CN1385435A - Process for synthesizing fosfomycin using cis-propenyl phosphonic acid as raw material - Google Patents

Process for synthesizing fosfomycin using cis-propenyl phosphonic acid as raw material Download PDF

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Publication number
CN1385435A
CN1385435A CN 02121110 CN02121110A CN1385435A CN 1385435 A CN1385435 A CN 1385435A CN 02121110 CN02121110 CN 02121110 CN 02121110 A CN02121110 A CN 02121110A CN 1385435 A CN1385435 A CN 1385435A
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phosphonomycin
salt
ethanol
water
phosphonic acids
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CN 02121110
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石鸿昌
王歆燕
樊新印
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Tsinghua University
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Tsinghua University
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Abstract

The method for synthesizing phosphonomycin by using cis-propene phosphonic acid as raw material relates to an epoxidation eraction of cis-propene phosphonic acid by using molybdate which is sodium salt or ammonium salt generally as catalyst in the course of synthesizing phosphonomycin. According to identical process sand invention can prepare phosphonomycin disodium salt, in terminal phosphonomycin product the molbdenum content only is 1/10 (10-15 ppm) of tungsteon content, so that the use of molbdate as catalyst can reduce residual of heavy metal and can reduce toxic side effect of medicine.

Description

A kind of method that is the synthetic phosphonomycin of raw material with suitable propylene phosphonic acids
Technical field
The present invention relates to a kind of is the method that raw material carries out the synthetic phosphonomycin of catalytic epoxidation with suitable propylene phosphonic acids.
Background technology
Suitable propylene phosphonic epoxidation was a step committed step during phosphonomycin was synthetic, all used tungstate as catalyzer at present both at home and abroad, typically used sodium wolframate (Na 2WO 42H 2O) (see: USP 4,222, and 970 1980; CN 1060470,1991; Chinese Journal of Pharmaceuticals 22 (9), 391-4,1991, etc.).. this kind catalyst is active high, can make along the propylene phosphonic acids and can realize epoxidation fully under lower temperature.But this reaction generally is to carry out in the solvent of ethanol and about 30% water, and sodium wolframate solubleness in containing volume alcoholic acid solvent system is little, therefore can crystallization separate out with product, and the W content in the last phosphonomycin product is exceeded standard greatly; Tungsten is a kind of heavy metal element of non-needed by human, even therefore the tungsten of trace also is deleterious for human body.Also there is other catalyzer of use to carry out this epoxidation reaction, as using the tetraisopropoxide complex compound (iso-PrO) of titanium 4Ti is a catalyzer, with metal peroxides (as BaO 2) and cross (two) ammonium sulfate ((NH 4) 2S 2O 8) for oxygenant (see: JP 78 05,120,1978; JP 78 05, and 121,1978), because the price height of catalyzer and oxygenant uses also inconvenience, so do not obtain industrial application.
Summary of the invention
The objective of the invention is to seek a kind of catalyzer new in phosphonomycin is synthetic replaces tungstate to carry out along propylene phosphonic epoxidation.This catalyzer must be able to use hydrogen peroxide as oxygenant and reach the catalytic effect same with tungstate, the more important thing is and can reduce the residual quantity of catalyzer in the product phosphonomycin, reduces the toxic side effect of residual heavy metal to greatest extent.
Purpose of the present invention and task are achieved by the following technical solution:
A kind of method that is the synthetic phosphonomycin of raw material with suitable propylene phosphonic acids: with suitable propylene phosphonic acids is raw material, ethanol, ethanol-water or water are solvent, under the condition of catalyzer and hydrogen peroxide existence, carry out it is characterized in that using the soluble molybdenum hydrochlorate as catalyzer along propylene phosphonic acid cyclic oxidizing reaction.
Described molybdate is generally sodium salt (Na 2MoO 42H 2O) or ammonium salt (NH 4) 6Mo 7O 244H 2O).
Described along the propylene phosphonic acids: the ratio of molybdate=1: 0.01-0.1 (weight ratio), its preferred proportion is 1: 0.03-0.06.
Method of the present invention is carried out as follows:
(1) will be along the propylene phosphonic acids in g/V=1: 3~5 ratio be dissolved in ethanol or ethanol-water or the water solvent, slowly drips the dextrorotation α-Ben Yian under 20~30 ℃, regulates PH=5.5-6.0;
(2) in along the propylene phosphonic acids: the ratio of molybdate=1: 0.01-0.1 (weight ratio) takes by weighing molybdate, stirs down it to be joined in the solution that step (1) makes;
(3) mixture with step (2) is warming up to 40--45 ℃, slowly drips the hydrogen peroxide that concentration is 30%-35%, and the control reacting liquid temperature surpasses 60 ℃, and the mol ratio of suitable propylene phosphonic acids and added hydrogen peroxide is 1: 1.1~1.3;
(4) continue reaction 1--2 hour at 55--65 ℃, reaction finishes, if use alcohol to make solvent, can place refrigerator and keep 12-24 hour at-5 ℃, and suction filtration is with adequate amount of ethanol flushing, drying; If with water is solvent, but vacuum is removed 60-70% water, adds adequate amount of ethanol again, dissolving is placed refrigerator then and was kept 12-24 hour at-5 ℃, suction filtration, and with the adequate amount of ethanol flushing, drying promptly gets (-)-phosphonomycin-(+)-α-Ben Yian salt;
(5) according to NaOH: H 2O=1: 2 weight ratio preparation NaOH solution, again by (-)-phosphonomycin-(+)-α-Ben Yian salt: the weight ratio of NaOH solution=9: 8, under 10-15 ℃ of stirring, (-)-phosphonomycin-(+)-α-Ben Yian salt dissolved in the layering that dissociates of NaOH solution, the upper strata is (+)-α-Ben Yian, and lower floor is (-)-phosphonomycin disodium salt aqueous solution;
(6) (-)-phosphonomycin disodium salt aqueous solution of step (5) preparation is slowly joined under effectively stirring in 50 ℃ the ethanol of 8 times of volumes (V/g) amount, separate out white crystal, suction filtration, use alcohol flushing, drying promptly gets (-)-the phosphonomycin disodium salt, is the finished product.
The inventor discovers that molybdate comes to this a kind of realization along the effective catalyzer of propylene phosphonic acid cyclic oxidation, and it can obtain the catalytic effect same with tungstate.Generally we are to use its sodium salt or ammonium salt (Na 2MoO 42H 2O, the ammonium salt principal constituent is NH 4) 6Mo 7O 244H 2O).Molybdenum is one of trace element of needed by human, what the solubleness wolframic acid salt of molybdate in containing volume alcoholic acid solvent system will be big simultaneously is many, the present invention uses molybdate to carry out epoxidation as catalyzer, according to same prepared phosphonomycin disodium salt, the content of molybdenum 1/10th (10-15ppm) of about W content only in the final phosphonomycin product.Therefore use the suitable propylene phosphonic acids epoxidation catalyst of molybdate conduct for reducing heavy-metal residual, reduce the toxic side effect of medicine, safeguard that human consumer's health should be significant, good application prospects is arranged.
Description of drawings
Fig. 1 is to be the cis-propene phosphoric acid epoxidation reaction formula of catalyzer with the molybdate.
Embodiment
Raw material used among the present invention is the industrial goods of content 83% along the propylene phosphonic acids.This reaction can be solvent with the ethanol-water of ethanol, water or arbitrary proportion, used oxygenant is the aqueous solution of hydrogen peroxide, the employing molybdate is catalyzer (generally adopting sodium salt and ammonium salt), suitable propylene phosphonic acids: the ratio of molybdate=1: 0.01-0.1 (weight ratio), its best proportion is 1: 0.03-0.06.Carry out at 50 ℃-70 ℃ along propylene phosphonic acid cyclic oxidizing reaction temperature, optimum temps is 55 ℃-65 ℃, and reaction in 1-2 hour finishes.
Following formula is to be the cis-propene phosphoric acid epoxidation reaction formula of catalyzer with the molybdate:
Embodiment 1
1. will be dissolved in the 30ml ethanol along propylene phosphonic acids 10g (content 83%, industrial goods), 25 ℃ and stir under slowly drip about 9ml (+)-α-Ben Yian, the pH value that makes this mixed solution is 5.5-6.0;
2. the Sodium orthomolybdate with 0.4g is dissolved in the 2.0ml water, stirs down it is joined in the above solution;
3. after being warming up to 40 ℃, under effectively stirring, slowly drip the hydrogen peroxide (H of 3.5ml 30% 2O 2), dropwising in 0.5 hour, the attentive response temperature is not above 60 ℃.Under this temperature, continue reaction 2 hours.
4. above reaction solution is placed refrigerator-5 ℃ to spend the night suction filtration, filter cake alcohol flushing, drying.Get (-)-phosphonomycin-(+)-α-Ben Yian salt 7.3g, yield 75%.
Ultimate analysis (C 11H 18NO 4P3/2H 2O) C, H, N measured value and theoretical value deviation are in ± 0.5%.
With (-)-phosphonomycin-(+)-α-Ben Yian salt of above gained according to step of the present invention (5), (6) preparation (-)-phosphonomycin disodium salt, 3.7g, yield 87%.
1HNMR(D 2O)δppm:1.29(d?Jz=5.53H),2.64(dd?Jz=18.9,5.1,1H),3.07(m,1H)。
Above result with use tungstate identical as the product of catalyzer.
Atomic absorption spectrophotometer is surveyed molybdenum content: 12ppm
Embodiment 2
1. cis-propene phosphoric acid 10g (content 83%, industrial goods) is dissolved in the 30ml deionized water, slowly drips 9ml (+)-α-Ben Yian under 25 ℃ of stirrings, and the pH value that makes this mixed solution is 5.5-6.0.
2. join in the above solution under the Sodium orthomolybdate stirring with 0.4g, stirred 10 minutes.
3. be warming up to 40-45 ℃ of H that under effectively stirring, slowly drips 3.5ml 30% 2O 2, dropwising in 0.5 hour, the attentive response temperature is not above 65 ℃.After this continue reaction 1.5 hours at 60 ℃.
4. above reaction solution vacuum is removed 70% water, adds the ethanol of 30ml 95%, and dissolving stirs, and places refrigerator-5 ℃ to spend the night.Suction filtration, filter cake alcohol flushing, drying.Get (-)-phosphonomycin-(+)-α-Ben Yian salt 7.4g, yield 76%.
Ultimate analysis (C 11H 18NO 4P3/2H 2O) C, H, N measured value and theoretical value deviation are in ± 0.5%.
With gained (-)-phosphonomycin-(+)-α-Ben Yian salt according to step 5 of the present invention, 6 preparation (-)-phosphonomycin disodium salts, 3.7g, yield 86%.
1HNMR (D 2O) δ ppm: identical with example 1.
Atomic absorption spectrophotometer is surveyed molybdenum content: 13ppm.
Embodiment 3
Change the Sodium orthomolybdate of the 0.4g among the embodiment 1 into the 0.4g ammonium molybdate, other processing condition are all identical with embodiment 1, and the yield of products obtained therefrom is also identical with quality.
Atomic absorption spectrophotometer is surveyed (-)-phosphonomycin disodium salt molybdenum content: 13ppm
The comparative example:
1. will be dissolved in the 30ml ethanol along propylene phosphonic acids 10g (content 83%, industrial goods), 25 ℃ and stir under slowly drip about 9ml (+)-α-Ben Yian, the pH value that makes this mixed solution is 5.5-6.0;
2. the sodium wolframate with 0.4g is dissolved in the 2.0ml water, stirs down it is joined in the above solution;
3. after being warming up to 40 ℃, under effectively stirring, slowly drip the hydrogen peroxide (H of 3.5ml 30% 2O 2), dropwising in 0.5 hour, the attentive response temperature is not above 55 ℃.Under this temperature, continue reaction 1 hour.
4. above reaction solution is placed refrigerator-5 ℃ to spend the night suction filtration, filter cake alcohol flushing, drying.Get (-)-phosphonomycin-(+)-α-Ben Yian salt 7.4g, yield 76%.
With (-)-phosphonomycin-(+)-α-Ben Yian salt of above gained according to step of the present invention (5), (6) preparation (-)-phosphonomycin disodium salt, 3.7g, yield 86%.
1HNMR (D 2O) δ ppm: identical with example 1.
Atomic absorption spectrophotometer is surveyed W content: 150ppm

Claims (4)

1. one kind is the method that raw material synthesizes phosphonomycin with suitable propylene phosphonic acids, with suitable propylene phosphonic acids is raw material, ethanol or alcohol-water or water are solvent, carry out it is characterized in that using the soluble aluminum hydrochlorate as catalyzer along propylene phosphonic acid cyclic oxidizing reaction under the condition of catalyzer and hydrogen peroxide existence.
2. according to right 1 described method, it is characterized in that: described molybdate is sodium salt or ammonium salt.
3. according to claim 1 or 2 described methods, it is characterized in that: suitable propylene phosphonic acids: molybdate=1: 0.01-0.1 (weight ratio), its preferred proportion is 1: 0.03-0.06.
4. according to the described method of claim 1, this method is carried out as follows:
(1) will be along the propylene phosphonic acids in g/V=1: 3~5 ratio be dissolved in ethanol or alcohol-water or the water solvent, slowly drips (+)-α-Ben Yian under 20~30 ℃, regulates pH=5.5-6.0;
(2) in along the propylene phosphonic acids: the ratio of molybdate=1: 0.01-0.1 (weight ratio) takes by weighing the soluble molybdenum hydrochlorate, stirs down it to be joined in the solution that step (1) makes;
(3) mixture with step (2) is warming up to 40--45 ℃, slowly drips the hydrogen peroxide that concentration is 30%-35%, and the control reacting liquid temperature surpasses 60 ℃, and the mol ratio of suitable propylene phosphonic acids and added hydrogen peroxide is 1: 1.1~1.3;
(4) continue reaction 1--2 hour at 55--65 ℃, reaction finishes, if use alcohol to make solvent, places refrigerator and keeps 12-24 hour at-5 ℃, and suction filtration is with adequate amount of ethanol flushing, drying; If be but that the solvent vacuum is removed 60-70% water, add adequate amount of ethanol again, dissolving with water; Place refrigerator and kept 12-24 hour at-5 ℃, suction filtration is with adequate amount of ethanol flushing, drying; Promptly get (-)-phosphonomycin-(+)-α-Ben Yian salt;
(5) according to NaOH: H 2O=1: 2 weight ratio preparation NaOH solution, again by (-)-phosphonomycin-(+)-α-Ben Yian salt: the weight ratio of NaOH solution=9: 8, under 10-15 ℃ of stirring, (-)-phosphonomycin-(+)-α-Ben Yian salt dissolved in the layering that dissociates of NaOH solution, the upper strata is (+)-α-Ben Yian, and lower floor is (-)-phosphonomycin disodium salt aqueous solution;
(6) (-)-fosfomycin sodium salt brine solution of step (5) preparation is slowly joined under effectively stirring in 50 ℃ the ethanol of 8 times of volumes (V/g) amount, separate out the white powder crystal, suction filtration, use alcohol flushing, drying promptly gets (-)-the phosphonomycin disodium salt, is the finished product.
CN 02121110 2002-06-07 2002-06-07 Process for synthesizing fosfomycin using cis-propenyl phosphonic acid as raw material Pending CN1385435A (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102372742A (en) * 2010-08-13 2012-03-14 王彦明 Technology for producing fosfomycin sodium through spray-drying method
CN102675117A (en) * 2006-06-30 2012-09-19 先灵公司 Synthesis of 3-(5-nitrocyclohex-1-enyl) acrylic acid and esters thereof
CN107098935A (en) * 2016-12-20 2017-08-29 武汉工程大学 It is a kind of to cool down the method that dissolved couples crystal refining fosfomycin phenylethylamine calt
CN108558947A (en) * 2018-05-14 2018-09-21 沈阳化工大学 A kind of method that one kettle way prepares fosfomycin sodium
CN108690077A (en) * 2018-05-24 2018-10-23 徐州诺克非医药科技有限公司 A kind of synthetic method of the right amine salt of the left phosphine of intermediate
CN109369718A (en) * 2018-12-07 2019-02-22 武汉工程大学 A kind of preparation method and phosphonomycin of the right ammonium salt of left phosphorus

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102675117A (en) * 2006-06-30 2012-09-19 先灵公司 Synthesis of 3-(5-nitrocyclohex-1-enyl) acrylic acid and esters thereof
CN102372742A (en) * 2010-08-13 2012-03-14 王彦明 Technology for producing fosfomycin sodium through spray-drying method
CN102372742B (en) * 2010-08-13 2015-09-23 王彦明 A kind of production technique adopting spray-drying process to make fosfomycin sodium
CN107098935A (en) * 2016-12-20 2017-08-29 武汉工程大学 It is a kind of to cool down the method that dissolved couples crystal refining fosfomycin phenylethylamine calt
CN107098935B (en) * 2016-12-20 2019-05-03 武汉工程大学 A kind of method of cooling-dissolved coupling crystal refining fosfomycin phenylethylamine calt
CN108558947A (en) * 2018-05-14 2018-09-21 沈阳化工大学 A kind of method that one kettle way prepares fosfomycin sodium
CN108690077A (en) * 2018-05-24 2018-10-23 徐州诺克非医药科技有限公司 A kind of synthetic method of the right amine salt of the left phosphine of intermediate
CN109369718A (en) * 2018-12-07 2019-02-22 武汉工程大学 A kind of preparation method and phosphonomycin of the right ammonium salt of left phosphorus

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