CN109721552B - Preparation method of gefitinib - Google Patents
Preparation method of gefitinib Download PDFInfo
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- CN109721552B CN109721552B CN201711033531.0A CN201711033531A CN109721552B CN 109721552 B CN109721552 B CN 109721552B CN 201711033531 A CN201711033531 A CN 201711033531A CN 109721552 B CN109721552 B CN 109721552B
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Abstract
The invention relates to the technical field of organic chemistry and medicines, in particular to a preparation method of gefitinib. The invention provides a preparation method of gefitinib, which is prepared from a compound shown in a formula I, wherein the preparation method of the compound shown in the formula I comprises the following steps: nitration reaction, oxidation reaction, selective demethylation reaction, reduction reaction, cyclization reaction and phenolic hydroxyl acetylation reaction. The preparation method provided by the invention can simultaneously reduce the cost, is easy to refine and purify, and prepare and control various related impurities, greatly optimizes the whole preparation process route, and is suitable for industrial large-scale production.
Description
Technical Field
The invention relates to the technical field of organic chemistry and medicines, in particular to a preparation method of gefitinib.
Background
Gefitinib (Gefitinib, irykur, iressa) is an oral epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitor (a small molecule compound) developed by asikang, marketed in japan in 2002 for the treatment of advanced non-small cell lung cancer, and marketed in china under the trade name iressa in 2005 for the treatment of locally advanced or metastatic non-small cell cancer that has previously received chemotherapy. Inhibition of EGFR-TK may block tumor growth, metastasis and angiogenesis, and increase apoptosis of tumor cells. Gefitinib (CAS number: 184475-35-2, molecular formula: C) 22 H 24 ClFN 4 O 3 Molecular weight: 446.90) has the following structure, chemical name: n- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholine-4-propoxy) quinazolin-4-amine.
Currently, there are many researches on the preparation of gefitinib, and there are the following methods for preparing gefitinib:
gibson (Zeneca limited) reports a gefitinib intermediate synthesis method (US5770599), and the synthesis route is as follows:
the method comprises the steps of taking 6, 7-dimethoxy quinazoline-4 (3H) ketone as a raw material, selectively demethylating by methanesulfonic acid and L-methionine to obtain 6-hydroxy-7-methoxy-3, 4-dihydro quinazoline-4-ketone, then acetylating on phenolic hydroxy to obtain a key intermediate 3, 4-dihydro-7-methoxy-4-oxo quinazoline-6-alcohol acetate, and then chlorinating, phenylating, deacetylating and etherifying a morpholine ring side chain to obtain a target product gefitinib. In the method, the selective demethylation of methanesulfonic acid and L-methionine is adopted, so that the yield is low, a large amount of methanesulfonic acid and L-methionine which are difficult to recover are used, the environmental pollution is large, the total yield of the route is low, and the industrial production is limited. 6, 7-dimethoxy quinazoline-4 (3H) ketone is not a general chemical raw material, and CN1150948 reports that 4, 5-dimethoxy-2-nitrobenzoic acid is required to be prepared through three steps of esterification, reduction and cyclization.
Another synthetic route for preparing gefitinib is reported by gilday (astrazeneca pharmaceuticals) in patent WO2004024703 as follows:
according to the method, 3-hydroxy-4-methoxybenzaldehyde is used as a starting material, aldehyde groups are converted into cyano groups, and then etherification, nitration, reduction, hydrolysis, cyclization and chloro-and aromatic amine substitution are carried out to obtain gefitinib through eight steps of reaction, although the defect that a large amount of methanesulfonic acid and L-methionine are used for demethylation is overcome, the starting material 3-hydroxy-4-methoxybenzaldehyde is expensive, is more than 20 times of 3, 4-dimethoxybenzaldehyde, and the yield of certain steps is low, so that the production cost is relatively high.
Chinese patent CN1733738 reports that gefitinib is synthesized by using 3, 4-dimethoxybenzoic acid as a raw material, and the route is as follows:
according to the method, 3, 4-dimethoxybenzoic acid is used as a raw material, and the gefitinib is obtained by nitration, demethylation, reduction, cyclization, chlorination and aromatic amine substitution and morpholine N-alkyl side chain introduction. In the fourth step of cyclization reaction, 2-amino-4-methoxy-5-hydroxybenzoic acid is directly cyclized with formamide to construct 4-carbonyl quinazoline parent ring, the reaction temperature is preferably 170-180 ℃, the reaction temperature is high, byproducts are more, and the yield is low. In addition, because of the existence of active group hydroxyl, side reaction is easy to occur in the next step of aromatic amine substitution reaction because the hydroxyl is not protected.
In addition, chinese patent publication nos. CN103130729A and CN105693630A report the preparation method of the chlorination reaction step of the intermediate 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate as a raw material, and do not relate to the preparation method of the intermediate.
Disclosure of Invention
In view of the disadvantages of the prior art mentioned above, the present invention aims to provide a preparation method of 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate (compound of formula I), and further to obtain gefitinib by the preparation of the compound of formula I, so as to solve the problems in the prior art.
In order to achieve the above objects and other related objects, a first aspect of the present invention provides a method for preparing gefitinib, which uses 3, 4-dimethoxybenzaldehyde (veratraldehyde) as a starting material, and prepares a key intermediate 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate (compound of formula I) through nitration, oxidation, selective demethylation, reduction, cyclization and phenolic hydroxyl acetylation, and further prepares gefitinib through the compound of formula I, wherein the method for preparing the compound of formula I comprises the following steps:
1) nitration reaction: 3, 4-dimethoxy benzaldehyde is nitrated to prepare a compound shown in a formula II;
2) and (3) oxidation reaction: oxidizing the compound of the formula II to prepare a compound of a formula III;
3) selective demethylation reaction: reacting a compound in a formula III in the presence of alkali to prepare a compound in a formula IV;
4) reduction reaction: reacting a compound shown in a formula IV in the presence of a catalyst in a hydrogen atmosphere to prepare a compound shown in a formula V;
5) and (3) cyclization reaction: reacting the compound shown in the formula V with formamidine acetate to prepare a compound shown in the formula VI;
6) and (3) acetylation reaction of phenolic hydroxyl: reacting the compound of formula VI with acetic anhydride in the presence of a base catalyst to obtain the compound of formula I.
The reaction route of the preparation method of the compound of the formula I is as follows:
in some embodiments of the present invention, in step 1), the nitration reagent used in the nitration reaction is one or more of nitric acid, mixed acid of nitric acid and sulfuric acid, mixed acid of nitric acid and acetic acid, and the like.
In some embodiments of the invention, in step 1), the nitrating agent is nitric acid, more specifically an aqueous solution of nitric acid, the concentration of which is 63 to 67 wt%.
In some embodiments of the invention, in the step 1), the molar ratio of the 3, 4-dimethoxybenzaldehyde to the nitrating agent in the nitration reaction is 1: 1.5-3.
In some embodiments of the present invention, in the step 1), the nitration reaction is performed in the presence of a solvent, and the solvent used in the nitration reaction is selected from one or more of dichloroethane, chloroform, acetic acid, n-hexane, and the like.
In some embodiments of the invention, in step 1), the reaction temperature is in the range of 25 to 45 ℃.
In some embodiments of the present invention, the post-treatment method of step 1) comprises: after the reaction is finished, adding water for extraction and separation to obtain an organic phase, washing off acid in the organic phase, and then desolventizing to obtain the compound shown in the formula II.
In some embodiments of the present invention, in the step 2), the oxidant used in the oxidation reaction is selected from one or more of sodium chlorite, hydrogen peroxide, sodium hypochlorite, and the like.
In some embodiments of the invention, in step 2), the oxidizing agent is sodium chlorite, more specifically an aqueous sodium chlorite solution, and the concentration of the aqueous sodium chlorite solution is 8 to 12 wt%.
In some embodiments of the invention, in step 2), the molar ratio of the compound of formula II to the oxidizing agent in the oxidation reaction is 1: 1.2-2.
In some embodiments of the present invention, in the step 2), the oxidation reaction is performed in the presence of a solvent, and the solvent used in the oxidation reaction is selected from one or more of acetonitrile, water, dimethyl sulfoxide, dimethylformamide and the like.
In some embodiments of the present invention, in the step 2), the oxidation reaction is performed in the presence of a pH buffer selected from one or more of potassium dihydrogen phosphate, sodium dihydrogen phosphate, and the like, and the concentration of the pH buffer is 0.15 to 0.25 mol/L.
In some embodiments of the invention, in step 2), the reaction temperature is 25 to 45 ℃.
In some embodiments of the present invention, the post-treatment method of step 2) comprises: after the reaction is finished, adjusting the pH value of the reaction system to be acidic, carrying out solid-liquid separation, and drying a solid phase substance to obtain the compound shown in the formula III. More specifically, after completion of the reaction, the pH of the reaction system was adjusted to pH 2 to 3.
In some embodiments of the present invention, in the step 3), the reaction is performed at pH 13 to 14.
In some embodiments of the present invention, in the step 3), the base is selected from one or more of NaOH, KOH, and the like.
In some embodiments of the invention, the reaction temperature in step 3) is 95-100 ℃.
In some embodiments of the present invention, the post-treatment method of step 3) comprises: after the reaction is finished, adjusting the pH value of the reaction system to be acidic, carrying out solid-liquid separation, and drying a solid phase substance to obtain the compound shown in the formula IV. More specifically, after completion of the reaction, the pH of the reaction system was adjusted to pH 2 to 3.
In some embodiments of the present invention, in the step 4), the catalyst is selected from one or more of palladium catalyst (e.g. palladium carbon), nickel catalyst (e.g. raney nickel), sodium hydrosulfite, and the like.
In some embodiments of the present invention, in the step 4), the catalyst is palladium on carbon, and more specifically, the palladium content in the palladium on carbon is 8 to 12 wt%.
In some embodiments of the present invention, in step 4), the catalyst is used in a catalytic amount, more specifically 5 to 10 wt% of the compound of formula IV.
In some embodiments of the present invention, in the step 4), the reduction reaction is performed in the presence of a solvent, and the solvent used in the reduction reaction is selected from one or more of methanol, ethanol, ethyl acetate and the like.
In some embodiments of the present invention, in the step 4), the reaction temperature is 30 to 40 ℃ and the reaction pressure is 1.5 to 2 atmospheres.
In some embodiments of the present invention, the post-treatment method of step 4) comprises: and after the reaction is finished, washing the product by using a solvent to obtain the compound shown in the formula V, wherein the solvent used for washing is selected from one or more of methanol, ethanol, ethyl acetate and the like.
In some embodiments of the invention, the molar ratio of the compound of formula V to formamidine acetate in step 5) is 1:2 to 2.5.
In some embodiments of the present invention, in the step 5), the cyclization reaction is performed in the presence of a solvent, and the solvent used in the cyclization reaction is selected from one or more of ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, xylene, and the like.
In some embodiments of the invention, in step 5), the reaction temperature is in the range of 110 ℃ to 120 ℃.
In some embodiments of the present invention, the post-treatment method of step 5) comprises: and after the reaction is finished, removing the solvent, washing with water, and drying to obtain the compound shown in the formula VI.
In some embodiments of the invention, the weight ratio of the compound of formula VI to acetic anhydride in step 6) is from 1:4 to 6.
In some embodiments of the present invention, in the step 6), the base catalyst is selected from one or more of pyridine, triethylamine, diisopropylethylamine and the like.
In some embodiments of the invention, the molar ratio of the compound of formula VI to the base catalyst in step 6) is 1:4 to 6.
In some embodiments of the present invention, in the step 6), the acetylation of the phenolic hydroxyl group is performed in the presence of a solvent, and the solvent used in the acetylation of the phenolic hydroxyl group is selected from one or more of N, N-dimethylformamide, N-dimethylacetamide and the like.
In some embodiments of the invention, in step 6), the reaction temperature is from 40 ℃ to 50 ℃.
In some embodiments of the present invention, the post-treatment method of step 6) comprises: adding water for crystallization after the reaction is finished, and carrying out solid-liquid separation to obtain the compound shown in the formula VI.
In the preparation method of gefitinib provided by the present invention, gefitinib can be obtained by preparing a compound of formula I, and the method for obtaining gefitinib by preparing a compound of formula I should be well known to those skilled in the art, for example, reference can be made to the preparation methods involved in the prior art documents US5770599, CN1733738, CN96193526, etc., wherein the reaction equation involved in the reaction is as follows:
in some embodiments of the invention, the process for preparing gefitinib from the compound of formula I comprises the steps of:
I) chlorination reaction: chloridizing a compound of formula I to obtain a compound of formula VII;
II) aromatic amine substitution reaction: reacting a compound shown in a formula VII with 3-chloro-4-fluoroaniline to prepare a compound shown in a formula VIII;
III) hydrolysis reaction: hydrolyzing the compound of formula VIII in the presence of a base to obtain a compound of formula IX;
IV) hydroxyl etherification reaction: and (3) reacting the compound shown in the formula IX with 3-chloro-4-fluoroaniline in the presence of a base to prepare the gefitinib.
In some embodiments of the invention, the reaction in step I) is carried out in the presence of a chlorinating agent selected from one or a combination of more of oxalyl chloride, thionyl chloride, phosphorus oxychloride and the like.
In some embodiments of the invention, the weight ratio of the compound of formula I to the chlorinating agent in step I) is from 1:4 to 8.
In some embodiments of the invention, the reaction temperature in step I) is from 60 ℃ to 70 ℃.
In some embodiments of the present invention, the post-treatment method of step I) comprises: adding a proper amount of organic solvent, removing the chlorination reagent, washing the solution to be alkalescent, and removing the solvent to obtain the compound shown in the formula VII.
In some embodiments of the invention, the molar ratio of the compound of formula VII to 3-chloro-4-fluoroaniline in step II) is from 1:1.1 to 1.5.
In some embodiments of the present invention, in the step II), the reaction is performed in the presence of a solvent, and the solvent in the aromatic amine substitution reaction is selected from one or more of ethanol, isopropanol, n-butanol, and the like.
In some embodiments of the invention, the reaction temperature in step II) is 80 to 110 ℃.
In some embodiments of the invention, the post-treatment method of step II) comprises: and after the reaction is finished, cooling, carrying out solid-liquid separation, washing and drying a solid phase substance to obtain the compound shown in the formula VIII.
In some embodiments of the invention, in the step III), the base is selected from one or more of ammonia methanol, ammonia ethanol, ammonia water and the like.
In some embodiments of the invention, the weight ratio of the base in step III) is 1:4 to 8.
In some embodiments of the invention, the post-treatment method of step III) comprises: and after the reaction is finished, carrying out solid-liquid separation, washing and drying a solid phase substance to obtain the compound shown in the formula IX.
In some embodiments of the invention, in step IV), the charge ratio of the compound of formula IX to N- (3-chloropropyl) morpholine is from 1:1 to 1.2.
In some embodiments of the invention, in step IV), the reaction temperature is from 80 ℃ to 85 ℃.
In some embodiments of the invention, in step IV), the base is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, and the like.
In some embodiments of the invention, in step IV), the base is fed in a ratio of 1: 2.5-4.
In some embodiments of the present invention, in the step IV), the reaction is performed in the presence of a solvent, and the solvent in the hydroxyl etherification reaction is selected from one or more of DMF, DMSO, and the like.
In some embodiments of the present invention, the post-treatment method of step IV) comprises: and removing a proper amount of solvent after the reaction is finished, then adding water for crystallization, and carrying out solid-liquid separation to obtain the gefitinib.
In some embodiments of the present invention, the post-treatment method of step IV) further comprises: and recrystallizing the solid product obtained by crystallization to obtain the gefitinib product, wherein the solvent used in recrystallization is one or more of methanol, ethanol, isopropanol and the like.
The method takes 3, 4-dimethoxybenzaldehyde with low price as a raw material, has mild reaction conditions, generates a single product in the preparation process, is stable and controllable, is environment-friendly, and has the characteristics of good yield, simple and convenient process, safety and the like; the veratraldehyde nitration is milder and has higher yield than the veratric acid nitration, the problem of selective demethylation is well solved through the positioning effect, the phenomenon that methanesulfonic acid and L-methionine are used for demethylation in the old process to generate a large amount of waste acid water is avoided, the reduction reaction is cleaner than the reduction of iron powder in the document CN1733738, the purity is higher, and the acetyl protection of the intermediate is also beneficial to the subsequent preparation of gefitinib. The compound of the formula I prepared by the preparation method has the advantages of excellent yield and quality, good stability, high purity, convenient storage and the like.
Generally speaking, the preparation method provided by the invention can simultaneously reduce the cost, is easy to refine and purify, and is easy to prepare and control various related impurities, the whole preparation process route is greatly optimized, and the preparation method is suitable for industrial large-scale production.
Drawings
FIG. 1 shows the 1H-NMR spectrum of the compound of formula I prepared in example 6 of the present invention.
FIG. 2 shows the mass spectrum of the compound of formula I prepared in example 6 of the present invention
FIG. 3 shows the 1H-NMR spectrum of gefitinib prepared in example 10 of the present invention.
Figure 4 shows the mass spectrum of gefitinib prepared in example 10 of the present invention.
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
It is to be understood that the process equipment or devices not specifically mentioned in the following examples are conventional in the art.
Furthermore, it is to be understood that one or more method steps mentioned in the present invention does not exclude that other method steps may also be present before or after the combined steps or that other method steps may also be inserted between these explicitly mentioned steps, unless otherwise indicated; it is also to be understood that a combined connection between one or more devices/apparatus as referred to in the present application does not exclude that further devices/apparatus may be present before or after the combined device/apparatus or that further devices/apparatus may be interposed between two devices/apparatus explicitly referred to, unless otherwise indicated. Moreover, unless otherwise indicated, the numbering of the various method steps is merely a convenient tool for identifying the various method steps, and is not intended to limit the order in which the method steps are arranged or the scope of the invention in which the invention may be practiced, and changes or modifications in the relative relationship may be made without substantially changing the technical content.
Example 1
Preparation of the compound of formula II:
200g (1.2mol) of 3, 4-dimethoxybenzaldehyde is added into a 2L three-necked bottle, 1L of dichloroethane is added, stirring is carried out at 25 ℃ until complete dissolution, 200mL (2.93mol) of 65% nitric acid is dropwise added into a reaction bottle, the dropwise adding temperature is controlled between 25 ℃ and 40 ℃, and the dropwise adding is finished within about 1 hour. Stirring was continued for 6 hours at 35 ℃ and the reaction was monitored by HPLC for completion. Water (1.5L) was added for extraction, the organic phase was collected, washed with saturated sodium bicarbonate solution 1 time, saturated brine 1 time, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give crude compound of formula ii, slurried with n-hexane, filtered to give 226.2g of yellow compound of formula ii, 89% molar yield and 98% purity. 1 H-NMR(CDCl 3 ，400MHz)δ4.04(3H，s)，4.05(3H，s)，7.42(1H，s)，7.65(1H，s)，10.45(1H，s)；MS(ESI，m/z)：212[M+H] + 。
Example 2
Preparation of the compound of formula III:
370g (1.75mol) of the compound of formula II was put into a 5L three-necked flask, 1.75L of acetonitrile, 0.7L of water and 64.4g (0.47mol) of potassium dihydrogen phosphate were added thereto, and the mixture was stirred to obtain a turbid solution. 2.38kg (2.63mol) of 10% sodium chlorite solution is dripped, the dripping temperature is controlled to be 25-35 ℃, stirring is continued for 1 hour after dripping, and the reaction is monitored by HPLC to be finished. 36% hydrochloric acid was added dropwise to a pH of about 2 to precipitate a large amount of solid, which was then filtered, collected and dried by blowing at 50 ℃ to obtain 350.5g of the yellow compound of formula III in a molar yield of 88% and a purity of 97%. 1 H-NMR(DMSO-d 6 ，400MHz)δ3.83(6H，s)，7.72(1H，s)，7.90(1H，s)，11.00(1H，s)；MS(ESI，m/z)：228[M+H] + 。
Example 3
Preparation of the compound of formula IV:
A2L three-necked flask is charged with 227g (1mol) of the compound of formula III, and a solution prepared from 224g (4mol) of 85% potassium hydroxide and 900mL of water, heated to 98-100 deg.C, stirred for 3-4 hours under constant temperature, and monitored by HPLC for the end of the reaction. Cooling to 10 deg.c, adding hydrochloric acid 36% dropwise to pH 2 to precipitate a large amount of solid, filtering, collecting the solid, and drying at 50 deg.c by blowing air to obtain 181g of yellow compound IV with 85% molar yield and 96% purity. 1 H-NMR(CDCl 3 ，400MHz)δ3.80(3H，s)，6.89(1H，s)，7.34(1H，s)；MS(ESI，m/z)：214[M+H] + 。
Example 4
Preparation of a Compound of formula V:
181g (0.85mol) of the compound of formula IV was charged into a 5L three-necked flask, 3L of anhydrous methanol was added, 18g of 10% palladium on carbon was added, hydrogen gas was replaced, the mixture was stirred at room temperature for 4 hours, and the reaction was monitored by HPLC to be completed. Filtering, eluting with methanol, and directly spin-drying the filtrate to obtain 143.2g of the off-white compound of formula V, with a molar yield of 92% and a purity of 94%. 1 H-NMR(DMSO-d 6 ，400MHz)δ3.73(3H，s)，6.29(1H，s)，7.09(1H，s),8.1-8.4(2H，brs)，9.27(1H，s)，13.11(1H，brs)；MS(ESI，m/z)：184[M+H] + 。
Example 5
Preparation of a Compound of formula VI:
120g (0.66mol) of the compound of the formula V is added into a 5L three-necked bottle, 2L of ethylene glycol monomethyl ether and 137.4g (1.32mol) of formamidine acetate are added, the reaction is heated and refluxed for 3 to 4 hours, and the reaction is monitored by HPLC to be finished. Ethylene glycol monomethyl ether is evaporated out under reduced pressure, 1L of water is added, stirring and pulping are carried out, filtering is carried out, solids are collected, and light brown compounds of the formula VI are obtained by blowing air and drying at 50 ℃, wherein the molar yield is 93 percent, and the purity is 98 percent. 1 H-NMR(DMSO-d 6 ，400MHz)δ3.88(3H，s)，7.08(1H，s)，7.36(1H，s)，7.89(1H，s)9.48(1H，s)，11.4(1H，brs)；MS(ESI，m/z)：193[M+H] + 。
Example 6
Preparation of Compounds of formula I:
2L three100g (0.52mol) of the compound of formula VI, 500mL of N, N-dimethylformamide and 200mL of pyridine are added into a mouth bottle, 500mL of acetic anhydride is added dropwise, and after the addition is finished, the temperature is raised to 40-45 ℃ for reaction for 1 hour. The reaction was monitored by HPLC for completion. The reaction solution was poured into 1.2L of ice water, crystallized, filtered, the solid was collected and dried by blowing air at 50 ℃ to obtain 117g of light brown compound I, the molar yield was 96% and the purity was 99%. 1 H-NMR(DMSO-d 6 ，400MHz)δ2.31(3H，s)，3.91(3H，s)，7.28(1H，s)，7.76(1H，s)，8.09(1H，s)12.22(1H，brs)；MS(ESI，m/z)：235[M+H] + 。
Example 7
Preparation of a Compound of formula VII:
A2L three-necked flask was charged with 200g (0.85mol) of the compound of formula I, 1.5L of oxalyl chloride was added, and the mixture was heated to reflux for 4 hours and monitored by HPLC for completion of the reaction. The oxalyl chloride was evaporated to dryness and 0.5L dichloromethane was added to carry away residual oxalyl chloride to give crude VII. Then 0.5L of dichloromethane is added to dissolve the VII crude product, the VII crude product is washed once by saturated sodium bicarbonate aqueous solution (400mL) and once by saturated salt water (400mL), the organic phase is collected and dried by anhydrous sodium sulfate, the filtration is carried out, about 200mL of dichloromethane is removed by rotary evaporation, and the residual liquid is poured into about 2L of normal hexane to be stirred and crystallized. Filtration, collection of the solid, forced air drying at 50 ℃ gave 180g of the pale yellow compound of formula VII, 84% molar yield, 98% purity. 1 H-NMR(DMSO-d 6 ，400MHz)δ2.08(3H，s)，3.73(3H，s)，7.50(1H，s)，7.55(1H，s)，9.44(1H，s)；MS(ESI，m/z)：253[M+H] + 。
Example 8
Preparation of a Compound of formula VIII:
A2L three-necked flask was charged with 150g (0.59mol) of the compound of formula VII, charged with 103g (0.71mol) of 3-chloro-4-fluoroaniline dissolved in 1.2L of ethanol, heated under reflux for 1 hour, and monitored by HPLC for completion of the reaction. Cooling, filtering, leaching filter cakes with acetone, collecting solids, and drying by blowing air at 50 ℃ to obtain 200g of a white compound shown in the formula VIII, wherein the molar yield is 84% and the purity is 99%. 1 H-NMR(DMSO-d 6 ，400MHz)δ2.36(3H，s)，3.98(3H，s)，7.49(1H，s)，7.52(1H，d，J＝9.1Hz)，7.72(1H，m)，8.02(1H，s)，8.71(1H，s)，8.91(1H，s)，11.40(1H，brs)；MS(ESI，m/z)：362[M+H] + 。
Example 9
Preparation of a Compound of formula IX:
A1L three-necked flask was charged with 180g (0.5mol) of the compound of formula VIII, 800mL of a 20% ammonia-methanol solution was added, the reaction was stirred at room temperature for 2 hours, and the reaction was monitored by HPLC for completion. The filter cake is leached by a small amount of methanol, the solid is collected and dried by blowing air at 50 ℃ to obtain 130g of the off-white compound of the formula IX, the molar yield is 82 percent and the purity is 99 percent. 1 H-NMR(DMSO-d 6 ，400MHz)δ3.98(3H，s)，7.22(1H，m)，7.41(1H，t，J＝9.1Hz)，7.78(1H，s)，7.84(1H，m)，8.21(1H，dd，J＝6.9,2.7Hz)，8.48(1H，d,J＝2.4Hz)，9.48(1H，s)，9.70(1H，s)；MS(ESI，m/z)：320[M+H] + 。
Example 10
Preparing gefitinib:
100g (0.31mol) of the compound of formula IX is added into a 2L three-necked flask, 141g (1.02mol) of potassium carbonate and 800 g of DMF800mL are added, the temperature is raised to 80-85 ℃, a 200mL DMF solution of 53.3g (0.32mol) of N- (3-chloropropyl) morpholine is added dropwise, the reaction is finished for 4 hours, and the reaction is monitored by HPLC. And (3) distilling about 600mL of DMF under reduced pressure, pouring into 3L of water, stirring, crystallizing for 1 hour, filtering, collecting the solid, and drying by blowing air at 50 ℃ to obtain 130g of off-white gefitinib crude product with the purity of 96%.
And adding 130g of the obtained crude gefitinib into 2.6L of methanol, heating and refluxing to be dissolved clearly, cooling to 25 ℃ for crystallization for 3 hours, filtering, collecting solids, and drying at 60 ℃ in vacuum to obtain 118g of white gefitinib, wherein the molar yield is 85.2 percent, and the purity is 99.6 percent. 1 H-NMR(DMSO-d 6 ，400MHz)δ2.01(2H，m)，2.44～2.52(6H，m)，3.60(4H，t，J＝4.4Hz)，3.94(3H，s)，4.18(2H，t，J＝6.4Hz)，7.19(1H，s)，7.43(1H，t,J＝8.8Hz)，7.80(2H，m)，8.14(1H，dd,J 1 ＝6.8Hz，J 2 ＝2.8Hz)，8.50(1H，s)，9.58(1H，s)；MS(ESI，m/z)：447[M+H] + 。
In conclusion, the present invention effectively overcomes various disadvantages of the prior art and has high industrial utilization value.
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 may be made by those skilled in the art without departing from the spirit and scope of the present invention as defined in the appended claims.
Claims (7)
1. A preparation method of gefitinib, which is prepared from a compound of formula I, the preparation method of the compound of formula I comprises the following steps:
1) nitration reaction: 3, 4-dimethoxy benzaldehyde is nitrated to prepare a compound shown in a formula II;
2) and (3) oxidation reaction: oxidizing the compound of the formula II to prepare a compound of a formula III;
3) selective demethylation reaction: reacting a compound in a formula III in the presence of alkali to prepare a compound in a formula IV;
4) reduction reaction: reacting a compound shown in a formula IV in the presence of a catalyst in a hydrogen atmosphere to prepare a compound shown in a formula V;
5) and (3) cyclization reaction: reacting the compound shown in the formula V with formamidine acetate to prepare a compound shown in the formula VI;
6) acetylation reaction of phenolic hydroxyl: reacting a compound shown in a formula VI with acetic anhydride in the presence of a base catalyst to prepare a compound shown in a formula I;
preparation of the compound of formula II: adding 1.2mol of 3, 4-dimethoxybenzaldehyde 200g into a 2L three-necked bottle, adding 1L of dichloroethane, stirring at 25 ℃ until the dichloroethane is completely dissolved, dropwise adding 2.93mol of 200mL of 65% nitric acid into the reaction bottle, controlling the dropwise adding temperature to be between 25 and 40 ℃, and finishing dropwise adding within about 1 hour; stirring is continued for 6 hours at 35 ℃, and the reaction is monitored by HPLC to be finished; adding 1.5L of water for extraction, collecting an organic phase, washing with a saturated sodium bicarbonate solution for 1 time, washing with a saturated salt solution for 1 time, drying the organic phase with anhydrous sodium sulfate, filtering the organic phase, concentrating under reduced pressure to obtain a crude product of a compound of a formula II, pulping with n-hexane, and filtering to obtain a yellow compound of the formula II;
preparation of the compound of formula III: 370g of compound shown in the formula II in an amount of 1.75mol, 1.75L of acetonitrile, 0.7L of water and 64.4g of monopotassium phosphate in an amount of 0.47mol are added into a three-necked flask with 5L, and stirred to obtain a turbid solution; 2.38kg of 2.63mol 10% sodium chlorite solution is dripped, the dripping temperature is controlled to be 25-35 ℃, stirring is continued for 1 hour after dripping, and HPLC monitoring reaction is finished; dropwise adding 36% hydrochloric acid until the pH value is about 2, precipitating a large amount of solid, filtering, collecting the solid, and drying by blowing air at 50 ℃ to obtain a yellow compound shown in the formula III;
2. the method of claim 1, further comprising one or more of the following features:
C1) in the step 3), the reaction is carried out under the condition of pH 13-14;
C2) in the step 3), the alkali is selected from one or more of NaOH and KOH;
C3) in the step 3), the reaction temperature is 95-100 ℃;
C4) the post-processing method of the step 3) comprises the following steps: after the reaction is finished, adjusting the pH value of the reaction system to be acidic, carrying out solid-liquid separation, and drying a solid phase substance to obtain the compound shown in the formula IV.
3. The method according to claim 2, wherein the pH of the reaction system is adjusted to pH 2 to 3 after the completion of the reaction.
4. The method of claim 1, further comprising one or more of the following technical features:
D1) in the step 4), the catalyst is selected from one or more of palladium catalyst, nickel catalyst and sodium hydrosulfite;
D2) in the step 4), the catalyst is used in an amount of 5-wt 10% of the compound of the formula IV;
D3) in the step 4), the reduction reaction is carried out in the presence of a solvent, wherein the solvent used in the reduction reaction is selected from one or more of methanol, ethanol and ethyl acetate;
D4) in the step 4), the reaction temperature is 30-40 ℃, and the reaction pressure is 1.5-2 atmospheric pressures;
D5) the post-processing method of the step 4) comprises the following steps: and after the reaction is finished, washing the product by using a solvent to obtain the compound shown in the formula V, wherein the solvent used for washing is one or a combination of more of methanol, ethanol and ethyl acetate.
5. The method of claim 1, further comprising one or more of the following technical features:
E1) in the step 5), the molar ratio of the compound shown in the formula V to formamidine acetate is 1: 2-2.5;
E2) in the step 5), the cyclization reaction is carried out in the presence of a solvent, and the solvent used in the cyclization reaction is selected from one or more of ethylene glycol monomethyl ether, ethylene glycol dimethyl ether and xylene;
E3) in the step 5), the reaction temperature is 110-120 ℃;
E4) the post-processing method of the step 5) comprises the following steps: and after the reaction is finished, removing the solvent, washing with water, and drying to obtain the compound shown in the formula VI.
6. The method of claim 1, further comprising one or more of the following technical features:
F1) in the step 6), the weight ratio of the compound in the formula VI to the acetic anhydride is 1: 4-6;
F2) in the step 6), the base catalyst is selected from one or more of pyridine, triethylamine and diisopropylethylamine;
F3) in the step 6), the molar ratio of the compound in the formula VI to the alkali catalyst is 1: 4-6;
F4) in the step 6), the acetylation of the phenolic hydroxyl group is carried out in the presence of a solvent, wherein the solvent used in the acetylation of the phenolic hydroxyl group is one or more selected from N, N-dimethylformamide and N, N-dimethylacetamide;
F5) in the step 6), the reaction temperature is 40-50 ℃;
F6) the post-processing method of the step 6) comprises the following steps: adding water for crystallization after the reaction is finished, and carrying out solid-liquid separation to obtain the compound shown in the formula VI.
7. The process according to claim 1, wherein gefitinib is prepared from the compound of formula I by the following steps:
I) chlorination reaction: chloridizing a compound of formula I to obtain a compound of formula VII;
II) aromatic amine substitution reaction: reacting a compound shown in a formula VII with 3-chloro-4-fluoroaniline to prepare a compound shown in a formula VIII;
III) hydrolysis reaction: hydrolyzing the compound of formula VIII in the presence of a base to obtain a compound of formula IX;
IV) hydroxyl etherification reaction: reacting a compound shown in a formula IX with 3-chloro-4-fluoroaniline in the presence of alkali to prepare gefitinib;
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