CN112028862A - Preparation method of ranitidine hydrochloride with low NDMA content - Google Patents
Preparation method of ranitidine hydrochloride with low NDMA content Download PDFInfo
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- CN112028862A CN112028862A CN202010828461.3A CN202010828461A CN112028862A CN 112028862 A CN112028862 A CN 112028862A CN 202010828461 A CN202010828461 A CN 202010828461A CN 112028862 A CN112028862 A CN 112028862A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Abstract
The invention relates to the technical field of preparation of ranitidine hydrochloride, in particular to a preparation method of ranitidine hydrochloride with low NDMA content, which comprises the following process steps: adding ranitidine alkali into ethanol, and stirring until the ranitidine alkali is completely dissolved; cooling the solution to-5 ℃; adding a hydrochloric acid aqueous solution at a controlled temperature, adjusting the pH value to 4.5-6.5, and uniformly stirring; adding seed crystals, and carrying out heat preservation, stirring and crystallization for 3-5 h; and filtering the crystals, washing, draining and drying to obtain the off-white crystalline solid ranitidine hydrochloride. The salification method has the following advantages: the method has the advantages of simple steps, easily obtained raw material hydrochloric acid aqueous solution, good product properties and low impurity content of the final product N-dimethyl Nitrosamine (NDMA).
Description
Technical Field
The invention relates to the technical field of preparation of ranitidine hydrochloride, and particularly relates to a preparation method of ranitidine hydrochloride with low NDMA content.
Background
Ranitidine Hydrochloride (Ranitidine Hydrochloride), with the chemical name of N' -methyl-N- [2[ [5- [ (dimethylamino) methyl-2-furyl ] methyl ] thio ] ethyl ] -2-nitro-1, 1-ethylene diamine Hydrochloride, has the following structural formula:
ranitidine hydrochloride is H2Receptor antagonists which have a marked inhibitory effect on physiological and pentagastrin-induced gastric acid secretion,the traditional Chinese medicine composition is used for relieving stomachache, heartburn and acid regurgitation caused by hyperchlorhydria, and has good treatment effects on benign gastric ulcer, duodenal ulcer, stomatocace, reflux esophagitis and Zollinger-Ellison syndrome.
The U.S. food and drug administration (FDA for short) issued a report on low dose carcinogenesis of ranitidine drugs from 2019 early 9, the report indicates that FDA found low concentration carcinogen dimethyl Nitrosoamine (NDMA) in some ranitidine drugs, and is studying to determine the source of contaminated components and their risks in these drugs.
Chinese patent CN1724526A discloses a method for forming ranitidine base into hydrochloride, which comprises the steps of adjusting the pH value of an ethanol solution of ranitidine base to 6.2-6.8 by using hydrochloric acid-ethanol, cooling to below 0 ℃, adding seed crystals, stirring for crystallization, keeping for 6 hours, and obtaining ranitidine hydrochloride through filtration and drying. Chinese patents CN102010389A and CN107915697A also use hydrochloric acid ethanol solution to adjust pH value, decolorize, cool and crystallize, filter and dry.
Through multiple experiments, the salification with ethanolic hydrochloride solution has the following disadvantages: the preparation process of the hydrochloric acid ethanol solution is complicated, the processing cost is high, the character and color of the salt-forming final product are poor, the ethanol solvent residue of the product exceeds the standard, and more importantly, the process can obviously increase the impurity content of N-dimethyl Nitrosamine (NDMA).
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a preparation method of ranitidine hydrochloride with low NDMA content, which is a salt forming method of ranitidine alkali with simple steps, low processing cost, good product properties, low ethanol residue of the product and less NDMA impurities.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a preparation method of ranitidine hydrochloride with low NDMA content comprises the following steps:
s1, adding ranitidine alkali into ethanol, and stirring until the ranitidine alkali is completely dissolved;
s2, cooling the solution to-5 ℃, adding a hydrochloric acid aqueous solution, adjusting the pH value to 4.5-6.5, and uniformly stirring;
s3, adding seed crystals, and carrying out heat preservation, stirring and crystallization for 3-5 hours;
s4, filtering the crystal, washing, draining and drying to obtain the off-white crystalline solid ranitidine hydrochloride.
Further, the mass ratio of ranitidine base and ethanol in step S1 is 1: 3 to 5.
Further, the concentration of the hydrochloric acid aqueous solution in step S2 is 20% to 38%, preferably 20% to 25%.
Further, the temperature of the heat preservation crystallization in the step S3 is-5 to 5 ℃, and the stirring speed is 100 to 300 rpm.
Further, the washing in step S4 employs absolute ethanol.
Further, the drying in the step S4 is vacuum drying, the temperature is controlled to be 65-75 ℃, the time is 3-5 hours, and the vacuum degree is 0.09 Mpa.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a preparation method of ranitidine hydrochloride with low NDMA content, which is simple to operate, directly uses a hydrochloric acid aqueous solution to salify, omits a step of preparing an ethanol hydrochloric acid solution, and reduces the processing cost. The product has good properties, the color of the finished product is improved from light brown to similar white, and the ethanol residue is not more than 0.4%. The NDMA impurity is obviously reduced and is not more than 0.05 ppm.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
A preparation method of ranitidine hydrochloride with low NDMA content comprises the following steps:
s1, adding ranitidine alkali into ethanol, and stirring until the ranitidine alkali is completely dissolved; the mass ratio of ranitidine alkali to ethanol is 1: 3-5;
s2, cooling the solution to-5 ℃, adding a hydrochloric acid aqueous solution, adjusting the pH value to 4.5-6.5, and uniformly stirring; the concentration of the hydrochloric acid aqueous solution is 20 to 38 percent, preferably 20 to 25 percent;
s3, adding seed crystals, and carrying out heat preservation, stirring and crystallization for 3-5 hours; the temperature of the heat preservation crystallization is-5 to 5 ℃, and the stirring speed is 100 to 300 rpm;
s4, filtering the crystal, washing, draining and drying to obtain the off-white crystalline solid ranitidine hydrochloride. Absolute ethyl alcohol is adopted for washing; the drying is vacuum drying, the temperature is controlled to be 65-75 ℃, the time is 3-5 hours, and the vacuum degree is 0.09 Mpa.
Example 1
Adding 50g of ranitidine base into a 500ml reaction bottle, adding 300ml of absolute ethyl alcohol, and stirring at room temperature to dissolve; cooling to about-5 ℃, and slowly adding 20% hydrochloric acid aqueous solution into the reaction bottle to adjust the pH value to be 4.5-5.5; adding seed crystals after the dropwise addition, keeping the temperature at minus 5 ℃, stirring and crystallizing for 5 hours at the rotating speed of 100 rpm; filtering to obtain solid, and leaching the filter cake with 50ml of absolute ethyl alcohol; the filter cake was vacuum dried at 65 ℃ for 5 hours under reduced pressure to give 44.79g of off-white crystalline solid with a molar yield of 80.28%. HPLC content 99.6%, ethanol residue 0.24%, NDMA content 0.018 PPM.
Example 2
Adding 120g of ranitidine base into a 1L reaction bottle, adding 600ml of absolute ethyl alcohol, and stirring at room temperature to dissolve; cooling to about 0 ℃, and slowly adding 23% hydrochloric acid aqueous solution into the reaction bottle to adjust the pH value to be between 5.0 and 6.0; adding seed crystals after the dropwise addition, keeping the temperature at about 0 ℃, stirring and crystallizing for 4 hours at the rotating speed of 200 rpm; filtering to obtain solid, and leaching the filter cake with 100ml of absolute ethyl alcohol; the filter cake was vacuum dried at 70 ℃ for 4 hours under reduced pressure to give 117.42g of off-white crystalline solid with a molar yield of 83.67%. HPLC content 99.7%, ethanol residue 0.31%, NDMA content 0.036 PPM.
Example 3
Adding 500g of ranitidine base into a 5L reaction bottle, adding 2L of absolute ethyl alcohol, and stirring at room temperature to dissolve; cooling to about 5 ℃, and slowly adding 25% hydrochloric acid aqueous solution into the reaction bottle to adjust the pH value to be between 5.5 and 6.5; adding seed crystals after the dropwise addition, keeping the temperature at 5 ℃, stirring and crystallizing for 5 hours; filtering to obtain solid, and leaching the filter cake with 300ml of absolute ethyl alcohol; the filter cake was vacuum dried at 75 ℃ for 3.5 hours under reduced pressure to give 474.90g of off-white crystalline solid with a molar yield of 85.12%. HPLC content 99.7%, ethanol residue 0.18%, NDMA content 0.045 PPM.
Example 4
Adding 50g of ranitidine base into a 500ml reaction bottle, adding 300ml of absolute ethyl alcohol, and stirring at room temperature to dissolve; cooling to about 0 ℃, and slowly adding a hydrogen chloride ethanol solution into the reaction bottle to adjust the pH value to be between 4.5 and 6.5; adding seed crystals after the dropwise addition, and keeping the temperature at 0 ℃, stirring and crystallizing for 5 hours; filtering to obtain solid, and leaching the filter cake with 100ml of absolute ethyl alcohol; the filter cake was dried under reduced pressure at 70 ℃ for 4 hours under vacuum to give 52.97g of a beige crystalline solid with a molar yield of 93.84%. HPLC content 99.3%, ethanol residue 0.87%, NDMA content 0.39 PPM.
The solid ranitidine hydrochloride prepared by the method has the yield range of about 83 percent, the HPLC content of more than 99.5 percent, the drying weight loss of less than or equal to 0.05 percent, the ethanol residue of less than or equal to 0.5 percent and the NDMA impurity of less than or equal to 0.05ppm, and all meet the national standard. Because NDMA impurity of ranitidine can be degraded, water in the salt forming solvent inhibits the degradation of ranitidine to a certain extent.
Through a comparative test with example 4, the total yield of salt formation by using the hydrochloric acid ethanol solution is higher, but the ethanol residue is higher than 0.5%, and the NDMA content of the finished product is also higher than the national standard. The product is light brown in color and poor in shape.
Although only the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the above embodiments, and various changes can be made without departing from the spirit of the present invention within the knowledge of those skilled in the art, and all changes are encompassed in the scope of the present invention.
Claims (6)
1. A preparation method of ranitidine hydrochloride with low NDMA content is characterized by comprising the following steps:
s1, adding ranitidine alkali into ethanol, and stirring until the ranitidine alkali is completely dissolved;
s2, cooling the solution to-5 ℃, adding a hydrochloric acid aqueous solution, adjusting the pH value to 4.5-6.5, and uniformly stirring;
s3, adding seed crystals, and carrying out heat preservation, stirring and crystallization for 3-5 hours;
s4, filtering the crystal, washing, draining and drying to obtain the off-white crystalline solid ranitidine hydrochloride.
2. The method of claim 1, wherein the preparation of ranitidine hydrochloride with low NDMA content is characterized by: the mass ratio of ranitidine alkali to ethanol in the step S1 is 1: 3 to 5.
3. The method of claim 1, wherein the preparation of ranitidine hydrochloride with low NDMA content is characterized by: the concentration of the hydrochloric acid aqueous solution in step S2 is 20% to 38%, preferably 20% to 25%.
4. The method of claim 1, wherein the preparation of ranitidine hydrochloride with low NDMA content is characterized by: and S3, keeping the temperature of crystallization at-5 to 5 ℃, and stirring at 100 to 300 rpm.
5. The method of claim 1, wherein the preparation of ranitidine hydrochloride with low NDMA content is characterized by: the washing in step S4 uses absolute ethanol.
6. The method of claim 1, wherein the preparation of ranitidine hydrochloride with low NDMA content is characterized by: the drying in the step S4 is vacuum drying, the temperature is controlled to be 65-75 ℃, the time is 3-5 hours, and the vacuum degree is 0.09 Mpa.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114591274A (en) * | 2022-03-09 | 2022-06-07 | 河北海力香料股份有限公司 | Preparation method of ranitidine hydrochloride |
| CN114839288A (en) * | 2022-04-27 | 2022-08-02 | 湖南省药品检验检测研究院 | Method for pretreating ranitidine hydrochloride sample |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR8604449A (en) * | 1985-09-27 | 1987-05-12 | Gea Farmaceutisk Fabrik As | PROCESS FOR PREPARING RANITIDIN, ITS ACID ADDITION SALTS AND INTERMEDIATE COMPOUNDS USED IN PREPARING RANITIDIN |
| CN1724526A (en) * | 2005-07-11 | 2006-01-25 | 石药集团中诺药业（石家庄）有限公司 | Synthesis method of ranitidine alkali and its hydrochloride |
| CN102010389A (en) * | 2009-09-04 | 2011-04-13 | 江苏汉斯通药业有限公司 | Method for preparing ranitidine hydrochloride |
| MX2010006056A (en) * | 2010-06-02 | 2011-12-14 | Senosiain S A De C V Lab | Process for preparing ranitidine hydrochloride form 2. |
| CN108017601A (en) * | 2017-12-28 | 2018-05-11 | 山西云鹏制药有限公司 | A kind of method of refined ranitidine alkali |
-
2020
- 2020-08-18 CN CN202010828461.3A patent/CN112028862A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR8604449A (en) * | 1985-09-27 | 1987-05-12 | Gea Farmaceutisk Fabrik As | PROCESS FOR PREPARING RANITIDIN, ITS ACID ADDITION SALTS AND INTERMEDIATE COMPOUNDS USED IN PREPARING RANITIDIN |
| CN1724526A (en) * | 2005-07-11 | 2006-01-25 | 石药集团中诺药业（石家庄）有限公司 | Synthesis method of ranitidine alkali and its hydrochloride |
| CN102010389A (en) * | 2009-09-04 | 2011-04-13 | 江苏汉斯通药业有限公司 | Method for preparing ranitidine hydrochloride |
| MX2010006056A (en) * | 2010-06-02 | 2011-12-14 | Senosiain S A De C V Lab | Process for preparing ranitidine hydrochloride form 2. |
| CN108017601A (en) * | 2017-12-28 | 2018-05-11 | 山西云鹏制药有限公司 | A kind of method of refined ranitidine alkali |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114591274A (en) * | 2022-03-09 | 2022-06-07 | 河北海力香料股份有限公司 | Preparation method of ranitidine hydrochloride |
| CN114839288A (en) * | 2022-04-27 | 2022-08-02 | 湖南省药品检验检测研究院 | Method for pretreating ranitidine hydrochloride sample |
| CN114839288B (en) * | 2022-04-27 | 2023-11-07 | 湖南省药品检验检测研究院 | Pretreatment method of ranitidine hydrochloride Ding Yangpin |
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Application publication date: 20201204 |