CN110563710A - Preparation method of afatinib maleate - Google Patents
Preparation method of afatinib maleate Download PDFInfo
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- CN110563710A CN110563710A CN201910895433.0A CN201910895433A CN110563710A CN 110563710 A CN110563710 A CN 110563710A CN 201910895433 A CN201910895433 A CN 201910895433A CN 110563710 A CN110563710 A CN 110563710A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/145—Maleic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of afatinib maleate. The afatinib maleate of the invention is prepared from N4- (3-chloro-4-fluorophenyl) -7- [ [ (3S) -tetrahydro-3-furanyl]Oxy radical]reacting 4, 6-quinazoline diamine with diethyl phosphorus acetic acid to obtain an intermediate I, adding dimethylamino acetal diethanol to perform Horner-Wadsworth-Emmons reaction to obtain an intermediate II, and salifying the intermediate II and maleic acid to obtain afatinib maleate. The afatinib maleate prepared by the method is low in impurity content, basically does not leave any solvent used in refining, and is stable in property.
Description
Technical Field
The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of afatinib maleate.
background
afatinib maleate is a potent and irreversible dual inhibitor of tyrosine kinase of the second generation Epidermal Growth Factor Receptor (EGFR) and the human epidermal growth factor receptor 2(HER2) developed by blinger invager, germany, and functions by undergoing michael addition reaction (Michaelreaction) with the thiol group of cysteine at position 797 in EGFR to irreversibly inhibit the activity of the tyrosine kinase, interrupt downstream information transmission, thereby preventing cancer cell growth and inducing cancer cell apoptosis.
Currently, chinese patent CN200480030555 discloses the following synthetic route:
The patent takes SM1 as a starting material, and reacts with SM2 under the action of carbonyldiimidazole to obtain a formula IIIa, then the formula IIIa reacts with SM3 to obtain a formula II, and the formula I is prepared by salifying. However, in the preparation method, impurities exist in the afatinib maleate product due to the existence of the corresponding isomers in the original raw materials, so that the yield and the quality are reduced.
Disclosure of Invention
the invention aims to provide a preparation method of afatinib maleate, which has low impurity content, basically does not leave any solvent used in refining, and has stable property.
In order to achieve the purpose, the invention adopts the following technical scheme:
A preparation method of afatinib maleate is provided, wherein the afatinib maleate is prepared from N4- (3-chloro-4-fluorophenyl) -7- [ [ (3S) -tetrahydro-3-furanyl]Oxy radical]Reacting 4, 6-quinazoline diamine with diethyl phosphorus acetic acid to obtain an intermediate I, adding dimethylamino acetal diethanol to perform Horner-Wadsworth-Emmons reaction to obtain an intermediate II, and salifying the intermediate II and maleic acid to obtain afatinib maleate.
Further, the preparation method comprises the following steps:
S1) preparation of intermediate i: mixing and stirring tetrahydrofuran and N, N-carbonyldiimidazole at room temperature, slowly adding a tetrahydrofuran solution of diethylphosphonoacetic acid, controlling the temperature to be 35-40 ℃ and stirring for 25-35 min after 25-35 min until the solution is clear to obtain a reaction solution A; reacting tetrahydrofuran with N4- (3-chloro-4-fluorophenyl) -7- [ [ (3S) -Tetrahydro-3-furanyl]Oxy radical]Adding 4, 6-quinazoline diamine into a reaction kettle A, stirring at room temperature, adding the reaction liquid A, controlling the temperature to be 35-40 ℃, stirring for 1-4 hours, monitoring the reaction by a thin-layer chromatography, cooling to 3-8 ℃, filtering, and drying to obtain an intermediate I;
S2) preparation of intermediate ii: adding hydrochloric acid into a reaction bottle, stirring in an ice-water bath, slowly dropwise adding dimethylamino acetal diethanol, controlling the temperature to be 35-40 ℃, reacting for 2-3 hours to obtain a reaction solution B, and storing in the ice-water bath; adding tetrahydrofuran into a reaction kettle B, sequentially adding the intermediate I and lithium chloride obtained in the step S1), slowly adding alkali dropwise, slowly adding the reaction liquid B, controlling the temperature to be-10 to-5 ℃, stirring for 1-1.5 h, monitoring the reaction completion by thin-layer chromatography, adding water into the reaction kettle B, carrying out reduced pressure concentration to remove tetrahydrofuran, transferring a water phase into a reaction kettle C, stirring for 25-35 min at room temperature, filtering, and drying to obtain an intermediate II;
S3) purification of intermediate II: taking tetrahydrofuran and the intermediate II obtained in the step S2) to mix at room temperature, filtering, adding n-heptane, stirring at 50-60 ℃ until the solution is clear, stopping heating, cooling to room temperature, stirring for 8-12 hours, filtering, drying, and repeating the operation for 1-2 times to obtain a refined product of the intermediate II;
S4) preparation of afatinib maleate: stirring maleic acid and dried absolute ethyl alcohol at room temperature until the solution is clear to obtain reaction liquid C; adding the dried absolute ethyl alcohol and the refined intermediate II in the step S3) into a reaction kettle C, stirring at 65 ℃, slowly adding the reaction liquid C, cooling to 0 ℃ after white solids are separated out, stirring for crystallization, filtering, and drying to obtain afatinib maleate.
Further, N in the step S1)4- (3-chloro-4-fluorophenyl) -7- [ [ (3S) -tetrahydro-3-furanyl]Oxy radical]-the molar ratio of 4, 6-quinazolinediamine, diethylphosphonoacetic acid and N, N-carbonyldiimidazole is 1: (1.1-1.5): (1.1-1.5).
Further, the molar ratio of the intermediate i, the dimethylamino acetal diethanol, the lithium chloride and the base in the step S2) is 1: (1.5-2.5): 1: (4.5-6.5).
Further, the alkali is an aqueous solution of sodium hydroxide or potassium hydroxide.
Further, the hydrochloric acid concentration in the step S2) is 37%.
further, the molar ratio of the intermediate II refined product in the step S4) to maleic acid is 1: 2.
Further, the step of preparing anhydrous ethanol after drying in the step S4) is: the anhydrous magnesium sulfate is dispersed in the anhydrous ethanol for drying and filtering to obtain the dried anhydrous ethanol.
Further, the thin layer chromatography in step S1) and step S2) monitors the reaction mixture of dichloromethane: methanol 20: 1 is developing agent, the color is developed by an ultraviolet lamp with 254nm, and the reaction is complete when the product spot is larger than or equal to the raw material spot.
the invention also provides afatinib maleate prepared by the preparation method.
In the preparation method of afatinib maleate, the intermediate II is refined, and tetrahydrofuran/n-heptane is used as a solvent during refining, so that a large amount of AF-I (enantiomer) can be removed, and the influence on salt formation reaction is avoided to obtain the afatinib maleate. Meanwhile, the inventor finds that the intermediate II is easy to degrade after contacting water to generate the impurity AF-ZZA, and therefore, the inventor removes water from the raw material before salt forming reaction to remove the impurity AF-ZZA, so that the prepared afatinib maleate has low impurity content and can be kept stable in a stability test of 6 months.
Compared with the prior art, the invention has the following beneficial effects:
The afatinib maleate prepared by the method is low in impurity content, basically free of solvent residues and stable in property.
Detailed Description
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples.
Example 1 preparation of Afatinib maleate
S1) preparation of intermediate I
The chemical reaction equation is as follows:
Taking 3.58L of tetrahydrofuran and N, N-carbonyldiimidazole (1433g, 8.84mol) to mix and stir at room temperature, slowly adding 2.43L of tetrahydrofuran solution of diethyl phosphoacetic acid (1734g, 8.84mol), controlling the temperature at 40 ℃ after 30min addition, and stirring for 30min until the solution is clear to obtain reaction liquid A; tetrahydrofuran 7.65L and N4- (3-chloro-4-fluorophenyl) -7- [ [ (3S) -tetrahydro-3-furanyl]Oxy radical]Adding (2550g, 6.8mol) of-4, 6-quinazolinediamine into a reaction kettle A, stirring at room temperature, adding the reaction solution A, controlling the temperature at 40 ℃, stirring for 1h, monitoring the reaction by thin-layer chromatography, cooling to 8 ℃, filtering, and drying to obtain an intermediate I.
Wherein thin layer chromatography monitors the concentration of dichloromethane: methanol 20: 1 is developing agent, the color is developed by an ultraviolet lamp with 254nm, and the reaction is complete when the product spot is larger than or equal to the raw material spot.
S2) preparation of intermediate II
Chemical reaction equation:
Adding 1605g of 37% hydrochloric acid (newly opened bottle) into a reaction bottle, stirring in an ice-water bath, slowly dropwise adding dimethylamino acetal diethanol (1313g, 8.14mol), controlling the temperature to be 40 ℃ to react for 3h to obtain a reaction solution B, and storing in the ice-water bath; adding 12L of tetrahydrofuran into a reaction kettle B, sequentially adding the intermediate I (3005g, 5.43mol) and lithium chloride (230g, 5.42mol) obtained in the step S1), slowly dropwise adding a 3M sodium hydroxide aqueous solution (8.14L, 24.4mol), slowly adding the reaction liquid B, controlling the temperature to be-5 ℃, stirring for 1h, monitoring the reaction completion by using a thin-layer chromatography, adding 12L of water into the reaction kettle B, concentrating under reduced pressure to remove the tetrahydrofuran, transferring the aqueous phase into a reaction kettle C, stirring for 30min at room temperature, filtering, and drying to obtain the afatinib maleate intermediate of the formula (AF-I).
Wherein the preparation steps of the dried absolute ethyl alcohol are as follows: the anhydrous magnesium sulfate is dispersed in the anhydrous ethanol for drying and filtering to obtain the dried anhydrous ethanol.
S3) purification of intermediate II
And (4) mixing tetrahydrofuran and the intermediate II obtained in the step S2) at room temperature, filtering, adding n-heptane, stirring at 60 ℃ until the solution is clear, stopping heating, cooling to room temperature, stirring for 12 hours, filtering, drying, and repeating the operation for 2 times to obtain a refined product of the intermediate II.
S4) preparation of afatinib maleate
Taking maleic acid (1005g, 8.66mol) and 21L of dried absolute ethyl alcohol, and stirring at room temperature until the solution is clear to obtain a reaction solution C; and (3) adding 10L of dried absolute ethyl alcohol and the refined product of the intermediate II (2105g, 4.33mol) obtained in the step S4) into a reaction kettle C, stirring at 65 ℃, slowly adding the reaction solution C, cooling to 0 ℃ after a white solid is separated out, stirring for crystallization, filtering, and drying to obtain afatinib maleate.
Example 2-3 preparation of Afatinib maleate
The difference from example 1 is that the raw material charging amounts of the above examples 2 to 3 are different, specifically referring to table one.
TABLE 1 examples 2-3 formula (AF-I) Afatinib maleate intermediate raw material auxiliary material charge amount
Comparative example 1 preparation of Afatinib maleate
Similar to example 1, except that: intermediate II was not purified, and the remaining parameters were the same as in example 1.
Comparative example 2 preparation of Afatinib maleate
Similar to example 1, except that: anhydrous ethanol and step S2) intermediate II were mixed at room temperature, and the remaining parameters were the same as in example 1.
Comparative example 3 preparation of Afatinib maleate
Similar to example 1, except that: and (3) mixing tetrahydrofuran and the intermediate II obtained in the step S2) at room temperature, filtering, adding methyl tert-butyl ether, stirring at 60 ℃ until the solution is clear, stopping heating, cooling to room temperature, stirring for 12 hours, filtering, drying, and repeating the operation for 2 times to obtain a refined product of the intermediate II, wherein the rest parameters are the same as those in the example 1.
Comparative example 4 preparation of Afatinib maleate
Similar to example 1, except that: and (3) mixing ethyl acetate and the intermediate II obtained in the step S2) at room temperature, filtering, adding n-heptane, stirring at 60 ℃ until the solution is clear, stopping heating, cooling to room temperature, stirring for 12 hours, filtering, drying, and repeating the operation for 2 times to obtain a refined product of the intermediate II, wherein the rest parameters are the same as those in the example 1.
Comparative example 5 preparation of Afatinib maleate
Similar to example 1, except that: the anhydrous ethanol was not dried over anhydrous magnesium sulfate, and the remaining parameters were the same as in example 1.
experiment one, yield calculation
1.1 calculation of yield of refined intermediate II
Calculating the formula:
Calculation results of purified product of intermediate II
From Table two, tetrahydrofuran/n-heptane and ethyl acetate/n-heptane were suitable for purification of intermediate II, preventing loss of intermediate II.
1.2 yield calculation of Afatinib maleate
Calculating the formula:
Intermediate II: afatinib maleate 485.94: 718.08
Calculation results of Afatinib dimaleate
From the table three, the afatinib maleate prepared in the examples 1-3 has high yield, and the yield of the example 1 is the highest, reaching 98.7%.
Test II, quality detection of Afatinib maleate
TABLE Afatinib dimaleate quality test results
Table five impurities abbreviated as reference table
from tables four and five, the comparative examples 1-4, afatinib maleate, had a high content of impurities, in particular the impurity AF-I (enantiomer), due to the different solvents chosen for purification, which could not be removed; the reason why the impurity AF-ZZA in Afatinib maleate in the comparative example 5 is high is that the intermediate I is degraded in the presence of a trace amount of water to generate the impurity AF-ZZA.
Test III, stability test
the test method comprises the following steps: example 1 the test results at 0, 1, 2, 3, 6 months during the test period were recorded according to the chinese pharmacopoeia 2010 edition of annex XIXC drug stability test guidelines and afatinib maleate quality standards.
TABLE six stability test results
As can be seen from the table VI, the afatinib maleate prepared by the method has no obvious change in each investigation project of the stability test, and has good stability.
the foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (10)
1. a preparation method of afatinib maleate is characterized in that the afatinib maleate is prepared from N4- (3-chloro-4-fluorophenyl) -7- [ [ (3S) -tetrahydro-3-furanyl]oxy radical]Reacting 4, 6-quinazoline diamine with diethyl phosphorus acetic acid to obtain an intermediate I, adding dimethylamino acetal diethanol to perform Horner-Wadsworth-Emmons reaction to obtain an intermediate II, and salifying the intermediate II and maleic acid to obtain afatinib maleate.
2. the process for preparing afatinib maleate according to claim 1, wherein the process comprises the steps of:
S1) preparation of intermediate i: taking out tetrahydroMixing and stirring furan and N, N-carbonyldiimidazole at room temperature, slowly adding a tetrahydrofuran solution of diethylphosphonoacetic acid, controlling the temperature to be 35-40 ℃ and stirring for 25-35 min after 25-35 min until the solution is clear to obtain a reaction solution A; reacting tetrahydrofuran with N4- (3-chloro-4-fluorophenyl) -7- [ [ (3S) -tetrahydro-3-furanyl]Oxy radical]Adding 4, 6-quinazoline diamine into a reaction kettle A, stirring at room temperature, adding the reaction liquid A, controlling the temperature to be 35-40 ℃, stirring for 1-4 hours, monitoring the reaction by a thin-layer chromatography, cooling to 3-8 ℃, filtering, and drying to obtain an intermediate I;
S2) preparation of intermediate ii: adding hydrochloric acid into a reaction bottle, stirring in an ice-water bath, slowly dropwise adding dimethylamino acetal diethanol, controlling the temperature to be 35-40 ℃, reacting for 2-3 hours to obtain a reaction solution B, and storing in the ice-water bath; adding tetrahydrofuran into a reaction kettle B, sequentially adding the intermediate I and lithium chloride obtained in the step S1), slowly adding alkali dropwise, slowly adding the reaction liquid B, controlling the temperature to be-10 to-5 ℃, stirring for 1-1.5 h, monitoring the reaction completion by thin-layer chromatography, adding water into the reaction kettle B, carrying out reduced pressure concentration to remove tetrahydrofuran, transferring a water phase into a reaction kettle C, stirring for 25-35 min at room temperature, filtering, and drying to obtain an intermediate II;
S3) purification of intermediate II: taking tetrahydrofuran and the intermediate II obtained in the step S2) to mix at room temperature, filtering, adding n-heptane, stirring at 50-60 ℃ until the solution is clear, stopping heating, cooling to room temperature, stirring for 8-12 hours, filtering, drying, and repeating the operation for 1-2 times to obtain a refined product of the intermediate II;
S4) preparation of afatinib maleate: stirring maleic acid and dried absolute ethyl alcohol at room temperature until the solution is clear to obtain reaction liquid C; adding the dried absolute ethyl alcohol and the refined intermediate II in the step S3) into a reaction kettle C, stirring at 65 ℃, slowly adding the reaction liquid C, cooling to 0 ℃ after white solids are separated out, stirring for crystallization, filtering, and drying to obtain afatinib maleate.
3. The method for preparing afatinib maleate according to claim 2, wherein N in step S1)4- (3-chloro-4-fluorophenyl) -7-, [ 2 ][ (3S) -tetrahydro-3-furanyl]Oxy radical]-the molar ratio of 4, 6-quinazolinediamine, diethylphosphonoacetic acid and N, N-carbonyldiimidazole is 1: (1.1-1.5): (1.1-1.5).
4. The method for preparing afatinib maleate according to claim 2, wherein the molar ratio of intermediate i, dimethylamino acetal diethanol, lithium chloride and base in step S2) is 1: (1.5-2.5): 1: (4.5-6.5).
5. the process of claim 2 or 4, wherein the base is an aqueous solution of sodium hydroxide or potassium hydroxide.
6. The method for preparing afatinib maleate according to claim 2, wherein the hydrochloric acid concentration in step S2) is 37%.
7. The method for preparing afatinib maleate according to claim 2, wherein the molar ratio of the intermediate ii refined product in step S4) to maleic acid is 1: 2.
8. The method for preparing afatinib maleate according to claim 2, wherein the step of preparing anhydrous ethanol after drying in step S4) is: the anhydrous magnesium sulfate is dispersed in the anhydrous ethanol for drying and filtering to obtain the dried anhydrous ethanol.
9. The process for preparing afatinib maleate according to claim 2 wherein the thin layer chromatography monitoring in steps S1) and S2) is performed with a dichloromethane: methanol 20: 1 is developing agent, the color is developed by an ultraviolet lamp with 254nm, and the reaction is complete when the product spot is larger than or equal to the raw material spot.
10. Afatinib maleate prepared according to any one of the preparation methods of claims 1 to 9.
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