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

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.