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US 2002/0002283 A1Published application
Process for preparing growth hormone secretagogues
AssigneePfizer Inc.
InventorsFrank R Busch, Charles K Chiu, Clifford N Meltz, Ronald J Post, Peter R Rose
Life of this patent
Estimating the term…
Abstract
This invention relates to improved processes for preparing compounds of Formula II, 1 and compounds of Formula III, 2 wherein R1, R2, R3 and Prt are defined as set forth in the specification.
Claims53
A process of preparing a compound of Formula II,
- 51
- wherein:
- R1 is —(C1-C10)alkyl optionally substituted with up to three fluoro atoms;
- R2 is phenylmethyl or 2-pyridylmethyl;
- R3 is —(C1-C5)alkyl-O—(C0-C5)alkylphenyl, where the phenyl substituent in the definition of R3 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,
- 52
- wherein R1 and R2 are as defined above,
- and an organic amine in a reaction inert solvent at a temperature of about −68° C. to about −40° C. to form a slurry;
- b) adding a compound of the Formula V,
- 53
- wherein R3 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.
14 more elements
A process for preparing a compound of Formula III,
- 60
- wherein:
- R1 is —(C1-C10)alkyl optionally substituted with up to three fluoro atoms;
- R2 is phenylmethyl or 2-pyridylmethyl;
- and
- R3 is —(C1-C5)alkyl-O—(C0-C5)alkylphenyl, where the phenyl substituent in the definition of R3 is optionally substituted with up to three fluoro atoms, comprising:
- a) mixing an appropriate chiral tartrate salt having the structure of Formula IV,
- 61
- wherein R1 and R2 are as defined above, and an organic amine in a reaction inert solvent at a temperature of about −68° C. to about −45° C. to form a slurry;
- b) adding a compound of the Formula V,
- 62
- wherein R3 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;
- c) adding a coupling reagent to said reaction mixture to form a compound of Formula II;
- and
- d) reacting said compound of Formula II with a suitable deprotecting reagent to form a compound of Formula III.
12 more elements
A process for preparing a L-tartrate salt of formula XX,
- 71
- 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.
5 more elements
A polymorph of a dihydrate of a compound of formula XX:
- 72
Dependencies are inferred from the claim text.