CN111484425B - Preparation method of benserazide hydrochloride impurity - Google Patents
Preparation method of benserazide hydrochloride impurity Download PDFInfo
- Publication number
- CN111484425B CN111484425B CN201910072067.9A CN201910072067A CN111484425B CN 111484425 B CN111484425 B CN 111484425B CN 201910072067 A CN201910072067 A CN 201910072067A CN 111484425 B CN111484425 B CN 111484425B
- Authority
- CN
- China
- Prior art keywords
- benserazide hydrochloride
- impurity
- preparation
- water
- benserazide
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention reports a preparation method of a benserazide hydrochloride impurity, in particular to a preparation method of a benserazide hydrochloride pharmacopoeia impurity B. The method has the advantages of simple and easy operation, mild condition, high yield, low energy consumption and less pollution, and is suitable for preparing laboratory-level standard substances.
Description
Technical Field
The invention reports a preparation method of benserazide hydrochloride impurities, in particular relates to a preparation method of benserazide hydrochloride pharmacopoeia impurities B, and belongs to the field of medicines.
Background
Benserazide hydrochloride (Benserazide Hydrochloride) is an active ingredient in a compound medicine of mecobab (Madopar) for treating parkinsonism. The original grinding company of the mecoba is Roshi pharmacy, and the effective components are the levodopa and the benserazide hydrochloride. The composition can increase dopamine content in brain cells, and improve Parkinson's disease. Benserazide hydrochloride is a dopa decarboxylase (Dopa decarboxylase) inhibitor, which can block the conversion of levodopa to dopamine before entering the brain, thereby increasing the content of dopamine in the brain and reducing its peripheral adverse effects. Benserazide hydrochloride in the mecoba is compatible with the levodopa according to the dosage ratio of 1:4.
The chemical name of the benserazide hydrochloride is 2-amino-3-hydroxy-N' - (2, 3, 4-trihydroxybenzyl) propionylhydrazine hydrochloride, and the chemical structural formula is as follows:
meadopa is currently marketed in China, japan and the European Union. Benserazide hydrochloride has been incorporated in the pharmacopoeia of the three places above. Among them, the European pharmacopoeia (EP 9.0) specifies a specific impurity B in the relevant substance detection item in its quality standard, the Chinese name being 2-amino-3-hydroxy-N ', N' -bis (2, 3, 4-trihydroxybenzyl) propionyl hydrazide, the structure of which is as follows:
in the research process, the impurities are almost inevitably present in the production process of the benserazide, and are main degradation impurities in the benserazide bulk drug and the preparation, but are very unstable and easy to be further degraded. Through literature query, the synthesis method of the impurity is found to be rarely reported.
In the preparation process of the raw material medicine, the impurity can also be obtained by performing column chromatography or preparation chromatography on the product or mother liquor rich in the impurity. However, the method is low in efficiency, long in time consumption and serious in waste. The more important reason is that the impurities themselves are poorly stable and are mostly destroyed during separation and concentration.
In summary, the impurity is used as a pharmacopoeia impurity, and is required to be used as a standard substance for positioning and content inspection in daily detection, but no efficient and convenient synthesis or separation means can prepare the impurity standard substance on a large scale at present.
The invention reports a preparation method of benserazide hydrochloride impurity B, which is simple and feasible in operation, mild in condition, high in yield, low in energy consumption and pollution and suitable for preparing laboratory-level standard substances.
Disclosure of Invention
The invention reports a preparation method of benserazide hydrochloride impurity, in particular to a preparation method of benserazide hydrochloride pharmacopoeia impurity B, which has the advantages of simple and easy operation, mild condition, high yield, low energy consumption and little pollution and is suitable for preparing laboratory-level standard products.
The method is characterized in that benserazide hydrochloride reacts under the action of water at a certain reaction temperature, and alcohol solvent I is used for carrying out first crystallization to obtain crude benserazide hydrochloride pharmacopoeia impurity B. And recrystallizing the crude product by water and an alcohol solvent II in a certain volume ratio to obtain the benserazide hydrochloride pharmacopoeia impurity B.
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
In order to further illustrate the invention, specific embodiments of the invention are described below in conjunction with the examples. It should be noted that the following description is only given for further illustrating the features and advantages of the present invention, and does not limit the scope of the claims of the present invention.
Example 1:
into a 100ml three-necked flask, 9.6g of benserazide hydrochloride and 30ml of water were added, the mixture was heated to 20-30℃and stirred for 16-20 hours, and the water was removed by concentration. Adding 20mL of methanol, cooling to 0-10 ℃, dropwise adding 80mL of ethanol, precipitating solid, preserving heat, stirring, and performing suction filtration to obtain a crude product. Adding 20mL of methanol and 10mL of water into the crude product at the temperature of 10-20 ℃ to stir and dissolve the crude product, then dripping 30mL of ethanol into the crude product to stir and crystallize, filtering and drying the crude product to obtain benserazide hydrochloride pharmacopoeia impurity B,4.1g, and the yield is 55.5%. 1 H NMR(400 MHz,DMSO-d 6 )δ9.83(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:
into a 100ml three-necked flask, 2.0g of benserazide hydrochloride and 6ml of water were added, and the mixture was heated to 30-40℃and stirred for 6-8 hours, and the water was removed by concentration. Adding 30mL of methanol, cooling to 0-10 ℃, precipitating solid, preserving heat, stirring, and performing suction filtration to obtain a crude product. Adding 20mL of methanol and 10mL of water into the crude product at the temperature of 10-20 ℃ to stir and dissolve the crude product, then dripping 30mL of methanol into the crude product to stir and crystallize, filtering and drying the crude product to obtain benserazide hydrochloride pharmacopoeia impurity B,0.82g, and the yield is 53.2%. 1 H NMR(400MHz,DMSO-d 6 )δ9.83 (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:
into a 100ml three-necked flask, 2.0g of benserazide hydrochloride and 6ml of water were added, and the mixture was heated to 30-40℃and stirred for 6-8 hours, and the water was removed by concentration. Adding 30mL of ethanol, cooling to 0-10 ℃, precipitating solid, preserving heat, stirring, and performing suction filtration to obtain a crude product. Adding 20mL of ethanol and 10mL of water into the crude product at the temperature of 10-20 ℃ to stir and dissolve the crude product, then dripping 30mL of ethanol into the solution, stirring and crystallizing the solution, filtering and drying the solution to obtain benserazide hydrochloride impurity B,0.88g, and the yield is 57.1%. 1 H NMR(400MHz,DMSO-d 6 )δ9.83 (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:
into a 100ml three-necked flask, 2.0g of benserazide hydrochloride and 6ml of water were added, and the mixture was heated to 40-50℃and stirred for 3-5 hours, and the water was removed by concentration. Adding 30mL of isopropanol, cooling to 0-10 ℃, precipitating solid, preserving heat, stirring, and carrying out suction filtration to obtain a crude product. Adding 20mL of isopropanol and 10mL of water into the crude product at the temperature of 10-20 ℃ to stir and dissolve, then dripping 30mL of isopropanol, stirring and crystallizing, filtering and drying to obtain benserazide hydrochloride pharmacopoeia impurity B,0.96g, and the yield is 62.3%. 1 H NMR(400MHz,DMSO-d 6 ) δ9.83(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:
10.0g of benserazide hydrochloride and 30ml of water are added into a 100ml three-necked flask, heated to 50-60 ℃ and stirred for 2-4 hours, and concentrated to remove water. Adding 20mL of methanol, cooling to 0-10 ℃, dropwise adding 100mL of isopropanol, precipitating solid, preserving heat, stirring, and performing suction filtration to obtain a crude product. Adding 20mL of methanol and 10mL of water into the crude product at the temperature of 10-20 ℃ to stir and dissolve the crude product, adding 80mL isopropanol, stirring and crystallizing, filtering and drying to obtain the benserazide hydrochloride pharmacopoeia impurity B,1.17g, and the yield is 76.0%. 1 H NMR (400MHz,DMSO-d 6 )δ9.83(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:
into a 100ml three-necked flask, 2.0g of benserazide hydrochloride and 6ml of water were added, and the mixture was heated to 60 to 80℃and stirred for 2 to 3 hours, and the water was removed by concentration. Adding 4mL of methanol, cooling to 0-10 ℃, dropwise adding 22mL of ethanol, precipitating solid, preserving heat, stirring, and performing suction filtration to obtain a crude product. Adding 4mL of ethanol and 2mL of water into the crude product at the temperature of 10-20 ℃ to stir and dissolve, adding 36mL of isopropanol, stirring and crystallizing, filtering and drying to obtain benserazide hydrochloride impurity B,0.96g, and the yield is 62.3%. 1 H NMR(400MHz, DMSO-d 6 )δ9.83(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].
The preparation method of the benserazide hydrochloride impurity B provided by the invention has been described by the examples, and the related technicians can obviously modify or appropriately modify and combine the preparation method of the benserazide hydrochloride impurity B described herein without departing from the content, spirit and scope of the invention, so as to realize the technology 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 included within the spirit, scope and content of the invention.
Claims (3)
1. A preparation method of benserazide hydrochloride impurity, in particular to a preparation method of benserazide hydrochloride pharmacopoeia impurity B,
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 alcohol solvent I is used for carrying out first crystallization to obtain crude benserazide hydrochloride pharmacopoeia impurity B; recrystallizing the crude product by water and an alcohol solvent II in a certain volume ratio to obtain benserazide hydrochloride pharmacopoeia impurity B;
wherein the reaction temperature is 20-80 ℃; the volume ratio of the water to the alcohol solvent II is selected from 1:5 to 1:20.
2. The process according to claim 1, wherein the alcoholic solvent I is selected from methanol, ethanol, isopropanol or a mixture thereof.
3. The process according to claim 1, wherein the alcoholic solvent II is selected from methanol, ethanol, isopropanol or a mixture thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910072067.9A CN111484425B (en) | 2019-01-25 | 2019-01-25 | Preparation method of benserazide hydrochloride impurity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910072067.9A CN111484425B (en) | 2019-01-25 | 2019-01-25 | Preparation method of benserazide hydrochloride impurity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111484425A CN111484425A (en) | 2020-08-04 |
| CN111484425B true CN111484425B (en) | 2023-06-23 |
Family
ID=71791397
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910072067.9A Active CN111484425B (en) | 2019-01-25 | 2019-01-25 | Preparation method of benserazide hydrochloride impurity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111484425B (en) |
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 |
-
2019
- 2019-01-25 CN CN201910072067.9A patent/CN111484425B/en active Active
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 |
|---|
| Hydroxy-1-aminoindans and Derivatives: Preparation, Stability, and Reactivity;Yaacov Herzig等;《J.Org.Chem.》;20060504;第71卷;第4136页Scheme 11，第4139页右栏第3段 * |
| 多巴丝肼胶囊有关物质的HPLC法测定;刘广娟 等;《中国医药工业杂志》;20141231;第45卷(第6期);第564-566页 * |
| 盐酸苄丝肼有关物质检查方法改进及杂质鉴定;熊婧 等;《药物分析杂志》;20141231;第34卷(第11期);第2035-2040页 * |
| 色谱质谱技术在化学药物杂质研究中的应用;李娜;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20150415(第4期);第24页图2-22 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111484425A (en) | 2020-08-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111072589A (en) | Recrystallization method and preparation method of mirabegron | |
| CN111484425B (en) | Preparation method of benserazide hydrochloride impurity | |
| CN113277957A (en) | Preparation method of oseltamivir phosphate key intermediate hydrochloride | |
| CN112047851B (en) | Preparation method of D-panthenol | |
| CN114685349B (en) | Process for preparing cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide | |
| CN111484418B (en) | Preparation method of 4-amino-2-cyclopentene-1-methanol hydrochloride | |
| CN102718675B (en) | Agomelatine methanesulfonic acid complex and preparation method thereof | |
| CN107304186B (en) | Refining method of olaparib | |
| CN114181117B (en) | Preparation method of peramivir intermediate | |
| CN114163411A (en) | Preparation method of enantiomer pure dihydromyricetin | |
| CN112375031B (en) | Preparation method of cilnidipine | |
| CN106187799B (en) | A method of preparing DL-lysine hydrochloride | |
| CN111377840A (en) | Preparation method of R- (+) -dihydrolipoic acid | |
| CN111454172A (en) | Production method for preparing glutaronitrile by aminolysis of ester substance | |
| CN105949127B (en) | A kind of method of purification of imidazophenylurea | |
| US7772280B2 (en) | Crystals of L-ornithine and process for producing the same | |
| CN103896784A (en) | Method for reducing nitro of Fingolimod intermediate to amino | |
| CN111606815B (en) | Preparation method of phenylephrine hydrochloride impurity standard | |
| CN112608286B (en) | Preparation method of high-purity pramipexole | |
| CN110669022B (en) | Micro-channel continuous preparation method of 5-methyl isoxazole-4-formic acid | |
| CN109422679B (en) | Purification of bedaquiline and preparation method of stable crystal form | |
| CN101250116B (en) | Method for suppressing impurity substance during preparation of benzo ammonia alcohol | |
| CN108863946B (en) | Preparation method of dibazole impurity reference substance | |
| CN109305962B (en) | Refining method of dalatavir hydrochloride | |
| CN106431934A (en) | Method for synthesizing S-shaped amino compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |