Process for preparing 4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid compounds
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 process for preparing a compound of formula I:
or a salt thereof, where 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; and each R 5 is independently selected from halo, —OH, —CH 3 , —OCH 3 , and —CF 3 ; the process comprising the step of reslurrying a compound of formula (1):
in an ether solvent to form a compound of formula I or a salt thereof.
2. The process of claim 1 , where the ether solvent is 2-methyltetrahydrofuran.
3. The process of claim 2 , where the ether solvent further comprises cyclopentyl methyl ether.
4. The process of claim 1 , where the compound of formula (1) is prepared by the acidic deprotection of a compound of formula (2):
where P 1 is an amino protecting group.
5. The process of claim 4 , where acidic deprotection is conducted with 3M HCl.
6. The process of claim 4 , where P 1 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, β-trimethylsilylethyloxycarbonyl, triphenylmethyl, and trityl.
7. The process of claim 6 , where P 1 is t-butoxycarbonyl.
8. A process for preparing a compound of formula IIa:
or a salt thereof, where 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; and each R 5 is independently selected from halo, —OH, —CH 3 , —OCH 3 , and —CF 3 ; the process comprising the steps of (a) activation of the carboxyl group of a compound of formula I:
and (b) reacting the resulting product with a reducing agent to form a compound of formula IIa or a salt thereof.
9. The process of claim 8 , where step (a) is conducted with isobutyl chloroformate in the presence of a tertiary amine base.
10. The process of claim 9 , where the tertiary amine base is N-methylmorpholine.
11. The process of claim 8 , where the reducing agent is sodium tetrahydroborate.
12. The process of claim 1 , where the ether solvent is diisopropyl ether.