CN114516874A - Methotrexate new crystal form and preparation method thereof - Google Patents
Methotrexate new crystal form and preparation method thereof Download PDFInfo
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- CN114516874A CN114516874A CN202210260942.8A CN202210260942A CN114516874A CN 114516874 A CN114516874 A CN 114516874A CN 202210260942 A CN202210260942 A CN 202210260942A CN 114516874 A CN114516874 A CN 114516874A
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- methotrexate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
- C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a novel methotrexate crystal form and a preparation method thereof, wherein the method comprises the following steps: s1), adding water to dissolve the methotrexate sodium salt with the structure of the formula I to obtain a clear solution; s2), adjusting the pH value of the clarified solution to 1-2 by adopting an acid solution, and stirring for crystallization for 1-2 h; s3), adding the solid obtained in the step S2) into a mixed solvent, adjusting the pH value to 4-5 by using triethylamine, stirring for 1-2 h, and performing suction filtration; s4), adding the solid obtained in the step S3) into a mixed solvent, stirring for 2-3 h, performing suction filtration to separate the solid, and drying to obtain the new methotrexate crystal form. According to the method, the new crystal form is prepared, the methotrexate raw material is also purified, the purity of the methotrexate reaches more than 99%, the purification operation of the methotrexate is simpler, the yield is higher, the production cost is reduced, and the method is more suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a novel methotrexate crystal form and a preparation method thereof.
Background
The chemical name of methotrexate is N- [4- [ [ (2, 4-diamino-6-pteridine) methyl ] methylamino ] benzoyl ] -L-glutamic acid, and the synthesis route of methotrexate is more according to literature reports.
The method comprises the following steps: post-synthesis pteridine ring method (A' + (B + C))
The method 2 comprises the following steps: one-pot method
The method is used for synthesizing the methotrexate by a one-pot method. Corresponding to the in situ generation of fragment A, followed by condensation with the B + C fragment.
The method 3 comprises the following steps: post-glutamic acid method
The method 4 comprises the following steps: condensation method (A + (B + C))
The reaction conditions of the route are mild, and both intermediates are commercially available.
From the above, the synthesis method is more, and the report of the methotrexate crystal form is not seen. Meanwhile, in the preparation, the crystal form of the raw material medicine directly or indirectly influences the preparation process of the corresponding preparation, and the in vivo and in vitro dissolution and absorption conditions of the corresponding preparation further influence the safety, effectiveness and quality controllability of the medicine.
Disclosure of Invention
In view of the above, the present invention aims to provide a novel form of methotrexate and a preparation method thereof, wherein the method can obtain the novel form of methotrexate, and the method is simple and has high yield and purity.
The invention provides a preparation method of a new methotrexate crystal form, which comprises the following steps:
s1), adding water to dissolve the methotrexate sodium salt with the structure of the formula I to obtain a clear solution;
s2), adjusting the pH value of the clarified solution to 1-2 by adopting an acid solution, and stirring for crystallization for 1-2 h;
S3), adding the solid obtained in the step S2) into a mixed solvent, adjusting the pH value to 4-5 by using triethylamine, stirring for 1-2 h, and performing suction filtration;
s4), adding the solid obtained in the step S3) into a mixed solvent, stirring for 2-3 h, filtering and separating the solid, and drying to obtain a methotrexate new crystal form:
in the invention, the mass-to-volume ratio of the methotrexate sodium salt with the structure of formula I to water is 1: 2-1: 4; preferably 1: 2.
in the present invention, the acid solution is selected from one or more of hydrochloric acid, sulfuric acid and phosphoric acid.
In the present invention, the mixed solvent is selected from one or more of an ethanol-water mixed solvent, a methanol-water mixed solvent, an acetone-water mixed solvent, and an isopropanol-water mixed solvent.
In the present invention, the mixed solvent is selected from the group consisting of 1: 1 mixed solvent of acetone and water; or the volume ratio is 1: 5 of a mixed solvent of ethanol and water; or the volume ratio of 1: 2, a mixed solvent of methanol and water.
The invention provides a novel methotrexate crystal form which is prepared by the preparation method in the technical scheme.
In the invention, the new methotrexate crystal form has diffraction peaks at 2 theta +/-0.2 degrees, and the 2 theta is 9.176 degrees, 10.102 degrees, 13.821 degrees, 14.681 degrees, 15.758 degrees, 22.181 degrees and 23.460 degrees. In a specific embodiment of the invention, the 2 θ of the new form of methotrexate is 9.176 °, 10.102 °, 13.821 °, 14.681 °, 15.758 °, 18.081 °, 19.861 °, 22.181 °, 23.460 °, 27.921 °, 19.478 °.
The diffraction peak is a characteristic powder diffraction peak of the methotrexate new crystal form, and the detection precision is +/-1 degrees.
Through detection, the purity of the obtained new methotrexate crystal reaches the use standard of medicines, and the new methotrexate crystal can be directly used as a raw material medicine.
The invention provides a preparation method of a new methotrexate crystal form, which comprises the following steps: s1), adding water to dissolve the methotrexate sodium salt with the structure of the formula I to obtain a clear solution; s2), adjusting the pH value of the clarified solution to 1-2 by adopting an acid solution, and stirring for crystallization for 1-2 h; s3), adding the solid obtained in the step S2) into a mixed solvent, adjusting the pH value to 4-5 by using triethylamine, stirring for 1-2 h, and performing suction filtration; s4), adding the solid obtained in the step S3) into a mixed solvent, stirring for 2-3 h, performing suction filtration to separate the solid, and drying to obtain the new methotrexate crystal form. According to the method, the methotrexate raw material is purified at the same time when the new crystal form is prepared, the purity of the methotrexate reaches more than 99%, the purification operation of the methotrexate is simpler, the yield is higher, the production cost is reduced, the method is more suitable for industrial production, and the new crystal form of the methotrexate raw material is obtained at the same time. The preparation method of the novel methotrexate crystal provided by the invention has the characteristics of strong environmental friendliness, controllable quality, low toxicity and harmlessness of used solvents and the like, and is more suitable for industrial production.
Drawings
FIG. 1 is a powder diffraction pattern of crystalline form of methotrexate prepared according to example 1 of the present invention;
figure 2 is a liquid phase diagram of a crystalline form of methotrexate prepared according to example 1 of the present invention.
Detailed Description
In order to further illustrate the present invention, a new form of methotrexate and a method for preparing the same are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Preparatory example (preparation of a semi-finished methotrexate)
Adding 50.0g of methotrexate sodium salt into a reaction bottle, adding 100ml of water, stirring and dissolving, adjusting the pH value to 1-2 by using sulfuric acid, and performing suction filtration to obtain 42g of methotrexate semi-finished product, wherein the water content is less than 5%. .
Example 1 (ethanol/Water slurry Wash-crystallization method, preparation of New crystalline form of methotrexate)
Adding 10g of semi-finished methotrexate (10g) prepared in the preparation example into a 100ml reactor, adding an ethanol/water mixed solution into the reactor (the volume ratio of ethanol to water is 1:5), adjusting the pH value to 4-5 by using triethylamine, stirring for 1-2 h, carrying out suction filtration, adding the obtained solid into ethanol/water 1:5, continuously stirring for 2-3 h, carrying out suction filtration, separating the solid, and drying to obtain the novel crystal form of methotrexate.
The yield of the new methotrexate crystal form is 75%, and the purity is 99.7%.
FIG. 1 is a powder diffraction pattern of crystalline form of methotrexate prepared according to example 1 of the present invention;
figure 2 is a liquid phase diagram of a crystalline form of methotrexate prepared according to example 1 of the present invention.
Example 2 (methanol/water slurry washing-crystallization method, preparation of novel methotrexate Crystal form)
The semi-finished methotrexate (10g) prepared in the preliminary example was added to a 100ml reactor, and a methanol/water mixed solution (methanol/water volume ratio 1:2) was added to the reactor, and the pH was adjusted to 4 to 5 using triethylamine, stirred for 1 to 2 hours, and filtered under suction. And adding the obtained solid into methanol/water (1: 2), continuously stirring for 2-3 h, performing suction filtration to separate the solid, and drying to obtain the methotrexate new crystal form.
The yield of the new methotrexate crystal form is 73 percent, and the purity is 99.5 percent.
Example 3 (acetone/water slurry washing-crystallization method, preparation of new methotrexate Crystal form)
The semi-finished methotrexate (10g) prepared in the preparation example was added to a 100ml reactor, and the acetone/water mixed solution was added to the reactor (acetone/water volume ratio 1:1), adjusted to pH 4-5 with triethylamine, stirred for 1-2 h, and filtered under suction. And adding the obtained solid into acetone/water (1: 1), continuously stirring for 2-3 h, performing suction filtration to separate the solid, and drying to obtain the methotrexate new crystal form.
The yield of the new methotrexate crystal form is 76 percent, and the purity of the new methotrexate crystal form is 99.6 percent.
From the above examples, the present invention provides a method for preparing a new crystal form of methotrexate, comprising the following steps: s1), adding water to dissolve the methotrexate sodium salt with the structure of the formula I to obtain a clear solution; s2), adjusting the pH value of the clarified solution to 1-2 by adopting an acid solution, and stirring for crystallization for 1-2 h; s3), adding the solid obtained in the step S2) into a mixed solvent, adjusting the pH value to 4-5 by using triethylamine, stirring for 1-2 h, and performing suction filtration; s4), adding the solid obtained in the step S3) into a mixed solvent, stirring for 2-3 h, performing suction filtration to separate the solid, and drying to obtain the new methotrexate crystal form. According to the method, the methotrexate raw material is purified at the same time when the new crystal form is prepared, the purity of the methotrexate reaches more than 99%, the purification operation of the methotrexate is simpler, the yield is higher, the production cost is reduced, the method is more suitable for industrial production, and the new crystal form of the methotrexate raw material is obtained at the same time. The preparation method of the novel methotrexate crystal provided by the invention has the characteristics of strong environmental friendliness, controllable quality, low toxicity and harmlessness of used solvents and the like, and is more suitable for industrial production.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and amendments can be made without departing from the principle of the present invention, and these modifications and amendments should also be considered as the protection scope of the present invention.
Claims (7)
1. A preparation method of the novel methotrexate crystal form comprises the following steps:
s1), adding water to dissolve the methotrexate sodium salt with the structure of the formula I to obtain a clear solution;
s2), adjusting the pH value of the clear solution to 1-2 by adopting an acid solution, and stirring for crystallization for 1-2 h;
s3), adding the solid obtained in the step S2) into a mixed solvent, adjusting the pH value to 4-5 by using triethylamine, stirring for 1-2 h, and performing suction filtration;
s4), adding the solid obtained in the step S3) into a mixed solvent, stirring for 2-3 h, performing suction filtration to separate the solid, and drying to obtain a new methotrexate crystal form:
2. the method of claim 1, wherein the sodium salt of methotrexate having the structure of formula i has a mass to water volume ratio of 1: 2-1: 4.
3. the method according to claim 1, wherein the acid solution is one or more selected from the group consisting of hydrochloric acid, sulfuric acid, and phosphoric acid.
4. The production method according to claim 1, wherein the mixed solvent is one or more selected from the group consisting of an ethanol-water mixed solvent, a methanol-water mixed solvent, an acetone-water mixed solvent, and an isopropanol-water mixed solvent.
5. The production method according to claim 1, wherein the mixed solvent is selected from a mixed solvent of acetone and water in a volume ratio of 1: 1; or a mixed solvent of ethanol and water in a volume ratio of 1: 5; or a mixed solvent of methanol and water in a volume ratio of 1: 2.
6. A new methotrexate crystal form prepared by the preparation method of any one of claims 1 to 5.
7. The novel form of methotrexate as claimed in claim 6, wherein the novel form of methotrexate has a diffraction peak at 2 Θ ± 0.2 ° and the 2 Θ is 9.176, 10.102, 13.821, 14.681, 15.758, 22.181, 23.460.
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| CN202210260942.8A CN114516874A (en) | 2022-03-11 | 2022-03-11 | Methotrexate new crystal form and preparation method thereof |
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| CN202210260942.8A CN114516874A (en) | 2022-03-11 | 2022-03-11 | Methotrexate new crystal form and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115197223A (en) * | 2022-05-25 | 2022-10-18 | 浙江致新医药科技有限公司 | Methotrexate crystal form A compound and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4224446A (en) * | 1977-08-12 | 1980-09-23 | Lonza Ltd. | Process for the production of methotrexate |
| CN1439641A (en) * | 2003-03-24 | 2003-09-03 | 中国药科大学 | Anti-cancer chemicals of methotrexate derivatives and their uses in pharmaceutical science |
| DE3752384D1 (en) * | 1986-09-03 | 2005-06-16 | Univ Strathclyde Glasgow | Pteridine derivative-containing pharmaceutical composition |
| CN103980279A (en) * | 2014-04-16 | 2014-08-13 | 悦康药业集团有限公司 | Methotrexate compound and methotrexate for injection |
| CN112851676A (en) * | 2021-01-25 | 2021-05-28 | 贵州医科大学 | Synthesis process of methotrexate |
| CN113461689A (en) * | 2021-06-30 | 2021-10-01 | 浙江浙北药业有限公司 | Preparation method of methotrexate compound |
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2022
- 2022-03-11 CN CN202210260942.8A patent/CN114516874A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4224446A (en) * | 1977-08-12 | 1980-09-23 | Lonza Ltd. | Process for the production of methotrexate |
| DE3752384D1 (en) * | 1986-09-03 | 2005-06-16 | Univ Strathclyde Glasgow | Pteridine derivative-containing pharmaceutical composition |
| CN1439641A (en) * | 2003-03-24 | 2003-09-03 | 中国药科大学 | Anti-cancer chemicals of methotrexate derivatives and their uses in pharmaceutical science |
| CN103980279A (en) * | 2014-04-16 | 2014-08-13 | 悦康药业集团有限公司 | Methotrexate compound and methotrexate for injection |
| CN112851676A (en) * | 2021-01-25 | 2021-05-28 | 贵州医科大学 | Synthesis process of methotrexate |
| CN113461689A (en) * | 2021-06-30 | 2021-10-01 | 浙江浙北药业有限公司 | Preparation method of methotrexate compound |
Non-Patent Citations (1)
| Title |
|---|
| N. SCHORMANN ET AL.: "Structure-based approach to pharmacophore identification, in silico screening, and three-dimensional quantitative structure–activity relationship studies for inhibitors of Trypanosoma cruzi dihydrofolate reductase function", 《PROTEINS》, pages 889 - 901 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115197223A (en) * | 2022-05-25 | 2022-10-18 | 浙江致新医药科技有限公司 | Methotrexate crystal form A compound and preparation method thereof |
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