CS254474B1 - Phosphonium salts and processes for their preparation - Google Patents

Abstract

New phosphonium salts of the general formula I t/c6H5/3p/+/cH2-A''c00R3cl/"/' where R denotes hydrogen or alkyl containing 1 to 3 carbon atoms, A denotes a furan, thiophene or N-methylpyrrole nucleus substituted in position 2 or 3 by the COOR group and attached to the CH2 group in position 4 or 5, have applications in the field of synthesis. Their method of production consists in treating compounds of the general formula C1CH2-A-COOR with triphenylphosphine in a molar ratio of reactants 1:1.3 to 2 in a solution of inert organic solvents at a temperature of 60 to 120 °C, after which the components are cooled and the precipitated crystals of the product of the general formula are filtered off with suction, washed with an aromatic hydrocarbon and dried.

Description

This invention relates to phosphonium salts of the formula I, [? C ₆ H _g / ₃ L ^{/ + /} CH ₂ -A-COORjci ^{/ - / 1X1} wherein R is hydrogen or alkyl containing 1-3 carbon atoms

A denotes a furan, thiophene or N-methylpyrrole core substituted at the 2-position or a COOR group and a CH ₂ group attached at the 4 or 5 position and a process for their preparation.

The phosphonium salts of the formula I are novel compounds. Their intended use is directed to the field of synthesis, particularly to the introduction of the alpha chain into the molecule of synthetic prostaglandin analogues. It is well known in the art that modifications in the alpha and omega chain of this type of compound increase both the time and the selectivity of their effects.

Generally, the preparation of phosphonium salts of type A, [/ ^C 6 H _5/3 P ^{/ + /} -R] x ^/ - ^/ / a /, wherein R represents a wide variety of substituents, and X represents halogen are described in the literature / see e.g. Methoden der Organischen Chemie (Houben-Weyl), Vol. XII (1), p. 79, G.Thieme Verlag Stuttgart 1963; Ditto, Volume E 1, p. 491, 1982]. Usually, an equimolar amount of triphenylphosphine and the corresponding organic halide is reacted in acetonitrile, tetrahydrofuran, benzene, toluene at different temperatures for 20 to 60 ° C.

In some cases, especially alpha-halo ketones, it has been recommended to add a catalytic amount of organic base to the reaction mixture. 33, 3 504 (1968). A disadvantage of the above processes is that they use highly toxic acetonitrile, furthermore the products usually have to be subsequently purified by reprecipitation or crystallization. In MS. No. 228,058 discloses a process for preparing phosphonium salts using an excess of triphenylphosphine in an aromatic hydrocarbon environment, preferably toluene, with the addition of aprotic polar solvents at elevated temperature. The advantages of this production method are high yields and product purity.

The production method according to AO No. 228 058 is followed by the method according to the invention, using good experience and simplicity of execution. The process according to the invention consists in reacting triphenylphosphine with the chloride of the formula II

C1CH ₂ -A-COOR / 11 / wherein A and R are as defined above is carried out in a mixture of hydrocarbon and Automatic aprotic polar solvent such as dimethylformamide, dimethylsulfoxide, and the like. In this reaction, 1.3 to 2 moles of triphenylphosphine are used per mole of the compound of formula II, the reaction being carried out at a temperature of 30 to 30 ° C. 150 ° C, preferably 80 to 120 ° C.

After cooling the reaction mixture to room temperature, or after previously concentrating the reaction mixture, the precipitated product of formula (I) is filtered off with suction, washed with a small amount of aromatic hydrocarbon and dried at 80 to 120 ° C at 20 to 300 Pa. The mother liquors are supplemented with an additional amount of triphenylphosphine and a compound of formula II and the operation is repeated.

The advantage of this process is low solvent consumption, simple design and high yields. The solvents used are environmentally friendly.

The process of the invention is illustrated by the following examples, which are not intended to limit the scope of the invention in any way.

Example 1/5-Methoxycarbonyl-2-furylmethyl / triphenylphosphinium chloride

A mixture of 7 g of methyl 5-chloromethylpyroslizane (Formula II wherein R is methyl, A at the 2- and 5-position is a substitute furan ring), 15.8 g of triphenylphosphine, 60 ml of toluene and 0.6 ml of dimethylformamide was heated to boiling 5. hours. Progress of the reaction was monitored by thin layer chromatography (chloroform). After cooling the reaction mixture, the precipitated crystals were filtered off with suction, washed 3 times with 20 ml of benzene, dried at 100 [deg.] C. and a pressure of 1 mmHg. 15.95 g of product were obtained, mp 219-221 ° C. The identity of the product was confirmed by spectral methods: ^{Χ Η} NMR spectrum in DMSO-d₆ / TMS internal standard / delta / ppm / 3.72 / 3H, s, _CH3 /, 5.58 to 5.72 / 2H, d, _CH2, J = 16 Hz /, 6.38 / 1H, t, CH /, 7.20 / 1H, d, CH /,

7.66 to 8.00 (15H, m, aromatic H). The infrared spectrum contains bands: 1700 cm corresponds to / C = O / - in the carboxyl group, 1310 cm corresponds to C-0 in the carboxyl group, 1590 and 1530 cm multiple bonds in the aromatic nucleus. Mass Spectrum 183/100 /, 36/97 /, 108/78 /, 399/53 /, 262/50 /, 51/47 /, 59/40 /, 107/28 /, 215/20 /, 340/15 /.

Example 2/5-Methoxycarbonyl-2-thienylmethyl / triphenylphosphonium chloride

7.05 g of 5-chloromethyl-2-thienylcarboxylic acid methyl ester / formula (II) wherein R is methyl and A is 2 and 5 is sust. thiophene ring], 14.7 g of triphenylphosphine, ml of benzene and 0.5 ml of dimethyl sulfoxide were heated to boiling for 10 hours. After analogous treatment of the reaction mixture as in Example 1, 14.6 g of product, mp 195-206 ° C, were obtained, the spectral characteristics of which correspond to the proposed structure. @ 1 H NMR Spectrum: .delta. (Ppm): 3.79 (3H, s, CH), 5.94-6.10 (2H, d, CH3, J = 16 Hz), 6.98 (1H) t, CH), 7.65 (1H, d, CH), 7.74.8, 16 (15H, m, aromatic H); IR spectrum, bands: 1715 cm @ ¹ corresponds to (CO) in the carboxyl, 1590 cm @ ^{1 of the} bond in the aromatic nucleus. Mass Spectrum: 262 (100), 183 (80), 357 (45), 28 (35), 277 (32), 261 (20), 263 (20), 44 (18), 173 (17), 97 / 13/.

Example 3 (4-Ethoxycarbonyl-2-thienylmethyl) triphenylphosphonium chloride

To a solution of 5.3 g of 5-chloromethyl-3-thiophenecarboxylate in 40 ml of toluene and 0.4 ml of dimethylformamide was added 10.2 g of triphenylphosphine and the resulting mixture was heated at 80 to 100 ° C for 12 hours. After working up analogously to Example 1, 11.8 g of crystalline product were obtained, mp 212-218 ° C. The spectral characteristics are in accordance with the proposed structure. 1 H NMR spectrum: δ, δ (ppm) signals: 2.2 (3H, q, CH ₃ ),

3.70 to 3.90 (2H, m, CH), 5.76 to 5.90 (2H, d, CH, J = 14 Hz), 7.00 (1H, d, CH), 7.22 (1H, s, CH), * -1.1 7.46 to 8.10 (15H, m, aromatic H); IR spectrum, bands: 1725 cm, 1590 cm. Mass Spectrum: 262 (100), 183 (70), 108 (33), 28 (28), 276 (22), 429 (20), 263 (20), 261 (20), 164 (17), 44 / 10 /.

Example 4/4-Methoxycarbonyl-2-furylmethyl / triphenylphosphonium chloride

The procedure was as in Example 1. From 7.0 g of 5-chloromethyl-3-furancarboxylic acid methyl ester ¹ , 15.8 g of triphenylphosphine in 60 ml of toluene and 0.6 ml of dimethylformamide, after 15 hours of boiling and work-up, 16 were obtained. 9 g of crystalline product, mp 162-172 ° C, whose spectral characteristics are in accordance with the proposed structure.

Example, 5/4-Carboxy-2-thienylmethyl / triphenylphosphonium chloride

1.08 g of 5-chloromethyl-3-thiophenecarboxylic acid and 2.4 g of triphenylphosphine in 20 ml of benzene and 0.1 ml of dimethylformamide were heated at reflux for 10 hours. After analogous work-up as in Example 1, 2.4 g of product were obtained, m.p. 263 DEG -273 DEG C. whose structure is in accordance with the interpretation of the infrared and proton NMR spectra.

Example 6 (5-Carboxy-2-thienylmethyl) triphenylphosphonium chloride

The procedure was as in Example 5. From 1.08 g of 5-chloromethyl-2-thiophenecarboxylic acid, 2.41 g of triphenylphosphine, 10 ml of toluene and 0.1 ml of dimethylforamide, after 10 hours of heating and working up the reaction mixture, 2.3 products were obtained. , tt 270 DEG-277 DEG C. whose structure was confirmed by infrared and NMR spectra.

Claims (3)

First phosphonium salts of the formula I | / C ₆ H _5/3 P ^{/ + /} CH ₂ Cl -A-COOR j ^{/ - /} / 1 / wherein R stands for hydrogen or alkyl containing 1-3 carbon atoms A represents a furan, thiophene or N-methylpyrrole core substituted in the 2-position or COOR 3 and CH ₂ group attached at position 4 or 5. 2. A process for the preparation of phosphonium salts according to claim 1, characterized in that the compounds of the formula XI, cich ₂ -a-coor (11) wherein R and A are as defined above are treated with triphenylphosphine in a molar ratio of reactants of 1: 1.3 The solution is cooled and the precipitated crystals of the product of formula I are filtered off with suction, washed with an aromatic hydrocarbon and dried. 3. A process according to claim 2, wherein the inert organic solvent is a C8-C8 aromatic hydrocarbon such as benzene, toluene, xylenes, optionally mixed with dimethylformamide, hexamethylphosphoric triamide, N-methylpyrrolidone or dimethylsulfoxide.