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Crystal form of NUC-1031 single isomer and preparation method thereof

A technology of sp-1 and rp-1, which is applied in the field of compound Sp-1 in crystal form and its preparation, and can solve problems such as difficulties

Active Publication Date: 2021-01-01
JINAN GAOHE MEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] At present, there is no report on the preparation method of a single isomer of NUC-1031 in the prior art. Since the two enantiomers of chiral P in the molecular structure of NUC-1031 are very similar in structure and very close in polarity, by NUC-1031 It becomes very difficult to separate a high-purity single isomer from a mixture, and it is even more difficult to take into account both purity and yield during the purification process.

Method used

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  • Crystal form of NUC-1031 single isomer and preparation method thereof
  • Crystal form of NUC-1031 single isomer and preparation method thereof
  • Crystal form of NUC-1031 single isomer and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] The preparation of embodiment 1 compound (61502):

[0083]

[0084] 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 19.3 g of triethylamine (diluted in 20 ml of dichloromethane) solution, and the mixture was stirred at room temperature for 4 h. The mixture was directly precipitated, and the residue was dissolved in ethyl acetate (200ml) and water (400ml). After separating the ethyl acetate, the aqueous phase was washed with ethyl acetate (2*100ml), the ethyl acetate phase was combined, and the acetic acid was washed 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

[0085] Preparation of Example 2 Compound (61501b):

[0086]

[0087] 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% , HPLC: 100.0% (as figure 1 shown).

Embodiment 3

[0088] The preparation of embodiment 3 compound (61501c):

[0089]

[0090] Add sodium carbonate (35.4g) to a mixed solution of compound (61501d) (20g) in tetrahydrofuran (200ml) and water (100ml) at room temperature, then add di-tert-butyl dicarbonate (17.5g), and stir at room temperature until the reaction is 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 relates to a crystal form of a compound (Sp-1) and a preparation method thereof. The preparation method specifically comprises the following steps of: carrying out isomer separation on areaction product in the first step; and then carrying out two-step chemical synthesis to prepare a composition containing the high-purity compound (Sp-1). The method is simple and convenient to operate and low in cost; the finally prepared single isomer (Sp-1) has high purity and the HPLC (high Performance liquid chromatography) purity is 97 percent or more and is further 99 percent or more; andthe method is suitable for industrial production and the prepared composition can meet the requirements of clinical researches.

Description

[0001] This application is a divisional application with the application number CN201510586447.6, the application date is September 16, 2015, and the title of the invention is "a composition enriched with NUC-1031 single isomer and its preparation method and application" . technical field [0002] The present invention relates to a composition enriched in NUC-1031 single isomer and its preparation method, and also relates to the use of the composition and a pharmaceutical composition containing the composition and at least one pharmaceutically acceptable excipient , the present invention also relates to compound Sp-1 in crystalline form and a process for its preparation. Background technique [0003] 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 Formula 1 below, i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7068C07H19/10C07H1/00C07H1/06A61P35/00
CPCA61K31/7068C07H1/00C07H19/10C07B2200/13C07H1/02A61P35/00Y02P20/55C07H19/06
Inventor 袁建栋黄仰青顾家宁梁朝华王征野
Owner JINAN GAOHE MEDICAL TECH CO LTD
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