CN1223593C

CN1223593C - Preparation of Leiliqusai

Info

Publication number: CN1223593C
Application number: CN 03140728
Authority: CN
Inventors: 赵志全
Original assignee: Lunan Pharmaceutical Group Corp
Current assignee: Lunan Pharmaceutical Group Corp
Priority date: 2003-06-04
Filing date: 2003-06-04
Publication date: 2005-10-19
Anticipated expiration: 2023-06-04
Also published as: CN1552709A

Abstract

The present invention relates to a new preparation process of raltitrexed, 5-nitro 2-thiophenecarboxylic acid is an initial raw material, and the raltitrexed is made by the following steps of esterification, nitroreduction, acetylization, methylation, hydrolysis, esterification, nucleophilic substitution, hydrolysis, acylation, acyl ammonia nucleophilic substitution, hydrolysis, acidification, etc. The new preparation process of the raltitrexed provided by the present invention can enhance yield and reduce cost by the controlling the factors, such as reaction temperature, reaction time, agitation effect, etc.

Description

The preparation technology of Raltitrexed

Technical field

The invention provides a kind of new preparation technology of Raltitrexed, belong to medical technical field.

Background technology

Colorectal carcinoma is one of common malignancy, is a kind of common cancers in western countries.Along with Chinese economic development, the variation of people life style and diet formula, its sickness rate is increasing year by year, especially in recent years, the speed increase with 4%.1993, the dead investigation result of China malignant tumour, colorectum mortality of carcinoma be in city and rural area, all the dead retrospective survey height than 1973.Epidemiological study is found, lipid content height in the diet of colorectal carcinoma country occurred frequently, content of cellulose is lower, other environmental factorss (as lacking molybdenum in the soil), schistosomicide, knot adenomas, pelvic cavity radiation, inflammation, smoking etc. also have certain relation with the colorectum oncogenesis, operative treatment is still the main method of colorectal carcinoma treatment, and success ratio depends on the advancing of disease degree.Often need chemotherapy after the operation.For the colorectal carcinoma patient in local late period, the preceding or auxiliary radiotherapy of postoperative of art, local relapse also has tangible reduction than simple surgical operation.

In in the past 35 years, Ro 2-9757 is modal chemotherapeutic always, but Ro 2-9757 has heavier toxic reaction and complicated medication, and application clinically has been subjected to very big restriction.Raltitrexed is the similar medicine of a kind of quinazoline folate, its antitumor action is to produce by the single-minded inhibition to thymidylate synthase, in the treatment to colorectal carcinoma, its curative effect is similar to Ro 2-9757, but toxic side effects and the complicated medication that can avoid Ro 2-9757 to produce.

In vitro study shows, the Raltitrexed active transport enters that very fast quilt is metabolized to a series of polymerization L-glutamic acid in a large number in the cell, and these metabolites are than the stronger enzyme inhibition of female medicine performance, and need not continue administration and can retention prolong action time in cell.Therefore alternative Ro 2-9757 in the treatment of colorectal carcinoma late has the very big market competitiveness.

In addition, this product is used for the treatment of prostate cancer, the children's of tumor of head and neck, hormone antagonist and becomes I～II phase of human leukemia, noumenal tumour and soft tissue, sarcoma to study and carries out.

There are deficiencies such as yield is low, severe reaction conditions in existing Raltitrexed raw material synthesis technique, has influenced the promotion and application of Raltitrexed.

N-[5-[N-[(3,4-dihydro-2-methyl-4-oxygen-6-quinazolyl)-methyl]-the N-methylamino-]-the 2-thienyl]-L-

L-glutamic acid is:

Through long term studies, we have invented a kind of synthesis technique, can improve final product quality and yield, reduce production costs by it.

Summary of the invention

The preparation were established of Raltitrexed provided by the present invention is as follows:

This preparation technology is a starting raw material with 5-nitro-thiophene-2-carboxylic acid, through (1) methanol esterification, and SOCl ₂As catalyzer, obtain 5-nitro-thiophene-2-carboxylic acid methyl esters; (2) nitro-catalytic hydrogenation, the said products is dissolved in methyl alcohol, adds palladium carbon, and shortening gets 5-aminothiophene-2-methyl-formiate; (3) acetylize, the said products are dissolved among the HOAc, drip diacetyl oxide, get 5-(N-ethanoyl-)-aminothiophene-2-methyl-formiate; (4) methylate, hydrolysis, the said products is dissolved in methyl alcohol, is added drop-wise in the sodium methylate, adds methyl-sulfate behind the stirring reaction, reaction back evaporate to dryness methyl alcohol adds vitriol oil hydrolysis, 5-(N-methyl-)-aminothiophene-2-carboxylic acid hydrochloride; (5) methanol esterification, the said products is dissolved in methyl alcohol, and the dripping thionyl chloride stirring reaction gets 5-(N-methyl-)-aminothiophene-2-carboxylate methyl ester; (6) nucleophilic substitution, alkaline hydrolysis, the said products is dissolved in DMF, adds salt of wormwood, bromide reaction, and products obtained therefrom is suspended in stirring reaction among the 1N NaOH, 2-[N-(2-methyl-4-oxygen quinazoline-6-methyl)-N-methyl is separated out in acidifying]-aminothiophene-2-formic acid; (7) acidylate, acyl ammonia nucleophilic substitution, the said products is dissolved in sulfur oxychloride, stir, be added drop-wise in glutamic acid dimethyl ester/methylene dichloride/triethylamine after adding the methylene dichloride dissolving, stir, washing, evaporate to dryness gets 2-[N-(2-methyl-4-oxygen quinazoline-6-methyl)-N-methyl]-amino-2-thiophene acyl-L-glutamic acid dimethyl ester; (8) step such as alkaline hydrolysis, hcl acidifying gets Raltitrexed, and whole route reaction is steady and easy to operate, and total yield of products is 22.89%.

The preparation technology of Raltitrexed provided by the present invention, by factors such as control reaction temperature, reaction times, mixing effects, can improve the synthesis yield and the final product quality of Raltitrexed, effectively reduce production costs, and reaction conditions is gentle, is easy to realize big production.

Embodiment

Further specify the present invention by following example, but it has no intention to limit the scope of patent application.Description in the following example all obtains by method known to those skilled in the art.

Example 1

The preparation of intermediate 2 (5-nitro-thiophene-2-carboxylic acid methyl esters): under the cryosel cooling, with 173g

Join in the 1000ml methyl alcohol, dripping 75mlSOCl down less than-10 ℃ ₂, add the back room temperature reaction and spend the night, solvent evaporated, underpressure distillation gets intermediate 2, and yield is 91.7%.Reaction formula is as (1):

Example 2

The preparation of intermediate 3 (5-aminothiophene-2-methyl-formiate): above-mentioned example 1 products therefrom (intermediate 2) is dissolved in the 200ml methyl alcohol, adds the palladium carbon of 1g10%, shortening filters, and solvent evaporated gets intermediate 3, and yield is 89.3%.Reaction formula is as (2):

Example 3

The preparation of intermediate 4 (5-(N-ethanoyl-)-aminothiophene-2-methyl-formiate): above-mentioned example 2 products therefroms (intermediate 3) are dissolved among the HOAc; drip the diacetyl oxide of equivalent; stirring at room is complete to raw material reaction, and solvent evaporated gets intermediate 4, and yield is 87.9%.Reaction formula is as (3):

Example 4

The preparation of intermediate 6 (5-(N-methyl-)-aminothiophene-2-carboxylic acid hydrochloride): above-mentioned example 3 products therefroms (intermediate 4) are dissolved in the 100ml anhydrous methanol, be added drop-wise in the sodium methylate of equivalent then gradually, stirred 1 hour, drip the methyl-sulfate of equivalent in the reaction flask, react the evaporate to dryness methyl alcohol that finishes, add the 200ml concentrated hydrochloric acid, refluxed 12 hours, solvent evaporated gets intermediate 6, and yield is 90.5%.Reaction formula is as (4):

Example 5

The preparation of intermediate 7 (5-(N-methyl-)-aminothiophene-2-carboxylate methyl ester): above-mentioned example 4 products therefroms (intermediate 6) are dissolved in the methyl alcohol, drip 1.1 normal sulfur oxychlorides, stirring at room is complete to raw material reaction, and precipitation gets intermediate 7, and yield is 89.6%.Reaction formula is as (5):

Example 6

The preparation of intermediate 9 (2-[N-(2-methyl-4-oxygen quinazoline-6-methyl)-N-methyl]-aminothiophene-2-formic acid): above-mentioned example 5 products therefroms (intermediate 7) are dissolved among the DMF, add 3 normal Anhydrous potassium carbonates, the bromide of equivalent, 50 ℃ of reactions are not till have a raw material.Pour in the water, filter intermediate 8 (2-[N-(2-methyl-4-oxygen quinazoline-6-methyl)-N-methyl]-aminothiophene-2-methyl-formiate).Intermediate 8 is suspended among the 1NNaOH stirred 12 hours, be acidified to pH=4, separate out solid, filter intermediate 9, yield is 52.6%.Reaction formula is as (6):

Example 7

The preparation of intermediate 11 (2-[N-(2-methyl-4-oxygen quinazoline-6-methyl)-N-methyl]-amino-2-thiophene acyl-L-glutamic acid dimethyl ester): above-mentioned example 6 products therefroms (intermediate 9) are dissolved in the 3 normal sulfur oxychlorides, stirred overnight at room temperature, evaporated under reduced pressure, add the methylene dichloride dissolving, be added drop-wise in the glutamic acid dimethyl ester/methylene dichloride/triethylamine of equivalent stirred overnight at room temperature, washing gradually, solvent evaporated gets intermediate 11, and yield is 82.7%.Reaction formula is as (7):

Example 8

The preparation of Raltitrexed: 465ml NaOH solution is added in the 500ml there-necked flask, and ice-water bath is lowered the temperature, and adds docking object, heats up stirring at room reaction 1 hour, the complete CHCl that uses of reaction naturally ₃Wash, aqueous phase adds activated carbon decolorizing, suction filtration, and filtrate drips the hydrochloric acid soln acidifying of 1N, and adjust pH has a large amount of solids to separate out to pH=3, continues to stir 30 minutes, and suction filtration gets pale brown look solid 104.4g, and yield is 90.2%.Reaction formula is as (8):

Claims

1, a kind of preparation method of Raltitrexed is characterized in that, is starting raw material with 5-nitro-thiophene-2-carboxylic acid, carries out the reaction of following steps successively:

(1) esterification;

(2) catalytic reduction nitro;

(3) with glycylization;

(4) methylate, hydrolysis then;

(5) esterification;

(6) nucleophilic substitution, alkaline hydrolysis then, wherein nucleophilic reagent is a 6-bromomethyl-3,4-dihydro-2-methyl-4-oxo quinazoline;

(7) make amino acidylate, with glutamic acid dimethyl ester acyl ammonia is carried out nucleophilic substitution then;

(8) alkaline hydrolysis, acidifying obtains the product Raltitrexed.

2, the described preparation method of claim 1 is characterized in that: employed esterifying agent is a methyl alcohol in the esterification of step (1) or (5).

3, the described preparation method of claim 1 is characterized in that: employed catalyzer is hydrogen/palladium carbon in the catalytic reduction reaction of step (2).

4, the described preparation method of claim 1, it is characterized in that: employed acetylizing agent is a diacetyl oxide in the acetylization reaction of step (3).

5, the described preparation method of claim 1 is characterized in that: in step (4), the employed reagent of methylation reaction wherein is methyl-sulfate or methylcarbonate, and that hydrolysis reaction wherein uses is HCl.

6, the described preparation method of claim 1 is characterized in that: employed reagent is mineral acid or mineral alkali in the hydrolysis reaction of step (6).

7, the described preparation method of claim 1, it is characterized in that: employed reagent is SOCl in the acylation reaction of step (7) ₂

8, preparation method as claimed in claim 1 wherein, in the esterif iotacation step of step (1) or (5), also comprises slow dropping SOCl ₂As catalyzer.

9, claim 7 or 8 described preparation methods is characterized in that in preparation process, slowly drip SOCl ₂The time control temperature be-30 ℃～10 ℃.

10, the described preparation method of claim 9 is characterized in that in preparation process, slowly drips SOCl ₂The time control temperature be-15 ℃～5 ℃.