NL7905313A - PROCESS FOR PREPARING SALTS OF (-) - CIS-1,2-EPOXY-PROPYLPHOSPHONIC ACID. - Google Patents

Description

- 1 - I - »Y.o. T959 _____; ___________________ · _______ ___________

Clesa S.p.A.

Vicenza

Italy

Process for preparing salts of (-) - cis-1,2-epoxypropylphosphonic acid

The invention relates to a new method. to prepare salts of (-) - cis-1,2-epoxypropylphosphonic acid, a broad spectrum antibiotic. In particular, the invention relates to a process for preparing salts of (-) - cis-1,2 - epoxypropylphosphonic acid having: formula 1 of the formula sheet and of a non-toxic base starting from cis-1 -propenylphosphonic acid of formula 2. and of L - (+) - threo-1 - (p-methyl mercaptophenyl) -2-amino-1,3-propanediol (hereinafter referred to as tbiomicaoin) as an acid splitting agent of formula 1.

The (-) - acid of formula 1 and bun salts with a non-toxic base are widely used both in the. human and animal medicine · om. inhibit the growth of both Gram-positive and Gram-negative pathogenic bacteria.

The preparation of the racemic epoxy acid of formula 1 is known from the literature. It is also known to cleave the racemic epoxy acid into their optically active isomers.

The cleavage agent most commonly used in the literature is (+) - α-phenethylamine.

Surprisingly, it has now been found that thicraicamine can also be used as a cleaving agent for the racemic epoxy acid of the formula I, whereby directly (-) - cis-1,2-epoxypropyl-phosphonic acid is obtained.

Furthermore, the process according to the invention makes it possible to recover almost all thiamieamine used (more than 93%).

According to the invention, the cis-1-propenylphosphonic acid of the formula 2 is oxidized to the racemic epoxy acid of the formula 1 using hydrogen peroxide in the presence of sodium tungsten dihydrate. After the excess hydrogen peroxide has completely decomposed, thiomicamine is added. The resulting slurry is made alkaline with 11QH to give a solution of. the sodium salt of (-) - cis-1,2-epoxypropylphosphonic acid, which is then converted to the salt of the 7905313 - 2 - * -S --- ^ -; ------- by an appropriate treatment. desired base.

The oxidation of the cis-1-propenylphosphonic acid to the corresponding racemic epoxy acid is carried out in known manner with hydrogen peroxide. as an oxidizing agent and in the presence of sodium tungstate dihydrate. After the oxidation. is complete, the excess hydrogen peroxide in the reaction mixture must be completely decomposed before the thiomicamine is added, otherwise it would be. are oxidized.

.10 Afterwards, of the. oxidation, the reaction mixture is treated with hydrazine hydrate; and a. catalytic amount reduced: copper at 45-60 ° C. The hydrogen peroxide then decomposes quickly.

The addition of thiomicamine to the reaction mixture, which is racemic. epoxy acid of formula I, is carried out gradually. while maintaining the pH at 5-6 by adding acid.

The invention is illustrated by the following examples Example Γ

Preparation of the calcium salt of (-) - cis-1,2-epaxypropylphosphonic acid monohydrate.

600 g (1 +, 91 mol) of cis-1-propenylphosphonic acid are dissolved in 3500 ml of water and the pH is adjusted to 5.9 with 30% sodium hydroxide solution. A solution of. 11.2 g of sodium tungstate dihydrate, U, 8 g of disodium edetate and 53 ml of water are added to the solution thus obtained with stirring at room temperature.

The solution thus obtained is heated to 1 + 5-50 ° C and then 620 g (7.3 mol) 1 + 0 # rs hydrogen peroxide solution is added slowly and with stirring. After everything has been added, the solution is left for an hour and a half at this temperature. '

Then 3.2 g (0.06 U mol) of hydrazine hydrate and 0.32 g of reduced copper are added to the solution.

The solution liberated from oxidizing agent is cooled to 20 ° C, decolorized, filtered and treated with 10h-5 g (h-, 91 mol) L - (+) - threo-1 - (p-methyl mercaptophenyl) -2-amino— 1,3-propanediol (thiomicamine) at room temperature and with stirring, while concentrated HCl is added simultaneously to maintain the pH between 5 and 6.

The thiomicamine is added gradually and each time a small amount of hydrochloric acid is added to the pH of the mixture. 5 and 6. After everything is added, the pH is 598.

The whole is allowed to stand under stirring for 1 hour at room temperature, then it is cooled to 0 ° C. After 2 hours, the precipitate formed is filtered off and washed with water. 265 g of thiomicamine are recovered from the mother liquor by making the solution alkaline. The precipitate obtained, which consists of the thicmicamine salt of (-) - cis-1,2-epozypropylphosphonic acid, is crystallized from isopropanol and suspended in 2700 ml of water. The mixture is stirred at room temperature and made alkaline with 10% NaOH solution.

1 hour later. the thiomicamine still present is filtered off with stirring. The dried thiomicamine weighs 570 g.

The corresponding calcium V is obtained from the aqueous solution which contains the sodium salt of (-) - cis-1,2-epoxypropylphosphonic acid. salt in the. shape of. the monohydrate precipitated by adding 760 g (3, 7 mol) solution of calcium chloride hexahydrate in J60 ml of water. The calcium salt formed is filtered off, washed with water and dried. Yield 250 g.

[α] ° °--6 ° (0.3 * H 2 O); [α] 25D -18 ° (0.3 * HgO).

Distillation of the isopropanol, which is still present in the mother liquors, followed by alkalizing the residue, yields 1 µl of thiomicamine.

Example II

Preparation of the calcium salt of (+} - cis-1,2-epozypropylphosphonic acid-2 monohydrate.

Proceed as in Example 1, but replace the L - (-) - threo-1- (p-methylmercaptophenyl) -2-amino-1,3-propanediol with the corresponding L - (+) compound and then obtain 2 ^ 5 g (+) - cis-1,2-epoxypropyl calcium phosphonate monohydrate.

30 [α] D 25 = + 6 ° (0.3 * HgO); [a] ^ = + 18 ° (0.3 * HgO)

Example III

Preparation of the disodium salt of (-) - cis-1,2-epozypropylphosphonic acid.

Proceed as in Example 1 until the aqueous solution containing the sodium salt of (-) - cis-1,2-epoxy-propyiphosphonic acid is obtained.

The pH of this solution is adjusted to 8.8 with acetic acid.

790 53 13

"V

* -, -. - - k -. - '

The whole is then evaporated to dryness in vacuo, whereby a syrup is obtained, from which the disodium salt of (-) - cis-1,2-epoxypropylphosphonic acid crystallizes by treatment with ethanol.

Yield 285 g of 5 [α] 25 ° -5 ° (5% 20); [a] | g5. = -17 ° (5% HgO).

7. * \ i 790 53 13

Claims (1)

-5.- * * -¾ COFFCHTSTB Process for preparing salts of (-) - cis-1,2-epoxypropylphosphonic acid with non-toxic "bases", oxidizing men-1-propenylphosphonic acid to the corresponding racemic epoxy acid, an optical splitting agent, alkalizes the resulting suspension of the salt of (-) - cis-1,2-epoxypropylphosphonic acid with the splitting agent, converts the sodium salt in the resulting solution to the salt of a desired other if desired base, characterized in that the optical splitting agent used is L - (+) - threo-1- (p-methyl mercaptophenyl) -2-am.no-1,3-propanediol. 7905313 r .1 'r. * 0 t / 0H CH3-CH - CH - V 2 ° h CH, -CH = CH-P, 0 CLESA S.p.A. 7905313