CN102875397A - Meclofenoxatum preparation method - Google Patents
Meclofenoxatum preparation method Download PDFInfo
- Publication number
- CN102875397A CN102875397A CN201210409046XA CN201210409046A CN102875397A CN 102875397 A CN102875397 A CN 102875397A CN 201210409046X A CN201210409046X A CN 201210409046XA CN 201210409046 A CN201210409046 A CN 201210409046A CN 102875397 A CN102875397 A CN 102875397A
- Authority
- CN
- China
- Prior art keywords
- preparation
- reaction
- meclofenoxate hydrochloride
- chlorophenoxyacetic acid
- meclofenoxatum
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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, pass into after the backflow esterification 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 in benzene, carry out esterification with dimethylaminoethanol, in propylene glycol, pass into hydrogen chloride gas salify (Ishibushi K. (p-Chlorophenoxy) acetate esters and theirsalt[P] .JP:7901692,1979-01-27).More than two kinds of methods all be by in solvent, passing into the hydrogen chloride gas salify, reaction time is longer, temperature of reaction is high, the reagent toxicity of use is large, product impurity is many, 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, under sulfur oxychloride and DMF (DMF) catalysis, prepare meclofenoxate hydrochloride with the dimethylaminoethanol reaction.Because DMF is high boiler (b.p.=153 ℃), in actual production, be difficult for removing and easily in distillation, decomposing, make lmpurities and exceed standard, should not control, and this patent documentation has used one kind solvent-benzene to have carcinogenesis, has been not suitable for using in the 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 with p-chlorophenoxyacetic acid, nitrogenous organic base and sulfur oxychloride react in toluene and generate the quaternary ammonium salt reaction solution, add dimethylaminoethanol direct esterification salify.
The invention provides a kind of preparation method of meclofenoxate hydrochloride, the method may further comprise the steps:
(A) p-chlorophenoxyacetic acid, nitrogenous organic base and sulfur oxychloride take mol ratio as 1: 0.15 ~ 0.25: 1.1 ~ 1.25 in toluene solution reaction generate the quaternary ammonium salt reaction solution, temperature of reaction is 50 ~ 100 ℃, the reaction times is more than 2 hours; Described nitrogenous organic base is triethylamine or diisopropylethylamine;
(B) in the quaternary ammonium salt reaction solution that step (A) generates, 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 to the greatest extent toluene, add monohydroxy-alcohol, the gac reflux decolour filters, and crystallisation by cooling obtains the meclofenoxate hydrochloride finished product.
Further, in the 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 the step (A), the consumption of toluene solution more preferably is 2 ~ 3 times of p-chlorophenoxyacetic acid.
In the step (B), the mol ratio of p-chlorophenoxyacetic acid and dimethylethanolamine is preferably 1.00: 1.02 ~ and 1.04; Add dimethylethanolamine afterreaction temperature and be controlled at 80 ℃, the reaction times is 2 ~ 3 hours.
In the 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, easily eliminates when distillation.
Salt forming agent--the sulfur oxychloride that the present invention adopts avoids using hydrogen chloride gas.
Next footwork esterification salify of processing condition of the present invention, yield has reached more than 80%, improves 5 ~ 10% than original production process, 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 present conventional process (passing into the hydrogen chloride gas salify in the 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 and the direct salify of hydrogenchloride that produces are avoided using hydrogen chloride gas, thereby have been simplified operation steps, reaction temperature and, improve working condition.
(3) method of the present invention has selected triethylamine or diisopropylethylamine to replace DMF among the German Democratic Republic patent DD121928 as phase-transfer catalyst, residual in still-process of the DMF that avoids and decompose the possibility that impurity reduction 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 cost, has improved the utilization ratio of raw material.
In sum, the inventive method raw material is easy to get, and by product is few, the gentle and easily control of reaction conditions, cost is lower, easily realizes industrialization, and throughput is large, and products obtained therefrom purity is high, steady quality meets 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 and only be used for explanation the present invention, and be not used in restriction range of application of the present invention.
Embodiment 1:
In three mouthfuls of 1L reaction flasks with 230g(1.23mol) p-chlorophenoxyacetic acid and 23g(0.23mol) triethylamine drops in the 600ml toluene, add 163g(1.37mol under the 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 doing, 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%, and 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 the 600ml toluene, add 163g(1.37mol under the 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 doing, 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
From table 1 as seen, embodiment 4,5,6,10,11 and 12 processing parameters that adopt have dropped on according in the scope of the present invention, that is: p-chlorophenoxyacetic acid, nitrogenous organic base, sulfur oxychloride and dimethylethanolamine take mol ratio as 1:0.15 ~ 0.25:1.1 ~ these embodiment of 1.25:1.00 ~ 1.10 have all obtained good yield, product yield is all more than 80%, fusing point all meets 2010 editions requirements of Chinese Pharmacopoeia at 137 ~ 141 ℃.
And embodiment 3,7,8,9,13,14 owing to do not adopt processing parameter of the present invention, and they are not so good as embodiment 4,5,6,10,11 and 12 aspect fusing point and yield.
More than show 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 describes in above-described embodiment and the specification sheets 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 may further comprise the steps:
(A) p-chlorophenoxyacetic acid, nitrogenous organic base and sulfur oxychloride take mol ratio as 1: 0.15 ~ 0.25: 1.1 ~ 1.25 in toluene solution reaction generate the quaternary ammonium salt reaction solution, temperature of reaction is 50 ~ 100 ℃, the reaction times is more than 2 hours; Described nitrogenous organic base is triethylamine or diisopropylethylamine;
(B) in the quaternary ammonium salt reaction solution that step (A) generates, 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 to the greatest extent toluene, add monohydroxy-alcohol, the gac reflux decolour filters, and crystallisation by cooling obtains the meclofenoxate hydrochloride finished product.
2. the preparation method of a kind of meclofenoxate hydrochloride according to claim 1 is characterized in that, in the 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 the step (A), the consumption of toluene solution is 2 ~ 3 times of p-chlorophenoxyacetic acid.
5. the preparation method of a kind of meclofenoxate hydrochloride according to claim 1 and 2 is characterized in that, in the 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 the 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 the step (C), described monohydroxy-alcohol is ethanol or Virahol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201210409046 CN102875397B (en) | 2012-10-24 | 2012-10-24 | Meclofenoxatum preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201210409046 CN102875397B (en) | 2012-10-24 | 2012-10-24 | Meclofenoxatum preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102875397A true CN102875397A (en) | 2013-01-16 |
| CN102875397B CN102875397B (en) | 2013-12-18 |
Family
ID=47476956
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201210409046 Active CN102875397B (en) | 2012-10-24 | 2012-10-24 | Meclofenoxatum preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102875397B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103214382A (en) * | 2013-04-24 | 2013-07-24 | 四川省惠达药业有限公司 | Meclofenoxate hydrochloride compound and pharmaceutical composition thereof |
| CN109400489A (en) * | 2017-08-15 | 2019-03-01 | 广东华南药业集团有限公司 | A kind of preparation method of meclofenoxate hydrochloride |
| CN110015966A (en) * | 2019-04-29 | 2019-07-16 | 广东先强药业有限公司 | A kind of preparation method of meclofenoxate hydrochloride |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB885801A (en) * | 1958-12-23 | 1961-12-28 | Ciba Ltd | Tertiary amines and process for their manufacture |
| CN1267674A (en) * | 1999-01-05 | 2000-09-27 | Ck韦特科公司 | Process for producing polyurethane foamed plastic |
| JP2005170831A (en) * | 2003-12-10 | 2005-06-30 | Kao Corp | Method for producing tertiary amine |
| US20060040954A1 (en) * | 2004-08-18 | 2006-02-23 | Parion Sciences, Inc. | Soluble amide & ester pyrazinoylguanidine sodium channel blockers |
| CN101798263A (en) * | 2010-04-16 | 2010-08-11 | 北京化工大学 | Method for preparing unsaturated adamantane ester |
| CN102229539A (en) * | 2011-05-12 | 2011-11-02 | 东北农业大学 | Synthetic process for 4-iodo-phenoxyacetic acid diethylaminoethanol ester |
-
2012
- 2012-10-24 CN CN 201210409046 patent/CN102875397B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB885801A (en) * | 1958-12-23 | 1961-12-28 | Ciba Ltd | Tertiary amines and process for their manufacture |
| CN1267674A (en) * | 1999-01-05 | 2000-09-27 | Ck韦特科公司 | Process for producing polyurethane foamed plastic |
| JP2005170831A (en) * | 2003-12-10 | 2005-06-30 | Kao Corp | Method for producing tertiary amine |
| US20060040954A1 (en) * | 2004-08-18 | 2006-02-23 | Parion Sciences, Inc. | Soluble amide & ester pyrazinoylguanidine sodium channel blockers |
| CN101798263A (en) * | 2010-04-16 | 2010-08-11 | 北京化工大学 | Method for preparing unsaturated adamantane ester |
| CN102229539A (en) * | 2011-05-12 | 2011-11-02 | 东北农业大学 | Synthetic process for 4-iodo-phenoxyacetic acid diethylaminoethanol ester |
Non-Patent Citations (2)
| Title |
|---|
| MARÍA L. DÍEZ-MARQUÉS等: "Losartan-Antioxidant Hybrids: Novel Molecules for the Prevention of Hypertension-Induced Cardiovascular Damage", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 张忠敏等: "氯醒醋的合成工艺改进", 《中国药物化学杂志》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103214382A (en) * | 2013-04-24 | 2013-07-24 | 四川省惠达药业有限公司 | Meclofenoxate hydrochloride compound and pharmaceutical composition thereof |
| 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 |
| CN109400489A (en) * | 2017-08-15 | 2019-03-01 | 广东华南药业集团有限公司 | A kind of preparation method of meclofenoxate hydrochloride |
| 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 |
| CN110015966A (en) * | 2019-04-29 | 2019-07-16 | 广东先强药业有限公司 | A kind of preparation method of meclofenoxate hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102875397B (en) | 2013-12-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101941969B (en) | Preparation method of moxifloxacin hydrochloride | |
| CN103360425A (en) | Synthesis method of tenofovir disoproxil and fumarate thereof | |
| CN101891649A (en) | Novel 3-cyano methyl benzoate preparing method | |
| CN112592356A (en) | Method for synthesizing lornoxicam | |
| CN105622609A (en) | Preparation method for linagliptin | |
| CN102875397B (en) | Meclofenoxatum preparation method | |
| CN101979391B (en) | Method for preparing tiotropium bromide | |
| CN109776547A (en) | Preparation method of tofacitinib citrate | |
| CN101979376B (en) | Method for preparing glycinamide hydrochloride | |
| CN102584693B (en) | Preparation method for high purity 2-chlorine-3-aminopyridine hydrochloride | |
| CN103664812B (en) | Preparation method of TTZ (thiotriazinone) | |
| CN103044468B (en) | Preparation method of N-(2-pyrazine carbonyl)-L-phenylalanine-L- leucine boracic acid | |
| CN103396330A (en) | Preparation method of N,N-dimethyl glycine ester based on silica gel sulfonic acid serving as catalyst | |
| CN101492430B (en) | Method for preparing high-purity cetirizine hydrochloride | |
| CN103664805A (en) | Method for preparing acipimox | |
| CN106397357A (en) | Method for preparing trimetazidine dihydrochloride | |
| CN103172497A (en) | Industrialized production process of new medicament benvitimod for treating psoriasis | |
| CN103242291A (en) | Mass production process of polycrystalline high-content benzoic acid alogliptin | |
| CN105017158B (en) | A kind of preparation method of cis Rosuvastatin calcium impurities | |
| CN104326927B (en) | A kind of preparation method of 1-[2-amino-1-(4-methoxyphenyl) ethyl] Hexalin sulfate | |
| CN103030599B (en) | Gefitinib intermediate and preparation method thereof | |
| CN102206185B (en) | Process for refining bendazac lysine and analogs thereof | |
| CN102351775B (en) | Preparation method of levo-5-hydroxytryptophan | |
| CN112341433A (en) | Preparation method of loratadine | |
| CN112645945A (en) | Preparation method of Wumei ammonium bromide intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: SHANGHAI WANXIANG PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: SHANGHAI WONDER PHARMACEUTICAL CO., LTD. Effective date: 20150630 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
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. |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
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. |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
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. |