SU289597A1 - A METHOD FOR SEPARATION OF A RACEMICAL MIXTURE (CIS-1,2- - Google Patents

Description

This invention relates to a process for the separation of racemic mixtures into enantiomers, namely, the separation into enantiomers of compounds (± (, 2-eloxypronyl) -phosphonic (-THEOPHOSPHONE) acids or their salts of the general formula / H 7 CH, -CH-CH-PY where X- oxygen, sulfur; Y and Z-OH, alkali metal or alkaline earth metal cation, substituted ammonium. (-) (Cys-1,2-epoxypropyl) - phosphonic acid or its salts, in contrast to (+) (cis1, 2-epoxypropyl -phosphonic acid, or its salts, are useful antimicrobial agents that inhibit the growth of both gram-positive and gram-negative pathogenic bacteria. This makes it possible to use (-) (, 2-epoxypropyl) -phosphonic acid or its salts as antiseptics to remove microorganisms from pharmaceutical, dental and other medical equipment. These compounds effectively inhibit the reproduction of unwanted bacteria in the water used in paper and paint and varnish production. (±) (1 {EC-1,2-EPOXYPROPIL) - PHOSPHONIC (-TIO phosphonic) acids or their salts a la enantiomers are based on a known method, which consists in the fact that EMAT are optically active reagent. The diastereomers thus formed are separated, and then each of them is converted into enantiomers of the substance to be cleaved. The proposed method of separating a racemic mixture into enantiomers allows the isolation of (±) {cis-1,2epoxypropyl) -phosphonic acid or its (-) (1 (is-1,2-epoxypropyl) -phosphonic acid salts or its salts from a racemic mixture, which are valuable antibiotics. This method consists in the fact that the derivatives of (±) (, 2-epoxypropyl) -phosphonic (-THEIOPHOSPHONE) acids of the general formula / H / CH, -CH-CH-R-Y where X is oxygen or sulfur; Y is halogen, SR, OR or NRR,; Z-OR, SR or NRR, OH, halo, SR, OR or NRRi, where R is a substituted or unsubstituted hydrocarbon radical (alkyl, alkenyl l, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aralkyl, heterocyclic group); R and R are hydrogen, are reacted with optically active compounds and the resulting diastereomers are separated by fractional crystallization followed by conversion of each diastereomer to (+) or ( -) (g ("c-1,2-epoxypropyl) -phosphonic (-thiophosphonic) acid or their salt and the selection of the target product by known methods. Diastereomers of derivatives (±) (cis-, 2EPOXIPROPIL) -PHOSPHONE (-THYPHOSPHONE)

acids of the above formula contain an optically active substituent or substituents that can be obtained from onnically active alcohols, such as (+) - or (-) - o, -phenethyl alcohol, L-2,2-dimethyl-5-oxy-6-phenyl- 1, 3-dioxane, (-) quinine, (-) morphine, methyl (-) - lactate, (-) 2-butanol, (-) menthol, dimethyl (-) - oxysuccinate, (+) (2.5- octamethylene-1,8-dioxy) -benzyl alcohol, (-) 4- (p-oxyethnlidene) -methylcyclohexane, etc.

These esters can be prepared, for example, by reacting an amip (cis-, 2epoxypropyl) -phosphonic acid salt with an alcohol in the presence of a suitable dehydrating agent such as S, K-dicyclohexylcarbodiimide or M, M-dimethylcarbodiimide. The resulting mixture of diastereomers can then be separated from the reaction mixture and the individual diastereomers obtained by crystallization, chromatography, ion exchange resins or by means of inclusion compounds.

The following are examples of diastereomers having optically active amides.

Dnamidy; NN-6uc- (+) -cc-phenethyl - (cis1, 2-enoxypropyl) -phosphoric and N, N-6wc- (+) - a-phenethyl - ((ggc-1,2-epoxypropyl) - thio-phosphonic acid ; Amides: O-benzyl-N (+) -phenethyl- (1 {is-1,2-epoxypronyl) - phosphonic 5-.methyl-N- (+) -phenethyl- (g {y-1,2-epoxycronyl ) -dithiophosphonate M-methyl-M- (+) -a-phenethyl-5-ethyl- (cis-1,2 - epoxypropyl) thiophosphonic acid, etc.

Diastereomers can also be optically active salts of compounds of the general formula

xx

-CH-CH-P-Y

sn,

where X is oxygen or sulfur;

Y-OR2, SR2 or NRaRi;

Z is ORs, SRs or NRsRi, where R is a hydrocarbon group, comprising an acid function capable of salt formation with bases, Rs is hydrogen, R2 or any hydrocarbyl group and Ri is hydrogen or a hydrocarbon radical.

The acid function of R2 can be an acidic group or function capable of salt formation with bases.

especially with optically active bases. Examples of such acidic functions are carboxy group, sulfonic, sulfinic, phosphonic acid, substituted phosphonic acid and the like. Examples of substances having an acid function can be 0, O-carboxes methyl- (g; ms-1,2-epoxypronyl) phosphonate; O- / g-sulfophenyl, hydrogen (cis-, 2-epoxypronyl) -phosphonate, bis- (2-sulfoethyl) - ({sy-1,2 - epoxypropyl) - phosphonate, benzyl-2,2 - dicarboxyethyl- (g {ys-1,2 - epoxypropyl) phosphonate or their salts. Thus, these compounds CAN react with optically active bases to form the corresponding diastereomers, which can then be separated, by crystallization, but from fractions of suitable solvents, such as lower alkanols or mixtures of such alcohols with other solvents, for example water .

The bases used can be bases containing nitrogen or their acid salts, such as (-) quinine, (-) brucine, (-) -) cc-phenethylamine, (-) a-phenethylamine; L- (+)

lysine, L - (-) tyrosine hydrazide, (+) cobalt gris- (ethylenediamine) -triodide, (-) menthylamine, L- (+) argnnin, (2,2) -2-aminoparacyclophane (+). methyl-methylphenylbenzylammonium bromide, (- a) methylallylphenylbenzylammonium bromide, 2,5- (octamethylene-1,8-dioxy) annlin, p-chloro-2,4,6-trimethyl-5-bromo-1 {y-qi-11amoylhydrazide, (-) 4- (p-aminoethylidene) -methylcyclohexag, 3-amino- / g-phenylene-1-decanone, (-) -6,6-dimethyl-2,2-biphenyldiamine, L-2,2-dimethyl-5-amino-6-fenn1, 3-dioxane, 1-yentilgidrazn, (-) strichnn, (4-) quinidine, (-) morphine, (-b) konyin, (-) konyin, (-) co.kain, or other bases such as (-f) "- beef 1Chlyl-2-naphthylfsnilphosphine, (-) pbnphenylyl-a-naphthylphenylphosphine, (+) 2-phenyl-2- / g-hydroxyphenyl-1, 2,3,4 - tetrahydroisophosphonnolium bromide, (-I) methyl ethyl phenyl befluorophosphate. Methylphenylphenyl (-) Methylphenylsulfoxide.

Such acid esters, thioesters and amides can be obtained from (cs-1,2-epoxypropyl) -phosphonic acid anhydrides by reacting with strong acids: halide hydrogen; sulfuric, sulfinic, sulfonic, phosphonic, phosphoric, phosphine; Noligarboxylic or other substituted acids with electrophobic or electronegative atoms or groups (halogen, sulfo, sulfonyl, sulfinyl, nitro, carbonyl), reactions with alcohols, thiosprites or amines.

New acid can be obtained by using dehydrating agents such as carbon carbamides or strong acid anhydrides (sulfur trioxide, phosphorus pentoxide, trifluoroacetic anhydride).

Esters can be derived from metal gols (gshs-1,2-epoxypropyl) -phosphonic acid; salts of alkaline, alkaline earth and transition metals and esters of strong acids.

Derivatives of a substituted acid can be obtained from (nis-1,2-epoxpropyl) -phosphoic acid or alkaline salts thereof by condensation with alcohols, thiospirits or amines, which also carry an acid group or a group that easily converts to acid. Dehydration agents, such as carbodiimides, strong acid anhydrides (sulfur trioxide, phosphorus pentoxide, trifluoroacetic anhydride) and others, esterification reaction catalysts or catalysts needed for the formation of amides, were previously known and used in this method.

Diastereomeric esters or amides of (1 {y-1,2-epoxypropyl) -phosphonic acid, where the ester or amide has an acid function, either free, or in the form of a salt, can be transformed into the desired derivatives (h "c- 1,2-epoxypronyl) -phosphonic acid, such as salts, by hydrolysis with water, with solutions of caustic soda, pl acid, when irradiated with various types of light or when treated with metal catalysts in a hydrogen atmosphere.

In addition, the derivatives of diastereomers of (1 ("c-1,2-epoxypropyl) phosphonic acid, which are separated, are compounds of the optically active salts of the formula

/ H /

CH, -CH-CH-P-Y

Z

where X is oxygen or sulfur; YOR, SR ,, NR; R ,;

ZORs; SR or NRR, where R is a group comprising a main function capable of forming salts with optically active acids; Rs is hydrogen, RJ and Ri are hydrogen or a hydrocarbon group.

Examples of compounds having the main function are bms-2-alpioethyl - (. 2 eioxypropyl) -phosphonate, 3-aminopropylbenzyl- (chys-1,2-eioxypropyl) -phosphonate, amide N, N-6wc - (2-aminoethyl) - (cg / s - 1,2-epoxypropyl) -phosphonic acid; 0, O-bns- (4-aminobenzyl) - (, 2-epoxypropyl) - phosphonate and dithioether 5,5-bg g- (4-a.Iiophenyl) - (, 2epoxypropyl) -phosphonic acid. Thus, these basic n-derivatives can react with an optically active acid, forming diastereomer salts, which can be separated by crystallization in fractions from suitable solvents, such as lower alkanols, especially methanol, ethanol, propanol, isopropanol, a mixture of water and these alcohols or mixtures with other solvents and solvents. You can use such optically active U Slots as Wynna, Gluconov, Mannon, Milk, Block, Clutamine, Almond, Sugar, Trioxyglutar, Gulop, Alanine, Series, Valine, etc.

Racemic (is-1,2-epoxypropyl) -phosphonic acid and its salts can be obtained by hydrogenation of 1-propynylphosphonic acid, and then by epoxidizing the obtained (g {g c-propenyl) -phosphoric acid.

The sodium proppropylphosphonic acid salt (1.2 g, 0.1 molar) was dissolved in 30 ml of water containing 1.67 ml of iurea, 83 g of zinc aietate and 0.3 g of Rene nickel, and the mixture was hydrogeiized. One equivalent of hydrogen

absorbed within 1 hour.

The catalyst was removed, the filtrate was sprinkled through a column containing 10 g of Dayekc-50 resin in the form of H +, and the column was limped with water. The eluates are neutralized to pH 5.5 with sodium hydroxide and

after removal of water in vacuo, the monoaturated salt of g {g / s-propenephosphonic acid is obtained

acids in the VID2 amorphous residue.

0.50 g (0.041 of this acid g is dissolved in 0.5 ml of water and the solution is neutralized to a pH of 5.5, carefully added am.mon monohydrate. Add the sodium salt of tungsten: oic acid (10 mg, 0.00034 mol) and the mixture is heated to 55 ° C in a water bath.

hydrogen (0.5 l / l) is added and heating is continued for 1 -1.5 hours. The reakinium mixture was cooled to bathing temperature and the solvent was removed. The residue is dissolved in 50 l / l of methanol, and the insoluble non-organic part is filtered off. After the solution is co-centrated, the crystalline ammonium salt of the racemic (g / s-1,2-epoxypropyl) phosphoric acid is obtained. The ammonium salt obtained in such a way

can be converted to other salts.

The ammonium salt is converted to racemic dichlorohydrin (g / s-1,2-epoxypropnl) -phosphonic acid in the following way.

To a mixture of 1.88 g (0.01 mol) of the ammonium salt of racemic (g {g / s-1,2-epoxpropl) phosphonic acid, 20 l / l of benzene and 1.6 ml of pnridium at 0 ° C are added to for 10 min with a displacement of 3.0 g (0.025 mol of thionyl chloride. After stirring at room temperature for 3 hours, the solution is decanted and then concentrated in vacuo at room temperature. The residue is distilled into a flask. Racemic dichlorohydride (; {g / s-1 , 2-enoxyronyl) -phosphonic acid is distilled at 33 ° C / 0.5. M Hg.

Example 1. Racemic monobenzylammonium- (, 2-epoxypropyl) -phosphonate (24.5 g 0.1 mol) is dissolved in 125 l of methanol at

acid polystyrene ion exchange resin B form H + at a speed of 20 ml / min.

The effluent is dripped into 200 ml of pyridine and then washed out with another 500 ml of cold mztaiol.

The resulting solution is concentrated in vacuo to a volume of 100 ml. To this solution are added 100 ml of anhydrous pyridine, then 200 ml of anhydrous toluene, in which (H, M-dicyclohexylcarbodin-imide (20.6 g, 0.1 mol) and (-) menthol 15.6 g, 0.1 mole). The resulting solution is placed at room temperature for 6 hours. The crystallized NN-dicyclohexyl urea is filtered off, washed with 100 ml of toluene, and the mother liquor collected, concentrated in vacuo to dryness at a maximum temperature of 40 ° C. Anhydrous toluene (300.il) is added to the residue and then the solution is again concentrated to dryness under vacuum at a maximum temperature of 40 ° C. 1 l of non-trace ether is added dropwise to a highly unbalanced oily liquid and stirred for about 1 hour. After 1 hour, a solid hydroscopic precipitate is formed, which is filtered off and quickly transferred to a vacuum desiccator, where it is dried at 1-5 mm Hg. Art. to constant weight. Monopyridinium mono (-) - menthyl (-) (, 2-enoxipropyl) -phosphonate melts at 145-175 ° C with decomposition.

Example 2. Monopyridinium mono - (-) menthyl (-) (cis-1,2-epoxypropyl) - phosphonate (27.6 g, 0.1 mol) is dissolved in 100 ml of water containing trimethylammonium bicarbonate

(38.6 g, 0.2 mol). This solution is placed in a quartz balloon and irradiated with ultraviolet light at a temperature of 25-30 ° C for 4 hours. The solution is evaporated to a weight of 75 g in vacuo and then 200 ml of isopropanol is added to it. The precipitated product is not placed for 2 hours, then filtered and washed with 50 ml of a cold mixture (4: 1) of isopropanol with water. The product bis- (trimethylammonium) (-) (, 2-epoxypropyl) -phosphonate is used to prepare disodium or calcium salt.

Bis - (trimethylammonium) (-) ({"c) -1,2-epoxypropyl) -phosphonate (51.2 g, 0.2 mol of dry salt) is transferred to 250 ml of methanol. To this solution was added 21.6 g of sodium methoxide dissolved in 250 ml of methanol. The reaction mixture was stirred for 2 hours at room temperature and then 500 ml of isopropanol was added to it. The mixture is concentrated in vacuo to a volume of 400 ml and filtered. The white product, disodium (-) (i {ac -) - l, 2epoxipropyl) -phosphonate, washed on the filter with 200 ml of isonropanol, and the eclipse is reduced to constant weight. ,,; - -14 ° (, NgO).

Bis - (trimethylammonium) (-) (1 {is-1,2-epoxypropyl) -phosphonate (0.2 mol dried salt 51.2 g) is dissolved in 250 ml of water. To this solution, 35.2 kg (0.2 mol) of calcium acetate monohydrate dissolved in 250 ml of water are added. The resulting precipitate is filtered, washed with 250 ml of hot water and dried. Calcium monohydrate of (-) {cis-1,2epoxypropyl) -phosphonate is obtained, cc-J 405 mmk 28 ° C - 12 ° {with 5%, 0.4 M ethylenediamine tetraacetic acid (rp 8.8).

Example 3. Racgmic monobenzylammonium- (cis-1,2-epoxypropyl) -phosphonate (24.5 g,

0.1 mol) is dissolved in 125 ml of methanol and passed at a rate of 10 ml / min through 50 ml of a strongly acidic polystyrene-type ion-exchange resin in the form of H + at 0 ° C. The effluent is collected in 200 ml of anhydrous pyridine. The ion exchange resin column is washed with 350 ml of cold methanol and all this is combined with the pyridine solution. The methanol is completely removed in vacuo and ethylenimine (8.6 g, 0.2 mol) is added. The reaction mixture was stirred at 50 ° C for 3 hours, cooled and the pyridine was distilled off in vacuo to dryness to form an orange oil. 200 ml of toluene are added to it and the solution is again evaporated under vacuum in the atmosphere.

nitrogen in order to dry and ward off the remaining pyridine from the oily product, which is racemic bist- (2-aminoethyl) - (h "c-1,2 - epoxypropyl) phosphonate.

Example 4. Racemic bms- (2-alloinoethyl) - (cis-1,2-enoxipronil) -phosphonate (22.6 g, 0.1 mol) is added to a mixture (4: 1) of isopropanol with water (240 ml) containing dissolved (+) tartaric acid (15.0 g,

0.1 mol), at 70 ° C.

The solution is cooled to 0 ° C and the precipitated (-) (g {"c-1,2-epoxypropyl) -phosphonyl0, O-bis-2-ethylammonium (+) tartrate precipitated in ()-фильт), and filtered off from it 60 ml of cold

(4: 1) isopropanol with water. The filtered product is recrystallized from 100 ml of a mixture (4: 1) of isopropanol with water, filtered, washed with 50 ml of the same mixture and then dried. Pure (-) (cis-1,2epoxypropyl) -phosphonyl-O, 0-2-ethylammonium (+) tartrate is obtained.

A solution of sodium nitrite (20.7 g, 0.3 mol) and sodium cobalt nitrite (80.8 g, 0.2 mol) in 155 ml of water is prepared at room temperature.

temperature 200 ml of benzene is added to it, and then solid (-) (g {S-l, 2-epoxy-propyl) -phosphonyl-O, O-bac - 2-ethylammonium (4-) tartrate (, 01 mol). The mixture is stirred

2 hours and the benzene layer comprising the desired product is separated, then washed

water and evaporated to dryness in vacuo to give bms- (2-nitroethyl) (-) (cis-, 2-epoxypropyl) -phosphonate, as an oil. Sodium methoxide (10.8 g, 0.2 mol) is dissolved in 100 ml of ethanol. To this solution is added a solution of b "c- (2-nitroethyl) (-) (cis - 1,2 - epoxypropyl) phosphonate (28.4 g. 0.1 mol) in 150 ml of ethanol. The resulting mixture is stirred

they are washed with 100 ml of ethanol and dried under vacuum at 60 ° C.

Example 5. Racemic dosimetry (iis1, 2-epoxypropyl) phosphonate (18.2 g, 0.1 mol was added to the mixture t / hst-butyl chloroacetate (37, -6 2, 0.025 mol and finely triturated sodium carbonate (2 g ) in 100 ml of dry benzene. The reaction mixture is refluxed under stirring for 5 hours and then filtered from sodium carbonate and sodium chloride. The filtrate is evaporated in vacuo. The remaining orange oil is racemic di- (g / e-butoxycarbonylmethyl) (, 2-epoxypropyl) -phosphonate, from which the residue of t / er-butyl chloroacetate is extracted under vacuum at 40 ° C and pressure of 1 - 4 mm Hg.

Example 6 Racemic di-treg-butyl (cis-1,2-epoxypropyl) -phosphonyl-OO-dna acetate (36.7 g, 0.1 mol dissolved in 250 ml of isopropanol. To this solution add {- a-phenethylamine (24.2 g. 0.2 mol and one drop of sulfuric acid. The resulting solution is refluxed for 4 hours and cooled to room temperature. The pasty mixture is filtered. The white product is washed with 200 ml of isopropanol and then crystallized from 300 ml of a hot 70% aqueous solution of isopropanol. The resulting mixture is cooled to 0 ° C, filtered, washing from 100 ml of 80% water. ora cold isopropanol and dried in vacuo at 40 ° C. The product is the di - (- L) -a-fenetilammony (-) (H1; a-1,2-epoxypropyl) phosphono-O, O-diatsgtatom.

49.7 g (0.1 mol) of this compound are placed in 400 ml of an 80% aqueous solution of isopropanol with 1 g of 10% palladium / charcoal. The paste mixture is placed under a hydrogen pressure of 6.4 atm in an autoclave with a stirrer and stirred vigorously until ng of 0.2 mol of hydrogen is consumed. The product is removed from the autoclave, heated to 75 ° C until complete dissolution and filtered from the palladium catalyst. The mother liquor is cooled to 0 ° C and filtered. The precipitated white product is mono- (-f) - "phenethylammonium (-) (g (sy-1, 2 - epoxypropyl) phosphonate, which is dried under vacuum at 40 ° C. Mp. 135-137 ° C ( with decomposition).

Wfo; L. -2.6 ° (c, H, 0).

This salt can then be converted to the disodium or calcium salt by the methods described in Example 2.

The combined filtrates, prepared as described above, are concentrated in vacuo to 150 ml. Isopropanol (600 ml is added to the 150 ml and again concentrated to 150 ml in vacuo. The precipitated white solid is filtered, washed with 100 ml of isopropanol and dried under vacuum at 40 ° C. Di (+) -a-feiethylammonium (H -) (nis1, 2-epoxyprocyl) -phosphonyl-O, O - diacetate.

cemic di-greg-butyl - (. (g; s-1,2-epoxypropyl) -phosphonyl-O, O-diacetate in 250 ml of isoprop) ol, 24.2 g (0.2: Yulia) ( -) a-pepetylamine and one drop of sulfuric acid. The resulting solution was refluxed for 4 hours. cooled t to room temperature i the pasty mass is filtered. The filtered white product was washed with 200 ml of isopropanol, dissolved in 300 ml of a hot aqueous solution of 70% isopropanol, and the resulting solution was cooled to 0 ° C. Di - (-) - afhenethnlammonium (-) (/ {N ( : -1,2-epoxypropyl) phosphopyl-O, 0-dna acetate. Product again

filtered, washed on the filter

100 ml of cold 90% aqueous solution

isopropanol and dried under vacuum

at 40 ° C.

The d - (-) - a-phenethylammonium (+) (cis-1,2-enoxypropyl) -phosphonyl-O, O-diacetate is converted to mono- (-) - a-phenethylammonium (-) (, 2-epoxypropyl) -phosphonate in as monohydrate or, calcium or sodium salt according to the processes described in

example 6.

Example 8. The drain mother liquors obtained in Example 7 are concentrated in vacuo to 150 ml. 600 ml of isopropiol are added to this solution and concentrated in vacuo to 150 ml. Then 600 ml of isopropanol are added and the solution is again concentrated in vacuo to 150 ml. The precipitated white solid is filtered off, washed with 100 ml of isopropanol and dried under vacuum at 40 ° C. The resulting dia - (- a-phenethylammolene (-} (iis - 1,2-enoxypropyl) phosphonnl-0, O-d-acetate) is obtained. This product is converted to a (-) - a-phenethyl ammonium calcium salt or disodium salt according to the procedures

described in example 6.

Example 9. Racemic dichlorohydrin ("./s-1,2-epoxypropyl) -phosphonic acid (0.1 mol in 400 ml of benzene is treated with N-methylmorpholine (20.2 g, 0.2 mol} and (+) -ephenethylamine (12.1 g, 0.1. mol. The mixture is decanted at 25 ° C for 2 hours and then benzoyl chloride (14.1 g, 0.1 mol. mole is added. The mixture is stirred for an additional 2 hours, the N-methylmorpholine hydrochloride is removed by filtration, and the mother liquors are concentrated to 50 ml. 50 ml of isopropanol are added and the solids are recrystallized from the hot mixture. The white product chlorohydride, amide-N-benzoyl -K - () a-phenethyl (-) ("ns-1,2-epoxypropyl) -phosphonic acid is filtered off, washed with bepzolol and dried under vacuum at room temperature.

Chloride, amide-K-benzonl-S - (- b

phenethyl (-) ("ng-1,2-epoxypropyl) - phosphonic acid (36.4 g, 0.1 mol is placed in a solution of 50 ml of water, 50 ml of acetic acid and 50 ml of niridip. The mixture is heated at 60 ° C for 1 hour, then add 400 ml

uume 300 ml of water are added and the mixture is extracted three times with 125 ml of methylene chloride. The aqueous layer was adjusted to pH 8.8 with sodium hydroxide. Calcium acetate monohydrate (17.6 g, 0.1 mol) in 10 ml of water is added to the reaction. The precipitated product, monohydrate (-) (, 2-enoxipronyl) -phosphonate calcium, filtered, washed with water and dried in vacuum at 60 ° C.

Example 10. Uterine solutions in the presence of chloroigandridamide-M-Beison-M- (-b) -phenethyl (-) ({is-1,2-epoxypropyl) -phosphonic acid are concentrated to dryness, and the concentrate is then recrystallized from 100 ml hot benzene. White product - 15 loraigndrid, amide-K-benzoyl-K - (+) - ot-phenenl (+) {g (is-1,2-eioxnpropyl) -phosphoic acid, filtered, washed with benzene and dried in air. According to the method of Example 9, this product is converted to the calcium salt of the monohydrate {+) (g {ms-1,2-enoxypropyl) phosphonate.

Example 11. Racemic dichlorohydrin (g / s-1,2-epoxypropyl) -phosphonic acid (0.1 mol in 400 ml of benzene processing .25 is wiped with N-methyl morpholium (20.2 g, 0.2 mol) and ( 4 -) - a-fayethylamine (24.2 g, 0.2 mol). The mixture was stirred at 60 ° C for an hour. N-methylmorpholine hydrochloride was filtered off from the hot mixture, the benzene was removed in 30 under vacuum. The solid was dissolved in 200 ml of hot methanol, the solution is cooled to 0 ° C and white nro., diamnd N, N-6wc | (-b) -a-phenethyl (-) (t {HC-1.2 - enoxipronil) phosphonic acid, filtered, washed with methanol and dried at 40 ° С in vac mind.

33.9 g (0.1 mol) of this compound are mixed with 200 ml of pyridine and acetic anhydride (22.4 g, 0.22 mol) is added. The mixture is stirred for 20 minutes at 25 ° C, cooled with an ice bath. Water (50 ml) and acetic acid (50 ml) are added and the mixture is heated at 60 ° C for 1 hour in order for the hydrolyzate to hydrate intermediate dnamid 45 N, M-diacetyl-CT. M-bggs- (+) -et -feetil (-) ({NС-1,2-enoxypropyl) -phosphonic acid. Another 400 ml of pyridine is added and the solution is evaporated to 100 ml in vacuo. Water (300 ml) is then added and the mixture is extracted three times 50 times with 125 ml of methylene chloride. The aqueous layer was adjusted to pH 8.8 with sodium hydroxide. Calcium acetate monohydrate (17.6 g, 0.1 mol) in 100 ml of water is added to the reaction. The precipitated product, (-) monohydrate (cis-1.2 1.2-epoxypropyl) -phosphonate calcium is filtered off, washed with water and dried in vacuum at 60 ° C.

Example 12. Racemic dichlorohydride (1HS-1,2-epoxypropyl) -phosphonic acid - 60 lots (0.1 mol) in 400 ml of benzene is treated with N-methylmorpholine (10.1 g, 0.1 mol) and M-methyl- (- | -) - a-phenethylamine (13.6 g, 0.1 mol). The mixture was stirred at 25 ° C for 2 hours. N-methylmorpholine hydrochloride 65

12

The mixture is filtered and the filtrate is stirred overnight with finely ground potassium ethyl thioate (13.3 g, 0.13 mol). The reaction mixture is extracted with 200 ml distilled water each and the organic layer is concentrated under vacuum to 50 ml. 50 ml of isonroianol are added and the solids are non-recrystallized from the hot mixture. The white product, amide M-methyl-L- (+) -a-phenethyl-5-ethyl (-) (g {is-1,2-epoxypropyl) -thiophosphonic acid, is filtered off, washed with benzene and dried in vacuum at room temperature . This product (26.8 g, 0.1 lyol) is dissolved in 400 ml of benzene and transferred for 18 hours with 30% hydrogen peroxide (40.8 ml, 0.4 mol). The reaction mixture containing amide, N-methyl-M- (+) -a-phenethyl-5-ethyl (-) (cis-, 2epoxypropyl) -thiophosphonate-H, 5,5-trioxide, stirred for 36 hours with 250 ml of water and. suspended calcium oxide (5.6 g, 0.1 mol). The resulting calcium monohydrate (g {y-1,2-epoxypropyl) phosphonate is filtered off, washed with water and dried.

The disodium salt is pulsed similarly to the calcium salt, except for the use of sodium hydroxide (8.0 g, 0.2 mol). After stirring at 25 ° C for 36 hours, the aqueous layer was separated, washed with benzene and evaporated to dryness in vacuo. Diatrium (-) (cis-1,2-epoxypropyl) phosphate is formed.

Example 13. The racemic mono-isylammonium - (cis-, 2 - epoxypropyl) - phosphonate (24.5 g, 0.1 mol) is dissolved in 125 ml of metaiol and passed at a speed of 10 ml min through 175 ml of a strongly acidic ion-exchange resin of polystyrene type in the form H + at 0 ° C. The stream is collected in 200 ml of anhydrous pyridine. The column is washed with 350 ml of cold methanol, which is then combined with a solution of pyridine. Methanol is completely removed in vacuo and S-ethylene oxide (12.0 g, 0.1 mol) is added. The reaction mixture is stirred under nitrogen at 25 ° C for 18 hours. Piri.1 .in is removed overnight in a vacuum, leaving an orange oil. Toluene (200 ml) is added to it and the solution is again evaporated to dryness under vacuum in a nitrogen atmosphere to remove the remaining pyridine from the oily product, racemic bis (2-thiohydroxyethne) - ({g / s-1,2 - enoxypropyl) phosphonate.

Racemicbis- (2-thiohydroxyethyl) (g {y-1,2-epoxypropyl) -phosphonate (25.8 g, 0.1 mol) is added to a solution of hydrogen peroxide (20.2 g, 0.6 mol) and bicarbonate Sodium (16.8 3, 0.2 mol) in 500 ml of water. The mixture is stirred for 18 hours at O-5 ° C. The reaction mixture is concentrated to 250 ml. A solution containing racemic disodium- (1 (ms-1,2-enoxynyl) -phosphoyl-O, O-b "c- (2-ethylsulfonate) is formed.

tylamine hydrochloride (31.5 g, 0.2 mol. The resulting liquid mass is heated to 80 ° C and the mountain is filtered. The bis- (+) -a-phenethylammonium (+) (-) (i {uc-, 2 epoxypropyl) - phosphonyl-0, O - bns- (2-ethylsulfonate).

After cooling the hot aqueous filtrate to 0 ° C and filtering, bis (+) - a-phenethylammonium (+) (cs-1,2-epoxypropyl) -phosphonyl-O, O-bns - (2-ethylsulfonate) is obtained.

(+) -a-phenethylammonium (-) (cis-1,2epoxypronyl) -phosphonyl - O, 0-bys - (2-ethylsulfonate) (59.7 g, 0.1 mol) is mixed with a solution of 1 l of water containing calcium oxide (10.9 g, 0.195 mol), and unmixed for 72 hours at 25 ° C. Wasp / calcium monohydrate (g {"c-1,2-epoxypropyl) -phosphonate calcium is filtered, tromped with water, stirred for I hour in 500 ml of methanol, filtered off and the solid product is washed with methanol and dried.

Example 14. Racemic disodium- (csi1, 2-epoxypropyl) -phosphonate (18.2 g, 0.1 mol) was dissolved in 500 ml of dry methanol at 5 ° C. To the cold solution was added benzyl bromide (17.1 g, 0.1 mol). The solution is unmixed for 18 hours at 5 ° C. The resulting solution contains a racemic mixture of sodium beisyl (g {is-1,2-epoxypropyl) -phosphonates. A - (- f) -phenethylamine hydrochloride (15.7 g, 0.1 mol) is added and the methanol is completely removed under vacuum at a temperature below 35 ° C under a nitrogen atmosphere. Racemic MOHO - (- f) cc-phenethylammonium benzyl - (g {is-1,2-epoxypropyl) -phosphonate mixed with sodium chloride and sodium bromide is formed. Isopropanol (125 ml) is added and the mixture is heated under reflux and then filtered while hot.

The filtrate is cooled to 25 ° C and the product is filtered off, washed with isopropanol and dried in air at 25 ° C. A mono- (+) -a-phenethylammonium phosphate (-) (cis1, 2-eioxypronyl) phosphonate is formed, having a high degree of optical purity.

The diastereomer of mono- (+) -et-phenethylammonium benzyl- (- | -) - (h "s-1,2 - enoxypropyl) phosphonate is obtained by concentrating the mother liquors to a constant weight (40 g), filtering the crystalline precipitate and washing its 10 L1L very cold isopronanol.

Example 15. Mono- (+) -a-phenethylammonium benzyl - ({{c-1,2-epoxypropyl) -phosphonate (34.7 g, 0.1 mol) is dissolved in 600 ml of water. 3 g of powdered 10% palladium on carbon is added to the solution. Inject the mixture at a hydrogen pressure of 4.16 atm. After that, the palladium catalyst is removed by filtration and the solution of mono- (- g) -cc-phengtnlammonium (-) (g {y-1,2-epoxypropyl) -phosphonate is stirred for 2 hours with magnesium oxide (8.0 g, 0 , 2 mol) at O-5 ° C. The excess of magnesium oxide is filtered, and the mother liquors

the solutions are concentrated in vacuo to a weight of 100 g. After adding 0.1 ml of methanol, cold ethanol (800.il) is added dropwise over 3 minutes. Te.perture support

-5 ° C. The solid product is taken up and washed with 200 ml of ethanol. The product is air-dried to constant weight at 25 ° C. 15.7 g of (-) (g7 g-1,2-epoxypropyl) phosphonate dihydrate magnesium are obtained.

Example 16. The racemic monobenzylammonium - {cis-, 2 - epoxypropyl) - phosphonate (24.5 g, 0.1 mol) is dissolved in 250 ml of water and 5 ° C. This solution is passed through 165 ml of strongly acidic cation-exchange.

resin type polystyrene in the form of H + at a speed of 15-20 ml / 1 .pin. Substance n washing water (350 ml) is collected in a flask, the temperature of which is maintained at-2 ° C. This cold aqueous solution containing racemic (, 2-epoxypropyl) -phosphonic acid, is mixed with diazomethium (the test is 9,24 g, 0.22 mol), obtained from Nmethyl-L-nitrosourea in 300 ml of ether, for 1 hour, irn O-5 ° C. The ether layer is removed and oxy-sodium hydroxide is added (4.0 g, 0 , 1 mol) to an aqueous solution of racemic dimethyl - (, 2-epoxypropyl) - phosphonate, which is unmixed for 12 hours at room temperature. To the obtained solution of the racemic methyl methyl sodium (g (c-1,2epoxyproiyl) phosphonate) ci: - (+) phenethylamine is added as a hydrate (15.7 g, 0.1 mol). The resulting solution is concentrated to dryness in vacuo to give crude racemic methylmio-a- (+) -fetiethylammonium (1 {is-1,2-epoxy-iroin) phosphonate. This salt is dissolved in 125 ml of hot isopropanol, the solution is cooled and the product is filtered off, washed with cold iso-iriolol.m and dried in air. Methylmono-cc (-f) -phenethylammonium (-) (h, c-1,2-epoxypropyl) phosphonate, having a high degree of purity is formed.

Example 17. Racemic (, 2-eioxyproiyl) phosphonate dichloride (0.1 mol) B 400. benzene is treated with 15.8 g of pyridine and 6.82 g of ethylene glycol. The mixture was stirred at 40 ° C for 18 h. The residue of pyridium hydrochloride is removed by filtration, and the filtrate containing the racemic O.O.-ethylene- (g (c-1,2-epoxy-iroyl) phosphonate) is heated under reflux for 2 hours with K D -dimethyl-et ( -f) -phenethylamine (0.1 mol). Besieged

Racemic mono- 2 - (, K-dimethyl-a - (- f) phenethylammonium) ethyl (, 2-epoxypropyl) phosphonate is filtered off and air dried.

The dried salt (10 g) is dissolved in 20, and

85% aqueous isopropanol and the solution is then cooled to room temperature. The precipitate is filtered off, washed with cold 85% isopropyol and dried with air to constant weight. About