WO2018133818A1 - 一种双环取代吡唑酮偶氮类衍生物的制备方法及其中间体 - Google Patents

一种双环取代吡唑酮偶氮类衍生物的制备方法及其中间体 Download PDF

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WO2018133818A1
WO2018133818A1 PCT/CN2018/073219 CN2018073219W WO2018133818A1 WO 2018133818 A1 WO2018133818 A1 WO 2018133818A1 CN 2018073219 W CN2018073219 W CN 2018073219W WO 2018133818 A1 WO2018133818 A1 WO 2018133818A1
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group
compound
formula
producing
alkyl group
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PCT/CN2018/073219
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刁艾青
高晓晖
边林
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江苏恒瑞医药股份有限公司
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Priority to CN201880001468.9A priority Critical patent/CN108884052A/zh
Publication of WO2018133818A1 publication Critical patent/WO2018133818A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
    • C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
    • C07D231/46—Oxygen atom in position 3 or 5 and nitrogen atom in position 4

Definitions

  • the invention relates to a preparation method of a bicyclic substituted pyrazolone azo derivative and an intermediate thereof.
  • thrombocytopenia includes idiopathic thrombocytopenic purpura (ITP), as well as thrombocytopenia caused by chemotherapy (interferon IFN, heparin, etc.), radiation therapy, bacterial or viral infections (HIV, hepatitis C, etc.) and liver disease.
  • ITP idiopathic thrombocytopenic purpura
  • IFN interferon IFN, heparin, etc.
  • radiation therapy bacterial or viral infections
  • HAV hepatitis C, etc.
  • Thrombopoietin is a hematopoietic growth factor that stimulates platelet production in the body. It can regulate the proliferation, differentiation and maturation of megakaryocytes by binding to a specific receptor (c-Mpl) to form platelets and increase the number of platelets in circulating blood.
  • c-Mpl specific receptor
  • Recombinant human thrombopoietin (rhTPO) and PEGylated recombinant human megakaryocyte growth factor (PEG-rHuMGDF) are the first generation of platelet growth factors in clinical trials, and their pharmacological properties are similar, which can effectively increase platelet levels.
  • thrombopoietin analog eltrombopag is disclosed by the GSK company in the patents WO2001089457A2, WO2006064957A1 and exhibits considerable activity; the preparation of azo compounds is disclosed in WO2001017349A1.
  • WO2009092276A1 protects a novel class of bicyclic substituted pyrazolone azo derivatives, and their use as TPO mimetics and TPO receptor agonists;
  • WO2010142137A1 discloses a series of bicyclic substituted pyrazolone azo derivatives pharmaceutically Acceptable salt forms are more potent TPO mimetics and TPO receptor agonists.
  • Example 1 Example 3, Example 6, Example 9, and Example 15 of WO2009092276A1 disclose a preparation method of Compound 15, which has a total of nine steps of reaction, and the specific reaction is as follows:
  • the method finally obtains the target product by HPLC, and the yield is only 39.8%.
  • the method has many problems such as more reaction steps, longer reaction time and low yield, which is not conducive to industrial expansion.
  • the technical problem to be solved by the present invention is to provide a method for preparing a compound of the formula (V) 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 producing a compound of the formula (V), which is characterized in that the compound represented by the formula (III) is reacted with a compound of the formula (IV) or a salt thereof to give a formula (V).
  • A is selected from a carbon atom or an oxygen atom
  • R is selected from a hydrogen atom or an alkyl group
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, an optionally substituted aryl group or a heteroaryl group, and the substituent is selected from the group consisting of an alkyl group, a halogen, and a hydroxy group, a tetrazolyl group, an imidazolyl group, a dihydroimidazolyl group, a carboxyl group or an alkoxycarbonyl group;
  • R 5 , R 6 , and R 7 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxyl group or an alkoxycarbonyl group;
  • R 8 , R 9 , R 10 , R 11 are each independently selected from a hydrogen atom or an alkyl group
  • n is selected from 0, 1, or 2.
  • the method further comprises
  • R, R 1 , R 2 , R 3 and R 4 are as defined in the formula (V).
  • the method further comprises
  • R 1 , R 2 , R 3 and R 4 are as defined in the formula (V).
  • the present invention provides a process for the preparation of a compound of formula (III), which is
  • R, R 1 , R 2 , R 3 and R 4 are as defined in the formula (V).
  • the method of preparing a compound of formula (III) further comprises
  • R 1 , R 2 , R 3 and R 4 are as defined in the formula (V).
  • the method of preparing the compound of the formula (III-1) further includes
  • the present invention also provides a compound as shown in formula (II),
  • R 1 , R 2 , R 3 and R 4 are as defined in the formula (V).
  • the compound has a structure represented by formula (IIA),
  • R 2 , R 3 , and R 4 are as defined in formula (V);
  • R a is selected from a hydrogen atom, a halogen, a hydroxyl group, an amino group, a cyano group, a carboxyl group, a tetrazolyl group, an alkyl group, an alkoxy group or an alkoxycarbonyl group;
  • n 0, 1, 2 or 3;
  • X is selected from N, O or S atoms.
  • the compound has a structure represented by formula (IIB),
  • R 2 , R 3 and R 4 are as defined in the formula (V).
  • the compound has a structure represented by formula (II-1),
  • the present invention also provides a process for the preparation of a compound of formula (II), characterized in that
  • R 1 , R 2 , R 3 and R 4 are as defined in the formula (V).
  • the present invention also provides a compound as shown in formula (IV) or a salt thereof,
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n, and A are as defined in the formula (V).
  • the compound has a structure represented by formula (IVA),
  • R 5 , R 6 , and R 7 are as defined in formula (V);
  • the salt is preferably a hydrochloride, a sulfate, a phosphate, an acetate, a trifluoroacetate, an oxalate, a tartrate, a maleate, a fumarate, a citrate or a p-toluenesulfonate. , benzenesulfonate, ethanesulfonate or methanesulfonate.
  • the compound has a structure represented by formula (IV-1),
  • the present invention also provides a process for the preparation of a compound of the formula (IV) or a salt thereof, characterized in that the method is
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n, and A are as defined in the formula (V).
  • the method is:
  • the present invention further provides a method for producing a compound of the formula (V-1), characterized in that the method is
  • the compound represented by the formula (III-1) is subjected to a diazo compound in an aqueous acid solution, under a low temperature condition and sodium nitrite, and the diazo compound is further subjected to a condensation reaction with the compound of the formula (IV-1) under basic conditions. Filtration, drying to obtain a solid; the acid is preferably hydrochloric acid or sulfuric acid, the low temperature is selected from -4 to 5 ° C, preferably -4 to -1 ° C; the base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydrogencarbonate, carbonic acid Potassium hydrogen or sodium hydroxide, preferably sodium hydroxide.
  • the invention also provides a preparation method of the compound represented by the formula (III-1),
  • the compound represented by the formula (II-1) is added to an alkaline solution, heated to reflux reaction, cooled, acidified and crystallized, filtered, washed, and dried to obtain a product;
  • the alkaline solution is selected from the group consisting of sodium hydroxide and potassium hydroxide.
  • a lithium hydroxide solution preferably a sodium hydroxide solution;
  • the acid is preferably hydrochloric acid.
  • the invention also provides a preparation method of the compound represented by the formula (II-1),
  • a compound represented by the formula (I) is formed into a diazo compound in an aqueous acid solution, under a low temperature condition and sodium nitrite; a cesium acid and copper chloride dihydrate are added to the solvent, and the above diazo compound is added dropwise to carry out a condensation reaction.
  • the product is filtered, washed and dried; the acid is preferably hydrochloric acid or sulfuric acid, the solvent is preferably water or acetone, and the low temperature is selected from -6 to 5 ° C, preferably -6 to -3 ° C.
  • the invention also provides a preparation method of the compound represented by the formula (IV-1),
  • the compound of the formula (IV-A-1) and ethyl acetoacetate are added to an organic solvent, and the reaction is heated under reflux. After cooling the reaction solution, the product is filtered and washed; the organic solvent is preferably an ester solvent, the ester.
  • the solvent-like solvent is preferably ethyl acetate.
  • the present invention also provides a process for the preparation of a pharmaceutically acceptable salt of the compound of the formula (V-1), which comprises the steps of the above scheme, and the reaction of the compound represented by the formula (V-1) with a base in an organic solvent.
  • the organic solvent is preferably an ether solvent, A mixed solvent of an alcohol solvent, an ether solvent, and an alcohol solvent.
  • 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,
  • aryl group as used in the present invention means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (that is, a ring sharing a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 8
  • the aryl group is more preferably a phenyl group, a fluorenyl group or a phenanthryl group, and most preferably a phenyl group.
  • heteroaryl refers to a 5- to 15-membered all-carbon monocyclic or fused polycyclic group having a conjugated ⁇ -electron system, further comprising from 1 to 4 heteroatoms, wherein the hetero atom is selected from One or more of oxygen, sulfur or nitrogen.
  • alkoxy group, alkoxycarbonyl group as used in the present invention means a group which is bonded in the form of alkyl-O-, alkyl-O-C(O)-, wherein “alkyl” is as defined above.
  • ester solvent means a combination of a lower organic acid having 1 to 4 carbon atoms and a lower alcohol having 1 to 6 carbon atoms, and specific examples include, but are not limited to, acetic acid. Ethyl ester, isopropyl acetate or butyl acetate.
  • 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, ethylene glycol, n-propanol or 2-propanol.
  • ether solvent as used in the present invention means a chain compound or a cyclic compound having an ether bond -O- and having 1 to 10 carbon atoms, and specific examples include, but are not limited to, propylene glycol methyl ether, tetrahydrofuran or , 4-dioxane.
  • the “mixed solvent” as used in the present invention means a solvent obtained by mixing one or more different kinds of organic solvents in a certain ratio, or a solvent obtained by mixing an organic solvent and water in a certain ratio.
  • reaction step is reduced, the reaction step disclosed in the prior art is 9 steps, and the reaction step of the present invention is 4 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 determined to be heavy water plus sodium hydroxide (D 2 O + NaOH), and the internal standard was tetramethylsilane (TMS).
  • MS measured using Waters Q-Tofmicro TM quadrupole - time of flight mass spectrometer.
  • HPLC measurements were performed using a Waters Alliance 2695 high performance liquid chromatograph, an Agilent 1200 Series liquid chromatograph with octadecylsilane bonded silica as the column packing.
  • the reactor was charged with purified water (14.80 kg), 7-aminobenzo[d]oxazole-2(3H)-one (2.00 kg, which can be prepared according to the method of patent application WO2005016898A2), hydrochloric acid (5.33 kg), liter.
  • purified water 14.80 kg
  • 7-aminobenzo[d]oxazole-2(3H)-one (2.00 kg, which can be prepared according to the method of patent application WO2005016898A2)
  • hydrochloric acid 5.33 kg
  • liter liter.
  • sodium nitrite aqueous solution 940g sodium nitrite, water 3.20kg
  • Acetone (28 L) was added to the reaction vessel, and citric acid (4.57 kg) and copper chloride dihydrate (232 g) were successively introduced, and the mixture was stirred until dissolved at 35 to 40 ° C, and the diazonium salt solution was added dropwise thereto while maintaining the internal temperature of 35 to 40 ° C. , continue to stir for 1.5h.
  • Purified water (60 L) was added, and the mixture was heated to 35 to 40 ° C and stirred for 30 minutes. After filtration, the filter cake was washed with purified water at 45 to 50 °C.
  • the filter cake was added to purified water (40 kg), adjusted to pH 8-9 with a 15% aqueous sodium hydroxide solution, filtered, and the filtrate was adjusted to pH 3-4 with 6 mol/L hydrochloric acid, filtered, and the filter cake was washed with purified water.
  • the solid was dried (1.63 kg, yield 50%).
  • step product (1.10 kg), purified water (27.5 kg) and hydrochloric acid (2.92 kg) were successively added to the reaction vessel, stirred and dissolved, cooled to -4 to -1 ° C, and an aqueous solution of sodium nitrite (sodium sulfite 346 g) was added dropwise. , water 5.5kg), continue to react for 15min after the addition. Cool down to -8 ⁇ -5 ° C. Sodium hydroxide (1.48 kg) was dissolved in purified water (13.2 kg) to obtain a 10% aqueous sodium hydroxide solution.
  • the filter cake was added to a 50% aqueous solution of tetrahydrofuran (19 kg), and then worked at room temperature for 2h, filtered, washed with 50% aqueous tetrahydrofuran, washed with water and dried.

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Abstract

提供一种双环取代吡唑酮偶氮类衍生物的制备方法及其中间体。

Description

一种双环取代吡唑酮偶氮类衍生物的制备方法及其中间体 技术领域
本发明涉及一种双环取代吡唑酮偶氮类衍生物的制备方法及其中间体。
背景技术
血小板是在止血和受损血管的修复过程中发挥重要作用的细胞。血小板的严重缺乏，也就是所谓的血小板减少症，可能造成严重后果甚至死亡。血小板减少症包括特发性的血小板减少症紫癜(ITP)，以及由化疗(干扰素IFN，肝素等)，放疗，细菌或病毒感染(HIV，hepatitis C等)和肝病引起的血小板减少。
血小板生成素(TPO)是体内刺激血小板生成的造血生长因子，可通过与特异性受体(c-Mpl)结合，调节巨核细胞增殖、分化、成熟，从而形成血小板，增加循环血中的血小板数。重组人血小板生成素(rhTPO)和聚乙二醇化重组人巨核细胞生长因子(PEG-rHuMGDF)是进入临床试验的第一代血小板生长因子，二者药理特性相似，均能有效升高血小板水平。但在临床试验中发现，PEG-rHuMGDF可诱导产生IgG中和性抗体，引起或加重血小板减少。因此对血小板生长因子的研发工作转向了无免疫原性的TPO模拟物，尤其是小分子非肽类的TPO模拟物因其服用方便和价格便宜等优势而倍受青睐。
GSK公司在专利WO2001089457A2、WO2006064957A1中公开血小板生成素类似物eltrombopag，并表现出了相当的活性；WO2001017349A1中公开了偶氮化合物的制备方法。
WO2009092276A1保护了一类新型的双环取代吡唑酮偶氮类衍生物，以及其作为TPO模拟物和TPO受体激动剂的用途；WO2010142137A1公开了一系列双环取代吡唑酮偶氮类衍生物药学上可接受的盐形式，是更有效TPO模拟物和TPO受体激动剂。
WO2009092276A1的实施例1、实施例3、实施例6、实施例9和实施例15公开了化合物15的制备方法，总计九步反应，具体反应如下所示：
Figure PCTCN2018073219-appb-000001
该方法最终通过HPLC纯化得到目标产物，产率仅为39.8％，该方法存在反应步数较多、反应时间较长、产率低等问题，不利于工业扩大生产。
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(V)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(V)所示化合物的方法，其特征在于，所述方法为式(III)所示化合物与式(IV)所示化合物或其盐反应得到式(V)所示化合物，
Figure PCTCN2018073219-appb-000002
其中，
A选自碳原子或氧原子；
R选自氢原子或烷基；
R 1、R 2、R 3、R 4各自独立地选自氢原子、烷基、烷氧基、卤素、任选取代的芳基或杂芳基，所述取代基选自烷基、卤素、羟基、四唑基、咪唑基、二氢咪唑 基、羧基或烷氧羰基；
R 5、R 6、R 7各自独立地选自氢原子、烷基、烷氧基、卤素、羟基、氨基、硝基、氰基、羧基或烷氧羰基；
R 8、R 9、R 10、R 11各自独立地选自氢原子或烷基；
n选自0、1或2。
优选的，所述方法还包括，
Figure PCTCN2018073219-appb-000003
其中，R、R 1、R 2、R 3、R 4如式(V)中所定义。
进一步优选的，所述方法还包括，
Figure PCTCN2018073219-appb-000004
其中，R 1、R 2、R 3、R 4如式(V)中所定义。
本发明提供式(III)化合物的制备方法，所述方法为，
Figure PCTCN2018073219-appb-000005
其中，R、R 1、R 2、R 3、R 4如式(V)中所定义。
制备式(III)化合物的方法还包括，
Figure PCTCN2018073219-appb-000006
其中，R 1、R 2、R 3、R 4如式(V)中所定义。
上述方案中优选的，制备式(III-1)化合物的方法为，
Figure PCTCN2018073219-appb-000007
制备式(III-1)化合物的方法还包括，
Figure PCTCN2018073219-appb-000008
本发明还提供一种化合物如式(II)所示，
Figure PCTCN2018073219-appb-000009
其中，R 1、R 2、R 3、R 4如式(V)中所定义。
优选的，所述化合物具有式(IIA)所示的结构，
Figure PCTCN2018073219-appb-000010
其中，R 2、R 3、R 4如式(V)中所定义；
R a选自氢原子、卤素、羟基、氨基、氰基、羧基、四唑基、烷基、烷氧基或烷氧羰基；
m选自0、1、2或3；
X选自N、O或S原子。
进一步优选的，所述化合物具有式(IIB)所示的结构，
Figure PCTCN2018073219-appb-000011
其中，R 2、R 3、R 4如式(V)中所定义。
更优选的，所述化合物具有式(II-1)所示的结构，
Figure PCTCN2018073219-appb-000012
本发明还提供一种制备式(II)化合物的方法，其特征在于，所述方法为，
Figure PCTCN2018073219-appb-000013
其中，R 1、R 2、R 3、R 4如式(V)中所定义。
本发明制备式(II-1)化合物的方法为，
Figure PCTCN2018073219-appb-000014
本发明还提供一种化合物如式(IV)所示或其盐，
Figure PCTCN2018073219-appb-000015
其中，R 5、R 6、R 7、R 8、R 9、R 10、R 11、n、A如式(V)中所定义。
优选的，所述化合物具有式(IVA)所示的结构，
Figure PCTCN2018073219-appb-000016
其中，R 5、R 6、R 7如式(V)中所定义；
所述盐优选盐酸盐、硫酸盐、磷酸盐、乙酸盐、三氟乙酸盐、草酸盐、酒石酸盐、马来酸盐、富马酸盐、柠檬酸盐、对甲苯磺酸盐、苯磺酸盐、乙磺酸盐或甲磺酸盐。
更优选的，所述化合物具有式(IV-1)所示的结构，
Figure PCTCN2018073219-appb-000017
本发明还提供一种制备式(IV)化合物或其盐的方法，其特征在于，所述方法为，
Figure PCTCN2018073219-appb-000018
其中，R 5、R 6、R 7、R 8、R 9、R 10、R 11、n、A如式(V)中所定义。
上述方案优选的，所述方法为，
Figure PCTCN2018073219-appb-000019
本发明进一步提供一种制备式(V-1)所示化合物的方法，其特征在于，所述方法为，
Figure PCTCN2018073219-appb-000020
将式(III-1)所示化合物在酸的水溶液中、低温条件和亚硝酸钠作用下生成重氮化合物，重氮化合物再与式(IV-1)化合物在碱性条件下发生缩合反应，过滤、干燥得固体；所述的酸优选盐酸或硫酸，所述低温选自-4～5℃，优选-4～-1℃；所述碱选自碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾或氢氧化钠，优选氢氧化钠。
本发明还提供式(III-1)所示化合物的制备方法，
Figure PCTCN2018073219-appb-000021
将式(II-1)所示化合物加入到碱性溶液中，加热至回流反应，冷却、酸化析晶，过滤、洗涤、干燥得产物；所述碱性溶液选自氢氧化钠、氢氧化钾、氢氧化锂溶液，优选氢氧化钠溶液；所述酸优选盐酸。
本发明还提供式(II-1)所示化合物的制备方法，
Figure PCTCN2018073219-appb-000022
式(I)所示化合物在酸的水溶液中、低温条件和亚硝酸钠作用下生成重氮化合物；将糠酸、二水合氯化铜加入溶剂中，滴加上述重氮化合物，进行缩合反应，过滤、洗涤、干燥得产物；所述的酸优选盐酸或硫酸，所述溶剂优选水或丙酮，所述低温选自-6～5℃，优选-6～-3℃。
本发明还提供式(IV-1)所示化合物的制备方法，
Figure PCTCN2018073219-appb-000023
将式(IV-A-1)所示化合物、乙酰乙酸乙酯加入到有机溶剂中，加热回流反应，冷却反应液后、过滤、洗涤得产物；所述有机溶剂优选酯类溶剂，所述酯类溶剂优选乙酸乙酯。
本发明还提供一种制备式(V-1)所示化合物的药学上可接受的盐方法，包括上述方案中的步骤，以及通过式(V-1)所示化合物与碱在有机溶剂中反应制备得到其药学上可接受的盐的步骤，所述碱选自氢氧化钠、赖氨酸、精氨酸、甲胺、二甲胺、三甲胺、乙胺、二乙胺、三乙胺、乙醇胺、哌嗪、二苄基乙二胺、葡甲胺、 氨丁三醇、四甲基季胺、四乙基季胺或氢氧化胆碱，优选乙醇胺；所述有机溶剂优选醚类溶剂、醇类溶剂、醚类溶剂与醇类溶剂的混合溶剂。
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。
本发明所述的“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至8元的芳基，更优选苯基、蒽基、菲基，最优选苯基。
本发明所述的“杂芳基”指具有共轭的π电子体系的5至15元全碳单环或稠合多环基团，进一步包含1至4个杂原子的，其中杂原子选自一个或多个氧、硫或氮。优选为5至8元的杂芳基，更优选为5元至6元的杂芳基，具体实例包括但不仅限于呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基、氮杂环庚三烯基、1,3-二氮杂环庚三烯基、氮杂环辛四烯基等；所述杂芳基还可以稠合于芳基、杂环基或环烷基环上。
本发明所述的“烷氧基、烷氧羰基”指以烷基-O-、烷基-O-C(O)-方式连接的基团，其中“烷基”如前文所定义。
本发明所述的“酯类溶剂”是指含碳原子数为1至4个的低级有机酸与含碳原子数为1至6个的低级醇的结合物，具体实例包括但不限于：乙酸乙酯、乙酸异丙酯或乙酸丁酯。
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、乙二醇、正丙醇或2-丙醇。
本发明所述的“醚类溶剂”是指含有醚键-O-且碳原子数为1至10个的链状化合物或环状化合物，具体实例包括但不限于：丙二醇甲醚、四氢呋喃或1,4-二氧六环。
本发明所述的“混合溶剂”是指一种或多种不同种类的有机溶剂按照一定比例混合而成的溶剂，或有机溶剂与水按照一定比例混合而成的溶剂。
发明的有益效果
与现有技术相比，本发明制备式(V)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9步，本发明的反应步骤为4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39.8％，本发明终产物产率为95％。
(4)反应的后处理简单，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，测定溶剂为重水加氢氧化钠(D 2O+NaOH)，内标为四甲基硅烷(TMS)。
MS的测定用Waters Q-Tofmicro TM四极杆-飞行时间质谱仪。
HPLC的测定使用Waters Alliance 2695高效液相色谱仪、Agilent 1200系列液相色谱仪，以十八烷基硅烷键合硅胶为色谱柱填料。
实施例1、3-甲基-1-(5,6,7,8-四氢萘-2-基)-1H-吡唑-5-醇盐酸盐的制备
Figure PCTCN2018073219-appb-000024
将(5,6,7,8-四氢萘-2-基)肼盐酸盐(1.3kg，可按照专利申请WO2009092276A1中的方法制备)、乙酰乙酸乙酯(1.17L)，加入到乙酸乙酯(5.2L)中。加热回流反应2小时。反应液冷却至室温，然后冷却至0～5℃，搅拌1小时，过滤，固体用少量乙酸乙酯洗涤，得到白色固体产物(1.4kg，产率81％)。
MS m/z(ESI):229.26[M-HCl+H]
实施例2、(Z)-5-(2-羟基-3-(2-(3-甲基-5-氧代-1-(5,6,7,8-四氢萘-2-基)-1,5-二氢-4H-吡唑-4-亚基)肼基)苯基)呋喃-2-羧酸(V-1)的制备
Figure PCTCN2018073219-appb-000025
第一步、中间体(II-1)的合成
反应釜中加入纯化水(14.80kg)、7-氨基苯并[d]噁唑-2(3H)-酮(2.00kg，可按照专利申请WO2005016898A2中的方法制备)、盐酸(5.33kg)，升至40～45℃，搅拌10min，降温至-3～-5℃，滴加亚硝酸钠水溶液(亚硝酸钠940g，水3.20kg)，保持内温不超过5℃，淀粉碘化钾试纸控制终点，继续搅拌15min；
向反应釜中加入丙酮(28L)，依次投入糠酸(4.57kg)、二水合氯化铜(232g)，35～40℃搅拌至溶解，滴加重氮盐溶液，期间保持内温35～40℃，继续搅拌1.5h。加入纯化水(60L)，升温至35～40℃搅拌30min。过滤，滤饼用45～50℃纯化水洗涤。将滤饼加入纯化水(40kg)中，用15％氢氧化钠水溶液中调pH至8～9，过滤，滤液用6mol/L盐酸调pH至3～4，过滤，滤饼用纯化水洗涤，干燥得固体(1.63kg，产率50％)。
第二步、中间体(III-1)的合成
将上步产物(1.4kg)、15％氢氧化钠水溶液(9.7kg)，氩气保护下，加热至回流，反应28h，将反应液倒入冰水(5～6kg)中，缓慢加入盐酸(6N，3L)调pH值至5～6，保持温度20℃以下，期间加入乙酸乙酯消除气泡，过滤，纯化水洗涤，干燥得固体(1.18kg，产率94％)。
第三步、中间体(V-1)的合成
向反应釜中依次加入上步产物(1.10kg)、纯化水(27.5kg)、盐酸(2.92kg)，搅拌溶解，冷却至-4～-1℃，滴加亚硝酸钠水溶液(亚硝酸钠346g，水5.5kg)，滴加完毕 继续反应15min。降温至-8～-5℃。将氢氧化钠(1.48kg)溶于纯化水(13.2kg)中，得10％的氢氧化钠水溶液。将5-甲基-2-(5,6,7,8-四氢萘-2-基)-2H-吡唑-3-醇盐酸盐(1.26kg)加入上述氢氧化钠水溶液(10kg)溶解，所得溶液一次性加入重氮盐溶液中，保持温度不高于10℃。加入剩余的10％的氢氧化钠水溶液，调pH至8～9，自然升温至8～12℃反应，反应4h。加入6N盐酸，调pH＝2～3，保持温度不超过20℃，过滤，滤饼用水洗涤至pH＝6～7。滤饼加入50％四氢呋喃水溶液(19kg)中，室温打浆2h，过滤，50％四氢呋喃水溶液洗涤，水洗涤，干燥。固体加入乙酸乙酯(20kg)，氩气保护下，40-45℃打浆2h，冷却至室温，过滤，乙酸乙酯洗涤，固体加入乙酸乙酯(20kg)中，氩气保护下，40～45℃打浆2h，冷却至室温，过滤，乙酸乙酯洗涤，干燥得固体(2.18kg，产率95％，纯度99.5％)。
MS m/z(ESI):457.1[M-1]
实施例3、(Z)-5-(2-羟基-3-(2-(3-甲基-5-氧代-1-(5,6,7,8-四氢萘-2-基)-1,5-二氢-4H-吡唑-4-亚基)肼基)苯基)呋喃-2-羧酸乙醇胺盐(1:2)的制备
Figure PCTCN2018073219-appb-000026
粗品的制备
常温下将式(V-1)化合物(1.8kg)悬浮于四氢呋喃/乙醇(14.5kg，V/V＝2:1)混合溶剂中，搅拌0.5h，冷却至10～15℃，滴加乙醇胺(479.6g)的四氢呋喃乙醇溶液(四氢呋喃91g和乙醇41g)。自然升温至室温反应20h。过滤，四氢呋喃/乙醇(V/V＝2:1)混合溶剂洗涤，乙酸乙酯洗涤，过滤，干燥得深红色固体(1.73kg，产率76％，纯度99.7％)。
1H-NMR(500MHz,D 2O+NaOH)δ7.725-7.741(d,1H),7.298-7.316(d,3H)，7.183-7.198(d,1H),7.131-7.149(m,2H),6.612-6.643(t,1H),3.574-3.596(t,4H)，2.759-2.778(br,4H),2.698-2.721(t,4H)，2.428(s,3H),1.772(br,4H).

Claims (17)

  1. 一种制备式(V)所示化合物的方法，其特征在于，所述方法为式(III)所示化合物与式(IV)所示化合物或其盐反应得到式(V)所示化合物，
    Figure PCTCN2018073219-appb-100001
    其中，
    A选自碳原子或氧原子；
    R选自氢原子或烷基；
    R 1、R 2、R 3、R 4各自独立地选自氢原子、烷基、烷氧基、卤素、任选取代的芳基或杂芳基，所述取代基选自烷基、卤素、羟基、四唑基、咪唑基、二氢咪唑基、羧基或烷氧羰基；
    R 5、R 6、R 7各自独立地选自氢原子、烷基、烷氧基、卤素、羟基、氨基、硝基、氰基、羧基或烷氧羰基；
    R 8、R 9、R 10、R 11各自独立地选自氢原子或烷基；
    n选自0、1或2。
  2. 如权利要求1所述的方法，其特征在于，所述方法还包括，
    Figure PCTCN2018073219-appb-100002
    其中，R、R 1、R 2、R 3、R 4如权利要求1中所定义。
  3. 如权利要求2所述的制备方法，其特征在于，所述方法还包括，
    Figure PCTCN2018073219-appb-100003
    其中，R 1、R 2、R 3、R 4如权利要求1中所定义。
  4. 一种制备式(III-1)化合物的方法，其特征在于，所述方法为，
    Figure PCTCN2018073219-appb-100004
  5. 如权利要求4所述的方法，其特征在于，所述方法还包括，
    Figure PCTCN2018073219-appb-100005
  6. 一种化合物如式(II)所示，
    Figure PCTCN2018073219-appb-100006
    其中，R 1、R 2、R 3、R 4如权利要求1中所定义。
  7. 如权利要求6所述化合物，其特征在于，所述化合物具有式(II-1)所示的结构，
    Figure PCTCN2018073219-appb-100007
  8. 一种制备式(II)化合物的方法，其特征在于，所述方法为，
    Figure PCTCN2018073219-appb-100008
    其中，R 1、R 2、R 3、R 4如权利要求1中所定义。
  9. 一种制备式(II-1)化合物的方法，其特征在于，所述方法为，
    Figure PCTCN2018073219-appb-100009
  10. 一种化合物如式(IV)所示或其盐，
    Figure PCTCN2018073219-appb-100010
    其中，R 5、R 6、R 7、R 8、R 9、R 10、R 11、n、A如权利要求1中所定义。
  11. 如权利要求10所述化合物，其特征在于，所述化合物具有式(IV-1)所示的结构，
    Figure PCTCN2018073219-appb-100011
  12. 一种制备式(IV-1)所示化合物或其盐的方法，其特征在于，所述方法为，
    Figure PCTCN2018073219-appb-100012
  13. 一种制备式(V-1)所示化合物的方法，其特征在于，所述方法为，
    Figure PCTCN2018073219-appb-100013
  14. 如权利要求13所述的方法，其特征在于，所述方法还包括，
    Figure PCTCN2018073219-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 PCTCN2018073219-appb-100015
  16. 如权利要求13所述的方法，其特征在于，所述方法还包括，
    Figure PCTCN2018073219-appb-100016
  17. 一种制备式(V-1)所示化合物的药学上可接受的盐方法，包括权利要求13-16中任一项所述的步骤，以及通过式(V-1)所示化合物与碱反应制备得到其药学上可接受的盐的步骤，所述碱选自氢氧化钠、赖氨酸、精氨酸、甲胺、二甲胺、三甲胺、乙胺、二乙胺、三乙胺、乙醇胺、哌嗪、二苄基乙二胺、葡甲胺、氨丁三醇、四甲基季胺、四乙基季胺或氢氧化胆碱，优选乙醇胺。
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