CN105503748A - Preparation method of gefitinib - Google Patents

Abstract

The invention discloses a preparation method of gefitinib, and belongs to the technical field of chemical pharmacy. The method provided by the invention has the following steps: carrying out esterolysis on a compound I at first to obtain a compound II, and then carrying out condensation reaction between the compound II and N-(3-chloropropyl) morpholine to obtain a compound III. According to the preparation method provided by the invention, high-pressure hydrogenation, cyanation, and nitro reduction are avoided, the reaction condition is mild and controllable, the reaction step is relatively short, the yield is relatively high, and the cost is relatively low, so that the preparation method is suitable for industrial production. The teaction formula is shown in the specification.

Description

A kind of preparation method of Gefitinib

Technical field

The present invention relates to a kind of preparation method of Gefitinib, belong to technical field of pharmaceutical chemistry.

Background technology

Gefitinib, Gefitinib, trade(brand)name: Iressa, Iressa; Being a kind of new type antineoplastic medicine developed by AstraZeneca company, is a kind of selective depressant of Urogastron (EGFR) Tyrosylprotein kinase that can be oral, the clinical treatment being mainly used in nonsmall-cell lung cancer at present.Be used for the treatment of in Japanese health ministry approval listing first on Iressa2002 July 5 and can not perform the operation or advanced Non-small cell lung (NSCLC), in May, 2003 gets permission the three line single therapy medicines as NSCLC in the U.S. and Australia, proposes: Iressa recommends to be used for the treatment of the nonsmall-cell lung cancer platiniferous class scheme of Locally Advanced or distant metastasis and the patient of Docetaxel chemotherapy failure during within 2003, lung cancer Professional Committee of Chinese Anti-Cancer Association guides the treatment of inoperable NSCLC.Approval in Nikkei State Food and Drug Administration February 25 in 2005 (SFDA) is formal at Discussion on Chinese Listed (commodity popular name: Gefitinib), for previously accepting chemotherapeutical Locally Advanced or Metastatic Nsclc.The development of this medicine undoubtedly will for clinical disease patient provide a kind of safer, effectively, medicine easily, good Social benefit and economic benefit will be produced after listing.Its chemical name: N-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline-4-amine, chemical structure is as follows:

The preparation method of Gefitinib has report respectively in CN1850807A (publication date: 2006-10-25), its chemistry N-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline-4-amine by name, structural formula is as follows:

Patent CN1850807A (publication date: 2006-10-25)

The disclosed preparation method of patent CN1850807A (publication date: 2006-10-25):

The cost of the disclosed preparation method's starting raw material 1 of patent CN1850807A (publication date: 2006-10-25) is higher; Compound 3 is prepared compound 4 reaction needed debenzylation and is carried out high-pressure hydrogenation reaction, requires higher to conversion unit.

The disclosed preparation method of patent CN101463012A (publication date: 2009-6-24) is as follows:

The disclosed preparation method of patent CN101463012A (publication date: 2009-6-24), reactions steps is too much; Adopt DMSO backflow when preparing compound 2, easily blast in this system, and temperature of reaction is that high temperature is high to equipment requirements, is not suitable for production.

The disclosed route of patent WO2008125867A2 (publication date: 2008-10-23) is as follows:

Note: X=Cl, Br, I

The disclosed route of patent WO2008125867A2 (publication date: 2008-10-23), first, reactions steps is too much; Preparing compound 5 temperature of reaction is 170-180 DEG C, high to equipment requirements; In addition, many steps use large water gaging to do aftertreatment, and a large amount of waste water is unfavorable for environmental protection.

Consider the Social benefit and economic benefit that Gefitinib is good and reaction yield, industrialized condition and environmental protection policy, the present invention develop a kind of can safely and hold the preparation method of manageable compound III

Summary of the invention

The object of the invention is to be difficult to the shortcoming of accomplishing scale production for existing method; by on the basis of great many of experiments, provide a kind of and effectively can avoid using that hypertoxic chemical reagent, reaction conditions are gentle, controllability is strong, reactions steps compared with short, yield compared with high, cost compared with low, environmental pollution is little, be applicable to the method preparing Gefitinib of suitability for industrialized production.The technical scheme taked is as follows:

The invention provides the preparation method of a kind of Gefitinib (formula III), the method first Compound I is obtained Compound II per through transesterify, again Compound II per and N-(3-chloropropyl) morpholine condensation reaction are obtained compound III, its reaction scheme is as follows:

Preferably, the reaction system methyl alcohol of Compound I and Compound II per, salt of wormwood, sodium carbonate or sodium hydroxide, temperature are 40-50 DEG C.

Preferably, Compound II per and N-(3-chloropropyl) morpholine condensation reaction, reaction solvent is methyl alcohol, ethanol or both mix polar solvent.

Preferably, Compound II per and N-(3-chloropropyl) morpholine setting-up point are 80-90 DEG C.

The step of described method is as follows:

1) preparation of 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol: stir add methyl alcohol in reaction vessel after, add 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester hydrochloride, salt of wormwood more respectively, temperature is risen to 40 DEG C ~ 50 DEG C, react 8 ~ 10 hours, stopped reaction.Underpressure distillation, obtains 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol;

2) preparation of Gefitinib crude product: N-(3-chloropropyl) morpholine and DMF are joined step 1) gained reactant in, temperature is increased to 70 DEG C ~ 100 DEG C reaction 6-8 hour, stopped reaction, filter after reducing temperature, after filtrate decompression distillation, drip pure water, then obtain crude product after agitation and filtration;

3) Gefitinib crude product is refining: by step 1) crude product of gained joins in methyl alcohol, and stirring and refluxing is to after all dissolving, and cooling crystallize out, carries out drying by filter cake after filtration again.

Preferably, step 1) described 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester hydrochloride and salt of wormwood, the ratio of the two is 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester hydrochloride: salt of wormwood=1.4-1.5:1.

Preferably, step 2) addition of described N-(3-chloropropyl) morpholine, with the mol ratio of Compound II per be: Compound II per: N-(3-chloropropyl) morpholine=1:1.1-1.3, temperature of reaction is 80-90 DEG C.

Preferably, step 3) described by step 1) crude product of gained joins methyl alcohol, is according to crude product quality: the ratio of methyl alcohol volume=1:20 is added; Described crystallize out, the time is 3h; Described drying is vacuum-drying 10h.

The concrete steps of described method are as follows:

1) preparation of 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol: add 5L methyl alcohol in 10L reaction flask, stir, add 1000g4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester hydrochloride and 694g salt of wormwood respectively, add and be warming up to 40 DEG C ~ 50 DEG C, react 8 ~ 10 hours, stopped reaction, obtains 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol after underpressure distillation;

2) preparation of Gefitinib crude product: to step 1) gained reactant in add N-(3-chloropropyl) morpholine of 493g, the DMF of 4L, be warming up to 80 DEG C ~ 90 DEG C reaction 6-8 hour, stopped reaction, filter after reducing reacting liquid temperature, filtrate decompression is distilled, and drips 10L purified water after completing, add stirring to filter after 1 hour, obtain crude product;

3) Gefitinib crude product is refining: by step 2) the 900g crude product that obtains joins in 18L methyl alcohol, and stirring and refluxing is to all dissolving, and cooling crystallize out 3h, filters, obtain fine work after Vacuum dry filter cake 10h.

Synthetic route of the present invention is shown below:

Beneficial effect of the present invention is further illustrated below by way of contrast optimization:

One, synthetic route one contrasts

The disclosed preparation method of patent CN1850807A (publication date: 2006-10-25):

the cost of this preparation method's starting raw material 1 is higher; Compound 3 is prepared compound 4 reaction needed debenzylation and is carried out high-pressure hydrogenation reaction, requires higher, and have certain risk to conversion unit.

In the present invention, synthetic route advantage is as follows: compare this method route, this route is shorter; Invention also avoids dangerous high-pressure hydrogenation reaction, be more suitable for production.

Two, synthetic route two contrasts

The route of patent CN101463012A (publication date: 2009-6-24) is as follows:

The disclosed preparation method of patent CN101463012A (publication date: 2009-6-24), reactions steps is too much; Adopt DMSO backflow when preparing compound 2, easily blast in this system, and temperature of reaction is that high temperature (189 DEG C) is high to equipment requirements, is not suitable for production.

Present invention, avoiding pyroreaction, reaction conditions is gentle, controllability strong and reactions steps compared with short, yield compared with high, cost compared with low, environmental pollution is little, be applicable to suitability for industrialized production.

Three, synthetic route three contrasts

The disclosed route of patent WO2008125867A2 (publication date: 2008-10-23) is as follows:

Note: X=Cl, Br, I

The disclosed route of patent WO2008125867A2 (publication date: 2008-10-23), first, reactions steps is too much; Preparing compound 5 temperature of reaction is 170-180 DEG C, high to equipment requirements; Secondly, many steps use large water gaging to do aftertreatment, and a large amount of waste water is unfavorable for environmental protection.

Route of the present invention is shorter; Avoid pyroreaction, reaction conditions is gentle, and three industrial wastes easily process.

Accompanying drawing explanation

Fig. 1 is the detected result of the HPLC of embodiment 1 gained Gefitinib.

Fig. 2 is the detected result of the HPLC of embodiment 2 gained Gefitinib.

Embodiment

Below in conjunction with specific embodiment, the present invention will be further described, but the present invention is not by the restriction of embodiment.

Following examples material therefor, reagent, instruments and methods, without specified otherwise, be this area conventional material, reagent, instruments and methods, those skilled in the art all obtain by commercial channel.

Embodiment 1

1,4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol

In 10L reaction flask, add methyl alcohol (3L), stir, add 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester hydrochloride (330g), salt of wormwood (231g).Add and be warming up to 40 DEG C ~ 50 DEG C, back flow reaction 8 ~ 10 hours.HPLC monitors, stopped reaction.Water pump underpressure distillation methyl alcohol.Obtain 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol, yellowish to yellow solid, be directly used in the next step.

2, N-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group-6-(3-morpholine-4-propoxy-) quinazoline-4-amine

In 10L reaction flask, add single step reaction thing add N-(3-chloropropyl) morpholine (164g), DMF (2L), stirring heating, concentrating under reduced pressure; Concentrated completely add DMF (1L), be warming up to 80 DEG C ~ 90 DEG C reactions 6-8 hour stopped reaction.Reaction solution is cooled to 40 DEG C ~ 50 DEG C, filters, filter cake DMF drip washing.Filtrate decompression is distilled; Concentrated complete dropping purified water, continues stirring 3 hours.Filter, filter cake purified water drip washing.Filter cake joins methanol eddy 6 hours, cold filtration, and uses methyl alcohol drip washing.Obtain N-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group-6-(3-morpholine-4-propoxy-) quinazoline-4-amine, i.e. crude product.

3, crude product refining

Gained crude product is joined in methyl alcohol, stirring and refluxing.Cooling stirring 3 hours crystallizatioies, are cooled to 25 DEG C ~ 30 DEG C, filter, filter cake methyl alcohol drip washing.Filter cake vacuum-drying 10 hours.Obtain Gefitinib product 177g, yield: 87%.HPLC is adopted to detect Gefitinib, as shown in Figure 1.

Embodiment 2

1, the preparation of 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol

Methyl alcohol (8L) is added in 30L reaction flask, stir, add 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester hydrochloride (1000g), salt of wormwood (694g), add and be warming up to 40 DEG C ~ 50 DEG C, back flow reaction 8 ~ 10 hours.HPLC monitors, stopped reaction.Water pump underpressure distillation methyl alcohol.Obtain 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol, be directly used in the next step.

2, the preparation of N-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group-6-(3-morpholine-4-propoxy-) quinazoline-4-amine

In 30L reaction flask, add single step reaction thing add N-(3-chloropropyl) morpholine (493g), DMF (5L), stirring heating, concentrating under reduced pressure; Concentrated completely add DMF (3L), be warming up to 80 DEG C ~ 90 DEG C reactions, 6 ~ 8 hours stopped reaction.Reaction solution is cooled to 40 DEG C ~ 50 DEG C, filters, filter cake DMF drip washing.Filtrate decompression is distilled; Concentrated complete dropping purified water, continues stirring 3 hours.Filter, filter cake purified water drip washing.Filter cake joins methanol eddy 6 hours, cold filtration, and uses methyl alcohol drip washing.Obtain N-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group-6-(3-morpholine-4-propoxy-) quinazoline-4-amine, i.e. crude product.

3, crude product refining

Gained crude product is joined in methyl alcohol, stirring and refluxing.Cooling stirring 3 hours crystallizatioies, are cooled to 25 DEG C ~ 30 DEG C, filter, filter cake methyl alcohol drip washing.Filter cake vacuum-drying 10 hours.Obtain Gefitinib product 540g, yield: 88%.HPLC is adopted to detect Gefitinib product, as shown in Figure 2.

Although the present invention with preferred embodiment openly as above; but it is also not used to limit the present invention, any person skilled in the art, without departing from the spirit and scope of the present invention; can do various change and modification, what therefore protection scope of the present invention should define with claims is as the criterion.

Claims (9)

1. the preparation method of a Gefitinib (formula III), it is characterized in that, first Compound I is obtained Compound II per through transesterify, then Compound II per and N-(3-chloropropyl) morpholine condensation reaction are obtained compound III, its reaction scheme is as follows:

2. method described in claim 1, is characterized in that, the reaction system methyl alcohol of Compound I and Compound II per, salt of wormwood, sodium carbonate or sodium hydroxide, temperature are 40-50 DEG C.

3. method described in claim 1, is characterized in that, Compound II per and N-(3-chloropropyl) morpholine condensation reaction, reaction solvent is methyl alcohol, ethanol or both mix polar solvent.

4. method described in claim 1, is characterized in that, Compound II per and N-(3-chloropropyl) morpholine setting-up point are 80-90 DEG C.

5. the arbitrary described method of claim 1-4, it is characterized in that, step is as follows:

1) preparation of 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol: stir add methyl alcohol in reaction vessel after, add 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester hydrochloride, salt of wormwood more respectively, temperature is risen to 40 DEG C ~ 50 DEG C, react 8 ~ 10 hours, stopped reaction.Underpressure distillation, obtains 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol;

2) preparation of Gefitinib crude product: N-(3-chloropropyl) morpholine and DMF are joined step 1) gained reactant in, temperature is increased to 70 DEG C ~ 100 DEG C reaction 6-8 hour, stopped reaction, filter after reducing temperature, after filtrate decompression distillation, drip pure water, then obtain crude product after agitation and filtration;

3) Gefitinib crude product is refining: by step 1) crude product of gained joins in methyl alcohol, and stirring and refluxing is to after all dissolving, and cooling crystallize out, carries out drying by filter cake after filtration again.

6. method described in claim 5, it is characterized in that, step 1) described 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester hydrochloride and salt of wormwood, the ratio of the two is 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester hydrochloride: salt of wormwood=1.4-1.5:1.

7. method described in claim 5, it is characterized in that, step 2) addition of described N-(3-chloropropyl) morpholine, with the mol ratio of Compound II per be: Compound II per: N-(3-chloropropyl) morpholine=1:1.1-1.3, temperature of reaction is 80-90 DEG C.

8. method described in claim 5, is characterized in that, step 3) described by step 1) crude product of gained joins methyl alcohol, is according to crude product quality: the ratio of methyl alcohol volume=1:20 is added; Described crystallize out, the time is 3h; Described drying is vacuum-drying 10h.

9. method according to claim 5, it is characterized in that, concrete steps are as follows:

1) preparation of 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol: add 5L methyl alcohol in 10L reaction flask, stir, add 1000g4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol acetic ester hydrochloride and 694g salt of wormwood respectively, add and be warming up to 40 DEG C ~ 50 DEG C, react 8 ~ 10 hours, stopped reaction, obtains 4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride-6-alcohol after underpressure distillation;

2) preparation of Gefitinib crude product: to step 1) gained reactant in add N-(3-chloropropyl) morpholine of 493g, the DMF of 4L, be warming up to 80 DEG C ~ 90 DEG C reaction 6-8 hour, stopped reaction, filter after reducing reacting liquid temperature, filtrate decompression is distilled, and drips 10L purified water after completing, add stirring to filter after 1 hour, obtain crude product;

3) Gefitinib crude product is refining: by step 2) the 900g crude product that obtains joins in 18L methyl alcohol, and stirring and refluxing is to all dissolving, and cooling crystallize out 3h, filters, obtain fine work after Vacuum dry filter cake 10h.