CS255124B1 - Process for refining dimethyl (2-oxoheptyl) phosphonate - Google Patents

Abstract

k'n3v\ XP CH., C CHO CH0 CH, CH, CH, (I) /1 2 11 2 2 2 2 3 CH3O o o CH3°\ ?H3 'PCHCCHCH CH CH CH (II) /11 11 CH3O O O The refining of dimethyl (2-oxoheptyl)phosphonate is carried out by converting the phosphonate of formula I, after previous dilution with an inert solvent, by the action of a strong base into a metallic salt, which, after filtering off or centrifuging the mother liquor, is washed with the solvent used for the metalation. The salt is decomposed back) with 1.1 to 1.5 equivalents of aqueous acetic acid, diluted in a ratio of 1:4. The liberated phosphonate of formula I is extracted into an organic solvent, the acidic reaction of the extract being removed by washing with a saturated sodium bicarbonate solution. The organic phase is dried with a desiccant, the solvent used is removed by evaporation under vacuum and the remaining oil is distilled under reduced pressure. Thus, the content of impurity II is reduced by more than 80% compared to the starting product.

Description

The invention relates to a method of refining dimethyl (2-oxoheptyl) phosphonate of formula I ^CH 3 ° \

CH, CH, CH, CH, CH, CH, (I), / 11 ² II ^{2 2 2 2 3}

CH 3 OO which is an important intermediate for the production of A, B, E, F and I prostaglandins and some of their analogs (see, e.g., PL Caton, TW Hart: Synthesis of Classical Prostaglandins, Adv. Prost. Thromb. Leuk. Res. 14, 73/1985).

These natural substances and their synthetic derivatives are characterized by a wide range of biological effects and some of them are used as medicaments in human and veterinary medical practice. The main areas of application include, among others, the treatment of certain diseases of the blood circulation, gastrointestinal tract and reproductive system.

Typically, the necessary phosphonate of formula I is obtained by acylating the lithium methyl methyl phosphonate of formula III with chloride or methyl ester of caproic acid of formula IV as described in the literature (see EJ Corey, GT Kwiatkowski: J. Amer. Chem. Soc. 8_8, 5654/1966) according to reaction (1) (III) (IV) ^CH 3 °>

^CH 3 °

P CH, CH, CH, CH, CH, CH, + II ² || ^{2 2 2 2 3}

O 0 (I) (1) where Z stands for Cl or CH 2 O (II)

However, the crude reaction product is contaminated to a greater or lesser extent with a methylated derivative of formula (II) whose structure has been demonstrated by its mass spectrum analysis, depending on the reaction conditions maintained. The amount of impurity II found by capillary gas chromatographic analysis is in the range of 2 to 10 wt. The commercial product of Janssen contained about 6 wt. %. Due to the physicochemical similarity of the two substances, the removal of the impurity of formula II from the crude reaction product by conventional separation processes is very difficult and therefore uneconomical.

Removal of the undesirable admixture of formula II from the crude phosphonate of formula I solves the process of its refining according to the invention. The principle of this process consists in the preferential metallation of the alpha-methylene group of the phosphonate of formula I over an analogous reaction on the methine group of the phosphonate of formula II under strong bases, isolation of the resulting crystalline salt and its decomposition to the original phosphonate of formula I. of the formula I, containing the methylphosphonate of the formula II in an amount expressed as mole fraction x, is mixed in a weight ratio of 1: 8 to 1:10 with an inert solvent such as an aliphatic or aromatic hydrocarbon, preferably n-hexane, toluene or mixtures thereof.

The resulting mixture was cooled with vigorous stirring and slowly added to (1-x) base reagent equivalent (k = 0.85 to 0.95) to maintain the temperature in the above range. As a basic agent, a 1.0 to 2.5 M solution of n-butyllithium in hexane or a 1.4 to 1.8 M target solution can be used. potassium butylate in tetrahydrofuran. The temperature of the reaction mixture is allowed to reach room temperature, the crystalline salt is separated by filtration under vacuum or by centrifugation (particularly suitable for the potassium salt), washed with a small amount of the solvent preferably used as in the actual reaction. is decomposed with 1.1 to 1.5 equivalents of dilute aqueous acetic acid (1: 4).

The oily fraction is extracted into an organic solvent, preferably 1,2-dichloroethane, the extract is washed with a saturated sodium bicarbonate solution until the acidic reaction of the solution is removed and dried with a suitable desiccant, for example, calcined magnesium sulfate. After filtering off the desiccant and evaporating the solvent under vacuum, the residual oil is distilled under reduced pressure.

Thus, approximately 70 to 80% of the theoretical amount of the phosphonate of formula I is obtained, i.e. = 116 to 120 ° C / 86 Pa, identical to the authentic sample. The impurity II is reduced by more than 80% compared to the starting product.

The invention and its effects are illustrated in more detail by the following examples, which are illustrative only and in no way limit the scope of the invention.

Example 1 g of dimethyl (2-oxoheptyl) phosphonate of formula I contaminated with 9 mol. Ϊ methylphosphonate of formula II was stirred with 332 ml of n-hexane, cooled under nitrogen with vigorous stirring to -70 ° C and gradually added dropwise with 51 ml of a 2.5 M solution of n-butyllithium in n-hexane so that the temperature did not exceed -70 ° C . The cooling bath was then removed, the mixture slowly warmed to room temperature, and the crystalline precipitate was filtered off under vacuum. After washing with 100 mL hexane, it was transferred to a flask, poured over 200 mL 1,2-dichloroethane, and 10 mL acetic acid diluted with 40 mL water was added to the mixture. The aqueous phase was separated, the organic layer was washed with 50 mL of saturated sodium bicarbonate solution and dried over magnesium sulfate. After filtering off the desiccant and evaporating the solvent on a rotary evaporator, the residual oil was distilled under reduced pressure. 21.9 g of a phosphonate of the formula I were obtained, m.p. = 116-120 ° C / 86 Pa, containing 0.7 wt. % of the contaminant of formula II.

Example 2

25.8 phosphonate of formula I contaminated with 10 mol. of the methyl phosphonate of formula II was dissolved in 200 ml of toluene under nitrogen and cooled to 0 ° C. 66 ml was slowly added dropwise to the solution

Of 1.5 M target solution. potassium butylate in tetrahydrofuran such that the temperature does not exceed 0 ° C. The mixture was warmed to room temperature and the gelled salt was centrifuged from the mother liquor, washed with 100 mL n-hexane, poured over 150 mL chloroform and quenched by the addition of 7.5 mL acetic acid diluted with 30 mL water. The mixture was shaken, the aqueous phase separated, the organic layer was washed with 35 mL of saturated sodium bicarbonate solution and dried over sodium sulfate.

After filtering off the desiccant and evaporating the solvent under vacuum on a rotary evaporator, the residual oil was distilled under reduced pressure. 18.8 g of a phosphonate of formula I containing 1.7 wt. % of the methylphosphonate of formula II.

Claims (5)

1. Process for refining dimethyl (2-oxoheptyl)phosphonate of formula I CH,0 From ¹ ch ₃ 0 o CH~ C CH ₉ il o CH _n CH _n ^CH 2 ^CH 3 (I) contaminated with an admixture of 2 to 10 wt. % dimethyl (1-methyl-2-oxoheptyl)phosphonate of formula II CH.,0 CH3 \ | 3 ^X P CH C CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ (II), ZII l| CH ₃ O oo characterized in that the phosphonate of formula I is converted, after prior dilution with an inert solvent, by the action of a strong base into a metallic salt, which, after filtering or centrifuging the mother liquor, is washed with the solvent used for metalation, the salt is decomposed again with 1.1 to 1.5 equivalents of aqueous acetic acid diluted in a ratio of 1:4, the liberated phosphonate of formula X is extracted into an organic solvent, the acidic reaction being removed by washing with a saturated sodium bicarbonate solution, the organic phase is dried with a desiccant, the solvent used is removed by evaporation under vacuum and the remaining oil is distilled under reduced pressure. 2. The method according to item 1, characterized in that the metallation is carried out at temperatures of 0 to -80 °C. 3. The method according to item 1, characterized in that n-butyllithium or potassium tertiary butylate is used as the base in an equivalent amount of k.(1-x), where k = 0.85 to 0.95 and x = molar fraction of the compound of formula II in the starting material. 4. The method according to item 1, characterized in that an aliphatic or aromatic hydrocarbon, or a mixture thereof, e.g. n-hexane, toluene and a phosphonate of formula I, which is mixed with the solvent in a weight ratio of 1:8 to 1:10, is used as an inert solvent for the reaction. 5. The method according to item 1, characterized in that 1,2-dichloroethane, chloroform or ethyl acetate is used as the organic solvent for the extraction of the phosphonate of formula I.