FI66833B - FOERFARANDE OCH MELLANPRODUKT FOER FRAMSTAELLNING AV FENYLALKYLKARBOXYLSYRADERIVAT - Google Patents

Description

I- ~ Ί r_, „„ AD PUBLICATION,, 0 - jjSBftf) ® ^ UTLÄGGN I NGSSKMFT 66833 • g \ 6 C (45) Patent nycr.nctty 10 12 1904 ^ (51) K ». * U / I» ta. 3 C 07 C 51/00, 67/00, 15A0 FINLAND — FINLAND pi) 76i833 (22) —AmBkninpdag 23.06.76 (23) Aftapahrt — GlklglMCKlaf 23.06.76 (41) ΤμΜμ | «ndMfc» l - Mhrtt offwtllf 25.12. 76 ^ »h · <M) ssrssts, sasr ^ csi s'-08-81 * (32) (33) (31) Phyydoty wmoWmm · 8»> * rJ yrtoitt 2A.06.75 V2.t2.75 Hungary-Hungary ( HU) C t-1595, 16A3 (71) CHINOIN Győrszer € s Vegyöszeti Termäkek Gyära Rt., 1-5, T <5 utca, Budapest IV, Hungary-Hungary (HU) (72) Endre Pälosi, Budapest, Gergely Häja, Budapest,

Dezsö Korbonits, Budapest, Csaba Gönczi, Budapest, Päl Kiss, Budapest, Rudolf Szebeni, Budapest,

Erzsäbet Molnär nee Bak <5, Szdclliget, Hungary -Hungary (HU) (7 * 0 Berggren Oy Ab (5 * 0 Process and intermediate for the preparation of derivatives of phenylalkylcarboxylic acids) -acylic acid derivatives and a new intermediate used in the process.

It is known that compounds of the formula R-CH-COOR1, O-R1 wherein R is hydrogen, alkyl or aralkyl, R is hydrogen or alkyl, R 'is hydrogen or halogen and R1 is alkyl, aralkyl, aryl, aryloxy or aroyl (aryl is phenyl or thienyl) can be used in therapy due to their excellent anti-inflammatory properties.

Methods for preparing the above compounds are described in the following publications: U.S. Patent 3,600 * 137, DE Patent 19 ^ 1,625, BE Patents 737 * 117 and 621,225, GB Patent 971,700, FR Patents 5 * 19,728 and 1 5 * 15 270 and HU patent applications RO-687 and JA-691.

Suitable methods for the preparation of compounds of formula A are as follows: 66833 12 3 a) compounds in which R, R and R are hydrogen, R is a C 1-6 alkyl group, an aroyl or aryloxy group can be prepared according to reaction formulas A and B;

COOH CH2-COOH

eu n CH 2 -CN

CH CH -Br 2 B) ^ _ i · j- η / = \ / \ / \

CH -COOH

.....— IX o / = \ 2 3 b) compounds in which R is an alkyl group, R is hydrogen, R is an aryloxy or aroyl group can be prepared according to reaction formulas C, D and E;

II

3,66833

o OH

C0CH3 COCHa CH-CHo ex -

Br-CH-CHo '-' I a NC-CH-CH, ch3 -ch- cooh - - o - ό ^ Ό D)

CHP - C / V £ - Cf / - CA / /? - CH-COOH

ό · ο "όο - ώ 0

£; -> R-CH-COOH

ό-ο - <Xo c) compounds in which R is hydrogen or a methyl group, R2 is hydrogen or halogen, lt2 is an aroyl group can be prepared according to reaction formula P: 66833 h F)

HOOC ^ ^ sCH-CN CiCO ^^ CH-CM

U? * ~ _

R-CH-CN R-CH-COOH

~ Ö-o ~~ & * 0 2. · D) compounds in which R is a methyl group, R is a hydrogen or halogen atom, R is an alkyl group can be prepared according to reaction formulas J, K, L and M.

ΐ ~ Π (Ίί * // s' CQQH

chz-cooc2h5 c% - ^ COH

11 0 O - ~ Q - R3 R3%

CHO-CU-000H

-o I * 5

COCOO Co,% Cl 10 CQOH

K) r ^ S

I li ... —n »» »I II" '-' -u ». I II

R3 V3 R3

II

5,66833

coch3 5 / = \ CH3 ch * - b-COOH

1 A R- \ J — r 3 A

UK kJ

R3 \ / * 3

II K

0 n (ch3) z

CH> -C-COOH CHi -CH- COOH

-Φ-Φ R3 I? 3

V

0 ^ 0v yi C0CH $ - c '-' cH-COOCzHs CH $ - c'-KCH-COONa Φ-Φ - Φ- R3 R3 R3

C /% - CH-CHO CHx-CH-C00H

-0 -0 R3 R3

In the above methods, the yield is reasonable (method A), or they give the desired product via intermediates which are difficult to purify, or the preparation method is complicated (methods B and C). Reactions according to reaction formulas D and E may present an explosion hazard when carried out on a large scale, their starting materials are poorly available and the yield is low.

The starting material according to Reaction Scheme F can only be prepared by a complex method which is difficult to carry out on a large scale and the yield is very poor.

In all of the above processes, the critical step in preparing a phenylalkylcarboxylic acid or phenylalkylacetonitrile that can be converted to a phenylalkylcarboxylic acid is to extend the carbon chain by forming a carbon-carbon bond. This is precisely the most difficult step to technically implement. As a result, the difficulties listed above may be overcome by using a method in which carbon chain extension is not necessary.

We, in an article by Killop in J. Am. Chem. Soc.

95, pp. 1296-1310 (1973) describes the oxidation of unsubstituted phenylacetylenes with thallium (III) nitrate at 60-70 ° C to phenylalkyl carboxylic acid esters.

In addition, U.S. Patent No. 3,803,245 describes a similar process for oxidizing 6-methoxy-2-naphthyl-substituted methylacetylene to 2- (6-methoxy-2-naphthyl) propionic acid.

It has now surprisingly been found that phenylacetylene derivatives having relatively large substituents on the phenyl ring can be converted in mild conditions into high purity phenylalkylcarboxylic acid derivatives in excellent yield.

-f-R

wherein R is hydrogen or methyl, R is hydrogen or methyl, R 1 is hydrogen or halogen, and R 3 is Tenoxy, benzoyl, C 1-4 alkyl, phenyl or tenoyl, and for the preparation of salts, which process is characterized in that a compound of the formula

II

7 66833

C = C - R

2 ii

ί- R

. ^ R5

p T

wherein R, R and RJ are as defined above, is reacted with thallium (III) nitrate in the presence of methanol, ethylene glycol methyl ether or diethyl ether at a temperature of 5 "to 15 ° C, and optionally converting the carbalkoxy group to a carboxyl group by hydrolysis and optionally converting the obtained product to a salt G).

C ^ c - R R- CH- COOR1 V r2 4 ^ R2 H3

II I

The acids of general formula I thus obtained can, if desired, be converted into their metal salts or acid addition salts, respectively with bases, for example alkali metal hydroxides, alkaline earth hydroxides or nitrogen-containing organic bases, in an aqueous medium or solvent.

The starting material used in the invention is an acetylene of formula II, in which R, R 'and R have the same meaning as above. The compound of formula II can be prepared very easily and in excellent yield according to reaction formula H.

8 66833 H.

Cl coch2-r c-ch-r Χ ° "Κ V ^^ L ·. R2 -— ^^ lLr2 - ^ -f- r2 r3> ^ r3 ^ / r3 · ^^ III IV 11... 2. 3

A compound of general formula III wherein R, R and R

are the same as above, are reacted with phosphorus pentachloride, and the chlorinated olefin of general formula IV thus obtained is converted into acetylene of general formula II by means of sodium alcoholate. The product obtained is reacted with thallium (III) nitrate in methanol, ethylene glycol methyl ether or diethyl ether at a temperature of 5-15 ° C. The obtained compound of general formula I wherein R, R2 and R are as defined above and R is methyl is isolated by extraction as an organic solvent, preferably a low-boiling, water-immiscible solvent such as ether, benzene, chloroform and distilling off the solvent in vacuo, or alternatively the compound obtained is converted directly into the acid of general formula I, 1 ...

wherein R is hydrogen, by conventional basic or acid hydrolysis in the presence of water.

Another embodiment of the method according to the invention. ·. . According to 23, acetylene of general formula II wherein R and R 2 are as defined above and R is hydrogen is reacted with thallium (III) nitrate in diethyl ether or ethylene glycol methyl ether in the presence of aqueous perchloric acid. In this case, it is obtained directly in excellent yield. . 2. 3

acids of general formula I, wherein R and R

i denote the same as above, and R and R denote hydrogen. The following examples illustrate the invention:

Examples 1-11 illustrate the preparation of final products of formula I and Examples 12-26 illustrate the preparation of intermediates of formulas II, III and IV according to reaction formula H.

Il 9 66833

Example 1 1.9 * 1 g of m-phenoxyphenylacetylene are added to a solution of 8.88 g of T1 (NO2) 2.3H2O and 25 ml of glycol methyl ether in 15 ml of water and 8 ml of 70 .mu.l of HClO2. The reaction mixture is stirred at room temperature for 2 hours, then water is added, and the mixture is extracted with benzene. The benzene layer is dried over Na 2 SO 4, evaporated to dryness, and the residue is recrystallized from a mixture of n-hexane and ethyl acetate using activated carbon to remove the color of the product.

1.9 g (83%) of m-phenoxyphenylacetic acid are obtained, m.p. 84-86 ° C.

Example 2 48.8 g of thallium (III) nitrate are suspended in 250 ml of methanol, 20.8 g of (m-phenoxyphenyl) methylacetylene are added to the suspension in small portions, taking care that the temperature does not rise above 15 ° C. The mixture is stirred for a further 3.5 hours at 10-15 ° C, the precipitated thallium (I) nitrate is filtered off, 250 ml of methylene chloride are added to the filtrate, the phases are separated and the aqueous phase is extracted with 2 x 150 ml of methylene chloride. The combined organic phase is evaporated. The residue is dissolved in 350 parts of methanol, 20 ml of aqueous sodium hydroxide solution (6 g) are added and the mixture is boiled for 3 hours, then evaporated to dryness. The residue is dissolved in 200 g of water, extracted with 2 x 150 ml of methylene chloride, the aqueous phase is treated to remove color with activated carbon and then filtered. The filtrate is acidified with 50% sulfuric acid, dried over sodium sulfate, the solvent is evaporated off and the residue is distilled off to give 20.5 g (85%) of m-phenoxyhydrotropic acid, b.p. 190-192 ° C / 0.4 mm Hg. [h = 1.575.

Example 3 36.8 g (0.083 mol) of thallium (III) nitrate hydrate are suspended in 200 parts of methanol, and 20.4 g (0.0755 mol) of 1- (benzoylphenyl) methylacetylene are added to the suspension. The mixture is stirred at room temperature for 3 hours. The precipitated thallium (I) nitrate is filtered into the filtrate, 14 ml of 40% sodium hydroxide are added and the mixture is refluxed for 6 hours. The solution is treated with activated carbon to remove color, boiled for a further 5 minutes and then filtered. The filtrate is evaporated in vacuo. The residue is dissolved in 100 ml of water, extracted with 30 ml of dichloromethane and the pH of the aqueous phase is adjusted to 2 with concentrated 10,66833 hydrochloric acid. The precipitate is filtered and washed with water to give a slowly solidifying oily product, m-benzoylhydrotropic acid (15.8 g), m.p. 92 ° C.

Example 4

To a solution of 16 g of (p-isobutylphenyl) methylacetylene in 225 ml of methanol is added 47.7 g of thallium (III) nitrate in small portions under stirring at less than 10 ° C. The reaction mixture is stirred at 10 ° C for 3 hours. The precipitated thallium (I) nitrate is filtered off, 42 ml of 5N sodium hydroxide solution are added to the methanolic filtrate and the reaction mixture is refluxed for 10 hours, then evaporated to dryness in vacuo. The residue is dissolved in water, extracted with chloroform, and the pH of the aqueous solution is adjusted to pH 2 with 5N hydrochloric acid. The separated oily product is extracted into chloroform, and the solution is dried over sodium sulfate. The chloroform is distilled off and the solidified oil is recrystallized from petroleum ether. 13.2 g of 4-iso-butylhydratroic acid are obtained, m.p. 74 ° C.

Example 5 5.6 Gran (p-isobutylphenyl) methylacetylene in 75 ml of methanol, 15.9 g of thallium (III) nitrate are added in small portions below 10 ° C with stirring, and the reaction mixture is stirred for 3 hours at 10 ° C. The precipitated thallium (I) nitrate is filtered off and washed with methanol. The filtrate is diluted with water, the separated oil is extracted with chloroform. The solution is dried over sodium sulfate and the chloroform is distilled off. The residual oil is vacuum distilled. 6 g (84%) of methyl 2- (p-isobutylphenyl) propionate are obtained. Kp. 112-118 ° C / 0.7 mm Hg.

Example 6 Granular methyl 2- (p-isobutylphenyl) propionate In 150 ml of alcohol is added 35 ml of 5N sodium hydroxide, and the reaction mixture is refluxed for 6 hours. The solution is then evaporated in vacuo, the residue is dissolved in water, extracted with chloroform and the aqueous phase is acidified with 35 ml of 5N hydrochloric acid. The separated oily product is dissolved in chloroform, and the solution is dried over sodium sulfate. The chloroform is distilled off to give 13 g of 2- (p-isobutylphenyl) propionic acid, m.p. 74 ° C (from petrol).

Example 7 21.1 g of (4-phenyl-3-fluorophenyl) methylacetylene are mixed with 245 ml of methanol, and 51.8 g of thallium (III) nitrate hydrate are added thereto in small portions under 10 ° C under stirring. The reaction mixture is then stirred for a further 3 hours at 10 ° C. The precipitated thallium (I) nitrate is filtered off, 46 ml of 5N sodium hydroxide solution are added to the filtrate and the reaction mixture is refluxed for 10 hours, then the mixture is evaporated in vacuo. The residue is dissolved and 2 g of activated carbon are added to the solution, then filtered. The pH of the filtrate is adjusted to 1 with 5N hydrochloric acid. The separated oil crystallizes on scratching. 19.7 g of 2- (4-phenyl-3-fluorophenyl) -propionic acid are obtained, m.p. 107-109 ° C.

Example 8

To a mixture of 11.3 g of 4- (2-thenoyl) -phenylmethylacetylene and 150 ml of methanol is added, with stirring, below 10 ° C in small portions, 22.2 g of thallium (III) nitrate. The reaction mixture is stirred for another 3 hours. The precipitated thallium (The nitrate is filtered off, washed with methanol and the filtrate is diluted with water. The separated oil is extracted with dichloromethane. The solution thus obtained is dried over sodium sulphate, decolorized with activated carbon and filtered, a small amount of diisopropyl ether, mp 60 ° C.

Example 9 To 8.2 g of methyl 4- (2-thenoyl) hydratropate in 100 ml of alcohol is added 30 ml of 5N sodium hydroxide solution, and the mixture is refluxed for 7 hours. The mixture is decolorized with activated carbon and evaporated in vacuo. The residue is dissolved in water, the pH is adjusted to pH 1 with 5N hydrochloric acid, and the separated oil is dissolved in chloroform. The solution is dried over sodium sulfate and concentrated. The residual oil is triturated with petroleum ether and the product obtained is filtered off. 6.3 g of 4- (2-thenoyl) hydratropic acid are obtained. The melting point is recrystallized from acetonitrile at 121-123 ° C.

Example 10

To a stirred mixture of 5.23 g of Z4- (2-thenoyl) -3-chlorophenyl] methylacetylene and 50 ml of methanol is added 8.8 g of thallium (III) nitrate trihydrate in small portions at a temperature below 10 ° C with stirring. The reaction mixture is stirred at 10 ° C for a further 3 hours. The precipitated thallium (I) nitrate is filtered off, 8.5 ml of 5N sodium hydroxide solution are added to the filtrate and the reaction mixture is refluxed for 10 hours. The methanol is filtered off. The residue is dissolved in water, the solution is decolorized with activated carbon, filtered and the pH of the filtrate is adjusted to 2 by adding 5N hydrochloric acid under cooling. The separated oil is extracted with chloroform, the solution is dried over sodium sulfate, filtered and evaporated in vacuo. The residual oil crystallizes on trituration in petroleum ether to give 4- (2-thenoyl-3-chloro) hydroproic acid, m.p. 79-8l ° C.

Example 11 48.8 g of thallium nitrate trihydrate were suspended in 250 ml of methanol and 19.2 g of 2-biphenylylmethyl acetylene were added in small portions, taking care not to raise the temperature above 20 ° C. The mixture was stirred for a further 3.5 hours at 10-15 ° C and the precipitated thallium nitrate was filtered off, 250 ml of methylene chloride were added to the filtrate, the phases were separated and the aqueous phase was extracted with 2 x 150 ml of methylene chloride. The combined organic layer was evaporated. The residue was dissolved in 350 ml of methanol, 20 ml of 6 g of aqueous sodium hydroxide solution were added and the mixture was boiled for three hours and then evaporated. The residue was dissolved in 200 ml of water, extracted with 2 x 200 ml of methylene chloride and the aqueous phase was filtered after decolorization with activated carbon. The filtrate was acidified with 50% sulfuric acid, dried over sodium sulfate, the solvent was evaporated and the residue was distilled in vacuo. 19 g (84%) of 2-phenylhydratrocyclic acid were obtained, m.p. 122-123 ° C from recrystallization from diethyl ether-petroleum ether.

Example 12 25 g of phosphorus pentachloride are added dropwise over about 3/4 hour at room temperature with stirring to 22.63 g of m-phenoxypropiophenone. The mixture is then stirred for 1 hour at room temperature and for 2 hours at 50-60 ° C. The phosphorus oxychloride obtained is then distilled off in vacuo from a water bath, and the residual oil is added dropwise to the solution of 56 g of potassium hydroxide in 350 ml of absolute ethanol under ice-cooling and stirring, followed by stirring for 2 hours at room temperature. The mixture is poured into 1 liter of water, extracted 3 times with 200 ml of dichloromethane, the organic layer is washed with water, dried and evaporated to dryness, the residue is distilled in vacuo to give 1- (m-phenoxy-phenyl) -prop-1-yne, boiling point: 1442-146 ° C / 0.6 mmHg.

Example 13 8.1 g of 1- (m-phenoxy-phenyl) -1-chloroprop-1-ene are dissolved in 13,66833 of 50 ml of dry dimethyl sulfoxide and 3.43 g of sodium methylate made of sodium metal are added with stirring and the mixture is stirred for one hour. time at room temperature. The mixture is then neutralized by adding 50% sulfuric acid until the pH is 6, 150 ml of water are added, the mixture is extracted 3 times with 30 ml of chloroform, the organic layer is washed with water, dried and evaporated to dryness. The residual oil is distilled in vacuo to give 1- (m-phenoxy-phenyl) -p-op-1-yne, boiling point: 142-146 ° C / 0.5 mmHg; nj ^ = 1.5941.

Analysis:

Calculated: C 86.51%, h 5.81%

Found: C 86.37%, H 5.93%

Example 14 To 47.6 g of m-benzoyl-propiophenone is added 42 g of phosphorus pentachloride. The mixture is stirred at room temperature for 1 hour, then in a water bath at 60-70 ° C for 3 hours, after which the mixture is poured onto 500 g of ice, extracted 3 times with 100 ml of chloroform, the combined organic layers are washed with water, dried and evaporated to dryness. The residual oil is distilled in vacuo to give 1- (m-benzoylphenyl) -1-chloroprop-1-ene, b.p. 165-166 ° C, 0.3 mmHg.

24 nD = 1.6133

Analysis:

Calculated: C 74.85%, H 5.1%, Cl 13.81%

Found: C 74.73%, H 5.41%, Cl 13.88%.

Example 15

A mixture of 41.5 g of m-phenoxyacetophenone and 50 g of phosphorus pentachloride is kept at 70-75 ° C with stirring until the evolution of hydrochloric acid ceases (about 20 minutes). The phosphorus pentoxide formed after cooling is removed by distillation in vacuo. The residual oil is added to a hot solution of 78 g of potassium hydroxide and 250 ml of dry ethyl alcohol, after which the mixture is heated at reflux for 2 hours. The reaction mixture is diluted with water and the precipitated oil is extracted with chloroform, the chloroform is distilled off after drying over magnesium sulfate, and the remaining oil is distilled off in vacuo. The main fraction is m-phenoxy-phenylacetylene with a boiling point of 112-114 ° C / 0.6 mmHg.

24 nD = 1.5981.

__ τ 14 66833

Example 16 4.82 g of m-phenoxypropiophenone are dissolved in 45 ml of dry diethyl ether, 14 g of phosphorus pentachloride are added and the mixture is heated at reflux for 18 hours. The mixture is then poured onto 300 g of ice and, after separation, the aqueous layer is extracted twice with 50 ml of ether. The combined organic layers are washed with water, dried and evaporated to dryness. The residual oil is distilled in vacuo to give 1- (m-phenoxy-phenyl) -1-chloroprop-1-ene, boiling point: 158-162 ° C / 0.8 mmHg. nj3b = 1.5949.

Analysis:

Calculated: C 73.50%, H 5.32%

Found: C 73.20%, H 5.42%

Example 17 40 g of phosphorus pentachloride are added portionwise to 30.6 g of p-isobutylpropiophenone with stirring. The mixture is then stirred for 1 hour at room temperature and then at 80-90 ° C until the evolution of hydrochloric acid ceases. The reaction mixture is fractionated in vacuo. The fraction boiling at 88-94 ° C under a vacuum of 1.2 mmHg is 1- (4-isobutylphenyl) -1-chloro-19-prop-1-ene, nD = 1.5380.

Analysis:

Calculated: C 4.8l%, H 8.21%, N 16.99%

Found: C 75.11%, H 8.44%, N 17.15%.

66833 15

Example 18

To a suspension of anhydrous aluminum chloride in 130 ml of dry ethylene chloride is added dropwise and stirred 31.7 g of isobutylbenzene keeping the temperature of the reaction mixture below 10 ° C. The reaction mixture is then allowed to stand overnight at room temperature and then the mixture is poured into a mixture of ice and concentrated hydrochloric acid. After separation of the organic layer, the aqueous layer is extracted twice with 100 ml of ethylene chloride. The combined ethylene chloride solutions are washed with water, then with 5% sodium hydroxide solution until the solution is neutral, and dried.

After the ethylene chloride has been distilled off, the remaining oil is distilled off in vacuo. This gives p-isobutylpropiophenone with a boiling point of 96-100 ° C under a vacuum of 0.4 mmHg. n 2 '= 1.5149 2,4-dinitrophenylhydrazone, m.p. 169-171 ° C.

Example 19

To a suspension of 11.9 g of sodium methylate in 100 ml of dry dimethylformamide is added portionwise and with stirring 10.6 g of 1- (4-isobutylphenyl) -1-chloroprop-1-ene. The reaction mixture is stirred for 5 hours at room temperature, cooled with ice-water and the mixture is neutralized with stirring with 50% sulfuric acid (pH = 6), after which the mixture is poured into 500 ml of water. The separated oil is extracted 3 times with 100 ml of chloroform and dried. After distilling off the chloroform, the residual oil is distilled in vacuo to give 1- (4-isobutylphenyl) -2-methylacetylene, which has a boiling point of 93-97 ° C / 0.3 mmHg. n ^ '^ = 1.5338.

Analysis:

Calculated: C 90.64%, H 9.36%

Found: C 89.88%, H 9.55%.

Example 20 To 22.8 g of 3-fluoro-4-phenylpropiophenone is added 25 g of phosphorus pentachloride, after which the reaction mixture is stirred at room temperature for one hour and then at 80 ° C until the evolution of hydrochloric acid ceases. The reaction mixture is fractionated in vacuo to give 1- (2-fluorobiphenylyl-4) -1-chloroprop-1-ene.

- - π 16 66833

Example 21

To a suspension of sodium methylate in 100 ml of dry dimethylformamide is added in small portions and with stirring 12.3 g of 1- (2-fluorobiphenyl-4) -1-chloroprop-1-ene. The reaction mixture is stirred for 5 hours at room temperature, then cooled with ice-water and neutralized with stirring with 50% sulfuric acid (pH = 5) and poured into 500 ml of water. The distinct oil product is extracted with chloroform. The chloroform is distilled off in a water bath and, after suction in vacuo, the residue is 1- (2-fluoro-4-biphenylyl) -2-methylacetylene.

Example 22 24.3 g of sodium methylate are suspended in 150 ml of dimethylformamide, then 37.7 g of 1- (3-benzoylphenyl) -1-chloroprop-1-ene dissolved in 50 ml of dimethylformamide are added dropwise at 20-22 ° C. The mixture is then stirred for a further four hours at 20-25 ° C and then acidified by adding 50% sulfuric acid until pH = 6. The mixture is poured into 1.2 liters of water and extracted 3 times with 200 ml of dichloromethane. The combined organic layers are washed with water, dried and evaporated to dryness. The residual oil is distilled in vacuo to give 1- (3-benzoyl-phenyl) -prop-1-yne, b.p. 156-158 ° C, 0.3 mmHgn 2 in vacuo, n = 1.6195.

Example 23 To 55.8 g of 4- (2-thenoyl) -3-chloropropiophenone is added with stirring 42 g of phosphorus pentachloride. The mixture is then warmed to room temperature for 1 hour, and for 3 hours in a water bath at 60-70 ° C. after which the mixture is poured onto 500 g of ice, extracted 3 times with 100 ml of dichloromethane. The combined organic layers are washed with water, dried and evaporated to dryness. There is thus obtained 1- [4- (2-thenoyl) -3-chlorophenyl] -1-chloroprop-1-ene.

Example 24 24.8 g of sodium methylate are suspended in 150 ml of dimethylformamide and 1- [4- (2-thenoyl) -3-chlorophenyl] -1-chloroprop-1-ene in 50 ml of dimethylformamide is added dropwise to the suspension at 20-25 ° C. the mixture is then stirred at 20-25 ° C for a further 4 hours and acidified by adding 50% sulfuric acid until the pH is = 6. The mixture is poured into 1.5 liters of water, extracted 3 times with 200 ml of dichloromethane, the combined organic layers are washed with water, dried and 1- [4- (2-thenoyl) -3-chlorophenyl] -prop-1-yne is obtained.

Example 25 To 48.8 grams of 4- (2-thenoyl) propiophenone is added 42 g of phosphorus pentachloride. The mixture is stirred for 1 hour at room temperature, for 3 hours in a water bath at 60-70 ° C, after which the mixture is poured onto 500 g of ice, extracted 3 times with 100 ml of dichloromethane. The combined organic layers are washed with water, dried and evaporated to dryness to give 1- [4- (2-thenoyl) phenyl] -1-chloroprop-1-ene.

Example 26 24.3 g of sodium methylate are suspended in 150 ml of dimethylformamide and a solution of 39.3 g of 1- [4- (2-thenoyl) phenyl] -2-chloroprop-1 -ene in 50 ml of dimethylformamide. The solution is then stirred for 4 hours at 20-25 [deg.] C. and then the mixture is acidified by adding 50% sulfuric acid until the pH is = 6, poured into 1.5 liters of water and extracted 3 times with 200 ml of dichloromethane. The combined organic layers are washed with water, dried and evaporated to dryness to give 1- [4- (2-thenoyl) -phenyl] -prop-1-yne.

, V s *

Claims (4)

A process for the preparation of phenylalkyl carboxylic acid derivatives of the formula R - CH - COOR1 "wherein R is hydrogen or methyl, R is hydrogen or methyl, 2 R is hydrogen or halogen, and 3 R is phenoxy, benzyl, C , or tenoyl and salts thereof, characterized by reacting a compound of formula ____ "C = C - R 6 - 3 R 2 3 wherein R, R and R are as defined above, with thallium (III) nitrate in the presence of methanol, ethylene glycol methyl ether or diethyl ether at a temperature of 5-15 ° C, and optionally convert the carbalkoxy group by hydrolysis to a carboxyl group and optionally transfer the obtained product into a salt thereof. Process according to claim 1 for the preparation of derivatives containing free carboxylic acid, characterized in that the reaction is carried out in diethyl ether or ethylene glycol methyl ether in the presence of aqueous perchloric acid. 3. A process according to claim 1, characterized in that the hydrolysis of the carbalkoxy group is carried out in acidic or alkaline medium in the presence of water. 4. An intermediate for the preparation of phenylalkylcarboxylic acid derivatives of the formula R - CH - COOR1 - - R 2 In R 3/1 2 where R is methyl, R is hydrogen or methyl, R is hydrogen or halogen and R β-alkyl, phenyl or tenoyl, and salts thereof, characterized in that the intermediate is a phenylacetylene derivative of the formula