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CAS No. : | 91271-65-7 | MDL No. : | MFCD04974050 |
Formula : | C12H17NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MWVQMAWLNHACQK-UHFFFAOYSA-N |
M.W : | 207.27 | Pubchem ID : | 2795499 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 62.55 |
TPSA : | 32.7 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) : | -7.07 cm/s |
Log Po/w (iLOGP) : | 2.52 |
Log Po/w (XLOGP3) : | 0.69 |
Log Po/w (WLOGP) : | 0.33 |
Log Po/w (MLOGP) : | 0.86 |
Log Po/w (SILICOS-IT) : | 2.13 |
Consensus Log Po/w : | 1.31 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.66 |
Solubility : | 4.56 mg/ml ; 0.022 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.95 |
Solubility : | 23.0 mg/ml ; 0.111 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.82 |
Solubility : | 0.311 mg/ml ; 0.0015 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.51 |
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 |
---|---|---|
70% | With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 120℃; for 0.333333h; Microwave irradiation; | B.27 To a mixture of intermediate compound 11 (200 mg, 0.64 mmol), intermediate compound 24 (267 mg, 1.28 mmol) and PPh3 (309 mg, 1.15 mmol) in THF (5 ml) was added di-tert-butylazodicarboxylate (279 mg, 1.21 mmol). The reaction mixture was microwaved at 120 0C over 20 min. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (eluting with a solvent gradient 10-20 % DCM / MeOH(NH3) to give the final compound 1-271 (219.7 mg, 70 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 2h; | The reaction was carried out under N2 atmosphere. To a solution of intermediate compound 23 (2 g, 0.0085 mol) in THF (12 ml), lithium aluminum hydride (1 M in THF) (17 ml, 0.017 mol) was slowly added. The reaction mixture was stirred at room temperature for 2 hours. Then, a saturated solution OfNaHCO3 was carefully added and the mixture was extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to yield intermediate compound 24 (1.75 g, 100 %) which was used in the next reaction step without further purification. |
85% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 2h; | To a solution of compound Int-44 (9 g, 38.3 mmol, 1.0 eq) in THF (45 mL) was added LiAlEE (2.9 g, 76.6 mmol, 2.0 eq) at 0 C and the mixture was stirred at room temperature for 2 h. TLC showed that the reaction reached completion. The mixture was cooled to 0C and quenched with H2O (2.9 mL), 15% aqueous NaOH. MgSCE was added and the mixture was filtered through diatomite. The filter cake was washed with EtOAc (50 mL) and the filtrate was concentrated under reduced pressure to afford compound Int-45 (6.76 g, 85%) as a white solid. |
74% | With methanol; sodium tetrahydroborate; In tetrahydrofuran; at 0℃; for 2h;Inert atmosphere; Reflux; | Step 2) (4-Morpholin-4-ylmethyl-phenyl)-methanol Sodium borohydride (2.57 g, 68 mmol) was added to a stuffed solution of 4-morpholin-4- ylmethyl-benzoic acid methyl ester (2g, 8.5 mmol) in a mixture of THF: MeOH (8:1) (56 mL) at0C under a nitrogen atmosphere. The reaction mixture was heated to reflux for 2 h. It was quenched with saturated ammonium chloride solution at 0 C and stuffed for 30 mm. It was extracted with ethyl acetate (2OmLX2), dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by column chromatography (silica gel, 2% MeOH/DCM) to give (4-morpholin-4-ylmethyl-phenyl)-methanol (1.3g, 74 %) as a white solid solid. MS calcd. for C12H17N02 [(M+H)’i 208, obsd. 208.1. |
52% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; | To a suspension of 33.9 g of LAH in 1.6L of dry THF under N2 at [0C] was added drop wise a solution of methyl [4-METHYLMORPHOLINOBENZOATE] in 233mL of dry THF over 30 min. The temperature remained under [15C] during the addition. The reaction was allowed to stir at rt overnight. It was then cooled to [0C] and quenched with 220mL of 10% aqueous [NAOH.] The [NAOH] was added drop wise (over 30 min) keeping the temperature below [10C.] It was then warmed up to rt and stirred for 2 h. The precipitate formed was filtered off and washed with 200mL of THF. The filtrate was concentrated affording a white solid that was taken up in EtOAc [(1L)] and heated up at [65C] for 45 min then cooled down to rt. The EtOAc solution was washed with brine (250mL). Then 700mL of the solvent were removed to give a suspension of the product and 300mL of hexane were added. The solution was cooled down to [4C] and held for 12 h. The crystals were filtered off and washed with a cold 1: 1 mixture of [ETOAC/ : HEXANE] (200mL) then dried at [40C] under vacuum overnight, affording 107.5 g of the title compound as white crystals [(52%] yield from methyl p-toluate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 20℃; for 5h; | 4.A {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}- acetic acid ethyl ester (274 mg; 0.58 mmol) was dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. (4-Morpholin-4-ylmethyl-phenyl)-methanol (100 mg;0.48 mmol) and tributylphosphine (0.21 mL; 0.87 mmol) was added followed by l,l'-(Azodi- carbonyl)dipiperidine (0.22 g; 0.87 mmol) dissolved in THF (10 mL). The reaction mixture was stirred at room temperature for 5 h, filtered and evaporated in vacuo. The crude product was purified by prep. HPLC (method A). Yield: 250 mg. HPLC-MS: m/z: 663.0 (M+H); Rt:2.47 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With manganese(IV) oxide; In dichloromethane; at 20℃; for 72h; | Step 3) 4-Morpholin-4-ylmethyl-benzaldehyde Manganese dioxide (3.28 g, 37.67 mmol) was added to a stirred solution of (4-morpholin-4- ylmethyl-phenyl)-methanol (1.3g, 6.28 mmol) in methylene dichloride (120 mL) at rt and stirred for 72 h. The reaction mixture was filtered through sintered funnel using celite and washed with methylene dichloride (50 mL). The solvent was evaporated under reduced pressure and purifiedby column chromatography (silica gel, 20% EtOAc/Hexanes) to give 4-morpholin-4-ylmethyl- benzaldehyde (1.2 g, 93%) as a white solid. MS calcd. for C12H15N02 [(M+H)?i 206, obsd. |
88% | Protection of the nitrogen at -70 C (COCl)2 (152mg, 1.2mmol) was added to DMSO (156mg, 2.0mmol) in DCM (10 mL), and stirring was continued to maintain a temperature of -70 C for 30 minutes, followed by addition of 4-(morpholinylmethyl)benzyl alcohol (207mg, 1.0mmol) 3mL DCM the solution stirred for 1 hour. Instillation of Et3N (405mg, 4.0mmol), maintaining the temperature at -70 C and stirring was continued for 1 hour was raised to 25 C, dropwise addition of water (10 mL) to quench the reaction, was added NaHCO3 solution (5mL). Liquid separation, the aqueous phase was extracted with 10mLDCM combined organic phase was concentrated after column chromatography (PE:EtOAc = 2:1) as a pale yellow oily product A405A (180mg, yield: 88%). | |
81% | To a solution of 4-bromoethyl-benzoic acid ethyl ester (4.0 g, 16.46 mmol) in THF (30 mL), morpholine (2.87 g, 32.92 mmol) was added and the reaction mixture was stirred for 48 h at room temperature. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over Na2SO4. The solvent was removed to give 3.4 g of crude product in 83% yield.LAH (0.571 g, 15.05 mmol) was added to a 3-neck dry flask and THF (50 mL) was added on cooling. A solution of 4-morpholin-4-ylmethyl)-benzoic acid ethyl ester (3.0 g, 12.04 mmol) in THF (10 mL) was added slowly on cooling. After completion of addition, the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled to 0 C. and a 10% NaOH solution was added carefully followed by water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed to give (4-morpholin-4-ylmethyl phenyl)methanol (2.0 g, 80%). To the 3-flask anhydrous CH2Cl2 (100 mL) was added and cooled to -78 C. Oxalyl chloride (1.47 g, 11.59 mmol) and DMSO (1.5 g, 19.32 mmol) were added at -78 C. The reaction mixture was stirred for 15 min at -78 C. A solution of (4-morpholin-4-ylmethyl phenyl)methanol (2.0 g, 9.66 mmol) in CH2Cl2 (10 mL) was added at -78 C. and the mixture was stirred at -78 C. for 1 h. Then, Et3N (3.9 g, 38.64 mmol) was added. The reaction mixture was allowed to come at room temperature. Water was added and the organic layer was isolated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, brine and dried over Na2SO4. Then solvent was removed to give crude 4-morpholin-4-ylmethyl benzaldehyde (1.6 g, 81%).To a solution of 2-amino-4,6-dimethoxy-benzamide (150 mg, 0.76 mmol) and 4-morpholin-4-ylmethyl benzaldehyde (156 mg, 0.76 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (150 mg, 0.84 mmol) and p-TSA (174 mg, 0.91 mmol) were added and the reaction mixture was heated at 150 C. for 5 h. The reaction mixture was cooled to room temperature, water was added and the mixture was neutralized with NaHCO3. The solvent was removed under reduced pressure to give the crude product, which was purified by column chromatography to give 5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one, which was converted to the hydrochloride salt (165 mg, 51%). Selected data: MS (ES) m/z: 382.07; MP 206-208 C. (at decomposition). |
With oxalyl dichloride; dimethyl sulfoxide; In dichloromethane; at -78℃; for 1h; | To the 3-flask anhydrous CH2Cl2 (100 mL) was added and cooled to -78 C. Oxalyl chloride (1.47 g, 11.59 mmol) and DMSO (1.5 g, 19.32 mmol) were added at -78 C. The reaction mixture was stirred for 15 min at -78 C. A solution of (4-morpholin-4-ylmethyl phenyl)methanol (2.0 g, 9.66 mmol) in CH2Cl2 (10 mL) was added at -78 C. and the mixture was stirred at -78 C. for 1 h. Then, Et3N (3.9 g, 38.64 mmol) was added. The reaction mixture was allowed to come at room temperature. Water was added and the organic layer was isolated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, brine and dried over Na2SO4. Then solvent was removed to give crude 4-morpholin-4-ylmethyl benzaldehyde (1.6 g, 81%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With lithium aluminium tetrahydride In tetrahydrofuran for 3h; Heating / reflux; | 66 To a solution of 4-bromoethyl-benzoic acid ethyl ester (4.0 g, 16.46 mmol) in THF (30 mL), morpholine (2.87 g, 32.92 mmol) was added and the reaction mixture was stirred for 48 h at room temperature. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over Na2SO4. The solvent was removed to give 3.4 g of crude product in 83% yield.LAH (0.571 g, 15.05 mmol) was added to a 3-neck dry flask and THF (50 mL) was added on cooling. A solution of 4-morpholin-4-ylmethyl)-benzoic acid ethyl ester (3.0 g, 12.04 mmol) in THF (10 mL) was added slowly on cooling. After completion of addition, the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled to 0° C. and a 10% NaOH solution was added carefully followed by water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed to give (4-morpholin-4-ylmethyl phenyl)methanol (2.0 g, 80%). To the 3-flask anhydrous CH2Cl2 (100 mL) was added and cooled to -78° C. Oxalyl chloride (1.47 g, 11.59 mmol) and DMSO (1.5 g, 19.32 mmol) were added at -78° C. The reaction mixture was stirred for 15 min at -78° C. A solution of (4-morpholin-4-ylmethyl phenyl)methanol (2.0 g, 9.66 mmol) in CH2Cl2 (10 mL) was added at -78° C. and the mixture was stirred at -78° C. for 1 h. Then, Et3N (3.9 g, 38.64 mmol) was added. The reaction mixture was allowed to come at room temperature. Water was added and the organic layer was isolated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, brine and dried over Na2SO4. Then solvent was removed to give crude 4-morpholin-4-ylmethyl benzaldehyde (1.6 g, 81%).To a solution of 2-amino-4,6-dimethoxy-benzamide (150 mg, 0.76 mmol) and 4-morpholin-4-ylmethyl benzaldehyde (156 mg, 0.76 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (150 mg, 0.84 mmol) and p-TSA (174 mg, 0.91 mmol) were added and the reaction mixture was heated at 150° C. for 5 h. The reaction mixture was cooled to room temperature, water was added and the mixture was neutralized with NaHCO3. The solvent was removed under reduced pressure to give the crude product, which was purified by column chromatography to give 5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one, which was converted to the hydrochloride salt (165 mg, 51%). Selected data: MS (ES) m/z: 382.07; MP 206-208° C. (at decomposition). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis of 4-(4-morpholin-4-ylmethyl-benzylsulfanyl)-benzoic acid methyl ester (1). A solution of (4-(morpholinomethyl)phenyl)methanol (207 mg, 1.0 mmol) and DIEA (192 mul, 1.1 mmol) in DCM (3 ml) was cooled to 0 C followed by the addition of MsCl (94 mul, 1.2 mmol). Reaction mixture was maintained at 0 C for 1 h followed by the addition of mixture of DIEA ( 192 mul, 1.1 mmol) and methyl-4-mercaptobenzoate (185 mg, 1.1 mmol). Temperature of the reaction mixture was allowed to rise to ambient. Reaction mixture was maintained at ambient temperature 40 min and diluted with EtOAc (80 ml). Organic layer was washed with 5% NaHCO3 (20 ml) and brine (20 ml) and dried over MgSO4 (anh.). Solvent was evaporated in vacuum. Residue (1) was used as is for the next transformation. LC-MS [M+H] 358.1 (C20H23NO3S +H, requires 358.49). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.1% | Stage #1: (4-morpholin-4-ylmethyl-phenyl)-methanol With sodium hydride In acetonitrile at 20℃; for 1h; Stage #2: (2-chloropyrimidin-4-yl)(4-ethyl-3H-thiazol-2ylidene)acetonitrile at 80℃; for 5h; Stage #3: trifluoroacetic acid | I; 129 Procedure I Example 129: (4-ethyl-1,3-thiazol-2(3H)-ylidene)(2-[4-(morpholin-4- [YLMETHYL) BENZYLLOXY} PYRIMIDIN-4-YL) ACETONITRILE] To a suspension of NaH (99 mg, 2.27 mmol) in ACN (4 mL) was added a solution of [N- (4-] [HYDROXYMETHYLBENZYL)] morpholine (313 mg, 1.51 [NMOL)] in ACN (4 [ML).] The mixture was stirred lh at [IT.] Then [(2-CHLOROPYRIMIDIN-4-YL)] (4-ethyl-1, [3-THIAZOL-2] (3H) - ylidene) acetonitrile (200mg, 0.76 mmol) was added portionwise. The resulting mixture was heated up at [80°C] for 5h. After cooling down to rt the ACN was evaporated. EtOAc [(5ML)] was added to the residue. After one night at [4°C,] the yellow solid was filtered off affording the title compound as a free base (HPLC (max plot) 73.9%). The solid was taken up in DCM and excess TFA then ether were added. The precipitate formed was [FITERED] off, washed with ether (3X) then dried under reduced pressure at [40°C] overnight, affording 409 mg of the title compound as a diTFA salt (Yellow powder, Y = 81. [1 %)] [H] NMR (DMSO-d6) 8 10.26 (br s, 1H), 7.76 (br d, [1H),] 7.61 (d, J= 7.9Hz, 2H), 7.53 (d, [J] [=] 7.9Hz, 2H), 6.90 (s, [1H),] 6.61 (br d, [1H),] 5.64 (s, 2H), 4.36 (s, 2H), 4.03-3. 85 [(M,] 2H), 3.74-3. 53 [(M,] 2H), 3.32-3. 04 (m, 4H), 2.66 (q, [J=] 7. 5Hz, 2H), 1.19 (br t, 3H). M+ (ES): 436.0 ; HPLC (max plot) 98.2% ; Rt: 1.82 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: (4-morpholin-4-ylmethyl-phenyl)-methanol With sodium hydride In tetrahydrofuran for 0.5h; Stage #2: p-toluenesulfonyl chloride In tetrahydrofuran at 20℃; for 2h; | 17.1 Step 1: 4-(morpholinomethyl)benzyl 4-methylbenzenesulfonate (4-(morpholinomethyl)phenyl)methanol (0.108 g, 0.52 mmol) and NaH 60% in mineral oil (13 mg, 0.52 mmol) in THF (2 mL) were stirred for 30 min. Tosyl Chloride (60 mg, 0.52 mmol) was added to this solution and stirred at room temperature for 2 hours. The crude reaction mixture was used in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: di-isopropyl azodicarboxylate / tetrahydrofuran / 0.75 h / 0 - 20 °C 1.2: 0 - 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.17 h / 0 °C | ||
Multi-step reaction with 2 steps 1.1: triphenylphosphine / tetrahydrofuran / 0.25 h / 20 °C 1.2: 0.5 h / 0 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.17 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride In dichloromethane at 20℃; for 3h; | 97A Example 97A4-[4-(Chloromethyl)benzyl]morpholine hydrochloride; At RT, 0.219 ml (3.00 mmol) of thionyl chloride was added to a solution of 207 mg (1.00 mmol) of [4-(morpholin-4-ylmethyl)phenyl]methanol in 7.5 ml of dichloromethane, and the mixture was then stirred at this temperature for 3 h. The mixture was then concentrated on a rotary evaporator, 10 ml of dichloromethane were added to the residue and the mixture was concentrated again. Addition of dichloromethane and concentration were then repeated three more times. 259 mg (93% of theory, purity 94%) in total of the title compound were obtained.1H-NMR (400 MHz, CDCl3, δ/ppm): 13.38 (s, broad, 1H), 7.71 (d, 2H), 7.49 (d, 2H), 4.60 (s, 2H), 4.38-4.26 (t, 2H), 4.16 (d, 2H), 3.98-3.90 (dd, 2H), 3.32 (d, 2H), 2.92-2.80 (m, 2H).LC/MS (method D, ESIpos): Rt=0.96 min, m/z=226/228 [M+H]+. | |
With thionyl chloride In dichloromethane at 0 - 25℃; | 11A Step A: 4-(morpholinomethyl)benzyl alcohol 1.5g, 7.2mmol) was dissolved in dichloromethane (20 mL), and cooled to 0 °C, was slowly added dropwise thionylchloride (2.6g, 21.8mmol), after completion of the dropwise addition, the reaction at 25 °C overnight. LCMS the reaction was complete. The reaction mixture was concentrated to give a white solid 4-(4-chloromethyl) phenyl morpholine hydrochloride 1.9g crude). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 48 h / 20 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / Reflux | ||
Multi-step reaction with 2 steps 1: tetrahydrofuran / 16 h / 20 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 1 h / -78 °C 2: sodium hydrogensulfite; toluene-4-sulfonic acid / N,N-dimethyl acetamide / 5 h / 150 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.0 g | With lithium aluminium tetrahydride In tetrahydrofuran for 3h; Reflux; | 61 LAH (0.571 g, 15.05 mmol) was added to a 3-neck dry flask and THF (50 mL) was added on cooling. A solution of 4-morpholin-4-ylmethyl)-benzoic acid ethyl ester (3.0 g, 12.04 mmol) in THF (10 mL) was added slowly on cooling. After completion of addition, the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled to 0° C. and a 10% NaOH solution was added carefully followed by water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed to give (4-morpholin-4-ylmethyl phenyl)methanol (2.0 g, 80%). To the 3-flask anhydrous CH2Cl2 (100 mL) was added and cooled to -78° C. Oxalyl chloride (1.47 g, 11.59 mmol) and DMSO (1.5 g, 19.32 mmol) were added at -78° C. The reaction mixture was stirred for 15 min at -78° C. A solution of (4-morpholin-4-ylmethyl phenyl)methanol (2.0 g, 9.66 mmol) in CH2Cl2 (10 mL) was added at -78° C. and the mixture was stirred at -78° C. for 1 h. Then, Et3N (3.9 g, 38.64 mmol) was added. The reaction mixture was allowed to come at room temperature. Water was added and the organic layer was isolated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, brine and dried over Na2SO4. Then solvent was removed to give crude 4-morpholin-4-ylmethyl benzaldehyde (1.6 g, 81%). |
With lithium aluminium tetrahydride In tetrahydrofuran for 3h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Stage #1: 3-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione With di-isopropyl azodicarboxylate In tetrahydrofuran at 0 - 20℃; for 0.75h; Stage #2: (4-morpholin-4-ylmethyl-phenyl)-methanol In tetrahydrofuran at 0 - 20℃; Stage #3: methanol In dichloromethane | 6.1.6.1 6.1.6 Step 1: To the solution of 3-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (2.5 g, 8.56 mmol) in THF (60 mL) was added triphenyl phosphine (polymer supported 1.6 mmol/g, 12 g, 18.8 mmol). The mixture was stirred at room temperature for 15 minutes. Diisopropyl azodicarboxylate (3.96 mL, 18.8 mmol) was added at 0° C., and the mixture was stirred at 0° C. for 30 minutes. (4-Morpholin-4-ylmethyl-phenyl)-methanol (2.62 g, 12.4 mmol) was added at 0° C., and the mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated. The resulting oil was purified on silica gel column eluted with methylene chloride and methanol (gradient, product came out at 6% methanol) to give 4-carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyric acid methyl ester (2.2 g, 54% yield). The product was used in the next step without further purification. |
54% | Stage #1: 3-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione With triphenylphosphine In tetrahydrofuran at 20℃; for 0.25h; Stage #2: With di-isopropyl azodicarboxylate In tetrahydrofuran at 0℃; for 0.5h; Stage #3: methanol; (4-morpholin-4-ylmethyl-phenyl)-methanol Further stages; | 1.6.1 To the solution of 3-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (2.5 g, 8.56 mmol) in THF (60 mL) was added triphenyl phosphine (polymer supported 1.6 mmol/g, 12 g, 18.8 mmol). The mixture was stirred at room temperature for 15 minutes. Diisopropyl azodicarboxylate (3.96 mL, 18.8 mmol) was added at 0° C., and the mixture was stirred at 0° C. for 30 minutes. (4-Morpholin-4-ylmethyl-phenyl)-methanol (2.62 g, 12.4 mmol) was added at 0° C. and the mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated. The resulting oil was purified on silica gel column eluted with methylene chloride and methanol (gradient, product came out at 6% methanol) to give 4-carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyric acid methyl ester (2.2 g, 54% yield). The product was used in the next step without further purification. |
Stage #1: 3-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione With di-isopropyl azodicarboxylate In tetrahydrofuran at 0℃; for 0.5h; Stage #2: (4-morpholin-4-ylmethyl-phenyl)-methanol In tetrahydrofuran at 0 - 20℃; Stage #3: methanol In dichloromethane | 1 Step 1 : To the solution of 3-(4-hydroxy-l-oxo-l,3-dihydro-isoindol-2-yl)-piperidine- 2,6-dione (2.5g, 8.56 mmol) in THF (60 mL) was added triphenyl phosphine (polymer supported 1.6mmol/g, 12 g, 18.8 mmol). The mixture was stirred at room temperature for 15 minutes. Diisopropyl azodicarboxylate (3.96 mL, 18.8 mmol) was added at 0°C, and the mixture was stirred at OoC for 30 minutes. (4-Morpholin-4-ylmethyl-phenyl)-methanol (2.62 g,12.4 mmol) was added at 0°C, and the mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated. The resulting oil was purified on silica gel column eluted with methylene chloride and methanol (gradient, product came out at 6% methanol) to give 4-carbamoyl-4-[4-(4-morpholin-4-ylmethyl- benzyloxy)-l-oxo-l,3-dihydro-isoindol-2-yl]-butyric acid methyl ester (2.2 g, 54% yield). The product was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 12 h / 0 °C 2: sodium tetrahydroborate; methanol / tetrahydrofuran / 2 h / 0 °C / Inert atmosphere; Reflux | ||
Multi-step reaction with 2 steps 1: tetrahydrofuran / 100 °C / Cooling with ice; Microwave irradiation 2: lithium aluminium tetrahydride / tetrahydrofuran / 20 °C / Cooling with ice | ||
Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 3 h / 0 - 20 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 2 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: manganese(IV) oxide / dichloromethane / 72 h / 20 °C 2: sodium methylate / methanol / 0.5 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: manganese(IV) oxide / dichloromethane / 72 h / 20 °C 2: sodium methylate / methanol / 0.5 h / 0 °C 3: 5,5-dimethyl-1,3-cyclohexadiene / 14 h / 20 - 90 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: manganese(IV) oxide / dichloromethane / 72 h / 20 °C 2.1: sodium methylate / methanol / 0.5 h / 0 °C 3.1: 5,5-dimethyl-1,3-cyclohexadiene / 14 h / 20 - 90 °C 4.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 4.2: 12 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: manganese(IV) oxide / dichloromethane / 72 h / 20 °C 2.1: sodium methylate / methanol / 0.5 h / 0 °C 3.1: 5,5-dimethyl-1,3-cyclohexadiene / 14 h / 20 - 90 °C 4.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 4.2: 12 h / 20 °C 5.1: n-butyllithium; diisopropylamine / tetrahydrofuran / 0.5 h / -78 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: manganese(IV) oxide / dichloromethane / 72 h / 20 °C 2.1: sodium methylate / methanol / 0.5 h / 0 °C 3.1: 5,5-dimethyl-1,3-cyclohexadiene / 14 h / 20 - 90 °C 4.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 4.2: 12 h / 20 °C 5.1: n-butyllithium; diisopropylamine / tetrahydrofuran / 0.5 h / -78 °C 6.1: toluene / 12 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: manganese(IV) oxide / dichloromethane / 72 h / 20 °C 2.1: sodium methylate / methanol / 0.5 h / 0 °C 3.1: 5,5-dimethyl-1,3-cyclohexadiene / 14 h / 20 - 90 °C 4.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 4.2: 12 h / 20 °C 5.1: n-butyllithium; diisopropylamine / tetrahydrofuran / 0.5 h / -78 °C 6.1: toluene / 12 h / 20 °C 7.1: ethanol / 16 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: manganese(IV) oxide / dichloromethane / 72 h / 20 °C 2.1: sodium methylate / methanol / 0.5 h / 0 °C 3.1: 5,5-dimethyl-1,3-cyclohexadiene / 14 h / 20 - 90 °C 4.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 4.2: 12 h / 20 °C 5.1: n-butyllithium; diisopropylamine / tetrahydrofuran / 0.5 h / -78 °C 6.1: toluene / 12 h / 20 °C 7.1: ethanol / 16 h / Reflux 8.1: caesium carbonate / tetrahydrofuran; methanol / 18 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: manganese(IV) oxide / dichloromethane / 72 h / 20 °C 2.1: sodium methylate / methanol / 0.5 h / 0 °C 3.1: 5,5-dimethyl-1,3-cyclohexadiene / 14 h / 20 - 90 °C 4.1: sodium hydride / tetrahydrofuran; mineral oil; N,N-dimethyl-formamide / 0.5 h / 0 °C 4.2: 1 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: manganese(IV) oxide / dichloromethane / 72 h / 20 °C 2.1: sodium methylate / methanol / 0.5 h / 0 °C 3.1: 5,5-dimethyl-1,3-cyclohexadiene / 14 h / 20 - 90 °C 4.1: sodium hydride / tetrahydrofuran; mineral oil; N,N-dimethyl-formamide / 0.5 h / 0 °C 4.2: 1 h / 0 - 20 °C 5.1: lithium diisopropyl amide / tetrahydrofuran / 0.58 h / -78 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: manganese(IV) oxide / dichloromethane / 72 h / 20 °C 2.1: sodium methylate / methanol / 0.5 h / 0 °C 3.1: 5,5-dimethyl-1,3-cyclohexadiene / 14 h / 20 - 90 °C 4.1: sodium hydride / tetrahydrofuran; mineral oil; N,N-dimethyl-formamide / 0.5 h / 0 °C 4.2: 1 h / 0 - 20 °C 5.1: lithium diisopropyl amide / tetrahydrofuran / 0.58 h / -78 °C 6.1: toluene / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: manganese(IV) oxide / dichloromethane / 72 h / 20 °C 2.1: sodium methylate / methanol / 0.5 h / 0 °C 3.1: 5,5-dimethyl-1,3-cyclohexadiene / 14 h / 20 - 90 °C 4.1: sodium hydride / tetrahydrofuran; mineral oil; N,N-dimethyl-formamide / 0.5 h / 0 °C 4.2: 1 h / 0 - 20 °C 5.1: lithium diisopropyl amide / tetrahydrofuran / 0.58 h / -78 °C 6.1: toluene / 0.5 h / 20 °C 7.1: potassium carbonate / ethanol / 2 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: manganese(IV) oxide / dichloromethane / 72 h / 20 °C 2.1: sodium methylate / methanol / 0.5 h / 0 °C 3.1: 5,5-dimethyl-1,3-cyclohexadiene / 14 h / 20 - 90 °C 4.1: sodium hydride / tetrahydrofuran; mineral oil; N,N-dimethyl-formamide / 0.5 h / 0 °C 4.2: 1 h / 0 - 20 °C 5.1: lithium diisopropyl amide / tetrahydrofuran / 0.58 h / -78 °C 6.1: toluene / 0.5 h / 20 °C 7.1: potassium carbonate / ethanol / 2 h / 80 °C 8.1: hydrogenchloride / ethanol; water / 0.17 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: oxalyl dichloride / dichloromethane; dimethyl sulfoxide / -78 °C 1.2: -78 - 20 °C 2.1: sulfuric acid / 72 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Stage #1: 4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydroisoindol-2-yl)butyric acid methyl ester In tetrahydrofuran at 20℃; for 0.25h; Stage #2: With di-isopropyl azodicarboxylate In tetrahydrofuran at 0℃; for 0.5h; Stage #3: (4-morpholin-4-ylmethyl-phenyl)-methanol In tetrahydrofuran at 0 - 20℃; | 6.1.6.1 [001 50j Step 1: To the solution of 3 -(4-hydroxy- 1 -oxo- 1,3 -dihydro-isoindol-2-yl)- piperidine-2,6-dione (2.5g, 8.56 mmol) in THF (60 mL) was added triphenyl phosphine (polymer supported 1 .6mmol/g, 12 g, 18.8 mmol). The mixture was stirred at room temperature for 15 minutes. Diisopropyl azodicarboxylate (3.96 mL, 18.8 mmol) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes. (4-Morpholin-4-ylmethyl-phenyl)- methanol (2.62 g,12.4 mmol) was added at 0°C, and the mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated. The resulting oil was purified on silica gel colunm eluted with methylene chloride and methanol (gradient, product came out at 6% methanol) to give 4-carbamoyl-4- [4-(4-morpholin-4-ylmethyl-benzyloxy)- 1 -oxo- 1,3 -dihydro-isoindol-2- yl]-butyric acid methyl ester (2.2 g, 54% yield). The product was used in the next step without further purification. |
54% | Stage #1: 4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydroisoindol-2-yl)butyric acid methyl ester With di-isopropyl azodicarboxylate In tetrahydrofuran at 0 - 20℃; for 0.75h; Stage #2: (4-morpholin-4-ylmethyl-phenyl)-methanol In tetrahydrofuran at 0 - 20℃; | 6.1.6.1 (6) 3-(4-((4-(morpholinomethyl)benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1 : To the solution of 3-(4-hydroxy-l-oxo-l, 3-dihydro-isoindol-2-yl)- piperidine-2, 6-dione (2.5g, 8.56 mmol) in THF (60 mL) was added triphenyl phosphine (polymer supported 1.6mmol/g, 12 g, 18.8 mmol). The mixture was stirred at room temperature for 15 minutes. Diisopropyl azodicarboxylate (3.96 mL, 18.8 mmol) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes. (4-Morpholin-4-ylmethyl-phenyl)- methanol (2.62 g,12.4 mmol) was added at 0°C, and the mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated. The resulting oil was purified on silica gel column eluted with methylene chloride and methanol (gradient, product came out at 6% methanol) to give 4-carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-l-oxo-l,3-dihydro-isoindol-2- yl]-butyric acid methyl ester (2.2 g, 54% yield). The product was used in the next step without further purification. |
54% | Stage #1: 4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydroisoindol-2-yl)butyric acid methyl ester With di-isopropyl azodicarboxylate In tetrahydrofuran at 0 - 20℃; for 0.75h; Stage #2: (4-morpholin-4-ylmethyl-phenyl)-methanol In tetrahydrofuran at 0 - 20℃; | 6.1.6.1 (6) 3-(4-((4-(morpholinomethyl)benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione Step 1 : To the solution of 3-(4-hydroxy-l-oxo-l, 3-dihydro-isoindol-2-yl)- piperidine-2, 6-dione (2.5g, 8.56 mmol) in THF (60 mL) was added triphenyl phosphine (polymer supported 1.6mmol/g, 12 g, 18.8 mmol). The mixture was stirred at room temperature for 15 minutes. Diisopropyl azodicarboxylate (3.96 mL, 18.8 mmol) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes. (4-Morpholin-4-ylmethyl-phenyl)- methanol (2.62 g,12.4 mmol) was added at 0°C, and the mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated. The resulting oil was purified on silica gel column eluted with methylene chloride and methanol (gradient, product came out at 6% methanol) to give 4-carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-l-oxo-l,3-dihydro-isoindol-2- yl]-butyric acid methyl ester (2.2 g, 54% yield). The product was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: di-isopropyl azodicarboxylate / tetrahydrofuran / 0.5 h / 0 °C 1.2: 0 - 20 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.17 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: oxalyl dichloride / dichloromethane; dimethyl sulfoxide / 1.5 h / -70 °C / Inert atmosphere 1.2: 1 h / -70 - 25 °C / Inert atmosphere 2.1: acetic acid / dichloromethane / 1 h / 30 °C 2.2: 18 h / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: oxalyl dichloride / dichloromethane; dimethyl sulfoxide / 1.5 h / -70 °C / Inert atmosphere 1.2: 1 h / -70 - 25 °C / Inert atmosphere 2.1: acetic acid / methanol / 40 °C / Inert atmosphere 2.2: 5 h / 760.05 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: oxalyl dichloride / dichloromethane; dimethyl sulfoxide / 1.5 h / -70 °C / Inert atmosphere 1.2: 1 h / -70 - 25 °C / Inert atmosphere 2.1: acetic acid / methanol / 40 °C / Inert atmosphere 2.2: 5 h / 760.05 Torr 3.1: thionyl chloride / tetrahydrofuran; dichloromethane / 2 h / -40 °C / Inert atmosphere 3.2: 0.5 h / -40 °C / Inert atmosphere 3.3: 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: oxalyl dichloride / dichloromethane; dimethyl sulfoxide / 1.5 h / -70 °C / Inert atmosphere 1.2: 1 h / -70 - 25 °C / Inert atmosphere 2.1: acetic acid / dichloromethane / 3 h / 25 °C 2.2: 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: thionyl chloride / dichloromethane / 0 - 25 °C 2: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: thionyl chloride / dichloromethane / 0 - 25 °C 2: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 4 h / 0 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: thionyl chloride / dichloromethane / 0 - 25 °C 2: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 4 h / 0 °C / Inert atmosphere 4: 1,1'-carbonyldiimidazole / acetonitrile / 20 - 95 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 1.2: 0.67 h / 0 - 20 °C 2.1: sodium hydroxide; water / 1,4-dioxane / 20 °C 2.2: pH ~ 5 3.1: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 1.2: 0.67 h / 0 - 20 °C 2.1: sodium hydroxide; water / 1,4-dioxane / 20 °C 2.2: pH ~ 5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 1.2: 0.67 h / 0 - 20 °C 2.1: sodium hydroxide; water / 1,4-dioxane / 20 °C 2.2: pH ~ 5 3.1: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 20 °C 4.1: hydroxylamine hydrochloride; sodium methylate / methanol / 0.08 h / -5 °C 4.2: -20 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: acetic acid / 1,2-dichloro-ethane / 0.67 h / 20 °C / Molecular sieve 1.2: 5 h / 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; | 12 [0239] To a solution of (S)-methyl 4-amino-2-(4-hydroxy-1-oxoisoindolin-2-yl)- 4-oxobutanoate (300 mg, 1.08 mmol), (4-(morpholinomethyl)phenyl)methanol (335 mg, 1.62 mmol) and triphenylphosphine (567 mg, 2.16 mmol in THF, 8 mL) at 0oC was added DEAD (376 mg, 2.16 mmol) and the mixture was stirred at RT overnight. The solvent was evaporated, and the residue was purified by prep-TLC (DCM/MeOH, 10 :1) to give (S)- methyl-4-amino-2-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-4- oxobutanoate (150 mg, 30% yield) as a white solid. MS (ESI) m/z = 468.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
500 mg | With potassium tert-butylate; In 1,4-dioxane; at 100℃; for 3h; | A solution of compound Int-45 (1.5 g, 7.24 mmol, 1.0 eq), <strong>[6636-55-1]methyl 6-chloropicolinate</strong> (1.24 g, 7.24 mmol, 1.0 eq), and /-BuOK (810 mg, 7.96 mmol, 1.1 eq) in dioxane (5 mL) was heated to 100 C for 3 h. TLC showed the reaction reached completion. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (hexanes/ ethyl acetate 30/1) to afford Int-46 (500 mg) as a yellow oil. NMR (400 MHz, CDCb): 57.63 - 7.77 (m, 2H), 7.46 (d, J= 78.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 7.8, 1H), 5.44 (s, 2H), 3.97 (s, 3H), 3.70 (t, J = 4.8 Hz, 4H), 3.50 (s, 2H), 2.44 (t, J= 4.8 Hz, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With thionyl chloride In dichloromethane at 20℃; for 3h; Reflux; | 10 4-(4-(Chloromethyl)benzyl)morpholine (Int-4) A solution of (4-(morpholinomethyl)phenyl)methanol (1 g, 4.83 mmol, 1.0 eq), SOCI2 (2 mL) in dichloromethane (8 mL) was stirred at room temperature for 3 h. Thin layer chromatography (TLC) showed that the reaction reached completion. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, aqueous NaOH (1 A) and brine, dried and concentrated by rotary evaporation to give compound Int-4 (1 g, 92%) as off-white solid. ESI-MS (EI+, m/z) : 226.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: thionyl chloride / dichloromethane / 3 h / 20 °C / Reflux 2: potassium carbonate / N,N-dimethyl-formamide / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: thionyl chloride / dichloromethane / 3 h / 20 °C / Reflux 2: potassium carbonate / N,N-dimethyl-formamide / 70 °C 3: water; lithium hydroxide monohydrate / methanol / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: thionyl chloride / dichloromethane / 3 h / 20 °C / Reflux 2: potassium carbonate / N,N-dimethyl-formamide / 70 °C 3: water; lithium hydroxide monohydrate / methanol / 3 h / 20 °C 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium <i>tert</i>-butylate / 1,4-dioxane / 3 h / 100 °C 2: water; lithium hydroxide monohydrate / methanol / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium <i>tert</i>-butylate / 1,4-dioxane / 3 h / 100 °C 2: water; lithium hydroxide monohydrate / methanol / 4 h / 20 °C 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: manganese(IV) oxide / dichloromethane 2.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 - -40 °C 2.2: 16 h / -78 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: manganese(IV) oxide / dichloromethane 2.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 - -40 °C 2.2: 16 h / -78 - 20 °C 3.1: triethylsilane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.5 h / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: manganese(IV) oxide / dichloromethane 2.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 - -40 °C 2.2: 16 h / -78 - 20 °C 3.1: triethylsilane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.5 h / Microwave irradiation 4.1: sodium hydride / mineral oil; tetrahydrofuran / 0 - 20 °C 4.2: 1 h / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: manganese(IV) oxide / dichloromethane 2.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 - -40 °C 2.2: 16 h / -78 - 20 °C 3.1: triethylsilane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.5 h / Microwave irradiation 4.1: sodium hydride / mineral oil; tetrahydrofuran / 0 - 20 °C 4.2: 1 h / 70 °C 5.1: water; acetonitrile / 20 h / Resolution of racemate; Cooling with acetone-dry ice |
Tags: 91271-65-7 synthesis path| 91271-65-7 SDS| 91271-65-7 COA| 91271-65-7 purity| 91271-65-7 application| 91271-65-7 NMR| 91271-65-7 COA| 91271-65-7 structure
[ 91271-64-6 ]
(3-(Morpholinomethyl)phenyl)methanol
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[ 91988-73-7 ]
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
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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