CN108069970B - Preparation method of pralatrexate - Google Patents
Preparation method of pralatrexate Download PDFInfo
- Publication number
- CN108069970B CN108069970B CN201611013247.2A CN201611013247A CN108069970B CN 108069970 B CN108069970 B CN 108069970B CN 201611013247 A CN201611013247 A CN 201611013247A CN 108069970 B CN108069970 B CN 108069970B
- Authority
- CN
- China
- Prior art keywords
- pralatrexate
- plqs
- temperature
- dropwise adding
- solid
- 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
- 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
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a pralatrexate finished product. The method comprises the following steps: the method comprises the steps of taking PLQS-6 as a raw material, respectively using acetone, methyl ethyl ketone, butanone, dioxane and the like as solvents, controlling the generation of impurities by controlling the temperature and dropwise adding an inorganic base in batches, dropwise adding a crystallization solvent after the reaction is finished to salt out and crystallize the pralatrexate, collecting pralatrexate salt-crystallized solid, adding purified water to dissolve the solid, washing the solid with dichloromethane, and adjusting the pH value with acetic acid to obtain the pralatrexate solid. The synthesis method is simple, easy to operate, high in yield and purity and suitable for industrial production, and impurities are easy to remove.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of pralatrexate.
Background
Pralatrexate (Pralatrexate), trade name Folotyn, is the first new targeted folic acid formulation approved by the FDA for the treatment of peripheral T-cell lymphoma. The chemical name of pralatrexate is 10-propargyl-10-deazaaminopterin. By Joseph i.degew; j William T.Colwell et al, Synthesis and anticancer activity of 10-propagyl-10-deazaaminopterin, J.medical chem.36:2228-2231 (1993). It was also studied next by Sirotaak et al and O' Connor et al. The molecular structure is shown as follows:
the synthesis of pralatrexate is carried out by taking p-carboxylphenylacetic acid as initial raw material and carrying out a series of chemical conversions. First, intermediate methyl 4-formate phenylacetate (PLQS-1), intermediate methyl a-propargyl- (4-formate) -phenylacetate (PLQS-2), intermediate 10-propargyl-10-carbomethoxy-4-deoxy-4-amino-10-deazapteroate (PLQS-3), intermediate 10-propargyl-10-carboxy-4-deoxy-4-amino-10-deazapteroate (PLQS-4), intermediate 10-propargyl-4-deoxy-4-amino-10-deazapteroate (PLQS-5), intermediate 10-propargyl-10-deazaaminopterin dimethyl ester (PLQS-6), finally, the final product of pralatrexate is obtained.
The pralatrexate is an amphoteric compound, is insoluble in organic solvents such as formic acid, acetic acid, low molecular alcohols, DCM, EA and the like at normal temperature, and is easily soluble in solutions such as alkaline solution, DMF, DMSO and the like, but in the alkaline solvent, the amino group on the pteridine in the structure of the pralatrexate is easily hydrolyzed into hydroxyl group, and the purification by using the alkaline solvent has no refining effect and also increases the impurities; when solvents such as DMF, DMSO and the like are used for refining, due to the fact that boiling points of DMSO and DMF are high, pralatrexate is unstable thermally, and DMF and DMSO residues exceed the standard; in the prior art, the refining requirements can not be met by pulping and purifying by using a mixed solution of methanol and methanol dichloromethane.
Researchers find that racemization of a pralatrexate finished product is easily caused when low-molecular alcohols such as absolute ethyl alcohol and methanol are used as reaction solvents in the prior art, the isomer ratio of the pralatrexate finished product is increased to more than 1.5%, and the reaction solvents become a factor for generating impurities; therefore, the generation of impurities in the reaction can be effectively solved by selecting a proper reaction solvent, and the problems of singleness and defects of the refining method in the prior art can be solved. The selection of a proper reaction solvent becomes an urgent problem to be solved in the preparation process of the pralatrexate.
Disclosure of Invention
The invention aims to solve the defects of the prior art, and takes an intermediate 10-propargyl-10-deazaaminopterin dimethyl ester (PLQS-6) as a raw material, acetone, methyl ethyl ketone, butanone, dioxane and the like as solvents respectively, a proper amount of inorganic alkaline solution is dripped for hydrolysis, the reaction is completed after the reaction solution is clarified, crystallization solvents such as ethanol, isopropanol, butanol, acetone and the like are added into the reaction solution after the temperature is reduced, pralatrexate is salted out for crystallization, the pralatrexate salt solid is dissolved in purified water, impurities in the water phase are washed by dichloromethane, activated carbon is added into the water phase after the washing is completed for decoloration and impurity removal, the pH value is adjusted by acetic acid, the crystallization is carried out, the filtration is carried out, and the solid is washed by the purified water, so that.
The inventors have conducted further studies on the hydrolysis solvent, hydrolysis temperature, amount of alkali used, hydrolysis time and crystallization pH of PLQS-6 through intensive studies and investigations.
Specifically, the invention is realized by the following technical scheme:
taking a Pralatrexate intermediate PLQS-6 as a raw material, adding a reaction solvent, stirring to form a suspension, controlling the temperature, adding a low-concentration inorganic alkali solution in batches, hydrolyzing, separating the batches at intervals of 2-3 hours, clarifying the reaction solution, and sampling for HPLC detection; and after hydrolysis, cooling, dropwise adding a crystallization solvent to salt out and crystallize the pralatrexate, dissolving the crystallized solid in purified water, washing with dichloromethane, decoloring the water solution with activated carbon at normal temperature, adjusting the pH value with acetic acid, crystallizing, filtering, and washing the filter cake with purified water to obtain the high-purity pralatrexate solid.
The reaction solvent is as follows: one of acetone, methyl ethyl ketone, butanone and dioxane; acetone is preferred.
The ratio of the mass of PLQS-6 to the volume of the reaction solvent is as follows: 1: 3-10 g/ml; preferably 1: 5 g/ml.
The mole ratio of PLQS-6 to inorganic base is as follows: 1: 2 to 2.5; preferably 1: 2.3.
the inorganic base is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; sodium hydroxide is preferred.
The molar concentration of the inorganic alkali solution is as follows: 0.1-2.0 mol/L; preferably 1.0 mol/L.
The volume ratio of the PLQS-6 to the crystallization solvent is as follows: 1: 20-100 g/ml; preferably: 1: 36 g/ml.
The hydrolysis temperature is as follows: 0-30 ℃; preferably: 10 to 15 ℃.
The crystallization solvent is one of ethanol, normal propyl alcohol, isopropanol, normal butanol and acetone; ethanol is preferred.
The pH value of the crystallization is 3.0-5.0; preferably 3.5.
Compared with the prior art, the invention has the following technical effects:
(1) acetone, methyl ethyl ketone, butanone, dioxane, etc. are used as reaction solvent to prevent racemization of PLQS-6 during hydrolysis, and the isomer ratio is reduced from 1.5% to below 0.2%.
(2) By dropwise adding the inorganic strong alkali solution in batches, excessive hydrolysis of the pralatrexate can be prevented, and the alkali concentration required by hydrolysis can be ensured.
(3) The pralatrexate is salted out and crystallized by adopting a crystallization solvent, and the effect of refining the pralatrexate salt can be achieved.
(4) The required solvents are low-boiling point solvents, so that the overproof of the DMF, DMSO and other solvent residues is avoided.
(5) The obtained pralatrexate finished product has high purity and yield, and the purity can reach more than 99.80 percent; and the yield can reach 90 percent.
(6) The method is simple to operate, reduces the influence of the solvent removed by evaporation on the product quality, and is suitable for industrial production.
Detailed Description
The benefits of the present invention will now be further illustrated by the following examples, which are intended for the purpose of illustration only and should not be construed as limiting the invention, and all such obvious modifications and variations that may be apparent to those skilled in the art are intended to be included within the scope of the invention.
Example 1
Adding 20g of PLQS-6 and 100ml of acetone into a 2L three-necked bottle, stirring, controlling the temperature to be about 10 ℃ to form suspension in the bottle, beginning to dropwise add 15ml of 1.0mol/L sodium hydroxide aqueous solution, controlling the dropwise adding speed to ensure that the temperature of the reaction bottle is 10-13 ℃, keeping the temperature and stirring for 2 hours, continuously dropwise adding 15ml of 1.0mol/L sodium hydroxide aqueous solution, repeating the operations until 91ml of sodium hydroxide aqueous solution is completely dropwise added, keeping the temperature and stirring for 2 hours, clarifying the reaction solution, sampling and carrying out HPLC detection; and (3) completely reacting, putting the three-necked flask into a cold bath, cooling to 0-5 ℃, dropwise adding 720ml of absolute ethyl alcohol, separating out yellow solid, continuing to keep the temperature and stir for 1h after dropwise adding, filtering, dissolving the filter cake with 200ml of purified water, stirring for 5-10 min with 200ml of dichloromethane, separating liquid, discarding the organic phase, continuing to stir for 5-10 min with 200ml of dichloromethane for liquid separation, discarding the organic phase, adding 1g of activated carbon into the aqueous phase, stirring for 0.5h at normal temperature, filtering, slowly dropwise adding glacial acetic acid into the filtrate, separating out solid, stopping dropwise adding glacial acetic acid when the pH value reaches 3.5, continuing to stir for 1-2 h, filtering, pulping and washing the filter cake with 200ml of purified water twice, filtering to obtain white-like solid, drying to obtain 17.1g of pale yellow solid, wherein the purity is 99.85%, the isomer ratio is 0.13%, and the yield is 90..
Example 2
Adding 20g of PLQS-6 and 200ml of dioxane into a 2L three-necked bottle, stirring, controlling the temperature to be about 10 ℃ to form suspension in the bottle, beginning to dropwise add 15ml of 1.0mol/L sodium carbonate aqueous solution, controlling the dropwise adding speed to ensure that the temperature of the reaction bottle is 10-13 ℃, keeping the temperature and stirring for 2 hours, continuously dropwise adding 15ml of 1.0mol/L sodium carbonate aqueous solution, repeating the above operations until 91ml of sodium carbonate aqueous solution is completely dropwise added, keeping the temperature and stirring for 4 hours, clarifying the reaction solution, sampling and carrying out HPLC detection; and (3) completely reacting, putting the three-necked flask into a cold bath, cooling to 0-5 ℃, dropwise adding 720ml of absolute ethyl alcohol, separating out yellow solid, continuing to keep the temperature and stir for 1h after dropwise adding, filtering, dissolving the filter cake with 200ml of purified water, stirring for 5-10 min with 200ml of dichloromethane, separating liquid, discarding the organic phase, continuing to stir for 5-10 min with 200ml of dichloromethane for liquid separation, discarding the organic phase, adding 1g of activated carbon into the aqueous phase, stirring for 0.5h at normal temperature, filtering, slowly dropwise adding glacial acetic acid into the filtrate, separating out solid, stopping dropwise adding glacial acetic acid when the pH value reaches 3.5, continuing to stir for 1-2 h, filtering, pulping and washing the filter cake with 200ml of purified water twice, filtering to obtain white-like solid, drying to obtain 16.4g of light yellow solid, wherein the purity is 99.80%, the isomer ratio is 0.18%, and the yield is 86..
Example 3
Adding 20g of PLQS-6 and 60ml of acetone into a 2L three-necked bottle, stirring, controlling the temperature to be about 10 ℃ to form suspension in the bottle, beginning to dropwise add 15ml of 1.0mol/L sodium hydroxide aqueous solution, controlling the dropwise adding speed to ensure that the temperature of the reaction bottle is 10-13 ℃, keeping the temperature and stirring for 2 hours, continuously dropwise adding 15ml of 1.0mol/L sodium hydroxide aqueous solution, repeating the operations until 91ml of sodium hydroxide aqueous solution is completely dropwise added, keeping the temperature and stirring for 2 hours, clarifying the reaction solution, sampling and carrying out HPLC detection; and (3) completely reacting, putting the three-necked flask into a cold bath, cooling to 0-5 ℃, dropwise adding 720ml of acetone, separating out yellow solid, continuing to keep the temperature and stir for 1h after dropwise adding, filtering, dissolving the filter cake with 200ml of purified water, stirring for 5-10 min with 200ml of dichloromethane, separating liquid, discarding the organic phase, continuing to stir for 5-10 min with 200ml of dichloromethane for liquid separation, discarding the organic phase, adding 1g of activated carbon into the aqueous phase, stirring for 0.5h at normal temperature, filtering, slowly dropwise adding glacial acetic acid into the filtrate, separating out solid, stopping dropwise adding glacial acetic acid when the pH value reaches 3.5, continuing to stir for 1-2 h, filtering, pulping and washing the filter cake with 200ml of purified water twice, filtering to obtain white-like solid, drying to obtain 16.9g of light yellow solid, wherein the purity is 99.83%, the isomer ratio is 0.17%, and the yield is 89..
Example 4
Adding 20g of PLQS-6 and 100ml of butanone into a 2L three-necked bottle, stirring, controlling the temperature to be about 10 ℃ to form suspension in the bottle, beginning to dropwise add 15ml of 1.0mol/L sodium hydroxide aqueous solution, controlling the dropwise adding speed to ensure that the temperature of the reaction bottle is 10-13 ℃, keeping the temperature and stirring for 2 hours after the dropwise adding is finished, continuing to dropwise add 15ml of 1.0mol/L sodium hydroxide aqueous solution, repeating the operations until 91ml of sodium hydroxide aqueous solution is completely dropwise added, keeping the temperature and stirring for 2 hours, clarifying the reaction solution, and sampling and carrying out HPLC detection; and (3) completely reacting, putting the three-necked bottle into a cold bath, cooling to 0-5 ℃, dropwise adding 400ml of isopropanol, separating out yellow solid, continuing to keep the temperature and stir for 1h after dropwise adding, filtering, dissolving the filter cake with 200ml of purified water, stirring for 5-10 min with 200ml of dichloromethane, separating liquid, discarding the organic phase, continuing to stir for 5-10 min with 200ml of dichloromethane for liquid separation, discarding the organic phase, adding 1g of activated carbon into the aqueous phase, stirring for 0.5h at normal temperature, filtering, slowly dropwise adding glacial acetic acid into the filtrate, separating out solid, stopping dropwise adding glacial acetic acid when the pH value reaches 3.5, continuing to stir for 1-2 h, filtering, pulping and washing the filter cake with 200ml of purified water twice, filtering to obtain white-like solid, drying to obtain 16.3g of light yellow solid, wherein the purity is 99.80%, the isomer ratio is 0.18%, and the yield is 86.3.
Example 5
Adding 20g of PLQS-6 and 100ml of acetone into a 3L three-necked bottle, stirring, controlling the temperature to be about 10 ℃ to form suspension in the bottle, beginning to dropwise add 15ml of 1.0mol/L sodium hydroxide aqueous solution, controlling the dropwise adding speed to ensure that the temperature of the reaction bottle is 10-13 ℃, keeping the temperature and stirring for 2 hours after the dropwise adding is finished, continuing to dropwise add 15ml of 1.0mol/L sodium hydroxide aqueous solution, repeating the operations until 91ml of sodium hydroxide aqueous solution is completely dropwise added, keeping the temperature and stirring for 2 hours, clarifying the reaction solution, sampling and carrying out HPLC detection; and (3) completely reacting, putting the three-necked bottle into a cold bath, cooling to 0-5 ℃, dropwise adding 2000ml of n-propanol, separating out yellow solid, continuing to keep the temperature and stir for 1h after dropwise adding, filtering, dissolving the filter cake with 200ml of purified water, stirring for 5-10 min with 200ml of dichloromethane, separating liquid, discarding the organic phase, continuing to stir for 5-10 min with 200ml of dichloromethane for liquid separation, discarding the organic phase, adding 1g of activated carbon into the aqueous phase, stirring for 0.5h at normal temperature, filtering, slowly dropwise adding glacial acetic acid into the filtrate, separating out solid, stopping dropwise adding glacial acetic acid when the pH value reaches 5.0, continuing to stir for 1-2 h, filtering, pulping and washing the filter cake with 200ml of purified water twice, filtering to obtain white-like solid, drying to obtain 16.5g of light yellow solid, wherein the purity is 99.82%, the isomer ratio is 0.17%, and the yield is 87.
Example 6
Adding 20g of PLQS-6 and 100ml of acetone into a 2L three-necked bottle, stirring, controlling the temperature to be about 10 ℃ to form suspension in the bottle, beginning to dropwise add 15ml of 1.0mol/L sodium hydroxide aqueous solution, controlling the dropwise adding speed to ensure that the temperature of the reaction bottle is 10-13 ℃, keeping the temperature and stirring for 2 hours, continuously dropwise adding 15ml of 1.0mol/L sodium hydroxide aqueous solution, repeating the operations until 91ml of sodium hydroxide aqueous solution is completely dropwise added, keeping the temperature and stirring for 2 hours, clarifying the reaction solution, sampling and carrying out HPLC detection; and (3) completely reacting, putting the three-necked bottle into a cold bath, cooling to 0-5 ℃, dropwise adding 720ml of n-butyl alcohol, separating out yellow solid at the moment, continuing to keep the temperature and stir for 1h after dropwise adding, filtering, dissolving the filter cake with 200ml of purified water, stirring for 5-10 min with 200ml of dichloromethane, separating out the organic phase, continuing to stir the aqueous phase with 200ml of dichloromethane for 5-10 min, separating out the organic phase, adding 1g of activated carbon into the aqueous phase, stirring for 0.5h at normal temperature, filtering, slowly dropwise adding glacial acetic acid into the filtrate, separating out solid, stopping dropwise adding glacial acetic acid when the pH value reaches 3.0, continuing to stir for 1-2 h, filtering, pulping and washing the filter cake with 200ml of purified water twice, filtering to obtain white-like solid, drying to obtain 16.3g of light yellow solid, wherein the purity is 99.81%, the isomer ratio is 0.19%, and.
Example 7
Adding 20g of PLQS-6 and 100ml of acetone into a 2L three-necked bottle, stirring, controlling the temperature to be about 30 ℃ to enable the bottle to be in a suspension state, beginning to dropwise add 15ml of 0.5mol/L sodium hydroxide aqueous solution, controlling the dropwise adding speed to enable the temperature of the reaction bottle to be 25-30 ℃, keeping the temperature and stirring for 2 hours after the dropwise adding is finished, continuing to dropwise add 15ml of 0.5mol/L sodium hydroxide aqueous solution, repeating the operations until all 182ml of sodium hydroxide aqueous solution is dropwise added, keeping the temperature and stirring for 2 hours, clarifying the reaction solution, and sampling and carrying out HPLC detection; and (3) completely reacting, putting the three-necked flask into a cold bath, cooling to 0-5 ℃, dropwise adding 720ml of absolute ethyl alcohol, separating out yellow solid, continuing to keep the temperature and stir for 1h after dropwise adding, filtering, dissolving the filter cake with 200ml of purified water, stirring for 5-10 min with 200ml of dichloromethane, separating liquid, discarding the organic phase, continuing to stir for 5-10 min with 200ml of dichloromethane for liquid separation, discarding the organic phase, adding 1g of activated carbon into the aqueous phase, stirring for 0.5h at normal temperature, filtering, slowly dropwise adding glacial acetic acid into the filtrate, separating out solid, stopping dropwise adding glacial acetic acid when the pH value reaches 5.0, continuing to stir for 1-2 h, filtering, pulping and washing the filter cake with 200ml of purified water twice, filtering to obtain white-like solid, drying to obtain 16.4g of light yellow solid, wherein the purity is 99.84%, the isomer ratio is 0.17%, and the yield is 86..
Example 8
Adding 20g of PLQS-6 and 100ml of methyl ethyl ketone into a 2L three-necked bottle, stirring, controlling the temperature to be about 10 ℃ to form suspension in the bottle, beginning to dropwise add 15ml of 1.0mol/L sodium hydroxide aqueous solution, controlling the dropwise adding speed to ensure that the temperature of the reaction bottle is 10-13 ℃, keeping the temperature and stirring for 2 hours after the dropwise adding is finished, continuing to dropwise add 15ml of 1.0mol/L sodium hydroxide aqueous solution, repeating the operations until 91ml of sodium hydroxide aqueous solution is completely dropwise added, keeping the temperature and stirring for 2 hours, clarifying the reaction solution, and sampling and detecting by HPLC; and (3) completely reacting, putting the three-necked flask into a cold bath, cooling to 0-5 ℃, dropwise adding 720ml of absolute ethyl alcohol, separating out yellow solid, continuing to keep the temperature and stir for 1h after dropwise adding, filtering, dissolving the filter cake with 200ml of purified water, stirring for 5-10 min with 200ml of dichloromethane, separating liquid, discarding the organic phase, continuing to stir for 5-10 min with 200ml of dichloromethane for liquid separation, discarding the organic phase, adding 1g of activated carbon into the aqueous phase, stirring for 0.5h at normal temperature, filtering, slowly dropwise adding glacial acetic acid into the filtrate, separating out solid, stopping dropwise adding glacial acetic acid when the pH value reaches 3.5, continuing to stir for 1-2 h, filtering, pulping and washing the filter cake with 200ml of purified water twice, filtering to obtain white-like solid, drying to obtain 16.7g of light yellow solid, wherein the purity is 99.80%, the isomer ratio is 0.19%, and the yield is 88..
Comparative example 1
Adding 20g of PLQS-6 and 100ml of absolute ethyl alcohol into a 2L three-necked bottle, controlling the temperature to be about 10 ℃ to enable the bottle to be turbid, beginning to dropwise add 15ml of 1.0mol/L sodium hydroxide aqueous solution, controlling the dropwise adding speed to enable the temperature of the reaction bottle to be 10-13 ℃, keeping the temperature and stirring for 2h, continuing to dropwise add 15ml of 1.0mol/L sodium hydroxide aqueous solution, repeating the operations until 45ml of sodium hydroxide aqueous solution is completely dropwise added, continuing to keep the temperature and stirring for 2h, and sampling and detecting by HPLC; and (3) completely reacting, putting the three-necked flask into a cold bath, cooling to 0-5 ℃, dropwise adding 720ml of absolute ethyl alcohol, separating out yellow solid, continuing to keep the temperature and stir for 1h after dropwise adding, filtering, dissolving the filter cake with 200ml of purified water, stirring for 5-10 min with 200ml of dichloromethane, separating liquid, discarding the organic phase, continuing to stir for 5-10 min with 200ml of dichloromethane for liquid separation, discarding the organic phase, adding 1g of activated carbon into the aqueous phase, stirring for 0.5h at normal temperature, filtering, slowly dropwise adding glacial acetic acid into the filtrate, separating out solid, stopping dropwise adding glacial acetic acid when the pH value reaches 3.0, continuing to stir for 1-2 h, filtering, pulping and washing the filter cake with 200ml of purified water twice, filtering to obtain white-like solid, drying to obtain 17.0g of pale yellow solid, wherein the purity is 99.50%, the isomer ratio is 1.5%, and the yield is 90.0.
Claims (17)
1. A preparation method of pralatrexate is characterized by comprising the following steps:
taking a Pralatrexate intermediate PLQS-6 as a raw material, adding a reaction solvent, stirring to form a suspension, controlling the temperature, adding an inorganic alkali solution in batches for hydrolysis, separating the batches at intervals of 2-3 hours, clarifying the reaction solution, and sampling for HPLC detection; after hydrolysis, cooling and dropwise adding a crystallization solvent to salt out and crystallize the pralatrexate, dissolving the crystallized solid in purified water, washing with dichloromethane, decoloring the water solution with activated carbon at normal temperature, adjusting the pH value with acetic acid, crystallizing, filtering, and washing the filter cake with purified water to obtain the pralatrexate solid; the reaction solvent is as follows: one of acetone, methyl ethyl ketone, butanone and dioxane; the molar concentration of the inorganic alkali solution is as follows: 0.1 to 2.0 mol/L.
2. The method of claim 1, wherein the reaction solvent is: acetone.
3. The process according to claim 1, wherein the ratio of mass of PLQS-6 to volume of reaction solvent is: 1: 3-10 g/ml.
4. The process according to claim 1, wherein the ratio of mass of PLQS-6 to volume of reaction solvent is 1: 5, g/ml.
5. The process according to claim 1, wherein the PLQS-6 and the inorganic base are present in a molar ratio of: 1: 2 to 2.5.
6. The process according to claim 1, wherein the PLQS-6 and the inorganic base are present in a molar ratio of 1: 2.3.
7. the method of claim 1, wherein the inorganic base is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.
8. The method of claim 1, wherein the inorganic base is sodium hydroxide.
9. The method according to claim 1, wherein the inorganic base solution has a molar concentration of 1.0 mol/L.
10. The process according to claim 1, wherein the PLQS-6 is present in a mass to volume ratio of crystallization solvent: 1: 20-100 g/ml.
11. The process according to claim 1, wherein the PLQS-6 is present in a mass to volume ratio of crystallization solvent: 1: 36 g/ml.
12. The method of claim 1, wherein the hydrolysis temperature is: 0 to 30 ℃.
13. The method of claim 1, wherein the hydrolysis temperature is: 10 to 15 ℃.
14. The method according to claim 1, wherein the crystallization solvent is one of ethanol, n-propanol, isopropanol, n-butanol, and acetone.
15. The method according to claim 1, wherein the crystallization solvent is ethanol.
16. The method according to claim 1, wherein the pH for crystallization is 3.0 to 5.0.
17. The method according to claim 1, wherein the pH for crystallization is 3.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611013247.2A CN108069970B (en) | 2016-11-18 | 2016-11-18 | Preparation method of pralatrexate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611013247.2A CN108069970B (en) | 2016-11-18 | 2016-11-18 | Preparation method of pralatrexate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108069970A CN108069970A (en) | 2018-05-25 |
| CN108069970B true CN108069970B (en) | 2020-06-02 |
Family
ID=62159933
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611013247.2A Active CN108069970B (en) | 2016-11-18 | 2016-11-18 | Preparation method of pralatrexate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108069970B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013177713A1 (en) * | 2012-05-31 | 2013-12-05 | Alphora Research Inc. | Process for preparation of an antifolate agent |
| CN103588775A (en) * | 2013-11-12 | 2014-02-19 | 连云港恒运医药科技有限公司 | Pralatrexate degradation impurity and preparation method thereof |
| CN103739604A (en) * | 2012-11-12 | 2014-04-23 | 国药一心制药有限公司 | Preparation method of Pralatrexate suitable for industrial large scale production |
-
2016
- 2016-11-18 CN CN201611013247.2A patent/CN108069970B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013177713A1 (en) * | 2012-05-31 | 2013-12-05 | Alphora Research Inc. | Process for preparation of an antifolate agent |
| CN103739604A (en) * | 2012-11-12 | 2014-04-23 | 国药一心制药有限公司 | Preparation method of Pralatrexate suitable for industrial large scale production |
| CN103588775A (en) * | 2013-11-12 | 2014-02-19 | 连云港恒运医药科技有限公司 | Pralatrexate degradation impurity and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108069970A (en) | 2018-05-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108658858B (en) | Preparation and refining method of hydroxychloroquine and preparation method of sulfate thereof | |
| CN101239985B (en) | Method for preparing cefodizime sodium | |
| CN106256824B (en) | Preparation method of high-purity delafloxacin meglumine salt | |
| CN101941969B (en) | Preparation method of moxifloxacin hydrochloride | |
| CN107311861B (en) | 4-methoxy ethyl acetoacetate and synthetic method thereof | |
| CN108069970B (en) | Preparation method of pralatrexate | |
| CN111471057A (en) | Process for preparing mezlocillin sodium by solvent crystallization | |
| CN113717063B (en) | Preparation and purification method of tulobuterol | |
| US5210288A (en) | Process for the preparation of d-(-)-4-hydroxyphenylglycine and l-(+)-4-hydroxyphenylglycine, starting from d.l.-4-hydroxyphenylglycine | |
| WO2011010579A1 (en) | Process for production of optically active nipecotamide | |
| CN116348110A (en) | Paroxetine hydrochloride purification method | |
| JPWO2008050829A1 (en) | Process for producing S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid and product produced by the process | |
| CN103755726A (en) | Cefalonium refinement purification method | |
| US20110172402A1 (en) | Crystallizing method of erythromycin | |
| JP4826133B2 (en) | S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid and process for producing the same | |
| CN112679453A (en) | Preparation method of D-pantoic acid lactone | |
| US7476760B2 (en) | Purification and production methods of 1-aminocyclopropanecarboxylic acid | |
| CN107488178B (en) | Preparation method of high-purity pralatrexate intermediate | |
| CN114195761B (en) | Preparation method of high-purity sitafloxacin hydrate 3/2 | |
| CN103012264A (en) | Method for resolving 3-substituted amino-hexahydro-1H-azacycloheptane | |
| CN109776448B (en) | Preparation method of febuxostat crystal form A | |
| CN112661719B (en) | Clean preparation process of aminothiazoly loximate | |
| CN102234244A (en) | D-cysteine hydrochloride monohydrate preparation method | |
| CN108069971B (en) | Refining method of pralatrexate intermediate | |
| CN117903125A (en) | Preparation method of raltitrexed |
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 |