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Sila piperidine derivative, preparation method and use thereof

A technology of silapiperidine and derivatives, which is applied in the field of drug synthesis, and can solve the problems of complex synthetic process routes, difficulty in large-scale production, and high production costs

Active Publication Date: 2014-05-07
微缔医药科技(杭州)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantages of this type of technical solution are: the synthetic process route is complex and the yield is low; and limited by the starting material camptothecin, it is difficult to produce on a large scale, and the production cost is relatively high
[0011] However, it has never been used as a pharmaceutical intermediate for the preparation of camptothecin sila derivatives; in addition, the synthesis method of sila piperidine derivatives has not been reported in the literature.

Method used

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  • Sila piperidine derivative, preparation method and use thereof
  • Sila piperidine derivative, preparation method and use thereof
  • Sila piperidine derivative, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] Example 1: Preparation of 4-methyl-4-(4-fluorophenyl)-[1,4]silapiperidine (No. 1)

[0106] Step 1, Preparation of Methyl-4-Fluorophenyldivinylsilane (Intermediate 2)

[0107] Take the starting material 1 methyl-(4-fluorophenyl)-dichlorosilane (318g, 1.52mol) and dissolve it in 5000ml of anhydrous ether, add vinylmagnesium chloride (2000ml, 1.6M) dropwise in an ice-water bath, and keep the temperature at 0-20°C. After the dropwise addition was completed, the temperature was raised naturally for 8-16 hours. After the reaction was completed, quenched with water at 0°C, filtered off the solid, and distilled off the solvent to obtain a light brown liquid, namely methyl-(4-fluorophenyl)-divinylsilane (intermediate product 2), with a yield of 82-89% %.

[0108] 1H NMR (400MHz, CDCl 3 ), δ(ppm)=7.45(d,J=8.4,2H),6.94(m,2H),6.32(d,J=16,2H),6.14(d,J=16,2H),5.77(d ,J=16,2H),0.43(s,3H).MS-ESI(M+H + )=193.10.

[0109] Step 2, the preparation of methyl-(4-fluorophenyl)-bis(2-br...

Embodiment 2

[0118] Example 2: Preparation of 4-methyl-4-(4-trifluoromethylphenyl)-[1,4]silapiperidine (No. 2)

[0119] Step 1, preparation of methyl-(4-trifluoromethylphenyl)-divinylsilane (intermediate 2)

[0120] Dissolve the starting material 1 methyl-(4-trifluoromethylphenyl)-dichlorosilane (389g, 1.50mol) in 5000ml of anhydrous ether, and add vinylmagnesium chloride (2000ml, 1.6M) dropwise under an ice-water bath , keep the temperature at 0-20°C. After the dropwise addition was completed, the temperature was raised naturally for 8-16 hours. After the reaction was completed, water was added to quench at 0°C, the solid was filtered off, and the solvent was distilled off to obtain a light brown liquid, which was methyl-(4-trifluoromethylphenyl)-divinylsilane (intermediate product 2), yield 79-84%.

[0121] 1H NMR (400MHz, CDCl 3 ), δ(ppm)=7.49(d,J=8.4,2H),7.46(d,J=8.4,2H),6.33(d,J=16,2H),6.15(d,J=16,2H) ,5.77(d,J=16,2H),0.44(s,3H).MS-ESI(M+H + )=243.08.

[0122] Step 2, the prepa...

Embodiment 3

[0131] Example 3: Preparation of 4-methyl-4-(4-methoxyphenyl)-[1,4]silapiperidine (No. 3)

[0132] Step 1, preparation of methyl-(4-methoxyphenyl)-divinylsilane (intermediate 2)

[0133] Take the starting material 1 methyl-(4-methoxyphenyl)-dichlorosilane (334g, 1.51mol) and dissolve it in 5000ml of anhydrous ether, add vinylmagnesium chloride (2000ml, 1.6M) dropwise under ice-water bath, Keep the temperature 0-20°C. After the dropwise addition was completed, the temperature was raised naturally for 8-16 hours. After the reaction was completed, water was added to quench at 0°C, the solid was filtered off, and the solvent was distilled off to obtain a light brown liquid, namely methyl-(4-methoxyphenyl)-divinylsilane (intermediate product 2), with a yield of 82 -85%.

[0134] 1H NMR (400MHz, CDCl 3 )δ(ppm)=7.39(d,J=8.4,2H),6.75(d,J=8.4,2H),6.32(d,J=16,2H),6.13(d,J=16,2H), 5.76(d,J=16,2H),0.44(s,3H).MS-ESI(M+H + )=205.07.

[0135] Step 2, the preparation of methyl-(4-metho...

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Abstract

The present invention provides a novel structure sila piperidine derivative or a pharmaceutically acceptable salt or solvate thereof, wherein the structure general formula is represented by a formula (I). The present invention further provides a drug composition containing a pharmaceutically effective amount of the sila piperidine derivative or the pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or additive. The present invention further discloses a synthesis method for the sila piperidine derivative, wherein dichloro-substituted silane is adopted as a starting raw material, and multi-step reactions are integrated and performed in one pot to obtain the high purity pharmaceutical intermediate for preparing the camptothecin sila derivative, wherein the synthesis route is short, the reaction environments, especially the temperature, the pressure and the like, are safe and controlled, and the characteristic of green environmental protection is provided. In addition, the preparation raw materials have the wide sources and are easy to obtain, the preparation method is simple and is easy to operate, the reaction conditions are mild, the synthesized product yield is high, and great industrial application values are provided.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a silapiperidine derivative and its preparation method and application, especially the application as an intermediate of irinotecan silicon derivative with antitumor activity. Background technique [0002] Cancer is a leading cause of death worldwide. According to statistics, 12 million people worldwide are diagnosed with cancer every year, causing 7.6 million deaths in 2008 (accounting for about 13% of all deaths). The 2010 World Cancer Awareness Day pointed out that cancer accounts for one-eighth of the annual death cases in the world. Up to now, the average annual incidence of cancer in my country is 1.8 to 2 million, and the death toll is 1.4 to 1.5 million. [0003] Irinotecan Hydrochloride (CPT-11 for short), the chemical name is 7-ethyl-10-[4-(1-piperidinyl)-1-piperidinyl]carboxycamptothecin hydrochloride , the molecular formula is C 33 h 38 N 4...

Claims

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Application Information

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IPC IPC(8): C07F7/10A61K31/695A61P35/00
Inventor 马凤森方多凤
Owner 微缔医药科技(杭州)有限公司
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