A kind of synthesis technique of raltitrexed key intermediate

A technology of raltitrexed and synthesis process, applied in the direction of organic chemistry and the like, can solve the problems of complex process route, high purification difficulty, unfavorable industrialization, etc., and achieve the effects of improving process yield, shortening process cycle and reducing preparation cost

Active Publication Date: 2020-07-17
HONGGUAN BIO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In this reaction route, in the process of introducing carboxyl functional groups, carbon insertion reaction is adopted. This reaction requires a large amount of dry ice or carbon dioxide gas. The reaction conditions are harsh and the reaction time is long, which is not conducive to controlling the reaction process and is not conducive to industrialization.
[0016] In view of the deficiencies in the synthesis process of key intermediates of raltitrexed reported above, such as: low reaction yield, difficult purification, harsh reaction conditions, complex process route, long preparation period, etc.

Method used

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  • A kind of synthesis technique of raltitrexed key intermediate
  • A kind of synthesis technique of raltitrexed key intermediate
  • A kind of synthesis technique of raltitrexed key intermediate

Examples

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Embodiment 1

[0040] Step 1: Preparation of Diethyl Glutamate in Isocyanate Solution

[0041] Add diethyl glutamate hydrochloride (100.0 g, 0.42 mol) and 400 mL of dichloromethane into a 1 L reaction flask, replace with nitrogen three times, cool down (internal temperature drops to -5°C to 5°C), and set aside.

[0042] In a 250ml reaction flask, under nitrogen protection, dichloromethane (100mL) and triphosgene (41.5 g, 0.14mol) were added in sequence, and stirred to dissolve. The dichloromethane solution of triphosgene was slowly dropped into the above-mentioned diethyl glutamate hydrochloride dichloromethane suspension, the internal temperature was controlled at -5°C to 5°C, and the system was stirred for 30 minutes after the addition was completed. Another triethylamine (92.8g, 0.92mol) was taken, and the internal temperature was controlled at -5°C to 5°C, slowly dropped into the reaction solution, and after the addition was completed, the reaction was stirred at 0°C to 10°C for 2 hours,...

Embodiment 2

[0048] Step 1: Preparation of Diethyl Glutamate in Isocyanate Solution

[0049] Add diethyl glutamate hydrochloride (100.0 g, 0.42 mol) and 400 mL of dichloromethane into a 1 L reaction flask, replace with nitrogen three times, cool down (internal temperature drops to -5°C to 5°C), and set aside.

[0050] 250mL reaction flask, under the protection of nitrogen, add dichloromethane (100mL) and diphosgene (27.7 g, 0.14mol) in sequence, stir to dissolve. Slowly add the diphosgene dichloromethane solution dropwise into the diethyl glutamate hydrochloride dichloromethane suspension, control the internal temperature -5°C to 5°C, and stir the system for 30 minutes after the addition. Another triethylamine (92.8g, 0.92mol) was taken, and the internal temperature was controlled at -5°C to 5°C, slowly dropped into the reaction solution, and after the addition was completed, the reaction was stirred at 0°C to 10°C for 2 hours, and the reaction was detected by TLC. completely.

[0051] T...

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Abstract

The invention relates to the technical field of medicine preparation, in particular to a synthesis process of a Raltitrexed key intermediate. According to the synthesis process of the Raltitrexed keyintermediate, forming an active intermediate (isocyanate) through glutamate diethyl ester, the active intermediate and N-methyl-(2-thienyl) tert-butyl carbamate are directly reacted, and a target product N-[5-[N-(t-butyloxycarboryl)-N-methyl amino]-2-thenoyl]-L-glutamate diethyl ester is prepared by two steps. The synthesis process avoids difficulties of potential risks of part of racemization ofa chiral center caused by amidation reaction, low yield, complicated operation and purification and the like. The synthesis process of the Raltitrexed key intermediate is simple to operate, short in line, environmentally friendly and high in yield.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a synthesis process of a key intermediate of raltitrexed. Background technique [0002] Raltitrexed, a quinazoline folate analogue, is a novel water-soluble inhibitor of thymidylate synthase, which can cause DNA fragmentation and cell death by inhibiting thymidylate synthase. Compared with 5-fluorouracil, raltitrexed has stronger selectivity, and can replace fluorouracil in the treatment of advanced colorectal cancer, and has become the first-line drug for the treatment of advanced colorectal cancer. [0003] Raltitrexed was developed and created by the British Zeneca Pharmaceutical Company. It was first launched in the UK in 1996. The trade name is Tomudex, and the chemical name is: N-[5-[N-methyl-N-(2-methyl-4-oxo Substitute-3,4-dihydroquinazoline-6-methyl)amino]thiophene-2-formyl]-L-glutamic acid, the structural formula is: [0004] [0005] About the synthet...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/38
Inventor 于学彬华羽倩朱金龙程宜兴杨继斌
Owner HONGGUAN BIO PHARMA CO LTD
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