WO2016019837A1 - 制备Himbacine类似物中间体的制备方法 - Google Patents

制备Himbacine类似物中间体的制备方法 Download PDF

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WO2016019837A1
WO2016019837A1 PCT/CN2015/085942 CN2015085942W WO2016019837A1 WO 2016019837 A1 WO2016019837 A1 WO 2016019837A1 CN 2015085942 W CN2015085942 W CN 2015085942W WO 2016019837 A1 WO2016019837 A1 WO 2016019837A1
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compound
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reaction
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袁建栋
陈耀
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博瑞生物医药技术(苏州)有限公司
信泰制药（苏州）有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof

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  • the present invention relates to the field of pharmaceutical synthesis, and in particular to a process for preparing a hebacine analog intermediate, and further relates to a compound of ⁇ [5-(3-fluorophenyl)pyridin-2-yl]alkyl ⁇ phosphonate Preparation method.
  • thromboin is known to have multiple activities in different cell types, and thrombin receptors are known to be present in, for example, human platelets, vascular smooth muscle cells, endothelial cells, and fibroblasts.
  • thromboin receptor antagonists are useful in the treatment of thrombotic, inflammatory, atherosclerotic, and fibroproliferative diseases, as well as other diseases in which thrombin and its receptors play a pathological role.
  • Other examples of thrombin receptor antagonists useful in the treatment of thrombotic diseases, inflammation, atherosclerosis and fibroproliferative diseases and the synthesis of these compounds are described in U.S. Patent Application Serial No. 20030216437.
  • One confirmed thrombin receptor antagonist is an orally bioavailable compound derived from a himbacine derivative having the structure of Compound 11:
  • the first step of the reaction of the method gives the product a hydrohalide salt which is easy to absorb moisture, is unstable, and has a long reaction time, and needs to be stirred at 45 ° C for 4 hours.
  • After the final step of the reaction it is necessary to wash with isobutyl acetate several times, the cost is high; the post-treatment is cumbersome, and after the liquid separation, Darco stirring and decolorization treatment is required to be added to the organic layer, and the final yield is only 75%.
  • the total yield after the four-step reaction was 66.7%.
  • the method is cumbersome to operate, and each step requires separation and purification by silica gel column chromatography.
  • the second step requires the use of Pd(PPh 3 ) 4 , which is environmentally unfriendly and has a reaction time of up to 22 hours.
  • the third step requires the use of a strong base LDA, the reaction temperature is -78 ° C, the reaction conditions are harsh, and the yield is only 32.5%. The total yield after the three-step reaction was only 25%.
  • Compound I is an essential intermediate for the preparation of the thrombin receptor antagonist himbacine analog.
  • the quality and yield of Compound I directly affect the purity and yield of the final product himbacine analog.
  • the existing methods generally have low yields, complicated operations, high requirements on equipment, high production cost, and are not suitable for industrial production.
  • the object of the present invention is to adopt a safer material, to achieve higher yield, easier operation, and suitable for industrial production of the compound of formula I,
  • the present invention provides the following technical solutions:
  • R 1 is H or an alkyl group having 1 to 10 carbon atoms, and the method comprises:
  • X 2 is Cl, Br, I, benzenesulfonate, p-toluenesulfonate, trifluoromethanesulfonate or methanesulfonate
  • R 2 and R 3 are independently selected from OH and optionally substituted C 1 a group consisting of -C 6 monohydric and diol, wherein R 2 and R 3 together may form a ring;
  • X 1 is benzenesulfonate, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, Cl, I or Br; preferably the sulfonylating reagent comprises benzenesulfonyl chloride, p-toluenesulfonyl chloride, A Sulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonic anhydride, p-toluenesulfonic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, and the like.
  • the boron ester compound used in the step 1) is 3-fluorophenylboronic acid (hence, preferably R 2 is H); preferably, in the step 1), both R 2 and R 3 are OH, or the compound V has the following Structure:
  • the X 1 halogenating agent used in step 2) is selected from the group consisting of SOCl 2 , PCl 3 , PCl 5 , POCl 3 , O 2 SCl 2 , (OCCl) 2 , OSBr 2 , PBr 3 , PBr 3 , POBr 3 , O 2 SBr.
  • sulfonylating reagents include benzenesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonic anhydride, p-toluenesulfonic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, etc.
  • the halogenating agent is more preferably thionyl chloride (hence, X 1 is more preferably Cl).
  • X 2 is Cl, Br or I.
  • the phosphite compound having the structure of formula A used in step 3) is a trialkyl phosphite, more preferably triethyl phosphite.
  • the catalyst is used in step 1); when the catalyst is used in the reaction of step 1), the catalyst is preferably carbon black supported palladium.
  • R 1 is an alkyl group having 1 to 10 carbon atoms, an aryl group, an arylalkyl group, a heteroaryl group or hydrogen, and more preferably, R 1 is an ethyl group.
  • the method of preparing Compound I provided by the present invention is prepared according to the method shown in the following Scheme (1):
  • the X 1 halogenating agent is selected from the group consisting of a chlorinating agent (X 1 is Cl) SOCl 2 , PCl 3 , PCl 5 , POCl 3 , O 2 SCl 2 , (OCCl) 2 , or a brominating agent (X 1 is Br) OSBr 2 , PBr 3 , PBr 3 , POBr 3 , O2SBr 2 , (OCBr) 2 ;
  • X 1 is the same everywhere and is selected from Cl or Br depending on the halogenating agent selected;
  • X 2 is Cl, Br or I;
  • R 1 is 1 An alkyl group of 10 to 10 carbon atoms, an aryl group, an arylalkyl group or an aralkyl group, more preferably an ethyl group; and R 2 and R 3 are independently selected from the group consisting of OH and optionally substituted C 1 -C 6 mono- and binary A group consisting of alcohols wherein R 2
  • R 1 is ethyl
  • R 2 is OH
  • X 1 is Cl
  • X 2 is Br
  • X 1 halogenating agent is preferably SOCl 2
  • the phosphite compound having the structure of formula A is used. Triethyl phosphate.
  • the compound IV and the compound V are added to a suitable solvent (for example, a mixed solution of an organic solvent and water, preferably isobutyl acetate and water are mixed in a volume ratio of 1 to 2:0 to 1), and are alkaline.
  • a suitable solvent for example, a mixed solution of an organic solvent and water, preferably isobutyl acetate and water are mixed in a volume ratio of 1 to 2:0 to 1.
  • the palladium reagent is preferably used to catalyze the reaction, and the reaction is carried out at a suitable reaction temperature (preferably 50 ° C to 100 ° C). After the reaction is completed, the reaction solution is made alkaline, and the product is isolated by extraction, which is the compound III.
  • the compound III is added to a suitable organic solvent (preferably toluene, acetonitrile or a mixed solution thereof) to react with a halogenating agent. After the reaction, the unreacted halogenation is neutralized with a weak base solution (such as potassium carbonate solution, sodium carbonate solution, etc.). The mixture is separated, and the organic layer is concentrated to obtain the product, which is the compound II.
  • a suitable organic solvent preferably toluene, acetonitrile or a mixed solution thereof
  • a halogenating agent preferably toluene, acetonitrile or a mixed solution thereof
  • a weak base solution such as potassium carbonate solution, sodium carbonate solution, etc.
  • Compound II and a phosphite compound having a structure of formula A are added to the reaction flask and stirred at a suitable temperature (e.g., 100 ° C to 160 ° C, preferably 130 ° C to 150 ° C).
  • a suitable temperature e.g. 100 ° C to 160 ° C, preferably 130 ° C to 150 ° C.
  • the reaction is carried out, and after the completion of the reaction, the temperature is lowered (preferably, the temperature is lowered to -10 ° C to 10 ° C, more preferably the temperature is lowered to 0 ° C to 5 ° C), and the mixture is separated and purified to obtain the objective compound I.
  • the present invention provides a method for preparing a compound of the formula
  • R 1 is H or an alkyl group having 1 to 10 carbon atoms
  • X 1 is a benzenesulfonic acid group, a p-toluenesulfonic acid group, a methanesulfonic acid group, a trifluoromethanesulfonic acid group, Cl, I or Br.
  • the present invention provides a method for preparing a compound of the formula
  • R 1 is H or an alkyl group having 1 to 10 carbon atoms
  • X 1 is a benzenesulfonic acid group, a p-toluenesulfonic acid group, a methanesulfonic acid group, a trifluoromethanesulfonic acid group, Cl, I or Br.
  • compound III is reacted with compound VI and compound VII to form:
  • R 2 and R 3 are independently selected from OH and optionally substituted C 1 a group consisting of -C 6 monohydric and diol, wherein R 2 and R 3 together may form a ring.
  • R2 and R3 are OH, or compound VI has the structure:
  • the invention also provides a method of preparing compound 11:
  • R 1 is selected from an alkyl group having 1 to 4 carbon atoms to form compound 11. Further, it is preferred that R 1 is an ethyl group.
  • each of the intermediates prepared by the present invention is solid and stable in nature.
  • a mixed solution of water and an organic solvent such as isobutyl acetate
  • ethyl acetate is used in the post-treatment instead of using isobutyl acetate in the prior art, which greatly reduces the reaction.
  • the present invention is one step in the Suzuki reaction, and the amount of the borate ester compound (such as 3-fluorophenylboronic acid) is significantly lower than that of the prior art (the amount of the phenylborate compound in the CN101511852B is 1.5 equivalent), which reduces environmental pollution and also has Significantly reduce costs.
  • the reaction step of the invention is small, and the post-treatment is simple. After the reaction is completed, a high-purity product can be obtained after a simple liquid separation extraction treatment.
  • the present invention greatly reduces the reaction time. Further, the yield of the compound 1 prepared by the present invention is generally higher than that of the prior art. Suitable for industrial production.
  • the preparation of the compound I and the compound 15 by the method of the present invention produces the himbacine analog (compound 11), which greatly reduces the production cost of the compound 11, simplifies the reaction step and the post-treatment, and is more suitable for industrial production.
  • Figure 1 shows a mass spectrum (MS) chart of Compound III prepared according to the method of Example 1.
  • Figure 2 shows a hydrogen-nuclear magnetic ( 1 H-NMR) spectrum of Compound III prepared according to the method of Example 1.
  • Figure 3 shows the mass spectrum of Compound II prepared according to the method of Example 2.
  • Figure 4 shows a hydrogen-nuclear magnetic diagram of Compound II prepared according to the method of Example 2.
  • Figure 5 shows the mass spectrum of Compound I prepared according to the method of Example 3.
  • Figure 6 shows a hydrogen-nuclear magnetic spectrum of Compound I prepared according to the method of Example 3.
  • Alkyl Suitable for "alkyl”, and “alkyl” moiety of "hydroxyalkyl”, “haloalkyl”, “alkoxy”, etc., said alkyl including straight-chain alkyl or branched alkyl And an aliphatic hydrocarbon group containing from 1 to about 24 carbon atoms in the chain.
  • the alkyl group contains from 1 to about 15 carbon atoms in the chain, and more optionally the alkyl group contains from 1 to 4 carbon atoms in the chain.
  • Aryl refers to a substituted or unsubstituted, aromatic, monocyclic or bicyclic, chemically feasible carbocyclic ring system having from 1 to 2 aromatic rings.
  • the aryl moiety usually has 6 to 14 carbon atoms such as phenyl, toluene, xylene, naphthyl and the like.
  • Heteroaryl refers to a monocyclic or polycyclic ring system having from about 5 to about 14 ring atoms, and that one living atom in the system is a non-carbon atom such as N, O or S.
  • it may be a pyridyl group, a pyrimidinyl group, a thiazolyl group, an imidazolylbenzothiazolyl group or the like.
  • the heterocyclic ring refers to an unsubstituted or substituted, saturated or unsaturated aromatic group composed of a carbon atom and one or more hetero atoms in the ring.
  • the heteroatoms are independently selected from the group consisting of O, N and S.
  • halogen refers to a fluorine, chlorine, bromine or iodine atom group.
  • the halide is preferably a chloride or a bromide.
  • Compound IV can be prepared by the method disclosed in the specification of CN101511852B, and can also be obtained by purchase.
  • the temperature of the reaction solution was lowered to 20-25 ° C, filtered, and the filter cake was washed twice with ethyl acetate (500 ml ⁇ 2), the filtrate was combined, the pH was adjusted to 12-13 using 25% NaOH, and the organic layer was further used for pH.
  • the organic layer was washed twice with water (700 ml ⁇ 2) of 12-13, and then the organic layer was washed with 20% sodium chloride solution (700 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure at 50 ° C to give white. 173.6 g of solid, yield: 85.4%, HPLC: 98.5%.
  • the temperature of the reaction solution was lowered to 20-25 ° C, filtered, and the filter cake was washed twice with ethyl acetate (500 ml ⁇ 2), the filtrate was combined, the pH was adjusted to 12-13 using 25% NaOH, and the organic layer was further used for pH.
  • the organic layer was washed twice with water (700 ml ⁇ 2) of 12-13, and then the organic layer was washed with 20% sodium chloride solution (700 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure at 50 ° C to give white. 176.8 g of solid, yield: 87%, HPLC: 98.9%.
  • the preparation of the compound V is obtained by the method disclosed in EP 2684887 A1, WO2014009169 or "Borylation using group IV metallocene under mild conditions (Tetrahedron Letters, Volume 55, Issue 10, Pages 1702-1705, 2014)".
  • Compound VI is prepared by the method disclosed in WO2013091096, WO2009074812 or WO2012167606.
  • the temperature of the reaction solution was lowered to 20-25 ° C, filtered, and the filter cake was washed twice with ethyl acetate (500 ml ⁇ 2), the filtrate was combined, the pH was adjusted to 12-13 using 25% NaOH, and the organic layer was further used for pH.
  • the organic layer was washed twice with water (700 ml ⁇ 2) of 12-13, and then the organic layer was washed with 20% sodium chloride solution (700 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure at 50 ° C to give white. 173.1 g of solid, yield: 85.2%, HPLC: 98.9%.
  • compound V.2 is prepared by the method disclosed in "A new preparative method of aryl sulfonate esters by using cyclic organobismuth reagents (Heterocycles (2007), 74, 771-790)” or “New preparative method of aryl tosylates by using organobismuth Reagents (Chemistry Letters (2007), 36(7), 928-929)".
  • the temperature of the reaction solution was lowered to -10 to 0 ° C, 550 ml of toluene was added, 20% potassium carbonate (840 ml) was added dropwise, and the temperature was controlled below 10 ° C. After the completion of the dropwise addition, the mixture was stirred for 10 minutes, and the organic layer was further neutralized with 20% chlorine.
  • the sodium chloride (400 ml) solution was washed once, dried over anhydrous sodium sulfate, and then evaporated to dryness to give the white solid. 159.2 g, yield: 95.0%, HPLC: 98.7%.
  • the mixture was kept at 0 to 5 ° C for 1 hour, and filtered, and the filter cake was heptane ( After washing twice with 150 ml ⁇ 2), it was dried under reduced pressure at 40 ° C to give a solid, 175.6 g, yield: 90.5%, HPLC: 99.1%.

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Abstract

本发明提供了一种制备Himbacine类似物中间体的制备方法。本发明所提供的方法包括先将5-卤代-2-羟基甲基吡啶与苯硼酸酯类化合物进行Suzuki反应，再将得到的偶联物与卤化剂反应，最后与亚磷酸酯反应，得到目标化合物{[5-(3-氟苯基)吡啶-2-基]烷基}膦酸二烷基酯化合物。本发明提供的方法操作简单，收率高，所用原料安全易得。

Description

制备Himbacine类似物中间体的制备方法 技术领域
本发明涉及药物合成领域，具体涉及制备himbacine类似物中间体的制备方法，更进一步的涉及{[5-(3-氟苯基)吡啶-2-基]烷基}膦酸二烷基酯化合物的制备方法。
背景技术
在美国专利US8273790B2，US8138180B2和US2006172397A1等已经公开了himbacine(喜巴辛)衍生物以及含有这些化合物的药物组合物，美国申请No.11331324中公开了himbacine类似物可用作凝血酶受体拮抗剂。已知凝血酶在不同细胞类型中具有多种活性，并已知凝血酶受体存在于诸如人血小板、血管平滑肌细胞、内皮细胞和成纤维细胞中。凝血酶受体拮抗剂可用于血栓、炎性、动脉粥样硬化和纤维增生疾病以及其中凝血酶和其受体起病理作用的其它疾病的治疗。在美国专利申请No.20030216437中描述了可用于治疗血栓形成病、炎症、动脉粥样硬化和纤维增殖病的凝血酶受体拮抗剂的其他实施例和这些化合物的合成。
已确认的一种凝血酶受体拮抗剂是由具有化合物11的结构的himbacine衍生物的口服生物有效化合物：
Figure PCTCN2015085942-appb-000001
这种和类似的himbacine类似物凝血酶受体拮抗剂的合成方法公开在WO2006076452和WO2006076565中。其中{[5-(3-氟苯基)吡啶-2-基]烷基}膦酸二烷基酯化合物(化合物I)的合成化合物11的一个关键中间体。
Figure PCTCN2015085942-appb-000002
中国专利CN101511852B公开的关于化合物I的制备方法如流程I：
Figure PCTCN2015085942-appb-000003
流程I
该方法第一步反应得到产物是氢卤酸盐，容易吸潮，不稳定，且反应时间较长，需要在45℃下搅拌4小时。最后一步反应结束后，需要多次用乙酸异丁酯洗涤，成本较高；后处理繁琐，分液后，需要向有机层加入Darco搅拌脱色处理等，并且最后一步收率仅为75％。四步反应后总收率66.7％。
美国申请US20080004449也公开了类似方法。
公开号为WO2011162562的专利公开制备化合物I(R1为乙基)的方法，具体如流程II：
Figure PCTCN2015085942-appb-000004
流程II
该方法操作繁琐，每一步反应均需要硅胶柱层析分离纯化，第二步反应需要用到，Pd(PPh3)4对环境不友好，并且反应时间长达22h。第三步反应需要用到强碱LDA，反应温度在-78℃，反应条件苛刻，收率仅32.5％。三步反应后总收率仅有25％。
化合物I是制备凝血酶受体拮抗剂himbacine类似物必不可少的中间体，化合物I的质量和收率直接影响了终产物himbacine类似物的纯度和收率。目前关于化合物I的制备方法研究的比较少，现有的方法收率普遍较低，操作复杂，对设备要求高，生产成本高，不适合工业生产。
发明内容
本发明的目的是采用更安全的材料，实现收率更高，操作更简便，并适合工业化生产的式I所示化合物的制备方法，
Figure PCTCN2015085942-appb-000005
为实现上述目的，本发明提供了以下技术方案：
一种下式化合物I的制备方法
Figure PCTCN2015085942-appb-000006
其中，R1为H或含1～10个碳原子的烷基，该方法包括：
1)、使化合物IV与化合物V反应，生成化合物III：
Figure PCTCN2015085942-appb-000007
其中，X2为Cl，Br、I、苯磺酸基、对甲苯磺酸基、三氟甲磺酸基或甲磺酸基，R2和R3独立的选自由OH和任意取代的C1～C6一元和二元醇组成的组，其中R2和R3在一起可以成环；
2)、使化合物III与X1对应的磺酰化试剂或卤化剂反应，生成化合物II：
Figure PCTCN2015085942-appb-000008
其中，X1为苯磺酸基、对甲苯磺酸基、甲磺酸基、三氟甲磺酸基、Cl、I或Br；优选磺酰化试剂包括苯磺酰氯、对甲苯磺酰氯、甲磺酰氯、三氟甲磺酰氯、苯磺酸酐、对甲苯磺酸酐、甲磺酸酐、三氟甲磺酸酐等。
3)、使化合物II与具有式A结构的亚磷酸酯化合物反应，生成化合物I：
Figure PCTCN2015085942-appb-000009
优选的，步骤1)中所用的硼酯化合物为3-氟苯基硼酸(因此，优选R2为H)；优选的，步骤1)中R2和R3均为OH，或化合物V具有如下的结构：
Figure PCTCN2015085942-appb-000010
优选的，步骤2)所用X1卤化剂选自SOCl2，PCl3，PCl5，POCl3，O2SCl2，(OCCl)2，OSBr2，PBr3，PBr3，POBr3，O2SBr2，(OCBr)2，磺酰化试剂包括苯磺酰氯、对甲苯磺酰氯、甲磺酰氯、三氟甲磺酰氯、苯磺酸酐、对甲苯磺酸酐、甲磺酸酐、三氟甲磺酸酐等；卤化剂更优选为亚硫酰氯(因此，X1更优选为Cl)。优选的，X2为Cl，Br或I。
优选的，步骤3)所用的具有式A结构的亚磷酸酯化合物是亚磷酸三烷基酯，更优选为亚磷酸三乙酯。优选的，在步骤1)中使用催化剂；在步骤1)的反应中使用催化剂时，该催化剂优选为炭黑负载的钯。优选的，R1为含1～10个碳原子的烷基，芳基，芳基烷基，杂芳基或氢，更优选的，R1为乙基。
在一些实施例中，本发明所提供的制备化合物I的方法是按照以下流程(1)所示的方法制备：
Figure PCTCN2015085942-appb-000011
流程(1)
其中X1卤化剂选自氯化剂(X1为Cl)SOCl2，PCl3，PCl5，POCl3，O2SCl2，(OCCl)2，或溴化剂(X1为Br)OSBr2，PBr3，PBr3，POBr3，O2SBr2，(OCBr)2；X1在各处相同并根据所选卤化剂选自Cl或Br；X2为Cl，Br或I；R1为含1～10个碳原子的烷基，芳基，芳杂基或芳烷基，更优选为乙基；且R2和R3独立的选自由OH和任意取代的C1～C6一元和二元醇组成的组，其中R2和R3在一起可以成环，优选R2为OH。在一些实施方式中，优选R1为乙基，R2为OH，X1为Cl，X2为Br，X1卤化剂优选为SOCl2，所用的具有式A结构的亚磷酸酯化合物为亚磷酸三乙酯。
具体的，将化合物IV与化合物V加入到合适的溶剂(如有机溶剂与水的混合溶液中，优选乙酸异丁酯与水以1～2:0～1的体积比混合)中，在碱性条件下，优选采用钯试剂催化反应，在合适的反应温度(优选为50℃～100℃)下反应，反应结束后，调节反应液为碱性，萃取分离出产物，即为化合物III。
将化合物III加入到合适的有机溶剂中(优选甲苯、乙腈或其混合溶液)与卤化剂反应，反应结束后，用弱碱溶液(如碳酸钾溶液，碳酸钠溶液等)中和未反应的卤化剂，分液，将有机层浓缩后，得到产物，即为化合物II。
将化合物II和具有式A结构的亚磷酸酯化合物(优选亚磷酸三烷基酯)加入到反应瓶中，搅拌，在适宜的温度(如100℃～160℃，优选130℃～150℃)条件下反应，反应结束后降低温度(优选温度降至-10℃～10℃，更优选温度降至0℃～5℃)，分离纯化，得到目标化合物I。
在另一实施方式中，本发明提供了一种下式化合物I的制备方法
Figure PCTCN2015085942-appb-000012
其包括：
1)、使化合物III与X1对应的磺酰化试剂或卤化剂反应，生成化合物II：
Figure PCTCN2015085942-appb-000013
2)、使化合物II与具有式A结构的亚磷酸酯化合物反应，生成化合物I：
Figure PCTCN2015085942-appb-000014
其中，R1为H或含1～10个碳原子的烷基，X1为苯磺酸基、对甲苯磺酸基、甲磺酸基、三氟甲磺酸基、Cl、I或Br。
在另一实施方式中，本发明提供了一种下式化合物I的制备方法
Figure PCTCN2015085942-appb-000015
其包括：
使化合物II与具有式A结构的亚磷酸酯化合物反应，生成化合物I：
Figure PCTCN2015085942-appb-000016
其中，R1为H或含1～10个碳原子的烷基，X1为苯磺酸基、对甲苯磺酸基、甲磺酸基、三氟甲磺酸基、Cl、I或Br。优选的，化合物III是由化合物VI与化合物VII反应，生成：
Figure PCTCN2015085942-appb-000017
其中，X2为Cl，Br、I、苯磺酸基、对甲苯磺酸基、三氟甲磺酸基或甲磺酸基，R2和R3独立的选自由OH和任意取代的C1～C6一元和二元醇组成的组，其中R2和R3在一起可以成环。优选的，R2和R3均为OH，或化合物VI具有如下的结构：
Figure PCTCN2015085942-appb-000018
另一方面，本发明还提供了一种化合物11的制备方法：
Figure PCTCN2015085942-appb-000019
包括，使用本发明所提供的方法制备的化合物I与下式化合物15反应，
Figure PCTCN2015085942-appb-000020
其中，R1选自含1～4个碳原子的烷基，生成化合物11。进一步的，优选R1为乙基。
中国专利CN101511852B和WO2006076452A2公开了化合物15的制备方法以及由化合物1与化合物15反应制备化合物11的方法，这些专利公开的全部内容通过引用结合到本发明。
本发明所提供的制备化合物I的方法与现有技术相比具有显著的效果，首先，本发明制备的各中间体均为固体，且性质稳定。本发明第一步反应，采用水和有机溶剂(如乙酸异丁酯)的混合溶液作为反应溶剂，并且在后处理中采用乙酸乙酯代替现有技术中使用乙酸异丁酯，大大降低了反应成本，另外本发明在Suzuki反应一步，硼酸酯类化合物(如3-氟苯硼酸)用量显著低于现有技术(CN101511852B中苯硼酸酯类化合物用量为1.5当量)，既减少了环境污染，也有显著降低成本。其次，本发明反应步骤少，后处理简单，反应结束后，经过简单的分液萃取处理后即可得到高纯度的产物。最后，本发明大大缩短了反应时间。另外本发明提供的制备化合物1的收率与现有技术相比，普遍较高。适合工业化生产。
采用本发明所述方法制备化合物I与化合物15反应，制备himbacine类似物(化合物11)，大大降低了化合物11的生产成本，简化了反应步骤和后处理，更适合工业化生产。
以下通过优选的具体实施例对本发明的内容以及其他优点做进一步阐明，并不用于限制本发明。
附图说明：
图1显示的是按照实施例1方法制备的化合物III的质谱(MS)图。
图2显示的是按照实施例1方法制备的化合物III的氢-核磁(1H-NMR)谱图。
图3显示的是按照实施例2方法制备的化合物II的质谱图。
图4显示的是按照实施例2方法制备的化合物II的氢-核磁图。
图5显示的是按照实施例3方法制备的化合物I的质谱图。
图6显示的是按照实施例3方法制备的化合物I的氢-核磁谱图。
具体实施方式
在本发明中使用的技术术语除非另有指明，均应适用于整篇说明书和权利要求书。
术语：
烷基：适用于“烷基”，以及“羟烷基”，“卤烷基”，“烷氧基”等的“烷基”部分，所述烷基包括直链烷基或支链烷基，并在链中包含1至大约24个碳原子的脂肪族烃基。优选烷基在链中包含1至大约15个碳原子，更有选的烷基在链中包含1至4个碳原子。
芳基：是指具有1～2个芳环的取代或未取代的，芳香族，单环或双环的、化学可行的碳环体系。芳基部分通常具有6～14个碳原子，如苯基，甲苯，二甲苯，萘基等。
杂芳基：是指具有约5～14个环原子的单环或多环环体系，并且该体系中一个活多个原子是非碳原子，如N、O或S。例如可以是吡啶基，嘧啶基，噻唑基，咪唑基苯并噻唑基等。所述杂环是指在环中由碳原子和一个或多个杂原子构成的未取代的或取代的、饱和的或不饱和的芳族。所述杂原子独立的选自O，N和S。本发明所述“卤素”，“卤代”和“卤化物”是指含氟，氯，溴或碘原子基团。卤化物优选氯化物，溴化物。
化合物IV可通过CN101511852B说明书中公开的方法制备获得，也可通过购买获得。
实施例1化合物III的制备
Figure PCTCN2015085942-appb-000021
氮气保护下，于5L瓶中加入乙酸异丁酯2.0L与水1.5L，搅拌下再加入5-溴-2-羟甲基吡啶188.0g(1.0mol)，3-氟苯硼酸167.8g(1.2mol)，碳酸钠370.9g(3.5mol)，10％钯碳1.6g(干重)，升温至70～80℃，并于70～80℃反应5h。将反应液温度降至20～25℃，过滤，乙酸乙酯(500ml×2)洗涤滤饼两次，合并滤液，使用25％NaOH调节pH至12～13，分液，有机层再用pH为12～13的水(700ml×2)洗涤有机层两次，然后用20％氯化钠溶液(700ml)洗涤有机层，无水硫酸钠干燥后，于50℃减压蒸除溶剂，得类白色固体173.6g，收率：85.4％，HPLC：98.5％。
或按照如下方法进行制备
Figure PCTCN2015085942-appb-000022
氮气保护下，于5L瓶中加入乙酸异丁酯2.0L与水1.5L，搅拌下再加入5-氯-2-羟甲基吡啶143.6g(1.0mol)，化合物V.1约288.7g(1.3mol)，碳酸钠370.9g(3.5mol)，10％钯碳1.6g(干重)，升温至75～80℃，并于75～80℃反应5h。将反应液温度降至20～25℃，过滤，乙酸乙酯(500ml×2)洗涤滤饼两次，合并滤液，使用25％NaOH调节pH至12～13，分液，有机层再用pH为12～13的水(700ml×2)洗涤有机层两次，然后用20％氯化钠溶液(700ml)洗涤有机层，无水硫酸钠干燥后，于50℃减压蒸除溶剂，得类白色固体176.8g，收率：87％，HPLC：98.9％.
其中化合物V的来源：EP2684887A1,WO2014009169或“Borylation using group IV metallocene under mild conditions (Tetrahedron Letters，Volume 55，Issue10，Pages 1702-1705，2014)”公开的方法制备获得。
或按照如下方法进行制备
Figure PCTCN2015085942-appb-000023
氮气保护下，于5L瓶中加入乙酸异丁酯2.5L与水1.5L，搅拌下再加入化合物VI约235.1g(1.0mol)，化合物VII约210g(1.2mol)，碳酸钠370.9g(3.5mol)，10％钯碳1.6g(干重)，升温至70～80℃，并于70～80℃反应5h。将反应液温度降至20～25℃，过滤，乙酸乙酯(500ml×2)洗涤滤饼两次，合并滤液，使用25％NaOH调节pH至12～13，分液，有机层再用pH为12～13的水(700ml×2)洗涤有机层两次，然后用20％氯化钠溶液(700ml)洗涤有机层，无水硫酸钠干燥后，于50℃减压蒸除溶剂，得类白色固体168.7g，收率：83％，HPLC：98.4％。
其中化合物VI参考WO2013091096、WO 2009074812或WO 2012167606公开的方法制备获得。
或按照如下方法进行制备
Figure PCTCN2015085942-appb-000024
氮气保护下，于5L瓶中加入乙酸异丁酯2.0L与水1.5L，搅拌下再加入化合物IV.2约152.9g(1.0mol)，化合物V.2约346.2g(1.3mol)，碳酸钠402.8g(3.8mol)，10％钯碳1.8g(干重)，升温至70～80℃，并于70～80℃反应5h。将反应液温度降至20～25℃，过滤，乙酸乙酯(500ml×2)洗涤滤饼两次，合并滤液，使用25％NaOH调节pH至12～13，分液，有机层再用pH为12～13的水(700ml×2)洗涤有机层两次，然后用20％氯化钠溶液(700ml)洗涤有机层，无水硫酸钠干燥后，于50℃减压蒸除溶剂，得类白色固体173.1g，收率：85.2％，HPLC：98.9％。
其中化合物V.2参考以下文献公开的方法制备获得：“A new preparative method of aryl sulfonate esters by using cyclic organobismuth reagents(Heterocycles(2007),74,771-790)”或者“New preparative method of aryl tosylates by using organobismuth reagents(Chemistry Letters(2007),36(7),928-929)”。
MS:ESI，[M+H]+：204，见附图1。
1H-NMR(400MHz，CDCl3)：δ8.75(s，1H)，7.86(d,1H)，7.26～7.48(m，4H)，7.10(m，1H)，4.83(2H)，见附图2。
实施例2化合物II的制备
Figure PCTCN2015085942-appb-000025
氮气保护下，于3L三口瓶中加入甲苯200ml与乙腈300ml，搅拌下再加入5-(3-氟苯基)-2-羟甲基吡啶101.6g(0.5mol)，滴加二氯亚砜107.1g(0.9mol)，控制温度低于30℃，滴加完毕升温至45℃，并于45℃反应1h。将反应液温度降至0～5℃，加入550ml甲苯，滴加20％碳酸钾(830ml)，控温10℃以下，滴完后保持搅拌10分钟，分液，有机层再用20％氯化钠(400ml)溶液洗涤一次，无水硫酸钠干燥后，减压蒸除溶剂，得类白色固体107.5g，收率：97.0％，HPLC：98.6％，MS:ESI，[M+H)+：222，见附图3；
1H-NMR(400MHz，CDCl3)：δ8.85(s，1H)，7.9～8.0(d，1H)，7.6(d，1H),7.53～7.47(m，1H)，7.39～7.45(m，1H)，7.30～7.35(m，1H)，7.11～7.20(m，1H)，4.80(s，2H)，见附图4。
化合物II的制备还可以按照如下方法进行制备：
Figure PCTCN2015085942-appb-000026
氮气保护下，于3L三口瓶中加入甲苯200ml与乙腈300ml，搅拌下再加入5-(3-氟苯基)-2-羟甲基吡啶101.6g(0.5mol)，滴加三氟甲磺酰氯134.8g(0.8mol)，控制温度低于-10℃，滴加完毕升温至0℃，并于0℃反应1h。将反应液温度降至-10～0℃，加入550ml甲苯，滴加20％碳酸钾(840ml)，控温10℃以下，滴完后保持搅拌10分钟，分液，有机层再用20％氯化钠(400ml)溶液洗涤一次，无水硫酸钠干燥后，减压蒸除溶剂，得类白色固体159.2g，收率：95.0％，HPLC：98.7％。
实施例3化合物I的制备
Figure PCTCN2015085942-appb-000027
氮气保护下，于2L三口瓶中加入5-(3-氟苯基)-2-氯甲基吡啶133.0g(0.6mol)，亚磷酸三乙酯414ml(2.4mol)，搅拌，升温至145℃，并于145℃保持反应3h。将反应液温度降至0～5℃，滴加6N HCl-EA溶液360ml，滴完后再滴加850ml庚烷，滴完后于0～5℃保持1小时，过滤，滤饼用庚烷(150ml×2)洗涤两次后，于40℃减压干燥，得到固体194.9g，收率：90.3％，HPLC：98.6％，MS:ESI，[M+H]+：324，见附图5；
1H-NMR(400MHz，CDCl3)：δ8.75(s，1H)，8.58(d，1H)，7.07～7.50(m，5H)，4.05～4.15(m，4H)，3.50～3.91(d，1H)，3.10～3.44(d，2H)，1.26～1.31(t，6H)，见附图6。
化合物I的制备还可以按照如下方法制备：
Figure PCTCN2015085942-appb-000028
氮气保护下，于2L三口瓶中加入化合物II.1约201.2g(0.6mol)，亚磷酸三乙酯414ml(2.4mol)，搅拌，升温至110℃，并于110℃保持反应3h。将反应液温度降至0～5℃，滴加6N HCl-EA溶液360ml，滴完后再滴加850ml庚烷，滴完后于0～5℃保持1小时，过滤，滤饼用庚烷(150ml×2)洗涤两次后，于40℃减压干燥，得到固体175.6g，收率：90.5％，HPLC：99.1％。
虽然本发明已结合上文给出的具体实施方案进行了描述，上述实施例仅为本发明的优选实施例而非限制性的，本领域普通技术人员可以想到本实施方案中的各种变动及修改何变化，在不背离本发明的范围或精神的情况下做出这些变动，修改和变化都在本发明保护范围内。

Claims (10)

  1. 一种下式化合物I的制备方法
    Figure PCTCN2015085942-appb-100001
    其包括：
    使化合物II与具有式A结构的亚磷酸酯化合物反应，生成：
    Figure PCTCN2015085942-appb-100002
    其中，R1为H或含1～10个碳原子的烷基，X1为苯磺酸基、对甲苯磺酸基、甲磺酸基、三氟甲磺酸基、Cl、I或Br。
  2. 根据权利要求1所述方法，其特征在于，化合物II是由化合物III与X1对应的磺酰化试剂或卤化剂反应，生成：
    Figure PCTCN2015085942-appb-100003
    其中，X1为苯磺酸基、对甲苯磺酸基、甲磺酸基、三氟甲磺酸基、Cl、I或Br。
  3. 根据权利要求2所述方法，其特征在于，化合物III是由化合物IV与化合物V反应，生成：
    Figure PCTCN2015085942-appb-100004
    其中，X2为Cl，Br、I、苯磺酸基、对甲苯磺酸基、三氟甲磺酸基或甲磺酸基，R2和R3独立的选自由OH和任意取代的C1～C6一元和二元醇组成的组，其中R2和R3在一起可以成环。
  4. 根据权利要求3所述方法，其特征在于，R2和R3均为OH，或化合物V具有如下的结构：
    Figure PCTCN2015085942-appb-100005
  5. 根据权利要求2所述方法，其特征在于，化合物III是由化合物VI与化合物VII反应，生成：
    Figure PCTCN2015085942-appb-100006
    其中，X2为Cl，Br、I、苯磺酸基、对甲苯磺酸基、三氟甲磺酸基或甲磺酸基，R2和R3独立的选自由OH和任意取代的C1～C6一元和二元醇组成的组，其中R2和R3在一起可以成环。
  6. 根据权利要求5所述方法，其特征在于，R2和R3均为OH，或化合物VI具有如下的结构：
    Figure PCTCN2015085942-appb-100007
  7. 根据权利要求3～6任一项所述方法，其特征在于，化合物IV与化合物V反应、或化合物VI与化合物VII反应在钯催化剂条件下进行。
  8. 根据权利要求1～3任一项所述方法，其特征在于，R1为乙基，X1为Cl。
  9. 根据权利要求2～3任一项所述方法，其特征在于，X1为Cl，X2为Br，R1为乙基，所述X1卤化剂为SOCl2、PCl3、PCl5、或SOBr2；所述的磺酰化试剂为苯磺酰氯、对甲苯磺酰氯、甲磺酰氯、或三氟甲磺酰氯。
  10. 一种制备下式化合物11的方法，
    Figure PCTCN2015085942-appb-100008
    其特征在于，使用权利要求1～3任一项所述方法制备的化合物I与化合物15反应：
    Figure PCTCN2015085942-appb-100009
    其中，R1选自含1～4个碳原子的烷基，生成化合物11。
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CN101137647A (zh) * 2005-01-14 2008-03-05 先灵公司 Himbacine类似物的合成
CN101193880A (zh) * 2005-01-14 2008-06-04 先灵公司 喜巴辛类似物的外型和非对映立体选择合成
CN101511852A (zh) * 2006-06-30 2009-08-19 先灵公司 Himbacine类似物合成中所用的{[5″(3-氟苯基)-吡啶-2-基]甲基}膦酸二乙酯的合成

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CN101137647A (zh) * 2005-01-14 2008-03-05 先灵公司 Himbacine类似物的合成
CN101193880A (zh) * 2005-01-14 2008-06-04 先灵公司 喜巴辛类似物的外型和非对映立体选择合成
CN101511852A (zh) * 2006-06-30 2009-08-19 先灵公司 Himbacine类似物合成中所用的{[5″(3-氟苯基)-吡啶-2-基]甲基}膦酸二乙酯的合成

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