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5-((alkoxy methylene) amino) thienyl-2-formyl group)-L-glutamic acid dialkyl ester and preparation method thereof

A methyl and alkyl technology, applied in the field of drug synthesis, can solve the problems of many by-products, long reaction time, inconvenient post-processing, etc., and achieve the effects of fast reaction, shortened reaction time, convenient post-processing and storage

Active Publication Date: 2017-07-18
NANJING CHIA TAI TIANQING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The technical problem to be solved in the present invention is to overcome the problems of lengthy reaction time, many by-products and inconvenient post-treatment caused by the above-mentioned methylation method, and provide a new method for rapidly preparing N-methylation with high yield and high purity. The method of base compound and antineoplastic drug raltitrexed (formula 1)

Method used

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  • 5-((alkoxy methylene) amino) thienyl-2-formyl group)-L-glutamic acid dialkyl ester and preparation method thereof
  • 5-((alkoxy methylene) amino) thienyl-2-formyl group)-L-glutamic acid dialkyl ester and preparation method thereof
  • 5-((alkoxy methylene) amino) thienyl-2-formyl group)-L-glutamic acid dialkyl ester and preparation method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: the preparation of compound 5 (R 1 for ethyl)

[0042]

[0043] 5-Nitrothiophene-2-formyl-L-glutamic acid diethyl ester (2.2g) was dissolved in methanol (5.2g), and added dropwise with iron powder (2.1g), methanol (5.2g), concentrated In the mixed solution of hydrochloric acid (2.8g), the temperature is controlled not to exceed 50°C. After the dripping is completed, the temperature is raised to 70-80°C for reaction. TLC monitors that the compound is completely reacted, filtered with suction, and concentrated under reduced pressure below 80°C. 20 g of toluene was divided into two times to take out the solvent, added ethyl acetate (9.9 g) to dissolve, suction filtered, added drinking water (11.0 g) to the filtrate, washed with 20% aqueous sodium carbonate solution (11.0 g), adjusted the pH to 8-9, The organic phase was obtained, and the organic phase was washed with saturated brine (8.8 g), dried over anhydrous sodium sulfate, and suction filtered, and t...

Embodiment 2

[0044] Embodiment 2: the preparation of compound 4a (R 2 for methyl)

[0045]

[0046]Compound 5 (13g) and trimethyl orthoformate (78g) were heated and dissolved, heated to 80°C, and reacted for 2 hours. TLC monitored that the reaction was complete, cooled to below 50°C, concentrated under reduced pressure to remove trimethyl orthoformate, and obtained The solid was 13.8g, the yield was 93%, and the HPLC purity was 99.7%. 1 H NMR (500MHz, CDCl 3 ):δ8.39(s,1H),8.01(d,J=10.0Hz,1H),7.58(dd,J=12.5Hz,1H),7.50(d,J=5.0Hz,1H),4.51(m ,1H),4.21(m,2H),4.13(m,2H),3.40(s,3H),2.35(dd,J=7.5Hz,2H),2.29(d,J=10.0Hz,2H),1.29 (s,3H),1.23(s,3H); MS(ES) m / z371.42[M+H] + .

Embodiment 3

[0047] Embodiment 3: the preparation of compound 4b (R 2 for ethyl)

[0048]

[0049] Compound 5 (13g) and triethyl orthoformate (78g) were heated and dissolved, heated to 90°C, and reacted for 2 hours. TLC monitored that the reaction was complete, cooled to below 50°C, concentrated under reduced pressure to remove triethyl orthoformate, and obtained Solid (14.2 g, yield 93%, HPLC purity 99.4%). 1 H NMR (500MHz, CDCl 3 ):δ8.36(s,1H),8.01(d,J=10.0Hz,1H),7.57(dd,J=12.5Hz,1H),7.50(d,J=5.0Hz,1H),4.52(m ,1H),4.37(m,2H),4.21(m,2H),4.13(m,2H),3.43(s,3H),2.35(dd,J=7.5Hz,2H),2.29(d,J= 10.0Hz,2H),1.29(s,3H),1.22(s,3H); MS(ES) m / z 385.32[M+H] + .

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Abstract

The invention belongs to the field of medicine synthesis, and discloses a compound of formula 4 as shown in the specification, a preparation method and application of the compound. The compound can be used as an intermediate to synthesize an anti-cancer medicine of formula 1 as shown in the specification, has the advantages of low cost, high purity, gentle reaction and simple and convenient posttreatment, and is applicable to industrially enlarged production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to the synthesis of a class of compound 5-((alkoxymethylene)amino)thienyl-2-formyl)-L-glutamic acid dihydrocarbyl ester, its preparation method and application . Background technique [0002] Colorectal cancer is one of the more common tumors in the world. With economic development in my country, people's diet structure has changed, resulting in an increase in the incidence of colorectal cancer year by year. [0003] Raltitrexed (Compound 1) is a drug jointly developed by the Cancer Research Department of the Royal Marsden Hospital in the UK and Zeneca. It is a thymus synthase inhibitor, a derivative of folic acid, used in the treatment of patients with advanced colorectal cancer. It was launched in the UK for the first time in 1996 under the trade name Tomudex, and it was launched in France and other countries in the same year. As a first-line treatment drug for advanced...

Claims

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Application Information

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IPC IPC(8): C07D333/38C07D409/12
CPCC07D333/38C07D409/12
Inventor 童耀王足兵葛书旺吴舰柴雨柱林峰徐丹朱春霞田舟山
Owner NANJING CHIA TAI TIANQING PHARMA
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