FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The patent Rules, 2003
COMPLETE SPECIFICATION
A Process for the preparation of Elvitegravir intermediate
SeQuent Scientific Limited
A Company Incorporated Under The Companies Act, 1956
Having Registered Office at
116 Vardhman Industrial Complex, L.B.S Marg,
Thane (W), Mumbai - 400601, India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:

Field of Invention
The present invention relates to a novel process for the preparation of intermediate of elvitegravir, a drug used for the treatment of infection with the human immunodeficiency virus (HIV),
Background of the Invention
Elvitegravir is a drug approved by U.S. Food and Drug Administration for people starting HIV treatment for the first time as part of the fixed dose combination known as Stribild. It acts as an integrase inhibitor. It has the ability to block the activity of the integrase enzyme and to prevent HIV DNA from entering healthy cell DNA. Patients taking once-daily elvitegravir boosted by ritonavir had greater reductions in viral load after 24 weeks compared to individuals randomized to receive a ritonavtr-boosted protease inhibitor.
The chemical name of elvitegravir is 6-[(3-Chloro-2-fluorophenyl) methyl]-l-[(2S)-l-hydroxy-3-methyl butan-2-yl]-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.


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

A major drawback in the above stated process is that it involves two Grignard reactions, costly raw material 1,3-dimethoxy-4,6-dibromo benzene and costly reagent imidazole and IJ'-carbonyl bis(lH-imidazole), which are not preferred on industrial level. Moreover, it is very lengthy and involves five reaction steps. Further the recovery of the reagent is very difficult and a number of by products are formed in the reaction.

US patent 7825252 discloses another process for the preparation of compound of formula II as shown in scheme-2 starting from 2,4-dimethoxy-5-bromobenzoic acid, which is further converted to elvitegravir of formula I.

A major drawback in the above stated process is that it involves butyl lithium reaction and also involves costlier raw material 2,4-dimethoxy-5-bromobenzoic acid and costly reagent imidazole and l,l'-carbonyl bis(lH-imidazole), which are not preferred on industrial level production. Moreover it is very lengthy and involves five reaction steps. Further the recovery of these reagents is very difficult. Further the recovery of the reagent is very difficult and a number of by-products are formed in the reaction.

US patent application 20090036684 describes a process for the preparation of ethyl 3-[5-(3-ch]oro-2-fluorobenzyl)-2,4-dimethoxy phenyl]-3-oxopropanoate of formula II starting from 2,4-Dimethoxybenzoic acid as shown in scheme-3.

Above process involves Negishi Coupling which are not preferred on industrial level and also involves costlier raw materials such as 2,4-dimethoxy benzoic acid for the preparation of compound of formula II, moreover it is very lengthy and involves six reaction steps.

Thus to overcome these problems, there is a need to develop a cost effective process for the preparation of compound of formula II, which is simple and less expensive and gives better purity and better yield. Keeping the above objectives in mind the present inventors developed a novel robust and cost -effective process for the preparation of this compound starting from inexpensive raw material such as 1,3-dim ethoxy benzene.
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-chtoro-2-fluorobenzyl)-2,4-dimethoxy phenyl]-3-oxopropanoate of formula II which comprises:
a) condensation of 1,3-dimethoxybenzene of formula VI with 3-chloro-2-fluorobenzoyl halide of formula VII using a reagent in presence of a solvent to form 5-(3-chloro-2-fluorophenyl)(2.4-dimethoxyphenyl)methanone of formula V;
b) reduction of 5-(3-chloro-2-fluorophenyl)(2,4-dimethoxyphenyl)methanone of formula V using a reducing agent in a solvent to obtain l-chloro-3-(2,4-dimethoxybenzy!)-2-fiuorobenzene of formula III; and
c) condensation of l-chloro-3-(2,4-dimethoxybenzyl)-2-fluorobenzene of formula III with ethyl 3-halo-3-oxopropanoate of formula IV using a reagent in presence of a solvent 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 - 4:


Where X =CI or Br
In another aspect of the present invention l-chloro-3-(2,4-dimethoxybenzyl)-2-fluorobenzene of formula III is novel and constitute a part of the present invention.


Detail Description of the Invention
Accordingly in an embodiment of the invention, 3-chloro-2-fluorobenzoyl halide is selected from 3-chloro-2-ftuorobenzoyl chloride or 3-chloro-2-fluorobenzoyl bromide. The condensation of 1,3-dimethoxybenzene of formula VI with 3-chloro-2-fluorobenzoyl halide of formula VII is carried out using a reagent which is Lewis acids selected from the group consisting of anhydrous ferric chloride, anhydrous aluminium trichloride and the like preferably anhydrous aluminium trichloride. The condensation is carried out in presence of a solvent preferably chlorinated solvents selected from the group comprising of methylenedichloride (MDC), ethylenedichloride (EDC), chloroform, monochlorobenzene, 1,2-dichlorobenzene etc., more preferably methylenedichloride. The reaction is carried out at a temperature in the range of about -20 to 15°C, preferably at -10 to 0°C.
In another embodiment of the invention, the reduction of 5-(3-chloro-2-fluorophenyl)(2,4-dimethoxyphenyl)methanone of formula V is carried out using a reducing agent selected from sodium borohydride in presence of BF3 etherate, raney nickel, palladium on carbon or platinum, preferably sodium borohydride in presence of BF3 etherate to obtain l-chloro-3-(2,4-dimethoxybenzyl)-2-fluorobenzene of formula IV. The reduction in step b) is carried out in presence of an inert organic solvent selected from ethyl acetate, toluene, benzene, xylene, dimethylformamide (DMF), tetrahydrofuran (THF) and the like, preferably tetrahydrofuran at a temperature in the range of about -20 to 15°C, preferably at -10 to 0°C.
In yet another embodiment of the invention, ethyl 3-halo-3-oxopropanoate in step c) is preferably selected from the group consisting of ethyl 3-chloro-3-oxopropanoate (ethyl malonyl chloride) and ethyl 3-bromo-3-oxopropanoate. The condensation of l-chloro-3-(2,4-dimethoxybenzyl)-2-fluorobenzene of formula III with ethyl 3-halo-3-oxopropanoate of formula IV is carried out using a Lewis acids such as ferric chloride, aluminium trichloride, boron trifluoride and the like, preferably aluminium trichloride. The condensation is carried out in presence of a solvent selected from chlorinated solvents preferably methylenedichloride (MDC), ethylenedichloride (EDC). chloroform, monochlorobenzene, 1,2-dichlorobenzene etc., more preferably methylenedichloride to obtain ethyl 3-[5-(3-chloro-2-

fluorobenzyl)-2,4-dimethoxy phenyl]-3-oxopropanoate of formula U. The reaction is carried out at a temperature in the range of about -20 to 15°C, preferably at -10 to 0°C.
In still another embodiment, some of the key advantages of the present invention are as below:
1. The process of the present invention avoids the use of Grignard reagents and butyl lithium which are very much undesired for industrial scale production.
2. The process of the present invention provides a three step process for the preparation of ethyl 3-[5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxy phenyl]-3-oxopropanoate of formula II as compared to six steps reported in the prior art,
3. The process of the present invention uses inexpensive raw materials which makes the process very cost effective.
The present invention can be illustrated by the following examples, which are not to limit the scope of invention.
Example 1: Preparation of ethyl 3-[5-(3-chloro-2-fluorobenzy])-2,4-dimethoxy phenyl]-3-oxopropanoate of formula II
(a) Preparation of (3-chloro-2-flourophenyl)(2,4-dimethoxyphenyl) methanone
Methylene chloride (400 mL) and anhydrous aluminium chloride (145 g) were charged into a flask at 0 to -10°C, 2-flouro-3-chloro benzoyl chloride (167 g) in MDC was slowly added to the above reaction mass and stirred for 30 minutes. A solution of 1,3-dimethoxy benzene (100 g) in MDC was slowly added and stirred for 1 to 2 hour at 0 to -10°C. After completion of reaction, the reaction mass was quenched to chilled water (1000 mL) at 0 to 10°C. Two layers were separated; the aqueous layer was extracted twice with MDC. The combined MDC layer was washed with 5% sodium hydroxide solution (250 mL) and water (250 mL). MDC was distilled out completely to form thick brown oil product.

Yield: 200 g
(b) Preparation of l-chloro-3-(2,4-dimethoxy benzyl)-2-flouro benzene
Tetrahydrofuran (1000 mL) and step (a) material (200g) were charged into a flask, cooled to 0 to -10°C. Sodium borohydride (130 g) was added in lots at 0 to -10°C and stirred for 1.0 to 2 hours. After completion of reaction, BF3 etherate (482 g) was added slowly to the above reaction mass at 0 to 5°C and allowed to attain room temperature. The reaction mass was stirred for 5 to 6 hrs at 25 to 35°C. 15% hydrochloric acid (500 mL) was added slowly at 25 to 35°Candstirred for 1 hour. Hexane (1000 mL) was added to the above reaction mass at 25 to 35°C, insoluble were filtered through hyflobed. The layers separated and aqueous layer was extracted twice with hexane (500 m). The combined organic layer was washed with water (500mL) and hexane was distilled out completely under vacuum to get pale yellow oil product.
Yield: 160 g
(c) Preparation of ethyl 3-[5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxy
phenyl]-3-oxopropanoate
Methylene chloride (800 mL) and aluminium chloride (112g) were charged into a flask at 0 to -I0°C, ethyl malonyl chloride (104 g) was slowly added and stirred for 30 minutes at 0 to -10°C.Step (b) material (160 g) in 320 mL MDC was slowly added to the above reaction mass, stirred for 2 to 3 hrs at 0 to -10°C. After completion of reaction, the reaction mass was quenched to chilled water at 0 to 10°C. Two layers were separated and the aqueous layer was extracted twice with MDC. The combined MDC layer was washed with 5 % sodium hydroxide solution (500 ml) and water (500mL). MDC was distilled out completely under vacuum, and hexane (320 ml) was added. Hexane was distilled under vacuum. Again a mixture of hexane and ethyl acetate (500 mL) was added to the mass (10:1) and stirred for 2 to 3 hours at 25 to 35°C. The mass was cooled to 5 to 10 °C and stirred for 30 minutes. The product was filtered, washed with chilled hexane (80 mL), suck dried and the material was dried at 35 to 45 °C under vacuum.
Yield: 125 g

We claim:
I. A process for the preparation of ethyl-3-[5-(3-chloro-2~fluorobenzyl)-2,4-dimethoxy phenyl]-3-oxopropanoate of formula II which comprises:

a) condensation of 1,3-dimethoxybenzene of formula VI with 3-chloro-2-fluorobenzoyl halide of formula VII using a reagent in presence of a solvent to form 5-(3-chloro-2-fluorophenyl)(2,4-dimethoxyphenyl)methanone of formula V;

b) reduction of 5-(3-chloro-2-fluorophenyl)(2,4-dimethoxyphenyl)methanone of formula V using a reducing agent in a solvent to obtain l-chloro-3-(2,4-dimethoxybenzyl)-2-fluorobenzene of formula III; and


c) Condensation of l-chloro-3-(2,4-dimethoxybenzyl)-2-fluorobenzene of formula III with ethyl 3-halo-3-ox.opropanoate of formula IV using a reagent in presence of a solvent to obtain ethyl 3-[5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxy phenyl]-3-oxopropanoate of formula II.

2. A process according to claim 1, wherein the reagent in step a) and c) is a Lewis acid selected from ferric chloride and aluminium trichloride.
3. A process according to claim 1, wherein the reagent in step a) and c) is aluminium trichloride.
4. A process according to claim I, wherein the reducing agent in step b) is selected from sodium borohydride in presence of BF3 etherate, raney nickel, palladium on carbon or platinum.
5. A process according to claim 1, wherein the reducing agent in step b) is sodium borohydride in presence of BF3 etherate.
6. A process according to claim I, wherein the solvent in step a) and step c) is a chlorinated solvent selected from the group comprising methylenedichloride, ethylenedichloride, monochloro benzene, 1,2-dichlorobenzeneand chloroform.
7. A process according to claim 1, wherein the solvent in step a) and step c) is methylenedichloride.

8. A process according to claim 1, wherein the solvent in step b) is selected from the group comprising ethyl acetate, toluene, benzene, xylene, dimethylformamide and tetrahydrofuran.
9. A process according to claim 1, wherein the reaction is carried out at temperatute -10to 10°C.
10. A compound of formula III