| Raltitrexed, which is a novel analog of quinazoline folate can inhibit the synthesis of thymidylate synthase. Raltitrexed is quickly metabolized into a series of polyglutamic acid by folic acid-based poly-glutamic acid synthase after ingested in vivo. These metabolites play a stronger inhibitory effect of thymidylate synthase by inhibiting DNA synthesis. What's more, they can retain in cells for a long time to play inhibition. The efficacy of raltitrexed is similar to fluorouracil in the treatment of colorectal cancer. However, raltitrexed has a lower incidence of side-effects and a easier way to be used which make it be accepted easily by patients.A phase II clinical trial in 176 patients with advanced colorectal cancer showed that administration of Raltitrexed,3mg/m2, once every 3 weeks, produced a comprehensive efficacy 25.6%. The average time from treatment to progress was 4.2 months and the overall survival time was 11.2 months. A phase II clinical trial in 1,300 patients with advanced colorectal cancer patients revealed that the objective efficacy of raltitrexed was similar to fluorouracil combined with folinic acid. The effective rates were 14.3%～19.3% and 15.2%-18.1% respectively. Two phase III clinical trials of raltitrexed and fluorouracil combined with folinic acid produced an average overall survival time of 10.9～12.3 months and 10.1～10.2 months respectively. Another study showed that the use of fluorouracil-folinic acid produced a higher survival rate (12.7 months) than Raltitrexed, but the former medication time was twice the time of Raltitrexed. Mitigation of raltitrexed for the symptoms of advanced colorectal cancer patients was similar with fluorouracil combined with folinic acid. The proportions of patients over 5% weight gain was 13%-21.1% and 15.7%～27.4% respectively.Colorectal cancer is one of the most common malignant tumors having a high mortality rate. In China, with the improvement of living standards and the change of lifestyles and diet, the incidence of colorectal cancer was increasing year by year. Since the 1970s, the incidence of colorectal cancer increases at a rate of 4.2% annually. Currently, the general treatment of colorectal cancer was combination of fluorouracil and fluorouracil-leucovorin. Compared with fluorouracil, raltitrexed has a lower toxicity, higher activity and an easier way. In western European countries, raltitrexed has already become the first-line drug to treat advanced colorectal cancer. Therefore, raltitrexed which has a huge potential market will bring substantial economic and social benefits to the enterprise.It was reported that the synthesis of raltitrexed was began with the hydrolytic condensation reaction of N-[5-(N-methylamino)-2-thenoyl]-L-glutamic acid diethyl ester with 2-methy-6-bromomethyl-3-hydrogen-quinazolin-4-one (NBS). The synthetic methods of the important intermediate N-[5-(N-methylamino)-2-thenoyl]-L-glutamic acid diethyl ester mainly have the three kinds as follow:(1) 2-thiophene carboxylic acid was used as the raw material. This route contains seven steps, and the total yield is only 1.67%. There are several security risks, using some expensive and toxic reagents like n-butyllithium. Especially, the route should be carried out at-78℃and under the protection of argon gas, which are difficult to be achieved in industrial production ; (2) 2-thienylformaldehyde is chosen as the starting material. This route has eight steps and the total yield is 22.5%,but the regioselectivity of N-methylation is difficult to control and the single N-methylated product is difficult to be separated; (3) 2-thienyl formaldehyde was used as the starting material.This reaction has 11 steps and the yield is low to only 12.9%. It is difficult to remove the Boc2O remaining in the reaction, what's more, trifluoroacetic acid should be used to remove the protective Boc-group. On the basis of the reported synthetic method 5-nitro-2-thienyl carboxylic acid was used as the starting material in this paper, the target compound raltitrexed was synthesized via 11 steps and the total yield was 20.4%(ref.12.9%).5-(N-acetyl) amino-thienyl-2-methyl formate was obtained by esterification, reduction and acylation with acetic anhydride, which reacted with methyl iodide at the present of potassium carbonate to give the N-methylated intermediate, after deprotected in hydrochloric acid and esterified 5-(N-methyl)-aminothienyl-2-methyl formate was obtained.5-(N-methyl)-aminothienyl-2-methyl formate condensed with the NBS under alkaline conditions, hydrolyzed, chloridized, and then reacted with diethyl L-glutamate, and hydrolyzed, raltitrexed was synthesized.The protected amino of intermediate (4) using acetic anhydride can be deprotected mildly in hydrochloric acid, compared to deprotection of Boc-group in Route 3,the reagent is cheap and the toxicity is low. Especially the intermediate can be used directly to the next reaction in the process of condensation with the NBS, hydrolysis, chlorination and condensation with diethyl L-glutamate without purification. The optimization reaction reduces the labor intensity and simplifies the process of post-processing, increased the total yield significantly.
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