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Preparation method of anticancer drug capable of destroying cell replication

A technology that destroys cells and formulas, applied in the field of pharmacy, can solve the problems of DNA damage, hidden dangers, equipment corrosion, etc., and achieve the effect of more process, convenient operation and environmental friendliness.

Inactive Publication Date: 2016-06-22
陈欣
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Not only there are certain safety hazards in operation, but also there is serious corrosion to the equipment.
Although Chinese patent 201110334019.6 uses a tetrahydropyran ring to protect the two hydroxyl groups on the glycosyl of the gemcitabine intermediate, p-toluenesulfonic acid is used as a catalyst for the docking reaction between the glycosyl and cytosine, and the residue of p-toluenesulfonic acid can lead to Later alcohol reagents react to generate tosylate, p-toluenesulfonate is a genotoxic impurity that is potentially destructive to DNA, so try to avoid using such substances in the process

Method used

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  • Preparation method of anticancer drug capable of destroying cell replication
  • Preparation method of anticancer drug capable of destroying cell replication
  • Preparation method of anticancer drug capable of destroying cell replication

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Put cytosine (22.2g, 0.2mol), hexamethyldisilazane (84mL, 0.4mol), and 0.10g ammonium sulfate in a 500mL three-neck flask, stir, heat and reflux until cytosine is completely dissolved and clarified, and then continue the insulation reaction After 0.5-1h, no ammonia gas is released. Then the temperature was lowered to 100° C. and the remaining hexamethyldisilazane was concentrated under reduced pressure to obtain a white solid of cytosine silyl ether protecting group. Add 100mL of isoamyl alcohol to a 500mL reaction flask, stir, heat to 70-80°C to dissolve the white solid, and transfer it to an insulated dropping funnel.

[0033] Add 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonate (45g, 0.1mol) and 0.5g to a 1L three-necked flask Phosphotungstic acid and 100mL isoamyl alcohol were stirred and heated to 128-132°C, and then the cytosine silyl ether protecting group was added dropwise. After 2.5 hours of dropwise addition, the tempe...

Embodiment 2

[0035] Put cytosine (22.2g, 0.2mol), hexamethyldisilazane (84mL, 0.4mol), and 0.10g ammonium sulfate in a 500mL three-neck flask, stir, heat and reflux until cytosine is completely dissolved and clarified, and then continue the insulation reaction After 0.5-1h, no ammonia gas is released. The temperature was lowered to 100° C. and the remaining hexamethyldisilazane was concentrated under reduced pressure to obtain a white solid of cytosine silyl ether protecting group. Add 100mL of isoamyl alcohol to a 500mL reaction flask, stir, heat to 70-80°C to dissolve the white solid, and transfer it to an insulated dropping funnel.

[0036] Add 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-benzhydryl-1-methanesulfonate (45g, 0.1mol) and 0.8g to a 1L three-necked flask Phosphomolybdic acid and 100mL isoamyl alcohol were stirred and heated to 128-132°C, then the cytosine silyl ether protecting group was added dropwise, after 3 hours of dropping, the temperature was raised to reflux fo...

Embodiment 3

[0038] Put cytosine (22.2g, 0.2mol), hexamethyldisilazane (84mL, 0.4mol), and 0.10g ammonium sulfate in a 500mL three-neck flask, stir, heat and reflux until cytosine is completely dissolved and clarified, and then continue the insulation reaction After 0.5-1h, no ammonia gas is released. Then the temperature was lowered to 100° C. and the remaining hexamethyldisilazane was concentrated under reduced pressure to obtain a white solid of cytosine silyl ether protecting group. Add 100mL of n-pentanol to a 500mL reaction flask and stir, heat to 70-80°C to dissolve the white solid and transfer it to an insulated dropping funnel.

[0039] Add 2-deoxy-2,2-difluoro-D-erythro-pentafuranose-3,5-diphenylmethyl ester-1-methanesulfonate (45g, 0.1mol) and 1.0g to a 1L three-necked flask Phosphomolybdic acid and 100mL of n-amyl alcohol were stirred and heated to 128-137°C, then the cytosine silyl ether protecting group was added dropwise, after 2 hours of dropping, the temperature was raise...

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Abstract

The invention relates to a preparation method of an anticancer drug capable of destroying cell replication. Cytosine used as a raw material reacts with HMDS (hexamethyldisilazane) to produce a silyl ether protecting group, the silyl ether protecting group is butt-jointed with 2-deoxy-2,2-difluoro-D-erythro-pentofuranose-3,5-dibenzoate-1-mathanesulfonate, and the final product is obtained after hydrochloric acid after-treatment. The method is simple in process, the operation condition is more convenient, the proportion of produced isomers in requirement is high, a solvent is green, no rigor reaction condition is required, and the method is suitable for industrial production.

Description

[0001] Divisional application, original application number 2014103946439, application date 2014.08.13, titled a preparation method of gemcitabine hydrochloride intermediate. technical field [0002] The invention belongs to the field of pharmacy, and in particular relates to a preparation method of a gemcitabine hydrochloride intermediate. Background technique [0003] Gemcitabine is a difluoronucleoside anticancer drug that destroys cell replication. It mainly acts on tumor cells in the DNA synthesis phase, that is, cells in the S phase. Under certain conditions, it can prevent the progression from the G1 phase to the S phase. Its chemical name It is 2'-deoxy-2',2'-difluorocytidine, and its chemical structure is as follows: [0004] [0005] There are many synthetic methods of gemcitabine hydrochloride reported so far, and most of the synthetic routes go through an important intermediate β-1-(2'-deoxy-2',2'-difluoro-3',5'-di-O -Benzoyl-D-ribofuranosyl)-4-aminopyrimidin-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/073C07H1/00
CPCY02P20/55C07H19/073C07H1/00
Inventor 不公告发明人
Owner 陈欣
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