CN103694196A - Cytochrome P450 monooxygenase inhibitor intermediate, and preparation methods and application thereof - Google Patents

Cytochrome P450 monooxygenase inhibitor intermediate, and preparation methods and application thereof Download PDF

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CN103694196A
CN103694196A CN201210366903.2A CN201210366903A CN103694196A CN 103694196 A CN103694196 A CN 103694196A CN 201210366903 A CN201210366903 A CN 201210366903A CN 103694196 A CN103694196 A CN 103694196A
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李金亮
赵楠
罗光顺
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上海迪赛诺化学制药有限公司
上海迪赛诺药业有限公司
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D277/00Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28Radicals substituted by nitrogen atoms

Abstract

The invention provides a cytochrome P450 monooxygenase inhibitor intermediate, and preparation methods and an application thereof. Specifically, the invention provides the intermediate compound represented by the formula IV and used for preparation of a cytochrome P450 monooxygenase inhibitor (cobicistat), wherein X represents bromine, chlorine or a sulfonate group, R represents a hydroxyl group, a substituted or unsubstituted C1-C8 straight-chain or branched-chain alkyl, a substituted or unsubstituted naphthenic group, or a substituted or unsubstituted C3-C20 aralkyl. The invention also provides the preparation methods of the intermediate, and a method for preparing cobicistat from the intermediate. The preparation methods have the advantages of simple preparation process and low cost, and are suitable for industrialized production.

Description

细胞色素P450单加氧酶抑制剂中间体及其制法和用途 Cytochrome P450 monooxygenase inhibitor intermediates preparation and use

技术领域 FIELD

[0001] 本发明属于药物合成领域,具体涉及一种细胞色素P450单加氧酶抑制剂的中间体及合成方法及其中间体的制备方法。 [0001] The present invention belongs to the field of drug synthesis, specifically relates to methods and synthetic intermediates and the preparation of intermediates a cytochrome P450 monooxygenase inhibitor.

背景技术 Background technique

[0002] 细胞色素P450酶的氧化代谢为药物代谢的主要机制之一,一般可通过给予细胞色素P450抑制剂维持或提高对细胞色素P450酶降解敏感的药物的血浆水平,以改善药物的药代动力学,可用于增强抗逆转录病毒药物的有效性。 [0002] oxidative metabolism by cytochrome P450 enzymes is one of the main mechanisms of drug metabolism, generally by administering a cytochrome P450 inhibitor to maintain or improve susceptible to degradation by cytochrome P450 enzymes drug plasma levels to improve the pharmacokinetic dynamics, can be used to enhance the effectiveness of antiretroviral drugs. 比如W02008010921公开了一种如式I化合物所示的细胞色素P450单加氧酶具体化合物(Cobicistat): W02008010921 discloses such a compound of formula I as cytochrome P450 monooxygenase specific compound (Cobicistat):

[0003] [0003]

Figure CN103694196AD00051

[0004] W02008010921公开的式I化合物的合成方法有多种,其中一种方法如下列路线所 [0004] There are a variety of synthetic methods disclosed in W02008010921 compound of formula I, wherein a method as the following scheme

示: It shows:

[0005] [0005]

Figure CN103694196AD00061

[0006] 该方法所用试剂昂贵,副产物较多且不易除去,反应时间长,成本高,不利于工业 [0006] This method is expensive reagents, and are more difficult to remove by-products, the reaction time is long, a high cost, is not conducive to industrial

化生产。 Production.

[0007] W02010115000对上述路线进行了改进: [0007] W02010115000 improved to said path:

[0008] [0008]

Figure CN103694196AD00062

[0009] 上述路线中第一步开环反应所用的试剂为三甲基碘硅烷,三甲基碘硅烷价格昂贵。 [0009] The first step in the ring-opening reaction scheme reagents used as trimethylsilyl iodide, trimethylsilyl iodide expensive. W02010115000报道的这步开环反应和随后的吗啡啉取代反应两步的收率也不高,仅有71%,使得仅三甲基碘硅烷一项原料成本就很高,不适合工业化生产。 W02010115000 reported yield of this step the ring-opening reaction and subsequent two-step reaction of substituted morpholine is not high, only 71%, so that only iodotrimethylsilane a raw material cost is high, is not suitable for industrial production.

[0010] 综上所述,本领域迫切需要一种低成本、高效率、适合工业化生产细胞色素P450单加氧酶抑制剂的方法。 [0010] In summary, there is an urgent need for a low cost, high efficiency, suitable for industrial production method of a cytochrome P450 monooxygenase inhibitor. 发明内容 SUMMARY

[0011] 本发明的一个目的是提供一种新型的用于制备细胞色素P450单加氧酶抑制剂的中间体化合物,及其制备方法。 [0011] An object of the present invention is to provide a novel intermediate compound for the preparation of a cytochrome P450 monooxygenase inhibitor, and its preparation method.

[0012] 本发明的另一个目的是开发一种适合工业化生产的制备细胞色素P450单加氧酶抑制剂的合成方法。 [0012] Another object of the present invention is to develop a synthetic method for preparing a cell suitable for industrial production of a cytochrome P450 monooxygenase inhibitor.

[0013] 本发明的第一方面,提供了一种式IV所示化合物; The first aspect of the [0013] present invention provides compounds of formula IV;

[0014] [0014]

Figure CN103694196AD00071

[0015] 其中,X为溴、氯或磺酸酯基; [0015] wherein, X is bromo, chloro or sulfonate group;

[0016] R为氢、取代或未取代的Cl~C8的直链、支链烷基或C3~C8环烷基、取代或未取代的C3~C20的芳烷基。 [0016] R is hydrogen, a substituted or unsubstituted Cl ~ C8 straight-chain, branched-chain alkyl group or a C3 ~ C8 cycloalkyl group, a substituted or unsubstituted C3 ~ C20 aralkyl.

[0017] 较佳地,所述的取代是具有一个或多个选自下组的取代基:卤素、苯基、Cl~C4烷基;其中所述的苯基包括未取代的苯基或具有I~3个选自羟基、Cl~C3烷基、卤素的取代基的取代苯基。 [0017] Preferably, the substitution is with one or more substituents selected from the group: halogen, phenyl, Cl ~ C4 alkyl; wherein said phenyl groups include unsubstituted phenyl or having I ~ 3 substituents selected from hydroxy, Cl ~ C3 alkyl group, a halogen-substituted phenyl group substituent.

[0018] 本发明的第二方面,提供了一种式IV所示化合物的制备方法,其特征在于,所述方法包括步骤: [0018] The second aspect of the invention, there is provided a process for preparing a compound of formula IV is shown, wherein, said method comprising the steps of:

[0019] (a)在惰性溶剂中,在卤化剂存在下,式III化合物与式ROH化合物反应,形成式IV化合物; [0019] (a) in an inert solvent, in the presence of a halogenating agent, the compound of formula III is reacted with a compound of formula ROH, to form a compound of formula IV;

[0020] [0020]

Figure CN103694196AD00072

[0021] 上述各式,X为溴或氯;而R为氢、取代或未取代的Cl~C8的直链、支链烷基或C3~C8环烷基、取代或未取代的C3~C20的芳烷基; [0021] In the above formulas, X is bromo or chloro; and R is hydrogen, a substituted or unsubstituted Cl ~ C8 straight-chain, branched-chain alkyl group or a C3 ~ C8 cycloalkyl group, a substituted or unsubstituted C3 ~ C20 aralkyl;

[0022] 较佳地,所述的取代是具有一个或多个选自下组的取代基:卤素、苯基、Cl~C4烷基;其中所述的苯基包括未取代的苯基或具有I~3个选自羟基、Cl~C3烷基、卤素的取代基的取代苯基。 [0022] Preferably, the substitution is with one or more substituents selected from the group: halogen, phenyl, Cl ~ C4 alkyl; wherein said phenyl groups include unsubstituted phenyl or having I ~ 3 substituents selected from hydroxy, Cl ~ C3 alkyl group, a halogen-substituted phenyl group substituent.

[0023] 或者所述方法包括步骤: [0023] Alternatively, the method comprises the steps of:

[0024] (b)在惰性溶剂中,式III化合物与碱MOH反应得到开环的中间体,然后该中间体与化合物RY反应得到式V化合物,式V化合物再与化合物R1-SO2Y反应,形成式IV化合物; [0024] (b) in an inert solvent, a compound of formula III with a base MOH ring opening reaction to give the intermediate, and this intermediate is reacted with RY to give a compound of formula V compound, a compound of formula V is then reacted with the compound R1-SO2Y, formed compound of formula IV;

[0025] [0025]

Figure CN103694196AD00081

[0026] 上述各式中, [0026] In the above formulas,

[0027] R为氢、取代或未取代的Cl~C8的直链、支链烷基或C3~C8环烷基、取代或未取代的C3~C20的芳烷基; [0027] R is hydrogen, a substituted or unsubstituted Cl ~ C8 straight-chain, branched-chain alkyl group or a C3 ~ C8 cycloalkyl group, a substituted or unsubstituted C3 ~ C20 aralkyl group;

[0028] 在另一优选例中,所述的取代是具有一个或多个选自下组的取代基:卤素、苯基、Cl~C4烷基;其中所述的苯基包括未取代的苯基或具有f 3个选自羟基、Cl~C3烷基、卤素的取代基的取代苯基。 [0028] In another preferred embodiment, said substitution is with one or more substituents selected from the group: halogen, phenyl, Cl ~ C4 alkyl; unsubstituted phenyl wherein said phenyl groups include f 3 group or having substituents selected from hydroxy, Cl ~ C3 alkyl group, a halogen-substituted phenyl group substituent.

[0029] X 为磺酸酯基R1-SO2O-; [0029] X is a sulfonate group R1-SO2O-;

[0030] R1为Cl~C8的直链或支链烷基或芳基;和 [0030] R1 is Cl ~ C8 straight or branched chain alkyl or aryl group;

[0031] Y为Cl 或或I; [0031] Y is Cl or or I;

[0032] M为碱金属或碱土金属,优选钠和钾。 [0032] M is an alkali metal or alkaline earth metal, preferably sodium and potassium.

[0033] 在另一优选例中,所述的R1-SO2Y包括烷基磺酰氯或芳基磺酰氯,更佳地为甲烷磺酰氯、对甲苯基磺酰氯、乙基磺酰氯、异丙基磺酰氯,或其组合。 [0033] In another preferred embodiment, the R1-SO2Y includes alkylsulfonyl chloride or arylsulfonyl chloride, more preferably methane sulfonyl chloride, p-toluenesulfonyl chloride, ethyl chloride, isopropyl sulfonamide chloride, or combinations thereof.

[0034] 在另一优选例中,在步骤(a)中,所述的惰性溶剂包括:四氢呋喃、二氯甲烷、氯仿、乙腈、二甲基甲酰胺、二甲基亚砜、2-甲基四氢呋喃、1,3-二甲基-2-咪唑烷酮、或其混合物;优选二氯甲烷。 [0034] In another preferred embodiment, in step (a), the inert solvents include: tetrahydrofuran, methylene chloride, chloroform, acetonitrile, dimethylformamide, dimethyl sulfoxide, 2-methyl tetrahydrofuran, 1,3-dimethyl-2-imidazolidinone, or mixtures thereof; preferably dichloromethane.

[0035] 在另一优选例中,在步骤(b)中,所述的惰性溶剂包括:四氢呋喃、二氯甲烷、氯仿、乙腈、二甲基甲酰胺、二甲基亚砜、2-甲基四氢呋喃、1,3-二甲基-2-咪唑烷酮、或其混合物;优选二氯甲烷。 [0035] In another preferred embodiment, in step (b), the inert solvents include: tetrahydrofuran, methylene chloride, chloroform, acetonitrile, dimethylformamide, dimethyl sulfoxide, 2-methyl tetrahydrofuran, 1,3-dimethyl-2-imidazolidinone, or mixtures thereof; preferably dichloromethane.

[0036] 在另一优选例中,所述的卤化剂为含有氯或溴的Lewis酸。 [0036] In another preferred embodiment, the halogenating agent is chlorine or bromine-containing Lewis acid.

[0037] 较佳地,所述的卤化剂选自下组:三甲基溴硅烷、三甲基氯硅烷、三乙基溴硅烷、三乙基氯硅烷、三异丙基溴硅烷、三异丙基氯硅烷、溴化氢、氯化氢,或其组合,优选三甲基溴硅烷或三甲基氯硅烷。 [0037] Preferably, the halogenating agent is selected from the group consisting of: trimethylsilyl bromide, trimethylsilyl chloride, triethylsilyl bromo silanes, triethylsilyl chloride, triisopropyl silane, triisopropyl propyl chlorosilane, hydrogen bromide, hydrogen chloride, or a combination thereof, preferably trimethylsilyl bromide or trimethylsilyl chloride.

[0038] 在另一优选例中,在步骤(a)中,式III化合物与溴化剂或者氯化剂的摩尔比为1:1 ~1:5,优选1:1 ~1:3。 [0038] In another preferred embodiment, in step (a), the molar ratio of compound of formula III with a chlorinating agent or brominating agent is from 1: 1 to 1: 5, preferably 1: 1 to 1: 3.

[0039] 在另一优选例中,其特征在于,反应温度为-5~25°C,优选O~20°C。 [0039] In another preferred embodiment, wherein the reaction temperature is -5 ~ 25 ° C, preferably O ~ 20 ° C.

[0040] 在另一优选例中,反应时间为0.1~24h。 [0040] In another preferred embodiment, the reaction time is 0.1 ~ 24h.

[0041] 本发明的第三方面,提供了一种具有如式II所示结构的化合物的制备方法,其特征在于,该方法包括以下步骤: [0041] The third aspect of the invention, there is provided a process for preparing a compound having the structure as shown in Formula II, wherein, the method comprising the steps of:

[0042] (i)在惰性溶剂中,式IV化合物与吗啡啉进行反应,形成式II化合物;[0043] [0042] (i) in an inert solvent, a compound of formula IV with morpholine, to form a compound of Formula II; [0043]

Figure CN103694196AD00091

[0044] 各式中,X为溴、氯或磺酸酯基; [0044] formulas, X is bromo, chloro or sulfonate group;

[0045] R为氢、取代或未取代的Cl~C8的直链、支链烷基或C3~C8环烷基、取代或未取代的C3~C20的芳烷基。 [0045] R is hydrogen, a substituted or unsubstituted Cl ~ C8 straight-chain, branched-chain alkyl group or a C3 ~ C8 cycloalkyl group, a substituted or unsubstituted C3 ~ C20 aralkyl.

[0046] 较佳地,所述的取代是具有一个或多个选自下组的取代基:卤素、苯基、Cl~C4烷基;其中所述的苯基包括未取代的苯基或具有I~3个选自羟基、Cl~C3烷基、卤素的取代基的取代苯基。 [0046] Preferably, the substitution is with one or more substituents selected from the group: halogen, phenyl, Cl ~ C4 alkyl; wherein said phenyl groups include unsubstituted phenyl or having I ~ 3 substituents selected from hydroxy, Cl ~ C3 alkyl group, a halogen-substituted phenyl group substituent.

[0047] 在另一优选例中,在步骤(i)之前还包括步骤:用本发明第二方面所述方法制备式IV化合物。 [0047] In another preferred embodiment, prior to step (i) further comprises the step of: preparing a compound of formula IV by the method of the second aspect of the present invention.

[0048] 在另一优选例中,将制得的式IV化合物,不经处理,直接用于步骤(i)的反应。 [0048] In another preferred embodiment, the compound of formula IV prepared, without treatment, was used directly in the reaction step (i) is.

[0049] 在另一优选例中,式IV化合物与吗啡啉的摩尔比为1:2~1:5,优选1:2.5~1:3.5。 [0049] In another preferred embodiment, the molar ratio of the compound of formula IV with a morpholine of 1: 2 to 1: 5, preferably 1: 2.5 to 1: 3.5.

[0050] 在另一优选例中,步骤⑴的反应温度为20~60°C,较佳地为20~40°C。 [0050] In another preferred embodiment, the reaction temperature in step ⑴ is 20 ~ 60 ° C, preferably of 20 ~ 40 ° C.

[0051] 在另一优选例中,反应时间为0.1~24h。 [0051] In another preferred embodiment, the reaction time is 0.1 ~ 24h.

[0052] 本发明的第四方面,提供了一种式I化合物的制备方法,其特征在于,该方法包括以下步骤: [0052] The fourth aspect of the present invention, there is provided a process for preparing a compound of Formula I, wherein, the method comprising the steps of:

[0053] (i)在惰性溶剂中,式IV化合物与吗啡啉反应,形成式II化合物; [0053] (i) in an inert solvent, a compound of Formula IV is reacted with morpholine to form a compound of Formula II;

[0054] (ϋ)在碱性条件下,式II化合物进行水解,形成式V化合物; [0054] (ϋ) under basic conditions, the hydrolysis of compound of formula II to form a compound of formula V;

[0055] (iii)将式V化合物与式VI化合物进行缩合,形成式I化合物。 [0055] (iii) The compound of formula V with a compound of formula VI is condensed to form a compound of formula I.

[0056] [0056]

Figure CN103694196AD00092

[0057] 本发明的第五方面,提供了一种如本发明第一方面所提供的化合物的用途,其特征在于,所述化合物作为中间体被用于制备式I所示的细胞色素P450单加氧酶抑制剂或式II化合物。 [0057] The fifth aspect of the present invention, there is provided the use of a compound of the first aspect of the present invention is provided, wherein the compound is shown for cytochrome P450 mono formula I as intermediates compound II or formula oxygenase inhibitor.

[0058] 应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。 [0058] It should be understood, in the range of the present invention, can be combined with each other between the technical features of the invention and in the following technical features (as described in Example) specifically described, thereby constituting a new or preferred technique Program. 限于篇幅,在 Due to space limitations, in

此不再一一累述。 This not going to be described herein.

具体实施方式 Detailed ways

[0059] 本发明人经过广泛而深入的研究,首次开发了一种具有如下式IV结构的化合物, [0059] The present inventors have conducted extensive and intensive studies, first we developed a compound having the structure of Formula IV,

及其制备方法: And preparation method thereof:

[0060] [0060]

Figure CN103694196AD00101

[0061] 其中,X为溴、氯或磺酸酯基洱为鉍、取代或未取代的Cl~C8的直链、支链烷基或C3-8环烷基、取代或未取代的C3~C20的芳烷基。 [0061] wherein, X is bromo, chloro or sulfonate group er bismuth, a substituted or unsubstituted Cl ~ C8 straight-chain, branched-chain alkyl group or C3-8 cycloalkyl group, a substituted or unsubstituted C3 ~ C20 aralkyl.

[0062] 以上述化合物作为中间体,可以低成本,高效地制得如式I化合物所示的细胞色素P450单加氧酶具体化合物(Cobicistat)。 [0062] In the above compounds as an intermediate, low cost, a compound represented by the cytochrome P450 monooxygenase specific compound (cobicistat) efficiently prepared as formula I. 在此基础上,本发明人完成了本发明。 On this basis, the present inventors have completed the present invention.

[0063] 术语 [0063] The term

[0064] 如本文所用,术语“式I化合物”、“细胞色素P450单加氧酶具体化合物”和“Cobicistat”可互换使用,均代表具有式I所示结构的化合物。 [0064] As used herein, the term "compound of Formula I", "cytochrome P450 monooxygenase specific compound" and "cobicistat" are used interchangeably to represent a compound having the structure shown in formula I.

[0065] 术语“烷基磺酰氯”指一个氯原子被烷基取代的磺酰氯。 [0065] The term "alkylsulfonyl chloride" means a chlorine atom is substituted with alkylsulfonyl chloride.

[0066] 术语“芳基磺酰氯”指一个氯原子被芳基取代的磺酰氯。 [0066] The term "arylsulfonyl chloride" means a chlorine atom substituted arylsulfonyl chloride.

[0067] 术语“含有氯或溴的Lewis酸”指是指能作为电子对接受体的原子,分子,离子或原子团,较佳地,在本发明中所用的含有氯或溴的Lewis酸为:三甲基溴硅烷、三甲基氯硅烷、三乙基溴硅烷、三乙基氯硅烷、三异丙基溴硅烷、三异丙基氯硅烷、溴化氢、氯化氢,或其组合,优选三甲基溴硅烷或三甲基氯硅烷。 [0067] The term "containing chlorine or bromine Lewis acid" refers to a means capable of a Lewis acid, electron pair of atoms, molecules, ions or radicals acceptor, preferably, in the present invention is used contains chlorine or bromine as: trimethylsilyl bromide, trimethylsilyl chloride, triethylsilyl bromo silanes, triethylsilyl chloride, triisopropyl silane, triisopropyl silane chloride, hydrogen bromide, hydrogen chloride, or combinations thereof, preferably three bromotrimethylsilane or chlorotrimethylsilane.

[0068] 术语“C1-C4烷基”指具有1-4个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。 [0068] The term "C1-C4 alkyl" refers to straight or branched chain alkyl group having 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec butyl, or the like.

[0069] 术语“C1-C8的直链、支链烷基”指具有1-8个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。 [0069] The term "C1-C8 straight-chain, branched-chain alkyl" means a straight-chain or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, , iso-butyl, sec-butyl, tert-butyl or similar groups.

[0070] 术语“C3-C8环烷基”指具有3-8个碳原子的环烷基,例如环丙烷基、甲基环丙烷基、或类似基团。 [0070] The term "C3-C8 cycloalkyl" means a cycloalkyl group having 3-8 carbon atoms, for example cyclopropyl, methylcyclopropyl group, or the like.

[0071] 术语“C3~C20的芳烷基”指具有1-8个碳原子的直链或支链芳烷基,例如苄基、苯乙基或类似基团。 [0071] The term "C3 ~ C20 aralkyl" refers to straight or branched chain aralkyl group having 1 to 8 carbon atoms, such as benzyl, phenethyl or the like.

[0072] 式IV化合物的制备 Preparation of compounds [0072] Formula IV

[0073] 式IV化合物可通过如下途径制备: [0073] The compounds of formula IV may be prepared by the following route:

[0074] [0074]

Figure CN103694196AD00111

[0075] 在有机溶剂中,式III化合物与溴化剂或氯化剂反应得到式IV化合物。 [0075] in an organic solvent, a compound of formula III is reacted with a chlorinating agent or a brominating agent to give a compound of formula IV. or

[0076] [0076]

Figure CN103694196AD00112

[0077] 在惰性溶剂中,式III化合物与碱反应得到开环的中间体,然后该中间体与RY反应得到式V化合物,式V化合物再与R1-SO2Y反应,形成式VI化合物; [0077] in an inert solvent, the reaction with a base to give a compound of Formula III intermediate ring opening, this intermediate is then reacted with RY to give a compound of formula V, a compound of formula V is then reacted with R1-SO2Y, to form a compound of formula Vl;

[0078] 原料式III化合物可通过常规方法制得,也可以通过购买得到。 [0078] The starting compounds of formula III may be prepared by conventional methods, can be obtained by purchase.

[0079] 在本发明中,溴化剂或氯化剂可为任意的含有氯或溴的Lewis酸。 [0079] In the present invention, a brominating agent or a chlorinating agent may be any of chlorine or bromine-containing Lewis acid. 优选的溴化剂或氯化剂包括但不限于:三甲基溴硅烷、三甲基氯硅烷、三乙基溴硅烷、三乙基氯硅烷、三异丙基溴硅烷、三异丙基氯硅烷、溴化氢、氯化氢,或其组合,较佳地,所述的溴化剂或氯化剂为三甲基溴硅烷、三甲基氯硅烷,或其组合。 Preferred brominating or chlorinating agents include, but are not limited to: trimethyl silane, chloro trimethyl silane, triethyl silane bromo, triethylsilyl chloride, triisopropyl silane, triisopropyl chloride silane, hydrogen bromide, hydrogen chloride, or a combination thereof, preferably the brominating or chlorinating agent is trimethylsilyl bromide, trimethylsilyl chloride, or a combination thereof.

[0080] 在另一优选例中,所述的R1-SO2Y包括烷基磺酰氯或芳基磺酰氯,更佳地为甲烷磺酰氯、对甲苯基磺酰氯、乙基磺酰氯、异丙基磺酰氯,或其组合。 [0080] In another preferred embodiment, the R1-SO2Y includes alkylsulfonyl chloride or arylsulfonyl chloride, more preferably methane sulfonyl chloride, p-toluenesulfonyl chloride, ethyl chloride, isopropyl sulfonamide chloride, or combinations thereof.

[0081] 式II化合物的制备 Preparation of compounds [0081] Formula II

[0082] 式II化合物可通过如下途径制备: Compound [0082] Formula II can be prepared by the following route:

[0083] [0083]

Figure CN103694196AD00113

[0084] 式IV化合物与吗啡啉反应,得到式II化合物。 [0084] The compound of formula IV is reacted with morpholine, to give a compound of formula II.

[0085] 原料式IV化合物可通过常规方法制得,较佳地,可通过本发明提供的方法制得。 [0085] The starting compounds of formula IV may be prepared by conventional methods, preferably, may be provided by the present invention methods.

[0086] 式I化合物的制备 Preparation of compounds [0086] Formula I

[0087] 式I化合物可通过如下途径制备: Compound [0087] Formula I may be prepared by the following route:

[0088] [0088]

Figure CN103694196AD00121

[0089] 式IV化合物与吗啡啉反应得到式II化合物,式II化合物在碱性条件下,水解得到式V化合物,再与式VI化合物缩合得到式I化合物。 [0089] The compound of formula IV is reacted with morpholine to give the compound of formula II, the compound of formula II under basic conditions, hydrolysis to give a compound of formula V, and then condensed with a compound of formula VI to give a compound of formula I.

[0090] 与现有技术相比,本发明主要具有以下优点: [0090] Compared with the prior art, the present invention has the following advantages:

[0091] 1.提供了结构新颖的用于制备式I化合物的中间体式IV化合物。 [0091] 1. The intermediate compounds of formula IV provides a novel structure for preparing a compound of formula I.

[0092] 2.本发明式IV化合物的制备方法中,开环所用的试剂为溴化剂或氯化剂,比如三甲基溴硅烷或三甲基氯硅烷,价格比现有技术的三甲基碘硅烷便宜一半以上。 Preparation Method [0092] 2. The compounds of the invention of formula IV, the ring opening agent used is a chlorinating agent or a brominating agent, such as trimethylsilyl bromide or three trimethylchlorosilane, price than the prior art iodide silane cheaper than half. 而且开环与吗啡啉取代的两步摩尔收率比现有技术提高了20%以上,生产成本低,适合工业化生产。 And ring-opening of substituted morpholine molar yield two steps higher than the prior art more than 20%, low production costs, suitable for industrial production.

[0093] 3.提供了一种新的式I化合`物的制备方法,该方法结合了新中间体及其制备方法,显著降低式I化合物的生产成本,适合工业化生产。 [0093] 3. To provide a novel method for preparing a compound of Formula I 'thereof, which incorporates a new method for preparing intermediates and significantly reduce the production cost of the compound of formula I, suitable for industrial production.

[0094] 下面结合具体实施例,进一步阐述本发明。 [0094] The following embodiments with reference to specific embodiments, further illustrate the present invention. 应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。 It should be understood that these embodiments are illustrative only and the present invention is not intended to limit the scope of the invention. 下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。 Experimental methods without specific conditions in the examples below, are performed under routine conditions, or in accordance with the conditions recommended by the manufacturer. 除非另外说明,否则百分比和份数按重量计算。 Unless otherwise indicated, percentages and parts are by weight. 本发明所用的原料或试剂,若无特别说明,均按常规方法制得或市售可得。 Used in the present invention, starting materials or reagents, unless otherwise specified, are by conventional methods or are commercially available.

[0095] 优选地,原料式II化合物、式VI化合物均可参考W02008010921制备得到。 [0095] Preferably, the compound of formula II starting material a compound of formula VI may be obtained with reference to the preparation of W02008010921.

[0096] 实施例1 (S)-4-溴-2-(3-((2-异丙基-4-噻唑基)甲基)_3_甲基脲基)-丁酸乙酯(式IV-a化合物)的制备 [0096] Example 1 (S) -4- bromo-2- (3 - ((2-isopropyl-4-thiazolyl) methyl) _3_ methyl ureido) - butyric acid ethyl ester (Formula IV preparation -a compound)

[0097] 将100g(0.336mol)化合物III,溶于500g 二氯甲烷,加入100g无水乙醇,冷却到O~10°C,滴加三甲基溴硅烷154g (1.0mol),室温反应至原料化合物III消失,TLC检测(二氯甲烷/甲醇=20/l(V/V))。 [0097] A 100g (0.336 mol) to compound III, was dissolved in 500g of methylene chloride, 100g ethanol is added, cooled to O ~ 10 ° C, was added dropwise bromotrimethylsilane 154g (1.0mol), stirred at rt until starting material compound III disappeared, TLC detection (dichloromethane / methanol = 20 / l (V / V)). 冷却到O~10°C,反应液用饱和碳酸氢钠100gX 3洗漆,分出有机层,浓缩得到化合物IV-a 120g,纯度95.1%。 Was cooled to O ~ 10 ° C, the reaction was washed with saturated sodium bicarbonate paint 100gX 3, the organic layer was separated and concentrated to give compound IV-a 120g, 95.1% purity. 摩尔收率92%。 Molar yield 92%. LC-MS:M+1=406.1 LC-MS: M + 1 = 406.1

[0098] 实施例2 (S)-4-溴-2-(3-((2-异丙基-4-噻唑基)甲基)_3_甲基脲基)-丁酸乙酯(式IV-a化合物)的制备 [0098] Example 2 (S) -4- bromo-2- (3 - ((2-isopropyl-4-thiazolyl) methyl) _3_ methyl ureido) - butyric acid ethyl ester (Formula IV preparation -a compound)

[0099] 将100g(0.336mol)化合物III,溶于500g 二氯甲烷,加入100g无水乙醇,冷却到10~20°C,滴加三乙基溴硅烷195g(l.0mol),室温反应至原料化合物III消失,TLC检测(二氯甲烷/甲醇=20/l(V/V))。 [0099] A 100g (0.336 mol) to compound III, was dissolved in 500g of methylene chloride, 100g ethanol is added, cooled to 10 ~ 20 ° C, bromine was added dropwise triethyl silane 195g (l.0mol), room temperature to III disappearance of the starting compound, TLC detection (dichloromethane / methanol = 20 / l (V / V)). 冷却到10~22°C,饱和碳酸氢钠100gX 3洗涤,分出有机层,浓缩得到化合物IV-a 112g,纯度92.2%。 Cooling to 10 ~ 22 ° C, saturated sodium bicarbonate 100gX 3, the organic layer was separated and concentrated to give compound IV-a 112g, 92.2% purity. 摩尔收率82%。 Molar yield 82%. LC-MS:M+1=406.1 LC-MS: M + 1 = 406.1

[0100] 实施例3 (S)-4-溴-2-(3-((2-异丙基-4-噻唑基)甲基)_3_甲基脲基)-丁酸甲酯(式IV-b化合物)的制备 [0100] Example 3 (S) -4- bromo-2- (3 - ((2-isopropyl-4-thiazolyl) methyl) _3_ methyl ureido) - butyric acid methyl ester (Formula IV -b preparation of compound)

[0101] 将实施例1中的乙醇换成甲醇,其他操作同实施例1,得到iv-b,纯度96.2%。 [0101] The Example 1 in ethanol replaced methanol, other operation is the same as in Example 1, to give iv-b, 96.2% purity. 摩尔收率85%。 Molar yield 85%. LC-MS:M+1=392.1 LC-MS: M + 1 = 392.1

[0102] 实施例4 (S)-4-溴-2-(3-((2-异丙基-4-噻唑基)甲基)_3_甲基脲基)-丁酸异丙酯(式IV-c化合物)的制备 [0102] Example 4 (S) -4- bromo-2- (3 - ((2-isopropyl-4-thiazolyl) methyl) _3_ methyl ureido) - butyric acid isopropyl ester (formula preparation of compound IV-c) to

[0103] 将实施例1中的乙醇换成异丙醇,其他操作同实施例1,得到化合物IV-c。 [0103] The ethanol in Example 1 into isopropanol, other operation is the same as in Example 1, to give compound IV-c. 纯度97.1%。 Purity of 97.1%. 摩尔收率83%。 Molar yield 83%. LC-MS:M+1=420.1 LC-MS: M + 1 = 420.1

[0104] 实施例5 (S)-4-溴-2-(3-((2-异丙基-4-噻唑基)甲基)_3_甲基脲基)-丁酸苄基酯(式IV-d化合物)的制备 [0104] Example 5 (S) -4- bromo-2- (3 - ((2-isopropyl-4-thiazolyl) methyl) _3_ methyl ureido) - butyric acid benzyl ester (formula preparation of compound IV-d) of

[0105] 将实施例1中的乙醇换成苄基醇,其他操作同实施例1,得到化合物IV-d,纯度92.3%。 [0105] The alcohol of Example 1 replaced by benzyl alcohol, other operation is the same as in Example 1, to give compound IV-d, 92.3% purity. 摩尔收率73%。 Molar yield 73%. LC-MS:M+1=468.1 LC-MS: M + 1 = 468.1

[0106] 实施例6 (S)-4-氯-2-(3-((2-异丙基-4-噻唑基)甲基)_3_甲基脲基)-丁酸乙酯(式IV-e化合物)的制备 [0106] Example 6 (S) -4- chloro-2- (3 - ((2-isopropyl-4-thiazolyl) methyl) _3_ methyl ureido) - butyric acid ethyl ester (Formula IV preparation -e compound)

[0107] 100g (0.336mol)化合物III,溶于500g 二氯甲烷,加入100g无水乙醇,冷却到O~10°C,滴加三甲基氯硅烷162g(l.5mol),室温反应至原料化合物III消失,TLC检测(二氯甲烷/甲醇=20/l(V/V))。 [0107] 100g (0.336mol) to compound III, was dissolved in 500g of methylene chloride, 100g ethanol is added, cooled to O ~ 10 ° C, was added dropwise trimethylsilyl chloride 162g (l.5mol), room temperature to the feedstock compound III disappeared, TLC detection (dichloromethane / methanol = 20 / l (V / V)). 冷却到O~10°C,反应液用饱和碳酸氢钠100gX 3洗漆,分出有机层,浓缩得到化合物IV-e 120g,纯度94.6%。 Was cooled to O ~ 10 ° C, the reaction was washed with saturated sodium bicarbonate paint 100gX 3, the organic layer was separated and concentrated to give compound IV-e 120g, 94.6% purity. 摩尔收率80%。 Molar yield 80%. LC-MS:M+1=362.9 LC-MS: M + 1 = 362.9

[0108] 实施例7 (S)-4-氯-2-(3-((2-异丙基-4-噻唑基)甲基)_3_甲基脲基)-丁酸甲酯(式IV-f化合物)的制备 [0108] Example 7 (S) -4- chloro-2- (3 - ((2-isopropyl-4-thiazolyl) methyl) _3_ methyl ureido) - butyric acid methyl ester (Formula IV preparation -f compound)

[0109] 将实施例6中的乙醇换成甲醇,其他操作同实施例6,得到化合物IV-f,纯度90.5%。 [0109] Example 6 in methanol was replaced by ethanol embodiments, other steps according to Example 6, to give compound IV-f, a purity of 90.5%. 摩尔收率79%。 Molar yield 79%. LC-MS:M+1=348.9 LC-MS: M + 1 = 348.9

[0110] 实施例8 (S)-4-氯-2-(3-((2-异丙基-4-噻唑基)甲基)_3_甲基脲基)-丁酸异丙酯(式IV-g化合物)的制备 [0110] Example 8 (S) -4- chloro-2- (3 - ((2-isopropyl-4-thiazolyl) methyl) _3_ methyl ureido) - butyric acid isopropyl ester (formula preparation of compound IV-g) of

[0111] 将实施例6中的乙醇换成异丙醇,其他操作同实施例6,得到化合物iv-g,纯度92.6%ο 摩尔收率83%。 [0111] Example 6 in ethanol replaced isopropanol embodiments, other steps according to Example 6 to give Compound iv-g, purity 92.6% ο 83% molar yield. LC-MSiM+1 = 376.9 LC-MSiM + 1 = 376.9

[0112] 实施例9 (S)-4-氯-2-(3-((2-异丙基-4-噻唑基)甲基)_3_甲基脲基)-丁酸节酯(式IV-h化合物)的制备 [0112] Example 9 (S) -4- chloro-2- (3 - ((2-isopropyl-4-thiazolyl) methyl) _3_ methyl ureido) - Section butyrate (Formula IV preparation -h compound)

[0113] 将实施例6中的乙醇换成苄基醇,其他操作同实施例6,得到化合物IV-h,纯度90.1%。 [0113] Example 6 in ethanol embodiment replaced benzyl alcohol, other steps according to Example 6, to give compound IV-h, 90.1% purity. 摩尔收率81%。 Molar yield 81%. LC-MS:M+1=425.0 LC-MS: M + 1 = 425.0

[0114] 实施例10 (S)-4-氯-2-(3-((2-异丙基-4-噻唑基)甲基)_3_甲基脲基)-丁酸乙酯(式IV-e化合物)的制备 [0114] Example 10 (S) -4- chloro-2- (3 - ((2-isopropyl-4-thiazolyl) methyl) _3_ methyl ureido) - butyric acid ethyl ester (Formula IV preparation -e compound)

[0115] 100g(0.336mol)化合物III,溶于500g 二氯甲烷,加入100g无水乙醇,冷却到10~20°C,分批加入三氯化铝195g(l.0mol),室温反应至原料化合物III消失,TLC检测(二氯甲烷/甲醇=20/l(V/V))。 [0115] 100g (0.336mol) to compound III, was dissolved in 500g of methylene chloride, 100g ethanol is added, cooled to 10 ~ 20 ° C, aluminum trichloride was added portionwise 195g (l.0mol), room temperature to the feedstock compound III disappeared, TLC detection (dichloromethane / methanol = 20 / l (V / V)). 冷却到10~22°C,饱和碳酸氢钠100gX 3洗涤,分出有机层,浓缩得到化合物IV-e 112g,纯度90.2%。 Cooling to 10 ~ 22 ° C, saturated sodium bicarbonate 100gX 3, the organic layer was separated and concentrated to give compound IV-e 112g, 90.2% purity. 摩尔收率79%。 Molar yield 79%. LC-MS:M+1=362.9 LC-MS: M + 1 = 362.9

[0116] 实施例11 (S)-4-甲烷磺酰氧基-2-(3-((2-异丙基-4-噻唑基)甲基)_3_甲基脲基)-丁酸苄酯(式IV-1化合物)的制备 [0116] Example 11 (S) -4- methanesulfonyloxy-2- (3 - ((2-isopropyl-4-thiazolyl) methyl) _3_ methyl ureido) - butyric acid benzyl preparation of the ester (compound of formula IV-1) is

[0117] 将100g(0.336mol)化合物III,加入38g的氢氧化钾45%乙醇溶液中,室温搅拌直到化合物III消失(TLC检测)。 [0117] A 100g (0.336mol) of Compound III, is added 38g of 45% potassium hydroxide in ethanol, stirred at room temperature until the disappearance of Compound III (TLC detection). 减压浓缩至干,加入300mLDMF和100g氯化苄,室温搅拌过夜。 And concentrated to dryness under reduced pressure, and 100g 300mLDMF benzyl chloride was added, stirred overnight at room temperature. 减压浓缩,残留物分散在300g水和300g 二氯甲烷中,分出二氯甲烷层,并用IOOmLX 3水洗涤,二氯甲烷相用无水硫酸钠干燥。 Concentrated residue was dispersed in 300g of water and 300g of methylene chloride, the methylene chloride layer was separated and washed with water IOOmLX dichloromethane phase was dried over anhydrous sodium sulfate under reduced pressure. 向溶液中投入三乙胺(0.370mol,37.3g),冷却到O~5°C,滴加甲烷磺酰氯(0.370mol,43.0g),在O~5°C下搅拌I小时,TLC检测原料消失。 Input to the solution was added triethylamine (0.370mol, 37.3g), cooled to O ~ 5 ° C, was added dropwise methanesulfonyl chloride (0.370mol, 43.0g), stirred at O ​​~ 5 ° C I h, TLC detection of feed disappear. 加入IOOmL水淬灭反应,分出二氯甲烷层,用硫酸钠干燥,旋转蒸发至干,得到化合物IV-1。 IOOmL water was added to quench the reaction, the methylene chloride layer was separated, dried over sodium sulfate, and rotary evaporated to dryness to give compound IV-1. 纯度95.1%。 Purity of 95.1%. 摩尔收率82%。 Molar yield 82%. LC-MS: M+1 =484.7[0118] 实施例12 (S)-4-对甲苯磺酰氧基-2-(3-((2-异丙基-4-噻唑基)甲基)_3_甲基脲基)-丁酸苄酯(式IV-j化合物)的制备 LC-MS: M + 1 = 484.7 [0118] Example 12 (S) -4- p-toluenesulfonyloxy-2- (3 - ((2-isopropyl-4-thiazolyl) methyl) 3 butyric acid benzyl ester (compound of formula IV-j) - a _ methylureido)

[0119] 将100g(0.336mol)化合物III,加入38g的氢氧化钾45%乙醇溶液中,室温搅拌直到化合物III消失(TLC检测)。 [0119] A 100g (0.336mol) of Compound III, is added 38g of 45% potassium hydroxide in ethanol, stirred at room temperature until the disappearance of Compound III (TLC detection). 减压浓缩至干,加入300mLDMF和100g氯化苄,室温搅拌过夜。 And concentrated to dryness under reduced pressure, and 100g 300mLDMF benzyl chloride was added, stirred overnight at room temperature. 减压浓缩,残留物分散在300g水和300g 二氯甲烷中,分出二氯甲烷层,并用IOOmLX 3水洗涤,二氯甲烷相用无水硫酸钠干燥。 Concentrated residue was dispersed in 300g of water and 300g of methylene chloride, the methylene chloride layer was separated and washed with water IOOmLX dichloromethane phase was dried over anhydrous sodium sulfate under reduced pressure. 向溶液中投入三乙胺(0.370mol,37.3g),冷却到O~5°C,加入对甲苯磺酰氯(0.370mol,70.5g),在O~5°C下搅拌I小时,TLC检测原料消失。 Input to the solution was added triethylamine (0.370mol, 37.3g), cooled to O ~ 5 ° C, was added p-toluenesulfonyl chloride (0.370mol, 70.5g), stirred for I h at O ​​~ 5 ° C, TLC detection of feed disappear. 加入IOOmL水淬灭反应,分出二氯甲烷层,用硫酸钠干燥,旋转蒸发至干,得到化合物IV-j ο 纯度94.5%。 IOOmL water was added to quench the reaction, the methylene chloride layer was separated, dried over sodium sulfate, and rotary evaporated to dryness to give compound IV-j ο ​​a purity of 94.5%. 摩尔收率84.3%。 Molar yield 84.3%. LC-MS:M+1=560.2 LC-MS: M + 1 = 560.2

[0120] 实施例13 (S)-2-(3-((2-异丙基-4-噻唑基)_甲基)_3_甲基脲基)_4_吗啡啉基丁酸乙酯(式ΙΙ-a化合物)的制备 [0120] Example 13 (S) -2- (3 - ((2- isopropyl-4-thiazolyl) _ methyl) ureido _3_ methyl) morpholine _4_ methylbutanoate (formula preparation ΙΙ-a compound)

[0121]将 IV-a(100g,0.246mol)溶于500g 二氯甲烷,滴加吗啡啉(43g,0.492mol),25 ~40°C下保温,TLC检测反应(二氯甲烷/甲醇=20/l(V/V))至化合物IV_a消失。 [0121] The IV-a (100g, 0.246mol) was dissolved in 500g of dichloromethane was added dropwise morpholine (43g, 0.492mol), at 25 ~ 40 ° C incubation, the reaction detecting TLC (dichloromethane / methanol = 20 / l (V / V)) to compound IV_a disappear. 过滤除去吗啡啉的溴化氢盐,母液用饱和碳酸氢钠洗涤,浓缩至干,得到化合物ΙΙ-a。 Morpholine was removed by filtration hydrogen bromide salt, the mother liquor was washed with saturated sodium bicarbonate, and concentrated to dryness to afford compound ΙΙ-a. 纯度为92.1%,摩尔收率78%ο LC-MSiM+1 = 413.6 Purity of 92.1%, molar yield 78% ο LC-MSiM + 1 = 413.6

[0122] 实施例14 (S)-2-(3-((2-异丙基-4-噻唑基)_甲基)_3_甲基脲基)_4_吗啡啉基丁酸乙酯(式ΙΙ-a化合物)的制备 [0122] Example 14 (S) -2- (3 - ((2- isopropyl-4-thiazolyl) _ methyl) ureido _3_ methyl) morpholine _4_ methylbutanoate (formula preparation ΙΙ-a compound)

[0123]将 IV-e(100g,0.277mol)溶于500g 二氯甲烷,滴加吗啡啉(48g,0.554mol),25 ~40°C下保温,TLC检测反应(二氯甲烷/甲醇=20/l(V/V))至化合物IV_e消失。 [0123] The IV-e (100g, 0.277mol) was dissolved in 500g of dichloromethane was added dropwise morpholine (48g, 0.554mol), at 25 ~ 40 ° C incubation, the reaction detecting TLC (dichloromethane / methanol = 20 / l (V / V)) to compound IV_e disappear. 过滤除去吗啡啉的溴化氢盐,母液用饱和碳酸氢钠洗涤,浓缩至干,得到化合物ΙΙ-a。 Morpholine was removed by filtration hydrogen bromide salt, the mother liquor was washed with saturated sodium bicarbonate, and concentrated to dryness to afford compound ΙΙ-a. 纯度为90.3%,摩尔收率74%ο LC-MSiM+1 = 413.6 Purity of 90.3%, molar yield 74% ο LC-MSiM + 1 = 413.6

[0124] 实施例15 (S)-2-(3-((2-异丙基-4-噻唑基)_甲基)_3_甲基脲基)_4_吗啡啉基丁酸乙酯(式ΙΙ-a化合物)的制备 [0124] Example 15 (S) -2- (3 - ((2- isopropyl-4-thiazolyl) _ methyl) ureido _3_ methyl) morpholine _4_ methylbutanoate (formula preparation ΙΙ-a compound)

[0125] 将100g(0.336mol)化合物III,溶于500g 二氯甲烷,加入100g无水乙醇,冷却到O~22°C,滴加TMSBr 154g (1.0mol),室温反应至原料化合物I消失。 [0125] A 100g (0.336 mol) to compound III, was dissolved in 500g of methylene chloride, 100g ethanol is added, cooled to O ~ 22 ° C, was added dropwise TMSBr 154g (1.0mol), stirred at rt until disappearance of the starting compound I. 冷却到O~22°C,滴加吗啡啉146g(l.68mol),保温20~30°C反应至化合物4消失。 Was cooled to O ~ 22 ° C, was added dropwise morpholine 146g (l.68mol), heat the reaction 20 ~ 30 ° C 4 compound to disappear. 反应液过滤,固体用适量二氯甲烷洗涤,母液用饱和碳酸氢钠100gX 3洗涤,分出有机层,浓缩得到化合物ΙΙ-a 100g,摩尔收率93%。 The reaction was filtered, the solid washed with an appropriate amount of dichloromethane, washed with saturated sodium bicarbonate mother liquor 100gX 3, the organic layer was separated and concentrated to give compound ΙΙ-a 100g, 93% molar yield. LC-MSiM+1 = 413.6 LC-MSiM + 1 = 413.6

[0126] 实施例16式I化合物的制备 Preparation of Compounds of Formula I Example 16 [0126] Embodiment

[0127] I1-a(20g)溶解于二氯甲烷中,加入50%K0H(5.5g)水溶液,控制内温不超过25°C,TLC分析ΙΙ-a消失。 [0127] I1-a (20g) was dissolved in dichloromethane, was added 50% K0H (5.5g) aqueous solution, controlling the internal temperature does not exceed 25 ° C, TLC analysis ΙΙ-a disappears. 冷却到O~10°C,加入(2R,5R)-5-氨基-1,6-二苯基-2-己基氨基甲酸5-噻唑甲基酯盐酸盐(14.8g),搅拌I~2小时,加入1-羟基苯并三氮唑(5.5g),搅拌I小时,加入1-乙基-(3- 二甲基氨基丙基)碳二亚胺盐酸盐(15g),保温5~10小时,TLC分析原料消失,反应结束。 Was cooled to O ~ 10 ° C, was added (2R, 5R) -5- amino-1,6-diphenyl-2-hexyl-5-thiazolyl-amino acid methyl ester hydrochloride (14.8g), stirred for I ~ 2 h, triazole and 1-hydroxybenzotriazole (5.5 g of), stirred for I hour, was added 1-ethyl - (3-dimethylaminopropyl) carbodiimide hydrochloride (15g), incubated for 5 ~ 10 hours, TLC analysis of the raw material disappeared, the reaction was completed. 反应液用醋酸水溶液淬灭,分出二氯甲烷层,用NaHCO3饱和水溶液洗涤,再用水洗涤,浓缩干。 The reaction was quenched with aqueous acetic acid, methylene chloride layer was separated, washed with saturated aqueous NaHCO3, washed with water, dried and concentrated. HPLC检测纯度为99.1%。 99.1% purity by HPLC. 加入无水乙醇,蒸馏除去部分乙醇得到产品化合物I在乙醇中的溶液。 Adding ethanol, the ethanol partially distilled off to obtain a solution of the product compound I in ethanol. 摩尔收率88%,LC-MS:M+1=777.1[0128] 在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。 Molar yield 88%, LC-MS: M + 1 = 777.1 [0128] are incorporated in this application in all documents mentioned herein incorporated by reference, as if each reference were individually incorporated by reference above. 此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。 Furthermore, it should be understood that, after reading the above teachings of the present invention, those skilled in the art that various changes or modifications may be made to the present invention, and these equivalents also fall within the present application as defined in the appended claims scope.

Claims (10)

1.一种式IV所示化合物; 1. A compound of the formula IV shown;
Figure CN103694196AC00021
其中,X为溴、氯或磺酸酯基; R为氢、取代或未取代的Cl~C8的直链、支链烷基或C3~C8环烷基、取代或未取代的C3~C20的芳烷基; 较佳地,所述的取代是具有一个或多个选自下组的取代基:卤素、苯基、Cl~C4烷基;其中所述的苯基包括未取代的苯基或具有1-3个选自羟基、Cl~C3烷基、卤素的取代基的取代苯基。 Wherein, X is bromo, chloro or sulfonate group; R is hydrogen, a substituted or unsubstituted Cl ~ C8 straight-chain, branched-chain alkyl group or a C3 ~ C8 cycloalkyl group, a substituted or unsubstituted C3 ~ C20 of aralkyl; preferably, the substitution is substituted with one or more groups selected from the group: halogen, phenyl, Cl ~ C4 alkyl; wherein said phenyl groups include unsubstituted phenyl group or having 1-3 substituents selected from hydroxy, Cl ~ C3 alkyl group, a halogen-substituted phenyl group substituent.
2.—种式IV所示化合物的制备方法,其特征在于,所述方法包括步骤: (a)在惰性溶剂中,在卤化剂存在下,式III化合物与式ROH化合物反应,形成式IV化合物; 2.- of formula IV as shown in the preparation of compounds, wherein said method comprising the steps of: (a) in an inert solvent, in the presence of a halogenating agent, the compound of formula III is reacted with a compound of formula ROH to form a compound of Formula IV ;
Figure CN103694196AC00022
上述各式,X为溴或氯;而R为氢、取代或未取代的Cl~C8的直链、支链烷基或C3~C8环烷基、取代或未取代的C3~C20的芳烷基; 较佳地,所述的取代是具有一个或多个选自下组的取代基:卤素、苯基、Cl~C4烷基;其中所述的苯基包括未取代的苯基或具有I~3个选自羟基、Cl~C3烷基、卤素的取代基的取代苯基; 或者所述方法包括步骤: (b)在惰性溶剂中,式III化合物与碱MOH反应得到开环的中间体,然后该中间体与化合物RY反应得到式V化合物,式V化合物再与化合物R1-SO2Y反应,形成式IV化合物; In the above formulas, X is bromo or chloro; and R is hydrogen, a substituted or unsubstituted Cl ~ C8 straight-chain, branched-chain alkyl group or a C3 ~ C8 cycloalkyl group, a substituted or unsubstituted C3 ~ C20 aralkyl group; preferably, the substitution is substituted with one or more groups selected from the group: halogen, phenyl, Cl ~ C4 alkyl; wherein said phenyl groups include unsubstituted phenyl or have I to 3 substituents selected from hydroxy, Cl ~ C3 alkyl group, a halogen-substituted phenyl group, substituted; or the method comprising the steps of: (b) in an inert solvent, a compound of formula III with a base MOH ring opening reaction to give intermediate , then the intermediate compound is reacted with RY to give a compound of formula V, a compound of formula V is then reacted with the compound R1-SO2Y, to form a compound of formula IV;
Figure CN103694196AC00023
上述各式中,R为氢、取代或未取代的Cl~C8的直链、支链烷基或C3~C8环烷基、取代或未取代的C3~C20的芳烷基; 较佳地,所述的取代是具有一个或多个选自下组的取代基:卤素、苯基、Cl~C4烷基;其中所述的苯基包括未取代的苯基或具有I~3个选自羟基、Cl~C3烷基、卤素的取代基的取代苯基; X为磺酸酯基R1-SO2O-; R1为Cl~C8的直链或支链烷基或芳基;和Y为CUr或I ; M为碱金属或碱土金属,优选钠和钾。 In the above formulas, R is hydrogen, a substituted or unsubstituted Cl ~ C8 straight-chain, branched-chain alkyl group or a C3 ~ C8 cycloalkyl group, a substituted or unsubstituted C3 ~ C20 aralkyl group; preferably, said substitution is with one or more substituents selected from the group: halogen, phenyl, Cl ~ C4 alkyl; wherein said phenyl groups include unsubstituted phenyl or an I ~ 3 substituents selected from hydroxy , Cl ~ C3 alkyl group, a halogen-substituted phenyl group, substituted; X is a sulfonate group R1-SO2O-; R1 is Cl ~ C8 straight or branched chain alkyl group or an aryl group; and Y or I CUr ; M is an alkali metal or alkaline earth metal, preferably sodium and potassium.
3.如权利要求2所述的制备方法,其特征在于,所述的卤化剂为含有氯或溴的Lewis酸。 3. The method as recited in claim 2, wherein the halogenating agent is chlorine or bromine-containing Lewis acid.
4.如权利要求2所述的制备方法,其特征在于,在步骤(a)中,式III化合物与溴化剂或者氯化剂的摩尔比为1:1~1:5,优选1:1~1:3。 4. The method as recited in claim 2, wherein, in step (a), the molar ratio of compound of formula III with a chlorinating agent or brominating agent is from 1: 1 to 1: 5, preferably 1: 1 to 1: 3.
5.如权利要求2所述的制备方法,其特征在于,反应温度为-5~25°C,优选O~20°C。 5. The method as recited in claim 2, wherein the reaction temperature is -5 ~ 25 ° C, preferably O ~ 20 ° C.
6.一种具有如式II所示结构的化合物的制备方法,其特征在于,该方法包括以下步骤: (i)在惰性溶剂中,式IV化合物与吗啡啉进行反应,形成式II化合物; A process for preparing a compound of Formula II has a structure shown, wherein, the method comprising the steps of: (i) in an inert solvent, a compound of formula IV is reacted with morpholine to form a compound of Formula II;
Figure CN103694196AC00031
各式中,X为溴、氯或磺酸酯基; R为氢、取代或未取代的Cl~C8的直链、支链烷氧基或C3~C8环烷基、取代或未取代的C3~C20的芳烷基; 较佳地,所述的取代是具有一个或多个选自下组的取代基:卤素、苯基、Cl~C4烷基;其中所述的苯基包括未取代的苯基或具有1-3个选自羟基、Cl~C3烷基、卤素的取代基的取代苯基。 Formulas, X is bromo, chloro or sulfonate group; Cl ~ C8 straight-chain, branched-chain alkyl group or a C3 ~ C8 cycloalkyl group and R is hydrogen, a substituted or unsubstituted, a substituted or unsubstituted C3 ~ C20 aralkyl group; preferably, the substitution is the group having one or more substituents selected from: halogen, phenyl, Cl ~ C4 alkyl; wherein said phenyl groups include unsubstituted or phenyl having 1-3 substituents selected from hydroxy, Cl ~ C3 alkyl group, a halogen-substituted phenyl group substituent.
7.如权利要求6所述的方法,其特征在于,式IV化合物与吗啡啉的摩尔比为1:2~1:5,优选1:2.5 ~1:3.5。 7. The method according to claim 6, wherein the molar ratio of the compound of formula IV with a morpholine of 1: 2 to 1: 5, preferably 1: 2.5 to 1: 3.5.
8.如权利要求6所述的方法,其特征在于,步骤(i)的反应温度为20~60°C,较佳地为20 ~40°C。 8. The method according to claim 6, wherein the reaction temperature of step (i) is 20 ~ 60 ° C, preferably of 20 ~ 40 ° C.
9.一种式I化合物的制备方法,其特征在于,该方法包括以下步骤: (i)在惰性溶剂中,式IV化合物与吗啡啉反应,形成式II化合物; (ϋ)在碱性条件下,式II化合物进行水解,形成式V化合物; (iii)将式V化合物与式VI化合物进行缩合,形成式I化合物。 A method for preparing a compound of formula I, wherein, the method comprising the steps of: (i) in an inert solvent, a compound of Formula IV is reacted with morpholine to form a compound of formula II; (ϋ) under basic conditions , hydrolyzing a compound of formula II to form a compound of formula V; (iii) the compound of formula V with a compound of formula VI is condensed to form a compound of formula I.
Figure CN103694196AC00041
10.一种如权利要求1所述的化合物的用途,其特征在于,所述化合物作为中间体被用于制备式I所示的细胞色素P450单加氧酶抑制剂或式II化合物。 The use claimed in claim 10. A compound of claim 1, wherein the compound is used a compound of formula I as shown in the cytochrome P450 monooxygenase of inhibitors or as intermediates of formula II.
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