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Preparation method and intermediate of nucleoside phosphoramidate prodrug

A technology of benzene sulfonate and camphor sulfonate, applied in the field of medicine, can solve the problems of inability to separate a single isomer, difficulty and the like

Pending 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.
The inventors have tried various methods such as conventional crystallization in the art, silica gel column chromatography, C18 silica gel-bonded reverse phase preparative chromatography, spherical silica gel normal phase preparative chromatography, and chiral column resolution to analyze NUC-1031 isomers. Separation, can not separate a single isomer with a purity of not less than 90%

Method used

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  • Preparation method and intermediate of nucleoside phosphoramidate prodrug
  • Preparation method and intermediate of nucleoside phosphoramidate prodrug
  • Preparation method and intermediate of nucleoside phosphoramidate prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0145] Example 1 Preparation of compound 61502:

[0146]

[0147] 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

[0148] Example 2 Preparation of compound 61501e:

[0149]

[0150] Compound (61502) (47g) was dissolved in methanol (470ml), prepared and purified by C18, 10μm packing preparation column, the preparation method is as follows Table 1: the mobile phase was methanol, 5‰ acetic acid / water, and the ratio of methanol increased from 70% to 85% % gradient elution.

[0151] Table 1: Preparation methods

[0152]

[0153] The eluate was collected in sections to obtain 12 g of compound (61501e), yield: 28%, HPLC: 99.8%.

Embodiment 3

[0154] Example 3 Preparation of compound 61501b:

[0155]

[0156] 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 (48.8g), with a yield of 40.6% , HPLC: 100% (such as figure 1 shown).

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Abstract

The present invention provides a new preparation method and an intermediate of a nucleoside phosphoramidate prodrug, specifically a first-step reaction product is subjected to isomer separation, and two-step chemical synthesis is performed to prepare the high-purity compound (Sp-1). According to the present invention, the method has characteristics of simple operation and low cost; the purity of the finally prepared single isomer (Sp-1) is high, and the HPLC purity is more than 97% and further more than 99%; and the method is suitable for industrial production and can meet the needs of clinical research. In addition, the present invention further provides a key intermediate phosphorus reagent for preparing the high-purity compound Sp-1, and a preparation method thereof.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method and an intermediate of nucleoside phosphoramidate prodrugs. 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] 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)-chlorophosphoric acid ester are used at a molar ratio of 1:3. In the presence of conditions, THF / pyridine was used as a solvent to react for 2 hours to obtain a crude product, which was sep...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/10C07H1/00C07F9/24
CPCC07F9/24C07H1/02C07H19/10A61P35/00Y02P20/55C07H1/00
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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