Sulfuric Acid → N2 (1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline dihydrate

Temperature

10 °C

Using N2 -(1-ethoxycarbonyl-3-oxo-3-phenylpropyl)-N6 -trifluoroacetyl-L-lysyl-L-proline [(1S/1R)=2] (5.0 g, 9.4 mmoles), the catalytic reduction was conducted in 70 ml of 7% (w/w) water-containing ethanol containing 1.4 N sulfuric acid according to the same manner as that described in Example 1 (amount of sulfuric acid based on substrate: 5 equivalents). Pd--C was removed by filtration and the Pd--C cake was washed with 20 ml of 7% (w/w) water-containing ethanol. Water (10 ml) was added to the resulting filtrate which was neutralized (pH 4.6) by slowly adding dropwise an aqueous 30% (w/w) sodium hydroxide solution. The filtrate was concentrated under reduced pressure at the inner temperature of 20° C. to remove ethanol. After cooling to 10° C., 50 ml of cold water was added, followed by extracting three times with 50 ml of methylene chloride at a range from 5° to 15° C. The resulting methylene chloride layer was washed with 20 ml of cold water at a range from 5° to 15 ° C., and then kept in a freezer for 2 days. After ice is removed, the layer was concentrated under reduced pressure at an inner temperature of at most 20° C. to give a concentrate containing N2 -(1-ethoxycarbonyl-3-phenylpropyl)-N6 -trifluoroacetyl-L-lysyl-L-proline [(1S/1R)=2]. The yield was 80%. The content of N2 -(1-ethoxycarbonyl-3-cyclohexylpropyl)-N6 -trifluoroacetyl-L-lysyl-L-proline was 0.2% (w/w) and the content of N2 -(1-carboxy-3-phenylpropyl)-N6 -trifluoroacetyl-L-lysyl-L-proline was 0.1% (w/w). The resulting concentrate was completely concentrated to dryness and, after dissolving it in 20 ml of methyl t-butyl ether, the solution was concentrated using an evaporator (bath temperature: 20° C.) to reduce the volume to half. A seed crystal of N2 -(1(S)-ethoxycarbonyl-3-phenylpropyl)-N6 -trifluoroacetyl-L-lysyl-L-proline was added and the solution was crystallized by allowing to stand in a refrigerator. The resulting crystal was rapidly filtered, and then washed with 2 ml of cooled methyl t-butyl ether/methylcyclohexane (7/3 (v/v)) immediately after filtration. The resulting wet crystal was dissolved in 10 ml of methyl t-butyl ether and the solution was crystallized by allowing to stand in a refrigerator. With vigorously stirring the slurry at 10° C., 3 ml of methylcyclohexane was slowly added. The resulting crystal was rapidly filtered, and then washed with 2 ml of cooled methyl t-butyl ether/methylcyclohexane (7/3 (v/v)) immediately after filtration. The resulting crystal was vacuum-dried (30 mmHg to 1 mmHg) at a range from 20° to 45° C. and mixed with a mixture of 10 ml of water and 0.24 g of sodium carbonate. An aqueous 10% (w/w) sodium hydroxide solution was slowly added at 40° C. to maintain the pH not less than 12.5. Four hours after the addition, the pH was adjusted to 8 with 35% (w/w) hydrochloric acid, 10 ml of methylene chloride was added, and then the pH was adjusted to 5 by adding 35% (w/w) hydrochloric acid. The methylene chloride layer was separated and the aqueous layer was concentrated under reduced pressure by using an evaporator (bath temperature: 45° C.). The aqueous layer was concentrated to reduce the volume to quarter, and then stirred at room temperature for 4 hours to give a thick slurry. The resulting crystal was filtered and washed with 2 ml of water. The resulting wet crystal was vacuum-dried (30 mmHg to 1 mmHg) at 5 0° C. to give N2 -(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline dihydrate (lysinoprildihydrate) (0.9 g, 2.1 mmoles). The yield was 33%. HPLC purity: 98% (w/w), the content of a diketopiperazine derivative: less than 0.1% (w/w).

1. customPd--C was removed by filtration
2. washthe Pd--C cake was washed with 20 ml of 7% (w/w) water-
3. additioncontaining ethanol
4. additionWater (10 ml) was added to the resulting filtrate which
5. additionby slowly adding dropwise an aqueous 30% (w/w) sodium hydroxide solution
6. concentrationThe filtrate was concentrated under reduced pressure at the inner temperature of 20° C.
7. customto remove ethanol
8. addition50 ml of cold water was added
9. extractionby extracting three times with 50 ml of methylene chloride at a range from 5° to 15° C
10. washThe resulting methylene chloride layer was washed with 20 ml of cold water at a range from 5° to 15 ° C.
11. customAfter ice is removed
12. concentrationthe layer was concentrated under reduced pressure at an inner temperature of at most 20° C.
13. customto give a concentrate
14. concentrationThe resulting concentrate
15. concentrationwas completely concentrated to dryness
16. dissolutionafter dissolving it in 20 ml of methyl t-butyl ether
17. concentrationthe solution was concentrated
18. customan evaporator (bath temperature: 20° C.)
19. additionA seed crystal of N2 -(1(S)-ethoxycarbonyl-3-phenylpropyl)-N6 -trifluoroacetyl-L-lysyl-L-proline was added
20. customthe solution was crystallized
21. filtrationThe resulting crystal was rapidly filtered
22. washwashed with 2 ml of cooled methyl t-butyl ether/methylcyclohexane (7/3 (v/v))
23. filtrationimmediately after filtration
24. dissolutionThe resulting wet crystal was dissolved in 10 ml of methyl t-butyl ether
25. customthe solution was crystallized
26. addition3 ml of methylcyclohexane was slowly added
27. filtrationThe resulting crystal was rapidly filtered
28. washwashed with 2 ml of cooled methyl t-butyl ether/methylcyclohexane (7/3 (v/v))
29. filtrationimmediately after filtration
30. customThe resulting crystal was vacuum-dried (30 mmHg to 1 mmHg) at a range from 20° to 45° C.
31. additionmixed with a mixture of 10 ml of water and 0.24 g of sodium carbonate
32. additionAn aqueous 10% (w/w) sodium hydroxide solution was slowly added at 40° C.
33. temperatureto maintain the pH not less than 12.5
34. additionFour hours after the addition
35. additionwas added
36. additionby adding 35% (w/w) hydrochloric acid
37. customThe methylene chloride layer was separated
38. concentrationthe aqueous layer was concentrated under reduced pressure
39. customan evaporator (bath temperature: 45° C.)
40. concentrationThe aqueous layer was concentrated
41. stirringstirred at room temperature for 4 hours
42. customto give a thick slurry
43. filtrationThe resulting crystal was filtered
44. washwashed with 2 ml of water
45. customThe resulting wet crystal was vacuum-dried (30 mmHg to 1 mmHg) at 5 0° C.

ORD record

ord-0edac2ae38af4d67a592976a304bdc7f

Source dataset

uspto-grants-2000_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06118010