WO2018082441A1 - Preparation method for 4-methylenepiperidine or acid addition salt thereof - Google Patents

Abstract

The present invention relates to a preparation method for 4-methylenepiperidine or an acid addition salt thereof. The preparation method is method I or method II. The preparation method of the present invention has mild reaction conditions and simple post-treatments, is environmentally friendly, has a low production cost, a high product purity and a high yield, and is suitable for industrial preparation of 4-methylenepiperidine or an acid addition salt thereof. Method I: formula A; and method II: formula B

Description

Method for preparing 4-methylene piperidine or acid addition salt thereof Technical field

The invention relates to a method for preparing 4-methylene piperidine or an acid addition salt thereof, and 4-methylene piperidine and an acid addition salt thereof are synthetic intermediates of the marketed drug Efinaconazole.

Background technique

Efinaconazole was jointly developed by Kaken and Valeant. It was first approved by the Health Canada in October 2013, then approved by the FDA in June 2014, and approved by PMDA in July for treatment of red buttercups. Onychomycosis caused by bacteria and trichophyton, under the trade name Jublia.

4-Methylene piperidine or its acid addition salt is an important intermediate of effluconazole, and its preparation method has been reported in many literatures. The literature Chemical and Pharmaceutical Bulletin, 1993, 41 (11), 1971-1986 reports the preparation method shown in Scheme 1, which uses 1-benzylpiperidin-4-one as a starting material and methyltriphenyl bromide. The phosphine undergoes Wittig reaction to give 1-benzyl-4-methylenepiperidine A, 1-benzyl-4-methylene piperidine and 1-chloroethyl chloroformate in reflux in dichloromethane, followed by The benzyl group was removed by refluxing with methanol. Disadvantages of this route: During the preparation of C from B, the reaction is strongly acidic, and impurities D, E and other impurities are generated under heating conditions, resulting in difficulty in product purification, low product purity, and inability to be industrially produced.

Route 1:

Patent CN1198156A and Chemical and Pharmaceutical Bulletin, 1999, 47(10), 1417-1425 report the preparation method shown in the following Scheme 2. Compound E is subjected to hydroxychloro, elimination and strong base hydrolysis to give 4-methylene piperidine. Disadvantages of the route: In the process of preparing I from F, a large amount of raw material G is substituted with potassium t-butoxide to form etherate J, resulting in low yield.

Route 2:

US2010/196321, EP1175402 and the like report the preparation method shown in the following Scheme 3. The Wittig reaction of the compound N-tert-butoxycarbonyl-piperidone and methyltriphenylphosphonium bromide gives N-tert-butoxycarbonyl-methylene group. Piperidine, N-tert-butoxycarbonyl-methylene piperidine is deprotected under acidic conditions such as hydrochloric acid to give 4-methylenepiperidine hydrochloride. The N-tert-butoxycarbonyl-piperidone used in this route is expensive, resulting in high production costs and lack of market competitiveness.

Route 3:

Therefore, it is very urgent to find a new method for preparing 4-methylene piperidine or an acid addition salt thereof which is suitable for industrial production with low cost, simple operation, high product purity and high yield.

Summary of the invention

The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and to provide an improved preparation method of 4-methylene piperidine and an acid addition salt thereof.

One aspect of the present invention provides a process for the preparation of 4-methylene piperidine or an acid addition salt thereof, which is one of the following methods:

method one,

Including the following steps a)

among them,

X ₁ is CH ₂ or oxygen;

A ₁ is a C ₁ -C ₆ alkyl group, a substituted or unsubstituted benzyl group, and the substituent on the substituted benzyl group is selected from the group consisting of fluorine, chlorine, bromine, iodine, nitro, C ₁ -C ₄ alkyl or One or more substituents in the C ₁ -C ₄ alkoxy group; preferably, the A ₁ is a C ₁ -C ₄ alkyl group, a substituted or unsubstituted benzyl group, and a substitution on the substituted benzyl group The substituent is selected from one or more substituents of fluorine, chlorine, bromine or iodine; more preferably, the A ₁ is methyl, ethyl or benzyl;

A ₂ is a halogenated or unsubstituted C ₁ -C ₆ alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, and the substituent on the substituted phenyl group or benzyl group is selected from fluorine One or more substituents in the group consisting of chlorine, bromine, iodine, nitro, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; preferably, the A ₂ is a C ₁ -C ₄ alkyl group a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, the substituent on the substituted phenyl or benzyl group being selected from one or more substituents of fluorine, chlorine, bromine, iodine or nitro group More preferably, the A ₂ is a methyl group, an ethyl group, a phenyl group or a benzyl group;

The compound (III) or a salt thereof is dissolved in a solvent, and reacted with the chloroformate A ₂ OOCCl to remove the group A ₁ to form the compound (IV) and the by-product A ₁ Cl, which are subjected to distillation or addition of a nucleophilic reagent. The by-product A ₁ Cl is converted into a substance which is easily separated from the compound (IV), thereby removing the by-product A ₁ Cl to obtain the compound (IV);

Preferably, method one,

among them,

X ₁ is CH ₂ or oxygen;

A ₁ is a C ₁ -C ₆ alkyl group, a substituted or unsubstituted benzyl group, and the substituent on the substituted benzyl group is selected from the group consisting of fluorine, chlorine, bromine, iodine, nitro, C ₁ -C ₄ alkyl or One or more substituents in the C ₁ -C ₄ alkoxy group; preferably, the A ₁ is a C ₁ -C ₄ alkyl group, a substituted or unsubstituted benzyl group, and a substitution on the substituted benzyl group The substituent is selected from one or more substituents of fluorine, chlorine, bromine or iodine; more preferably, the A ₁ is methyl, ethyl or benzyl;

A ₂ is a halogenated or unsubstituted C ₁ -C ₆ alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, and the substituent on the substituted phenyl group or benzyl group is selected from fluorine One or more substituents in the chlorine, bromine, iodine, nitro, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy group; preferably, the A ₂ is a C ₁ -C ₄ alkyl group a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, the substituent on the substituted phenyl or benzyl group being selected from one or more substituents of fluorine, chlorine, bromine, iodine or nitro group More preferably, the A ₂ is a methyl group, an ethyl group, a phenyl group or a benzyl group;

Method one includes the following steps:

When X ₁ is CH ₂ ,

a) dissolving the compound (III-A) or a salt thereof in a solvent, and reacting with the chloroformate A ₂ OOCCl to remove the group A ₁ to form the compound (IV-A) and the by-product A ₁ Cl, which are subjected to distillation. Or adding a nucleophile to convert the by-product A ₁ Cl into a substance which is easily separated from the compound (IV-A), thereby removing the by-product A ₁ Cl, to obtain a compound (IV-A) having a higher purity;

b) Compound (IV-A) is subjected to a hydrolysis reaction in a solvent to remove an acyl group to obtain 4-methylene piperidine (I), and if necessary, an aqueous solution of acid HX is added to 4-methylene piperidine (I). Or a solution of an organic solvent of acid HX to obtain a salt-forming compound (IA);

or,

When X ₁ is O,

a) dissolving the compound (III-B) or a salt thereof in a solvent, and reacting with the chloroformate A ₂ OOCCl to remove the group A ₁ to form the compound (IV-B) and the by-product A ₁ Cl, which are subjected to distillation. Or adding a nucleophile to convert the by-product A ₁ Cl into a substance which is easy to separate from the compound (IV-B), thereby removing the by-product A ₁ Cl, to obtain a compound (IV-B) having a higher purity;

h) Compound (IV-B) undergoes Wittig reaction in a solvent to obtain compound (IV-A);

b) Compound (IV-A) is subjected to a hydrolysis reaction in a solvent to remove an acyl group to obtain 4-methylene piperidine (I), and if necessary, an aqueous solution of acid HX is added to 4-methylene piperidine (I). Or a solution of an organic solvent of acid HX to obtain a salt-forming compound (IA);

among them,

In step a),

The reaction of the removal group A ₁ is carried out in the presence of a base or in the absence of a base; the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, barium hydroxide, potassium carbonate, One or more of sodium carbonate, lithium carbonate, cesium carbonate or 4-dimethylaminopyridine.

The chloroformate A ₂ OOCCl is selected from the group consisting of methyl chloroformate, ethyl chloroformate, butyl chloroformate, isobutyl chloroformate, phenyl chloroformate, benzyl chloroformate, 1-chloroethyl chloroformic acid. Ester or 2,2,2-trichloroethyl chloroformate; preferably, the chloroformate is methyl chloroformate, ethyl chloroformate, phenyl chloroformate or benzyl chloroformate;

The solvent is selected from the group consisting of toluene, xylene, chlorobenzene, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, methyl tert-butyl ether, One or more of cyclopentyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethoxymethane, n-heptane, n-hexane, cyclohexane or dimethoxymethane ;

The temperature at which the removal group A _{1 is} reacted is not limited, and is preferably -30 ° C to 120 ° C, more preferably 0 to 90 ° C; the by-product A ₁ Cl is an alkyl chloride or a benzyl chloride, which needs to be removed. Avoiding the reaction of A ₁ Cl and compound (IV) in the next hydrolysis reaction to regenerate compound (III);

In one embodiment of the present invention, the by-product A ₁ Cl is a volatile alkyl chloride, and the specific method of removing the by-product A ₁ Cl is that the alkyl chloride can be removed by distillation;

In one embodiment of the invention, the by-product A ₁ Cl is a non-volatile alkyl chloride or benzyl chloride, and the by-product A ₁ Cl is removed by adding a nucleophile which is readily reactive with A ₁ Cl. A ₁ Cl undergoes a nucleophilic substitution reaction to be converted into an organic amine or a quaternary ammonium salt which is easily separated from the compound (IV), and then directly extracted or added with a dilute acid to form an ammonium salt into the aqueous phase and then extracted. Separation. The dilute acid is a common inorganic acid or a water-soluble organic acid having a mass concentration of 0.1% to 20%, such as dilute hydrochloric acid, dilute sulfuric acid, dilute acetic acid and the like.

The nucleophilic reagent is one or more of an organic amine compound, ammonia gas, and ammonia water; the organic amine compound may be an organic primary amine, an organic secondary amine or an organic tertiary amine, and may be exemplified by organic Amines such as methylamine, ethylamine, propylamine, butylamine, aniline, benzylamine; organic secondary amines such as dimethylamine, diethylamine, dibutylamine, dicyclohexylamine, dibenzylamine; organic tertiary amines such as trimethylamine, Triethylamine, tri-n-butylamine, diisopropylethylamine, pyridine, 2,6-lutidine, and the like.

The nucleophilic substitution reaction of the nucleophile with the by-product A ₁ Cl is carried out in the presence or absence of an acid-binding agent which is an inorganic base capable of neutralizing hydrogen chloride such as sodium hydroxide or hydrogen. One or more of potassium oxide, calcium hydroxide, lithium hydroxide, barium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, barium carbonate, etc. (if the nucleophilic reagent is an organic tertiary amine, no acid is required; It is also possible to have an appropriate excess of the amine nucleophile, i.e., the amine nucleophile itself as an acid binding agent).

In addition, after the reaction of the removal group A ₁ is completed, a conventional post-treatment may be employed. For example, the crude compound (IV) obtained by extraction and separation may also be purified by column chromatography to remove the by-product A ₁ Cl to obtain a pure product ( IV).

In step b),

The specific process is that a hydrolysis reaction is carried out in a solvent to remove an acyl group, and after removing an acyl group, a crude 4-methylene piperidine is obtained by distillation under reduced pressure, and further distillation is carried out to obtain a pure 4-methylenepiperidine according to If necessary, a solution of an aqueous solution of HX or an organic solvent of HX is added to the crude 4-methylene piperidine or the pure 4-methylene piperidine to form a salt, and a poor solvent is added to precipitate the product, which is filtered and dried under reduced pressure to obtain 4 - methylene piperidic acid addition salt pure product;

The solvent is dimethyl sulfoxide, sulfolane, toluene, xylene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, diisopropyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether , diethoxymethane, dimethoxymethane, ethylene glycol, 1,2-propanediol, 1,3-propanediol, glycerol, methanol, ethanol, isopropanol, n-butanol, tert-butanol, uncle One or more of pentanol or water;

The hydrolysis reaction is carried out in the presence of an acid or a base selected from one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid or methanesulfonic acid; the base is selected from the group consisting of hydrogen One or more of sodium oxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, barium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate or barium carbonate;

The poor solvent is selected from one or more of ethyl acetate, isopropyl acetate, and methyl tert-butyl ether;

The HX is hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, chloric acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid or Toluenesulfonic acid; the HX is preferably hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid, more preferably hydrochloric acid, further preferably, the solution of the HX organic solvent may be hydrogen chloride/methanol solution, hydrogen chloride/ethanol solution, hydrogen chloride One or more of a /dioxane solution, a hydrogen chloride/ethyl acetate solution, a hydrogen chloride/isopropanol solution, and the like, and the solution of the aqueous solution of HX or the organic solvent of HX has a mass concentration ranging from 0.1 to 50%.

The temperature at which the acyl removal reaction is carried out is not limited, but is preferably 30 ° C to 150 ° C, and more preferably 60 to 130 ° C.

The 4-methylene piperidine acid addition salt obtained in the step b) can also be used as a base 4-methylpiperidine pure product by a base method by a conventional method. Before adding a poor solvent, it is necessary to concentrate the system under reduced pressure to a small volume. In one embodiment of the present invention, A ₂ is a halogenated C ₁ -C ₆ alkyl group, and step b) can be directly subjected to an acid or base-catalyzed reaction to directly remove an acyl group in a mixed solvent of an alcohol and water to obtain a 4-methylene group. Piperidine hydrohalide (hydrohalic acid is produced during the deacylation reaction).

The steps a) and b) can be carried out stepwise or in a one-pot process.

In step h),

The Wittig reaction is carried out under basic conditions, and the Wittig reagent used is an organophosphorus Wittig reagent, preferably methyltriphenylphosphonium bromide;

The solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, toluene, xylene, chlorobenzene, tetrahydrofuran, methyl Tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, diethoxymethane, dimethoxymethane, n-heptane, n-hexane, One or more of cyclohexane or water;

The base is selected from the group consisting of sodium t-butoxide, potassium t-butoxide, lithium t-butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, lithium hydride, sodium hexamethyldisilazide (NaHMDS), and two (three) Methylsilyl) lithium amide (LiHMDS), hexamethyldisilazide potassium (KHMDS), lithium diisopropylamide (LDA), lithium tetramethylpiperidine (LiTMP) or butyl lithium (BuLi One or more of them;

The temperature of the Wittig reaction is not limited, preferably from -10 to 80 ° C, more preferably from 10 to 40 ° C;

Method Two:

among them,

LG is mesylate, p-toluenesulfonate, triflate, chlorine, bromine or iodine;

HX is an acid of an acid addition salt, and as an acid which forms a 4-methylene piperidic acid addition salt, it is basically an acid which can form a salt with an amine, and, for example, hydrochloric acid, hydrobromic acid, and hydrogen are mentioned. Mineral acids such as iodic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, chloric acid, carbonic acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Not limited to these; preferred examples of the acid are hydrochloric acid, hydrobromic acid or hydroiodic acid;

Method two includes:

d) compound (V) in the presence of a base, in a solvent with a sulfonylation reagent or halogenation reagent sulfonylation or halogenation reaction to form compound VI;

e) compound (VI) in the presence of a base, in a solvent to eliminate the reaction to give compound (VII);

f) Compound (VII) is simultaneously deprotected in the presence of acid HX to form a salt to give compound (I-A) in salt form.

among them,

In step d),

The solvent is selected from the group consisting of dichloromethane, 1,2-dichloroethane, toluene, xylene, chlorobenzene, acetonitrile, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, N,N - dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, methyl tert-butyl ether, diethoxymethane, dimethoxymethane, diisopropyl ether, ethylene glycol dimethyl ether, One or more of diethylene glycol dimethyl ether, tetrahydrofuran or methyl tetrahydrofuran;

The base is selected from the group consisting of pyridine, imidazole, triethylamine, ethyldiisopropylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- One or more of diazabicyclo[4.3.0]non-5-ene (DBN), sodium carbonate, potassium carbonate or cesium carbonate;

The sulfonylating agent is selected from one or more of methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethanesulfonyl chloride;

The halogenating agent is thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, triphenylphosphine (PPh ₃ )/N-bromosuccinimide ( NBS), PPh ₃ /N-chlorosuccinimide (NCS), PPh ₃ /I ₂ , PPh ₃ /dibromohydantoin, PPh ₃ /dichlorohydantoin;

The sulfonylating agent or halogenating agent is used in an amount of 1 to 2 molar equivalents, preferably 1 to 1.5 molar equivalents based on the compound (V);

The temperature of the sulfonylation reaction or the halogenation reaction is not limited, and is preferably 0 ° C to 100 ° C, more preferably room temperature to 100 ° C;

The time of the sulfonylation reaction or halogenation reaction is 0.5 to 24 hours, preferably 0.5 to 5 hours;

The sulfonylation reaction or halogenation reaction can be carried out under any pressure, usually under normal pressure;

In step e),

The solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, toluene, xylene, chlorobenzene, tetrahydrofuran, methyl One or more of tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, diethoxymethane, dimethoxymethane, acetonitrile or benzonitrile;

The base is selected from the group consisting of 1,8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), N, One of N-diisopropylethylamine (DIPEA), potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, magnesium t-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate or Multiple

The base is used in an amount of 1 to 5 molar equivalents, preferably 1 to 4 molar equivalents based on the compound (VI);

The temperature for eliminating the reaction is not limited, and is preferably 0 ° C to 100 ° C, more preferably room temperature to 100 ° C;

The time for eliminating the reaction is 0.5 to 24 hours, preferably 0.5 to 5 hours;

The elimination reaction can be carried out under any pressure, usually under normal pressure.

In step f),

To the compound (VII), a solution of an aqueous solution of HX or an organic solvent of HX is added, and after completion of the reaction, a poor solvent is added to precipitate a product, which is filtered, and dried under reduced pressure to obtain a pure product of 4-methylenepiperidinic acid addition salt; Before the poor solvent, it is necessary to concentrate the system under reduced pressure to a small volume. The obtained 4-methylene piperidine acid addition salt can also be used by a conventional method to obtain a basic 4-methylenepiperidine pure product by base free.

The poor solvent is selected from one or more of ethyl acetate, isopropyl acetate or methyl tert-butyl ether;

The aqueous solution of HX or the solution of organic solvent of HX, the solution of the organic solvent of HX may be hydrogen chloride/methanol solution, hydrogen chloride/ethanol solution, hydrogen chloride/dioxane solution, hydrogen chloride/ethyl acetate solution, hydrogen chloride/ The isopropanol solution or the like, the solution of the aqueous solution of HX or the organic solvent of HX has a mass concentration ranging from 0.1 to 50%.

The reactant compound (III-A) of the present invention can be obtained by Wittig reaction of the compound (III-B) with methyltriphenylphosphonium bromide in a solvent in the presence of a base, as shown in the following reaction formula:

In step c),

The solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, toluene, xylene, chlorobenzene, tetrahydrofuran, Tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, diethoxymethane, dimethoxymethane, n-heptane, n-hexane One or more of cyclohexane or water;

The base is selected from the group consisting of sodium t-butoxide, potassium t-butoxide, lithium t-butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, lithium hydride, sodium hexamethyldisilazide (NaHMDS), and two (three) Methylsilyl) lithium amide (LiHMDS), hexamethyldisilazide potassium (KHMDS), lithium diisopropylamide (LDA), lithium tetramethylpiperidine (LiTMP) or butyl lithium (BuLi One or more of them;

The Wittig reaction is completed, and the compound (III-A) solution can be directly subjected to the step a) by a conventional post-treatment, or the salt of the compound (III-A) can be obtained as a solid in the form of a salt to carry out the step a).

The salt of the compound (III-A) may be any organic or inorganic acid salt, and examples thereof include a hydrochloride, a hydrobromide, a hydroiodide, a sulfate, a nitrate, a phosphate, a borate, and the like. a mineral acid salt such as a chlorate or a carbonate; or a formate, acetate, trifluoroacetate, propionate, oxalate, methanesulfonate, besylate or p-toluenesulfonate The organic acid salt is not limited to these. Preferably, the salt of Compound III is a hydrochloride, a hydrobromide, a hydroiodide, a sulfate, more preferably a hydrochloride.

A preferred embodiment of the invention is as follows:

Another preferred embodiment of the invention is as follows:

Another preferred embodiment of the invention is as follows:

Another preferred embodiment of the invention is as follows:

Another preferred embodiment of the invention is as follows:

Another preferred embodiment of the invention is as follows:

In the above preferred embodiment, a solution of an aqueous solution of acid HX or an organic solvent of acid HX may be added to the product 4-methylene piperidine as needed to obtain an acid addition salt.

Another preferred embodiment of the invention is as follows:

Another preferred embodiment of the invention is as follows:

Beneficial effect

The high-purity 4-methylene piperidine free base or 4-methylene piperidic acid addition salt obtained by the method of the present invention can be used as a starting material for the synthesis of the drug fluconazole.

Due to the implementation of the above technical solutions, the present invention has the following advantages compared with the prior art:

The raw materials used in the first embodiment of the invention, such as methyl piperidone, benzyl piperidone, ethyl chloroformate and methyl chloroformate, are all cheap and easy to obtain, and the column chromatography operation reported in the literature is omitted in the preparation process. Industrial scale production, in addition, the oil compound (III) is purified by distillation, and the purity of the product is 99.5% or more. Scheme 2 avoids the use of methyltriphenylphosphonium bromide, which has little green pollution and greatly improves atomic economy; the removal of the Boc protecting group and the salt formation reaction simultaneously, simplifying the operation steps and increasing the reaction yield.

Instruction sheet

Figure 1 is an HPLC chromatogram of 4-methylene piperidine hydrochloride prepared in Example 11.

detailed description

Embodiments of the invention are illustrated by the following examples. However, the embodiments of the present invention are not limited to the specific details of the following embodiments, and other variations are known and apparent to those of ordinary skill in the art in view of this disclosure.

The sample data was determined by nuclear magnetic resonance spectroscopy ( ¹ H-NMR) using a Bruker Avance III 300 NMR spectrometer; the WFH-203B tri-use UV analyzer used for color development, with wavelengths of 254 nm and 365 nm. Column chromatography silica gel (100-200 mesh, 300-400 mesh) is produced by Qingdao Marine Chemical Plant; TLC silica gel plate is HSGF-254 thin-layer chromatography silica gel plate produced by Yantai Chemical Plant, and chromatography is used for thin layer chromatography. The thickness of the plate is 0.2±0.03mm, the thickness of the pre-prepared plate for pre-preparation is 0.4-0.5mm; the petroleum ether (boiling range 60-90°C), dichloromethane, ethyl acetate and methanol are all analytically pure. , tert-butyl-4-(hydroxymethyl) piperidine-1-carboxylate, N-methyl-4-piperidone, benzylpiperidone provided by Sinopharm Chemical Reagent Co., Ltd., reagents and solvents used Unless otherwise stated, there is no special treatment. All temperatures are expressed in ° C (degrees Celsius), and room temperature or ambient temperature means 20 to 25 ° C.

Example 1 4-((((Methanesulfonyl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester

100 g (464 mmol) of tert-butyl-4-(hydroxymethyl) piperidine-1-carboxylate was dissolved in 1000 mL of dichloromethane, 56.4 g (558 mmol) of triethylamine was added, and the temperature was controlled at 10 ° C in an ice water bath. In the following, 63.8 g (557 mmol) of methanesulfonyl chloride was added dropwise, and the reaction was continued for 3 hours, and 50 mL of water was added thereto, and the mixture was stirred, and the organic layer was dried over anhydrous sodium sulfate. . ¹ H-NMR (CDCl ₃ ): δ (ppm) 4.17 (2H, d), 4.09 (2H, d), 3.03 (3H, s), 2.78-2.68 (2H, m), 2.00-1.88 (1H, m ), 1.76 (2H, d), 1.47 (9H, s), 1.29-1.19 (2H, m).

Example 2 4-Methylene piperidine-1-carboxylic acid tert-butyl ester

tert-Butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (100 g, 340 mmol) was dissolved in DMF (500 mL). Cool to 0 to 10 ° C under nitrogen. t-BuOK (57.2 g, 510 mmol) was added portionwise. The temperature was raised to 50 to 60 ° C and stirred for 1 hour. Cool to room temperature and add 1500 mL of water. Extract with ethyl acetate (1000 mL x 2). The combined organic layer was washed with brine (500 mL), dried over anhydrous sodium sulfate. ¹ H-NMR (CDCl ₃ ): δ (ppm) 4.73 (2H, s), 3.41 (4H, t), 2.17 (4H, t), 1.46 (9H, s).

Example 3 4-Methylene piperidine hydrochloride

37-(34 mmol) 30% hydrogen chloride/methanol solution was added dropwise to tert-butyl 4-methylene piperidine-1-carboxylate (20 g, 101.4 mmol) at 20 to 30 ° C, and reacted for 10 hours, then transferred to a reaction flask. 300 g of ethyl acetate was added thereto, and a solid was precipitated, which was filtered and dried under reduced pressure to give 10.97 g of 4-methylenepiperidine hydrochloride in a yield of 81%. ¹ H-NMR (CDCl ₃ ): δ (ppm) 9.71 (2H, brs), 4.90 (2H, s), 3.23 (4H, m), 2.59 (4H, m).

Example 4 N-Methyl-4-methylene piperidine hydrochloride

Methyltriphenylphosphonium bromide (472 g, 1.32 mol) and 1600 mL of toluene were added to a three-neck bottle. The nitrogen gas was cooled to 10 to 20 ° C, and t-BuOK (148 g, 1.32 mol) was added portionwise. Incubate at 10 to 20 ° C for 1 hour. N-methyl-4-piperidone (100 g, 0.884 mol) was added dropwise at 10 to 20 °C. The reaction was kept at 10 to 20 ° C for 1 hour. The reaction solution was warmed to 80 ° C, and a mixture of N-methyl-4-methylenepiperidine and toluene was concentrated under reduced pressure. Concentrated hydrochloric acid was added, and toluene was concentrated to remove 110.8 g of N-methyl-4-methylenepiperidine hydrochloride in a yield of 85%. ¹ H-NMR (DMSO-d ₆ ): δ (ppm) 11.35 (1H, s), 4.87 (2H, s), 3.40 (2H, m), 2.87 (2H, m), 2.71 (3H, s), 2.58 (2H, m), 2.40 (2H, m).

Example 5 4-Methylene piperidine-1-carboxylate

To 100 mL of toluene, 1-methyl-4-methylenepiperidine hydrochloride (40 g, 271 mmol) and 57.4 g (541 mmol) of sodium carbonate were added, and the mixture was heated to 90-95 ° C, and ethyl chloroformate (88 g, 811 mmol), completion of dropwise addition, refluxing for 1.5 hours, and cooling to room temperature. Add 200 mL of water, separate the layers, and wash the organic phase with 200 mL of water. Concentration to oil gave 34.4 g of ethyl 4-methylenepiperidine-1-carboxylate in a yield of 75%. ¹ H-NMR (CDCl ₃ ): δ (ppm) 4.76 (2H, s), 4.15 (2H, q), 3.48 (4H, t), 2.20 (4H, t), 1.27 (3H, t).

Example 6 4-Methylene piperidine hydrochloride

4-Methylpiperidine-1-carboxylic acid ethyl ester (30 g, 177 mmol) was added to 150 mL of ethanol, 42.6 g (1.06 mol) of sodium hydroxide was added, and the reaction was carried out at 80-85 ° C for 16 hours, and ethanol and N were distilled off under reduced pressure. a mixture of -methyl piperidene, adding 25.9 g (213 mmol) of a 30% hydrogen chloride / ethanol solution, then concentrating the ethanol under reduced pressure, adding 100 mL of ethyl acetate, separating the solid, filtering under reduced pressure, and drying under reduced pressure to give 17.76 g of product. 75%. The NMR spectrum of this compound was determined to be the same as the product of Example 3.

Example 7 Methyl 4-methylene piperidine-1-carboxylate

To 2000 mL of toluene was added 1-methyl-4-methylenepiperidine hydrochloride (200 g, 1.35 mol), 287 g (2.7 mol) of sodium carbonate, and the temperature was raised to 90-95 ° C, and methyl chloroformate was added dropwise (192 g, 2.03 mol), completed by dropwise addition, refluxed for 4 hours, and cooled to room temperature. Add 1000 mL of water, separate the layers, and wash the organic phase with 400 mL of water. Concentration under reduced pressure gave 172.4 g of ethyl 4-methylenepiperidine-1-carboxylate in a yield of 82%. ¹ H-NMR (CDCl ₃ ): δ (ppm) 4.77 (2H, s), 3.72 (3H, s), 3.48 (4H, m), 2.20 (4H, m).

Example 8 4-Methylene piperidine hydrochloride

Methyl 4-methylene piperidine-1-carboxylate (100 g, 0.644 mol) was added to 500 mL of ethanol, 77.3 g of sodium hydroxide (1.93 mol) was added, and the reaction was carried out at 80-85 ° C for 10 hours, and ethanol was distilled off under reduced pressure. A mixture of 4-methylenepiperidine was added to a solution of 94.1 g (0.773 mol) of a 30% hydrogen chloride in ethanol, then the ethanol was concentrated under reduced pressure, and ethyl acetate (200 mL) was added to precipitate a solid. Methylene piperidine hydrochloride, yield 79%. The NMR spectrum of this compound was determined to be the same as the product of Example 3.

Example 9 4-Methylene piperidine hydrochloride

1-Methyl-4-methylenepiperidine hydrochloride (13.3 g, 90 mmol) was added to toluene (150 mL). The temperature was lowered to 0 to 10 ° C, 1-chloroethyl chloroformate (15.4 g, 107.7 mmol) was added dropwise, the reaction was stirred at 80 ° C for 4-5 h, then 10 mL of methanol was added, and stirring was continued at this temperature for 1 to 2 hour. Add 10 mL of water and dispense. The aqueous phase was extracted once with 30 mL of toluene. The aqueous phase was concentrated to dryness, and then evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The yield was 72%. The NMR spectrum of this compound was determined to be the same as the product of Example 3.

Example 10 1-Benzyl-4-methylenepiperidine

To a 250 mL three-necked flask was added 40 mL of toluene, 7.6 g (79.2 mmol, 1.5 eq) of sodium t-butoxide and 28.4 g of methyltriphenylphosphonium bromide (79.2 mmol, 1.5 eq), replaced with nitrogen, and stirred at 20-30 °C. After 2 h, 10 g of benzylpiperidone (52.8 mmol, 1 eq) was added dropwise, and the reaction was kept at 20-30 ° C for 1 h. The reaction was monitored by TLC. 50 g of water was added and stirred for half an hour to separate the lower aqueous phase. The organic phase was added with 30 g of water, adjusted to pH 3-4 with 18% hydrochloric acid, stirred, and separated, and the aqueous phase was extracted once again with 100 mL of toluene. 100 mL of toluene was added to the aqueous phase, and the pH was adjusted to 9 to 10 with a 20% sodium hydroxide solution, and the mixture was separated and concentrated under reduced pressure to give a solution of 1-benzyl-4-methylenepiperidine and toluene. 0.1 ml of this solution was concentrated under reduced pressure to remove toluene for nuclear magnetic analysis, ¹ H-NMR (CDCl ₃ ): δ (ppm) 7.40-7.25 (5H, m), 4.69 (2H, s), 3.56 (2H, s), 2.49 (4H, t), 2.29 (4H, t).

To the above mixture, 2.8 g of sodium carbonate (26.4 mmol, 0.5 eq) was added, and the temperature was controlled at 20 to 30 ° C, and 8.6 g of ethyl chloroformate (79.2 mmol, 1.5 eq) was added dropwise, and the temperature was further increased to 40 to 50. The reaction was carried out at ° C for 2 hours, dropped to 0 to 10 ° C, 100 g of water and 11.2 g of sodium carbonate (105.6 mmol, 2 eq) were added, 8.5 g (79.2 mmol, 1.5 eq) of benzylamine was added dropwise to remove benzyl chloride, and stirred at 40-50 ° C. Reaction for 8 hours. Adding a mass concentration of 5% hydrochloric acid to the reaction solution, adjusting the pH to 3 to 4, separating the aqueous phase, and concentrating the organic phase at 60 ° C under reduced pressure to obtain 7.6 g of ethyl 4-methylenepiperidine-1-carboxylate. 85%. The NMR spectrum of this compound was determined to be the same as the product of Example 5.

Example 11 4-Methylene piperidine hydrochloride

Add 4-methylenepiperidine-1-carboxylic acid ethyl ester (2 g, 11.8 mmol, 1.0 eq) to a 25 mL reaction flask, 10 g of ethylene glycol, 2.36 g of sodium hydroxide (59 mmol, 5.0 eq), and replaced with nitrogen. After reacting at 130 to 150 ° C for 13 hours, the mixture was cooled, and a mixture of ethanol and 4-methylenepiperidine was distilled off under reduced pressure. To the mixture was added 2.87 g (23.6 mmol, 2 eq) of a 30% hydrogen chloride/ethanol solution, and then concentrated under reduced pressure. Pyridine hydrochloride, yield 81%. The NMR spectrum of this compound was determined to be the same as the product of Example 3. The HPLC purity was 99.94%.

HPLC determination conditions

Chromatography UV detector: DAD

Chromatography pump: 1100 quaternary pump

Column: Agilent ZOBRAX SB-C18 4.6×250mm, 5μm P.N.880975-902 S.N.USCL056164

Chromatographic conditions:

Mobile phase A: water-acetonitrile-perchloric acid (95:5:0.2)

Mobile phase B: water-acetonitrile-methanol (15:85:1)

Injection volume: 5 μL, flow rate: 1.0 mL/min, column temperature: room temperature, detection wavelength: 200 nm.

Table 1 HPLC chromatogram information of 4-methylene piperidine hydrochloride prepared in Example 11

As can be seen from Table 1, the purity of 4-methylene piperidine hydrochloride prepared in this example was more than 99%, and the impurity content was less than 0.1%.

Example 12 Ethyl 4-oxopiperidine-1-carboxylate

1-methyl-4-piperidone (10 g, 88.4 mmol) and 0.94 g (8.8 mmol) of sodium carbonate were added to 30 mL of toluene, and the temperature was raised to 40 to 45 ° C, and ethyl chloroformate (10.5 g, 97.2 mmol) was added dropwise. After the dropwise addition was completed in about 1 hour, the temperature was further raised to 80 to 85 ° C for 3 hours, and the temperature was lowered to room temperature. 20 mL of water was added, the layers were separated, and the organic phase was washed once more with 20 mL of water. The oil was concentrated under reduced pressure to give 11.7 g of ethyl 4-chloropiperidine-1-carboxylate. ¹ H-NMR (CDCl ₃ ): δ (ppm) 4.15 (2H, q), 3.74 (4H, t), 2.42 (4H, t), 1.26 (3H, t).

Example 13 Ethyl 4-oxopiperidine-1-carboxylate

1-Benzyl-4-piperidone (50 g, 264.2 mmol) and 2.8 g (26.4 mmol) of sodium carbonate were added to 200 mL of toluene, and the temperature was raised to 30 to 35 ° C, and ethyl chloroformate (31.4 g, 290.6 mmol) was added dropwise. After the dropwise addition was completed for about 1.5 hours, the temperature was further raised to 50 to 55 ° C for 2 hours, and the temperature was lowered to room temperature. 100 ml of water and 42 g of sodium carbonate (396.8 mmol, 1.5 eq) were added, 34 g (317.5 mmol, 1.2 eq) of benzylamine was added dropwise to remove the benzyl chloride, and the reaction was stirred at 40-50 ° C for 8 hours. To the reaction mixture, a mass concentration of 5% hydrochloric acid was added to adjust the pH to 3 to 4, and the aqueous phase was separated. The organic phase was concentrated under reduced pressure at 60 ° C to give 41.1 g of ethyl 4-chloropiperidine-1-carboxylate.

Example 14 Ethyl 4-oxopiperidine-1-carboxylate

1-Benzyl-4-piperidone (50 g, 264.2 mmol) and 2.8 g (26.4 mmol) of sodium carbonate were added to 200 mL of toluene, and the temperature was raised to 30 to 35 ° C, and ethyl chloroformate (31.4 g, 290.6 mmol) was added dropwise. After the dropwise addition was completed for about 1.5 hours, the temperature was further raised to 50 to 55 ° C for 2 hours, and the temperature was lowered to room temperature. Add 100 mL of water, separate the layers, and wash the organic phase with 50 mL of water. The oil was concentrated to give a crude material, which was purified from silica gel column chromatography (hexane / ethyl acetate: 15:1) to yield 40.7 g of ethyl 4-chloropiperidine-1-carboxylate.

Example 15 4-Methylene piperidine-1-carboxylate

Methyltriphenylphosphonium bromide (15.6 g, 43.8 mmol) and 100 mL of tetrahydrofuran were added to a three-necked flask. The nitrogen gas was cooled to 10 to 20 ° C, and t-BuOK (3.27 g, 43.8 mmol) was added portionwise. Incubate at 10 to 20 ° C for 1 hour. Ethyl 4-carbonylpiperidine-1-carboxylate (5 g, 29.2 mmol) was added dropwise at 10 to 20 °C. The reaction was kept at 20 to 30 ° C for 1 hour. The tetrahydrofuran was concentrated under reduced pressure, and 100 ml of n-hexane and 100 ml of water were added, filtered, and the filter cake was washed once with 20 ml of n-hexane. The combined organic layers were concentrated under reduced vacuolululululululululululululululululululululululululululu

Example 16 4-Methylene Piperidine

Add 4-methylenepiperidine-1-carboxylic acid ethyl ester (2 g, 11.8 mmol, 1.0 eq) to a 25 mL reaction flask, 10 g of ethylene glycol, 2.36 g of sodium hydroxide (59 mmol, 5.0 eq), and replaced with nitrogen. After reacting at 130-150 ° C for 13 hours, the temperature was lowered, and distilled under reduced pressure to obtain a crude 4-methylenepiperidine. The fraction of 48-50 ° C was continuously collected under rectification conditions of 60 mmHg, and rectification was carried out to obtain 52.8 g of 4-ya. Pure methylpiperidine, yield 92%. ¹ H-NMR (CDCl ₃ ): δ (ppm) 4.66 (2H, s), 2.85 (4H, t), 2.44 (1H, s), 2.20 (4H, t). The HPLC purity was 99.04% and the test conditions were consistent with the detection of 4-methylene piperidine hydrochloride in Example 11.

Claims (11)

1. A method for preparing 4-methylene piperidine or an acid addition salt thereof, characterized in that

   The method comprises the following steps a)

   

   among them,

   X ₁ is CH ₂ or oxygen;

   A ₁ is a C ₁ -C ₆ alkyl group, a substituted or unsubstituted benzyl group, and the substituent on the substituted benzyl group is selected from the group consisting of fluorine, chlorine, bromine, iodine, nitro, C ₁ -C ₄ alkyl or One or more substituents in the C ₁ -C ₄ alkoxy group; preferably, the A ₁ is a C ₁ -C ₄ alkyl group, a substituted or unsubstituted benzyl group, and a substitution on the substituted benzyl group The substituent is selected from one or more substituents of fluorine, chlorine, bromine or iodine; more preferably, the A ₁ is methyl, ethyl or benzyl;

   A ₂ is a halogenated or unsubstituted C ₁ -C ₆ alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, and the substituent on the substituted phenyl group or benzyl group is selected from fluorine One or more substituents in the group consisting of chlorine, bromine, iodine, nitro, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; preferably, the A ₂ is a C ₁ -C ₄ alkyl group a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, the substituent on the substituted phenyl or benzyl group being selected from one or more substituents of fluorine, chlorine, bromine, iodine or nitro group More preferably, the A ₂ is a methyl group, an ethyl group, a phenyl group or a benzyl group;

   The compound (III) or a salt thereof is dissolved in a solvent, and reacted with the chloroformate A ₂ OOCCl to remove the group A ₁ to form the compound (IV) and the by-product A ₁ Cl, which are subjected to distillation or addition of a nucleophilic reagent. The by-product A ₁ Cl is converted into a substance which is easily separated from the compound (IV), thereby removing the by-product A ₁ Cl to give the compound (IV).
2. The preparation method according to claim 1, wherein in the step a),

   The reaction of removing the group A ₁ is carried out in the presence of a base or in the absence of a base;

   The base is selected from one or more of sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, barium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate or 4-dimethylaminopyridine;

   The solvent is selected from the group consisting of toluene, xylene, chlorobenzene, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, methyl tert-butyl ether, One or more of cyclopentyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethoxymethane, n-heptane, n-hexane, cyclohexane or dimethoxymethane ;

   The temperature at which the removal group A _{1 is} reacted is not limited, but is preferably -30 ° C to 120 ° C, and more preferably 0 to 90 ° C.
3. The preparation method according to claim 1, wherein in the step a),

   The nucleophile is selected from one or more of an organic amine compound, ammonia gas or ammonia water; preferably, the nucleophilic reagent is ammonia gas, ammonia water, methylamine, ethylamine, propylamine, butylamine, Aniline, benzylamine, dimethylamine, diethylamine, dibutylamine, dicyclohexylamine, dibenzylamine, trimethylamine, triethylamine, tri-n-butylamine, diisopropylethylamine, pyridine or 2,6 One or more of lutidine.
4. The preparation method according to claim 1, wherein in the step a),

   The chloroformate A ₂ OOCCl is selected from the group consisting of methyl chloroformate, ethyl chloroformate, butyl chloroformate, isobutyl chloroformate, phenyl chloroformate, benzyl chloroformate, 1-chloroethyl chloroformic acid. Ester or 2,2,2-trichloroethyl chloroformate, preferably methyl chloroformate, ethyl chloroformate, phenyl chloroformate or benzyl chloroformate.
5. A method of preparation as claimed in claim 1, wherein the method comprises the steps of:

   

   among them,

   A ₁ is a C ₁ -C ₆ alkyl group, a substituted or unsubstituted benzyl group, and the substituent on the substituted benzyl group is selected from the group consisting of fluorine, chlorine, bromine, iodine, nitro, C ₁ -C ₄ alkyl or One or more substituents in the C ₁ -C ₄ alkoxy group; preferably, A ₁ is a C ₁ -C ₄ alkyl group, a substituted or unsubstituted benzyl group, and a substituent on the substituted benzyl group is selected One or more substituents from fluorine, chlorine, bromine or iodine; more preferably, A ₁ is methyl, ethyl or benzyl;

   A ₂ is a halogenated or unsubstituted C ₁ -C ₆ alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, and the substituent on the substituted phenyl group or benzyl group is selected from fluorine One or more substituents in the group consisting of chlorine, bromine, iodine, nitro, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; preferably, the A ₂ is a C ₁ -C ₄ alkyl group a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, the substituent on the substituted phenyl or benzyl group being selected from one or more substituents of fluorine, chlorine, bromine, iodine or nitro group More preferably, the A ₂ is a methyl group, an ethyl group, a phenyl group or a benzyl group;

   a) dissolving the compound (III-A) or a salt thereof in a solvent, and reacting with the chloroformate A ₂ OOCCl to remove the group A ₁ to form the compound (IV-A) and the by-product A ₁ Cl, which are subjected to distillation. Or adding a nucleophile to convert the by-product A ₁ Cl into a substance which is easily separated from the compound (IV-A), thereby removing the by-product A ₁ Cl to obtain the compound (IV-A);

   b) Compound (IV-A) is subjected to a hydrolysis reaction in a solvent to remove an acyl group to obtain 4-methylene piperidine (I), and if necessary, an aqueous solution of acid HX is added to 4-methylene piperidine (I). Or a solution of an organic solvent of acid HX to obtain a compound in the form of a salt;

   The HX is hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, chloric acid, carbonic acid, A Acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid; the HX is preferably hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid, more preferably hydrochloric acid.
6. The preparation method according to claim 5, wherein in the step b),

   The solvent is dimethyl sulfoxide, sulfolane, toluene, xylene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, diisopropyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether , diethoxymethane, dimethoxymethane, ethylene glycol, 1,2-propanediol, 1,3-propanediol, glycerol, methanol, ethanol, isopropanol, n-butanol, tert-butanol, uncle One or more of pentanol or water;

   The hydrolysis reaction is carried out in the presence of an acid or a base selected from one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid or methanesulfonic acid;

   The base is one or more of sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, barium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate or barium carbonate;

   The temperature of the reaction for removing the acyl group is not limited, but is preferably 30 ° C to 150 ° C, and more preferably 60 to 130 ° C.
7. A method of preparation as claimed in claim 1, wherein the method comprises the steps of:

   

   among them,

   A ₁ is a C ₁ -C ₆ alkyl group, a substituted or unsubstituted benzyl group, and the substituent on the substituted benzyl group is selected from the group consisting of fluorine, chlorine, bromine, iodine, nitro, C ₁ -C ₄ alkyl or One or more substituents in the C ₁ -C ₄ alkoxy group; preferably, the A ₁ is a C ₁ -C ₄ alkyl group, a substituted or unsubstituted benzyl group, and a substitution on the substituted benzyl group The substituent is selected from one or more substituents of fluorine, chlorine, bromine or iodine; more preferably, the A ₁ is methyl, ethyl or benzyl;

   A ₂ is a halogenated or unsubstituted C ₁ -C ₆ alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, and the substituent on the substituted phenyl group or benzyl group is selected from fluorine One or more substituents in the group consisting of chlorine, bromine, iodine, nitro, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; preferably, the A ₂ is a C ₁ -C ₄ alkyl group a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, the substituent on the substituted phenyl or benzyl group being selected from one or more substituents of fluorine, chlorine, bromine, iodine or nitro group More preferably, the A ₂ is a methyl group, an ethyl group, a phenyl group or a benzyl group;

   a) dissolving the compound (III-B) or a salt thereof in a solvent, and reacting with the chloroformate A ₂ OOCCl to remove the group A ₁ to form the compound (IV-B) and the by-product A ₁ Cl, which are subjected to distillation. Or adding a nucleophile to convert the by-product A ₁ Cl into a substance which is easily separated from the compound (IV-B), thereby removing the by-product A ₁ Cl, thereby obtaining a compound (IV-B) having a higher purity;

   h) Compound (IV-B) undergoes Wittig reaction in a solvent to obtain compound (IV-A),

   b) Compound (IV-A) is subjected to a hydrolysis reaction in a solvent to remove an acyl group to obtain 4-methylenepiperidine (I), and if necessary, an aqueous solution of acid HX is added to (I) in 4-methylenepiperidine. Or a solution of an organic solvent of acid HX to obtain a compound in the form of a salt;

   The HX is hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, chloric acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid or Toluenesulfonic acid; the HX is preferably hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid, more preferably hydrochloric acid.
8. The preparation method according to claim 7, wherein in the step h),

   The Wittig reaction is carried out under basic conditions, and the Wittig reagent used is an organophosphorus Wittig reagent, preferably methyltriphenylphosphonium bromide;

   The solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, toluene, xylene, chlorobenzene, tetrahydrofuran, methyl Tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, diethoxymethane, dimethoxymethane, n-heptane, n-hexane, One or more of cyclohexane or water;

   The base is selected from the group consisting of sodium t-butoxide, potassium t-butoxide, lithium t-butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, lithium hydride, sodium hexamethyldisilazide, bis(trimethylsilyl) One or more of lithium amide, potassium hexamethyldisilazide, lithium diisopropylamide, lithium tetramethylpiperidine or butyllithium;

   The temperature of the Wittig reaction is not limited, and is preferably -10 to 80 ° C, more preferably 10 to 40 ° C.
9. A method for preparing a 4-methylene piperidine acid addition salt, characterized in that the method comprises the following steps:

   

   among them,

   LG is mesylate, p-toluenesulfonate, triflate, chlorine, bromine or iodine;

   HX is hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, chloric acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid The HX is preferably hydrochloric acid or hydrogen Bromo acid, hydroiodic acid or sulfuric acid, more preferably hydrochloric acid;

   d) compound (V) in the presence of a base, in a solvent with a sulfonylation reagent or halogenation reagent sulfonylation or halogenation reaction to form compound (VI);

   e) compound (VI) in the presence of a base, in a solvent to eliminate the reaction to give compound (VII);

   f) Compound (VII) is simultaneously deprotected in the presence of acid HX to form a salt to give compound (I-A) in salt form.
10. The preparation method according to claim 9, wherein in the step d),

    The solvent is selected from the group consisting of dichloromethane, 1,2-dichloroethane, toluene, xylene, chlorobenzene, acetonitrile, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, N,N - dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, methyl tert-butyl ether, diethoxymethane, dimethoxymethane, diisopropyl ether, ethylene glycol dimethyl ether, One or more of diethylene glycol dimethyl ether, tetrahydrofuran or methyl tetrahydrofuran;

    The base is selected from the group consisting of pyridine, imidazole, triethylamine, ethyldiisopropylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diaza One or more of bicyclo[4.3.0]non-5-ene, sodium carbonate, potassium carbonate or cesium carbonate;

    The sulfonylating agent is one or more of methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethanesulfonyl chloride;

    The halogenating reagent is thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, triphenylphosphine/N-bromosuccinimide, PPh ₃ /N -chlorosuccinimide, PPh ₃ /I ₂ , PPh ₃ /dibromohydantoin, PPh ₃ /dichlorohydantoin;

    The sulfonylating agent or halogenating agent is used in an amount of 1 to 2 molar equivalents, preferably 1 to 1.5 molar equivalents based on the compound (V);

    The temperature of the sulfonylation reaction or the halogenation reaction is not limited, and is preferably 0 ° C to 100 ° C, more preferably room temperature to 100 ° C;

    The sulfonylation or halogenation reaction is carried out for a period of from 0.5 to 24 hours, preferably from 0.5 to 5 hours.
11. The preparation method according to claim 9, wherein in the step e),

    The solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, toluene, xylene, chlorobenzene, tetrahydrofuran, methyl One or more of tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, diethoxymethane, dimethoxymethane, acetonitrile or benzonitrile;

    The base is selected from the group consisting of 1,8-diazabicycloundec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, N,N-diisopropyl One or more of ethylamine, potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, magnesium t-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate;

    The base is used in an amount of 1 to 5 molar equivalents, preferably 1 to 4 molar equivalents based on the compound (VI);

    The temperature for eliminating the reaction is not limited, and is preferably 0 ° C to 100 ° C, more preferably room temperature to 100 ° C;

    The time for eliminating the reaction is from 0.5 to 24 hours, preferably from 0.5 to 5 hours.

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