Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Preparation method and application of NUC-1031 single isomer

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

Inactive Publication Date: 2017-03-08
江苏万高药业股份有限公司
View PDF3 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] At present, there is no report on the preparation method of a single isomer of NUC-1031 in the prior art. Since the two corresponding isomers 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method and application of NUC-1031 single isomer
  • Preparation method and application of NUC-1031 single isomer
  • Preparation method and application of NUC-1031 single isomer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Preparation of Example 1 compound (61502):

[0082]

[0083] 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

[0084] Preparation of Example 2 Compound (61501b):

[0085]

[0086] 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

[0087] The preparation of embodiment 3 compound (61501c):

[0088]

[0089] 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%.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention relates to a preparation method and an application of an NUC-1031 single isomer. The method comprises specific steps as follows: a reaction product in the first step is subjected to isomer separation and then subjected to two-step chemical synthesis, and composition containing a high-purity compound (Sp-1) is prepared. The method is simple to operate and low in cost, the purity of the single isomer (Sp-1) contained in the finally prepared composition is high, and HPLC purity is 97% or higher and further reaches 99% or higher; the method is suitable for industrial production, and the prepared composition can meet clinical research demands. Besides, the invention further relates to an application of the composition and pharmaceutical composition containing the composition and at least one pharmaceutically acceptable excipient.

Description

[0001] The present invention is a divisional application of a patent with the application number 201510586447.6, the filing 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 the foll...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07H19/10C07H1/00A61K31/7068A61P35/00
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 江苏万高药业股份有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products