WO2022135300A1 - 1-苄基-4-甲基-5-烷氧基-1,2,3,6-四氢吡啶衍生物的合成及应用 - Google Patents

1-苄基-4-甲基-5-烷氧基-1,2,3,6-四氢吡啶衍生物的合成及应用 Download PDF

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WO2022135300A1
WO2022135300A1 PCT/CN2021/139218 CN2021139218W WO2022135300A1 WO 2022135300 A1 WO2022135300 A1 WO 2022135300A1 CN 2021139218 W CN2021139218 W CN 2021139218W WO 2022135300 A1 WO2022135300 A1 WO 2022135300A1
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compound
acid
benzyl
sodium
reaction
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PCT/CN2021/139218
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French (fr)
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李运峰
郑志国
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浙江奥翔药业股份有限公司
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Priority to EP21909296.2A priority Critical patent/EP4269391A1/en
Publication of WO2022135300A1 publication Critical patent/WO2022135300A1/zh

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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
    • C07D211/72—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 hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • 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
    • C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—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 no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • 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

Definitions

  • the invention relates to the field of synthesis of pharmaceutical intermediates, in particular to the field of synthesis of key intermediates used for preparing anti-rheumatoid arthritis medicine tofacitinib.
  • the present invention relates to 1-benzyl-4-methyl-5-alkoxy-1,2,3,6-tetrahydropyridine compound, its synthesis method, and its key in the preparation of tofacitinib Use of the intermediate cis-1-benzyl-3-methylamino-4-methylpiperidine.
  • Tofacitinib citrate is the first JAK pathway inhibitor developed by Pfizer for the treatment of rheumatoid arthritis. The product was first approved for marketing in the United States on November 6, 2012. The synthesis of tofacitinib is generally obtained by transformation of the key intermediate compound of formula VI (3R,4R)-1-benzyl-3-methylamino-4-methylpiperidine (Scheme 1).
  • Patent CN108610279A reported that 3-amino-4-methylpyridine was used as a raw material, and the racemic intermediate was synthesized in three steps through reductive amination, salt formation, and reduction (scheme 5).
  • the starting materials of this route are expensive and difficult to obtain, and the post-processing of the products obtained by reduction and acidification is cumbersome.
  • Patent WO2014097150 and CN108689915A reported that 3-bromo-4-picoline was used as starting material, and Ullmann reaction was used to realize amine methylation. After methylation, the salt is formed (Scheme 6). In this route, the Ullmann reaction has the disadvantages of harsh reaction conditions, low yield and cumbersome post-processing.
  • the present invention provides a new synthesis method of compound VI.
  • the method has the characteristics of convenient operation, cheap and readily available raw materials, high product yield, good purity of intermediates and target products, etc., and is easy to carry out industrial production.
  • alkyl refers to a straight or branched chain monovalent saturated hydrocarbon group consisting of carbon and hydrogen atoms.
  • C 1 -C 10 alkyl means an alkyl group having 1 to 10 carbon atoms, preferably a C 1 -C 6 alkyl group.
  • C 1 -C 6 alkyl means a branched or straight chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl Butyl, n-pentyl, isopentyl, n-hexyl.
  • Halogen means fluorine, chlorine, bromine, iodine.
  • Haloalkyl means an alkyl group as described above substituted with one or more halogens, preferably a halogenated C1 - C6 alkyl group, such as trifluoromethyl.
  • Cycloalkyl means a cyclic saturated alkyl group consisting of carbon atoms and hydrogen atoms, preferably a C3 - C7 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • Aryl refers to a monocyclic or fused bicyclic aromatic ring composed of carbon atoms and hydrogen atoms.
  • C 5-10 aryl refers to an aryl group containing 5-10 carbon atoms.
  • a C5-10 aryl group can be phenyl or naphthyl.
  • Alkyl refers to an alkyl group as described above substituted with an aryl group as described above, eg, benzyl.
  • Substituted alkyl mean alkyl, halogen, haloalkyl, hydroxy, and/or amino, respectively, as described above
  • Substituted alkyl, cycloalkyl, aryl and aralkyl groups as described above. Examples of them include, but are not limited to, 2-hydroxy-ethyl, 2-amino-ethyl, 3-hydroxypropyl, 4-hydroxy-butyl, methylcyclohexyl, 2-methylphenyl, 4-methyl Phenyl, 4-propylbenzyl, 4-methylbenzyl, etc.
  • C1 - C4 alcohol refers to an alcohol having 1 to 4 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol.
  • the purpose of the present invention is to provide a key intermediate for the preparation of tofacitinib, that is, a synthesis method of cis-1-benzyl-3-methylamino-4-methylpiperidine.
  • the advantages of the method are that the route is short, the raw materials are readily available, the conditions are mild, the purification is convenient, the yield is high, and it is easy to realize large-scale production.
  • the present invention provides a compound of formula I, named 1-benzyl-4-methyl-5-alkoxy-1,2,3,6-tetrahydropyridine, with the following structure:
  • R is selected from: alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, aralkyl, or substituted aralkyl.
  • R is selected from: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2-hydroxy-ethyl, 2-amino-ethyl, 3-hydroxypropyl , 4-hydroxy-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, methylcyclohexyl, phenyl, 2-methylphenyl, p-methylphenyl, benzyl, 4-propylbenzyl or 4-methylbenzyl.
  • R is selected from: C1 - C6 alkyl, cyclohexyl, 2-hydroxyethyl, 2-aminoethyl, 3-hydroxypropyl, 4-hydroxybutyl, benzyl or phenyl.
  • R is selected from: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclohexyl, 2-hydroxyethyl, 2-aminoethyl, 3-hydroxypropyl or benzyl.
  • the present invention provides a preparation method of the compound of formula I,
  • L is a leaving group
  • R is as described above for the compound of formula I
  • M is a metal element
  • n is selected from 1, 2 or 3
  • X is a halogen
  • Step (1) compound IV reacts with ROH or (RO) n M to generate compound III,
  • Step (2) Compound III is reacted with a benzyl halide to form Compound II, and
  • Step (3) Compound II is reduced to compound I under the action of a reducing agent.
  • the specific reaction conditions are as follows:
  • Step (1) Under the atmosphere of inert gas, in a polar solvent, compound IV and ROH or (RO) n M undergo a substitution reaction under the catalysis of copper ion or palladium catalyst to generate compound III.
  • Described copper ion catalyst is selected from cuprous chloride, cupric chloride, cuprous bromide, cupric bromide, cuprous iodide, copper iodide, copper sulfate, copper nitrate, copper acetate, copper hydroxide, or acetyl Acetone copper.
  • the palladium ion catalyst is selected from palladium chloride, triphenylphosphine palladium chloride and palladium acetate.
  • L is halogen, such as F, Cl, Br or I, or L is -OCOR 1 , -OR 2 or -ONO 2 .
  • R 1 is alkyl or haloalkyl, such as CF 3 or CH 3 .
  • R 2 is alkylsulfonyl or arylsulfonyl, or substituted alkylsulfonyl or arylsulfonyl, such as p-toluenesulfonyl, p-bromobenzenesulfonyl, nitrobenzenesulfonyl, trifluoromethanesulfonyl, Methylsulfonyl, 5-(dimethylamino)naphthalene-1-sulfonyl.
  • M is a metal element
  • M can be selected from lithium, sodium, potassium, calcium, magnesium, aluminum, zinc or iron
  • n is the valence of metal M
  • n is selected from 1, 2 or 3.
  • L is Cl or Br.
  • the (RO) n M is a solid alkali metal salt or a solution thereof.
  • the alkali metal salts are lithium, sodium or potassium salts
  • solutions of alkali metal salts include solutions of lithium, sodium, and potassium salts in C1 - C4 alcohols.
  • the (RO) nM solution can be prepared in situ by adding a strong base to react with ROH.
  • the strong base is selected from lithium metal, sodium metal, potassium metal, sodium hydride, potassium hydride, calcium hydride, sodium tert-butoxide, potassium tert-butoxide, hydroxide One or more of sodium, potassium hydroxide or Grignard reagent.
  • the Grignard reagent is an alkylmagnesium halide or an arylmagnesium halide, such as methylmagnesium bromide, ethylmagnesium bromide, ethylmagnesium iodide, propylmagnesium bromide, butylmagnesium bromide, phenyl bromide Magnesium.
  • the feed ratio of compound IV to ROH is 1.0:1.0-20.0.
  • the feed ratio of compound IV to (RO)nM is 1.0:(1.0-20.0)/ n , and n is selected from 1, 2 or 3.
  • Described copper ion is I-valent or II-valent copper ion, including but not limited to cuprous chloride, cuprous bromide, cuprous iodide, cupric chloride, cupric bromide, copper iodide, copper sulfate, copper nitrate, Copper acetate.
  • the amount of catalyst is 0.1-20.0 mol%, preferably 0.5-10.0 mol%.
  • the reaction solvent is a polar aprotic solvent, a protic solvent or a mixture thereof, including N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylmorpholine, Methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, ethylene glycol, propylene glycol, butylene glycol, or a mixture of any two or more thereof.
  • a aprotic solvent including N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylmorpholine, Methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, ethylene glycol, propylene glycol, butylene glycol, or a mixture of any two or more thereof.
  • the reaction temperature is 20-150°C, such as 60-150°C, preferably 100-130°C.
  • the reaction time is 1.0-10.0 hours.
  • Step (2) Compound III is reacted with benzyl halide to form compound II.
  • the benzyl halide can be benzyl chloride, benzyl bromide or benzyl iodide.
  • the feed ratio of compound III to benzyl halide is 1:1.0-3.0.
  • the reaction temperature is 0 to 150°C, preferably 10 to 80°C.
  • the reaction time is 2 ⁇ 48h.
  • Step (3) Compound II is reduced by a reducing agent in a protic solvent to form a compound of formula I.
  • the protic solvent may be methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, ethylene glycol, propylene glycol or a mixture thereof.
  • the reducing agent may be a reducing agent commonly used in the art, such as lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, lithium triethylborohydride or borane.
  • the reaction temperature is -5-30°C.
  • the reaction time is 0.5-24h.
  • the present invention also provides a synthesis method for the key intermediate compound of formula VI for the preparation of tofacitinib (that is, cis-1-benzyl-3-methylamino-4-methylpiperidine), so The method includes the following steps:
  • Step (4) the compound of formula I is hydrolyzed under acidic conditions to obtain the compound of formula V, and
  • Step (5) Compound V is subjected to reductive amination with methylamine in the presence of a reducing agent, and salified with hydrochloric acid to form a compound of formula VI.
  • the specific reaction conditions are as follows:
  • Step (4) Compound 1-benzyl-4-methyl-5-alkoxy-1,2,3,6-tetrahydropyridine of formula I undergoes hydrolysis reaction under acidic conditions to obtain compound 1-benzyl of formula V -4-Methylpiperidin-3-one.
  • the acid used in the reaction is an inorganic acid or an organic acid.
  • inorganic acids may include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, hypochlorous acid, hypobromous acid, hypophosphorous acid, hyposulfuric acid.
  • Organic acids may include formic acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, citric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid.
  • the acid used in the reaction is preferably hydrochloric acid, such as 6M hydrochloric acid solution.
  • the feeding ratio of the compound of formula I to the acid is 1:1 to 1:10.
  • the reaction solvent is a protic or aprotic organic solvent, such as methanol, ethanol, n-propanol, isopropanol, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, and the reaction temperature is 0- 110°C, the reaction time is 0.5 to 10 hours.
  • a protic or aprotic organic solvent such as methanol, ethanol, n-propanol, isopropanol, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene
  • the reaction temperature is 0- 110°C
  • the reaction time is 0.5 to 10 hours.
  • Step (5) the compound of formula V reacts with methylamine to form a Schiff base, then reacts with a reducing agent to obtain the compound of formula VI 1-benzyl-3-methylamino-4-methylpiperidine, and the compound of formula VI forms a salt with hydrochloric acid further purification.
  • the methylamine is an acid addition salt of methylamine or an alcohol solution of methylamine.
  • the acid addition salt of methylamine is hydrochloride, hydrobromide, hydroiodide, sulfate, formate or acetate of methylamine.
  • the reducing agent is a reducing agent commonly used in the art, such as sodium cyanoborohydride, sodium triacetoxyborohydride, lithium triethylborohydride, borane, (S)-2-methyl-CBS-oxa oxazaborolane, or the above reducing agent can be prepared in situ according to conventional methods, for example, the preparation method of sodium triacetoxyborohydride can be referred to Org.process.Res.Dev.2003,7,115-120.
  • the method for preparing the compound of formula VI comprises the steps of:
  • Step (1) compound IV reacts with ROH or (RO) n M to generate compound III,
  • Step (2) compound III reacts with benzyl halide to generate compound II,
  • Step (3) Compound II is reduced to form Compound I under the action of a reducing agent
  • Step (4) Compound I is hydrolyzed under acidic conditions to obtain Compound V, and
  • Step (5) compound V and methylamine carry out reductive amination in the presence of a reducing agent, and form a salt with hydrochloric acid to generate a compound of formula VI,
  • L is a leaving group
  • R is as claimed in claim 1
  • M and n are as claimed in claim 3
  • X is halogen.
  • reaction conditions for each of steps (1), (2), (3), (4), (5) are as described above.
  • reaction mixture was cooled to room temperature, the reaction solution was concentrated to dryness, petroleum ether was added, stirred and dispersed at room temperature, the petroleum ether was removed by suction filtration, and the filter cake was suction-dried to obtain 18.3 g of an off-white solid with a crude yield of 98.0%.
  • the product was used directly in the next reaction without purification.
  • reaction mixture was cooled to room temperature, methanol was evaporated under reduced pressure, 50 mL of water was added, NaOH solid was added to adjust the pH to greater than 11, 50 mL of ethyl acetate was added for extraction, the organic layer was washed with water, and rotary evaporated to dryness to obtain 21.0 g of a reddish-brown crude product. The yield was 100%, and it was directly used in the next reaction without purification. A small amount of the crude product was subjected to column chromatography to obtain a light yellow liquid for structural identification.
  • the reaction mixture was cooled to room temperature, methanol was evaporated under reduced pressure, 20 mL of water was added, NaOH solid was added to adjust the pH to greater than 11, 15 mL ⁇ 2 of ethyl acetate was added for extraction, the organic layer was washed with water, and rotary evaporated to dryness to obtain 2.1 g of a dark yellow crude product. The yield was 100%, which was directly used in the next reaction.
  • reaction mixture was cooled to room temperature, methanol was evaporated under reduced pressure, 20 mL of water was added, NaOH solid was added to adjust the pH to greater than 11, 15 mL of ethyl acetate was added for extraction, the organic layer was washed with water, and rotary evaporated to dryness to obtain 2.13 g of a dark yellow crude product. The yield was 100%, which was directly used in the next reaction.

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Abstract

本发明涉及药物中间体合成领域，特别是涉及用于制备抗类风湿关节炎药物托法替布的关键中间体合成领域。具体地说，本发明提供了1-苄基-4-甲基-5-烷氧基-1,2,3,6-四氢吡啶化合物、其合成方法、以及其在制备托法替布的关键中间体顺式1-苄基-3-甲氨基-4-甲基哌啶中的应用。

Description

1-苄基-4-甲基-5-烷氧基-1,2,3,6-四氢吡啶衍生物的合成及应用 技术领域
本发明涉及药物中间体合成领域，特别是涉及用于制备抗类风湿关节炎药物托法替布的关键中间体合成领域。具体地说，本发明涉及1-苄基-4-甲基-5-烷氧基-1,2,3,6-四氢吡啶化合物、其合成方法、以及其在制备托法替布的关键中间体顺式1-苄基-3-甲氨基-4-甲基哌啶中的应用。
背景技术
枸橼酸托法替布(Tofacitinib citrate)是辉瑞公司研发的首个作用于JAK通路的抑制剂，用于治疗类风湿性关节炎。该产品于2012年11月6日在美国首先批准上市。托法替布的合成通常由关键中间体式VI化合物(3R,4R)-1-苄基-3-甲氨基-4-甲基哌啶经转化得到(流程1)。
Figure PCTCN2021139218-appb-000001
中间体式VI化合物的合成方法已有较多报道，文献Org.process.Res.Dev.2003,7,115-120报道了以4-甲基吡啶为原料，经与苄基卤化物反应，还原，硼氢化氧化，并继续氧化成酮，再与甲胺进行还原胺化得到外消旋的中间体，再经拆分得到产物(流程2)。该合成路线较长，硼氢化氧化步骤操作繁琐，后续氧化步骤使用危险和管制的过氧化氢和三氧化硫吡啶试剂，不利于工业化生产。
Figure PCTCN2021139218-appb-000002
文献Org.process.Res.Dev.2005,9,51-56报道了以3-氨基-4-甲基吡啶为原料，通过氨基上保护，氢化，还原，苄基化得到1-苄基-3-甲氨基-4-甲基吡啶，最后拆分(流程3)。此路线总收率较低，仅为14.6％，且用到价格昂贵的金属Rh/C 催化剂以及危险还原剂氢化铝锂，限制了工业化生产。
Figure PCTCN2021139218-appb-000003
文献J.Med.Chem,2008,51,8102-8018报道了合成托法替布一系列衍生物的方法(流程4)。但该方法路线冗长繁琐，使用了昂贵的金属催化剂二氧化铂，且得到的中间体为4种异构体，完全不适合工业化。
Figure PCTCN2021139218-appb-000004
专利CN108610279A报道了以3-氨基-4-甲基吡啶为原料，经还原胺化，成盐，还原三步合成外消旋中间体(流程5)。该路线起始原料价格贵且不易获得，还原和酸化得到的产物后处理比较繁琐。
Figure PCTCN2021139218-appb-000005
专利WO2014097150与CN108689915A报道了以3-溴-4-甲基吡啶为起始原料，利用Ullmann反应实现胺甲基化，其区别在于前者先成盐后进行胺甲基化反应，后者先进行胺甲基化后成盐(流程6)。该路线中Ullmann反应存在反应条件较苛刻，产率不高，后处理繁琐等缺点。
Figure PCTCN2021139218-appb-000006
综上所述，目前已报道的化合物VI的制备方法关键在于哌啶环构建和氨甲基化两个步骤，但目前已知的每种方法，均存在工艺操作繁琐、使用管制和危险试剂、使用贵金属催化剂、收率不理想、反应条件苛刻等问题。因此，有必要进一步研究适合化合物VI的工业化生产的简洁高效的合成方法。
为了克服现有技术存在的缺点与不足，本发明提供了一种新的化合物VI的合成方法。该方法具有操作便利，原材料廉价易得，产物收率高，中间体和目标产物的纯度好等特点，且易于进行工业化生产。
发明内容
在本发明中，下列术语具有以下所述的含义：
单独或与其他基团组合的术语“烷基”表示由碳和氢原子组成的直链或支链的单价饱和烃基团。“C 1-C 10烷基”表示具有1至10个碳原子的烷基，优选C 1-C 6烷基。“C 1-C 6烷基”表示具有1至6个碳原子的支链或直链烷基，例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基、异戊基、正己基。
“卤素”是指氟、氯、溴、碘。
“卤代烷基”表示被一个或多个卤素取代的如上所述的烷基，优选卤代C 1-C 6烷基，例如三氟甲基。
“环烷基”是指由碳原子和氢原子组成的环状的饱和烷基基团，优选C 3-C 7环烷基，例如环丙基、环丁基、环戊基、环己基或环庚基。
“芳基”是指由碳原子和氢原子组成的单环或稠合双环的芳香环。“C 5-10芳基”是指含有5-10个碳原子的芳基。例如，C 5-10芳基可以是苯基或萘基。
“芳烷基”是指被如上所述的芳基取代的如上所述的烷基，例如苄基。
“取代的烷基”、“取代的环烷基”、“取代的芳基”和“取代的芳烷基”分别是指被如上所述的烷基、卤素、卤代烷基、羟基和/或氨基所取代的如上所述的烷基、环烷基、芳基和芳烷基。它们的实例包括但不限于2-羟基-乙基、2-氨基-乙基、3-羟基丙基、4-羟基-丁基、甲基环己基、2-甲基苯基、4-甲基苯基、4-丙基苄基、4-甲基苄基等。
“C 1-C 4醇”是指具有1-4个碳原子的醇，例如甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇或叔丁醇。
本发明的目的在于提供一种用于制备托法替布的关键中间体，即顺式-1-苄基-3-甲氨基-4-甲基哌啶的合成方法。该方法优点为路线简短、原料易得、条件温和、提纯方便、收率较高且容易实现规模化生产。
本发明所要解决的技术问题是通过如下技术方案实现的。
第一方面，本发明提供式I化合物，命名为1-苄基-4-甲基-5-烷氧基-1,2,3,6-四氢吡啶，结构如下：
Figure PCTCN2021139218-appb-000007
其中R选自：烷基，取代的烷基，环烷基，取代的环烷基，芳基，取代的芳基，芳烷基，或取代的芳烷基。
例如，R选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、2-羟基-乙基、2-氨基-乙基、3-羟基丙基、4-羟基-丁基、戊基、环戊基、己基、环己基、甲基环己基、苯基、2-甲基苯基、对甲基苯基、苄基、4-丙基苄基或4-甲基苄基。
在一个优选的实施方案中，R选自：C 1-C 6烷基、环己基、2-羟基乙基、2-氨基乙基、3-羟基丙基、4-羟基丁基、苄基或苯基。
更优选地，R选自：甲基、乙基、正丙基、异丙基、正丁基、异丁基、环己基、2-羟基乙基、2-氨基乙基、3-羟基丙基或苄基。
第二方面，本发明提供了式I化合物的制备方法，
Figure PCTCN2021139218-appb-000008
其中，L为离去基团，R如上文对式I化合物所述，M为金属元素，n选自1、2或3，X为卤素，所述方法包括以下步骤：
步骤(1)：化合物IV与ROH或(RO) nM反应生成化合物III，
步骤(2)：化合物III与苄基卤化物反应生成化合物II，和
步骤(3)：化合物II在还原剂作用下被还原生成化合物I。
在一些优选的实施方案中，具体反应条件如下：
步骤(1)：在惰性气体氛围下，在极性溶剂中，化合物IV与ROH或(RO) nM在铜离子或钯催化剂的催化作用下发生取代反应生成化合物III。
所述的铜离子催化剂选自氯化亚铜、氯化铜、溴化亚铜、溴化铜、碘化亚铜、碘化铜、硫酸铜、硝酸铜、乙酸铜、氢氧化铜、或乙酰丙酮铜。
所述的钯离子催化剂选自氯化钯、三苯基膦氯化钯、醋酸钯。
所述化合物IV中，L为卤素，例如F、Cl、Br或I，或者L为-OCOR 1、-OR 2 或-ONO 2。
R 1为烷基或卤代烷基，例如CF 3或CH 3。
R 2为烷基磺酰基或芳基磺酰基，或取代的烷基磺酰基或芳基磺酰基，例如对甲苯磺酰基，对溴苯磺酰基，硝基苯磺酰基，三氟甲磺酰基，甲磺酰基，5-(二甲氨基)萘-1-磺酰基。
所述的(RO) nM中，M为金属元素，M可以选自锂、钠、钾、钙、镁、铝、锌或铁，n为金属M的化合价，且n选自1、2或3.
在一些具体的实施方案中，当M为锂、钠、钾时，n为1；当M为钙、镁或锌时，n＝2；当M为铝或铁时，n＝3。
在更优选的实施方案中，L为Cl或Br。
所述的(RO) nM中R取代基如上所述。
优选地，所述的(RO) nM为固体的碱金属盐或其溶液。
例如，碱金属盐为锂盐、钠盐或钾盐，碱金属盐的溶液包括锂盐、钠盐、钾盐在C 1-C 4醇中的溶液。或者，可通过加入强碱与ROH反应在原位制备所述(RO) nM溶液。
在所述原位制备(RO) nM溶液的方法中，强碱选自金属锂、金属钠、金属钾、氢化钠、氢化钾、氢化钙、叔丁醇钠、叔丁醇钾、氢氧化钠、氢氧化钾或格式试剂中的一种或几种。
所述的格式试剂为烷基卤化镁或芳基卤化镁，例如甲基溴化镁、乙基溴化镁、乙基碘化镁、丙基溴化镁、丁基溴化镁、苯基溴化镁。
化合物IV与ROH的投料比为1.0:1.0-20.0。
化合物IV与(RO) nM的投料比为1.0:(1.0-20.0)/n，n选自1、2或3。
所述铜离子为I价或II价铜离子，包括且不限于氯化亚铜、溴化亚铜、碘化亚铜、氯化铜、溴化铜、碘化铜、硫酸铜、硝酸铜、乙酸铜。
催化剂用量为0.1-20.0mol％，优选为0.5-10.0mol％。
所述反应溶剂为极性非质子溶剂、质子溶剂或其混合物，包括N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、N-甲基吗啉、甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、乙二醇、丙二醇、丁二醇、或它们的任意两种或两种以上的混合物。
所述反应温度为20-150℃，例如60-150℃，优选为100-130℃。
反应时间为1.0-10.0小时。
步骤(2)：化合物III与苄基卤化物反应生成化合物II。
所述苄基卤化物可以是氯化苄、溴化苄或碘化苄。化合物III与苄基卤化物的投料比为1:1.0-3.0。
反应温度为0～150℃，优选10～80℃。
反应时间为2～48h。
步骤(3)：化合物II在质子溶剂中，经还原剂还原生成式I化合物。
所述质子溶剂可以为甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、乙二醇、丙二醇或其混合物。
所述还原剂可以为本领域常用的还原剂，例如硼氢化锂、硼氢化钠、硼氢化钾、氰基硼氢化钠、三乙基硼氢化锂或硼烷。
反应温度为-5-30℃。
反应时间为0.5-24h。
第三方面，本发明还提供了用于制备托法替布的关键中间体式VI化合物(即，顺式-1-苄基-3-甲氨基-4-甲基哌啶)的合成方法，所述方法包括以下步骤：
Figure PCTCN2021139218-appb-000009
步骤(4)：式I化合物在酸性条件下水解得到式V化合物，和
步骤(5)：化合物V与甲胺在还原剂存在下进行还原胺化，并与盐酸成盐生成式VI化合物。
在一些优选的实施方案中，具体反应条件如下：
步骤(4)：式I化合物1-苄基-4-甲基-5-烷氧基-1,2,3,6-四氢吡啶在酸性条件下发生水解反应得到式V化合物1-苄基-4-甲基哌啶-3-酮。
反应所用的酸为无机酸或有机酸。例如，无机酸可包括盐酸、氢溴酸、氢碘酸、硫酸、磷酸、硝酸、次氯酸、次溴酸、次磷酸、次硫酸。有机酸可包括甲酸、乙酸、三氟乙酸、草酸、酒石酸、柠檬酸、对甲苯磺酸、三氟甲磺酸。
反应所用的酸优选为盐酸，例如6M盐酸溶液。
式I化合物与酸的投料比为1:1～1:10。
反应溶剂为质子或非质子有机溶剂，例如甲醇、乙醇、正丙醇、异丙醇、二 氯甲烷、四氢呋喃、2-甲基四氢呋喃、1,4-二噁烷、甲苯，反应温度为0-110℃，反应时间为0.5～10小时。
步骤(5)：式V化合物与甲胺反应形成希夫碱，然后与还原剂反应得到式VI化合物1-苄基-3-甲氨基-4-甲基哌啶，式VI化合物与盐酸成盐进一步纯化。
所述的甲胺为甲胺的酸加成盐或甲胺的醇溶液。其中甲胺的酸加成盐为甲胺的盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、甲酸盐或乙酸盐。
所述的还原剂为本领域常用的还原剂，例如氰基硼氢化钠、三乙酰氧基硼氢化钠、三乙基硼氢化锂、硼烷、(S)-2-甲基-CBS-噁唑硼烷，或者可按照常规方法在原位制备上述还原剂，例如，三乙酰氧基硼氢化钠制备方法可参考文献Org.process.Res.Dev.2003,7,115-120。
在一个优选的实施方案中，制备式VI化合物的方法包括以下步骤：
Figure PCTCN2021139218-appb-000010
步骤(1)：化合物IV与ROH或(RO) nM反应生成化合物III，
步骤(2)：化合物III与苄基卤化物反应生成化合物II，
步骤(3)：化合物II在还原剂作用下被还原生成化合物I，
步骤(4)：化合物I在酸性条件下水解得到化合物V，和
步骤(5)：化合物V与甲胺在还原剂存在下进行还原胺化，并与盐酸成盐生成式VI化合物，
其中，L为离去基团，R如权利要求1所述，M和n如权利要求3所述，且X为卤素。
在进一步优选的实施方案中，步骤(1)、(2)、(3)、(4)、(5)各自的反应条件如上文所述。
具体实施方式
通过以下实施例对本发明的方法进行进一步的说明。应当理解，提供以下实施例的目的仅仅是为了能够更好的理解本发明，而不是以任何方式限定本发明的范围。
实施例1-4通过以下路线制备1-苄基-5-甲氧基-4-甲基-1,2,3,6-四氢吡啶。
Figure PCTCN2021139218-appb-000011
实施例1
3-甲氧基-4-甲基吡啶的制备：
氮气保护下，向250mL三口瓶中加入3-溴-4-甲基吡啶17.2g和DMF 100.0mL溶清后，加入甲醇钠10.8g和CuBr 0.72g，反应液升温至130℃搅拌5小时。TLC(PE：EA＝2:1)监测原料反应完全，有白色固体NaBr逐渐生成，反应混合物降至室温，加水40.0mL淬灭反应，混合液加入甲基叔丁基醚60mL×3提取，合并有机层，加入20.0mL饱和NaCl洗涤，旋蒸浓缩得深黄色液体17.50g，粗收率100％，GC纯度91.5％，无需纯化直接用于下一步反应。 1H-NMR(400MHz,CDCl 3)δ8.16(s,1H),8.12(d,J＝4.8Hz,1H),7.06(d,J＝4.8Hz,1H),3.91(s,3H),2.23(s,3H)。
实施例2
1-苄基-3-甲氧基-4-甲基吡啶鎓氯化物的制备：
氮气保护下，向250mL反应瓶中加入上述反应产物3-甲氧基-4-甲基吡啶17.5g，溶于乙腈120mL，加入氯化苄13.8mL，加热至80℃回流搅拌7小时，TLC(PE：EA＝2:1)显示原料反应完全，颜色逐渐变深。反应混合物降至室温，将反应液旋转蒸发至干，加入石油醚，室温搅拌分散，抽滤除去石油醚，滤饼抽干，得灰白色固体22.6g，粗收率90.4％，产物不经纯化直接用于下一步反应。
实施例3
1-苄基-5-甲氧基-4-甲基-1,2,3,6-四氢吡啶的制备：
向500mL反应瓶中加入上述1-苄基-3-甲氧基-4-甲基吡啶鎓氯化物22.6g，溶于220mL甲醇，控制内温10-25℃，分批加入NaBH 4 10.26g，反应剧烈，放 气放热。加料完毕后室温继续搅拌2小时，TLC(DCM：MeOH＝10:1)监测反应完全。加水80mL淬灭反应，蒸去甲醇，加入EtOAc 100mL×2次，合并有机层，水洗，蒸馏至干，得浅黄色液体17.0g，收率87.0％。 1H-NMR(400MHz,CDCl 3)δ7.36-7.25(m,5H),3.59(s,2H),3.48(s,3H),2.98-2.96(m,2H),2.50(t,J＝5.6Hz,2H),2.07-2.05(m,2H),1.63(s,3H)； 13C-NMR(100MHz,CDCl 3)δ145.8,137.9,129.2,128.2,127.1,113.3,62.6,57.4,51.7,49.8,30.0,14.9ppm.；MS(EI):217.2,(C 14H 19NO[M] +)。
实施例4
1-苄基-5-甲氧基-4-甲基-1,2,3,6-四氢吡啶的制备：
向50mL反应瓶中加入上述1-苄基-3-甲氧基-4-甲基吡啶鎓氯化物2.70g，溶于20mL甲醇，控制内温10-25℃下分批加入NaBH 4 1.05g，反应放气放热，加料完毕室温继续搅拌2小时，TLC(v/v DCM：MeOH＝10:1)监测反应完全。加水10mL淬灭反应，蒸去甲醇，加入EtOAc 10mL×2提取，合并有机层，水洗，蒸馏至干，得浅黄色液体1.64g，收率82.1％。
实施例5-7通过以下路线合成1-苄基-5-乙氧基-4-甲基-1,2,3,6-四氢吡啶：
Figure PCTCN2021139218-appb-000012
实施例5
3-乙氧基-4-甲基吡啶的制备：
氮气保护下，向250mL三口瓶中加入3-溴-4-甲基吡啶17.2g和DMF 100mL溶清后，加入乙醇钠13.6g，加入CuCl 2 0.67g，加热至130℃搅拌反应7小时。TLC(v/v PE：EA＝2:1)监测原料反应完全，有白色固体NaBr逐渐生成，反应混合物降至室温，加水40mL淬灭反应，加入甲基叔丁基醚60mL×3提取，合并有机层，水洗，浓缩至干得深黄色液体11.20g，粗收率81.8％。 1H-NMR(400MHz,CDCl 3)δ8.15(s,1H),8.10(d,J＝4.0Hz,1H),7.05(d,J＝4.4Hz,1H),4.12(q,J＝6.8Hz,2H),2.23(s,3H),1.44(t,J＝7.2Hz,3H)。
实施例6
1-苄基-3-乙氧基-4-甲基吡啶鎓氯化物的制备：
氮气保护下，向250mL反应瓶中加入上述反应产物3-乙氧基-4-甲基吡啶11.2g(82mmol)和乙腈120mL溶清后，加入氯化苄12.4g，加热至80℃回流搅拌7小时，TLC(v/v PE：EA＝2:1)监测原料反应完全，颜色逐渐变深。反应混合物降至室温，将反应液浓缩至干，加入石油醚，室温搅拌分散，抽滤除去石油醚，滤饼抽干，得灰白色固体18.3g，粗收率98.0％。产物不经纯化直接用于下一步反应。
实施例7
1-苄基-5-乙氧基-4-甲基-1,2,3,6-四氢吡啶的制备：
向500mL反应瓶中加入上述1-苄基3-乙氧基-4-甲基吡啶鎓氯化物18.3g和200mL乙醇溶清后，控制内温10-25℃分批加入NaBH 4 8.78g，反应缓慢放气放热。加料完毕室温继续搅拌2小时，TLC(DCM：MeOH＝10:1)监测反应完全。加水80mL淬灭反应，蒸去乙醇，加入EtOAc 100mL×2提取，合并有机层，水洗，蒸馏至干，得到浅黄色液体产物16.7g，收率90.0％。 1H-NMR(400MHz,CDCl 3)δ7.35-7.24(m,5H),3.66(q,J＝6.8Hz,2H),3.58(s,2H),2.96(s,2H),2.50(t,J＝4.2Hz,2H),2.06(m,2H),1.63(s,3H),1.21(t,J＝7.2Hz,3H)； 13C-NMR(100MHz,CDCl 3)δ144.8,138.2,129.2,128.2,127.1,113.7,65.1,62.6,52.5,49.9,30.1,15.6,15.2ppm.；MS(EI):231.1,(C 15H 21NO[M] +)。
实施例8-10通过以下路线合成1-苄基-5-异丙氧基-4-甲基-1,2,3,6-四氢吡啶：
Figure PCTCN2021139218-appb-000013
实施例8
3-异丙氧基-4-甲基吡啶的制备：
氮气保护下，向250mL三口瓶中加入异丙醇20mL，控温-5-5℃分批加入NaH 2.0g(60％)制备异丙醇钠，然后依次加入DMF 40mL、反应底物3-溴-4-甲基吡啶4.3g和CuBr 180mg，体系变浅蓝色。加热至130℃搅拌反应4小时，TLC(PE：EA＝2:1)监测原料基本反应完全。冷却至室温，加20mL水淬灭反应，减压蒸除剩余异丙醇，剩余液加入甲基叔丁基醚20mL×3提取，有絮状 物生成，过滤，合并有机相，水洗，浓缩至干，得浅黄色液体2.4g，收率63.6％。产物不经纯化直接用于下一步反应。 1H-NMR(400MHz,CDCl 3)δ8.18(s,1H),8.09(d,J＝4.4Hz,1H),7.06(d,J＝4.4Hz,1H),4.63-4.57(m,1H),2.22(s,3H),1.36(d,J＝6.0Hz,6H)。
实施例9
1-苄基-3-异丙氧基-4-甲基吡啶鎓氯化物的制备：
氮气保护下，向100mL反应瓶中加入上述反应产物3-异丙氧基-4-甲基吡啶2.4g和乙腈30mL溶清后，加入氯化苄2.43g，加热至80℃回流搅拌5小时，TLC(PE：EA＝2:1)监测原料反应完全。降至室温，将反应液浓缩至干，加入石油醚，室温搅拌分散，抽滤除去石油醚，滤饼抽干，得白色固体4.0g，粗收率90.0％。产物不经纯化直接用于下一步反应。
实施例10
1-苄基-5-异丙氧基-4-甲基-1,2,3,6-四氢吡啶的制备
向100mL反应瓶中加入上述1-苄基-3-异丙氧基-4-甲基吡啶鎓氯化物4.0g和甲醇40mL溶清后，控制内温10-25℃，分批加入NaBH 4 1.64g，反应放气放热。加料完毕室温继续搅拌1小时，TLC(DCM：MeOH＝10:1)监测反应完全。加水20mL淬灭反应，蒸去甲醇，加入EtOAc 40mL×2提取，合并有机层，水洗，浓缩至干，得产物为无色液体2.97g，收率84.2％。 1H-NMR(400MHz,CDCl 3)δ7.34-7.22(m,5H),3.98-3.92(m,1H),3.57(s,2H),2.92(s,2H),2.50(t,J＝4.2Hz,2H),2.07(s,2H),1.62(s,3H),1.15(d,J＝6.0Hz,6H)； 13C-NMR(100MHz,CDCl 3)δ143.3,138.3,129.1,128.2,127.0,114.2,70.3,62.6,53.2,50.0,30.2,22.7,15.7ppm.；MS(EI):245.2,(C 16H 23NO[M] +)。
实施例11-13通过以下路线合成1-苄基-5-(2-羟基-乙氧基)-4-甲基-1,2,3,6-四氢吡啶。
Figure PCTCN2021139218-appb-000014
实施例11
3-(2-羟基-乙氧基)-4-甲基吡啶的制备：
氮气保护下，向100mL三口瓶中加入乙二醇12.4g、3-溴-4-甲基吡啶3.44g、NaOH 1.6g和CuCl 2 134mg，混合后，体系变深蓝色。加热到130℃搅拌反应3个小时，TLC(v/v DCM:MeOH＝10：1)监测反应基本完全。冷却至室温，减压蒸馏除去乙二醇，加入二氯甲烷40mL×2萃取，合并有机相，水洗，浓缩至干，加入正己烷结晶，过滤得浅黄色固体2.14g产物，收率70.0％。 1H-NMR(400MHz,CDCl 3)δ8.12(s,1H),8.08(d,J＝4.4Hz,1H),7.04(d,J＝4.4Hz,1H),4.15-4.13(t,2H),3.99-3.96(t,2H),2.22(s,3H)。
实施例12
1-苄基-3-(2-羟基-乙氧基)-4-甲基吡啶鎓氯化物的制备：
向100mL反应瓶中加入上一步产物3-(2-羟基-乙氧基)-4-甲基吡啶2.14g和乙腈25ml，加入氯化苄2.12g，升温回流搅拌6小时，TLC(DCM:MeOH＝10：1)监测原料反应完全。冷却至室温，有固体析出，浓缩乙腈，加入30mL甲基叔丁基醚分散，抽滤，得灰白色固体3.7g，产率94.0％。
实施例13
1-苄基-5-(2-羟基-乙氧基)-4-甲基-1,2,3,6-四氢吡啶的制备
向100mL反应瓶中加入1-苄基-3-(2-羟基-乙氧基)-4-甲基吡啶鎓氯化物3.65g，溶于50mL甲醇，降温至10℃，分批加入NaBH 4 1.25g，加毕升至室温搅拌3h，TLC(v/v DCM:MeOH＝10：1)监测反应基本完全。加入水10mL淬灭反应，旋蒸除去甲醇，加入乙酸乙酯20mL×2萃取，水洗，浓缩至干，得到2.75g浅黄色液体，产率85％。 1H-NMR(400MHz,CDCl 3)δ7.42-7.27(m,5H),3.75-3.74(m,6H),3.14(m,2H),2.64-2.66(m,2H),2.16(m,2H),2.16(s,3H)； 13C-NMR(100MHz,CDCl 3)δ143.6,135.7,129.7,128.6,127.9,114.6,71.3,62.0,61.8,51.6,49.3,29.2,15.2ppm；MS(ESI):248.05,(C 15H 21NO 2,[M+1] +)。
实施例14-17举例说明了从式I化合物制备中间体化合物VI的合成方法
Figure PCTCN2021139218-appb-000015
实施例14
1-苄基-4-甲基哌啶-3-酮(化合物V)的制备方法一：
向250mL反应瓶中加入17.0g的1-苄基-5-甲氧基-4-甲基-1,2,3,6-四氢吡啶和150mL甲醇，溶清后，加入6M HCl 39mL，将反应液加热至60℃回流2h，TLC(v/v PE:EA＝2:1)监测原料完全转化。反应混合物降至室温，减压蒸去甲醇，加入水50mL，加入NaOH固体调pH至大于11，加入乙酸乙酯50mL×2提取，有机层水洗，旋蒸至干得红棕色粗品21.0g，粗收率100％，无需纯化直接用于下一步反应。取少量粗品经柱层析，得浅黄色液体用于结构鉴定。 1H-NMR(400MHz,CDCl 3)δ7.34-7.26(m,5H),3.58-3.57(m,2H),3.25-3.21(d,J＝14.0Hz,1H),2.95-2.92(m,1H),2.80-2.77(d,J＝14.0Hz,1H),2.47-2.45(m,1H),2.36-2.33(m,1H),2.06-2.01(m,1H),1.66-1.63(m,1H),1.08(d,J＝6.4Hz,3H)； 13C-NMR(100MHz,CDCl 3)δ208.6,137.2,129.2,128.4,127.5,64.1,62.6,51.9,43.0,32.9.,14.2ppm；ESI-MS:204.05,(C 13H 17NO,[M+1] +)。
实施例15
1-苄基-4-甲基哌啶-3-酮(化合物V)的制备方法二：
向100mL反应瓶中加入2.0g 1-苄基-5-乙氧基-4-甲基-1,2,3,6-四氢吡啶和20mL MeOH溶清后，加入4.8mL 6M HCl，反应液加热至60℃回流2h，TLC(v/v PE：EA＝2:1)监测原料完全转化。反应混合物降至室温，减压蒸去甲醇，加入水20mL，加入NaOH固体调pH至大于11，加入乙酸乙酯15mL×2提取，有机层水洗，旋蒸至干得深黄色粗品2.1g，粗收率100％，直接用于下一步反应。
实施例16
1-苄基-4-甲基哌啶-3-酮(化合物V)的制备方法三：
向100mL反应瓶中加入2.66g 1-苄基-5-(2-羟基-乙氧基)-4-甲基-1,2,3,6-四氢吡啶和20mL甲醇溶清后，加入5mL 6M HCl，反应液加热至60度回流2h，TLC(v/v PE：EA＝2:1)监测原料完全转化。反应混合物降至室温，减压蒸去 甲醇，加入水20mL，加入NaOH固体调pH至大于11，加入乙酸乙酯15mL×2提取，有机层水洗，旋蒸至干得深黄色粗品2.13g，粗收率100％，直接用于下一步反应。
实施例17
1-苄基-3-甲氨基-4-甲基哌啶盐酸盐的制备：
氮气保护下，向250mL反应瓶中加入1-苄基-4-甲基哌啶-3-酮21.0g和甲苯60mL溶清后，控温15℃，滴加30％的甲胺的乙醇溶液50mL，再加入AcOH 4.8mL，加毕后室温搅拌2h制备亚胺中间体，倒入滴液漏斗中。向500mL三口瓶中，加入NaBH 4 3.95g，溶于80mL THF，冷却到10度，缓慢滴加乙酸28.3g，剧烈放气放热，滴加完毕于15℃搅拌2h原位制备NaBH(OAc) 3。控制内温低于20℃，将上述亚胺反应液滴加入该体系中，滴加完毕体系自然升至室温反应，TLC(v/v PE:EA＝2:1)监测反应完全。加入30％NaOH水溶液调节pH至11-12，分层，水层用甲苯50mL×2提取，合并有机层，减压浓缩至干得游离碱粗品。将粗品溶于100mL EtOH，室温下缓慢滴加浓盐酸14mL，滴毕搅拌30min，固体逐渐析出，控制内温为5-10℃继续缓慢搅拌1h，抽滤得粉白色固体，加入EtOAc 80mL室温打浆，过滤，得白色固体17.8g。两步总收率80.4％。游离后分析GC含量100％，dr值：99.2:0.8。 1H-NMR(400MHz,CDCl 3)δ7.28-7.18(m,5H),3.53(d,J＝12.8Hz,1H),3.39(d,J＝12.8Hz,1H),2.69-2.62(m,2H),2.40(s,1H),2.29(s,3H),2.12-2.02(m,2H),1.66(s,1H),1.47-1.43(m,3H),0.92(d,J＝7.2Hz,3H)； 13C-NMR(100MHz,CDCl 3)δ138.8,128.9,128.1,126.8,63.1,59.1,54.5,52.6,34.5,33.2,29.8,16.3ppm；MS(EI):218.2,(C 14H 22N 2[M] +)。

Claims (16)

  1. 式I所示的化合物：1-苄基-4-甲基-5-烷氧基-1,2,3,6-四氢吡啶，
    Figure PCTCN2021139218-appb-100001
    其中：R选自：烷基，取代的烷基，环烷基，取代的环烷基，芳基，取代的芳基，芳烷基，或取代的芳烷基。
  2. 根据权利要求1所述的化合物，其特征在于R为：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、2-羟基-乙基、2-氨基-乙基、3-羟基丙基、4-羟基-丁基、戊基、环戊基、己基、环己基、甲基环己基、苯基、2-甲基苯基、对甲基苯基、苄基、4-丙基苄基或4-甲基苄基。
  3. 制备式(I)化合物的方法，包括以下三个步骤：
    Figure PCTCN2021139218-appb-100002
    其中，L为离去基团，R如权利要求1所述，M为金属元素，n选自1、2或3，X为卤素，
    步骤(1)：化合物IV与ROH或(RO) nM反应生成化合物III，
    步骤(2)：化合物III与苄基卤化物反应生成化合物II，和
    步骤(3)：化合物II在还原剂作用下被还原生成化合物I。
  4. 根据权利要求3的方法，其特征为：
    L为卤素，例如F、Cl、Br或I，或者L为-OCOR 1、-OR 2或-ONO 2，
    R 1为烷基或卤代烷基，例如CF 3或CH 3，和/或
    R 2为烷基或芳基磺酰基，或取代的烷基或芳基磺酰基，例如对甲苯磺酰基，对溴苯磺酰基，硝基苯磺酰基，三氟甲磺酰基，甲磺酰基或5-(二甲基氨基)萘-1-磺酰基。
  5. 根据权利要求3或4任一项所述的方法，其中步骤(1)是在铜离子或钯催 化剂的催化下进行。
  6. 根据权利要求3-5任一项所述的方法，其特征在于(RO) nM中M选自锂、钠、钾、钙、镁、铝、锌或铁。
  7. 根据权利要求6所述的方法，其特征在于所述的(RO) nM为固体的碱金属盐或其溶液，例如锂盐、钠盐、钾盐或其在C 1-C 4醇中的溶液，或加入强碱与ROH反应原位制备所述(RO) nM溶液。
  8. 根据权利要求7所述的方法，其中加入强碱与ROH反应原位制备所述(RO) nM溶液，其特征在于所述的强碱为选自金属锂、金属钠、金属钾、氢化钠、氢化钾、氢化钙、叔丁醇钠、叔丁醇钾、氢氧化钠、氢氧化钾或格式试剂中的一种或几种。
  9. 根据权利要求8所述的方法，其中所述格式试剂为烷基卤化镁或芳基卤化镁，例如甲基溴化镁、乙基溴化镁、乙基碘化镁、丙基溴化镁、丁基溴化镁或苯基溴化镁。
  10. 根据权利要求3所述的方法，其特征在于步骤(1)的反应溶剂为极性非质子溶剂、质子溶剂或其混合物，例如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、N-甲基吗啉、甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、乙二醇、丙二醇、丁二醇、或它们的任意两种或两种以上的混合物。
  11. 根据权利要求3所述的方法，其特征在于步骤(2)中X为氯、溴或碘。
  12. 根据权利要求3所述的制备方法，其特征在于步骤(3)中还原剂选自硼氢化锂、硼氢化钠、硼氢化钾、氰基硼氢化钠、三乙基硼氢化锂或硼烷。
  13. 制备式VI化合物的方法，包括以下两个步骤：
    Figure PCTCN2021139218-appb-100003
    步骤(4)：式I化合物在酸性条件下水解得到式V化合物，和
    步骤(5)：化合物V与甲胺在还原剂存在下进行还原胺化，并与盐酸成盐生成式VI化合物。
  14. 根据权利要求13所述的方法，其中步骤(4)中所用的酸为有机或无机酸， 例如盐酸、氢溴酸、氢碘酸、硫酸、磷酸、硝酸、甲酸、乙酸、三氟乙酸、草酸、酒石酸、柠檬酸、对甲苯磺酸或三氟甲磺酸。
  15. 根据权利要求13或14所述的方法，其中步骤(5)中所用的还原剂为氰基硼氢化钠、三乙酰氧基硼氢化钠、三乙基硼氢化锂、硼烷、(S)-2-甲基-CBS-噁唑硼烷、或者按照常规方法原位制备的上述还原剂。
  16. 如权利要求13-15任一项所述的方法，包括以下步骤：
    Figure PCTCN2021139218-appb-100004
    步骤(1)：化合物IV与ROH或(RO) nM反应生成化合物III，
    步骤(2)：化合物III与苄基卤化物反应生成化合物II，
    步骤(3)：化合物II在还原剂作用下被还原生成化合物I，
    步骤(4)：化合物I在酸性条件下水解得到化合物V，和
    步骤(5)：化合物V与甲胺在还原剂存在下进行还原胺化，并与盐酸成盐生成式VI化合物，
    其中，L为离去基团，R如权利要求1所述，M和n如权利要求3所述，且X为卤素。
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