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Composition gathering NUC-1031 single isomers and preparation method and application thereof

A composition and enrichment technology, which can be used in the preparation of sugar derivatives, drug combinations, organic chemistry methods, etc., can solve problems such as difficulties

Active Publication Date: 2017-03-29
济南高合医疗科技有限公司
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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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  • Composition gathering NUC-1031 single isomers and preparation method and application thereof
  • Composition gathering NUC-1031 single isomers and preparation method and application thereof
  • Composition gathering NUC-1031 single isomers and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Example 1 Preparation of compound (61502):

[0081]

[0082] 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

[0083] Example 2 Preparation of compound (61501b):

[0084]

[0085] 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% (such as figure 1 shown).

Embodiment 3

[0086] Example 3 Preparation of compound (61501c):

[0087]

[0088] 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 composition gathering compounds (Sp-1). The in-vitro tumor cell proliferative activity suppression effect of the composition is remarkably higher than that of NUC-1031 and a compound (Rp-1). The invention further relates to a preparation method of the compound. The preparation method specifically comprises the step that reaction products are subjected to isomer separation and then two steps of chemical synthesis, and the composition containing high-purity compound (Sp-1) is obtained. The method is easy and convenient to implement and low in cost, the purity of the single isomers (Sp-1) in the finally obtained composition is high, and the purity of HPLC reaches 97% or over and further reaches 99% or over. The method is suitable for industrialized production, and the prepared composition can meet clinical research requirements. In addition, the invention further relates to application of the composition and a pharmaceutical composition containing the composition and at least one pharmaceutically acceptable excipient.

Description

technical field [0001] 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 [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, including (Rp-1) and (Sp-1) two single isomers: [0003] , [0004] , . [0005] The specific structure and preparation method of NUC-1031 are disclosed on page 70 of the WO2005012327 specification. Specifically, gemcitabine and benzyl-(benzoyl-L-alanine)-chlor...

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 袁建栋黄仰青缪林峰顾家宁梁朝华王征野孙占莉
Owner 济南高合医疗科技有限公司
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