CN101088997A

CN101088997A - Improved process of preparing Raltitrexed

Info

Publication number: CN101088997A
Application number: CN 200610044811
Authority: CN
Inventors: 魏秀华
Original assignee: Individual
Current assignee: Individual
Priority date: 2006-06-16
Filing date: 2006-06-16
Publication date: 2007-12-19

Abstract

The improvement in the process of preparing Raltitrexed as antitumor medicine includes the reaction between N-(5-aminothienyl-2-formoxyl)-L-diethyl glutarate and methyl iodide at temperature raised to 100 deg.c in lucifugous condition with yield raised to 91 %; the replacement of sodium sulfide for iron powder as reductant to facilitate post-treatment and raise yield; the replacement of re-crystallization in mixed solvent of methanol and ether for column separation to expand the production capacity; and oxidizing 5-nitrothienyl-2-formaldehyde with chromic acid, rather than bromine, to eliminate toxicity and raise safety. The improved preparation process of Raltitrexed has high yield, great production capacity, low solvent consumption and high safety.

Description

The improvement of the processing method of Raltitrexed

Technical field

The invention belongs to medical technical field, is a kind of improvement of processing method of antitumor drug Raltitrexed.

Background technology

Raltitrexed is an antitumour drug, be used for the treatment of the prostate cancer of colorectal carcinoma in late period, tumor of head and neck, hormone antagonist etc., be over 30 years first at the new cytotoxic agent of a line of the treatment colorectal cancer of Britain registration, late period, straight treatment of colon cancer field did not have new drug to occur in 40 years, the effect of its treatment colon, the rectum cancer is described as the major progress over 35 years.Raltitrexed is a kind of quinazoline folate analogue, and its antitumous effect is that the single-minded inhibition by thymidylate synthase produces.Its characteristics: (1) curative effect is similar to Fluracil; (2) toxic side effects is few; (3) alternative Fluracil.

Raltitrexed prepares patent US4220793; the technology that adopts is for being starting raw material with thiophene phenol-2-formaldehyde; with the vitriol oil and nitrated (the 5-nitro thiophene phenol-2-formaldehyde diethyl ester) I that gets of nitrosonitric acid; hydrochloric acid hydrolysis gets (5-nitro thiophene phenol-2-formaldehyde) II; get (5-nitro thiophene phenol-2-formic acid) III through the bromine oxidation; then sulfur oxychloride reaction make behind the acyl chlorides with L-diethyl glutamate hydrochloride IV react (N-(5-nitro thiophene phenol-2-formyl radical)-L-glutamate diethyl ester) V; get (N-(the amino thiophene phenol of 5--2-formyl radical)-L-glutamate diethyl ester) VI through iron powder reducing; then respectively with methyl iodide and 2-methyl-6-brooethyl-4-oxo-3; 4-dihydroquinazoline VII carries out the reaction of ammonia alkane and makes N-[5-[N-methyl-N-(2-methyl-4-oxo-3; 4-dihydroquinoline-6-methyl) amino]-the 2-thenoyl]-L-glutamate diethyl ester VIII, reaction makes the finished product Raltitrexed to this intermediate through alkaline hydrolysis after column chromatography is purified.This process recovery ratio is low to be 7% with thiophene phenol-2-formaldehyde rate of collecting, and uses the amplification that the column chromatography purification has limited this product, and it is bigger to use bromine toxicity, and these have all limited the industrialization of this kind.

Summary of the invention

The purpose of this invention is to provide a kind of improvement of processing method of antitumor drug Raltitrexed.

The present invention is achieved in that specific as follows:

1, (N-(the amino thiophene phenol of 5--2-formyl radical)-L-glutamate diethyl ester) is increased to 100 degrees centigrade with the iodomethane reaction temperature by 80 degrees centigrade, changes the lucifuge operation into by the exposure reaction, and this step reaction yield brings up to 91% by 70%.

2, with sodium sulphite replace iron powder reducing solve difficult and wherein batch mixing cause the low problem of yield.

3, be 1 with mixed solvent methanol and ether volume ratio: 5-1: 10 recrystallizations replace post to separate, and output can further be amplified.

4, the oxidation of 5-nitro thiophene phenol-2-formaldehyde replaces bromine with chromic acid, has solved toxicity and safety issue.

Compared with the prior art the present invention has following characteristics:

By improving temperature of reaction and taking the lucifuge reactive measures to improve the yield of intermediate, replace iron powder reducing to improve reaction yield with sodium sulphite, make the lab scale process recovery ratio of Raltitrexed project bring up to 18% from 7% of literature value.By constantly groping to replace post to separate, output can further be amplified, and solvent-oil ratio reduce, for industrialization lays the foundation with mixed solvent recrystallization.Use bromine in the former technology, toxicity is unfavorable for production in the future more greatly, and has potential safety hazard, has realized replacing bromine with chromic acid under the situation that does not reduce yield by groping, and has solved toxicity and safety issue, makes this product be more conducive to industrialization.

Embodiment

Embodiment one: the preparation of N-(5-methylamino-thiophene phenol-2-formyl radical)-L-glutamate diethyl ester

Will (N-(the amino thiophene phenol of 5--2-formyl radical)-L-glutamate diethyl ester) (60g), 2,6-lutidine (29.35g, 19.5ml), DMF (150ml), logical nitrogen protection heats up.Under 50 ℃ of left and right sides lucifuges of temperature, drip methyl iodide (25.98g, 11.43ml).Dropwise, in 100 ℃ of insulation reaction 24 hours.Insulation is finished, and cooling adds entry 500ml, extracts (3 * 500ml) with ethyl acetate; Merge organic layer, (2 * 500ml), anhydrous magnesium sulfate drying removes organic solvent under reduced pressure and gets brown oily product 57.1g, yield: 91.2% with the saturated common salt water washing.

Embodiment two: the preparation of (N-(the amino thiophene phenol of 5--2-formyl radical)-L-glutamate diethyl ester)

In the there-necked flask of 2000ml, drop into successively (N-(5-nitro thiophene phenol-2-formyl radical)-L-glutamate diethyl ester) (180g), methyl alcohol (500ml) and water (500ml), sodium sulphite (195g) slowly is warmed up to 70 ℃, insulation reaction 5 hours.TLC (developping agent: ethyl acetate: detection reaction terminal point normal hexane=2: 1), after reaction solution does not have the raw material spot, stopped reaction adds diatomite, suction filtration, filtrate is concentrated into dried back adds methylene dichloride 500ml, wash twice with water, anhydrous magnesium sulfate drying, suction filtration, after concentrating, filtrate decompression gets brown oil 135g, yield: 82.1%.

Embodiment three: N-[5-[N-methyl-N-(2-methyl-4-oxo-3,4-dihydroquinoline-6-methyl) amino]-the 2-thenoyl]-preparation of L-glutamate diethyl ester

With N-(5-methylamino-thiophene phenol-2-formyl radical)-L-glutamate diethyl ester (25g), 2,6-lutidine (7.82g;), DMF (430ml) and 2-methyl-6-brooethyl-4-oxo-3; 4-dihydroquinazoline (21.44g) adds in the 1000ml reaction flask; heat up and logical nitrogen protection, in 80 ℃ of-85 ℃ of insulation reaction 18 hours.Insulation is finished, and removes DMF under reduced pressure.Cooling adds entry 500ml, extracts (3 * 600ml) with ethyl acetate; Merge organic layer, with the saturated common salt water washing (2 * 500ml), anhydrous magnesium sulfate drying, remove organic solvent under reduced pressure after, add methyl alcohol 60ml in the resistates, move in the reaction flask, stir and slowly drip the 300ml ether down, crystallization, suction filtration get product 35.8g, yield: 95.1%.

Embodiment four: the preparation of 5-nitro thiophene phenol-2-formic acid

In the flask of 2000ml, add 5-nitro thiophene phenol-2-formaldehyde (120g), distilled water (750ml) and chromic acid (122g).Be warmed up to 75 ℃, the temperature control reaction was reduced to room temperature after 3 hours, and the aqueous sodium carbonate of dropping 10% is molten entirely to solid, stirring at room 1 hour, the frozen water cooling drips the concentrated hydrochloric acid of 190ml then, insulated and stirred 5 hours is separated out solid, filters, filter cake washes with water, get solid 123g, yield 92.50%, fusing point: 158～160 ℃.

Claims

1, the improvement of the processing method of antitumor drug Raltitrexed is characterized in that:

(1) N-(the amino thiophene phenol of 5--2-formyl radical)-L-glutamate diethyl ester and methyl iodide and 2-methyl-6-brooethyl-4-oxo-3,4-dihydroquinazoline temperature of reaction under the lucifuge condition is 90 ℃-110 ℃;

(2) N-(5-nitro thiophene phenol-2-formyl radical)-L-glutamate diethyl ester with sodium sulphite reduction solve difficult and wherein batch mixing cause the low problem of yield;

(3) N-[5-[N-methyl-N-(2-methyl-4-oxo-3,4-dihydroquinoline-6-methyl) amino]-the 2-thenoyl]-purification of L-glutamate diethyl ester mixed solvent methyl alcohol and ether, volume ratio is 1: 5-1: 10;

(4) 5-nitro thiophene phenol-2-formaldehyde gets 5-nitro thiophene phenol-2-formic acid with the chromic acid oxidation.