CN117903068A - Preparation method of gefitinib - Google Patents

Preparation method of gefitinib Download PDF

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CN117903068A
CN117903068A CN202211248255.0A CN202211248255A CN117903068A CN 117903068 A CN117903068 A CN 117903068A CN 202211248255 A CN202211248255 A CN 202211248255A CN 117903068 A CN117903068 A CN 117903068A
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gefitinib
mmol
compound
reaction
chloro
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翟立海
王少林
余军厚
徐杰
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Shandong New Time Pharmaceutical Co Ltd
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Shandong New Time Pharmaceutical Co Ltd
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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of gefitinib. According to the invention, 7-methoxy-6- [3- (4-morpholinyl) propoxy ] quinazoline-4 (3H) -ketone is taken as a substrate, and is subjected to free radical reaction with 3-chloro-4-fluoroaniline under the action of a catalyst and a free radical initiator, so that efficient synthesis of gefitinib is realized. The method avoids using extremely toxic chloridizing reagent, has less waste emission, small pollution and low environmental protection cost, simplifies the synthetic route, has high safety, reduces the process cost and is more suitable for industrial amplification.

Description

Preparation method of gefitinib
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of gefitinib.
Background
Gefitinib (Gefitinib) is a novel antitumor agent developed by the company aslick pharmaceutical in uk, and is a selective Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor. The medicine is firstly marketed in Japan in 2002, is approved by the national food and drug administration to be marketed in China (trade name: iressa) in 2005, and is suitable for treating local advanced or metastatic non-small cell lung cancer which has been subjected to chemotherapy in the past or is unsuitable for chemotherapy. Gefitinib has a chemical name of 4- (3-chloro-4-fluoroanilino) -7-methoxy-6- [3- (4-morpholinyl) propoxy ] quinazoline, a CAS number of 184735-35-2, a molecular formula of C 22H24ClFN4O3, a molecular weight of 446.9 and a structural formula as follows:
In the preparation method of gefitinib reported in the prior art, most of the gefitinib needs to take a quinazolinone derivative (A) as a substrate, firstly synthesizes a corresponding key intermediate 4-chloroquinazoline derivative (B), and then is aminated with 3-chloro-4-fluoroaniline to obtain a gefitinib parent nucleus (C), wherein the reaction general formula is as follows:
for the preparation method of gefitinib, the following routes are mainly provided:
Route one: chinese patent application CN201110184804 reports that after 6, 7-dimethoxy quinazoline-4 (3H) -ketone is used as a substrate and reacts with a chloro reagent thionyl chloride and the like to obtain 6, 7-dimethoxy-4-chloro-quinazoline hydrochloride, the 6, 7-dimethoxy quinazoline hydrochloride reacts with 3-chloro-4-fluoroaniline to obtain 4- (3-chloro-4-fluoroanilino) -6, 7-dimethoxy quinazoline; then removing 6-methyl with aluminum triiodide/thiophenol, and finally reacting with 3- (4-morpholine) propyl bromide to obtain gefitinib. Aluminum triiodide has extremely strong hygroscopicity, can be rapidly decomposed when meeting water, generates fuming heat, and has higher potential danger; in addition, the demethylation reaction can generate a 7-methyl-free byproduct and a demethylation byproduct, and the yield is reduced and the difficulty is brought to the subsequent product separation:
Route two: chinese patent application CN201510867762 reports that 6-hydroxy-7-methoxy-3H-quinazoline-4-ketone is taken as a substrate, and is subjected to chlorination reaction with thionyl chloride, phosphorus pentachloride, phosphorus trichloride or phosphorus oxychloride to obtain 4-chloro-7-methoxy quinazoline-6-alcohol, then is subjected to amination substitution reaction with 3-chloro-4-fluoroaniline, and finally is subjected to nucleophilic substitution reaction with N-bromopropyl morpholine to obtain gefitinib. This route simplifies the synthesis procedure and avoids the use of aluminum triiodide compared to route one, but due to the presence of highly reactive hydroxyl groups in the substrate, 6-chloro and 4, 6-dichloro byproducts are formed during chloro:
Route three: chinese patent application CN201210181491, volume 5, 3 of Chinese modern pharmaceutical application, pages 162-163 report that 7-methoxy-6- (3-chloropropoxy) quinazoline-4 (3H) -ketone is taken as a substrate, and is subjected to chlorination reaction with thionyl chloride to obtain 4-chloro-7-methoxy-6- (3-chloropropoxy) quinazoline, and is subjected to amination substitution reaction with 3-chloro-4-fluoroaniline to obtain 4- (3-chloro-4-fluoroanilino) -7-methoxy-6- (3-chloropropoxy) quinazoline, and finally is subjected to nucleophilic substitution reaction with morpholine to obtain gefitinib. The 4-chloro-7-methoxy-6- (3-chloropropoxy) quinazoline in the route also has double active reaction sites (namely-Cl groups), and is easy to generate double substitution byproducts when nucleophilic substitution is carried out:
Route four: chinese patent applications CN200710172473, CN200910192850, CN201310507382, CN201410144485, CN201710386228, literature "chemistry research and applications", 2017,29 (9): 1398-1401; pages 741-744 of 1, 21 of today's pharmaceutical; the method comprises the steps of taking 7-methoxy-6- [3- (4-morpholinyl) propoxy ] quinazoline-4 (3H) -ketone as a substrate, halogenating carbonyl at a 4-position under the action of thionyl chloride to generate 4-chloro-7-methoxy-6- [3- (4-morpholinyl) propoxy ] quinazoline, and carrying out amination substitution reaction with 3-chloro-4-fluoroaniline to obtain gefitinib. Compared with the first, second and third routes, the method has the advantages of simple synthesis process, avoidance of double reaction sites and capability of effectively reducing the generation of byproducts. However, in the four routes, a strong pollution and high toxicity chlorinating agent (thionyl chloride, phosphorus pentachloride, phosphorus trichloride or phosphorus oxychloride) needs to be used, excessive chlorinating agent is removed by a reduced pressure distillation mode after the reaction is finished, the abandoned chlorinating agent reacts vigorously in water or humid air to generate strong acid (sulfuric acid, phosphoric acid) and hydrogen chloride, the potential danger is high, the waste acid and the waste water amount is large, and the environmental protection cost is high:
Route five: chinese patent application CN201710244546 reports that 2-amino-4-methoxy-5- (3-morpholinopropoxy) benzonitrile is taken as a substrate, and is cyclized with formamide or formamidine acetate to obtain 7-methoxy-6- [3- (4-morpholinopropoxy) -4-quinazolinamine, then diazotization reaction is carried out with sodium nitrite in a mixed acid aqueous solution to generate diazonium salt, halogenation reaction is carried out to obtain 4-chloro-7-methoxy-6- [3- (4-morpholino) propoxy ] quinazoline, and finally amination substitution reaction is carried out with 3-chloro-4-fluoroaniline to obtain gefitinib. Although the route avoids using strong pollution chlorinating agents such as thionyl chloride or phosphorus oxychloride, the price of the starting materials is high, the intermediate diazonium salt has poor stability and is easy to decompose, and byproducts are not easy to remove:
In summary, in the existing technology, regarding the preparation of gefitinib, on one hand, quinazolinone derivative is used as a substrate, and when the corresponding 4-chloroquinazoline derivative is generated under the action of a chlorinating agent, a strongly-polluted and highly-toxic chlorinating agent is needed, so that the environmental protection cost is higher; on the other hand, 2-amino-4-methoxy-5- (3-morpholinopropoxy) benzonitrile is taken as a substrate, but industrial raw materials are not easy to obtain, the price is high, and the production cost is high, so that a novel preparation method of gefitinib is sought, and the method is a problem which needs to be solved by the technicians in the field.
Disclosure of Invention
Aiming at the defects, the invention aims to provide a synthetic route and a method suitable for industrial production of gefitinib. The method avoids the use of extremely toxic and strongly polluted chlorinating agents (thionyl chloride, phosphorus pentachloride, phosphorus trichloride or phosphorus oxychloride) and has small pollution, and simultaneously simplifies the synthetic route, has high safety and low material cost, reduces the process cost and is more suitable for industrial amplification.
The invention is realized by the following technical scheme:
7-methoxy-6- [3- (4-morpholinyl) propoxy ] quinazoline-4 (3H) -ketone is taken as a substrate, and is subjected to free radical reaction with 3-chloro-4-fluoroaniline under the action of a catalyst and a free radical initiator, so that the efficient synthesis of gefitinib is realized, and the synthesis route is as follows:
a preparation method of gefitinib comprises the following specific steps:
adding the compound SM-1, the compound SM-2, an initiator and a catalyst into an organic solvent, controlling the temperature until the reaction is finished, and cooling and crystallizing the reaction solution to obtain gefitinib.
Preferably, the initiator is selected from one of di-t-butyl peroxide, dicumyl peroxide, dibenzoyl peroxide, azobisisobutyronitrile, with di-t-butyl peroxide being particularly preferred.
Preferably, the catalyst is selected from one of copper acetylacetonate, copper trifluoromethane sulfonate, copper bis (hexafluoroacetylacetonate), copper bis (2, 6-tetramethyl-3, 5-heptanedione) oxide, among which copper acetylacetonate is particularly preferred.
Preferably, the feeding mole ratio of the compound SM-1 to the compound SM-2 to the initiator to the catalyst is as follows: 1.0:1.0 to 1.8:1.8 to 2.5:0.02 to 0.1, with 1.0:1.1:2.0:0.05 being particularly preferred.
Preferably, the organic solvent is selected from one of N, N-dimethylformamide, N-diethylformamide, N-ethyl-N-methyl-formamide, of which N, N-dimethylformamide is particularly preferred.
Preferably, the reaction temperature is 90 to 130 ℃.
Preferably, in a preferred embodiment, after the reaction is completed, a post-treatment is required, and the post-treatment is performed as follows: cooling, pouring the reaction liquid into water, stirring for crystallization, carrying out suction filtration, pulping a filter cake by using ethanol/ethyl acetate, carrying out suction filtration, and drying to obtain white solid gefitinib.
Compared with the prior art, the invention has the technical effects that:
1. The synthetic method has few reaction steps and high atom economy;
2. The use of a highly toxic chlorination reagent is avoided, the waste emission is less, the pollution is low, and the environmental protection cost is low;
3. Effectively reduces side reactions of active sites in the structure, reduces the generation of impurities, has simple purification, high yield and low material cost, and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples. It should be correctly understood that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
The structure of the compound obtained by the invention is confirmed:
Gefitinib structural characterization
ESI-MS(m/z)447.17[M+H]+;1H NMR(400MHz,DMSO-d6):δ＝9.50(s,1H),8.46(s,1H),8.14(dd,1H),7.80～7.85(m,2H),7.41(t,1H),7.21(s,1H),4.15(t,2H),3.91(s,3H),3.55(t,4H),2.42～2.54(m,6H),1.97(t,2H).
Preparation of gefitinib
Example 1
To N, N-dimethylformamide (500 mL) was added compound SM-1 (63.87 g,200 mmol), compound SM-2 (32.02 g,220 mmol), di-t-butyl peroxide (58.49 g,400 mmol), copper acetylacetonate (2.62 g,10 mmol), and the mixture was reacted at 100℃for 10 hours. The reaction solution was cooled, poured into water (2.5L), stirred for crystallization, and suction-filtered. Pulping the filter cake with ethanol/ethyl acetate (1.0L, volume ratio 1:1) for 2-3 hours, suction filtering, drying at 50-60 ℃ to obtain an off-white solid product, wherein the yield is 98.6%, and the HPLC purity is 99.91%.
Example 2
To N, N-dimethylformamide (500 mL), compound SM-1 (63.87 g,200 mmol), compound SM-2 (29.0 g,200 mmol), dicumyl peroxide (108.15 g,400 mmol), and copper acetylacetonate (2.62 g,10 mmol) were added and reacted at 100℃for 10 hours. The reaction solution was cooled, poured into water (2.5L), stirred for crystallization, and suction-filtered. Pulping the filter cake with ethanol/ethyl acetate (1.0L, volume ratio 1:1) for 2-3 hours, suction filtering, drying at 50-60 ℃ to obtain an off-white solid product, wherein the yield is 94.3%, and the HPLC purity is 99.68%.
Example 3
To N, N-dimethylformamide (500 mL) was added compound SM-1 (63.87 g,200 mmol), compound SM-2 (52.20 g,360 mmol), dibenzoyl peroxide (96.89 g,400 mmol), and copper acetylacetonate (2.62 g,10 mmol), and the mixture was reacted at 100℃for 10 hours. The reaction solution was cooled, poured into water (2.5L), stirred for crystallization, and suction-filtered. Pulping the filter cake with ethanol/ethyl acetate (1.0L, volume ratio 1:1) for 2-3 hours, suction filtering, drying at 50-60 ℃ to obtain an off-white solid product, wherein the yield is 95.0%, and the HPLC purity is 99.55%.
Example 4
To N, N-dimethylformamide (500 mL) was added compound SM-1 (63.87 g,200 mmol), compound SM-2 (32.02 g,220 mmol), di-t-butyl peroxide (52.64 g,360 mmol), copper triflate (3.62 g,10 mmol), and the mixture was reacted at 100℃for 10 hours. The reaction solution was cooled, poured into water (2.5L), stirred for crystallization, and suction-filtered. Pulping the filter cake with ethanol/ethyl acetate (1.0L, volume ratio 1:1) for 2-3 hours, suction filtering, drying at 50-60 ℃ to obtain an off-white solid product, wherein the yield is 94.1%, and the HPLC purity is 99.71%.
Example 5
To N, N-dimethylformamide (500 mL) was added compound SM-1 (63.87 g,200 mmol), compound SM-2 (32.02 g,220 mmol), di-t-butyl peroxide (73.12 g,500 mmol), and copper bis (hexafluoroacetylacetonate) (4.78 g,10 mmol), and the mixture was reacted at 100℃for 10 hours. The reaction solution was cooled, poured into water (2.5L), stirred for crystallization, and suction-filtered. Pulping the filter cake with ethanol/ethyl acetate (1.0L, volume ratio 1:1) for 2-3 hours, suction filtering, drying at 50-60 ℃ to obtain an off-white solid product, wherein the yield is 95.3%, and the HPLC purity is 99.64%.
Example 6
To N, N-diethylformamide (500 mL) was added compound SM-1 (63.87 g,200 mmol), compound SM-2 (32.02 g,220 mmol), azobisisobutyronitrile (65.68 g,400 mmol), copper acetylacetonate (1.05 g,4.0 mmol), and the mixture was reacted at 90℃for 10 hours. The reaction solution was cooled, poured into water (2.5L), stirred for crystallization, and suction-filtered. Pulping the filter cake with ethanol/ethyl acetate (1.0L, volume ratio 1:1) for 2-3 hours, suction filtering, drying at 50-60 ℃ to obtain an off-white solid product, wherein the yield is 95.6%, and the HPLC purity is 99.70%.
Example 7
To N-ethyl-N-methyl-formamide (500 mL) was added compound SM-1 (63.87 g,200 mmol), compound SM-2 (32.02 g,220 mmol), azobisisobutyronitrile (65.68 g,400 mmol), copper acetylacetonate (5.24 g,20 mmol), and the mixture was reacted at 130℃for 10 hours. The reaction solution was cooled, poured into water (2.5L), stirred for crystallization, and suction-filtered. Pulping the filter cake with ethanol/ethyl acetate (1.0L, volume ratio 1:1) for 2-3 hours, suction filtering, drying at 50-60 ℃ to obtain an off-white solid product, wherein the yield is 94.0%, and the HPLC purity is 99.42%.
Example 8
Compound SM-1 (63.87 g,200 mmol), compound SM-2 (29.0 g,200 mmol), di-tert-butyl peroxide (43.87 g,300 mmol), copper bis (2, 6-tetramethyl-3, 5-heptanedione) oxide (0.86 g,2 mmol) were added to N, N-dimethylformamide (500 mL) and reacted at 85℃for 10 hours. The reaction solution was cooled, poured into water (2.5L), stirred for crystallization, and suction-filtered. Pulping the filter cake with ethanol/ethyl acetate (1.0L, volume ratio 1:1) for 2-3 hours, suction filtering, drying at 50-60 ℃ to obtain an off-white solid product, wherein the yield is 84.3%, and the HPLC purity is 98.55%.
Example 8
To N, N-dimethylformamide (500 mL) was added compound SM-1 (63.87 g,200 mmol), compound SM-2 (58.0 g,400 mmol), di-t-butyl peroxide (78.96 g,540 mmol), and copper acetylacetonate (5.76 g,22 mmol), and the mixture was reacted at 135℃for 10 hours. The reaction solution was cooled, poured into water (2.5L), stirred for crystallization, and suction-filtered. Pulping the filter cake with ethanol/ethyl acetate (1.0L, volume ratio 1:1) for 2-3 hours, suction filtering, drying at 50-60 ℃ to obtain an off-white solid product, wherein the yield is 80.9%, and the HPLC purity is 97.45%.

Claims (6)

1. The preparation method of gefitinib is characterized by comprising the following steps of:
Adding a compound SM-1, a compound SM-2, an initiator and a catalyst into an organic solvent, controlling the temperature until the reaction is finished, and cooling and crystallizing the reaction solution to obtain gefitinib;
The synthetic route is as follows:
2. The method according to claim 1, wherein the initiator is one selected from the group consisting of di-t-butyl peroxide, dicumyl peroxide, dibenzoyl peroxide, and azobisisobutyronitrile.
3. The method according to claim 1, wherein the catalyst is one selected from the group consisting of copper acetylacetonate, copper trifluoromethane sulfonate, copper bis (hexafluoroacetylacetonate), copper bis (2, 6-tetramethyl-3, 5-heptanedione).
4. The preparation method according to claim 1, wherein the compound SM-1, compound SM-2, initiator and catalyst are fed in the following molar ratios: 1.0:1.0-1.8:1.8-2.5:0.02-0.1.
5. The method according to claim 1, wherein the organic solvent is one selected from the group consisting of N, N-dimethylformamide, N-diethylformamide, and N-ethyl-N-methyl-formamide.
6. The process according to claim 1, wherein the reaction temperature is 90 to 130 ℃.
CN202211248255.0A 2022-10-12 2022-10-12 Preparation method of gefitinib Pending CN117903068A (en)

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