Process for Manufacturing Optically Pure (R) or (S)-5-(2-Aminopropyl)-2-Methoxybenzene Sulfonamide

Abstract

The invention relates to an improved process for the manufacture of enantiomerically pure R-(+) or S-(+)-5-(2-amino-propyl)-2-methoxybenzene sulfonamide by resolution of (R,S)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide with D-(−) or L-(+)-tartaric acid to form a mixture of diastereomeric salts, separating the diastereomeric salts by kinetic resolution in a mixture of solvent systems of the kind such as herein described, in the specified time and temperature range to provide said R-(−)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide or S-(+)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide with excellent chiral purity more than 99.9%.

Description

EXAMPLE 1

Resolution of (R,S)-(−)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide

300.0 g (R,S)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide was added in 3000 ml of methanol:water mixture (95:5% v/v) and then heated to 60-65° C. for complete dissolution. 202.9 g of D-(−)-tartaric acid was slowly added at 60-65° C. in the reaction mixture and then maintained 60-65° C. temperature for 6 hours. The crystals were collected by filtration at same temperature (60-65° C.), washed with 2×75 ml methanol and dried at 65-75° C. temperature till constant weight to provide 187.3 g of R-(−)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide tartarate.

Yield: 77.46%

Melting point: 194-195° C. (dec.)

$\left[\alpha \right]\underset{D}{25}-{19.4}^{\circ }\left(c=1.0,H_2O\right)$

EXAMPLE 2

Resolution of (R,S)-(−)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide

250 g of (R,S)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide was added in 2550 ml of methanol:dimethyl formamide mixture (80:20% v/v) then heated to 60-65° C. for complete dissolution. 169 g of D-(−)-tartaric acid was slowly added at 60-65° C. in the reaction mixture and then maintained 60-65° C. temperature for 6 hours. The crystals were filtered off. The wet product was taken in 750 ml of methanol and stirred for half an hour, at ambient temperature, was filtered off and washed with 2×62.5 ml methanol, thereby affording 193.3 g. of R-(−)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide tartarate.

Yield: 95.92%

Melting point: 193-194° C. (dec.)

$\left[\alpha \right]\underset{D}{25}-{19.16}^{\circ }\left(c=1.0,H_2O\right)$

EXAMPLE 3

Resolution of (R,S)-(−)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide

75.5 kg of (R,S)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide was added in 770.1 L of methanol:dimethyl formamide mixture (8.5:1.7% v/v) then heated to 60-65° C. for complete dissolution. 51.0 kg of D-(−)-tartaric acid was slowly added at 60-65° C. in the reaction mixture and then maintained 60-65° C. temperature for 6 hours. The crystals were filtered off. The wet product was taken in 226.5 L of methanol and stirred for half an hour, at ambient temperature, was filtered off and washed with 2×18.87 L methanol, thereby affording 45.0 kg of R-(−)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide tartarate.

Yield: 95.92%

Melting point: 193-194° C. (dec.)

$\left[\alpha \right]\underset{D}{25}-{19.16}^{\circ }\left(c=1.0,H_2O\right)$

1^st Purification of R-(−)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide tartarate

EXAMPLE 4

[A] A mixture of 100 g of R-(−)-5-(2-aminopropyl)-2-methoxybenzene 5 sulfonamide tartarate (obtained in Example-2), 400 ml methanol and 250 ml water was refluxed for 1 hour. The clear solution was slowly cooled to 40-45° C. and maintained for 2 hours at 40-45° C. The reaction mass further cooled to 28-30° C. and stirred for 6 hours at same temperature. The product was filtered at same temperature and washed with 2×25 ml methanol, dried the solid at 50-55° C. till constant weight to give 63.3 g of R-(−)-5-(2-aminopropyl)-2-methoxy benzene sulfonamide tartarate. [ee:98.38%].

[B] A mixture of 20 g of R-(−)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide tartarate (obtained in Example-2), 160 ml methanol and 60 ml water was refluxed for 1 hour. The clear solution was slowly cooled to 40-45° C. and maintained at 40-45° C. for 2 hours. The reaction mass further cooled to 28-30° C. and stirred for 6 hours at same temperature The product was filtered at same temperature and washed with 2×5 ml methanol, dried the solid at 50-55° C. till constant weight to give 11.1 g of R-(−)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide tartarate. [ee:98.02%].

[C] A mixture of 97.0 g of R-(−)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide tartarate (obtained in Example-2), 388 ml methanol and 170 ml water was refluxed for 1 hour. The clear solution was slowly cooled to 45-48° C. and maintained at 45-48° C. for 2 hours. The reaction mass further cooled to 28-30° C. and stirred for 6 hours at same temperature. The product was filtered at same temperature and washed with 2×24 ml methanol, dried the solid at 50-55° C. till constant weight to give 67.7 g of R-(−)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide tartarate. [ee:96.89%].

[D] A mixture of 101.0 g of R-(−)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide tartarate (obtained in Example-2), 404 ml methanol and 202 ml water was refluxed for 1 hour. The clear solution was cooled to 45-47° C. and maintained at 45-47° C. for 2 hours. The reaction mass further cooled to 28-30° C. and stirred for 6 hours at same temperature. The product was filtered at same temperature and washed with 2×25 ml methanol, dried the solid at 50-55° C. till constant weight to give 64.0 g of R-(−)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide tartarate having ee=97-97.5%.

[E] A mixture of 45.0 kg of R-(−)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide tartarate (obtained in Example-3), 180 L methanol and 90.0 L water was refluxed for 1 hour. The clear solution was cooled to 45-47° C. and maintained at 45-47° C. for 2 hours. The reaction mass further cooled to 28-30° C. and stirred for 6 hours at same temperature. The product was filtered at same temperature and washed with 2×11.25 L methanol, dried the solid at 50-55° C. till constant weight to give 27.1 kg of R-(−)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide tartarate having ee=97-97.5%.

EXAMPLE 5

II Purification of R-(−)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide tartarate

[A] A mixture of 56.0 g of R-(−)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide tartarate (obtained in Example-4A), 224 ml methanol and 140 ml water was refluxed for 1 hour. The clear solution was slowly cooled to 40-45° C. and maintained at 40-45° C. for 2 hours. The reaction mass further cooled to 28-30° C. and stirred for 6 hours at same temperature. The product was filtered at same temperature and washed with 2×14 ml methanol, dried the solid at 50-55° C. till constant weight to give 40.7 g of R-(−)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide tartarate having ee=99.98-100.0%.

[B] A mixture of 63.0 g of R-(−)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide tartarate (obtained in Example-4C), 252 ml methanol and 110.2 ml water was refluxed for 1 hour. The clear solution was slowly cooled to 50-55° C. and maintained at 50-55° C. for 2 hours. The reaction mass further cooled to 28-30° C. and stirred for 6 hours at same temperature. The product was filtered at same temperature and washed with 2×15 ml methanol, dried the solid at 50-55° C. till constant weight to give 49.6 g of R-(−)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide tartarate having ee=99.40-99.70%.

[C] A mixture of 59.0 g of R-(−)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide tartarate (obtained in Example-4D), 236 ml methanol and 118 ml water was refluxed for 1 hour. The clear solution was slowly cooled to 50-55° C. and maintained at 50-55° C. for 2 hours. The reaction mass further cooled to 28-30° C. and stirred for 6 hours at same temperature. The product was filtered at same temperature and washed with 2×14 ml methanol, dried the solid at 50-55° C. till constant weight to give 44.7 g of R-(−)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide tartarate having ee=99.40-99.60%.

[D] A mixture of 27.1 kg of R-(−)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide tartarate (obtained in Example-4E), 108.4 L methanol and 54.2 L water was refluxed for 1 hour. The clear solution was slowly cooled to 50-55° C. and maintained at 50-55° C. for 2 hours. The reaction mass further cooled to 28-30° C. and stirred for 6 hours at same temperature. The product was filtered at same temperature and washed with 2×6.77 L methanol, dried the solid at 50-55° C. till constant weight to give 19.6 kg of R-(−)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide tartarate having ee=99.40-99.60%.

EXAMPLE 6

Preparation of R-(−)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide

To 10 g tartarate salt (obtained in Example-5A) of R-(−)-5-(2-aminopropyl)-2-methoxybenzene sulfonamide in 10 ml water was added 40% aq. sodium hydroxide solution, to adjust pH between 9.5 -10.0. The reaction mixture was stirred for 1 hour at 25-30° C. temperature. The product obtained was filtered and washed with 2.5 ml water. Dried the product at 55-60° C. till constant weight. 6.0 g of R-(−)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide was collected. Chiral purity: >99.9%

Melting point: 166° C.-167° C.

$\left[\alpha \right]\underset{D}{23}-{17.31}^{\circ }\left(c=1.07,\mathrm{Methanol}\right)$

Claims

1. A process for the manufacture of highly optical pure R-(−) or S-(+)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide which comprises: (a) resolving (R,S)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide with D-(−)- or L-(+)-tartaric acid to form a mixture of diastereomeric salts(b) separating the diastereomeric salt by filtration at desired temperature range(c) subjecting diastereomeric salt kinetic resolution in a solvent system of the kind such as hereinbefore described;(d) liberating of optically pure R-(−) or S-(+)-5-(2-aminopropyl)-2-methoxy benzenesulfonamide with optical purity more than 99.9%.

2. A process as claimed in claim 1, wherein said D-(−)- or L-(+)-tartaric acid is employed in 1-1.5 molar ratio with that of (R,S)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide.

3. A process as claimed in claim 2 wherein D-(−)- or L-(+)-tartaric acid is preferably employed in 1.1 molar ratio with that of (R,S)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide.

4. A process as claimed in claim 1, wherein in step (a) protic solvents containing C1-C6 are employed for resolution alone or along with varying proportions of dipolar solvents like N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrilodone and water.

5. A process as claimed in claim 4, wherein said protic solvents are selected from methanol, ethanol, 1-propanol and 2-propanol.

6. A process as claimed in claim 5, wherein ratio of the dipolar solvent to alcoholic solvent varies from 5-20% (v/v).

7. A process as claimed in claim 6, wherein amount of a single solvent or a solvents combination employed as that of (R,S)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide is 5-25 volume.

8. A process as claimed in claim 7, wherein the most preferable amount of methanol and N,N-dimethylformamide employed as that of (R,S)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide is 8.5 and 1.7 volumes respectively.

9. A process as claimed in claim 8, wherein resolution is carried out at a temperature in the range of 20-70° C., preferably, 60-65° C.

10. A process as claimed in claim 9, wherein the reaction mixture is stirred for 0-26 hours, preferably, 6 hours.

11. A process as claimed in claim 1, wherein in step (a), the diastereomeric salt contains the (R) isomer in an amount of from 60-96% and (S) isomer in an amount of from 40-4%, preferably, 80-90% and 20-10% respectively.

12. A process as claimed in claim 1, wherein in step (b), said diastereomeric salt is separated by filtration over nutsche filter or by centrifugation at temperature 30-70° C.

13. A process as claimed in claim 12, wherein the filtration or centrifugation is carried out preferably at a temperature in the range of 60-65° C.

14. A process as claimed in claim 1, wherein I step (b) said kinetic resolution of moderately resolved diastereomeric salt is accomplished in 5-15 volumes of a single solvent or a solvent mixture containing primary, secondary or tertiary alcohol (C1-C6) with water to get desired optical purity.

15. A process as claimed in claim 14, wherein said kinetic resolution of moderately resolved diastereomeric salt is accomplished in solvent mixture of 0-10 volumes, preferably, 4 volumes of methanol and 0-5 volumes, preferably 2.5 volumes of water to get desired optical purity.

16. A process as claimed in claim 1, wherein in step (c) the reaction mixture is refluxed for 0.5-4 hours, preferably 1 hour.

17. A process as claimed in claim 1, wherein in step (c) the clear solution is cooled from reflux temperature (65-100° C.) to 30-60° C., in first cooling, preferably 40-55° C. to get optimum results.

18. A process as claimed in claim 24, wherein the temperature of reaction mixture is maintained for 0-10 hours, preferably 2 hours.

19. A process is claimed in claim 18, wherein the reaction mixture is further cooled to 10-40° C., preferably, 30-35° C. in second cooling.

20. A process as claimed in claim 18, wherein the reaction mixture is aged for 0-12 hours preferably 6 hours, before filtration.

21. A process as claimed in claim 20, wherein the diastereomeric salt contains R-isomer in an amount of 93-99%, preferably 98-99% and S-isomer 1-7%, preferably, 1-2%.

22. A process as claimed in claim 1, wherein in step (c) kinetically resolved diastereomeric salt is subjected to 1-2 more purification steps.

23. A process as claimed in claim 22, wherein the optical purity of R-(−)-isomer of 5-(2-aminopropyl)-2-methoxybenzenesulfonamide is enhanced from 98 to 99.95% by methanol: water purification.

24. A process as claimed in claim 1, wherein in step (d) pure diastereomeric salts having optical purity >99.5% is treated with aqueous solution of base i. e. alkali metal hydroxides, carbonates and bicarbonates to get free R-(−) or S-(+)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide with optical purity between 99.5-99.9%, but most preferably aqueous sodium hydroxide solution is used.

25. A process as claimed in claim 1, wherein the mother liquor obtained from I and II purification contains diastereomeric salts, having optical purity 70-85% of R-(−) or S-(+)-5-(2-aminopropyl)-2-methoxy benzenesulfonamide, that can be mixed in another batch during I purification to enhance the productivity.