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A kind of preparation method of gemcitabine hydrochloride intermediate

A technology of white solid and cytosine, applied in the field of pharmacy, can solve problems such as safety hazards, equipment corrosion, DNA damage, etc., and achieve the effects of convenient operation, environmental friendliness, safe and green process

Active Publication Date: 2016-06-01
嘉善正丰电子厂
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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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  • A kind of preparation method of gemcitabine hydrochloride intermediate
  • A kind of preparation method of gemcitabine hydrochloride intermediate
  • A kind of preparation method of gemcitabine hydrochloride intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0031] 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.

[0032] 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

[0034] 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.

[0035] 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

[0037] 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.

[0038] 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 a gemcitabine hydrochloride intermediate. The preparation method comprises the steps of preparing a silyl-ether protecting group by using cytosine serving as raw material and hexamethyldisilazane; then, abutting the silyl-ether protecting group and 2-deoxy-2, 2-difluoro-D-erythro-pentofuranose-3, 5-dibenzoate-1-methanesulfonate; and aftertreating by using hydrochloric acid to obtain a finial product. The method has the advantages that the process is simple, operation conditions are more convenient, the ratio of required isomers is high, the solvent is green, rigorous reaction conditions are not needed; therefore, the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a preparation method of a gemcitabine hydrochloride intermediate. Background technique [0002] 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: [0003] [0004] 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-2-one hydrochloride, the structural formula is as formula (I). It is deprotected and salified, and the final product is in the form of hydrochloride. [0005] [0006] The ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/073C07H1/00
CPCY02P20/55
Inventor 伦俊杰孙宗丽
Owner 嘉善正丰电子厂
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