ES2257959B1 - ACID PREPARATION PROCEDURE (1R, 2S) -1. 2-EPOXIPROPILFOSFONICO. - Google Patents

Abstract

Preparation procedure of the acid (1R, 2S) -1, 2-epoxypropylphosphonic acid. Procedure for obtaining 1,2-epoxypropylphosphonic acid, its sodium salt, (+) PEA or its benzylamine salt, enriched in the acid stereoisomer (1R, 2S) -1,2-epoxypropylphosphonate (phosphomycin) by enantio-selective epoxidation of (Z) -propenylphosphonic acid catalyzed by diox tungsten complexes, which are formed by reacting sodium tungstate with chiral hydroxy acid compounds. The use of said dioxes tungsten compounds in asymmetric epoxidation reactions for the preparation of (1R, 2S) -1,2-epoxypropylphosphonic acid, its sodium salt, (+) PEA or its benzylamine salt.

Description

Acid preparation procedure (1R, 2S) -1,2-epoxypropylphosphonic.

State of the art

Phosphomycin is the international common denomination of the acid (1 R, 2S) -1,2-epoxypropylphosphonic acid formula (I). It is an antibiotic originally isolated from the fermentation of Streptomyces fradiae broth, being effective against gram-positive and gram-negative bacteria.

The general procedure that is followed for obtaining phosphomycin in its racemic form, with slight modifications, is the one described in J. Org. Chem., Vol. 35, No. 10, 1970, 3510-3512 which is described in Scheme 1. According to this method, it is done by salt epoxidation R (+) - α-phenylethylamine [(+) PEA] (Z) -propenylphosphonic acid with hydrogen peroxide as oxidant and sodium tungstate dihydrate (Na 2 WO 4 2H 2 O) as catalyst. With the use of this catalyst can form a maximum of 50% of the salt (+) PEA of the acid (1R, 2S) -1,2-epoxypropylphosphonic, compound that crystallizes in the reaction medium, which is the form phosphomycin active while the other 50%, its diastereoisomer, the salt (+) PEA of the acid (1S, 2R) -epoxypropylphosphonic, remains in dissolution, of which no practical application is known. From salts of (+) acid PEA (1R, 2S) -epoxypropylphosphonic salts are formed sodium, potassium or tris (hydroxymethyl) ammonium for Pharmacological formulation

The use of salt (+) PEA meets two functions; the first condition the pH of the medium in the reaction epoxidation of (Z) -propenylphosphonic acid. The second, act as a resolution agent for the two possible formed diastereomers.

Scheme one

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one

Whereas, in the epoxidation reaction of (Z) -propenylphosphonic acid, the yield maximum that can be obtained from the salt (+) PEA of the acid (1R, 2S) -epoxypropylphosphonic, active material of the fosfomycin, is 50%, an important achievement would be to obtain an excess of acid enantiomer (1R, 2S) -epoxypropylphosphonic to the detriment of its acid enantiomer (1S, 2R) -epoxypropylphosphonic.

In J. Org. Chem. 1989, 54,1470-1473, the synthesis of fosfomycin according to Scheme 2:

Scheme 2

Stage one

Monoster Acid Preparation (Z) -propenylphosphonic acid derivatives tartaric (3b)

2

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Stage 2

Bromohydroxylation of (5)

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Stage 3

Halohydrin cyclization and sodium salt formation of the fosfomycin

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The synthetic process, until the end of the stage 2, elapses with a reaction yield between the 63-72% However, it should be noted that you get a mixture of diastereoisomers 6 and 7 with a 20-40% diastereoselectivity in favor of diastereoisomer 6. From this stage, the optical richness of the final reaction reaction product is determined by 1H-NMR without insulating (1R, 2S) -epoxypropylphosphonic, and therefore not It is a suitable industrial technology for obtaining fosfomycin.

In Tetrahedron: Asymmetry 1995, 6 (9): 2127-2130, the asymmetric synthesis of the fosfomycin (1) based on stereosective addition of trimethylsilyldibenzyl phosphite (3) (TMSDBP) to the compound (S) -triisopropylsilyl-oxylactaldehyde (2). See Scheme 3.

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(Scheme turns to page next)

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Scheme 3

5

This synthetic method reaches 52% of reaction yield until obtaining derivatives 5a and 5b The separation of the 5a isomer and its subsequent conversion into the Phosphomycin sodium salt is carried out with a yield of 58%, the overall yield being then of the order of 30%.

In Tetrahedron 60 (2004) 10993-998 describes the use as asymmetric acid epoxidation catalysts cis-1-propenylphosphonic (CPPA), molybdenum and tungsten complexes formed with ligands of type They leave whose structures are:

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They are also used as catalysts for asymmetric epoxidation of propenylphosphonic acid, complexes 2-pyridinyl alcoholates as WO 2 [(+) - campy] 2 and MoO 2 [(+) - campy] 2 and WO 2 [(-) - fenpy] 2 and MoO 2 [(-) - fenpy] 2 whose structures are:

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where the standard ligand for (+) - campy es (1R, 2R, 4R) -1,7,7-trimethyl-2- (2'-pyridinyl) bicyclo- [2,2,1] heptan-2-ol and for the (-) - fenpy is (1 R, 2R, 4S) -1,3,3-trimethyl-2- (2'-pyridiyl) bicyclo- [2,2,1] heptan-2-ol.

The reaction yields obtained are 98% and enantiomeric excesses, measured by 1 H-NMR with europium salts, correspond to 60-80% However, given the nature of the catalysts, industrial synthesis, and the nature of products, its industrial setting is problematic.

Description of the invention

In accordance with a first aspect of the present This invention refers to a process for preparing the acid (1R, 2S) -1,2-epoxypropylphosphonic, its sodium salt of (+) PEA or its benzylamine salt in which it is used as a catalyst a tungsten diox complex.

In accordance with this first aspect of the invention, it is possible to obtain 1,2-epoxypropylphosphonic acid, its sodium salt, (+) PEA or its benzylamine salt, enriched in the acid stereoisomer (1R, 2S) -1, 2-epoxypropylphosphonate ( fosfomycin ) by enantio-selective epoxidation of (Z) -propenylphosphonic acid catalyzed by tungsten dioxo complexes.

According to a preferred embodiment, it is uses the dioxcomplex S-malate as a catalyst of tungsten and sodium (Λ-Na 3 [WO 2 H (S-mal) 2]).

According to another preferred embodiment, uses the diox complex as a catalyst (2R, 3R) -Tungsten sodium tartrate (Λ-Na 4 WO 2 (2S, 3S) - (tart) 2]).

In a preferred embodiment, the catalyst is in an aqueous solution and is used after obtaining it in situ , the residence time being between 1 and 3 hours.

According to a more preferred embodiment, the process comprises contacting the catalyst with the salt sodium, (+) PEA or acid benzylamine (Z) -propenylphosphonic, dissolved in alcohols of short chain According to a more preferred embodiment, the catalyst dissolves in a mixture of short chain alcohols and water. In an even more preferred embodiment, the alcohols are selected from the group consisting of methanol, ethanol, propanol and Isopropanol and its mixtures. In a preferred embodiment the alcohol Employee is propanol.

According to a preferred embodiment the proportion of alcohol: water is in relation 65:35 to 85:15. In a most preferred embodiment, the alcohol: water ratio is in a 75:25 ratio

In another preferred embodiment, to the solution above a solution of hydrogen peroxide is added as oxidizing According to another preferred embodiment, the solution of hydrogen peroxide is in a 1 to 10 molar ratio with respect to (Z) -propenylphosphonic acid.

In another preferred embodiment, the pH is between 3 and 8. According to a more preferred embodiment, the pH is 6.

In a preferred embodiment of the invention, the temperature at which epoxidation is performed is comprised between 30ºC and 90ºC. More preferred at 55 ° C.

The molar relationship between the solution of catalyst and salt of (Z) -propenylphosphonic acid It is between 1:10 and 1: 300.

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In accordance with another aspect of this invention, this provides two new compounds, salt (Z) -propenylphosphonic acid benzylamine and the acid benzylamine salt (1R, 2S) -epoxypropylphosphonic.

With the use of these catalysts are obtained acid epoxidation yields (Z) -propenylphosphonic higher than 98% and excesses of  compound enantiomer (1R, 2S) -1,2-epoxypropylphosphonic, active form of fosfomycin, of the order of 30%; completing the total resolution by fractional crystallization in the case of salt (+) acid PEA (1R, 2S) -epoxypropylphosphonic.

In accordance with another aspect of this invention, this provides two new compounds, salt (Z) -propenylphosphonic acid benzylamine and the acid benzylamine salt (1R, 2S) -epoxypropylphosphonic. Both structures are describe for the first time using single crystal X-rays, where the Flack parameter value, listed in Annex I, indicates that the asymmetric epoxidation process presents excesses of (1R, 2S) -epoxypropylphosphonic acid enantiomers 76% This value of excess enantiomer is quantified, also, by means of the optical rotation the calcium salt of the acid epoxypropylphosphonic, whose formation is carried out previously benzylamine release.

A third aspect of the present invention is refers to the use of tungsten diox complexes formed by reaction of sodium tungstate with chiral hydroxy acid compounds, as catalysts for obtaining sodium salts, of (+) - PEA or Stereisomer Benzylamine (1R, 2S) of epoxypropylphosphonic acid. In a preferred embodiment, said chiral hydroxy acid compounds are of natural origin, such as (S) -malic acid (bad) and (2R, 3R) -tartaric (tart) and its enantiomers. Thus they form the homochiral complex of S-malate tungsten (SAW) {\ Lambda-Na 3 [WO 2 H (S-mal) 2]}, and the homochiral complex (2R, 3R) tungsten tartrate (VI), {\ Lambda-Na4 WO2 (2R, 3R) - (tart) 2]}, which are used as catalysts in reactions of asymmetric acid epoxidation (Z) -propenylphosphonic and its salts.

For those skilled in the art, other objects, advantages and features of the invention will be partly detached of the description and in part of the practice of the invention. The following examples and drawings are provided by way of illustration, and are not intended to be limiting of the present invention.

Examples

Example one

Synthesis of the dioxcomplex tungsten malate catalyst and sodium. S-malate tungstate (VI); λ-Na 3 [WO 2 H (S-mal) 2]

Catalyst synthesis S-malate tungstate (VI), the title is performed following the method described in Inorganica Chimica Acta 2001, 314: 184-188.

Briefly, to an aqueous acid solution S-malic (15 mmol) and S-malate sodium dihydrogen (15 mmol), formed by acid reaction S-malic and sodium hydroxide tungstate is added sodium dihydrate (15 mmol). The resulting mixture has a pH of 3.5. The solution obtained is heated in a 75 ° C water bath. for 5 hours and leave in the refrigerator for several days. The resulting solid is washed with ethanol to give a white solid (6g, Rto. 73%) corresponding to the S-malate complex tungsten (VI) Λ-Na 3 [WO 2 H (S-mal) 2],  characterized by elemental analysis, IR, and diffraction of X-rays. IR (KBr): v_ {as} (C = O) 1666, v_ {s} (C = O) 1409, 1381, v_ {s} (W = O) 929, 895, 865 cm -1.

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Example 2

Synthesis of the dioxcomplex tungsten tartrate catalyst and sodium. (2S, 3S) -tungstate tartrate (VI); Λ-Na 4 WO 2 (2S, 3S) - (tart) 2]

The synthesis of the catalyst (2S, 3S) -tungstate tartrate (VI) of the title is performed following the method described in Revue de Chimie Minérale, 1976, 13: 564.

Briefly, an aqueous solution of acid (2S, 3S) -tartaric (4.53 g, 30 mmol) is treated with sodium hydroxide up to (pH = 3-6) and, is added sodium tungstate dihydrate (4.95 g, 15 mmol). Mix resulting is brought to the temperature of 75 ° C with stirring during 1.5 hours The optical rotation of the solution measured with lamp of sodium at 22 ° C, [α] = -79 / 81 ° (H2O) versus [α] = -12 / 13 ° (H2O) corresponding to the sodium salt of starting tartaric acid. The solvent is removed under pressure reduced and a white crystalline solid that disintegrates is obtained with methanes at 50 ° C for purification.

1 H NMR analyzes and 13 C-NMR differ from the starting acid as consequence of the formation of the complex (2S, 3S) -Tungsten sodium tartrate.

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Example 3

Epoxidation of (+) PEA acid salt (Z) -propenylphosphonic with the catalyst tungsten-sodium S-malate diox complex

Procedure: (Z) -propenylphosphonic acid with a double bond richness of 75% (10 g., 61.5 mmol pure) is dissolved in 60 ml of propanol / water (75:25). The addition of (+) PEA (10 g., 79 mmol) is started until pH = 6. To the reaction mixture is added the catalyst S-sodium tungsten malate (0.650 g, 1.18 mmol), and EDTANa2 (25 mg., 0.067 mmol). Once the products are dissolved, 30% hydrogen peroxide (H2O2) (7.358g, 67.5 mmol) is added dropwise and the temperature is brought to 55 ° C while stirring is maintained for 2.5 hours at that temperature. The reaction mixture is cooled to (-10 ° C) and the precipitate obtained is recrystallized from propanol / water (75:25), and a white solid 6,280 g (Rt. 41%) of mp 1332-134 ° C is obtained. This product corresponds to the (+) PEA epoxypropylphosphonic acid (1R, 2S) monohydrate salt. C 11 H 18 NO 4 P 4 H 2 O Pm = 277.24; [α] 436 = 16.6 ° (C = 3, DMF). IR (KBr): 3015, 1260, 1166, 1053, 913, 848, 563. 1 H-NMR: 7.30-7.40 (m, 5H, aromatic), 4.46 (c, 1H, J = 6.90, H_ { 2 N-CH-CH 3), 3.27 (ddc, 1H, J H2-H3 = 5.59, J H2-H1 = 5.00, J H2-P = 5.23, CH_ 2} CH {1} P), 2.87 (dd, 1H, J {H1-H2} = 5.00, J {H1-P} = 22.67, CH {2} CH {1} P), 1.57 (d, 3H, J = 6.9, H 2 N-CH-CH 3), 1.40 (dd, 3H, J H3-H2 = 5.59, J H3-P = 0.66, CH 3 -CH 2 CH 1 P). 31 P-NMR: 13.37 (dd, J P-H1 = 22.52, J P-H2 = 5.23). 13 C-NMR: 137.82 (s, C_ {ipso}), 129.29 (dm, C_ {meta}, J = 161.80), 129.19 (dm, C_ ortho, J = 161.80), 126.55 (dc, C_ {para}, J = 157.90), 54.49 (dm, J = 179.30, H 3 C_ {3} -HC_ {2} -HC_ {1} P), 52.09 (dm, J = 168.62, CH_ {3 } -HC 2 -HC 1 P), 51.20 (dd, J = 144.97, H 2 N-CH-CH 3), 19.65 (dc, J = 128.17, H 2 N- CH-CH 3), 13.65 (dc, J = 127.4, H 3 C 3 -C 2 HC 1 HP).

Example 4

Epoxidation of the acid benzylamine salt (Z) -propenylphosphonic with the catalyst tungsten-sodium S-malate diox complex

Procedure: Z-propenylphosphonic acid with a double bond richness of 75% (10 g., 61.5 mmol pure) is dissolved in 60 ml of propanol / water (75:25). Benzylamine (8,780 g., 82 mmol) is added until pH = 6 followed by the catalyst (S) -tungsten malate (0.650 g, 1.18 mmol) and EDTANa2 (25 mg., 0.067 mmol). Next, 30% hydrogen peroxide (H 2 O 2) (7.358g, 67.5 mmol) is added dropwise and the temperature is raised to 55 ° C while stirring for 2.5 hours. The reaction mixture is cooled to 3-4 ° C with crystals appearing, which after being filtered and dried under vacuum, yield 3.785g (Rt 28%) of a product of mp 151-153 ° C which corresponds mostly to the benzylamine salt of the acid (1R , 2S) -epoxypropylphosphonic. IR (KBr): 3015, 1260, 1166, 1053, 913, 848, 563. 1 H-NMR: 7.30-7.40 (m, 5H, aromatic), 4.10 (s, 2H, H 2 N- CH2 -Ph), 3.28 (ddc, 1H, J H2-H3 = 5.60, J H2-H1 = 5.00, J H2-P = 5.70, CH2CH_ { 1} P), 2.89 (dd, 1H, J {H1-H2} = 5.00, J {H1-P} = 22.60, CH {2} CH {1} P), 1.41 (dd, 3H, J {H3-H2 = 5.60, J H3-P = 0.66, CH 3 -CH 2 CH 1 P). 31 P-NMR: 13.37 (dd, J P-H1 = 23.03, J P-H2 = 5.9). <13> C-NMR: 132.60 (s, C_ {ipso}), 129.24 (d, J = 157.20, C_ {meta}), 128.85 (d, J = 161.3, C_ ortho), 126.40 (s, C_ {para}), 54.50 (d, J = 176.00, CH_ {3} -HC_ {2} -HC_ {1} P), 52.11 (d, J = 165.00, CH_ {3} -HC_ {2} -HC_ {1} P), 43.32 (t, J = 146.26, H 2 N-CH 2 -Ph), 13.66 (c, J = 126.55, CH 3 -C 2 HC 1 HP ). The analysis of the crystals obtained by monocrystalline X-ray diffraction show excesses of enantiomer of the order of 35% in favor of the isomer (1R, 2S) of the epoxypropylphosphonic acid. This data is corroborated by optical rotation measurements of the calcium salt of the reaction product, after release of the amine, benzylamine, with sodium hydroxide and subsequent treatment with calcium chloride.

Example 5

Epoxidation of the salt (+) PEA of the acid (Z) -propenylphosphonic with the catalyst Dioxocomplex (2R, 3R) -Tungsten Tartrate and sodium

Procedure: (Z) -propenylphosphonic acid with a double bond richness of 75% (10 g., 61.5 mmol pure) is dissolved in 60 ml of propanol / water (75:25). (+) - PEA (10 g., 79 mmol) is added until pH = 6 and the catalyst (2R, 3R) - tungsten tartrate (0.620 g, 1.18 mmol) and EDTANa2 (25 mg., 0.067 mmol). Then, 30% hydrogen peroxide (H2O2) (7.358g, 67.5 mmol) is added dropwise. Stirring is maintained for 2.5 hours at 50 ° C. The reaction mixture is cooled to (-10 ° C) and the solid obtained is recrystallized from propanol / water (75:25) to obtain 7,353 g, Rto. 48%, of a white solid of mp 132-134 ° C, corresponding to the salt (+) - PEA acid monohydrate (1R, 2S) -epoxypropylphosphonic acid. C 11 H 18 NO 4 P 4 H 2 O Pm = 277.24; IR (KBr): 3015, 1260, 1166, 1053, 913, 848, 563. 1 H-NMR: 7.30-7.40 (m, 5H, aromatic), 4.46 (c, 1H, J = 6.90, H_ { 2 N-CH-CH 3), 3.27 (ddc, 1H, J H2-H3 = 5.59, J H2-H1 = 5.00, J H2-P = 5.23, CH_ 2} CH {1} P), 2.87 (dd, 1H, J {H1-H2} = 5.00, J {H1-P} = 22.67, CH {2} CH {1} P), 1.57 (d, 3H, J = 6.9, H 2 N-CH-CH 3), 1.40 (dd, 3H, J H3-H2 = 5.59, J H3-P, = 0.66, CH 3 } -CH 2 CH 1 P). 31 P-NMR: 13.37 (dd, J P-H1 = 22.52, J P-H2 = 5.23). 13 C-NMR: 137.82 (s, C_ {ipso}), 129.29 (dm, C_ {meta}, J = 161.80), 129.19 (dm, C_ ortho, J = 161.80), 126.55 (dc, C_ {para}, J = 157.90), 54.49 (dm, J = 179.30, H 3 C_ {3} -HC_ {2} -HC_ {1} P), 52.09 (dm, J = 168.62, CH_ {3 } -HC 2 -HC 1 P), 51.20 (dd, J = 144.97, H 2 N-CH-CH 3), 19.65 (dc, J = 128.17, H 2 N- CH-CH 3), 13.65 (dc, J = 127.4, H 3 C 3 -C 2 HC 1 HP).

Example 6

Epoxidation of salt (+) acid PEA (Z) -propenylphosphonic with the diox complex of (2R, 3R) -Tungsten Tartrate, and sodium catalyst generated in the reaction medium itself

Procedure: (Z) -propenylphosphonic acid, with a double bond richness of 75% (10 g., 61.5 mmol pure), is dissolved in 60 ml of PrOH / H2O (75:25) and added (+) - PEA (10 g., 79 mmol) until pH = 6. Next, an aqueous solution prepared with (2R, 3R) -tartaric acid (4.53 g, 30 mmol) treated with sodium hydroxide up to pH 3-6 and sodium tungstate dihydrate (4.95g, 15 mmol) is added. The reaction mixture is heated at 75 ° C for 1.5 hours. Then EDTANa2 (25 mg., 0.067 mmol) is added and the resulting pH is 6. To the solution obtained is added hydrogen peroxide (H2O2) at 30% (7.358g, 67.5 mmol) to drip and the temperature is brought to 55 ° C and maintained for 3 hours with stirring at said temperature. The reaction mixture is cooled (-10 ° C) and a white solid is obtained which is recrystallized from propanol / water (75:25) to obtain 7,353 g, Rto. 48%. This solid, with mp = 132-134 ° C, corresponds to the salt (+) - PEA acid monohydrate (1R, 2S) -epoxypropylphosphonic acid C11 H18 NO_ {4} P \ cdotH2 O Pm = 277.24; [α] 436 = 16.6 ° (C = 3, DMF). IR (KBr): 3015, 1260, 1166, 1053, 913, 848, 563. 1 H-NMR: 7.30-7.40 (m, 5H, aromatic), 4.46 (c, 1H, J = 6.90, H_ { 2 N-CH-CH 3), 3.27 (ddc, 1H, J H2-H3 = 5.59, J H2-H1 = 5.00, J H2-P = 5.23, CH2 } CH {1} P), 2.87 (dd, 1H, J {H1-H2} = 5.00, J {H1-P} = 22.67, CH {2} CH {1} P), 1.57 (d, 3H , J = 6.9, H 2 N-CH-CH 3), 1.40 (dd, 3H, J H3-H2 = 5.59, J H3-P = 0.66, CH 3 - CH 2 CH 1 P). 31 P-NMR: 13.37 (dd, J P-H1 = 22.52, J P-H2 = 5.23). 13 C-NMR: 137.82 (s, C_ {ipso}), 129.29 (dm, C_ {meta}, J = 161.80), 129.19 (dm, C_ ortho, J = 161.80), 126.55 (dc, J = 157.90), 54.49 (dm, J = 179.30, H 3 C 3 -HC_ {2} -HC_ {1} P), 52.09 (dm, J = 168.62, CH_ {3} -HC_ {2 } -HC_ {1} P), 51.20 (dd, J = 144.97, H 2 N-CH-CH 3), 19.65 (dc, J = 128.17, H 2 N-CH-CH 3 }), 13.65 (dc, J = 127.4, H 3 C 3 -C 2 HC 1 HP.

Example 7

Epoxidation of the acid benzylamine salt (Z) -propenylphosphonic with dioxocomplexes of (2R, 3R) -Tungsten sodium tartrate

Procedure: Z-propenylphosphonic acid with a double bond richness of 75% (10 g., 61.5 mmol pure) is dissolved in 60 ml of propanol / water (75:25). Benzylamine (8,780 g., 82 mmol) is added until pH = 6 followed by the tungsten tartrate catalyst (0.620 g, 1.18 mmol) and EDTANa2 (25 mg., 0.067 mmol). Next, 30% hydrogen peroxide (H 2 O 2) (7.358g, 67.5 mmol) is added dropwise and the temperature is raised to 55 ° C while stirring for 2.5 hours. The reaction mixture is cooled to 3-4 ° C with crystals appearing, which after being filtered and dried under vacuum, yield 4,054g (30% Rt) of a product of mp 145-148 ° C, which corresponds mostly to the benzylamine salt of the acid (1 R, 2S) -epoxypropylphosphonic. IR (KBr): 3015, 1260, 1166, 1053, 913, 848, 563. 1 H-NMR: 7.30-7.40 (m, 5H, aromatic), 4.10 (s, 2H, H 2 N- CH2 -Ph), 3.28 (ddc, 1H, J H2-H3 = 5.60, J H2-H1 = 5.00, J H2-P = 5.70, CH2CH_ { 1} P), 2.89 (dd, 1H, J {H1-H2} = 5.00, J {H1-P} = 22.60, CH {2} CH {1} P), 1.41 (dd, 3H, J {H3-H2 = 5.60, J H3-P = 0.66, CH 3 -CH 2 CH 1 P). 31 P-NMR: 13.37 (dd, J P-H1 = 23.03, J P-H2 = 5.9). <13> C-NMR: 132.60 (s, C_ {ipso}), 129.24 (d, J = 157.20, C_ {meta}), 128.85 (d, J = 161.3, C_ ortho), 126.40 (s, C_ {para}), 54.50 (d, J = 176.00, CH_ {3} -HC_ {2} -HC_ {1} P), 52.11 (d, J = 165.00, CH_ {3} -HC_ {2} -HC_ {1} P), 43.32 (t, J = 146.26, H 2 N-CH 2 -Ph), 13.66 (c, J = 126.55, CH 3 -C 2 HC 1 HP ).

The analysis of the crystals obtained by the monocrystalline X-ray diffraction technique shows that said crystals are composed of 88% of the isomer (1R, 2S), that is, fosfomycin, and 12% of its enantiomer, (1S, 2R). This fact means that the epoxidation process takes place with 76% of excess enantiomer. Diffraction analysis data they are collected in tables 1 to 7. This data is corroborated by the optical rotation measurements of the calcium salt of the product of reaction, after release of the amine, benzylamine.

TABLE 1 Crystal data and structure refinement for monobenzylamine salt of epoxypropylphosphonic acid

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Formula empirical C 10 H 16 O 4 P Weight molecular 245.21 Temperature 293 (2) K Wavelength 0.71073 \ ring {A} Crystalline system Monoclinic, PC Cell dimensions a = 12.051 (15) \ ring {A} \ alpha = 90º. b = 4,798 (2) \ ring {A} ? = 116.16 (5) º. c = 11,801 (3) \ ring {A}  γ = 90 °.

TABLE 1 (continued)

Volume 612.4 (8) \ ring {A} 3 Z, calculated density 2, 1.330 Mg / m3 Absorption Coefficient 0.224 mm-1 F (000) 260 Size of Cristal 0.1 x 0.1 x 0.2 mm Theta range for data collection 3.46 a 29.98º. Indexes limiting 0 <= h <= 16, -6 <= k <= 0, 16 <= | <= 14 Reflections collected / unique 1847/1847 [R (int) = 0.0403] Completeness to theta = 29.98 99.6% Absorption correction None Method of refinement Full-matrix least-squares on F2 Data / restraints / parameters 1847/2/166 Goodness-of-fit on F2 1,084 Final R indices [I> 2 \ sigma (I)] R1 = 0.0588, wR2 = 0.1502 R indices (all data) R1 = 0.0667, wR2 = 0.1590 Absolute structure parameter 0.0 (2) Largest diff. peak and hole 0.884 and -0.753 e. \ ring {A} ^ - 3}

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TABLE 2 Atomic coordinates (x 10 4) and parameters of equivalent isotropic displacement ({{2} x 10 3) for the monobenzylamine salt of epoxypropylphosphonic acid. U (eq) is defined as one third of the tensor stroke Orthogonalized UJ

x Y z U (eq) P (1) 2754 (1) 8281 (1) 3252 (1) 32 (1) O (1) 2320 (3) 9105 (5) 4211 (3) 38 (1) O (2) 2515 (4) 10564 (6) 2219 (3) 56 (1) O (3) 2207 (3) 5644 (5) 2525 (3) 43 (1) O (4) 5216 (4) 9699 (9) 4962 (4) 64 (1) N (1) 11535 (3) 3961 (6) 4901 (3) 34 (1) C (1) 4443 (4) 7799 (11) 3976 (4) 50 (1) C (2) 5215 (4) 6797 (11) 5260 (5) 57 (1) C (3) 4749 (5) 6031 (14) 6188 (5) 66 (1) C (4) 10210 (4) 3320 (8) 4085 (4) 45 (1) C (5) 9317 (4) 5533 (8) 4101 (4) 39 (1) C (6) 8411 (4) 6602 (10) 2979 (4) 50 (1) C (7) 7544 (5) 8501 (11) 2972 (6) 60 (1) C (8) 7564 (5) 9389 (11) 4079 (6) 59 (1) C (9) 8468 (5) 8354 (11) 5214 (6) 62 (1) C (10) 9335 (5) 6437 (10) 5234 (5) 52 (1)

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TABLE 3 Link lengths [\ ring {A}] and angles [º] for monobenzylamine acid salt epoxypropylphosphonic

       \ vskip1.000000 \ baselineskip
    

       \ dotable {\ tabskip \ tabcolsep # \ hfil \ + # \ hfil \ + # \ hfil \ tabskip0ptplus1fil \ dddarstrut \ cr} {
 P (1) -O (1) \ + \ hskip3cm \ +
1,493 (3) \ cr P (1) - O (3) \ + \ +
1,508 (3) \ cr P (1) - O (2) \ + \ +
1,569 (3) \ cr P (1) - C (1) \ + \ +
1.843 (6) \ cr O (4) - C (2) \ + \ +
1,436 (7) \ cr O (4) - C (1) \ + \ +
1,448 (6) \ cr N (1) - C (4) \ + \ +
1,489 (5) \ cr C (1) - C (2) \ + \ +
1,467 (7) \ cr C (2) - C (3) \ + \ +
1,481 (7) \ cr C (4) - C (5) \ + \ +
1.518 (5) \ cr C (5) - C (6) \ + \ +
1,391 (6) \ cr C (5) - C (10) \ + \ +
1,397 (6) \ cr C (6) - C (7) \ + \ +
1,384 (7) \ cr C (7) - C (8) \ + \ +
1,364 (9) \ cr C (8) - C (9) \ + \ +
1,393 (8) \ cr C (9) - C (10) \ + \ +
1,384 (6) \ cr \ + \ + \ cr
O (1) - P (1) - O (3)
\ + \ + 116.3 (2) \ cr
O (1) - P (1) - O (2)
\ + \ + 113.48 (17) \ cr
O (3) - P (1) - O (2)
\ + \ + 105.01 (17) \ cr
O (1) - P (1) - C (1)
\ + \ + 111.48 (18) \ cr
O (3) - P (1) - C (1)
\ + \ + 106.0 (2) \ cr
O (2) - P (1) - C (1)
\ + \ + 103.6 (3) \ cr
C (2) - O (4) - C (1)
\ + \ + 61.1 (3) \ cr
O (4) - C (1) - C (2)
\ + \ + 59.0 (3) \ cr
O (4) - C (1) - P (1)
\ + \ + 118.8 (3) \ cr
C (2) - C (1) - P (1)
\ + \ + 126.0 (3) \ cr
O (4) - C (2) - C (1)
\ + \ + 59.8 (3) \ cr
O (4) - C (2) - C (3)
\ + \ + 117.6 (5) \ cr
C (1) - C (2) - C (3)
\ + \ + 124.9 (4) \ cr
N (1) - C (4) - C (5)
\ + \ + 114.3 (3) \ cr
C (6) - C (5) - C (10)
\ + \ + 118.1 (4) \ cr
C (6) - C (5) - C (4)
\ + \ + 120.6 (4) \ cr
C (10) - C (5) - C (4)
\ + \ + 121.2 (4) \ cr
C (7) - C (6) - C (5)
\ + \ + 121.5 (5) \ cr
C (8) - C (7) - C (6)
\ + \ + 120.4 (4) \ cr
C (7) - C (8) - C (9)
\ + \ + 119.0 (4) \ cr
C (10) - C (9) - C (8)
\ + \ + 121.2 (5) \ cr
C (9) - C (10) - C (5)
\ + \ +
119.8 (5) \ cr}
    

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TABLE 4 Hydrogen bond lengths [\ ring {A}] and angles [º] for the monobenzylamine salt of the acid epoxypropylphosphonic

       \ vskip1.000000 \ baselineskip
    

       \ dotable {\ tabskip \ tabcolsep # \ hfil \ + # \ hfil \ + # \ hfil \ tabskip0ptplus1fil \ dddarstrut \ cr} {
 O (2) -H (2O) \ + \ hskip3cm \ +
0.91 (7) \ cr N (1) - H (1C) \ + \ +
0.8900 \ cr N (1) - H (1A) \ + \ + 0.8900 \ cr
N (1) - H (1B) \ + \ + 0.8900 \ cr
C (1) - H (1) \ + \ + 0.98 (7) \ cr
C (2) - H (2) \ + \ + 0.9800 \ cr
C (3) - H (3A) \ + \ + 0.9600 \ cr
C (3) - H (3B) \ + \ + 0.9600 \ cr
C (3) - H (3C) \ + \ + 0.9600 \ cr
C (4) - H (4B) \ + \ + 0.9700 \ cr
C (4) - H (4A) \ + \ + 0.9700 \ cr
C (6) - H (6) \ + \ + 0.92 (8) \ cr
C (7) - H (7) \ + \ + 0.94 (6) \ cr
C (8) - H (8) \ + \ + 0.9300 \ cr
C (9) - H (9) \ + \ + 1.01 (6) \ cr
C (10) - H (10) \ + \ + 0.9300 \ cr \ + \ + \ cr
P (1) - O (2) - H (2O)
\ + \ + 103 (4) \ cr
C (4) - N (1) - H (1C)
\ + \ + 109.5 \ cr
C (4) - N (1) - H (1A)
\ + \ + 109.5 \ cr
H (1C) - N (1) - H (1A)
\ + \ + 109.5 \ cr
C (4) - N (1) - H (1B)
\ + \ + 109.5 \ cr
H (1C) - N (1) - H (1B)
\ + \ + 109.5 \ cr
H (1A) - N (1) - H (1B)
\ + \ + 109.5 \ cr
O (4) - C (1) - H (1)
\ + \ + 118 (4) \ cr
C (2) - C (1) - H (1)
\ + \ + 112 (4) \ cr
P (1) - C (1) - H (1)
\ + \ + 113 (4) \ cr
O (4) - C (2) - H (2)
\ + \ + 114.4 \ cr
C (1) - C (2) - H (2)
\ + \ + 114.4 \ cr
C (3) - C (2) - H (2)
\ + \ + 114.4 \ cr
C (2) - C (3) - H (3A)
\ + \ + 109.5 \ cr
C (2) - C (3) - H (3B)
\ + \ + 109.5 \ cr
H (3A) - C (3) - H (3B)
\ + \ + 109.5 \ cr
C (2) - C (3) - H (3C)
\ + \ + 109.5 \ cr
H (3A) - C (3) - H (3C)
\ + \ + 109.5 \ cr
H (3B) - C (3) - H (3C)
\ + \ + 109.5 \ cr
N (1) - C (4) - H (4B)
\ + \ + 108.7 \ cr
C (5) - C (4) - H (4B)
\ + \ + 108.7 \ cr
N (1) - C (4) - H (4A)
\ + \ + 108.7 \ cr
C (5) - C (4) - H (4A)
\ + \ + 108.7 \ cr
H (4B) - C (4) - H (4A)
\ + \ + 107.6 \ cr
C (7) - C (6) - H (6)
\ + \ + 106 (5) \ cr
C (5) - C (6) - H (6)
\ + \ + 133 (5) \ cr
C (8) - C (7) - H (7)
\ + \ + 127 (4) \ cr
C (6) - C (7) - H (7)
\ + \ + 112 (4) \ cr
C (7) - C (8) - H (8)
\ + \ + 120.5 \ cr
C (9) - C (8) - H (8)
\ + \ +
120.5 \ cr}
    

TABLE 4 (continued)

       \ dotable {\ tabskip \ tabcolsep # \ hfil \ + # \ hfil \ + # \ hfil \ tabskip0ptplus1fil \ dddarstrut \ cr} {

C (10) -C (9) -H (9)
\ + \ hskip3cm \ + 118 (3) \ cr
C (8) - C (9) - H (9)
\ + \ + 120 (3) \ cr
C (9) - C (10) - H (10)
\ + \ + 120.1 \ cr
C (5) - C (10) - H (10)
\ + \ +
120.1 \ cr}
    

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TABLE 5 Anisotropic Displacement Parameters ({{2 x 10 <3>) for the monobenzylamine salt of the acid epoxypropylphosphonic. The exponent of the displacement factor Anisotropic takes the form: -2 \ pi2 [h2] a \ text {*} ^ {2} U_ {11} + ... + 2 h k a \ text {*} b \ text {*} U_ {12}]

U_ {11} U_ {22} U_ {33} U_ {23} U_ {13} U_ {12} P (1) 40 (1) 24 (1) 33 (1) 0 (1) 18 (1) 1 (1) O (1) 41 (1) 36 (1) 42 (1) 2 (1) 24 (1) 7 (1) O (2) 103 (3) 27 (1) 47 (1) 7 (1) 43 (2) 7 (1) O (3) 52 (2) 26 (1) 43 (1) -2 (1) 14 (1) -1 (1) O (4) 54 (2) 73 (2) 67 (2) -16 (2) 26 (2) -29 (2) N (1) 35 (1) 31 (1) 38 (1) -2 (1) 19 (1) 2 (1) C (1) 47 (2) 58 (2) 52 (2) -11 (2) 30 (2) -4 (2) C (2) 37 (2) 67 (3) 61 (3) -8 (2) 16 (2) 0 (2) C (3) 50 (2) 79 (3) 56 (3) 13 (2) 11 (2) 3 (2) C (4) 36 (2) 41 (2) 54 (2) -10 (2) 16 (2) 0 (1) C (5) 33 (2) 38 (2) 48 (2) 2 (1) 18 (1) 0 (1) C (6) 46 (2) 53 (2) 44 (2) 0 (2) 12 (2) -1 (2) C (7) 41 (2) 58 (3) 65 (3) 12 (2) 9 (2) 7 (2) C (8) 41 (2) 55 (3) 90 (4) 13 (2) 37 (2) 14 (2) C (9) 60 (3) 74 (3) 68 (3) 12 (2) 43 (2) 24 (2) C (10) 53 (2) 59 (2) 48 (2) 8 (2) 26 (2) 19 (2)

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TABLE 6 Hydrogen coordinates (x 10 4) and parameters of isotropic displacement ({{2} x 10 <3>) for salt epoxypropylphosphonic acid monobenzylamine

x Y z U (eq) H (1C) 12003 2582 4847 fifty H (1A) 11656 4139 5698 fifty H (1B) 11737 5545 4647 fifty H (2) 5955 5775 5356 68 H (3A) 5426 5426 6958 99 H (3B) 4157 4549 5852 99 H (3C) 4361 7621 6356 99 H (4B) 10007 1564 4356 53 H (4A) 10094 3082 3223 53 H (8) 6982 10667 4076 71 H (10) 9927 5752 6000 63 H (1) 4750 (60) 7160 (140) 3380 (70) 60 (16) H (6) 8200 (80) 6230 (130) 2150 (70) 80 (20) H (7) 7050 (70) 9190 (140) 2160 (60) 59 (16) H (9) 8610 (60) 9290 (120) 6030 (60) 50 (14) H (2O) 2670 (60) 12190 (160) 2670 (60) 61 (17)

TABLE 7 Hydrogen bonds for monobenzylamine salt of epoxypropylphosphonic acid [\ ring {A} and º.].

D - - H .. TO d (D-H) d (H ... A) d (D ... A) <(DHA) N (1) - - H (1A) .. OR (3) [ 2665.02] 0.89 1.96 2,840 (6) 170 N (1) - - H (1B) .. OR (1) [ 1655.02] 0.89 2.00 2,887 (6) 175 N (1) - - H (1C) .. OR (1) [ 1645.02] 0.89 1.94 2,770 (5) 155 O (2) - - H (2O) .. OR (3) [ 1565.02] 0.92 (7) 1.73 (8) 2,515 (5) 142 (6)

Translation of ARU-code to Equivalent Position Code [1645.] = 1 + x, -1 + y, z [1655.] = 1 + x, y, z [2665.] = 1 + x, 1 -y, 1/2 + z [1565.] = x, 1 + y, z

H-Bond classification [G.A. Jeffrey, H. Maluszynska & J. Mitra., Int. J. Biol. Macromol. (1985), 7, 336-348].

Claims (18)

1. Procedure for preparing (1R, 2S) -1,2-epoxypropylphosphonic acid, its sodium salt, (+) PEA or its benzylamine salt characterized in that in the epoxidation process of (Z) -propenylphosphonic acid is used as Catalyst a dioxcomplex of tungsten. 2. Method according to the preceding claim, characterized in that the sodium-tungsten-sodium diox complex (λ-Na 3 [WO 2 H (S-mal) 2)] is used as catalyst. . 3. Method according to claim 1, characterized in that dioxcomplex (2R, 3R) -Tungsten-sodium tartrate (λ-Na 4 WO 2 (2S, 3S) - (tart) is used as catalyst. _{2}]). Method according to any one of the preceding claims 1 to 3, characterized in that it comprises contacting the dissolved catalyst in a mixture of short chain alcohols and water, with the sodium salt, (+) PEA or acid benzylamine (Z) -propenylphosphonic. 5. Method according to any of the preceding claims 1 to 4, characterized in that the alcohols are selected from the group consisting of methanol, ethanol, propanol and isopropanol and mixtures thereof. Method according to any one of the preceding claims 1 to 5, characterized in that a solution of hydrogen peroxide is added as an oxidant. 7. Method according to any of the preceding claims 1 to 6, characterized in that the alcohol-water ratio is in the ratio of 65:35 to 85:15. Method according to any one of the preceding claims 1 to 7, characterized in that the hydrogen peroxide solution is in a 1 to 10 molar ratio with respect to (Z) -propenylphosphonic acid. 9. Method according to any one of the preceding claims 1 to 8, characterized in that the hydrogen peroxide solution is at a pH between 3 and 8. Method according to any one of the preceding claims 1 to 9, characterized in that it is carried out at a temperature between 30 ° C and 90 ° C. Method according to any one of the preceding claims 1 to 10, characterized in that the molar ratio between the catalyst solution and the salt of (Z) -propenylphosphonic acid is between 1:10 and 1: 300. 12. Method according to any of the preceding claims 1 to 11, characterized in that the residence time is between 1 and 3 hours. 13. Method according to any of the preceding claims 1 to 12, characterized in that the benzylamine salt of (Z) -propenylphosphonic acid is used as the starting product. 14. The acid benzylamine salt (Z) -propenylphosphonic. 15. The benzylamine salt of acid (1R, 2S) -epoxypropylphosphonic. 16. Use of tungsten diox complexes as catalysts in asymmetric epoxidation reactions for acid preparation (1R, 2S) -1,2-epoxypropylphosphonic, its sodium salt of (+) PEA or its benzylamine salt. 17. The use according to the preceding claim, characterized in that the diox tungsten complex is formed in situ in the reaction medium, by reaction of sodium tungstate with chiral hydroxy acid compounds. 18. The use according to any of the preceding claims characterized in that said chiral hydroxy acid compounds are selected from the group consisting of (S) -malic acid (bad), (2R, 3R) -tartaric acid (tart) and their compounds enantiomers