WO2019011200A1 - 一种吡啶甲酰胺类衍生物的制备方法及其中间体 - Google Patents

一种吡啶甲酰胺类衍生物的制备方法及其中间体 Download PDF

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WO2019011200A1
WO2019011200A1 PCT/CN2018/094947 CN2018094947W WO2019011200A1 WO 2019011200 A1 WO2019011200 A1 WO 2019011200A1 CN 2018094947 W CN2018094947 W CN 2018094947W WO 2019011200 A1 WO2019011200 A1 WO 2019011200A1
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compound
formula
acid
preparation
reaction
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PCT/CN2018/094947
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French (fr)
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姚飞
邱振均
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江苏恒瑞医药股份有限公司
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Priority to CN201880004432.6A priority Critical patent/CN109983008A/zh
Publication of WO2019011200A1 publication Critical patent/WO2019011200A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a process for the preparation of a pyridine carboxamide derivative and an intermediate thereof.
  • Diuretics are widely recommended as first-line antihypertensive drugs in national hypertension guidelines for mild to moderate hypertension, especially in elderly hypertension or complicated heart failure.
  • ROMK antihypertensive diuretic development of new targets ROMK for the inward rectifier K + channels (inwardly rectifying K channels, Kir) a family, belong Kir1 type, the maintenance of renal potassium ions play a crucial balance effect.
  • ROMK1, ROMK2, and ROMK3 are at least three subtypes of ROMK channels: ROMK1, ROMK2, and ROMK3.
  • Most of ROMK2 is distributed in the ascending limb of Henle (TALH); ROMK1 and ROMK3 are mainly expressed on the cortical collecting duct (CCD).
  • WO2016091042A1 discloses a class of extrarenal medulla secretory potassium channel (ROMK) inhibitors, chemical name (R)-5-cyano-N-(1-(2-hydroxy-2) a compound of (4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-methoxypyridinecarboxamide, relative
  • ROMK inhibitors increases the polar group, lowers the ClogP, enhances the hERG selectivity and increases the safety based on the activity of the ROMK inhibitor, and its structure is as shown in the formula (A).
  • Example 1 of WO2016091042A1 discloses a preparation method of Compound A, which has a total of five steps of reaction, and the specific reaction is as follows:
  • the method has the problems of more reaction steps, small batch size, post-treatment method using thin layer chromatography purification, low yield, etc., wherein the yield of the second step reaction is 22.4%, and the yield of the product prepared in the last step is only 11.3. % is not conducive to industrial expansion of production, it is necessary to improve its preparation method.
  • the technical problem to be solved by the present invention is to provide a process for preparing a compound of the formula (I) which is completely different from the prior art, and to change the starting materials and intermediates to prepare the target product, by shortening the reaction step, starting materials, etc.
  • the reactants are simple and easy to purchase, the reaction conditions are simple and controllable, and the post-reaction treatment method is simple, and the preparation method is optimized to improve the yield and facilitate industrial expansion.
  • the present invention provides a process for the preparation of a compound of the formula (I), which comprises a compound of the formula (III) or a salt thereof and a compound of the formula (II) or a salt thereof under the action of a condensing agent a step of obtaining a compound of the formula (I),
  • the X is selected from the group consisting of -OH, alkoxy, alkoxy-substituted acyl, halogen, preferably -OH.
  • the method is
  • the compound represented by the formula (III-1) and the compound of the formula (II-1) are subjected to an acylation reaction under the conditions of a condensing agent selected from the group consisting of CDI, EDC.HCl/HOBT, DIC/HOBT, EDC. .HCl/DMAP, HATU, HBTU, DIC/DMAP, preferably DIC/HOBT.
  • a condensing agent selected from the group consisting of CDI, EDC.HCl/HOBT, DIC/HOBT, EDC. .HCl/DMAP, HATU, HBTU, DIC/DMAP, preferably DIC/HOBT.
  • the method further includes
  • the compound of the formula (IV) is subjected to a Boc protecting group reaction under acidic conditions; the acidic condition is selected from the group consisting of HCl gas/ethanol, HCl gas/tetrahydrofuran, HCl gas/ethyl acetate, HCl gas/1, 4 - Dioxane, the product can be precipitated from hydrochloric acid with hydrochloric acid, preferably HCl gas / ethyl acetate.
  • the method further includes
  • the compound represented by the formula (VI) and the compound of the formula (V) are subjected to a nucleophilic substitution reaction in an organic solvent;
  • the organic solvent is selected from an alcohol solvent or a nitrile solvent, preferably methanol, ethanol, isopropanol or acetonitrile. More preferably, ethanol.
  • the present invention also provides a compound of the formula (III-1),
  • the present invention further provides a process for the preparation of a compound of the formula (III-1), which comprises the step of reacting a compound of the formula (IV) to obtain a compound of the formula (III-1).
  • the method further includes
  • the present invention also provides a compound of the formula (IV),
  • the present invention further provides a process for the preparation of a compound of the formula (IV) or a salt thereof, which comprises reacting a compound of the formula (VI) with a compound of the formula (V) to give a formula (IV).
  • a process for the preparation of a compound of the formula (IV) or a salt thereof which comprises reacting a compound of the formula (VI) with a compound of the formula (V) to give a formula (IV).
  • the method further includes
  • the method further includes
  • the present invention also provides a compound of the formula (a),
  • the present invention further provides a process for the preparation of a compound of the formula (a), which comprises reacting a compound of the formula (c) with a compound of the formula (b) to give a compound of the formula (a). step,
  • the method further includes
  • the present invention also provides a compound of the formula (c),
  • the present invention further provides a process for the preparation of a compound of the formula (c), which comprises the step of reacting a compound of the formula (d) to obtain a compound of the formula (c),
  • the compound of formula (d) is reacted under the action of an oxidizing agent to form a compound of formula (c);
  • the oxidizing agent is selected from the group consisting of osmium tetroxide, potassium citrate/potassium ferricyanide; more preferably potassium citrate/iron Potassium cyanide.
  • the present invention further provides a process for the preparation of a compound of the formula (I), which comprises reacting a compound of the formula (VI) with a compound of the formula (V) to give a compound of the formula (IV), Step of reacting a compound of the formula (IV) to obtain a compound of the formula (III-1), a compound of the formula (III-1) and a compound of the formula (II-1) to obtain a compound of the formula (I). ,
  • the invention further relates to a process for the preparation of a pharmaceutically acceptable salt of a compound of formula (I), comprising the steps of the preceding scheme, and the preparation of a pharmaceutically acceptable compound obtained by reacting a compound of formula (I) with an acid a step of salt, the acid being selected from the group consisting of organic or inorganic acids, preferably organic acids; the organic acid being selected from the group consisting of tartaric acid, malic acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid or P-toluenesulfonic acid, preferably L-tartaric acid or malic acid; the inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.
  • halogen or halogen atom as used in the present invention means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like.
  • alkyl group in the present invention means a linear or branched alkyl group having 1 to 20 carbon atoms, and includes, for example, "C 1-6 alkyl group", “C 1-4 alkyl group”, etc., specific examples Including but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, Neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2, 2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2- Ethyl butyl,
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • alkoxy-substituted acyl refers to -C(O)(alkoxy).
  • the "alcohol solvent” as used in the present invention means a group derived from one or more "hydroxyl groups” substituted by one or more hydrogen atoms on the "alkyl group", as defined above, specifically Examples include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol or trifluoroethanol.
  • nitrile solvent as used in the present invention means a group derived from one or more "cyano” substituted one or more hydrogen atoms on the "alkyl group", which is as defined above. Specific examples include, but are not limited to, acetonitrile or propionitrile.
  • reaction step is reduced, the reaction step disclosed in the prior art is 5 steps, and the reaction step of the present invention is 3 steps.
  • the starting materials and intermediates of the present invention are different, providing a completely different synthetic method, and the starting materials and reactants are simple and easy to purchase.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured using a Bruker AVANCE-500 nuclear magnetic apparatus, and the solvent was DMSO-d 6 and the internal standard was tetramethylsilane (TMS).
  • reaction was quenched by adding 200 mL of potassium carbonate aqueous solution (containing 66.0 g of potassium carbonate) under ice-cooling, and concentrated under reduced pressure, water (200 mL) and ethyl acetate (800 mL) ⁇ 1,400 mL ⁇ 2), and the organic phase was combined with EtOAc EtOAc (EtOAc m. Drying gave 150.0 g of product.
  • the cuprous cyanide (123.0 g) was added to N,N-dimethylformamide (500 mL), and the material g (150.0 g) was dissolved in N,N-dimethylformamide (250 mL), and added to the dropping funnel. Under an argon atmosphere, after heating to 140-150 ° C, the N,N-dimethylformamide solution of the raw material g was added dropwise, and the reaction was stirred at 145 ° C for 2 hours. After the reaction was completed, the temperature was lowered to 90-95 ° C, and the mixture was added dropwise. Ionized water (62 mL), reacted for 18 hours, stopped the reaction, and cooled to room temperature.
  • the residue was slowly added to deionized water (3 L) and stirred for 1 hour. Filtration, the filter cake was washed with ethanol (50 mL ⁇ 3), and the filter cake was dried to give 133.0 g of crude product.
  • the starting material f (26.0 g) was dissolved in dichloromethane (520 mL), triethylamine (33 mL) was added, and the mixture was cooled to -5-0 ° C and added trifluoromethanesulfonic anhydride (29.2 mL), 0-10 After reacting at ° C for 2 hours, the reaction was stopped. Under ice-cooling conditions, water (250 mL) was added dropwise to the reaction mixture to quench the reaction, and the mixture was separated, and the aqueous phase was extracted with dichloromethane (100 mL ⁇ 2).
  • Potassium ferricyanide (279.0 g) was added to the reaction flask, followed by potassium carbonate (116.0 g) and hydrogenated quinidine 1,4-(2,3-naphthyridinyl)diether ((DHQD) 2 PHAL , 1.1g) and potassium citrate dihydrate (103mg), add 2L of deionized water, stir for 30 minutes, add tert-butanol (1.5L) under argon atmosphere, stir for 15 minutes, 0-5 ° C raw material d ( 49.0g) was added in portions, stirred at 0-5 ° C for 4 hours, warmed to room temperature and stirred for 18 hours, the reaction was stopped, saturated sodium sulfite solution (800 mL) and ethyl acetate (1000 mL) were added, stirred until fully dissolved, layered, The aqueous layer was extracted with EtOAc (EtOAc (EtOAc) (EtOAc (EtOAc)
  • the raw material c (54.0 g) was added to dichloromethane (600 mL), and the mixture was white turbid. Under argon atmosphere, b (46.9 g) was added, stirred at room temperature for 10 minutes, cooled to 0 ° C, and trimethylchlorosilane was added dropwise. (54.0g), stirring at 0 ° C for 30 minutes, the solution became clear, warmed to room temperature for 1 hour, then cooled to 0 ° C, added b (23.0g), raised to room temperature for 30 minutes, stop the reaction, the reaction solution Concentration under reduced pressure gave the crude title product which was used in the next step without purification.
  • the raw material q (70.3 g) was dissolved in phosphorus oxychloride (210 mL), stirred at 110 ° C for 2 hours under reflux, concentrated under reduced pressure to remove phosphorus oxychloride, and the residue was added to acetonitrile (350 mL).
  • Add diisopropylethylamine (117.0 g) dilute the solution to a black suspension, add the suspension to the ammonia water (350 mL) under ice bath, drop the reaction for 30 minutes, ethyl acetate (500 mL ⁇ 3) Extraction, the organic phase was combined, washed with saturated sodium chloride (500 mL), dried over anhydrous sodium sulfate, filtered and evaporated. (44.7 g), yield 51%.
  • the raw material r (44.3 g) was added to dichloromethane (440 mL) under an argon atmosphere, and the temperature was controlled to 0-5 ° C under ice-cooling, triethylamine (58.6 g) was added dropwise, and the mixture was stirred for 10 minutes. Trifluoroacetic anhydride (58.5g) was added dropwise, the addition was completed, and the reaction was carried out for 1 hour in an ice bath. The reaction was stopped, the pH of the reaction mixture was 7-8, and the reaction was quenched by adding water (400 mL), and the mixture was separated.
  • the filter cake was washed three times with ethyl acetate (1.0 L ⁇ 3), and the filter cake was dried under vacuum at 40-45 ° C for 6-8 h to give a solid (322.8 g) in a yield of 99.3%;
  • the ratio of hydrochloric acid was determined by silver nitrate titration to be 20.5%.
  • N,N-dimethylformamide (2.0 L) was added to the crude product (290.4 g) with stirring.
  • the reaction solution was heated to 70-75 ° C, 20.3 g of activated carbon (7% w/w) was added, and the mixture was stirred for 1 h.

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Abstract

本发明涉及一种吡啶甲酰胺类衍生物的制备方法及其中间体，该方法缩短了反应步骤、提高了反应产率、简单易操控、利于工业扩大生产。

Description

一种吡啶甲酰胺类衍生物的制备方法及其中间体 技术领域
本发明涉及一种吡啶甲酰胺类衍生物的制备方法及其中间体。
背景技术
利尿剂在各国高血压指南中被普遍推荐为一线降压药物，适用于轻中度高血压，尤其是老年高血压或并发心力衰竭时。
临床上，传统的利尿剂有导致低血钾症的风险。ROMK是抗高血压利尿剂开发的新靶点，ROMK为内向整流的K +通道(inwardly rectifying K channels，Kir)家族的一员，属于Kir1型，对维持肾脏钾离子平衡起到至关重要的作用。在鼠肾中，至少存在三种亚型的ROMK通道：ROMK1、ROMK2和ROMK3型。ROMK2大部分分布于髓袢升支粗段(ascending limb of Henle，TALH)；ROMK1和ROMK3主要在集合管上(Cortical collecting duct，CCD)表达。表达于TALH的ROMK与Na +/K +/2Cl -转运体一起调节钠钾离子的分泌和重吸收，表达于CCD的ROMK与Na +/K +转运体一起调节钾离子的分泌。因此，阻断ROMK位点既可以通过抑制Na +的重吸收利尿降压，又不至于使血钾过度降低导致低钾血症，是一个良好的利尿剂研究方向。
WO2016091042A1(公开日2016-06-16)公开了一类肾外髓质分泌钾通道(ROMK)抑制剂，化学名为(R)-5-氰基-N-(1-(2-羟基-2-(4-甲基-1-氧代-1,3-二氢异苯并呋喃-5-基)乙基)哌啶-4-基)-4-甲氧基吡啶甲酰胺的化合物，相对于其他ROMK抑制剂，该化合物增加了极性基团，在保持ROMK抑制剂活性的基础上，降低了ClogP，提升了hERG选择性，增加了安全性，其结构如式(A)所示。
Figure PCTCN2018094947-appb-000001
WO2016091042A1的实施例1公开了化合物A的制备方法，总计五步反应，具体反应如下所示：
Figure PCTCN2018094947-appb-000002
该方法存在反应步数较多、批量小、后处理方法使用薄层色谱法纯化、产率低等问题，其中第二步反应的产率为22.4％，最后一步制备产物的产率仅为11.3％，不利于工业扩大生产，有必要改进其制备方法。
发明内容
本发明要解决的技术问题是提供一种与现有技术完全不相同的制备式(I)所示化合物的方法，改变起始原料和中间体制备目标产物，通过缩短反应步骤、起始原料等反应物简单易购买、反应条件简单可控、反应后处理方法简单等途径优化制备方法，提高产率、利于工业扩大生产。
本发明的技术方案如下：
本发明提供一种制备式(I)所示化合物的方法，其特征在于，所述方法包括式(III)所示化合物或其盐与式(II)所示化合物或其盐在缩合剂作用下得到式(I)所示化合物的步骤，
Figure PCTCN2018094947-appb-000003
所述X选自-OH、烷氧基、烷氧基取代的酰基、卤素，优选-OH。
在本发明一个优选的方案中，所述方法为
Figure PCTCN2018094947-appb-000004
将式(III-1)所示化合物与式(II-1)所示化合物在缩合剂的条件下发生酰化反应，所述缩合剂选自CDI、EDC.HCl/HOBT、DIC/HOBT、EDC.HCl/DMAP、HATU、HBTU、DIC/DMAP，优选DIC/HOBT。
上述方案中，所述方法还包括
Figure PCTCN2018094947-appb-000005
将式(IV)所示化合物在酸性条件下进行脱除Boc保护基反应；所述酸性条件选自采用HCl气体/乙醇，HCl气体/四氢呋喃，HCl气体/乙酸乙酯，HCl气体/1,4-二氧六环，使产物可以与盐酸成盐从反应液中析出，优选HCl气体/乙酸乙酯。
上述方案中，所述方法还包括
Figure PCTCN2018094947-appb-000006
将式(VI)所示化合物与式(V)所示化合物在有机溶剂中发生亲核取代反应；所述有机溶剂选自醇类溶剂或腈类溶剂，优选甲醇、乙醇、异丙醇或乙腈；更优选乙醇。
本发明还提供一种式(III-1)所示化合物，
Figure PCTCN2018094947-appb-000007
本发明进一步提供一种制备式(III-1)所示化合物的方法，其特征在于，所述方法包括式(IV)所示化合物反应后得到式(III-1)所示化合物的步骤，
Figure PCTCN2018094947-appb-000008
上述方案中，所述方法还包括
Figure PCTCN2018094947-appb-000009
本发明还提供一种式(IV)所示化合物，
Figure PCTCN2018094947-appb-000010
本发明进一步提供一种制备式(IV)所示化合物或其盐的方法，其特征在于，所述方法包括式(VI)所示化合物与式(V)所示化合物反应得到式(IV)所示化合物的步骤，
Figure PCTCN2018094947-appb-000011
上述方案中，所述方法为
Figure PCTCN2018094947-appb-000012
上述方案中，所述方法还包括
Figure PCTCN2018094947-appb-000013
上述方案中，所述方法还包括
Figure PCTCN2018094947-appb-000014
本发明还提供一种式(a)所示化合物，
Figure PCTCN2018094947-appb-000015
本发明进一步提供一种制备式(a)所示化合物的方法，其特征在于，所述方法包括式(c)所示化合物与式(b)所示化合物反应得到式(a)所示化合物的步骤，
Figure PCTCN2018094947-appb-000016
上述方案中，所述方法还包括
Figure PCTCN2018094947-appb-000017
本发明还提供一种式(c)所示化合物，
Figure PCTCN2018094947-appb-000018
本发明进一步提供一种制备式(c)所示化合物的方法，其特征在于，所述方法包括式(d)所示化合物反应后得到式(c)所示化合物的步骤，
Figure PCTCN2018094947-appb-000019
将式(d)所示化合物在氧化剂作用下发应生成式(c)所示化合物；所述氧化剂选自选自四氧化锇、锇酸钾/铁氰化钾；更优选锇酸钾/铁氰化钾。
本发明进一步提供一种制备式(I)所示化合物的方法，其特征在于，所述方法包括式(VI)所示化合物与式(V)所示化合物反应得到式(IV)所示化合物、式(IV)所示化合物反应后得到式(III-1)所示化合物、式(III-1)所示化合物与式(II-1)所示化合物反应得到式(I)所示化合物的步骤，
Figure PCTCN2018094947-appb-000020
本发明还涉及一种制备式(I)所示化合物的药学上可接受的盐的方法，包括前述方案中的步骤，以及通过式(I)所示化合物与酸反应制备得到其药学上可接受的盐的步骤，所述酸选自有机酸或无机酸，优选有机酸；所述有机酸选自酒石酸、苹果酸、柠檬酸、马来酸、富马酸、甲磺酸、苯磺酸或对甲苯磺酸，优选L-酒石酸或苹果酸；所述无机酸选自盐酸、氢溴酸、硫酸或磷酸。
发明详述
为了更容易理解本发明，以下具体定义了某些技术和科学术语。除显而易见在本文件中的它处另有明确定义，否则本文使用的所有其它技术和科学术语都具有本发明所属领域的一般技术人员通常理解的含义。
本发明所述“卤素或卤素原子”是指氟原子、氯原子、溴原子、碘原子等。
本发明所述“烷基”是指直链或支链的含有1-20个碳原子的烷基，包括例如“C 1-6烷基”、“C 1-4烷基”等，具体实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语术语“烷氧基取代的酰基”指-C(O)(烷氧基)。
本发明所述的“醇类溶剂”是指一个或多个“羟基”取代“烷基”上的一个 或多个氢原子所衍生的基团，所述“烷基”如前文所定义，具体实例包括但不限于：甲醇、乙醇、异丙醇、正丙醇、异戊醇或三氟乙醇。
本发明所述的“腈类溶剂”是指一个或多个“氰基”取代“烷基”上的一个或多个氢原子所衍生的基团，所述“烷基”如前文所定义，具体实例包括但不限于：乙腈或丙腈。
发明的有益效果
与现有技术相比，本发明制备式(I)所示化合物的技术方案具有以下优点：
(1)反应步骤减少，现有技术公开的反应步骤为5步，本发明的反应步骤为3步。
(2)与现有技术比较，本发明的起始原料和中间体不相同，提供了一种完全不同思路的合成方法，并且起始原料和反应物均简单、易购买。
(3)产率提高，现有技术公开的终产物产率为11.3％，本发明终产物产率为73.7％。
(4)反应的后处理简单，粗品可直接用于下一步反应，不需要每一步产物纯化后才能投入下一步反应，易于工业扩大生产。
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制本发明的范围。
本发明实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-500核磁仪，测定溶剂为DMSO-d 6，内标为四甲基硅烷(TMS)。
实施例1、(R)-4-甲基-5-(环氧乙烷-2-基)异苯并呋喃-1(3H)-酮的制备
Figure PCTCN2018094947-appb-000021
Figure PCTCN2018094947-appb-000022
第一步、式(h)化合物的制备
将硼氢化钠(57.8g)溶于四氢呋喃(2000mL)中，氩气保护下，冷却至0℃，将原料i(130.0g)分批加入，5-10℃搅拌反应1小时，5-10℃滴加三氟化硼乙醚(237mL)，室温搅拌4小时，停止反应，滴加甲醇(800mL)淬灭反应，搅拌，滴加1N盐酸(1000mL)溶液，0-20℃搅拌1小时，减压蒸馏除去有机溶剂，析出固体，过滤，水洗涤(50mL×2)得到粗品，加入乙酸乙酯(700mL)溶解，再次过滤，乙酸乙酯(100mL×2)洗涤，滤液用无水硫酸钠干燥，浓缩得到标题产物(95g)，产率80.5％。
第二步、式(g)化合物的制备
将原料h(120.0g)和三氟乙酸(64mL)溶于乙腈(1L)中，搅拌，冰浴下冷却至0-5℃，分批加入固体N-溴代丁二酰亚胺(147.0g)，反应温度控制在0-8℃，反应结束后，冰浴下，加入200mL的碳酸钾水溶液(含66.0g碳酸钾)淬灭反应，减压浓缩，用水(200mL)和乙酸乙酯(800mL×1，400mL×2)萃取，合并有机相，饱和氯化钠溶液(500mL×1)洗涤，无水硫酸钠干燥，减压浓缩，得到粗品，用二氯甲烷(380mL)打浆1h，过滤，干燥，得到产物150.0g。
第三步、式(f)化合物的制备
将氰化亚铜(123.0g)加入N,N-二甲基甲酰胺(500mL)中，原料g(150.0g)溶于N,N-二甲基甲酰胺(250mL)加入滴液漏斗中，氩气气氛下，加热至140-150℃后开始滴加原料g的N,N-二甲基甲酰胺溶液，145℃搅拌反应2小时，反应结束后，降温至90-95℃，滴加去离子水(62mL)，反应18小时，停止反应，降至室温，反应液加入乙酸异丙酯/甲醇(V/V＝4:1，1500mL)的混合溶剂中，搅拌30分钟，垫硅胶和硅藻土过滤，滤饼用乙酸异丙酯/甲醇(V/V＝4:1，100mL×3)洗涤，滤液减压浓缩，残余物缓慢加至去离子水(3L)中，搅拌1小时，过滤，滤饼用乙醇(50mL×3)洗涤，滤饼干燥，得到粗品133.0g，粗品加入乙酸乙酯/甲醇(V/V＝4:1，2.0L)中，加热至回流，1小时后过滤，滤饼用乙酸乙酯/甲醇(V/V＝4:1，100mL×2)洗涤，滤液减压浓缩，得到标题产物(99.0g)，产率87％。
第四步、式(e)化合物的制备
将原料f(26.0g)溶于二氯甲烷(520mL)中，加入三乙胺(33mL)，冰盐浴冷却至-5-0℃滴加三氟甲烷磺酸酐(29.2mL)，0-10℃反应2小时，停止反应，冰浴条件下，向反应液中滴加水(250mL)淬灭反应，分层，水相用二氯甲烷(100mL×2)萃取，合并有机相，用饱和氯化钠溶液(300mL)洗涤，用无水硫酸钠干燥，减压浓缩，得到 粗品(50.0g)，加入石油醚和乙酸乙酯(V/V＝5:1，600mL)的混合溶液中，加热至70℃溶解，分出上层清液，下层油状物用石油醚和乙酸乙酯(V/V＝5:1)的混合溶液(300mL×2)溶解分层，合并有机相，减压浓缩，得到(41.0g)粗品，用石油醚和乙酸乙酯(V/V＝5:1，200mL)混合溶液结晶，得到标题产物(31.7g)，产率67.7％。
第五步、式(d)化合物的制备
将原料e(50.1g)溶于异丙醇(500mL)中，加入乙烯三氟硼酸钾(29.5g)和1,1'-双二苯基膦二茂铁二氯化钯(1.25g)，再加入三乙胺(71mL)，氩气气氛下，回流反应1.5小时，停止反应，冷却至室温，过滤，用乙酸乙酯(20mL×3)洗涤滤饼，合并滤液，浓缩后经硅胶柱层析(洗脱剂为乙酸乙酯:石油醚＝1:5-1:3)纯化得到标题产物(29.0g)，产率98％。
第六步、式(c)化合物的制备
将铁氰化钾(279.0g)加入反应瓶中中，依次加入碳酸钾(116.0g)、氢化奎尼定1,4-(2,3-二氮杂萘)二醚((DHQD) 2PHAL，1.1g)和二水合锇酸钾(103mg)，加入2L去离子水，搅拌30分钟，氩气气氛下，加入叔丁醇(1.5L)，搅拌15分钟，0-5℃将原料d(49.0g)分批加入，0-5℃下搅拌4小时，升温至室温搅拌反应18小时，停止反应，加入饱和亚硫酸钠溶液(800mL)和乙酸乙酯(1000mL)，搅拌至全溶，分层，水层用乙酸乙酯(300mL×3)萃取，合并有机相，用饱和氯化钠溶液(200mL)洗涤，减压蒸馏，残余物加入乙酸乙酯(100mL)和石油醚(100mL)回流10分钟，自然冷却至室温，过滤，滤饼用石油醚(50mL×3)洗涤，得到标题产物(54.0g)，产率92％。
第七步、式(a)化合物的制备
将原料c(54.0g)加入二氯甲烷(600mL)中，搅拌为白色浑浊，氩气气氛下，加入b(46.9g)，室温搅拌10分钟，冷却至0℃，滴加三甲基氯硅烷(54.0g)，0℃下搅拌30分钟，溶液变澄清，升温至室温反应1小时，再冷却至0℃，补加b(23.0g)，升至室温反应30分钟，停止反应，将反应液减压浓缩，得到粗品标题产物，不经纯化直接用于下一步反应。
第八步、式(VI)化合物的制备
将原料a(69.6g)加入甲醇(1000mL)中，加入碳酸钾(90.0g)，室温搅拌2小时，停止反应，减压蒸馏，加入乙酸乙酯(500mL)和水(200mL)，分层，水相用乙酸乙酯(100mL×2)萃取，合并有机相，用饱和氯化钠溶液(100mL)洗涤，用无水硫酸钠干燥，过滤，减压蒸馏得到粗品，用乙酸乙酯(50mL)溶解，加入石油醚(200mL)，50℃下搅拌20分钟，自然冷却至室温，过滤，滤饼用石油醚(50mL×3)洗涤，烘干得到标题产物(35.0g)，产率71％。
实施例2、5-氰基-4-甲氧基吡啶甲酸盐酸盐的制备
Figure PCTCN2018094947-appb-000023
第一步、式(p)化合物的制备
将原料n(110.0g)、o(150.0g)、乙酸酐(151.5g)加入反应瓶中回流反应4小时，停止反应，减压浓缩，所得残余物控制温度在0-10℃滴加氨水和水(V/V＝1:1，600mL)的混合溶液，当有大量固体生成时，加入冰水(400mL)，滴毕，搅拌30分钟，用浓盐酸调节至pH为2-3，搅拌30分钟，过滤，滤饼抽干，用无水乙醇(500mL)打浆1小时，抽滤，滤饼用冷的无水乙醇(100mL×3)洗涤，烘干滤饼，得到标题产物(80.0g)，产率59％。
第二步、式(q)化合物的制备
冰浴下将氢氧化钠(43.6g)加入于水(800mL)中，将原料p(79.8g)分批加入到上述氢氧化钠水溶液中，撤去冰浴，加热至回流反应2小时，终止反应，将反应液冰水冷却至室温，滴加2M盐酸溶液调节pH至2-3，搅拌30分钟，过滤，滤饼用冰水(100mL)、冷的乙醇(100mL)洗涤，所得固体干燥，得到标题产物(71.2g)，产率100％。
第三步、式(r)化合物的制备
将原料q(70.3g)溶于三氯氧磷(210mL)中，110℃回流搅拌2小时，减压浓缩除去三氯氧磷，残余物加入至乙腈(350mL)中，冰浴条件下，滴加二异丙基乙胺(117.0g)，滴毕溶液为黑色悬浊液，将悬浊液滴加至冰浴下的氨水(350mL)中，滴毕反应30分钟，乙酸乙酯(500mL×3)萃取，合并有机相，用饱和氯化钠溶液(500mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到棕黄色固体，加入异丙醇(250mL)中重结晶，得到标题产物(44.7g)，产率51％。
第四步、式(s)化合物的制备
氩气氛下，将原料r(44.3g)加入于二氯甲烷(440mL)中，冰浴条件下，控制温度0-5℃，滴加三乙胺(58.6g)，滴加完毕搅拌10分钟，滴加三氟乙酸酐(58.5g)，滴加完毕，冰浴下反应1小时，停止反应，反应液pH为7-8，加入水(400mL)淬灭反应，分层，水相用二氯甲烷(200mL)萃取，合并有机相，用饱和氯化钠(100mL)洗 涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物加入异丙醇(200mL)热打浆，得到标题产物(36.3g)，产率91％。
第五步、式(t)化合物的制备
将原料s(25.6g)、碳酸铯(49.2g)溶于N,N-二甲基甲酰胺(260mL)中，冰浴降温至0℃，冰浴下滴加甲醇(9.5g)，0℃反应6小时，升至20-25℃搅拌12小时，停止反应，反应液中加入水(650mL)淬灭反应，用乙酸乙酯(200mL×3)萃取，合并有机相，用饱和氯化钠(200mL)洗涤，用无水硫酸钠干燥，减压浓缩，残余物用正己烷和乙酸乙酯(V/V＝1.5:1，80mL)的混合溶液重结晶，得到标题产物(16.8g)，产率67％。
第六步、式(II-1)化合物的制备
将t(22.0g)、醋酸钯(1.46g)、1,3-双(二苯基膦)丙烷(2.68g)、三乙胺(36mL)加入混合溶液中，用一氧化碳加压到10bar，升温至70℃反应18小时，停止反应，浓缩除去有机溶剂，水相加饱和氯化钠溶液、二氯甲烷萃取(300mL×3)，合并有机相，活性炭脱色，过滤，有机相用浓盐酸调节pH＝1，有固体析出，加入50mL异丙醇后，浓缩除去二氯甲烷，过滤干燥得产物(23.6g)，产率84.3％。
实施例3、(R)-5-氰基-N-(1-(2-羟基-2-(4-甲基-1-氧代-1,3-二氢异苯并呋喃-5-基)乙基)哌啶-4-基)-4-甲氧基吡啶甲酰胺(式(I))的制备
Figure PCTCN2018094947-appb-000024
第一步、中间体(IV)的合成
在反应瓶中投入4.0L无水乙醇，搅拌条件下加入(R)-4-甲基-5-(环氧乙烷-2-基)-苯并异呋喃-1(3H)-酮(274.8g)，4-Boc-氨基哌啶(341.2g)，加热至65-70℃，搅拌反应18-20h，停止加热。自然冷却至50-55℃，搅拌条件下加入8.0L正己烷，搅拌至温度自然降至20-25℃，析出大量固体，冰水浴条件下降温至0-5℃，搅拌，抽 滤，滤饼用正己烷洗涤两次(250ml×2)，干燥，得固体(354.3g)，产率62.8％。
第二步、中间体(III-1)的合成
在玻璃瓶中投入5.2L乙酸乙酯，搅拌条件下降温至0-5℃。停止搅拌，通入氯化氢气体(0.48kg)，通氯化氢过程中控制反应液温度低于5℃。缓慢搅拌下，将上步产物(349.3g)加入反应液中。加毕，搅拌反应3-4小时，反应温度自然升至20-25℃，停止搅拌。抽滤，滤饼用乙酸乙酯洗涤三次(1.0L×3)，滤饼在40-45℃真空干燥6-8h，得固体(322.8g)，产率99.3％；产物二盐酸盐中的盐酸比例用硝酸银滴定法测定为20.5％。
第三步、式(I)化合物的合成
在反应瓶中投入4.0L N,N-二甲基甲酰胺，搅拌下依次加入上步产物(317.8g)，5-氰基-4-甲氧基吡啶甲酸盐酸盐II-1(205.9g)，三乙胺(528.2g)，1-羟基苯并三氮唑(152.7g)，N,N-二异丙基碳二亚胺(142.6g)。加毕，氩气置换三次，加热至40-45℃搅拌反应16-18h。停止加热，将反应液倾入冰水(30L)中，搅拌1h。抽滤，滤饼用纯化水洗涤三次，抽干后用无水乙醇(3.0L)在20-25℃打浆1h。抽滤，干燥10-12h得粗品(290.4g)，产率73.7％，纯度：97.76％；
搅拌下将N,N-二甲基甲酰胺(2.0L)加入(290.4g)粗品中，反应液加热至70-75℃，加入20.3g活性炭(7％w/w)，保温搅拌1h，趁热过滤，用热的N,N-二甲基甲酰胺(70-75℃，200mL)洗涤滤渣，合并滤液，将滤液加热至70-75℃，搅拌下加入热的(65-70℃，5L)无水乙醇至上步反应液中，搅拌析晶，待温度自然降至20-25℃，将反应瓶转移至冰水浴中继续搅拌1h，抽滤，滤饼用无水乙醇洗涤，干燥得固体219.5g，总产率55.7％，纯度：99.69％。
1H-NMR(400MHz,DMSO-d 6)δ8.88(s,1H),8.75(d,1H),7.77(s,1H),7.71-7.69(m,2H),5.43-5.40(m,2H),5.35(s,1H),5.08(s,1H),4.09(s,3H),3.78(s,1H),2.95(s,3H),2.38(s,1H),2.27(s,3H),2.25(s,2H),1.72(s,4H).

Claims (19)

  1. 一种制备式(I)所示化合物的方法，其特征在于，所述方法包括式(III)所示化合物或其盐与式(II)所示化合物或其盐在缩合剂作用下得到式(I)所示化合物的步骤，
    Figure PCTCN2018094947-appb-100001
    所述X选自-OH、烷氧基、烷氧基取代的酰基、卤素，优选-OH。
  2. 如权利要求1所述的方法，其特征在于，所述方法为
    Figure PCTCN2018094947-appb-100002
  3. 如权利要求1所述的方法，其特征在于，所述方法还包括
    Figure PCTCN2018094947-appb-100003
  4. 如权利要求2所述的方法，其特征在于，所述方法还包括
    Figure PCTCN2018094947-appb-100004
  5. 一种式(III-1)所示化合物，
    Figure PCTCN2018094947-appb-100005
  6. 一种制备式(III-1)所示化合物的方法，其特征在于，所述方法包括式(IV)所示化合物反应后得到式(III-1)所示化合物的步骤，
    Figure PCTCN2018094947-appb-100006
  7. 如权利要求6所述的方法，其特征在于，所述方法还包括
    Figure PCTCN2018094947-appb-100007
  8. 一种式(IV)所示化合物，
    Figure PCTCN2018094947-appb-100008
  9. 一种制备式(IV)所示化合物或其盐的方法，其特征在于，所述方法包括式(VI)所示化合物与式(V)所示化合物反应得到式(IV)所示化合物的步骤，
    Figure PCTCN2018094947-appb-100009
  10. 一种制备式(VI)所示化合物的方法，其特征在于，所述方法包括式(a)所示化合物反应后得到式(VI)所示化合物的步骤，
    Figure PCTCN2018094947-appb-100010
  11. 如权利要求10所述的方法，其特征在于，所述方法还包括
    Figure PCTCN2018094947-appb-100011
  12. 如权利要求11所述的方法，其特征在于，所述方法还包括
    Figure PCTCN2018094947-appb-100012
  13. 一种式(a)所示化合物，
    Figure PCTCN2018094947-appb-100013
  14. 一种制备式(a)所示化合物的方法，其特征在于，所述方法包括式(c)所示化合物与式(b)所示化合物反应得到式(a)所示化合物的步骤，
    Figure PCTCN2018094947-appb-100014
  15. 如权利要求14所述的方法，其特征在于，所述方法还包括
    Figure PCTCN2018094947-appb-100015
  16. 一种式(c)所示化合物，
    Figure PCTCN2018094947-appb-100016
  17. 一种制备式(c)所示化合物的方法，其特征在于，所述方法包括式(d)所示化合物反应后得到式(c)所示化合物的步骤，
    Figure PCTCN2018094947-appb-100017
  18. 一种制备式(I)所示化合物的方法，其特征在于，所述方法包括式(VI)所示化合物与式(V)所示化合物反应得到式(IV)所示化合物、式(IV)所示化合物反应后得到式(III-1)所示化合物、式(III-1)所示化合物与式(II-1)所示化合物反应得到式(I)所示化合物的步骤，
    Figure PCTCN2018094947-appb-100018
  19. 一种制备式(I)所示化合物的药学上可接受的盐的方法，包括权利要求1至4中任一项所述的步骤或权利要求18所述的步骤，以及通过式(I)所示化合物与酸反应制备得到其药学上可接受的盐的步骤，所述酸选自有机酸或无机酸，优选有机酸；所述有机酸选自酒石酸、苹果酸、柠檬酸、马来酸、富马酸、甲磺酸、苯磺酸或对甲苯磺酸，优选L(+)-酒石酸或苹果酸；所述无机酸选自盐酸、氢溴酸、硫酸或磷酸。
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