Patent EA-003218-B1 (EA)
Title: Process for preparing growth hormone secretagogues
Inventor: BUSCH FRANK R
IPC: C07D/
Filed: 2000-02-25
Abstract: 1. A process of preparing a compound of Formula II, wherein: A is hydrogen or Prt R<1> is -(C1-C10)alkyl optionally substituted with up to three fluoro atoms; R<2> is phenylmethyl or 2-pyridylmethyl; R<3> is -(C1-C5)alkyl-O-(C0-C5)alkylphenyl, where the phenyl substituent in the definition of R is optionally substituted with up to three fluoro atoms; and Prt is an amine protecting group, comprising: a) mixing an appropriate chiral tartrate salt having the structure of Formula IV, wherein R<1> and R<2> are as defined above, and an organic amine in a reaction inert solvent at a temperature of about -68 DEG C to about -40 DEG C to form a slurry; b) adding a compound of the Formula V, wherein R<3> and Prt are as defined above, to said slurry to form a reaction mixture comprising the tartrate salt of the organic amine, the free base of a compound of Formula IV and a compound of the formula V; and c) adding a coupling reagent to said reaction mixture to form a compound of Formula II, wherein A is Prt. 2. A process of claim 1 wherein indicated compound of Formula IV is suspended in indicated solvent prior to the addition of indicated organic amine. 3. A process of claim 2 wherein said slurry is warmed to about -50 DEG C prior to step b. 4. A process of claim 1 wherein: in step a, said organic amine is triethylamine; in step b, R<3> is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl and Prt is t-butyloxycarbonyl; and in step c, said coupling reagent is propane phosphonic acid anhydride. 5. A process of claim 4 wherein R<1> is methyl or 2,2,2-trifluoroethyl and R<2> is phenylmethyl or 2-pyridylmethyl. 6. A process of claim 5 wherein the compound of Formula II selected from (1-(2-(1 (R)-(2,4-difluorobenzyloxymethyl)-3a(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c ]pyridin-5-yl)- 2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acid tert-butyl ester and (1-(2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl )-1-methyl-ethyl)-carbamic acid tert-butyl ester is prepared. 7. A process of claim 5 wherein a compound of Formula IIA, is prepared. 8. A process of claim 5 wherein a compound of Formula IIB, is prepared. 9. A process of claim 2 wherein: in step a, said organic amine is triethylamine; in step b, R3 is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl and Prt is t-butyloxycarbonyl; and in step c, said coupling reagent is propane phosphonic acid anhydride. 10. A process of claim 9 wherein R<1> is methyl or 2,2,2-trifluoroethyl and R<2> is phenylmethyl or 2-pyridylmethyl. 11. A process of claim 10 wherein the compound of Formula II selected from (1-(2-(1(R)-(2,4-difluorobenzyloxymethyl)-3a(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazo lo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acid tert-butyl ester and (1-(2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl )-1-methyl-ethyl)-carbamic acid tert-butyl ester is prepared. 12. A process of claim 10 wherein a compound of Formula IIA, is prepared. 13. A process of claim 10 wherein a compound of Formula IIB, is prepared. 14. A process of claim 3 wherein: in step a, said organic amine is triethylamine; in step b, R<3> is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl and Prt is t-butyloxycarbonyl; and in step c, said coupling reagent is propane phosphonic acid anhydride. 15. A process of claim 14 wherein R<1> is methyl or 2,2,2-trifluoroethyl and R<2> is phenylmethyl or 2-pyridylmethyl. 16. A process of claim 15 wherein the compound of Formula II selected from (1-(2-(1 (R)-(2,4-difluorobenzyloxymethyl)-3a(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c ]pyridin-5-yl)- 2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acid tert-butyl ester and (1-(2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl )-1-methyl-ethyl)-carbamic acid tert-butyl ester is prepared. 17. A process of claim 15 wherein a compound of Formula IIA, is prepared. 18. A process of claim 15 wherein a compound of Formula IIB, is prepared. 19. A process of claim 1 wherein said Prt is a Boc group, which is removed by reacting said compound of Formula II with an acid. 20. A process of claim 19 wherein said acid is methanesulfonic acid. 21. A process of claim 20 wherein: R<3> is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl; in step b, said organic amine is triethylamine; and in step c, said coupling reagent is propane phosphonic acid anhydride. 22. A process of claim 21 wherein R<1> is methyl or 2,2,2-trifluoroethyl and R is phenylmethyl or 2-pyridylmethyl. 23. A process of claim 22 wherein said compound of Formula III selected from 2-amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo-[4,3-c]pyridin-5-yl-1 (R)-benzyloxylmethyl-2-oxo-ethyl]-isobutyramide and 2-amino-N-(1(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl-2-methyl-propionamide is prepared. 24. A process of claim 22 wherein a compound of formula IIIA, is prepared. 25. A process of claim 22 wherein a compound of formula IIIB, is prepared. 26. A process of claim 19 wherein said acid is trifluoroacetic acid. 27. A process of claim 26 wherein: R<3> is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl; in step b, said organic amine is triethylamine; and in step c, said coupling reagent is propane phosphonic acid anhydride. 28. A process of claim 27 wherein R<1> is methyl or 2,2,2-trifluoroethyl and R<2> is phenylmethyl or 2-pyridylmethyl. 29. A process of claim 28 wherein said compound of Formula III selected from 2-amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo-[4,3-c]pyridin-5-yl-1(R)-benzyloxylmethyl-2-oxo-ethyl]- isobutyramide and 2-amino-N-(1 (R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyr azolo[4,3-c]pyridin-5-yl)-ethyl-2-methyl-propionamide is prepared. 30. A process of claim 30 wherein a compound of formula IIIA, is prepared. 31. A process of claim 28 wherein a compound of formula IIIB, is prepared. 32. A process of claim I wherein said Prt is Boc and said Boc is removed by reacting said compound of Formula II with an acid. 33. A process of claim 32 wherein said acid is methanesulfonic acid. 34. A process of claim 33 wherein: R<3> is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl; in step b, said organic amine is triethylamine; and in step c, said coupling reagent is propane phosphonic acid anhydride. 35. A process of claim 34 wherein R<1> is methyl or 2,2,2-trifluoroethyl and R<2> is phenylmethyl or 2-pyridylmethyl. 36. A process of claim 35 wherein said compound of Formula III selected from 2-amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo-[4,3-c]pyridin-5-yl-1(R)-benzyloxylmethyl-2-oxo-ethyl]- isobutyramide and 2-amino-N-(1 (R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyr azolo[4,3-c]pyridin-5-yl)-ethyl-2-methyl-propionamide. 37. A process of claim 35 wherein a compound of formula IIIA, is prepared. 38. A process of claim 35 wherein a compound of formula IIIB, is prepared. 39. A process of claim 32 wherein said acid is trifluoroacetic acid. 40. A process of claim 39 wherein: R<3> is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl; in step b, said organic amine is triethylamine; and in step c, said coupling reagent is propane phosphonic acid anhydride. 41. A process of claim 40 wherein R<1> is methyl or 2,2,2-trifluoroethyl and R<2> is phenylmethyl or 2-pyridylmethyl. 42. A process of claim 41 wherein said compound of Formula III selected from 2-amino-N-[2-(3a(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo-[4,3-c]pyridin-5-yl-1 (R)-benzyloxylmethyl-2-oxo-ethyl]-isobutyramide and 2-amino-N-(1 (R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyr azolo[4,3-c]pyridin-5-yl)-ethyl-2-methyl-propionamide. 43. A process of claim 41 wherein a compound of formula IIIA, is prepared. 44. A process of claim 43 wherein a compound of formula IIIB, is prepared. 45. A process for preparing a L-tartrate salt of formula XX, comprising the following consecutive steps: a) reacting said 4-oxo-piperidinecarboxylic acid methyl ester, hydrochloride with di-t-butyl-dicarbonate and triethylamine in isopropyl ether to form 4-oxo-1,3-piperidinedicarboxylic acid 1-(1-dimethylethyl) 3-methyl ester; b) reacting said 4-oxo-1,3-piperidinedicarboxylic acid 1-(1-dimethylethyl) 3-methyl ester with benzyl bromide and potassium carbonate in tetrahydrofuran to form 4-oxo-(phenylmethyl)-1,3-piperidinedicarboxylic acid 1-(1-dimethylethyl) 3-methyl ester; c) reacting said 4-oxo-(phenylmethyl)-1,3-piperidinedicarboxylic acid 1-(1-dimethylethyl) 3-methyl ester with methylhydrazine in acetic acid and methyl-t-butyl ether to form 2,3a,4,5,6,7-hexahydro-2-methyl-3-oxo-3a-(phenylmethyl)-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid 1,1-dimethylethyl ester; and d) reacting said 2,3a,4,5,6,7-hexahydro-2-methyl-3-oxo-3a-(phenylmethyl)-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid 1,1-dimethylethyl ester with trifluoroacetic acid to form (3aR)-2,3a,4,5,6,7-hexahydro-2-methyl-3a-(phenylmethyl)-3H-pyrazolo[4,3-c]pyridin-3-one; e) reacting said (3aR)-2,3a,4,5,6,7-hexahydro-2-methyl-3a-(phenylmethyl)-3H-pyrazolo[4,3-c]pyridin-3-one with L-tartaric acid in acetone and water to form said L-tartrate salt of formula XX. 46. A process of claim 45 wherein said L-tartaric acid is added without isolating said (3aR)-2,3a,4,5,6,7-hexahydro-2-methyl-3a-(phenylmethy