GB1591052A - Process for the preparation of 2,3-dichloro-1-(lower alkoxy) benzenes - Google Patents

Description

(54) PROCESS FOR THE PREPARATION OF 2,3 DICHLORO- l-(LOWER ALKQXY)BENZENES (71) We, SMITHKLINE CORPORATION, of 1500 Spring Garden Street, Philadelphia, Pennsylvania 19101, United States of America, a corporation organized under the laws of the Commonwealth of Pennsylvania, one of the United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention concerns a process for preparing 2,3-dichloroanisole.

2,3-Dichloroanisole and its congeners are important intermediates for preparing pharmaceutical products such as ticrynafen (U.S. Patent- Specification No. 3,758,506) or as ingredients in insecticides, weed controllers, or plant hormones.

The prior art recognizes that alkali metal lower alkoxides react with unactivated aryl halides poorly. Chlorides particularly gave - poor yields if unactivated by aromatic substitution, such as by a nitro substituent in an ortho- or para-position. A recent publication (J. E. Shaw et al., J. Org. Chem. 41, 732, 1976) summarizes the state of the art and also describes the reaction of mono- and dichlorobenzenes with sodium methoxide in hexamethylphosphoramide as solvent.

This solvent has been ruled hazardous as a carcinogen, and it should not be used commercially without special conditions.

According to the present invention there is prdvided a process for preparing a 2,3-dichloro-l-(C,~7)1Ower-alkoxybenzene which comprises reacting 1,2,3trichlorobenzene with an alkali metal (C17)lower alkoxide with heating at 100 200"C. for from 1/4-24 hours in an inert organic solvent in which the reactants are soluble or miscible, the solvent having a dielectric constant of 2050.

Despite 1 ,2,3-trichlorobenzene having three unactivated chlorine atoms, it can be made to react with an alkali metal lower alkoxide to give substantial yields 2,3-dichloro-lower alkoxybenzenes. The reaction is preferably carried out with sodium or potassium methoxide. If desired, other alkoxides can also be used, such as alkali metal lower alkoxides of from 1-7 carbons, for example methoxide, butoxide, propoxide, isopropoxide, pentyloxide, isopentyloxide, hexyloxide.

Lithium alkoxides can be used, if desired, but for practical purposes the most commercially useful alkoxide is sodium methoxide, which is used herein to illustrate preferred embodiments of the invention.

Yields of the desired 2,3-dichloroanisole have been about 2/3 of theoretical, that is 65--75 of very pure product. The remaining material is the isomeric 2,6dichloroanisole.

The reaction is preferably carried out with about a stoichiometric amount of reactants, or more preferably with an excess of the alkoxide. Usually 10-L50 excess of alkoxide is used. The temperature and reaction duration are interdependent. For example, the reaction can be run at 10--1200C. for 16-24 hours, and at 175--2000C. for 1/2 hour. Therefore the overall ranges are 100- 200"C. for from 1/4-24 hours. A range of from 100175 C. for 1/4 to 1 hour has proved most useful, for example when the alkoxide is sodium methoxide and the solvent is dimethylacetamide containing from 50 to 75van of methanol. The progress of the reaction can be easily studied by gas chromatography during the reaction.

The alkoxide can be added in many forms, such as the solid reactant itself or as an alcoholic solution. Sodium methoxide is most conveniently used as a --commercially available 25% solution in methanol.

The solvent for the reaction is critical. For example, attempts to run the reaction in xylene at 1440C. for three hours only gave unreacted starting material, as did reaction in formamide at 100owe. for 16 hours or at 1600C. for three hours. A solvent in which the reactants are substantially soluble or miscible, which has a dielectric constant of 2050, and is inert under the conditions of the reaction, are essential to the reaction. For example, dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMS), sulfolane, glyme or mixtures of these solvents can be used. Preferred are dimethylacetamide, dimethylformamide and dimethylsulfoxide.

The 670%',, yields of the 2,3-isomer or the 2/3-1/3 ratio of 2,3- to 2,6 isomers- can be altered significantly to obtain yields of 85950Xo of the- desired 2,3 dichloroanisole isomer if a significant proportion of ethanol, or preferably methanol, is present in the reaction mixture. The methanol should be present in quantities to give a homogeneous reaction mixture. For convenience l750Xo, preferably 460v0 or even up to 650/,, of the initial solvent should be methanol.

The- methanol is conveniently allowed to distil from the reaction mixture during reaction and it can be optionally replaced as necessary. The alcohol is desirably -present in sufficient quantities to solvate the unreacted metal alkoxide. Since the various chloroalkoxybenzenes can be purified easily by fractional distillation, any trichlorobenzene-containing starting material can be used.

The reaction mixture after completion of the reaction as studied by gas chromatography can be worked up by standard procedures. For example, the mixture is cooled and quenched in an excess of water. The organic material is extracted into a water-immiscible organic liquid such as ether, toluene, benzene or xylene, After washing, drying and evaporating the extracts, the product is isolated from the residue by distillation. Residual product left unextracted can be obtained by extraction with a second organic solvent such as methylene chloride. The solvents can be recovered by known techniques.

The reaction can be represented as follows:

in which M is an alkali metal, preferably sodium or potassium, and R is lower alkyl of 1--7 carbon atoms.

2,3-Dichloroanisole prepared in accordance with the invention. is preferably subsequently reacted with thiophene-2-carboxylic acid chloride in the presence of aluminium chloride to give (2,3-dichloro-4-methoxyphenyl) (2-thienyl) ketone which is then demethylated and the resulting hydroxyphenyl ketone is condensed with ethyl chloroacetate and thereafter saponified to give 4-(2-thienylketo)-2,3dichlorophenoxyacetic acid (tienilic acid).

The following Examples are intended to further illustrate specific embodiments of this invention. All melting points are Centigrade.

EXAMPLE 1 The trichlorobenzene-solvent mixtures given below are heated on an oil bath to 600. Solid sodium methoxide is added over one minute, and the oil bath temperature is then raised to 95--1000C. for 16 hours. The reaction mixture is cooled and then poured into 100 ml of water. The quenched mixture is extracted wit11 ether and petroleum ether repeatedly. The dried extracts are evaporated, and the residue is examined by gas chromatography with the following results: Trichloro Sodium benzene methoxide Solvent Temp. Crude Ratio (g) (g) (ml) time yield isomers Comments 3.62 1.30 formamide 100 /16 hr 007o - dark; no (20 mm) (24 mm) product 3.62 1.30 DMF 40 110"/16 her 70own > 2.04/1 - 14.5 5.60 DMA 130 110 /115 82% > 2.2/1 16hr 3.62 1.30 DMS/HMPA 110"/16 her 65% > 1.54/1 30/15 3.62 1.30 sulfolane 110"/16 her 65% > 1.54/1 - *Gas chromatography showed 2,3:2,6 isomer ratio of 92:8.

EXAMPLE 2 Quantities: Trichlorobenzene 363 g Sodium methoxide 650 ml 25% commercial solution in methanol Dimethyl acetamide 600 ml Procedure: Trichlorobenzene (363 g, 2 moles) was dissolved in 600 ml of dimethyl acetamide, and 650 ml of 25% sodium methoxide in methanol solution were added all at once. The solution was stirred and heated to 1660 as the methanol slowly distilled out. The solution was held at 1660 for 30 minutes, cooled, quenched with 5 times its volume of water, and extracted with toluene (2x 1000 ml). The toluene extracts were washed with water (1 L) and dried over sodium sulfate. The toluene was removed by distillation under reduced pressure, and the residue was fractionated to yield the pure 2,3-dichloroanisole, bp 140 /28 mm. Yield 212 g (60%). (Considerable material remains in the aqueous DMAC layer and can be recovered by repeated extractions with methylene chloride.) EXAMPLE 3 Following the procedures of.the above Examples, the following results were obtained.

Solvent Methoxide Form2 Temp. Time Isomer Ratio3 DMA solid 166 30 min 70:30 DMA 25% in methanol 160" 6 hrs 92:8 DMF 25% in methanol 155 2 hrs 72:284 xylene solid 144" 3 hrs only starting material Formamide 25% in methanol 1600 3 hrs mostly starting material DMF solid 155 1 her 70:30 2 either as solid sodium methoxide or as commercial 25% solution in methanol 3 2,3-isomer: 2,6-isomer contains some starting material EXAMPLE 4 The following alkoxides can be substituted for the sodium methoxide of Example 2: potassium methoxide, lithium ethoxide, sodium phenoxide, potassium pentyloxide, sodium heptyloxide, sodium isopropoxide, potassium propoxide and sodium butoxide. These give the corresponding known 2,3-dichloro- 1- alkoxybenzenes.

EXAMPLE 5 363 g (1 mole) of 1,2,3-trichlorobenzene are dissolved in 600 ml dimethyl acetamide and heated to 1250 with stirring. 500 ml of 25% commercial sodium methoxide in methanol is then added at such a rate that the temperature is maintained at 125130 . After the addition is complete, the temperature is maintained at 1300 for 30 minutes. The mixture is diluted with water, and the water is extracted with toluene. The toluene extracts are washed with brine, dried, and the toluene is removed by distillation. The residue is fractionated to yield 200 g of the desired 2,3-dichloro-anisole, bp 140 /29 mm. By appropriate fractionation, the minor isomer 2,6-dichloroanisole can also be obtained.

Dimethylformamide and dimethylsulfoxide can also be used with only slight variations in yield.

Reaction of sodium methoxide with 1,2,3-trichlorobenzene, for example in dimethylformamide, the dimethyl ether of ethylene glycol, the dimethyl ether of ethylene glycol, the dimethyl ether of diethyleneglycol or mixtures thereof, can also be carried out in the presence of catalytic quantities of copper in the form of cuprous iodide, bromide, or cuprous oxide, at temperatures ranging between 70"C and the boiling temperature of the solvent used.

The following Examples illustrate this aspect of the invention.

EXAMPLE 6 12.2 g of sodium are dissolved in 250 ml of anhydrous methanol, and then the solvent is removed in order to isolate the solvation product, sodium methoxide/2 methanol. This is placed in suspension in 60 ml of dimethyl ether of ethyleneglycol and this suspension is poured into 200 ml of anhydrous dimethylformamide. Then 80 g of trichlorobenzene and 2 g of cuprous iodide are added to the mixture which is maintained at about 75"C for at least 8 hours. During this period, sodium methoxide can be added to hasten the reaction. After cooling, the solution is filtered and poured into 4 volumes of water saturated with sodium chloride.

Dichloroanisole and dichlorbenzene are extracted from this mixture with dichiorethane. After drying the solution and evaporation of the solvents, 16 g of dichloroanisole are obtained in the form of an oil, which contains a small amount of trichlorobenzene.

In order to isolate the desired product, instead of pouring the reaction mixture into the water after filtration, it is also possible to eliminate the solvents under reduced pressure. In order to separate the dichloroanisole from the remaining traces of trichlorobenzene, the crude oil obtained is distilled under ordinary pressure (B.P.=2300C) or under reduced pressure (B.P.15=l 140C) or the mixture is steam distilled, trichlorobenzene being distilled first. In this way, pure crystallized 2,3-dichloroanisole is -obta'ined (m.p.=33"C) in a yield of more than 85%.

It is also possible in this reaction to use sodium methoxide desolvated by -heating at a temperature greater than 200"C. There is also the possibility of not adding the stoichiometric quantity of methoxide to the mixture at the beginning of the reaction, but several times during heating.

EXAMPLE 7 0.1 mole of sodium methoxide is prepared by dissolving 2.3 g of sodium in 50 ml of -methanol. 100 ml of anhydrous dimethylformamide are then poured into the solution and the methanol is rapidly evaporated under reduced pressure. Then 5.45 g of trichlorobenzene and I g of cuprous iodide are added to the mixture, which brought to 1200C in 2 hours. The reaction mixture is cooled, filtered and poured into 3 volumes of water. The solution is saturated, e.g. by adding sodium chloride, after which it is placed in contact with a solvent not miscible with water, such as ethyl ether or dichloroethane. The organic phase is decanted and dried, after which the solvent is evaporated. 5 g of oily.residue is obtained, which contains a mixture of dichloroanisole (80%) and of starting material. This mixture is purified as described in Example 6.

WHAT WE CLAIM IS: 1. A process for preparing 2,3-dichloro-l-(C,~7)1Ower-alkoxybenzene which comprises reacting 1,2,3-trichlorobenzene with an alkali metal (C,~7)10wer alkoxide with heating at 100--2000C. for from 1/424 hours in an inert organic solvent in which the reactants are soluble or miscible, the solvent having a dielectric constant of 2050.

2. A process according to claim 1, in which the solvent is dimethylformamide, dimethylacetamide or dimethylsulfoxide.

3. A process according to claim 2, in which the metal alkoxide is sodium or potassium methoxide or ethoxide.

4. A process according to claim 3, in which the metal alkoxide is sodium or potassium methoxide.

5. A prdcess according to claim 1, in which methanol or ethanol is present in the reaction mixture in a quantity sufficient to solvate the metal alkoxide.

6. A process according to claim 2, in which methanol is present in the reaction mixture in a quantity sufficient to solvate the metal alkoxide.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (17)

**WARNING** start of CLMS field may overlap end of DESC **. Dimethylformamide and dimethylsulfoxide can also be used with only slight variations in yield. Reaction of sodium methoxide with 1,2,3-trichlorobenzene, for example in dimethylformamide, the dimethyl ether of ethylene glycol, the dimethyl ether of ethylene glycol, the dimethyl ether of diethyleneglycol or mixtures thereof, can also be carried out in the presence of catalytic quantities of copper in the form of cuprous iodide, bromide, or cuprous oxide, at temperatures ranging between 70"C and the boiling temperature of the solvent used. The following Examples illustrate this aspect of the invention. EXAMPLE 6 12.2 g of sodium are dissolved in 250 ml of anhydrous methanol, and then the solvent is removed in order to isolate the solvation product, sodium methoxide/2 methanol. This is placed in suspension in 60 ml of dimethyl ether of ethyleneglycol and this suspension is poured into 200 ml of anhydrous dimethylformamide. Then 80 g of trichlorobenzene and 2 g of cuprous iodide are added to the mixture which is maintained at about 75"C for at least 8 hours. During this period, sodium methoxide can be added to hasten the reaction. After cooling, the solution is filtered and poured into 4 volumes of water saturated with sodium chloride. Dichloroanisole and dichlorbenzene are extracted from this mixture with dichiorethane. After drying the solution and evaporation of the solvents, 16 g of dichloroanisole are obtained in the form of an oil, which contains a small amount of trichlorobenzene. In order to isolate the desired product, instead of pouring the reaction mixture into the water after filtration, it is also possible to eliminate the solvents under reduced pressure. In order to separate the dichloroanisole from the remaining traces of trichlorobenzene, the crude oil obtained is distilled under ordinary pressure (B.P.=2300C) or under reduced pressure (B.P.15=l 140C) or the mixture is steam distilled, trichlorobenzene being distilled first. In this way, pure crystallized 2,3-dichloroanisole is -obta'ined (m.p.=33"C) in a yield of more than 85%. It is also possible in this reaction to use sodium methoxide desolvated by -heating at a temperature greater than 200"C. There is also the possibility of not adding the stoichiometric quantity of methoxide to the mixture at the beginning of the reaction, but several times during heating. EXAMPLE 7 0.1 mole of sodium methoxide is prepared by dissolving 2.3 g of sodium in 50 ml of -methanol. 100 ml of anhydrous dimethylformamide are then poured into the solution and the methanol is rapidly evaporated under reduced pressure. Then 5.45 g of trichlorobenzene and I g of cuprous iodide are added to the mixture, which brought to 1200C in 2 hours. The reaction mixture is cooled, filtered and poured into 3 volumes of water. The solution is saturated, e.g. by adding sodium chloride, after which it is placed in contact with a solvent not miscible with water, such as ethyl ether or dichloroethane. The organic phase is decanted and dried, after which the solvent is evaporated. 5 g of oily.residue is obtained, which contains a mixture of dichloroanisole (80%) and of starting material. This mixture is purified as described in Example 6. WHAT WE CLAIM IS:

1. A process for preparing 2,3-dichloro-l-(C,~7)1Ower-alkoxybenzene which comprises reacting 1,2,3-trichlorobenzene with an alkali metal (C,~7)10wer alkoxide with heating at 100--2000C. for from 1/424 hours in an inert organic solvent in which the reactants are soluble or miscible, the solvent having a dielectric constant of 2050.

2. A process according to claim 1, in which the solvent is dimethylformamide, dimethylacetamide or dimethylsulfoxide.

3. A process according to claim 2, in which the metal alkoxide is sodium or potassium methoxide or ethoxide.

4. A process according to claim 3, in which the metal alkoxide is sodium or potassium methoxide.

5. A prdcess according to claim 1, in which methanol or ethanol is present in the reaction mixture in a quantity sufficient to solvate the metal alkoxide.

6. A process according to claim 2, in which methanol is present in the reaction mixture in a quantity sufficient to solvate the metal alkoxide.

7. A process according to claim 3, in which methanol is present in the reaction

mixture in a quantity sufficient to solvate the sodium or potassium methoxide or ethoxide.

8. A process according to claim 4, in which the solvent contains 460% of methanol.

9. A process according to claim 1, in which the alkoxide is sodium methoxide, the solvent is dimethylacetamide containing from 50 to 75% of methanol, the temperature of the reaction is from 100--175"C. and the duration of the reaction is from 1/4 to 1 hour.

10. A process according to claim 1, in which a cuprous catalyst is present in the reaction mixture and the alkali metal alkoxide is sodium methoxide.

11. A process according to claim 10, in which cuprous iodide, bromide or oxide is used as the catalyst.

12. A process according to claim 11, in which a mixture of dimethyl ether of ethylene glycol and dimethylformamide is used as the solvent.

13. A process according to claim 4 or claim 10, wherein the 2,3-dichloroanisole formed is reacted with thiophene-2-carboxylic acid chloride in the presence of aluminum chloride to give (2,3-dichloro-4-methoxyphenyl) (2-thienyl) ketone which is demethylated, and the hydroxyphenyl ketone produced is condensed with ethyl chloroacetate followed by saponification to give 4-(2-thienylketo)-2,3 dichlorophenoxyacetic acid (tienilic acid).

14. A process according to claim 1, substantially as herein described.

15. A process for preparing a 2,3-dichloro-l-(C,~7)1Ower alkoxybenzene substantially as herein described in any of the Examples.

16. 2,3-Dichloro-l-(C17)lower alkoxybenzenes when prepared by a process according to any of claims 1 to 12, 14 and 15.

17. 4-(2-Thienylketo)-2,3-dichlorophenoxyacetic acid when prepared by a process according to claim 13.