Process for preparing fluoroleucine alkyl esters

Patent metadata

Field	Value
Publication number	US-9493400-B2
Application number	US-201314387945-A
Country	US
Kind code	B2
Filing date	Mar 25, 2013
Priority date	Mar 30, 2012
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

This invention relates to a resolution process for the preparation of fluoroleucine alkyl esters.

First claim

What is claimed is:

1. A processes for preparing a compound of formula IA:

comprising the steps of:
a. alkylating an imine carboxylate of formula IIA with methallyl halide to form a substituted imine of formula IIIA;

b. deprotecting the substituted imine of formula IIIA with an acid to yield an amine of formula IVA;

c. resolving the amine of formula IVA with a chiral protic acid selected from the group consisting of D-(+)-camphor-10-sulfonic acid, D-BOC-proline, di-p-tolyl-D-tartaric acid, N-acetyl-D-phenyl alanine and mixtures thereof, in the presence of 5-nitrosalicylaldehyde;
d. fluorinating the resolved amine to yield the compound of formula IA;
wherein X is H 2 SO 4 , L-tartaric acid, D-BOC proline, L-(−)-10-camphorsulfonic acid or N-acetyl-D-phenyl alanine.

2. The process of claim 1 , wherein step a. is performed in the presence of a strong base.

3. The process of claim 2 , wherein the strong base is selected from the group consisting of potassium t-butoxide, lithium t-butoxide, sodium t-butoxide, LDA, sodium hydride, n-BuLi, sec-BuLi, t-BuLi, LiHMDS, NaHMDS, KHMDS, LiTMP and mixtures thereof.

4. The process of claim 1 , wherein step a. is performed in the presence of a polar aprotic solvent.

5. The process of claim 1 , wherein the acid is selected from the group consisting of hydrochloric acid, triflic acid, sulfuric acid, p-toluenesulfonic acid, naphthalene disilfonic acid, trifluoroacetic acid and mixtures thereof.

6. The process of claim 1 , wherein step d. is performed with a fluorinating agent selected from the group consisting of Olah's reagent, HF-pyridine, HF-triethylamine, HF-Urea, HF-melamine, HF and mixtures thereof.

7. The process of claim 6 wherein the fluorinating agent is Olah's reagent.

8. The process of claim 1 , wherein the chiral protic acid is D-(+)-camphor-10-sulfonic acid.

9. A compound of formula IA.

wherein X is L-Tartaric acid, D-BOC proline, L-(−)-10-camphorsulfonic acid or N-acetyl-D-phenyl alanine.

10. A compound of formula

Assignees

• Merck Sharp & Dohme

Inventors

• Rivera Nelo
• Pendri Yadagiri R
• Mende Sreenivas
• Reddy Bramhananda N

Classifications

• C07C229/20

  the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups · CPC title

• C07C309/19

  of a saturated carbon skeleton containing rings · CPC title

• C07C227/34

  by separation of optical isomers · CPC title

• C07C249/02

  of compounds containing imino groups · CPC title

• C07C229/08

  the nitrogen atom of the amino group being further bound to hydrogen atoms · CPC title