CN103772425B - Sila piperidine derivative and preparation method thereof and purposes - Google Patents

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

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:

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,

as is known from the above-mentioned route of the semi-synthetic method, camptothecin 1 is usually used as a starting material to be alkylated at the 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, promingNovel Compounds 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:

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):

wherein,

R₁is selected from H or

R₂，R₃Each independently selected from H, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_1-10Alkyl with substituents, C_2-10Alkenyl with substituents, C_2-10Alkynyl with substituents, C_3-10Cycloalkyl with substituents, C_1-10And optionally substituted aryl or heteroaryl; the substituent is hydroxyl, nitryl, amino, carboxyl, halogen atom, sulfydryl and C_1-6Alkylthio radical, C_1-6Alkoxy radical、C_1-6One or more of alkoxycarbonyl and amide; the substituted group on the aryl or heteroaryl is hydroxyl, amino, nitro, halogen atom, C_1-6Alkyl radical, C_1-6Alkylthio radical, C_1-6One or more of alkoxy and carboxyl;

R₄is selected from C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_1-10Alkyl with substituents, C_2-10Alkenyl with substituents, C_2-10Alkynyl with substituents, C_3-10A substituted cycloalkyl, aryl or optionally substituted aryl; the substituent is hydroxyl, nitryl, amino, carboxyl, halogen atom, sulfydryl and C_1-6Alkylthio radical, C_1-6Alkoxy radical, C_1-6One or more of alkoxycarbonyl and amide; the substituted group on the aryl is hydroxyl, amino, nitro, halogen atom, C_1-6Alkyl radical, C_1-6Alkylthio radical, C_1-6One 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 timeStructure, wherein: r₂Is H or C_1-6An alkyl group;

R₃is C_2-10Alkyl radical, C_3-10Cycloalkyl radical, C_2-10Alkyl with substituents, C_3-10Cycloalkyl with substituents, aryl, and optionallyA substituted aryl or heteroaryl group; the substituent is hydroxyl, nitryl, amino, carboxyl, halogen atom, sulfydryl and C_1-6Alkylthio radical, C_1-6Alkoxy radical, C_1-6One or more of alkoxycarbonyl and amide; the substituted group on the aryl or heteroaryl is hydroxyl, amino, nitro, halogen atom, C_1-6Alkyl radical, C_1-6Alkylthio radical, C_1-6One or more of alkoxy and carboxyl;

R₄is C_1-10Alkyl radical, C_3-10Cycloalkyl radical, C_1-10Alkyl with substituents, C_3-10A substituted cycloalkyl, aryl or optionally substituted aryl or heteroaryl group; the substituent is hydroxyl, nitryl, amino, carboxyl, halogen atom, sulfydryl and C_1-6Alkylthio radical, C_1-6Alkoxy radical, C_1-6One or more of alkoxycarbonyl and amide; the substituted group on the aryl or heteroaryl is hydroxyl, amino, nitro, halogen atom, C_1-6Alkyl radical, C_1-6Alkylthio radical, C_1-6One or more of alkoxy and carboxyl.

In a further preferred embodiment, in the general formula (Ia), R₂Is H or C_1-6An alkyl group;

R₃is C_2-10Alkyl radical, C_2-10Alkyl with substituents, C_3-10Cycloalkyl 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, C_1-6One or more of alkyl, methylthio, methoxy and carboxyl;

R₄is C_1-10Alkyl radical, C_1-10Substituted alkyl or optionally substituted phenyl; the substituent is one or more of hydroxyl, carboxyl, halogen atom, methoxyl and methane oxycarbonyl; the phenyl-substituted group isHydroxy, halogen atom, C_1-6One 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 ofWhen it is, thenStructure (II) wherein R₂Is H or C_1-6An alkyl group;

R₃is C_1-10Alkyl radical, C_1-10Substituted 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, C_1-6One or more of alkyl, methylthio, methoxy and carboxyl;

R₄is C_1-10Alkyl radical, C_1-10Substituted 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, C_1-6One 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 branched_1-10Hydroxyalkyl of (2), or C_2-10Wherein 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, C_1-6Alkylthio radical, C_1-6Alkoxy radical, C_1-6One or more of alkoxycarbonyl and amido, and optionally alkane ester and alkaneThe ether may be substituted at any carbon atom position, i.e., these groups may be co-substituted with the hydroxy group in various combinations.

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 C_1-10To form a structural form such as R-COOR 'OR R-OR', wherein R may be C_1-5Alkyl or C_2-5Alkenyl, R' may be C_1-6Alkyl radical, C_2-6An alkenyl group; similarly, the foregoing are exemplified by hydroxy, nitro, amino, carboxyl, halogen, mercapto, C_1-6Alkylthio radical, C_1-6Alkoxy radical, C_1-6One or more of alkoxycarbonyl and acylamino, and can also be mono-substituted or polysubstituted on any carbon atom of alkyl ester and alkyl ether; 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 C_1-10Alkyl, preferably C_1-6Alkyl 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 C_2-10Alkenyl, preferably C_2-6Alkenyl 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 C_2-10Alkynyl, preferably C_2-6Alkynyl groups include, but are not limited to, acetylene, propyne, butyne, and the like.

In the present invention, "cycloalkyl" is C_3-10Cycloalkyl, preferably C_3-6Cycloalkyl groups including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; and "cycloalkyl" is optionally substituted with the foregoingAnd (4) substituting the group.

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, "C_1-6Alkylthio "and" C_1-6C in alkoxy ″)_1-6Alkyl groups are as defined above and "C_1-6Alkylthio is preferably methylthio and C_1-6Alkoxy "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 C_1-6A 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:

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:

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:

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:

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 bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, lithium diisopropylamide, potassium tert-butoxide, sodium tert-butoxide, and the like; 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 C_1-6Alkyl 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:

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.

The steps are as followsIn the reaction formulae of (1) to (5), R₂，R₃Each independently selected from H, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_1-10Alkyl with substituents, C_2-10Alkenyl with substituents, C_2-10Alkynyl with substituents, C_3-10Cycloalkyl with substituents, C_1-10And optionally substituted aryl or heteroaryl; the substituent is hydroxyl, nitryl, amino, carboxyl, halogen atom, sulfydryl and C_1-6Alkylthio radical, C_1-6Alkoxy radical, C_1-6One or more of alkoxycarbonyl and amide; the substituted group on the aryl or heteroaryl is hydroxyl, amino, nitro, halogen atom, C_1-6Alkyl radical, C_1-6Alkylthio radical, C_1-6One or more of alkoxy and carboxyl;

R₄is selected from C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_1-10Alkyl with substituents, C_2-10Alkenyl with substituents, C_2-10Alkynyl with substituents, C_3-10A substituted cycloalkyl, aryl or optionally substituted aryl; the substituent is hydroxyl, nitryl, amino, carboxyl, halogen atom, sulfydryl and C_1-6Alkylthio radical, C_1-6Alkoxy radical, C_1-6One or more of alkoxycarbonyl and amide; the substituted group on the aryl is hydroxyl, amino, nitro, halogen atom, C_1-6Alkyl radical, C_1-6Alkylthio radical, C_1-6One 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:

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:

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(m5H),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:

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 (6)

1. A silapiperidine derivative, or a pharmaceutically acceptable salt thereof, having the following structural formula (i):

wherein,

R₁is composed of

R₃Is C_1-10Alkyl radical, C_1-10Substituted alkyl, phenyl, and substituted phenyl or heteroaryl; said C is_1-10The substituent on the alkyl 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, C_1-6One or more of alkyl, methylthio, methoxy and carboxyl;

R₄is C_1-10Alkyl radical, C_1-10Substituted alkyl, phenyl, and substituted phenyl; said C is_1-10The substituent on the alkyl is one or more of hydroxyl, nitryl, amino, carboxyl, halogen atom, methylthio, methoxyl, methane oxycarbonyl and acylamino; the substituted group on the phenyl is hydroxyl, amino, nitro, halogen atom and C_1-6One or more of alkyl, methylthio, methoxy and carboxyl.

2. The silapiperidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the halogen atom is F, Cl or Br.

3. The silapiperidine derivative or a pharmaceutically acceptable salt thereof according to claim 2, wherein the heteroaryl group is selected from the group consisting of: 2-furan, 3-furan, 2-thiophene, 3-thiophene, 2-pyridine, 3-pyridine, 4-pyridine, 2-pyrrole or 3-pyrrole.

4. The silapiperidine derivative, or a pharmaceutically acceptable salt thereof, according to claim 3, selected from the group consisting of:

4, 4-dimethyl-1- (piperidin-4-yl) - [1,4] silapiperidine;

4-methyl-4-phenyl-1- (piperidin-4-yl) - [1,4] silapiperidine.

5. A process for the preparation of a silapiperidine derivative of general formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, comprising the steps of:

(1) dissolving chloroethylene-based magnesium or bromoethylene-based magnesium 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 shown as follows:

the organic solvent is one or more of anhydrous ether, tetrahydrofuran and toluene solution;

(2) dissolving the divinyl substituted silane obtained in the step (1) in an organic solvent, and performing anti-Markov addition reaction to obtain the di (2-bromoethyl) substituted silane of the formula 3, wherein the reaction formula is as follows:

the organic solvent is one or more of petroleum ether, n-hexane, n-heptane or cyclohexane;

(3) dissolving the bis (2-bromoethyl) substituted silane obtained in the step (2) in an organic solvent, carrying out cyclization reaction with benzylamine under alkaline conditions, and washing with ethyl acetate or methanol to obtain the N-benzyl substituted silapiperidine of the formula 4, wherein the reaction formula is as follows:

the organic solvent is one or more of chloroform, dioxane and N, N-dimethylformamide;

(4) dissolving the N-benzyl substituted silapiperidine 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:

the organic solvent is one or more of methanol, ethanol and isopropanol;

the catalyst is one or more of ruthenium, nickel, platinum and palladium;

(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 as follows:

the organic solvent is one or more of methanol, tetrahydrofuran, dichloromethane, chloroform, dioxane, ethyl acetate and dichloromethane;

the reducing agent is one or more of sodium cyanoborohydride and sodium triacetoxyborohydride;

in the reaction formulae of the above steps (1) to (5),

R₃is C_1-10Alkyl radical, C_1-10Substituted alkyl, phenyl, and substituted phenyl or heteroaryl; said C is_1-10The substituent on the alkyl 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, C_1-6One or more of alkyl, methylthio, methoxy and carboxyl;

R₄is C_1-10Alkyl radical, C_1-10Substituted alkyl, phenyl, and substituted phenyl; said C is_1-10The substituent on the alkyl is one or more of hydroxyl, nitryl, amino, carboxyl, halogen atom, methylthio, methoxyl, methane oxycarbonyl and acylamino; the substituted group on the phenyl is hydroxyl, amino, nitro, halogen atom and C_1-6One or more of alkyl, methylthio, methoxy and carboxyl.

6. Use of the silapiperidine derivative of any one of claims 1-4 or a pharmaceutically acceptable salt thereof as a pharmaceutical intermediate in the preparation of camptothecin siladerivatives.