Field of Invention

The present invention relates to a novel process for the preparation of intermediate of elvitegravir, a drug under experimental investigation for use in the treatment of infection with the human immunodeficiency virus (HIV).

Background of the Invention

Elvitegravir is a drug under experimental investigation for use in the treatment of infection with the human immunodeficiency virus (HIV), acting as an integrase inhibitor.lt has the ability to block the activity of the integrase enzyme and to prevent HIV DNA from entering healthy cell DNA.

The results of the phase II clinical trial evaluated that Norvir (ritonavir) is used to boost elvitegravir in the bloodstream, hence making elvitegravir more effective against WV. The chemical name of elvitegravir is 6-[(3-Chloro-2-fluorophenyl) methylj- I -[(2S)- 1 -hydroxy-3 -methyl butan-2-ylJ -7-methoxy-4-oxoquinoline-3-carboxylic acid represented by formula 1 The compound ethyl 3 -[5 -(3-chloro-2-fluorobenzyl)-2,4-dimethoxy phenyl]-3 - oxopropanoate of formula II is a key intermediate in the preparation of Elvitegravir of formula I.

COQEt

CI

‘3

I

II

There are few process reported for the preparation of ethyl 3-[5-(3-chloro-2- fluorobenzyl)-2,4-dimethoxy phenylj-3-oxopropanoate of formula II. US patent 7825252
discloses a process for the preparation of compound of formula 11 as shown in scheme-i,
which is further converted to elvitegravir of formula 1.

Scheme-I

+ NNNN - 0

KO0C2HS

A major drawback in the known process of preparation of compound of formula II is the use of costly reagents such as Imidazole and 1,1’-carbonyl bis(1H-imidazole). Also the recovery of these reagents is very difficult. Further these processes involve formation of number of by-products.

Thus, to overcome these problems, there is a need to develop a cost effective process for the preparation of compound of formula 11, which gives better purity and better yield and avoids the formation of unwanted by-products. Keeping the above objectives in mind the present inventors are working on a novel process for the preparation of this compound which is described in this specification.

F

II

Summary of the invention

According to the principal aspect of the present invention there is disclosed a novel process for the preparation of ethyl 3-[5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxy phenyl]-3- oxopropanoate of formula II which comprises:

a) converting 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoic acid of formula V into 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoyl chloride of formula IV in presence of a suitable reagent;

b) reacting compound of formula IV with diethyl malonate to obtain 2-[5-(3-Chloro-2- fluoro-benzyl)-2,4-dimethoxy-benzoyl]-malonic acid diethyl ester of formula III; and
c) decarboxylating compound of formula III to obtain ethyl 3-[5-(3-chloro-2- fluorobenzyl)-2,4-dimethoxy phenyl]-3-oxopropanoate of formula II.

The present invention can be illustrated by the below reaction scheme: b

In another aspect of the present invention [5-(3-Chloro-2-fluoro-benzyl)-2,4-dimethoxy- benzoyl]-malonic acid diethyl ester of formula III is novel and constitute a part of the present invention.

Detail Description of the Invention

H3CO.

V IV

F

In an embodiment of the invention, the present invention can be illustrated by the following examples, without limiting the scope of invention.

Example 1: Preparation of Ethyl 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoyl acetate (a) Preparation of 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoyl chloride To 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoic acid (10 g) was added thionyl chloride (50 mE), the mixture was refluxed for 3 hours and then concentrated to residue to give 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoyl chloride (9.4 g).

(b) Preparation of Diethyl [5-(3-chloro-2-fluorobenzyl)-2,4- dimethoxybenzoylj malonate To magnesium ethoxide (4.08 g) was added diethyl malonate (4.86 g) in anhydrous toluene (50 ml) drop wise and the mixture was warmed for 2 hours at 50-60 °C and then cooled to 10 °C.

To the mixture was added a solution of the acid chloride in toluene (15 mL) drop wise over 15 minutes. After stirring for 1 hour at 0-5 °C, ice water (40 mL) containing concentrated sulfuric acid (8 mL) was added to the mixture and the organic layer was separated. The layer was washed with saturated saline solution, dried over anhydrous sodium sulfate and then concentrated to give diethyl 5-(3-chloro-2-fluorobenzyl)-2,4- dimethoxybenzoyl malonate (11.78 g).

(c) Preparation of Ethyl 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoyl acetate
To the malonate (11.78 g) were added water (25 ml) and p-toluenesulfonic acid (15 mg) and the mixture was refluxed for 9 hours. After cooling, the reaction mixture was extracted with dichioromethane and the organic layer was washed with 7% aqueous sodium bicarbonate solution and with saturated saline solution successively, dried over anhydrous sodium sulfate and then concentrated to give Ethyl 5-(3-chloro-2-fluorobenzyl)-2,4- dimethoxybenzoyl acetate (9.1 g).

We claim:

1. A process for the preparation of ethyl 3-[5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxy phenyl]-3 -oxopropanoate which comprises:

a) converting 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoic acid into 5-(3-chloro- 2-fluorobenzyl)-2,4-dimethoxybenzoyl chloride in presence of a suitable reagent;

b) reacting 5 -(3-ehloro-2-fluorobenzyl)-2,4-dimethoxybenzoyl chloride with diethyl malonate to obtain 2-[5 -(3 -Chloro-2-fluoro-benzyl)-2,4-dimethoxy-benzoyll- malonic acid diethyl ester; and

c) decarboxylating 2-[5-(3-Chloro-2-fluoro-benzyl)-2,4-dimethoxy-benzoylj-malonic acid diethyl ester to obtain ethyl 3-[5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxy phenyl]-3-oxopropanoate.

2. The compound [5-(3-Chloro-2-fluoro-benzyl)-2,4-dimethoxy-benzoyl] -malonic acid diethyl ester.