CH622485A5 - Process for the preparation of substituted phenylacetylenes - Google Patents

Description

The subject of the present invention is a process for the preparation of new phenylacetylenes of general formula I:

(I)

in which R1 is hydrogen, an alkyl of 1 to 6 carbon atoms, an aralcoyl in which the alkyl residue has 1 to 6 carbon atoms or a diaralkyl in which the alkyl residue has 2 to 6 carbon atoms, R2 is hydrogen or halogen, R3 is hydrogen, an alkyl of 1 to 6 carbon atoms, an aralkyl in which the alkyl residue has 1 to 6 carbon atoms, an aryl, an aryloxy or an aroyl group of formula ArCO— where Ar is phenyl or 2-thienyl, R2 and R3 do not, however, simultaneously represent hydrogen, characterized in that a compound of formula II is reacted

io in which R1 is hydrogen, an alkyl of 1 to 6 carbon atoms, an aralcoyl in which the alkyl residue has 1 to 6 carbon atoms, or a diarylalkyl in which the alkyl residue has from 2 to 6 carbon atoms , R2 is hydrogen or halogen, R3 is hydrogen, an alkyl of 1 to 6 carbon atoms, an aralkyl i5 in which the alkyl residue has 1 to 6 carbon atoms, an aryl, an aryloxy or a group aroyl of formula ArCO - in which Ar is phenyl or 2-thienyl, R2 and R3 however not being hydrogen simultaneously.

The new compounds of formula I are prepared by reacting a compound of formula II

(II)

(II)

30

in which the substituents R1 to R3 are as defined above, with a halogenating compound, preferably a phosphorus halide, so as to obtain a compound of general formula III

(III)

= CH - R

(m)

where X is a halogen and the substituents R1 to R3 are as already defined, then, if desired and without isolating the compound III, by reacting the latter with a strong base.

n / a According to a preferred embodiment of the invention, the compound II is reacted with PCI5 in the presence of an inert organic solvent such as diethyl ether, or in the absence of such a solvent, to a temperature from 20 to 100 ° C, preferably at the boiling-tion of this solvent. Preferably, one operates in a solvent between 55 50 and 90 ° C.

The hydrogen halide is removed with a strong base, preferably alkali hydroxides, especially KOH, or alkali alcoholates such as sodium methylate or sodium or potassium tert-butoxide, preferably in an organic solvent . As organic solvents, it is possible to use alcohols or aromatic hydrocarbons, preferably toluene.

Preferably, to remove the hydrogen halide, CHsONa and, as solvent, dimethylsulfoxide 65 (DMSO) or dimethylformamide (DMF).

To carry out this elimination, the operation is preferably carried out from 20 to 130 ° C and, preferably, at the boiling point of the solvent considered; in the case of DMSO, this point is 70 ° C.

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622,485

When working on a large scale, the hydrogen halide is preferably removed from the halogenated olefin obtained by halogenation of II without isolating and purifying the latter.

The new phenylacetylene compounds of formula I can be used in the pharmaceutical industry as useful intermediates for the preparation of compounds with pharmacological action of great value. Until now, the compounds of the present invention had not been prepared due to technical problems in the application of the synthesis methods, one of them being the difficulty of obtaining starting materials.

The invention is illustrated by the following examples.

Example 1:

22.63 g of m-phenoxypropiophenone was added dropwise over about 45 min to 25 g of PCI5 while stirring at room temperature. Stirring was continued for 1 hour at room temperature, then 2 hours at 50-60 ° C. By distillation in a water bath, the POCI3 which formed was removed and the oily residue was added dropwise to a stirring solution of 56 g of KOH in 350 ml of absolute ethanol while cooling with ice, then stirring was continued for 2 h at room temperature. The reaction mixture was poured into 1 liter of water, then extracted with 3 200 ml portions of dichloromethane; the extracts were washed with water, dried and evaporated. The residue was distilled in vacuo and thus obtained 1- (m-phenoxyphenyl) -prop-1-yne; Eb. 142-146 ° C / 0.6 torr.

Example 2:

To a solution of 8.1 g of 1- (m-phenoxyphenyl) -1-chloro-prop-1-ene in 50 ml of dry DMSO was added 3.43 g of freshly prepared sodium methylate and stirred for 1 hour at room temperature. The mixture was then neutralized with 50% sulfuric acid to pH 6, then 150 ml of water was added and the mixture was extracted with 3 successive portions of chloroform. The organic extracts were washed with water and dried and concentrated by evaporation. Finally, the oily residue was distilled in vacuo, which provided 1- (m-phenoxyphenyl) prop-1-yne; Eb. 142-146 ° C / 0.6 torr; nD30 = 1.5941.

Analysis for:

Calculated: C 86.51 H 5.81%

Found: C 86.37 H 5.93%

Example 3:

42 g of PCI5 were added to 47.6 g of m-benzoylpropiophene-none. The mixture was stirred 1 hour at room temperature, then 3 hours in a water bath at 60-70 ° C; then the mixture was poured onto 500 g of ice and the aqueous mixture was extracted with 3 portions of 100 ml of CHCl 3; the organic extracts were combined, washed with water, dried and concentrated in vacuo. Then the residual oil was distilled under reduced pressure, which gave 1- (m-benzoylphenyl) 1-chloroprop-1-en, bp: 165-166 ° C / 0.3 torr; nD24 = 1.6133.

Analysis for:

Calculated: C 74.85 H 5.1 Cl 13.81%

Found: C 74.73 H 5.41 Cl 13.88%

Example 4:

A mixture of 41.5 g of m-phenoxyacetophenone and 50 g of PCI5 was kept stirring at 70-75 ° C. until the release of FC1 was stopped (approximately 20 min). After cooling, the phosphorus pentoxide formed was removed by vacuum distillation. The oily residue was then added to a hot solution of 78 g of KOH in 250 ml of anhydrous ethanol and the whole was heated for 2 h at reflux. Then diluted with water and extracted the oil which separated with chloroform; after drying with anhydrous Mg sulfate, the CHCl 3 was removed by distillation and the residue was distilled under reduced pressure. The main fraction consisting of m-phenoxyphenylacetylene was collected; Eb. 112-114 ° C / 0.6 torr; nD24 = 1.5981.

Example 5:

To a solution of 4.82 g of m-phenoxypropiophenone in 45 ml of dry diethyl ether, 14 g of PCI5 were added and the whole was heated for 18 h at boiling point. The mixture was then poured onto 300 g of ice and, after separation of the organic layer, the aqueous phase was further extracted using 2 portions of 50 ml of ether. The extracts combined with the organic phase were then washed with water, dried and concentrated under reduced pressure. The residual oil was finally distilled in vacuo and thus 1- (m-phenoxyphenyl) 1-chloroprop-1-ene was obtained; Eb. 158-162 ° C / 0.8 torr; nD25 = 1.5949.

Analysis for:

Calculated: C 73.50 H 5.32%

Found: C 73.20 H 5.42%

Example 6:

41.6 g of m-bromopropiophenone and 52 g of PCI5 were mixed and the whole heated in a water bath at 75 ° C. until the evolution of HCl ceased, that is to say for approximately 20-25 min. . Then, after cooling, the mixture was subjected to fractional vacuum distillation and the fraction was collected; Eb. 108-112 ° C / 1.5 torr (31 g). This fraction was dissolved in 150 ml of anhydrous toluene, 70 g of sodium tert.-butyrate were added thereto and the mixture was heated for 7 h with vigorous stirring. Then the reaction mixture was decomposed with water and separated the organic phase; the aqueous phase was further extracted with 3 portions of 100 ml of toluene which were combined with the main fraction. After drying, the toluene was distilled off and the residue was subjected to fractionation under reduced pressure. The fraction was thus collected; Eb. 110-112 ° C / 1.5 torr consisting of 1- (3-bromophenyl) 2-methyl-lacetylene; nD24 = 1.5885.

Analysis for:

Calculated: Bromine 40.98%

Found: Bromine 41.40%

40 g of PCI5 were added in successive portions while stirring to 30.6 g of p-isobutylpropiophenone. Stirring was then continued for 1 hour at room temperature, then heated to 80-90 ° C and continued stirring until the evolution of HCl ceased. The reaction mixture was then subjected to fractional distillation and the boiling fraction was collected at 94 ° C / 0.2 torr, which consisted of 1- (4-isobutylphenyl) 1-chloroprop-1-ene; nD19 = 1.5380.

Analysis for:

Calculated: C 74.81 H 8.21 N 16.99%

Found: C 75.11 H 8.44 N 17.15%

Example 8:

31.7 g of isobutylbenzene was added dropwise, while stirring and keeping the temperature below 10 ° C, to a suspension of AICI3 in 130 ml of dry ethylene chloride. The whole was left to stand overnight at room temperature, then the mixture was poured onto a mixture of ice and concentrated hydrochloric acid. After separation of the organic layer, the aqueous phase was extracted with 2 portions of 100 ml of ethylene chloride. The combined ethylene chloride solutions were washed with water, with a 5% NaOH solution until neutral and finally dried. After distilling off the ethylene chloride, the residual oil was distilled in vacuo. P-isobutylpropiophenone was thus obtained; Eb. 96-100 ° C / 0.4 torr;

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622,485

4

nß2'5 = 1.5149. The dinitrophenylhydrazone of this ketone has a m.p. from 169 to 171 ° C.

Example 9:

10.6 g of 1- (4-isobutyl-phenyl) 1-chloroprop-1-ene were added in successive portions to 11.9 g of sodium methylate in 100 ml of dry DMF, with stirring. Stirring was continued for 5 h at room temperature, then the mixture was cooled with ice water and neutralized to pH 6 with 50% H2SO4, while stirring; then it was poured into 500 ml of water. The oil which formed was separated and the aqueous phase was extracted with 3 portions of 100 ml of CHCl3. The organic fractions were combined, dried, and the CHCl3 was removed by distillation. The residual oil was distilled under vacuum, which made it possible to collect the (4-isobutylphé-nyl) methylacetylene; Eb. 93-97 ° C / 0.3 torr; nD24'5 = 1.5338.

Analysis for:

Calculated: C 90.64 H 9.36%

Found: C 89.88 H 9.55%

Example 10:

25 g of PCI5 were added to 22.8 g of 3-fluoro-4-phenylpropio-phenone and the mixture was stirred for 1 h at room temperature and then at 80 ° C. until the hydrochloric acid was stopped. By fractional distillation of this mixture, 1- (2-fluoro-biphenyl-4) -1-chloroprop-1-ene was obtained.

Example 11:

12.3 g of 1- (2-fluorobiphenyl-4) -1-chloroprop-1-ene were added in small portions while stirring to a suspension of sodium methylate in 100 ml of dry DMF. It was then stirred for a further 5 hours at room temperature, then cooled with ice water and neutralized the mixture to pH 6 with 50% H2SO4, while stirring; this mixture was then poured into 500 ml of water. The oily product which separated was extracted with CHCI3. This chloroform was removed by distillation, first in a water bath and then under vacuum, which left, as residue, (2-fluoro-4-biphé-nyl) methylacétylène.

Example 12:

To a suspension of 24.3 g of sodium methylate in 150 ml of DMF, a solution of 37.7 g of 1- (3-benzoylphenyl) -1 was added dropwise at 20-22 ° C. chloroprop-l-ene in 50 ml of DMF. Then stirred for another 4 h at 20-25 ° C,

then the mixture was acidified with 50% H2SO4 to pH 6. The mixture was poured into 1.21 of water and extracted with 3 portions of

200 ml of dichloromethane. The combined organic phases were washed with water, dried and concentrated in vacuo. Then the residual oil was distilled in vacuo and thus obtained 1- (3-benzoyl-phenyl) prop-1-yne; Eb. 156-158 ° C / 0.3 torr; nD25 = 1.6195.

5

Example 13:

42 g of PCI5 were added with stirring to 55.8 g of 4- (2-thenoyl) -3-chloropropiophenone. Then stirred 1 hour at room temperature and 3 hours at 60-70 ° C in a water bath; then the whole was poured onto 500 g of ice and, after melting of this, it was extracted with 3 successive portions of 100 ml of dichloroethane. The organic extracts were washed, washed with water, dried and concentrated in vacuo. There was thus obtained 1- [4- (2-thenoyl) -3-chlorophenyl] -1-chloroprop-1-ene.

15

Example 14:

1- [4- (2-Thenoyl) -3-chlorophenyl] -1-chloroprop-1-ene dissolved in 50 ml of DMF in a suspension of 24.8 was added dropwise at 20-25 ° C g of sodium methylate in 150 ml of DMF. The mixture was stirred for a further 4 h at 20-25 ° C, then acidified to pH 6 with 50% H2SO4. The mixture was poured into 1.51 of water and extraction was carried out with 3 portions of 200 ml of dichloromethane; the organic extracts were combined, washed with water, dried and concentrated and thus

25

obtained 1- [4- (2-thenoyl) -3-chlorophenyl] -prop-1-yne.

Example 15:

42 g of PCI5 were added to 48.8 g of 4- (2-thénoyl) propiophé-30 none. It was stirred for 1 h at room temperature, 3 h at 60-70 ° C in a water bath, then the mixture was poured onto 500 g of ice and, after melting thereof, it was extracted in 3 portions of 100 ml of dichloromethane. By combining the extracts, washing with water, drying them and concentrating, 1- [4- (2-thenoyl) phenyl] -1-chloroprop-1-ene was obtained.

Example 16:

24.3 g of sodium methylate were suspended in 150 ml of dimethylformamide (DMF) and 39.3 g of 1- [4- (2) were added dropwise to 40 drop at 20-22 ° C. -thénoyI) phenyl] -2-chloroprop-1-ene in 50 ml of DMF. The mixture was stirred for a further 4 h at 20-25 ° C and acidified to pH 6 with 50% sulfuric acid; then the mixture was poured into 1.51 of water and extraction was carried out with 3 portions of 200 ml of dichloromethane. The combined 45 organic parts were washed with water, dried and concentrated and thus obtained 1- [4- (2-thenoyl) phenyl] prop-1-yne.

R

Claims (4)

622,485 1. Process for the preparation of the new compounds of general formula I ^ s C - R C s C - R (I) - CH_ - R in which R1 to R3 are defined as above with a halogenating compound so as to obtain an intermediate compound of formula III "CH - R where X is a halogen and R1 to R3 are defined as above, then the latter is reacted with a strong base. 2. Method according to claim 1, characterized in that phosphorus pentachloride is used as the halogenating compound in the presence of an organic solvent at 20-100 ° C or, preferably, in the absence thereof, at 50-90 ° C. 2 3. Method according to claim 2, characterized in that a strong base is used as an alkali hydroxide or alcoholate. 4. Method according to claim 3, characterized in that sodium methylate is used in the presence of dimethylsulphoxide or dimethylformamide.