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CAS No. : | 32634-68-7 | MDL No. : | MFCD00008552 |
Formula : | C20H18O8 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CMIBUZBMZCBCAT-HOTGVXAUSA-N |
M.W : | 386.35 | Pubchem ID : | 263211 |
Synonyms : |
|
Num. heavy atoms : | 28 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 9 |
Num. H-bond acceptors : | 8.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 96.42 |
TPSA : | 127.2 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) : | -6.31 cm/s |
Log Po/w (iLOGP) : | 1.96 |
Log Po/w (XLOGP3) : | 3.31 |
Log Po/w (WLOGP) : | 2.22 |
Log Po/w (MLOGP) : | 2.38 |
Log Po/w (SILICOS-IT) : | 2.51 |
Consensus Log Po/w : | 2.48 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -4.04 |
Solubility : | 0.0349 mg/ml ; 0.0000904 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -5.66 |
Solubility : | 0.000851 mg/ml ; 0.0000022 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -3.85 |
Solubility : | 0.0552 mg/ml ; 0.000143 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 3.6 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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 |
---|---|---|
374.4g | With water In toluene for 5 h; Reflux; Large scale | Taking d-tartaric acid 150g, toluene 200 ml of the 1000 ml three-neck bottle, added under stirring 1.5g copper sulfate, methylbenzoyl chloride to begin dropping 330g, 3 hours drop end, to continue reaction 6 hours, discharging to centrifuge, shall then d-p-methyldibenzoyl tartaric anhydride 495.4g, will in 2000 ml three-neck bottle, adding water and toluene all 495.4g, heated up to reflow, holding 5 hours, cooling to normal temperature discharge, shall then d-p-methyldibenzoyl tartaric acid 374.4 g. The embodiment of thed d-p-methyldibenzoyl tartaric acid for TEM test, test structure as shown in Figure 1, can be known from the graph, the finished d-p-methyldibenzoyl tartaric acid content is purity 99.61percent, total yield of 96.6percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99 % ee | With sodium hydroxide In water at 20 - 30℃; for 1 h; | Comparative Example 2 A 2-liter three-neck flask equipped with a stirrer, Dimroth condenser and thermometer was charged with 220.4 g of the diastereomer salt obtained in Example 4 {60.4 g (0.39 mole) of (R)-2-cyclopropylaminocyclohexanol and 150.2 g (0.39 mole) of di-p-toluoyl-D-tartaric acid} and 513 ml of water, and the mixture was stirred at 20 to 30°C. Then, 157 g (0.79 mole) of 20percent sodium hydroxide aqueous solution was added dropwise, taking about 1 hour, to cause salt dissociation. The aqueous solution was extracted with 600 g of toluene 3 times, but the recovery rate of (R)-2-cyclopropylaminocyclohexanol was as low as 56percent. The water layer as extraction residue was adjusted to lower than pH 1 using 95percent sulfuric acid, and the crystals precipitated were collected by filtration. The chemical purity of di-p-toluoyl-D-tartaric acid was about 93percent, and it contained p-toluic acid produced by hydrolysis.; Comparative Example 2; A 2-liter three-neck flask equipped with a stirrer, Dimroth condenser and thermometer was charged with 220.4 g of the diastereomer salt obtained in Example 4 {60.4 g (0.39 mole) of (R)-2-cyclopropylaminocyclohexanol and 150.2 g (0.39 mole) of di-p-toluoyl-D-tartaric acid} and 513 ml of water, and the mixture was stirred at 20 to 30°C. Then, 157 g (0.79 mole) of 20percent sodium hydroxide aqueous solution was added dropwise, taking about 1 hour, to cause salt dissociation. The aqueous solution was extracted with 600 g of toluene 3 times, but the recovery rate of (R)-2-cyclopropylaminocyclohexanol was as low as 56percent. The water layer as extraction residue was adjusted to lower than pH 1 using 95percent sulfuric acid, and the crystals precipitated were collected by filtration. The chemical purity of di-p-toluoyl-D-tartaric acid was about 93percent, and it contained p-toluic acid produced by hydrolysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.1% | In methanol; isopropyl alcohol; at 20℃; for 2.25h;Reflux; | A mixture of di-p-toluoyl-d-tartaric acid (23.8 g, 0.0617 mol), 100 ml ethanol, and (R,S)-nicotine (10 g, 0.0617 mol) was stirred for 1 hr, refluxed for 15 min, cooled to room temperature and stirred for 1 hr. The salt was filtered and further recrystallized using ethanol to obtain S-nicotine di-p-toluoyl-d-tartrate (10.5 g, 62.1% yield). The salt was further treated as in example 1 to get (S)-nicotine (3 g, 60% yield) 87.9% chiral purity by HPLC. |
In ethanol; at 20℃; | A series of experiments were performed to investigate the effects of different parameters on yield of (S)(-)-nicotine, ee of (S)(-)-nicotine, and optical rotation, the parameters including the type of chiral acid (i.e., L-PTTA or D-PTTA), acid equivalent to nicotine, solvent, filtration temperature, and number of salt recrystallizations. Data appear in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 25 - 35℃; for 0.5h; | Example-5:Preparation of Dimethyl] [3-(nahthalen-l-yloxy)-l-phenyl-propyl-amine p-ditoluyl tartarate salt: <n="13"/>The solution of 250 g of Dapoxetine Base is prepared in a 250 mL of methylene dichloride and was allowed to stirred for 15 to 20 minutes at 25 to 350C. 316.6 g of p- ditoluyl D-(+)-tartaric acid (DTTA) is added into the reaction mixture at 25 to 350C. 175 mL of methylene dichloride is further added into the reaction mixture at 25 to 350C and was allowed to stir for 30 minutes at same temperature. The solid product precipitates out. Further 825 mL of methylene dichloride is added into the reaction mixture at 25 to 350C. The reaction mixture is filtered and the bed is washed with 2 x 250 mL of methylene dichloride. The material is dried in oven at 50 to 55C to obtain the desired product i.e. (H-)-Dapoxetine p-ditolyl tartaric acid salt [Compound (e)]. Purification:The solution of 190 g of (+)-Dapoxetine p-ditolyl tartaric acid salt is prepared in 1560 mL of methylene dichloride at 25 to 35C. The reaction mixture is heated to reflux temperature for 1 hour at 38 to 4O0C. The reaction mixture is cooled to 250C to 3O0C. The reaction mixture is further stirred at 1O0C to 15C for 1 hour and is filtered at same temperature, washed with 2 x 195 mL of methylene dichloride. Final Purification:The solution of 165 g of (+)-Dapoxetine p-ditolyl tartaric acid salt is prepared in 330 mL of methylene dichloride at 25 to 350C. The reaction mixture is heated to reflux temperature for 30 minutes at 35 to 4O0C. 495 mL of ethyl acetate is added into the reaction mixture at the same temperature within 1-1.5 hours. After the addition is over the reaction mixture is cooled to 25C to 3O0C and stirred for 1 hour. The reaction mixture is further cooled at 1O0C to 150C and stirred for 1 hour and is filtered at same temperature, washed with 2 x 82.5 mL of methylene dichloride:Ethyl acetate (2:3) to obtain pure (+)-Dapoxetine p-ditolyl tartaric acid salt |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In ethanol; at 20 - 40℃; for 19h;Heating / reflux; | Di-p-toluoyl-D-tartaric acid (5.79 g, 14.99 mmol) was dissolved in ethanol (100 ml) on warming to 400 C. and then synthetic racemic narwedine (8.52 g, 29.86 mmol) was added and the mixture was heated at reflux for 1 h then cooled to 400 C. and stirred for 16 hours at this temperature. The mixture was cooled to ambient temperature, stirred for 2 h and then the resultant white solid was isolated by filtration to give the 2:1 diastereomeric salt [(-)-narwedine]2[di-p-toluoyl-D-tartrate] (11.86 g, 83% yield, 94% e.e.). |
79% | In ethanol; at 40℃;Heating / reflux; | Racemic narwedine (100 mg, 0.35 mmol) was dissolved in ethanol (3 ml) upon heating to reflux. Di-p-toluoyl-D-tartaric acid (58 mg, 0.17 mmol) was added and the mixture was cooled slowly to 400 C., maintained at this temperature overnight, then cooled to ambient temperature. The white solid was isolated by filtration to afford the 2:1 diastereomeric salt [(-)-arwedine]2[di-p-toluoyl-D-tartrate] (79% yield, 98% e.e (-)-narwedine in salt). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In ethanol; at 40℃;Heating / reflux; | Racemic narwedine (100 mg, 0.35 mmol) was dissolved in ethanol (3 ml) on heating to reflux. Di-p-toluoyl-D-tartaric acid (58 mg, 0.17 mmol) was added then the reaction mixture was cooled to ambient temperature. The resulting white solid was isolated by filtration to afford the 1:1 diastereomeric salt [(-)-narwedine][di-p-toluoyl-D-tartrate] (90% yield, 98% e.e (-)-narwedine). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 4-methyl-2-pentanone; at 20℃; | ()-ERYTHRO mefloquine (500 mg, 1.32 MMOL) was dissolved in of MIBK and a solution of O, O-DI-P-TOLUOYL-D-TARTARIC acid monohydrate (511 mg, 1.32 mmol, 1.0 equiv. ) dissolved in 1 ml in MIBKWAS added. (-)-Erythro mefloquine O, 0-di-p-toluoyl-D-tartaric acid salt (5mg) was added as seed crystals. The solution was allowed to stir for 3 hours then left overnight to stand at room temperature, afterwhich any solid was filtered under reduced pressure and washed with the relevant solvent (2 x 5 ml) to yield (-)-ERYTHRO mefloquine O, O-DI-P-TOLUOYL-D-TARTARIC acid salt. The combined supernatant and washings were reduced to dryness to give a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 20℃; | To a solution of intermediate 52 (759 mg) in dry THF (4 mL), a solution of di-p-toluoyl-D- tartaric acid (1.3 g) in dry THF (4 mL) was added. The solution was stirred at r. t. overnight. The suspension obtained was filtered and the solid residue washed with dry THF (13 mL). The solid (1.8 g) was crystallised from dry THF (15 mL) by heating to reflux for 1 hour, cooling to r. t. and stirring for 2 hours. The suspension was filtered and the solid residue (1 g) washed with dry THF (15 mL) and recristallised as described above twice to give [[1- (3, 5-DICHLORO-PHENYL)-ETHYL]-METHYLAMINE DI-P-TOLUOYL-D-TARTRATE SALT] (690 mg). The solid was stirred in a mixture of saturated sodium hydrogen carbonate solution (20 mL) and DCM (20 mL). The organic phase was washed with water (20 mL), dried and concentrated in vacuo to give the title compound intermediate 55 (230 mg) as colourless oil. The mother liquors from the precipitation and crystallizations were collected, concentrated in vacuo, treated with saturated sodium hydrogen carbonate solution (20 mL) and extracted with DCM (20 mL). The colourless oil thus obtained (550 g) was processed with [DI-P-TOLUOYL-L-TARTARIC] acid (1.04 g) in dry THF as described above (one precipitation and three recristallisations) to give [[1- (3, 5-DICHLORO-PHENYL)-ETHYL]-METHYLAMINE DI-P-TOLUOYL-L-] tartrate salt (820 mg). The solid was stirred in a mixture of saturated sodium hydrogen carbonate solution (20 mL) and DCM (20 mL). The organic phase was washed with water (20 mL), dried and concentrated in vacuo to give the title compound intermediate 54 (238 mg) as colourless oil. Intermediate 54: NMR (CDCI3) : [8] (ppm) 7.3 (m, 3H); 3.6 (q, 1H); 2.3 (s, 3H); 1.35 (d, 3H). MS (ES/+): m/z=204 [M+H] +. HPLC (column : [CHIRAL-AGP] 15cm x 2mm, [5TM] ; injection [VOLUME=111L] ; mobile phase: ammonium phosphate buffer [100MM] pH=4. [4/CH3CN] isocratic 96/4 % v/v; flow rate= 0.13 [ML/MIN] ; detection: [S=210 NM)] : retention time = 5.2 minutes; purity (a/a %) 100%. Intermediate 55: NMR [(CDCI3)] : [8] (ppm) 7.3 (m, 3H); 3.6 (q, [1H)] ; 2.3 (s, 3H); 1.35 (d, 3H). MS (ES/+): [M/Z=204] [[M+H] +.] HPLC (column : Chiral-AGP 15cm x 2mm, [5M] ; injection [VOLUME=1PL] ; mobile phase: ammonium phosphate buffer [100MM] pH=4. 4/CH3CN isocratic 96/4 % v/v; flow rate= 0.13 [ML/MIN] ; detection: [B=210] nm): retention time = 5.5 minutes; purity (a/a %) 98.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 20℃; | To a solution of intermediate 53 (1.3 g) in dry THF (7 mL), a solution of [DI-P-TOLUOYL-D-] tartaric acid (1.7 g) in dry THF (7 mL) was added. The solution was stirred at r. t. overnight. The suspension obtained was filtered and the solid residue washed with dry THF (2 x 10 mL). The solid obtained (1.2 g) was crystallised from dry THF (15 mL) by heating to reflux for 1 hour, cooling to r. t. and stirring for 2 hours. The suspension was filtered and the solid residue (0.88 g) washed with dry THF (15 mL) and recristallised as described above twice to give [[1- (3, 5-DIBROMO-PHENYL)-ETHYL]-METHYLAMINE DI-P-TOLUOYI-D-] tartrate salt (542 mg). The solid was stirred in a mixture of saturated sodium hydrogen carbonate solution (20 mL) and DCM (20mL). The organic phase was washed with water (20 mL), dried and concentrated in vacuo to give the title compound intermediate 57 (180mg) as colourless oil. The two first mother liquors were collected, concentrated in vacuo and treated with saturated sodium hydrogen carbonate solution (20 mL) and extracted with DCM (20 mL). The colourless oil thus obtained (880 mg) was processed with di-p-toluoyl-L-tartaric acid (1.16 g) in dry THF as described above (one precipitation and three recristallisations) to give the [[1- (3, 5-DIBROMO-PHENYL)-ETHYL]-METHYLAMINE DI-P-TOLUOYL-L-TARTRATE SALT] (603 mg). The solid was stirred in a mixture of saturated sodium hydrogen carbonate solution (20 mL) and DCM (20 mL). The organic phase was washed with water (20 mL), dried and concentrated in vacuo to give the title compound intermediate 56 (225 mg) as colourless oil. Intermediate 56: NMR [(CDCI3)] : 8 (ppm) 7.6 (t, [1H)] ; 7.4 (d, 2H); 3.6 (q, 1H) ; 2.3 (s, 3H); 1.3 (d, 3H). MS (ES/+): m/z=294 [M+H]+. HPLC (column : Chiral-AGP 15cm x 2mm, [5, UM] ; injection [VOLUME=1PL] ; mobile phase: ammonium phosphate buffer [100MM] pH=4. 4/acetonitrile isocratic [96/4] % v/v; flow rate= 0.13 [ML/MIN] ; detection: [B=210] nm): retention time = 7.7 minutes; purity (a/a %) 98. 2%. Intermediate 57: NMR (CDCI3) : [8] (ppm) 7.6 (t, 1H) ; 7.4 (d, 2H); 3.6 (q, [1 H)] ; 2.3 (s, 3H); 1.3 (d, 3H). MS (ES/+): [M/Z=294] [M+H] [+.] HPLC (column : [CHIRAL-AGP] 15cm x 2mm, 5mum ; injection [VOLUME=1 L ; MOBILE] phase: ammonium phosphate buffer [100MM] pH=4. 4 / acetonitrile isocratic 96/4 % [V/V] ; flow rate= 0.13 [ML/MIN] ; detection: [No.=210 ] nm): retention time = 9. 1 minutes; purity (a/a %) 99.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In propan-1-ol; at 20℃; for 20 - 25h; | 10 g of a racemic mixture of the R(-)-I and S(+)-I enantiomers resuspended in 50 ml of a 5% mixture of n-propanol are heated until dissolution, and 9.46 g (1 equivalent) of (-)-di-p-toluyl tartaric acid are incorporated. The solution formed is slowly cooled to room temperature and is left stirring for 20-25 hours. Well formed crystals precipitate, which are isolated by filtration. The salt obtained is neutralized in an ethyl acetate and sodium hydroxide mixture to isolate the resulting base. The rotatory power of the product obtained is measured at a concentration of c=0.35 in methanol, obtaining a value of practically 0, which indicates that neither of the two [R(-)-I] or [S(+)-I] enantiomers has been selectively isolated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol; at -20℃; for 24h; | 5.80g(20.0mmol) of 2-(3' ,4' -dimethoxyphenyl)-2-isopropyl-5-methylamino pentanenitrile was dissolved in 50ml of isopropanol, and 7.73g(20.0mmol) of di-p-toluoyl-D-tartaric acid was added thereto while being stirred. The mixture was cooled at -20C for 1 day, and the depositing crystals were collected by filtration. The first and second crystals were combined and suspended again in isopropanol and washed. The organic layers obtained by filtration were combined and the solvent was evaporated out. 50ml of water was added to the residue and then 10ml of 48% sodium hydroxide solution was further added while being cooled with ice. After being stirred for 10 minutes, the reaction mixture was extracted twice with 100ml of ethyl acetate, and then washed with water. The organic layer was filtrated through 1PS filter paper and the solvent was evaporated out. The residue was purified by silica gel column chromatography, and dissolved in 20ml of isopropanol. 2.90g(7.5mmol) of di-p-toluoyl-L-tartaric acid was added to the solution while being stirred. The solution was cooled at -20C for 1 day and the depositing crystals were collected by filtration, to give 3.57g(26%, optical rotation (-) 69.0 (C=1.0, abs. EtOH)) of (R)-2-(3' ,4' -dimethoxyphenyl)-2-isopropyl-5-methylaminopentanenitrile di-p-toluoyl- L-tartarate. 20ml of water was added to 3.57g(5.3mmol) of the diastereomeric salt and then 4ml of 48% sodium hydroxide solution was further added while being cooled with ice. After being stirred for 10 minutes, the mixture was extracted twice with 50ml of ethyl acetate, to give 1.45g(5.0mmol, 25%) of (R)-2-(3' ,4' -dimethoxyphenyl)-2-isopropyl-5-methylamino pentanenitrile.1H-NMR (d, CDCl3):0.80 (3H, d, J=6.5Hz), 1.20 (3H, d, J=6.5Hz), 1.14-1.23 (1H, m), 1.54-1.61 (1H, m), 1.86-1.95 (1H, m), 2.08 (1H, sept, J=6.5Hz), 2.14-2.22 (1H, m), 2.27 (1H, br-s), 2.37 (3H, s), 2.51-2.61 (2H, m), 3.88 (3H, s), 3.90 (3H, s), 6.83-6.6.87 (2H, m), 6.91-6.95 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile; at 20℃; for 5h;Heating / reflux; | This preparative example of an intermediate illustrate the synthesis of optically enriched isomeric form of 1,2-diphenyl-propane-1,2-diamine that can be employed in the syntheses of various imidazole compounds of the present invention following the synthetic procedures as disclosed herein. [0647] 1,2-Diphenyl-propane-1,2-diamine (7.5 grams, 0.033 mol) and (+)-di-p-toluoyl-D-tartaric acid (12.8 grams, 0.33 mol) are dissolved in a refluxing mixture of 200 mL acetonitrile and 40 mL water. The mixture is stirred and cooled to room temperature during 3 hours. The stirring is continued for additional two hours at room temperature. The precipitate so formed is collected by filtration and rinsed with 90% aqueous acetonitrile, 12.1 grams of the salt is isolated with an e.e. of 50% for the diamine. Recrystallization from a mixture of 170 mL acetonitrile and 35 mL water gave 8.5 g salt (chiral yield (c.y.)=42% and enantiomeric excess (e.e.) of 80% for the diamine). Another recrystallization from a mixture of 170 mL acetonitrile and 35 mL water gave 6.8 g salt (c.y.=34% and e.e. of >95% for the diamine). The cis:trans ratio is 6 to 1 based on 1H-NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; at 60℃;Resolution of racemate; | A 200 ml three-neck flask equipped with a stirrer, Dimroth condenser and thermometer was charged with 4.4 g (0.06 mole) of racemic 1,2-diaminopropane, 11.6 g (0.03 mole, optical purity 99.5% ee) of recovered di-p-toluoyl-D-tartaric acid, 51 g of water and 5.6 g (0.054 mole) of 35% hydrochloric acid; and with stirring, the mixture was heated up to 60C for dissolution. Then, with stirring, the solution was cooled to 25C, to precipitate crystals which were collected by filtration to obtain 11.2 g of a diastereomer salt. The optical purity of the 1,2-diaminopropane contained in the precipitated diastereomer salt was 75% ee. The results were almost the same as those of Example 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; at 60℃;Resolution of racemate; | A 300 ml three-neck flask equipped with a stirrer, Dimroth condenser and thermometer was charged with 14.8 g (0.2 mole) of racemic 1,2-diaminopropane, 40.4 g (0.1 mole, optical purity 99.5% ee) of di-p-toluoyl-D-tartaric acid, 170 g of water and 18.8 g (0.18 mole) of 35% hydrochloric acid, and with stirring, the mixture was heated up to 60C for dissolution. Then, with stirring, the mixture was cooled to 25C, for precipitation, and the crystals were collected by filtration to obtain 37.5 g of a diastereomer salt and 203.5 g of a filtered mother liquor. The optical purity of the 1,2-diaminopropane contained in the precipitated diastereomer salt was 76% ee. The obtained diastereomer salt was recrystallized with water, and the crystals were collected by filtration and dried to obtain 20.8 g of a diastereomer salt. The optical purity of the 1, 2-diaminopropane contained in the precipitated diastereomer salt was 98.5% ee. A 300 ml three-neck flask equipped with a stirrer, Dimroth condenser and thermometer was charged with 6.7 g (0.07 mole) of 95% sulfuric acid and 115 g of water, and with stirring at 25 to 30C, 0.5 g of di-p-toluoyl-D-tartaric acid was added. The mixture was stirred till it became a smooth slurry, when 0.5 g of said diastereomer salt was added, and the mixture was stirred for 10 minutes. It was confirmed that the di-p-toluoyl-D-tartaric acid precipitated due to salt exchange was crystallized, and the remaining 20.8g of the diastereomer salt was added little by little, taking 1 hour. The mixture was stirred for further 2 hours, to precipitate crystals which were collected by filtration and dried to obtain 17.6 g of d-p-toluoyl-D-tartaric acid. The recovery rate was 98.0%, and the optical purity was 99.5% ee. In neither the optical resolution step nor the salt dissociation step, any racemization occurred concurrently. In HPLC, no impurity peak was detected. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.8% | With hydrogenchloride; In methanol; water; at 20 - 70℃; for 2.5h;Resolution of racemate; | A 2-liter three-neck flask equipped with a stirrer, Dimroth condenser and thermometer was charged with 155.2 g (1.0 mole) of racemic 2-cyclopropylaminocyclohexanol, 270.4 g (0.7 mole, optical purity 99.5% ee) of di-p-toluoyl-D-tartaric acid, 430 g of methanol, 184 g of water and 10.9 g of 35% hydrochloric acid, and the mixture was stirred at 70C for 1 hour for dissolution. Then, the mixture was cooled to 50C, and 0.1 g of seed crystal was added. The mixture was stirred for 30 minutes to precipitate crystals, and was cooled to room temperature, being stirred for further 1 hour. The precipitated crystals were collected by filtration to obtain 258.2 g of a diastereomer salt. The obtained salt was recrystallized with a mixed solvent of 192 g of methanol and 56 g of water, to precipitate and obtain 220.4 g of a diastereomer salt. The optical purity of the 2-cyclopropylaminocyclohexanol contained in the precipitated crystals was 99.0% ee (R-isomer), and as a result of analysis, the purity content was 60.4 g while the yield was 77.8% (in terms of R-isomer). The amount of the contained di-p-toluoyl-D-tartaric acid was found to be 150.2 g as a result of purity analysis. A 2-liter three-neck flask equipped with a stirrer, Dimroth condenser and thermometer was charged with 900 ml of water and 48.1 g of 95% sulfuric acid, and the mixture was stirred at 25 to 30C, when 10.0 g of di-p-toluoyl-D-tartaric acid was added. The mixture was stirred for 20 minutes till it became a smooth slurry. Then, with stirring, 1 g of the diastereomer salt was added, and the mixture was stirred for 5 minutes to dissociate the salt with precipitation. It was confirmed that the precipitated di-p-toluoyl-D-tartaric acid became crystalline, and the remaining diastereomer salt was added, taking about 2 hours. The mixture was stirred for further 4 hours, to precipitate di-p-toluoyl-D-tartaric acid which was isolated using a small centrifugal dehydrator. For rising, 50 g of water was used. The isolated crystals were dried to obtain 155.0 g of di-p-toluoyl-D-tartaric acid. The recovery rate was 96. 8%, and the optical purity did not decline. The chemical purity measured by HPLC was also good. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In acetonitrile; at 82℃; for 1 - 24h;Product distribution / selectivity; | EXAMPLE 1; A racemic mixture of 4-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene (1.0 g, 4.0 mmol, 1.0 equivalent) is dissolved in 10-20 ml of acetonitrile followed by addition of di-p-toluoyl-D-(-)-tartaric acid (1.8 g, 4.0 mmol, 1.0 equivalent) at 22 C. under N2. The suspension that is formed is heated to 82 C. for 1 to 24 hours until enantiomeric purity is confirmed by chiral HPLC. The suspension is cooled to 35 C., filtered, and air dried for 1 hour. The crude (1S,8R)-(+)-4-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene di-p-toluoyl-D-(-)-tartaric acid salt is then dried under vacuum at 40 C. for 24 hours to yield 1.3 grams of a white solid (2.1 mmol, 94% yield, 96% enantiomeric enrichment). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 34 - 36℃;Resolution of racemate;Product distribution / selectivity; | Example 2a 4-[(5S, 9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile semi (+)-DTTA salt To a suspension of 4-[(5S*,9R*)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile hydrochloric acid salt (1.00 kg, 2.21 mol) in dichloromethane (10.67 L) was added diispopropylethylamine (0.29 kg, 2.21 mol). The mixture was stirred to a clear solution, to which (+)-Di-p-toluoyl-D-tartaric acid (0.21 kg, 0.55 mol) was added. The resulting solution was warmed to 34-36 C. and seeded immediately. It was cooled to 20-25 C. in 1.5-2.0 hours. Crystallization occurred during cooling. TBME (2.75 L) was added in 0.5 hours. The suspension was stirred at 20-25 C. for 16 hours and then filtered. The filter cake was washed with dichloromethane/TBME (2/1, 1.00 L), TBME (1 L) and dried at maximum 35 C. to a constant weight. 4-[(5S, 9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile semi (+)-DTTA salt (0.47 kg, 35%) was obtained as a white crystalline solid. mp=175-177 C. 1H NMR (DMSO-d6): 7.86 (2H, d, J=8.1 Hz), 7.81 (2H, d, J=8.3 Hz), 7.61 (1H, m), 7.28 (2H, d, J=8.1 Hz), 7.22 (2H, 8.5 Hz), 6.68 (2H, m), 5.71 (1H, s), 3.81(1H, m), 3.50 (4H, m), 3.06 (3H, s), 2.34 (3H, s). 13C NMR (DMSO-d6): 24 Carbons (171.45, 169.40, 165.04, 152.88, 143.61, 138.99, 133.88, 133.08, 132.16, 129.26, 129.20, 128.76, 127.84, 126.99, 124.51, 118.25, 110.78, 72.81, 73.38, 48.15, 47.51, 46.30, 24.90, 21.14). Anal. Calcd for C30H25Cl2N4O6+0.5 H2O: C, 58.40; H, 4.17; N, 9.08; Cl, 11.49. Found C, 58.58; H, 4.06; N, 8.94; Cl, 11.38; KF, 1.59. |
Yield | Reaction Conditions | Operation in experiment |
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In ethanol; at 20℃; for 22h; | To a solution of Compound A free base (1.00 g) in 20 mL of ETOH was added 1.12 g of (+)-(2S,3S)-di-O-(4-methylbenzoyl)tartaric acid, and the mixture was stirred at room temperature for 22 hours. The resulting precipitates were collected by filtration to give 1.60 g of the title compound as white crystals. 1H-NMR(DMSO-d6: 70 C.): 1.53-1.88(4H,m),2.15(1H,brs),2.32-2.38(6H,m),2.76-3.16(7H,m),3.42(1H,ddd,J=13.6,8.8,5.2 Hz),3.50(1H,dd,J=14.4,8.8 Hz),3.90(1H,dt,J=13.2,5.2 Hz),4.88(1H,dt,J=8.8,4.4 Hz),5.64(2H,s),6.23(1H,s),7.11-7.34(13H,m),7.77-7.84(4H,m). Peak top temperature of endothermia in DSC: 160 C. FIG. 19 shows a powder X-ray diffraction pattern of the compound in Example 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; at 18 - 22℃; for 4h; | In a 1 L RBF was added benzyl 2-oxo-1,2-dihydro-1'H-spiro[indole-3,3'- pyrrolidine]-1'-carboxylate (1.000 equiv [Limiting Reagent]; 155.1 mmoles; 50.00 g) followed by tetrahydrofuran (6.103 moles; 440.0 g; 500.0 ml_) and sodium borohydride (5.000 equiv; 775.5 mmoles; 29.34 g). The reaction was cooled to -20 to -100C. In a separate flask was added tetrahydrofuran (3.051 moles; 220.0 g; 250.0 mL) followed by iodine (2.000 equiv; 310.2 mmoles; 78.73 g). This solution was transferred to an addition funnel and added to the 1 L RBF over a period of 6.5 to 7.5 hr while maintaining the 1 L RBF at a temperature of -10 to 0C. The reaction was heated from -15C to a temperature of 18 to 22C over a period of 10 to 14 hr and held for 4 to 8 hr at 18 to 22C. Water (27.48 moles; 495.0 g; 500.0 mL) was added slowly followed by the slow addition of hydrochloric acid (37 wt % in water, 2.000 equiv; 310.2 mmoles; 36.68 g; 30.57 mL). This mixture was held for 25 to 35 min at 18 to 220C and was cooled frorn 200C to a temperature of -5 to 5C. Tert-butyl methyl ether (2.939 moles; 259.0 g; 350.0 mL) was added followed by water (13.74 moles; 247.5 g; 250.0 mL) and sodium hydroxide (50% solution in water, 2.000 equiv; 310.2 mmoles; 37.47 g; 24.81 mL) to reach a pH of 9-10. The phases were separated and to the organic phase was added sodium sulfate (352.0 mmoles; 50.00 g) and the resulting suspension was agitated for 1.5 to 2 hr at 18 to 22C. The suspension was filtered and the filter cake was washed with tert-butyl methyl ether (839.6 mmoles; 74.00 g; 100.0 mL). This material was concentrated in vacuo and ethyl acetate (5.051 moles; 445.0 g; 500.0 mL) was added followed by di-p-toluoyl-D-tartaric acid, (made from the unnatural enantiomer of tartaric acid) (97%, 1.000 equiv; 155.1 mmoles; 64.66 g). The mixture was held for 4 hr at 18 to 22C and then cooled to a temperature of -0.2 to 0.2C. The suspension was filtered and then the filter cake was washed with ethyl acetate (1.010 moles; 89.00 g; 100.0 mL) while maintaining the filter at a temperature of -2.5 to 2.5C. The solid was dried at 35 to 450C (at 100 mm Hg) for 8 to 16 hr to provide benzyl (3S)-1 ,2-dihydro-1'H-spiro[indole-3,3'- pyrrolidine]-1'-carboxylate (108.6 mmoles; 33.48 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Charge about 4.1 kg of 1 -((i?)-2-(Dimethylamino)- 1 -(4-methoxyphenyl)ethyl) cyclohexanol hydrochloride, about 28 kg of ethyl acetate and about 21 kg of 1 N sodium hydroxide to a suitable reactor and mix until the neutralization is complete. Separate the phases and wash the organic phase with water. Charge the organic phase with a solution of about 2.9 kg of di-p-toluoyl-D-tartaric acid (DTTA) in about 13 kg of ethyl acetate and 4 kg of methanol and heat the mixture to reflux and then cool to about 0 C. The resulting slurry is filtered and washed with ethyl acetate and methanol to yield about 2.4 kg of the desired product. The product can be EPO <DP n="20"/>recrystallized from about 20 kg of an ethyl acetate : methanol solution (6.5 : 1 wt : wt, ethyl acetate : methanol) to yield about 2 kg of l-((R)-2-(dimethylamino)-l-(4- methoxyphenyl) ethyl)cyclohexanol hemi-ditoluoyl tartaric acid salt (>99% ee). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis of (S)-1-[(S)-1-(2,6-difluoropyridin-3-yl)ethylamino]propan-2-ol (+)-di-p-toluoyl-D-tartrate A solution of 1-(2,6-difluoropyridin-3-yl)ethanol (216 g) in toluene (300 mL) was added to a solution of thionyl bromide (337 g) in toluene (1,500 mL) under ice-cooling, and the reaction solution was stirred at room temperature for three hours. Ice water and toluene were added to the reaction solution, and the organic layer was separated. The organic layer was washed with water (1,000 mL) three times. The organic layer was dried over anhydrous magnesium sulfate and then filtered through a silica gel pad. (S)-1-amino-2-propanol (157 g), cesium carbonate (1.28 kg), and DMF (2,500 mL) were added to the filtrate, and the reaction solution was stirred at room temperature overnight. The reaction solution was filtered, and then the mother liquor was concentrated under reduced pressure. The residue was diluted with ethanol (1,000 mL). Then, a solution of (+)-di-p-toluoyl-D-tartaric acid (152 g) in ethanol (500 mL) was added, and the reaction solution was stirred at room temperature for one hour. The precipitated crystals were collected by filtration and washed with ethanol. The crystals were dried at 80 C. for two hours and suspended in an ethanol (2,000 mL)-heptane (1,000 mL) mixed solvent. Then, the reaction solution was heated and stirred at 80 C. One hour later, the reaction solution was returned to room temperature, and the crystals were collected by filtration. The crystals were washed with ethanol and dried at 80 C. overnight to obtain 155 g of the title compound. 1H-NMR(DMSO-d6) delta (ppm): 1.02(d,J=6.0 Hz,6H), 1.37(d,J=6.8 Hz,6H), 2.36(s,6H), 2.37-2.51(m,4H), 3.67-3.71(m,2H), 4.14-4.16(m,2H), 5.65(s,2H), 7.21(dd,J=8.0,2.0 Hz,2H), 7.31(d,J=8.4 Hz,4H), 7.82(d,J=8.4 Hz,4H), 8.27(dd,J=17.6,8.0 Hz,2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | In methanol; tert-butyl methyl ether; at 50 - 55℃; for 4h; | Into a 1 L round bottom flask was charged 175 mL of methanol and 69.5 g of D-DTTA, with heating to 50 C. to obtain a solution. Over a one hour period, into the flask was added the entire amount of MTBE solution prepared in Example 5 containing 175.0 g of the mixture of compounds of Formulae VIIa and VIIb. The addition funnel used to add the solution was rinsed with 10 mL MTBE which was added to the reaction mixture. The reaction mixture was agitated for 3 hours while being heated to reflux (approximately 50 C. to 55 C.). The reaction mixture was cooled to 40 C. and the precipitate was isolated by filtration. The solids were washed with three 60 mL aliquots of methanol at 40 C., and dried at 40 C. under atmosphere to obtain 58.6 g of the DTTA salt. Calculated yield was 50% based on the amount of methyl ester used. Enantiomeric excess of (1R,2S,5S) enantiomer was 97.5%. |
40 - 42% | In methanol; tert-butyl methyl ether; at 15 - 50℃; for 3h; | To a flask were charged 4.2 g of D-DTTA (10. mmoles) and 22 ml_ of methanol at room temperature. The reaction mixture was stirred until dissolved. Next, 4.2 g of 3.7g (21.9 mmoles) of VIIA in 41 ml of TBME was added over a 10 min period and the reaction mixture was stirred for 30 min or until salt started to form. The reaction mixture was then warmed to 40-50 0C and held at that temperature for 1 hour. The mixture was then cooled to a temperature between 15-25 0C over a 20 min. period and stirred for 1 hour. The suspension was filtered and the filter cake was washed TBME (15 ml). The cake was dried at a temperature of 40-50 0C to give a typical yield of 4.86-5.0 g (40-42%) of IB with a 95-97% e.e. 1H NMR (400 MHz, CDCl3) delta 7.92 (d, J = 8.2 Hz, 4 H), 7.16 (d, J = 8.1 Hz, 4 H), 7.05 (broad s, 3 H), 5.70 (S, 2 H), 4.21 (d, J = 1.0 Hz, 1 H), 3.74 (s, 3 H), 3.68 (dd, J = 12.4, 6.2 Hz, 1 H), 3.30-3.27 (m, 1 H), 2.36 (s, 6 H), 1.66-1.64 (m, 1 H), 1.53-1.49 (m, 1 H), 0.97 (s, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With acetic acid; In chloroform; butan-1-ol; at 60℃; for 1h; | To a 100 mL three-necked flask equipped with a stirring blade and a thermometer were added racemic 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl ) -benzonitrile free form (3) 10 g (29.3 mmol),45 mL of 1-butanol (4.5 parts by volume based on 1 part by mass of the free form (3)),4.4 mL of chloroform (0.44 parts by volume based on 1 part by weight of the free form (3)) was added.The resulting mixture was heated to 60 C.,30 mL of 1-butanol (3.0 parts by volume based on 1 part by mass of the free form (3)),Acetic acid in 0.4 mL of a mixed solutionA solution of 4.5 g (11.7 mmol) of (+) - di- (p-toluoyl) tartaric acid was mixed,The free form (3) was tartarylated.After tartarylation,1-butanol 75 mL (tartrate (4)9.4 parts by volume based on 1 part by mass),While maintaining the solvent composition of 4.4 mL of chloroform (0.44 parts by volume based on 1 part by weight of tartrate (4)),Seed crystal 25 mg was added,The mixture was stirred at 60 C. for 1 hour,The precipitation of crystals was visually confirmed.After precipitation of crystals was confirmed,Cooling to 20 C at a cooling rate of 20 C / hr,Further aging was carried out at the same temperature for 3 hours to precipitate crystals.After aging, crystals precipitated by vacuum filtration were filtered off,By 1 mL of 1-butanol (1 part by volume based on 1 part by mass of the free form (3)),The filtered crystals were washed twice.The obtained white crystals were dried under reduced pressure at 40 C. for 12 hours,As white crystals(10.4 mmol) of tartaric acid salt (4) (yield: 38%Chemical purity 99.83%Impurity 1 0.002%,Impurity 2 0.015%,Optical purity 98.83%). |
25.6% | In isopropyl alcohol; at 25 - 35℃; | A 2000 mL four-necked flask equipped with a thermometer and a stirring blade was charged with racemic200 g of 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile (3a) 800 mL of isopropyl alcohol was added and dissolved by stirring at 35 C.Further, 88 g of (+) - di- (p-toluoyl) and 700 mL of isopropyl alcohol were added to a 1,000 mL four-necked flask equipped with a thermometer and a stirring blade and dissolved by stirring at 25 C. After confirming the dissolution, a solution of (+) - di- (p-toluoyl) tartaric acid was added to a 2000 mL four-necked flask, and the free form (3a) was precipitated by tartarylation to obtain an optically active crude product(1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+) - di- (p-toluoyl ) Tartrate salt (4) (chemical purity: 99.787%, optical purity: 95.94%). The crude product was recrystallized with 5 mL of methanol (0.8 parts by mass based on 1 part by mass of the tartrate salt) and 45 mL of acetonitrile (7.1 parts by mass based on 1 part by mass of the tartrate salt) to obtain white (Yield: 25.6%, chemical purity: 99.882%, optical purity: 99.91%) as crystals (4.2 g (7.8 mmol) of the above tartrate salt) |
25.6% | In isopropyl alcohol; at 25 - 35℃; | thermometer,2000 mL with stirring feathers attachedNecked flask, 200 g of racemic 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile (3a)800 mL of isopropyl alcohol was added,And dissolved by stirring at 35 C. In addition,1000 mL of a stirring blade attachedNecked flask, 88 g of (+) - di- (p-toluoyl)700 mL of isopropyl alcohol was added,And dissolved by stirring at 25 C.After confirming dissolution,A solution of (+) - di- (p-toluoyl) tartaric acid was added to a 2000 mL four-necked flask,The free form (3a) is precipitated by tartarylation,(1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+) - di- (p-toluoyl ) Tartrate (4) 80 g (yield 25.6%, chemical purity: 99.787%, impurity 1: 0.030%, impurity 2: 0.034%, optical purity: 95.94%) . |
In isopropyl alcohol; at 20 - 60℃; for 4.08333 - 16.1667h;Resolution of racemate;Purification / work up; | 1.44g of 4-(4-fluoro-benzoyl)-3-hydroxymethyl-benzonitrile (5.6mmol, 1.0eq.) and 1.01g of 1S.2S-N- methylpseudoephedrine (5.6mmol, 1.0eq.) are dissolved in a two-necked round bottomed flask in 2OmL of toluene under an inert atmosphere (N2). At room temperature 1.17mL of diisopropoxymethyl borane 97% (6.3mmol, 1.13eq.) are added. After 2 minutes a clear solution is obtained. The reaction is warmed to 700C for 30 minutes. The reaction mixture is then cooled to 45C and ~18mL of a mixture of toluene / 2- propanol is gently removed under reduced pressure (~60mbar) within 30 minutes. 2OmL of toluene are added and the reaction is cooled to -800C. 4.16mL (2eq.) of a 2.7M solution of dimethylaminopropyl magnesium chloride in THF are slowly added (duration: 5 minutes). Stirring is continued for 10 minutes at -800C. HPLC control indicated a conversion of >98%. The ratio of S-diol (4-[(S)-4-dimethylamino-1-(4- fluorophenyl)-1-hydroxy-butyl]-3-hydroxymethyl-benzonitrile) to R-diol (4-[(R)-4-dimethylamino-1-(4- fluorophenyl)-1-hydroxy-butyl]-3-hydroxymethyl-benzonitrile) is 95.0:5.0 (enantiomeric excess = 90.0%). The reaction mixture is slowly added to 12mL of cold 2M aqueous H2SO4. The layers are separated and the toluene layer is washed once with 3mL of cold 2M aqueous H2SO4. Toluene layer is discarded. The aqueous layers are combined and 15mL of MTBE are added. The pH is adjusted to 9 with 5M aqueous NaOH. After phase separation the aqueous layer is extracted once again with 1OmL of MTBE at pH 9. MTBE is removed under reduced pressure. The crude product is purified by column chromatography (eluent ethyl acetate / cyclohexane / Et3N 1 / 1 / 0.1) on silica gel. The product containing fractions are combined and the solvent is removed under reduced pressure. Crystallization in 12mL of 2-propanol with 1.05g of (+)-di-0-toluoyl tartaric acid gives 2.3g of (S)-4-(4-dimethylamino)-1-(4'-flourphenyl)-1- hydroxybutyl-3-hydroxymethylbenzonitrile, hemi (+)-di-O-toluoyl-tartaric acid salt (contains 0.5 equivalents of 2-propanol and water) in 71% yield (ee = 99%, mp 134C).1H-NMR (DMSO-d6, 300MHz) delta.1.04 (d, 2xCH3,so. 6/2H, J 6Hz), 1.26 (m, CH2 DIOL, 1H), 1.53 (m, CH2 DIOL, 1H), 2.13 (m, CH2 D,OL. 1H), 2.27 (m, CH2 DI0L. 1H), 2.37 (bs, 2XCH3 DTTA + N(CH3J2 ?«., 9H) 2.71 (m, CH2 D10L, 2H), 3.78 (m, CH iotaso. 1/2H), 4.02 (d, CH2OH D1OL, 1 H, J 15.7Hz), 4.57 (d, CH2OH DIOL, 1H, J 15.7Hz), 5.70 (s, CHOR DTTA, 2/2H), 7.07 (t, 2H, J 8.7Hz), 7.21 (m, 2H), 7.33 (d, 2H1 J 9Hz), 7.74-7.91 (m, 5H).; Example 5: 1 S,2S-N-methylpseudoephedrine as amino alcohol, -65C in toluene, diisopropoxymethyl borane as linker, isolation of (S)-4-(4~dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl-3- hydroxymethylbenzonitrile, hemi (+)-di-O-toluoyl-tartaric acid salt1.42g of 4-(4-fluoro-benzoyl)-3-hydroxymethyl-benzonitrile (5.6mmol, 1.0eq.) and 1.00g of 1S.2S-N- methylpseudoephedrine (5.6mmol, 1.Oeq.) are dissolved in a two-necked round bottomed flask in 2OmL of toluene under an inert atmosphere (N2)- At room temperature 1.17mL of diisopropoxymethyl borane 97% (6.3mmol, 1.13eq.) are added. After 2 minutes a clear solution is obtained. The reaction is warmed to 500C for 30 minutes. The reaction mixture is then cooled to 45C and -2OmL of a mixture of toluene / 2- propanol is gently removed under reduced pressure (~70mbar) within 20 minutes. 2OmL of toluene are added and the reaction is cooled to -65C. 3.36mL (2 eq.) of a 3.25M solution of dimethylaminopropyl magnesium chloride in THF are slowly added (duration: 10 minutes). Stirring is continued for 10 minutes at -65C. HPLC control indicated a conversion of >99%. The ratio of S-diol (4-[(S)-4-dimethylamino-1-(4- fluorophenyl)-1-hydroxy-butyl]-3-hydroxymethyl-benzonitrile) to R-diol (4-[(R)-4-dimethylamino-1-(4- fluorophenyl)-1-hydroxy-butyl]-3-hydroxymethyl-benzonitrile) is 95.2:4.8 (enantiomeric excess = 90.4%). The reaction mixture is slowly added to 12mL of cold 2M aqueous H2SO4. The layers are separated and the toluene layer is washed once with 3mL of cold 2M aqueous H2SO4. Toluene layer is discarded. The aqueous layers are combined and 15mL of methyl tert-butyl ether are added. The pH is adjusted to 9 with 5M aqueous NaOH. After phase separation the aqueous layer is extracted with 1OmL of methyl terf-butyl ether at pH 9. The combined organic layers are washed twice with 0.2M aqueous pivalic acid. The combined pivalic acid layers are extracted twice with 1OmL of methyl tert-butyl ether. The combined methyl terf-butyl ether (-4OmL) layers are washed with 5mL of 5M aqueous NaOH. After phase separation, the major part of methyl terf-butyl ether is removed under reduced pressure. 12mL of 2- propanol are added. At 35C 1.04g of (+)-di-O-toluoyl tartaric acid are added. Within 5 minutes crystals start to form. After 4h the white precipitate is removed by filtration to give 2.2g of the title compound (69% yield, ee = 99%, mp 134C).; Example 18:Synthesis and isolation of (S)-4-(4-Dimethylamino)-1-(4'-fluorophe... | |
In dichloromethane; isopropyl alcohol; at 20 - 60℃; for 16.6667h;Resolution of racemate;Purification / work up; | 10.0g of 4-(4-fluoro-benzoyl)-3-hydroxymethyl-benzonitrile (MW: 255.25, assay: 96.7%; 37.9mmol) are dissolved in 14OmL of toluene. 7.77g of (S)-2-lambda/,lambda/-dimethylaminophenylethanol (MW: 165.24, 47.0mmol, 1.24 eq.) and 2.51g of methylboronic acid (MW: 59.86, assay: 98%, 41.1mmol, 1.08eq.) are added. The solution becomes slightly turbid and drops of water are rapidly formed. The mixture is heated to 500C. At reduced pressure (~60-70mbar) -10OmL of toluene / water are carefully removed. 10OmL of toluene are added and -10OmL of toluene / water are removed. 12OmL of toluene are added and about -2OmL of toluene / water are removed to get a solution of mixed boronate (~80mmol) in about 25OmL of solvent. The water content is below 0.1% as determined by a Karl Fischer titration. The reaction is cooled to - 65C. Within about 10-20 minutes 38.OmL of a -2M solution of dimethylaminopropyl magnesiumchloride in THF (-2 eq.) are added. Thereby, the temperature does not exceed -500C. The solution is stirred for another 30 minutes. Reaction control is performed with HPLC (ee = 90%). After complete conversion (area% 4-(4-fluoro-benzoyl)-3-hydroxymethyl-benzonitrile <2%) the reaction is worked up.2OmL of water are and 35mL of 2M aqueous H2SO4 (70mmol) are added to get a pH of -1.5 in the aqueous layer. After phase separation, the organic layer is washed once with 2OmL water, adjusted to pH 1 with 2M aqueous H2SO4. 15OmL of CH2CI2 are added to the combined aqueous layers. 7M aqueous NH3 is now added (29mL) until a pH of -9.0 is reached. After phase separation the aqueous layer is washed twice with 25mL of MED (at pH 9.0). The combined CH2CI2 layers are washed with 15mL of water. 7OmL of H2O are added. 10.7mL of 2M aqueous H2SO4 are added to adjust the pH to 6.4. After stirring for 10 minutes the layers are separated (pH 6.4). 35mL of water are added to the CH2CI2 layer. Addition of 1.5mL of 2M aqueous H2SO4 gives a pH of 6.4. After stirring for 10 minutes the layers are separated. 8OmL of CH2CI2 are added to the combined aqueous layers. Addition of 2mL of 7M aqueous <n="25"/>RG/G-50021-BCK9987NH3 gives a pH of 6.4 (after equilibration). The layers are separated. The combined organic layers are washed with 2OmL of water. The layers are separated. The combined CH2CI2 layer contains the enantiomerically enriched diol. The combined aqueous layer contains -90% of the chiral auxiliary. 20OmL of CH2Cl2 are removed. 6OmL of 2-propanol are added. 3OmL of 2-propanol / CH2CI2 are removed under reduced pressure. 3OmL of 2-propanol are added to obtain -13g of CIT-DIOL in 6OmL of ISO. To this solution 6.59g of (+)-ditoluoyl tartaric acid (MW: 386.36; assay: 99%; 17.1mmol, 0.45eq.), dissolved in 42mL of 2-propanol and 8mL of CH2CI2, are added. The product starts to crystallize after 5 minutes (or immediately after seeding). The mixture is stirred for 90 minutes at 35C, for 10 minutes at 600C and than slowly cooled down to room temperature (within ~5hours) and crystallized without stirring for 10 hours. The product is isolated by filtration to give 17.2g of S-CIT-DIOLlambda' (+)-DTTA.lambda1 ISO.lambda1 H2O (yield: 81.0%; ee: 99.0%, assay: 61.0%) after drying for IOhours at 400C and 20mbar. | |
In propan-1-ol; | 10 g of racemic 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile free form (3b) was dissolved in 10 mL of 1-propanol , And 35 mL of a 1-propanol solution in which 4.5 g of (+) - di- (p-toluoyl) tartaric acid was dissolved was added to precipitate the free form (3b) by tartarylation to obtain an optically active crude product, That is(1 S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl)-1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi(+) - di- (p-toluoyl) tartrate(4a) (optical purity 94.14%, purity 99.86%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
>= 95 % ee | In acetone for 2 - 3h; Heating / reflux; | 3 Zopiclone (50 g) was added to a solution of 50 g (+)Di-p-toluyl-D-tartaric acid in 1000 ml of acetone followed by reflux for 2-3 hours. The salt was obtained by filtration at room temperature and had an enantiomeric purity of not less than 95% as measured by chiral HPLC. [0062] Next, the pure dextroisomer of Di-p-toluyl-D-tartate salt of zopiclone was obtained by leaching the salt with 500 ml of methanol followed by filtration. The pure dextroisomer of Di-p-toluyl-D-tartate salt of zopiclone had an enantiomeric purity of not less than 97% as measured by chiral HPLC. |
>= 95 % ee | In methanol for 5h; Heating / reflux; | 4 Zopiclone (50 g) was added to a solution of 50 g (+)Di-p-toluyl-D-tartaric acid in 400 ml of methanol followed by reflux for 5 hours. The crude salt was obtained by filtration at room temperature and had an enantiomeric purity of not less than 95 % as measured by chiral HPLC.[0065] Next, the pure dextroisomer of Di-p-toluyl-D-tartate salt of zopiclone was obtained by leaching the above salt with 500 ml of acetone followed by the filtration. The pure dextroisomer of Di-p-toluyl-D-tartate salt of zopiclone had an enantiomeric purity of not less than 97 % as measured by chiral HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran for 1h; | 1 A solution of zopiclone (25 g, 0.064 mol) in tetrahydrofuran (1000 ml) was added to a solution of anhydrous (+) Di-p-toluyl-D-tartaric acid (25 g, 0.064 mol) in tetrahydrofuran (125 ml). The reaction mixture was stirred for 1 hour and concentrated under vacuum to obtain the crude salt. Ethanol (375 ml) was added to the crude salt, followed by evaporation of solvent to remove any traces of tetrahydrofuran. Ethanol (375 ml) was again added to precipitate the salt. The crude diastereomeric salt was purified in a mixture of ethyl alcohol and isopropyl ether (7:3) under reflux for 15 minutes and allowed to cool to at room temperature followed by filtration. The resulting salt was further recrystallised under the same conditions to obtain the pure salt. | |
In methanol | 2 A solution of 300 g (+)Di-p-toluyl-D-tartaric acid in 1500 ml methanol was added to a suspension of 300 g zopiclone in 9000 ml methanol. Methanol was evaporated under vacuum distillation followed by addition of 4500 ml of methanol. The resulting crude salt was obtained by filtration.[0059] Next, the pure dextroisomer of Di-p-toluyl-D-tartate salt of zopiclone was obtained by crystallizing the crude salt with 17000 ml of methanol and 13000 ml of isopropyl ether. The resulting pure salt was further recrystallised under the same conditions to obtain the pure salt. |
Yield | Reaction Conditions | Operation in experiment |
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40.0 - 41.3% | With N-ethyl-N,N-diisopropylamine; In methanol; water; at 0 - 45℃; for 3h;Product distribution / selectivity; | Examples 1 and 2 and Comparative Examples 1 and 2Effect of Tertiary Amine Base and Resolving Agent Equivalents on Yield and Enantiomeric Purity of D-threo-Methylphenidate/Chiral Acid SaltThreo-methylphenidate hydrochloride (10.0 g, 0.037 mol) was suspended in methanol (36 g) and di-p-toluoyl-d-tartaric acid (D-TA) was charged (see Table 1 for charge quantities) and the formed mixture was heated to 45 C. to provide a clear solution. The mixture was treated with diisopropylethylamine (DIPEA, see Table 1 for charge quantities) while an internal temperature below 45 C. was maintained. Deionized water was added to the mixture at about 45 C. until a cloudy point was achieved. The resulting slurry was cooled to 20 C. over 1 hour, aged for 2 hours, cooled to 0 C. and aged for 1 hour. The formed precipitate of D-threo-Methylphenidate/Chiral Acid Salt (Dex-TA) was filtered and washed sequentially with 20 ml of cold (0-5 C.) MeOH/water (2:1 w/w) mixture, 40 ml of deionized water and 40 ml acetone. The Dex-TA wet cake was dried at 50 C. in vacuum overnight. A reference sample of Dex-TA exhibits mp 161.8 C. and alpha25D +121.8 (c 1 wt %, MeOH). TABLE 1 D-TA DIPEA Dex-TA Equiv g Equiv g Water g g Yield, % EE, % Ex 1 0.5 7.2 0.5 2.4 25 9.3 40.4 99.2 C 0.5 7.2 1.0 4.8 123 n/a* n/a n/a Ex 1 Ex 2 1.0 14.3 0.5 2.4 24 9.2 40.0 99.5 C 1.0 14.3 1.0 4.8 21 16.0 69.5 45.5 Ex 2 *No crystallization took place Examples 3 Through 8Effect of Various Tertiary Amine Bases on Yield and Enantiomeric Purity of D-threo-Methylphenidate/Chiral Acid SaltThe procedure of Example 1 was repeated, except that different amounts of and/or differing tertiary amines were substituted for the DIPEA (charged tertiary amine and associated charge amounts are shown in Table 2). TABLE 2 D-TA DIPEA TEA NMM Dex-TA Equiv g Equiv g Equiv g Equiv g g Yield % EE % Ex 3 0.55 7.9 0.55 2.6 9.5 41.3 99.8 Ex 4 0.70 10.0 0.55 2.6 9.5 41.3 99.9 Ex 5 0.55 7.9 0.50 1.9 9.2 40.0 99.9 Ex 6 0.55 7.9 0.55 2.1 9.4 40.9 99.9 Ex 7 0.55 7.9 0.55 2.1 9.8 42.7 99.5 Ex 8 0.55 7.9 0.55 2.1 9.4 40.9 99.6 The foregoing resolution processes further illustrate the advantageous incorporation of tertiary amine base allowing the beneficial use of less than an equivalent amounts of base and/or chiral acid without significant sacrifice to ee and yield. |
40.0 - 40.9% | With triethylamine; In methanol; water; at 0 - 45℃; for 3h;Product distribution / selectivity; | Examples 3 Through 8Effect of Various Tertiary Amine Bases on Yield and Enantiomeric Purity of D-threo-Methylphenidate/Chiral Acid SaltThe procedure of Example 1 was repeated, except that different amounts of and/or differing tertiary amines were substituted for the DIPEA (charged tertiary amine and associated charge amounts are shown in Table 2). TABLE 2 D-TA DIPEA TEA NMM Dex-TA Equiv g Equiv g Equiv g Equiv g g Yield % EE % Ex 3 0.55 7.9 0.55 2.6 9.5 41.3 99.8 Ex 4 0.70 10.0 0.55 2.6 9.5 41.3 99.9 Ex 5 0.55 7.9 0.50 1.9 9.2 40.0 99.9 Ex 6 0.55 7.9 0.55 2.1 9.4 40.9 99.9 Ex 7 0.55 7.9 0.55 2.1 9.8 42.7 99.5 Ex 8 0.55 7.9 0.55 2.1 9.4 40.9 99.6 The foregoing resolution processes further illustrate the advantageous incorporation of tertiary amine base allowing the beneficial use of less than an equivalent amounts of base and/or chiral acid without significant sacrifice to ee and yield. |
40.9 - 42.7% | With 4-methyl-morpholine; In methanol; water; at 0 - 45℃; for 3h;Product distribution / selectivity; | Examples 3 Through 8Effect of Various Tertiary Amine Bases on Yield and Enantiomeric Purity of D-threo-Methylphenidate/Chiral Acid SaltThe procedure of Example 1 was repeated, except that different amounts of and/or differing tertiary amines were substituted for the DIPEA (charged tertiary amine and associated charge amounts are shown in Table 2). TABLE 2 D-TA DIPEA TEA NMM Dex-TA Equiv g Equiv g Equiv g Equiv g g Yield % EE % Ex 3 0.55 7.9 0.55 2.6 9.5 41.3 99.8 Ex 4 0.70 10.0 0.55 2.6 9.5 41.3 99.9 Ex 5 0.55 7.9 0.50 1.9 9.2 40.0 99.9 Ex 6 0.55 7.9 0.55 2.1 9.4 40.9 99.9 Ex 7 0.55 7.9 0.55 2.1 9.8 42.7 99.5 Ex 8 0.55 7.9 0.55 2.1 9.4 40.9 99.6 The foregoing resolution processes further illustrate the advantageous incorporation of tertiary amine base allowing the beneficial use of less than an equivalent amounts of base and/or chiral acid without significant sacrifice to ee and yield. |
31.3 - 41.7% | With sodium acetate; In methanol; water; at 0 - 45℃; for 3h;Product distribution / selectivity; | Examples 9 through 12Effect of NaOAc Base and Resolving Agent Equivalents on Yield and Enantiomeric Purity of D-threo-Methylphenidate/Chiral Acid SaltThreo-methylphenidate hydrochloride (10.0 g, 0.037 mol) was suspended in methanol (36 g) and di-p-toluoyl-d-tartaric acid (D-TA) was charged (see Table 3 for charge quantities) followed by heating to 45 C. to provide a clear solution. To the formed solution NaOAc was added as a solid (see Table 3 for charge quantities). Deionized water was added to the mixture at about 45 C. to cause the reaction mixture to go clear and then upon continuous addition turn cloudy. The resulting slurry was cooled to 20 C. over 1 hour, aged for 2 hours, cooled to 0 C. and aged for 1 hour. The formed Dex-TA precipitate was filtered and washed sequentially with 20 ml of cold (0-5 C.) MeOH/water (2:1 w/w) mixture, 40 ml of deionized water and 40 ml acetone. The Dex-TA wet cake was dried at 50 C. in vacuum overnight. TABLE 3 D-TA NaOAc Dex-TA Equiv g Equiv g Water g g Yield % EE % Ex 9 0.5 7.2 0.5 1.52 24 7.2 31.3 99.7 Ex 10 0.5 7.2 1.0 3.04 22 8.7 37.8 99.6 Ex 11 1.0 14.3 0.5 1.52 38 8.1 35.2 97.2 Ex 12 1.0 14.3 1.0 3.04 15 9.6 41.7 99.6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.5% | With N-ethyl-N,N-diisopropylamine; In methanol; water; at 0 - 45℃; for 3h;Product distribution / selectivity; | Examples 1 and 2 and Comparative Examples 1 and 2Effect of Tertiary Amine Base and Resolving Agent Equivalents on Yield and Enantiomeric Purity of D-threo-Methylphenidate/Chiral Acid SaltThreo-methylphenidate hydrochloride (10.0 g, 0.037 mol) was suspended in methanol (36 g) and di-p-toluoyl-d-tartaric acid (D-TA) was charged (see Table 1 for charge quantities) and the formed mixture was heated to 45 C. to provide a clear solution. The mixture was treated with diisopropylethylamine (DIPEA, see Table 1 for charge quantities) while an internal temperature below 45 C. was maintained. Deionized water was added to the mixture at about 45 C. until a cloudy point was achieved. The resulting slurry was cooled to 20 C. over 1 hour, aged for 2 hours, cooled to 0 C. and aged for 1 hour. The formed precipitate of D-threo-Methylphenidate/Chiral Acid Salt (Dex-TA) was filtered and washed sequentially with 20 ml of cold (0-5 C.) MeOH/water (2:1 w/w) mixture, 40 ml of deionized water and 40 ml acetone. The Dex-TA wet cake was dried at 50 C. in vacuum overnight. A reference sample of Dex-TA exhibits mp 161.8 C. and alpha25D +121.8 (c 1 wt %, MeOH). TABLE 1 D-TA DIPEA Dex-TA Equiv g Equiv g Water g g Yield, % EE, % Ex 1 0.5 7.2 0.5 2.4 25 9.3 40.4 99.2 C 0.5 7.2 1.0 4.8 123 n/a* n/a n/a Ex 1 Ex 2 1.0 14.3 0.5 2.4 24 9.2 40.0 99.5 C 1.0 14.3 1.0 4.8 21 16.0 69.5 45.5 Ex 2 *No crystallization took place |
Yield | Reaction Conditions | Operation in experiment |
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With ammonia; In water; | [2S]-Phenyl-piperidin-[3S]-ylamine [2S,3S]-bis(4-methyl-benzoyloxy)-succinic acid salt (1 :1 ) (6.9g) was taken up in concentrated 0.880 aqueous ammonia solution (100ml) and shaken for a few minutes. The basic solution was extracted with chloroform (3x150ml) , dried (Na2SO4), and concentrated in vacuo to give [2S]-phenyl-piperidin-[3S]-ylamine (1.85g) as a colourless oil. [Ot]20D (HCI salt) = +65.48 (C=0.006 g/ml) 1 H NMR (HCI salt, D2O) delta 2.05 (m, 2H), 2.30 (m, 2H), 3.36 (m, 1 H), 3.74 (m, 1 H), 4.16 (q, 1 H, J=4Hz), 4.99 (d, 1 H, J=4Hz), 7.45 (m, 2H), 7.59 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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Venlafaxine hydrochloride was prepared from venlafaxine freebase by the addition of hydrochloric acid in an appropriate solvent or according to US patent No. 4535186. [00247] A mixture of 2.50 kg of 1-(2-(dimethylamino)-1-(4-methoxyphenyl)ethyl) cyclohexanol hydrochloride, 16.8 kg of ethyl acetate and 14.0 kg of 1 N NaOH (aq) was stirred for 15 min. The stirring was stopped and the lower layer removed. The organic layer was washed twice with 3.5 kg of water. 2.4 kg of methanol and 1.78 kg of di-p-toluoyl-D-tartaric acid in 7.9 kg ethyl acetate was added. The mixture was stirred at reflux (-65 0C) for 15 min and cooled to 550C. The solution was seeded with 43 g of (f?)-1-(2-(dimethylamino)-1-(4- methoxyphenyl) ethyl)cyclohexanol-hemi-D-di-p-toluoyltartaric acid salt in 0.750 kg of ethyl acetate. The slurry was aged at 55C for 15 minutes, cooled to 300C over 110 minutes. The mixture was then cooled to 00C over 1 hour and filtered. The cake was washed twice with a mixture of 0.23 kg of methanol and 2.3 kg ethyl acetate and dried in vacuo at 40-500C to yield 1.53 kg of (R)-1-(2-(dimethylamino)-1-(4-methoxyphenyl) ethyl)cyclohexanol-hemi-D-di-p- toluoyltartaric acid salt (99.1% ee). 1H NMR (DMSO-D6): 0.80 - 1.6 (m, 10H), 2.35 (s, 9H), 2.86 (m, 1 H)1 2.98 (m, 1 H), 3.33 (m, 1H), 3.72 (s, 3H), 5.62 (s, 2H), 6.81 (d, 2H, J = 8.5 Hz ), 7.12 (d, 2H, J = 8.5 Hz)1 7.31 (d, 4H1 J = 8.3 Hz), 7.85 (d, 4H, J = 8.3 Hz). |
Yield | Reaction Conditions | Operation in experiment |
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76.2% | 2-((3-Pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (5.40 kg, 25.2 mol) and methanol (40.5 L) were added to a 72 L reaction vessel under an inert atmosphere equipped with a mechanical stirrer, temperature probe, low-pressure gas regulator system, and pressure gauge. The headspace was filled with nitrogen, and the mixture was stirred to obtain a clear yellow solution. To the flask was added 10% palladium on carbon (50% wet) (270 g). The atmosphere of the reactor was evacuated using a vacuum pump, and the headspace was replaced with hydrogen to 10 to 20 inches water pressure. The evacuation and pressurization with hydrogen were repeated 2 more times, leaving the reactor under 20 inches water pressure of hydrogen gas after the third pressurization. The reaction mixture was stirred at 20 C.+/-5 C. for a minimum of 12 h, and the reaction was monitored via TLC. Upon completion of the reaction, the suspension was filtered through a bed of Celite545 (1.9 kg) on a sintered glass funnel, and the filter cake was washed with methanol (10.1 L). The filtrate was concentrated to obtain a semi-solid which was transferred, under an nitrogen atmosphere, to a 200 L reaction flask fitted with a mechanical stirrer, condenser, and temperature probe. The semi-solid was dissolved in ethanol (57.2 L), and di-p-toluoyl-D-tartaric acid (DTTA) (9.74 kg, 25.2 mol) was added. The stirring reaction mixture was heated at reflux for a minimum of 1 h, and for an additional minimum of 12 h while the reaction was cooled to between 15 C. and 30 C. The suspension was filtered using a tabletop filter, and the filter cake was washed with ethanol (11.4 L). The product was dried under vacuum at ambient temperature to obtain 11.6 kg (76.2% yield, 59.5% factored for purity) of (2S)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one di-p-toluoyl-D-tartrate salt. |
Yield | Reaction Conditions | Operation in experiment |
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With acetic acid; In propan-1-ol; toluene; at 20 - 40℃; for 4h;Product distribution / selectivity; | Experiment 1: (+)-O,O'-Di-/?-toluoyl-(S,S)-tartaric acid (0.39 eq) was dissolved in 1-propanol (3.44 V). The mixture was heated up to ca. 40 0C and acetic acid (0.2 eq.) was added. This solution was transferred within one hour to a solution of 4-[4-(dimethylamino)- l-(4 '-fluorophenyl)- l-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile free base in 1-propanol (0.95 V) containing 0.1 V of toluene. The resolution mixture, containing now in total 4.4 V 1-propanol was seeded with seed crystals comprising S-4-[4-(dimethylamino)-l-(4 '-fluorophenyl)- l-hydroxybutyl]-3-(hydroxymethyl)- benzonitrile and (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid and then stirred at 40 0C for 2 hours. The mixture was cooled to 20-25 0C within 2 hours. The product was filtered and washed twice with 1-propanol. The enantiomeric purity was typically in the range from about 91% to about 98% S. Experiment 2: (+)-O,O'-Di-/?-toluoyl-(S,S)-tartaric acid (0.4 eq) was dissolved in 1-propanol (3.5 V). The mixture was heated up to ca. 40 0C, acetic acid (0.2 eq.) was added and then the solution is transferred to a solution of 4-[4-(dimethylamino)-l-(4'-fluorophenyl)- l-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile free base in 1-propanol containing <n="11"/>0.1 V toluene. The resolution mixture, containing now in total 4.5 V 1-propanol was seeded with seed crystals comprising S-4-[4-(dimethylamino)-l-(4'-fluorophenyl)- l-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile and (+)-O,O'-di-/?-toluoyl- (S,S)-tartaric acid and then stirred at 40 0C for two hours. The mixture was cooled to 20-25 0C in two hours. The product was filtered (filter reactor) and washed with 1-propanol.The enantiomeric purity was typically around 97% S or higher. An exemplary batch gave molar yield: 33.8%, enantiomeric purity: 99.0% S. | |
In propan-1-ol; dichloromethane; at 20 - 40℃;Product distribution / selectivity; | Experiment 28: Experiment 11 was repeated except that the crystallization mixture did not contain toluene, a mixture of 1-propanol and dichloromethane (85:15) was used as the solvent in stead of 1-propanol in a total volume of 4.5 V, 0.5 eq of (+)-O,O'-di-/?-toluoyl- (S,S)-tartaric acid was used, and the holding time before filtration was overnight. Molar yield: 37.8%, enantiomeric purity: 98.8% S. | |
In propan-1-ol; ethyl acetate; toluene; at 20 - 40℃;Product distribution / selectivity; | Experiment 36: Experiment 11 was repeated except that a mixture of 1-propanol and ethylacetate (31:69) was used as the solvent in stead of 1-propanol in a total volume of 4.5 V whereupon extra 2 V 1-propanol was added, 0.25 eq of (+)-O,O'-di-/?-toluoyl-(S,S)- tartaric acid was used, and the holding time before filtration was 0.5 h. Molar yield: 28.6%, enantiomeric purity: 98.4% S. |
In propan-1-ol; toluene; acetonitrile; at 20 - 40℃;Product distribution / selectivity; | Experiment 33: Experiment 11 was repeated except that a mixture of 1-propanol and acetonitrile (15:85) was used as the solvent in stead of 1-propanol in a total volume of 4.5 V, 0.5 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was 0.5 h. Molar yield: 25.9%, enantiomeric purity: 99.2% S.Experiment 34: Experiment 11 was repeated except that a mixture of 1-propanol and acetonitrile (85:15) was used as the solvent in stead of 1-propanol in a total volume of 4.5 V, 0.5 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was overnight. Molar yield: 18.5%, enantiomeric purity: 99.4% S.Experiment 35: Experiment 11 was repeated except that a mixture of 1-propanol and acetonitrile (90:10) was used as the solvent in stead of 1-propanol in a total volume of 4.5 V, 0.5 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was overnight.Molar yield: 29.9%, enantiomeric purity: 99.3% S. | |
In toluene; acetonitrile; at 20 - 40℃;Product distribution / selectivity; | Experiment 21Experiment 11 was repeated except that acetonitrile was used as the solvent in stead of 1-propanol in a total volume of 10 V, 0.25 eq of (+)-O,O'-di-/?-toluoyl-(S,S)- tartaric acid was used, and the holding time before filtration was overnight. Molar yield: 30.0%, enantiomeric purity: 96.0% S. <n="16"/>Experiment 22Experiment 11 was repeated except that acetonitrile was used as the solvent in stead of 1-propanol in a total volume of 4.5 V, 0.50 eq of (+)-O,O'-di-/?-toluoyl-(S,S)- tartaric acid was used, and the holding time before filtration was overnight. Molar yield: 24.7%, enantiomeric purity: 99.2% S. | |
In propan-1-ol; ethanol; toluene; at 20 - 40℃;Product distribution / selectivity; | Experiment 37: Experiment 11 was repeated except that a mixture of 1-propanol and ethanol (50:50) was used as the solvent in stead of 1-propanol in a total volume of 4.4 V, 0.5 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was 0.5 h. Molar yield: 27.4%, enantiomeric purity: 99.4% S. | |
In propan-1-ol; water; toluene; at 20 - 40℃; for 4h;Product distribution / selectivity; | Experiment 7: The general procedure of Experiment 2 was applied. No acetic acid was present in the system. The experiment was carried out with a small amount of water (0.0 IV) An exemplary batch gave molar yield: 32.5%; enantiomeric purity: 98.7% S. Experiment 8: The general procedure of Experiment 2 was applied. No acetic acid was present in the system. The experiment was carried out with a higher amount of water (0.05V) Exemplary batches gave: Molar yield: 34.7%; enantiomeric purity: 99.0% S. | |
In ethanol; for 1h;Product distribution / selectivity; | Experiment 10: 100 g (0.292 moles) of 4-(4-dimethylamino-l-(4'-fluorophenyl)-l-hydroxybutyl)- 3-(hydroxymethyl)-benzonitrile were dissolved in 150 ml of pure ethanol at 40 0C.Maintaining the temperature around 40 0C, a solution made of 57.5 g (0.148 moles) of(+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid and 350 ml of pure ethanol was added in one <n="13"/>hour. The mixture was seeded and then cooled to room temperature overnight. The suspension was cooled to O0C and then filtered. Molar yield 29.5%, enantiomeric purity 98.2 % S. | |
In propan-1-ol; water; at 20 - 40℃; for 4h;Product distribution / selectivity; | Experiment 4: The general procedure of Experiment 2 was applied. To the 4-[4-(dimethylamino)- l-(4'-fluorophenyl)-l-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile free base solution in 1-propanol was added 0.05 V of water. No toluene or acetic acid was present in the system. An exemplary batch gave molar yield: 29.3%; enantiomeric purity: 99.3% S. | |
In propan-1-ol; water; at 20 - 40℃; for 4h;Product distribution / selectivity; | Experiment 9: The general procedure of Experiment 2 was applied. Additionally a small amount of water (0.05 V) was added to the 4-[4-(dimethylamino)-l-(4'-fluorophenyl)- l-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile free base solution in 1-propanol. An exemplary batch gave molar yield: 33.0%; enantiomeric purity: 99.1% S. | |
In propan-1-ol; at 20 - 40℃; for 4h;Product distribution / selectivity; | Experiment 3: The general procedure of Experiment 2 was applied, however 0.5 eq of (+)-O,O'-di- /?-toluoyl-(S,S)-tartaric acid and 10V of 1-propanol were used. No toluene or acetic acid was present in the system. An exemplary batch gave molar yield: 29.5%; enantiomeric purity: 99.2% S. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In propan-1-ol; toluene; at 20 - 40℃;Product distribution / selectivity; | Experiment 5: The general procedure of Experiment 2 was applied using only 0.25 eq of (+)-O,O'- di-/?-toluoyl-(S,S)-tartaric acid. No acetic acid was present in the system. An exemplary batch gave molar yield: 29.4%; enantiomeric purity: 99.0% S. Experiment 6: The general procedure of Experiment 2 was applied. No acetic acid was present in the system. An exemplary batch gave molar yield: 32.6%; enantiomeric purity: 98.0% S. Experiment 11(+)-O,O'-Di-/?-toluoyl-(S,S)-tartaric acid (0.25 eq) was dissolved in 1-propanol (200 ml). The mixture was heated up to ca. 40 0C and then the solution was transferred to a solution of 4-[4-(dimethylamino)-l-(4 '-fluorophenyl)- l-hydroxybutyl]-3-(hydroxyl- methyl)-benzonitrile free base (100 g) in 1-propanol (100 ml) containing H g toluene. The resolution mixture, containing now in total 3 V 1-propanol was seeded at 40 0C with seed crystals comprising S-4-[4-(dimethylamino)-l-(4'-fluorophenyl)- l-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile and (+)-O,O'-di-/?-toluoyl- (S,S)-tartaric acid and then stirred at 40 0C for two hours. The mixture was cooled to 20 0C in two hours and kept at 20 0C overnight. The product was filtered (filter reactor) and washed with 1-propanol. Molar yield: 31.8%, enantiomeric purity: 95.5% S.Experiment 12Experiment 11 was repeated except that the total volume of 1-propanol was 10 V. Molar yield: 30.7%, enantiomeric purity: 98.9% S.Experiment 13Experiment 11 was repeated except that the total volume of 1-propanol was 4.3 V and 0.39 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used. This example was repeated several times. The crystallization batches were kept at 20 0C for up to 16 h, typically up to 8 h. Molar yields: about 35%, enantiomeric purity: > 98% S. Experiment 14Experiment 11 was repeated except that the total volume of 1-propanol was 4.5 V, 0.50 eq of (+)-0,0'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was 0.5 h.Molar yield: 36%, enantiomeric purity: 97.2% S.Experiment 15Experiment 11 was repeated except that the total volume of 1-propanol was 4.4 V, 0.60 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was 0.5 h. Molar yield: 38.9%, enantiomeric purity: 82.8% S.Experiment 16Experiment 11 was repeated except that the total volume of 1-propanol was 4.5 V, 0.675 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was overnight. Molar yield: 35.2%, enantiomeric purity: 76.2% S.Experiment 17Experiment 11 was repeated except that the total volume of 1-propanol was 6 V, 0.75 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was 0.5 h. Molar yield: 24.8%, enantiomeric purity: 99.4% S. Experiment 18Experiment 11 was repeated except that the total volume of 1-propanol was 6 V, 0.75 eq of (+)-0,0'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was overnight.Molar yield: 31%, enantiomeric purity: 99.4% S.Experiment 19Experiment 11 was repeated except that the total volume of 1-propanol was 4.5 V, 0.75 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was overnight. Molar yield: 30.3%, enantiomeric purity: 99.0% S.Experiment 20Experiment 11 was repeated except that the total volume of 1-propanol was 4.5 V, 0.75 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was 4 days. Molar yield: 32.2%, enantiomeric purity: 92.8% S. | |
In propan-1-ol; dichloromethane; toluene; at 20 - 40℃;Product distribution / selectivity; | Experiment 23Experiment 11 was repeated except that a mixture of 1-propanol and dichloromethane (50:50) was used as the solvent in stead of 1-propanol in a total volume of 2 V (The (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid and 4-[4-(dimethylamino)-l-(4'-fluoro- phenyl)-l-hydroxybutyl]-3-(hydroxylmethyl)-benzonitrile free base were dissolved in 4.5 V dichloromethane, 3.5 V dichloromethane was distilled off and 1 V 1-propanol was added), 0.25 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was overnight. Molar yield: 18.5%, enantiomeric purity: 96.9% S.Experiment 24Experiment 11 was repeated except that a mixture of 1-propanol and dichloromethane (95:5) was used as the solvent in stead of 1-propanol in a total volume of 4.5 V, 0.35 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was overnight. Molar yield: 35.7%, enantiomeric purity: 78.8% S.Experiment 25Experiment 11 was repeated except that a mixture of 1-propanol and dichloromethane (85:15) was used as the solvent in stead of 1-propanol in a total volume of 4.5 V, 0.4 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was overnight. <n="17"/>Molar yield: 31%, enantiomeric purity: 98.2% S.Experiment 26Experiment 11 was repeated except that a mixture of 1-propanol and dichloromethane (50:50) was used as the solvent in stead of 1-propanol in a total volume of 4.4 V, 0.5 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was overnight. Molar yield: 16.4%, enantiomeric purity: 98.9% S.Experiment 27Experiment 11 was repeated except that a mixture of 1-propanol and dichloromethane (75:25) was used as the solvent in stead of 1-propanol in a total volume of 4.5 V, 0.5 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was overnight. Molar yield: 34.2%, enantiomeric purity: 98.8% S.Experiment 29Experiment 11 was repeated except that a mixture of 1-propanol and dichloromethane (85:15) was used as the solvent in stead of 1-propanol in a total volume of 4.5 V, 0.5 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was overnight. Molar yield: 36.6%, enantiomeric purity: 97.6% S.Experiment 29aExperiment 11 was repeated except that a mixture of 1-propanol and dichloromethane (90:10) was used as the solvent in stead of 1-propanol in a total volume of 4.5 V, 0.5 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was overnight. This experiment was performed twice with the following results. Molar yield: 38.9%, enantiomeric purity: 97.7% S. Molar yield: 35.8%, enantiomeric purity: 98.5% S.Experiment 30Experiment 11 was repeated except that a mixture of 1-propanol and dichloromethane (92.5:7.5) was used as the solvent in stead of 1-propanol in a total volume of 6.0 V, 0.5 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was overnight. This experiment was performed twice with the following results. Molar yield: 35.1%, enantiomeric purity: 98.6% S. Molar yield: 39.0%, enantiomeric purity: 81.3% S.Experiment 31Experiment 11 was repeated except that a mixture of 1-propanol and dichloromethane (95:5) was used as the solvent in stead of 1-propanol in a total volume of 4.5 V, 0.5 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was 0.5 h. Molar yield: 35.0%, enantiomeric purity: 98.4% S. Experiment 32Experiment 11 was repeated except that a mixture of 1-propanol and dichloromethane (90:10) was used as the solvent in stead of 1-propanol in a total volume of 4.6 V, 0.6 eq of (+)-O,O'-di-/?-toluoyl-(S,S)-tartaric acid was used, and the holding time before filtration was overnight. Molar yield: 38.5%, enantiomeric purity: 99.1% S. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(+/-)-Diol oxalate (VIa) (225 g, 0.52 mol) was suspended in a mixture of DM water (2250 ml) and toluene (2250 ml) at 30-35 C. and pH was raised to 9.8 using aqueous ammonia solution. The organic layer was separated, was washed with DM water and concentrated at 50-55 C. under reduced pressure. The obtained residue was dissolved in isopropyl alcohol (1125 ml) at 50-55 C. (+)-Di-p-toluoyl-D-tartaric acid (105 g, 0.27 mol) was added and slowly cooled to 25-30 C. and stirred for 10 h. The crystals formed in the reaction mixture were filtered and washed with isopropyl alcohol (2×110 ml) to obtain180 g product (chiral purity:>96%).The above salt was suspended in isopropyl alcohol (1500 ml) and heated to 80 C. to obtain a clear solution. The resulting solution was cooled to 20-25 C. and stirred for 1 hr. The solids were filtered and washed with isopropyl alcohol (2×50 ml) and thereafter dried to yield 102 g of the above salt. Chiral purity (by HPLC): 99.94%; [alpha]D: +8.0 (c=1, in methanol, on anhydrous basis). | ||
(+/-)-Diol oxalate (Via) (225 g, 0.52 mol) was suspended in a mixture of DM water (2250 ml) and toluene (2250 ml) at 30-35c and pH was raised to 9.8 using aqueous ammonia solution. The organic layer was separated, was washed with DM water and concentrated at 50-55C under reduced pressure. The obtained residue was dissolved in isopropyl alcohol (1125 ml) at 50-55C. (+)-Di-p- toluoyl-D-tartaric acid (105 g, 0.27 mol) was added and slowly cooled to 25-30C and stirred for 1O h. The crystals formed in the reaction mixture were filtered and washed with isopropyl alcohol (2x110 ml) to obtain ~ 180 g product (chiral purity: >96%).The above salt was suspended in isopropyl alcohol (1500 ml) and heated to 80C to obtain a clear solution. The resulting solution was cooled to 20-25C and stirred for 1 hr. The solids were filtered and washed with isopropyl alcohol (2 x 50 ml) and thereafter dried to yield 102 g of the above salt. Chiral purity (by HPLC): 99.94%; [alpha]o: +8.0 (c=l, in methanol, on anhydrous basis). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The 100-mL, 4-necked round-bottomed flask equipped with a mechanical stirrer, addition funnel, digital thermometer and condenser with nitrogen inlet-outlet is charged with 4.77 g (0.0244 mol) of crude compound D-7 (diastereomeric mixture 1 : 1) and 50 mL of ethanol 200 proof. Then add the solution of 9.44 g (0.0244 mol) of (+)-di-p-toluoyl-D- tartaric acid 30 mL of ethanol 200 proof over 7 minutes while maintaining an internal temperature at 20 - 25 0C and stir the mixture at an internal temperature 22 +/- 2 0C for 14 h. Warm up the mixture to internal temperature 50 +/- 2 0C and stir at this temperature for an additional 2 h. Collect the solid by hot filtration over a Bchner funnel, and wash the solid with 3 x 5 mL of ethanol 200 proof. Concentrate the filtrate under reduced pressure (100 -12 mbar) at an internal temperature 35- 40 0C. To the residue add 20 mL of water and 8 mL of 6 N aqueous solution of sodium hydroxide to pH ~ 12. Then add 3 x 35 mL of isopropyl acetate and separated the phases. Combine the organic layers and wash with 25 mL of 15% aqueous solution of sodium chloride. Separate the phases and concentrate the organic layer under reduced pressure (100 -12 mbar) at an internal temperature 35- 40 0C. To the residue (~ 3.1 g; 0.0159 mol) add 20 mL of ethanol 200 proof and then add the solution of 4.29 g (0.0111 mol) of (-)-di-p-toluoyl-L-tartaric acid in 10 mL of ethanol 200 proof over 7 minutes while maintaining an internal temperature at 20 - 23 0C. Stir the reaction mixture at an internal temperature 22 +/- 2 0C for 7 h. Warm up the mixture to an internal temperature 50 +/- 2 0C and stir at this temperature for an additional 2 h. Cool to an internal temperature 22 +/- 2 0C and collect the solid by filtration over a Bchner funnel, and wash the solid with 3 x 5 mL of ethanol 200 proof. Then suspend the solid ( ~ 2.03 g) in 25 mL of ethanol 200 proof at an internal temperature 22 +/- 2 0C and warm up the mixture to an internal temperature 77 +/- 2 0C. Then add slowly 40 mL of methanol to get a solution at reflux. Cool the solution to an internal temperature 40 +/- 2 0C and <n="132"/>concentrate the solution under reduced pressure (50-40 mbar) at an internal temperature 38 +/- 2 0C to a batch volume of - 25 -30 mL ( light suspension). Then cool to an internal temperature 22 +/- 2 0C and stir the suspension for 48 h. Collect the solid by filtration over a Bchner funnel, and wash the solid with 3 x 2 mL of ethanol 200 proof. Dry the solid under reduced pressure (20 mbar) at 35 0C for 12 h to give 1.27 g of D-8 salts in ratio of desired diastereomer / undesired = 97.4 / 2.6. (The desired diastereomer is forming salt with (-)-di-p-toluoyl-L-tartaric acid in ratio 2 / 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In water; butan-1-ol; at 20 - 25℃;Resolution of racemate; | Example 3: Resolution of racemic pregabalin (2) by a method similar to the one depicted in Scheme 2 but using O,O -di-p-toluoyl-(D)-tartaric acid; Preparation of (S)-pregabalin 0.0 '-di-p-toluoyl-(D)-tartrate (6):A mixture of racemic 3-aminoethyl-5-methylhexanoic acid (2) (10Og), 0,0 '-di-p-toluoyl- (D)-tartaric acid (126g), t-butanol (1.01) and water (200ml) was stirred at 20-250C to obtain a clear solution. Then the clear solution was filtered, cooled to 0-50C, and stirred at 0-50C for 4 hours. The solid obtained was filtered off and dried under vacuum at 40-450C. Yield: 168g (98% molar, 49% w/w). Enantiomeric purity: 96.0% S-isomer {as measured by chiral HPLC). Chemical purity: 99.50% (as measured by HPLC). No lactam impurity was observed by HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Reference Example 12 4-Aminothiophenol (2.5 g) was dissolved in water (2.5 ml) and isopropanol (10 ml). Triethylamine (5.5 ml) was added thereto, and then the mixture was cooled to -15 to -10C. A solution of 5-(chloromethyl)-1-propyl-1H-imidazole hydrochloride (3.9 g) in water (2.5 ml) was added dropwise thereto at -15 to -10C, and the mixture was stirred at the same temperature for 1 hour. After isopropanol was distilled off under reduced pressure, methyl isobutyl ketone (25 ml) was then added, and the organic layer was washed with water. To the organic layer was added activated carbon (0.1 g), and the mixture was stirred at room temperature for 10 minutes. The organic layer was concentrated and dissolved in methyl isobutyl ketone (30 ml). Separately, di-p-toluoyl-(D)-tartaric acid (7.7 g) was dissolved in a mixed solution of toluene (90 ml) and methyl isobutyl ketone (60 ml), and to the solution was added water (3.6 ml). Then, the above methyl isobutyl ketone solution was slowly added dropwise over 2 hours. After stirring the resulting mixture for 1 hour, 30% hydrogen peroxide solution (6.8 g) was added thereto, and the mixture was stirred at room temperature for 24 hours. Methanol (30 ml) was added thereto and the mixture was stirred at 50C for 8 hours. Water (30 ml) was added thereto, and the mixture was stirred at room temperature for 5 hours. The precipitated crystals were collected by filtration and washed with water (30 ml) to give (-)-4-[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenylamine di-p-toluoyl-D-tartrate monohydrate (7.1 g). m.p. 134-136C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Reference Example 54 4-Aminothiophenol (2.5 g) was dissolved in water (2.5 ml) and isopropanol (10 ml). Triethylamine (5.5 ml) was added thereto, and then the mixture was cooled to -15 to -10C. A solution of 5-(chloromethyl)-1-propyl-1H-imidazole hydrochloride (3.9 g) in water (2.5 ml) was added dropwise at -15 to -10C, and the mixture was stirred at the same temperature for 1 hour. After isopropanol was distilled off under reduced pressure, methyl isobutyl ketone (25 ml) was added thereto, and the organic layer was washed with water. To the organic layer was added activated carbon (0.1 g), and the mixture was stirred at room temperature for 10 minutes. The organic layer was concentrated and dissolved in methyl isobutyl ketone (30 ml). Separately, di-p-toluoyl-(D)-tartaric acid (7.7 g) was dissolved in a mixed solution of toluene (90 ml) and methyl isobutyl ketone (60 ml), and to the solution was added water (3.6 ml). Then, the above methyl isobutyl ketone solution was slowly added dropwise over 2 hours. After stirring the resulting mixture for 1 hour, aqueous 30% hydrogen peroxide (6.8 g) was added thereto, and the mixture was stirred at room temperature for 24 hours. Methanol (30 ml) was added thereto and the mixture was stirred at 50C for 8 hours. Water (30 ml) was added thereto, and the mixture was stirred at room temperature for 5 hours. The precipitated crystals were collected by filtration and washed with water (30 ml) to give (-)-4-[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenylamine di-p-toluoyl-D-tartrate monohydrate (7.1 g). m.p. 134-136C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A reactor was charged with compound 2 (10.8 kg) and ethyl acetate (48 kg). The mixture was maintained at 20 to 25 C. for a minimum of 30 minutes until all of the solids have dissolved. The solution was cooled to 0 to 5 C. Triethylamine (0.4 kg) was charged to the reactor and the transfer equipment was rinsed forward with ethyl acetate (1 kg). Ethyl chloroformate (5.6 kg) was charged to the reactor while maintaining a temperature of 0 to 15 C. The transfer equipment was rinsed forward with ethyl acetate (3 kg). The mixture was maintained at 20 to 25 C. for a minimum of 3 hours. Sodium hydroxide, 50% (7.6 kg) was charged to the reactor while maintaining a temperature of 0 to 38 C. The transfer equipment was rinsed forward with water (17 L). The solution was maintained at 20 to 25 C. for a minimum of 20 minutes and the pH of the solution was checked to ensure it was above 10. The biphasic solution was separated and the organic layer was washed twice with water (22 L). The organic solution was dried via azeotropic distillation, and then reduced to a concentrate volume of 20 to 24 L via atmospheric distillation. The solution was cooled to 40 to SOC. Ethanol 1× (60 kg) was charged to the reactor. The solution was reduced to a concentrate volume of 30 to 34 L via atmospheric distillation and cooled to 55 to 60 C. A glass-lined reactor was charged with (+)-di-p-toluoyl-D-tartaric acid (15.8 kg) and ethanol 1× (51 kg). With moderate agitation, the temperature was adjusted to 60 to 65 C. The reaction mixture was transferred into the acid solution while maintaining a temperature of 60 to 70 C. The transfer equipment was rinsed forward with ethanol 1× (17 kg). The solution was maintained at 60 to 65 C. for a period of 1 to 1.5 hours. The suspension was cooled to 50 to 55 C. and maintained for a period of 2 to 2.5 hours. The suspension was cooled to 20 to 25 C. over a minimum of 3 hours and maintained for a minimum of 10 hours. The solid was isolated by filtration, washed with ethanol 1× (17 kg), dried and packaged. The packaged crude product was sampled and tested for chiral purity of compound 3. A reactor was charged with the crude product and ethanol 1× (as per calculation). The mixture was adjusted to 60 to 65 C. and maintained for a period of 2 to 2.5 hours. The suspension was cooled to 20 to 25 C. over a minimum of 2 hours. The suspension was cooled to 0 to 5 C. and maintained for a minimum of 3 hours. The solid compound 3 was isolated via filtration, washed with cold ethanol 1× (17 kg), dried and packaged. The packaged product was sampled, tested, HPLC purity not less than 99.0% a/a; Chiral HPLC, not less than 99.5% and released prior to use in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47%; 52% | In ethanol; at 20℃; for 2h; | To a solution of compound 6 (222.3 g, 0,73 mol) in ethanol (5.5 L) at room temperature was quickly added a solution of di-/>-toluoyl-i>tartaric acid (292.2 g, 0.73 mol) in ethanol (1.0 L) with no internal temperature increase noted. The reaction solution was stirred at room temperature. Precipitate started to form within 10 min. After stirring for 2 h, the reaction slurry was filtered and the cake was dried at 600C in vacuo for 12 h to give the (45)-enriched tartrate salt (265.0 g, 52%, with a ratio of enantiomers of approximately 84: 16, CHIRALCEL AD, heptane:IPA:diethyl amine 90:10: 0.01). The filtrate was concentrated in vacuo and <n="28"/>dried at 600C to give the 4i?-enriched tartrate salt (238.0 g, 47%., ratio of enantiomers of approximately 3:97). The desired 4S enriched tartrate salt was treated with aqueous sodium hydroxide and separated by preparative chiral chromatography to give pure compound 7. (Preparative chiral chromatography was carried out in two batches of enriched racemate, 117g and 93 g, respectively. The following conditions were used for the 117g batch: Thar 350 SFC; Column: CHIRALPAK AD-H, 5 X 25 cm; Mobile phase: 30% IPA + 0.05% DEA/CO2; Pressure: 100 bar; Temperature:450C; Flow rate: 240 g/min; Solution concentration -250 mg/ml; Injection amount: 8 mL; Cycle time: 10.5 min/inj; Detector: 254 nM; Throughput: 11-12 g/hr. The sample was dissolved in warm 275 mL MeOH and 95 mL EPA with 0.5 mL DEA added). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol; at 40℃; for 1h; | Step (b): The mother liquor obtained in the resolution as well as purification in step a) was distilled completely. The residue was treated with aqueous ammonia in a mixture of water and toluene. The organic layer was separated and distilled completely to obtain 60 gm of second mixture of isomers as residue.300 ml of isopropyl alcohol was charged to the above residue and stirred to dissolve. 30 gm of (+) -DPTTA was added to the above solution and heated to about 40 C. The reaction mixture was stirred for one hour and <n="23"/>then cooled to room temperature. The reaction suspension was stirred for about- 2 hours for complete isolation of the solid. The reaction mixture was filtered and washed with IPA (20 ml). The wet solid was charged in 200 ml of IPA, heated to reflux and stirred for about 30 minutes. The reaction mixture was cooled to room temperature and stirred for about 30 minutes, filtered the solid and washed with IPA (20 ml). The wet solid was dried to obtain 64 gm of title compound as solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In ethanol; | Optical resolution of (+/-)-lofexidine hydrochloride by using the classical methods of salt formation with a chiral acid such as, [( Di-p-toluoyl-D-tartaric acid [D]D20 +142 (c=l, CH3OH)] as shown in Figure 1, yielded (-)-lofexidine hydrochloride and (+)-lofexidine hydrochloride enantiomers (yield = 87%). The method comprised the following steps: [0032] A racemic form of lofexidine (10 mmol) was placed in ethanol (100 mL), and the chiral acid (+)-Di-p-toluoyl-D-tartaric acid was added in order to form a mixture of the (+)(-) and (+)(+) diastereomeric lofexidine salts. The diastereomeric salts i.e.: (+)(-) lofexidine Di-p- toluoyl-D-tartarate salt was separated from the (+)(+) lofexidine Di-p-toluoyl-D-tartarate salt by a process of fractional crystallization. 10 mL methanol and 1 ml water was added and the mixture was heated for 1 hour at 55-65 0C. After the mixture became clear it was left to cool down at room temperature. The crystals were isolated after two days, dried under vacuum. Recrystallization was performed using ethanol (20 volumes). Final yield was 87%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol; at 20 - 45℃;Heating; | 350 ml of isopropyl alcohol was charged to the residue and heated and stirred, then cooled to room temperature. 35 gm of (+)-DPTTA was added to the above solution and stirred for one hour at room temperature to isolation of the solid. The reaction mixture was heated to about 40-45 C, stirred for about 2 hours. The reaction mixture was cooled to room temperature, filtered the solid and dried to get 39 gm of the title compound. | |
In isopropyl alcohol; at 20 - 45℃; for 3h;Product distribution / selectivity; | 350 ml of isopropyl alcohol was charged to the residue and heated and stirred, then cooled to room temperature. 35 gm of (+)-DPTTA was added to the above solution and stirred for one hour at room temperature to isolation of the solid. The reaction mixture was heated to about 40-45C., stirred for about 2 hours. The reaction mixture was cooled to room temperature, filtered the solid and dried to get 39 gm of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In ethyl acetate; at 25 - 65℃; for 0.75h; | Racemic cinacalcet (32 g, 0.0896 mol) was transferred along with 20 ml of ethyl acetate and (-)-di-para-D-toluoyl tartaric acid (36 g, 0.0896 mol) was added lot wise (Exotherm was observed) and stirred for 15 minutes at 25-30C and further stirred at 65C for 30 minutes. The reaction mass was cooled to 0-50C, stirred for 2 hours and the solid obtained was filtered and washed twice with 50 mL of chilled ethyl acetate and suck dried. The obtained DPTTA salt of cinacalet was dried in vacuum oven at 55-60C for 10 hours. The so obtained salt was further recrystallised from ethyl acetate. Yield - 25 g (78% of theory) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.3% | In ethyl acetate; at 25 - 65℃; for 0.75h; | The compound VI obtained from example 4 (70 g, 0.18 mol) was dissolved in 250 mL of ethyl acetate in a clean flask and (-)-di-para-D-toluoyl tartaric acid (70 g, 0.18 mol) was added lot wise (Exotherm was observed). The reaction mass was stirred for 15 minutes at 25- 3O0C and further stirred at 65C temperature for 30 minutes. The reaction mass was cooled to 0-50C, stirred for 2 hours and the solid obtained was filtered and washed twice with 50 mL of chilled ethyl acetate and suck dried. The solid was dried in vacuum oven at 55-600C for 10 hours. Yield- 53 g (74.3% of theory) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.5% | In ethanol; at 20℃;Reflux; | Example 25: (R)-5-((E)-2-Pyrrolidin-3-ylvinyl)pyrimidine hemi-di-p-toluoyl-D- tartarateSolid di-p-toluoyl-D-tartarate salts was obtained according to the "hemi" salt screening procedure from isopropyl acetate or acetonitrile by evaporation, or by evaporation if isopropyl acetate followed by maturation with tetrahydrofuran or by evaporation of acetonitrile followed by maturation with isopropyl alcohol.The following procedure was used to make a larger quantity of the salt. (+)- 0,0'-Di-p-toluoyl-D-tartaric acid (1.103 g, 2.85mmol) was added as a solid to a stirring, warm solution of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine free base (1.007 g, 5.74 mmol) in ethanol (10 mL). A few insoluble solids precipitated that failed to dissolve upon heating the mixture to reflux. The light amber solution (with a few fine solids) was stirred for 4-5 h and then allowed to stand at ambient temperature overnight. The precipitation of the salt as a light beige powder was slow. After stirring for 15 days, the solids were filtered, washed with ethanol (5 mL) and dried in a vacuum oven at 50 0C for 21 h to give 1.50 g (71.5%) of an off-white to slightly yellow-tinged powder, mp 178-180 0C. 1H NMR (DMSO-d6) confirms the 1 :0.5 base:acid salt stoichiometry. 1H NMR (DMSO-d6): delta 10.30 (broad s, ~1 H), 9.02 (s, 1 H), 8.80 (s, 2H), 7.87 (d, 2H, -C6H4-, indicating a hemi-salt stoichiometry), 7.27 (d, 2H, -C6H4-, indicating a hemi-salt stoichiometry), 6.40 (dd, 1 H), 6.34 (d, 1 H), 5.58 (s, 1 H, CH(CO2H)-O- of acid moiety, indicating a hemi-salt stoichiometry), 3.21 (dd, 1 H), 3.14 (m, 1 H), 3.00 (m, 1 H), 2.86 (m, 1 H), 2.75 (dd, 1 H), 2.30 (s, 3H, -CH3 of acid moiety, indicating a hemi-salt stoichiometry), 1.93 (m, 1 H), 1.61 (m, 1 H). |
71.5% | In ethanol;Reflux; | Solid di-p-toluoyl-D-tartarate salts was obtained according to the "hemi" salt screening procedure from isopropyl acetate or acetonitrile by evaporation, or by evaporation if isopropyl acetate followed by maturation with tetrahydrofuran or by evaporation of acetonitrile followed by maturation with isopropyl alcohol.The following procedure was used to make a larger quantity of the salt. (+)-0,0'-Di- p-toluoyl-D-tartaric acid (1.103 g, 2.85mmol) was added as a solid to a stirring, warm solution of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine free base (1.007 g, 5.74 mmol) in ethanol (10 mL). A few insoluble solids precipitated that failed to dissolve upon heating the mixture to reflux. The light amber solution (with a few fine solids) was stirred for 4-5 h and then allowed to stand at ambient temperature overnight. The precipitation of the salt as a light beige powder was slow. After stirring for 15 days, the solids were filtered, washed with ethanol (5 mL) and dried in a vacuum oven at 50 C for 21 h to give 1.50 g (71.5%) of an off-white to slightly yellow-tinged powder, mp 178-180 C. 1H NMR (DMSO-d6) confirms the 1 :0.5 base:acid salt stoichiometry. 1H NMR (DMSO-d6): delta 10.30 (broad s, ~1 H), 9.02 (s, 1 H), 8.80 (s, 2H), 7.87 (d, 2H, -C6H4-, indicating a hemi-salt stoichiometry), 7.27 (d, 2H, - C6H4-, indicating a hemi-salt stoichiometry), 6.40 (dd, 1 H), 6.34 (d, 1 H), 5.58 (s, 1 H, CH(C02H)-0- of acid moiety, indicating a hemi-salt stoichiometry), 3.21 (dd, 1 H), 3.14 (m, 1 H), 3.00 (m, 1H), 2.86 (m, 1 H), 2.75 (dd, 1 H), 2.30 (s, 3H, -CH3 of acid moiety, indicating a hemi-salt stoichiometry), 1.93 (m, 1H), 1.61 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.1% | In ethanol;Reflux; | Example 28: (R)-5-((E)-2-Pyrrolidin-3-ylvinyl)pyrimidine mono-di-p-toluoyl-D- tartarateSolid di-p-toluoyl-D-tartarate salts were obtained according to the "mono" salt screening procedure from isopropyl acetate or acetonitrile by evaporation.The following procedure was used to make a larger quantity of the salt. (+)- 0,0'-Di-p-toluoyl-D-tartaric acid (2.205 g, 5.71 mmol) was added as a solid to a stirring, warm solution of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine free base (1.000 g, 5.70 mmol) in ethanol (21 ml_). Precipitation of the salt was immediate. After gently heating the stirring mixture on a hot plate to near reflux, the resulting mixture was cooled to ambient temperature. The resulting solids were filtered, washed with ethanol (3 x 5 mL), and dried in a vacuum oven at 50 0C for 13 h to give 3.081 g (96.1%) of a light-beige powder, mp 181-184 0C. 1H NMR (DMSO-d6) confirmed the 1 :1 salt stoichiometry. .1H NMR (DMSO-d6): delta 9.60 (broad s, ~1H), 9.03 (s, 1H), 8.82 (s, 2H), 7.83 (d, 4H, -C6H4-, indicating a mono-salt stoichiometry), 7.27 (d, 4H, -C6H4- , indicating a mono-salt stoichiometry), 6.44 (d, 2H), 5.62 (s, 2H, CH(CO2H)-O- of acid moiety, indicating a mono-salt stoichiometry), 3.30 (dd, 1 H), 3.23 (m, 1 H), 3.09 (m, 1 H), 2.95 (m, 1 H), 2.85 (dd, 1 H), 2.33 (6H, -CH3 of acid moiety, indicating a mono-salt stoichiometry), 2.02 (m, 1 H), 1.69 (m, 1 H). |
96.1% | In ethanol;Reflux; | Solid di-p-toluoyl-D-tartarate salts were obtained according to the "mono" salt screening procedure from isopropyl acetate or acetonitrile by evaporation.The following procedure was used to make a larger quantity of the salt. (+)-0,0'-Di- p-toluoyl-D-tartaric acid (2.205 g, 5.71 mmol) was added as a solid to a stirring, warm solution of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine free base (1.000 g, 5.70 mmol) in ethanol (21 mL). Precipitation of the salt was immediate. After gently heating the stirring mixture on a hot plate to near reflux, the resulting mixture was cooled to ambient temperature. The resulting solids were filtered, washed with ethanol (3 x 5 mL), and dried in a vacuum oven at 50 C for 13 h to give 3.081 g (96.1%) of a light-beige powder, mp 181- 184 C. H NMR (DMSO-d6) confirmed the 1 :1 salt stoichiometry. .1H NMR (DMSO-d6): delta 9.60 (broad s, ~1 H), 9.03 (s, 1 H), 8.82 (s, 2H), 7.83 (d, 4H, -C6H4-, indicating a mono-salt stoichiometry), 7.27 (d, 4H, -C6H4-, indicating a mono-salt stoichiometry), 6.44 (d, 2H), 5.62 (s, 2H, CH(C02H)-0- of acid moiety, indicating a mono-salt stoichiometry), 3.30 (dd, 1 H), 3.23 (m, 1 H), 3.09 (m, 1 H), 2.95 (m, 1 H), 2.85 (dd, 1 H), 2.33 (6H, -CH3 of acid moiety, indicating a mono-salt stoichiometry), 2.02 (m, 1 H), 1.69 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.7% | With toluene-4-sulfonic acid; In methanol; water; at 25 - 60℃;Product distribution / selectivity; | Step-I: Purification of (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine di-p-toluoyl-D-tartaric acid salt to improve chiral purity(S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine di-p-toluoyl-D-tartaric acid salt (70 g) was taken in a mixture of methanol (420 ml) and water (280 ml), and the resulting mixture was heated at 55-60 C. for 1 hour. The reaction mass was cooled to 25-30 C. and stirred for 2 hours. The precipitated solid was filtered and washed with (1:1) methanol water mixture (140 ml) and then dried at 50-55 C. for 3-4 hours to give 60 g of (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine di-p-toluoyl-D-tartaric acid salt (Yield: 85.7%). |
Yield | Reaction Conditions | Operation in experiment |
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Example 2: Preparation of M galantamine tartarate; Racemic galantamine hydrobromide (100 gm) was dissolved in water (3200 ml) andthe solution was filtered through celite bed. The celite bed was washed with water (300ml) and washings were combined with the filtrate. The combined aqueous layer waswashed with dichloromethane (300 ml) and the organic layer was discarded. To theaqueous layer, dichloromethane (1000 ml) was charged and pH of the aqueous layerwas adjusted to 8.9 to 9.1 using aqueous ammonia at 0 - 5C. The aqueous layer wasseparated and extracted with dichloromethane (100 ml). The combined organic layerswere washed with water (2 x 300 ml) and the organic layer was concentrated undervacuum at 30 - 35C. The residue was dissolved in methanol (200 ml) and cooled to 5- 10C. Di-p-toluoyl-D-tartaric acid (105 gm) was separately dissolved in methanol(300 ml) and cooled to 5 - 10C. The solution of tartaric acid was added to the solutionof the compound and additional quantity of methanol (250 ml) was used to wash theflask containing solution of tartaric acid. This mixture was stirred for 30 min at 5 -10C and for 24 hours at 0 - 2C. The solids were filtered and washed with coldmethanol (300 ml). The wet product was crystallized in ethanol (400 ml) by refluxingfor 30 minutes followed by stirring at 0 - 2C for 3 hours,.solid was filtered andwashed with cold ethanol (100 ml). Crystallization in ethanol was repeated again.Finally, the product was refluxed with methanol (400 ml) for 30 minutes, cooled to 15- 20C, stirred for 3 hours and filtered. It was washed with methanol (100 ml) and airdried at 50 - 55 C till loss on drying was not more than 1.0%.Yield: 57 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; ethyl acetate; at 25℃; for 5h;Resolution of racemate; Reflux; | The hydrobromide salt of racemic 4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxy-butyl]-3-(hydroxymethyl)-benzonitrile (50 g) was placed into a round bottom flask. Ethyl acetate (125 mL) was added and the mixture was stirred at 25-35 C. Aqueous sodium carbonate solution (19 g in 125 mL water) was added and the mixture was stirred at about 25-35 C. for 20 minutes. The layers were separated. The aqueous layer was extracted with ethyl acetate (125 mL). The organic layers were combined and washed with water (125 mL) followed by 10% sodium chloride solution (125 mL). The organic layer was evaporated under reduced pressure. The obtained residue was mixed with isopropanol (250 mL) and the mixture was heated at 40-50 C. for 10 minutes. (-)-Di-p-toluoyltartaric acid (23.8 g) was added. The mixture was stirred at 40-50 C. for 5 hours. The formed solid was filtered and washed with isopropanol (40 mL). The filtrate was evaporated under reduced pressure. The residue was mixed with ethyl acetate (125 mL). Aqueous sodium carbonate solution (12.3 g in 125 mL water) was added and the mixture was stirred at 25-35 C. for 20 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (125 mL). The organic layers were combined and washed with water (125 mL) followed by 10% sodium chloride solution (125 mL). The solvent was evaporated under reduced pressure and the residue was mixed with a solvent mixture containing 3% by volume methanol in ethyl acetate (400 mL). (+) Di-p-toluoyltartaric acid (15 g) was added and the mixture was stirred at 25-35 C. for 3 hours. The mixture was heated to reflux, maintained at that temperature for 2 hours, and was cooled to 25-35 C. The solid was filtered, washed with a solvent mixture containing 3% methanol in ethyl acetate (50 mL) and dried at 50 C. Yield 83.8% of single enantiomer, chiral purity 98.35%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | In ethanol; water; at 65℃; for 0.5h;Inert atmosphere; Industry scale; | Example 1 Preparation of (-)-2-(2-Aminoethyl)-1-methylpyrrolidine, 0, 0 -Di-p-toluoyl-D-tartaric acid saltA stock solution of aqueous ethanol was prepared by mixing ethanol (10370 mL) and water (2080 mL). A mixture of O,O'-di-p-tolouyl-D-tartaric acid (1624 g, 4.203 mol) and a portion of the above described stock solution of aqueous ethanol (9050 mL) was stirred at around 65C under a nitrogen atmosphere. Separately, racemic 2-(2- aminoethyl)-1-methylpyrrolidine (700 g, 5.35 mol) was dissolved in a portion of the aqueous ethanol stock solution (3400 mL). The amine solution was then added drop- wise to the tartaric acid solution so that the temperature was maintained at about 65C and no solids formed during the addition. The reaction was held at about 65C for no less than 30 min before being cooled to about 0C. The precipitate was collected by filtration. A stream of nitrogen was pulled through the collected solid until no longer wet. The solid was recrystallized from ethanol (15950 mL)/water (2457 mL) affording the desired product as a colorless solid: 1322.4 g (44%), >99.5% ee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | In water; acetonitrile; at 20 - 77℃;Reflux; Inert atmosphere; Industry scale; | Add (+)-di-1,4-toluoyl-D-tartaric acid (2.30 kg, 5.95 mol) in one portion to a solution of racemic-trans-1-amino-7-bromo-1,2,3,4-tetrahydronaphthalen-2-ol (1.40 kg, 5.78 mol) in acetonitrile (16.0 L) and water (3.50 L). Heat the thick suspension to reflux (77 C.) under nitrogen for 30 min. The stirrer does not start to stir until about 46 C. Turn off the heat to the oil bath and allow the mixture to cool to room temperature with stirring. After 5 hr., filter the thick slurry through a Buechner funnel and rinse with acetonitrile (2 L). Continue to filter for one hour until no more solvent is collected. Dry the wet cake in air at room temperature overnight to obtain the desired salt as a yellow solid (1.70 kg). Add the solid into acetonitrile (15 L) and water (3.3 L) and heat the resulting thick slurry to reflux (77 C.) under nitrogen with stirring for 30 min. Turn off the heat to the oil bath and allow to cool to room temperature with stirring. After 5 hr., filter the thick slurry through a Buechner funnel and rinse with acetonitrile (2 L). Continue to filter for 30 min. until no more solvent is collected. Dry the wet cake at room temperature for 48 h to obtain the desired salt as a pale yellow solid (800 g, 22%). LC-ES/MS m/z (79Br) 242 [M+H]+ for the free base. 99.0% ee. Analytical conditions for enantiomeric excess determination by supercritical fluid chromatography (SFC): Column: CHIRALPAK AD-H (0.46x250 mm, 5 mum), carbon dioxide flow rate: 2.55 mL/min., co-solvent: methanol with 0.1% diethyl amine, co-solvent flow rate: 0.45 mL/min., back pressure: 150 bar, column temperature: 40.9 C. Isomer 1 TR=7.36 min, 0.5% area and isomer 2 (title compound) TR=8.46 min., 99.5% area. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | In tetrahydrofuran; water; at -11 - 20℃; for 19h; | Preparation of (3 S ,4R)- 4-(4-fluorophenyl)- 1 -(2-methoxyethyl)pyrrolidin-3 - amine (2S,3S)-2,3-bis(4-methylbenzoyloxy)succinate: To a solution of (3S,4R)-4-(4- fluorophenyl)-l-(2-methoxyethyl)pyrrolidin-3-amine (120 g, 504 mmol) in THF (3.0 L) and H20 (333 mL) was added di-/?-toluoyl-D-tartaric acid (195 g, 504 mmol). Stirred at ambient temperature for 1 hour, then placed in a freezer (-11 C) for 18 hours. The mixture was stirred to give a slurry, filtered, and rinsed with Et20 (4 x 100 mL). The solid was dried in vacuum oven (40 C) for 4 hours, then recrystallized twice by the following procedure: the solid was dissolved in THF (1.06 mL) and H20 (118 mL) with heating to 45 C, then allowing to cool to ambient temperature over 2 hours, then placed in a freezer (-11 C) for 18 hours; the mixture was stirred to give a slurry, filtered, and rinsed with Et20 (4 x 100 mL). After two recrystallizations, the solid was dried in vacuum oven (40 C) for 18 hours to afford the title compound as a white crystalline solid (96 g, 31% yield). MS (apci) m/z = 239.2 (M+H). |
31% | In tetrahydrofuran; water; at 20℃; for 1h; | 1005021 Step D: Preparation of (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3 -amine (2S.3 S)-2,3 -bis(4-methylbenzoyloxy)succinate: To a solution of (3S,4R)-4-(4-fluorophenyl)-1 -(2-methoxyethyl)pyrrolidin-3-amine (120 g, 504 mmol) in THF (3.0 L) and H20 (333 mE) was added di-p-toluoyl-D-tartaric acid (195 g, 504 mmol). Stirred at ambient temperature for 1 hour, then placed in a freezer (-11 C) for 18 hours. The mixture was stirred to give a slurry, filtered, and rinsed with Et20 (4 x 100 mE). The solid was dried in vacuum oven (40 C) for 4 hours, then recrystallized twice by the following procedure: the solid was dissolved in THF (1.06 mL) and H20 (118 mL) with heating to 45 C, then allowing to cool to ambient temperature over 2 hours, then placed in a freezer (-11 C) for 18 hours; the mixture was stirred to give a slurry, filtered, and rinsed with Et20 (4 x 100 mL). After two recrystallizations, the solid was dried in vacuum oven (40 C) for 18 hours to afford the title compound as a white crystalline solid (96 g, 31% yield). MS (apci) mlz = 239.2 (M+H). |
31% | In tetrahydrofuran; water; at 20℃; for 1h; | 1005521 Step D: Preparation of (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (2S.3 S)-2,3 -bis(4-methylbenzoyloxy)succinate: To a solution of (3 S,4R)-4-(4-fluorophenyl)- 1 -(2-methoxyethyl)pyrrolidin-3-amine (120 g, 504 mmol) in THF (3.0 L) and H20 (333 mL) was added di-p-toluoyl-D-tartaric acid (195 g, 504 mmol). The mixture was stirred at ambient temperature for 1 hour, then placed in a freezer (- 11 C) for 18 hours. The mixture was stirred to give a slurry, filtered, and rinsed with Et20 (4 x 100 mL). The solid was dried in vacuum oven (40 C) for 4 hours, then recrystallized twice by the following procedure: the solid was dissolved in THF (1.06 mL) and H20 (118 mL) with heating to 45 C, then allowing to cool to ambient temperature over 2 hours, then placed in a freezer (-11 C) for 18 hours; the mixture was stirred to give a slurry, filtered, and rinsed with Et20 (4 x 100 mL). After two recrystallizations, the solid was dried in vacuum oven (40 C) for 18 hours to afford the title compound as a white crystalline solid (96 g, 31% yield). MS (apci) mlz = 239.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40.4% | In acetonitrile; at 20℃; for 16h; | [0160] At 20 C., 116.4 g (301.2 mmol) of di-p-toluoyl-D-tartaric acid were added to a suspension of 64.9 g (286.8 mmol) of (I-11-A) in 1.3 l of acetonitrile and the mixture was stirred for 16 h at 20 C. The mixture was filtered with suction and the residue was washed twice with in each case 90 ml of acetonitrile. It was dried in vacuo at 40 C. to dryness, giving 71.1 g of (I-11-A-R-D-Tol-Tart.) This corresponded to a yield of 40.4%. [0161] HPLC method A: retention time for (I-11-A-D-Tart): 9.6 min (36.2%) & 14.7 min (63.8%). [0162] HPLC method B (L159-16EE): Chiralpak IC (DAICEL) length: 250 mm, internal diameter: 4.6 mm, particle size: 5 mum, gradient: 1:1 n-heptane/isopropanol isocratic; flow: 1.0 ml/min, detection at 252 nm, T=35 C. [0163] Retention time for R enantiomer: 9.3 min; retention time for S enantiomer: 8.4 min; Enantiomer excess (ee): 99.6%. [0164] MS (ES+): [M+H]+=227; MS (ES-): [M-H]-=385 [0165] 1H NMR (400 MHz, DMSO-d6) delta ppm 0.91-1.06 (m, 3H) 1.10-1.20 (m, 1H) 2.41 (s, 6H) 2.72-2.84 (m, 1H) 4.64 (s, broad, 1H) 5.82 (s, 2H) 7.40 (d, J=8.07 Hz, 4H) 7.90 (d, J=8.07 Hz, 4H) 8.09-8.20 (m, 2H) 8.33-8.52 (m, 2H) 13.85 (s, broad, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | In tetrahydrofuran; water; at -11 - 20℃; for 19h; | 1003591 Step D: Preparation of (3 S,4R)-4-(4-fluorophenyl)- 1 -(2-methoxyethyl)pyrrolidin-3-amine (2S,3 S)-2,3 -bis(4-methylbenzoyloxy)succinate: To a solution of (3 S,4R)-4-(4-fluorophenyl)- 1 -(2-methoxyethyl)pyrrolidin-3 -amine (120 g, 504 mmol) in THF (3.0 L) and H20 (333 mL) was added di-p-toluoyl-D-tartaric acid (195 g, 504 mmol). Stirred at ambient temperature for 1 hour, then placed in a freezer (-11 C) for 18 hours. The mixture was stirred to give a slurry, filtered, and rinsed with Et20 (4 x 100 mL). The solid was dried in vacuum oven (40 C) for 4 hours, then recrystallized twice by the following procedure: the solid was dissolved in THF (1.06 mL) and H20 (118 mL) with heating to 45 C, then allowing to cool to ambient temperature over 2 hours, then placed in a freezer (-11 C) for 18 hours; the mixture was stirred to give a slurry, filtered, and rinsed with Et20 (4 x 100 mL). After two recrystallizations, the solid was dried in vacuum oven (40 C) for 18 hours to afford the title compound as a white crystalline solid (96 g, 31% yield). MS (apci) m/z = 239.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | In water; acetonitrile; at 20℃; for 1h; | The mixture of methyl (±)-4-([2-amino-1-(3-hydroxymethylphenyl)ethyl]thio}methyl)benzoate (2) (2.19 g, 6.61mmol) and (+)-di-p-toluoyl-D-tartaric acid (2.55 g, 6.60mmol) in MeCN (44 mL) and water (4.4 mL) was heated to clear the solution and cooled to room temperature. After being stirred for 1 h, the slurry was filtered to give 1.53 g colorless crystals. The mixtureof the crystals, MeCN (15 mL), and water (4.6 mL) was heated to clear the solution, and MeCN (15.6 mL) was added, then cooled to room temperature. After being stirred for 1 h, the slurry was filtered and dried to give 2a (664 mg, 0.925mmol, 14.0% yield) as a colorless crystal. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52%; 47% | In ethanol; at 20℃; for 2.16667h; | Preparation of (S)-7-methoxy-2-methyl-4-(naphthalen-2-yl)-1,2,3,4-tetrahydroisoquinoline (Compound 7) To a solution of compound 6 (222.3 g, 0.73 mol) in ethanol (5.5 L) at room temperature was quickly added a solution of di-p-toluoyl-D-tartaric acid (292.2 g, 0.73 mol) in ethanol (1.0 L) with no internal temperature increase noted. The reaction solution was stirred at room temperature. Precipitate started to form within 10 min. After stirring for 2 h, the reaction slurry was filtered and the cake was dried at 60 C. in vacuo for 12 h to give the (4S)-enriched tartrate salt (265.0 g, 52%, with a ratio of enantiomers of approximately 84:16, CHIRALCEL AD, heptane:IPA:diethyl amine 90:10:0.01). The filtrate was concentrated in vacuo and dried at 60 C. to give the 4R-enriched tartrate salt (238.0 g, 47%, ratio of enantiomers of approximately 3:97). |
Yield | Reaction Conditions | Operation in experiment |
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141 kg | In ethyl acetate; at 0 - 20℃; for 76h;Large scale; | A solution of {8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazoline-4-yl}methyl acetate (Example 3A, 129.2 kg) in chlorobenzene (800 l) is heated to reflux and azeotropically dried. Phosphorous oxychloride (144 kg) is added, and the reaction mixture is agitated for 3 h at reflux. Then, DBU (95 kg) and chlorobenzene (45 l) are added and agitated for additional 9 h at reflux. The reaction mixture is cooled to room temperature, hydrolyzed by adding water, diluted with chlorobenzene (80 l), and neutralized with an aqueous solution of ammonia (25%). The phases are separated, the organic phase is washed with water and the solvent is distilled off. The remaining residue is dissolved in dioxane (170 l). 3-methoxyphenylpiperazine (66 kg), DBU (52 kg), and an additional 90 l of dioxane are added and the reaction mixture is heated for 4 h at reflux. The reaction mixture is cooled to room temperature, added to ethyl acetate (1300 l), washed once with water, 3 times with 0.2 N HCl, and once with an aqueous solution of NaCl, and the solvent is distilled off. The resulting residue is dissolved in ethyl acetate (800 l) and added to a solution of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (121 kg) in ethyl acetate (600 l). The resulting mixture is agitated for approx. 60 min. at room temperature and then inoculated with (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]-succinic acid-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)-phenyl]-3,4-dihydroquinazoline-4-yl}methyl acetate and agitated for 3 days at room temperature. It is then cooled to 0-5 C. and agitated for an additional 3 h. The suspension is filtered and the remaining solid is rewashed in batches with ethyl acetate. A total of about 141 kg (calculated as dry weight) of the salt is thus obtained as a solid, corresponding to around 46.2% of theory, in three stages (chlorination, amination and crystallization) compared to the racemate). 1H NMR (300 MHz, d6-DMSO): delta=7.90 (d, 2J=7.8, 4H), 7.56 (d, 2J=8.3, 1H), 7.40 (d, 2J=7.8, 4H), 7.28-7.05 (m, 4H), 6.91-6.86 (m, 2H), 6.45 (d, 2J=8.3, 1H), 6.39-6.36 (m, 2H), 5.82 (s, 2H), 4.94 (m, 1H), 4.03 (q, 2J=7.1, 2H), 3.83 (brs, 3H), 3.69 (s, 3H), 3.64 (s, 3H), 3.47-3.36 (m, 8H and water, 2H), 2.98-2.81 (m, 5H), 2.58-2.52 (m, 1H), 2.41 (s, 6H), 1.99 (s, 3H), 1.18 (t, 2J=7.2, 3H) ppm; HPLC (Method 1): RT=16.6 and 18.5 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46.2% | A solution of {8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazoline-4-yl}methyl acetate (Example 3A, 129.2 kg) in chlorobenzene (800 l) is heated to reflux and azeotropically dried. Phosphorous oxychloride (144 kg) is added, and the reaction mixture is agitated for 3 h at reflux. Next, DBU (95 kg) and chlorobenzene (45 l) are added and agitated for an additional 9 h at reflux. The reaction mixture is cooled to room temperature, hydrolyzed by adding water, diluted with chlorobenzene (80 l), and neutralized with an aqueous solution of ammonia (25%). The phases are separated, the organic phase is washed with water and the solvent is distilled off. The remaining residue is dissolved in dioxane (170 l). 3-methoxyphenylpiperazine (66 kg), DBU (52 kg), and an additional 90 l of dioxane are added and the reaction mixture is heated for 4 h at reflux. The reaction mixture is cooled to room temperature, added to ethyl acetate (1300 l), washed once with water, 3 times with 0.2 N HCl, and once with an aqueous solution of NaCl, and the solvent is distilled off. The resulting residue is dissolved in ethyl acetate (800 l) and added to a solution of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]-succinic acid (121 kg) in ethyl acetate (600 l). The resulting mixture is agitated for approx. 60 min. at room temperature and then inoculated with (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]-succinic acid-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)-phenyl]-3,4-dihydroquinazoline-4-yl}methyl acetate and agitated for 3 days at room temperature. It is then cooled to 0-5 C. and agitated for an additional 3 h. The suspension is filtered and the remaining solid is rewashed in batches with ethyl acetate. A total of about 141 kg (calculated as dry weight) of the salt is thus obtained as a solid, corresponding to around 46.2% of theory, in three stages (chlorination, amination, and crystallization) compared to the racemate. 1H NMR (300 MHz, d6-DMSO): delta=7.90 (d, 2J=7.8, 4H), 7.56 (d, 2J=8.3, 1H), 7.40 (d, 2J=7.8, 4H), 7.28-7.05 (m, 4H), 6.91-6.86 (m, 2H), 6.45 (d, 2J=8.3, 1H), 6.39-6.36 (m, 2H), 5.82 (s, 2H), 4.94 (m, 1H), 4.03 (q, 2J=7.1, 2H), 3.83 (brs, 3H), 3.69 (s, 3H), 3.64 (s, 3H), 3.47-3.36 (m, 8H and water, 2H), 2.98-2.81 (m, 5H), 2.58-2.52 (m, 1H), 2.41 (s, 6H), 1.99 (s, 3H), 1.18 (t, 2J=7.2, 3H) ppm; HPLC (Method 1): RT=16.6 and 18.5 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | To a suspension of compound 6 (12.5 g, 16.6 mmol) in 125 mL of toluene was added 50 mL of 0.43M aqueous K3P04. The resulting reaction was allowed to stir for 1 hour at room temperature and the reaction mixture was transferred to a separatory funnel. The organic phase was collected, washed once with 30 mL 0.43M aqueous K3P04 then cooled to 0 C and aqueous K3P04 (60 mL, 0.43 M, 25.7 mmol) was added. To the resulting solution was added a room temperature solution of ((lS,2S,4S,5R)-l-(3,5-bis(trifluoromethyl)benzyl)-2-((R)- hydroxy( 1 -(3 -(trifluoromethyl)benzyl)quinolin- 1 -ium-4-yl)methyl)-5-vinylquinuclidin- 1 -ium bromide) (0.704 g, 0.838 mmol) in 1.45 mL of DMF. The resulting reaction was allowed to stir at 0 C until the reaction was complete (monitored by HPLC), then the reaction mixture was transferred to a separatory funnel and the organic phase was collected and washed sequentially with 1M glycolic acid (25 mL) and water (25 mL). The organic phase was filtered through solka flok and concentrated in vacuo to a total volume of 60 mL. Ethyl acetate (20 mL) was added to the resulting solution, followed by (S,S)-Di-P-Toluoyl-D-tartaric acid (5.61 g, 14.1 mmol). Penultimate seed (0.2 g) was added the resulting solution was allowed to stir at room temperature for 12 hours. The solution was then filtered and the collected solid was washed twice with ethyl acetate, then dried in vacuo to provide compound 7 as its DTTA salt ethyl acetate solvate (13.8 g, 78%) . 'H NMR (500 MHz, d6-DMSO): deltaEta 13.95 (2H, br s), 7.90 (4H, d, J= 8.1 Hz), 7.55 (1H, dd, J= 8.6, 1.3 Hz), 7.38 (4H, d, J= 8.1 Hz), 7.26 (1H, d, J= 7.8 Hz), 7.09-7.05 (3H, m), 6.91-6.86 (2H, m), 6.44 (1H, dd, J= 8.2, 1.7 Hz), 6.39 (1H, t, J= 2.0 Hz), 6.36 (1H, dd, J= 8.2, 2.0 Hz), 5.82 (2H, s), 4.94 (1H, t, J= 7.1 Hz), 4.02 (2H, q, J= 7.1 Hz), 3.83 (3H, br s), 3.68 (3H, s), 3.64 (3H, s), 3.47 (2H, br s), 3.37 (2H, br s), 2.95 (2H, br s), 2.87- 2.80 (3H, m), 2.56 (1H, dd, J= 14.3, 7.0 Hz), 2.39 (6H, s), 1.98 (3H, s), 1.17 (3H, t, J= 7.1 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.18 g | In methanol; acetonitrile; at 20 - 50℃; for 67.5h; | 3f. 3-amino-2-(2,4-difluorophenyl)- 1,1 -difluoro- 1 -(5-(4-(trifluoromethoxy)phenyl)pyridin-2- yl)propan-2-ol (1-6 or 1-7)p Typical Procedure for Converting ±1-6 to 1-6 or 1-7(This experimental procedure describes resolution of ±1-6, but conditions used for DPPTAresolution of 1-6 or 1-7 are essentially the same.)Amino-alcohol ±1-6 (7.0 g, 15 mmoles) was dissolved in a mixture of acetonitrile (84 mL) and methanol (21 mL). (D)-DPTTA (5.89 g, 15 mmoles) was added, and the reaction was wamed to 50C and held for 2.5 h. The heat was then removed and the suspension was allowed to cool and stir at 20-25C for 65 h. The suspension was cooled in an ice bath and stirred for an additional 2 h. Solid was isolated by vacuum filtration, and the cake was washedwith cold 8:2 ACN/MeOH (35 mL). After drying at 50C, 5.18 g of 1-6 or 1-7TDPPTA salt was isolated, HPLC purity = 99.0, cc = 74.The 1-6 or 1-7TDPPTA salt (5.18 g) was combined with 8:2 ACN/MeOH (68 mL) and the suspension was heated to 50C and held for 20 mm. After cooling to 20-25C the mixture was stirred for 16 h. Solids were isolated by vacuum filtration, and the cake washed with cold 8:2ACN/MeOH (30 mL), and pulled dry on the funnel. 2.82 g of 1-6 or 1-7TDPPTA salt was obtained, 44.4% yield (from crude ±1-6), cc = 97.5. The resulting solids were freebased to provide 1-6 or 1-7 with the same achiral and chiral purity as the DPPTA salt. |
(This experimental procedure describes resolution of ±1-6, but conditions used for DPPTAresolution of 1-6 or 1-7 are essentially the same.)Amino-alcohol ±1-6 (7.0 g, 15 mmoles) was dissolved in a mixture of acetonitrile (84 mL) and methanol (21 mL). (D)-DPTTA (5.89 g, 15 mmoles) was added, and the reaction was wamed to 50C and held for 2.5 h. The heat was then removed and the suspension was allowed to cool and stir at 20-25C for 65 h. The suspension was cooled in an ice bath and stirred for an additional 2 h. Solid was isolated by vacuum filtration, and the cake was washedwith cold 8:2 ACN/MeOH (35 mL). After drying at 50C, 5.18 g of 1-6 or 1-7TDPPTA salt was isolated, HPLC purity = 99.0, cc = 74.The 1-6 or 1-7TDPPTA salt (5.18 g) was combined with 8:2 ACN/MeOH (68 mL) and the suspension was heated to 50C and held for 20 mm. After cooling to 20-25C the mixture was stirred for 16 h. Solids were isolated by vacuum filtration, and the cake washed with cold 8:2ACN/MeOH (30 mL), and pulled dry on the funnel. 2.82 g of 1-6 or 1-7TDPPTA salt was obtained, 44.4% yield (from crude ±1-6), cc = 97.5. The resulting solids were freebased to provide 1-6 or 1-7 with the same achiral and chiral purity as the DPPTA salt. | ||
5.18 g | In methanol; acetonitrile; at 50℃; for 69.5h;Cooling with ice; | 3f. 3-amino-2-(2,4-difluorophenyl)- 1,1 -difluoro- 1 -(5-(4-(trifluoromethoxy)phenyl)pyridin-2- yl)propan-2-ol (16* or 1-7) Typical Procedure for Converting ±1-6 to 16* or 1-7(This experimental procedure describes resolution of ±1-6, but conditions used for DPPTA resolution of 1-6 or 1-7 are essentially the same.)Amino-alcohol ±1-6 (7.0 g, 15 mmoles) was dissolved in a mixture of acetonitrile (84 rnL) and methanol (21 mL). (D)-DPTTA (5.89 g, 15 mmoles) was added, and the reaction waswaniied to 50C and held for 2.5 h. The heat was then removed and the suspension was allowed to cool and stir at 20-25C for 65 h. The suspension was cooled in an ice bath and stirred for an additional 2 h. Solid was isolated by vacuum filtration, and the cake was washed with cold 8:2 ACN/MeOH (35 mL). After drying at 50C, 5.18 g of 16* or 17*JDPPTA salt was isolated, HPLC purity = 99.0, ee = 74.The 16* or 17*/DPPTA salt (5.18 g) was combined with 8:2 ACN/MeOH (68 mL) and the suspension was heated to 50C and held for 20 mill. After cooling to 20-25C the mixture was stirred for 16 h. Solids were isolated by vacuum filtration, and the cake washed with cold :2 ACN/MeOH (30 mL), and pulled dry on the funnel. 2.82 g of 16* or 17*/DPPTA salt was obtained, 44.4% yield (from crude ±1-6), cc = 97.5. The resulting solids were freebased toprovide 16* or 1-7 with the same achiral and chiral purity as the DPPTA salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | In methanol; water; at 50℃; for 0.0833333h; | (trans)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (125 mg, 0.52 mmol) and (28,3S)-2,3- bis((4-methylbenzoyl)oxy)succinic acid (222.9 mg, 0.58 mmol) were weighed into a 4 mL vial, then treated with MeOH (1.57 mL) followed by water (0.175 mL). The vial was capped and the reaction mixture was stirred at 50 C for 5 minutes, then allowed to cool slowly to ambient temperature over 17 hours. The resulting solids were filtered, washed with Et20 (4 x 0.2 mL) and dried under vacuum to afford (38, 4R)-4-(3 -fluorophenyl)- 1 -(2-methoxyethyl)pyrrolidin-3 - amine(2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate (131.6 mg, 40% yield) as a white solid. Chiral SFC analysis of a free-based sample indicated> 95% ee. This material was used as seed crystals in the following step: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31.8% | With 1-methoxy-2-propanol; at 22℃; for 18h; | A solution of di-p-toluoyl-L-tartaric acid (348.6 g, 884 mmol) in 1-methoxy-2- propanol (1.13 L) is added to a solution of [(3R,4S)-1-allyl-4-amino-4-(2- fluorophenyl)pyrrolidin-3 -yllmethanol (225.9 g, 902 mmol), in 1 -methoxy-2-propanol (1.13 L) previously heated at 40 C. The reaction is cooled to 22 C and stirred for 18 hours. A white solid is collected by filtration and washed with 1-methoxy-2-propanol(600 ml). The collected solid is dried to give the title compound (183.01 g, 3 1.8%). ES/MS (mlz): 251 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.8% | To 8-hydroxy -4,5-dibromo-(1, 2, 6, 7-tetrahydro -8H-indeno [5,4-b] furan-8-yl) acetonitrile (10g, 26.8mmol) in mass percentage of 10% suspension of ethanol solutions of ammonia (the quality percent means that ammonia quality of ethanol ammonia solution total mass percentage, 150 ml) in, add quality totally ratio is 95% of the Raney nickel (0.2g, the quality percent means that nickel quality of Raney's nickel percentage of the total weight of the reagent), and in the hydrogen atmosphere (2.5 MPa) in, 55 C stirring under the conditions of 15h. Filtering the reaction solution, concentrate to dry, add 30mLH2O and 30 ml ethyl acetate extraction, ethyl acetate for 30 ml extraction the aqueous phase 2 times, combined with the phase, the saturated salt water, drying by anhydrous sodium sulfate. Filter the desiccant, by adding L-(-)-di-P-toluene Carbamoyl tartaric acid (ee % > 98%, 12 . 429g, 32.2mmol) stirring, in the 20 C stirring the precipitated white solid, 45 min after filtration, the white solid obtained 13.854g (a salt of compound II), yield: 87.8%, HPLC purity > 99.5%, mass spectrometry and nuclear magnetic resonance data with embodiment 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | In isopropyl alcohol; at 65 - 75℃; for 18h;Sonication; | A mixture of tert-butyl-3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1 g, 4.62 mmol) and (+)-<strong>[32634-68-7]O,O'-di-p-toluoyl-D-tartaric acid</strong> (893 mg, 2.31 mmol) was suspended in isopropanol (5 mL) and the mixture was sonicated until mostly dissolved. The resultant suspension was heated at 65 C. for a few min and sonicated again resulting in a homogeneous mixture. The pale yellow solution was heated at 65 C. After ?5 min, the mixture became a white suspension, and stirring was continued at 65-70 C. for 18 h. The suspension was allowed to cool to room temperature over 1 h. The suspension was filtered, the solids were rinsed with a small volume of isopropanol and dried in a vacuum oven at 50 C. for 1 h to give the title compound (773 mg, 41%) as a white solid. 1H NMR (400 MHz, D2O) delta 8.05 (d, J=7.8 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 5.71 (s, 1H), 3.78 (s, 2H), 3.64-3.52 (m, 4H), 2.46 (s, 3H), 2.28-2.13 (m, 2H), 1.49 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.96% | In isopropyl alcohol; at 25 - 70℃;Resolution of racemate; | To a solution of Racemic cyanodiol (300g, 0.88 moles) in isopropyl alcohol (1800 ml) at 25-35C (+)-Di-p-toluoyl-D-tartaric acid (169.2g, 0.44 mole) was added. The reaction mixture was then heated and maintained at 60-70 C for lhour. After maintaining was over the reaction mass was cooled and maintained at 28- 32 C for 2-4 hours. The precipitated solid was then filtered, washed with isopropyl alcohol (300 ml) and suck dried for 30minutes. The filtrate was preserved for the recovery of Racemic cyanodiol and (+)-Di-p-toluoyl-D-tartaric acid. The obtained wet cake of (S)-cyanodiol - (+)-DPTTA was suspended in isopropyl alcohol (1200 ml), heated and maintained at 55-65C for 60 minutes. After maintaining was over the reaction mass was cooled to 28-32C where it was maintained for 60 minutes. The precipitated solid was then filtered, washed with isopropyl alcohol (300 ml) and finally dried under vacuum at 60-70 C which provided the title compound (VI) as a white solid. The obtained filtrate was combined with the earlier obtained filtrate for the recovery of Racemic cyanodiol and (+)-Di-p-toluoyl-D-tartaric acid. Yield: 145g (61.96% by Theory) Purity by HPLC: 99.71% Chiral Purity: S-Isomer - 99.59% R-Isomer - 0.41% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
374.4g | With water; In toluene; for 5h;Reflux; Large scale; | Taking d-tartaric acid 150g, toluene 200 ml of the 1000 ml three-neck bottle, added under stirring 1.5g copper sulfate, methylbenzoyl chloride to begin dropping 330g, 3 hours drop end, to continue reaction 6 hours, discharging to centrifuge, shall then d-p-methyldibenzoyl tartaric anhydride 495.4g, will in 2000 ml three-neck bottle, adding water and toluene all 495.4g, heated up to reflow, holding 5 hours, cooling to normal temperature discharge, shall then d-p-methyldibenzoyl tartaric acid 374.4 g. The embodiment of thed d-p-methyldibenzoyl tartaric acid for TEM test, test structure as shown in Figure 1, can be known from the graph, the finished d-p-methyldibenzoyl tartaric acid content is purity 99.61%, total yield of 96.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | 1.41 g of 5-azaspiro [2.4] heptane-6-carboxylic acid and 6 mL of acetic acid were added to a 50 mL reaction flask equipped with a magnet and a thermometer,Heating to 60 ,Followed by the addition of 1.93 g of D-p-methylbenzoyl tartaric acid,After stirring for 20 minutes, 24 mL of ethyl acetate was added,There is a lot of solid precipitation,The reaction was continued for 1.5 hours and then cooled to 50 C,Then add 0.072 g salicylaldehyde,The reaction was stirred at 50 C for 18 hours and then allowed to cool to room temperature,Filter,The filter cake was dried under vacuum at 60 C overnight to give 2.77 g of product,The yield was 83%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | In dichloromethane; at 15℃; for 0.5h; | Daboxignin will be mixed with 10g, 50ml of methylene chloride was added to three bottles,15 under stirring to dissolve,D - (+) - di-p-methylbenzoyl tartaric acid 12.65g,Stirring 0.5h, adding ethyl acetate 50ml, stirring was continued 1h crystallization, filtration, the filter cake was washed with methylene chloride,Ethyl acetate (1: 1) and dried at 40 C to obtain Dapoxetine DTTA salt 10.42g, yield 46% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | In methanol; at 50℃; for 3h; | [0142] N-[4-(1 -Aminoethyl)-2,6-difluorophenyl] -methanesulfonamide (mixture of R and S stereoisomers) was prepared according to the preparation method described in Bioorganic & Medicinal Chemistry 15(18), 6043-6053; 2007. 1 equivalent of the prepared N-[4-(1-aminoethyl)-2, 6-difluorophenyl]-methanesulfonamide was mixed with 1 equivalent of the chiral auxiliary described in Tables 2 and3. To the resulting mixture was added a solvent (differentsolvents as described in the tables) of 10 times (vol.) based on the weight of the N-[4-(1 -aminoethyl)-2,6-difluorophe- nyl]-methanesulfonamide. The resulting mixture solution was refluxed at 50 C. for 3 hours and then cooled to 25 C. The resulting solid was filtered using a Buechner flannel to obtain each N-[4-(1 -aminoethyl)-2,6-difluorophenyl]-meth- anesulfonamide chiral acid salt. The obtained salt is a once-resolved salt.The obtained salt is a once-resolved salt. The obtained once-resolved N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide salt was subjected to the above-described procedure of refluxing after adding the solvent of 10 times based on weight, cooling and then filtering for 1 and 2 times to obtain twice-resolved and thrice-resolved N-[4-(1-aminoethyl)-2,6-difluorophenyl]-methanesulfonamide salts. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | In methanol; ethanol; at 40℃; for 1h; | 3.5 g di-p-toluoyl-D-tartaric acid was formed into B solution in 15 mL methanol at 40 C. 5 g of compound of formula 3 was dissolved in 20 mL of ethanol at 40 C. to form a solution C, then the solution of C was slowly added dropwise to solution of B, and stirring and refluxing continued for 60 minutes. Cooling, filtration and recrystallization of the filter cake from methanol gave 2.9 g of the compound of formula 4 as a white solid with a yield of 71% and an ee of 99.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | To a 1 L reaction flask was added Intermediate III 30 g (1.0 eq)Methylamine 6.87 g (1.5 eq), acetic acid 10.6 g and ethanol 150 mL and stirred for 3 h at 25 C;TLC monitoring reaction was basically completed, and then to the reaction system was added NaBH4 8.37g (1.5eq), at 25 C conditions,Stirring 4h; TLC monitoring reaction is basically completed,To the reaction solution was slowly added 150 mL of water, filtered,The filter cake was washed with dichloromethane and the filtrate was extracted twice with 100 mL of dichloromethane. The organic phases were combined,In the external temperature 40 ~ 45 C conditions, concentrated to dryness under reduced pressure,To obtain a crude product; to the crude product isopropanol 240mL and methanol 60mL, L-di-p-methyl27.2 g (1.1 eq) of benzoyl tartaric acid aqueous solution,The mixture was heated to reflux 3h, slowly cooled to room temperature,Filtration gave a white solid which was dried in vacuo at 40-50 C to give (3R, 4R) -1-benzyl-N, 4-dimethylpiperidin-3-amine L-p-toluyltartrate 43.7 g, yield 36%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | In methanol; acetone; at 20 - 50℃; for 4h; | A solution of (+)-O,O?-di-p-toluoyl-D-tartaric acid (5.2 g, 13.4 mmol, 1.03 equiv) in methanol (11 mL) was added at 50 C to a suspension of crude isothiazole 37 and the corresponding diastereomer (7.9 g, 13.1 mmol, 1 equiv) in acetone (16 mL). The mixture was slowly cooled to room temperature and stirred for 4 hours, at which time white precipitate formed. The solid was filtered, washed with methanol and dried in a vacuum oven at 50 C for 1 hour to give 3-(4-(((1R,2R)-2- (Nitromethyl)cyclohexyl)methyl)piperazin- 1 -yl)benzo[d] -i sothiazole (+)-O, 0 ?-di-ptoluoyl-D-tartaric salt 38 (4.76 g, 48% yield) as a white foam. ?H-NIVIR analysis indicated less than 3% of the undesired diastereomer |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetone; at 20℃; for 16h;Resolution of racemate; | [0214] (±)-<strong>[718635-93-9]Tetrabenazine</strong> (Compound 1 , 200 gr, 0.62 mol, 1 eq) was dissolved in 2 L of Acetone (10 V vs. <strong>[718635-93-9]Tetrabenazine</strong> v/wt) in a 3 L glass reactor. Then (-)-0,0'-Di-p- toluoyl-L-tartaric acid ((-)-DPTTA) was added (243.6 gr, 0.62 mol, 1 eq). The reaction mixture was stirred at RT for 16 h. The precipitated product was filtrated and washed with Acetone (2x0.5 V vs. <strong>[718635-93-9]Tetrabenazine</strong> v/wt). The mother liquor after precipitation was distilled off. The obtained residue was dissolved in 1 L of Acetone (5 V vs. <strong>[718635-93-9]Tetrabenazine</strong> v/wt) in a 3 L reactor, heated to 60 C and stirred for 2 hours. The solution was then cooled to RT and stirred for 16h. The precipitated product was filtrated and washed with Acetone (2x0.5 V vs. <strong>[718635-93-9]Tetrabenazine</strong> v/wt). The precipitated product- (+)-<strong>[718635-93-9]Tetrabenazine</strong>-(-)-DPTTA salt from both steps was combined and dissolved in EtOH (6 V vs. (+)<strong>[718635-93-9]Tetrabenazine</strong>-(-)-DPTTA salt v/wt) in a 3 L glass reactor and cooled to 0C. The pH was adjusted to pH=8-8.5 with NH4OH. Water (10V vs. (+)-<strong>[718635-93-9]Tetrabenazine</strong>-(-)-DPTTA salt v/wt) was added drop wise and the reaction mixture was stirred at 0C for 1 h. The precipitated product was filtrated and washed with water (2 V, vs. (+)-<strong>[718635-93-9]Tetrabenazine</strong>-(-)-DPTTA salt v/wt) to obtain the desired (+)- <strong>[718635-93-9]Tetrabenazine</strong> (R,R) enantiomer (Compound 2, 134 gr, 67% overall yield, 97-98% chiral purity). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.32 g | To a stirred mixture of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l- yl)propan-2-yl) octanamide oxalate (100.0 g) and methanol (700 ml), sodium borohydride (9.6 g) was added in 10 equal lots with 10 minute intervals at -20 to -10 C . The reaction mixture was stirred for 1 h. After completion of the reaction, the reaction mixture was quenched with dilute hydrochloric acid (37 ml) solution in 40 ml water within 30 min. The reaction mixture was allowed to warm at 25-35 C and then water (700 ml) and dichloromethane (700 ml) were added to the reaction mixture. The pH of the reaction mixture was adjusted to 8.0-10.0 with 20% potassium carbonate solution. The reaction mixture was stirred for 30 min. and then the layers were separated. The organic layer was washed with water (200 ml), distilled out under vacuum and then azeotroped with methanol (100 ml). The obtained crude product (VII) was dissolved in methanol (700 ml), and then a solution of di-p-tolyl-D-tartaric acid (74.5 g) in methanol (300 ml) was added at 50-60 C. The reaction mixture was stirred at 50-60 C for 1 h. Then the reaction mixture was cooled at 25-35 C and stirred for 2 h. The solid was filtered and washed with methanol (50 ml X 2). Suck dry and mixed the obtained wet cake with methanol (750 ml). The reaction mixture was heated to reflux for 1 h, then the reaction mixture was cooled at 25-35 C and stirred for 2 h. The solid was filtered and washed with methanol (50 ml X 2). The solid was dried at 25-35 C for 2 h and then at 55-65 C for 8 h to give the title product (43.32 g). 1H NMR (DMSO-d6)5: 0.83-0.87 (3H, t), 0.99-1.02 (2H, m), 1.14-1.29 (8H, m), 1.81 (4H, s), 1.95-2.00 (2H, m), 2.37 (6H, s), 3.02-3.24 (6H, m), 4.18-4.22 (5H, m), 4.64-4.65 (1H, d), 5.64 (2H, s), 6.72 (2H, s), 6.79 (1H, s), 7.30-7.32 (4H, d), 7.66-7.68 (1H, d), and 7.82-7.84(4H, d) Mass: 405.3 [M+H] + (0219) Chiral HPLC: Eliglustat (100%), Other isomers (Not Detected) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With acetic anhydride; at 85℃; for 2h; | A suspension of (+)-2,3-di-O-toluoyl-D-tartaric acid (15.0 g, 38.82 mmol) in acetic anhydride (45 mL) was warmed to 85 C. with stirring. After 2 h, the solution was cooled in an ice bath and the resulting suspension was filtered, washed with 1:1 hexanes/diethyl ether (100 mL) and dried in vacuo to afford (3 S,4 S)-2,5-dioxotetrahydrofuran-3 ,4-diylbis(4-methylbenzoate) (10.85 g, 76%) as a white crystalline solid. NMR (400 MHz, CDCl3) delta 7.95 (d, J=8.3 Hz, 4H) 7.28 (d, J=8.3 Hz, 4H) 5.92 (s, 2H) 2.42 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.2% | A 250 mL round bottom flask equipped with a magnetic stirrer was charged with 3-amino-5- phenyl-l,3-dihydro-2H-benzo[b]azepin-2-one (racemic, 2.05 g, 8.19 mmol), compound 2, (+)-0,0 -Di-p-toluoyl-D-tartaric acid (3.16 g, 8.19 mmol) and 1,4-dioxane (82 ml). The reaction was stirred at 20 ± 5C for 24 hours under air and monitored by chiral HPLC. The white solid was filtered off under vacuum, aspirated for > 2 hours then transferred into a 50 mL round bottom flask. 1M sodium hydroxide (25 mL, 12.5 volumes) was added to the flask along with a magnetic stirrer. The suspension was stirred at 20 ± 5C for 4 hours under air. The solid was filtered off under vacuum, washed with water (3 x 10 mL) aspirated for > 1 hour then dried under vacuum at room temperature for > 16 hours to afford (5 -3-amino-5- phenyl-l,3-dihydro-2H-benzo[b]azepin-2-one (1.5 g, 5.99 mmol, 73.2 % yield) as a white solid. NMR (400 MHz, DMSO-c e) delta 10.33 (s, 1H), 7.40 - 7.32 (m, 4H), 7.24 - 7.20 (m, 3H), 7.12 - 7.05 (m, 2H), 5.88 (d, J = 5.4 Hz, 1H), 3.38 (d, J= 5.5 Hz, 1H). LCMS m/z = 251.8 [M+H]+ HPLC purity = 99.4% a/a. Chiral purity = 99.0 (ee%). | |
73.2% | A 250 mL round bottom flask equipped with a magnetic stirrer was charged with 3-amino-5- phenyl-1,3-dihydro-2H-benzo[b]azepin-2-one (2.05 g, 8.19 mmol), (2S,3S)-2,3-bis((4- methyl-benzoyl)oxy)succinic acid (3.16 g, 8.19 mmol) and dioxane (82 ml). The reaction was stirred at 20 ± 5 C for 24 hours under air and monitored by chiral HPLC. The white solid was filtered off under vacuum, aspirated for 2 hours then transferred into a 50 mL round bottom flask. 1M sodium hydroxide (25 mL, 12.5 volumes) was added to the flask along with a magnetic stirrer. The suspension was stirred at 20 ± 5C for 4 hours under air. The solid was filtered off under vacuum, washed with water (3 x 10 mL) aspirated for 1 hour then dried under vacuum at room temperature for 16 hours to afford (S)-3-amino-5-phenyl- 1,3-dihydro-2H-benzo[b]azepin-2-one (1.5 g, 5.99 mmol, 73.2 % yield) as a white solid.1H NMR (400 MHz, DMSO-d6) delta 10.33 (s, 1H), 7.40- 7.32 (m, 4H), 7.24- 7.20 (m, 3H), 7.12 - 7.05 (m, 2H), 5.88 (d, J = 5.4 Hz, 1H), 3.38 (d, J = 5.5 Hz, 1H). LCMS m/z: 251.8 [M+H]+. Chiral purity = 99.0 (ee%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | 50 mL round bottom flask equipped with a magnetic stirrer was charged with compound 8, 3-amino-9-fluoro-5-phenyl-l,3-dihydro-2H-benzo[e] [l,4]diazepin-2-one (racemic mixture, 250 mg, 0.928 mmol), compound 2, (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinic acid (359 mg, 0.928 mmol) and Dioxane (9284 mu). The reaction was stirred at room temperature overnight. The white solid was filtered off under vacuum, aspirated for 30 mins then transferred into a 50 mL round bottom flask. 1M sodium hydroxide (3.5 mL) was added to the flask along with a magnetic stirrer. The suspension was stirred at room temperature for 4 hours under air. To the homogeneous solution, 10 drops of 4M HC1 (aq) was added, which precipitated a white solid. The solid was filtered off under vacuum, washed with water (3 x 10 mL) aspirated for > 1 hour to afford example 4, (S)-3-amino-9-fluoro-5-phenyl-l,3- dihydro-2H-benzo[e] [l,4]diazepin-2-one (170 mg, 0.631 mmol, 68.0 % yield). 96% ee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With air; In 1,4-dioxane; at 20℃; for 24h; | An 8 mL scintillation vial equipped with a magnetic stirrer was charged with compound 8, (i?)-3-amino-5-phenyl-l,3-dihydro-2H-benzo[e] [l ,4]diazepin-2-one (100 mg, 0.398 mmol, 1 equiv.), compound 2, (+)-0,0'-Di-p-toluoyl-D-tartaric acid (154 mg, 0.398 mmol, 1 equiv.) and 1 ,4-dioxane (4 ml, 40 volumes). The reaction was stirred at 20 ± 5C for at least 24 hours under air and monitored by chiral HPLC. The solid was filtered off under vacuum to afford compound 3, (5 -3-amino-5-phenyl-l,3-dihydro-2H-benzo[e] [l ,4]diazepin-2-one (25',35)-2,3-bis((4-methylbenzoyl)oxy)succinate (294 mg, >100%) as an off white solid. The chiral purity of the isolated solid = 99.89:0.1 1 area% / (S):(R). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.73 kg | In acetonitrile; at 75℃; for 0.5h;Inert atmosphere; Large scale; | 30.00 kg of 4-amino-N-[(1-ethyl-2-pyrrolidinyl) methyl]-5-(ethylsulfonyl)-2-methoxybenzamide and 32.00 kg of di-p-toluoyl-D-tartaric acid was added to a 1000 L glass-lined reactor equipped with reflux condenser, nitrogen purge, thermocouple and retreat curve impeller. 630.2 kg of acetonitrile was added to the reactor and stirred. 40.80 kg of water was then added to the reaction slurry and heated to 75 C. The mixture was held for 30 minutes at 75 C. and cooled to 15 C. at a rate of 0.25 C per minute. The mixture was then held at 15 C. for 17 hours and then filtered. The resultant cake was washed twice with 90.00 kg of acetonitrile and then dried with a nitrogen flow. 29.78 kg of crude Di-p-toluoyl-D-tartrate of (R)-(+)-4-amino-N-[(1 -ethyl-2- pyrrolidinyl)methyl] -5-(ethylsulfonyl)-2-methoxybenz-amide was obtained. The solid contained enantiomers as R:S =95.83:4.17 ratio by chiral HPLC. (yield=49%). The 29.68 kg of crude Di-p-toluoyl-D-tartrate of (R)-(+)-4-amino-N-[(1 -ethyl-2-pyrrolidinyl)methyl]-5-(eth- ylsulfonyl)-2-methoxybenzamide and 341.3 kg of methanol was charged into a 1000 L glass-lined reactor equipped with reflux condenser, nitrogen purge, thermocouple and retreat curve impellet The mixture was heated to 64 C. and a clear solution was created. The solution was cooled to 58 C. and 0.58 kg of seed added. A slurry formed seeding. The slurry was agitated for 1 hours, then cooled to 0 C. at a rate of 0.3 C per minute. The slurry was held at 0 C. for 15 hour and then filtered. The cake was washed with 103.9 kg of methanol and then dried with a nitrogen flow. 26.73 kg of Di-p-toluoyl-D-tartrate of (R)-(+)-4-amino-N-[(1 -ethyl-2- pyrrolidinyl)methyl] -5-(ethylsulfonyl)-2-methoxybenz- amide was obtained. The solid contained enantiomers as R:S=99.24:0.76 ratio of by chiral HPLC. (yield=90%). The DSC of the solid obtained is shown in FIG. 19, indicating an endothermic event at 147 C. An NMR spectrum of Di-p-toluoyl-D-tartrate of (R)-(+)-4-amino-N-[(1 -ethyl-2-pyrrolidinyl)methyl]-5-(eth- ylsulfonyl)-2-methoxybenzamide was obtained in Example bE, having the following characteristics: ?H NMR (400 MHz, DMSO-d5) oe ppm 1.07-1.15 (m, 6H) 1.59-1.67 (m,1H) 1.73-1.87 (m,2H) 1.97-2.07 (m,1H) 2.35 (s,6H) 2.81-2.96 (m,2H) 3.09-3.21 (m, 3H) 3.37-3.59 (m, 4H) 5.67 (s, 2H) 6.46 (s, 1H) 6.54 (s, 2H) 7.29 (d, J=7.93 Hz, 4H) 7.82 (d, J=8.54 Hz, 4H) 8.08 (s, 1H) 8.36 (br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In acetonitrile; at 40℃; for 12h;Large scale; | 278.0 kg of acetonitrile and 58.9 kg of 1-benzyl-3-methylpiperidin-4-one were added to the reactor, and the temperature was raised to 40 ± 2 C. 129.0 kg of (2S, 3S) -2,3-bis ((4-methylbenzoyl) oxy) succinic acid hydrate was added. Stir at 40 ± 2 C. for 12 ± 2 hours. After filtration it was washed with 92.7 kg of acetonitrile. Vacuum drying at 40 C. afforded the title compound (70.7 kg, 83%, 99% ee). |
83% | In acetonitrile; at 40℃; for 12h;Large scale; | 278.0 kg of acetonitrile and 58.9 kg of 1-benzyl-3-methylpiperidin-4-one were added to the reactor, and the temperature was raised to 40 ± 2 C.129.0 kg of (2S, 3S) -2,3-bis ((4-methylbenzoyl) oxy) succinic acid hydrate was added. Stir at 40 ± 2 C. for 12 ± 2 hours.After filtration it was washed with 92.7 kg of acetonitrile. Drying in vacuo at 40 C. gave the title compound (70.7 kg, 83%, 99% ee). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.24 g | In ethyl acetate at 20℃; for 24h; Resolution of racemate; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24.8g | In isopropyl alcohol; at 15 - 25℃; for 16h; | (1) (RS) -4-(4-(Dimethylaminopropyl)-1-(4-fluorophenyl)_1-hydroxybutyl)_3-hydroxymethylbenzonitrile hydrobromide at room temperature The salt (85.0 g, 0.2 mol) was added to 200 ml of a solution containing 12.0 g of NaOH, and dichloromethane (200 ml) was added and stirred for 0.5 hour. The mixture was separated and the aqueous layer was evaporated.The residual dichloromethane was removed with isopropyl alcohol (20 ml).The oil was obtained, heated to 70 C by adding isopropanol (200 ml), and after completely dissolved, D-(+)-di-p-methylbenzoyltartaric acid (30.3 g, 0.075 mol) was added, and after completely dissolved, stirring was stopped. Naturally cool down to 20-25 C, add a little seed crystal (1%.) at 60 C, static crystallization 16 smallThe mixture was filtered under reduced pressure, washed with isopropyl alcohol solution (50 ml), and dried at 45 C to give a white solid 34.3 g, yield 32%, optical purity () 90.2%(2) The crude product prepared in the above step (1) was added to 86 ml of ethanol, heated to reflux, and completely dissolved. Then, 172 ml of ethyl acetate was added, the stirring was stopped, the temperature was naturally lowered to 15-25 C, and the crystal was allowed to stand for 16 hours. The mixture was filtered under reduced pressure, washed with ethyl acetate (50 ml), and evaporated to dryness to afford white solid (36.6 g, yield: 85%), optical purity (ee) 99.0%.(3) The crude product prepared in the above step (2) was added to 73 ml of ethanol, heated to reflux, and completely dissolved. Then, 146 ml of ethyl acetate was added, the stirring was stopped, the temperature was naturally lowered to 15-25 C, and the crystal was allowed to stand for 16 hours. The mixture was Filtration under reduced pressure, washed with ethyl acetate (30 ml), dried at 45 C to give a white solid 24.8 g, yield 87%, optical purity (ee) 99.97% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With potassium hydroxide; In water; at 20℃; for 7h; | A methanol solution (2.50 ml) of d-H2DTTA (38.60 mg,0.10 mmol) was added to a 25 ml round-bottomed flask. Anaqueous solution (2.50 ml) of EuCl36H2O (17.00 mg,0.066 mmol) was added slowly to the solution. KOH(150.00 ml, 0.20 mol l1) was added carefully to the solution.After stirring for 7 h at room temperature, the filtrate was leftundisturbed for one week. Colourless prismatic crystals of (I)were obtained in 28% yield based on d-H2DTTA. EA calculated (%) for C63H63EuO27: C 53.89, H 4.52; found:C 53.77, H 4.61. IR (KBr, /cm1): 3467 (m), 2951 (w), 1734(s), 1708 (s), 1668 (s), 1611 (s), 1510 (w), 1412 (m), 1338 (w),1301 (w), 1267 (s), 1180 (s), 1109 (s), 1020 (m), 906 (w), 840(w), 752 (s), 689 (w), 654 (w), 609 (w), 564 (w), 477 (w). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40.53% | BB-3A-5 (10.00 g, 40.43 mmol, 1.00 eq) was dissolved in methyl isobutyl ketone (600 mL) and toluene (1.2 L), followed by addition of p-dimethylbenzoyl-D-tartaric acid (15.62 g, 40.43 mmol, 1.00 eq) at room temperature. The mixture was stirred for 10 hours at room temperature, and cooled to 0 C, followed by dropwise addition of H2O2 (13.75 g, 121.29 mmol, 11.65 mL, 30% purity, 3.00 eq) at room temperature. The mixture was stirred for 96 hours at room temperature. The mixture was quenched with saturated aqueous solution of sodium sulfite, followed by addition of water (200 mL), sodium hydroxide (3.08 g, 76.96 mmol, 1.00 eq) and ethyl acetate (500 mL), and stirred for 30 minutes at room temperature. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude material was dissolved in water (100 mL) and ethylene glycol dimethyl ether (100 mL), and concentrated after stirring for 14 hours at room temperature. The crude product was washed with acetonitrile: water = 1:1 (80 mL) and filtered to obtain BB-3A-6 (8.00 g, 12.31 mmol, yield 40.53%). |
Tags: 32634-68-7 synthesis path| 32634-68-7 SDS| 32634-68-7 COA| 32634-68-7 purity| 32634-68-7 application| 32634-68-7 NMR| 32634-68-7 COA| 32634-68-7 structure
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