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Method for synthesizing 5-N-tert-butyloxycarbonyl-5-N-methylamino-2-thiophenic acid

A kind of tert-butoxycarbonyl and methylamino technology, applied in the field of raltitrexed intermediate preparation and compound preparation, can solve problems such as being unfavorable to industrialized production, harsh conditions, difficult to operate, etc., and achieve easy industrialized production and easily controllable conditions. , the effect of easy operation

Active Publication Date: 2014-06-04
安徽尖峰北卡药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there are only three steps in this route, the first step uses curtius rearrangement, and the yield is relatively low. The third step uses n-butyllithium to extract hydrogen, and the temperature needs to be controlled at -60 ~ -80 ° C, which is not easy to operate and the conditions are harsh.
Therefore, this method is not conducive to industrial production.

Method used

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  • Method for synthesizing 5-N-tert-butyloxycarbonyl-5-N-methylamino-2-thiophenic acid
  • Method for synthesizing 5-N-tert-butyloxycarbonyl-5-N-methylamino-2-thiophenic acid
  • Method for synthesizing 5-N-tert-butyloxycarbonyl-5-N-methylamino-2-thiophenic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] 1.1 The preparation of compound III i.e. 5-bromothiophene-2-amine

[0055] Dissolve the raw material 2-bromo-5-nitrothiophene (10g48.3mmol) in a mixed solvent of 80ml ethanol and 25ml water, add 10.1g ammonium chloride, add 12.5g iron powder, and slowly heat to 70°C under nitrogen protection , and reacted for 8 hours. After the reaction, when the system was cooled to 50°C, it was filtered while it was hot, and the filtrate was evaporated with a water pump and a rotary evaporator (0.01MPa, 40°C) to remove the organic solvent, and then oiled with an oil pump (0.001MPa). The bath was distilled under reduced pressure, the temperature of the oil bath was 100-120°C, and the fraction was extracted at 80-81°C to obtain 6.9g of compound III with a yield of 80.7%.

[0056] 1 H NMR (CDCl 3 ,400MHz): δ=6.98(s,2H),6.44(d,1H),5.74(d,1H).

[0057] MS (EI): m / e=177.

[0058] 1.2 Preparation of compound III, namely 5-bromothiophene-2-amine

[0059] Dissolve the raw material 2-bromo...

Embodiment 2

[0071] 2.1 Preparation of compound IV i.e. tert-butyl 5-bromothiophene-2-carbamate

[0072] Dissolve the compound III 5-bromothiophene-2-amine (5g, 28.3mmol) obtained in Example 1 in 40ml of methanol, add 3.54g of triethylamine and 7.6g of di-tert-butyl dicarbonate, and react for 4 hours at 25°C ; After the reaction, add 50ml ethyl acetate and 90ml water for extraction, the extraction temperature is 15-20°C, separate the organic phase, first wash the residual alkali in the system with 1M dilute hydrochloric acid, then wash the excess acid with saturated sodium bicarbonate, and finally saturate Wash with sodium chloride solution, dry the organic phase with sodium sulfate, filter with suction, evaporate the filtrate with a water pump and a rotary evaporator (0.01MPa, 40°C) to remove the organic solvent, and obtain 9 g of crude compound IV. Then it was dissolved in a mixed solvent of 36ml ethyl acetate and 12ml petroleum ether, heated to reflux, and after 40min, when it was slowl...

Embodiment 3

[0088] 3.1 Preparation of Compound V, tert-butyl 5-bromothiophene-2-(N-methylamino)carboxylate

[0089] Compound IV 5-bromothiophene-2-carbamate tert-butyl ester (4g, 14.4mmol) obtained in Example 2 was dissolved in 30ml of tetrahydrofuran, and sodium hydride (60wt%) 0.88 g, after reacting for half an hour, add 3.08g of methyl iodide, continue to react at -5-0°C for 0.5 hours, remove the ice bath, and react at room temperature 20°C for 3 hours; under ice bath (-5-0°C), add saturated chlorine ammonium chloride solution, adjust PH=5~6, add 60mL water and 40ml ethyl acetate for extraction, separate the organic phase, wash with saturated sodium chloride solution, dry the organic phase with sodium sulfate, filter with suction, and use a water pump and rotary evaporator for the filtrate (0.01MPa, 40°C) to distill off the solvent to obtain 5.0g of the crude product of compound V, then add a total of 30mL of ethyl acetate and petroleum ether with a volume ratio of 4:1 to dissolve, hea...

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Abstract

The invention relates to a method for synthesizing 5-N-tert-butyloxycarbonyl-5-N-methylamino-2-thiophenic acid. The method comprises the following steps: obtaining 5-bromo thiophene-2-amine (a compound III) through reduction reaction of 2-bromo-5-nitrothiophene (a compound II), iron powder and ammonium chloride; then obtaining 5-bromo thiophene-2-tert-butyl carbamate (a compound IV) by reacting the compound III with di-tert-butyl dicarbonate; obtaining 5-bromo thiophene-2-(N-methylamino) tert-butyl formate (a compound V) by reacting the compound IV with organic base, methyl iodide or dimethyl sulfate; enabling halogen metal exchange reaction to happen between the compound V and a metal organic reagent under salt bath and nitrogen atmospheres, then using carbon dioxide for replacing nitrogen in a system, and continuously reacting so as to obtain the 5-N-tert-butyloxycarbonyl-5-N-methylamino-2-thiophenic acid. The method has the advantages of short synthetic route, simplicity and convenience to operate, high yield and facilitation of industrialization.

Description

technical field [0001] The present invention relates to the technical field of compound preparation, in particular to the technical field of preparation of raltitrexed intermediates, more specifically, a method for synthesizing 5-N-tert-butoxycarbonyl-5-N-methylamino-2-thiophenecarboxylic acid Methods. Background technique [0002] Raltitrexed is an anti-tumor drug developed by the British company Zeneca, which was first launched in the UK in 1996, and then launched in France, Australia, Spain, Canada and other countries. Raltitrexed is a specific thymidylate synthase inhibitor, mainly used for the treatment of advanced colorectal cancer, clinical trials show that the effect of raltitrexed is better than or equivalent to 5-fluorouracil and leucovorin Useful. And the adverse reaction of 5-fluorouracil and the complicated administration method are avoided. [0003] The compound 5-N-tert-butoxycarbonyl-5-N-methylamino-2-thiophenecarboxylic acid is a key intermediate in the s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/38
CPCC07D333/38
Inventor 张五军孙婧张平李倩康立涛
Owner 安徽尖峰北卡药业有限公司