3-sulfhydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride crystal and preparation method thereof

An azetidine and thiazoline technology, applied in the field of organic drug synthesis, can solve the problems of easy moisture absorption, unstable chemical properties, unfavorable preservation and the like, and achieve the effects of less impurities, good quality and favorable preservation

Active Publication Date: 2013-03-06
天津市医药集团技术发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] 3-Mercapto-1-(1,3-thiazolin-2-yl)-azetidine hydrochloride, which we synthesized by referring to known methods, is chemically unstable and easy to absorb moisture, which is not conducive to storage

Method used

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  • 3-sulfhydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride crystal and preparation method thereof
  • 3-sulfhydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride crystal and preparation method thereof
  • 3-sulfhydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride crystal and preparation method thereof

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Experimental program
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Effect test

Embodiment 1

[0040]

[0041] Add 20.8g (60mmol) bis-[1-(1,3-thiazoline-2-yl) azetidin-3-yl] disulfide (compound Ⅱ) in a 500ml three-necked flask, 36.4g ( 180mmol) tributylphosphine, 6.5ml (360mmol) water, 42ml (500mmol) concentrated hydrochloric acid, 200ml Virahol, stirred at 50°C for 8 hours, evaporated the solvent to dryness, obtained about 48g oil, added 455ml acetonitrile / isopropyl ether ( Volume ratio 1 / 12), stirred for 1 hour at 20°C, filtered to obtain 23.8g of white solid, see X-ray powder diffraction pattern figure 1 , yield 94%, melting point: 119-121.5°C.

Embodiment 2

[0043]In a 250ml three-necked flask, add 8.7g (25mmol) compound II, 17.7g (87.5mmol) tributylphosphine, 3.4ml (187.5mmol) water, 19ml (227.5mmol) concentrated hydrochloric acid, 120ml isopropanol, and stir at 55°C After 7 hours, the solvent was evaporated to dryness to obtain about 18g of oily substance, and 160ml of methanol / dichloromethane (volume ratio 1 / 10) was added, stirred at 10°C for 1 hour, filtered, and 10.1g of white solid was obtained by filtration, X-ray powder diffraction pattern See figure 1 , yield 95%, melting point: 119.5-121.5°C.

Embodiment 3

[0045] In a 250ml three-necked flask, add 5.2g (15mmol) compound II, 12.5g (62mmol) tributylphosphine, 2.6ml (144mmol) water, 13ml (155mmol) concentrated hydrochloric acid, 95ml isopropanol, and stir at 45°C for 7 hours. Evaporate the solvent to dryness to obtain about 10g of oil, add 75ml of methanol / methyl isobutyl ketone (volume ratio 1 / 3), stir at 10°C for 1 hour, filter to obtain 5.8g of white solid, X-ray powder diffraction pattern See figure 1 , yield 93%, melting point: 119-121°C.

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Abstract

The invention provides a 3-sulfhydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride crystal. X-ray powder diffraction detection indicates that a characteristic absorption peak exists at a diffraction angle (2 theta), as shown in Figure 1. The invention also provides a preparation method of the 3-sulfhydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride crystal, which comprises the following steps: adding grease containing 3-sulfhydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride into one or two mixed solvents, and crystallizing at 0-40 DEG C; and filtering to obtain the crystalline 3-sulfhydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride. The 3-sulfhydryl-1-(1,3-thiazoline-2-yl)-azetidine hydrochloride crystal provided by the invention has a unique crystal shape; and the crystal has the characteristics of high purity and stability and the like, and is beneficial to preservation.

Description

technical field [0001] The invention belongs to the technical field of organic drug synthesis, and relates to crystalline azetidine compounds and a preparation method thereof, especially 3-mercapto-1-(1,3-thiazoline-2-yl)-azetidine Hydrochloride crystals and methods for their preparation. Background technique [0002] In recent years, as pharmaceutical intermediates, quaternary azetidine compounds have been used in group modification and structural modification of various drugs, and a large number of new compounds have been successfully prepared, many of which have good pharmaceutical activity. [0003] Crystalline form of 3-mercapto-1-(1,3-thiazolin-2-yl)-azetidine hydrochloride (Ⅰ) is an important intermediate of tibipenem, which is used for condensation and desorption of MAP Preparation of carbapenem antibacterial drug tibipenem by removing carboxyl protection and esterification. [0004] [0005] Tebipenem Pivoxil (Tebipenem Pivoxil) is the first marketed oral carba...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/04C07D477/06C07D477/20
Inventor 周永健赵一飞边颖苏艳华宫雪冯昱
Owner 天津市医药集团技术发展有限公司
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