CN114315808A - Preparation method of afatinib maleate with high yield - Google Patents

Abstract

The invention discloses a preparation method of afatinib maleate with high yield, which is realized by the following steps: by adopting N-4- (3-chloro-4-fluorophenyl) -7- [ [ (3)S) -tetrahydro-3-furanyl]Oxy radical]The 4, 6-quinazoline diamine is used as a starting material, and the afatinib maleate raw material drug meeting the drug quality requirement is obtained through two-step synthesis, two-step refining and salifying. The method has the advantages of simple reaction, no hazardous articles, mild conditions, easy control, high yield in each step, stable process, easily obtained raw materials and suitability for industrial production, and the purification method does not involve column chromatography which is an industrially difficult operation method.

Description

Preparation method of afatinib maleate with high yield

Technical Field

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of afatinib maleate with high yield.

Background

Afatinib maleate, chemical name: n- [4- [ (3-chloro-4-fluorophenyl) amino group]-7- [ [ (3S) -tetrahydro-3-furanyl]Oxy radical]-6-quinazolinyl]-4- (dimethylamino) - (2E) -butenamide, bis-Z-butenedioate, formula: c₂₄H₂₅ClFN₅O₃·2C₄H₄O₄Molecular weight: 718.08 (wherein the free base: 485.94) having the following chemical formula:

afatinib is an irreversible EGFR-HER2 dual tyrosine kinase receptor inhibitor. Is used for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC). For metastatic non-small cell lung cancer (NSCLC) patients with exon 19 deletion or exon 21(L858R) substitution mutation of tumor Epidermal Growth Factor Receptor (EGFR).

On 12.7.2013, afatinib (trade name: Gilotrif) developed by bliringer hagahne was approved by the U.S. Food and Drug Administration (FDA) to be marketed as a first-line treatment drug. It can irreversibly bind with EGFR-HER2 tyrosine kinase to inhibit its tyrosine kinase activity, further block EGFR-HER2 mediated tumor cell signal transduction, inhibit proliferation and metastasis of tumor cell, and promote apoptosis of tumor cell.

The synthetic route of the compound has been disclosed. For example, scheme 1, document US 2005/0085495A1, filing date 2003.10.17

According to the synthetic route, the yield of each step is high, the process is stable, the number of steps is moderate, raw material reagents are cheap and easy to obtain, dangerous articles and dangerous operations are not involved in each reaction process, and the synthetic route is very suitable for industrial production.

Scheme 2, document WO 2007/085638A1, filing date 2006.1.26

The synthesis route has low yield which is about 50 percent generally, and the related first two purification methods are column chromatography and are not suitable for industrial production; furthermore, the bromide used in the first step is not sold in large quantities in the market, the purity is not high, generally 80%, but if the bromide is synthesized by self, thionyl chloride is needed, the corrosivity is high, and the bromide is not suitable for industrial production and industrial environmental protection requirements.

Scheme 3.

The route has short steps and high yield, but the starting materials are expensive and not easy to obtain.

Disclosure of Invention

Aiming at the technical problems, the invention improves the preparation method of afatinib maleate. The preparation method of afatinib maleate is mild in reaction conditions, free of high-corrosivity materials, less in impurities and high in total yield.

The technical scheme adopted by the invention for solving the technical problems is as follows: the preparation method of afatinib maleate with high yield is provided, and specifically comprises the following steps:

(1) reacting N-4- (3-chloro-4-fluorophenyl) -7- [ [ (3S) -tetrahydro-3-furyl ] oxy ] -4, 6-quinazolinediamine with diethylphosphonoacetic acid to obtain diethyl P- [2- [ [4- [ (3-chloro-4-fluorophenyl) amino ] -7- [ [ (3S) -tetrahydro-3-furyl ] oxy-6-quinazolinyl ] amino ] -2-oxoethyl ] phosphonate (intermediate I), washing with a lotion, and drying, wherein the lotion is one or more selected from water, diethyl ether, methyl tert-butyl ether, preferably methyl tert-butyl ether and water.

(2) P- [2- [ [4- [ (3-chloro-4-fluorophenyl) amino ] -7- [ [ (3S) -tetrahydro-3-furanyl ] oxy-6-quinazolinyl ] amino ] -2-oxoethyl ] phosphonic acid diethyl ester and dimethylaminoethal, preferably in the presence of lithium chloride as a catalyst, preferably under alkaline conditions, to give a crude product of afatinib.

(3) The crude afatinib is purified by crystallization (e.g., two recrystallizations) after salification with maleic acid, for example, by purification with ethyl acetate and n-heptane.

(4) And salifying the maleic acid and the refined product of afatinib to obtain the afatinib maleate.

Preferably, after the reaction in the step (1) is completed, directly filtering with suction, and only leaching with methyl tertiary butyl ether.

Preferably, the temperature of the process of the step (2) is raised to 10-25 ℃, and water is added

Preferably, the solvents ethyl acetate and n-heptane are purified in the above step (3).

Preferably, the dropping temperature of the maleic acid ethanol solution in the step (4) is 30-50 ℃.

The route for synthesizing afatinib maleate is shown as follows:

compared with the prior art, the method has the advantages of selecting cheaper and safer reagents, reducing the dosage of the solvent, lowering the reaction temperature, saving the cost and reducing the generation of degradation impurities.

Detailed Description

Example 1: preparation ofP- [2- [ [4- [ (3-chloro-4-fluorophenyl) amino group]-7- [ [ (3S) -tetrahydro-3-furanyl]Oxygen gas6-quinazolinyl radical]Amino group]-2-oxoethyl group]Phosphonic acid diethyl ester

Adding 64ml of tetrahydrofuran and 18g N, N-carbonyl-diimidazole into a reaction bottle, uniformly stirring, controlling the temperature to be 10-40 ℃, dropwise adding 22g of tetrahydrofuran (32ml) solution of diethylphosphonoacetic acid, controlling the temperature to be 35-45 ℃, and reacting for 0.5-2 h to obtain an orange clear solution.

Adding 128ml of tetrahydrofuran and 32g N-4- (3-chloro-4-fluorophenyl) -7- [ [ (3S) -tetrahydro-3-furyl ] oxy ] -4, 6-quinazolinediamine into a reaction bottle, heating to 30-40 ℃, stirring to completely dissolve the tetrahydrofuran and the 7- [ [ (3S) -tetrahydro-3-furyl ] oxy ] -4, 6-quinazolinediamine, adding the mixture into the solution, controlling the temperature to be 30-40 ℃ and reacting for 1.5-2.5 hours.

And after the reaction is finished, cooling to the system temperature of 10-20 ℃, filtering, and washing a filter cake once by using 128ml of methyl tert-butyl ether, 160ml of pure water and 32ml of methyl tert-butyl ether respectively. Dry matterDrying to obtain 32g of white solid (intermediate I), the yield is 68.4 percent, and the purity is 99 percent. (ES, M/z) < M +23]⁺＝575，¹H NMR(600MHz,DMSO)δ9.88(s,1H),9.48(s,1H),8.94(s,1H),8.52(s,1H),8.09(dd,J＝6.7,2.3Hz,1H),7.87–7.70(m,1H),7.42(t,J＝9.1Hz,1H),7.25(s,1H),5.31(d,J＝1.8Hz,1H),4.11(p,J＝6.9Hz,4H),4.06–4.00(m,2H),3.96(dd,J＝15.3,7.7Hz,1H),3.80(td,J＝8.1,4.9Hz,1H),3.41(s,1H),3.37(s,1H),2.35(dt,J＝14.3,7.1Hz,1H),2.24–2.15(m,1H),1.27(t,J＝7.0Hz,6H).

Example 2: preparation of Afatinib

Preparation of dimethylamino acetal solution: adding 19ml of pure water and 24ml of concentrated hydrochloric acid into a reaction bottle, stirring, controlling the temperature to be 0-30 ℃, dropwise adding 24g of dimethylamino acetal, controlling the temperature to be 25-35 ℃ after dropwise adding, reacting for 15-20 hours to obtain an orange solution, and cooling to be 0-20 ℃ in an ice water bath for later use.

Preparation of KOH aqueous solution: adding 130ml of pure water and 26g of KOH into a beaker, controlling the temperature to be 0-30 ℃, stirring, completely dissolving, and freezing to obtain a transparent aqueous solution at the temperature of 0-20 ℃ for later use.

And adding 130ml of tetrahydrofuran, 32g of intermediate I and 32g of anhydrous lithium chloride into a reaction bottle, uniformly stirring to obtain a white turbid liquid, controlling the temperature to be-20-5 ℃, and dropwise adding KOH aqueous solution until the dropwise adding is finished. Controlling the temperature to be-20 to-5 ℃, dropwise adding the dimethylamino acetal solution, and controlling the temperature to be-5 to-20 ℃ to react for 1.5 to 2.5 hours after the dropwise adding is finished.

And after the reaction is finished, heating the system to 15-30 ℃, pumping 650ml of pure water, stirring, cooling to-5 ℃, centrifuging, and washing the filter cake once by using the pure water to obtain the white-like filter cake.

Adding the filter cake and 130ml of pure water into a reaction bottle, and stirring to obtain a white turbid liquid; and controlling the temperature to be 0-25 ℃, dropwise adding 2mol/L hydrochloric acid until the pH value is 4-5, basically clarifying the system to be yellow green, extracting the system twice by using 195ml of ethyl acetate, and then extracting twice by using 130ml of ethyl acetate. Adding the water phase into a reaction bottle, controlling the temperature to be 0-25 ℃, dropwise adding 2mol/L sodium hydroxide solution to adjust the pH value to be 8-10, separating out a large amount of white solid, keeping the temperature, stirring and reacting for 0.5-2 h, filtering, washing a filter cake with pure water until the filtrate is neutral, and drying the filter cake in an oven at 40-60 ℃ to constant weight to obtain 25g of white-like solid which is a crude afatinib product with the yield of 87% and the purity of 99%.

Example 3: refining of Afatinib

Refining the crude product for the first time: adding 220mL of ethyl acetate and 25g of afatinib crude product into a reaction bottle, stirring, heating to 55-60 ℃, dissolving, adding 1.5g of activated carbon, controlling the temperature to 55-60 ℃, stirring for 0.5-1 h, performing suction filtration, leaching a filter cake with 26mL of ethyl acetate at 40-60 ℃, transferring the filtrate into the reaction bottle, controlling the temperature to 55-60 ℃, dropwise adding 220mL of n-heptane, after dropwise adding, cooling to 0-20 ℃, separating out a solid, stirring for 1-2 h, filtering, leaching the filter cake with n-heptane (22mL), drying a white-like filter to obtain 19.8g of a primary refined product, wherein the yield is 90%, and the purity is 99%.

And (3) refining the crude product for the second time: adding 190mL of ethyl acetate and 19g of the first refined afatinib product into a reaction bottle, stirring, heating to 55-60 ℃, dissolving, controlling the temperature to 50-60 ℃, dropwise adding 190mL of n-heptane, cooling to 0-20 ℃ after dropwise adding, separating out solids, stirring for 1-2 hours, filtering, leaching a filter cake with n-heptane (20mL), drying a white filter to obtain 15g of a second refined product, wherein the yield is 77%, and the purity is 99%.

The total yield of the secondary refining was 62%.

Example 4: preparation of afatinib maleate

Adding 260mL of absolute ethyl alcohol and 15g of afatinib secondary refined product into a reaction bottle in sequence, controlling the temperature to be 30-35 ℃, stirring to dissolve the absolute ethyl alcohol, dropwise adding an absolute ethyl alcohol solution of maleic acid (7 g of maleic acid is dissolved in 92mL of absolute ethyl alcohol), separating out a solid after the dropwise adding is finished, cooling to 0-20 ℃, stirring for 1-2 hours, performing suction filtration, washing a filter cake with 160mL of absolute ethyl alcohol, placing the filter cake in a reduced-pressure oven, and drying to constant weight at 40-50 ℃. 20g of light yellow solid is obtained, the yield is 88 percent, and the purity is 99 percent. (ES, M/z) < M +1]⁺＝486，¹H-NMR(400MHz,DMSO-d6):δ2.15–2.38(m,2H),2.85(s,6H),3.79–3.95(m+m,2H),3.99–4.02(m,4H),5.30-5.31(d,1H),6.17(s,4H),6.83(d,J＝4.8,2H),7.28(s,1H),7.45(t,J＝9.0Hz,1H),7.73-7.78(m,1H),8.10(d,J＝4.2,1H),8.62(s,1H),8.99(s,1H),9.80(s,1H),10.17(br,1H)。

Claims (5)

1. A preparation method of afatinib maleate with high yield sequentially comprises the following steps:

n-4- (3-chloro-4-fluorophenyl) -7- [ [ (3)S) -tetrahydro-3-furanyl]Oxy radical]Reacting 4, 6-quinazoline diamine with diethyl phosphorus acetic acid to obtain P- [2- [ [4- [ (3-chloro-4-fluorophenyl) amino group]-7-[[(3S) -tetrahydro-3-furanyl]Oxy-6-quinazolinyl]Amino group]-2-oxoethyl group]Washing diethyl phosphonate (intermediate I) with a lotion and drying, wherein the lotion is one or more selected from water, diethyl ether and methyl tert-butyl ether, preferably methyl tert-butyl ether and water;

p- [2- [ [4- [ (3-chloro-4-fluorophenyl) amino group]-7-[[(3S) -tetrahydro-3-furanyl]Oxy-6-quinazolinyl]Amino group]-2-oxoethyl group]Reacting diethyl phosphonate with dimethylamino acetal to obtain an afatinib crude product;

after the afatinib crude product and the maleic acid are salified, the afatinib raw material medicine of the maleic acid which meets the medicine quality requirement is obtained through crystallization (such as twice recrystallization) and salification.

2. The method of claim 1, wherein, in step (ii), the step (iii) is carried out

The method comprises the following steps: dissolving N, N-carbonyl-diimidazole and diethylphosphonoacetic acid in tetrahydrofuran solvent, controlling the temperature in the whole process at 10-50 ℃ (the optimal temperature is 35-45 ℃), stirring for 0.5-2 h (preferably 1 h), and then adding N-4- (3-chloro-4-fluorophenyl) -7- [ [ (3-methyl-ethyl-phenyl-4-phenyl-ethyl-2 h)S) -tetrahydro-3-furanyl]Oxy radical]And (4) -4, 6-quinazoline diamine, wherein the reaction temperature is controlled to be 20-50 ℃ (preferably 30-40 ℃ for reaction for 1.5-2.5 h).

3. The method of claim 1, wherein, in step (ii), the step (iii) is carried out

The method comprises the following steps: the temperature for preparing the dimethylamino acetal solution is controlled to be 20-40 ℃; the dimethylamino acetal solution is drippedWhen in use, the temperature is controlled below 20 ℃; when reacting intermediate I with a dimethylamino acetal solution, lithium chloride is used as a catalyst; the reaction is carried out under alkaline conditions, which are achieved by adding aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, aqueous sodium carbonate solution, aqueous potassium carbonate solution and/or aqueous lithium carbonate solution (preferably aqueous potassium hydroxide solution); the reaction is controlled to be below 0 ℃, preferably-5 to-20 ℃; the reaction is carried out for 0.5-3 h; after the reaction is stopped, adjusting the pH value to 3-6 by using dilute hydrochloric acid, extracting impurities by using an organic solvent (the organic solvent is selected from ester organic solvents, such as methyl acetate, ethyl acetate and isopropyl acetate, preferably ethyl acetate), and adjusting the pH value to 7.5-11.5 by using an alkaline solution condition to separate out a solid afatinib crude product.

4. The method of claim 1, wherein, in step (ii), the step (iii) is carried out

The process of medium crystallization comprises: the organic solvent used for dissolving the crude afatinib or the first-time crystalline product of afatinib during crystallization (preferably twice crystallization) is acetone, ethyl acetate or dichloromethane, preferably ethyl acetate; the organic solvent used for dropwise adding and separating out the afatinib is an ether organic solvent or a saturated alkane organic solvent, such as petroleum ether, diethyl ether, methyl tert-butyl ether, n-hexane or n-heptane, preferably n-heptane; the volume ratio of the two organic solvents is 1: 0.5-1: 2, preferably 1: 1; the temperature at which the solid precipitates is maintained at 0 to 20 ℃.

5. The method of claim 1, wherein, in step (ii), the step (iii) is carried out

The process of medium salt formation comprises the following steps: the salt-forming reaction strip uses an organic solvent to dissolve the crystallization product, and the organic solvent is an alcohol compound, such as ethanol, methanol and isopropanol, and preferably ethanol; the ratio of afatinib to the organic solvent is 1: 10-1: 25, preferably 1: 20.