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