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Phosphoramidate compound and preparation method and crystal thereof

A compound and crystal technology, applied in the field of medicinal chemistry, can solve the problems such as the preparation method and crystal form of compound 61501b that are not reported in the literature

Inactive Publication Date: 2017-03-29
江苏万高药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In the prior art, there are relatively few studies on the preparation method and crystal form of compound 61501b. Only the structure of compound 61501b is disclosed in WO2012075140. At present, there are no literature reports on the preparation method and crystal form of compound 61501b.

Method used

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  • Phosphoramidate compound and preparation method and crystal thereof
  • Phosphoramidate compound and preparation method and crystal thereof
  • Phosphoramidate compound and preparation method and crystal thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Example 1 Preparation of Compound 61502

[0073] To a solution of 61501h (20g) in dichloromethane (60ml) was added 61501g (20.6g) at -80°C, followed by a solution of 19.3g triethylamine (diluted in 20ml dichloromethane). The mixture was stirred overnight at room temperature. To the mixture was added 61501f, followed by the addition of 19.3g triethylamine (diluted with 20ml dichloromethane) solution, and the mixture was stirred at room temperature for 4h. The mixture was directly precipitated, and the residue was dissolved in ethyl acetate (200ml) and water (400ml). After separating the ethyl acetate, wash the aqueous phase with ethyl acetate (2*100ml), combine the ethyl acetate phase, and wash the acetic acid with brine ethyl ether phase and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off to obtain the target compound (61502), which was directly used in the next step of purification.

Embodiment 2

[0074] Example 2 Preparation of compound 61501b:

[0075] Compound 61502 (120g) was dissolved in ethyl acetate (240ml), stirred continuously, and petroleum ether (720ml) was slowly added dropwise at room temperature, crystals were precipitated, and the filtrate was removed by filtration to obtain compound 61501b (49.5g), with a yield of 41.2%. Its XRPD spectrum is as figure 1 Shown, HPLC is 100% (such as figure 2 shown).

Embodiment 3

[0076] Example 3 Preparation of compound 61501c:

[0077]

[0078] Sodium carbonate (35.4g) was added to a mixed solution of compound 61501d (20g) in tetrahydrofuran (200ml) and water (100ml) at room temperature, followed by di-tert-butyl dicarbonate (17.5g), and stirred at room temperature until the reaction was complete. The mixture was extracted with ethyl acetate (3*200ml), and the combined ethyl acetates were washed with brine and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel chromatography (2.5%~10% methanol / dichloromethane) to obtain 18 g of compound (61501c), yield: 67%.

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Abstract

The invention discloses a phosphoramidate compound and a preparation method and crystal thereof, and relates to a composition enriched with a compound 61501b, wherein the purity of the compound 61501b is 95% or above. The compound has the prominent advantage of preparing high-purity compound Sp-1. In addition, the invention provides a preparation method of the composition enriched with the compound 61501b. According to the method, a crystallization method is adopted for separation and purification, operation is easy and convenient, the reproducibility is good, the purity of the compound 61501b in the prepared compound is high, and the quality is high. The invention further relates to a novel crystal form of the compound 61501b.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a phosphoramidate compound and its preparation method and crystal form. The present invention also relates to a composition of a phosphoramidate compound containing a high-purity single isomer, its preparation method, its crystal form and its Use in the preparation of anti-HCV compounds. Background technique [0002] NUC-1031 is a gemcitabine prodrug, developed by NuCana BioMed, currently in clinical phase II, for the treatment of advanced solid tumors, pancreatic cancer, breast cancer and other cancers. The CAS of NUC-1031 is 840506-29-8, which has the structure shown in the following formula 1, the following formula R p -1 and S p -1 are enantiomers of P of NUC-1031 respectively: [0003] , [0004] , . [0005] WO2005012327 discloses a large number of phosphoramidate nucleoside prodrugs, and these phosphoramidate nucleoside prodrugs mostly exist in the for...

Claims

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Application Information

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IPC IPC(8): C07F9/24C07F9/6558
CPCC07H19/10C07H1/02C07H1/00C07H19/06C07H19/073C07H19/16C07B2200/07C07B2200/13C07F9/025C07F9/222
Inventor 袁建栋黄仰青缪林峰顾家宁梁朝华王征野孙占莉
Owner 江苏万高药业股份有限公司
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