equiv), n-propyl bromide (18.9 mg,0.0876mmol, 1.2equiv) and N, N-diisopropylethylamine (29.9mg, 0.219mmol, 3equiv) were added together to 10mL ofThen, NMP (2 mL) was added to the reaction tube, and the reaction was performed in an oil bath at 110 ° C for 6 hours. The reaction solution was cooled to room temperature, and then a C18 reversed-phase column was used.Preparation, eluent (v / v): acetonitrile / ice + 0.1% TFA) = 10% -100%, acetonitrile was distilled off under reduced pressure, and the target was obtained after lyophilizationCompound SIAIS1204083A (yellow solid, 18.5mg, 84%)
59% With potassium carbonate; potassium iodide In acetonitrile Reflux; 2.1. 3-(1-oxo-4-(propylamino)isoindolin-2-yl)piperidine-2,6-dione (1a) K2CO3 (0.30 g, 2 mmol), KI (0.05 g, cat.) and 1-Bromopropane (1.30 g, 1.1 mmol) was added to a solution of 10 (0.26 g, 1 mmol) in ACN (20 mL). The mixture was allowed heated to reflux until the start material was consumed which monitored by TLC. After cood to room tempreture, the mixture was filtered and the filtrate was concentrateed under reduced pressure. The residue was recrystallization from MeOH/DCM to yield 1a as a yellow solid. Yield 59%. 1H-NMR (400 MHz, CDCl3) δ: 0.89 (3H, t, J=7.2 Hz), 1.53 (2H, m), 2.12 (1H, m), 2.25 (1H, m), 2.83 (1H, m), 2.93 (1H, m), 3.72 (2H, m), 3.83 (2H, s), 4.21 (2H, q, J=17.9 Hz), 5.16 (1H, q, J=5.2 Hz), 6.84 (1H, q, J=7.3 Hz), 7.29 (2H, m). 13C-NMR (100 MHz, CDCl3) δ: 6.6, 16.5, 18.0, 24.9, 27.4, 37.3, 40.3, 47.7, 109.5, 113.3, 121.5, 124.7, 127.6, 136.5, 165.1, 165.2, 166.2; LC-MS (ESI) m/z 301.1502 (M+H)+
  • 24
  • [ 98-88-4 ]
  • [ 191732-72-6 ]
  • [ 444289-22-9 ]
YieldReaction ConditionsOperation in experiment
86% With triethylamine In tetrahydrofuran at 20℃; for 6h; 2.8. N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2,2,2-trifluoroacetamide (2a) General procedure: Thionyl chloride (0.26 g, 2.1 mmol) was added to a solution of trifluoroacetate (0.26 g, 2 mmol) in DCM (10 mL). After the mixture was heated to reflux for 1h, it was concentrateed under reduced pressure to give a yellow oil.TEA (0.50 g, 5 mmol) was added to a solution of 10 (0.26 g, 1 mmol) in THF (20 mL), then the yellow oil in THF (10 mL) was added. The mixture was stirred at room tempreture for 6h, then H2O (1 mL) was added. After the start material was consumed which monitored by TLC, the mixture was concentrateed under reduced pressure. The residue was added 1N HCl (25 mL) and stirred for half an hour. Filter and wash the filter cake with water to yield 2a as a yellow solid.
  • 25
  • [ 874-60-2 ]
  • [ 191732-72-6 ]
  • N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-4-methylbenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% With triethylamine In tetrahydrofuran at 20℃; for 6h; 2.8. N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2,2,2-trifluoroacetamide (2a) General procedure: Thionyl chloride (0.26 g, 2.1 mmol) was added to a solution of trifluoroacetate (0.26 g, 2 mmol) in DCM (10 mL). After the mixture was heated to reflux for 1h, it was concentrateed under reduced pressure to give a yellow oil.TEA (0.50 g, 5 mmol) was added to a solution of 10 (0.26 g, 1 mmol) in THF (20 mL), then the yellow oil in THF (10 mL) was added. The mixture was stirred at room tempreture for 6h, then H2O (1 mL) was added. After the start material was consumed which monitored by TLC, the mixture was concentrateed under reduced pressure. The residue was added 1N HCl (25 mL) and stirred for half an hour. Filter and wash the filter cake with water to yield 2a as a yellow solid.
  • 26
  • [ 403-43-0 ]
  • [ 191732-72-6 ]
  • N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-4-fluorobenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With triethylamine In tetrahydrofuran at 20℃; for 6h; 2.8. N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2,2,2-trifluoroacetamide (2a) General procedure: Thionyl chloride (0.26 g, 2.1 mmol) was added to a solution of trifluoroacetate (0.26 g, 2 mmol) in DCM (10 mL). After the mixture was heated to reflux for 1h, it was concentrateed under reduced pressure to give a yellow oil.TEA (0.50 g, 5 mmol) was added to a solution of 10 (0.26 g, 1 mmol) in THF (20 mL), then the yellow oil in THF (10 mL) was added. The mixture was stirred at room tempreture for 6h, then H2O (1 mL) was added. After the start material was consumed which monitored by TLC, the mixture was concentrateed under reduced pressure. The residue was added 1N HCl (25 mL) and stirred for half an hour. Filter and wash the filter cake with water to yield 2a as a yellow solid.
  • 27
  • [ 122-01-0 ]
  • [ 191732-72-6 ]
  • 4-chloro-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% With triethylamine In tetrahydrofuran at 20℃; for 6h; 2.8. N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2,2,2-trifluoroacetamide (2a) General procedure: Thionyl chloride (0.26 g, 2.1 mmol) was added to a solution of trifluoroacetate (0.26 g, 2 mmol) in DCM (10 mL). After the mixture was heated to reflux for 1h, it was concentrateed under reduced pressure to give a yellow oil.TEA (0.50 g, 5 mmol) was added to a solution of 10 (0.26 g, 1 mmol) in THF (20 mL), then the yellow oil in THF (10 mL) was added. The mixture was stirred at room tempreture for 6h, then H2O (1 mL) was added. After the start material was consumed which monitored by TLC, the mixture was concentrateed under reduced pressure. The residue was added 1N HCl (25 mL) and stirred for half an hour. Filter and wash the filter cake with water to yield 2a as a yellow solid.
  • 28
  • [ 122-04-3 ]
  • [ 191732-72-6 ]
  • N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-4-nitrobenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With triethylamine In tetrahydrofuran at 20℃; for 6h; 2.8. N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2,2,2-trifluoroacetamide (2a) General procedure: Thionyl chloride (0.26 g, 2.1 mmol) was added to a solution of trifluoroacetate (0.26 g, 2 mmol) in DCM (10 mL). After the mixture was heated to reflux for 1h, it was concentrateed under reduced pressure to give a yellow oil.TEA (0.50 g, 5 mmol) was added to a solution of 10 (0.26 g, 1 mmol) in THF (20 mL), then the yellow oil in THF (10 mL) was added. The mixture was stirred at room tempreture for 6h, then H2O (1 mL) was added. After the start material was consumed which monitored by TLC, the mixture was concentrateed under reduced pressure. The residue was added 1N HCl (25 mL) and stirred for half an hour. Filter and wash the filter cake with water to yield 2a as a yellow solid.
  • 29
  • [ 527-69-5 ]
  • [ 191732-72-6 ]
  • N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)furan-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With triethylamine In tetrahydrofuran at 20℃; for 6h; 2.8. N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2,2,2-trifluoroacetamide (2a) General procedure: Thionyl chloride (0.26 g, 2.1 mmol) was added to a solution of trifluoroacetate (0.26 g, 2 mmol) in DCM (10 mL). After the mixture was heated to reflux for 1h, it was concentrateed under reduced pressure to give a yellow oil.TEA (0.50 g, 5 mmol) was added to a solution of 10 (0.26 g, 1 mmol) in THF (20 mL), then the yellow oil in THF (10 mL) was added. The mixture was stirred at room tempreture for 6h, then H2O (1 mL) was added. After the start material was consumed which monitored by TLC, the mixture was concentrateed under reduced pressure. The residue was added 1N HCl (25 mL) and stirred for half an hour. Filter and wash the filter cake with water to yield 2a as a yellow solid.
  • 30
  • [ 879-18-5 ]
  • [ 191732-72-6 ]
  • N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-1-naphthamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% With triethylamine In tetrahydrofuran at 20℃; for 6h; 2.8. N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2,2,2-trifluoroacetamide (2a) General procedure: Thionyl chloride (0.26 g, 2.1 mmol) was added to a solution of trifluoroacetate (0.26 g, 2 mmol) in DCM (10 mL). After the mixture was heated to reflux for 1h, it was concentrateed under reduced pressure to give a yellow oil.TEA (0.50 g, 5 mmol) was added to a solution of 10 (0.26 g, 1 mmol) in THF (20 mL), then the yellow oil in THF (10 mL) was added. The mixture was stirred at room tempreture for 6h, then H2O (1 mL) was added. After the start material was consumed which monitored by TLC, the mixture was concentrateed under reduced pressure. The residue was added 1N HCl (25 mL) and stirred for half an hour. Filter and wash the filter cake with water to yield 2a as a yellow solid.
  • 31
  • [ 102-92-1 ]
  • [ 191732-72-6 ]
  • N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)cinnamamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% With triethylamine In tetrahydrofuran at 20℃; for 6h; 2.8. N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2,2,2-trifluoroacetamide (2a) General procedure: Thionyl chloride (0.26 g, 2.1 mmol) was added to a solution of trifluoroacetate (0.26 g, 2 mmol) in DCM (10 mL). After the mixture was heated to reflux for 1h, it was concentrateed under reduced pressure to give a yellow oil.TEA (0.50 g, 5 mmol) was added to a solution of 10 (0.26 g, 1 mmol) in THF (20 mL), then the yellow oil in THF (10 mL) was added. The mixture was stirred at room tempreture for 6h, then H2O (1 mL) was added. After the start material was consumed which monitored by TLC, the mixture was concentrateed under reduced pressure. The residue was added 1N HCl (25 mL) and stirred for half an hour. Filter and wash the filter cake with water to yield 2a as a yellow solid.
  • 32
  • [ 98-09-9 ]
  • [ 191732-72-6 ]
  • N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)benzenesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With pyridine In tetrahydrofuran at 20℃; 2.20. N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-1,1,1-trifluoromethanesulfonamide (3a) General procedure: Pyridine (2 mL) and trifluoromethanesulfonyl chloride (0.17 g, 1 mmol) was added to a solution of 8 (0.26 g, 1 mmol) in THF (20 mL). The mixture was stirred at room tempreture. After the start material was consumed which monitored by TLC, the mixture was concentrateed under reduced pressure. The residue was added 1N HCl (25 mL) and stirred for half an hour. Filter and wash the filter cake with water to yield 3a as a yellow solid. Yield 31%.
  • 33
  • [ 98-59-9 ]
  • [ 191732-72-6 ]
  • N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-4-methylbenzenesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% With pyridine In tetrahydrofuran at 20℃; 2.20. N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-1,1,1-trifluoromethanesulfonamide (3a) General procedure: Pyridine (2 mL) and trifluoromethanesulfonyl chloride (0.17 g, 1 mmol) was added to a solution of 8 (0.26 g, 1 mmol) in THF (20 mL). The mixture was stirred at room tempreture. After the start material was consumed which monitored by TLC, the mixture was concentrateed under reduced pressure. The residue was added 1N HCl (25 mL) and stirred for half an hour. Filter and wash the filter cake with water to yield 3a as a yellow solid. Yield 31%.
  • 34
  • [ 349-88-2 ]
  • [ 191732-72-6 ]
  • N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-4-fluorobenzenesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With pyridine In tetrahydrofuran at 20℃; 2.20. N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-1,1,1-trifluoromethanesulfonamide (3a) General procedure: Pyridine (2 mL) and trifluoromethanesulfonyl chloride (0.17 g, 1 mmol) was added to a solution of 8 (0.26 g, 1 mmol) in THF (20 mL). The mixture was stirred at room tempreture. After the start material was consumed which monitored by TLC, the mixture was concentrateed under reduced pressure. The residue was added 1N HCl (25 mL) and stirred for half an hour. Filter and wash the filter cake with water to yield 3a as a yellow solid. Yield 31%.
  • 35
  • [ 98-74-8 ]
  • [ 191732-72-6 ]
  • N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-4-nitrobenzenesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% With pyridine In tetrahydrofuran at 20℃; 2.20. N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-1,1,1-trifluoromethanesulfonamide (3a) General procedure: Pyridine (2 mL) and trifluoromethanesulfonyl chloride (0.17 g, 1 mmol) was added to a solution of 8 (0.26 g, 1 mmol) in THF (20 mL). The mixture was stirred at room tempreture. After the start material was consumed which monitored by TLC, the mixture was concentrateed under reduced pressure. The residue was added 1N HCl (25 mL) and stirred for half an hour. Filter and wash the filter cake with water to yield 3a as a yellow solid. Yield 31%.
  • 36
  • [ 121-51-7 ]
  • [ 191732-72-6 ]
  • N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-3-nitrobenzenesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With pyridine In tetrahydrofuran at 20℃; 2.20. N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-1,1,1-trifluoromethanesulfonamide (3a) General procedure: Pyridine (2 mL) and trifluoromethanesulfonyl chloride (0.17 g, 1 mmol) was added to a solution of 8 (0.26 g, 1 mmol) in THF (20 mL). The mixture was stirred at room tempreture. After the start material was consumed which monitored by TLC, the mixture was concentrateed under reduced pressure. The residue was added 1N HCl (25 mL) and stirred for half an hour. Filter and wash the filter cake with water to yield 3a as a yellow solid. Yield 31%.
  • 37
  • [ 1694-92-4 ]
  • [ 191732-72-6 ]
  • N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-nitrobenzenesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With pyridine In tetrahydrofuran at 20℃; 2.20. N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-1,1,1-trifluoromethanesulfonamide (3a) General procedure: Pyridine (2 mL) and trifluoromethanesulfonyl chloride (0.17 g, 1 mmol) was added to a solution of 8 (0.26 g, 1 mmol) in THF (20 mL). The mixture was stirred at room tempreture. After the start material was consumed which monitored by TLC, the mixture was concentrateed under reduced pressure. The residue was added 1N HCl (25 mL) and stirred for half an hour. Filter and wash the filter cake with water to yield 3a as a yellow solid. Yield 31%.
  • 38
  • [ 98-68-0 ]
  • [ 191732-72-6 ]
  • N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-4-methoxybenzenesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% With pyridine In tetrahydrofuran at 20℃; 2.20. N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-1,1,1-trifluoromethanesulfonamide (3a) General procedure: Pyridine (2 mL) and trifluoromethanesulfonyl chloride (0.17 g, 1 mmol) was added to a solution of 8 (0.26 g, 1 mmol) in THF (20 mL). The mixture was stirred at room tempreture. After the start material was consumed which monitored by TLC, the mixture was concentrateed under reduced pressure. The residue was added 1N HCl (25 mL) and stirred for half an hour. Filter and wash the filter cake with water to yield 3a as a yellow solid. Yield 31%.
  • 39
  • [ 15084-51-2 ]
  • [ 191732-72-6 ]
  • 4-(tert-butyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)benzenesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% With pyridine In tetrahydrofuran at 20℃; 2.20. N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-1,1,1-trifluoromethanesulfonamide (3a) General procedure: Pyridine (2 mL) and trifluoromethanesulfonyl chloride (0.17 g, 1 mmol) was added to a solution of 8 (0.26 g, 1 mmol) in THF (20 mL). The mixture was stirred at room tempreture. After the start material was consumed which monitored by TLC, the mixture was concentrateed under reduced pressure. The residue was added 1N HCl (25 mL) and stirred for half an hour. Filter and wash the filter cake with water to yield 3a as a yellow solid. Yield 31%.
  • 40
  • [ 121-60-8 ]
  • [ 191732-72-6 ]
  • N-(4-(N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)sulfamoyl)phenyl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With pyridine In tetrahydrofuran at 20℃; 2.20. N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-1,1,1-trifluoromethanesulfonamide (3a) General procedure: Pyridine (2 mL) and trifluoromethanesulfonyl chloride (0.17 g, 1 mmol) was added to a solution of 8 (0.26 g, 1 mmol) in THF (20 mL). The mixture was stirred at room tempreture. After the start material was consumed which monitored by TLC, the mixture was concentrateed under reduced pressure. The residue was added 1N HCl (25 mL) and stirred for half an hour. Filter and wash the filter cake with water to yield 3a as a yellow solid. Yield 31%.
  • 41
  • [ 16629-19-9 ]
  • [ 191732-72-6 ]
  • N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thiophene-2-sulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% With pyridine In tetrahydrofuran at 20℃; 2.20. N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-1,1,1-trifluoromethanesulfonamide (3a) General procedure: Pyridine (2 mL) and trifluoromethanesulfonyl chloride (0.17 g, 1 mmol) was added to a solution of 8 (0.26 g, 1 mmol) in THF (20 mL). The mixture was stirred at room tempreture. After the start material was consumed which monitored by TLC, the mixture was concentrateed under reduced pressure. The residue was added 1N HCl (25 mL) and stirred for half an hour. Filter and wash the filter cake with water to yield 3a as a yellow solid. Yield 31%.
  • 42
  • 4-[(3-methoxypropyl)amino]-4-oxobutanoic acid [ No CAS ]
  • [ 191732-72-6 ]
  • N<SUP>1</SUP>-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N<SUP>4</SUP>-(3-methoxypropyl)succinamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% Stage #1: 4-[(3-methoxypropyl)amino]-4-oxobutanoic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: Lenalidomide In N,N-dimethyl-formamide at 20℃; 3 N1-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N4-(3- methoxypropyl)succinamide (SM1-133): General procedure: Method A1: A mixture of carboxylic acid (1.2-1.5 equiv.), HATU (2.0 equiv.), DIPEA (4.0 equiv.) in DMF (0.3-1 M) was stirred at room temperature for 30 min. The amine (1.0 equiv.) was added to the acid mixture and the entire solution was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. Water (10 mL) was added and extracted with DCM (2 × 10 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (SiO2) eluting with DCM in MeOH (0-8%) to provide the title compound.
74% Stage #1: 4-[(3-methoxypropyl)amino]-4-oxobutanoic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: Lenalidomide In N,N-dimethyl-formamide at 20℃; General method A General procedure: A mixture of acid (1.2-1.5 equiv.), HATU (2.0 equiv.), DIPEA (4.0 equiv.) in DMF (0.3-1 M) was stirred at room temperature for 30 min. The amine (1.0 equiv.) was added to the acid mixture and the solution was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. Water (10 mL) was added and extracted with DCM (2 x 10 mL). The combined organic layers were dried (Na2S04) and concentrated. The resulting residue was purified by SiCT column chromatography eluting with MeOH in DCM (0- 8% MeOH, gradient elution) to provide the title compound.
  • 43
  • [ 27219-07-4 ]
  • [ 191732-72-6 ]
  • tert-butyl (5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-5-oxopentyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% Stage #1: 5-(N-tert-butyloxycarbonyl)aminopentanoic acid With 4-methyl-morpholine; 1-[(1-(cyano-​2-​ethoxy-​2-​oxoethylidenaminooxy)​dimethylamino-​morpholino)]-uronium hexafluorophosphate In N,N-dimethyl-formamide for 0.0166667h; Stage #2: Lenalidomide With dmap In N,N-dimethyl-formamide at 20℃; for 2h; 11 tert-butyl (5-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)-5- oxopentyl)carbamate (SI-1) 5-((tert-butoxycarbonyl)amino)pentanoic acid (823 mg, 0.37 mmol, 1 eq.), COMU (1.54 g, 0.36 mmol, 0.95 eq.), and N-methylmorpholine (840 pL, 7.6 mmol, 2 eq.) were dissolved in 4 mL of DMF and incubated for 1 min. Lenalidomide (648 mg, 2.5 mmol, 0.66 eq.) and catalytic 4-dimethylaminopyridine were added in 6 mL of DMF and the reaction was stirred at room temperature for 2h. The reaction mixture was diluted with ethyl acetate (20 mL), washed with 1N HC1 (30 mL), water (30 mL), and brine (30 mL). The organic layer was dried over anhydrous MgS04 and filtered. This solution was left overnight at 4 °C after which a white precipitate was found. The precipitate was filtered and dried to provide the title compound as a white amorphous solid (860 mg, 75%). 1H NMR (600 MHz, DMSO-d6) d 11.02 (s, 1H), 9.76 (s, ), 7.81 (dd, J = 7.4, 1.6 Hz, 1H), 7.54 - 7.40 (m, 2H), 6.81 (t, J = 5.7 Hz, 1H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.38 (d, J = 17.4 Hz, 1H), 4.34 (d, J = 17.4 Hz, 1H), 2.97 - 2.89 (m, 3H), 2.61 (dt, J = 17.3, 3.3 Hz, 1H), 2.35 (t, J = 7.3 Hz, 3H), 2.03 (dtd, J = 12.5, 5.1, 2.2 Hz, 1H), 1.58 (p, J = 7.5 Hz, 2H), 1.42 (p, J = 7.2 Hz, 2H), 1.37 (s, 9H). HRMS (ESI) [M+Na]+ for CisHso^OeNa 481.2057, found 481.2063.
Stage #1: 5-(N-tert-butyloxycarbonyl)aminopentanoic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 0.166667h; Stage #2: Lenalidomide In N,N-dimethyl-formamide for 0.5h; 16 EXAMPLE 16 Synthesis of 5-amino-N-(2-(2,6-dioxopiperidin-3-yl)- l-oxoisoindolin-4-yl)pentanamide HATU (380 mg, 1 mmol) and N,N-diisopropylethylamine (0.44 mL, 2.5 mmol) were added to a solution of Boc-5-aminopentanoic acid (110 mg, 0.5 mmol) in 3 mL DMF and stirred. After 10 minutes, Lenalidomide (200 mg, 0.75 mmol) was added to the reaction. After 30 minutes, the solvent was removed and the crude was dissolved in 10 mL DCM and 2 mL trifluoroacetic acid. The reaction was stirred for 30min and then the solvent was removed by vacuo. The residue was purified by reverse phase chromatography over C18 column to yield 5-amino-N-(2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-4-yl)pentanamide as colorless oil.
With pyridine; trichlorophosphate In acetonitrile at 20℃; for 3h; 4.1.3. General procedure for the preparation of 35a-f General procedure: A mixture of 33a-f (0.85 mmol), lenalidomide (0.77 mmol), pyridine(2.31 mmol) and phosphorus oxychloride (0.93 mmol) in acetonitrile(10 mL) was stirred at room temperature for 3 h. After the reactionwas completed, the mixture was concentrated and then dilutedwith water (10 mL) and extracted with ethyl acetate (10 mL × 3). Thecombined organic layer was dried over anhydrous Na2SO4 and concentratedunder reduced pressure. The crude residue was purified byflash column chromatography (dichloromethane/methanol = 35:1) to give 34a-f (about 40% yield).
  • 44
  • [ 6139-84-0 ]
  • [ 191732-72-6 ]
  • C17H20ClN3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
10% With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 12h; 29 To a solution of lenalidomide (950 mg, 3.66 mmol, 1.0 eq) and 4-chloro-l- butanal (429 mg, 4.03 mmol, 1.1 eq) in 30 mL of DCE was added acetic acid (0.2 mL, 3.66 mmol, 1.0 eq) and sodium triacetoxyborohydride (1.55 g, 7.32 mmol, 2.0 eq). The suspended solution was stirred at room temperature for 12 h. The reaction mixture was quenched with brine and the product was extracted with DCM. The combined organic layer was dried over anhydrous Na2S04 and the solvent was evaporated to give the crude product, which was purified by flash column chromatography with DCM/MeOH to afford the desired product S 16 as a white solid (128 mg, 10% yield). UPLC-MS calculated for Ci7H2iClN303 [M+l]+ : 350.13, found 350.11.
10% With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 12h; 5 Synthesis of 3-(4-((4-(4-((4-(4-chlorophenyl)-3 ,9-dimethyl-6H-thieno[3 ,2-fj [1 ,2,4jtriazolo[4,3-aj [1 ,4jdiazepin-2-yl)ethynyl)- 1H- 1 ,2,3-triazol- 1- yl)butyl)amino)- 1 -oxoisoindolin-2-yl)piperidine-2,6-dione (Cpd. No. 5) To a solution of lenalidomide (950 mg, 3.66 mmol, 1.0 eq) and 4-chloro-1- butanal (429 mg, 4.03 mmol, 1.1 eq) in 30 mL of DCE was added acetic acid (0.2 mL, 3.66 mmol, 1.0 eq) and sodium triacetoxyborohydride (1.55 g, 7.32 mmol, 2.0 eq). The suspended solution was stirred at room temperature for 12 h. The reaction mixture was quenched with brine and the product was extracted with DCM. The combined organic layer was dried over anhydrous Na2504 and the solvent was evaporated to give the crude product, which was purified by flash column chromatography with DCM/MeOH to afford the desired product S16 as a white solid (128 mg, 10% yield). UPLC-MS calculated for C17H21C1N303 [M+1j:350.13, found 350.11.
  • 45
  • C11H11NO [ No CAS ]
  • [ 191732-72-6 ]
  • 3-(4-((4-(6-ethynylpyridin-3-yl)butyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 12h; 30 Synthesis of 3-(4-((4-(6-ethynylpyridin-3-yl)butyl)amino)-l-oxoisoindolin-2- yl)piperidine-2,6-dione To a solution of lenalidomide (1.01 g, 3.9 mmol, 1.0 eq) and compound S24 (680 mg, 3.9 mmol, 1.0 eq) in 50 mL of DCE was added acetic acid (0.23 mL, 3.9 mmol, 1.0 eq) and sodium triacetoxyborohydride (1.66 g, 3.9 mmol, 2.0 eq). The suspended solution was stirred at room temperature for 12 h. DCM and saturated NaHC03 aqueous solution was added. After extraction, the combined organic layer was dried 974 mg, 60% yield). UPLC-MS calculated for C24H25N403 [M+l]+ : 417.19, found 416.98.
60% With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 12h; 7 Synthesis of 3-(4-((4-(6-((4-(4-chlorophenyl)-3 ,9-dimethyl-6H-thieno [3 ,2-fj [1 ,2,4j triazolo [4,3 -aj [1 ,4j diazepin-2-yl)ethynyl)pyridin-3 -yl)butyl)amino)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione (Cpd. No. 7) To a solution of lenalidomide (1.01 g, 3.9 mmol, 1.0 eq) and compound S24 (680 mg, 3.9 mmol, 1.0 eq) in 50 mL of DCE was added acetic acid (0.23 mL, 3.9 mmol, 1.0 eq) and sodium triacetoxyborohydride (1.66 g, 3.9 mmol, 2.0 eq). The suspended solution was stirred at room temperature for 12 h. DCM and saturated NaHCO3 aqueous solution was added. After extraction, the combined organic layer was dried 974 mg, 60% yield). UPLC-MS calculated for C24H25N403 [M+1j: 417.19, found 416.98.
  • 46
  • 3‐{2‐[2‐(2‐[(tert‐butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}propanoic acid [ No CAS ]
  • [ 191732-72-6 ]
  • tert-butyl(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3-oxo-propoxy)ethoxy)ethoxy)ethyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
56% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 25℃; for 12h; 4.2. General procedure A General procedure: Boc-protected acids (1.1 mmol, 1.1 equiv) were added to a stirring solution of lenalidomide/VHL ligand (1.0 equiv), HATU (1.2equiv) and DIPEA (2.0 equiv) in dry DMF (0.22 M) at 25° C. The reaction mixture was allowed to stir at 25° C for 12 h. Upon completion of the reaction as determined via TLC, the mixture was acidified with dilute HCl (5%, 5 mL) and extracted with EtOAc (3x).The organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure in vacuo. The crude reaction mixture was purified by silica gel chromatography using EtOAc in hexanes (30-100% EtOAc) to yield the desired products as a white solid in 18-56% yields.
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.5h; 14 EXAMPLE 14 Synthesis of 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin- -4-yl)propanamide DMF To a round-bottom flask, N,N-diisopropylethylamine (50 mg) were added to a solution of 3-(4-amino-l-oxoisoindolin-2-yl)piperidine-2,6-dione (20 mg), HATU (30 mg), and 2,2-dimethyl-4-oxo-3,8,l l,14-tetraoxa-5-azaheptadecan-17-oic acid (50 mg) in DMF (1 mL) at room temperature. The mixture was stirred for 30 min and the solvent was evaporated as much as possible and the residue was poured into water. After extraction with ethyl acetate for three times, the combined organic layer was washed with brine and dried over anhydrous Na2S04. After filtration and evaporation, the crude residue was dissolved in 3 mL of DCM and TFA (2: 1). After stirring for 1 h, the solvent was evaporated to give the crude product which was purified by flash column chromatography to yield 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-N-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)propanamide. ESI-MS calculated for C22H3iN407[M+H]+ = 463.2; Observed: 463.4.
  • 47
  • [ 79099-07-3 ]
  • [ 191732-72-6 ]
  • tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
93.7% Stage #1: N-tert-butyloxycarbonylpiperidin-4-one; Lenalidomide With acetic acid In 1,2-dichloro-ethane at 20℃; for 4h; Molecular sieve; Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; 5.1 Step 1: 13-2 (1924) Brought tert-butyl 4-oxopiperidine-1-carboxylate (76.8 mg, 0.3856 mmol) and 3-(4- amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione 13-1 (50 mg, 0.1928 mmol) up in DCE (1.92 mL )/ acetic acid (200 µL, 3.31 mmol) and added 4A MS (small scoop, activated) and stirred at r.t. for 4 hours. Added sodium triacetoxyborohydride (40.8 mg, 0.1928 mmol) and stirred O/N at r.t. In AM quenched with sat sodium bicarb solution and extracted into dcm x2. Dried combined organic layers over sodium sulfate and concentrated. Purified by isco 12g column 0-10% MeOH/DCM to give tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)piperidine-1-carboxylate 13-2 (80.0 mg, 0.1807 mmol, 93.7 %) as an oil.
93.7% Stage #1: N-tert-butyloxycarbonylpiperidin-4-one; Lenalidomide With acetic acid In 1,2-dichloro-ethane at 20℃; for 4h; Molecular sieve; Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; Brought tert-butyl 4-oxopiperidine-1-carboxylate (76.8 mg, 0.3856 mmol) and 3-(4- amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (29-1) (50 mg, 0.1928 mmol) up in DCE (1.92 mL )/ acetic acid (200 µL, 3.31 mmol) and added 4A MS (small scoop, activated) and stirred at r.t. for 4 hours. Added sodium triacetoxyborohydride (40.8 mg, 0.1928 mmol) and stirred O/N at r.t. In AM quenched with sat sodium bicarb solution and extracted into dcm x2. Dried combined organic layers over sodium sulfate and concentrated. Purified by isco 12g column 0-10% MeOH/DCM to give tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)piperidine-1-carboxylate (80.0 mg, 0.1807 mmol, 93.7 %) as an oil. LC/MS (ES-): m/z 441 [M-H]- Brought tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)piperidine-1-carboxylate (80 mg, 0.1807 mmol) up in DCM (1 mL ) and added 2,2,2- trifluoroacetic acid (0.3 mL, 3.91 mmol) . After stirring at r.t. for 3 hours, concentrated from toluene 3x to give 3-(1-oxo-4-(piperidin-4-ylamino)isoindolin-2-yl)piperidine-2,6-dione 2,2,2- trifluoroacetate (29-2) (80.0 mg, 0.1752 mmol, 97.0 %) as a yellow oil. LCMS (ES+): m/z 343 [M + H]+
50% With acetic acid In 1,2-dichloro-ethane at 20℃; 11.4; 11.5 Steps 4 and 5: Synthesis of 3-(1-oxo-4-(piperidin-4-ylamino)isoindolin-2- yl)piperidine-2,6-dione (Intermediate 5) To a round flask with Lenalidomide (259.3mg, 1 mmol, 1 eq) in 10 mL of DCE was added tert-butyl 4-oxopiperidine-1-carboxylate (299 mg, 1.5 mmol, 1.5 eq) and HOAc (90 mg, 1.5 mmol, 1.5 eq). The reaction mixture was stirred overnight at room temperature. Then the solvent of the resulting material was evaporated and purified by flash column chromatography with DCM/MeOH to afford the intermediate 4, tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)- 1 -oxoisoindolin-4-yl)amino)piperidine- 1 -carboxylate.Yield: 50 %. UPLC-MS [M+1j: 443.32.
22% Stage #1: N-tert-butyloxycarbonylpiperidin-4-one; Lenalidomide With acetic acid In 1,2-dichloro-ethane at 30℃; for 4h; Molecular sieve; Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 30℃; for 12h; 1 Step 1-Tert-butyl 4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]amino]piperidine-1-carboxylate To a solution of 3-(4-amino-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (400 mg, 1.54 mmol, CAS191732-72-6) and tert-butyl 4-oxopiperidine-1-carboxylate (615 mg, 3.09 mmol) in a mixed solvent of DCE (10 mL) and HOAc (1.05 g, 17.5 mmol) was added molecular sieves (200 mg, 386 umol, 4 ). The reaction mixture was stirred at 30° C. for 4 hrs. Then, NaBH(OAc)3 (327 mg, 1.54 mmol) was added. The resulting reaction mixture was stirred at 30° C. for 12 hrs. On completion, the reaction mixture was concentrated in vacuo to give the crude product which was purified by reversed-phase chromatography (0.1% FA condition) to give the title compound (168 mg, 22% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.29 (t, J=7.6 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 5.35 (d, J=8.4 Hz, 1H), 5.12 (dd, J=5.2, 12.8 Hz, 1H), 4.31-4.10 (m, 2H), 3.92 (d, J=12.6 Hz, 2H), 3.02-2.85 (m, 3H), 2.71-2.59 (m, 1H), 2.38-2.23 (m, 1H), 2.09-2.00 (m, 1H), 1.92-1.90 (m, 2H), 1.41 (s, 9H), 1.33-1.29 (m, 2H) LC-MS (ESI+) m/z 387.1 (M-56)+.

  • 48
  • tert-butyl (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)carbamate [ No CAS ]
  • [ 191732-72-6 ]
YieldReaction ConditionsOperation in experiment
82.3% With trifluoroacetic acid In dichloromethane at 10℃; Inert atmosphere; 1.2 2) Under nitrogen protection, 10 g of 3-(7-tert-butoxycarbonylamino-3-oxo-1H-isoindol-1-yl)piperidine-2,6-dione was dissolved in 30 ml of methylene chloride. ,Cool down to 10° C., add 5 ml of trifluoroacetic acid dropwise, complete the dropwise addition, keep stirring at the temperature overnight, and pour the reaction mixture into saturated aqueous sodium bicarbonate solution.The organic phase is separated and washed with saturated sodium bicarbonate, sodium chloride,It was then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from petroleum ether to give lenalidomide (5.6 g) in a yield of 82.3% with an HPLC purity of 99.45%.
  • 49
  • [ 191732-72-6 ]
  • 3-(4-iodo-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% Stage #1: Lenalidomide With sulfuric acid; sodium nitrite In methanol; water at 0 - 20℃; for 0.333333h; Stage #2: With potassium iodide In methanol; water at 80℃; for 3h; 13 Synthesis of 3 -(4-(5-(6-((4-(4-chlorophenyl)-3 ,9-dimethyl-6H-thieno [3 ,2-fj [1 ,2,4j triazolo [4,3 -aj [1 ,4j diazepin-2-yl)ethynyl)pyridin-3 -yl)pent- 1 -yn- 1-yl)- 1 -oxoisoindolin-2-yl)piperidine-2,6-dione (Cpd. No. 13) To a suspended solution of lenalidomide (1.04 g, 4.0 mmol, 1.0 eq) and NaNO2 (0.83 g, 12.0 mmol, 3.0 eq) in 40 mL of water at 0 °C was added diluted sulfuric acid (4.0 mL in 10 mL of water). Then the solution was stirred at room temperature for 20 mm. Then a solution of KI (3.32 g, 20.0 mmol, 5.0 eq) in 20 mL of water was added and the solution was heated to 80 °C to stir for 3 h. After cooling to room temperature, NaOH (aq) was added to neutralize the solution and the concentrated residue was purified by flash column chromatography with DCM/ MeOH to afford the compound S38 as a slightly yellow solid (1.26 g, 85% yield). UPLC-MS calculated for C,3H,21N203 [M+1j:370.99, found 370.95.
67% Stage #1: Lenalidomide With hydrogenchloride; sodium nitrite In water at -5℃; for 1h; Stage #2: With potassium iodide In water at 20℃; 1 Take S1 (260mg, 1mmol) and dissolve it in concentrated hydrochloric acid/water (5mL/5mL), and slowly add aqueous sodium nitrite solution dropwise at -5°C(138 mg, 2 mmol, dissolved in 1 mL of water), continue stirring for 1 hour, and then dropwise add potassium iodide aqueous solution (332 mg, 2 mmol, dissolved in 1 mL of water)water), move to room temperature and stir overnight after adding dropwise, after TLC (dichloromethane/methanol=15/1) monitoring raw material reaction is complete, filter waterWash three times to get brown solid S11 (250mg, 67%
  • 50
  • 2-azidoethoxyacetyl chloride [ No CAS ]
  • [ 191732-72-6 ]
  • 2‐(2‐azidoethoxy)‐N‐[2‐(2,6‐dioxopiperidin‐3‐yl)‐1‐oxo‐3H‐isoindol‐4‐yl]acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
58.16% In 1-methyl-pyrrolidin-2-one at 20℃; for 4h; 1.6 Step 6: 2-(2-azidoethoxy)-N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]acetamide (1f) The lenalidomide (0.3 g, 1.16 mmol) was dissolved in 3 mL of N-methylpyrrolidone.Add 1e (0.38g, 2.31mmol),After reacting for 4 hours at room temperature,Add 20 mL of water, precipitate a solid, filter by suction, and dry to obtain a crude product.Purified by silica gel column chromatography,Using dichloromethane / methanol (V / V = 150 / 1-100 / 1) to afford a yellow solid,The weight was 0.26 g, and the yield was 58.16%.
55.13% In 1-methyl-pyrrolidin-2-one at 20℃; for 4h; 1.6 Step 6)2-(2-azidoethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide(1f) lenalidomide (0.26g, 0.95mmol) is dissolved in 3mL In N-methylpyrrolidone,Add 1e (0.32g, 1.9 mmol),After 4 hours at room temperature, 20 mL of water was added. Precipitation occurred, suction filtration, drying to give crude product, Purification by column chromatography on silica gel using dichloromethane/methanol (V/V=150/1-100/1)Elution gives a yellow solid,Weight 0.21g,Yield 55.13%
In 1-methyl-pyrrolidin-2-one at 20℃; for 3h; 4.1.12. General procedure for the preparation of 44a-h General procedure: Lenalidomide (0.73 mmol) and 43a-d (1.46 mmol) were dissolvedin NMP (3 mL) and stirred at room temperature for 3 h. Then the reactionmixture was diluted with water (15 mL) and extracted with ethylacetate (15 mL). The organic layer was washed twice with saturatedbrine and dried over anhydrous sodium sulfate. After concentration, thecrude residue was purified by flash column chromatography (dichloromethane/methanol = 30:1) to give 44a-d. Intermediates 44e-hwere obtained by the same procedure starting from pomalidomide and43a-d.
0.26 g In 1-methyl-pyrrolidin-2-one at 20℃; for 4h; 4.1.14.5. 2-(2-azidoethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (31a). To a solution of 30a (0.29 g,2.03 mmol) in DCM were added thionyl chloride (1 mL) and two drops of DMF at room temperature. The mixture was then refluxed for4 h. The reaction mixture was evaporated in vacuo and the resulting acyl chloride was used without further purification. To a solution of lenalidomide (0.3 g, 1.16 mmol) in 1-methyl-2-pyrrolidinone (3 mL)was added the acyl chloride and then stirred at room temperature for 4 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (MeOH/DCM, 1/100) to afford31a (0.26 g, 58%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 11.02 (s, 1H), 9.74 (s, 1H), 7.77 (d, J = 7.4 Hz, 1H), 7.54 (dt,J = 15.3, 7.5 Hz, 2H), 5.23-5.10 (m, 1H), 4.37 (q, J = 17.3 Hz, 2H),4.18 (s, 2H), 3.75 (d, J = 4.4 Hz, 2H), 3.52 (d, J = 4.3 Hz, 2H),3.02-2.85 (m, 1H), 2.60 (d, J = 17.9 Hz, 1H), 2.35 (d, J = 12.8 Hz,1H), 2.03 (s, 1H).

  • 51
  • [ 73183-34-3 ]
  • [ 191732-72-6 ]
  • 3-(1-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
75.6% With tert.-butylnitrite; dibenzoyl peroxide In acetonitrile at 20℃; for 4h;
55% With tert.-butylnitrite In acetonitrile at 20℃; for 18h; 1.1 3-(1-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)isoindolin-2-yl)piperidine -2,6-Dione (1b) 3-(7-Amino-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione 1a (5 g, 19.3 mmol), pinacol biboronate (7.35 g) were mixed at room temperature g, 29.0 mmol) and acetonitrile (100 mL) were combined, then tert-butyl nitrite (2.19 g, 21.3 mmol) was added. The mixture was stirred at room temperature for 18 hours, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1) to obtain the target product 1b (3.9 g, 55%).
54.1% With tert.-butylnitrite In acetonitrile at 20℃; for 4h; 1.1 1.1 Synthesis of Compound 1 Compound a (5.0 g, 19.3 mmol) and diboronic acid pinacol ester (5.4 g, 1.26 mmol) were added to a 250 ml flask, stirred with 100 ml of acetonitrile, then tert-butyl nitrite (3.44 ml, 28.95 mmol) was added The reaction system was reacted at room temperature for 4 hours. The reaction was monitored by TLC, and the solvent was concentrated under reduced pressure to give a crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane:methanol=100:1) to give Compound 1 as a white solid (3.86 g, yield: 54.1%).
  • 52
  • [ 3543-75-7 ]
  • [ 879126-98-4 ]
  • 4-(5-(bis(2-chloroethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)butanamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% With dmap; triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 40℃; Lenalidomide (la, 259 mg, 1.0 mmol) was dissolved in 10 ml of anhydrous CH2CI2.Then add <strong>[3543-75-7]<strong>[3543-75-7]bendamustine</strong> hydrochloride</strong> hydrate (2b, 454mg, 1 · lmmol), HATU (2.Ommol), DMAP (130mg, 50%) and triethylamine (404mg, 4.Ommol), all After dissolution, the mixture was heated to reflux at 40 C. After the completion of the reaction by TLC, the solvent was evaporated under reduced pressure.The crude product was purified by column chromatography (mobile phase methanol: dichloromethane =1:30-1:15) 305mg of pale yellow solid, yield 51%.
  • 53
  • [ 6404-29-1 ]
  • [ 191732-72-6 ]
  • tert-butyl(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-6-oxohexyl) carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 25℃; for 12h; 4.2. General procedure A General procedure: Boc-protected acids (1.1 mmol, 1.1 equiv) were added to a stirring solution of lenalidomide/VHL ligand (1.0 equiv), HATU (1.2equiv) and DIPEA (2.0 equiv) in dry DMF (0.22 M) at 25° C. The reaction mixture was allowed to stir at 25° C for 12 h. Upon completion of the reaction as determined via TLC, the mixture was acidified with dilute HCl (5%, 5 mL) and extracted with EtOAc (3x).The organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure in vacuo. The crude reaction mixture was purified by silica gel chromatography using EtOAc in hexanes (30-100% EtOAc) to yield the desired products as a white solid in 18-56% yields.
With pyridine; trichlorophosphate In acetonitrile at 20℃; for 3h; 4.1.3. General procedure for the preparation of 35a-f General procedure: A mixture of 33a-f (0.85 mmol), lenalidomide (0.77 mmol), pyridine(2.31 mmol) and phosphorus oxychloride (0.93 mmol) in acetonitrile(10 mL) was stirred at room temperature for 3 h. After the reactionwas completed, the mixture was concentrated and then dilutedwith water (10 mL) and extracted with ethyl acetate (10 mL × 3). Thecombined organic layer was dried over anhydrous Na2SO4 and concentratedunder reduced pressure. The crude residue was purified byflash column chromatography (dichloromethane/methanol = 35:1) to give 34a-f (about 40% yield).
Stage #1: 6-(tert-butoxycarbonylamino)hexanoic acid With N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate In N,N-dimethyl-formamide at 25℃; for 0.75h; Inert atmosphere; Stage #2: Lenalidomide In N,N-dimethyl-formamide at 60℃; 6 Example 6: Synthesis of R6NBoc: Add 0.277 g (1.2 mmol) of Boc aminocaproic acid to a three-necked flask, replace it with N2 three times, inject 7.5 mL of anhydrous DMF with a syringe, stir at 25 ° C, inject 0.8 mL of DIPEA, and add 0.57 g (1.5 mmol) of HATU. After reacting at 25 ° C for about 45 minutes, 0.26 g (1.0 mmol) of lenalidomide was added and reacted at 60 ° C overnight.Post-treatment: the reaction solution is poured into water, and the precipitated solid is the product, which is used in the next step without purification.
  • 54
  • [ 80-48-8 ]
  • [ 191732-72-6 ]
  • 3-(4-(methylsulfanyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% Stage #1: methyl p-toluene sulfonate With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h; Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃; 1 4.2.1. General procedure for the synthesis of compounds 3a-r To a stirred solution of sodium thiosulfate pentahydrate(8.12 mmol, 7 eq), copper(II) sulfate pentahydrate (0.12 mmol, 0.1eq), 2,2'-dipyridyl (0.12 mmol, 0.1 eq) in water (5 mL) and MeOH (5 mL) was added corresponding compound 2a-r (8.12 mmol, 7 eq).The reaction was stirred at 80 °C for 2 h, then compound 1(1.16 mmol, 1 eq) and tert-butyl nitrite (1.74 mmol, 1.5 eq) wasadded at 0 °C. The mixture was then stirred at room temperaturefor 10 min and heated to 80 °C for 4-8 h. The mixturewas cooled toroom temperature, EtOAc was added and the layers were partitionedand separated. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated to give the corresponding crude product which werepurified by column chromatography to afford desired compounds 3a-r. 4.2.1.1. 3-(4-(methylthio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(3a). White solid (242 mg, 72%). m.p.156 e158 °C; 1H NMR(400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.62e7.50 (m, 3H), 5.13 (dd,J 13.2, 4.6 Hz, 1H), 4.27 (dd, J 58.2, 17.3 Hz, 2H), 2.98e2.83 (m,1H), 2.65e2.55 (m, 4H), 2.47e2.39 (m, 1H), 2.07e1.95 (m, 1H). 13CNMR (101 MHz, DMSO-d6) δ 172.86, 170.98, 167.81, 139.42, 133.70,131.67, 129.16, 127.95, 119.41, 51.59, 46.41, 31.18, 22.31, 14.12. HRMS(EI) m/z calcd for C14H14N2O3S [MH]: 291.0798, found: 291.0795.
  • 55
  • [ 110-53-2 ]
  • [ 191732-72-6 ]
  • 3-(1-oxo-4-(pentylthio)isoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
69% Stage #1: 1-Bromopentane With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h; Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃; 2 3-(4-(methylthio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3a) 4.2.1.2 3-(1-Oxo-4-(pentylthio)isoindolin-2-yl)piperidine-2,6-dione (3b) White solid (276 mg, 69%). m.p.172 ─173 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.59-7.50 (m, 2H), 5.13 (dd, J = 13.2, 5.0 Hz, 1H), 4.28 (dd, J = 57.3, 17.4 Hz, 2H), 3.07 (t, J = 7.2 Hz, 2H), 2.99-2.85 (m, 1H), 2.59 (d, J = 16.6 Hz, 1H), 2.49-2.40 (m, 1H), 2.08-1.96 (m, 1H), 1.66-1.53 (m, 2H), 1.46-1.21 (m, 4H), 0.85 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 172.83, 170.96, 167.78, 140.85, 132.09, 131.99, 130.10, 129.10, 120.10, 51.60, 46.64, 31.35, 31.18, 30.21, 28.25, 22.31, 21.60, 13.79. HRMS (EI) m/z calcd for C18H22N2O3S [M+H]+: 347.1252, found: 347.1249.
  • 56
  • [ 100-39-0 ]
  • [ 191732-72-6 ]
  • 3-(4-(benzylthio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% Stage #1: benzyl bromide With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h; Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃; 3 3-(1-Oxo-4-(pentylthio)isoindolin-2-yl)piperidine-2,6-dione (3b) 4.2.1.3 3-(4-(benzylthio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3c) White solid (360 mg, 85%). m.p.159 ─160 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.37-7.20 (m, 5H), 5.10 (dd, J = 13.2, 4.9 Hz, 1H), 4.33 (s, 2H), 4.19 (q, J = 17.5 Hz, 2H), 2.96-2.81 (m, 1H), 2.59 (d, J = 16.9 Hz, 1H), 2.46-2.32 (m, 1H), 2.03-1.88 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.84, 170.90, 167.68, 141.54, 137.12, 131.99, 131.62, 131.40, 129.04, 128.80, 128.40, 127.23, 120.81, 51.53, 46.59, 36.27, 31.16, 22.32. HRMS (EI) m/z calcd for C20H18N2O3S [M+H]+: 367.1116, found: 367.1114.
  • 57
  • [ 104-81-4 ]
  • [ 191732-72-6 ]
  • 3-(4-((4-methylbenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% Stage #1: 4-Methylbenzyl bromide With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h; Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃; 4 3-(4-(benzylthio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3c) 4.2.1.4 3-(4-((4-methylbenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3d) White solid (334 mg, 76%). m.p.179 ─181 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.4 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.22 (d, J = 7.8 Hz, 2H), 7.09 (d, J = 7.7 Hz, 2H), 5.10 (dd, J = 13.4, 5.0 Hz, 1H), 4.28 (s, 2H), 4.18 (q, J = 17.5 Hz, 2H), 2.97-2.82 (m, 1H), 2.59 (d, J = 17.0 Hz, 1H), 2.49-2.35 (m, 1H), 2.25 (s, 3H), 2.01-1.92(m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.82, 170.88, 167.69, 141.53, 136.41, 134.00, 131.97, 131.62, 131.51, 128.96, 128.69, 120.75, 51.54, 46.59, 36.07, 31.17, 22.32, 20.64. HRMS (EI) m/z calcd for C21H20N2O3S [M+H]+: 381.1267, found: 381.1264.
  • 58
  • [ 620-13-3 ]
  • [ 191732-72-6 ]
  • 3-(4-((3-methylbenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% Stage #1: 1-bromomethyl-3-methyl-benzene With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h; Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃; 5 3-(4-((4-methylbenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3d) 4.2.1.5 3-(4-((3-methylbenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3e) White solid (308 mg, 70%). m.p.135 ─137 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.20-7.10(m, 3H), 7.05 (d, J = 7.1 Hz, 1H), 5.11 (dd, J = 13.2, 4.9 Hz, 1H), 4.29 (d, J = 13.3 Hz, 2H), 4.18 (q, J = 17.4 Hz, 2H), 2.99-2.82 (m, 1H), 2.59 (d, J = 16.9 Hz, 1H), 2.48-2.33 (m, 1H), 2.24 (s, 3H), 2.03-1.92 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.82, 170.88, 167.69, 141.62, 137.55, 136.93, 131.98, 131.71, 131.51, 129.38, 129.05, 128.29, 127.89, 125.88, 120.82, 51.55, 46.61, 36.42, 31.17, 22.32, 20.87. HRMS (EI) m/z calcd for C21H20N2O3S [M+H]+: 381.1267, found: 381.1264.
  • 59
  • [ 552-45-4 ]
  • [ 191732-72-6 ]
  • 3-(4-((2-methylbenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
66% Stage #1: 1-chloromethyl-2-methylbenzene With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h; Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃; 6 3-(4-((3-methylbenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3e) 4.2.1.6 3-(4-((2-methylbenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3f) White solid (290 mg, 66%). m.p.151 ─153 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.22-7.13 (m, 3H), 7.07 (t, J = 6.9 Hz, 1H), 5.10 (dd, J = 13.2, 4.8 Hz, 1H), 4.30 (s, 2H), 4.25-4.07 (m, 2H), 2.99-2.80 (m, 1H), 2.58 (d, J = 17.3 Hz, 1H), 2.46-2.28 (m, 4H), 2.02-1.91 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.82, 170.87, 167.68, 142.00, 136.58, 134.61, 132.37, 132.01, 131.46, 130.31, 129.67, 129.11, 127.61, 125.86, 121.04, 51.55, 46.61, 35.16, 31.15, 22.32, 18.68. HRMS (EI) m/z calcd for C21H20N2O3S [M+H]+: 381.1267, found: 381.1265.
  • 60
  • [ 874-86-2 ]
  • [ 191732-72-6 ]
  • 4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)methyl)benzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% Stage #1: 4-cyanobenzyl chloride With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h; Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃; 7 3-(4-((2-methylbenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3f) 4.2.1.7 4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)methyl)benzonitrile (3g) White solid (335 mg, 74%). m.p.188 ─190 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.75 (d, J = 7.5 Hz, 2H), 7.64 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 7.8 Hz, 3H), 5.11 (dd, J = 13.2, 4.9 Hz, 1H), 4.42 (s, 2H), 4.21 (q, J = 17.5 Hz, 2H), 2.99-2.81 (m, 1H), 2.59 (d, J = 17.5 Hz, 1H), 2.47-2.29 (m, 1H), 2.08-1.90 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.81, 170.87, 167.60, 143.44, 141.98, 132.30, 132.18, 132.13, 130.38, 129.73, 129.11, 121.27, 118.66, 109.93, 51.56, 46.62, 35.86, 31.16, 22.33. HRMS (EI) m/z calcd for C21H17N3O3S [M+H]+: 392.1063, found: 392.1060.
  • 61
  • [ 28188-41-2 ]
  • [ 191732-72-6 ]
  • 3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)methyl)benzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% Stage #1: m-(bromomethyl)benzonitrile With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h; Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃; 8 4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)methyl)benzonitrile (3g) 4.2.1.8 3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)methyl)benzonitrile (3h) White solid (319 mg, 70%). m.p.157 ─159 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.77 (s, 1H), 7.73-7.63 (m, 3H), 7.61 (d, J = 7.1 Hz, 1H), 7.51 (dt, J = 12.6, 6.2 Hz, 2H), 5.11 (dd, J = 13.3, 5.0 Hz, 1H), 4.38 (s, 2H), 4.21 (dd, J = 43.2, 17.5 Hz, 2H), 2.99-2.82 (m, 1H), 2.59 (d, J = 17.1 Hz, 1H), 2.48-2.35(m, 1H), 2.03-1.93 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.82, 170.85, 167.60, 142.03, 139.25, 133.68, 132.25, 132.15, 131.02, 130.39, 129.66, 129.11, 121.28, 118.51, 111.25, 51.55, 46.63, 35.37, 31.15, 22.31. HRMS (EI) m/z calcd for C21H17N3O3S [M+H]+: 392.1063, found: 392.1060.
  • 62
  • [ 22115-41-9 ]
  • [ 191732-72-6 ]
  • 2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)methyl)benzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% Stage #1: 2-(bromomethyl)benzonitrile With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h; Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃; 9 3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)methyl)benzonitrile (3h) 4.2.1.9 2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)methyl)benzonitrile (3i) White solid (342 mg, 73%). m.p.175 ─176 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.69-7.63 (m, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 5.10 (dd, J = 13.2, 5.0 Hz, 1H), 4.50-4.33 (m, 2H), 4.18 (q, J = 17.5 Hz, 2H), 3.02-2.77 (m, 1H), 2.59 (d, J = 17.2 Hz, 1H), 2.47-2.29 (m, 1H), 2.01-1.87 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.78, 170.78, 167.55, 143.21, 140.99, 134.03, 133.19, 132.28, 130.22, 129.51, 129.24, 128.30, 122.12, 117.21, 111.63, 51.57, 46.69, 35.75, 31.14, 22.34. HRMS (EI) m/z calcd for C21H17N3O3S [M+H]+: 392.1063, found: 392.1061.
  • 63
  • [ 104-83-6 ]
  • [ 191732-72-6 ]
  • 3-(4-((4-chlorobenzyl)sulfanyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% Stage #1: 1-Chloro-4-(chloromethyl)benzene With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h; Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃; 10 2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)methyl)benzonitrile (3i) 4.2.1.10 3-(4-((4-chlorobenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3j) White solid (402 mg, 87%). m.p.201 ─202 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.3 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.34 (s, 4H), 5.12 (dd, J = 13.2, 4.7 Hz, 1H), 4.32 (s, 2H), 4.20 (q, J = 17.5 Hz, 2H), 3.02-2.82 (m, 1H), 2.59 (d, J = 16.7 Hz, 1H), 2.47-2.34 (m, 1H), 2.04-1.91 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.82, 170.88, 167.64, 141.77, 136.41, 132.06, 131.93, 131.81, 130.90, 130.61, 129.07, 128.36, 121.03, 51.55, 46.61, 35.49, 31.17, 22.33. HRMS (EI) m/z calcd for C20H17ClN2O3S [M+H]+: 401.0721, found: 401.0718.
  • 64
  • [ 766-80-3 ]
  • [ 191732-72-6 ]
  • 3-(4-((3-chlorobenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% Stage #1: 1-bromomethyl-3-chlorobenzene With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h; Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃; 11 3-(4-((4-chlorobenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3j) 4.2.1.11 3-(4-((3-chlorobenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3k) White solid (378 mg, 82%). m.p.148 ─150 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.39 (s, 1H), 7.30 (s, 3H), 5.12 (dd, J = 13.2, 4.9 Hz, 1H), 4.34 (s, 2H), 4.22 (q, J = 17.5 Hz, 2H), 2.98-2.84 (m, 1H), 2.60 (d, J = 17.0 Hz, 1H), 2.48-2.35 (m, 1H), 2.05-1.91 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.83, 170.87, 167.64, 141.83, 139.90, 132.90, 132.09, 131.97, 130.79, 130.23, 129.08, 128.58, 127.45, 127.18, 121.10, 51.56, 46.62, 35.59, 31.16, 22.33. HRMS (EI) m/z calcd for C20H17ClN2O3S [M+H]+: 401.0721, found: 401.0717.
  • 65
  • [ 611-19-8 ]
  • [ 191732-72-6 ]
  • 3-(4-((2-chlorobenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% Stage #1: 1-chloro-2-(chloromethyl)benzene With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h; Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃; 12 3-(4-((3-chlorobenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3k) 4.2.1.12 3-(4-((2-chlorobenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3l) White solid (394 mg, 85%). m.p.182 ─183 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.65 (dd, J = 17.2, 7.5 Hz, 2H), 7.52 (t, J = 7.5 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.36-7.18 (m, 3H), 5.11 (dd, J = 13.0, 4.5 Hz, 1H), 4.36 (s, 2H), 4.19 (q, J = 17.4 Hz, 2H), 3.02-2.79 (m, 1H), 2.59 (d, J = 16.7 Hz, 1H), 2.46-2.29 (m, 1H), 2.05-1.88 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.81, 170.85, 167.64, 142.53, 134.65, 133.14, 133.03, 132.13, 131.14, 130.56, 129.52, 129.33, 129.16, 127.22, 121.51, 51.56, 46.66, 34.97, 31.16, 22.33. HRMS (EI) m/z calcd for C20H17ClN2O3S [M+H]+: 401.0721, found: 401.0717.
  • 66
  • [ 459-46-1 ]
  • [ 191732-72-6 ]
  • 3-(4-((4-fluorobenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% Stage #1: 4-Fluorobenzyl bromide With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h; Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃; 13 3-(4-((2-chlorobenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3l) 4.2.1.13 3-(4-((4-fluorobenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3m) White solid (337 mg, 76%). m.p.187 ─189 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.42-7.31 (m, 2H), 7.11 (t, J = 8.6 Hz, 2H), 5.11 (dd, J = 13.2, 4.9 Hz, 1H), 4.33 (s, 2H), 4.21 (dd, J = 38.0, 17.5 Hz, 2H), 2.98-2.84 (m, 1H), 2.58 (d, J = 17.1 Hz, 1H), 2.45-2.34 (m, 1H), 2.04-1.91 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.81, 170.88, 167.66, 162.48, 160.09, 141.72, 133.44, 132.04, 131.87, 131.09, 130.78, 130.70, 129.05, 120.95, 115.29, 51.55, 46.62, 35.46, 31.16, 22.30. HRMS (EI) m/z calcd for C20H17FN2O3S [M+H]+: 385.1017, found: 385.1014.
  • 67
  • [ 456-41-7 ]
  • [ 191732-72-6 ]
  • 3-(4-((3-fluorobenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% Stage #1: 1-(Bromomethyl)-3-fluorobenzene With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h; Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃; 14 3-(4-((4-fluorobenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3m) 4.2.1.14 3-(4-((3-fluorobenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3n) White solid (356 mg, 80%). m.p.159 ─161 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.3 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.33 (dd, J = 14.1, 7.4 Hz, 1H), 7.17 (d, J = 7.7 Hz, 2H), 7.06 (t, J = 7.6 Hz, 1H), 5.13 (dd, J = 13.1, 4.8 Hz, 1H), 4.35 (s, 2H), 4.23 (dd, J = 39.6, 17.4 Hz, 2H), 3.02-2.84 (m, 1H), 2.60 (d, J = 17.1 Hz, 1H), 2.48-2.34 (m, 1H), 2.08-1.92 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.83, 170.88, 167.67, 163.18, 160.75, 141.76, 140.24, 131.86, 130.89, 130.26, 129.07, 124.87, 121.04, 115.59, 113.95, 51.58, 46.63, 35.67, 31.16, 22.32. HRMS (EI) m/z calcd for C20H17FN2O3S [M+H]+: 385.1017, found: 385.1013.
  • 68
  • [ 446-48-0 ]
  • [ 191732-72-6 ]
  • 3-(4-((2-fluorobenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% Stage #1: o-fluorobenzyl bromide With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h; Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃; 15 3-(4-((3-fluorobenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3n) 4.2.1.15 3-(4-((2-fluorobenzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3o) White solid (340 mg, 76%). m.p.169 ─170 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.31 (q, J = 7.2 Hz, 2H), 7.17 (t, J = 9.2 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 5.10 (dd, J = 13.3, 4.9 Hz, 1H), 4.32 (s, 2H), 4.18 (q, J = 17.4 Hz, 2H), 3.06-2.77 (m, 1H), 2.58 (d, J = 17.4 Hz, 1H), 2.46-2.33 (m, 1H), 2.04-1.89 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.82, 170.85, 167.63, 161.47, 159.03, 142.32, 132.71, 132.10, 131.15, 130.61, 129.65, 129.13, 124.37, 121.40, 115.48, 51.54, 46.62, 40.10, 39.89, 39.68, 39.48, 39.27, 39.06, 31.15, 30.29, 22.31. HRMS (EI) m/z calcd for C20H17FN2O3S [M+H]+: 385.1017, found: 385.1015.
  • 69
  • [ 71831-21-5 ]
  • [ 879126-98-4 ]
  • 3-(4-((4-(hydroxymethyl)benzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% 4.2.1.16 3-(4-((4-(hydroxymethyl)benzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3p) White solid (398?mg, 87%). m.p.180 ?182?C; 1H NMR (400?MHz, DMSO-d6) delta 10.99 (s, 1H), 7.67 (d, J?=?7.6?Hz, 1H), 7.58 (d, J?=?7.3?Hz, 1H), 7.50 (t, J?=?7.6?Hz, 1H), 7.30 (d, J?=?8.0?Hz, 2H), 7.23 (d, J?=?8.0?Hz, 2H), 5.12 (dt, J?=?13.3, 5.3?Hz, 2H), 4.46 (d, J?=?5.6?Hz, 2H), 4.32 (s, 2H), 4.20 (q, J?=?17.5?Hz, 2H), 3.01-2.78 (m, 1H), 2.59 (d, J?=?17.0?Hz, 1H), 2.47-2.31 (m, 1H), 2.06-1.89 (m, 1H). 13C NMR (101?MHz, DMSO-d6) delta 172.82, 170.90, 167.69, 141.59, 141.49, 135.36, 132.00, 131.56, 131.49, 129.04, 128.53, 126.48, 120.75, 62.56, 51.57, 46.61, 36.08, 31.17, 22.32. HRMS (EI) m/z calcd for C21H20N2O4S [M+H]+: 397.1217, found: 397.1213.
  • 70
  • [ 108052-76-2 ]
  • [ 191732-72-6 ]
  • tert-butyl 4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4yl)thio)methyl)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% Stage #1: 4-(bromomethyl)benzoic acid 1,1-dimethylethyl ester With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h; Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃; 17 3-(4-((4-(hydroxymethyl)benzyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3p) 4.2.1.17 tert-butyl4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4yl)thio)methyl)benzoate (3q) White solid (389 mg, 72%). m.p.186 ─187 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.81 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 7.7 Hz, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H), 5.11 (dd, J = 13.2, 5.0 Hz, 1H), 4.46-4.34 (m, 2H), 4.20 (s, 2H), 3.03-2.84 (m, 1H), 2.58 (d, J = 17.1 Hz, 1H), 2.49-2.33 (m, 1H), 1.99-1.90 (m, 1H), 1.52 (s, 9H). 13C NMR (101 MHz, DMSO-d6) δ 172.78, 170.85, 167.61, 164.60, 142.59, 141.91, 132.12, 132.07, 130.70, 130.15, 129.10, 128.94, 121.13, 80.65, 51.55, 46.62, 35.97, 31.16, 27.73, 22.31. HRMS (EI) m/z calcd for C25H26N2O5S [M+H]+: 467.1635, found: 467.1627.
  • 71
  • [ 2417-72-3 ]
  • [ 191732-72-6 ]
  • methyl 4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)methyl)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% Stage #1: Methyl 4-(bromomethyl)benzoate With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h; Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃; 18 tert-butyl4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4yl)thio)methyl)benzoate (3q) 4.2.1.18 Methyl 4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)methyl)benzoate (3r) White solid (368 mg, 75%). m.p.193 ─195 °C; 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.49 (dd, J = 13.9, 7.8 Hz, 3H), 5.10 (dd, J = 13.1, 4.8 Hz, 1H), 4.41 (s, 2H), 4.20 (q, J = 17.4 Hz, 2H), 3.83 (s, 3H), 3.02-2.78 (m, 1H), 2.58 (d, J = 16.8 Hz, 1H), 2.47-2.32 (m, 1H), 2.12-1.81 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 172.79, 170.85, 167.62, 165.89, 143.04, 141.96, 132.18, 132.08, 130.67, 129.25, 129.13, 128.45, 127.93, 123.51, 122.99, 121.17, 52.07, 51.56, 46.63, 36.02, 31.15, 22.32. HRMS (EI) m/z calcd for C22H20N2O5S [M+H]+: 425.1166, found: 425.1163.
  • 72
  • [ 106-94-5 ]
  • [ 191732-72-6 ]
  • 3-(4-amino-1-oxoisoindolin-2-yl)-1-propylpiperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
58% With potassium carbonate; potassium iodide In acetonitrile at 110℃; for 2h;
58% With potassium carbonate; potassium iodide In acetonitrile at 100℃; for 2h; Comparative Examples: According to Scheme E, future lenalidomide (20 mg, 0.073 mmol, 1 equiv), n-propyl bromide (18.9 mg,0.0876 mmol, 1.2 equiv), KI (3.8 mg, 0.0146 mmol, 0.2 equiv) and potassium carbonate (21.3 mg, 0.146 mmol,3equiv)-Add to a 10mL reaction tube, then add acetonitrile (2mL), and react with a 100C oil bath at reflux for 2h. Reaction solutionReduce the temperature to room temperature, evaporate the acetonitrile under reduced pressure, and then use a C18 reversed-phase column to prepare the solvent.10% -100%, compound 3- (4-amino-1-oxoisoindolin-2-yl) -1-propylpiperidine-2,6-dione is obtained after lyophilization(3- (4-amino-1-oxoisoindolin-2-yl) -1-propylpiperidine-2,6-dione; SIAIS1204083B)(Yellow solid, 12.8mg, 58%)
  • 73
  • [ 5292-43-3 ]
  • [ 191732-72-6 ]
  • tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)amino)acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
9.3% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 110℃; for 8h; Sealed tube; 45.1 Step 1: tert-butyl (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) glycinate A mixture of 3- (4-amino-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (3 g, 11.58 mmol) , tert-butyl 2-bromoacetate (2.5 g, 12.74 mmol) and DIPEA (5 g, 38.11 mmol) in NMP (20 mL) was stirred at 110 in a sealed tube for 8 h. LCMS showed the reaction was completed. Saturated aqueous NaCl was added to quench the reaction and the reaction mixture was extracted with DCM. The organic layer was dried over anhydrous Na2SO4and evaporated in vacuum to afford the crude product, which was further purified with pre-TLC (DCM: MeOH = 50: 1) to give the product (0.4 g, 9.3%) . [M+H]+= 374.0.
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 110℃; for 12h;
150 mg With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; 15.1 Step 1: preparation of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)amino) acetate A solution of Lenalidomide (259mg, 1.0mmol) dissolved in N,N-dimethylformamide (20ml) was provided, and tert-butyl bromoacetate (234mg, 1.2mmol), and potassium carbonate (276mg, 2.0mmol), potassium iodide (8mg , 0.05mmol) were added to the solution. The mixture was stirred at 80°C. After the reaction was completed, ethyl acetate and water were added, and the organic phase was washed with water for twice. The organic phase was separated, and purified by silica gel chromatography to obtain tert-butyl 2-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindol-4-yl)amino) acetate(150mg).
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 110℃; for 12h; 35 General Synthesis Method for Intermediate LM (Lenalidomide Alkyl Carbon Chain Linker): General procedure: A single-neck flask was charged with lenalidomide (2 mmol, 1 equiv), NMP (10 mL) and corresponding tert-butyl bromide (2.4 mmol, 1.2 equiv) and DIPEA (6 mmol, 3 equiv). The mixture was stirred at 110° C. for 12 h. After cooling to room temperature, the resulting solution was subjected to reverse-phase C18 column chromatography (eluent (v/v): acetonitrile/(water+0.1%TFA)=10% -100%) for separation and purification, to yield the desired tert-butyl ester intermediate. This intermediate was treated with TFA in DCM for 1 h at room temperature. After concentration under reduced pressure and freeze-drying, the desired product was obtained; (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)aminoacetic acid (SIAIS1204057) was prepared according to scheme 6, except that the starting material tert-butyl bromide was tert-butyl 2-bromoacetate. The target product SIAIS1204057 was obtained as yellow solid (1 g, 48% yield). 1H NMR (500 MHz, DMSO) δ 11.01 (s, 1H), 7.28 (t, J=7.7 Hz, 1H), 6.98 (d, J=7.3 Hz, 1H), 6.66 (d, J=8.0 Hz, 1H), 5.94 (s, 1H), 5.12 (dd, J=13.3, 5.1 Hz, 1H), 4.26 (d, J=17.0 Hz, 1H), 4.16 (d, J=17.0 Hz, 1H), 3.92 (s, 2H), 2.98-2.85 (m, 1H), 2.62 (d, J=17.3 Hz, 1H), 2.39-2.26 (m, 1H), 2.08-1.99 (m, 1H). HRMS (ESI) m/z: calcd for C15H16N3O5+ [M+H]+, 318.1084; found, 318.1098.
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 110℃; for 12h; 35 General Synthesis Method for Intermediate LM (Lenalidomide Alkyl Carbon Chain Linker): General procedure: A single-neck flask was charged with lenalidomide (2 mmol, 1 equiv), NMP (10 mL) and corresponding tert-butyl bromide (2.4 mmol, 1.2 equiv) and DIPEA (6 mmol, 3 equiv). The mixture was stirred at 110° C. for 12 h. After cooling to room temperature, the resulting solution was subjected to reverse-phase C18 column chromatography (eluent (v/v): acetonitrile/(water+0.1%TFA)=10% -100%) for separation and purification, to yield the desired tert-butyl ester intermediate. This intermediate was treated with TFA in DCM for 1 h at room temperature. After concentration under reduced pressure and freeze-drying, the desired product was obtained; (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)aminoacetic acid (SIAIS1204057) was prepared according to scheme 6, except that the starting material tert-butyl bromide was tert-butyl 2-bromoacetate. The target product SIAIS1204057 was obtained as yellow solid (1 g, 48% yield). 1H NMR (500 MHz, DMSO) δ 11.01 (s, 1H), 7.28 (t, J=7.7 Hz, 1H), 6.98 (d, J=7.3 Hz, 1H), 6.66 (d, J=8.0 Hz, 1H), 5.94 (s, 1H), 5.12 (dd, J=13.3, 5.1 Hz, 1H), 4.26 (d, J=17.0 Hz, 1H), 4.16 (d, J=17.0 Hz, 1H), 3.92 (s, 2H), 2.98-2.85 (m, 1H), 2.62 (d, J=17.3 Hz, 1H), 2.39-2.26 (m, 1H), 2.08-1.99 (m, 1H). HRMS (ESI) m/z: calcd for C15H16N3O5+ [M+H]+, 318.1084; found, 318.1098.
150 mg With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; 15.1 Step 1: preparation of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)amino) acetate A solution of Lenalidomide (259mg, 1.0mmol) dissolved in N,N-dimethylformamide (20ml) was provided, and tert-butyl bromoacetate (234mg, 1.2mmol), and potassium carbonate (276mg, 2.0mmol), potassium iodide (8mg , 0.05mmol) were added to the solution. The mixture was stirred at 80°C. After the reaction was completed, ethyl acetate and water were added, and the organic phase was washed with water for twice. The organic phase was separated, and purified by silica gel chromatography to obtain tert-butyl 2-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindol-4-yl)amino) acetate(150mg).

  • 74
  • [ 88987-42-2 ]
  • [ 191732-72-6 ]
  • tert-butyl 5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
63% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 100℃; for 12h; 40 Based on Scheme 11, Preparation of tert-butyl 5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentanoate (SIAIS184046) Based on Scheme 11, Preparation of tert-butyl 5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentanoate (SIAIS184046) In a 25 mL of round-bottom flask, to a stirred solution of Lenalidomide (259.3 mg, 1 mmol) in NMP (8 mL) was added N,N-diisopropylethylamine (25 mmol, 5.0 equiv) and tert-butyl 5-bromopentanoate (284.6 mg, 1.2 mmol). After addition, the mixture was stirred for 12 h at 100° C. Once the starting material was consumed completely, the mixture was purified via C18 reverse phase preparative HPLC column (eluent gradient: acetonitrile/(H2O+0.1% TFA)=10%-100%) to afford desired product (SIAIS184046) as a light yellow solid (260 mg, 63% yield). 1H NMR (500 MHz, DMSO) δ 11.00 (s, 1H), 7.28 (t, J=7.7 Hz, 1H), 6.92 (d, J=7.2 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 5.58 (s, 1H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.22 (d, J=17.1 Hz, 1H), 4.12 (d, J=17.1 Hz, 1H), 3.12 (t, J=6.1 Hz, 2H), 2.95-2.89 (m, 1H), 2.62 (d, J=16.7 Hz, 1H), 2.36-2.19 (m, 3H), 2.08-1.96 (m, 1H), 1.59 (dd, J=8.4, 5.1 Hz, 4H), 1.39 (d, J=6.1 Hz, 9H). HRMS (ESI) m/z: calcd C22H30N3O5+ [M+H]+, 416.2180; found, 416.1274.
63% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 100℃; for 12h; 4.1.46. 5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentanoic acid (S33) The compound lenalidomide S31 (259.3 mg, 1 mmol) was addedto a 25 ml egg-like bottle, followed by anhydrous NMP (5 ml), N,Ndiisopropylethylamine (387.7 mg, 3 mmol) and tert-butyl bromopentate(284.6 mg, 1.2 mmol). The solution was then added, slowlyraised to 100 C and stirred overnight. After that, the reaction waspurified by C18 reverse phase column to afford target compoundS32 with a pale yellow solid, 260 mg, (yield 63%).The obtained intermediate S32 (260 mg, 0.62 mmol), TFA (2 mL)and anhydrous dichloromethane (10 mL) were added to a 50 mLegg-shaped bottle and stirred for 2 h at room temperature. Afterthat, the reaction solvent was removed by decompression, and thecrude product was prepared by C18 reversed phase column toafford compound (S33) with a white solid, 210 mg, (yield 93%).
53.39% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 90℃; Inert atmosphere; 8.1 Step 1: Preparation of tert-butyl 5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentanoate To a stirred mixture of lenalidomide (100.00 mg, 0.386 mmol, 1.00 equiv) and tert-butyl 5- bromopentanoate (109.76 mg, 0.463 mmol, 1.20 equiv) in NMP (1.5 mL) was added DIEA (149.55 mg, 1.157 mmol, 3.00 equiv) dropwise at room temperature under an atmosphere of dry nitrogen. The resulting mixture was stirred overnight at 90 °C. The mixture was diluted with EtOAc (10 mL) and it was washed with brine (2 x 10 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated and the residue purified by reversed phase flash chromatography to afford tert-butyl 5-((2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentanoate (93 mg, 53.39%) as a yellow solid. LCMS (ESI) m/z [M+H]+ = 416
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 110℃; for 12h;

  • 75
  • [ 51100-47-1 ]
  • [ 191732-72-6 ]
  • N-(6-carboxyhexyl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-aminium 2,2,2-trifluoroacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 12 h / 110 °C 2: dichloromethane / 1 h / 25 °C
  • 76
  • [ 51100-47-1 ]
  • [ 191732-72-6 ]
  • C24H33N3O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 110℃; for 12h;
  • 77
  • [ 5292-43-3 ]
  • [ 191732-72-6 ]
  • 2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}acetic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
64% Stage #1: bromoacetic acid <i>tert</i>-butyl ester; Lenalidomide With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 110℃; for 12h; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; for 1h; 1 Example 1: Preparation of (2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindololin-4-yl) aminoacetic acid ((2- (2,6-dioxopiperidin- 3-yl) -1-oxoisoindolin-4-yl) glycine; SIAIS1204057) According to the method of scheme A, in the future lenalidomide (259 mg 3 mg, 1 mmol, 1 equiv), 2-bromoacetic acid tert-butyl acetate (1 · 2mmol, 1 · 2equiv) and N, N-diisopropylethylamine (387 · 7mg, 3mmol, 3equiv) were added together in a reaction of 25mL Then, NMP (5 mL) was added to the tube, and the reaction was carried out in a 110C oil bath for 12 h. The reaction solution was cooled down to room temperature, and then a C18 reversed-phase column was used. Preparation, eluent (v / v): acetonitrile / (water + 0% 1% TFA) = 10% -100%, acetonitrile was distilled off under reduced pressure, and the intermediate was obtained after lyophilization; The compound was then added to a 25 mL single-necked flask, 1 mL of dichloromethane and 3 mL of trifluoroacetic acid were added in that order, and the mixture was stirred at room temperature for 1 h. Less The reaction solvent was distilled off under pressure, and the target compound SIAIS1204057 (yellow solid, 203 mg, yield 64%) was obtained by lyophilization with water;
48% Stage #1: bromoacetic acid <i>tert</i>-butyl ester; Lenalidomide With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 110℃; for 12h; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; for 1h; 35 Intermediate Preparation Example 35:Preparation of (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)aminoacetic acid (SIAIS 1204057) According to Scheme 8, in the future, lenalidomide (2mmol, 1equiv), NMP (8mL),Corresponding starting material bromo tert-butyl ester, ie 2-bromoacetic acid tert-butyl ester (2.4 mmol, 1.2 equiv) andN,N-diisopropylethylamine (6 mmol, 3 equiv) was added to a single-mouth bottle and reacted at 110 ° C for 12 h.The reaction solution was cooled to room temperature and prepared by a C18 reverse phase column. The eluent (v/v): acetonitrile / (water + 0.1% TFA) = 10% - 100%,The obtained compound was added single-neck flask, was added DCM (6mL) and TFA (2 mL), stirred at rt for 1h.The reaction solvent was evaporated under reduced pressure and lyophilized with water to give the title compound (SIAIS 1204057).The target product was a yellow solid, 1.0 g, yield 48%.
  • 78
  • [ 57294-38-9 ]
  • [ 191732-72-6 ]
  • C22H28N4O6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% Stage #1: N-(tert-butoxycarbonyl)-4-aminobutanoic acid With N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; triethylamine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: Lenalidomide In N,N-dimethyl-formamide at 20℃; for 48h; 1.IV-1 IV- 1. General procedure: [00308] N-Boc amino acids (lminoi) was dissolved in 3mL dimethylformamide (DMF). HATU (0.57g, l.Smmol) and EtsN (0.28mL, 2.0mmol) were added into the solution. The solution was stirred for lOmin at r.t. before lenalidomide (0.26g, l.Ommol) was introduced. (0668) The reaction was stirred at r.t. for 48 hours. Then it was diluted with EtOAc, washed with brine twice. The aqueous solution was extracted with EtOAc. The combined organic layer was dried over MgSOr, filtered, and evaporated under reduced pressure. The crude materials were then subjected to normal phase chromatography using CombiFlash Rf+ system (10% to 50% MeOH in EtOAc), then reverse phase HPLC (MeCN/TEO w/0.5%o TFA) to afford purified products as off-white solid (n=3, 78%. n=4, 80%. n=5, 69%).
With pyridine; trichlorophosphate In acetonitrile at 20℃; for 3h; 4.1.3. General procedure for the preparation of 35a-f General procedure: A mixture of 33a-f (0.85 mmol), lenalidomide (0.77 mmol), pyridine(2.31 mmol) and phosphorus oxychloride (0.93 mmol) in acetonitrile(10 mL) was stirred at room temperature for 3 h. After the reactionwas completed, the mixture was concentrated and then dilutedwith water (10 mL) and extracted with ethyl acetate (10 mL × 3). Thecombined organic layer was dried over anhydrous Na2SO4 and concentratedunder reduced pressure. The crude residue was purified byflash column chromatography (dichloromethane/methanol = 35:1) to give 34a-f (about 40% yield).
  • 79
  • [ 7460-82-4 ]
  • [ 191732-72-6 ]
  • 2-(2-((2-(2,6-piperidinedione-3-yl)-1-oxoindololin-4-yl)amino)ethoxy)ethyl-4-methylbenzenesulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2h; 1.1 (1) Preparation of 2- (2-((2- (2,6-piperidindione-3-yl) -1-oxoindololin-4-yl) amino) ethoxy) ethyl-4 -Mesylate (2-1): In a 25 mL three-necked flask, add diethylene glycol bis-p-toluenesulfonate (414 mg, 1 mmol), II-a (258 mg, 1 mmol), potassium carbonate (150 mg, 1.2 mmol) and 10 mL of DMF, and react at 100 ° C under nitrogen protection. After 2 hours, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and separated by medium chromatography to obtain 296 mg of a pale yellow solid with a yield of 60%.
60% With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2h; Inert atmosphere; 1.1 (1) Preparation of 2-(2-((2-(2,6-piperidindione-3-yl)-1-oxoindololin-4-yl)amino)ethoxy)ethyl 4-methylbenzenesulfonate (2-1): Diethylene glycol bis-p-toluenesulfonate (414mg, 1mmol), Lenalidomide (258 mg, 1 mmol), potassium carbonate (150 mg, 1.2 mmol) and 10 mL of DMF. Reaction at 100 °C for 2 hours under nitrogen protection. Pour the reaction solution into water. It was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and separated by medium chromatography to obtain 296 mg of a pale yellow solid with a yield of 60%.
22.9% With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 8h; Inert atmosphere; 1.1 1) Synthesis of compound II-2 (m = 1) Weigh sequentially 2.452 g (9.46 mmol) of commercially available lenalidomide (I), 3.920 g (9.46 mmol) of diethylene glycol di-p-toluenesulfonic acid (III-2), and 1.567 g (11.35 mmol) of K2CO3, and add them to 50 mL. In a three-necked flask, 20 mL of anhydrous DMF was added to dissolve it, and the reaction was started at 90 ° C under the protection of nitrogen. After 8 h, the reaction progress was detected by TLC (EA). The reaction was cooled to room temperature of 25 ° C, 30 mL of water was added and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed once with a small amount of saturated NaCl, then dried over anhydrous sodium sulfate. The filtrate was concentrated and separated by column chromatography. PE: EA = 3: 1 gradient elution gave 1.085 g of a pale yellow solid with a yield of about 22.9%.
  • 80
  • [ 191732-72-6 ]
  • 3-(4-azido-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% With fluorosulfonyl azide; potassium hydrogencarbonate In tert-butyl methyl ether; water; N,N-dimethyl-formamide at 20℃; for 4h; General procedure for the preparation of the isolated azide compounds. General procedure: To a 50-ml glass round-bottom flask was added sequentially the primary amine 2 (1.0 mmol; aliphatic, aromatic or heteroaromatic; as free naked amine or as HCl, MsOH, TsOH or tartrate salt), FSO2N3 solution (containing 1.0 mmol FSO2N3, approximately 200 mM in DMF/MTBE 1:1, v/v, approximately 5 ml, volume adjusted according to the concentration; prepared according to the above procedure and diluted with equal volume of DMF) and aqueous KHCO3 solution (3.0 M, 1.33 ml, containing 4.0 mmol KHCO3). The reaction mixture was stirred for 5 min at room temperature, while monitoring by LC-MS. After completion, EtOAc (40 ml) was added and the mixture was washed sequentially with brine (60 ml × 6), water (60 ml × 2) and brine (60 ml), dried over Na2SO4, concentrated by rotary evaporation and dried under vacuum to afford the azide product 3. For products containing acidic functional groups, this extraction process was modified with acidified aqueous phase (acidified with aqueous HCl). Detailed procedures and the various modifications, as well as the characterization data for each compound, can be found in Supplementary Information 1.
Stage #1: Lenalidomide With sodium nitrite In tetrahydrofuran; water at 0℃; for 0.166667h; Stage #2: With hydrogenchloride In tetrahydrofuran; water for 0.5h; Stage #3: With sodium azide In tetrahydrofuran; water for 10h; 1 Combine 2.6 g of 3-(7-amino-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione and 1.35 g of sodium nitrite,Add to the mixed solution of 20mL of tetrahydrofuran and 10mL of water,Stir at 0 for 10min,Slowly add 8mL of 6mol/L hydrochloric acid solution,After dripping, stir again for 30 minutes,Then add 10 mL of an aqueous solution containing 1.3 g of sodium azide,Continue to stir for 10h,TLC monitors the complete reaction of raw materials,Then add dichloromethane to extract,Separate the organic phase,Adjust the pH of the organic phase to neutral with saturated sodium carbonate solution,Separate the organic phase,After concentration, 3-(4-azido-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is obtained;
Stage #1: Lenalidomide With sodium nitrite In tetrahydrofuran; water at 0℃; for 0.166667h; Stage #2: With hydrogenchloride In tetrahydrofuran; water for 0.5h; Stage #3: With sodium azide In tetrahydrofuran; water for 10h; 4 Example 4 Add lenalidomide/pomalidomide (0.1mol) and sodium nitrite (13.8g, 0.2mol) to 50mL mixed solution (V water:V tetrahydrofuran=1:1), stir at 0 for 10min, then Slowly add 5 mL of 0.01mol/L hydrochloric acid solution dropwise, stir again for 30min after the dropwise addition, and then add an aqueous solution of sodium azide (8.1g, 0.125mol), continue stirring for 10h, TLC track the progress of the reaction (petroleum ether/ Ethyl acetate = 1/1). After the reaction, the pH of the reaction solution was adjusted to neutral with saturated sodium carbonate solution, and then the reaction solution was extracted 3 times with 30 mL of dichloromethane. The organic phases were combined and concentrated to obtain lenalidomide/ Pomalidomide azide compound.
With fluorosulfonyl azide; potassium hydrogencarbonate In tert-butyl methyl ether; dimethyl sulfoxide at 20℃; for 48h; Inert atmosphere;

  • 81
  • [ 89711-08-0 ]
  • [ 191732-72-6 ]
  • tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% With sodium cyanoborohydride; acetic acid In methanol at 50℃; for 12h; Tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethyl)carbamate(18) To a solution of lenalidomide (311mg, 1.2 mmol) and tert-butyl (2-oxoethyl) carbamate (190 mg, 1.2 mmol) in MeOH (10 mL) was added NaBH3CN (114 mg, 1.8 mmol), and 1 drop AcOH. The mixture was stirred at 50 oC for 12 h. The reaction mixture was quenched with H2O and extracted with EtOAc. The organic layer was separated, washed with brine, dried, and evaporated. The residue was purified by flash column chromatography to afford 18 as a white solid (215 mg, 45% yield).
With sodium cyanoborohydride In methanol at 50℃;
  • 82
  • [ 4530-20-5 ]
  • [ 191732-72-6 ]
  • tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-2-oxoethyl)- carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0℃; 1 Take above-mentioned S1 (2.6g, 10mmol),N-(tert-butoxycarbonyl)glycine (1.93 g, 11 mmol) was dissolved in 15 mL of anhydrousN,-dimethylformamide, add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate at 0°C(5.7g, 15mmol), diisopropylethylamine (5.0mL, 3.0mmol), continue to stir at 0°C until the reaction of the raw materials is complete, add water to diluteReleased with white solid and separated out, filtered and washed three times to obtain white solid product S16 (3.6g, 87%),
64% Stage #1: BOC-glycine With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.333333h; Inert atmosphere; Stage #2: Lenalidomide In N,N-dimethyl-formamide for 2h; Inert atmosphere; 3.1 Step 1: N-Boc-glycine (405 mg, 2.31 mmol) was dissolved in dry DMF (10 ml). HATU (1.10 g, 2.9 mmol) and DIPEA (516 mg, 4 mmol) were added at room temperature, and stirred for 20 min. Then lenalidomide (500 mg, 1.93 mmol) was added and stirred for another 2 hrs until TLC showed the raw materials were completely reacted. The reaction solution was poured into water, and extracted with EtOAc. The organic phase was washed with water and brine, dried, and concentrated. The crude product was separated by column chromatography to afford the intermediate 42-1 (511 mg, 64%).
Stage #1: BOC-glycine With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Stage #2: Lenalidomide In N,N-dimethyl-formamide at 20℃; for 1h; 1 tert-Butyl (2-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)amino)-2-oxoethyl)- carbamate To a solution of (tert-butoxycarbonyl)glycine (2.1 g, 12 mmol), DIEA (5 mL, 30 mmol) in DMF (30 mL) was added l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- bjpyridinium 3-oxid hexafluorophosphate (HATU) (4.94 g, 13 mmol), stirred for 0.5h, and then Lenalidomide (2.59 g, 10 mmol) was added, the mixture was then stirred at room temperature for another lh. The mixture was then purified by silica gel (MeOH/DCM = 0-10%) to obtain the title compound.LCMS (m/z): 417 [M+H]+.
  • 83
  • [ 30100-16-4 ]
  • [ 191732-72-6 ]
  • 8-amino-N-(2–(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)octanamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% Stage #1: 8-tert-butoxycarbonylaminooctanoic acid; Lenalidomide With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; for 12h; Inert atmosphere; Stage #2: With trifluoroacetic acid In dichloromethane at 25℃; for 2h; 1.1 (1) Preparation of 8-amino-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)octanamide (2-1): Add lenalidomide (10 mmol) to a 50 mL round bottom flaskAnd 8-((tert-butoxycarbonyl) amino) caprylic acid (10 mmol),Add 10mL of anhydrous DMF (N, N-dimethylformamide) to dissolve,Then HATU (10.5 mmol, 2- (7-benzotriazole)-N, N, N ', N'-tetramethylurea hexafluorophosphate)And TEA (10.5 mmol, triethylamine),The reaction was performed at 25 ° C for 12 hours under a nitrogen atmosphere.After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a crude white product without purification;Take 1.0 mmol of the crude product and add TFA / DCM (1: 5, v / v), a mixed solvent of 3mLTFA (trifluoroacetic acid) and DCM (dichloromethane), and react at 25 ° C for 2 hours.After the reaction was completed, toluene (10 mL × 3) was added to reduce the pressure and spin-evaporate to obtain a crude product. The methanol was recrystallized to obtain a yellow solid with a yield of 77%.
  • 84
  • tert-butyl 2-(2-(toluenesulfonyloxy)ethoxy)acetate [ No CAS ]
  • [ 191732-72-6 ]
  • 2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)acetic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% Stage #1: tert-butyl 2-(2-(toluenesulfonyloxy)ethoxy)acetate With sodium iodide In acetone Heating; Stage #2: Lenalidomide With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 110℃; for 12h; Stage #3: With trifluoroacetic acid In dichloromethane at 20℃; for 1h; 7; 7-1 Example 7: Preparation of 2- (2-((2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindololin-4-yl) amino) ethoxy) acetic acid (2- (2-((2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) amino) ethoxy) acetic acid; SIAIS1204115) According to the method of Scheme B1, tert-butyl 2- (2- (toluenesulfonyloxy) ethoxy) acetate (1equiv) and iodinated Sodium (2equiv) was added to a 25 mL egg-shaped bottle, followed by acetone (5 mL), and the mixture was refluxed at 60 ° C for 2 h. Acetone Spin dry, then add NMP (3mL), lenalidomide (0.8equiv) and N, N-diisopropylethylamine (3equiv), 110C oil bath Reaction for 12h. The reaction solution was cooled to room temperature, and then prepared using a C18 reversed-phase column. = 10% -100%, acetonitrile was distilled off under reduced pressure, and the intermediate was obtained after lyophilization; the compound was then added to a 25mL single-necked bottle, according to Add 1 mL of dichloromethane and 3 mL of trifluoroacetic acid one time, and stir at room temperature for 1 h. The reaction solvent was evaporated under reduced pressure, and the target compound was lyophilized by adding water. SIAIS1204115 (yellow solid, 134mg, yield 77%)
Same Skeleton Products
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[ 191732-72-6 ]

Chemical Structure| 1243329-97-6

A451300[ 1243329-97-6 ]

3-(4-Amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride

Reason: Free-salt