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US 2003/0158414 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
- D- or L-tartaric acid
- 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
- D- or L-tartaric acid
- 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.
14 more elements
A process for preparing a L-tartrate salt of formula XX,
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- 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:
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Dependencies are inferred from the claim text.