TW201910336A - Preparation method of imidazoisoindole derivatives - Google Patents

Preparation method of imidazoisoindole derivatives Download PDF

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TW201910336A
TW201910336A TW107127443A TW107127443A TW201910336A TW 201910336 A TW201910336 A TW 201910336A TW 107127443 A TW107127443 A TW 107127443A TW 107127443 A TW107127443 A TW 107127443A TW 201910336 A TW201910336 A TW 201910336A
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黃建
尤凌峰
姜威
羅揚
王軍政
馮君
賀峰
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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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    • 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
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    • 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

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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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 resolving compound of formula (II) to obtain high optical purity compound of formula (III). Then reacting compound of formula (III) as raw material to obtain the final product. The final product has high optical purity, low cost, more economical and more suitable for 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，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，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. A large number of studies have shown that IDO is highly expressed in leukemia cells. Suppresses local T cell proliferation, suppresses T-cell-mediated immune response, blocks T-cell activation signal transduction, and thereby mediates tumor cells to escape the attack of the immune system. 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公開了一種新的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 IDO inhibitor, the compound structure of which is shown in formula (I),

該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，然後經過手性解析製得。 This compound showed excellent IDO inhibitory effect. At present, the synthesis method of these compounds is mainly obtained by the reaction of halophenylpyrazole with piperidylimidazoisoindole, and then by chiral analysis.

在製備過程中我們發現，最後一步的手性解析產率很低，特別是採用手性管柱解析時，由於消旋體和產品在洗脫劑中溶解度不高，在製備過程中容易析出造成手性管柱堵塞，嚴重影響解析效率。 During the preparation process, we found that the yield of the chiral analysis in the last step is very low, especially when the chiral column analysis is used, because the racemate and the product are not highly soluble in the eluent, it is easy to precipitate during the preparation process. The chiral tubing is blocked, which seriously affects the analysis efficiency.

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新的反應中間體，如式III所示化合物， 式IV所示化合物， One aspect of the present invention provides a novel reaction intermediate, such as a compound represented by Formula III, A compound represented by formula IV,

其中，X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，R為C1~C6烷基；較佳為-Cl、-Br、-I、三氟甲磺醯氧基、甲磺醯氧基或苯磺醯氧基。 Wherein X is selected from the group consisting of -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, ethoxyl or phosphate, -SR,- SO 2 R, R is a C 1 to C 6 alkyl group; preferably -Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy or benzenesulfonyloxy.

式VII所示化合物， A compound represented by formula VII,

其中，R2選自羥基保護基；以及式d所示化合物， Wherein R2 is selected from a hydroxyl protecting group; and a compound represented by formula d,

本發明另一方面提供了如式III所示的化合物的製備方法，包括手性解析式II所示化合物的步驟， Another aspect of the present invention provides a method for preparing a compound represented by Formula III, including a step of chiral analysis of a compound represented by Formula II,

該手性解析的方法可以是化學解析、膜解析、色譜解析、毛細管電泳解析及生物解析等。 Methods for this chiral analysis can be chemical analysis, membrane analysis, chromatographic analysis, capillary electrophoresis analysis, and biological analysis.

在某些實施方式中，該手性解析的方法為色譜解析。 In some embodiments, the method of chiral analysis is chromatographic analysis.

在某些實施方式中，該手性解析的方法為化學解析。使用的解析劑可以是有機酸等，例如L-酒石酸、D-酒石酸、二苯甲醯-L-酒石酸(L-DBTA)、二苯甲醯-D-酒石酸(D-DBTA)、 二對甲苯甲醯-L-酒石酸(L-DTTA)或二對甲苯甲醯-D-酒石酸(D-DTTA)、R-樟腦磺酸、S-樟腦磺酸、D-扁桃酸、L-扁桃酸、L-谷胺酸、D-谷胺酸、L-天門冬胺酸、D-天門冬胺酸等，較佳為L-DTTA、D-DTTA、L-谷胺酸、D-谷胺酸、L-天門冬胺酸、D-天門冬胺酸，更佳為D-DTTA。 In some embodiments, the method of chiral resolution is chemical resolution. The resolving agent used may be an organic acid and the like, such as L-tartaric acid, D-tartaric acid, benzophenone-L-tartaric acid (L-DBTA), benzophenone-D-tartaric acid (D-DBTA), xylene Formamidine-L-tartaric acid (L-DTTA) or dimethyl p-toluene-D-tartaric acid (D-DTTA), R-camphorsulfonic acid, S-camphorsulfonic acid, D-mandelic acid, L-mandelic acid, L -Glutamic acid, D-glutamic acid, L-aspartic acid, D-aspartic acid, etc., preferably L-DTTA, D-DTTA, L-glutamic acid, D-glutamic acid, L -Aspartic acid, D-aspartic acid, more preferably D-DTTA.

該解析劑與式II所示化合物的莫耳比可以是1：1~4：1。 The molar ratio of the resolving agent to the compound represented by Formula II may be 1: 1 to 4: 1.

解析劑解析式II所示的化合物的過程可以在一般的溶劑中進行，較佳的溶劑包括水或親水性有機溶劑(例如C1~C6醇類，例如甲醇和乙醇；酮類，例如丙酮和甲基乙基酮；醚類，例如四氫呋喃和二噁烷；乙腈；N,N-二甲基甲醯胺；及N,N-二甲亞碸)；或其混合溶劑，更佳為甲醇或乙醇。 The process of resolving the compound represented by Formula II by a resolving agent can be performed in a general solvent. Preferred solvents include water or hydrophilic organic solvents (such as C 1 to C 6 alcohols such as methanol and ethanol; ketones such as acetone). And methyl ethyl ketone; ethers, such as tetrahydrofuran and dioxane; acetonitrile; N, N-dimethylformamide; and N, N-dimethylmethane); or a mixed solvent thereof, more preferably methanol Or ethanol.

游離中間體解析鹽的過程是一般的，可使用鹼來游離，游離所用的鹼較佳為鹼金屬的氫氧化物水溶液，較佳為氫氧化鈉水溶液；溶劑可以是一般的溶劑，例如二氯甲烷、四氫呋喃、氯仿等。 The process of analysing the salt of the free intermediate is general. A base can be used for the free. The base used for the free is preferably an aqueous solution of an alkali metal hydroxide, preferably an aqueous solution of sodium hydroxide; the solvent can be a common solvent, such as dichloride. Methane, tetrahydrofuran, chloroform, etc.

為了提高解析所得到的化合物III的光學純度，可以對解析所得到的中間體解析鹽進行再結晶。本發明中解析成鹽的過程一般可以在常溫下進行，必要時也可以在加熱的條件下進行，而再結晶的步驟一般可以在加熱的條件下進行，先加熱使解析鹽在該溶劑中溶解，然後在室溫條件下緩慢地完成再結晶的過程。 In order to improve the optical purity of the compound III obtained by the analysis, the intermediate analytical salt obtained by the analysis may be recrystallized. The process of resolving into salts in the present invention can generally be carried out at normal temperature, if necessary, under heating conditions, and the recrystallization step can generally be carried out under heating conditions, first heating to dissolve the resolved salts in the solvent , And then slowly complete the recrystallization process at room temperature.

本方面還提供了一種如式I所示化合物或其藥學上可接受的鹽的製備方法，包括根據本發明的方法製備如式III 所示的化合物的步驟。 This aspect also provides a method for preparing a compound represented by Formula I or a pharmaceutically acceptable salt thereof, comprising a step of preparing a compound represented by Formula III according to the method of the present invention.

進一步地，本發明所述的如式I所示的化合物或其藥學上可接受的鹽的製備方法還包括以式III所示化合物為反應物製備得到式IV所示化合物的步驟。 Further, the method for preparing the compound represented by Formula I or a pharmaceutically acceptable salt thereof according to the present invention further includes a step of preparing a compound represented by Formula IV by using the compound represented by Formula III as a reactant.

其中，X為離去基團，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，R為C1~C6烷基；X較佳為-Cl、-Br、-I、三氟甲磺醯氧基、甲磺醯氧基或苯磺醯氧基。 Wherein X is a leaving group selected from -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, acetamyloxy or phosphate , -SR, -SO 2 R, R is C 1 ~ C 6 alkyl; X is preferably -Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy or benzenesulfonyl Oxygen.

該方法可以是一步反應(例如Buckwald偶聯)，也可以是多步反應(例如先與環己二酮反應生成哌啶基苯酚中間體，再合成化合物IV)。 This method can be a one-step reaction (such as Buckwald coupling) or a multi-step reaction (such as first reacting with cyclohexanedione to form a piperidinylphenol intermediate and then synthesizing compound IV).

進一步地，該方法還包括將式IV所示化合物與式V所示化合物在催化劑存在的條件下進行偶聯反應製備式VI所示化合物的步驟。 Further, the method further includes the step of preparing a compound represented by formula VI by subjecting a compound represented by formula IV to a compound represented by formula V to a coupling reaction in the presence of a catalyst.

其中，Y選自-BF3K、-BRaRb、-Sn(Rc)m或-Zn-X’；Ra和Rb獨立地選自-OH、烷基、烷氧基或視需要經取代的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；m為0、1、2、3或4的整數；R1選自氫或羥基保護基。 Wherein, Y is selected -BF 3 K, -BR a R b , -Sn (R c) m or -Zn-X '; R a and R b are independently selected from -OH, alkyl, alkoxy or optionally requires 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; m is an integer of 0, 1, 2, 3 or 4; R 1 is selected from hydrogen or a hydroxy protecting group.

在某些較佳的實施方式中，Y選自BF3K和BRaRb，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，即該催化劑可以包括PdLp、PdCl2Lp、Pd(OAc)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-雜環碳烯配體，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 preferred embodiments, Y is selected from BF 3 K and BR a R b , wherein R a and R b in BR a R b are independently selected from -OH, alkyl, alkoxy, or BR a R b is a pinacol borate, ie The catalyst may include 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), where L is a phosphine-containing ligand or an N-heterocyclic carbene ligand, and the phosphine-containing ligand may be PPh 3 , dppf, PCy 3 , tBu 3 P, P (OMe) 3 , dppe or dppb, p is an integer independently selected from 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(OAc)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 (OAc) 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一般溶劑，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 used in this reaction may be a general 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.

在某些實施方式中，R1為羥基保護基，該方法還包括將式VI所示化合物脫保護製備得到式I所示化合物的步驟。 In some embodiments, R 1 is a hydroxy protecting group, and the method further includes a step of deprotecting the compound represented by Formula VI to obtain a compound represented by Formula I.

本發明通過解析化合物II得到高光學純度的化合物III再進行反應，得到的後續產物始終保持高的光學純度，後期的偶聯反應中產物並未消旋，得到的終產品光學純度高，避免了最後手性製備堵管柱的問題，工藝穩定易再現。另外，在化合物II處解析成本低，更經濟，也更加適合工業化生產。 In the present invention, compound III is obtained by analyzing compound II to obtain compound III with high optical purity and then reacted. The subsequent products obtained always maintain high optical purity. The product is not racemic in the subsequent coupling reaction, and the final product has high optical purity, which avoids Finally, the problem of chilled pipe string preparation is stable and easy to reproduce. In addition, the analysis at Compound II is low in cost, more economical, and more suitable for industrial production.

在解析化合物II時，使用色譜解析和化學解析均能有效的分離出化合物III。當使用解析劑解析時，反應迅速，後處理簡便，副產品可回收再利用，得到的化合物III光學純度高，非常適合工業放大生產。 When analyzing compound II, both chromatographic and chemical analysis can effectively isolate compound III. When using a resolving agent for analysis, the reaction is fast, the post-treatment is simple, the by-products can be recycled and reused, and the obtained compound III has high optical purity, which is very 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, the terms used in the specification and the scope of the patent application 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。較佳為含有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。更較佳為的是含有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 are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, third butyl, or pentyl, and the like. 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 Base 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, hydroxy, nitro, cyano, and cycloalkane Group, 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(也就是共享毗鄰碳原子對的環)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 sharing 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, Alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, 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。較佳為包括3至12個環原子，其中1至4個是雜原子，更佳為環烷基環包含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 hydroxyl 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1     Example 1    

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，得到化合物II 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 compound II. The product was directly subjected to the next reaction without purification.

實施例2     Example 2    

將化合物II 128.6g進行手性製備(分離條件：手性製備管柱Superchiral S-AY(Chiralway),2cm I.D.*25cm Length,5um；流動相：CO2/EtOH/DEA=60/40/0.05(v/v/v)，流速：50g/min)，收集目標組分，過程中製備管柱無堵塞情況發生，減壓濃縮，得到化合物III 63.6g，光學純度：99.4%，化學純度：99.2%。 Chiral preparation of 128.6 g of compound II (isolation conditions: chiral preparation column Superchiral S-AY (Chiralway), 2cm ID * 25cm Length, 5um; mobile phase: CO 2 /EtOH/DEA=60/40/0.05 ( v / v / v), flow rate: 50g / min), collect the target components, no clogging occurred during the preparation of the column, and concentrated under reduced pressure to obtain 63.6g of compound III, optical purity: 99.4%, chemical purity: 99.2% .

實施例3     Example 3    

在25-30℃下，將化合物II(35.1g)溶於乙醇600mL中，加入D-DTTA 142g的乙醇溶液600ml，在25-30℃攪拌16小時，出現大量淺黃色固體，過濾，將濾餅加入乙醇600mL中，加熱回流後降溫至25-30℃，過濾，濾餅烘乾得到51.5g白色固體，將固體加入二氯甲烷750mL和水500mL，攪拌下用2N的氫氧化鈉溶液調節pH值至10-11。分液，水層用二氯甲烷(400mL*3)萃取。合併有機相，無水硫酸鈉乾燥，過濾，旋蒸除去溶劑得到淺黃色固體化合物III 12.85g，光學純度：99.2%，化學純度：99.5%，收率為36.6%，有效異構體收率73.2%。 Dissolve Compound II (35.1g) in 600mL of ethanol at 25-30 ° C, add 600ml of 142g of D-DTTA in ethanol, and stir at 25-30 ° C for 16 hours. A large amount of light yellow solid appears. Filter and filter cake. Add 600 mL of ethanol, heat to reflux and lower the temperature to 25-30 ° C, filter, and dry the filter cake to obtain 51.5 g of a white solid. Add the solid to 750 mL of dichloromethane and 500 mL of water, and adjust the pH with 2N sodium hydroxide solution while stirring To 10-11. The layers were separated, and the aqueous layer was extracted with dichloromethane (400 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain 12.85 g of pale yellow solid compound III, optical purity: 99.2%, chemical purity: 99.5%, yield of 36.6%, and effective isomer yield of 73.2%. .

實施例4     Example 4    

第一步     First step    

將化合物III(75g，292mmol)溶於2L乙醇中，依次加入化合物c(49.1g，438mmol)和10% Pd/C 7.5g，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 54.1g，產率：53%。 Compound III (75 g, 292 mmol) was dissolved in 2 L of ethanol, compound c (49.1 g, 438 mmol) and 10% Pd / C 7.5 g were sequentially added, 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 54.1 g of compound d, yield: 53%.

第二步     Second step    

將化合物d(54.1g，0.155mol)溶於700mL二氯甲烷中。降溫至0℃，加入吡啶(61.3g，0.775mol)，再滴加Tf2O(56.8g，0.201mol)。升溫至室溫，攪拌反應1小時。 反應結束後，反應液中加入60mL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 41g，產率：55%。 Compound d (54.1 g, 0.155 mol) was dissolved in 700 mL of dichloromethane. The temperature was lowered to 0 ° C, pyridine (61.3 g, 0.775 mol) was added, and Tf 2 O (56.8 g, 0.201 mol) was added dropwise. The temperature was raised to room temperature, and the reaction was stirred for 1 hour. After the reaction, 60 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, and 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 41 g of compound e in a yield of 55%.

實施例5     Example 5    

將化合物e(41g，85mmol)和化合物f(40.5g，170mmol，按照CN105189461A公開的方法製備)溶於800mL 1,4-二噁烷和水(V：V=5：1)的混合溶劑中，依次加入碳酸鈉(27g，255mmol)和Pd(dppf)Cl2(6.2g，8.5mmol)，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200mL水，室溫攪拌30min，過濾，濾餅用水淋洗，收集濾餅，用750mL甲醇分散，加入濃鹽酸(22mL)，攪拌30min，濃縮除去甲醇，加入1.2L水，攪拌30min，過濾，固體用水淋洗，合併水相，用乙酸乙酯反萃(400mL×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I 23.9g，產率63.5%，光學純度：99.7%。 Compound e (41 g, 85 mmol) and compound f (40.5 g, 170 mmol, prepared according to the method disclosed in CN105189461A) were dissolved in 800 mL of a mixed solvent of 1,4-dioxane and water (V: V = 5: 1), Sodium carbonate (27 g, 255 mmol) and Pd (dppf) Cl 2 (6.2 g, 8.5 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, the reaction solution was cooled to room temperature, 200 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 750 mL of methanol, concentrated hydrochloric acid (22 mL) was added, and the mixture was stirred for 30 min. Add 1.2 L of water, stir for 30 min, filter, rinse the solid with water, combine the aqueous phases, back extract with ethyl acetate (400 mL x 2), collect the aqueous phase, adjust the pH to basic with saturated NaHCO 3 solution, and precipitate a solid. A solid was obtained by filtration, washed with water, and dried under vacuum to obtain 23.9 g of Compound I with a yield of 63.5% and optical purity: 99.7%.

由於已根據其特殊的實施方案描述了本發明，某些修飾和等價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疇內。 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 (26)

一種式III所示化合物， A compound of formula III, 一種式IV所示化合物， 其中，X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為C 1~C 6烷基。 A compound of formula IV, Wherein X is selected from the group consisting of -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, ethoxyl or phosphate, -SR,- SO 2 R, R is C 1 to C 6 alkyl. 如申請專利範圍第2項所述之式IV所示化合物，其中，該X選自-Cl、-Br、-I、三氟甲磺醯氧基、甲磺醯氧基或苯磺醯氧基。     The compound represented by formula IV as described in item 2 of the scope of patent application, wherein the X is selected from -Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy or benzenesulfonyloxy .     一種式VII所示化合物， 其中，R 2選自羥基保護基。 A compound of formula VII, Wherein, R 2 is selected from a hydroxy protecting group. 一種式d所示化合物， A compound represented by formula d, 一種如式III所示的化合物的製備方法，包括手性解析式II所示化合物的步驟， A method for preparing a compound represented by formula III, comprising the steps of chiral analysis of a compound represented by formula II, 如申請專利範圍第6項所述的製備方法，其中，該手性解析的方法選自化學解析、膜解析、色譜解析、毛細管電泳解析和生物解析。     The preparation method according to item 6 of the scope of patent application, wherein the method of chiral analysis is selected from chemical analysis, membrane analysis, chromatographic analysis, capillary electrophoresis analysis, and biological analysis.     如申請專利範圍第7項所述的製備方法，其中，該手性解析的方法選自化學解析和色譜解析。     The preparation method according to item 7 of the scope of patent application, wherein the method of chiral analysis is selected from chemical analysis and chromatographic analysis.     如申請專利範圍第7或8項所述的製備方法，其中，該化學解析所使用的解析劑選自L-酒石酸、D-酒石酸、L-DBTA、D-DBTA、L-DTTA或D-DTTA、R-樟腦磺酸、S-樟腦磺酸、D-扁桃酸、L-扁桃酸、L-谷胺酸、D-谷胺酸、L-天門冬胺酸、D-天門冬胺酸。     The preparation method according to item 7 or 8 of the scope of the patent application, wherein the resolving agent used in the chemical analysis is selected from the group consisting of L-tartaric acid, D-tartaric acid, L-DBTA, D-DBTA, L-DTTA or D-DTTA , R-camphorsulfonic acid, S-camphorsulfonic acid, D-mandelic acid, L-mandelic acid, L-glutamine, D-glutamic acid, L-aspartic acid, D-aspartic acid.     如申請專利範圍第9項所述的製備方法，其中，該化學解析所使用的解析劑選自L-DTTA、D-DTTA、L-谷胺酸、D-谷胺酸、L-天門冬胺酸、D-天門冬胺酸。     The preparation method according to item 9 of the scope of patent application, wherein the resolving agent used in the chemical analysis is selected from the group consisting of L-DTTA, D-DTTA, L-glutamic acid, D-glutamic acid, and L-aspartamine Acid, D-aspartic acid.     如申請專利範圍第10項所述的製備方法，其中，該化學解析所使用的解析劑為D-DTTA。     The preparation method according to item 10 of the scope of patent application, wherein the resolving agent used in the chemical analysis is D-DTTA.     如申請專利範圍第7或8項所述的製備方法，其中，該化學解析所使用的解析劑與式II所示化合物的莫耳比為1：1~4：1。     The preparation method according to item 7 or 8 of the scope of patent application, wherein the molar ratio of the resolving agent used in the chemical analysis to the compound represented by Formula II is 1: 1 to 4: 1.     如申請專利範圍第7或8項所述的製備方法，其中，該化學解析的反應溶劑選自水、C 1~C 6醇類、丙酮、甲基乙基酮、四氫呋喃、二噁烷、乙腈、N，N-二甲基甲醯胺、N，N-二甲亞碸中的一種或多種。 The preparation method according to item 7 or 8 of the scope of patent application, wherein the chemically resolved reaction solvent is selected from the group consisting of water, C 1 to C 6 alcohols, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, and acetonitrile. Or N, N-dimethylformamide, N, N-dimethylformamide. 如申請專利範圍第13項所述的製備方法，其中，該化學解析的反應溶劑選自甲醇或乙醇。     The preparation method according to item 13 of the patent application scope, wherein the chemically resolved reaction solvent is selected from methanol or ethanol.     一種如式I所示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6至14項中任一項的方法製備如式III所示的化合物的步驟。 A method for preparing a compound represented by formula I or a pharmaceutically acceptable salt thereof, comprising the steps of preparing a compound represented by formula III by a method according to any one of claims 6 to 14 of the scope of application for a patent. 如申請專利範圍第15項所述的製備方法，其中，該方法還包括以式III所示化合物為反應物製備式IV所示化合物的步驟， 其中，X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為C 1~C 6烷基。 The preparation method according to item 15 of the scope of patent application, wherein the method further comprises the step of preparing a compound represented by formula IV by using the compound represented by formula III as a reactant, Wherein X is selected from the group consisting of -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, ethoxyl or phosphate, -SR,- SO 2 R, R is C 1 to C 6 alkyl. 如申請專利範圍第16項所述的製備方法，其中，該X選自-Cl、-Br、-I、三氟甲磺醯氧基、甲磺醯氧基或苯磺醯氧基。     The preparation method according to item 16 of the application, wherein the X is selected from -Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy, or benzenesulfonyloxy.     如申請專利範圍第15項所述的製備方法，其中，該方法還包括將式IV所示化合物與式V所示化合物在催化劑存在的條件下進行偶聯反應製備式VI所示化合物的步驟， 其中，X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為C 1~C 6烷基；Y選自-BF 3K、-BR aR b、-Sn(R c) m或-Zn-X’；R a和R b獨立地選自-OH、烷基、烷氧基或視需要經取代的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；m為0、1、2、3或4的整數；R 1選自氫或羥基保護基。 The preparation method according to item 15 of the scope of patent application, wherein the method further comprises the step of preparing a compound represented by formula VI by performing a coupling reaction with a compound represented by formula IV and a compound represented by formula V in the presence of a catalyst, Wherein X is selected from the group consisting of -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, ethoxyl or phosphate, -SR,- SO 2 R, R is C 1 ~ C 6 alkyl group; the Y is selected from -BF 3 K, -BR a R b , -Sn (R c) m or -Zn-X '; R a and R b are independently selected from From -OH, alkyl, alkoxy, or optionally substituted C 1 to C 6 mono- and diol, or R a and R b together to form a ring, R c is independently selected from C 1 -C 6 alkane group, X 'is selected from -Cl, -Br, -I; m is an integer of 3 or 4; R 1 is selected from hydrogen or a hydroxy protecting group. 如申請專利範圍第18項所述的製備方法，其中，該X選自-Cl、-Br、-I、三氟甲磺醯氧基、甲磺醯氧基或苯磺醯氧基。     The preparation method according to item 18 of the scope of patent application, wherein the X is selected from -Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy, or benzenesulfonyloxy.     如申請專利範圍第18項所述的製備方法，其中，該Y 選自BF 3K和BR aR b，其中，該BR aR b中R a和R b獨立地選自-OH、烷基、烷氧基，或BR aR b為頻哪醇硼酸酯。 The preparation method according to item 18 of the scope of application for a patent, wherein the Y is selected from BF 3 K and BR a R b , wherein R a and R b in the BR a R b are independently selected from -OH, alkyl , Alkoxy, or BR a R b is a pinacol borate. 如申請專利範圍第18至20項中任一項所述的製備方法，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)，其中L為含膦配體或N-雜環碳烯配體，該含膦配體選自PPh 3、dppf、PCy 3、tBu 3P、P(OMe) 3、dppe或dppb，p獨立的選自0、1、2、3或4的整數。 The preparation method according to any one of claims 18 to 20, 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), where L is a phosphine-containing ligand or N-hetero A cyclocarbene ligand, the phosphine-containing ligand is selected from the group consisting of PPh 3 , dppf, PCy 3 , tBu 3 P, P (OMe) 3 , dppe, or dppb, and p is independently selected from 0, 1, 2, 3, or 4 Integer. 如申請專利範圍第21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 21 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22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 22 of the scope of patent application, wherein the catalyst is Pd (PPh 3 ) 2 Cl 2 . 如申請專利範圍第18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 18 of the scope of patent application, wherein the reaction is performed in the presence of a basic substance.     如申請專利範圍第24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 24 of the scope of patent application, wherein the basic substance is selected from Li 2 CO 3 , Na 2 CO 3 , Ba (OH) 2 , K 3 PO 4 , Cs 2 CO 3 , 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25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 25 of the scope of patent application, wherein the basic substance is selected from one or more of Na 2 CO 3 or K 2 CO 3 .
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