HU213233B - New process for producing 2-phenyl-3,3,3-trifluoro-propionic acid - Google Patents

Abstract

In accordance with the present invention, a propionic acid amide of formula (III) or a propionic acid ester is reacted with a sulfonic acid chloride, the resulting compound of formula (IV) is reacted with a reducing agent and the resulting compound of formula (V) is hydrolyzed. According to the invention, it is also possible to react with a cyanohydrin of formula (III) by phosphorus pentazulfide and to hydrolyze the resulting propionitrile (V). (III) // cf3 - R OSO2R2 PF3 R (IV) (V) HU 213 233 B Scope of the description: 6 pages (including 1 sheet)

Description

The present invention relates to a novel process for the preparation of 2-phenyl-3,3,3-trifluoropropionic acid of formula (I). The compound of formula (I) is useful as an intermediate in the preparation of (E) -1,2-diphenyl-3,3,3-trifluoro-1- {4- [2- (2-hydroxyethylamino) -ethoxy] of formula (II). -phenyl} -propene. This latter compound is known as panomifen and is useful in the treatment of breast cancer. Hungarian Patent Specification].

The compound of formula (I) is one known process [J.

Fluorine Chem., 22 (6), 561-574 (1983)] is prepared from 5-step synthesis of commercially unavailable pentafluoro chloroacetone. Total production is only 11%.

According to another known method [J. Org. Chem., 32,

2797-2803 (1967)] provides a compound of formula (I) in a four step synthesis. In the first step, triphenylphosphine is reacted with chloromethyl methyl ether in benzene for 60 hours. The resulting triphenylmethoxymethylphosphonium chloride is reacted with trifluoroacetophenone in a Wittig reaction and the resulting enol ether is hydrolyzed with aqueous sulfuric acid to the corresponding aldehyde. In the final step, the compound of formula (I) is obtained by oxidation with potassium permanganate. With a total production of 29%, this known process is also quite uneconomical. The above anteriority also describes 2-phenyl-3,3,3-trifluoropropionic acid amide.

It is also known to prepare the ethyl ester of the compound of formula I from diethyl phenyl malonate in 2 steps [J. Org. Chem. 49, 3702-3706 (1984)]. As the ethyl ester can be obtained only in 36% yield and the by-products formed are difficult to dispose of, this economical route cannot be based on this pathway either. Enzymatic hydrolysis of alkyl 2-phenyl-3,3,3-trifluoropropionic acid ester according to U.S. Patent No. 0,463,598. Japanese Patent Publication [Chem. Abstr. 117: 110133 (1992)].

It is an object of the present invention to provide an economically feasible process for the preparation of 2-phenyl-3,3,3-trifluoropropionic acid (I).

We have found that the above goal will be achieved if

a) a propionic acid amide or propionic acid ester of formula (III) wherein R is a -CONH ₂ group or a -COOR ¹ group where R ¹ is a C 1 -C 4 alkyl group with a sulfonic acid chloride of formula R ² -SO ₂ Cl, wherein R ² is C 1 -C 4 alkyl, phenyl or tolyl, in the presence of an acid acceptor, reacting the resulting propionic acid amide of formula (IV) or propionic acid ester, wherein R and R ² are as defined above, with the resulting reducing agent; or hydrolyzing an ester of propionic acid, wherein R is as defined above; obsession

b) reacting a cyanohydrin of formula (III) wherein R is a -CN group with phosphorus pentasulfide and hydrolyzing the resulting propionitrile of formula (V) wherein R is as defined above. It is surprising to those skilled in the art that starting from the compound of formula (ΠΙ), the compound of formula (I) can be prepared simply and economically since J. Org. Chem., 32, 2797-2803 (1967), found that in principle the compound of formula (I) could be prepared from a compound of formula (ΠΙ) wherein R is cyano, but the carboxylic acid obtained by hydrolysis thereof; it is not possible to reduce the alpha-hydroxypropionic acid of formula (én) containing a carboxyl group to the desired propionic acid of formula (I). Thus, the authors of the above article advised the person skilled in the art to develop a synthesis starting from the compound of formula (ΙΠ).

In the process (a) of the present invention, the reaction of the propionic acid amide or propionic acid ester of formula (ΙΠ) with the sulfonic acid chloride of formula R ² -SO ₂ Cl is carried out in water or in an organic solvent. The organic solvent is, for example, an aliphatic or cyclic ether, a dipolar aprotic solvent such as acetonitrile, acetone, dimethyl sulfoxide, nitrobenzene, a basic organic solvent such as pyridine, triethylamine and the like. may. Preferably, acetonitrile or tetrahydrofuran is used as the solvent. An acid acceptor is also added to bind the hydrochloric acid liberated during the reaction. The acid scavenger may be an organic or inorganic base, preferably triethylamine or potassium hydroxide. Optionally, the acid scavenger may also serve as a solvent.

The reaction is generally carried out at low temperature. Preferably, the temperature is between 0 ° C and -20 ° C. The starting materials are suitably used in equimolar amounts, but excess sulfonic acid chloride may be used.

Preferably the sulfonic acid chloride is methylsulfonyl chloride. The resulting propionic acid amide or propionic acid ester (IV) is conveniently reacted with hydrogen as the reducing agent and activated with a catalyst. The catalyst is preferably palladium on charcoal. The solvent used for the catalytic hydrogenation is generally a polar solvent such as water, alcohols, esters, organic acids, preferably methanol, ethyl acetate or acetic acid. Particularly preferably, the catalytic hydrogenation is carried out in methanol, at atmospheric pressure or under pressure, preferably at a temperature of from 0 to 50 ° C, preferably at room temperature.

The propionamide of formula (IV) the reduction is preferably 4-8x10 ⁵ torr, while the propionic acid ester of formula (IV): The reduction usually takes place at atmospheric pressure.

The resulting propionic acid amide or propionic acid ester of formula (V) is converted by hydrolysis to the desired propionic acid of formula (I). The hydrolysis is generally carried out with a mineral acid such as hydrochloric acid or sulfuric acid, which is used either in catalytic amounts or in excess. The propionic acid amide of formula (V) is suitably hydrolyzed with an aqueous sulfuric acid solution, such as an aqueous sulfuric acid solution at a concentration of about 50%, preferably in an amount of 8 to 12 times, more preferably about 10 times. The propionic acid ester of formula (V) is conveniently hydrolyzed in a mixture of dioxane and water, which is preferably a mineral acid.

Contains hydrochloric acid. Proven 2: 1 by weight mixture of dioxane and water.

The hydrolysis of both the propionic acid amide V and the propionic acid ester is carried out at a temperature between 70 ° C and the boiling point of the reaction mixture, preferably between 90 ° C and 140 ° C.

In process (b) of the present invention, the cyanohydrin of formula (III) is reduced in equimolar or excess amounts of phosphorus pentasulfide. Suitable solvents are primarily aromatic hydrocarbons such as toluene or xylene. Preferably, toluene is used. The reaction is generally carried out at a temperature between 20 ° C and the boiling point of the solvent used, preferably at the boiling point of the solvent. The reduction of the cyanohydrin of formula (ΙΠ) usually takes from 1 to 8 hours.

The propionitrile (V) formed by the reduction can be converted to the desired propionic acid (I) by methods known per se. Preferably, hydrolysis with concentrated sulfuric acid at room temperature yields the corresponding propionic acid amide of formula (V), which may be further hydrolyzed with or without aqueous sulfuric acid, e.g.

Because the propionic acid of formula (I) contains a chiral carbon atom, the invention relates to the preparation of both individual optical isomers and mixtures thereof in any proportion.

Starting compounds of formula III are known [J. Org. Chem., 34, 2543-2549 (1969), J. Chem. Soc. Perkin Trans. I., 1951-1957 (1990)].

Propionic acid amide (IV) and propionic acid ester (IV) used as intermediates in the process of the invention and propionitrile (V) are novel compounds.

The process according to the invention is simple and economical and requires no special equipment.

The invention is illustrated in detail by the following examples.

Example 1

2-Phenyl-3,3,3-trifluoro-propionic acid

A) 2-Phenyl-3,3,3-trifluoro-2- (methylsulfonyloxy) propionic acid amide

10.95 g (0.05 mol) of 2-phenyl-3,3,3-trifluoro-2-hydroxypropionic acid amide, 20.2 g (0.20 mol) of triethylamine and

To a mixture of 27.6 cm ^{3 of} acetonitrile was added dropwise 15.6 cm ³ (22.9 g, 0.20 mol) of methanesulfonyl chloride at (-10) to (-20) ° C. After stirring for 15 minutes at (-10) to (-20), the reaction mixture was poured into 400 cm <^{3> of} ice water and extracted with ³ x 100 cm <^{3> of} chloroform, the combined organic solutions dried over anhydrous magnesium sulfate and evaporated. The residual oil was crystallized by trituration with water. 14 g (94%) of the title compound are obtained. 120-123 ° C.

Elemental Analysis: Calculated for C ₁₀ H ₁₀ F ₃ NO ₄ S (297.26): C 40.41%, H 3.39%, N 4.71%, S 10.79%; Found: C 40.55%, H 3.46%, N 4.78%, S 11.08%.

IR (KBr): 3420; 3184; 1719; 1362; 1197; 1171 cm -1. 1 H-NMR (CDCl ₃ ): δ 7.70-7.67 (2H, m); 7.52-7.47 (3H,

m); 6.29 (2H, br s); 3.23 (3H, s).

¹³ C-NMR (CE> Cl ₃ ): δ 165.4; 130.4; 130.3; 128.5; 127.7;

121 (9 (q, Jcf 287 Hz); 87.8 (q, 1 _σ 28 Hz); 40.6.

B) 2-Phenyl-3,3,3-trifluoropropionic acid amide

5.82 g (0.02 mol) of 2-phenyl-3,3,3-trifluoro-2- (methylsulfonyloxy) propionic acid amide in 60 cm ^{3 of} methanol are 0.58 g of 10% palladium on carbon ( óxlO hydrogenated for 3 hours at ⁵ torr, 25 ° C Selco-Q) presence. The catalyst was filtered off and the solution was evaporated. The remaining solution was crystallized by trituration with 6 cm ^{3 of} water. 3.6 g (90%) of the title compound are obtained, m.p. 99-103 ° C, for the next step. Recrystallized from water, m.p. 108-109 ° C.

Elemental Analysis: Found: C, 53.21; H, 3.97; N, 6.89;

Found: C, 53.12; H, 3.85; N, 6.94.

IR (KBr): 3455; 3331; 3196; 1678 cm -1.

1 H-NMR (CDCl ₃ ): δ 7.48-7.38 (5H, m); 6.15 (1H, br s);

5.76 (1H, br s); 4.21 (1H, q, Jf 8.9 Hz).

¹³ C-NMR (CDCl ₃ ): δ 168.0; 130.4; 129.3; 128.8; 128.6;

121.4 (q, Jcp 280 Hz); 54.8 (q, J = 28.7 Hz).

C) 2-Phenyl-3,3,3-trifluoropropionic acid

2-Phenyl-3,3,3-trifluoropropionic acid amide (10.15 g, 0.05 mol) was stirred in 100 cm ^{3 of} 50% sulfuric acid for 1 hour in an oil bath at 130 ° C. After cooling to room temperature, the mixture was poured into ice water (70 cm ³ ) and extracted with chloroform ( ³ x 60 cm ³ ). The combined organic layers were washed with water (2 x 50 cm ³ ), dried over anhydrous magnesium sulfate and evaporated. The residual oil was crystallized by adding 20 cm ^{3 of} hexane. 8.2 g (81%) of the title compound are obtained, m.p.

77-78 ° C [J. Org. Chem. 32, 2797-2803 (1967)], 73-75 ° C [J. Fluorine Chem. 22 (6): 561-574 (1983).

Elemental Analysis: Found: C, 52.95; H, 3.46; F, 27.92;

Found: C, 52.65; H, 3.38; F, 28.21.

IR (KBr): 1726; 1121 cm ^-1 .

1 H-NMR (CDCl ₃ ): δ 11.24 (1H, br s); 7.48-7.39 (5 H, m);

4.35 (1H, q, J _HF 8.4 Hz).

¹³ C-NMR (CDCl ₃ ): δ 172.5 (q, 1 _σ 3 Hz); 129.6; 129.5;

129.1; 128.6; 123.4 (q, 1 _σ 279 Hz); 55.3 (q, J _CF 29 Hz).

Example 2

2-Phenyl-3,3,3-trifluoro-propionic acid

A) 2-Phenyl -3,3,3-trifluoropropionitrile

To a solution of 2-phenyl-3,3,3-trifluoro-2-hydroxypropionitrile (28.2 g, 0.14 mol) in toluene (280 cm ^{3) was} added 31.1 g (0.14 mol) of phosphorus pentasulfide and the mixture was stirred at room temperature for 4 hours. boil for an hour. The solid was filtered off and washed with toluene. The toluene filtrate was washed with 2x130 cm ^{3 of} 1M sodium bicarbonate solution and then with 80 cm ^{3 of} water. The toluene was distilled off in vacuo and the oily residue was distilled at 2-10 ³ Pa (15 mmHg). The fraction distilling at 83-85 ° C was 16.8 g (65%) of the title compound. Fp .: 199 ° C (10 ⁵ Pa); n [a] §: 1.4479.

HU 213 233 B

Elemental Analysis: Calculated for C ₉ H ₆ F ₃ N (185.16): C 58.38%, H 3.27%, N7.57%;

Found: C 58.28%, H3.31%, N7.34%.

IR (film): 3044; 2937; 2260; 1601; 1497; 1458; 1323;

1250; 1192; 1128; 760; 704 cm ¹ .

1 H-NMR (CDCl ₃ ): δ 7.46 (5H, s); 4.52 (1H, q, J _HF)

7.5 Hz).

¹³ C-NMR (CDCl ₃ ): δ 130.2; 129.4; 129.1; 125.9;

122.0; (q, J _CF 281.5 Hz); 113.5; 43.0 (q, J _CF

32.9 Hz).

B) 2-Phenyl-3,3,3-trifluoropropionic acid (2 g) (0.27 mol) in 2-phenyl-3,3,3-trifluoropropionitrile was combined with 250 cm ^{3 of} concentrated sulfuric acid and allowed to stand overnight. Under vigorous stirring, 250 cm ^{3 of} water was added and the resulting mixture was stirred for 1 hour on a 140 'Cos oil bath. It is then poured into 400 cm ^{3 of} water, extracted three times with 400 cm ^{3 of} dichloromethane and the combined organic phases are washed twice with 300 cm ^{3 of} water. Concentrate in vacuo and recrystallize the residue from hexane (5 cm ³ / g). Weight of product obtained

49.4 g (89%), m.p.

Example 3

2-Phenyl-3,3,3-trifluoro-propionic acid

A) Ethyl [2-phenyl-3,3,3-trifluoro-2- (methylsulfonyloxy] propionate]

2.4 g (0.01 mol) of ethyl (2-phenyl-3,3,3-trifluoro-2-hydroxypropionate), 5.5 cm ³ (4.0 g, 0.04 mol) of triethyl- [between - - (5) ° C 0] 3.1 cm ³ (4.6 g, 0.04 mole) of methanesulfonyl chloride was added dropwise to an ice-salt cooled mixture of amine and 15 cm ³ of tetrahydrofuran. After 15 minutes, the mixture was poured into ice water (100 g), extracted with chloroform ( ³ x 30 cm ³⁾ , and the organic layer was dried over anhydrous magnesium sulfate and concentrated. The residual brown oil (3.8 g) was distilled in vacuo. 2.3 g (72%) of the title compound are obtained, m.p.

Analysis: Calculated for C ₁₃ H _I2 F ₃ O ₅ S (326.30) Analysis: C 44.17%, H4,02%, S 9.83%;

Found: C, 43.88; H, 3.86; S, 9.81.

IR (film): 1762; 1374; 1186 cm ^-1 .

1 H-NMR (CDCl ₃ ): δ 7.65-7.54 (2H, m); 7.50-7.40 (3 H, m); 4.42 (2H, q, J 7.1 Hz); 3.27 (3H, s); 1.35 (3H, t, J 7.1 Hz).

¹³ C-NMR (CDCl ₃ ): δ 163.9; 130.3; 130.1; 128.6;

126.5; 121.5 (q, J _CF 285.9 Hz); 86.6 (q, J _CF 29 Hz);

63.5; 40.7; 13.4.

B) Ethyl (2-phenyl-3,3,3-trifluoropropionate)

9.8 g (30 mmol) of ethyl [2-phenyl-3,3,3-trifluoro-2- (methylsulfonyloxy) propionate] in 200 cm ^{3 of} methanol,

Hydrogenation (1.5 g) in 10% palladium on carbon (Selcat-Q) was carried out for 1 hour at 25 ° C. After filtration of the catalyst, methanol was distilled off in vacuo. To the residue 60 cm ³ of water and extracted three times with 25 cm ³ of dichloromethane. The combined organic layer was washed with 1M sodium bicarbonate solution (50 cm ³ ) and water (2 x 25 cm ³ ) and evaporated. The residue was distilled in vacuo to give 5.9 g (85%) of the title compound, b.p. 67-71 ° C / 263 Pa.

Elemental analysis cannot be performed because the product is a volatile oil.

IR (film): 2991; 1749; 1375; 1350; 1302; 1277;

1259; 1221; 1155; 1111; 1026; 700 cm ¹ .

1 H-NMR (C ₆ H ₆ ): δ 7.35-7.25 (2 H, m); 7.15-7.00 (3 H, m); 4.12 (1H, q, J _HF 8.6 Hz); 3.90 (1H, dq, J _d 10 Hz, J _q 7.1 Hz); 3.81 (1H, dq, J _d 10 Hz, J _q 7.1 Hz); 0.81 (3H, t, J 7.2 Hz).

C) 2-Phenyl-3,3,3-trifluoropropionic acid

18.8 g (81 mmol) of ethyl (2-phenyl-3,3,3-trifluoropropionate) are heated in a mixture of 180 cm ^{3 of} dioxane and 90 cm ^{3 of} concentrated hydrochloric acid for 30 hours. The cooled mixture was extracted three times with 50 cm ^{3 of} dichloromethane. From the combined dichloromethane phase, the product is dissolved in 200 cm ^{3 of} 1 M sodium bicarbonate solution and 50 cm ^{3 of} water. 1.5 g (8%) of the unmodified ester is recovered from the organic phase and can be reused. The aqueous phase was washed with 50 cm ^{3 of} dichloromethane, acidified to pH 1 with 70 cm ^{3 of} 2 M hydrochloric acid and extracted with ³ x 50 cm ^{3 of} dichloromethane. After evaporation, crystallization from hexane gave 12.1 g (80%) of the title compound, m.p. 74-75 ° C.

Example 4

2-Phenyl-3,3,3-trifluoro-propionic acid

2-Phenyl-3,3,3-trifluoropropionitrile (10.0 g, 0.054 mol) in cm ^{3 of} concentrated sulfuric acid was allowed to stand overnight. Pour into 100 g of ice and extract with ³ x 50 cm ^{3 of} dichloromethane. The combined organic phases are washed with 100 cm ^{3 of} water and evaporated. Recrystallization from water gave 9.22 g (84%) of 2-phenyl-3,3,3-trifluoropropionic acid amide, m.p. 108-109 ° C. The procedure of Example 1 (c) was followed and the title compound was obtained in 81% yield, m.p. 74-76 ° C.

Claims (4)

A process for the preparation of 2-phenyl-3,3,3-trifluoropropionic acid of the formula I, characterized in that a) a propionic acid amide or propionic acid ester of formula (III) wherein R is a -CONH ₂ group or a -COOR ¹ group where R ¹ is a C 1 -C 4 alkyl group with a sulfonic acid chloride of formula R ² -SO ₂ Cl, wherein R ² is C 1 -C 4 alkyl, phenyl or tolyl, in the presence of an acid acceptor, reacting the resulting propionic acid amide of formula (IV) or propionic acid ester, wherein R and R ² are as defined above, with the resulting reducing agent; or hydrolyzing an ester of propionic acid, wherein R is as defined above; obsession b) reacting a cyanohydrin of formula (III) wherein R is a -CN group with phosphorus pentasulfide and hydrolyzing the resulting propionitrile of formula (V) wherein R is as defined above. Method a) according to claim 1, characterized by The methyl sulfonyl chloride is used as the sulfonic acid chloride. Process (a) according to claim 1, characterized in that the reducing agent is hydrogen activated with a catalyst. A process according to claim 1, wherein the hydrolysis of the compound of formula V, wherein R is as defined in claim 1, is carried out with an aqueous solution of a mineral acid.