A kind of preparation method of 2-(1-(tert-butoxycarbonyl) azetidinyl-3-) cyclopropyl formic acid

An azetidine, cyclopropylcarboxylic acid technology, applied in the direction of organic chemistry and the like, can solve the problems such as no suitable industrial synthesis method, and achieve the effects of avoiding inflammability and explosion, convenient operation and novel reaction

Active Publication Date: 2018-10-16
武汉药明康德新药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Mainly solve the technical problem that there is no suitable industrial synthesis method at present

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0010] Example 1: a. Dissolve compound 1 (100 g, 0.5 mol) in tetrahydrofuran (2 L), add sodium hydride (36 g, 1.5 mol) at 10°C to 20°C and stir for 30 minutes, then add methyl iodide (142 g, 1.0 mol) was added dropwise to the reaction system at 5°C to 10°C. The reaction system was stirred at 15°C to 25°C for 16 hours. TLC (petroleum ether / ethyl acetate=1 / 1, volume ratio, the same below) showed that the reaction was complete. The reaction system was poured into ice water (2 L) and extracted with ethyl acetate (1.5 L x 3). The obtained organic phases were combined, washed with saturated brine, dried and filtered, and concentrated under reduced pressure to obtain compound 2 (100 g), with a yield of 95%.

[0011] δ4.328-4.315 (m, 2H), 4.100-4.070 (m, 2H), 3.68 (s, 3H), 3.070-3.050 (m, 1H), 1.380 (s, 9H).

[0012] b. Suspend lithium aluminum hydride (27 g, 0.70 mol) in THF, control the reaction system at -10°C to 0°C, add compound 2 (100 g, 0.47 mol) in tetrahydrofuran (200 mL) ...

Embodiment 2

[0021] Example 2: a. Dissolve compound 1 (500 g, 2.5 mol) in tetrahydrofuran (8 L), add NaH (180 g, 7.5 mol) at 10°C to 20°C and stir for 30 minutes, then MeI (710 g, 5.0 mol) into the reaction system dropwise at 5°C to 10°C. The reaction system was stirred at 15°C to 25°C for 16 hours. TLC (petroleum ether / ethyl acetate = 1 / 1) showed the reaction was complete. The reaction system was poured into ice water (8 L) and extracted with ethyl acetate (4 L x 3). The obtained organic phases were combined, washed with saturated brine, dried and filtered, and concentrated under reduced pressure to obtain compound 2 (500 g), with a yield of 95%.

[0022] δ4.328-4.315 (m, 2H), 4.100-4.070 (m, 2H), 3.68 (s, 3H), 3.070-3.050 (m, 1H), 1.380 (s, 9H).

[0023] b. Suspend lithium aluminum hydride (135 g, 3.5 mol) in tetrahydrofuran, control the reaction system at -10°C to 0°C, add compound 2 (500 g, 2.35 mol) in tetrahydrofuran (800 mL) dropwise to in the reaction system. The reaction was ...

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Abstract

The invention relates to a preparation method of 2-(1-(tertbutyloxycarbonyl)azacyclobutyl-3-yl)cyclopropanecarboxylic acid. The preparation method solves the problem that the existing appropriate 2-(1-(tertbutyloxycarbonyl)azacyclobutyl-3-yl)cyclopropanecarboxylic acid industrial synthesis method does not exist. The preparation method comprises that 1, a compound 1 and iodomethane undergo a reaction under alkaline conditions to produce a compound 2, 2, the compound 2 is treated by sodium borohydride to form a compound 3, 3, the compound 3 is oxidized by Dess-Martin periodinane to form a compound 4, 4, the compound 4 and a compound 5 undergo a reaction to produce a compound 6, 5, the compound 6 and trimethylsulfoxonium iodide undergo a reaction to produce a compound 7, and 6, the compound 7 is hydrolyzed under alkaline conditions to form an end product compound 8. The reaction equation is shown in the following description. The 2-(1-(tertbutyloxycarbonyl)azacyclobutyl-3-yl)cyclopropanecarboxylic acid is a useful intermediate or product for synthesis of many drugs.

Description

technical field [0001] The invention relates to a synthesis method of 2-(1-(tert-butoxycarbonyl)azetidinyl-3-)cyclopropylcarboxylic acid (CAS: 1391732-39-0). Background technique [0002] 2-(1-(tert-butoxycarbonyl)azetidinyl-3-)cyclopropylcarboxylic acid and related derivatives are widely used in medicinal chemistry and organic synthesis. At present, the synthesis of 2-(1-(tert-butoxycarbonyl)azetidinyl-3-)cyclopropyl formic acid has not been reported in the literature. Compounds with similar structures use Grignard reagents and ketones to introduce cyclopropyl structures. Addition method. This method has many problems such as long route, low yield, and unfavorable amplification. Therefore, it is necessary to develop an industrial synthetic method with readily available raw materials, convenient operation, easy control of the reaction, and suitable overall yield. Contents of the invention [0003] The purpose of this invention is to develop a kind of 2-(1-(tert-butoxyca...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D205/04
Inventor 沈万军毕增梁王海慧万晓军彭雁南程圆邵文庆陈玉燕袁晓斌于凌波李磊哈维杰柴艳萍周乐乐吴璇朱喜雯马坤艳陈远丽何振民马汝建
Owner 武汉药明康德新药开发有限公司
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