GB1560082A

GB1560082A - Process for producing an x-aryl-substituted propionic acid alkyl ester

Info

Publication number: GB1560082A
Application number: GB5221776A
Authority: GB
Original assignee: Dynamit Nobel AG
Current assignee: Dynamit Nobel AG
Priority date: 1975-12-18
Filing date: 1976-12-14
Publication date: 1980-01-30
Also published as: FR2335489B1; DE2557011A1; JPS5277029A; BE849467A; NL7614045A; FR2335489A1; IT1074222B

Description

(54) A PROCESS FOR PRODUCING AN cr-ARYL-SUBSTITUTED PROPIONIC ACID ALKYL ESTER (71) We, DYNAMIT NOBEL AKTIENGESELLSCHAFT, a German Company of 521 Troisdorf, Bez Koln, Postfach 1209, Germany, 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 relates to a process for producing an a-substituted propionic acid alkyl ester having the general formula

where R' represents hydrogen or an alkyl group, and R2 represents an alkyl group.

Conventional processes for producing cr-aryl-substituted propionic acid alkyl esters adhere to the general methods of producing carboxylic acid esters such as are described, for example, in "Methoden der Organischen Chemie", Vol. VIII, Sauerstoffverbindungen (Oxygen Compounds) III, Georg Thieme Verlag, Stuttgart (1952), page 508.

Thus, German Auslegeschrift No. 1,433,429 and UK patent specification No.

971,700 describe several methods of producing a-substituted propionic acids and esters of general formula I, some of which methods are mentioned by way of example: 1. hydrolysing a corresponding nitrile of the general formula

2. reacting a Grignard compound corresponding to the general formula

with carbon dioxide 3. decarboxylating a malonic acid derivative of the general formula

4. oxidising an alcohol corresponding to the general formula

or an aldehyde corresponding to the general formula CH3 R1-C6114-CH-CHO UK patent specification No. 1,160,725 describes processes for producing - aryl-substituted propionic acids from an acetophenone of the general formula

by way of a glycidic acid ester corresponding to the general formula

According to Austrian Patent specification No. 279,592, a-aryl-substituted propionic acid is obtained from the above-mentioned acetophenone by way of a hydantoin.

These processes mentioned by way of example comprise numerous reaction stages from the starting compound to the required end product. In most cases, however, the starting compound is also difficult to obtain. On account of the numerous stages involved and the resulting poor overall yield, none of these processes is suitable for working on an industrial scale.

Accordingly, there is a need to find a simple process for the production of a- aryl-substituted propionic acid esters and hence, thc corresponding acids, which is suitable for working on a commercial scale.

Accordingly, the present invention provides a process for producing an a- substituted propionic acid alkyl ester having the general formula

in which R' represents hydrogen or an alkyl group, and R2 represents an alkyl group, which process comprises reacting, in the presence of a catalyst, a halogen compound having the general formula

where R' is as defined above and X represents a halogen atom, carbon monoxide and an alcoholate having the formula MOR2 or M'(OR2)2 where M represents an alkali metal, M' represents an alkaline earth metal and R2 is as defined above, to form the desired ester.

Preferably, the catalyst used is dicobalt octacarbonyl and the alkyl groups represented by R' and/or R2 are primary secondary or tertiary alkyl groups having up to 8 carbon atoms. More preferably, Rl and/or R2 are methyl and/or ethyl.

The reaction takes place in accordance with the following equation:

in which R1, R2 and X are as defined above, M is an alkali metal, preferably Na K or Li and Mis an alkaline earth metal, preferably Mg. It is preferred for X to represent a chlorine or bromine atom although it may represent an iodine atom.

The starting materials are the corresponding acetophenones of general formula Ill which may readily be reduced by known methods, for example with complex hydrides, such as LiAIH4 and Nabs4, or catalytically with Ni-catalysts. to give high yields of the corresponding alcohols. These may in turn be substantially quantitatively converted. for example with concentrated HCI, into the l-aryl- substituted ethyl chlorides or, optionally, with HBr or HI into the bromides or iodides.

The reaction is preferably carried out by heating the catalyst, preferably Co2(CO)8, to the desired reaction temperature together with the alkali or alkaline earth metal alcoholate, which may be in the form of an alcoholic solution of an alkali or alkaline earth metal hydroxide, and thereafter adding the l-aryl- substituted ethyl halide, preferably over a period of from 1 to 5 hours. On the other hand, however, it is also possible initially to introduce an alcoholic solution of the catalyst and then to add alcoholate or an alcoholic solution of an alkali metal hydroxide together with the halogen compound.

A constant carbon monoxide pressure is preferably maintained during the reaction.

It is of advantage for the pH-value of the reaction solution, which is alkaline, i.e. of pH 7 to 14, by virtue of the presence of the alcoholate, not to fall below 10 during the reaction and preferably to remain between pH 10 and 12, because otherwise the yield of ester decreases in favour of ether, in addition to which p-aryl- substituted propionic acid alkyl esters are formed to an increased extent. The 1aryl-substituted l-alkoxy ethanes may readily be converted back into the chlorine compounds, for example with concentrated HCI, so that they may be reused for the carbonylation reaction. This enables the starting materials to be utilised with particular advantage.

The stoichiometric quantity of alkali or alkaline earth metal alcoholate amounts to 1 mole of an alkali metal alcoholate or to 0.5 mole of an alkaline earth metal alcoholate per mole of halogen compound. However, it is preferred to use a small excess of around 5% in order to ensure that a pH-value above 10 is also maintained towards the end of the reaction. Accordingly, the alcoholates are added with particular advantage in such quantities that the pH-value is adjusted and remains intact.

Preferred alcoholates are, in particular, lithium, potassium and magnesium alcoholate. They are generally used in the form of highly concentrated solutions, preferably in an alcohol having an alkyl radical which is the same as that of the alcoholate.

The alcohols used are preferably primary secondary or tertiary alcohols containing from 1 to 8 carbon atoms, more preferably methanol and ethanol.

The above-mentioned reactants are preferably reacted at temperatures in the range from OOC to 1 500C and more preferably at temperatures in the range from 20"C to 80"C. The reaction time usually varies from 1 to 5 hours, depending upon the temperature applied and the concentration of the catalyst.

Reaction of the a-aryl-substituted ethyl halides may be carried out at a carbon monoxide pressure of only 0.5 atms gauge, however pressures of up to 100 atms gauge and higher are possible. It is preferred to work at pressures of from 1 atm gauge to 20 atms gauge.

Co2(CO)8 is preferably used as the catalyst, the molar ratio of the catalyst to halogen compound (II) preferably being from 1:1 to 1:500 and more preferably from 1:10 to 1:200.

A pH-value above 10 is preferably maintained during the reaction in order to obtain a high level of selectivity of the reaction. Although lower pH-values are possible, they promote the formation of undesirable secondary products.

The a-aryl-substituted propionic acid alkyl esters obtained by the process according to the invention and the acids and salts obtainable from them by hydrolysis are valuable medicinally active compounds, especially for the treatment of rheumatism.

The following Examples 1 to 6 illustrate the preparation of esters in accordance with the invention. Example 7 describes the additional process step of hydrolysing an ester to the corresponding acid. Percentages represent % by weight unless otherwise stated.

EXAMPLE 1 10 g of Co2(CO)8 in 100 ml of methanol were introduced under a CO-pressure of 1.8 atms gauge and at a temperature of 55"C, into a glass flask equipped with a stirrer, two dropping funnels, a gas inlet tube, a reflux condenser and a single-rod glass pH-electrode. 216 g (1.2 moles) of 30 ' Na-methylate were introduced through one of the dropping funnels at such a rate that a pH-value of 10.0 was maintained. 140.5 g (1 mole) of l-phenylethyl chloride were then added from the second dropping funnel over a period of about 1 hour, the pH-value being kept constant at pH 10 by the addition of Na-methylate. A constant CO-pressure of 1.8 atms gauge was maintained during the reaction by means of a mercury plunger.

After the reaction components had been added, they were left to react for 1 hour. The NaCI which was precipitated was filtered off and the methanol present in the reaction solution was distilled off in a light vacuum through a short Vigreux column. The residue was acidified with a little semiconcentrated H2SO4 and then extracted with ether. The ether extracts were dried over Na2SO4 and the ether was distilled off. Further distillation in vacuo gave 84.0 g (51% yield) of hydratropic acid methyl ester (b.P.,2 1000C), 15 g (9% yield) of hydrocinnamic acid methyl ester (b.p.12 1080C) and 40 g (30 yield) of l-methoxy-l-phenylethane (b.P.,2 58 C). The remainder was non-distillable residue.

EXAMPLE 2 The procedure and conditions were the same as in Example 1, except that all the Na-methylate was added before the beginning of the reaction. Working up gave 86 g (52.5 ,' yield) of hydratropic acid methyl ester, 13 g (8 /n yield) of hydrocinnamic acid methyl ester and 37 g (27% yield) of l-methoxy-l- phenylethane.

EXAMPLE 3 The reaction was carried out in the same way as in Example 1, but with 317 g (1.1 mole) of 24.3% K-methylate instead of Na-methylate and at a pH-value of from 7.0 to 8.0. Working up gave 44 g (27% yield) of hydratropic acid methyl ester, 52.5 g (32 ' yield) of hydrocinnamic acid methyl ester and 41 g (30% yield) of l-methoxy- I-phenylethane.

EXAMPLE 4 The procedure was as in Example 1, except that the Na-methylate was replaced by 410 g (1.2 moles) of 20% Na-ethylate. The desired ethyl ester and 1ethoxy-l-phenyl-ethane were obtained in the same yield.

EXAMPLE 5 The procedure was as in Example 4, except that 1.1 mole of 10% Na-n-hexylate was used. The desired n-hexyl ester was primarily obtained in a high yield.

EXAMPLE 6 The procedure was as in Example 1, except that 196.5 g (1.0 mole) of l-(p isobutylphenyl)- 1 -chloroethane were reacted instead of l-phenyl-l-chloroethane.

Working up gave 73 g (33% yield) of a-(p-isobutylphenyl)-propionic acid methyl ester (b.p.,o 1 150C), 5.5 g (2.5 % yield) of ,B-(p-isobutylphenyl)-propionic acid methyl ester (h.p.88 140"C) and 96 g (50% yield) of l-(p-isobutylphenyl)-lmethoxyethane (b.p.10 82"C.

EXAMPLE 7 40 g (0.18 mole) of a-(p-isobutylphenyl)-propionic acid methyl ester were boiled under reflux for 1 hour with 0.6 mole of KOH in 200 ml of H2O. After cooling, the reaction mixture was acidified with semiconcentrated H2SO4 and extracted 3 times with 100 ml of ether. The ether extracts were dried over Na2SO4 and the ether was then distilled off. The residue of 33.5 g, melting at 73--740C, was recrystallised from petroleum ether (60--80"C). a-(p.Iso-butylphenyl)-propionic acid melting at 75--76"C (Lit. 74--76.5"C) was obtained in a yield of 27 g (72%).

WHAT WE CLAIM IS: 1. A process for producing an a-substituted propionic acid alkyl ester having the general formula

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

Claims

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

stirrer, two dropping funnels, a gas inlet tube, a reflux condenser and a single-rod glass pH-electrode. 216 g (1.2 moles) of 30 ' Na-methylate were introduced through one of the dropping funnels at such a rate that a pH-value of 10.0 was maintained. 140.5 g (1 mole) of l-phenylethyl chloride were then added from the second dropping funnel over a period of about 1 hour, the pH-value being kept constant at pH 10 by the addition of Na-methylate. A constant CO-pressure of 1.8 atms gauge was maintained during the reaction by means of a mercury plunger.

After the reaction components had been added, they were left to react for 1 hour. The NaCI which was precipitated was filtered off and the methanol present in the reaction solution was distilled off in a light vacuum through a short Vigreux column. The residue was acidified with a little semiconcentrated H2SO4 and then extracted with ether. The ether extracts were dried over Na2SO4 and the ether was distilled off. Further distillation in vacuo gave 84.0 g (51% yield) of hydratropic acid methyl ester (b.P.,2 1000C), 15 g (9% yield) of hydrocinnamic acid methyl ester (b.p.12 1080C) and 40 g (30 yield) of l-methoxy-l-phenylethane (b.P.,2 58 C). The remainder was non-distillable residue.

EXAMPLE 2 The procedure and conditions were the same as in Example 1, except that all the Na-methylate was added before the beginning of the reaction. Working up gave 86 g (52.5 ,' yield) of hydratropic acid methyl ester, 13 g (8 /n yield) of hydrocinnamic acid methyl ester and 37 g (27% yield) of l-methoxy-l- phenylethane.

EXAMPLE 3 The reaction was carried out in the same way as in Example 1, but with 317 g (1.1 mole) of 24.3% K-methylate instead of Na-methylate and at a pH-value of from 7.0 to 8.0. Working up gave 44 g (27% yield) of hydratropic acid methyl ester, 52.5 g (32 ' yield) of hydrocinnamic acid methyl ester and 41 g (30% yield) of l-methoxy- I-phenylethane.

EXAMPLE 4 The procedure was as in Example 1, except that the Na-methylate was replaced by 410 g (1.2 moles) of 20% Na-ethylate. The desired ethyl ester and 1ethoxy-l-phenyl-ethane were obtained in the same yield.

EXAMPLE 5 The procedure was as in Example 4, except that 1.1 mole of 10% Na-n-hexylate was used. The desired n-hexyl ester was primarily obtained in a high yield.

EXAMPLE 6 The procedure was as in Example 1, except that 196.5 g (1.0 mole) of l-(p isobutylphenyl)- 1 -chloroethane were reacted instead of l-phenyl-l-chloroethane.

Working up gave 73 g (33% yield) of a-(p-isobutylphenyl)-propionic acid methyl ester (b.p.,o 1 150C), 5.5 g (2.5 % yield) of ,B-(p-isobutylphenyl)-propionic acid methyl ester (h.p.88 140"C) and 96 g (50% yield) of l-(p-isobutylphenyl)-lmethoxyethane (b.p.10 82"C.

EXAMPLE 7

40 g (0.18 mole) of a-(p-isobutylphenyl)-propionic acid methyl ester were boiled under reflux for 1 hour with 0.6 mole of KOH in 200 ml of H2O. After cooling, the reaction mixture was acidified with semiconcentrated H2SO4 and extracted 3 times with 100 ml of ether. The ether extracts were dried over Na2SO4 and the ether was then distilled off. The residue of 33.5 g, melting at 73--740C, was recrystallised from petroleum ether (60--80"C). a-(p.Iso-butylphenyl)-propionic acid melting at 75--76"C (Lit. 74--76.5"C) was obtained in a yield of 27 g (72%).

WHAT WE CLAIM IS: 1. A process for producing an a-substituted propionic acid alkyl ester having the general formula

in which R' represents hydrogen or an alkyl group, and R2 represents an alkyl group, which process comprises reacting, in the presence of a catalyst, a halogen compound having the general formula

where R' is as defined above and X represents a halogen atom, carbon monoxide, and an alcoholate having the formula MOR2 or M'(OR2)2 where M represents an alkali metal, M' represents an alkaline earth metal and R2 is as defined above, to form the desired ester.
2. A process according to Claim 1 wherein the catalyst is dicobalt octacarbonyl.
3. A process according to Claim 1 or 2 wherein the molar ratio of catalyst to halogen compound (II) is in the range 1:1 to 1:500.
4. A process according to Claim 3 wherein the molar ratio of catalyst to halogen compound (II) is in the range 1:10 to 1:200.
5. A process according to any one of the preceding claims wherein the alkyl groups R' and/or R2 have up to 8 carbon atoms.
6. A process according to Claim 5 wherein the alkyl groups R' and/or R2 are methyl and/or ethyl.
7. A process according to any one of the preceding claims wherein the alcoholate is used in up to 5% excess of the stoichiometrically required amount, based on the weight of halogen compound (II).
8. A process according to any one of the preceding claims wherein the alkali metal M is sodium, potassium or lithium.
9. A process according to any one of Claims 1 to 7 wherein the alkaline earth metal M' is magnesium.
10. A process according to any one of the preceding claims wherein the alcoholate is used in solution in an alcohol of formula R2OH.
11. A process according to any one of the preceding claims wherein the alcoholate comprises a solution of alkali or alkaline earth metal hydroxide in alcohol of formula R2OH.
12. A process according to any one of the preceding claims wherein the halogen atom X represents chlorine or bromine.
13. A process according to any one of the preceding claims when carried out in the pH range 10 to 12.
14. A process according to any one of the preceding claims whenever carried out at a temperature of from 0 to 150"C.
15. A process according to Claim 14 when carried out at a temperature of from 20 to 800C.
16. A process according to any one of the preceding claims wherein the carbon monoxide is at a pressure of from 1 to 20 atmospheres gauge.
17. A process according to any one of the preceding claims wherein the catalyst is first admixed with the alcoholate and thereafter the halogen compound (II) is added to the admixture.
18. A process according to Claim 1 substantially as described in any one of the Examples 1 to 6.
19. An a-substituted propionic acid alkyl ester of general formula (I) whenever produced by the process according to any one of the preceding claims.
20. A process according to any one of Claims 1 to 18 which includes the additional step of hydrolysing the ester of formula (I) which is produced, to form the corresponding acid.
21. A process according to Claim 20 substantially as described in Example 7.
22. An acid corresponding to the ester of general formula (I) whenever produced by the process according to Claim 20 or 21.