WO2004104011A1 - Novel process for preparation of [6-(2-amino-ethyl)-2-aryl-[1,3,2]dioxaborinan-4-yl]- acetic esters - Google Patents

Abstract

A novel process for the preparation of compounds of formula (I) by reacting a compound of formula (II) with a reducing agent, sodium borohydride in presence of metal halide.preferably NiCl2.6H2O.

Description

Novel process for preparation of [6-(2-amino-ethyl)-2- aryl-[l,3,23dioxaborinan-4-yI]- acetic esters. FIELD OF INVENTION

The present invention relates to a novel process for preparing amine derivatives of formula I which are useful intermediates for the synthesis of HMG-CoA enzyme inhibitors.

BACKGROUND OF INVENTION

Amine derivatives of the formula I

Ar = any aryl R = any alkyl or aryl

Formula I are valuable chiral synthons for anti-hyptercholesterolemic agents e.g. [R-(R*,R*)]-2-(4-fluorophenyl)-B,D-dihydroxy -5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-lh-pyrrole-l-heptanoic acid. (US 5,273,995).

The most common approach for achieving synthesis of compounds of formula I is catalytic hydrogenation of compound of formula II. Ar

I o'^B-o o

^NC OR

Ar = any aryl R = any alkyl or aryl Formula II

The catalysts usually employed for hydrogenation are hazardous and pyrophoric. It is imperative to use special, expensive equipments for hydrogenation. Hydrogen is extremely flammable and a potential fire hazard.

WO 02/057274 discloses compounds of formula I and II as well as process for their preparation. However the process involves catalytic hydrogenation and the catalyst employed is Raney-Nickel which is pyrophoric and hazardous. The objective of the present invention is to provide a safe, simple, industrially scalable and cost effective process for the reduction of compounds of formula II, leading to preparation of compound of formula I employing inexpensive and non-hazardous reagents.

SUMMARY OF THE INVENTION The present invention details a novel process for the preparation of compounds of formula I

Ar = any aryl

R = any alkyl or aryl

Formula I by reacting a compound of formula II Ar

1 o'^B-o 0

Ar = any aryl

R = any alkyl or aryl

Formula II

with sodium borohydride in presence of metal halides, preferably NiCI₂.6H₂0.

Detailed Description of the invention Compounds of formula I are important intermediates for the preparation of HMG Co-A reductase inhibitors. The HMG Co-A reductase inhibitors are useful as inhibitors of the enzyme 3-hydroxy-3- methylglutaryl-coenzyme A reductase (HMG CoA reductase) and are thus useful as hypolipidemic or hypocholesterolemic agents.

The process of the present invention is a new, improved, non- hazardous, industrially scalable and commercially feasible method for preparing intermediate used for the preparation of HMG CoA reductase inhibitors. The process of the present invention is outlined in Scheme 1. The present invention details a novel process for the preparation of compound of formula I

Ar = = any aryl

R = any i alkyl or aryl Formula I by reacting a compound of formula II

Ar o-^o O

NC\

OR

Ar = any aryl

R = any alkyl or aryl

Formula II

with sodium borohydride in presence of metal halides, preferably - NiCI₂.6H₂0.

Compounds of formula I are important intermediates for the preparation of HMG Co-A reductase inhibitors as shown in Scheme 2.

The following non-limiting examples illustrate the inventors' preferred method for preparing the compounds of the invention.

EXAMPLES

Example 1

Preparation of [6-(2-amino-ethyl)-2-phenyl-[l,3,2]dioxaborinan-4- yl]- acetic acid te/f-butyl ester: To a chilled mixture (0 to -2° C) of (6- cyanomethyl— 2-phenyl-[l,3,2]dioxaborinan-4-yl)-acetic acid tert-bu yl ester (50 g, 0.16 mol) and NiCI₂.6H₂0 (56.5 g, 0.24 mol) in methanol (1.25 L), sodium borohydride (42.2 g, 1.11 mol) was added in portions over a period of 2 h. The reaction mixture was stirred at room temperature for 48 h. After cooling the reaction mixture to 0° C, cone. HCI (35 ml_) was added followed by celite (50 g) and stirred for 15 minutes. The reaction mixture was filtered and pH of the filtrate adjusted to 7.5 by adding sodium bicarbonate. The mixture was filtered again and concentrated to get title compound. Yield: 48 g (94%). Example 2

Preparation of [6-(2-amino-ethyl)-2- -tolyl-[l,3,2]dioxaborinan-4- yl]- acetic acid te t-butyl ester: To a chilled mixture (0 to -2° C) of (6- cyanomethyl— 2- -tolyl-[l,3,2]dioxaborinan-4-yi)-acetic acid te/t-butyl ester (52.7 g, 0.16 mol) and NiCI₂.6H₂0 (56.5 g, 0.24 mol) in methanol (1.25 L), sodium borohydride (42.2 g, 1.11 mol) was added in portions over a period of 2 h. The reaction mixture was stirred at room temperature for 48 h. After cooling the reaction mixture to 0° C, cone. HCI (35 ml_) was added followed by celite (50 g) and stirred for 15 minutes. The reaction mixture was filtered and pH of the filtrate adjusted to 7.5 by adding sodium bicarbonate. The mixture was filtered again and concentrated to get title compound. Yield: 51 g (96%). Example 3

Preparation of [6-(2-amino-ethyl)-2-(4-methoxy-phenyl)l- [l,3,2]dioxaborinan-4-yl]- acetic acid te/t-butyl ester: To a chilled mixture (0 to -2° C) of (6-cyanomethyl— 2-(4-methoxy-phenyl)l - [l,3,2]dioxaborinan-4-yl)-acetic acid te/ -butyl ester (55.2 g, 0.16 mol) and NiCI₂.6H₂0 (56.5 g, 0.24 mol) in methanol (1.25 L), sodium borohydride (42.2 g, 1.11 mol) was added in portions over a period of 2 h. The reaction mixture was stirred at room temperature for 48 h. After cooling the reaction mixture to 0° C, cone. HCI (35 ml_) was added followed by celite (50 g) and stirred for 15 minutes. The reaction mixture was filtered and pH of the filtrate adjusted to 7.5 by adding sodium bicarbonate. The mixture was filtered again and concentrated to get title compound. Yield: 50 g (89.5%).

Scheme - 1: Preparation of compound of formula I

Ar = any aryl Ar = any aryl

R = any alkyl or aryl R = any alkyl or aryl

Claims

CLAIMSWe claim:

1. A process for the preparation of compounds of formula I

Ar = any aryl

R = any alkyl or aryl

Formula I by reacting a compound of formula II

Ar = any aryl

R = any alkyl or aryl

Formula II

with a reducing agent, sodium borohydride in presence of metal halide.

2. A process in claim 1, wherein the metal halide is NiCI₂.6H₂0.

3. A process in claim 1, wherein the compound of formula I is further used for production of HMG CoA Reductase inhibitors.

4. A process as in claim 3, wherein the HMG CoA Reductase inhibitor is Atorvastatin.