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Compound with cyclophosphamide structure and preparation method thereof

A cyclophosphamide and compound technology, applied in the field of compounds with cyclophosphamide structure and its preparation, can solve the problems of low bioavailability, in vivo instability, poor pharmacokinetic properties, etc., and achieve easy-to-obtain raw materials and significant industrial advantages , The effect of production process safety

Active Publication Date: 2016-11-09
CHENGDU BRILLIANT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its main mechanism of action is that it is metabolized by enzymes in the body into the form of the active ingredient uridine triphosphate, and exerts antiviral effects by inhibiting the RNA polymerase NS5B of the hepatitis C virus. Low degree (only 10%~20%), too much dose (400mg / day), poor pharmacokinetic properties, etc.

Method used

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  • Compound with cyclophosphamide structure and preparation method thereof
  • Compound with cyclophosphamide structure and preparation method thereof
  • Compound with cyclophosphamide structure and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: 1-((2S,3R,4R,5R)-3-fluoro-4-hydroxyl-3-methyl-5-(((2-oxo-4-phenyl-1,3,2- Preparation of oxazaphosphorin-2-yl)oxy)methyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (1)

[0033]

[0034] The specific synthesis steps are as follows:

[0035]

[0036] Step 1: 1-((2S,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl )-3-fluoro-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (SF-2)

[0037] At room temperature, to 1-((3R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)- To a DMF solution (200 mL) of diketone (SF-1) (10.4 g, 40 mmol) and imidazole (8.2 g, 120 mmol) was slowly added dropwise a DMF solution (25 mL) of TBSCl (9.0 g, 60 mmol). The reaction system was stirred at 50° C. for 6 h. After TLC showed that the reaction was complete, it was cooled to room temperature, and 150 mL of water was added to quench the reaction, followed by EA extraction (100 mL×4). Combine...

Embodiment 2-7

[0060] Examples 2-7 are obtained through the synthesis route of Example 1, using the above-mentioned intermediates 2b, 3b, 4b, and 5b to obtain the target compound, and the purification is all obtained by reverse-phase preparation. The reverse-phase preparation conditions are as follows:

[0061] 1. Separation solvent: acetonitrile + water

[0062] 2. Separation conditions:

[0063] B% (acetonitrile)

time

Flow rate (mL / min)

5％

5min

20

5％-30％

15min

20

30％-40％

15min

20

95％

5min

20

[0064] The raw materials 2a, 3a, 4a, 5a used are prepared by the following method:

[0065]

[0066] (1) Preparation of xa-2:

[0067] At room temperature, diethyl malonate (1eq) and ammonium acetate (1.5eq) were added sequentially to a solution of the starting material arylaldehyde xa-1 (1eq) in ethanol (about 1.2mol / L). The reaction mixture started to react under the reflux state. After 30 minutes, a large amount of pre...

Embodiment 6

[0073] The target compound 6 of embodiment 6 is prepared through the following reaction with the target compound 5 prepared in embodiment 5:

[0074]

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PUM

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Abstract

The invention discloses a compound with a cyclophosphamide structure. The compound can be used for treating mammal hepatitis c infection. The invention also discloses a preparation method of the compound. Diphenyl phosphite is used as a raw material so that a phosphor atom is introduced and through deprotection and self-cyclisation, a cyclophosphamide structure is synthesized.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a compound with a cyclophosphamide structure and a preparation method thereof. Background technique [0002] Hepatitis C virus (referred to as hepatitis C, hepatitis C) is a kind of viral hepatitis caused by hepatitis C virus (HCV) infection. The HCV genome contains 10 genes, encoding membrane proteins E1 and E2, core protein, p7 and nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B. Among them, the non-structural gene NS5B polymerase is composed of 1773 bases encoded into 591 amino acids. NS5B RNA-dependent RNA polymerase (RdRp), responsible for the replication of HCV RNA chain, effectively inhibits and prevents the formation of double-stranded HCV RNA. It is absolutely necessary for viral gene replication and the proliferation of hepatitis C virus in host cells, so it is also Drug targets for the treatment of HCV. [0003] Nucleoside inhibitors targetin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/10C07H1/00A61P31/14
CPCC07H1/00C07H19/10
Inventor 黄浩喜董研君刘冠锋吴鲜财杜振军陈垌珲李英富
Owner CHENGDU BRILLIANT PHARMA CO LTD
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