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5-deoxidized-D-ribose derivative

A technology of derivatives and ribose, applied in the field of 5-deoxy-D-ribose derivatives and its preparation, can solve the problems of unsuitability for industrial production, high cost and low yield

Active Publication Date: 2020-07-07
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] CN102241721A discloses the use of 1-O-acetyl-2,3,5-tri-benzoyl-D-ribose and N-[(n-pentyloxy) Carbonyl] 5-fluorocytosine for the reaction, the 2,3,5-position phenylacyl group of the sugar, especially the introduction of the 5-position large group can effectively avoid the generation of α-isomers, but in the subsequent reaction, the The 5-position deoxygenation reaction of sugar has very low yield and high cost in actual production, and is not suitable for industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Synthesis of Intermediate I

[0068] Add 268g of 5-deoxy-D-ribose and 2680mL of anhydrous methanol into a 5000mL three-necked flask, and stir at room temperature <25°C until the solid is completely dissolved, and the system is a light yellow transparent solution. Add 900 mL of 1% HCl-methanol solution dropwise through a constant pressure funnel; after the dropwise addition, stir for 1 hour. TLC detection, after the reaction was completed, 100 mL of pyridine was added, and stirring was continued for 30 minutes. After suction filtration, the filtrate was evaporated to dryness under reduced pressure to obtain an oily intermediate I with a yield of 98.6% and a HPLC purity of 99.5%.

[0069] Synthesis of Intermediate II

[0070] Under the protection of nitrogen, 292g (1.97mol) of intermediate I, 1600mL chloroform, and 373g (4.7mol) of pyridine were added to a dry 5000mL three-necked flask, and the temperature in the reaction system was controlled between -15°C and 10°C. T...

Embodiment 2

[0074] Synthesis of Intermediate I

[0075] Add 268g of 5-deoxy-D-ribose and 3216mL of anhydrous methanol into a 5000mL three-necked flask, and stir at room temperature <25°C until the solid is completely dissolved, and the system is a light yellow transparent solution. Add 950 mL of 1% HCl-methanol solution dropwise through a constant pressure funnel; after the dropwise addition, stir for 1 hour. TLC detection, after the reaction was completed, 120 mL of pyridine was added, and stirring was continued for 30 minutes. After suction filtration, the solvent was evaporated to dryness under reduced pressure to obtain an oily intermediate I with a yield of 97.9% and a HPLC purity of 99.6%.

[0076] Synthesis of Intermediate II

[0077] Under the protection of nitrogen, 290g (1.96mol) of intermediate I, 1600mL chloroform, and 387.1g (5mol) pyridine were added to a dry 5000mL three-necked flask, and the temperature in the reaction system was controlled between -15°C and 10°C. The m...

Embodiment 3

[0081] Synthesis of Intermediate I

[0082] Add 268g of 5-deoxy-D-ribose and 2680mL of anhydrous methanol into a 5000mL three-necked flask, stir at room temperature <25°C until the solid is completely dissolved, and the system is a light yellow transparent solution. Add 900 mL of 1% sulfuric acid-methanol solution dropwise through a constant pressure funnel; after the dropwise addition is complete, stir for 1 hour. TLC detection, after the reaction was completed, 150 mL of pyridine was added, and stirring was continued for 30 minutes. After suction filtration, the solvent was evaporated to dryness under reduced pressure to obtain an oily intermediate I with a yield of 98.6% and a HPLC purity of 99.6%.

[0083] Synthesis of Intermediate II

[0084] Under nitrogen protection, 292g (1.97mol) of intermediate I, 1600mL chloroform, and 389g (4.9mol) of pyridine were added to a dry 5000mL three-neck flask, and 1169g of Fmoc-Cl was added dropwise to control the temperature in the re...

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Abstract

The invention belongs to the field of medicine synthesis, and provides a 5-deoxidized-D-ribose derivative (III). When capecitabine is prepared by using the derivative (III), the stereoselectivity is good, and the yield is high. The invention also provides a preparation method of the derivative. The preparation method comprises the following steps: a, performing oxygen methylation on a 1-site hydroxyl group of 5-deoxidized-D-ribose; b, protecting a 2-site hydroxyl group and a 3-site hydroxyl group by using Fmoc-; finally protecting the 1-site hydroxyl group by using acetylation. The method is easy and convenient to operate, does not need special equipment, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and specifically relates to a 5-deoxy-D-ribose derivative, its preparation method and application. Background technique [0002] Capecitabine (capecitabine), the chemical name is 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]cytidine, and its structural formula is as shown in Formula I: [0003] [0004] Capecitabine is a new type of 5-fluorocytosine prodrug developed by Roche. It is an oral cytotoxic preparation with selective activity on tumor cells; It reacts and converts into 5-fluorouracil (5-Fu) in tumor cells to play a highly selective anti-tumor effect. It has obvious cell targeting and pharmacokinetic characteristics of simulating continuous 5-Fu intravenous infusion. Solid tumors are more active. Approved by the US FDA in September 1998, it is clinically used to treat advanced primary or metastatic breast cancer that is ineffective to drugs such as paclitaxel and doxorubicin. It ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H1/00C07H3/08C07H19/06
CPCC07H1/00C07H3/08C07H19/06C07H13/12A61P35/00A61K31/7068Y02P20/55
Inventor 张贵民白文钦郑艺
Owner LUNAN PHARMA GROUP CORPORATION
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