TW201908321A - Preparation method of imidazoisoindole derivatives - Google Patents

Preparation method of imidazoisoindole derivatives

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TW201908321A
TW201908321A TW107124287A TW107124287A TW201908321A TW 201908321 A TW201908321 A TW 201908321A TW 107124287 A TW107124287 A TW 107124287A TW 107124287 A TW107124287 A TW 107124287A TW 201908321 A TW201908321 A TW 201908321A
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preparation
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TW107124287A
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邵啟雲
徐超
張浩宇
尤凌峰
馮君
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大陸商江蘇恆瑞醫藥股份有限公司
大陸商上海恆瑞醫藥有限公司
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Publication of TW201908321A publication Critical patent/TW201908321A/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention relates to preparation method for imidazo isoindole derivative. Specifically, the present invention relates to preparation method for imidazo isoindole derivative of formula (I), comprising the step of reacting compound of formula (II) with compound of formula (III). The yield of the preparation method is greatly improved compared with the prior art, the purity of the product is higher, is easier to conduct subsequent reaction, and the post-processing operation is reduced, and is conducive to industrial production.

Description

一種咪唑并異吲哚類衍生物的製備方法    Preparation method of imidazoisoindole derivatives   

本發明屬於醫藥領域，涉及一種咪唑并異吲哚類衍生物的製備方法。 The invention belongs to the field of medicine and relates to a method for preparing imidazoisoindole derivatives.

吲哚胺-吡咯-2,3-雙加氧酶(Indoleamine-pyrrole-2,3-dioxygenase，IDO)是一種含鐵血紅素單體蛋白，由403個胺基酸殘基組成，包括兩個折疊的α-螺旋結構域，大結構域包含催化口袋，受質可在催化口袋內與IDO發生疏水等作用。IDO是催化色胺酸轉化為甲醯犬尿胺酸的酶，廣泛分佈在人和其他哺乳動物(兔、鼠)除肝臟以外的組織中，是肝臟以外唯一可催化色胺酸分解代謝的限速酶，而色胺酸是細胞維持活化和增殖所必需的胺基酸，也是構成蛋白質不可缺少的重要成分。目前大量研究表明IDO在白血病細胞中較高表達，使局部T細胞增殖受抑制，抑制T-細胞介導的免疫反應，使T-細胞活化信號轉導受阻，從而介導腫瘤細胞逃逸免疫系統的攻擊。已經發現大多數人類腫瘤組成性地表達IDO。因此，IDO是一個具潛力的癌症免疫治療的靶標。 Indoleamine-pyrrole-2,3-dioxygenase (IDO) is a heme-containing monomeric protein consisting of 403 amino acid residues, including two The folded α-helical domain, the large domain contains a catalytic pocket, and the substrate can interact with IDO in the catalytic pocket. IDO is an enzyme that catalyzes the conversion of tryptophan to formine canine urate. It is widely distributed in humans and other mammals (rabbit and rat) in tissues other than the liver. Fast enzyme, and tryptophan is an amino acid necessary for the cell to maintain activation and proliferation, and is also an indispensable important component of protein. A large number of studies have shown that IDO is highly expressed in leukemia cells, inhibits local T cell proliferation, inhibits T-cell-mediated immune responses, blocks T-cell activation signal transduction, and thereby mediates tumor cells to escape the immune system. attack. Most human tumors have been found to constitutively express IDO. Therefore, IDO is a promising target for cancer immunotherapy.

IDO抑制劑作為藥物在醫藥行業具有良好的應用前景。WO2016169421公開了一類新的IDO抑制劑，其化合物結構如式(I)所示， IDO inhibitors have good application prospects as pharmaceuticals in the pharmaceutical industry. WO2016169421 discloses a new class of IDO inhibitors, the compound structure of which is shown in formula (I),

該類化合物顯示出了優異的IDO抑制作用。目前該類化合物的合成方法主要是由鹵苯基吡唑與哌啶基咪唑并異吲哚反應製得。該方法存在操作複雜，成本高，收率低，不易於放大生產等缺點。 These compounds show excellent IDO inhibitory effects. At present, the synthesis methods of these compounds are mainly prepared by the reaction of halophenylpyrazole and piperidylimidazoisoindole. This method has the disadvantages of complicated operation, high cost, low yield, and difficult to scale up production.

為了克服現有技術的不足，本發明的目的在於提供一種新的咪唑并異吲哚類衍生物的製備方法。 In order to overcome the shortcomings of the prior art, the object of the present invention is to provide a new method for preparing imidazoisoindole derivatives.

本發明一方面提供了如式I所示化合物的製備方法，包括將式II所示化合物與式III所示化合物反應的步驟。 One aspect of the present invention provides a method for preparing a compound represented by Formula I, comprising the steps of reacting a compound represented by Formula II with a compound represented by Formula III.

其中，R1相同或不同，且各自獨立地選自氫原子、烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥 基、氰基、環烷基、雜環基、芳基和雜芳基；R2選自-CH2-CH2-OR3，較佳為氫；R3選自氫或羥基保護基；X和Y中一個為離去基團，另一個選自-BF3K、-BRaRb、-Sn(Rc)m或-Zn-X’，其中該離去基團選自-Cl、-Br、-I、-F、三氟甲磺醯氧基、甲磺醯氧基、苯磺醯氧基、乙醯氧基或磷酸酯基、-SR，-SO2R；Ra和Rb獨立地選自-OH、烷基、烷氧基或任意取代的C1~C6一元和二元醇，或Ra和Rb在一起成環，Rc獨立地選自C1~C6烷基，X’選自-Cl、-Br、-I，R為C1~C6烷基；n為0、1、2、3或4的整數，m為0、1、2、3或4的整數。 Wherein R 1 is the same or different, and each is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amine group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, Heterocyclyl, aryl and heteroaryl; R 2 is selected from -CH 2 -CH 2 -OR 3 , preferably hydrogen; R 3 is selected from hydrogen or hydroxyl protecting group; one of X and Y is a leaving group And another is selected from -BF 3 K, -BR a R b , -Sn (R c ) m or -Zn-X ', wherein the leaving group is selected from -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy acyl group, acyl group methanesulfonamide, benzenesulfonamide acyl group, an acetyl group or a phosphate group, -SR, -SO 2 R; R a and R b are independently selected from -OH, alkoxy , alkoxy or optionally substituted C 1 ~ C 6 mono- and dihydric alcohols, or R a and R b, together form a ring, R c is independently selected from C 1 ~ C 6 alkyl group, X 'is selected from - cl, -Br, -I, R is C 1 ~ C 6 alkyl group; n is an integer of 3 or 4, m is an integer of 3 or 4.

其中所該離去基團較佳為Cl、Br、I、三氟甲磺醯氧基、甲磺醯氧基或苯磺醯氧基；在某些實施方式中，X為離去基團；在某些實施方式中，Y為離去基團。 Wherein the leaving group is preferably Cl, Br, I, trifluoromethanesulfonyloxy, methanesulfonyloxy or benzenesulfonyloxy; in some embodiments, X is a leaving group; In certain embodiments, Y is a leaving group.

在某些實施方式中，X為離去基團，Y選自BF3K和BRaRb；在某些實施方式中，Y為離去基團，X選自BF3K和BRaRb。 In certain embodiments, X is a leaving group and Y is selected from BF 3 K and BR a R b ; in certain embodiments, Y is a leaving group and X is selected from BF 3 K and BR a R b .

在某些實施方式中，該BRaRb中Ra和Rb獨立地選自-OH、烷基、烷氧基，或BRaRb為頻哪醇硼酸酯，即；在某些實施方式中，該式II所示化合物與式III所示 化合物較佳在催化劑的存在下進行偶聯反應，該催化劑可以包括PdLp、PdCl2Lp、Pd(OAe)2Lp、Pd2(dba)3Lp、Pd(II)Lp、Pd(0)、NiCl2Lp、Ni(COD)2Lp、NiCl2(NEt3)2或NiCl2(bipy)，其中L為含膦配體或N-雜環卡賓配體，該含膦配體可以是PPh3、dppf、PCy3、tBu3P、P(OMe)3、dppe或dppb，p獨立的選自0、1、2、3或4的整數。 In certain embodiments, the BR a R b wherein R a and R b are independently selected from -OH, alkyl, alkoxy, or BR a R b is a pinacol boronic ester, i.e., In some embodiments, the compound represented by Formula II and the compound represented by Formula III are preferably subjected to a coupling reaction in the presence of a catalyst, and the catalyst may include PdL p , PdCl 2 L p , Pd (OAe) 2 L p , Pd 2 (dba) 3 L p , Pd (II) L p , Pd (0), NiCl 2 L p , Ni (COD) 2 L p , NiCl 2 (NEt 3 ) 2 or NiCl 2 (bipy), Wherein L is a phosphine-containing ligand or an N-heterocyclic carbene ligand, the phosphine-containing ligand may be PPh 3 , dppf, PCy 3 , tBu 3 P, P (OMe) 3 , dppe or dppb, and p is independently selected from An integer of 0, 1, 2, 3, or 4.

例如，該催化劑可以是Pd(PPh3)2Cl2、Pd(PPh3)4、Pd(dppf)Cl2、鈀碳、Pd(OAe)2、PCy3/Pd2(dba)3、NiCl2(dppf)、NiCl2(PPh3)2、Ni{P(OMe)3}2Cl2、NiCl2(PCy3)2、NiCl2(dppe)，NiCl2(dppb)，NiCl2(NEt3)2、NiCl2(bipy)、NiCl2．6H2O、NiCl2，或Ni(COD)2，較佳為Pd(PPh3)2Cl2、Pd(PPh3)4、Pd(dppf)Cl2、鈀碳、Pd(OAc)2、PCy3/Pd2(dba)3，更佳為Pd(PPh3)2Cl2。 For example, the catalyst may be Pd (PPh 3 ) 2 Cl 2 , Pd (PPh 3 ) 4 , Pd (dppf) Cl 2 , palladium carbon, Pd (OAe) 2 , PCy 3 / Pd 2 (dba) 3 , NiCl 2 (dppf), NiCl 2 (PPh 3 ) 2 , Ni {P (OMe) 3 } 2 Cl 2 , NiCl 2 (PCy 3 ) 2 , NiCl 2 (dppe), NiCl 2 (dppb), NiCl 2 (NEt 3 ) 2 , NiCl 2 (bipy), NiCl 2 . 6H 2 O, NiCl 2 , or Ni (COD) 2 , preferably Pd (PPh 3 ) 2 Cl 2 , Pd (PPh 3 ) 4 , Pd (dppf) Cl 2 , palladium carbon, Pd (OAc) 2 , PCy 3 / Pd 2 (dba) 3 , more preferably Pd (PPh 3 ) 2 Cl 2 .

在某些實施方式中，該反應在鹼性物質存在下反應，其中鹼性物質較佳為Li2CO3、Na2CO3,Ba(OH)2、K3PO4、Cs2CO3、K2CO3、TlOH、KF、CsF、Bu4NF、LiOH、NaOH、KOH、三乙胺、DIPEA、DABCO、NaOR、KOR、TlOR中的一種或多種，其中R獨立地選自C1~C6烷基。其中NaOR、KOR或TlOR例如可以是NaOMe，NaOEt，KOtBu或TlOEt。該鹼性物質更佳為Na2CO3或K2CO3中的一種或多種。 In some embodiments, the reaction is performed in the presence of a basic substance, wherein the basic substance is preferably Li 2 CO 3 , Na 2 CO 3 , Ba (OH) 2 , K 3 PO 4 , Cs 2 CO 3 , One or more of K 2 CO 3 , TlOH, KF, CsF, Bu 4 NF, LiOH, NaOH, KOH, triethylamine, DIPEA, DABCO, NaOR, KOR, TlOR, where R is independently selected from C 1 ~ C 6 alkyl group. Wherein NaOR, KOR or TlOR may be NaOMe, NaOEt, KOtBu or TlOEt, for example. The alkaline substance is more preferably one or more of Na 2 CO 3 or K 2 CO 3 .

該反應的溶劑可以是常規溶劑，例如可以是二甲基甲醯胺、1-甲基-2-吡咯烷酮、四氫呋喃、二噁烷、甲苯、二甲亞碸、二甲基醚、異丙醇、乙醇、水中的一種或多種，較佳為二甲基甲醯胺、二甲基醚、二噁烷、水中的一種或多種。反應溫度可以是60℃~150℃。 The solvent of the reaction may be a conventional solvent, and may be, for example, dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, dioxane, toluene, dimethylmethylene, dimethyl ether, isopropyl alcohol, One or more of ethanol and water, preferably one or more of dimethylformamide, dimethyl ether, dioxane, and water. The reaction temperature may be 60 ° C to 150 ° C.

應該理解，本發明中式(I)化合物中含有手性碳原子，前述未指明構型的結構代表了任何的可能性，包括但不限於消旋體或者其中任意的異構體，當反應得到的式(I)化合物為消旋體形式時，可以進一步使用拆分等手段得到異構體形式。 It should be understood that the compound of formula (I) in the present invention contains a chiral carbon atom, and the structure of the aforementioned unspecified configuration represents any possibility, including but not limited to a racemate or any isomer thereof. When the compound of formula (I) is in the form of a racemate, it may be further obtained by means such as resolution.

在某些實施方式中，該式I化合物較佳自以下結構： 其中，R3的定義與前述相同；該式II化合物較佳自以下結構： In certain embodiments, the compound of formula I is preferably from the following structure: Among them, the definition of R 3 is the same as above; the compound of formula II preferably has the following structure:

其中，X的定義與前述相同；該式III化合物較佳自以下結構： Among them, the definition of X is the same as above; the compound of formula III preferably has the following structure:

其中，Y、R3的定義與前述相同。 The definitions of Y and R 3 are the same as those described above.

在某些實施方式中，該式I化合物較佳自以下結構： In certain embodiments, the compound of formula I is preferably from the following structure:

本發明另一方面提供了一種如式Ia所示的化合物或其藥學上可接受的鹽的製備方法，包括根據本發明所述的方法製備如式I所示化合物的步驟，該方法還包括手性拆分式I所示化合物的步驟，該手性拆分的方法較佳為化學拆分、膜拆分、色譜拆分或毛細管電泳拆分， Another aspect of the present invention provides a method for preparing a compound represented by Formula Ia or a pharmaceutically acceptable salt thereof, comprising the step of preparing a compound represented by Formula I according to the method of the present invention. For the chiral resolution of the compound represented by formula I, the method of chiral resolution is preferably chemical resolution, membrane resolution, chromatographic resolution or capillary electrophoresis resolution,

其中，R1、R2、n的定義與前述相同。 The definitions of R 1 , R 2 , and n are the same as those described above.

在某些實施方式中，式Ia所示的化合物可以是 In certain embodiments, the compound represented by Formula Ia may be

在某些實施方式中，當R3為氫或羥基保護基時，反應都可順利進行並得到目標產物。當R3為羥基保護基時，脫除保護基的過程中容易生成微量的脫羥乙基雜質，該雜質存在一定的藥理毒性，這將對化合物Ib製成藥物產生一定影響；當R3為氫時，反應過程中未檢測到脫羥乙基雜質的產生。 In certain embodiments, when R 3 is hydrogen or a hydroxy protecting group, the reaction can proceed smoothly and the target product can be obtained. When R 3 is a hydroxy protecting group, a small amount of dehydroxyethyl impurity is easily generated during the removal of the protecting group. This impurity has a certain pharmacological toxicity, which will have a certain effect on the preparation of the compound Ib as a drug; when R 3 is In the case of hydrogen, no generation of dehydroxyethyl impurities was detected during the reaction.

本發明所述的咪唑并異吲哚類衍生物的製備方法具有操作安全、簡單，使用的反應試劑更加安全，反應條件更加溫和，成本更低，適合工業化生產等特點，反應效果均優於現有技術，具有顯著的社會效益和經濟效益。其中，化合物II與化合物III偶聯反應的產率大大提高，相比現有技術產物純度更高，更易於後續反應，減少了後處理操作，也更加適合工業放大生產。 The preparation method of the imidazoisoindole derivatives of the invention has the characteristics of safe and simple operation, safer reaction reagents used, milder reaction conditions, lower cost, suitable for industrial production, and the like, and the reaction effects are better than the existing ones. Technology has significant social and economic benefits. Among them, the yield of the coupling reaction between the compound II and the compound III is greatly improved, the purity is higher than that of the prior art product, the subsequent reaction is easier, the post-processing operation is reduced, and it is more suitable for industrial scale-up production.

除非有相反陳述，在說明書和申請專利範圍中使用的術語具有下述含義。 Unless stated to the contrary, terms used in the specification and the scope of patent applications have the following meanings.

“烷基”指飽和的脂族烴基團，包括1至20個碳原子的直鏈和支鏈基團。較佳含有1至10個碳原子的烷基，例如甲基、乙基、丙基、2-丙基、正丁基、異丁基、第三丁基或戊基等。更佳的是含有1至6個碳原子的低級烷基，例如甲基、乙基、丙基、2-丙基、正丁基、異丁基或第三丁基、戊基、庚基等。烷基可以是取代的或未取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自烷氧基、鹵素、羥基、硝基、氰基、環烷基、雜環基、芳基、雜芳基、羰基。 "Alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, third butyl or pentyl, and the like are preferred. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or third butyl, pentyl, heptyl, etc. . The alkyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, hydroxyl, nitro, cyano, and cycloalkyl , Heterocyclyl, aryl, heteroaryl, carbonyl.

“芳基”指具有共軛的π電子體系的6至14員全碳單環或稠合多環(也就是共用毗鄰碳原子對的環)基團，較佳為6至10員的芳基，更佳為苯基和萘基，最佳為苯基。芳基可以是取代的或未取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、 氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基。 "Aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) group, preferably a 6 to 10 membered aryl group, having a conjugated pi-electron system , More preferably phenyl and naphthyl, and most preferably phenyl. Aryl may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Naphthene.

“雜芳基”指包含1至4個雜原子，5至14個環原子的雜芳族體系，其中雜原子包括氧、硫和氮。較佳為6至10員。雜芳基較佳為是5員或6員，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。該雜芳基環可以稠合於芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為雜芳基環。雜芳基可以是視需要取代的或未取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、硫醇、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羰基、-羧酸或羧酸酯。 "Heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms include oxygen, sulfur, and nitrogen. It is preferably 6 to 10 members. Heteroaryl is preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, carbonyl, -carboxylic acid or carboxylic acid ester.

“雜環基”指飽和或部分不飽和單環或多環環狀烴取代基，其包括3至20個環原子，其中一個或多個環原子選自氮、氧或S(O)n(其中n是整數0至2)的雜原子，但不包括-O-O-、-O-S-或-S-S-的環部分，其餘環原子為碳。較佳包括3至12個環原子，其中1~4個是雜原子，更佳環烷基環包含3至10個環原子。單環環烷基的非限制性實施例包含吡咯烷基、哌啶基、哌嗪基、嗎啉基、硫嗎啉基、高哌嗪基等。多環環烷基包括螺環、稠環和橋環的雜環基。 "Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent that includes 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O) n ( Where n is a heteroatom of the integer 0 to 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. It preferably includes 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, and more preferably the cycloalkyl ring contains 3 to 10 ring atoms. Non-limiting examples of monocyclic cycloalkyl include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic cycloalkyls include spiro, fused and bridged heterocyclic groups.

“烷氧基”指-O-(烷基)和-O-(未取代的環烷基)，其中烷基的定義如上所述。非限制性實施例包含甲氧基、乙氧基、 丙氧基、丁氧基、環丙氧基、環丁氧基、環戊氧基、環己氧基等。烷氧基可以是視需要取代的或未取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自為烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、硫醇、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羰基、羧酸或羧酸酯。“羥基”指-OH基團。 "Alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, carbonyl, carboxylic acid or carboxylic acid ester. "Hydroxy" refers to the -OH group.

“羥基保護基”是本領域已知的適當的用於羥基保護的基團，參見文獻(“Protective Groups in Organic Synthesis”，5Th Ed.T.W.Greene & P.G.M.Wuts)中的羥基保護基團。作為示例，較佳地，該羥基保護基可以是(C1-10烷基或芳基)3矽基，例如：三乙基矽基，三異丙基矽基，第三丁基二甲基矽基，第三丁基二苯基矽基等；可以是C1-10烷基或取代烷基，較佳為烷氧基或芳基取代的烷基，更佳為C1-6烷氧基取代的C1-6烷基或苯基取代的C1-6烷基，最佳為C1-4烷氧基取代的C1-4烷基，例如：甲基，第三丁基，烯丙基，苄基，甲氧基甲基(MOM)，乙氧基乙基，2-四氫吡喃基(THP)等；可以是(C1-10烷基或芳香基)醯基，例如：甲醯基，乙醯基，苯甲醯基等；可以是(C1-6烷基或C6-10芳基)磺醯基；也可以是(C1-6烷氧基或C6-10芳基氧基)羰基。 "Hydroxy protecting group" is a suitable group for protecting hydroxy groups known in the art, see the hydroxy protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & PGMWuts). As an example, preferably, the hydroxy-protecting group may be (C 1-10 alkyl or aryl) 3 silyl, for example: triethylsilyl, triisopropylsilyl, third butyldimethyl Silyl, tert-butyldiphenylsilyl, etc .; may be C 1-10 alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C 1-6 alkoxy substituted C 1-6 alkyl or phenyl substituted with C 1-6 alkyl, most preferably C 1-4 alkoxy substituted C 1-4 alkyl, for example: methyl, tert-butyl, Allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), etc .; may be (C 1-10 alkyl or aromatic) fluorenyl, For example: formamyl, ethylamyl, benzamyl and the like; it can be (C 1-6 alkyl or C 6-10 aryl) sulfonyl; it can also be (C 1-6 alkoxy or C 6-10 aryloxy) carbonyl.

“視需要”或“視需要地”意味著隨後所描述地事件或環境可以但不必發生，該說明包括該事件或環境發生或不發生地場合。例如，“視需要被烷基取代的雜環基團”意味著 烷基可以但不必須存在，該說明包括雜環基團被烷基取代的情形和雜環基團不被烷基取代的情形。 "As needed" or "as needed" means that the event or environment described later may, but need not, occur, and the description includes the place where the event or environment occurs or does not occur. For example, "heterocyclic group substituted with an alkyl group as necessary" means that the alkyl group may but need not exist, and the description includes a case where the heterocyclic group is substituted with an alkyl group and a case where the heterocyclic group is not substituted with an alkyl group .

以下將結合具體實例詳細地解釋本發明，使得本專業技術人員更全面地理解本發明具體實例僅用於說明本發明的技術方案，並不以任何方式限定本發明。 The following will explain the present invention in detail in conjunction with specific examples, so that those skilled in the art can more fully understand that the specific examples of the present invention are only used to explain the technical solution of the present invention, and do not limit the present invention in any way.

實施例1Example 1

第一步 First step

將化合物a(177g，0.495mol，根據WO2016169421公開方法製備)溶於1.5L二氯甲烷中，加入300mL 1,4-二噁烷，冰水浴冷卻下，滴加濃鹽酸(412mL，4.95mol)，升至室溫，攪拌反應2小時。反應結束後，向反應液中加入600mL水，萃取分離水相。將氫氧化鈉(215g，5.38mol)溶於215mL水中，緩慢滴入上述水相，調節至pH值8~9，水相用二氯甲烷萃取，合併有機相，無水硫酸鈉乾燥，過 濾，濾液減壓濃縮，得到粗品b 144.8g，產品不經純化直接進行下一步反應。 Compound a (177 g, 0.495 mol, prepared according to the method disclosed in WO2016169421) was dissolved in 1.5 L of dichloromethane, 300 mL of 1,4-dioxane was added, and concentrated hydrochloric acid (412 mL, 4.95 mol) was added dropwise under cooling in an ice-water bath. The temperature was raised to room temperature, and the reaction was stirred for 2 hours. After the reaction was completed, 600 mL of water was added to the reaction solution, and the aqueous phase was separated by extraction. Dissolve sodium hydroxide (215 g, 5.38 mol) in 215 mL of water, slowly drop into the above aqueous phase, adjust to pH 8-9, extract the aqueous phase with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, and filtrate Concentrated under reduced pressure to obtain 144.8 g of crude product b. The product was directly subjected to the next reaction without purification.

第二步 Second step

將粗品b(144.8g，563mmol)溶於2L乙醇中，依次加入化合物c(94.6g，844mmol)和10% Pd/C 14.5g，升溫至75℃，通空氣，攪拌反應28小時。反應結束後，過濾除去Pd/C，濾餅用甲醇淋洗，將濾液減壓濃縮，真空乾燥，得到化合物d 94.4g，產率：48%。 The crude product b (144.8 g, 563 mmol) was dissolved in 2 L of ethanol. Compound c (94.6 g, 844 mmol) and 10% Pd / C 14.5 g were added in this order. The temperature was raised to 75 ° C., and the reaction was stirred for 28 hours with air. After the reaction, Pd / C was removed by filtration, the filter cake was rinsed with methanol, and the filtrate was concentrated under reduced pressure and dried under vacuum to obtain 94.4 g of compound d, yield: 48%.

第三步 third step

將化合物d(94.4g，0.27mol)溶於1.2L二氯甲烷中。降溫至0℃，加入吡啶(106.8g，1.35mol)，再滴加Tf2O(99g，0.351mol)。升溫至室溫，攪拌反應1小時。反應結束後，反應液中加入100mL水，用1M鹽酸調節pH值至2，靜置分層，分離有機相，水相用二氯甲烷萃取，合併有機相，無水硫酸鎂乾燥，過濾，濾液減壓濃縮，所得殘餘物管柱層析(洗脫劑：DCM：MeOH=10：1)，得到化合物e 73g，產率：56.1%。 Compound d (94.4 g, 0.27 mol) was dissolved in 1.2 L of dichloromethane. The temperature was lowered to 0 ° C, pyridine (106.8 g, 1.35 mol) was added, and Tf 2 O (99 g, 0.351 mol) was added dropwise. The temperature was raised to room temperature, and the reaction was stirred for 1 hour. After the reaction, 100 mL of water was added to the reaction solution, the pH was adjusted to 2 with 1 M hydrochloric acid, and the layers were allowed to stand. The organic phase was separated. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was reduced. The solution was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography (eluent: DCM: MeOH = 10: 1) to obtain 73 g of compound e in a yield of 56.1%.

實施例2Example 2

第一步 First step

將化合物e(73g，0.15mol)和化合物f(74.1g，0.23mol，採用“Journal of Medicinal Chemistry,2012,55(18),8091-8109”製備而得)溶於1.1L 1,4-二噁烷和水(V：V=5：1)的混合溶劑中，依次加入碳酸鈉(47.7g，450mmol)和Pd(PPh3)2Cl2(15.8g，22.5mmol)，氬氣保護下升溫至回流，攪拌反應17小時。反應結束後，反應液冷卻至室溫，過濾除去催化劑固體，濾液減壓濃縮，殘餘物中加入300mL水，用二氯甲烷萃取，合併有機相，無水硫酸鎂乾燥，減壓濃縮，所得殘餘物管柱層析(洗脫劑：DCM：MeOH=50：1~20：1)，得到淺棕色固體化合物g 48g，產率：60.7%，HPLC純度88.1%。 Compound e (73 g, 0.15 mol) and compound f (74.1 g, 0.23 mol, prepared using " Journal of Medicinal Chemistry , 2012, 55 (18), 8091-8109") were dissolved in 1.1 L of 1,4-di To a mixed solvent of oxane and water (V: V = 5: 1), sodium carbonate (47.7 g, 450 mmol) and Pd (PPh 3 ) 2 Cl 2 (15.8 g, 22.5 mmol) were sequentially added, and the temperature was raised under the protection of argon. To reflux, the reaction was stirred for 17 hours. After the reaction, the reaction solution was cooled to room temperature, the catalyst solid was removed by filtration, and the filtrate was concentrated under reduced pressure. 300 mL of water was added to the residue, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Column chromatography (eluent: DCM: MeOH = 50: 1-20: 1), 48 g of light brown solid compound g was obtained, yield: 60.7%, HPLC purity 88.1%.

第二步 Second step

將化合物g(36g，68.27mmol)溶於400mL甲醇，加入濃鹽酸(12mL，136.55mmol)，升溫至40℃，攪拌反應2小時。反應液減壓濃縮，加入二氯甲烷200mL，加入150mL飽和碳酸鉀溶液，攪拌，過濾，濾餅用少量二氯甲烷淋洗，正己烷淋洗，收集濾餅真空乾燥，得到淺棕色固體化合物h 20.8g，產率：69%，HPLC純度92%。 Compound g (36 g, 68.27 mmol) was dissolved in 400 mL of methanol, concentrated hydrochloric acid (12 mL, 136.55 mmol) was added, the temperature was raised to 40 ° C, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, 200 mL of dichloromethane was added, 150 mL of saturated potassium carbonate solution was added, stirred, filtered, the filter cake was rinsed with a small amount of dichloromethane, and n-hexane was collected. The filter cake was collected and dried under vacuum to obtain a light brown solid compound h 20.8 g, yield: 69%, HPLC purity 92%.

實施例3Example 3

將化合物e(73g，152mmol)和化合物i(72.2g，304 mmol，按照CN105189461A公開的方法製備)溶於1500mL 1,4-二噁烷和水(V：V=5：1)的混合溶劑中，依次加入碳酸鈉(48.3g，456mmol)和Pd(dppf)Cl2(11.1g，15.2mmol)，氬氣保護下升溫至回流，攪拌反應3小時。反應結束後，反應液冷卻至室溫，加入400mL水，室溫攪拌30min，過濾，濾餅用水淋洗，收集濾餅，用1.2L甲醇分散，加入濃鹽酸(40mL)，攪拌30min，濃縮除去甲醇，加入2L水，攪拌30min，過濾，固體用水淋洗，合併水相，用乙酸乙酯反萃(600mL×2)，收集水相，用飽和NaHCO3溶液調pH至鹼性，析出固體，過濾得固體，水洗，真空乾燥，得化合物h 41.8g，產率62%，化學純度：94.4%。 Compound e (73 g, 152 mmol) and compound i (72.2 g, 304 mmol, prepared according to the method disclosed in CN105189461A) were dissolved in 1500 mL of a mixed solvent of 1,4-dioxane and water (V: V = 5: 1) Then, sodium carbonate (48.3 g, 456 mmol) and Pd (dppf) Cl 2 (11.1 g, 15.2 mmol) were added in this order, the temperature was raised to reflux under argon protection, and the reaction was stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 400 mL of water was added, and the mixture was stirred at room temperature for 30 min, filtered, and the filter cake was rinsed with water. The filter cake was collected, dispersed with 1.2 L of methanol, concentrated hydrochloric acid (40 mL) was added, stirred for 30 min, and concentrated to remove Methanol was added to 2 L of water, stirred for 30 min, filtered, and the solids were rinsed with water. The aqueous phases were combined, back-extracted with ethyl acetate (600 mL x 2), and the aqueous phase was collected. The pH was adjusted to alkaline with a saturated NaHCO 3 solution, and the solid was precipitated. The solid obtained by filtration was washed with water and dried under vacuum to obtain 41.8 g of compound h with a yield of 62% and a chemical purity of 94.4%.

實施例4Example 4

將化合物h 11.59g進行手性製備(分離條件：手性製備管柱Superchiral S-AS(Chiralway),2cm I.D.*25cm Length,5um；流動相：CO2/MeOH/DEA=60/40/0.05(v/v)，流速：50mL/min)，收集目標群組分，減壓濃縮，得到化合物Ib 4.49g，光學純度：99.6%。 Chiral preparation of 11.59 g of compound h (separation conditions: chiral preparation column Superchiral S-AS (Chiralway), 2cm ID * 25cm Length, 5um; mobile phase: CO2 / MeOH / DEA = 60/40 / 0.05 (v / v), flow rate: 50 mL / min), the target group fractions were collected and concentrated under reduced pressure to obtain 4.49 g of compound Ib, optical purity: 99.6%.

由於已根據其特殊的實施方案描述了本發明，某些修飾和均等變化對於精通此領域的技術人員是顯而易見的且包括在本發明的範圍內。 Since the invention has been described in terms of its specific embodiments, certain modifications and equivalent variations will be apparent to those skilled in the art and are included within the scope of the invention.

Claims (21)

一種如式I所示化合物的製備方法，包括將式II所示化合物與式III所示化合物反應的步驟， 其中，R 1相同或不同，且各自獨立地選自氫原子、烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、環烷基、雜環基、芳基和雜芳基；R 2選自-CH 2-CH 2-OR 3；R 3選自氫或羥基保護基；X和Y中一個為離去基團，另一個選自-BF 3K、-BR aR b、-Sn(R c) m或-Zn-X’，其中該離去基團選自-Cl、-Br、-I、-F、三氟甲磺醯氧基、甲磺醯氧基、苯磺醯氧基、乙醯氧基或磷酸酯基、-SR，-SO 2R；R a和R b獨立地選自-OH、烷基、烷氧基或任意取代的C 1~C 6一元和二元醇，或R a和R b在一起成環，R c獨立地選自C 1~C 6烷基，X’選自-Cl、-Br、-I，R為C 1~C 6烷基；n為0、1、2、3或4的整數，m為0、1、2、3或 4的整數。 A method for preparing a compound represented by formula I, comprising the steps of reacting a compound represented by formula II with a compound represented by formula III, Wherein R 1 is the same or different, and each is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amine group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, Heterocyclyl, aryl and heteroaryl; R 2 is selected from -CH 2 -CH 2 -OR 3 ; R 3 is selected from hydrogen or hydroxy protecting group; one of X and Y is a leaving group and the other is selected from -BF 3 K, -BR a R b , -Sn (R c ) m or -Zn-X ', wherein the leaving group is selected from -Cl, -Br, -I, -F, trifluoromethanesulfonium group, acyl group methanesulfonamide, benzenesulfonamide acyl group, an acetyl group or a phosphate group, -SR, -SO 2 R; R a and R b are independently selected from -OH, alkyl, alkoxy, or optionally substituted C 1 ~ C 6 mono- and dihydric alcohols, or R a and R b, together form a ring, R c is independently selected from C 1 ~ C 6 alkyl group, X 'is selected from -Cl, -Br, -I, R is a C 1 to C 6 alkyl group; n is an integer of 0, 1, 2, 3, or 4, and m is an integer of 0, 1, 2, 3, or 4. 如申請專利範圍第1項所述的製備方法，其中，R 3為氫。 The preparation method according to item 1 of the scope of patent application, wherein R 3 is hydrogen. 如申請專利範圍第1項所述的製備方法，其中，該反應在催化劑的存在下進行，其中L為含膦配體或N-雜環卡賓配體，p獨立的選自0、1、2、3或4的整數。     The preparation method according to item 1 of the scope of patent application, wherein the reaction is performed in the presence of a catalyst, wherein L is a phosphine-containing ligand or an N-heterocyclic carbene ligand, and p is independently selected from 0, 1, 2 An integer of 3, 4 or 4.     如申請專利範圍第3項所述的製備方法，其中，該催化劑選自PdL p、PdCl 2L p、Pd(OAc) 2L p、Pd 2(dba) 3L p、Pd(II)L p、Pd(0)、NiCl 2L p、Ni(COD) 2L p、NiCl 2(NEt 3) 2或NiCl 2(bipy)。 The preparation method according to item 3 of the scope of patent application, wherein the catalyst is selected from the group consisting of PdL p , PdCl 2 L p , Pd (OAc) 2 L p , Pd 2 (dba) 3 L p , Pd (II) L p , Pd (0), NiCl 2 L p , Ni (COD) 2 L p , NiCl 2 (NEt 3 ) 2 or NiCl 2 (bipy). 如申請專利範圍第3項所述的製備方法，其中，該含膦配體選自PPh 3、dppf、PCy 3、tBu 3P、P(OMe) 3、dppe或dppb。 The preparation method according to item 3 of the scope of patent application, wherein the phosphine-containing ligand is selected from PPh 3 , dppf, PCy 3 , tBu 3 P, P (OMe) 3 , dppe, or dppb. 如申請專利範圍第4項所述的製備方法，其中，該催化劑選自Pd(PPh 3) 2Cl 2、Pd(PPh 3) 4、Pd(dppf)Cl 2、鈀碳、Pd(OAc) 2、PCy 3/Pd 2(dba) 3。 The preparation method according to item 4 of the scope of patent application, wherein the catalyst is selected from the group consisting of Pd (PPh 3 ) 2 Cl 2 , Pd (PPh 3 ) 4 , Pd (dppf) Cl 2 , palladium carbon, and Pd (OAc) 2 , PCy 3 / Pd 2 (dba) 3 . 如申請專利範圍第6項所述的製備方法，其中，該催化劑為Pd(PPh 3) 2Cl 2。 The preparation method according to item 6 of the patent application scope, wherein the catalyst is Pd (PPh 3 ) 2 Cl 2 . 如申請專利範圍第1項所述的製備方法，其中，該反應在鹼性物質存在下進行反應。     The preparation method according to item 1 of the scope of patent application, wherein the reaction is carried out in the presence of a basic substance.     如申請專利範圍第8項所述的製備方法，其中，該鹼性物質選自Li 2CO 3、Na 2CO 3、Ba(OH) 2、K 3PO 4、Cs 2CO 3、K 2CO 3、TlOH、KF、CsF、Bu 4NF、LiOH、NaOH、KOH、 三乙胺、DIPEA、DABCO、NaOR、KOR、TlOR中的一種或多種，其中R獨立地選自C 1~C 6烷基。 The preparation method according to item 8 of the scope of patent application, wherein the basic substance is selected from the group consisting of Li 2 CO 3 , Na 2 CO 3 , Ba (OH) 2 , K 3 PO 4 , Cs 2 CO 3 , and K 2 CO 3 , one or more of TlOH, KF, CsF, Bu 4 NF, LiOH, NaOH, KOH, triethylamine, DIPEA, DABCO, NaOR, KOR, TlOR, wherein R is independently selected from C 1 ~ C 6 alkyl . 如申請專利範圍第9項所述的製備方法，其中，該鹼性物質選自Na 2CO 3或K 2CO 3中的一種或多種。 The preparation method according to item 9 of the scope of the patent application, wherein the basic substance is selected from one or more of Na 2 CO 3 or K 2 CO 3 . 如申請專利範圍第1項所述的製備方法，其中，該反應的溶劑為二甲基甲醯胺、1-甲基-2-吡咯烷酮、四氫呋喃、二噁烷、甲苯、二甲亞碸、二甲基醚、異丙醇、乙醇、水中的一種或多種。     The preparation method according to item 1 of the scope of the patent application, wherein the solvent of the reaction is dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, dioxane, toluene, dimethylmethylene, diamine One or more of methyl ether, isopropyl alcohol, ethanol, and water.     如申請專利範圍第11項所述的製備方法，其中該溶劑選自二甲基甲醯胺、二甲基醚、二噁烷、水中的一種或多種。     The preparation method according to item 11 of the application, wherein the solvent is one or more selected from the group consisting of dimethylformamide, dimethyl ether, dioxane, and water.     如申請專利範圍第1項所述的製備方法，其中，X為離去基團，Y選自-BF 3K或-BR aR b，其中，該R a和R b獨立地選自-OH、烷基、烷氧基。 The preparation method according to item 1 of the application, wherein X is a leaving group and Y is selected from -BF 3 K or -BR a R b , wherein R a and R b are independently selected from -OH , Alkyl, alkoxy. 如申請專利範圍第13項所述的製備方法，其中，該離去基團選自-Cl、-Br、-I、三氟甲磺醯氧基、甲磺醯氧基、苯磺醯氧基。     The preparation method according to item 13 of the scope of patent application, wherein the leaving group is selected from the group consisting of -Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy, and benzenesulfonyloxy .     如申請專利範圍第13項所述的製備方法，其中，該BR aR b為頻哪醇硼酸酯。 The preparation method according to item 13 of the patent application scope, wherein the BR a R b is a pinacol borate. 如申請專利範圍第1項所述的製備方法，其中，該式I化合物為 The preparation method according to item 1 of the scope of patent application, wherein the compound of formula I is 如申請專利範圍第1項所述的製備方法，其中，該式II化合物為 The preparation method according to item 1 of the scope of patent application, wherein the compound of formula II is 一種如式Ia所示的化合物或其藥學上可接受的鹽的製備方法，包括如申請專利範圍第1至17項中任一項的方法製備如式I所示化合物的步驟，該方法還包括手性拆分式I所示化合物的步驟， 其中，R 1、R 2、n的定義如申請專利範圍第1項所述。 A method for preparing a compound represented by Formula Ia or a pharmaceutically acceptable salt thereof, comprising the steps of preparing a compound represented by Formula I as a method according to any one of claims 1 to 17, which method further comprises Steps for chiral resolution of a compound of formula I, The definitions of R 1 , R 2 , and n are as described in item 1 of the scope of patent application. 如申請專利範圍第18項所述的製備方法，其中，該手性拆分的方法為化學拆分、膜拆分、色譜拆分或毛細管電泳拆分。     The preparation method according to item 18 of the scope of application for a patent, wherein the method of chiral resolution is chemical resolution, membrane resolution, chromatographic resolution, or capillary electrophoresis resolution.     如申請專利範圍第18項所述的製備方法，其中，該式Ia化合物為 The preparation method according to item 18 of the scope of patent application, wherein the compound of formula Ia is 如申請專利範圍第1至15項中任一項所述的製備方法， 其中，該式I化合物為 The preparation method according to any one of claims 1 to 15, wherein the compound of formula I is
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