CN103772425A - Sila piperidine derivative, preparation method and use thereof - Google Patents

Sila piperidine derivative, preparation method and use thereof Download PDF

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CN103772425A
CN103772425A CN201210400901.0A CN201210400901A CN103772425A CN 103772425 A CN103772425 A CN 103772425A CN 201210400901 A CN201210400901 A CN 201210400901A CN 103772425 A CN103772425 A CN 103772425A
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silapiperidine
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hydroxyl
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CN103772425B (en
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马凤森
方多凤
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HANGZHOU HAIHANG BIOLOGICAL MEDICAL TECHNOLOGY CO LTD
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Abstract

本发明提供了一种结构新颖的硅杂哌啶衍生物或其药学上可接受的盐或溶剂化物，其结构通式如（Ⅰ）所示；同时，还提供了包含药物有效量的所述硅杂哌啶杂衍生物或其药学上可接受的盐或溶剂化物，以及药学上可接受的赋形剂或添加剂的药物组合物。与此同时，本发明还公开了一种硅杂哌啶衍生物的合成方法，以二氯取代硅烷为起始原料，整合多步反应一锅进行，可以得到高纯度的医药中间体用于制备喜树碱硅杂衍生物，其合成路线短，反应环境尤其是温度、压力等安全可控，绿色环保。本发明的制备原料来源广泛易获取，制备方法简便易操作，反应条件温和，合成产物收率高，具有极大的工业应用价值。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

Silapidine derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a silapiperidine derivative, a preparation method and application thereof, in particular to application of the silapiperidine derivative as an intermediate of an irinotecan silicon derivative with antitumor activity.
Background
Cancer is a leading cause of death worldwide, with 1200 million people globally diagnosed as cancer statistically each year, resulting in 760 million deaths (accounting for approximately 13% of all deaths) in 2008. The 2010 world cancer publicity date indicates that: cancer accounts for one eighth of the annual death cases worldwide. At present, the number of cancer attacks is 180-200 ten thousand and the number of deaths is 140-150 ten thousand in China.
Irinotecan Hydrochloride (Iriontecan Hydrochloride, CPT-11 for short) with chemical name of 7-ethyl-10- [4- (1-piperidyl) -1-piperidyl]A carboxyoxy camptothecin hydrochloride having a molecular formula of C33H38N4O6HCI, molecular weight 677.19, was developed by Daiichi Seiyaku and Yakult Honsha, Japan, and was first marketed in 1994 in Japan as an effective drug for metastatic colorectal cancer, which is attracting widespread attention all over the world and has the following structural formula:
Figure BDA00002278602400011
from the CA structure novelty and patent publication, the structural modification of irinotecan and its derivatives is mainly carried out on the mother ring CPT framework, the structural modification at the piperidyl part is not involved, and the preparation mostly adopts a semi-synthesis method,
Figure BDA00002278602400012
as is known from the above-mentioned route of the semi-synthetic method, camptothecin 1 is usually used as a starting material to alkylate its 7-position to 7-ethylcamptothecin 2, 10-hydroxy-7-ethylcamptothecin 3 is further prepared from 2, and 3 is reacted with phosgene and then with piperidinyl to obtain the target product 4, irinotecan (Eckardt JR, Burris HA, Rothenberg ML, et al, formulating Novelcompounds content [ J ], Oncol, 1993.4: 47). The technical scheme has the following defects that: the synthesis process route is complex and the yield is low; and is limited by the starting material camptothecin, so that the large-scale production is difficult and the production cost is high.
The horse-Fenseng et al researchers found that piperidine structure is an important intermediate in the development of new drugs, and many drugs contain the structure. The introduction of silicon atom can change the conformation of piperidine ring, so that a new method is developed for preparing silapiperidine (CAS accession number: 25475-94-9, molecular formula is C)4H11NSi) introduces an antitumor drug irinotecan for structural modification, and the obtained camptothecin sila derivative is more favorable for improving the performance of the irinotecan. It can be seen from the patent application named camptothecin sila derivative, composition containing the camptothecin sila derivative and pharmaceutical application thereof, that the efficacy of the camptothecin sila derivative is better than that of the commercially available irinotecan hydrochloride.
Further, from the examination of CA structure and published patent, the compounds related to the structure of silapiperidine now are disclosed as four:
Figure BDA00002278602400021
but has not been used as a medical intermediate for preparing camptothecin sila derivatives; in addition, the synthesis method of the silapiperidine derivative is not reported in the literature.
Disclosure of Invention
The invention aims to provide a silapiperidine derivative which has simple synthesis process, mild reaction condition and high product yield and can be used as an intermediate for preparing camptothecin sila derivatives.
The invention adopts the following technical scheme:
the invention provides a silapiperidine derivative or a pharmaceutically acceptable salt or solvate thereof, which has the following structural general formula (I):
Figure BDA00002278602400031
wherein,
R1is selected from H or
Figure BDA00002278602400032
R2，R3Each independently selected from H, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C1-10Alkyl with substituents, C2-10Alkenyl with substituents, C2-10Alkynyl with substituents, C3-10Cycloalkyl with substituents, C1-10And optionally substituted aryl or heteroaryl; the substituent is hydroxyl, nitryl, amino, carboxyl, halogen atom, sulfydryl and C1-6Alkylthio radical, C1-6Alkoxy radical, C1-6One or more of alkoxycarbonyl and amide; the substituted group on the aryl or heteroaryl is hydroxyl, amino, nitro, halogen atom, C1-6Alkyl radical, C1-6Alkylthio radical, C1-6One or more of alkoxy and carboxyl;
R4is selected from C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C1-10Alkyl with substituents, C2-10Alkenyl with substituents, C2-10Alkynyl with substituents, C3-10A substituted cycloalkyl, aryl or optionally substituted aryl; the substituent is hydroxyl, nitryl, amino, carboxyl, halogen atom, sulfydryl and C1-6Alkylthio radical, C1-6Alkoxy radical, C1-6One or more of alkoxycarbonyl and amide;the substituted group on the aryl is hydroxyl, amino, nitro, halogen atom, C1-6Alkyl radical, C1-6Alkylthio radical, C1-6One or more of alkoxy and carboxyl;
but excluding the following compounds:
4, 4-dimethyl- [1,4] silapiperidine;
4, 4-diphenyl- [1,4] silapiperidine;
4-methyl-4-phenyl- [1,4] silapiperidine;
4, 4-bis (4-chlorophenyl) - [1,4] silapiperidine.
According to a preferred embodiment of the invention, R in the general formula (I)1At H, i.e. at this time
Figure BDA00002278602400033
Structure, wherein: r2Is H or C1-6An alkyl group;
R3is C2-10Alkyl radical, C3-10Cycloalkyl radical, C2-10Alkyl with substituents, C3-10Cycloalkyl with substituents, aryl, and optionally substituted aryl or heteroaryl; the substituent is hydroxyl, nitryl, amino, carboxyl, halogen atom, sulfydryl and C1-6Alkylthio radical, C1-6Alkoxy radical, C1-6One or more of alkoxycarbonyl and amide; the substituted group on the aryl or heteroaryl is hydroxyl, amino, nitro, halogen atom, C1-6Alkyl radical, C1-6Alkylthio radical, C1-6One or more of alkoxy and carboxyl;
R4is C1-10Alkyl radical, C3-10Cycloalkyl radical, C1-10Alkyl with substituents, C3-10A substituted cycloalkyl, aryl or optionally substituted aryl or heteroaryl group; the substituent is hydroxyl, nitryl, amino, carboxyl, halogen atom, sulfydryl and C1-6Alkylthio radical, C1-6Alkoxy radical, C1-6An alkoxycarbonyl group,One or more of amide groups; the substituted group on the aryl or heteroaryl is hydroxyl, amino, nitro, halogen atom, C1-6Alkyl radical, C1-6Alkylthio radical, C1-6One or more of alkoxy and carboxyl.
In a further preferred embodiment, in the general formula (Ia), R2Is H or C1-6An alkyl group;
R3is C2-10Alkyl radical, C2-10Alkyl with substituents, C3-10Cycloalkyl with substituents, phenyl, and optionally substituted phenyl or heteroaryl; the substituent is one or more of hydroxyl, nitryl, amino, carboxyl, halogen atom, methylthio, methoxyl, methane oxycarbonyl and acylamino; the substituted group on the phenyl or the heteroaryl is hydroxyl, amino, nitro, halogen atom, C1-6One or more of alkyl, methylthio, methoxy and carboxyl;
R4is C1-10Alkyl radical, C1-10Substituted alkyl or optionally substituted phenyl; the substituent is one or more of hydroxyl, carboxyl, halogen atom, methoxyl and methane oxycarbonyl; the substituted group on the phenyl is hydroxyl, halogen atom and C1-6One or more of alkyl and methoxyl.
In a further preferred embodiment, in the general formula (Ia), the halogen atom is F or Br.
According to a preferred embodiment of the invention, R in the general formula (I)1Is composed of
Figure BDA00002278602400041
When it is, then
Figure BDA00002278602400042
Structure (II) wherein R2Is H or C1-6An alkyl group;
R3is C1-10Alkyl radical, C1-10Alkyl and phenyl with substituentAnd optionally substituted phenyl or heteroaryl; the substituent is one or more of hydroxyl, nitryl, amino, carboxyl, halogen atom, methylthio, methoxyl, methane oxycarbonyl and acylamino; the substituted group on the phenyl or the heteroaryl is hydroxyl, amino, nitro, halogen atom, C1-6One or more of alkyl, methylthio, methoxy and carboxyl;
R4is C1-10Alkyl radical, C1-10Substituted alkyl, phenyl, and optionally substituted phenyl or heteroaryl; the substituent is one or more of hydroxyl, nitryl, amino, carboxyl, halogen atom, methylthio, methoxyl, methane oxycarbonyl and acylamino; the substituted group on the phenyl or the heteroaryl is hydroxyl, amino, nitro, halogen atom, C1-6One or more of alkyl, methylthio, methoxy and carboxyl.
In a further preferred embodiment, in the general formula (Ib), the halogen atom is F, Cl or Br.
According to a preferred embodiment of the invention, the heteroaryl groups of formula (I), formula (Ia) and formula (Ib) are each selected from the following groups: 2-furan, 3-furan, 2-thiophene, 3-thiophene, 2-pyridine, 3-pyridine, 4-pyridine, 2-pyrrole or 3-pyrrole.
According to a preferred embodiment of the present invention, the silapiperidine derivatives or pharmaceutically acceptable salts or solvates thereof in general formula (I), general formula (Ia) and general formula (Ib) are selected from the following compounds numbered 1-10:
number 1: 4-methyl-4- (4-fluorophenyl) - [1,4] silapiperidine;
number 2: 4-methyl-4- (4-trifluoromethylphenyl) - [1,4] silapiperidine;
number 3: 4-methyl-4- (4-methoxyphenyl) - [1,4] silapiperidine;
number 4: 4-methyl-4- (4-methylphenyl) - [1,4] silapiperidine;
number 5: 4, 4-bis- (4-fluorophenyl) - [1,4] silapiperidine;
number 6: 4-methyl-4- (3, 4-difluorophenyl) - [1,4] silapiperidine;
number 7: 4, 4-bis- (4-methoxyphenyl) - [1,4] silapiperidine;
number 8: 4-ethyl-4- (4-fluorophenyl) - [1,4] silapiperidine;
number 9: 4, 4-dimethyl-1- (piperidin-4-yl) - [1,4] silapiperidine;
number 10: 4-methyl-4-phenyl-1- (piperidin-4-yl) - [1,4] silapiperidine.
As previously described, R3、R4C which may be straight-chain or branched1-10Hydroxyalkyl of (2), or C2-10Wherein the hydroxy group may be mono-or polysubstituted at any carbon atom to form a structural form such as R-OH or R (R' -OH) -OH; meanwhile, the aforementioned groups are, for example, hydroxyl, nitro, amino, carboxyl, halogen, mercapto, C1-6Alkylthio radical, C1-6Alkoxy radical, C1-6One or more of the alkoxycarbonyl and the amide groups can be substituted on any carbon atom position of the alkane ester and the alkane ether, namely, the groups and the hydroxyl can form various combinations for common substitution.
More preferably, the hydroxyl group may undergo esterification or etherification, and thus R is in the present invention3、R4May also be linear or branched, saturated or unsaturated C1-10To form a structural form such as R-COOR 'OR R-OR', wherein R may be C1-5Alkyl or C2-5Alkenyl, R' may be C1-6Alkyl radical, C2-6An alkenyl group; similarly, the foregoing are exemplified by hydroxy, nitro, amino, carboxyl, halogen, mercapto, C1-6Alkylthio radical, C1-6Alkoxy radical, C1-6One or more of alkoxycarbonyl and acylamino, or mono-substitution on any carbon atom of alkyl ester or alkyl etherOr polysubstituted; for example: the amino and hydroxyl groups can be connected to different carbon atoms on the alkane ester and the alkane ether, or the amino group can be connected with a plurality of alkane alcohols.
In the present invention, "alkyl" is a straight or branched chain alkyl group, such as C1-10Alkyl, preferably C1-6Alkyl groups, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like.
In the present invention, "alkenyl" is a straight or branched chain alkenyl group, such as C2-10Alkenyl, preferably C2-6Alkenyl groups include, but are not limited to, ethylene, propylene, butene, isobutylene, pentene, isopentene, hexene, and the like.
In the present invention, "alkynyl" is a straight or branched chain alkynyl group, such as C2-10Alkynyl, preferably C2-6Alkynyl groups include, but are not limited to, acetylene, propyne, butyne, and the like.
In the present invention, "cycloalkyl" is C3-10Cycloalkyl, preferably C3-6Cycloalkyl groups including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; and "cycloalkyl" is optionally substituted with the aforementioned substituent groups.
In the present invention, "aryl" is a monocyclic or bicyclic aromatic hydrocarbon group such as phenyl, naphthyl and the like, preferably phenyl.
In the present invention, "C1-6Alkylthio "and" C1-6C in alkoxy ″)1-6Alkyl groups are as defined above and "C1-6Alkylthio is preferably methylthio and C1-6Alkoxy "is preferably methoxy.
In the present invention, the term "pharmaceutically acceptable salt" includes, but is not limited to, salts with inorganic acids, such as hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, and the like; also included are salts with organic acids such as lactic acid, oxalic acid, malic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, citric acid, lactic acid salts, sulfonic acid salts, methanesulfonic acid salts, p-toluenesulfonic acid salts, 2-isethionic acid salts, benzoic acid salts, salicylic acid salts, stearic acid salts, acetic acid salts, and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.
In the present invention, the term "solvate" refers to a solvate of a silapiperidine derivative of formula (I) or a pharmaceutically acceptable salt thereof with a solvent, preferably water or a lower aliphatic alcohol, such as C1-6A fatty alcohol, the solvate preferably being a hydrate or an alcoholate.
The invention also provides a method for preparing the silapiperidine derivative or the pharmaceutically acceptable salt or solvate thereof, which takes dichloro substituted silane as a starting material to prepare a target product shown in the formula Ia through Grignard reaction, reverse Ma addition, benzylamine ring closure and hydrogenation debenzylation; on the basis, the target product shown in the formula Ib is prepared by further reactions such as reductive amination and HCl debo protection, and the general reaction route is as follows:
Figure BDA00002278602400061
the general reaction route mainly comprises the following synthesis steps:
(1) dissolving alkyl magnesium halide and dichloro substituted silane of a formula 1 in an organic solvent, and carrying out Grignard reaction to obtain divinyl substituted silane of a formula 2, wherein the reaction formula is as follows:
Figure BDA00002278602400071
in the step (1), the organic solvent is one or more of anhydrous ether, tetrahydrofuran and toluene solution; anhydrous diethyl ether solutions are preferred.
In the step (1), the alkyl magnesium halide is chloroethylene magnesium or bromoethylene magnesium; preferably magnesium chloroethylene.
In the step (1), the reaction temperature is 0-20 ℃, and preferably 0-15 ℃.
In the Grignard reaction in the step (1), a Grignard reagent (namely alkyl magnesium halide) is slowly dropped into an ether solution of the starting material at 0 ℃, the reaction temperature is kept at 0-20 ℃, the molar ratio of the Grignard reagent to the dichloro-substituted silane of the starting material is 2.05-3, and the optimal ratio is 2.05-2.15.
In the invention, the Grignard reaction is carried out at 0-20 ℃, the reaction is quenched at 0 ℃ after the reaction is finished, and the product can be obtained after the solid is filtered and the solvent is removed by evaporation and used for the next reaction without further purification.
(2) The divinyl substituted silane (namely, the formula 2) obtained in the step (1) is dissolved in an organic solvent, and after an anti-Markov addition reaction, the di (2-bromoethyl) substituted silane of the formula 3 is obtained, wherein the reaction formula is shown as follows:
Figure BDA00002278602400072
in the step (2), the organic solvent is one or more of petroleum ether, n-hexane, n-heptane or cyclohexane; n-heptane is preferred.
In the step (2), the reaction temperature is 15-50 ℃, and preferably 20-35 ℃.
In the anti-Markov addition reaction in the step (2), benzoyl peroxide is used as a free radical initiator, and is dissolved in n-heptane at 15-50 ℃ for reaction, wherein HBr gas is generated by commercially available or 48% HBr aqueous solution and phosphorus pentoxide. Controlling the amount of HBr gas used in the reaction is an important cost saving aspect, and thus the completion of the reaction needs to be monitored.
In the step (2), the ratio of the divinyl-substituted silane to HBr is 1: 2.4-10, and the preferable ratio is 1: 2.4-2.6; the ratio of the divinyl substituted silane to the benzoyl peroxide is 1: 0.01-0.2, and the preferable ratio is 1: 0.01-0.03.
In the invention, the anti-Markov addition reaction with the n-heptane can be carried out at room temperature, and the anti-Markov addition reaction can be obtained after the solvent is removed by simple washing with water or alkali liquor and evaporation and used for the next reaction without further purification.
(3) Dissolving the bis (2-bromoethyl) substituted silane (shown as a formula 3) obtained in the step (2) in an organic solvent, carrying out cyclization reaction with benzylamine under an alkaline condition, and washing with ethyl acetate or methanol to obtain the N-benzyl substituted silapiperidine shown as a formula 4, wherein the reaction formula is shown as follows:
Figure BDA00002278602400081
in the step (3), the organic solvent is one or more of chloroform, dioxane and N, N-dimethylformamide; chloroform is preferred.
In the step (3), the reaction temperature is 50-80 ℃, and preferably 65-75 ℃; the reaction time is 6-24 h.
In the step (3), the molar ratio of the bis (2-bromoethyl) substituted silane to benzylamine is 1: 6-12, and the preferable ratio is 1: 7-8.
In the present invention, "alkaline condition" means that a certain kind of compound is alkaline in water or a solvent, that is, the pH of a solution>7.0, such compounds include hydrides, hydroxides, alkali metal salts or alkoxides, or compounds such as amines, which are capable of adsorbing acid ions or accepting protons in water or solvents. Examples of the above-mentioned basic compound include, but are not limited to, the following: such as hydrides including but not limited to potassium, sodium, lithium hydrides; such as hydroxides including, but not limited to NaOH, LiOH, Mg (OH)2、Ca(OH)2Etc.; alkali metal salts or alkoxides include, but are not limited to, sodium bicarbonateSodium carbonate, potassium bicarbonate, potassium carbonate, lithium diisopropylamide, potassium tert-butoxide, sodium tert-butoxide, etc.; alkylated disilazanes such as hexamethyldisilazane, lithium hexamethyldisilazide, and the like; alkylamines such as triethylamine, etc., wherein the above alkoxides, alkyl groups preferably being straight or branched C1-6Alkyl group of (1). In step (3), triethylamine may be added as a preferred basic environment.
In the present invention, the cyclization reaction with benzylamine, the solvent and the excess benzylamine can be removed by distillation under reduced pressure, and the product can be purified by distillation under reduced pressure without recrystallization or column chromatography separation means.
(4) Dissolving the N-benzyl substituted silapiperidine (formula 4) obtained in the step (3) in an organic solvent, and obtaining a target product of a formula (Ia) through debenzylation by hydrogenation reaction under the presence of a catalyst, wherein the reaction formula is as follows:
in the step (4), the organic solvent is one or more of methanol, ethanol and isopropanol; methanol is preferred.
In the step (4), the catalyst is one or more of ruthenium, nickel, platinum and palladium, the catalyst usually appears in a form that metal is loaded on activated carbon, and if the catalyst is palladium, the catalyst mostly appears in a form of palladium carbon; preferably the catalyst is palladium on carbon.
In the step (4), the reaction temperature is 30-70 ℃, and preferably 45-55 ℃; the reaction time is 3-50 h.
In the invention, 10% palladium carbon can be selected as a catalyst, and the mass ratio of the catalyst to the raw material is 2-8%; and under the hydrogen pressure of 1-5 atm, the catalyst is filtered out through the catalytic hydrogenation reaction of N-benzyl substituted silapiperidine, and the catalyst is obtained by decompressing and distilling off the solvent without further purification.
(5) Dissolving the target product of the formula (Ia) obtained in the step (4) in an organic solvent, carrying out amination reduction reaction on the target product and N-Boc-piperidin-4-one to obtain 1- (tert-butoxycarbonyl) -4- (silapiperidinyl) piperidine of the formula 5, then removing Boc protecting group under acidic condition, and carrying out alkali neutralization to obtain the target product of the formula (Ib), wherein the reaction formula is shown as follows:
Figure BDA00002278602400091
in the step (5), the organic solvent is one or more of methanol, tetrahydrofuran, dichloromethane, chloroform, dioxane, ethyl acetate and dichloromethane; methanol or ethyl acetate are preferred.
In the step (5), the reducing agent is one or more of sodium cyanoborohydride and sodium triacetoxyborohydride; preferably sodium cyanoborohydride.
In the step (5), the reaction temperature is 10-30 ℃, and preferably 20-25 ℃.
In the step (5), the acid is selected from one or more of concentrated hydrochloric acid and trifluoroacetic acid, and preferably concentrated hydrochloric acid; the "alkali" is selected from one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, triethylamine and pyridine, and is preferably sodium hydroxide.
In the reaction formulae of the above steps (1) to (5), R2，R3Each independently selected from H, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C1-10Alkyl with substituents, C2-10Alkenyl with substituents, C2-10Alkynyl with substituents, C3-10Cycloalkyl with substituents, C1-10And optionally substituted aryl or heteroaryl; the substituent is hydroxyl, nitryl, amino, carboxyl, halogen atom, sulfydryl and C1-6Alkylthio radical, C1-6Alkoxy radical, C1-6One or more of alkoxycarbonyl and amideSeed growing; the substituted group on the aryl or heteroaryl is hydroxyl, amino, nitro, halogen atom, C1-6Alkyl radical, C1-6Alkylthio radical, C1-6One or more of alkoxy and carboxyl;
R4is selected from C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C1-10Alkyl with substituents, C2-10Alkenyl with substituents, C2-10Alkynyl with substituents, C3-10A substituted cycloalkyl, aryl or optionally substituted aryl; the substituent is hydroxyl, nitryl, amino, carboxyl, halogen atom, sulfydryl and C1-6Alkylthio radical, C1-6Alkoxy radical, C1-6One or more of alkoxycarbonyl and amide; the substituted group on the aryl is hydroxyl, amino, nitro, halogen atom, C1-6Alkyl radical, C1-6Alkylthio radical, C1-6One or more of alkoxy and carboxyl.
In the present invention, the starting material 1 may be commercially available or may be prepared by itself.
The invention also provides a pharmaceutical composition, which comprises a pharmaceutically effective amount of the silapiperidine derivative with the structural general formula (I) or pharmaceutically acceptable salt or solvate thereof, and pharmaceutically acceptable excipient or additive. The pharmaceutical compositions may be in the form of oral preparations, for example tablets or capsules, or they may be in the form of sterile solutions, suspensions or emulsions for parenteral injection, for example, intravenous, subcutaneous, intramuscular or intravascular injection.
The invention also provides application of the silapiperidine derivative shown as the structural general formula (I) or pharmaceutically acceptable salt or solvate thereof as a medical intermediate in preparing the camptothecin siladerivative. The preparation route of the camptothecin silicone derivatives is shown in Chinese patent application 'camptothecin silicone derivatives, compositions containing the derivatives and pharmaceutical applications thereof' of professor ma feng si:
Figure BDA00002278602400101
the invention has the following advantages:
the invention has reasonable design, and the high-purity medical intermediate, namely the silapiperidine derivative with the structural general formula (I), can be obtained through the synthetic route so as to be used for preparing the camptothecin siladerivatives. The invention has short synthetic route, safe and controllable reaction environment, particularly temperature, pressure and the like, and is green and environment-friendly; the preparation raw materials of the invention have wide and easily obtained sources, the preparation method is simple and easy to operate, the reaction conditions are mild, the yield of the synthesized product is high, and the invention has great industrial application value.
Detailed Description
The present invention is further illustrated below with reference to specific examples, but the scope of the present invention is not limited to the scope disclosed in the following examples.
The compound with the number of 1-8 is prepared into a target product shown in the formula Ia according to the following synthetic route:
Figure BDA00002278602400102
example 1: preparation of 4-methyl-4- (4-fluorophenyl) - [1,4] silapiperidine (code 1)
Step 1, preparation of methyl-4-fluorophenyldivinyl silane (intermediate 2)
Starting material 1 methyl- (4-fluorophenyl) -dichlorosilane (318 g,1.52 mol) was dissolved in 5000ml of anhydrous ether and vinylmagnesium chloride (2000 ml, 1.6M) was added dropwise under ice-water bath maintaining the temperature at 0-20 ℃. After the dropwise addition, naturally raising the temperature and reacting for 8-16 h. After the reaction is finished, water is added at 0 ℃ for quenching, the solid is filtered out, the solvent is distilled off to obtain light brown liquid, namely methyl- (4-fluorophenyl) -divinyl silane (intermediate product 2), and the yield is 82-89%.
1H NMR（400MHz，CDCl3）,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。
Step 2, preparation of methyl- (4-fluorophenyl) -bis (2-bromoethyl) silane (intermediate 3)
Intermediate 2 (551 g,2.87 mol) obtained in step 1 above was dissolved in 5000ml of n-heptane, benzoyl peroxide (12.1 g,5 mmol) was added in portions, HBr gas was introduced, the temperature was maintained at 20-40 deg.C, HBr introduction was stopped until the reaction solution became slightly orange. Washing the reaction solution with sodium carbonate aqueous solution, drying the reaction solution by anhydrous sodium sulfate, and evaporating the solvent to obtain brown liquid, namely methyl- (4-fluorophenyl) -bis (2-bromoethyl) silane (intermediate product 3), wherein the yield is 87-93%.
1H NMR（400MHz，CDCl3）,δ（ppm）=7.45(d,J=8.4,2H),6.94(m,2H)，3.51（m,4H），1.66（m,4H）,0.38(s,3H).MS-ESI(M+H+)=352.88。
Step 3, preparation of N-benzyl-4-methyl-4- (4-fluorophenyl) - [1,4] silapiperidine (intermediate 4)
Intermediate 3 (220 g,0.62 mol) obtained in step 2 above, benzylamine (534 g) and triethylamine (261 ml) were dissolved in chloroform (6L) and reacted under reflux for 8-12 h. Cooling the reaction liquid, washing with water, drying, evaporating to remove the solvent, and distilling the obtained residue under reduced pressure to obtain colorless liquid. The colorless liquid is dissolved in ethyl acetate and cooled to about 0 ℃, and HCl gas is introduced until the TLC detection reaction is complete. Filtering, washing the solid with ethyl acetate, and drying to obtain the hydrochloride of the N-benzyl-4-methyl-4- (4-fluorophenyl) - [1,4] silapiperidine (intermediate 4), wherein the yield is 51-65%.
1H NMR（400MHz，DMSO），δ（ppm）=7.49(d,J=8.4,2H),7.29(m，5H)，6.96(m，2H),3.63（s,2H）,3.21（m,4H）,1.30（m,2H），0.97（m,2H）0.31(s,3H).MS-ESI(M+H+)=,300.11。
Step 4, 4-methyl-4- (4-fluorophenyl) - [1,4] silapiperidine (target product Ia)
Intermediate 4 (215 g,0.64 mol) was dissolved in methanol (700 ml) in an autoclave, 15g of 10% palladium on carbon (containing 50% water) was added, and the reaction was carried out under 2-3atm hydrogen pressure for 8-24 hours with temperature control at 35-50 ℃. TLC detection reaction, after the completion of the reaction, the catalyst is filtered (recovered), and the solvent is distilled off to obtain the target product 4-methyl-4- (4-fluorophenyl) - [1,4] silapiperidine shown in the formula Ia with the yield of 84-91%.
1H NMR（400MHz，DMSO），δ（ppm）=8.93(b,2H)，7.47(d,J=8.4,2H),6.97(m，2H),3.20（m,4H）,1.33（m,2H），1.10（m,2H）0.39(s,3H).MS-ESI(M+H+)=210.07。
Example 2: preparation of 4-methyl-4- (4-trifluoromethylphenyl) - [1,4] silapiperidine (code 2)
Step 1, preparation of methyl- (4-trifluoromethylphenyl) -divinylsilane (intermediate 2)
Starting material 1 methyl- (4-trifluoromethylphenyl) -dichlorosilane (389 g,1.50 mol) was dissolved in 5000ml of anhydrous ether, and vinylmagnesium chloride (2000 ml, 1.6M) was added dropwise in an ice-water bath, maintaining the temperature at 0-20 ℃. After the dropwise addition, naturally raising the temperature and reacting for 8-16 h. After the reaction is finished, water is added at 0 ℃ for quenching, the solid is filtered out, the solvent is distilled off to obtain light brown liquid, namely methyl- (4-trifluoromethylphenyl) -divinyl silane (intermediate product 2), and the yield is 79-84%.
1H NMR（400MHz，CDCl3）,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。
Step 2, preparation of methyl- (4-trifluoromethylphenyl) -bis (2-bromoethyl) silane (intermediate 3)
Intermediate 2 (690 g,2.85 mol) from step 1 above was dissolved in 5000ml of n-heptane, benzoyl peroxide (11.9 g,5 mmol) was added in portions, HBr gas was introduced, the temperature was maintained at 20-40 ℃ and HBr introduction was stopped until the reaction solution became slightly orange. Washing the reaction solution with sodium carbonate aqueous solution, drying the reaction solution by anhydrous sodium sulfate, and evaporating the solvent to obtain brown liquid, namely methyl- (4-trifluoromethylphenyl) -bis (2-bromoethyl) silane (intermediate product 3), wherein the yield is 85-92%.
1H NMR（400MHz，CDCl3）,δ（ppm）=7.47(d,J=8.4,2H),7.44(d,J=8.4,2H)，3.44（m,4H），1.65（m,4H）,0.38(s,3H).MS-ESI(M+H+)=402.88。
Step 3, preparation of N-benzyl-4-methyl-4- (4-trifluoromethylphenyl) - [1,4] silapiperidine (intermediate 4)
Intermediate 3 (251 g,0.62 mol) obtained in step 2 above, benzylamine (534 g) and triethylamine (261 ml) were dissolved in chloroform (6L) and reacted under reflux for 8-12 h. Cooling the reaction liquid, washing with water, drying, evaporating to remove the solvent, and distilling the obtained residue under reduced pressure to obtain colorless liquid. The colorless liquid is dissolved in ethyl acetate and cooled to about 0 ℃, and HCl gas is introduced until the TLC detection reaction is complete. Filtering, washing the solid with ethyl acetate, and drying to obtain the hydrochloride of the N-benzyl-4-methyl-4- (4-trifluoromethylphenyl) - [1,4] silapiperidine (intermediate 4), wherein the yield is 48-63%.
1H NMR（400MHz,DMSO），δ（ppm）=7.46(d,J=8.4,2H),7.43(d,J=8.4,2H)，7.27(m 5H),3.64(s,2H),3.23（m,4H）,1.31（m,2H），0.99（m,2H）0.33(s,3H).MS-ESI(M+H+)=,350.13。
Step 4, 4-methyl-4- (4-trifluoromethylphenyl) - [1,4] silapiperidine (target product Ia)
Intermediate 4 (247 g,0.64 mol) was dissolved in methanol (700 ml) in an autoclave, 15g of 10% palladium on carbon (containing 50% water) was added and the reaction was carried out under 2-3atm hydrogen pressure for 8-24h, with the temperature controlled at 35-50 ℃. TLC detection reaction, after the completion of the reaction, the catalyst is filtered (recovered), and the solvent is distilled off to obtain the target product 4-methyl-4- (4-trifluoromethylphenyl) - [1,4] silapiperidine shown in the formula Ia, with the yield of 84-90%.
1H NMR（400MHz,DMSO），δ（ppm）=8.98(b,2H)，7.45(d,J=8.4,2H),7.41(d,J=8.4,2H),3.21（m,4H）,1.30（m,2H），1.09（m,2H）0.38(s,3H).MS-ESI(M+H+)=260.07。
Example 3: preparation of 4-methyl-4- (4-methoxyphenyl) - [1,4] silapiperidine (code 3)
Step 1, preparation of methyl- (4-methoxyphenyl) -divinylsilane (intermediate 2)
Starting material 1 methyl- (4-methoxyphenyl) -dichlorosilane (334 g,1.51 mol) was dissolved in 5000ml of anhydrous ether, and vinylmagnesium chloride (2000 ml, 1.6M) was added dropwise in an ice-water bath, maintaining the temperature at 0-20 ℃. After the dropwise addition, naturally raising the temperature and reacting for 8-16 h. After the reaction is finished, water is added at 0 ℃ for quenching, the solid is filtered out, the solvent is distilled off to obtain light brown liquid, namely methyl- (4-methoxyphenyl) -divinyl silane (intermediate product 2), and the yield is 82-85%.
1H NMR（400MHz，CDCl3）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。
Step 2, preparation of methyl- (4-methoxyphenyl) -bis (2-bromoethyl) silane (intermediate 3)
Intermediate product 2 (586 g,2.87 mol) from step 1 above was dissolved in 5000ml of n-heptane, benzoyl peroxide (12.1 g,5 mmol) was added in portions, HBr gas was introduced, the temperature was maintained at 20-40 deg.C, HBr introduction was stopped until the reaction solution became slightly orange. Washing the reaction solution with sodium carbonate aqueous solution, drying the reaction solution by anhydrous sodium sulfate, and evaporating the solvent to obtain brown liquid, namely methyl- (4-methoxyphenyl) -bis (2-bromoethyl) silane (intermediate product 3), wherein the yield is 88-92%.
1H NMR（400MHz，CDCl3）,δ（ppm）=7.38(d,J=8.4,2H),6.76(d,J=8.4,2H)，3.50（m,4H），1.67（m,4H）,0.38(s,3H).MS-ESI(M+H+)=364.88。
Step 3, preparation of N-benzyl-4-methyl-4- (4-methoxyphenyl) - [1,4] silapiperidine (intermediate 4)
Intermediate 3 (227 g,0.62 mol) obtained in the above step 2, benzylamine (534 g) and triethylamine (261 ml) were dissolved in chloroform (6L) and reacted under reflux for 8 to 12 hours. Cooling the reaction liquid, washing with water, drying, evaporating to remove the solvent, and distilling the obtained residue under reduced pressure to obtain colorless liquid. The colorless liquid is dissolved in ethyl acetate and cooled to about 0 ℃, and HCl gas is introduced until the TLC detection reaction is complete. Filtering, washing the solid with ethyl acetate, and drying to obtain the hydrochloride of the N-benzyl-4-methyl-4- (4-methoxyphenyl) - [1,4] silapiperidine (intermediate 4), with the yield of 55-65%.
1H NMR（400MHz,DMSO），δ（ppm）=7.38(d,J=8.4,2H),7.28(m 5H),6.77(d,J=8.4,2H),3.75（s,3H），3.64(s,2H),3.40（m,4H）,1.31（m,2H），0.97（m,2H）0.30(s,3H).MS-ESI(M+H+)=312.15。
Step 4, 4-methyl-4- (4-methoxyphenyl) - [1,4] silapiperidine (target product Ia)
The intermediate 4 (223 g,0.64 mol) was dissolved in methanol (700 ml) in an autoclave, 15g of 10% palladium on carbon (containing 50% water) was added and the reaction was carried out under 2-3atm hydrogen pressure for 8-24h, with the temperature controlled at 35-50 ℃. TLC detection reaction, after the completion of the catalyst (recovery), the target product 4-methyl-4- (4-methoxyphenyl) - [1,4] silapiperidine as shown in formula Ia is obtained by evaporating the solvent, and the yield is 84-91%.
1H NMR（400MHz，DMSO）δ（ppm）=8.95(b,2H)，7.38(d,J=8.4,2H),6.77(d,J=8.4,2H),3.75（s,3H）3.21（m,4H）,1.32（m,2H），1.10（m,2H），0.38(s,3H).MS-ESI(M+H+)=222.10。
Example 4: preparation of 4-methyl-4- (4-methylphenyl) - [1,4] silapiperidine (No. 4)
Step 1, preparation of methyl- (4-methylphenyl) -divinylsilane (intermediate 2)
Starting material 1 methyl- (4-methylphenyl) -dichlorosilane (308 g,1.50 mol) was dissolved in 5000ml of anhydrous ether, and vinylmagnesium chloride (2000 ml, 1.6M) was added dropwise in an ice-water bath, maintaining the temperature at 0-20 ℃. After the dropwise addition, naturally raising the temperature and reacting for 8-16 h. After the reaction is finished, water is added at 0 ℃ for quenching, the solid is filtered out, the solvent is distilled off to obtain light brown liquid, namely methyl- (4-methylphenyl) -divinyl silane (intermediate product 2), and the yield is 82-85%.
1H NMR（400MHz，CDCl3）δ（ppm）=7.37(d,J=8.4,2H),7.04(d,J=8.4,2H),6.33(d,J=16,2H),6.13(d,J=16,2H),5.76(d,J=16,2H),2.35（s,3H），0.44(s,3H).MS-ESI(M+H+)=189.12
Step 2, preparation of methyl- (4-methylphenyl) -bis (2-bromoethyl) silane (intermediate 3)
Intermediate 2 (539 g,2.86 mol) obtained in step 1 above was dissolved in 5000ml of n-heptane, benzoyl peroxide (11.9 g,5 mmol) was added in portions, HBr gas was introduced, the temperature was maintained at 20-40 ℃ until the reaction solution became slightly orange, and HBr introduction was stopped. Washing the reaction solution with sodium carbonate aqueous solution, drying the reaction solution by anhydrous sodium sulfate, and evaporating the solvent to obtain brown liquid, namely methyl- (4-methylphenyl) -bis (2-bromoethyl) silane (intermediate product 3), wherein the yield is 88-93%.
1H NMR（400MHz，CDCl3），δ（ppm）=7.37(d,J=8.4,2H),7.04(d,J=8.4,2H),3.49（m,4H），2.34（s,3H），1.67（m,4H）,0.39(s,3H).MS-ESI(M+H+)=348.89。
Step 3, preparation of N-benzyl-4-methyl-4- (4-methylphenyl) - [1,4] silapiperidine (intermediate 4)
Intermediate 3 (217 g,0.62 mol) obtained in the above step 2, benzylamine (534 g) and triethylamine (261 ml) were dissolved in chloroform (6L) and reacted under reflux for 8 to 12 hours. Cooling the reaction liquid, washing with water, drying, evaporating to remove the solvent, and distilling the obtained residue under reduced pressure to obtain colorless liquid. The colorless liquid is dissolved in ethyl acetate and cooled to about 0 ℃, and HCl gas is introduced until the TLC detection reaction is complete. Filtering, washing the solid with ethyl acetate, and drying to obtain the hydrochloride of the N-benzyl-4-methyl-4- (4-methylphenyl) - [1,4] silapiperidine (intermediate 4), wherein the yield is 53-60%.
1H NMR（400MHz，DMSO）δ（ppm）=8.95(b,2H)，7.38(d,J=8.4,2H),7.06(d,J=8.4,2H),3.63(s,2H),3.22（m,4H）,2.35（s,3H）,1.33（m,2H），1.12（m,2H），0.40(s,3H).MS-ESI(M+H+)=296.20。
Step 4, 4-methyl-4- (4-methylphenyl) - [1,4] silapiperidine (target product Ia)
Intermediate 4 (212 g,0.64 mol) was dissolved in methanol (700 ml) in an autoclave, 15g of 10% palladium on carbon (containing 50% water) was added, and the reaction was carried out under 2-3atm hydrogen pressure for 8-24 hours with temperature control at 35-50 ℃. TLC detection reaction, after the completion of the catalyst (recovery), the target product 4-methyl-4- (4-methylphenyl) - [1,4] silapiperidine as shown in formula Ia is obtained by evaporating the solvent, and the yield is 84-91%.
1H NMR（400MHz，DMSO）δ（ppm）=8.97(b,2H)，7.37(d,J=8.4,2H),7.05(d,J=8.4,2H),2.33（s,3H）3.21（m,4H）,1.32（m,2H），1.11（m,2H），0.39(s,3H).MS-ESI(M+H+)=206.17。
Example 5: preparation of 4, 4-bis (4-fluorophenyl) - [1,4] silapiperidine (code 5)
Step 1, preparation of bis (4-fluorophenyl) -divinylsilane (intermediate 2)
Starting material 1 bis (4-fluorophenyl) -dichlorosilane (440 g,1.52 mol) was dissolved in 5000ml of anhydrous ether and vinylmagnesium chloride (2000 ml, 1.6M) was added dropwise under ice-water bath maintaining the temperature at 0-20 ℃. After the dropwise addition, naturally raising the temperature and reacting for 8-16 h. After the reaction is finished, water is added at 0 ℃ for quenching, solid is filtered out, and the solvent is distilled off to obtain light brown liquid, namely bis (4-fluorophenyl) -divinyl silane (intermediate product 2), wherein the yield is 83-87%.
1H NMR（400MHz，CDCl3）,δ（ppm）=7.46(d,J=8.4,4H),6.95(m，4H),6.32(d,J=16,2H),6.13(d,J=16,2H),5.76(d,J=16,2H),0.42(s,3H).MS-ESI(M+H+)=273.10。
Step 2, preparation of bis (4-fluorophenyl) -bis (2-bromoethyl) silane (intermediate 3)
The intermediate product 2 (782 g,2.87 mol) obtained in step 1 above was dissolved in 5000ml of n-heptane, benzoyl peroxide (12.1 g,5 mmol) was added in portions, HBr gas was introduced, the temperature was maintained at 20-40 deg.C, HBr introduction was stopped until the reaction solution became slightly orange. Washing the reaction solution with sodium carbonate aqueous solution, drying the reaction solution by anhydrous sodium sulfate, and evaporating the solvent to obtain brown liquid, namely bis (4-fluorophenyl) -bis (2-bromoethyl) silane (intermediate product 3), wherein the yield is 86-92%.
1H NMR（400MHz,CDCl3），δ（ppm）=7.46(d,J=8.4,4H),6.95(m,4H),3.49（m,4H），1.67（m,4H）,0.40(s,3H).MS-ESI(M+H+)=433.01。
Step 3, preparation of N-benzyl-4, 4-bis (4-fluorophenyl) - [1,4] silapiperidine (intermediate 4)
Intermediate 3 (269 g,0.62 mol) from step 2 above, benzylamine (534 g) and triethylamine (261 ml) were dissolved in chloroform (6L) and reacted under reflux for 8-12 h. Cooling the reaction liquid, washing with water, drying, evaporating to remove the solvent, and distilling the obtained residue under reduced pressure to obtain colorless liquid. The colorless liquid is dissolved in ethyl acetate and cooled to about 0 ℃, and HCl gas is introduced until the TLC detection reaction is complete. Filtering, washing the solid with ethyl acetate, and drying to obtain the hydrochloride of the N-benzyl-4, 4-bis (4-fluorophenyl) - [1,4] silapiperidine (intermediate 4), wherein the yield is 49-64%.
1H NMR（400MHz，DMSO），δ（ppm）=8.96(b,2H)，7.46(d,J=8.4,4H),6.95(m，4H),3.63(s,2H),3.43（m,4H）,1.31（m,2H），0.99（m,2H）0.32(s,3H).MS-ESI(M+H+)=,380.09。
Step 4,4, 4-bis (4-fluorophenyl) - [1,4] silapiperidine (target product Ia)
The intermediate 4 (209 g,0.64 mol) was dissolved in methanol (700 ml) in an autoclave, 15g of 10% palladium on carbon (containing 50% water) was added, and the reaction was carried out under 2-3atm hydrogen pressure for 8-24 hours with temperature control at 35-50 ℃. TLC detection reaction, after the completion of the reaction, the catalyst is filtered (recovered), and the solvent is distilled off to obtain the target product 4, 4-bis (4-fluorophenyl) - [1,4] silapiperidine shown in the formula Ia, wherein the yield is 88-93%.
1H NMR（400MHz，DMSO），δ（ppm）=8.96(b,2H)，7.46(d,J=8.4,4H),6.95(m，4H),3.21（m,4H）,1.32（m,2H），1.09（m,2H）0.40(s,3H).MS-ESI(M+H+)=290.07。
Example 6: preparation of 4-methyl-4- (3, 4-difluorophenyl) - [1,4] silapiperidine (code 6)
Step 1, preparation of methyl-4- (3, 4-difluorophenyl) -divinylsilane (intermediate 2)
Starting material 1 methyl-4- (3, 4-difluorophenyl) -dichlorosilane (345 g,1.52 mol) was dissolved in 5000ml of anhydrous ether, and vinylmagnesium chloride (2000 ml, 1.6M) was added dropwise in an ice-water bath, maintaining the temperature at 0-20 ℃. After the dropwise addition, naturally raising the temperature and reacting for 8-16 h. After the reaction is finished, water is added at 0 ℃ for quenching, the solid is filtered, the solvent is distilled off to obtain light brown liquid, namely methyl-4- (3, 4-difluorophenyl) -divinyl silane (intermediate product 2), and the yield is 85-89%.
1H NMR（400MHz，CDCl3），δ（ppm）=7.22(m，2H),6.91(m,1H),6.33(d,J=16,2H),6.14(d,J=16,2H),5.78(d,J=16,2H),0.43(s,3H).MS-ESI(M+H+)=211.10。
Step 2, preparation of methyl-4- (3, 4-difluorophenyl) -bis (2-bromoethyl) silane (intermediate 3)
Intermediate 2 (604 g,2.87 mol) from step 1 above was dissolved in 5000ml of n-heptane, benzoyl peroxide (12.0 g,5 mmol) was added in portions, HBr gas was introduced, the temperature was maintained at 20-40 deg.C, HBr introduction was stopped until the reaction solution became slightly orange. Washing the reaction solution with sodium carbonate aqueous solution, drying the reaction solution by anhydrous sodium sulfate, and evaporating the solvent to obtain brown liquid, namely methyl-4- (3, 4-difluorophenyl) -bis (2-bromoethyl) silane (intermediate product 3), wherein the yield is 89-93%.
1H NMR（400MHz，CDCl3），δ（ppm）=7.23(m，2H),6.92(m,1H),3.47（m,4H），1.68（m,4H）,0.39(s,3H).MS-ESI(M+H+)=370.93。
Step 3, preparation of N-benzyl-4-methyl-4- (3, 4-difluorophenyl) - [1,4] silapiperidine (intermediate 4)
Intermediate 3 (231 g,0.62 mol) obtained in the above step 2, benzylamine (534 g) and triethylamine (261 ml) were dissolved in chloroform (6L) and reacted under reflux for 8 to 12 hours. Cooling the reaction liquid, washing with water, drying, evaporating to remove the solvent, and distilling the obtained residue under reduced pressure to obtain colorless liquid. The colorless liquid is dissolved in ethyl acetate and cooled to about 0 ℃, and HCl gas is introduced until the TLC detection reaction is complete. Filtering, washing the solid with ethyl acetate, and drying to obtain hydrochloride of N-benzyl-4-methyl-4- (3, 4-difluorophenyl) - [1,4] silapiperidine (intermediate 4), wherein the yield is 47-61%.
1H NMR（400MHz，DMSO），δ（ppm）=8.95(b,2H)，7.26(m，7H),6.93(m,1H),3.64(s,2H),3.22（m,4H）,1.30（m,2H），1.10（m,2H）0.40(s,3H).MS-ESI(M+H+)=,318.14。
Step 4, preparation of 4, 4-methyl-4- (3, 4-difluorophenyl) - [1,4] silapiperidine (target product Ia)
Intermediate 4 (227 g,0.64 mol) was dissolved in methanol (700 ml) in an autoclave, 15g of 10% palladium on carbon (containing 50% water) was added, and the reaction was carried out under 2-3atm hydrogen pressure for 8-24 hours with temperature control at 35-50 ℃. TLC detection reaction, after the completion of the reaction, the catalyst is filtered (recovered), and the solvent is distilled off to obtain the target product 4-methyl-4- (3, 4-difluorophenyl) - [1,4] silapiperidine shown in the formula Ia, wherein the yield is 87-91%.
1H NMR（400MHz，DMSO），δ（ppm）=8.96(b,2H)，7.20(m，2H),6.91(m,1H),3.21（m,4H）,1.33（m,2H），1.08（m,2H）0.39(s,3H).MS-ESI(M+H+)=228.06。
Example 7: preparation of 4, 4-bis (4-methoxyphenyl) - [1,4] silapiperidine (code 7)
Step 1, preparation of bis (4-methoxyphenyl) -divinylsilane (intermediate 2)
Starting material 1 bis (4-methoxyphenyl) -dichlorosilane (476 g,1.52 mol) was dissolved in 5000ml of anhydrous ether and vinylmagnesium chloride (2000 ml, 1.6M) was added dropwise in an ice-water bath, maintaining the temperature at 0-20 ℃. After the dropwise addition, naturally raising the temperature and reacting for 8-16 h. After the reaction is finished, water is added at 0 ℃ for quenching, the solid is filtered out, the solvent is distilled off to obtain light brown liquid, namely the bis (4-methoxyphenyl) -divinyl silane (the intermediate product 2), and the yield is 82-86%.
1H NMR（400MHz，CDCl3），δ（ppm）=7.43(d,J=8.4,4H),6.84(d,J=8.4,4H),3.77（s,6H）,6.31(d,J=16,2H),6.13(d,J=16,2H),5.78(d,J=16,2H),0.42(s,3H).MS-ESI(M+H+)=297.11。
Step 2, preparation of bis (4-methoxyphenyl) -bis (2-bromoethyl) silane (intermediate 3)
Intermediate product 2 (851 g,2.87 mol) from step 1 above was dissolved in 5000ml of n-heptane, benzoyl peroxide (12.1 g,5 mmol) was added in portions, HBr gas was introduced, the temperature was maintained at 20-40 ℃ and HBr introduction was stopped until the reaction solution became slightly orange. Washing the reaction solution with sodium carbonate aqueous solution, drying the reaction solution by anhydrous sodium sulfate, and evaporating the solvent to obtain brown liquid, namely bis (4-methoxyphenyl) -bis (2-bromoethyl) silane (intermediate 3), wherein the yield is 88-93%.
1H NMR（400MHz，CDCl3），δ（ppm）=7.40(d,J=8.4,4H),6.81(d,J=8.4,4H),3.76（s,6H），3.49（m,4H），1.66（m,4H）,0.39(s,3H).MS-ESI(M+H+)=456.96。
Step 3, preparation of N-benzyl-4, 4-bis (4-methoxyphenyl) - [1,4] silapiperidine (intermediate 4)
Intermediate 3 (284 g,0.62 mol) obtained in step 2 above, benzylamine (534 g) and triethylamine (261 ml) were dissolved in chloroform (6L) and reacted under reflux for 8-12 h. Cooling the reaction liquid, washing with water, drying, evaporating to remove the solvent, and distilling the obtained residue under reduced pressure to obtain colorless liquid. The colorless liquid is dissolved in ethyl acetate and cooled to about 0 ℃, and HCl gas is introduced until the TLC detection reaction is complete. Filtering, washing the solid with ethyl acetate, and drying to obtain the hydrochloride of the N-benzyl-4, 4-di (4-methoxyphenyl) - [1,4] silapiperidine (intermediate 4), with the yield of 53-62%.
1H NMR（400MHz，DMSO），δ（ppm）=8.97(b,2H)，7.39(d,J=8.4,4H),7.27(m,5H),6.79(d,J=8.4,4H),3.75（s,6H）,3.63(s,2H),3.22（m,4H）,1.33（m,2H），1.13（m,2H）,0.40(s,3H).MS-ESI(M+H+)=,404.23。
Step 4,4, 4-bis (4-methoxyphenyl) - [1,4] silapiperidine (target product Ia)
Intermediate 4 (282 g,0.64 mol) was dissolved in methanol (700 ml) in an autoclave, 15g of 10% palladium on carbon (containing 50% water) was added, and the reaction was carried out under 2-3atm hydrogen pressure for 8-24 hours with temperature control at 35-50 ℃. TLC detection reaction, after finishing the reaction, filtering out the catalyst (recovering), evaporating to remove the solvent to obtain the target product 4, 4-di (4-methoxyphenyl) - [1,4] silapiperidine shown in the formula Ia with the yield of 83-91 percent.
1H NMR（400MHz，DMSO），δ（ppm）=8.96(b,2H)，7.39(d,J=8.4,4H),6.78(d,J=8.4,4H),3.74（s,6H）,3.21（m,4H）,1.30（m,2H），1.12（m,2H）0.39(s,3H).MS-ESI(M+H+)=314.15。
Example 8: preparation of 4-Ethyl-4- (4-fluorophenyl) - [1,4] silapiperidine (code 8)
Step 1, preparation of Ethyl-4- (4-fluorophenyl) -divinylsilane (intermediate 2)
Starting material 1 ethyl-4- (4-fluorophenyl) -dichlorosilane (339 g,1.52 mol) was dissolved in 5000ml of anhydrous ether and vinylmagnesium chloride (2000 ml, 1.6M) was added dropwise in an ice-water bath maintaining the temperature at 0-20 ℃. After the dropwise addition, naturally raising the temperature and reacting for 8-16 h. After the reaction is finished, water is added at 0 ℃ for quenching, the solid is filtered out, the solvent is distilled off to obtain light brown liquid, namely ethyl-4- (4-fluorophenyl) -divinyl silane (intermediate product 2), and the yield is 80-90%.
1H NMR（400MHz，CDCl3），δ（ppm）=7.49(d,J=8.4,2H),6.96(m，2H),6.32(d,J=16,2H),6.14(d,J=16,2H),5.77(d,J=16,2H),1.59(m,2H),0.90(s,3H).MS-ESI(M+H+)=207.07。
Step 2, preparation of Ethyl-4- (4-fluorophenyl) -bis (2-bromoethyl) silane (intermediate 3)
Intermediate 2 (592 g,2.87 mol) from step 1 above was dissolved in 5000ml of n-heptane, benzoyl peroxide (12.0 g,5 mmol) was added in portions, HBr gas was introduced, the temperature was maintained at 20-40 ℃ and HBr introduction was stopped until the reaction solution became slightly orange. Washing the reaction solution with sodium carbonate aqueous solution, drying the reaction solution by anhydrous sodium sulfate, and evaporating the solvent to obtain brown liquid, namely ethyl-4- (4-fluorophenyl) -bis (2-bromoethyl) silane (intermediate product 3), wherein the yield is 87-93%.
1H NMR（400MHz，CDCl3），δ（ppm）=7.48(d,J=8.4,2H),6.97(m，2H)，3.49（m,4H），1.67（m,4H）,1.59(m,2H),0.90(s,3H).MS-ESI(M+H+)=366.97。
Step 3, preparation of N-benzyl-4-ethyl-4- (4-fluorophenyl) - [1,4] silapiperidine (intermediate 4)
Intermediate 3 (228 g,0.62 mol) obtained in the above step 2, benzylamine (534 g) and triethylamine (261 ml) were dissolved in chloroform (6L) and reacted under reflux for 8 to 12 hours. Cooling the reaction liquid, washing with water, drying, evaporating to remove the solvent, and distilling the obtained residue under reduced pressure to obtain colorless liquid. The colorless liquid is dissolved in ethyl acetate and cooled to about 0 ℃, and HCl gas is introduced until the TLC detection reaction is complete. Filtering, washing the solid with ethyl acetate, and drying to obtain hydrochloride of the N-benzyl-4-ethyl-4- (4-fluorophenyl) - [1,4] silapiperidine (intermediate 4), wherein the yield is 49-67%.
1H NMR（400MHz，DMSO），δ（ppm）=8.96(b,2H)，7.47(d,J=8.4,2H),6.98(m，2H),3.65(s,2H),3.20（m,4H）,1.59(m,2H)，1.48（m,2H）,1.32（m,2H），1.11（m,2H）0.90(s,3H).MS-ESI(M+H+)=,314.16。
Step 4, 4-Ethyl-4- (4-fluorophenyl) - [1,4] silapiperidine (target product Ia)
The intermediate 4 (224 g,0.64 mol) was dissolved in methanol (700 ml) in an autoclave, 15g of 10% palladium on carbon (containing 50% water) was added and the reaction was carried out under 2-3atm hydrogen pressure for 8-24h, with the temperature controlled at 35-50 ℃. TLC detection reaction, after the completion of the reaction, the catalyst is filtered (recovered), and the solvent is distilled off to obtain the target product 4-ethyl-4- (4-fluorophenyl) - [1,4] silapiperidine shown in the formula Ia, wherein the yield is 84-91%.
1H NMR（400MHz，DMSO），δ（ppm）=8.94(b,2H)，7.46(d,J=8.4,2H),6.96(m，2H),3.22（m,4H）,1.58(m,2H)，1.49（m,2H）,1.33（m,2H），1.10（m,2H）0.89(s,3H).MS-ESI(M+H+)=224.09。
The compound with the number of 9-10 is prepared into a target product shown in the formula Ib according to the following synthetic route:
Figure BDA00002278602400191
example 9: preparation of 4, 4-dimethyl-1-piperidin-4-yl- [1,4] silapiperidine (code 9)
Step 1, preparation of dimethyl-divinylsilane (intermediate 2)
Starting material 1 dimethyl-dichlorosilane (196 g,1.52 mol) was dissolved in 5000ml of anhydrous ether and vinylmagnesium chloride (2000 ml, 1.6M) was added dropwise in an ice-water bath, maintaining the temperature at 0-20 ℃. After the dropwise addition, naturally raising the temperature and reacting for 8-16 h. After the reaction is finished, water is added at 0 ℃ for quenching, the solid is filtered out, the solvent is distilled off to obtain light brown liquid, namely dimethyl-divinyl silane (intermediate product 2), and the yield is 85-90%.
1H NMR（400MHz，CDCl3），δ（ppm）=6.42(d,J=16,2H),6.22(d,J=16,2H),5.85(d,J=16,2H),0.44(s,6H).MS-ESI(M+H+)=113.12。
Step 2, preparation of dimethyl-bis (2-bromoethyl) silane (intermediate 3)
Intermediate 2 (500 g, 4.45 mol) from step 1 above was dissolved in 5000ml of n-heptane, benzoyl peroxide (13.3 g, 5.5 mmol) was added in portions, HBr gas was introduced, the temperature was maintained at 20-40 ℃ and HBr introduction was stopped until the reaction solution became slightly orange. Washing the reaction solution with sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, evaporating to remove the solvent to obtain brown liquid, namely dimethyl-di (2-bromoethyl) silane (intermediate product 3), with the yield of 85-91%.
1H NMR（400MHz，CDCl3），δ（ppm）=3.51（m,4H），1.68（m,4H）,0.40(s,6H).MS-ESI(M+H+)=272.94。
Step 3, preparation of N-benzyl-4, 4-dimethyl- [1,4] silapiperidine (intermediate 4)
Intermediate 3 (170 g,0.62 mol) obtained in step 2 above, benzylamine (534 g) and triethylamine (261 ml) were dissolved in chloroform (6L) and reacted under reflux for 8-12 h. Cooling the reaction liquid, washing with water, drying, evaporating to remove the solvent, and distilling the obtained residue under reduced pressure to obtain colorless liquid. The colorless liquid is dissolved in ethyl acetate and cooled to about 0 ℃, and HCl gas is introduced until the TLC detection reaction is complete. Filtering, washing the solid with ethyl acetate, and drying to obtain the hydrochloride of the N-benzyl-4, 4-dimethyl- [1,4] silapiperidine (intermediate 4), wherein the yield is 53-61%.
1HNMR（400MHz，DMSO）δ（ppm）=2.82（m,4H）,1.33（m,2H），0.99（m,2H）0.33(s,6H).MS-ESI(M+H+)=220.11。
Step 4,4, 4-dimethyl- [1,4] silapiperidine (target product Ia)
Intermediate 4 (205 g, 0.8 mol) was dissolved in methanol (700 ml) in an autoclave, 15g of 10% palladium on carbon (containing 50% water) was added, and the reaction was carried out under 2-3atm hydrogen pressure for 8-24 hours with temperature control at 35-50 ℃. TLC detection reaction, after the completion of the reaction, the catalyst is filtered (recovered), and the solvent is distilled off to obtain the target product 4, 4-dimethyl- [1,4] silapiperidine shown in the formula Ia with the yield of 84-91%.
1H NMR（400MHz，CDCl3），δ（ppm）=8.91(b,2H),3.22（m,4H）,1.13（m,2H），1.34（m,2H）0.39(s,6H).MS-ESI(M+H+)=130.08。
Step 5, preparation of 4, 4-dimethyl-1- (piperidin-4-yl) - [1,4] silapiperidine (target product Ib)
First, the target product of the formula Ia obtained in step 4 (25.8 g, 0.2 mol) and 4-tert-butoxycarbonylpiperidinone (68.8 g, 0.22 mol) were dissolved in 250ml of anhydrous methanol, and sodium cyanoborohydride (25.2 g, 0.4 mol) was added in portions at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent is removed by evaporation, and the residue is subjected to silica gel column chromatography to obtain a white solid, namely the intermediate product shown in the formula 5, with the yield of 83-88%.
1H NMR（400MHz，CDCl3），δ（ppm）=3.35(m,4H),2.72(m,4H),2.60(m,1H),1.63(m,2H),1.45(m,2H),1.39(s,9H),0.88(m,4H),0.39(s,6H).MS-ESI(M+H+)=313.10。
Then, the intermediate product of formula 5 (31.3 g, 0.1 mol) was dissolved in 300ml of dichloromethane, and 100ml of 4mol/L hydrochloric acid methanol solution was added dropwise at 0-5 ℃. Concentrating, washing the obtained solid with diethyl ether, dissolving in water, alkalifying with 2N NaOH solution to pH =12, extracting with dichloromethane, and concentrating to obtain white solid, namely the target product 4, 4-dimethyl-1- (piperidine-4-yl) - [1,4] silapiperidine shown in formula Ib with the yield of 87-92%.
1H NMR（400MHz，CDCl3），δ（ppm）=2.75(m,4H),2.61(m,1H),2.54(m,4H),2.2(br,1H),1.61(m,2H),1.42(m,2H),0.87(m,4H),0.41(s,6H).MS-ESI(M+H+)=213.28。
Example 10: preparation of 4-methyl-4-phenyl-1- (piperidin-4-yl) - [1,4] silapiperidine (code 10)
Step 1, preparation of methylphenyl-divinyl silane (intermediate 2)
Starting material 1 methylphenyl-dichlorosilane (249.3 g,1.52 mol) was dissolved in 5000ml of anhydrous ether and vinylmagnesium chloride (2000 ml, 1.6M) was added dropwise in an ice-water bath, maintaining the temperature at 0-20 ℃. After the dropwise addition, naturally raising the temperature and reacting for 8-16 h. After the reaction is finished, water is added at 0 ℃ for quenching, the solid is filtered out, and the solvent is distilled off to obtain light brown liquid, namely the methyl phenyl-divinyl silane (the intermediate product 2), wherein the yield is 82-89%.
1HNMR（400MHz，CDCl3）,δ（ppm）=7.53(m2H),7.36(m 3H),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+)=175.12。
Step 2, preparation of methylphenyl-bis (2-bromoethyl) silane (intermediate 3)
Intermediate 2 (500 g,2.87 mol) from step 1 above was dissolved in 5000ml of n-heptane, benzoyl peroxide (12.1 g,5 mmol) was added in portions, HBr gas was introduced, the temperature was maintained at 20-40 ℃ and HBr introduction was stopped until the reaction solution became slightly orange. Washing the reaction solution with sodium carbonate aqueous solution, drying with anhydrous sodium sulfate, evaporating to remove the solvent to obtain brown liquid, namely the methyl phenyl-bis (2-bromoethyl) silane (intermediate product 3), wherein the yield is 87-93%.
1H NMR（400MHz，CDCl3），δ（ppm）=7.45(m 5H),3.49（m,4H），1.66（m,4H）,0.39(s,3H).MS-ESI(M+H+)=334.96。
Step 3, preparation of N-benzyl-4-methyl-4-phenyl- [1,4] silapiperidine (intermediate 4)
Intermediate 3 (210 g,0.62 mol) obtained in the above step 2, benzylamine (534 g) and triethylamine (261 ml) were dissolved in chloroform (6L) and reacted under reflux for 8 to 12 hours. Cooling the reaction liquid, washing with water, drying, evaporating to remove the solvent, and distilling the obtained residue under reduced pressure to obtain colorless liquid. The colorless liquid is dissolved in ethyl acetate and cooled to about 0 ℃, and HCl gas is introduced until the TLC detection reaction is complete. Filtering, washing the solid with ethyl acetate, and drying to obtain the hydrochloride of the N-benzyl-4-methyl-4-phenyl- [1,4] silapiperidine (intermediate 4), wherein the yield is 51-65%.
1HNMR（400MHz，DMSO），δ（ppm）=7.37(m 10H),2.80（m,4H）,1.31（m,2H），0.96（m,2H）0.31(s,3H).MS-ESI(M+H+)=282.09。
Step 4, 4-methyl-4-phenyl- [1,4] silapiperidine (target product Ia)
The intermediate 4 (200 g,0.64 mol) was dissolved in methanol (700 ml) in an autoclave, 15g of 10% palladium on carbon (containing 50% water) was added and the reaction was carried out under 2-3atm hydrogen pressure for 8-24h with temperature control at 35-50 ℃. TLC detection reaction, after the completion of the reaction, the catalyst is filtered (recovered), and the solvent is distilled off, thus obtaining the target product 4-methyl-4-phenyl- [1,4] silapiperidine shown in the formula Ia with the yield of 84-91%.
1H NMR（400MHz，DMSO），δ（ppm）=8.97(b,2H)7.59(m 2H),7.40(m 3H),3.20（m,4H）,1.10（m,2H），1.32（m,2H）0.38(s,3H).MS-ESI(M+H+)=192.13。
Step 5, preparation of 4-methyl-4-phenyl-1- (piperidin-4-yl) - [1,4] silapiperidine (target product Ib)
First, the target product of the formula Ia obtained in step 4 (38.2 g, 0.2 mol) and 4-tert-butoxycarbonylpiperidinone (68.8 g, 0.22 mol) were dissolved in 250ml of anhydrous methanol, and sodium cyanoborohydride (25.2 g, 0.4 mol) was added in portions at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent is removed by evaporation, and the residue is subjected to silica gel column chromatography to obtain a white solid, namely the intermediate product shown in the formula 5, wherein the yield is 85-86%.
1H NMR（400MHz，CDCl3），δ（ppm）=7.59(m，2H),7.40(m，3H),3.31(m,4H),2.74(m,4H),2.60(m,1H),1.38(s,9H),1.28(m,2H),1.12(m,2H),0.89(m,4H),0.41(s,3H)..MS-ESI(M+H+)=375.29。
Then, the intermediate product of formula 5 (37.4 g, 0.1 mol) was dissolved in 300ml of dichloromethane and 100ml of 4mol/L hydrochloric acid methanol solution was added dropwise at 0-5 ℃. Concentrating, washing the obtained solid with ether, dissolving in water, alkalifying with 2N NaOH solution to pH =12, extracting with dichloromethane, and concentrating to obtain white solid, namely the target product 4-methyl-4-phenyl-1- (piperidine-4-yl) - [1,4] silapiperidine shown in formula Ib with the yield of 89-91%.
1H NMR（400MHz，CDCl3），δ（ppm）=7.61(m，2H),7.45(m，3H),2.79(m,4H),2.65(m,1H),2.56(m,4H),2.30（br,1H）,1.30(m,2H),1.16(m,2H),0.91(m,4H),0.44(s,3H).MS-ESI(M+H+)=274.31。
It should be appreciated by those skilled in the art that the present invention is not limited to the above embodiments, and any changes and modifications to the present invention are within the scope of the present invention.

Claims (10)

1.一种硅杂哌啶衍生物或其药学上可接受的盐或溶剂化物，具有如下结构通式（Ⅰ）：1. A silapiperidine derivative or a pharmaceutically acceptable salt or solvate thereof, having the following general structural formula (I):
Figure FDA00002278602300011
Figure FDA00002278602300011
 其中，R1选自H或
Figure FDA00002278602300012
Wherein, R 1 is selected from H or
Figure FDA00002278602300012
 R2、R3各自独立地选自H、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、C1-10带取代基的烷基、C2-10带取代基的烯基、C2-10带取代基的炔基、C3-10带取代基的环烷基、C1-10的醚、芳基，以及任选取代的芳基或杂芳基；所述取代基为羟基、硝基、氨基、羧基、卤原子、巯基、C1-6烷硫基、C1-6烷氧基、C1-6烷氧基羰基、酰胺基中的一种或几种；所述芳基或杂芳基上取代的基团为羟基、氨基、硝基、卤原子、C1-6烷基、C1-6烷硫基、C1-6烷氧基、羧基中的一种或几种；R 2 and R 3 are each independently selected from H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 1-10 substituted alkyl C 2-10 substituted alkenyl, C 2-10 substituted alkynyl, C 3-10 substituted cycloalkyl, C 1-10 ether, aryl, and optionally substituted aryl or heteroaryl; the substituents are hydroxyl, nitro, amino, carboxyl, halogen, mercapto, C 1-6 alkylthio, C 1-6 alkoxy, C 1-6 alkoxy One or more of carbonyl and amide groups; the substituted groups on the aryl or heteroaryl are hydroxyl, amino, nitro, halogen, C 1-6 alkyl, C 1-6 alkylthio One or more of C 1-6 alkoxy, carboxyl; R4选自C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、C1-10带取代基的烷基、C2-10带取代基的烯基、C2-10带取代基的炔基、C3-10带取代基的环烷基、芳基或任选取代的芳基；所述取代基为羟基、硝基、氨基、羧基、卤原子、巯基、C1-6烷硫基、C1-6烷氧基、C1-6烷氧基羰基、酰胺基中的一种或几种；所述芳基上取代的基团为羟基、氨基、硝基、卤原子、C1-6烷基、C1-6烷硫基、C1-6烷氧基、羧基中的一种或几种；R 4 is selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 1-10 substituted alkyl, C 2-10 substituted Alkenyl, C 2-10 substituted alkynyl, C 3-10 substituted cycloalkyl, aryl or optionally substituted aryl; the substituents are hydroxyl, nitro, amino, One or more of carboxyl, halogen atom, mercapto, C 1-6 alkylthio, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, amido; the group substituted on the aryl The group is one or more of hydroxyl, amino, nitro, halogen, C 1-6 alkyl, C 1-6 alkylthio, C 1-6 alkoxy, carboxyl; 但不包括以下化合物：However, the following compounds are not included: 4,4-二甲基-[1,4]硅杂哌啶；4,4-Dimethyl-[1,4]silapiperidine; 4,4-二苯基-[1,4]硅杂哌啶；4,4-Diphenyl-[1,4]silapiperidine; 4-甲基-4-苯基-[1,4]硅杂哌啶；4-Methyl-4-phenyl-[1,4]silapiperidine; 4,4-二(4-氯苯基)-[1,4]硅杂哌啶。4,4-bis(4-chlorophenyl)-[1,4]silapiperidine. 2.根据权利要求1所述的硅杂哌啶衍生物或其药学上可接受的盐或溶剂化物，其特征在于，所述通式（Ⅰ）中：2. The silapiperidine derivative or its pharmaceutically acceptable salt or solvate according to claim 1, characterized in that, in the general formula (I): R1为H； R1 is H; R2为H或C1-6烷基；R 2 is H or C 1-6 alkyl; R3为C2-10烷基、C3-10环烷基、C2-10带取代基的烷基、C3-10带取代基的环烷基、芳基，以及任选取代的芳基或杂芳基；所述取代基为羟基、硝基、氨基、羧基、卤原子、巯基、C1-6烷硫基、C1-6烷氧基、C1-6烷氧基羰基、酰胺基中的一种或几种；所述芳基或杂芳基上取代的基团为羟基、氨基、硝基、卤原子、C1-6烷基、C1-6烷硫基、C1-6烷氧基、羧基中的一种或几种；R 3 is C 2-10 alkyl, C 3-10 cycloalkyl, C 2-10 substituted alkyl, C 3-10 substituted cycloalkyl, aryl, and optionally substituted aryl or heteroaryl; the substituents are hydroxyl, nitro, amino, carboxyl, halogen, mercapto, C 1-6 alkylthio, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, One or more of amido groups; the group substituted on the aryl or heteroaryl is hydroxyl, amino, nitro, halogen atom, C 1-6 alkyl, C 1-6 alkylthio, C One or more of 1-6 alkoxy groups and carboxyl groups; R4为C1-10烷基、C3-10环烷基、C1-10带取代基的烷基、C3-10带取代基的环烷基、芳基或任选取代的芳基或杂芳基；所述取代基为羟基、硝基、氨基、羧基、卤原子、巯基、C1-6烷硫基、C1-6烷氧基、C1-6烷氧基羰基、酰胺基中的一种或几种；所述芳基或杂芳基上取代的基团为羟基、氨基、硝基、卤原子、C1-6烷基、C1-6烷硫基、C1-6烷氧基、羧基中的一种或几种。R 4 is C 1-10 alkyl, C 3-10 cycloalkyl, C 1-10 substituted alkyl, C 3-10 substituted cycloalkyl, aryl or optionally substituted aryl or heteroaryl; said substituent is hydroxyl, nitro, amino, carboxyl, halogen atom, mercapto, C 1-6 alkylthio, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, amide one or more of the radicals; the substituted groups on the aryl or heteroaryl are hydroxyl, amino, nitro, halogen atom, C 1-6 alkyl, C 1-6 alkylthio, C 1 -One or more of 6 alkoxy groups and carboxyl groups. 3.根据权利要求2所述的硅杂哌啶衍生物或其药学上可接受的盐或溶剂化物，其特征在于，所述通式（Ⅰ）中：3. The silapiperidine derivative or its pharmaceutically acceptable salt or solvate according to claim 2, characterized in that, in the general formula (I): R1为H； R1 is H; R2为H或C1-6烷基；R 2 is H or C 1-6 alkyl; R3为C2-10烷基、C2-10带取代基的烷基、C3-10带取代基的环烷基、苯基，以及任选取代的苯基或杂芳基；所述取代基为羟基、硝基、氨基、羧基、卤原子、甲硫基、甲氧基、甲烷氧基羰基、酰胺基中的一种或几种；所述苯基或杂芳基上取代的基团为羟基、氨基、硝基、卤原子、C1-6烷基、甲硫基、甲氧基、羧基中的一种或几种；R 3 is C 2-10 alkyl, C 2-10 substituted alkyl, C 3-10 substituted cycloalkyl, phenyl, and optionally substituted phenyl or heteroaryl; the The substituent is one or more of hydroxyl, nitro, amino, carboxyl, halogen atom, methylthio, methoxy, methaneoxycarbonyl, amido; the substituted group on the phenyl or heteroaryl The group is one or more of hydroxyl, amino, nitro, halogen, C 1-6 alkyl, methylthio, methoxy, carboxyl; R4为C1-10烷基、C1-10带取代基的烷基或任选取代的苯基；所述取代基为羟基、羧基、卤原子、甲氧基、甲烷氧基羰基中的一种或几种；所述苯基上取代的基团为羟基、卤原子、C1-6烷基、甲氧基中的一种或几种。R 4 is C 1-10 alkyl, C 1-10 substituted alkyl or optionally substituted phenyl; the substituent is hydroxyl, carboxyl, halogen atom, methoxy, methoxycarbonyl One or more; the substituted group on the phenyl is one or more of hydroxyl, halogen atom, C 1-6 alkyl and methoxy. 4.根据权利要求3所述的硅杂哌啶衍生物或其药学上可接受的盐或溶剂化物，其特征在于，所述卤原子为F或Br。4. The silapiperidine derivative or a pharmaceutically acceptable salt or solvate thereof according to claim 3, wherein the halogen atom is F or Br. 5.根据权利要求1所述的硅杂哌啶衍生物或其药学上可接受的盐或溶剂化物，其特征在于，所述通式（Ⅰ）中：5. The silapiperidine derivative or its pharmaceutically acceptable salt or solvate according to claim 1, characterized in that, in the general formula (I): R1为
Figure FDA00002278602300021
 R1 is
Figure FDA00002278602300021
 R2为H或C1-6烷基；R 2 is H or C 1-6 alkyl; R3为C1-10烷基、C1-10带取代基的烷基、苯基，以及任选取代的苯基或杂芳基；所述取代基为羟基、硝基、氨基、羧基、卤原子、甲硫基、甲氧基、甲烷氧基羰基、酰胺基中的一种或几种；所述苯基或杂芳基上取代的基团为羟基、氨基、硝基、卤原子、C1-6烷基、甲硫基、甲氧基、羧基中的一种或几种；R 3 is C 1-10 alkyl, C 1-10 substituted alkyl, phenyl, and optionally substituted phenyl or heteroaryl; the substituents are hydroxyl, nitro, amino, carboxyl, One or more of halogen atom, methylthio group, methoxy group, methaneoxycarbonyl group, amido group; the group substituted on the phenyl or heteroaryl group is hydroxyl, amino group, nitro group, halogen atom, One or more of C 1-6 alkyl, methylthio, methoxy, carboxyl; R4为C1-10烷基、C1-10带取代基的烷基、苯基，以及任选取代的苯基或杂芳基；所述取代基为羟基、硝基、氨基、羧基、卤原子、甲硫基、甲氧基、甲烷氧基羰基、酰胺基中的一种或几种；所述苯基或杂芳基上取代的基团为羟基、氨基、硝基、卤原子、C1-6烷基、甲硫基、甲氧基、羧基中的一种或几种。R 4 is C 1-10 alkyl, C 1-10 substituted alkyl, phenyl, and optionally substituted phenyl or heteroaryl; the substituents are hydroxyl, nitro, amino, carboxyl, One or more of halogen atom, methylthio group, methoxy group, methaneoxycarbonyl group, amido group; the group substituted on the phenyl or heteroaryl group is hydroxyl, amino group, nitro group, halogen atom, One or more of C 1-6 alkyl, methylthio, methoxy, and carboxyl. 6.根据权利要求5所述的硅杂哌啶衍生物或其药学上可接受的盐或溶剂化物，其特征在于，所述卤原子为F、Cl或Br。6. The silapiperidine derivative or a pharmaceutically acceptable salt or solvate thereof according to claim 5, wherein the halogen atom is F, Cl or Br. 7.根据权利要求1~6任一项所述的硅杂哌啶衍生物或其药学上可接受的盐或溶剂化物，其特征在于，所述杂芳基选自如下基团：2-呋喃，3-呋喃，2-噻吩，3-噻吩，2-吡啶，3-吡啶，4-吡啶，2-吡咯或3-吡咯。7. The silapiperidine derivative or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 6, wherein the heteroaryl group is selected from the following groups: 2-furan , 3-furan, 2-thiophene, 3-thiophene, 2-pyridine, 3-pyridine, 4-pyridine, 2-pyrrole or 3-pyrrole. 8.根据权利要求7所述的硅杂哌啶衍生物或其药学上可接受的盐或溶剂化物，其特征在于，选自如下化合物：8. The silapiperidine derivative or its pharmaceutically acceptable salt or solvate according to claim 7, characterized in that it is selected from the following compounds: 编号1：4-甲基-4-(4-氟苯基)-[1,4]硅杂哌啶；Code 1: 4-methyl-4-(4-fluorophenyl)-[1,4]silapiperidine; 编号2：4-甲基-4-(4-三氟甲基苯基)-[1,4]硅杂哌啶；Code 2: 4-methyl-4-(4-trifluoromethylphenyl)-[1,4]silapiperidine; 编号3：4-甲基-4-(4-甲氧基苯基)-[1,4]硅杂哌啶；Code 3: 4-methyl-4-(4-methoxyphenyl)-[1,4]silapiperidine; 编号4：4-甲基-4-(4-甲基苯基)-[1,4]硅杂哌啶；Code 4: 4-methyl-4-(4-methylphenyl)-[1,4]silapiperidine; 编号5：4,4-二-(4-氟苯基)-[1,4]硅杂哌啶；Code 5: 4,4-bis-(4-fluorophenyl)-[1,4]silapiperidine; 编号6：4-甲基-4-(3,4-二氟苯基)-[1,4]硅杂哌啶；Code 6: 4-methyl-4-(3,4-difluorophenyl)-[1,4]silapiperidine; 编号7：4，4-二-(4-甲氧基苯基)-[1,4]硅杂哌啶；Code 7: 4,4-bis-(4-methoxyphenyl)-[1,4]silapiperidine; 编号8：4-乙基-4-(4-氟苯基)-[1,4]硅杂哌啶；Code 8: 4-ethyl-4-(4-fluorophenyl)-[1,4]silapiperidine; 编号9：4,4-二甲基-1-(哌啶-4-基)-[1,4]硅杂哌啶；Number 9: 4,4-Dimethyl-1-(piperidin-4-yl)-[1,4]silapiperidine; 编号10：4-甲基-4-苯基-1-(哌啶-4-基)-[1,4]硅杂哌啶。Code 10: 4-Methyl-4-phenyl-1-(piperidin-4-yl)-[1,4]silapiperidine. 9.一种制备如权利要求1所述通式（Ⅰ）的硅杂哌啶衍生物或其药学上可接受的盐或溶剂化物的方法，其按如下步骤：9. A method for preparing a silapiperidine derivative of general formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt or solvate thereof, comprising the following steps: （1）将烷基卤化镁与式1的二氯取代硅烷溶于有机溶剂，经格氏反应后得到式2的二乙烯基取代硅烷，反应式见下：(1) Dissolve the alkyl magnesium halide and the dichloro-substituted silane of formula 1 in an organic solvent, and obtain the divinyl-substituted silane of formula 2 after Grignard reaction. The reaction formula is as follows: 所述有机溶剂为无水乙醚、四氢呋喃、甲苯溶液中的一种或几种；The organic solvent is one or more of anhydrous ether, tetrahydrofuran, toluene solution; 所述烷基卤化镁为氯乙烯基镁或溴乙烯基镁；The alkyl magnesium halide is vinyl magnesium chloride or vinyl magnesium bromide; （2）步骤（1）所得的二乙烯基取代硅烷溶于有机溶剂，经反马氏加成反应后得到式3的二（2-溴乙基）取代硅烷，反应式如下：(2) The divinyl-substituted silane obtained in step (1) is dissolved in an organic solvent, and the bis(2-bromoethyl)-substituted silane of formula 3 is obtained after reverse Markov addition reaction, and the reaction formula is as follows:
Figure FDA00002278602300032
Figure FDA00002278602300032
 所述有机溶剂为石油醚、正己烷、正庚烷或环己烷中的一种或几种；The organic solvent is one or more of petroleum ether, n-hexane, n-heptane or cyclohexane; （3）步骤（2）所得的二（2-溴乙基）取代硅烷溶于有机溶剂，与苄胺在碱性条件下经环化反应后，用乙酸乙酯或甲醇洗涤，得到式4的N-苄基取代硅杂哌啶，反应式如下：(3) The bis(2-bromoethyl) substituted silane obtained in step (2) is dissolved in an organic solvent, and after a cyclization reaction with benzylamine under basic conditions, it is washed with ethyl acetate or methanol to obtain the compound of formula 4 N-benzyl substituted sila piperidine, the reaction formula is as follows:
Figure FDA00002278602300041
Figure FDA00002278602300041
 所述有机溶剂为氯仿、二氧六环、N,N-二甲基甲酰胺中的一种或几种；The organic solvent is one or more of chloroform, dioxane, and N,N-dimethylformamide; （4）步骤（3）所得的N-苄基取代硅杂哌啶溶于有机溶剂，在催化剂下经氢化反应脱苄得到式（Ⅰa）的目标产物，反应式如下：(4) The N-benzyl substituted silapiperidine obtained in step (3) is dissolved in an organic solvent, and debenzylated under a catalyst to obtain the target product of formula (Ia). The reaction formula is as follows:
Figure FDA00002278602300042
Figure FDA00002278602300042
 所述有机溶剂为甲醇、乙醇、异丙醇中的一种或几种；Described organic solvent is one or more in methanol, ethanol, Virahol; 所述催化剂为钌、镍、铂、钯中的一种或几种；The catalyst is one or more of ruthenium, nickel, platinum and palladium; （5）步骤（4）所得式（Ⅰa）的目标产物溶于有机溶剂，与N-Boc-哌啶-4-酮经胺化还原反应得到式5的1-(叔丁氧羰基)-4-(硅杂哌啶基)哌啶，然后在酸性条件下脱除Boc保护基，并经碱中和得到式（Ⅰb）的目标产物，反应式如下：(5) The target product of formula (Ia) obtained in step (4) is dissolved in an organic solvent, and reacted with N-Boc-piperidin-4-one through amination reduction reaction to obtain 1-(tert-butoxycarbonyl)-4 of formula 5 -(silapiperidinyl) piperidine, then remove the Boc protecting group under acidic conditions, and obtain the target product of formula (Ib) through alkali neutralization, the reaction formula is as follows:
Figure FDA00002278602300043
Figure FDA00002278602300043
 所述有机溶剂为甲醇、四氢呋喃、二氯甲烷、氯仿、二氧六环、乙酸乙酯、二氯甲烷中的一种或几种；The organic solvent is one or more of methanol, tetrahydrofuran, methylene chloride, chloroform, dioxane, ethyl acetate, and methylene chloride; 所述还原剂为氰基硼氢化钠、三乙酰氧基硼氢化钠中的一种或几种；The reducing agent is one or more of sodium cyanoborohydride and sodium triacetoxyborohydride; 上述步骤（1）~（5）的反应式中，R2、R3各自独立地选自H、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、C1-10带取代基的烷基、C2-10带取代基的烯基、C2-10带取代基的炔基、C3-10带取代基的环烷基、C1-10的醚、芳基，以及任选取代的芳基或杂芳基；所述取代基为羟基、硝基、氨基、羧基、卤原子、巯基、C1-6烷硫基、C1-6烷氧基、C1-6烷氧基羰基、酰胺基中的一种或几种；所述芳基或杂芳基上取代的基团为羟基、氨基、硝基、卤原子、C1-6烷基、C1-6烷硫基、C1-6烷氧基、羧基中的一种或几种；In the reaction formula of the above steps (1)~(5), R 2 and R 3 are each independently selected from H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3- 10 cycloalkyl, C 1-10 substituted alkyl, C 2-10 substituted alkenyl, C 2-10 substituted alkynyl, C 3-10 substituted cycloalkyl, C 1-10 ether, aryl, and optionally substituted aryl or heteroaryl; said substituent is hydroxyl, nitro, amino, carboxyl, halogen atom, mercapto, C 1-6 alkylthio, C One or more of 1-6 alkoxy, C 1-6 alkoxycarbonyl, amido; the group substituted on the aryl or heteroaryl is hydroxyl, amino, nitro, halogen atom, One or more of C 1-6 alkyl, C 1-6 alkylthio, C 1-6 alkoxy, carboxyl; R4选自C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、C1-10带取代基的烷基、C2-10带取代基的烯基、C2-10带取代基的炔基、C3-10带取代基的环烷基、芳基或任选取代的芳基；所述取代基为羟基、硝基、氨基、羧基、卤原子、巯基、C1-6烷硫基、C1-6烷氧基、C1-6烷氧基羰基、酰胺基中的一种或几种；所述芳基上取代的基团为羟基、氨基、硝基、卤原子、C1-6烷基、C1-6烷硫基、C1-6烷氧基、羧基中的一种或几种。R 4 is selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 1-10 substituted alkyl, C 2-10 substituted Alkenyl, C 2-10 substituted alkynyl, C 3-10 substituted cycloalkyl, aryl or optionally substituted aryl; the substituents are hydroxyl, nitro, amino, One or more of carboxyl, halogen atom, mercapto, C 1-6 alkylthio, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, amido; the group substituted on the aryl The group is one or more of hydroxyl group, amino group, nitro group, halogen atom, C 1-6 alkyl group, C 1-6 alkylthio group, C 1-6 alkoxy group, and carboxyl group. 10.一种药物组合物，它包含药物有效量的如权利要求1~8任一项所述的硅杂哌啶衍生物或其药学上可接受的盐或溶剂化物，以及药学上可接受的赋形剂或添加剂。10. A pharmaceutical composition comprising a pharmaceutically effective amount of the silapiperidine derivative or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 8, and a pharmaceutically acceptable excipients or additives.
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TILMAN HEINRICH等，: "4-Silapiperidine and 4-silapiperidinium derivatives: syntheses and structural characterization", 《JOURNAL OF ORGANOMETALLIC CHEMISTRY》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116969986A (en) * 2023-06-13 2023-10-31 四川大学 1,4-Si-nitrogen heterocyclic compounds and their synthesis methods and applications

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