WO2018082441A1 - Procédé de préparation de 4-méthylènepipéridine ou d'un sel d'addition d'acide de celle-ci - Google Patents

Procédé de préparation de 4-méthylènepipéridine ou d'un sel d'addition d'acide de celle-ci Download PDF

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WO2018082441A1
WO2018082441A1 PCT/CN2017/106398 CN2017106398W WO2018082441A1 WO 2018082441 A1 WO2018082441 A1 WO 2018082441A1 CN 2017106398 W CN2017106398 W CN 2017106398W WO 2018082441 A1 WO2018082441 A1 WO 2018082441A1
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acid
group
compound
substituted
methyl
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PCT/CN2017/106398
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朱富强
张健
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山东特珐曼药业有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

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  • 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.
  • 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.
  • 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.
  • 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:
  • 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
  • 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);
  • 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 pheny
  • Method one includes the following steps:
  • 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);
  • 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;
  • 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.
  • an acid-binding agent which is an inorganic base capable of neutralizing hydrogen chloride such as sodium hydroxide or hydrogen.
  • an acid-binding agent which is an inorganic base capable of neutralizing hydrogen chloride such as sodium hydroxide or hydrogen.
  • an acid-binding agent which is an inorganic base capable of neutralizing hydrogen chloride such as sodium hydroxide or hydrogen.
  • an acid-binding agent which is an inorganic base capable of neutralizing hydrogen chloride such as sodium hydroxide or hydrogen.
  • 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).
  • 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
  • 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
  • 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.
  • 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.
  • 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;
  • 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.
  • preferred examples of the acid are hydrochloric acid, hydrobromic acid or hydroiodic acid;
  • Method two includes:
  • 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;
  • 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
  • DBU 1,8-diazabicycloundec-7-ene
  • DBN 1,5-diazabicyclo[4.3.0]non-5-ene
  • DIPEA N-diisopropylethylamine
  • potassium t-butoxide sodium t-butoxide
  • lithium 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.
  • step f)
  • 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 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:
  • 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.
  • the salt of Compound III is a hydrochloride, a hydrobromide, a hydroiodide, a sulfate, more preferably a hydrochloride.
  • 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.
  • 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.
  • 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.
  • Figure 1 is an HPLC chromatogram of 4-methylene piperidine hydrochloride prepared in Example 11.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • Mobile phase A water-acetonitrile-perchloric acid (95:5:0.2)
  • Injection volume 5 ⁇ L, flow rate: 1.0 mL/min, column temperature: room temperature, detection wavelength: 200 nm.
  • the purity of 4-methylene piperidine hydrochloride prepared in this example was more than 99%, and the impurity content was less than 0.1%.
  • 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.

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  • Hydrogenated Pyridines (AREA)
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Abstract

La présente invention concerne un procédé de préparation de 4-méthylènepipéridine ou d'un sel d'addition d'acide de celle-ci. Le procédé de préparation est le procédé I ou le procédé II. Le procédé de préparation de la présente invention présente des conditions de réaction modérées et des post-traitements simples, est écologique, a un faible coût de production, avec une pureté de produit élevée et un rendement élevé, et est approprié pour la préparation industrielle de 4-méthylenepipéridine ou d'un sel d'addition d'acide de celle-ci. Procédé I : formule A ; et procédé II : formule B.
PCT/CN2017/106398 2016-11-01 2017-10-17 Procédé de préparation de 4-méthylènepipéridine ou d'un sel d'addition d'acide de celle-ci WO2018082441A1 (fr)

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CN111454214A (zh) * 2020-05-27 2020-07-28 龙曦宁（上海）医药科技有限公司 一种2-甲氧基1-嘧啶乙胺盐酸盐的合成方法
CN112574032A (zh) * 2020-12-29 2021-03-30 山东省农药科学研究院 一种制备(z,e)-12-十四碳烯-1-醇乙酸酯的改进方法
CN114364668A (zh) * 2019-06-21 2022-04-15 甘李药业股份有限公司 Cdk4/6抑制剂、及其盐和中间体的制备方法
CN116640104A (zh) * 2023-05-24 2023-08-25 杭州科耀医药科技有限公司 一种替洛利生的工业合成方法

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