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Capecitabine intermediate

A technology for capecitabine and intermediates, which is applied in the field of capecitabine intermediates and preparations, and can solve the problems of unstable 5-fluorocytosine protective agent, high cost, and low conversion rate of 5-fluorocytosine

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

CN102190695A discloses a preparation method of 5'-deoxy-2', 3'-diacetyl-5-fluorocytidine, and the 5-fluorocytosine protective agent is unstable, causing 5-fluorocytosine to generate impurity N-iso Constructs, so that the conversion rate of 5-fluorocytosine is low
CN102241721 discloses to react with 1-O-acetyl-2,3,5-tri-benzoyl-D-ribose and N-[(n-pentyloxy)carbonyl]5-fluorocytosine, the 2,3 , the 5-position phenylacyl group, especially the introduction of the 5-position large group can effectively avoid the generation of α-isomers, but in the subsequent reaction, the 5-position deoxygenation reaction of the sugar is required, and the yield in actual production is very low. High cost, not suitable for industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Synthesis of 5-Fluorocytosine Ⅳ Activated by Hexamethyldisilazane

[0072] In a 3000mL three-neck flask, add 258g (2mol) of 5-fluorocytosine, 728mL of toluene, 421g (2.6mol) of HMDS, 14.3g (0.13mol) of trimethylchlorosilane, stir and heat up to 100°C, and react 3-4 After the reaction was completed, the solvent was evaporated under reduced pressure to dryness to obtain white solid particles with a yield of 90%. used directly in the next reaction.

[0073] Synthesis of Capecitabine Intermediate Ⅴ

[0074] Under nitrogen protection, add 620 g (1 mol) of 5-deoxy-D-ribose derivative (Ⅲ) and 357.5 g of hexamethyldisilazane-activated 5-azacytosine IV in a 5000 mL three-necked flask (1.3mol) of the acetonitrile suspension prepared, then add 1000mL of acetonitrile, under stirring, the reaction system is kept at 5 ℃, add dropwise a solution of 200gTMSOTf (0.9mol) and 400mL of acetonitrile, TLC detection of the reaction process; after the reaction, add 1.5L chloroform, wash twi...

Embodiment 2

[0076] Synthesis of 5-Fluorocytosine Ⅳ Activated by Hexamethyldisilazane

[0077] Preparation reaction is with embodiment 1

[0078] Synthesis of Capecitabine Intermediate Ⅴ

[0079] Under nitrogen protection, add 620 g (1 mol) of 5-deoxy-D-ribose derivative (Ⅲ) and 412.5 g of hexamethyldisilazane-activated 5-azacytosine IV in a 5000 mL three-necked flask (1.5mol) of the acetonitrile suspension prepared, then add 1000mL of acetonitrile, under stirring, the reaction system is kept at 0 ℃, dropwise add a solution of 288.6gTMSOTf (1.3mol) and 500mL of acetonitrile, TLC detection of the reaction process; after the reaction, add to the reaction solution Add 1.5 L of chloroform, wash twice with 2 L of water; adjust the pH to 7.5 with saturated sodium bicarbonate solution, let stand, and separate the liquids; wash the organic phase with 2 L of saturated saline; dry the organic phase with anhydrous sodium sulfate for 3 to 4 hours ; Filtrate, evaporate the solvent under reduced press...

Embodiment 3

[0081] Synthesis of 5-Fluorocytosine Ⅳ Activated by Hexamethyldisilazane

[0082] Preparation reaction is with embodiment 1

[0083] Synthesis of Capecitabine Intermediate Ⅴ

[0084] Under nitrogen protection, in a 5000mL three-necked flask, add 620g (1mol) of 5-deoxy-D-ribose derivative (Ⅲ) and 385g (1.4 mol) of acetonitrile suspension prepared by adding 1000mL of acetonitrile, under stirring, the reaction system was kept at 5°C, and a solution of 222.2gTMSOTf (1.0mol) and 500mL of acetonitrile was added dropwise, and the reaction progress was detected by TLC; after the reaction was completed, 1.5 L chloroform, wash twice with 2L water; adjust the pH to 7.5 with saturated sodium bicarbonate solution, let stand, and separate the liquid; wash the organic phase with 2L saturated brine; dry the organic phase with anhydrous sodium sulfate for 3 to 4 hours; filter , the solvent was evaporated under reduced pressure to obtain a pale yellow foamy solid, which was dissolved by addin...

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Abstract

The invention belongs to the field of medicine synthesis, and discloses a capecitabine intermediate (V) and a preparation method thereof. The preparation method comprises the step of under the actionof a catalyst, enabling derivatives (III) of 5-deoxy-D-ribose of which 2,3-hydroxyl is protected with Fmoc- and activated 5-flucytosine (IV) to be coupled to obtain the capecitabine intermediate (V).The method is simple and easy to operate, simple in post-treatment, high in product purity and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a capecitabine intermediate and a preparation method. 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 was launched in ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/06C07H1/00
CPCC07H19/06C07H1/00C07B2200/07Y02P20/55
Inventor 白文钦王友国
Owner LUNAN PHARMA GROUP CORPORATION
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