CN111484425A - Preparation method of benserazide hydrochloride impurity - Google Patents
Preparation method of benserazide hydrochloride impurity Download PDFInfo
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- CN111484425A CN111484425A CN201910072067.9A CN201910072067A CN111484425A CN 111484425 A CN111484425 A CN 111484425A CN 201910072067 A CN201910072067 A CN 201910072067A CN 111484425 A CN111484425 A CN 111484425A
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C241/00—Preparation of compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C241/04—Preparation of hydrazides
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Abstract
The invention reports a preparation method of benserazide hydrochloride impurities, and particularly relates to a preparation method of benserazide hydrochloride pharmacopoeia impurities B. The method has the advantages of simple and easy operation, mild conditions, high yield, low energy consumption and low pollution, and is suitable for preparing laboratory-level standard products.
Description
Technical Field
The invention reports a preparation method of benserazide hydrochloride impurities, in particular to a preparation method of benserazide hydrochloride pharmacopoeia impurities B, and belongs to the field of medicines.
Background
Benserazide Hydrochloride (Benserazide Hydrochloride) is an effective component in a compound medicine Madopar (Madopar) for treating Parkinson. The original research company of MEDOPA is Roche pharmaceutical, and the effective components are levodopa and benserazide hydrochloride. The composition can increase dopamine content in brain cells, and improve Parkinson's disease. Benserazide hydrochloride is a Dopa decarboxylase (Dopa decarbonylase) inhibitor that blocks the conversion of levodopa to dopamine before entering the brain, thereby increasing the amount of dopamine in the brain and reducing its peripheral adverse reactions. Benserazide hydrochloride in the MEDOPA and the levodopa are compatible according to the dosage ratio of 1: 4.
The chemical name of benserazide hydrochloride is 2-amino-3-hydroxy-N' - (2,3, 4-trihydroxy benzyl) propionyl hydrazine hydrochloride, and the chemical structural formula is as follows:
Medopa is currently on the market in china, japan and the european union. Benserazide hydrochloride is already recorded in the pharmacopoeia of the above three places. Wherein, the European pharmacopoeia (EP 9.0) specifies a specific impurity B in related substance detection items in the quality standard thereof, the name of the impurity B is 2-amino-3-hydroxy-N ', N' -bis (2,3, 4-trihydroxybenzyl) propionohydrazide, and the structure of the impurity B is as follows:
In the research process, the impurity is almost inevitably present in the production process of the benserazide, is also a main degradation impurity in the benserazide bulk drugs and preparations, but is very unstable and easy to further degrade. Through literature query, the synthesis method of the impurity is rarely reported.
In the preparation process of the raw material medicine, the product or the mother liquor rich in the impurities can be subjected to column chromatography or preparative chromatographic separation to obtain the impurities. However, the method has low efficiency, long time consumption and serious waste. The more important reason is that the impurities themselves are not stable enough to be destroyed in most of the separation and concentration processes.
In summary, the impurities are used as pharmacopeia impurities and need to be used as standard substances for positioning and content detection in daily detection, but at present, no efficient and convenient synthesis or separation means can be used for preparing the impurity standard substances on a large scale.
The invention reports a preparation method of benserazide hydrochloride pharmacopoeia impurity B, which is simple and easy to operate, mild in condition, high in yield, low in energy consumption and pollution and suitable for preparing laboratory-level standard products.
Disclosure of Invention
The invention reports a preparation method of benserazide hydrochloride impurities, and particularly relates to a preparation method of benserazide hydrochloride pharmacopoeia impurities B.
The method is characterized in that benserazide hydrochloride reacts under the action of water at a certain reaction temperature, and primary crystallization is carried out through an alcohol solvent I to obtain crude benserazide hydrochloride pharmacopoeia impurity B. And recrystallizing the crude product by using water and an alcohol solvent II at a certain volume ratio to obtain impurity B in benserazide hydrochloride pharmacopoeia.
The reaction temperature is 20-80 ℃.
The alcohol solvent I is selected from methanol, ethanol, isopropanol or a mixture thereof.
The alcohol solvent II is selected from methanol, ethanol, isopropanol or a mixture thereof.
The volume ratio of the water to the alcohol solvent II is selected from 1:5 to 1: 20.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
To further illustrate the present invention, specific embodiments of the present invention are described below with reference to examples. It is noted that the following description is only intended to further illustrate the features and advantages of the present invention, and not to limit the scope of the claims of the present invention.
Example 1:
adding 9.6g benserazide hydrochloride and 30ml water into a 100ml three-neck flask, heating to 20-30 deg.C, stirring for 16-20 hr, concentrating to remove water, adding 20m L A cooling to 0-10 ℃ with alcohol, dropwise adding 80m L ethanol, keeping the temperature of precipitated solid, stirring, and performing suction filtration to obtain a crude product, adding 20m L methanol and 10m L water into the crude product at 10-20 ℃, stirring to dissolve the crude product clearly, dropwise adding 30m L ethanol, stirring to crystallize, filtering and drying to obtain benserazide hydrochloride pharmacopeia impurity B, 4.1g, and the yield is 55.5%. 1H NMR(400 MHz,DMSO-d6)9.83(s,1H),8.76(s,2H),8.16(s,4H),6.35(d,J＝8.3Hz,2H),6.14(d,J ＝8.2Hz,2H),5.39(t,J＝4.9Hz,1H),4.30(d,J＝4.1Hz,1H),3.81–3.64(m,1H),3.73(d, 4H),3.51–3.33(m,2H).Mass:396.1[M+H].
Example 2:
adding 2.0g benserazide hydrochloride and 6ml water into a 100ml three-necked bottle, heating to 30-40 ℃, stirring for 6-8 hours, concentrating to remove water, adding 30m L methanol, cooling to 0-10 ℃, separating out solid, keeping the temperature, stirring, filtering to obtain a crude product, adding 20m L methanol and 10m L water into the crude product at 10-20 ℃, stirring to dissolve, dropwise adding 30m L methanol, stirring to crystallize, filtering and drying to obtain benserazide hydrochloride pharmacopoeia impurity B, 0.82g and the yield of 53.2%. 1H NMR(400MHz,DMSO-d6)9.83 (s,1H),8.76(s,2H),8.16(s,4H),6.35(d,J＝8.3Hz,2H),6.14(d,J＝8.2Hz,2H),5.39(t,J ＝4.9Hz,1H),4.30(d,J＝4.1Hz,1H),3.81–3.64(m,1H),3.73(d,4H),3.51–3.33(m, 2H).Mass:396.1[M+H].
Example 3:
adding 2.0g benserazide hydrochloride and 6ml water into a 100ml three-necked bottle, heating to 30-40 ℃, stirring for 6-8 hours, concentrating to remove water, adding 30m L ethanol, cooling to 0-10 ℃, separating out solid, keeping the temperature, stirring, filtering to obtain a crude product, adding 20m L ethanol and 10m L water into the crude product at 10-20 ℃, stirring to dissolve, dropwise adding 30m L ethanol, stirring, crystallizing, filtering, and drying to obtain benserazide hydrochloride pharmacopoeia impurity B, 0.88g, wherein the yield is 57.1%. 1H NMR(400MHz,DMSO-d6)9.83 (s,1H),8.76(s,2H),8.16(s,4H),6.35(d,J＝8.3Hz,2H),6.14(d,J＝8.2Hz,2H),5.39(t,J ＝4.9Hz,1H),4.30(d,J＝4.1Hz,1H),3.81–3.64(m,1H),3.73(d,4H),3.51–3.33(m, 2H).Mass:396.1[M+H].
Example 4:
adding 2.0g benserazide hydrochloride and 6ml water into a 100ml three-neck flask, heating to 40-50 deg.C, stirring for 3-5 hr, concentrating to remove water, adding 30m L isopropanol, cooling to 0 and (3) carrying out heat preservation and stirring on the precipitated solid at the temperature of minus 10 ℃, carrying out suction filtration to obtain a crude product, adding 20m L isopropanol and 10m L water into the crude product at the temperature of 10-20 ℃, stirring and dissolving the crude product to be clear, then dropwise adding 30m L isopropanol, stirring and crystallizing, filtering and drying to obtain benserazide hydrochloride pharmacopeia impurity B of 0.96g, and the yield is 62.3%. 1H NMR(400MHz,DMSO-d6) 9.83(s,1H),8.76(s,2H),8.16(s,4H),6.35(d,J＝8.3Hz,2H),6.14(d,J＝8.2Hz,2H), 5.39(t,J＝4.9Hz,1H),4.30(d,J＝4.1Hz,1H),3.81–3.64(m,1H),3.73(d,4H),3.51– 3.33(m,2H).Mass:396.1[M+H].
Example 5:
adding 10.0g of benserazide hydrochloride and 30ml of water into a 100ml three-necked bottle, heating to 50-60 ℃, stirring for 2-4 hours, concentrating to remove water, adding 20m L methanol, cooling to 0-10 ℃, dropwise adding 100m L isopropanol, separating out solid, keeping the temperature, stirring, performing suction filtration to obtain a crude product, adding 20m L methanol and 10m L water into the crude product at 10-20 ℃, stirring to dissolve the crude product, adding 80 m L isopropanol, stirring to crystallize, filtering and drying to obtain benserazide hydrochloride pharmacopoeia impurity B, 1.17g, and the yield of 76.0%. 1H NMR (400MHz,DMSO-d6)9.83(s,1H),8.76(s,2H),8.16(s,4H),6.35(d,J＝8.3Hz,2H),6.14 (d,J＝8.2Hz,2H),5.39(t,J＝4.9Hz,1H),4.30(d,J＝4.1Hz,1H),3.81–3.64(m,1H), 3.73(d,4H),3.51–3.33(m,2H).Mass:396.1[M+H].
Example 6:
adding 2.0g benserazide hydrochloride and 6ml water into a 100ml three-necked bottle, heating to 60-80 ℃, stirring for 2-3 hours, concentrating to remove water, adding 4m L methanol, cooling to 0-10 ℃, dropwise adding 22m L ethanol, separating out solid, keeping the temperature, stirring, performing suction filtration to obtain a crude product, adding 4m L ethanol and 2m L water into the crude product at 10-20 ℃, stirring to dissolve the crude product, adding 36m L isopropanol, stirring to perform crystallization, filtering and drying to obtain benserazide hydrochloride pharmacopoeia impurity B, 0.96g, and the yield is 62.3%. 1H NMR(400MHz, DMSO-d6)9.83(s,1H),8.76(s,2H),8.16(s,4H),6.35(d,J＝8.3Hz,2H),6.14(d,J＝8.2 Hz,2H),5.39(t,J＝4.9Hz,1H),4.30(d,J＝4.1Hz,1H),3.81–3.64(m,1H),3.73(d,4H), 3.51–3.33(m,2H).Mass:396.1[M+H].
While the process for the preparation of benserazide hydrochloride pharmacopeia impurity B as set forth herein has been described by way of example, it will be apparent to those skilled in the art that the techniques of the present invention may be practiced with modification, or with appropriate modification and combination, of the process for the preparation of benserazide hydrochloride pharmacopeia impurity B as set forth herein without departing from the spirit, scope, or concept of the invention. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and content of the invention.
Claims (5)
1. The invention reports a preparation method of benserazide hydrochloride impurity, in particular to a preparation method of benserazide hydrochloride pharmacopoeia impurity B,
The method is characterized in that benserazide hydrochloride reacts under the action of water at a certain reaction temperature, and primary crystallization is carried out through an alcohol solvent I to obtain crude benserazide hydrochloride pharmacopoeia impurity B. And recrystallizing the crude product by using water and an alcohol solvent II at a certain volume ratio to obtain impurity B in benserazide hydrochloride pharmacopoeia.
2. The reaction temperature as set forth in claim 1 is 20 to 80 degrees celsius.
3. The alcoholic solvent I as claimed in claim 1 is selected from methanol, ethanol, isopropanol or mixtures thereof.
4. The alcoholic solvent II as claimed in claim 1 is selected from methanol, ethanol, isopropanol or a mixture thereof.
5. The volume ratio of water to the alcoholic solvent II as claimed in claim 1 is selected from the range of 1:5 to 1: 20.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103951587A (en) * | 2014-04-11 | 2014-07-30 | 浙江耐司康药业有限公司 | Synthetic method for intermediate of benserazide hydrochloride |
| WO2015197909A1 (en) * | 2014-06-27 | 2015-12-30 | Fermion Oy | Process for the preparation of a crystalline polymorph of 2-amino-3-hydroxy-n'-(2,3,4-trihydroxybenzyl)propanehydrazide (benserazide) hydrochloride |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103951587A (en) * | 2014-04-11 | 2014-07-30 | 浙江耐司康药业有限公司 | Synthetic method for intermediate of benserazide hydrochloride |
| WO2015197909A1 (en) * | 2014-06-27 | 2015-12-30 | Fermion Oy | Process for the preparation of a crystalline polymorph of 2-amino-3-hydroxy-n'-(2,3,4-trihydroxybenzyl)propanehydrazide (benserazide) hydrochloride |
Non-Patent Citations (4)
| Title |
|---|
| YAACOV HERZIG等: "Hydroxy-1-aminoindans and Derivatives: Preparation, Stability, and Reactivity", 《J.ORG.CHEM.》 * |
| 刘广娟 等: "多巴丝肼胶囊有关物质的HPLC法测定", 《中国医药工业杂志》 * |
| 李娜: "色谱质谱技术在化学药物杂质研究中的应用", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
| 熊婧 等: "盐酸苄丝肼有关物质检查方法改进及杂质鉴定", 《药物分析杂志》 * |
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