CN104829478A - Preparation process of D-phenylglycine methyl ester hydrochloride crystals - Google Patents
Preparation process of D-phenylglycine methyl ester hydrochloride crystals Download PDFInfo
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- CN104829478A CN104829478A CN201510249330.9A CN201510249330A CN104829478A CN 104829478 A CN104829478 A CN 104829478A CN 201510249330 A CN201510249330 A CN 201510249330A CN 104829478 A CN104829478 A CN 104829478A
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Abstract
The invention belongs to the technical field of the chemical industry, and in particular relates to a preparation process of D-phenylglycine methyl ester hydrochloride crystals. The preparation process comprises the following steps: sequentially adding methanol and D-phenylglycine into a reactor, stirring uniformly, and slowly adding sulfoxide chloride; controlling the temperature in the reactor below 55DEG C, and controlling the temperature in the reactor to be 55-65DEG C after adding sulfoxide chloride; performing reflux reaction, then performing vacuum azeotropic distillation, and finally performing temperature controlled cooling crystallization; and filtering, washing and drying to obtain a D-phenylglycine methyl ester hydrochloride crystal product. The preparation process provided by the invention is high in one-pass yield, the prepared product is high in purity, good in color grade and stable in quality, the preparation process is low in production cost, and the operation is easy to control.
Description
Technical field
The invention belongs to the preparation field of pharmaceutical intermediate, be specifically related to a kind of preparation technology of D-PG methyl ester hydrochloride salt.
Background technology
D-PG methyl ester hydrochloride, English name D-(-)-α-phenylglycine methyl esterhydrochloride (CAS No.:19883411), molecular formula C
9h
11nO
2.HCl, fusing point 189-191 DEG C, relative molecular mass 201.65, specific rotatory power ([α] 20/D) :+120 ° of (c=1, H
2o), D-PG methyl ester hydrochloride is white powder or crystallization, if product understands yellowish or grey when being wherein mixed with impurity, and the easy moisture absorption.Structural formula is shown below:
D-PG methyl esters is the active side chain of enzymatic clarification cefaclor, Cephalexin Monohydrate Micro/Compacted, containing amino in its molecular structure, oxidizable, is easily polymerized, poor stability, is unfavorable for preserving, is therefore necessary to protect its amino.At present, usually this problem is solved by form D-PG methyl esters being made D-PG methyl ester hydrochloride.Though D-PG methyl ester hydrochloride has comparatively strong absorptive, its stability is high, can exist in solid form, is conducive to long-term preservation, is more conducive to the screening of active biological enzyme and the determination of charge ratio in experimentation, very easy to use.
The synthetic method of the D-PG methyl ester hydrochloride mentioned in " synthesis of cefaclor active side chain Phenylglycine methyl ester hydrochloride " that Zheng Guixian (Zhejiang Onlly pharmaceutical Co. Ltd) delivers for 2014 adopts sulfur oxychloride method.Below 35 DEG C, thionyl chloride is slowly joined in methanol solution, generate protochloride methyl sulfate, this process heat release is serious, need cool temperature control; After thionyl chloride drips off, in reaction system, add D-PG, be heated to 55 ~ 60 DEG C of backflow certain hours, generate D-PG methyl ester hydrochloride, then cooling is stirred and product is separated out with the form of crystal, reclaims reaction mother liquor and waits to apply mechanically.There is following subject matter in the method: one in building-up process, and the first step reaction is thermopositive reaction, needs to control temperature of reaction by cooling; And second step requires to carry out at relatively high temperatures, need heat temperature raising, whole building-up process does not make full use of reaction heat, and production energy consumption is higher.They are two years old, adopt a productive rate of this kind of method synthesis D-PG methyl ester hydrochloride low, do not meet the requirement of suitability for industrialized production, in order to improve total recovery, it proposes reaction mother liquor and needs time use, but in mother liquid recycle process, impurity can be accumulated in mother liquor, mother liquor is turned yellow, thus affects the quality index such as purity and look level of product, and easily cause unstable product quality.The purity of the D-PG methyl ester hydrochloride after time use can drop to less than 98%, and look level reaches more than 3#.Difficulty is caused to the production of down-stream enterprise.
Summary of the invention
The present invention is for solving the problems of the prior art, and provide a kind of preparation technology of D-PG methyl ester hydrochloride, this technique building-up process makes full use of reaction heat and carries out system intensification, does not need the external world to provide low-temperature receiver and thermal source, and Energy harvesting is more reasonable; The product purity prepared is high, look level is excellent, a yield is high, and constant product quality production technique is easy, easy to operate, and production cost is low, is suitable for large-scale industrial and produces.
For solving the problems of the technologies described above, the present invention is implemented by the following technical solutions:
A preparation technology for D-PG methyl ester hydrochloride, comprises the following steps:
A. by D-PG and methyl alcohol in mass ratio (16 ~ 40): the ratio of 100 adds in reactor, open and stir, after being fully formed suspension liquid, sulfur oxychloride is slowly added in reaction system, control adds speed, utilize reaction heat to make reactor temperature be no more than 55 DEG C, described sulfur oxychloride and D-PG mass ratio are (1 ~ 1.5): 1;
B., after the reinforced end of sulfur oxychloride, insulation, makes reactor temperature maintain 55 ~ 65 DEG C, back flow reaction 0.5 ~ 2.5h;
C. back flow reaction terminates, then reactor temperature maintains 30-60 DEG C, liquid in stirred reactor, in reactor, add entrainer carry out azeotroped in vacuo distillation, in reactor, vacuum tightness maintains 0.05 ~ 0.1MPa, the feed way of entrainer is that gradation is added or added continuously, in question response device in solution the mass content of methyl alcohol lower than after 5-20%, stop azeotroped in vacuo distillation, carry out temperature control crystallisation by cooling, cooling end of a period reactor temperature controls at 0 ~ 15 DEG C, keep reactor temperature constant, Keep agitation 20 ~ 100 minutes, then after filtration, obtain filter cake,
D. with 10% ~ 30% of filter cake volume, temperature is the methanol wash filter cake of 0 ~ 5 DEG C, vacuum-drying 1.5 ~ 3h at 55 ~ 60 DEG C, obtains D-PG methyl ester hydrochloride salt product.Product purity can reach more than 99%, and look level reaches 1#.
Preferably, the order of addition(of ingredients) in described reaction process is: D-PG, methyl alcohol, sulfur oxychloride.
Preferably, the additional way of described entrainer is: when gradation is added, and the number of times that gradation is added is 2 ~ 6 times;
Preferably, the additional way of described entrainer is: when adding continuously, needs to maintain liquid level in reactor constant.
Preferably, described entrainer is one or more in hexanaphthene, normal hexane, benzene, toluene, ethyl acetate, methyl propionate.
Preferably, in described step a, the mass ratio of D-PG and methyl alcohol is (20 ~ 30): 100;
Preferably, in described step b, reactor temperature maintains 60 DEG C, and reflux time is 1.5 ~ 2h;
Preferably, after in described step c, back flow reaction terminates, reactor temperature maintains 40 ~ 50 DEG C;
Preferably, the preparation technology of described a kind of D-PG methyl ester hydrochloride salt, comprises following concrete steps:
Take D-PG 70g, measure methyl alcohol 300mL, add in 500mL four-hole boiling flask reactor successively, open and stir, after mixing, measure sulfur oxychloride 60mL, by constant pressure funnel, sulfur oxychloride is slowly added in flask, 1.5h drip off, reactor temperature is made to maintain 55 DEG C in dropping process, after dropwising, maintaining reactor temperature is 60 DEG C, backflow 0.5h, reaction terminates, then reactor temperature is controlled at 45 DEG C, liquid in stirred reactor, in reactor, add hexanaphthene carry out azeotroped in vacuo distillation, in reactor, vacuum tightness maintains 0.05MPa, the additional way of entrainer is for add continuously, maintain liquid level in reactor constant, in question response device in solution the mass content of methyl alcohol lower than after 20%, stop azeotroped in vacuo distillation, carry out temperature control crystallisation by cooling, cooling finishing temperature controls at 15 DEG C, keep the constant Keep agitation of reactor temperature 50 minutes, then after filtration, and be the methanol wash filter cake of 5 DEG C by the temperature of 30% of filter cake volume, vacuum-drying 3h at 55 DEG C, obtain D-PG methyl ester hydrochloride salt product.
The present invention compared with prior art has following significant advantage:
The preparation technology of D-PG methyl ester hydrochloride salt provided by the invention changes existing synthesis and crystallization processes.Propose D-PG, methyl alcohol, sulfur oxychloride three kinds of reactants new addition sequence process is made full use of reaction heat carries out heating up, Energy harvesting is more reasonable, shorten the reaction times, improve production capacity; In crystallisation process, use azeotroped in vacuo to distill crystallization substitute existing cooling and crystallizing process, a productive rate is improved greatly, product purity can reach more than 99%, owing to avoiding applying mechanically of mother liquor, makes product purity high, look level is excellent, can reach 1# look level, constant product quality, production technique is simple and easy to operate, production cost is low, is conducive to industrial production.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.
Embodiment 1:
Take D-PG 70g, measure methyl alcohol 300mL, add in 500mL four-hole boiling flask reactor successively, open and stir, after mixing, measure sulfur oxychloride 60mL, by constant pressure funnel, sulfur oxychloride is slowly added in flask, 1.5h drip off, make reactor temperature maintain 55 DEG C, after dropwising in dropping process, maintaining reactor temperature is 60 DEG C, backflow 0.5h, reaction terminates.Then reactor temperature is controlled at 45 DEG C, liquid in stirred reactor, in reactor, add hexanaphthene carry out azeotroped in vacuo distillation, in reactor, vacuum tightness maintains 0.05MPa, the additional way of entrainer, for add continuously, maintains liquid level in reactor constant.In question response device in solution the mass content of methyl alcohol lower than after 20%, stop azeotroped in vacuo distillation, carry out temperature control crystallisation by cooling, cooling finishing temperature controls at 15 DEG C, keeping reactor temperature constant Keep agitation 50 minutes, then after filtration, and is the methanol wash filter cake of 5 DEG C by the temperature of 30% of filter cake volume, vacuum-drying 3h at 55 DEG C, obtains D-PG methyl ester hydrochloride salt product.
Embodiment 2:
Take D-PG 25g, measure methyl alcohol 200mL, add in 500mL four-hole boiling flask reactor successively, open and stir, to be mixed evenly after, measure sulfur oxychloride 20mL, by constant pressure funnel, sulfur oxychloride is slowly added in reaction system, in dropping process, make reactor temperature maintain 50 DEG C, after dropping terminates, controlling temperature of reactor is 65 DEG C, and backflow 1h, reacts complete.Then reactor temperature is controlled at 40 DEG C, liquid in stirred reactor, the entrainer toluene of liquor capacity in reactor 30% is added rapidly in reactor, carry out azeotroped in vacuo distillation, in reactor, vacuum tightness maintains 0.08MPa, when distillate volume reaches the volume of toluene added, again add the toluene of same volume, after adding 4 times, in question response device in solution the mass content of methyl alcohol lower than 10%, stop azeotroped in vacuo distillation, carry out temperature control crystallisation by cooling, cooling finishing temperature controls at 5 DEG C, keep the constant Keep agitation of reactor temperature 30 minutes, then after filtration, and be the methanol wash filter cake of 5 DEG C by the temperature of 20% of filter cake volume, vacuum-drying 3h at 55 DEG C, obtain D-PG methyl ester hydrochloride salt product.
Embodiment 3:
Take D-PG 94g, measure methyl alcohol 300mL, add in 500mL four-hole boiling flask reactor successively, open and stir, after mixing, measure sulfur oxychloride 85mL, slowly added in reaction system by sulfur oxychloride by constant pressure funnel, 1.5h drips off, reactor temperature is made to maintain 50 DEG C in dropping process, after dropping terminates, temperature of reactor is controlled, at 60 DEG C of backflow 1h, react complete.Then controlled by reactor temperature at 40 DEG C, liquid in stirred reactor, add normal hexane and carry out azeotroped in vacuo distillation in reactor, the additional way of entrainer, for add continuously, maintains liquid level in reactor constant.In reactor, vacuum tightness maintains 0.07MPa, in question response device in solution the mass content of methyl alcohol lower than 5%, stop azeotroped in vacuo distillation, carry out temperature control crystallisation by cooling, cooling finishing temperature controls at 0 DEG C, keeps the constant Keep agitation of reactor temperature 30 minutes, then after filtration, and be the methanol wash filter cake of 0 DEG C by the temperature of 10% of filter cake volume, vacuum-drying 1.5h at 55 DEG C, obtains D-PG methyl ester hydrochloride salt product.
Embodiment 4:
Take D-PG 82g, measure methyl alcohol 300mL, add in 500mL four-hole boiling flask reactor successively, open and stir, after mixing, measure sulfur oxychloride 50mL, slowly added in reaction system by sulfur oxychloride by constant pressure funnel, 1.5h drips off, reactor temperature is made to maintain 55 DEG C in dropping process, after dropping terminates, temperature of reactor is controlled, at 55 DEG C of backflow 2.5h, react complete.Then controlled by reactor temperature at 60 DEG C, liquid in stirred reactor, add methyl propionate and carry out azeotroped in vacuo distillation in reactor, the additional way of entrainer, for add continuously, maintains liquid level in reactor constant.In reactor, vacuum tightness maintains 0.09MPa, in question response device in solution the mass content of methyl alcohol lower than 10%, stop azeotroped in vacuo distillation, carry out temperature control crystallisation by cooling, cooling finishing temperature controls at 10 DEG C, keeps the constant Keep agitation of reactor temperature 90 minutes, then after filtration, and be the methanol wash filter cake of 0 DEG C by the temperature of 30% of filter cake volume, vacuum-drying 2h at 55 DEG C, obtains D-PG methyl ester hydrochloride salt product.
Claims (9)
1. a preparation technology for D-PG methyl ester hydrochloride, is characterized in that, comprises the following steps:
A. by D-PG and methyl alcohol in mass ratio (16 ~ 40): the ratio of 100 adds in reactor, open and stir, after being fully formed suspension liquid, sulfur oxychloride is slowly added in reaction system, control adds speed, utilize reaction heat to make reactor temperature be no more than 55 DEG C, described sulfur oxychloride and D-PG mass ratio are (1 ~ 1.5): 1;
B., after the reinforced end of sulfur oxychloride, insulation, makes reactor temperature maintain 55 ~ 65 DEG C, back flow reaction 0.5 ~ 2.5h;
C. back flow reaction terminates, then reactor temperature maintains 30-60 DEG C, liquid in stirred reactor, in reactor, add entrainer carry out azeotroped in vacuo distillation, in reactor, vacuum tightness maintains 0.05 ~ 0.1MPa, the feed way of entrainer is that gradation is added or added continuously, in question response device in solution the mass content of methyl alcohol lower than after 5-20%, stop azeotroped in vacuo distillation, carry out temperature control crystallisation by cooling, cooling end of a period reactor temperature controls at 0 ~ 15 DEG C, keep reactor temperature constant, Keep agitation 20 ~ 100 minutes, then after filtration, obtain filter cake,
D. with 10% ~ 30% of filter cake volume, temperature is the methanol wash filter cake of 0 ~ 5 DEG C, vacuum-drying 1.5 ~ 3h at 55 ~ 60 DEG C, obtains D-PG methyl ester hydrochloride salt product.
2. the preparation technology of a kind of D-PG methyl ester hydrochloride salt as claimed in claim 1, it is characterized in that, the order of addition(of ingredients) in described reaction process is: D-PG, methyl alcohol, sulfur oxychloride.
3. the preparation technology of a kind of D-PG methyl ester hydrochloride salt as claimed in claim 1, is characterized in that the additional way of described entrainer is: when gradation is added, the number of times that gradation is added is 2 ~ 6 times.
4. the preparation technology of a kind of D-PG methyl ester hydrochloride salt as claimed in claim 1, is characterized in that the additional way of described entrainer is: when adding continuously, needs to maintain liquid level in reactor constant.
5. the preparation technology of a kind of D-PG methyl ester hydrochloride salt as claimed in claim 1, is characterized in that described entrainer is one or more in hexanaphthene, normal hexane, benzene, toluene, ethyl acetate, methyl propionate.
6. the preparation technology of a kind of D-PG methyl ester hydrochloride salt as claimed in claim 1, is characterized in that the mass ratio of D-PG and methyl alcohol in described step a is for (20 ~ 30): 100.
7. the preparation technology of a kind of D-PG methyl ester hydrochloride salt as claimed in claim 1, it is characterized in that in described step b, reactor temperature maintains 60 DEG C, reflux time is 1.5 ~ 2h.
8. the preparation technology of a kind of D-PG methyl ester hydrochloride salt as claimed in claim 1, after it is characterized in that in described step c, back flow reaction terminates, reactor temperature maintains 40 ~ 50 DEG C.
9. the preparation technology of a kind of D-PG methyl ester hydrochloride salt as claimed in claim 1, is characterized in that comprising following concrete steps:
Take D-PG 70g, measure methyl alcohol 300mL, add in 500mL four-hole boiling flask reactor successively, open and stir, after mixing, measure sulfur oxychloride 60mL, by constant pressure funnel, sulfur oxychloride is slowly added in flask, 1.5h drip off, reactor temperature is made to maintain 55 DEG C in dropping process, after dropwising, maintaining reactor temperature is 60 DEG C, backflow 0.5h, reaction terminates, then reactor temperature is controlled at 45 DEG C, liquid in stirred reactor, in reactor, add hexanaphthene carry out azeotroped in vacuo distillation, in reactor, vacuum tightness maintains 0.05MPa, the additional way of entrainer is for add continuously, maintain liquid level in reactor constant, in question response device in solution the mass content of methyl alcohol lower than after 20%, stop azeotroped in vacuo distillation, carry out temperature control crystallisation by cooling, cooling finishing temperature controls at 15 DEG C, keep the constant Keep agitation of reactor temperature 50 minutes, then after filtration, and be the methanol wash filter cake of 5 DEG C by the temperature of 30% of filter cake volume, vacuum-drying 3h at 55 DEG C, obtain D-PG methyl ester hydrochloride salt product.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110128285A (en) * | 2019-06-24 | 2019-08-16 | 华北制药股份有限公司 | D-PG methyl ester hydrochloride/D- dihydro phenyl glycine methyl ester hydrochloride preparation method |
| CN110606811A (en) * | 2019-09-23 | 2019-12-24 | 湖北宇阳药业有限公司 | Synthetic method of L-serine methyl ester hydrochloride |
| CN113100125A (en) * | 2021-04-07 | 2021-07-13 | 浙江省海洋水产研究所 | Method for improving survival rate of coilia ectenes parents |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3887606A (en) * | 1971-06-02 | 1975-06-03 | Glaxo Lab Ltd | Process for the preparation of DL-phenylglycine esters |
| JP2005082524A (en) * | 2003-09-08 | 2005-03-31 | Ihara Chem Ind Co Ltd | Manufacturing method of aminoalcohol derivative |
-
2015
- 2015-05-15 CN CN201510249330.9A patent/CN104829478B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3887606A (en) * | 1971-06-02 | 1975-06-03 | Glaxo Lab Ltd | Process for the preparation of DL-phenylglycine esters |
| JP2005082524A (en) * | 2003-09-08 | 2005-03-31 | Ihara Chem Ind Co Ltd | Manufacturing method of aminoalcohol derivative |
Non-Patent Citations (2)
| Title |
|---|
| AGNIESZKA KUDELKO等: "The reaction of optically active a-aminocarboxylic acid hydrazides with triethyl orthoesters", 《TETRAHEDRON》 * |
| 宋霞等: "二氯亚砜-甲醇溶液中合成氨基酸甲酯盐酸盐的研究", 《化学试剂》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110128285A (en) * | 2019-06-24 | 2019-08-16 | 华北制药股份有限公司 | D-PG methyl ester hydrochloride/D- dihydro phenyl glycine methyl ester hydrochloride preparation method |
| CN110128285B (en) * | 2019-06-24 | 2022-03-01 | 华北制药股份有限公司 | Preparation method of D-phenylglycine methyl ester hydrochloride/D-dihydrophenylglycine methyl ester hydrochloride |
| CN110606811A (en) * | 2019-09-23 | 2019-12-24 | 湖北宇阳药业有限公司 | Synthetic method of L-serine methyl ester hydrochloride |
| CN110606811B (en) * | 2019-09-23 | 2022-12-02 | 湖北宇阳药业有限公司 | Synthetic method of L-serine methyl ester hydrochloride |
| CN113100125A (en) * | 2021-04-07 | 2021-07-13 | 浙江省海洋水产研究所 | Method for improving survival rate of coilia ectenes parents |
| CN113100125B (en) * | 2021-04-07 | 2022-08-30 | 浙江省海洋水产研究所 | Method for improving survival rate of coilia ectenes parents |
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