CN103113250A - Preparation method of D-para hydroxybenzene glycine methyl ester - Google Patents
Preparation method of D-para hydroxybenzene glycine methyl ester Download PDFInfo
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- CN103113250A CN103113250A CN2013100743461A CN201310074346A CN103113250A CN 103113250 A CN103113250 A CN 103113250A CN 2013100743461 A CN2013100743461 A CN 2013100743461A CN 201310074346 A CN201310074346 A CN 201310074346A CN 103113250 A CN103113250 A CN 103113250A
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Abstract
The invention provides a preparation method of D-para hydroxybenzene glycine methyl ester. The method comprises the following steps of: firstly, preparing a hydrochloric acid methanol solution; adding D-para hydroxybenzene glycine into the hydrochloric acid methanol solution to perform reflux reaction for 2-4 hours at 65-80 DEG C; performing pressure reduction distillation and removing methanol; and adding water to obtain a D-para hydroxybenzene glycine methyl ester aqueous solution. Based on that, the invention also provides anenzymatic synthesis method of amoxicillin. The method comprises the following steps of: adding 6-APA and immobilized penicillin acylase into the D-para hydroxybenzene glycine methyl ester aqueous solution to react for 1-8 hours at 10-30 DEG C; regulating the pH value of a reaction liquid to 0.8-1.0 by using hydrochloric acid or sulfuric acid aqueous solution; regulating the pH value to 4.5-6.0 by using ammonia water or sodium hydroxide aqueous solution to crystallize for 1-5 hours at 0-30 DEG C; separating solid from liquid; collecting a solid; and washing and drying to obtain amoxicillin. The method is simple in steps, and low in cost; and the obtained -para hydroxybenzene glycine methyl ester is high in yield and less in impurities and can be directly applied to anenzymatic synthesis of amoxicillin.
Description
Technical field
The invention belongs to the technology of pharmaceutical engineering field, specifically, relate to a kind of method of the synthetic D-pHPG methyl esters of enzyme process of amoxycilline Trihydrate bp.
Background technology
Amoxycilline Trihydrate bp (Amoxicillin) is a kind of the most frequently used β-lactam antibitics.The synthetic method of amoxycilline Trihydrate bp has two kinds usually: a kind of is chemical synthesis, and another kind of is enzyme catalysis synthesis method (abbreviation enzyme process).Enzyme process utilizes the katalysis of immobilized penicillin acylase, generates the amoxycilline Trihydrate bp by parent nucleus 6-amino-penicillanic acid (being called for short 6-APA) and the reaction of side chain D-pHPG methyl esters.Compare with chemical synthesis, enzyme process need not to use organic solvent, gentle, low, the convenient operation of energy consumption of reaction conditions, and quality product is more excellent.
At present, the raw material D-pHPG methyl esters of the synthetic amoxycilline Trihydrate bp of enzyme process, its conventional preparation method reacts D-pHPG, methyl alcohol under the condition that thionyl chloride exists.The method produces a large amount of hydrogen chloride gas when thionyl chloride operates, etching apparatus also brings immense pressure to environmental protection easily.Chinese patent application 201210196387.3 discloses a kind of synthetic method of p-hydroxyphenylglycine methyl ester, may further comprise the steps: 1, take D-pHPG or its salt as starting raw material, react with methyl alcohol in the presence of solid acid; 2, reaction complete after, with reaction solution cooling, the filtered and recycled solid acid; 3, liquid phase concentrating under reduced pressure, enriched material is water-soluble, and being neutralized to pH with alkali is 7.0-9.0; 4, filter, dry to get p-hydroxyphenylglycine methyl ester.Although the method has been avoided the corrosion of equipment to a certain extent, have the advantage of environmental protection, its step is still comparatively loaded down with trivial details, wayward, and especially yield and product purity are still not fully up to expectations.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of step D-pHPG methyl esters simple, with low cost, the enzyme process that the method products obtained therefrom can be directly used in the amoxycilline Trihydrate bp synthesizes.
For realizing the object of the invention, the invention provides a kind of preparation method of D-pHPG methyl esters, step is as follows:
A, pass into hydrogen chloride gas in methyl alcohol, obtain hydrogen chloride methanol solution, wherein the mass volume ratio concentration of hydrogenchloride is 7-14%;
B, in hydrogen chloride methanol solution, add D-pHPG, in 65-80 ℃ of lower back flow reaction 2-4 h, obtain D-pHPG methyl esters methanol solution;
Methyl alcohol is removed in c, underpressure distillation, adds water, obtains the D-pHPG methyl esters aqueous solution.Wherein, the concentration of D-pHPG methyl esters is preferably 130 ~ 165mol/L.
In the b step of the present invention, the mol ratio of D-pHPG, hydrogenchloride is preferably 2-3.5:1, and esterification reaction rate is fast under this condition, and reaction is carried out fully.
The described underpressure distillation of c step of the present invention, its temperature is preferably 40-70 ℃, vacuum tightness should be not less than-0.08MPa, be preferably-0.08 ~-0.09MPa, under this condition Methanol Recovery fully, the synthetic intermediate stable in properties.
The described hydrogen chloride gas of a step of the present invention can prepare by in following two kinds of methods any one: method one is to make the vitriol oil, ammonium chloride reaction, collects the hydrogen chloride gas that reaction produces; Method two is to add Thickish hot hydrochloric acid, collects the hydrogen chloride gas that volatilization produces.
In addition, the present invention also provides the method for the synthetic amoxycilline Trihydrate bp of a kind of enzyme process, and the method is take the above-mentioned D-pHPG methyl esters aqueous solution as raw material; in 10-30 ℃ of lower reaction 1-8h; remove immobilized penicillin acylase, add hydrochloric acid or aqueous sulfuric acid and regulate the pH value to 0.8-1.4, then add ammoniacal liquor or aqueous sodium hydroxide solution and regulate the pH value to 4.5-6.0; in 0-30 ℃ of lower crystallization 1-5 h; filter, collect solid, washing; drying obtains the amoxycilline Trihydrate bp.
In the aforesaid method, the mol ratio of D-pHPG methyl esters, 6-APA is preferably 1-1.6:1, prepares the amoxycilline Trihydrate bp according to this ratio, and side reaction is few, and reaction is carried out fully.
The present invention prepares the D-pHPG methyl esters aqueous solution take hydrogen chloride methanol solution, D-pHPG as raw material, this preparation method's D-pHPG methyl esters yield is higher than prior art, and improved product purity, after measured, the transformation efficiency of D-pHPG methyl esters is not less than 96.8%.The enzyme process that the prepared D-pHPG methyl esters aqueous solution of method of the present invention can be directly used in the amoxycilline Trihydrate bp synthesizes, the operations such as the in the past necessary crystallization of D-pHPG methyl esters preparation process, separation, washing and drying have been changed, simplified operation steps, reduced energy consumption, reduce factory building, facility investment, thereby reached the purpose that reduces the integral production cost.On this basis; the invention provides take the above-mentioned D-pHPG methyl esters aqueous solution, 6-APA, immobilized penicillin acylase and prepare the production technique of amoxycilline Trihydrate bp as raw material; this processing step is simple, energy-conserving and environment-protective, and product amoxycilline Trihydrate bp yield is high, purity is high.
Description of drawings
Fig. 1 is the preparation of D-pHPG methyl esters of the present invention and the process flow sheet of the synthetic amoxycilline Trihydrate bp of enzyme process.
Embodiment
The below further specifies content of the present invention with specific embodiment, but and means never in any form and limit the invention.Method therefor is ordinary method if no special instructions in the following example.
Embodiment 1
The preparation of hydrogen chloride gas: get 49g ammonium chloride and join gas generating unit, drip the 90g vitriol oil, it is for subsequent use that collection obtains the 13.9g hydrogen chloride gas.
The preparation of D-pHPG methyl esters (as shown in Figure 1):
A, pass into previously prepared hydrogen chloride gas in methyl alcohol, obtain hydrogen chloride methanol solution, wherein the mass volume ratio concentration of hydrogenchloride is 7%.
B, add D-pHPG in above-mentioned hydrogen chloride methanol solution, wherein, the mol ratio of D-pHPG, hydrogenchloride is 2:1, then heating in water bath to 65 ℃, back flow reaction 2h obtains D-pHPG methyl esters methanol solution, and reaction conversion ratio is 96.8%.
C, above-mentioned D-pHPG methyl esters methanol solution is placed under 40 ℃, the condition of vacuum tightness-0.08MPa, underpressure distillation is to steaming without cut, the concentration that adds water to the D-pHPG methyl esters is 135mol/L, obtain the D-pHPG methyl esters aqueous solution, after measured, wherein the weight yield of D-pHPG methyl esters is 104.9%.
Embodiment 2
Prepare according to a conventional method hydrogen chloride gas: get 40g ammonium chloride and join gas generating unit, drip the 73g vitriol oil, it is for subsequent use that collection obtains the 15.27g hydrogen chloride gas.
The preparation of D-pHPG methyl esters:
A, pass into previously prepared hydrogen chloride gas in methyl alcohol, obtain hydrogen chloride methanol solution, wherein the mass volume ratio concentration of hydrogenchloride is 14%.
B, add D-pHPG in above-mentioned hydrogen chloride methanol solution, wherein, the mol ratio of D-pHPG, hydrogenchloride is 3.5:1, then heating in water bath to 80 ℃, back flow reaction 4h obtains D-pHPG methyl esters methanol solution, and reaction conversion ratio is 97.6%.
C, above-mentioned D-pHPG methyl esters methanol solution is placed under 70 ℃, the condition of vacuum tightness-0.09MPa, underpressure distillation is to steaming without cut, the concentration that adds water to the D-pHPG methyl esters is 148mol/L, obtain the D-pHPG methyl esters aqueous solution, after measured, wherein the weight yield of D-pHPG methyl esters is 105.6%.
Embodiment 3
The preparation of hydrogen chloride gas: measure concentrated hydrochloric acid 500mL, heating, it is for subsequent use that collection obtains the 8.2g hydrogen chloride gas.
The preparation of D-pHPG methyl esters:
A, pass into previously prepared hydrogen chloride gas in methyl alcohol, obtain hydrogen chloride methanol solution, wherein the mass volume ratio concentration of hydrogenchloride is 10%.
B, add D-pHPG in above-mentioned hydrogen chloride methanol solution, wherein, the mol ratio of D-pHPG, hydrogenchloride is 2.5:1, then heating in water bath to 75 ℃, back flow reaction 3h obtains D-pHPG methyl esters methanol solution, and reaction conversion ratio is 98.5%.
C, above-mentioned D-pHPG methyl esters methanol solution is placed under 50 ℃, the condition of vacuum tightness-0.085MPa, underpressure distillation is to steaming without cut, the concentration that adds water to the D-pHPG methyl esters is 165mol/L, obtain the D-pHPG methyl esters aqueous solution, after measured, wherein the weight yield of D-pHPG methyl esters is 106.7%.
The comparative example 1
Prepare the D-pHPG methyl esters according to existing method:
A, take D-pHPG as starting raw material, in the presence of 50-80 degree centigrade, silicotungstic acid with the methyl alcohol reaction, react complete after, reaction solution is cooled off the filtered and recycled solid acid;
B, will filter gained liquid phase concentrating under reduced pressure, enriched material is water-soluble, and being neutralized to pH with alkali is 7.0-9.0, obtains the D-pHPG methyl esters aqueous solution, and after measured, wherein the weight yield of D-pHPG methyl esters is 92.3%.Compare with embodiment 1 ~ 3, the weight yield of existing method gained D-pHPG methyl esters is lower.
The comparative example 2
Respectively take the prepared D-pHPG methyl esters aqueous solution of embodiment 3, comparative example 1 as raw material, according to the synthetic amoxycilline Trihydrate bp (as shown in Figure 1) of following steps.
A, in the D-pHPG methyl esters aqueous solution, add respectively 6-APA, immobilized penicillin acylase, carry out the enzyme catalysis building-up reactions.Wherein, the mol ratio of D-pHPG methyl esters, 6-APA is 1-1.6:1; The concentration of immobilized penicillin acylase is 6000 activity units/L in the reaction solution.Then in 10-30 ℃ of lower reaction 1-8h, suction filtration is removed immobilized penicillin acylase, obtains containing the reaction solution of amoxycilline Trihydrate bp.
B, employing concentration are that the hydrochloric acid of 6mol/L carries out acidification to the reaction solution that contains the amoxycilline Trihydrate bp, obtain the pH value and be the acidizing fluid of 0.8-1.4, then be that 4mol/L ammoniacal liquor to pH value is 4.5-6.0 to wherein adding concentration, in 0-30 ℃ of lower crystallization 1-5h, obtain the amoxycilline Trihydrate bp crystal solution, carry out suction filtration and process, collect solid, washing, drying obtains the amoxycilline Trihydrate bp.
After measured, by the amoxycilline Trihydrate bp of embodiment 3 gained D-pHPG methyl esters preparation, its weight yield is 176.3%, and content is 100.78%.By the amoxycilline Trihydrate bp of comparative example's 1 gained D-pHPG methyl esters preparation, its weight yield is 97.3%, and content is 87.6%.By above result as can be known, the enzyme process that the D-pHPG methyl esters aqueous solution that the method for the invention obtains can be directly used in the amoxycilline Trihydrate bp synthesizes, and the products therefrom yield is high, purity is high.
Claims (7)
1. the preparation method of a D-pHPG methyl esters is characterized in that may further comprise the steps:
A, pass into hydrogen chloride gas in methyl alcohol, obtain hydrogen chloride methanol solution, wherein the mass volume ratio concentration of hydrogenchloride is 7-14%;
B, in hydrogen chloride methanol solution, add D-pHPG, in 65-80 ℃ of lower back flow reaction 2-4 h, obtain D-pHPG methyl esters methanol solution;
Methyl alcohol is removed in c, underpressure distillation, adds water, obtains the D-pHPG methyl esters aqueous solution.
2. the preparation method of described D-pHPG methyl esters according to claim 1, it is characterized in that: the described D-pHPG methyl esters of the c step aqueous solution, wherein the concentration of D-pHPG methyl esters is 130 ~ 165mol/L.
3. the preparation method of described D-pHPG methyl esters according to claim 1, it is characterized in that: in the b step, the mol ratio of described D-pHPG, hydrogenchloride is 2-3.5:1.
4. the preparation method of described D-pHPG methyl esters according to claim 1 and 2, it is characterized in that: the described underpressure distillation of c step, its temperature are 40-70 ℃, and its vacuum tightness is not less than-0.08MPa.
5. the preparation method of described D-pHPG methyl esters according to claim 1 and 2, it is characterized in that: the described hydrogen chloride gas of a step, its preparation method are to make the vitriol oil, ammonium chloride reaction, or add Thickish hot hydrochloric acid.
6. the method for the synthetic amoxycilline Trihydrate bp of an enzyme process; it is characterized in that: add 6-APA, immobilized penicillin acylase in the D-pHPG methyl esters aqueous solution of the described method preparation of any one in the claim 1 ~ 5; in 10-30 ℃ of lower reaction 1-8h; remove immobilized penicillin acylase; add hydrochloric acid or aqueous sulfuric acid and regulate the pH value to 0.8-1.4; then add ammoniacal liquor or aqueous sodium hydroxide solution and regulate the pH value to 4.5-6.0; in 0-30 ℃ of lower crystallization 1-5 h; filter; collect solid; washing, drying obtains the amoxycilline Trihydrate bp.
7. the method for the synthetic amoxycilline Trihydrate bp of described enzyme process according to claim 6, it is characterized in that: the mol ratio of described D-pHPG methyl esters, 6-APA is 1-1.6:1.
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Cited By (5)
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| CN103553949A (en) * | 2013-10-11 | 2014-02-05 | 孟兰尊 | Preparation method for alpha-amino-methyl p-hydroxyphenylacetate or sulfate thereof |
| CN105567777A (en) * | 2016-03-07 | 2016-05-11 | 内蒙古常盛制药有限公司 | Method for recycling amoxicillin mother solution |
| WO2016202252A1 (en) * | 2015-06-16 | 2016-12-22 | 山西新宝源制药有限公司 | Method for synthesizing d-para-hydroxyphenylglycine methyl ester |
| CN109400491A (en) * | 2018-11-02 | 2019-03-01 | 威海海洋职业学院 | A kind of crystallization preparation method of D-HPG methyl esters |
| CN109867687A (en) * | 2017-12-05 | 2019-06-11 | 上海朝瑞化工有限公司 | A kind of highly-water-soluble Amoxicillin and preparation method thereof |
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| WO2012175587A2 (en) * | 2011-06-23 | 2012-12-27 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Novel crystalline cefoperazone intermediate |
| CN102660621A (en) * | 2012-05-04 | 2012-09-12 | 联邦制药(内蒙古)有限公司 | Improved method for preparing amoxicillin by enzymic method |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103553949A (en) * | 2013-10-11 | 2014-02-05 | 孟兰尊 | Preparation method for alpha-amino-methyl p-hydroxyphenylacetate or sulfate thereof |
| CN103553949B (en) * | 2013-10-11 | 2016-01-13 | 河北远大中正生物科技有限公司 | The preparation method of a kind of alpha-amino group-p-hydroxyphenylaceticacid methyl esters or its vitriol |
| WO2016202252A1 (en) * | 2015-06-16 | 2016-12-22 | 山西新宝源制药有限公司 | Method for synthesizing d-para-hydroxyphenylglycine methyl ester |
| CN105567777A (en) * | 2016-03-07 | 2016-05-11 | 内蒙古常盛制药有限公司 | Method for recycling amoxicillin mother solution |
| CN109867687A (en) * | 2017-12-05 | 2019-06-11 | 上海朝瑞化工有限公司 | A kind of highly-water-soluble Amoxicillin and preparation method thereof |
| CN109867687B (en) * | 2017-12-05 | 2021-08-17 | 上海朝瑞化工有限公司 | High water-soluble amoxicillin and preparation method thereof |
| CN109400491A (en) * | 2018-11-02 | 2019-03-01 | 威海海洋职业学院 | A kind of crystallization preparation method of D-HPG methyl esters |
| CN109400491B (en) * | 2018-11-02 | 2021-03-23 | 威海海洋职业学院 | Crystallization preparation method of L-p-hydroxyphenylglycine methyl ester |
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Application publication date: 20130522 |