CN102875397B - Meclofenoxatum preparation method - Google Patents
Meclofenoxatum preparation method Download PDFInfo
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- CN102875397B CN102875397B CN 201210409046 CN201210409046A CN102875397B CN 102875397 B CN102875397 B CN 102875397B CN 201210409046 CN201210409046 CN 201210409046 CN 201210409046 A CN201210409046 A CN 201210409046A CN 102875397 B CN102875397 B CN 102875397B
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Abstract
The invention belongs to the field of chemical synthesis and provides a meclofenoxatum preparation method. The meclofenoxatum is also called as meclofenoxate and is one of widely applicable central stimulants. In the meclofenoxatum preparation method, salt is obtained by esterifying by one-step method, and the process is improved by the phase transfer catalytic method. The meclofenoxatum preparation method is few in side products, mild in reaction conditions, easy to control, low in cost, easy to realize industrialization and high in production capacity and provides an environment-friendly meclofenoxatum synthesis way, raw materials are easy to obtain, and products obtained are high in purity, stable in quality and accord with pharmacopeia provision.
Description
Technical field
The invention belongs to the field of chemical synthesis, be specifically related to a kind of preparation method of central nervous stimulant meclofenoxate hydrochloride.
Background technology
Meclofenoxate hydrochloride (Meclofenoxatum) has another name called meclofenoxate, chemistry p-chlorophenoxyacetic acid dimethylaminoethyl hydrochloride (2-(dimethylamino) ethyl 4-chlorophenoxyacetate hydrochoride) by name, chemical structural formula is as follows:
Meclofenoxate hydrochloride has the cellular oxidation of promotion reduction process, promotes the utilization to carbohydrate, regulates the neurocyte metabolism, treatment brain stupor, cerebral trauma, in the wind-induced disturbance of consciousness, senile dementia, one of blunt widely used central nervous system stimulants of Growth of Intelligence in Children.
The production technique of taking both at home and abroad at present has two kinds, a kind of be under acidic conditions p-chlorophenoxyacetic acid and dimethylaminoethanol in dimethylbenzene, after the backflow esterification, pass into the hydrogen chloride gas salify obtain finished product (national bulk drug technique compilation [M]. Shanghai: medicine management general bureau of country, 1980).Another kind is that p-chlorophenoxyacetic acid and anhydride reaction obtain the p-chlorophenoxyacetic acid acid anhydride, then carry out esterification with dimethylaminoethanol in benzene, pass into hydrogen chloride gas salify (Ishibushi K. (p-Chlorophenoxy) acetate esters and theirsalt[P] .JP:7901692,1979-01-27) in propylene glycol.Above two kinds of methods are all that reaction time is longer by pass into the hydrogen chloride gas salify in solvent, and temperature of reaction is high, and the reagent toxicity of use is large, and product impurity is many, and commercial production conditions is comparatively harsh.
German Democratic Republic patent DD121928 in 1976, denomination of invention is that " Para-chlorophenoxy aceticacid beta-dimethylamino ethyl ester prepn.-by reacting p-chlorophenoxy aceticacid with technical thionyl chloride and formic acid di-methylamide; thendimethylamino-ethanol " once reported p-chlorophenoxyacetic acid, react and prepare meclofenoxate hydrochloride with dimethylaminoethanol under sulfur oxychloride and DMF (DMF) catalysis.Because DMF is high boiler (b.p.=153 ℃), be difficult for removing and easily decomposing in distillation in actual production, make lmpurities and exceed standard, should not control, and this patent documentation has been used one kind solvent-benzene to have carcinogenesis, be not suitable for using in current raw material pharmaceutical production.
Summary of the invention
Purpose of the present invention is exactly the synthetic method that a kind of new meclofenoxate hydrochloride will be provided, and it not only can effectively improve purity and the yield of product, and is conducive to environment protection.
Employing single stage method esterification salify of the present invention, and adopted phase transfer catalysis process to carry out process modification, at first by p-chlorophenoxyacetic acid, nitrogenous organic base and sulfur oxychloride react and generate the quaternary ammonium salt reaction solution in toluene, add dimethylaminoethanol direct esterification salify.
The invention provides a kind of preparation method of meclofenoxate hydrochloride, the method comprises the following steps:
(A) p-chlorophenoxyacetic acid, nitrogenous organic base be take mol ratio and are reacted in toluene solution and generate the quaternary ammonium salt reaction solution as 1: 0.15 ~ 0.25: 1.1 ~ 1.25 with sulfur oxychloride, and temperature of reaction is 50 ~ 100 ℃, and the reaction times is more than 2 hours; Described nitrogenous organic base is triethylamine or diisopropylethylamine;
(B) in the quaternary ammonium salt reaction solution generated in step (A), add dimethylethanolamine, the mol ratio of p-chlorophenoxyacetic acid and dimethylethanolamine is 1.00: 1.00 ~ 1.10, and temperature of reaction is 80 ~ 90 ℃, and the reaction times is more than 2 hours;
(C) steam toluene to the greatest extent, add monohydroxy-alcohol, the gac reflux decolour, filter, and crystallisation by cooling, obtain the meclofenoxate hydrochloride finished product.
Further, in step (A), p-chlorophenoxyacetic acid, the mol ratio of nitrogenous organic base and sulfur oxychloride is preferably 1: 0.18 ~ and 0.20: 1.1; Temperature preferably is controlled at 60 ℃; Reaction times is preferably 2 ~ 3 hours.
In step (A), the consumption of toluene solution more preferably, is 2 ~ 3 times of p-chlorophenoxyacetic acid.
In step (B), the mol ratio of p-chlorophenoxyacetic acid and dimethylethanolamine is preferably 1.00: 1.02 ~ and 1.04; After adding dimethylethanolamine, temperature of reaction is controlled at 80 ℃, and the reaction times is 2 ~ 3 hours.
In step (C), described monohydroxy-alcohol preferred alcohol or Virahol.
Triethylamine (b.p.=89 ℃) or diisopropylethylamine (b.p.=127 ℃) that the present invention adopts, boiling point is relatively low, when distillation, easily eliminates.
Salt forming agent--the sulfur oxychloride that the present invention adopts, avoid using hydrogen chloride gas.
Next footwork esterification salify of processing condition of the present invention, yield has reached more than 80%, than original production process, improves 5 ~ 10%, and 138 ~ 141 ℃ of product fusing points conform to the reference substance collection of illustrative plates through the infrared spectra conclusive evidence.
The present invention has following beneficial effect;
(1) adopt current conventional process (passing into the hydrogen chloride gas salify in solvent) under acidic conditions, p-chlorophenoxyacetic acid and dimethylaminoethanol reflux more than 20 hours in dimethylbenzene.Adopt method of the present invention to adopt phase-transfer catalyst single stage method esterification salify, greatly shortened the reaction times.
(2) water byproduct in the sulfur oxychloride absorption reaction the direct salify of hydrogenchloride that produces, avoid using hydrogen chloride gas, thereby simplified operation steps, reaction temperature and, improve working condition.
(3) method of the present invention has selected triethylamine or diisopropylethylamine to replace DMF in German Democratic Republic patent DD121928 as phase-transfer catalyst, and residual in still-process of the DMF avoided and decomposing reduces the possibility that impurity is brought into.Reliability and the security of product have been improved.
(4) the present invention brings up to the yield of product more than 80%, thereby reduces costs, and has improved the utilization ratio of raw material.
In sum, the inventive method raw material is easy to get, and by product is few, reaction conditions gentleness and easily control, cost is lower, easily realizes industrialization, and throughput is large, and products obtained therefrom purity is high, steady quality, meet the pharmacopeia regulation, and a more route of synthesis of the meclofenoxate hydrochloride of environmental protection is provided.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should understand these embodiment only for the present invention is described, and be not used in restriction range of application of the present invention.
Embodiment 1:
In three mouthfuls of 1L reaction flasks by 230g(1.23mol) p-chlorophenoxyacetic acid and 23g(0.23mol) triethylamine drops in 600ml toluene, add 163g(1.37mol under stirring at room) sulfur oxychloride, be warming up to subsequently 70 ℃ of insulations 30 minutes, continue to be warming up to 100 ℃, temperature remains between 70 ~ 100 ℃, add dimethylaminoethanol 113g(1.27mol), dropwise rear insulation 2 hours, reclaim solvent to dry, add Virahol 250g heating for dissolving, add the proper amount of active carbon decolouring, filter, cooling and stirring white crystals body is separated out 289.5g, yield: 82.5%, 138 ~ 141 ℃ of fusing points are the product meclofenoxate hydrochloride.Structure is proved conclusively (IR(KBr) δ through infrared spectra: 2940,1740,1580,1490,1380,1090,810,710cm-1)
Reaction equation is as follows:
P-chlorophenoxyacetic acid, the dimethylaminoethanol meclofenoxate hydrochloride
Embodiment 2:
230g(1.23mol) p-chlorophenoxyacetic acid and 31.8g(0.25mol) N, the N-diisopropylethylamine drops in 600ml toluene, add 163g(1.37mol under stirring at room) sulfur oxychloride, be warming up to subsequently 75 ℃ of insulations 30 minutes, continue to be warming up to 100 ℃, temperature remains between 70 ~ 100 ℃, add dimethylaminoethanol 113g(1.27mol), dropwise rear insulation 2 hours, reclaim solvent to dry, add dehydrated alcohol 250g heating for dissolving, add the proper amount of active carbon decolouring, filter, cooling and stirring white crystals body is separated out 290.1g, yield: 82.3%, 137 ~ 140 ℃ of fusing points.
Embodiment 3 ~ embodiment 14:
The processing parameter of embodiment 3 ~ embodiment 14 is except table 1 is listed, and all the other are with embodiment 1.
Processing parameter, product purity and the yield of table 1 embodiment 3 ~ embodiment 12
Annotate: above each amounts of components is the molar weight with respect to p-chlorophenoxyacetic acid
As seen from Table 1, embodiment 4,5,6,10,11 and 12 processing parameters that adopt have dropped on according in scope of the present invention, that is: p-chlorophenoxyacetic acid, nitrogenous organic base, sulfur oxychloride and dimethylethanolamine be take mol ratio and have all been obtained good yield as these embodiment of 1:0.15 ~ 0.25:1.1 ~ 1.25:1.00 ~ 1.10, and product yield is all more than 80%, and fusing point all meets 2010 editions requirements of Chinese Pharmacopoeia at 137 ~ 141 ℃.
And embodiment 3,7,8,9,13,14 is owing to not adopting processing parameter of the present invention, they aspect fusing point and yield not as embodiment 4,5,6,10,11 and 12.
Above demonstration and described ultimate principle of the present invention, principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that in above-described embodiment and specification sheets, describes just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (7)
1. the preparation method of a meclofenoxate hydrochloride, the method comprises the following steps:
(A) p-chlorophenoxyacetic acid, nitrogenous organic base be take mol ratio and are reacted in toluene and generate the quaternary ammonium salt reaction solution as 1: 0.15～0.25: 1.1～1.25 with sulfur oxychloride, and temperature of reaction is 50～100 ℃, and the reaction times is more than 2 hours; Described nitrogenous organic base is triethylamine or diisopropylethylamine;
(B) in the quaternary ammonium salt reaction solution generated in step (A), add dimethylethanolamine, the mol ratio of p-chlorophenoxyacetic acid and dimethylethanolamine is 1.00: 1.00～1.10, and temperature of reaction is 80～90 ℃, and the reaction times is more than 2 hours;
(C) steam toluene to the greatest extent, add monohydroxy-alcohol, the gac reflux decolour, filter, and crystallisation by cooling, obtain the meclofenoxate hydrochloride finished product.
2. the preparation method of a kind of meclofenoxate hydrochloride according to claim 1, is characterized in that, in step (A), and p-chlorophenoxyacetic acid, the mol ratio of nitrogenous organic base and sulfur oxychloride is 1: 0.18～0.20: 1.1.
3. the preparation method of a kind of meclofenoxate hydrochloride according to claim 1 and 2, is characterized in that, step (A) temperature of reaction is 60 ℃; Reaction times is 2～3 hours.
4. the preparation method of a kind of meclofenoxate hydrochloride according to claim 1 and 2, is characterized in that, in step (A), the consumption of toluene is p-chlorophenoxyacetic acid 2～3 times.
5. the preparation method of a kind of meclofenoxate hydrochloride according to claim 1 and 2, is characterized in that, in step (B), the mol ratio of p-chlorophenoxyacetic acid and dimethylethanolamine is 1.00: 1.02～1.04.
6. the preparation method of a kind of meclofenoxate hydrochloride according to claim 5, is characterized in that, in step (B), temperature of reaction is 80 ℃; Reaction times is 2～3 hours.
7. the preparation method of a kind of meclofenoxate hydrochloride according to claim 1 and 2, is characterized in that, in step (C), described monohydroxy-alcohol is ethanol or Virahol.
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| CN103214382B (en) * | 2013-04-24 | 2014-04-02 | 四川省惠达药业有限公司 | Meclofenoxate hydrochloride compound and pharmaceutical composition thereof |
| CN109400489B (en) * | 2017-08-15 | 2021-07-09 | 广东华南药业集团有限公司 | Preparation method of meclofenoxate hydrochloride |
| CN110015966B (en) * | 2019-04-29 | 2022-04-22 | 广东先强药业有限公司 | Preparation method of meclofenoxate hydrochloride |
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Owner name: SHANGHAI WANXIANG PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: SHANGHAI WONDER PHARMACEUTICAL CO., LTD. Effective date: 20150630 |
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Effective date of registration: 20150630 Address after: 201512 Shanghai City, Jinshan District Jinshanwei town old Weiqing Road No. 1089 Building 1 room 1159 Patentee after: Shanghai Wanxiang Pharmaceutical Co., Ltd. Address before: 201518 Jinshan District Jin Zhang Road, Shanghai, No. 2068 Patentee before: Shanghai Wonder Pharmaceutical Co., Ltd. |
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Effective date of registration: 20151125 Address after: 201512 Shanghai City, Jinshan District Jinshanwei town old Weiqing Road No. 1089 Building 1 room 1159 Patentee after: Shanghai Wanxiang Pharmaceutical Co., Ltd. Patentee after: Shanghai Wonder Pharmaceutical Co., Ltd. Address before: 201512 Shanghai City, Jinshan District Jinshanwei town old Weiqing Road No. 1089 Building 1 room 1159 Patentee before: Shanghai Wanxiang Pharmaceutical Co., Ltd. |
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Effective date of registration: 20161229 Address after: 200540 Shanghai city Jinshan District China Road No. 298 Patentee after: Shanghai Wanxiang Pharmaceutical Co., Ltd. Address before: 201512 Shanghai City, Jinshan District Jinshanwei town old Weiqing Road No. 1089 Building 1 room 1159 Patentee before: Shanghai Wanxiang Pharmaceutical Co., Ltd. Patentee before: Shanghai Wandai Pharmaceutical Co., Ltd. |