Process for preparing 4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid compound

Patent metadata

Field	Value
Publication number	US-9676742-B2
Application number	US-201514751389-A
Country	US
Kind code	B2
Filing date	Jun 26, 2015
Priority date	Feb 15, 2012
Publication date	Jun 13, 2017
Grant date	Jun 13, 2017

Abstract

The invention provides processes for preparing intermediates useful for preparing compounds of the formula:

or a tautomer or salt thereof, where R 1 -R 5 , a, b, X and P 2 , are as defined in the specification.

First claim

What is claimed is:

1. A compound of formula IV:

where:
R 1 is selected from H, —C 1-8 alkyl, —C 1-3 alkylene-C 6-10 aryl, —[(CH 2 ) 2 O] 1-3 CH 3 , —C 1-6 alkylene-OC(O)R 10 , —C 1-6 alkylene-NR 11 R 12 , —C 1-6 alkylene-C(O)R 13 , —C 0-6 alkylenemorpholinyl, —C 1-6 alkylene-SO 2 —C 1-6 alkyl,

R 10 is selected from —C 1-6 alkyl, —O—C 1-6 alkyl, —O—C 3-7 cycloalkyl, —CH[CH(CH 3 ) 2 ]—NH 2 , and —CH[CH(CH 3 ) 2 ]—NHC(O)O—C 1-6 alkyl; R 11 and R 12 are —C 1-6 alkyl or are taken together as —(CH 2 ) 3-6 —, —C(O)—(CH 2 ) 3 —, or —(CH 2 ) 2 (CH 2 ) 2 —; R 13 is selected from —O—C 1-6 alkyl, —O-benzyl, and —NR 11 R 12 ;
X is selected from pyrazole, imidazole, triazole, benzotriazole, tetrazole, oxazole, isoxazole, thiazole, pyrimidine, pyridazine, benzimidazole, pyran, and pyridyltriazole;
R 2 is absent or selected from H; halo; —C 0-5 alkylene-OH; —C 1-6 alkyl; —C 3-7 cycloalkyl; —C 0-2 alkylene-O—C 1-6 alkyl; —C(O)C 1-6 alkyl; —C 0-1 alkylene-COOH; —C(O)NR 20 R 21 , NHC(O)-phenylene-OCH 3 ; ═O; phenyl optionally substituted with one or two groups independently selected from halo, —OH, and —OCH 3 ; pyridinyl; and pyrazinyl; R 20 is H or —C 1-6 alkyl; R 21 is selected from H, —C 1-6 alkyl, —(CH 2 ) 2 OH, —(CH 2 ) 2 OCH 3 , —(CH 2 ) 2 SO 2 NH 2 , and —C 0-1 alkylene-C 3-7 cycloalkyl; or R 20 and R 21 are taken together to form a saturated or partially unsaturated —C 3-5 heterocycle optionally substituted with halo or —OH, and optionally containing an oxygen atom in the ring; and R 2 , when present, is attached to a carbon atom;
R 3 is selected from H; —OH; —C 1-6 alkyl; —C 1-2 alkylene-COOH; —CH 2 OC(O)CH(R 30 )NH 2 ; —CH[CH(CH 3 ) 2 ]—NHC(O)O—C 1-6 alkyl; pyridinyl; and phenyl or benzyl optionally substituted with one or more groups selected from halo and —OCH 3 ; R 30 is selected from H, —CH(CH 3 ) 2 , phenyl, and benzyl; and R 3 is attached to a carbon or nitrogen atom; and when R 3 is attached to nitrogen atom, R 3 can be P 4 , where P 4 is an amino protecting group;
a is 0 or 1; R 4 is selected from halo, —CH 3 , —CF 3 , and —CN;
b is 0 or an integer from 1 to 3; each R 5 is independently selected from halo, —OH, —CH 3 , —OCH 3 , and —CF 3 ;
P 2 is an alcohol protecting group;
and where each alkyl group in R 1 , R 2 , and R 3 is optionally substituted with 1 to 8 fluoro atoms;
or a tautomer or salt thereof.

2. The compound of claim 1 , where R 1 is:

3. The compound of claim 1 , where X is triazole.

4. The compound of claim 1 , where R 2 is H.

5. The compound of claim 1 , where P 4 is selected from acetyl, adamantyl-oxycarbonyl, t-amyloxycarbonyl, benzothiophene sulfone-2-methoxycarbonyl, benzoyl, benzyl, benzyloxycarbonyl, 2-(p-biphenylyl)propyl-2-oxycarbonyl, t-butoxycarbonyl, 2-(t-butyl sulfonyl)-2-propenyloxycarbonyl, 3,4-dimethoxybenzyl, 2,2-dimethyl-3,5-dimethyloxybenzyloxycarbonyl, dithiasuccinoyl, formyl, 9-fluorenylmethoxycarbonyl, 2-furanmethyloxycarbonyl, p-methoxybenzyl, p-methoxybenzyl carbonyl, 1-methylcyclobutyloxycarbonyl, o-nitrophenylsulfenyl, 2-phenylpropyl-2-oxycarbonyl, 2-(p-phenylazophenyl)propyl-2-oxycarbonyl, silyl ethers, tosyl, trifluoroacetyl, β-trimethylsilylethyloxycarbonyl, triphenylmethyl, and trityl.

6. The compound of claim 5 , where R 3 is P 4 , and P 4 is trityl.

7. The compound of claim 1 , where P 2 is selected from acetyl, benzoyl, benzyl, p-methoxybenzyl ether, β-methoxyethoxymethyl ether, methylthiomethyl ether, pivaloyl, silyl ethers, tetrahydropyranyl, triphenylmethyl, and trityl.

8. The compound of claim 7 , where P 2 is tetrahydropyranyl.

Assignees

• Rapta Miroslav
• Theravance Biopharma R&D Ip Llc

Inventors

• Rapta Miroslav

Classifications

• C07D317/34

  Oxygen atoms · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07D207/263

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms · CPC title

• C07D407/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title