CZ288244B6 - Process for preparing phosphonium salts - Google Patents

Abstract

In the present invention there is described a process for preparing phosphonium salts of the general formula I, in which R represents an alkyl group containing 1 to 4 carbon atoms, being optionally substituted with 1 to 2 fluorine atoms or an alkoxy group containing 1 to 3 carbon atoms, Re1 represents alkyl, alkenyl, alkynyl containing 2 to 6 carbon atoms or cycloalkyl, containing 5 to 10 carbon atoms or an cycloalkenylalkyl group having 5 to 10 carbon atoms, wherefrom 2 to 6 carbon atoms form the alkyl moiety, Re2 represents a hydrogen atom or tetrahydropyran-2-yl, trialkylsilyl, 1-ethoxyethyl-, 1-metyl-1-methoxyethyl group and X represents iodine or bromine atom. These compounds are significant intermediates in synthesis of therapeutically interesting prostaglandins being modified in {omega}-chain. These are especially preparations exhibiting cytoprotective activity and which are used for prevention and treatment of ulcerous disease of esophagus, stomach and duodenum induced by antipyretics based on salicylates and non-steroidal antiphlogistic medicaments based on arylacetic and propionic acids. The present invention is characterized by novel synthesis process of phosphonium salts, where the starting compounds are 1-substituted 3-oxoalkanes, which are treated in a medium of an ether solvent with a corresponding alkyl, alkenyl, and alkynyl magnesium halide. In the obtained substituted tertiary alcohol the original substituent is substituted either directly or after protection of the hydroxyl function with iodine or bromine atom and by treatment with triphenylphosphine in an organic solvent medium and at elevated temperature a corresponding phosphonium salt of the above specified general formula I is obtained in high yield.

Description

Technical field

The invention relates to a process for the preparation of phosphonium salts of the general formula I:

where

R represents an alkyl group having 1 to 4 carbon atoms optionally substituted by 1 to 2 fluorine atoms or an alkoxy group having 1 to 3 carbon atoms,

R @ ¹ denotes an alkyl, alkenyl, alkynyl group containing in each case 2 to 6 carbon atoms or a cycloalkyl containing 5 to 10 carbon atoms or a cycloalkenylalkyl group having 5 to 10 carbon atoms, of which 2 to 6 carbons form an alkyl part,

R ² is hydrogen or tetrahydropyran-2-yl, trialkylsilyl, 1-ethoxyethyl, 1-methyl-lmethoxyethyl group,

X represents an iodine or bromine atom.

Said compounds of formula I are important intermediates in the synthesis of therapeutically interesting ω-chain modified prostaglandins. In particular, they are cytoprotective agents which are indicated in the prevention and treatment of oesophageal, stomach and duodenal ulcer caused by salicylate-based antipyretics and non-steroidal anti-inflammatory drugs based on arylacetic and propionic acids (Med. Res. Rev. 10,149 (1990); Chem., Rev. 93, 1533 (1993).

BACKGROUND OF THE INVENTION

To date, only one of the derivatives of formula I (R = CH ₃ , R ¹ -butyl, X = iodo) is described in the literature. The process for the preparation of this substance, as disclosed in WO 88/07537 (1988), is illustrated in the following scheme:

-1 CZ 288244

B6

1) Zn / BrCH3COOC3H5

------------- ►

2) LiAlH4

1) Ph ₃ P / CBr ₄

------->

2) NaI / acetone

PhaP

The scheme shows the difficult preparation of this compound using hazardous and toxic reagents (ethyl bromoacetate, L1AlH4), and the individual intermediates need to be purified by column chromatography.

Recently, this substance has also been reported in Bull. Korean. Chem. Soc. 14.2 (1993); viz. Chem. Abstr. 119, 49089 (1993), but the available information does not make it possible to evaluate the method of its manufacture.

SUMMARY OF THE INVENTION

The above-mentioned process for the preparation of the phosphonium salt is followed by a novel variant according to the invention, which starts from compounds of the 1-Xi-3-oxoalkanes of the general formula II:

Wherein R is as defined above and

X 1 is tosyloxy, chloro or bromo.

Halogen-containing substances (Xi = Cl, Br) are readily obtained in high yield by reacting the corresponding acyl halide with ethylene under catalysis with Lewis acid, in particular anhydrous aluminum chloride (Methoden der Organischen Chemie (Houben-Weyl), Band 5/3, p. 967, G. Thieme Verlag, Stuttgart 1962) and Band 7 / 2b, Teil II, p. 1460, G. Thieme Verlag, Stuttgart 1976). The corresponding tosyl derivatives (X1 = P-CH3C6H4SO3) are readily obtained from the corresponding 3-oxo-1-alkanols by reaction with p-toluenesulfonyl chloride (Protective Groups in Organic Synthesis, Second Edition, J. Wiley, New York, 1991; Methoden der Organischen Chemie (Houben) Weyl), Band VI / 1b, Teil III, p. 735, G. Thieme Verlag, Stuttgart 1984).

In the next reaction step, the compound of formula II is treated in an ethereal solvent environment at a temperature of -60 to -40 ° C with the corresponding alkyl (alkenyl, alkynyl) magnesium halide of formula ΠΙ:

R 1 -Mg-X ₂ wherein R ¹ is as defined above a

X ₂ represents a chlorine, bromine or iodine atom.

The ether solvent used is preferably diethyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxy or 1,2 diethoxyethane. After completion of the reaction, the reaction mixture is allowed to slowly warm to 0 ± 5 ° C and is then quenched by successive treatment with aqueous ammonium chloride or sulphate and diluted with sulfuric acid. The corresponding substituted target alcohol of formula IV is isolated from the reaction mixture:

wherein R, R ¹ and Xi are as defined above and

R ² is hydrogen.

Further, the hydroxyl function can be protected by conventional and well-known methods (Protective Groups in Organic Synthesis, Second Edition, J. Wiley, New York, 1991; Methoden der Organischen Chemie (Houben-Weyl) Band Vl / lb, Teil III, p. 735, G). Thieme Verlag, Stuttgart 1984) to readily prepare compounds of formula IV wherein R, R ¹ , X ¹ are as defined above and R ² is tetrahydropyran-2-yl, trialkylsilyl-, 1-ethoxyethyl-, 1-methyl-1. a methoxyethyl group.

Appropriate iodo derivatives are prepared by reacting compounds of formula IV wherein R, R ¹ , R ² are as defined above and X 1 is chlorine, bromine or tosyloxy with anhydrous sodium iodide in anhydrous acetone, 2-butanone (Finkelstein reaction - Methoden der Organischen Chemie (Houben-Weyl), Band 5/4, p. 595, G. Thieme Verlag, Stuttgart 1960) at the boiling point of the solvent and with vigorous stirring of the reaction mixture. For a successful reaction, it is advantageous to add a small amount (1-5%) of sodium bicarbonate or calcium carbonate to the reaction mixture. We have shown that under these conditions it is possible to use the crude product from the previous reaction. This modification greatly increases the iodo derivative yields and simplifies the process. This procedure yields iodo derivatives of formula (V):

wherein R, R ¹ and R ² are as defined above.

-3GB 288244 B6

Treatment of triphenylphosphine with iodo derivatives of formula (V) or bromo derivatives of formula (IV) wherein R, R ¹ , R ² are as defined above and X 1 represents bromine in the organic solvent at elevated temperatures of 60 to 120 ° C yields the desired phosphonin in high yield. a salt of formula (I) wherein R, R ¹ , R ² are as defined above and X represents a bromine or iodine atom. The reaction is preferably carried out in an aromatic hydrocarbon environment such as benzene and benzene, respectively. toluene or acetonitrile, dimethylformamide, or mixtures thereof. The product is isolated by conventional techniques, either by crystallization from a suitable solvent or by column chromatography. Mixtures of lower alkanols or ketones with alkyl acetates such as acetone and ethyl acetate may be used as a suitable solvent for crystallization.

The process according to the invention is simple, provides relatively high yields at the various stages of the synthesis and can be easily carried out on a technological scale.

The method according to the invention is demonstrated in several embodiments, which are only illustrative and do not limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

4-Hydroxy-2-butanone

The apparatus consisted of a three-necked flask (1000 ml), a packed column (length 75 cm, glass coils) with a heating mantle, a reflux condenser and an aqueous formaldehyde dispenser (micro pump).

522 g (15 mol, 601 ml) of acetone and 15 ml of a 10% aqueous solution of citric acid 30 were charged to the boiling flask. After heating the flask to the relfux and heating the column to 60 ° C, dosing of aqueous formaldehyde solution (240 ml of 36% solution, filtered with aqueous 10% NaOH solution to pH 10.2) was started, flow rate of 30 ml / h. After the addition (8 h), the mixture was heated to reflux for 10 min, after cooling the reflux condenser was replaced with a rectification adapter and most of the acetone was distilled off through the same column (up to 88 ° C in the digester). Then, the residue was distilled in vacuo, the acetone residue, water and the b.p. 68 ° C / 1.86 kPa began to distill the front fraction (water, diacetone alcohol, product).

1. Front fraction 68-75 ° C / 1.86 kPa 15.3 g

2. 75 to 76 ° C / 1.86 kPa 149.7 g product, yield 54%

Example 2

3-Oxobutyl-p-toluenesulfonate (Formula II where R = CH ₃ , Xi-p-CH ₃ C ₆ H ₄ SO 3)

To a mixture of 14.5 g (76 mmol) of p-toluenesulfonyl chloride, 7.3 g (100 mmol) of triethylamine, 0.1 g of dimethylaminopyridine and 80 ml of dichloromethane was added dropwise with stirring while stirring at 0 ° C, 6.7 g (76 g). mmol) of 4-hydroxy-2-butanone. The mixture was stirred at room temperature for 2 h, poured into ice water (200 mL), the aqueous layer was washed with dichloromethane (2 x 25 mL) and the combined organic solutions were washed with water (30 mL), brine (30 mL) and dried over anhydrous. magnesium sulfate. The solution was evaporated on a rotary evaporator (bath temperature 20 ° C) and the dark red residue (12.3 g; 70%) was used immediately for the next step.

-4GB 288244 B6

Example 3

3-Hydroxy-3-methylheptyl) p-toluenesulfonate (Formula IV wherein R = CH ₃ , R '= nC ₄ H ₉ , R ² = H, X 1 = p-CH ₃ C ₆ H ₄ SO ₃ )

To a solution of 7.0 g (29 mmol) of crude tosylate II (R = CH ₃ , X 1 = p-CH ₃ C ₆ H ₄ SO ₃ ) in 40 mL of 1,2-dimethoxyethane was stirred at -40 to -50 ° with stirring and cooling. 50 ml of an ethereal solution of butylmagnesium bromide prepared from 10.0 g (73 mmol) of butyl bromide and 1.75 g of magnesium were added over 30 min. After 1 h at this temperature, the reaction mixture was quenched with saturated ammonium chloride solution (10 mL), then glacial 5% sulfuric acid until acidic (pH 3), warmed to 0 ° C, and the layers separated. The aqueous layer was washed with chloroform (50 mL), the combined organic solutions were washed with water (100 mL), brine (40 mL) and dried over anhydrous magnesium sulfate. After evaporation of the solvents, chromatography of the residue (4.0 g) on a silica gel column (eluent chloroform) yielded 2.17 g (25%) of the product as a dark oil, the spectral characteristics of which were consistent with the proposed structure.

Example 4 1-Chloro-3-methyl-3-heptanol (Formula IV, R = CH ₃ , R 1 = n C ₄ H ₉ , R ² = H, X 1 = Cl)

To 44.0 g (1.81 mol) of iodine activated magnesium in a reflux condenser flask (6 L) with a dropping funnel was added 500 mL of dry ether and a mixture of 245 g (1.79 mol) of butyl bromide in 600 was gradually added. ml of ether. After the reaction subsided, the mixture was heated on a water bath to boiling for 1 hour, when almost all of the magnesium dissolved. After cooling to room temperature, 103 g (0.967 mol) of 4-chloro-2-butanone in 100 ml of ether was slowly added dropwise with stirring and external ice cooling to maintain the temperature in the flask at 15-20 ° C. The cooling bath was removed and the mixture was stirred for 1h at room temperature. Under ice-cooling, the mixture was quenched with cooled dilute sulfuric acid (70 mL to 700 mL water), the aqueous layer was washed with 2 x 200 mL ether after separation, washed with saturated sodium bicarbonate solution, brine and dried over anhydrous magnesium sulfate. After evaporation of the ether on a rotary evaporator, the residue was distilled under a water pump vacuum. The major part distills in the range of b.p. 107 DEG-112 DEG C./2.92 kPa. Since partial decomposition occurred during distillation, to remove acidity from the product, the distillate was diluted with benzene (300 mL), washed with saturated sodium bicarbonate solution, brine, and dried over anhydrous magnesium sulfate. After evaporation of the benzene, 103.2 g (65%) of the product was obtained by redistillation in an oil pump vacuum. 61-63 ° C / 40 Pa. Other boiling points observed are 57-59 ° C / 27 Pa and 81-85 ° C / 93 Pa.

Example 5 1-Iodo-3-methyl-3-heptanol (Formula V, R = CH ₃ , R 1 = n C ₄ H ₉ , R ² = H)

PROCEDURE

A mixture of 20.0 g (0.121 mol) of chloro derivative of formula IV (X = Cl, R = CH _3, R ^{1 =} nC ₄ H 9, R ² = H), 36 g of dried sodium iodide, 2.0 g of sodium bicarbonate and 300 ml of of dry acetone (potash dried, distilled and redistilled from sodium iodide) was heated to boiling with stirring. After 6 h an additional 19 g of sodium iodide was added. Total heating was 19 h. After cooling, the mixture was filtered through a frit and the solid phase washed with acetone. The acetone solution was evaporated and the residue was shaken with 300 ml of benzene and filtered through a frit, the solid phase was washed with benzene. Benzene

The solution was washed with 100 ml of 2% sodium thiosulfate solution, brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 30.0 g of a red oil which, according to gas chromatography analysis (5% OV-17 or 10% E301.370 cm, 145 ° C column and feed temperature), contained 88% product, 6% starting chloride and 6% impurities. After re-distillation of the crude residue, the product b.p. 98-101 ° C at 27 Pa (partial decomposition).

PROCEDURE

A mixture of 1.68 g (5.48 mmol) of the tosylate of formula IV (R = CH ₃ , R 1 = nC ₄ H ₉ , R ² = H, X 1 = pCH ₃ C ₆ H ₄ SO 3), 1.06 g (7.1 mmol) dry Sodium iodide and 30 ml of acetone were heated to boiling for 3 h. After cooling, the solid phase was filtered off, washed with acetone (10 ml) and the filtrate was evaporated on a rotary evaporator. The residue was suspended in dichloromethane (50 mL), filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent benzene) to obtain 0.73 g (52%) of iodo alcohol V, where R = CH ₃ , R '= nC ₄ H ₉ , R ² = H, whose physicochemical and spectral characteristics are consistent with the standard.

Example 6

3-Hydroxy- (3-methylheptyl) triphenylphosphonium iodide (Formula I where R = CH ₃ , R * = nC ₄ H ₉ , R ² = H, X = I)

PROCEDURE

A mixture of 30.0 g (0.103 mol) of crude iodide of formula V (R = CH ₃ , R ^{1 =} nC ₄ H ₉ , R ² = H), 35.1 g (0.134 mol) triphenylphosphine, 250 ml dry benzene and 2 ml dimethylformamide was heated to boiling under stirring for 20 h. After cooling, the lower oil layer was separated and diluted with a small amount of ethyl acetate. The crystals were aspirated, washed with ethyl acetate and recrystallized from ethyl acetate / acetone 3: 1. 31.2 g (55%) of phosphonium salt I, mp 128-132 ° C, were obtained. Recrystallization gave the product mp 132-136 ° C.

PROCEDURE

A mixture of 30.0 g (0.103 mol) of crude iodide V (see Procedure A), 70 g of triphenylphosphine and 250 ml of dry acetonitrile was heated under stirring to boiling for 8 h, after cooling the excess crystallized triphenylphosphine was aspirated and washed with a small amount of acetonitrile. The combined solutions were evaporated to dryness and the oily product was crystallized from ethyl acetate / acetone 3: 1. The crystalline product was aspirated and washed with a small amount of solvent. 46.7 g (82%) of the salt was obtained, m.p. Mp 133-136 ° C. An additional 4.0 g of product was isolated from the mother liquors by column chromatography (eluent ethyl acetate then ethyl acetate / acetone 2: 1), overall yield 89%.

Example 7

3-Methyl-3- (tetrahydropyran-2-yloxy) heptyl / phosphonium iodide (Formula I wherein R = CH ₃ , R ^{1 =} nC ₄ H ₉ , R ² = THP-2-yl, X = I)

A mixture of 4.04 g of the iodo derivative V (R = CH ₃ , R ^{1 =} nC ₄ H ₉ , R ² = THP-2-yl), 9.75 g of triphenylphosphine and 35 ml of acetonitrile was heated to reflux for 8 h under a nitrogen atmosphere. After cooling, the precipitated triphenylphosphine was aspirated, the organic portion was concentrated in vacuo and chromatography of the residue on a silica gel column (eluent ethyl acetate / acetone) yielded 5.3 g of an oily phosphonium salt whose spectral characteristics were consistent with the proposed structure.

-6GB 288244 B6

Example 8

3-Methyl-3- (tert-butyldimethylsilyloxy) heptyl / phosphonium iodide (Formula I where R = CH ₃ , R ^{1 =} n-C ⁴ H 9, R ² = t-Bu (CH 3) ₂ Si -, X = I)

A mixture of 4.92 g of the iodo derivative V (R = _CH3, ^{R1 =} n-C4H9, ^R2 = t-Bu (CH 3) ₂ Si-), 9.75 g of triphenylphosphine and 35 ml of acetonitrile under nitrogen atmosphere was heated to reflux After cooling, the excess triphenylphosphine was removed by suction, the solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography using ethyl acetate-acetone. From the pooled fractions containing pure product by gas chromatography analysis, 5.7 g of the phosphonium salt was obtained by evaporation of the solvent in vacuo, the spectral characteristics of which were consistent with the proposed structure.

Claims (7)

PATENT CLAIMS 1. Process for preparing phosphonium salts of formula I: OR ² where R represents a (C 1 -C 4) alkyl group optionally substituted by (1 to 2 fluorine atoms) or an (C 1 -C 3) alkoxy group, R @ ¹ denotes an alkyl, alkenyl, alkynyl group containing in each case 2 to 6 carbon atoms or a cycloalkyl of 5 to 10 carbon atoms or a cycloalkenylalkyl group of 5 to 10 carbon atoms, of which 2 to 6 carbon atoms form an alkyl part, R ² is hydrogen or tetrahydropyran-2-yl, trialkylsilyl, 4-ethoxyethyl or 1-methyl-1-methoxyethyl group, X represents an iodine or bromine atom, starting from 1-Xi-3-oxoalkanes of formula II: RC (Π) Wherein R is as defined above and Xi is a tosyloxy group or a chlorine or bromine atom, characterized in that the compound of the formula II is treated in an ethereal solvent medium at a temperature of -60 to -40 ° C corresponding to the alkyl, alkenyl, alkynyl magnesium halide of the formula III: R 1 -Mg-X ₂ (III), wherein R ¹ is as defined above a X ₂ denotes chlorine, bromine or iodine, after completion of the reaction and decomposition of the reaction mixture by sequential treatment with an aqueous solution of ammonium chloride or sulphate and dilute sulfuric acid at 0 ± 5 ° C, the corresponding substituted tertiary alcohol is isolated from the reaction mixture. optionally protecting the hydroxyl group in the form of an ether or mixed acetal to give an optionally protected derivative of the general formula IV: wherein R, R ¹ , R ² and X 1 are as defined above and which upon reaction with dry sodium iodide in anhydrous acetone or 2-butanone at boiling point of the solvent with vigorous stirring provides the corresponding iodo derivative of general formula wherein R, R ¹ and R ² have as defined above, wherein quaternization with triphenylphosphine in an organic solvent at 60 to 120 ° C affords the desired phosphonin salt of Formula I wherein R, R ¹ and R ² are as defined above, and X is an iodine atom, and to prepare the corresponding phosphonium bromide of formula I wherein X is bromine, an analogous procedure is used in which the quaternization is carried out directly using the corresponding bromo derivative of formula IV wherein R, R ¹ and R ² have the above meaning a X 1 represents a bromine atom. Process according to claim 1, characterized in that diethyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane or 1,2-diethoxyethane or a mixture thereof are used as solvents in the Grignard reaction. Method according to claim 1, characterized in that dihydropyran, ethyl vinyl ether, 1-methoxypropene in the presence of acid reacting agents or trimethyl or tertiary butyldimethylsilyl chloride in the presence of bases, preferably imidazole, are used as hydroxyl protecting agent. Process according to Claim 1, characterized in that in the quaternization reaction of the halogenated derivative with triphenylphosphine an aromatic hydrocarbon such as benzene and toluene or acetonitrile, dimethylformamide or mixtures thereof is used as solvent. Process according to claim 1, characterized in that the quartemization is carried out at an elevated temperature of 60 to 120 ° C and vigorous stirring. The process according to claim 1, characterized in that a small amount of 1 to 5% sodium bicarbonate or calcium carbonate is added to the reaction mixture according to claims 4 and 5. 7. The process of claim 1 wherein the target product of formula I is purified by crystallization by column chromatography.