HU215208B - Method for producing 5-chloro-2-nitro-phenylacetic acide alkylesters - Google Patents

Abstract

The 5-chloro-2-nitro-phenylacetic acid alkyl esters having the general formula (I) in which R represents a straight or branched C 1 -C 7 alkyl radical are produced by heat 4-chloronitrile-benzene in the alkyl portion 1 Reaction with a -7-carbonate chloroacetic acid alkyl ester at a temperature of n, -30 C to -40 ázisC. Compounds of general formula (I) are intermediate intermediates in the preparation of 5-chloro-2,3-dihydro-2-octane. ŕ

Description

The present invention relates to a process for the preparation of 5-chloro-2-nitrophenylacetic acid alkyl esters of formula (I). In the general formula (I)

R is a straight or branched C 1 -C 7 alkyl group.

The above compounds are important intermediates in the preparation of 5-chloro-2,3-dihydro-2-oxoindole (II). 5-Chloro-2,3-dihydro-2-oxoindole is an important intermediate for pharmacologically active substances, e.g.

1,3-disubstituted 2-oxoindoles (U.S. Patent No. 4,721,712).

Several processes for the preparation of 5-chloro-2,3-dihydro-2-oxoindole are known.

U.S. Patent No. 4,761,485, for example, is based on 5-chloroindole. 5-Chloroindole with pyridine bromide perbromide

3.3-dibromo-5-chloro-oxoindole which is catalytically hydrogenated in the presence of palladium on charcoal to 5-chloro-2,3-dihydro-2-oxoindole.

The disadvantage of the process is that the starting material, i.e. 5-chloroindole, is difficult to access and the yield of 5-chloro-2,3-dihydro-2-oxoindole is low.

U.S. Patent No. 4730004 also relates to the preparation of 5-chloro-2,3-dihydro-2-oxoindole. Starting from 5-chloroisatin, it is reacted with hydrazine hydrate and the resulting 5-chloro-5-hydrosone-2-oxoindole is converted to 5-chloro-2,3-dihydro-2-oxoindole with sodium methanolate. This process also has the disadvantage that the starting material, 5-chloroisatin, is difficult to access and the yield of the desired end product is low.

213,634 teaches another procedure. U.S. Patent No. 4,600,612, which discloses the catalytic hydrogenation of an alkyl ester of chloronitrophenylacetic acid (for example of formula (I)) and the resulting amine of formula (III) in the presence of an acid of 5-chloro-2,3 (II). cyclized to -dihydro-2-oxoindole.

It is an object of the present invention to provide the starting material for the latter process.

Accordingly, the present invention relates to a process for the preparation of 5-chloro-2-nitrophenylacetic acid alkyl esters of formula (I), wherein R is a straight or branched C 1 -C 7 alkyl group. According to the invention, 4-chloro-nitrobenzene is reacted with an alkyl ester of chloroacetic acid (IV) in which R is as defined above in the presence of a base.

Suitable alkyl esters of chloroacetic acid having from 1 to 7 carbon atoms are those in which the alkyl is methyl, ethyl, propyl, isopropyl, tert-butyl or tert-pentyl. C 1 -C ₇ alkyl is preferably ethyl.

The chloroacetic acid (C 1 -C 7 alkyl) ester is preferably used in an excess relative to the chloronitrobenzene. Preferably, 1.3 to 1.7 moles of ester are used per mole of chloronitrobenzene.

Non-polar solvents include, for example, toluene, diethyl ether, tetrahydrofuran or tert-butyl methyl ether. Toluene is preferred.

The reaction is carried out in the presence of a base. The base is preferably an alkali metal amide or alkali metal hydroxide, sodium or potassium amide, or sodium or potassium hydroxide.

Alkali metal amide is preferably used as the base, particularly preferably in the form of a solution in liquid ammonia. The alkali metal amide is preferably formed in situ from the appropriate elemental metal and liquid ammonia, optionally in the presence of a catalyst.

In a particularly preferred embodiment of the process of the invention, the in situ formed alkali metal amide is used in the presence of an alcohol of formula (V), wherein R is as defined above. Preferred alcohols of formula (V) are those wherein R is methyl, ethyl, propyl, isopropyl, tert-butyl or tert-pentyl. The tert-butyl group is particularly preferred.

The alcohol and the alkali metal amide are preferably reacted in equimolar amounts.

In the process of the invention, the reaction temperature is -30 ° C to -40 ° C. The reaction time is usually from 0.1 to 2 hours, after which the 5-chloro-2-nitrophenylacetic acid alkyl ester of formula I can be isolated by the addition of ammonium chloride in a conventional manner.

Execution examples

Example 1

Preparation of ethyl chloro-2-nitrophenylacetic acid ester

250 ml of ammonia were condensed in a dry argon-rinsed flask (Kryomat refrigerator temperature -40 ° C). After the addition of a small amount of sodium, the solution turns blue and is then colorless again after the addition of 250 mg of ferric nitrate nonahydrate. 5.75 g (250 mmol) of chopped sodium are added over 15 minutes and the mixture is stirred for 10 minutes. A solution of t-butanol (18.53 g, 250 mmol) in toluene (3 mL) was added over 15 minutes, and the mixture was stirred for 35 minutes to give a gray suspension.

A solution of 15.76 g (250 mmol) of 4-chloro-nitrobenzene and 18.38 g (150 mmol) of ethyl chloroacetic acid in 20 ml of toluene is added dropwise over 15 minutes. The suspension turns blue. Stirring was continued for another hour, then solid ammonium chloride (26.75 g, 500 mmol) was carefully added. The dry ice cooler was removed and the mixture was stirred for ca. Heat to 10 ° C over 30 minutes to remove ammonia. 200 ml of toluene was then added dropwise over 20 minutes (Kryomat temperature 10 ° C) and after 30 minutes the mixture was filtered through a G3 glass filter (celite). The filtrate was concentrated in a rotary evaporator at 35 DEG C. and a pressure of 2500 Pa. Dry for 30 minutes.

27.14 g of product are obtained, which is 78.8% by HPLC. This corresponds to a yield of 87% of starting material.

HU 215 208 Β

Example 2

5-Chloro-2-nitrophenylacetic acid ethyl ester prepared according to the invention as an intermediate. for the preparation of 5-chloro-2,3-dihydro-2-oxoindole according to Hungarian patent specification 213 634.

1st step

Preparation of 2-Amino-5-chlorophenylacetic acid ethyl ester

26.73 g crude product of Example 1 was dissolved at room temperature in 135 ml ethanol containing 1.0 g of platinum on carbon was added, the autoclave is rinsed three times with hydrogen gas, and the mixture was stirred at room temperature for 7.5 hours with 5 * 1 O ⁵ psi hydrogenated . The mixture was then filtered, the filter cake washed with ethanol (25 mL) and the combined solution washed directly with Step 2.

Step 2

Preparation of 5-chloro-2,3-dihydro-2-oxoindole

To the filtrate obtained at the end of Step 1, toluene-4-sulfonic acid monohydrate (1.90 g, 10 mmol) was added and the mixture was refluxed for 30 minutes. A total of 125 ml of ethanol was distilled over 4.5 hours to form a slurry. The reaction mixture was cooled to room temperature and filtered.

The filter cake was washed with ethanol (3 ^x 20 mL) and dried at 35 ° C (4000 Pa) for 12 hours.

12.07 g of product are obtained in the form of a pink solid having a purity of 94.5% by HPLC.

Claims (4)

PATENT CLAIMS 1. A process for the preparation of 5-chloro-2-nitrophenylacetic acid alkyl esters of the formula I in the formula I R is a linear or branched C 1 -C 7 -alkyl group characterized in that 4-chloro-nitrobenzene with an alkyl ester of chloroacetic acid of formula (IV) - in the presence of a base in formula (IV) - The reaction is carried out at a temperature between C and -40 ° C. Process according to claim 1, characterized in that the base is an alkali metal amide. 3. A process according to claim 1 or 2, wherein the alkali metal amide is used in the presence of an alcohol of formula V, wherein R is as defined in claim 1. 4. A process according to any one of claims 1 to 3, wherein the alcohol is tert-butanol and the alkali metal amide is sodium amide.