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

Patent metadata

Field	Value
Publication number	US-10011581-B2
Application number	US-201715593849-A
Country	US
Kind code	B2
Filing date	May 12, 2017
Priority date	Feb 15, 2012
Publication date	Jul 3, 2018
Grant date	Jul 3, 2018

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 III′:

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 O(CH 2 ) 2 —; R 13 is selected from —O—C 1-6 alkyl, —O— benzyl, and —NR 11 R 12 ;
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;
U is H or P 3 , where P 3 is an amino protecting group;
and where each alkyl group in R 1 is optionally substituted with 1 to 8 fluoro atoms;
or a salt thereof.

2. The compound of claim 1 , where P 2 is selected from acetyl, benzoyl, benzyl, p-methoxybenzyl ether, (3-methoxyethoxymethyl ether, methylthiomethyl ether, pivaloyl, silyl ethers, tetrahydropyranyl, triphenylmethyl, and trityl.

3. The compound of claim 2 , where P 2 is tetrahydropyranyl.

4. The compound of claim 1 , where P 3 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-butylsulfonyl)-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, (3-trimethylsilylethyloxycarbonyl, triphenylmethyl, and trityl.

5. The compound of claim 4 , where U is H or t-butoxycarbonyl.

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

7. The compound of claim 1 , wherein R 1 is H.

8. The compound of claim 1 , wherein R 1 is —C 1-8 alkyl.

9. The compound of claim 1 , wherein R 1 is —CH 3 , —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 3 CH 3 , —(CH 2 ) 4 CH 3 , —(CH 2 ) 2 CH(CH 3 ) 2 , —(CH 2 ) 5 CH 3 , or —(CH 2 ) 6 CH 3 .

10. The compound of claim 1 , wherein R 1 is —C 1-3 alkylene-C 6-10 aryl.

11. The compound of claim 1 , wherein R 1 is benzyl.

12. The compound of claim 1 , wherein U is P 3 and P 3 is t-butoxycarbonyl.

13. The compound of claim 1 , wherein a is 0.

14. The compound of claim 1 , wherein b is 2.

15. The compound of claim 1 , wherein each R 5 is independently selected from halo.

16. The compound of claim 1 , wherein b is 2 and R 5 is 2′-fluoro-5′-chloro.

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

• Rapta Miroslav

Classifications

• C07D319/06

  not condensed with other rings · CPC title

• C07D207/20

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to 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

• C07D207/267

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