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Cyclophosphamide synthetic method

A synthetic method and technology of cyclophosphamide, applied in the field of pharmaceutical chemical synthesis, can solve the problems of low yield and many side reactions, and achieve the effects of high yield, simple steps and convenient operation

Active Publication Date: 2018-04-20
SHANDONG BOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In this reaction process, the yield is low, and there are many side reactions

Method used

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  • Cyclophosphamide synthetic method
  • Cyclophosphamide synthetic method

Examples

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Effect test

Embodiment 1

[0030] Example 1. Add 500ml of dichloroethane into a 1000ml reaction flask, slowly add 60g of phosphorus oxychloride, cool down to -5°C, start to add dropwise a mixed solvent of 30g of 3-aminopropanol and 60g of triethylamine, and add dropwise After completing the reaction for 18 hours, a 2-chloro-2-oxo-[1.3.2]oxazaphosphorinane solution was obtained, and the solution was transferred into a pressure reaction flask, 60 g of triethylamine was added, and the temperature was controlled at 20° C. Pass through ammonia gas, keep the pressure not lower than 0.05mpa and react for 2 hours. After the reaction is completed, transfer the reaction solution to a 1000ml reaction bottle, add 200ml of ice-water mixture, stir for 30 minutes, separate the organic phase, and add 200ml of 10% hydrochloric acid solution Wash, separate the organic phase, control the temperature of the water bath to 50°C and concentrate the organic phase to dryness under reduced pressure, add 80ml of purified water, he...

Embodiment 2

[0031] Example 2. Add 500ml of dichloroethane into a 1000ml reaction flask, slowly add 70g of phosphorus oxychloride, cool down to -5°C, start to dropwise add a mixed solvent of 35g of 3-aminopropanol and 69g of triethylamine, and add dropwise After completing the reaction for 18 hours, a 2-chloro-2-oxo-[1.3.2]oxazaphosphorinane solution was obtained, and the solution was transferred to a pressure reaction flask, 69 g of triethylamine was added, and the temperature was controlled at 21° C. Pass through ammonia gas, keep the pressure not lower than 0.05mpa and react for 2 hours. After the reaction is completed, transfer the reaction solution to a 1000ml reaction bottle, add 200ml of ice-water mixture, stir for 30 minutes, separate the organic phase, and add 200ml of 10% hydrochloric acid solution Wash, separate the organic phase, control the temperature of the water bath to 50°C and concentrate the organic phase to dryness under reduced pressure, add 80ml of purified water, heat...

Embodiment 3

[0032] Example 3. Add 500ml of dichloroethane into a 1000ml reaction flask, slowly add 66g of phosphorus oxychloride, cool down to -5°C, start to dropwise add a mixed solvent of 33g of 3-aminopropanol and 60g of triethylamine, dropwise add After completing the reaction for 18 hours, a 2-chloro-2-oxo-[1.3.2]oxazaphosphorinane solution was obtained, and the solution was transferred into a pressure reaction flask, 60 g of triethylamine was added, and the temperature was controlled at 20° C. Pass through ammonia gas, keep the pressure not lower than 0.05mpa and react for 2.3 hours. After the reaction is completed, transfer the reaction solution to a 1000ml reaction bottle, add 200ml of ice-water mixture, stir for 30 minutes, separate the organic phase, and add 200ml of 10% hydrochloric acid solution Wash, separate the organic phase, control the temperature of the water bath to 50°C and concentrate the organic phase to dryness under reduced pressure, add 80ml of purified water, heat...

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Abstract

The invention provides a cyclophosphamide synthetic method. The cyclophosphamide synthetic method is characterized by comprising the following steps: adding dichloroethane into a reaction flask; slowly adding phosphorus oxychloride; starting to drip a 3-amino propanol and triethylamine mixed solvent; performing a reaction after finish of dripping to prepare a 2-chloro-2-oxo-[1,3,2] oxaphosphorinane solution; then transferring the 2-chloro-2-oxo-[1,3,2] oxaphosphorinane solution into the pressure reaction flask; adding triethylamine; controlling the temperature; continuously pumping into ammonia gas; keeping a certain pressure for a reaction; separating an organic phase from a reaction liquid; performing vacuum concentration on the organic phase till the organic phase is dry; adding a solvent; and performing crystallization to obtain cyclophosphamide. The cyclophosphamide synthetic method is high in yield, less in byproduct, simple in step and convenient to operate and facilitates industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a synthesis method of cyclophosphamide. Background technique [0002] Cyclophosphamide (Cyclophosphamide, CTX, C 7 h 15 C l2 N 2 o 2 P, whose chemical name is N,N-bis-(β-chloroethyl)-N'-(3-hydroxypropyl)phosphoramide lactone)) is an excessive Nitrogen mustard derivatives that are hydrolyzed by phosphoramidase or phosphatase to become activated phosphoramidite nitrogen mustards. It has a broad anti-tumor spectrum, and is the first so-called "latent" broad-spectrum anti-tumor drug, which is effective for both leukemia and solid tumors. [0003] This product has no activity in vitro, and it mainly plays its role through the hydrolysis of P450 enzymes in the liver into aldophosphamide and then transported to the tissues to form phosphoramide mustard. Cyclophosphamide can be inactivated by dehydrogenase conversion to carboxyphosphamide or excreted as...

Claims

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Application Information

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IPC IPC(8): C07F9/6584
CPCC07F9/65846
Inventor 赵孝杰苏曼
Owner SHANDONG BOYUAN PHARM CO LTD
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