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CAS No. : | 1072833-77-2 | MDL No. : | MFCD18251438 |
Formula : | C14H19BCl2N2O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MXAYKZJJDUDWDS-LBPRGKRZSA-N |
M.W : | 361.03 | Pubchem ID : | 25183872 |
Synonyms : |
MLN2238
|
Num. heavy atoms : | 23 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.43 |
Num. rotatable bonds : | 9 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 4.0 |
Molar Refractivity : | 90.44 |
TPSA : | 98.66 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.73 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 2.49 |
Log Po/w (WLOGP) : | 1.27 |
Log Po/w (MLOGP) : | 1.24 |
Log Po/w (SILICOS-IT) : | 0.78 |
Consensus Log Po/w : | 1.16 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.25 |
Solubility : | 0.205 mg/ml ; 0.000567 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.21 |
Solubility : | 0.0224 mg/ml ; 0.0000621 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -4.16 |
Solubility : | 0.0253 mg/ml ; 0.00007 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 2.8 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.5% | With hydrogenchloride In di-isopropyl ether at 20℃; for 5 h; | The pinanediol boronate ester (5 g) of compound of formula Tb was mixed with amixture of concentrated hydrochloric acid (5 mL) and boric acid (1.9 g) indiisopropyl ether (100 mL) at ambient temperature. The reaction mixture wasstirred for 5 hours and solid was filtered and washed with diisopropyl ether (25mL). The isolated solid was dried under vacuum to obtain Txazomib. (Yield: 86.5percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.5% | With hydrogenchloride; Dihydroxy-isobutyl-boran In methanol; hexane; water | Compound VI (317 mg, 0.49 mmol) was dissolved in 3 mL of MeOH and isobutylboronic acid (247 mg,2.43 mmol), n-hexane (3 mL) and IN HCl (1.2 mL, 1.2 mmol) were added and the reaction stirred overnight.TLC detection reaction, n-hexane The methanol phase was washed once with MeOH (2 x 3 mL) and n-hexane (3 mL). The methanol, CH2Cl2 (2 x 2 mL) The aqueous phase was washed twice with saturated brine (3 x 5 mL) to the aqueous phase. The solvent was distilled off under reduced pressure and separated by column chromatography A yield of 76.5percent was obtained from 193 mg of pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.4% | With hydrogenchloride; Dihydroxy-isobutyl-boran; In methanol; hexane; | General procedure: I-3a the compound (317 mg, 0 . 49mmol) dissolved in 3 ml of in MeOH, adding isobutyl boric acid (247 mg, 2 . 43mmol), hexane (3 ml) and 1NHCl (1.2 ml, 1 . 2mmol), reaction stirring overnight. TLC detection reaction, MeOH-hexane phase with (2×3 ml) to extract 2 times, hexane (3 ml) washing methyl alcohol 1 time, reducing pressure and evaporating methanol, CH2Cl2(2×2 ml) extraction the aqueous phase 2 times, with saturated salt water (3×5 ml) to wash the organic phase to aqueous phase is neutral. Evaporating solvent under reduced pressure, column chromatography separation to obtain the pure product 193 mg, yield 76.5%. |
With hydrogenchloride; Dihydroxy-isobutyl-boran; In methanol; hexane; at 20℃; | General procedure: (4) After the intermediate S-1-3 is obtained, the hydrolysis reaction of the boric acid ester is carried out, and as shown in the above route, 5.1 g of the intermediate S-1-3 (9.5 mmol) obtained in the step (3) is obtained. 40 mL of methanol, 4.5 mL of 1N hydrochloric acid solution, 2.7 g (23.6 mmol) of isobutylboronic acid, and 40 mL of n-hexane were mixed, and stirred at room temperature overnight. The solvent n-hexane was separated, the methanol was concentrated under reduced pressure, 20 mL of water was added, 1N sodium hydroxide was neutralized and the pH was adjusted to 8-9, and 20 mL of dichloromethane was extracted in portions. The remaining alkali water liquid was adjusted to pH 6 with a 1N aqueous solution of hydrochloric acid, and then extracted twice with dichloromethane. The organic layer was dried and concentrated to dryness to give a pale yellow solid. The solid contains an I-1-1 compound and a small amount of a trimer which can be directly used in the synthesis of the compound of the present invention. If further purification, a methanol/water (1:19) mixed solid can be used and stirred for 6 hours, and lyophilized to give the object white powder compound I-1-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | In ethyl acetate; at 20℃; | A 15 mL one neck round bottom flask equipped with a stir bar and nitrogen inlet is charged with 0.5 g (1.39 mmol) of Compound 1 (98.5Apercent purity) and 5 mL of ethyl acetate then stirred for five minutes at room temperature to dissolve the solids. N- Methyldiethanol amine (166 mg, 1.39 mmol) is charged and stirred at room temperature overnight. The white precipitate is collected by vacuum filtration, washed with 5 mL of ethyl acetate and dried overnight under nitrogen on the filter to give 410 mg (0.92 mmol, 66percent) of the desired product with an HPLC purity of 97.9Apercent. After storing for approximately one (1) year at ambient indoor temperature and humidity (in a vial at the rear of a fume hood), the HPLC purity was 99.6Apercent. 1H NMR (d6-DMSO, 400 MHz) delta8.95 (t, 1H, J = 5.96 Hz), 7.56 (s, 2H), 7.49 (s, 1H), 6.5 (d, 1H, J = 9.88 Hz), 3.77 (d, 2H, J = 6.08 Hz), 3.72 (m, 3H), 3.62 (m, 1H), 3.2 (m, 3H), 3.1 (m, 1H), 2.9 (m, 1H), 2.59 (s, 3H), 1.51 (m 1H), 1.23 (dq, 2H, J = 8.92, 4.28 Hz), 0.835 (d, 3H, J = 6.48 Hz), 0.803 (d, 3H, J = 6.68 Hz). The N-methyldiethanol amine ester of Compound 1 is a crystalline solid having an x-ray powder diffraction (XRPD) pattern as shown in Fig. 3. Representative peaks are provided in Table 3. Table 3. XRPD peaks of N-methyldiethanol amine ester of Compound 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In ethyl acetate; at 20℃; for 2h;Product distribution / selectivity; | A 100 mL three neck round bottom flask equipped with a stir bar, thermocouple and nitrogen inlet is charged with 6.0 g (16.6 mmol) of Compound 1 (98.5Apercent purity) and 60 mL of ethyl acetate then stirred for five minutes at room temperature to dissolve the solids. Diethanol amine (1.68 g, 16.0 mmol) is charged and solids begin to form when addition is only 2/3 complete. The white slurry is stirred at room temperature for two hours and then the solids are collected by vacuum filtration, washed with 50 mL of ethyl acetate and dried overnight in a vacuum oven at 40°C. A quantitative yield of the desired product is obtained as a crystalline solid with an HPLC purity of 99.7Apercent. After storing for approximately one (1) year at ambient indoor temperature and humidity (in a vial at the rear of a fume hood), the HPLC purity was 99.9Apercent. 1H NMR (d6-DMSO, 400 MHz) delta 8.8 (t, 1H, J = 5.88 Hz), 7.55 (s, 2H), 7.52 (s, 1H), 6.99 (d, 1H, J = 8.36 Hz), 6.57 (s, b, 1H), 3.85 (dq, 1H, J= 16.1, 5.92 Hz), 3.69 (m, 2H), 3.57 (m, 1H), 3.14 (m, 1H), 2.99 (m, 2H), 2.75 (m, 1H), 2.69 (m, 1H), 1.59 (m, 1H), 1.31 (m, 1H), 1.22 (m, 1H), 0.824 (d, 3H, J = 6.64 Hz), 0.797 (D, 3h, J = 6.48 Hz)The diethanolamine ester of Compound 1 (i.e., boronic ester of Formula X) is a crystalline solid having an x-ray powder diffraction (XRPD) pattern as shown in Fig. 1. Representative peaks are provided in Table 1.Table 1. XRPD peaks of diethanolamine ester of Compound 1 (boronic ester ofFormula X). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | In ethyl acetate; at 20℃; | A 15 mL one neck round bottom flask equipped with a stir bar and nitrogen inlet is charged with 0.5 g (1.39 mmol) of Compound 1 (98.5Apercent purity) and 5 mL of ethyl acetate then stirred for five minutes at room temperature to dissolve the solids.Diisopropanolamine (185 mg, 1.39 mmol) is charged and stirred at room temperature.The white precipitate is collected by vacuum filtration, washed with 5 mL of ethyl acetate and dried overnight under nitrogen on the filter to give 410 mg (0.895 mmol, 64percent) of the desired product with an HPLC purity of 99.4Apercent. After storing for approximately one (1) year at ambient indoor temperature and humidity (in a vial at the rear of a fume hood), the HPLC purity was 99.8Apercent. 1H NMR (d6-DMSO, 400 MHz) delta 8.8 (m, 1H), 7.54 (t, 2H, J =1.08 Hz), 7.52 (s, 1H), 7.2 (m, 0.25 H), 6.8 (m, 0.75 H), 6.7 (m, 0.75H), 6.5 (m, 0.25H),3.9 (m, b, 4H), 2.9 (m, b, 2H), 2.5 (m, b, 2H), 2.0 (m, 1H), 1.6 (m, 1H), 1.3 (m, 1H), 1.2 (m, 1H), 1.1 (d, 3H, J = 6.04 Hz), 1.0 (d, 3H, J = 5.92 Hz), 0.82 (d, 3H, J = 6.6 Hz), 0.79 (d, 3H, J = 6.6 Hz).The diisopropanolamine ester of Compound 1 (i.e., boronic ester of Formula IX) is a crystalline solid having an x-ray powder diffraction (XRPD) pattern as shown in Fig. 2. Representative peaks are provided in Table 2. Table 2. XRPD peaks of diisopropanolamine ester of Compound 1 (boronic ester of Formula IX). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.4% | In dimethyl sulfoxide; toluene; for 18h;Reflux; | A 250 mL three neck round bottom flask equipped with a stir bar, thermocouple,Dean-Stark trap, condenser, nitrogen outlet, heating mantle and controller is charged with 1.0 g (2.77 mmol) of Compound 1 (97.9Apercent purity), 50 mL of toluene, 10 mL of DMSO and 0.42 g (2.77 mmol) of N-methylimino diacetic acid. The reaction is heated to reflux and agitated for 18 hours while removing water via the Dean-Stark trap. After cooling to room temperature the solvent is removed in vacuo and the residue is partitioned between dichloromethane (50 mL) and DI water (50 mL). After separating the layers, the organic phase is washed with water (2 X 50 mL), dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give the desired product as a white solid. A total of 1.09 g (2.3 mmol, 83.4percent) is isolated with an HPLC purity of 98.4Apercent. After storing for approximately one (1) year at ambient indoor temperature and humidity (in a vial at the rear of a fume hood), the HPLC purity was 84.4Apercent. 1H NMR (d6-DMSO, 400 MHz) delta 8.8 (t, b, 1H), 7.64 (s, 2H), 7.63 (s, 1H), 7.34 (d, 1H, J = 1.8 Hz), 4.15 (dd, 2H, J = 16.72, 5.84), 3.9 (ddd, 2H, J = 16.56, 16.51 Hz), 3.89 (m, 1H), 3.8 (dd, 1H), 3.77 (dt, 1H), 3.9 (s, 3H), 1.57 (m, b, 1H), 1.42 (t, b, 1H), 1.24 (t, b, 1H), 0.90 (d, 3H, J = 6.44 Hz), 0.87 (d, 3H, J = 6.56 Hz).The N-methylimino diacetic acid ester of Compound 1 has an x-ray powder diffraction (XRPD) pattern as shown in Fig. 4. Representative peaks are provided inTable 4.Table 4. XRPD peaks of N-methylimino diacetic acid ester of Compound 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
557 mg | In ethyl acetate; at 60 - 74℃; for 3h; | The diethanolamine (160 mg, 1 . 52mmol) dissolved in 8 ml of ethyl acetate, the temperature is increased to 74 °C, by adding dissolved in 1.5 ml MLN2238 of ethyl acetate (500 mg, 1 . 38mmol), slow cooling to 60 °C, reaction 3h, then slowly cooling to 25 °C sleepovers. TLC detection reaction, filtration, the filter cake vacuumdrying pure product 557 mg, yield 85.4percent. The yield is 93.6percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.0 mg | The pinacol aminoboronate ester S43 was dissolved in CH2CI2 (5 mL) under argon and the solution was cooled to -78 °C in a dry ice/acetone bath. BCI3 (0.6 mL, 1.0 M in CH2CI2, 3.0 equiv.) was added dropwise, after which the mixture was stirred for 1 h at -78 °C. The mixture was then allowed to warm up to room temperature, and the volatiles were removed in vacuo. Anhydrous methanol (5 mL) was added and the mixture was stirred for 10 minutes when the methanol was removed in vacuo. An additional portion of methanol (5 mL) was added; the mixture was stirred for 10 minutes before it is concentrated in vacuo. This process was repeated for three times. The resulting residue was then purified by preparative reverse-phase HPLC (10-60percent CH3CN/H20 over 35 min, both CH3CN and H20 containing 0.1 percent TFA) to afford Ninlaro (1 , 23.0 mg, 32percent over 2 steps). 1H NMR (600 MHz, MeOH-d4): delta 7.60 (t, J = 1 .5 Hz, 1 H), 7.49 - 7.47 (m, 2H), 4.24 (s, 2H), 2.79 (t, J = 7.6 Hz, 1 H), 1 .68 (ddt, J = 14.7 Hz, 13.0 Hz, 6.4 Hz, 1 H), 1 .38 (tdd, J = 13.8 Hz, 10.4 Hz, 5.9 Hz, 2H), 0.94 (dd, J = 6.6 Hz, 1 .5 Hz, 6H); 13C NMR (151 MHz, MeOH-d4): delta 175.6, 168.8, 138.0, 134.0, 132.7, 132.5, 130.7, 130.2, 44.7 (br, a to boron), 40.9, 40.2, 27.1 , 23.7, 22.4. HRMS (ESI-TOF, m/z): calc'd for C14H18BCI2N2O3 [M-H20+H]+ 343.0782; found 343.0779; [a]D20 = -0.6 (c 1 .0, MeOH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; water; In ethyl acetate; at 20℃; for 0.5h; | IV (0.88 g,2.05 mmol) was added to a mixture consisting of 20 ml of ethyl acetate and 20 ml of water,Dropping 4N hydrochloric acid 1 ml,After reaction at room temperature for 30 min,The water is removed by liquid separation,The ethyl acetate layer was washed three times with saturated brine,Dried over anhydrous sodium sulfate.filter,The solvent was evaporated under reduced pressure to give a white foamy solid V,Yield 90-98percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In acetone; at 20℃; for 0.5h; | The Txazomib (5 g) was added in a solution of citric acid (2.93 g) in acetone (100 mL) at ambient temperature. The reaction mixture was stirred for 30 minutes andfiltered. The filtrate was stirred for 4-5 hours. The solid was collected by filtration and dried to give <strong>[1072833-77-2]Ixazomib</strong> citrate. (Yield- 95 percent) |
In ethyl acetate; at 60℃; for 0.5h; | Aqueous citric acid (398 mg, 2.07 mmol)Was added to 4 ml of ethyl acetate,Heated to 60 ° C. V (680 mg, 1.88 mmol) was dissolved in 3 ml of ethyl acetate,Was added dropwise to the citric acid in ethyl acetate solution and after reaction for 30 min,Cooled to room temperature,Filter,Ethyl acetate,Dried to a white solid product I,Yield 85-95percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.5% | With hydrogenchloride; Dihydroxy-isobutyl-boran; In methanol; hexane; water; | Compound VI (317 mg, 0.49 mmol) was dissolved in 3 mL of MeOH and isobutylboronic acid (247 mg,2.43 mmol), n-hexane (3 mL) and IN HCl (1.2 mL, 1.2 mmol) were added and the reaction stirred overnight.TLC detection reaction, n-hexane The methanol phase was washed once with MeOH (2 x 3 mL) and n-hexane (3 mL). The methanol, CH2Cl2 (2 x 2 mL) The aqueous phase was washed twice with saturated brine (3 x 5 mL) to the aqueous phase. The solvent was distilled off under reduced pressure and separated by column chromatography A yield of 76.5% was obtained from 193 mg of pure product. |
63% | With hydrogenchloride; Dihydroxy-isobutyl-boran; In methanol; hexane; at 20℃; | Dissolve Intermediate III (300 mg, 0.6 mmol) in 3 mL of methanol, and add isobutylboronic acid (306 mg, 3 mmol) and n-hexane (3 mL) in this order.And 4N hydrochloric acid (0.37 mL, 1.5 mmol),Stir overnight at room temperature. Separating n-hexane from methanol,N-hexane was extracted twice with methanol (2 * 3 mL),Methanol was washed once with n-hexane (3 mL).The methanol phases were combined, and the methanol was distilled off under reduced pressure. The aqueous phase was extracted with dichloromethane (3 × 3 mL). The dichloromethane was washed with saturated brine (3 × 5 mL), and dried over anhydrous sodium sulfate.Concentration through the column gave a white solid IV of 136 mg with a yield of 63%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.6% | With dimethylsulfoxide-d6; water-d2; potassium carbonate; In tetrahydrofuran; at 65℃; for 5h; | Compound VII (500 mg, 1.38 mmol) was dissolved in 16 ml of anhydrous tetrahydrofuran and potassium carbonate (191.4 mg,1.38 mmol), DMSO-d6 (3.75 ml), heavy water (2.5 ml) and an oil bath at 65 ° C for 5 hours. LC-MS test the end of the reaction After the tetrahydrofuran was distilled off under reduced pressure, a small amount of water was added, extracted with ethyl acetate, and then the organic phase was washed twice with water, saturated brine And the solvent was distilled off under reduced pressure. The product was purified by column chromatography to obtain 278 mg of pure product, and the yield was 55.6percent. |
630 mg | With water-d2; sodium methylate; at 0℃; for 72h; | Dissolving the compound IIm (722mg) in D2O, (5mL), at 0 °C, was added CH3ONa (27mg), After the reaction was stirred at 0°C for 72 hours, NMR showed the reaction was complete, the reaction was quenched with 1N hydrochloric acid, extracted with methylene chloride, and concentrated to give after purification compound IIc (630mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.5% | With hydrogenchloride; In di-isopropyl ether; at 20℃; for 5h; | The pinanediol boronate ester (5 g) of compound of formula Tb was mixed with amixture of concentrated hydrochloric acid (5 mL) and boric acid (1.9 g) indiisopropyl ether (100 mL) at ambient temperature. The reaction mixture wasstirred for 5 hours and solid was filtered and washed with diisopropyl ether (25mL). The isolated solid was dried under vacuum to obtain Txazomib. (Yield: 86.5percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51 mg | In acetic acid butyl ester; at 90℃; for 14h; | The compound IIm (50 mg), D2-citric acid (66 mg) was dissolved in 4 mL of butyl acetate, and the reaction was heated at 90 °C for 2 h, allowed to cool slowly to room temperature, and stirring was continued for 12 h, and the white solid was filtered. The ethyl acetate was washed to give a white solid compound (51 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53 mg | In acetic acid butyl ester; at 90℃; for 14h; | Compound IIi (50 mg), D4-citric acid (66 mg) was dissolved in 4 mL of butyl acetate, and the reaction was heated at 90 °C for 2 h, allowed to cool slowly to room temperature, and stirring was continued for 12 h, and the white solid was filtered. The ethyl acetate was washed to give the white solid compound Io (53 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In ethyl acetate; at 60 - 74℃; for 3h; | Dissolve citric acid (292 mg, 1.52 mmol) in 8 mL of ethyl acetate, warm to 74 C, add intermediate IV (500 mg, 1.4 mmol) dissolved in 1.5 mL of ethyl acetate, and slowly cool to 60 C , React for 3 h, and then slowly lower the temperature to 25 C. and stir overnight. It was then filtered with suction and the filter cake was dried under vacuum to obtain 557 mg of pure product with a yield of 94%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | In ethyl acetate for 0.666667h; | 3 Preparation Comparison 3: Synthesis of Compound 8l: 2-chloro-5-chloro-N-[2-({(1R)-3-methyl-1-[(5R)-4-oxo-5-phenyl-1,3,2-dioxaborolan-2-yl]butyl}amino)-2-oxoethyl]benzamide 0.46 g of R-mandelic acid (3.0 mmol) was added into a 100 mL round-bottom flask with 10 mL of ethyl acetate, heated to 700 to completely dissolve the R-mandelic acid, and then added with 1.08 g of raw material [(1R)-1-([(2-chloro-5-chloro-benzoyl)amino]acetyl}amino)-3-methylbutyl]boric acid (compound 7-2, 3.0 mmol). The obtained reaction mixture was stirred for 10 minutes, a large amount of white solid was precipitated in the obtained system, the reaction mixture was continuously stirred for half an hour and then cooled down to room temperature, added with 10 mL of n-hexane and stirred for half an hour, and then was subjected to suction filtration, a filter cake was washed with a mixed liquid of the ethyl acetate and the n-hexane, and dried in vacuum, a total of 0.81 g of white solid product 2-chloro-5-chloro-N-[2-({(1R)-3-methyl-1-[(5R)-4-oxo-5-phenyl-1,3,2-dioxaborolan-2-yl]butyl}amino)-2-oxoethyl]benzamide (the compound 8l) was obtained, with a yield of 57%. 1H NMR (400 MHz, DMSO) δ=10.90 (s, 1H), 9.24 (s, 1H), 7.79-7.56 (m, 3H), 7.54-7.21 (m, 5H), 5.19 (s, 1H), 4.36 (d, J=5.2 Hz, 2H), 2.82 (m, 1H), 1.68 (m, 1H), 1.39 (m, 2H), 0.93 (d, J=6.8 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate at 20℃; | 1.4 Step 4: Preparation of compound I-1 Compound I-1-B (210 mg, 0.5 mmol) and compound Ixazomib (180 mg, 0.5 mmol) were dissolved in ethyl acetate (5 mL) and stirred at room temperature overnight.The solid was collected by suction filtration and washed with ethyl acetate to obtain compound I-1 (268 mg, 71%), an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In chloroform-d1 | Synthesis of A7 To a solution of A5 (20 mg, 0.06 mmol) dissolved in 0.6 mL of CDCl3 was added ixazomib (Ixa) (25 mg, 0.069 mmol). The reaction was then left to stir overnight and completion of the reaction was confirmed by 1H NMR. CDCl3 was evaporated under reduced pressure and CHCl3 with ethanol as a stabilizer was added and the solution was filtered with a syringe filter. The product A6 was purified by preparatory GPC in 67% yield (32 mg, 0.040 (0694) [0402] To a vial, yne-MM (170.5 mg, 0.051 mmol, 1.0 eq), A7 (41.0 mg, 0.058 mmol, 1.15 eq), and DCM (5.0 mL) were added. CuOAc (a pinch) was then added and the reaction mixture was stirred under N2 atmosphere. The reaction was complete in ~1 h as determined by LC-MS. The crude mixture was ran through an aluminum oxide plug. The collected solution was concentrated under vacuum, redissolved in CHCl3, filtered through a 0.45 µm filter (Nalgene), and subjected to recycling preparative HPLC. The fractions containing the product were concentrated under vaccum and dried overnight, affording the pure product as a solid (185.5 mg, 90% yield). NMR (500 MHz, CDCl3) d(ppm) 7.71, 7.68, 7.62, 7.44-7.38, 7.33, 6.94-6.90, 6.83, 6.70, 6.57, 6.26, 4.58, 4.51, 4.47, 4.20-4.10, 3.84, 3.74-3.33, 3.23, 3.13, 2.68, 2.64, 2.53, 2.44, 2.33, 2.27, 1.63-1.48, 1.40, 1.31-1.16, 0.88. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: ammonium hydroxide / dichloromethane / -5 °C / pH 9 2.1: benzotriazol-1-ol / dichloromethane / 0.17 h / -5 °C 2.2: -5 °C 3.1: Dihydroxy-isobutyl-boran; methanol / hexane / 0.17 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: benzotriazol-1-ol / dichloromethane / 0.17 h / -5 °C 1.2: -5 °C 2.1: Dihydroxy-isobutyl-boran; methanol / hexane / 0.17 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With methanol; Dihydroxy-isobutyl-boran In hexane for 0.166667h; | 1 Compound 7 (1g, 2.02mmol) was dissolved in MeOH/n-hexane (10mL/4mL), Then add isobutyl boric acid (1.03g, 10.1mmol) and stir for 10 minutes, Then 1N HCl (5.05ml, 5.05mmol) was added. After the reaction is complete, Extract multiple times with n-hexane, combine the aqueous phases, extract multiple times with ethyl acetate, After the organic phases are combined, they are dried over anhydrous sodium sulfate, and the solvent is evaporated to obtain compound 8. The yield is 90%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | In ethyl acetate at 50℃; | 1 Take the compound 2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)hexahydro-4,7-epoxybenzo[d][1,3,2]dioxaborolane-5-carboxylic acid 32 is prepared as an example: Compound 8 (100 mg, 0.28 mmol) and compound 23 (49 mg, 0.28 mmol) were dissolved in anhydrous EA (10 ml) and refluxed at 50°C. After the reaction is completed, the solvent is evaporated to dryness, and compound 32 is prepared under high pressure with a yield of 64%. |
60 % | In ethyl acetate at 50℃; | 4.2.21. 2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)hexahydro- 4,7-epoxybenzo[d][1,3,2]dioxaborole-5-carboxylic acid(18m) To a solution of 3a (49 mg, 0.28 mmol) dissolved in ethyl acetate (5mL) at 50 C, 18a (100 mg, 0.28 mmol) dissolved in ethyl acetate (5 mL)was added dropwise and then the mixture was stirred for 12 h. Themixture was evaporated in vacuo and purified by chromatography togive 18m (80 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 1H),7.55 (d, J = 1.5 Hz, 2H), 4.23 (dd, J = 11.5, 5.8 Hz, 1H), 4.16 (dd, J =9.2, 5.7 Hz, 1H), 4.10 (s, 2H), 4.07 (d, J = 5.6 Hz, 1H), 3.99 (d, J = 5.6Hz, 1H), 2.78 (m, 1H), 2.44 (t, J = 7.7 Hz, 1H), 1.79-1.59 (m, 2H),1.57-1.43 (m, 1H), 1.31-1.20 (m, 2H), 0.84 (d, J = 6.4 Hz, 6H). 13CNMR (100 MHz, DMSO-d6) δ 174.29, 173.41, 166.00, 137.49, 132.02,131.47, 129.47, 81.53, 81.25, 80.72, 78.78, 43.78, 39.08, 27.54, 25.38,23.54, 22.91. HRMS calcd for C21H25BCl2N2O7: [M+Na] 521.1028,found 521.1034. |
60 % | In ethyl acetate at 50℃; | 4.2.21. 2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)hexahydro- 4,7-epoxybenzo[d][1,3,2]dioxaborole-5-carboxylic acid(18m) To a solution of 3a (49 mg, 0.28 mmol) dissolved in ethyl acetate (5mL) at 50 C, 18a (100 mg, 0.28 mmol) dissolved in ethyl acetate (5 mL)was added dropwise and then the mixture was stirred for 12 h. Themixture was evaporated in vacuo and purified by chromatography togive 18m (80 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 1H),7.55 (d, J = 1.5 Hz, 2H), 4.23 (dd, J = 11.5, 5.8 Hz, 1H), 4.16 (dd, J =9.2, 5.7 Hz, 1H), 4.10 (s, 2H), 4.07 (d, J = 5.6 Hz, 1H), 3.99 (d, J = 5.6Hz, 1H), 2.78 (m, 1H), 2.44 (t, J = 7.7 Hz, 1H), 1.79-1.59 (m, 2H),1.57-1.43 (m, 1H), 1.31-1.20 (m, 2H), 0.84 (d, J = 6.4 Hz, 6H). 13CNMR (100 MHz, DMSO-d6) δ 174.29, 173.41, 166.00, 137.49, 132.02,131.47, 129.47, 81.53, 81.25, 80.72, 78.78, 43.78, 39.08, 27.54, 25.38,23.54, 22.91. HRMS calcd for C21H25BCl2N2O7: [M+Na] 521.1028,found 521.1034. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: benzotriazol-1-ol / dichloromethane / 0.17 h / -5 °C 1.2: -5 °C 2.1: dichloromethane / 3.5 h / -5 - 20 °C 3.1: ammonium hydroxide / dichloromethane / -5 °C / pH 9 4.1: benzotriazol-1-ol / dichloromethane / 0.17 h / -5 °C 4.2: -5 °C 5.1: Dihydroxy-isobutyl-boran; methanol / hexane / 0.17 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: dichloromethane / 3.5 h / -5 - 20 °C 2.1: ammonium hydroxide / dichloromethane / -5 °C / pH 9 3.1: benzotriazol-1-ol / dichloromethane / 0.17 h / -5 °C 3.2: -5 °C 4.1: Dihydroxy-isobutyl-boran; methanol / hexane / 0.17 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.4 % | With hydrogenchloride; Dihydroxy-isobutyl-boran In methanol; hexane at 20℃; | To a solution of 17a (2.1 g, 3.9 mmol) and isobutyl boronic acid (1.9g, 19.3 mmol) dissolved in methanol (25 mL) and hexane (25 mL) wasadded 1 N HCl (10 mL). The mixture was stirred at room temperature for22 h. The methanolic phase was washed with hexane (3 × 25 mL), andthe hexane layer was extracted with methanol (3 × 25 mL). The combinedmethanolic layers were evaporated in vacuo, and the residue wasdissolved in DCM (20 mL). The solution was washed with brine (3 × 20mL), and the organic layer was dried over anhydrous Na2SO4, evaporated,and purified by chromatography to give 18a of yellow foam solid(0.8 g, 52.4%). 1H NMR (400 MHz, Methanol-d4) δ 7.61 (d, J = 1.5 Hz,1H), 7.49 (t, J = 1.5 Hz, 2H), 4.25 (s, 2H), 2.79 (t, J = 7.6 Hz, 1H), 1.69(m, 1H), 1.48-1.27 (m, 2H), 0.94 (d, J = 6.6 Hz, 3H). 13C NMR (100MHz, Methanol-d4) δ 174.41, 167.43, 136.53, 132.59, 131.21, 129.35,128.76, 39.50, 38.68, 25.64, 22.37, 21.00. HRMS calcd forC14H19BCl2N2O4:[M+Na] 383.0709, found 383.0724. |
52.4 % | With hydrogenchloride; Dihydroxy-isobutyl-boran In methanol; hexane at 20℃; | To a solution of 17a (2.1 g, 3.9 mmol) and isobutyl boronic acid (1.9g, 19.3 mmol) dissolved in methanol (25 mL) and hexane (25 mL) wasadded 1 N HCl (10 mL). The mixture was stirred at room temperature for22 h. The methanolic phase was washed with hexane (3 × 25 mL), andthe hexane layer was extracted with methanol (3 × 25 mL). The combinedmethanolic layers were evaporated in vacuo, and the residue wasdissolved in DCM (20 mL). The solution was washed with brine (3 × 20mL), and the organic layer was dried over anhydrous Na2SO4, evaporated,and purified by chromatography to give 18a of yellow foam solid(0.8 g, 52.4%). 1H NMR (400 MHz, Methanol-d4) δ 7.61 (d, J = 1.5 Hz,1H), 7.49 (t, J = 1.5 Hz, 2H), 4.25 (s, 2H), 2.79 (t, J = 7.6 Hz, 1H), 1.69(m, 1H), 1.48-1.27 (m, 2H), 0.94 (d, J = 6.6 Hz, 3H). 13C NMR (100MHz, Methanol-d4) δ 174.41, 167.43, 136.53, 132.59, 131.21, 129.35,128.76, 39.50, 38.68, 25.64, 22.37, 21.00. HRMS calcd forC14H19BCl2N2O4:[M+Na] 383.0709, found 383.0724. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate at 50℃; | 4.2.21. 2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)hexahydro- 4,7-epoxybenzo[d][1,3,2]dioxaborole-5-carboxylic acid(18m) General procedure: To a solution of 3a (49 mg, 0.28 mmol) dissolved in ethyl acetate (5mL) at 50 C, 18a (100 mg, 0.28 mmol) dissolved in ethyl acetate (5 mL)was added dropwise and then the mixture was stirred for 12 h. Themixture was evaporated in vacuo and purified by chromatography togive 18m (80 mg, 60%). | |
In ethyl acetate at 50℃; | 4.2.21. 2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)hexahydro- 4,7-epoxybenzo[d][1,3,2]dioxaborole-5-carboxylic acid(18m) General procedure: To a solution of 3a (49 mg, 0.28 mmol) dissolved in ethyl acetate (5mL) at 50 C, 18a (100 mg, 0.28 mmol) dissolved in ethyl acetate (5 mL)was added dropwise and then the mixture was stirred for 12 h. Themixture was evaporated in vacuo and purified by chromatography togive 18m (80 mg, 60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 13 h / -10 - 20 °C 2: Dihydroxy-isobutyl-boran; hydrogenchloride / methanol; hexane / 22 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: trifluoroacetic acid / dichloromethane / 4 h / -5 - 20 °C 2: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 13 h / -10 - 20 °C 3: Dihydroxy-isobutyl-boran; hydrogenchloride / methanol; hexane / 22 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate at 50℃; | 4.2.21. 2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)hexahydro- 4,7-epoxybenzo[d][1,3,2]dioxaborole-5-carboxylic acid(18m) General procedure: To a solution of 3a (49 mg, 0.28 mmol) dissolved in ethyl acetate (5mL) at 50 C, 18a (100 mg, 0.28 mmol) dissolved in ethyl acetate (5 mL)was added dropwise and then the mixture was stirred for 12 h. Themixture was evaporated in vacuo and purified by chromatography togive 18m (80 mg, 60%). | |
In ethyl acetate at 50℃; | 4.2.21. 2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)hexahydro- 4,7-epoxybenzo[d][1,3,2]dioxaborole-5-carboxylic acid(18m) General procedure: To a solution of 3a (49 mg, 0.28 mmol) dissolved in ethyl acetate (5mL) at 50 C, 18a (100 mg, 0.28 mmol) dissolved in ethyl acetate (5 mL)was added dropwise and then the mixture was stirred for 12 h. Themixture was evaporated in vacuo and purified by chromatography togive 18m (80 mg, 60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate at 50℃; | 4.2.21. 2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)hexahydro- 4,7-epoxybenzo[d][1,3,2]dioxaborole-5-carboxylic acid(18m) General procedure: To a solution of 3a (49 mg, 0.28 mmol) dissolved in ethyl acetate (5mL) at 50 C, 18a (100 mg, 0.28 mmol) dissolved in ethyl acetate (5 mL)was added dropwise and then the mixture was stirred for 12 h. Themixture was evaporated in vacuo and purified by chromatography togive 18m (80 mg, 60%). | |
In ethyl acetate at 50℃; | 4.2.21. 2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)hexahydro- 4,7-epoxybenzo[d][1,3,2]dioxaborole-5-carboxylic acid(18m) General procedure: To a solution of 3a (49 mg, 0.28 mmol) dissolved in ethyl acetate (5mL) at 50 C, 18a (100 mg, 0.28 mmol) dissolved in ethyl acetate (5 mL)was added dropwise and then the mixture was stirred for 12 h. Themixture was evaporated in vacuo and purified by chromatography togive 18m (80 mg, 60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 13 h / -10 - 20 °C 2: trifluoroacetic acid / dichloromethane / 4 h / -5 - 20 °C 3: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 13 h / -10 - 20 °C 4: Dihydroxy-isobutyl-boran; hydrogenchloride / methanol; hexane / 22 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate at 50℃; | 4.2.21. 2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)hexahydro- 4,7-epoxybenzo[d][1,3,2]dioxaborole-5-carboxylic acid(18m) General procedure: To a solution of 3a (49 mg, 0.28 mmol) dissolved in ethyl acetate (5mL) at 50 C, 18a (100 mg, 0.28 mmol) dissolved in ethyl acetate (5 mL)was added dropwise and then the mixture was stirred for 12 h. Themixture was evaporated in vacuo and purified by chromatography togive 18m (80 mg, 60%). | |
In ethyl acetate at 50℃; | 4.2.21. 2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)hexahydro- 4,7-epoxybenzo[d][1,3,2]dioxaborole-5-carboxylic acid(18m) General procedure: To a solution of 3a (49 mg, 0.28 mmol) dissolved in ethyl acetate (5mL) at 50 C, 18a (100 mg, 0.28 mmol) dissolved in ethyl acetate (5 mL)was added dropwise and then the mixture was stirred for 12 h. Themixture was evaporated in vacuo and purified by chromatography togive 18m (80 mg, 60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate at 50℃; | 4.2.21. 2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)hexahydro- 4,7-epoxybenzo[d][1,3,2]dioxaborole-5-carboxylic acid(18m) General procedure: To a solution of 3a (49 mg, 0.28 mmol) dissolved in ethyl acetate (5mL) at 50 C, 18a (100 mg, 0.28 mmol) dissolved in ethyl acetate (5 mL)was added dropwise and then the mixture was stirred for 12 h. Themixture was evaporated in vacuo and purified by chromatography togive 18m (80 mg, 60%). | |
In ethyl acetate at 50℃; | 4.2.21. 2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)hexahydro- 4,7-epoxybenzo[d][1,3,2]dioxaborole-5-carboxylic acid(18m) General procedure: To a solution of 3a (49 mg, 0.28 mmol) dissolved in ethyl acetate (5mL) at 50 C, 18a (100 mg, 0.28 mmol) dissolved in ethyl acetate (5 mL)was added dropwise and then the mixture was stirred for 12 h. Themixture was evaporated in vacuo and purified by chromatography togive 18m (80 mg, 60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate at 50℃; | 4.2.21. 2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)hexahydro- 4,7-epoxybenzo[d][1,3,2]dioxaborole-5-carboxylic acid(18m) General procedure: To a solution of 3a (49 mg, 0.28 mmol) dissolved in ethyl acetate (5mL) at 50 C, 18a (100 mg, 0.28 mmol) dissolved in ethyl acetate (5 mL)was added dropwise and then the mixture was stirred for 12 h. Themixture was evaporated in vacuo and purified by chromatography togive 18m (80 mg, 60%). | |
In ethyl acetate at 50℃; | 4.2.21. 2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)hexahydro- 4,7-epoxybenzo[d][1,3,2]dioxaborole-5-carboxylic acid(18m) General procedure: To a solution of 3a (49 mg, 0.28 mmol) dissolved in ethyl acetate (5mL) at 50 C, 18a (100 mg, 0.28 mmol) dissolved in ethyl acetate (5 mL)was added dropwise and then the mixture was stirred for 12 h. Themixture was evaporated in vacuo and purified by chromatography togive 18m (80 mg, 60%). |
Tags: 1072833-77-2 synthesis path| 1072833-77-2 SDS| 1072833-77-2 COA| 1072833-77-2 purity| 1072833-77-2 application| 1072833-77-2 NMR| 1072833-77-2 COA| 1072833-77-2 structure
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H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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