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Preparing method of gemcitabine intermediate

A gemcitabine and intermediate technology, applied in the field of pharmaceutical intermediate synthesis, can solve the problems of large operation difficulty coefficient, out-of-control reaction, low product yield, etc., and achieve the effects of avoiding severe reaction, good synergy and high product yield.

Active Publication Date: 2018-09-04
江苏八巨药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, although the reaction is completed by mixing the raw materials into the reactor, because the Reformatsky reaction is violent, the requirements for temperature and operation are particularly high. The addition method is also easy to cause safety hazards such as reaction out of control and explosion, and the operation difficulty coefficient is relatively large, and the product yield of the reaction is also low, which is not conducive to industrial production

Method used

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  • Preparing method of gemcitabine intermediate
  • Preparing method of gemcitabine intermediate
  • Preparing method of gemcitabine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The active zinc powder in this embodiment can be activated by the action of zinc in hydrochloric acid.

[0028] Put 70g of tetrahydrofuran and 40g of activated zinc powder into the clean reactor, stir evenly and raise the temperature to 40-42°C, start adding 74g of ethyl difluorobromoacetate dropwise, and control the temperature at 40-42°C after the dropwise addition Insulate the reaction to obtain the organic zinc intermediate after the reaction is complete, let it stand, take the supernatant (reaction solution containing the organic zinc intermediate), add 0.01 g of iodine particles, and set aside.

[0029] combine figure 1The equipment flow diagram shows that the organic zinc intermediate reaction liquid obtained in the previous step is transferred into the corresponding organic zinc intermediate reaction liquid storage tank, and then the organic zinc intermediate reaction liquid is pumped into the microchannel reactor by a constant flow pump. Another constant flow ...

Embodiment 2

[0031] The active zinc powder in this embodiment can be activated by the action of zinc in hydrochloric acid.

[0032] Put 80g of tetrahydrofuran and 40g of activated zinc powder into a clean reactor, stir evenly and raise the temperature to 45°C, start to add 78g of ethyl difluorobromoacetate dropwise, and control the temperature at 43-45°C for heat preservation reaction after the dropwise addition , to obtain the organic zinc intermediate after the reaction is complete, let it stand, get the supernatant (containing the organic zinc intermediate reaction solution), add 0.008g of iodine particles, and set aside.

[0033] to combine figure 1 The equipment flow diagram shows that the organic zinc intermediate reaction liquid obtained in the previous step is transferred into the corresponding organic zinc intermediate reaction liquid storage tank, and then the organic zinc intermediate reaction liquid is pumped into the microchannel reactor by a constant flow pump. Another const...

Embodiment 3

[0035] The active zinc powder in this embodiment can be activated by the action of zinc in hydrochloric acid.

[0036] Put 100g of tetrahydrofuran and 40g of activated zinc powder into a clean reactor, stir evenly and raise the temperature to 42°C, start to add 75g of ethyl difluorobromoacetate dropwise, after the dropwise addition, control the temperature at 41-43°C for heat preservation reaction , after the reaction is complete, the organozinc intermediate is obtained, let it stand, get the supernatant (the reaction solution containing the organozinc intermediate), add 0.023g of iodine particles, and set aside.

[0037] The reaction solution of the organozinc intermediate obtained in the previous step is pumped into the microchannel reactor with a constant-flow pump, and simultaneously the tetrahydrofuran solution (containing 45g acetonylidene glyceraldehyde, 80g tetrahydrofuran) of acetonylidene glyceraldehyde is pumped with another constant-flow pump The two solutions are ...

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Abstract

The invention relates to a preparing method of a gemcitabine intermediate, and belongs to the technical field of medicine intermediate synthesis. In order to solve the problems that an existing methodis violent in reaction and not stable in yield, the preparing method of the gemcitabine intermediate is provided. The method includes the steps of adding iodine powder to an organic zinc intermediate-state reaction solution obtained through the reaction of ethyl bromodifluoroacetate and activated zinc powder in a first solvent, adding acetonylidene glyceraldehyde to a second solvent to obtain a corresponding acetonylidene glyceraldehyde solution, synchronous pumping the organic zinc intermediate-state reaction solution and the acetonylidene glyceraldehyde solution into a micro-channel reactorfor a condensation reaction to obtain outflow liquid, and conducting acidification to obtain the corresponding product (gemcitabine intermediate). The problem of the violent reaction can be effectively overcome, and the effects of mild reaction and high product yield are achieved.

Description

technical field [0001] The invention relates to a preparation method of a gemcitabine intermediate, belonging to the technical field of synthesis of pharmaceutical intermediates. Background technique [0002] Gemcitabine hydrochloride is a difluoronucleoside antimetabolite anticancer drug that destroys cell replication. It has a good inhibitory effect on human leukocytes and human tumor xenografts. As an important intermediate of gemcitabine, furanose plays a key role in the synthesis process. In the prior art, the Reformatsky reaction is usually used to prepare the key intermediate, and acetonide and ethyl difluorobromoacetate are mixed together in a one-pot method under the catalysis of metal zinc to react in a reactor. Such as Chinese patent application (publication number: CN102617678B) discloses a kind of preparation method of gemcitabine hydrochloride, specifically discloses the preparation method of this key intermediate, by making BrF in an inert solvent 2 CCOOC 2...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D317/30
Inventor 王福军汪东海刘玉坤卢文才付自强
Owner 江苏八巨药业有限公司
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