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Technological synthesis method of 1-amino cyclopropyl acetylene

A synthesis method and amino ring technology, which are applied in the preparation of amino compounds, chemical instruments and methods, and the preparation of carbamic acid derivatives, etc., can solve the problems of cost increase, expensive dimethyl phosphonate, unfavorable market competition, etc., and achieve cost reduction. The effect of low cost, high safety, and simple post-processing

Inactive Publication Date: 2016-02-24
SHANGHAI HAOYUAN CHEMEXPRESS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Patent WO2015095227 reports another synthetic method, which obtains 1-aminocyclopropyne through the Seyferth-Gilbert Homologation reaction, using the Bestmann-Ohira reagent (1-diazo-2-oxopropyl) dimethyl phosphonate The price is very expensive and the cost increases, which is not conducive to market competition

Method used

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  • Technological synthesis method of 1-amino cyclopropyl acetylene
  • Technological synthesis method of 1-amino cyclopropyl acetylene
  • Technological synthesis method of 1-amino cyclopropyl acetylene

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041]

[0042] Add compound 1A (7g, 0.037mol, 1eq) and dichloromethane (50mL) to 500mL there-necked flask, add 4-OH-TEMPO (0.06g, 0.37mmol, 0.01eq), add saturated NaHCO 3 Aqueous solution (200mL) was cooled to 0°C, 10% NaClO aqueous solution (50g, 0.067mol, 1.8eq) was added dropwise, the temperature was naturally raised to room temperature, and reacted for 1h. Add 100 mL of water, extract with dichloromethane (150 mL*2), combine the organic phases, and wash once with water (200 mL), concentrate the organic phase to obtain compound 2A as a light yellow solid (6.3 g, yield: 91%, purity: 94.2% )

[0043] 1 HNMR (400MHz, CDCl 3 ): δ=9.181(s, 1H), 5.142(t, 1H), 1.483(m, 2H), 1.413(s, 9H), 1.270(m, 2H)ppm; ESI / MS: m / z=186( M+H)+.

Embodiment 2

[0045]

[0046] Add triphenylphosphine (45.4g, 0.17mol, 4eq) and DCM (255g) into a 250mL three-necked flask, cool the reaction solution to 0-5°C, add CBr 4 (28.6g, 0.086mol, 2eq), the color of the solution changed from colorless to red, and a solid precipitated out after 20min. Compound 2A (8 g, 0.043 mol, 1 eq) was added in 4 batches, the exotherm was obvious, and the reaction was carried out at 0°C for 0.5 h. The solid was removed by filtration, concentrated, brushed with silica gel, and the eluent was concentrated to obtain 13.7 g of a light yellow solid.

[0047] 1 HNMR (400MHz, CDCl 3):δ=6.687(s,1H), 1.453(s,9H), 1.288(m,2H), 1.253(m,2H)ppm; ESI / MS: m / z=342(M+H)+.

[0048] Add the light yellow solid to THF (270mL), cool down to -78°C, add 2.5Mn-BuLi / hexane solution (53mL, 0.130mol, 3eq) dropwise, react at -78°C for 30min, then slowly raise the temperature to -40°C, React for 30 minutes. Water (100 mL) was slowly added dropwise at -40°C, the temperature was slowly ...

Embodiment 3

[0051]

[0052] Compound 3A (2.9g, 0.016mol, 1eq) and 7.1M HCl / MTBE solution (25mL, 0.178mol, 11eq) were added into a 100mL three-necked flask, and stirred overnight at room temperature. Filtration, the filter cake was rinsed with MTBE (10mL), the solid was collected and dried to obtain compound 4 as a white solid (1.7g, 90%, purity: 99%)

[0053] 1 HNMR (400MHz, CDCl 3 ): δ=9.082(s, 3H), 3.562(s, 1H), 1.331(t, 2H), 1.126(t, 2H) ppm; ESI / MS: m / z=82(M+H)+.

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Abstract

The invention discloses a technological synthesis method of 1-amino cyclopropyl acetylene. The method includes: taking compound 1 as the starting material, and carrying out oxidation, Corey-Fuchs reaction, and amino protection group removal so as to obtain the 1-amino cyclopropyl acetylene. The reagents and raw materials used by the method provided by the invention are cheap and easily available, and low in cost. With the advantages of high reaction safety, simple operation and high yield, the method is suitable for industrial scale-up production. (with the synthesis process shown as the specification).

Description

Technical field: [0001] The invention relates to a process synthesis method of a pharmaceutical intermediate 1-aminocyclopropylacetylene, which belongs to the field of organic synthesis. Background technique: [0002] 1-Aminocyclopropylacetylene is a useful small molecular compound, which contains two active reactive sites, and can be used as an important small molecule building group for drug molecules. In recent years, 1-aminocyclopropylacetylene has attracted more and more attention, and its application in active pharmaceutical molecules has gradually increased. In 2014, Merck’s patent WO2014066490 disclosed a new compound with good activity in treating neuropathic pain disorders, with a structural formula such as formula 1; in 2015, Taisho’s patent WO2015056799 disclosed a new compound with good antibacterial Activity, structural formula such as formula 2, has introduced 1-aminocyclopropyl acetylene. Therefore, 1-aminocyclopropylacetylene has broad application prospect...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/40C07C209/62
CPCY02P20/55C07C209/62C07C231/12C07C269/06C07C211/40C07C271/24C07C233/06C07C233/32
Inventor 宋敬威杨成武王河清曹丹李硕梁高强郑保富
Owner SHANGHAI HAOYUAN CHEMEXPRESS
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