CN107488172B - Preparation method of afatinib - Google Patents
Preparation method of afatinib Download PDFInfo
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- CN107488172B CN107488172B CN201610406782.8A CN201610406782A CN107488172B CN 107488172 B CN107488172 B CN 107488172B CN 201610406782 A CN201610406782 A CN 201610406782A CN 107488172 B CN107488172 B CN 107488172B
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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Abstract
The invention belongs to the technical field of medicines, and particularly discloses a preparation method of afatinib. The method has simple process, economy, environmental protection and high purity of the final product, and is suitable for the requirement of technological amplification.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a novel preparation method of an afatinib compound.
Background
Afatinib maleate is a multi-target oral small molecule drug developed by bliringer-jehn, germany, and is an irreversible inhibitor of Epidermal Growth Factor Receptor (EGFR) and human epidermal receptor 2(HER2) tyrosine kinase. It is a second generation highly potent dual non-reversible tyrosine kinase inhibitor. The drug was approved by the U.S. FDA in 2013 on 7, 12 months. Under the trade name Gilotrif. Afatinib, chemical name 4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] amino } -7- ((S) -tetrahydrofuran-3-yloxy) -quinazoline.
The preparation method of afatinib is reported in the primary chinese patent CN1867564B of the business of bouling invager: taking mother nucleus 4- [ (3-chloro-4-fluorophenyl) amino ] -6-nitro-7-fluoroquinazoline as an initial raw material, and carrying out substitution reaction of halogen fluorine with S-3-hydroxy-tetrahydrofuran under the catalysis of a basic catalyst potassium tert-butoxide to generate 4- [ (3-chloro-4-fluorophenyl) amino ] -6-nitro-7- [ (S) - (tetrahydrofuran-3-yl) oxy ] quinazoline; the intermediate is reduced by the nitro group at the 6-position to obtain a corresponding amino compound; the compound and diethyl phosphoacetic acid are subjected to amidation reaction to obtain an intermediate, and the intermediate is subjected to Wittig-Horner-Emmons reaction with dimethylamino acetaldehyde diethyl acetal to obtain afatinib.
According to other literature analysis, starting material 4- [ (3-chloro-4-fluorophenyl) amino ] -6-nitro-7-fluoroquinazoline is butted with chiral intermediate S-3-hydroxy-tetrahydrofuran, and then subsequent reaction is carried out to obtain afatinib. The following defects are found in the prior literature through experiments:
1) the chiral intermediate S-3-hydroxy-tetrahydrofuran is expensive and has large loss in subsequent multi-step reactions;
2) the afatinib which is a final product generated by the Wittig-Horner-Emmons reaction carried out by the intermediate 3 has more impurities and is not easy to remove.
In order to solve the problems, it is necessary to find a more economical and practical route for synthesizing afatinib.
Disclosure of Invention
The invention aims to search for a new preparation way and provide a preparation method of afatinib according to an atom economic synthesis concept of green chemistry, and the preparation method has the advantages of easily available raw materials, simple process, economy and environmental protection, is beneficial to industrial production of the medicine and promotes the development of economic technology of the raw material medicine.
In order to achieve the purpose, the main technical scheme provided by the invention is as follows: a preparation method of afatinib (I) comprises the following steps of carrying out substitution reaction on an intermediate (II) and (S) -3-hydroxytetrahydrofuran to obtain afatinib (I);
the preparation method of afatinib comprises the step of adding the compounds (II), (S) -3-hydroxytetrahydrofuran, alkali A and an organic solvent B into a reaction vessel for substitution reaction to obtain the compound (I).
In the preparation method of afatinib, the base A is selected from one of sodium hydride, potassium hydride, calcium hydride and potassium tert-butoxide, and potassium tert-butoxide is preferred.
In the preparation method of afatinib, the organic solvent B is selected from aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, amides, glycol derivatives, ester solvents or phenol; preferably one or more of benzene, toluene, cyclohexane, methanol, ethanol, tert-butanol, diethyl ether, acetone, trichloroethylene and ethyl acetate; more preferably a mixed solvent of t-butanol and methanol.
The preparation method of afatinib comprises the step of enabling the molar ratio of (S) -3-hydroxytetrahydrofuran (88.11) to intermediate II (417) to be 1-3:1, preferably 1.2-1.5: 1.
According to the preparation method of afatinib, the volume-mass ratio of the organic solvent B to the intermediate II is 10-20ml/g, preferably 12-15 ml/g.
The invention has novel route, less impurities in the final product and low cost, and is suitable for industrial requirements.
Intermediate ii was prepared by the following route:
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.
Example 1
The first step is as follows:
3.4g of compound V and 153mgFeCl were taken350mL of mixed solution of ethanol and acetone (the volume ratio of ethanol to acetone is 3:4) is put into a single-mouth bottle, electromagnetic stirring is started, air is replaced by nitrogen for 3 times, nitrogen is replaced by hydrogen for 3 times, heat preservation and pressure maintaining are carried out for 4 hours, after the reaction is finished, the catalyst is removed by vacuum filtration, filtrate is evaporated to dryness in a rotary manner, and the yield is 99.6%.
The second step is that:
2.0g of diethylphosphonoacetic acid and 50ml of tetrahydrofuran are put into a 250ml three-necked flask, stirring is started, 2.0g of CDI is slowly added, the temperature is kept at 40 ℃ for 1 hour of reaction, then 3.0g of intermediate IV is added, the temperature is kept for 1 hour of reaction, after the reaction is finished, a large amount of solid is separated out, 50ml of methyl tert-butyl ether is added, stirring is carried out for 1 hour, and then suction filtration and drying are carried out to obtain an intermediate III, wherein the yield is 98.1%.
The third step:
firstly, dimethyl amino acetaldehyde diethyl acetal is deprotected to generate dimethyl amino acetaldehyde.
Weighing 4.5g of the intermediate III, placing the intermediate III into a 250ml three-neck flask, adding 50ml of tetrahydrofuran and 40ml of a tetrahydrofuran solution of dimethylaminoacetaldehyde, stirring and dissolving, cooling to 0 ℃ in an ice bath, starting to dropwise add 30g of 25% KOH aqueous solution, controlling the temperature to be 0-5 ℃, after dropwise adding, naturally heating to room temperature, pouring reaction liquid into 300ml of water after the reaction is finished, stirring and crystallizing for 2 hours, performing suction filtration, and drying to obtain an intermediate II, wherein the yield is 97.4%, and the purity is 99.8%.
Example 2
Weighing 40.0g of the intermediate II, placing the intermediate II in a 5000ml three-necked bottle, adding 400ml of tert-butyl alcohol, adding 8.5g of (S) -3-hydroxytetrahydrofuran, slowly adding potassium tert-butoxide, controlling the temperature to be not more than 50 ℃, stirring for reaction for 1h, pouring the reaction liquid into 2000ml of drinking water after the reaction is finished, adjusting the pH to 6 by using 10% acetic acid water solution, performing suction filtration, and drying to obtain the Afatinib I with the yield of 90.1%, the purity of 99.6% and the single impurity content of less than 0.1%.
Example 3
Weighing 40.0g of the intermediate II, placing the intermediate II in a 5000ml three-necked bottle, adding 600ml of tert-butyl alcohol and 200ml of methanol, adding 25.5g of (S) -3-hydroxytetrahydrofuran, slowly adding potassium tert-butoxide, controlling the temperature to be not more than 50 ℃, stirring for reaction for 1h after the addition is finished, pouring the reaction liquid into 4000ml of drinking water, adjusting the pH to 7 by using 10% acetic acid aqueous solution, performing suction filtration, and drying to obtain the Afatinib I, wherein the yield is 90.3.1%, the purity is 99.6%, and the single impurity content is less than 0.1%.
Example 4
Weighing 40.0g of intermediate II, placing the intermediate II in a 5000ml three-necked bottle, adding 400ml of tert-butyl alcohol and 80ml of methanol, adding 10.2g of (S) -3-hydroxytetrahydrofuran, slowly adding potassium tert-butoxide, controlling the temperature to be not more than 50 ℃, stirring for reaction for 1h after the addition is finished, pouring the reaction liquid into 3000ml of drinking water, adjusting the pH to 6.5 by using 10% acetic acid aqueous solution, performing suction filtration, and drying to obtain the afatinib I, wherein the yield is 91.9%, the purity is 99.7%, and the single impurity content is less than 0.1%.
Example 5
Weighing 40.0g of the intermediate II, placing the intermediate II in a 5000ml three-necked bottle, adding 450ml of tert-butyl alcohol and 150ml of methanol, adding 12.75g of (S) -3-hydroxytetrahydrofuran, slowly adding potassium tert-butoxide, controlling the temperature to be not more than 50 ℃, stirring for reaction for 1h after the addition is finished, pouring the reaction solution into 3000ml of drinking water, adjusting the pH to 6 by using 10% acetic acid aqueous solution, performing suction filtration, and drying to obtain the Afatinib I, wherein the yield is 92.5%, the purity is 99.8%, and the single impurity content is less than 0.1%.
Comparative example 1
Weighing 40.0g of the intermediate II, placing the intermediate II in a 5000ml three-necked flask, adding 150ml of tert-butyl alcohol and 50ml of methanol, adding 4.23g of (S) -3-hydroxytetrahydrofuran, slowly adding potassium tert-butoxide, controlling the temperature to be not more than 50 ℃, stirring to react for 1h, pouring the reaction liquid into 1000ml of drinking water after the reaction is finished, adjusting the pH to 6 by using 10% acetic acid aqueous solution, performing suction filtration, and drying to obtain the afatinib I, wherein the yield is 75.5% and the purity is 95.8%.
Comparative example 2
Weighing 40.0g of the intermediate II, placing the intermediate II in a 5000ml three-necked bottle, adding 700ml of tert-butyl alcohol and 300ml of methanol, adding 33.8g of (S) -3-hydroxytetrahydrofuran, slowly adding potassium tert-butoxide, controlling the temperature to be not more than 50 ℃, stirring for reaction for 1h after the addition is finished, pouring the reaction liquid into 5000ml of drinking water, adjusting the pH to 6 by using 10% acetic acid aqueous solution, performing suction filtration, and drying to obtain the afatinib I, wherein the yield is 78.5% and the purity is 96.1%.
Comparative example 3
Weighing 40.0g of the intermediate II, placing the intermediate II in a 5000ml three-necked bottle, adding 600ml of n-hexane, adding 12.75g of (S) -3-hydroxytetrahydrofuran, slowly adding sodium hydroxide, controlling the temperature to be not more than 50 ℃, stirring for reacting for 1h, pouring the reaction liquid into 3000ml of drinking water after the reaction is finished, adjusting the pH to 6.5 by using 10% acetic acid water solution, performing suction filtration, and drying to obtain afatinib I, wherein the yield is 74.3% and the purity is 94.8%.
Claims (7)
1. A preparation method of afatinib (I) is characterized in that an intermediate (II), (S) -3-hydroxytetrahydrofuran, alkali A and an organic solvent B are added into a reaction vessel to carry out substitution reaction to obtain afatinib (I);
2. The process of claim 1, wherein the base A is selected from the group consisting of sodium hydride, potassium hydride, calcium hydride, and potassium tert-butoxide.
3. The process for preparing afatinib (i) according to claim 2, wherein base a is potassium tert-butoxide.
4. The method for preparing afatinib (i) according to claim 1, wherein the molar ratio of (S) -3-hydroxytetrahydrofuran to intermediate (ii) is 1-3: 1.
5. The method for preparing afatinib (i) according to claim 1, wherein the molar ratio of (S) -3-hydroxytetrahydrofuran to intermediate (ii) is 1.2-1.5: 1.
6. The preparation method of afatinib (i) according to claim 1, wherein the volume-to-mass ratio of the organic solvent B to the intermediate (ii) is 10 to 20 ml/g.
7. The preparation method of afatinib (i) according to claim 1, wherein the volume-to-mass ratio of the organic solvent B to the intermediate (ii) is 12 to 15 ml/g.
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| CN201610406782.8A CN107488172B (en) | 2016-06-10 | 2016-06-10 | Preparation method of afatinib |
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| CN201610406782.8A CN107488172B (en) | 2016-06-10 | 2016-06-10 | Preparation method of afatinib |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1867564A (en) * | 2003-10-17 | 2006-11-22 | 贝林格尔·英格海姆国际有限公司 | Process for preparing amino crotonyl compounds |
| CN104710413A (en) * | 2013-12-16 | 2015-06-17 | 江苏豪森药业股份有限公司 | Preparation method of afatinib dimaleate |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10221018A1 (en) * | 2002-05-11 | 2003-11-27 | Boehringer Ingelheim Pharma | Use of inhibitors of EGFR-mediated signal transduction for the treatment of benign prostatic hyperplasia (BPH) / prostatic hypertrophy |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1867564A (en) * | 2003-10-17 | 2006-11-22 | 贝林格尔·英格海姆国际有限公司 | Process for preparing amino crotonyl compounds |
| CN104710413A (en) * | 2013-12-16 | 2015-06-17 | 江苏豪森药业股份有限公司 | Preparation method of afatinib dimaleate |
Non-Patent Citations (1)
| Title |
|---|
| "PROCESS FOR THE PREPARATION OF AFATINIB";Disclosed Anonymously;《IP.com Journal》;20150930;第15卷(第10A期);第1-3页 * |
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Denomination of invention: A preparation method of afatinib Effective date of registration: 20211224 Granted publication date: 20200612 Pledgee: Industrial and Commercial Bank of China Limited Feixian sub branch Pledgor: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980016193 |
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Date of cancellation: 20221028 Granted publication date: 20200612 Pledgee: Industrial and Commercial Bank of China Limited Feixian sub branch Pledgor: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980016193 |
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Denomination of invention: A preparation method of alfatinib Effective date of registration: 20221103 Granted publication date: 20200612 Pledgee: Industrial and Commercial Bank of China Limited Feixian sub branch Pledgor: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Registration number: Y2022980020531 |