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Silapiperidine derivatives and their preparation methods and uses

A technology of silapiperidine and its derivatives, which is applied in the field of drug synthesis and can solve problems such as complex synthetic process routes, low yields, and difficulty in large-scale production

Active Publication Date: 2018-07-27
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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  • Silapiperidine derivatives and their preparation methods and uses
  • Silapiperidine derivatives and their preparation methods and uses
  • Silapiperidine derivatives and their preparation methods and uses

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] Dissolve the starting material 1 methyl-(4-methoxyphenyl)-dichlorosilane (334g, 1.51mol) in 5000ml of anhydrous ether, add vinylmagnesium chloride (2000ml, 1.6M) dropwise in an 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-methoxyphenyl)-bi...

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Abstract

The present invention provides a novel silapiperidine derivative or its pharmaceutically acceptable salt or solvate, the general structural formula of which is shown in (I); at the same time, it also provides the said A pharmaceutical composition comprising a silaperidine derivative or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or additive. At the same time, the present invention also discloses a synthesis method of silapiperidine derivatives, which uses dichloro-substituted silane as the starting material and integrates multi-step reactions in one pot to obtain high-purity pharmaceutical intermediates for the preparation of The camptothecin silane derivative has a short synthesis route, and the reaction environment, especially the temperature and pressure, is safe and controllable, and is environmentally friendly. The preparation raw material of the present invention has a wide range of sources and is easy to obtain, the preparation method is simple and easy to operate, the reaction conditions are mild, the yield of the synthetic product is high, and it has great industrial application value.

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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Patent Type & Authority Patents(China)
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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