CS217162B1 - Method of making the derivatives of the 3,3-difluor-4-methyl-2-oxopentylphosphorous acid - Google Patents

Description

(54) A method for producing 3,3-difluoro-4-methyl-2-oxopentylphosphoric acid derivatives

The present invention relates to a process for the preparation of 3,3-difluoro-4-methyl-2-oxopentylphosphoric acid of the formula I:

R-R ² / P-CH, -CO-CF, -C-CH, (I) / 11 2 2 i 2

RO ^from O CH ₃ where denotes

R is C 1 -C 3 alkyl,

R ¹ and R ^{2 are} hydrogen, halogen, C 1 -C 3 alkoxy, or R ¹ together with R ² form a double bond.

In the known synthetic procedures for the preparation of prostaglandin analogues, biologically active derivatives of prostanoic acid, the so-called Homer-Emmons-Wittlg reaction is often used to attach the complete ω-chain of the prostaglandin skeleton. One of the reaction components in this reaction is an appropriately substituted alkylphosphoric ester. This method has also been used in the preparation of some fluorinated analogues of prostaglandins.

The processes described in the literature for the preparation of fluoroalkyl phosphonates are based on the fluorination of a suitable starting compound, usually an organic acid or a derivative thereof, with more or less selective fluorinating agents. The disadvantage of this process is the use of difficult-to-access, usually highly aggressive, handling-intensive fluorinating agents, limiting the selection of sensitive functional groups in the starting compound and, last but not least, separation of the reaction mixtures after fluorination by chromatographic methods. These known processes are followed in a positive manner by the process according to the invention, which overcomes the disadvantages of the known processes.

The process according to the invention is characterized in that the esters of formula II,

X f ¹ _? ²

CH ₃ -COO-CH-CF ₂ -C-CH ₂ (ID

CH ₃ wherein X represents chloro, fluoro or acetoxy;

2

R and R are as defined above, acting with a solution of a mineral acid in a lower alcohol (e.g. methanol, ethanol). The acylate group is thereby converted to the aldehyde function and the resulting aldehyde of formula (III). ť 0 = CH-CF ₂ - (j -CH ₂ (III)

CH,

Where R and R are as defined above, after neutralization of the mineral acid with alkali metal hydroxide and evaporation of the solvent, it is isolated by distillation or without isolation directly oxidized in an aqueous organic solvent with chromic acid or hydrogen peroxide in the presence of selenium dioxide to the corresponding acid of formula IV;

H00C-CF ₂ (IV) wherein R and R are as defined above. The reaction mixture was basified, the organic solvents were evaporated in vacuo and the impurities were removed by extraction with an organic solvent. After acidification of the aqueous phase with mineral acid, the liberated organic acid is extracted with ether, the extract is dried and the ether is evaporated in vacuo, the major acid is purified by vacuum distillation or converted without further purification by chlorinating agents (e.g. phosphorus pentachloride, thionyl chloride) to the corresponding acyl chloride formula V,

C1OC-CF

R ¹ R ²

- ¹

CH, (V)

CH,

Wherein R and R are as defined above, which is isolated by vacuum distillation of the reaction mixture or, after distillation of excess chlorinating agent, the crude product is used directly for further processing. Aeyl chloride of formula V dissolved in ether or tetrahydrofuran is acylated at low temperatures with an alkali metal dialkyl methylphosphonate salt of formula; VI, (RO) ₂ P (O) CH ₂ Me (VI) wherein Me represents lithium or sodium and R is as defined above, prepared in situ from a dialkylmethylphosphonate by the action of a strong base (e.g. n-butyllithium). After acidification of the reaction mixture with acetic acid and evaporation of the solvents, the desired product of formula (I) is isolated by extraction with an organic solvent, evaporation of the solvent under vacuum and possible vacuum distillation of the residue.

The advantage of the production method according to the invention is that it utilizes readily available fluorinated starting compounds from domestic raw materials (I. Veselý, candidate dissertation, ICT, 1977), thereby circumventing the need for special fluorinating agents and all reaction steps are so unambiguous that distillation can be used for most of the intermediates and end products in sufficient purity.

The invention is explained in more detail in the following examples of a specific embodiment.

Example 1

To a solution of (3,4-dibromo-1-chloro-2,2-difluoro-3-methylbutyl) acetate of formula II wherein r '= R ² = Br, X = Cl, in an amount (1.78 g) in 5 ml methanol, 0.3 ml conc. sulfuric acid and the mixture was left at room temperature for 3 days. After neutralization of the acid with a methanolic solution of 10% potassium hydroxide, the methanol was evaporated in vacuo and the residue was distilled to give 1.12 g of 3,4-dibromo-2,2-difluoro-3-methylbutenal of formula III wherein R ¹ = R ² = Br m.p. = 75-78 ° C / 25 mm Hg.

Example 2

To a solution of 2,2-difluoro-3-methyl-3-butenal of the formula III, wherein R ¹ from the axis R together form a double bond in an amount of 12 g tert. 20 g of butylalcohol, 0.5 g of selenium dioxide was added and an aqueous solution of 30% hydrogen peroxide (11 ml total) was added dropwise over 5 minutes with stirring so that the temperature did not exceed 40 ° C. The mixture was stirred at room temperature for 22 hours, then basified with 15 ml of 30% sodium hydroxide solution and the solvent was evaporated in vacuo. The residue was dissolved in water and extracted with ether, 2 x 10 mL. The aqueous phase was acidified with 25% sulfuric acid to pH = 2 and extracted with ether 12x 40 ml. After drying the combined ether extracts with magnesium sulfate and evaporating the ether under vacuum, 10.3 g of 2,2-difluoro-3-methyl-12 were obtained by distillation of the residual oil.

-3-butene of the general formula IV, in which R together with R forms a double bond, m.p. = 73-79 ° C / 101.3 kPa.

Example 3

2

To a solution of butenal of formula III, where R = R = CH 2 O-, at 14.5 g in acetone (100 mL), was added a solution of chromium trioxide (8.8 g) in 15% sulfuric acid (110 mL). The mixture was heated to boiling for 1 hour. The excess oxidizing agent was reduced with sodium sulfite. After neutralization of the mixture with 40% sodium hydroxide solution, the chromium salts were precipitated by addition of saturated bicarbonate solution, the precipitate was filtered off with suction, and the filtrate was acidified with cono. sulfuric acid to pH = 2 and the organic acid was extracted with ether.

The combined ether portions were dried over magnesium sulphate and the solvent was evaporated to give an acid of formula IV wherein R and R are CH 2 O-, by distillation of the residual oil (7.8 g, t = 144-150 ° C / 2), 90 kPa.

Example 4

To 75 g of phosphorus pentachloride was added, under ice-cooling, the acid of formula IV, in which R together with R forms a double bond, over 30 minutes. The reaction mixture was then left at room temperature for 20 hours, and the reaction products were distilled off from excess reagent at 78-105 ° C / 101.3 kPa. 22.5 g of 2,2-difluoro-3-methyl-3-butenoyl chloride of the general formula V in which R @ ¹ and R @ 2 form a double bond were isolated after rectification on a packing column, m.p. = 84 DEG-89 DEG C./101 , 3 kPa.

Example

A solution of dimethylmethylphosphonate of formula VI, wherein R = methyl, 18.7 g in 180 ml of dry tetrahydrofuran, was cooled to -75 ° C under nitrogen, and n-butyllithium (100 ml, 1.6 molar) was added dropwise with stirring. solution in hexane) such that the temperature does not exceed -60 ° C. The mixture was stirred at -75 ° C for 15 minutes, and then a solution of the chloride of formula V wherein R together with R formed a double bond of 7 g in dry tetrahydrofuran (30 mL) was added dropwise such that the temperature did not exceed -60 ° C. Then the mixture was stirred at -75 ° C for 2 hours and at room temperature for 16 hours. After acidifying the mixture with glacial acetic acid (9.5 ml), the solvent was distilled off in vacuo, the residue was extracted with 200 ml of ether, the extract was washed with sodium bicarbonate solution, dried with magnesium sulfate and distilled off the residual oil

217162 4 yielded 5.13 g of a phosphonate of the formula I, wherein R = methyl, r 'together with R ² form a double bond, v = 98 to 06 ° C / 0.31 kPa.

Example6

To a solution of diethyl methyl phosphonate VI, where R = ethyl, 19.3 g in 200 mL dry ether, n-butyllithium (100 mL, 1.6 molar solution in hexane) was added dropwise with stirring at -75 ° C. so that the temperature does not exceed -60 ° C. The mixture was stirred for 15 minutes at -75 ° C and then a solution of chloride of formula V wherein r 1 = R ² = CH 2 O- was added in an amount of 7.5 g dissolved in dry ether (35 mL). The temperature was maintained at -75 ° C for 2 hours and then the mixture was stirred at room temperature for 10 hours. After processing the mixture reakění analogously příkidu 5, the distillation of the crude product afforded 4.92 g of the phosphonate of formula I wherein R = ethyl, R 'and R ² = CH-O-, TV = 160-170 ° ^C / 0.29 kPa.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of 3,3-difluoro-4-methyl-2-oxopentylphosphoric acid derivatives of the general formula I, R-O. RO 1 -CH ₂ -CO-CF where denotes II _2- c -ch ₂ Oh ₃ (I) R is C 1 -C 3 alkyl, 12 12 R and R is hydrogen, halogen, alkoxy of 1-3 carbon atoms, or R together with R forms a double bond, wherein the solvolyzed esters of formula II, ^{R 1 '2',} CH ₃ -COO-CH-CF ₂ -C-CH ₂ (II) _OCH3 wherein X represents chloro, fluoro, or an acetoxy group and 1 2 R and R are as defined above, the formed aldehyde of formula III, O = CH-CF, -C-NH, CH, where R and R are as defined above, is oxidized to the corresponding acid of formula IV, (III) HOOC-CF 3 -O-CH ₂ (IV) Where R and R are as defined above, the resulting acid is converted by chlorination to the acyl chloride of formula V, _H 1 r ² V V Cl-OC-CF ₂ - < -CH ₂ CH ₃ wherein R ¹ and R ² are as defined above, (V) acylating an alkali metal dialkyl methylphosphonate salt of formula VI, (ROgPiOCHgMe (VI) wherein Me denotes lithium or sodium and R is as defined above) .