TWI662019B - Fused tricyclic γ-amino acid derivative, preparation method and application thereof in medicine - Google Patents

Fused tricyclic γ-amino acid derivative, preparation method and application thereof in medicine Download PDF

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TWI662019B
TWI662019B TW105143554A TW105143554A TWI662019B TW I662019 B TWI662019 B TW I662019B TW 105143554 A TW105143554 A TW 105143554A TW 105143554 A TW105143554 A TW 105143554A TW I662019 B TWI662019 B TW I662019B
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cyclobutane
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TW201726592A (en
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李瑤
石宗軍
徐波
李升�
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大陸商四川海思科製藥有限公司
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/28—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/32—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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Abstract

本發明關於一種稠合三環γ-胺基酸衍生物及其在醫藥上的應用，具體而言關於如通式(I)所示的稠合環γ-胺基酸衍生物，或者其立體異構物、溶劑化物、代謝產物、前藥、藥學上可接受的鹽或共晶，包含其的藥物組合物以及本發明化合物或組合物在鎖痛領域的用途，其中，通式(I)中各取代基的定義與說明書的定義相同 The invention relates to a fused tricyclic γ-amino acid derivative and its application in medicine, in particular to a fused tricyclic γ-amino acid derivative represented by the general formula (I), or a stereo Isomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or co-crystals, pharmaceutical compositions containing the same, and the use of a compound or composition of the present invention in the field of analgesia, wherein the general formula (I) The definition of each substituent in the same as that in the specification

Description

稠合三環γ-胺基酸衍生物、製備方法及其在醫藥上的應用 Fused tricyclic γ-amino acid derivative, preparation method and application in medicine

本發明關於一種通式(I)所示的稠合三環γ-胺基酸衍生物，或者其立體異構物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，其藥物組合物以及在鎮痛領域的用途。 The present invention relates to a fused tricyclic γ-amino acid derivative represented by the general formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, Its pharmaceutical composition and use in the field of analgesia.

電壓門控性鈣離子通道由α1亞單位和輔助蛋白α2δ、β、γ亞基共同構成。α2δ蛋白可以調節鈣離子通道的密度及鈣離子通道電壓依賴性動力學(Felix et al (199 7)J.Neuroscience 17：6884- 6891；Klugbauer et al(1999)J.Neuroscience 19：684-691；Hobom et al(2000)Eur.J.Neuroscience 12：1217-1226；and Qin et al(2002)Mol.Pharmacol.62：485-496)。已經證實，對電壓依賴性鈣離子通道亞基α2δ表現出高親合力結合的化合物可有效治療疼痛，例如普瑞巴林和加巴噴丁。在哺乳動物中，α2δ蛋白有4個亞型，每個亞型均由不同的基因編碼。α2δ亞型1和亞型2與普瑞巴林表現出高親和力，而α2δ亞型3和亞型4無顯著的藥物結合力。 The voltage-gated calcium channel is composed of α1 subunit and auxiliary proteins α2δ, β, γ subunits. α2δ protein can regulate the density of calcium channels and voltage-dependent kinetics of calcium channels (Felix et al (199 7) J. Neuroscience 17: 6884- 6891; Klugbauer et al (1999) J. Neuroscience 19: 684-691; Hobom et al (2000) Eur. J. Neuroscience 12: 1217-1226; and Qin et al (2002) Mol. Pharmacol. 62: 485-496). Compounds that have shown high affinity binding to the voltage-dependent calcium channel subunit α2δ have been shown to be effective in treating pain, such as pregabalin and gabapentin. In mammals, there are four subtypes of the α2δ protein, each of which is encoded by a different gene. α2δ subtype 1 and subtype 2 showed high affinity with pregabalin, while α2δ subtype 3 and subtype 4 had no significant drug-binding ability.

然而，對於加巴噴丁，其較大程度改善糖尿病周圍經神經病變患者病痛的比例約為60%(Acta Neurol.Scand.101：359-371,2000)，對於普瑞巴林，雖然其耐受性優於加巴噴丁，但其安全性更低，且有濫用或者使患者 產生依賴的可能(Am J Health Syst Pharm.2007；64(14)：1475-1482)。 However, for gabapentin, the proportion of patients with diabetic peripheral neuropathy that greatly improves the pain is about 60% (Acta Neurol. Scand. 101: 359-371, 2000). Gabapentin, but it is less safe and abuses or causes patients The possibility of dependence (Am J Health Syst Pharm. 2007; 64 (14): 1475-1482).

鑒於加巴噴丁和普瑞巴林的局限性，需要開發新的具有更好藥效的化合物。 Given the limitations of gabapentin and pregabalin, new compounds with better efficacy are needed.

WO2002085839描述了可治療癲癇、經神經變性障礙、疼痛等疾病的二環胺基酸類似物及其衍生物、前藥以及可藥用鹽和溶劑化物，其中R1、R2各自獨立地選自氫、C1-6直鏈或支鏈烷基、C3-6環烷基、苯基或苯甲基，且式(XVII)中，R1、R2同時為氫。該發明與本發明的化合物結構差異較大，不應認為此專利中的具體描述是本發明的一部分。該發明之通式化合物如下： WO2002085839 describes bicyclic amino acid analogs and their derivatives, prodrugs, and pharmaceutically acceptable salts and solvates that can treat diseases such as epilepsy, neurodegeneration, and pain, wherein R 1 and R 2 are each independently selected from Hydrogen, C 1-6 straight or branched chain alkyl, C 3-6 cycloalkyl, phenyl or benzyl, and in formula (XVII), R 1 and R 2 are simultaneously hydrogen. The structure of this compound is quite different from that of the compound of this invention, and the specific description in this patent should not be considered as part of this invention. The general compound of the invention is as follows:

WO2004031124說明書中記載了其發明化合物作為中間體可製得的下式胺基酸衍生物，其中n選自0、1或2，R1、R1a、R2、R2a、R3、R3a、R4和R4a各自獨立地選自氫、C1-6直鏈或支鏈烷基，或者R1和R2、或R2和R3結合形成任選被1或2個C1-6烷基取代的C3-7環烷基。該發明與本發明的化合物結構差異較大，不應認為此專利中的具體描述是本發明的一部分。該發明之通式化合物如下： The specification of WO2004031124 describes amino acid derivatives of the following formula which can be prepared by using the compound of the invention as an intermediate, wherein n is selected from 0, 1 or 2, and R 1 , R 1a , R 2 , R 2a , R 3 , R 3a , R 4 and R 4a are each independently selected from hydrogen, C 1-6 straight or branched chain alkyl, or R 1 and R 2 , or R 2 and R 3 are combined to form an optionally 1 or 2 C 1- 6 alkyl substituted C 3-7 cycloalkyl. The structure of this compound is quite different from that of the compound of this invention, and the specific description in this patent should not be considered as part of this invention. The general compound of the invention is as follows:

WO2009041453描述了可治療疼痛的稠合環γ-胺基酸衍生物或其藥用鹽，其中R1、R2、R2'、R4、R5、R6、R7、R8、R8'各自獨立地選自氫、鹵素、C1-6烷基或者R2和R2'與它們結合的碳原子一起形成C3-7環烷基，R3為氫、鹵素、C1-6烷基、C1-6烷基鹵基團、羥基C1-6烷基、硫烷基C1-6烷基、C1-6烷氧基C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷基硫烷基、C1-6烷基硫烷基C1-6烷基、C2-7醯基硫代C1-6烷基、C2-7醯氧基C1-6烷基或C3-7環烷基。該發明與本發明的化合物結構差異較大，不應認為此專利中的具體描述是本發明的一部分。該發明之通式化合物如下： WO2009041453 describes a fused ring γ-amino acid derivative or a pharmaceutically acceptable salt thereof for treating pain, wherein R 1 , R 2 , R 2 ′ , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 ′ are each independently selected from hydrogen, halogen, C 1-6 alkyl or R 2 and R 2 ′ together with the carbon atom to which they are bonded to form a C 3-7 cycloalkyl group, and R 3 is hydrogen, halogen, C 1- 6 alkyl, C 1-6 alkyl halide, hydroxy C 1-6 alkyl, sulfanyl C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylsulfanyl, C 1-6 alkylsulfanyl C 1-6 alkyl, C 2-7 fluorenyl Thio C 1-6 alkyl, C 2-7 methoxy C 1-6 alkyl or C 3-7 cycloalkyl. The structure of this compound is quite different from that of the compound of this invention, and the specific description in this patent should not be considered as part of this invention. The general compound of the invention is as follows:

WO2010079668描述了可治療疼痛的稠合環γ-胺基酸衍生物或其藥用鹽，其中R1、R5各自獨立地選自氫或C1-6烷基，R2、R3、R4和R4'各自獨立地選自氫原子、C1-6烷基或C3-6環烷基，或者R4和R4'相結合形成C3-6環烷基，R6選自氫、C1-6烷基或氨基保護基，R7選自氫、C1-6烷基或羧基保護基，R8和R8'相同或不同，各自獨立地選自氫、鹵素、C1-6烷基硫基、C1-6烷氧基或C1-6硫烷基，或者R8和R8'與它們結合的碳原子一起形成C3-6環烷基。該發明與本發明的化合物結構差異較大，不應認為此專利中的具體描述是本發明的一部分。該發明之通式化合物如下： WO2010079668 describes a fused ring γ-amino acid derivative or a pharmaceutically acceptable salt thereof for treating pain, wherein R 1 and R 5 are each independently selected from hydrogen or C 1-6 alkyl, R 2 , R 3 , R 4 and R 4 ′ are each independently selected from a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group, or R 4 and R 4 ′ are combined to form a C 3-6 cycloalkyl group, and R 6 is selected from Hydrogen, C 1-6 alkyl or amino protecting group, R 7 is selected from hydrogen, C 1-6 alkyl or carboxy protecting group, R 8 and R 8 ′ are the same or different, each independently selected from hydrogen, halogen, C 1-6 alkylthio, C 1-6 alkoxy, or C 1-6 sulfanyl, or R 8 and R 8 ′ together with the carbon atom to which they are bound form a C 3-6 cycloalkyl. The structure of this compound is quite different from that of the compound of this invention, and the specific description in this patent should not be considered as part of this invention. The general compound of the invention is as follows:

本發明的目的是提供一種結構新穎、藥效好的稠合三環γ-胺基酸衍生物，或者其所有的立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或者前藥，其藥物組合物以及其在鎮痛領域的用途。 The object of the present invention is to provide a fused tricyclic γ-amino acid derivative with novel structure and good efficacy, or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, and co-crystals thereof. Or prodrugs, their pharmaceutical compositions and their use in the field of analgesia.

本發明關於一種通式(I)所示的化合物，或者其所有的立體異構物、溶劑化物、前藥代謝產物、藥學上可接受的鹽或共晶： The present invention relates to a compound represented by general formula (I), or all stereoisomers, solvates, prodrug metabolites, pharmaceutically acceptable salts or co-crystals thereof:

其中：R1、R2、R2’、R3、R4、R4’或R5各自獨立地選自H、F、Cl、Br、I、羥基、氰基、C1-6烷基、C1-6烷氧基、C1-6硫烷基、C2-6烯基、C2-6炔基、3至 6員碳環基或者3至6員雜環基，所述的烷基、烷氧基、硫烷基、烯基、炔基、碳環基或者雜環基任選進一步被0至6個選自F、Cl、Br、I、羥基、C1-6烷基或者3至6員碳環基所取代，所述的雜環基含有1至2個選自N、O或者S的雜原子；選擇性的，R1與R2、R2與R2’、R2與R3、R3與R4、R4與R4’、R4與R5任意一組相結合與其相連的原子一起形成雙鍵(例如R1與R2之間的鍵形成雙鍵，或R2與R2’之間的鍵形成雙鍵，或R2與R3之間的鍵形成雙鍵，依此類推。)，所述的雙鍵任選進一步被0至2個選自F、Cl、Br、I、C1-6烷基、被1至3個鹵素取代的C1-6烷基或者3至6員碳環基所取代，所述的鹵素選自F、Cl或者Br；選擇性的，R2與R2’、R3與R4、R4與R4’、R4與R5任意一組與其連接的碳原子一起形成3至6員碳環基，所述的碳環基任選進一步被0至6個選自F、Cl、Br、I、C1-6烷基、C1-6烷氧基或者C1-6硫烷基所取代；R6選自H、C1-6烷基或者氨基保護基；R7選自H、C1-6烷基或者羧基保護基。 Where: R 1 , R 2 , R 2 ' , R 3 , R 4 , R 4' or R 5 are each independently selected from H, F, Cl, Br, I, hydroxyl, cyano, C 1-6 alkyl , C 1-6 alkoxy, C 1-6 sulfanyl, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 6-membered carbocyclyl, or 3 to 6-membered heterocyclyl, said Alkyl, alkoxy, sulfanyl, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally further selected from 0 to 6 selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl Or 3 to 6 membered carbocyclic groups, wherein the heterocyclic group contains 1 to 2 heteroatoms selected from N, O, or S; optionally, R 1 and R 2 , R 2 and R 2 ′ , Any group of R 2 and R 3 , R 3 and R 4 , R 4 and R 4 ' , R 4 and R 5 combined with their connected atoms to form a double bond (for example, the bond between R 1 and R 2 forms a double bond Bond, or a bond between R 2 and R 2 ′ forms a double bond, or a bond between R 2 and R 3 forms a double bond, and so on.), Said double bond is optionally further 0 to 2 is selected from F, Cl, Br, I, C 1-6 alkyl, substituted with 1-3 halo or C 1-6 alkyl substituted with 3-6 carbocyclyl, said halogen is selected from F, Cl or Br; optionally, R 2 and R 2 ' , R Any one of 3 and R 4 , R 4 and R 4 ′ , R 4 and R 5 forms a 3 to 6-membered carbocyclic group together with the carbon atoms to which they are attached, and the carbocyclic group is optionally further selected by 0 to 6 Substituted from F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 sulfanyl; R 6 is selected from H, C 1-6 alkyl or amino protecting group R 7 is selected from H, C 1-6 alkyl or carboxy protecting group.

本發明提供之一方案，包括通式(I)所示的化合物，或者其所有的立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或前藥：其中：R1、R2、R2’、R3、R4、R4’或R5各自獨立地選自H、F、Cl、Br、羥基、C1-6烷基、C1-4烷氧基、C1-4硫烷基、C2-6烯基、C2-6炔基、3至6員碳環基或者3至6員雜環基，較佳地，R1、R2、R2’、R3、R4、R4’或R5各自獨立地選自H、F、Cl、羥基、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基或者3至6員碳環基，更佳地，R1、R2、R2’、R3、R4、R4’或R5各自獨立地選 自H、F、羥基、C1-4烷基、C1-4烷氧基、C2-4烯基或者3至6員碳環基，所述的烷基、烷氧基、硫烷基、烯基、炔基、碳環基或者雜環基任選進一步被0至6個選自F、Cl、Br、I、羥基、C1-6烷基或者3至6員碳環基所取代，較佳進一步被0至4個選自F、Cl、Br、羥基或者C1-4烷基所取代，所述的雜環基含有1至2個選自N、O或者S的雜原子；選擇性的，R1與R2、R2與R2’、R2與R3、R3與R4、R4與R4’、R4與R5任意一組相結合與其相連的原子一起形成雙鍵，所述的雙鍵任選進一步被0至2個選自F、Cl、Br、I、C1-6烷基、被1至3個鹵素取代的C1-6烷基或者3至6員碳環基所取代，較佳進一步被0至2個選自F、Cl、Br或者C1-4烷基所取代，所述的鹵素選自F、Cl或者Br；選擇性的，R2與R2’、R3與R4、R4與R4’、R4與R5任意一組與其連接的碳原子一起形成3至6員碳環基，所述的碳環基任選進一步被0至6個選自F、Cl、Br、I、C1-6烷基、C1-6烷氧基或者C1-6硫烷基所取代，較佳進一步被0至4個選自F、Cl、Br、C1-4烷基、C1-4烷氧基或者C1-4硫烷基所取代，更佳進一步被0至4個選自F、Cl或者C1-4烷基所取代；R6選自H、C1-4烷基或者氨基保護基；R7選自H、C1-4烷基或者羧基保護基。 The present invention provides a solution, which includes a compound represented by the general formula (I), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, or prodrugs thereof: wherein: R 1 , R 2 , R 2 ′ , R 3 , R 4 , R 4 ′ or R 5 are each independently selected from H, F, Cl, Br, hydroxyl, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 sulfanyl, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 6-membered carbocyclyl or 3 to 6-membered heterocyclyl, preferably, R 1 , R 2 , R 2 ', R 3, R 4, R 4' or R 5 are each independently selected from H, F, Cl, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl or 3 to 6-membered carbocyclyl, more preferably, R 1 , R 2 , R 2 ′ , R 3 , R 4 , R 4 ′ or R 5 are each independently selected from H, F, hydroxyl , C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl or 3- to 6-membered carbocyclyl, said alkyl, alkoxy, sulfanyl, alkenyl, alkynyl , Carbocyclyl or heterocyclyl is optionally further substituted with 0 to 6 selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl or 3 to 6 membered carbocyclyl, preferably further substituted by 0 to 4 substituents selected from F, Cl, Br, hydroxy or C 1-4 Group substituted with the heterocyclic group containing 1 to 2 heteroatoms selected from N, O or S heteroatom; and selective, R 1 and R 2, R 2 and R 2 ', R 2 and R 3, R 3 and R 4 , R 4 and R 4 ′ , R 4 and R 5 combine to form a double bond with the atoms to which they are connected, and the double bond is optionally further selected from 0 to 2 selected from F, Cl, br, I, C 1-6 alkyl, substituted with 1-3 halo or C 1-6 alkyl substituted with 3-6 carbocyclyl, further preferably 0-2 selected from F, Cl, Br or C 1-4 alkyl, the halogen is selected from F, Cl or Br; optionally, R 2 and R 2 ′ , R 3 and R 4 , R 4 and R 4 ′ , R 4 and Any group of R 5 together with the carbon atom to which it is attached forms a 3- to 6-membered carbocyclic group, said carbocyclic group optionally further being 0 to 6 selected from F, Cl, Br, I, C 1-6 alkyl , C 1-6 alkoxy or C 1-6 sulfanyl, preferably further substituted by 0 to 4 selected from F, Cl, Br, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 sulfanyl, more preferably substituted by 0 to 4 selected from F, Cl or C 1-4 alkyl; R 6 is selected from H, C 1-4 alkyl or amino protecting group; R 7 is selected from H, C 1-4 alkyl Or a carboxyl protecting group.

本發明提供之一方案，包括通式(I)所示的化合物，或者其所有的立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或前藥：其中：R1、R2、R2’、R3、R4、R4’或R5各自獨立地選自H、F、Cl、Br、羥基、甲基、乙基、正丙基、異丙基、正丁基、第二丁基、新丁基、第三丁 基、CH2F、CHF2、CF3、CH2CH2F、CHFCH3、CHFCH2F、羥基甲基、羥基乙基、甲氧基、乙氧基、丙氧基、異丙氧基、甲硫基、乙硫基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、環丙基、環丁基、環戊基或者環己基；選擇性的，R1與R2、R2與R2’、R2與R3、R3與R4、R4與R4’、R4與R5任意一組相結合與其相連的原子一起形成雙鍵，所述的雙鍵任選進一步被0至2個選自F、Cl、Br、I、甲基、乙基、正丙基、異丙基、正丁基、第二丁基、新丁基、第三丁基、CH2F、CHF2、CF3、CH2CH2F、CHFCH3、CHFCH2F、環丙基、環丁基、環戊基或者環己基所取代；選擇性的，R2與R2’、R3與R4、R4與R4’、R4與R5任意一組與其連接的碳原子一起形成環丙基、環丁基、環戊基、環己基、氟代環丙基、2,2-二氟代環丙基、氟代環丁基、氟代環戊基、環丁基-2-烯基、環戊基-2-烯基、環己基-2-烯基；R6選自H、甲基、乙基、第三丁基；R7選自H、甲基、乙基、第三丁基。 The present invention provides a solution, which includes a compound represented by the general formula (I), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, or prodrugs thereof: wherein: R 1 , R 2 , R 2 ′ , R 3 , R 4 , R 4 ′ or R 5 are each independently selected from H, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n- Butyl, second butyl, neobutyl, third butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, hydroxymethyl, hydroxyethyl, methoxy Base, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl Or cyclohexyl; optionally, any of R 1 and R 2 , R 2 and R 2 ' , R 2 and R 3 , R 3 and R 4 , R 4 and R 4' , R 4 and R 5 Combined with the atom to which it is attached to form a double bond, said double bond is optionally further selected from 0 to 2 selected from F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl , Second butyl, neobutyl, third butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; optionally, R 2 and R 2 ′ , R 3 and R 4 , R 4 and R 4 ' , R 4 and R 5 together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluorocyclopropyl, 2,2-difluorocyclopropyl, fluorine Substituted cyclobutyl, fluorocyclopentyl, cyclobutyl-2-enyl, cyclopentyl-2-enyl, cyclohexyl-2-enyl; R 6 is selected from H, methyl, ethyl, Tributyl; R 7 is selected from H, methyl, ethyl, and third butyl.

本發明提供之一方案，包括通式(Ia)或者(Ib)所示的化合物，或者其所有的立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或前藥： 或者 The present invention provides a solution comprising a compound represented by the general formula (Ia) or (Ib), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof: or

其中：R1、R2、R2’、R3、R4、R4’或R5各自獨立地選自H、F、Cl、Br、I、羥 基、氰基、C1-6烷基、C1-6烷氧基、C1-6硫烷基、C2-6烯基、C2-6炔基、3至6員碳環基或者3至6員雜環基，較佳地，R1、R2、R3、R4或R5各自獨立地選自H、F、Cl、羥基、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基或者3至6員碳環基，更佳地，R1、R2、R3、R4或R5各自獨立地選自H、F、羥基、C1-4烷基、C1-4烷氧基、C2-4烯基或者3至6員碳環基，所述的烷基、烷氧基、硫烷基、烯基、炔基、碳環基或者雜環基任選進一步被0至6個選自F、Cl、Br、I、羥基、C1-6烷基或者3至6員碳環基所取代，較佳進一步被0至4個選自F、Cl、Br、羥基或者C1-4烷基所取代，所述的雜環基含有1至2個選自N、O或者S的雜原子；選擇性的，R1與R2、R2與R2’、R2與R3、R3與R4、R4與R4’、R4與R5任意一組相結合與其相連的原子一起形成雙鍵，所述的雙鍵任選進一步被0至2個選自F、Cl、Br、I、C1-6烷基、被1至3個鹵素取代的C1-6烷基或者3至6員碳環基所取代，所述的鹵素選自F、Cl或者Br；選擇性的，R2與R2’、R3與R4、R4與R4’、R4與R5任意一組與其連接的碳原子一起形成3至6員碳環基，所述的碳環基任選進一步被0至6個選自F、Cl、Br、I、C1-6烷基、C1-6烷氧基或者C1-6硫烷基所取代，較佳進一步被0至4個選自F、Cl、Br、C1-4烷基、C1-4烷氧基或者C1-4硫烷基所取代，更佳進一步被0至4個選自F、Cl或者C1-4烷基所取代；R6選自H、C1-6烷基或者氨基保護基，較佳為H或者C1-6烷基；R7選自H、C1-6烷基或者羧基保護基，較佳為H或者C1-6烷基。 Where: R 1 , R 2 , R 2 ' , R 3 , R 4 , R 4' or R 5 are each independently selected from H, F, Cl, Br, I, hydroxyl, cyano, C 1-6 alkyl , C 1-6 alkoxy, C 1-6 sulfanyl, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 6-membered carbocyclyl or 3 to 6-membered heterocyclyl, preferably R 1 , R 2 , R 3 , R 4 or R 5 are each independently selected from H, F, Cl, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl or 3 to 6 membered carbocyclyl, more preferably R 1 , R 2 , R 3 , R 4 or R 5 are each independently selected from H, F, hydroxyl, C 1-4 alkyl , C 1-4 alkoxy, C 2-4 alkenyl or 3- to 6-membered carbocyclyl, said alkyl, alkoxy, sulfanyl, alkenyl, alkynyl, carbocyclyl or heterocyclic The group is optionally further substituted with 0 to 6 selected from F, Cl, Br, I, hydroxyl, C 1-6 alkyl, or 3 to 6 membered carbocyclic groups, and is preferably further substituted with 0 to 4 selected from F, Cl, Br, hydroxy or C 1-4 alkyl substituted, said heterocyclic group contains 1 to 2 heteroatoms selected from N, O or S; optionally, R 1 and R 2 , R 2 and R 2 ' , R 2 and R 3 , R 3 and R 4 , R 4 and R 4' , R 4 and R 5 The connected atoms together form a double bond, said double bond optionally further being 0 to 2 C 1- selected from F, Cl, Br, I, C 1-6 alkyl, substituted by 1 to 3 halogens 6 alkyl or 3 to 6-membered carbocyclyl, the halogen is selected from F, Cl or Br; optionally, R 2 and R 2 ′ , R 3 and R 4 , R 4 and R 4 ′ , R 4 and R 5 form a 3- to 6-membered carbocyclic group together with any of the carbon atoms to which they are attached. The carbocyclic group is optionally further selected from 0 to 6 selected from F, Cl, Br, I, C 1- 6 alkyl, C 1-6 alkoxy or C 1-6 sulfanyl, preferably further substituted by 0 to 4 selected from F, Cl, Br, C 1-4 alkyl, C 1-4 alkane Substituted with oxy or C 1-4 sulfanyl, more preferably with 0 to 4 selected from F, Cl or C 1-4 alkyl; R 6 is selected from H, C 1-6 alkyl or amino The protecting group is preferably H or C 1-6 alkyl; R 7 is selected from H, C 1-6 alkyl or carboxy protecting group, preferably H or C 1-6 alkyl.

本發明之一方案，包括通式(Ia)或者(Ib)所示的化合物，或者其所有的立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或前藥： 其中：R1、R2、R2’、R3、R4、R4’或R5各自獨立地選自H、F、Cl、Br、羥基、甲基、乙基、正丙基、異丙基、正丁基、第二丁基、新丁基、第三丁基、CH2F、CHF2、CF3、CH2CH2F、CHFCH3、CHFCH2F、羥基甲基、羥基乙基、甲氧基、乙氧基、丙氧基、異丙氧基、甲硫基、乙硫基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、環丙基、環丁基、環戊基或者環己基；選擇性的，R1與R2、R2與R2’、R2與R3、R3與R4、R4與R4’、R4與R5任意一組相結合與其相連的原子一起形成雙鍵，所述的雙鍵任選進一步被0至2個選自F、Cl、Br、I、甲基、乙基、正丙基、異丙基、正丁基、第二丁基、新丁基、第三丁基、CH2F、CHF2、CF3、CH2CH2F、CHFCH3、CHFCH2F、環丙基、環丁基、環戊基或者環己基所取代；選擇性的，R2與R2’、R3與R4、R4與R4’、R4與R5任意一組與其連接的碳原子一起形成環丙基、環丁基、環戊基、環己基、氟代環丙基、2,2-二氟代環丙基、氟代環丁基、氟代環戊基、環丁基-2-烯基、環戊基-2-烯基、環己基-2-烯基；R6選自H、甲基、乙基、第三丁基；R7選自H、甲基、乙基、第三丁基。 An embodiment of the present invention includes a compound represented by the general formula (Ia) or (Ib), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, or prodrugs thereof: wherein : R 1, R 2, R 2 ', R 3, R 4, R 4' or R 5 are each independently selected from H, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, Base, n-butyl, second butyl, neobutyl, third butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, hydroxymethyl, hydroxyethyl , Methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl , Cyclopentyl or cyclohexyl; optionally, R 1 and R 2 , R 2 and R 2 ′ , R 2 and R 3 , R 3 and R 4 , R 4 and R 4 ′ , R 4 and R 5 A group of atoms bonded to form a double bond together, said double bond optionally further being 0 to 2 selected from F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, CH 2 F, CHF 2, CF 3 CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl substituted; selective, R 2 and R 2 ', R 3 and R 4, R 4 and R 4 ' , R 4 and R 5 together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluorocyclopropyl, 2,2-difluorocyclopropyl group , Fluorocyclobutyl, fluorocyclopentyl, cyclobutyl-2-enyl, cyclopentyl-2-enyl, cyclohexyl-2-enyl; R 6 is selected from H, methyl, ethyl And third butyl; R 7 is selected from H, methyl, ethyl, and third butyl.

本發明之一方案，包括通式(I)、(Ia)或者(Ib)所示的化合物，或者其所有的立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或前藥：其中：R1、R2、R2’各自獨立地選自H，或者R1與R2、R2與R2’任意一組相結 合與其相連的原子一起形成雙鍵，所述的雙鍵任選進一步被0至2個選自F、Cl、C1-6烷基或者3至6員碳環基所取代；R3、R4、R4’或R5各自獨立地選自H、F、Cl、羥基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、3至6員碳環基或者3至6員雜環基，所述的烷基、烷氧基、烯基、炔基、碳環基或者雜環基任選進一步被0至6個選自F、Cl、Br、羥基、C1-6烷基或者3至6員碳環基所取代，所述的雜環基含有1至2個選自N、O或者S的雜原子；選擇性的，R4與R4’、R4與R5任意一組相結合與其相連的原子一起形成雙鍵，所述的雙鍵任選進一步被0至2個選自F、Cl、C1-6烷基或者3至6員碳環基所取代；選擇性的，R4與R4’可與其相連的碳原子一起形成3至6員碳環，所述的碳環任選進一步被0至6個選自F、Cl、Br、I、C1-6烷基、C1-6烷氧基或者C1-6硫烷基所取代；R6選自H或者C1-6烷基；R7選自H或者C1-6烷基。 An embodiment of the present invention includes a compound represented by the general formula (I), (Ia), or (Ib), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, or Prodrugs: wherein: R 1 , R 2 , and R 2 ′ are each independently selected from H, or any combination of R 1 and R 2 , R 2 and R 2 ′ forms a double bond with its connected atoms, said The double bond is optionally further substituted by 0 to 2 selected from F, Cl, C 1-6 alkyl or 3 to 6 membered carbocyclic groups; R 3 , R 4 , R 4 ′ or R 5 are each independently selected From H, F, Cl, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 6 member carbocyclyl or 3 to 6 member Heterocyclyl, said alkyl, alkoxy, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally further selected from 0 to 6 selected from F, Cl, Br, hydroxyl, C1-6 alkane Or a 3 to 6-membered carbocyclic group, said heterocyclic group containing 1 to 2 heteroatoms selected from N, O or S; optionally, R 4 and R 4 ' , R 4 and R 5 Any group of atoms combined with its connected atom to form a double bond, said double bond optionally further being 0 to 2 selected from F, Cl, C 1-6 alkyl or 3 to 6-membered carbocyclyl; optionally, R 4 and R 4 ′ may form a 3 to 6-membered carbocyclic ring with the carbon atom to which they are attached, said carbocyclic ring optionally being further 0 to 6 substituted with F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 sulfanyl; R 6 selected from H or C 1-6 alkane R 7 is selected from H or C 1-6 alkyl.

本發明之一方案，包括通式(I)、(Ia)或者(Ib)所示的化合物，或者其所有的立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或前藥：其中：R1、R2、R2’各自獨立地選自H；R3、R4、R4’或R5各自獨立地選自H、F、Cl、羥基或者C1-4烷基；選擇性的，R4與R4’、R4與R5任意一組相結合與其相連的原子一起形成雙鍵，所述的雙鍵任選進一步被0至2個選自F、Cl、C1-4烷基或者3至6員碳環基所取代； 選擇性的，R4與R4’可與其相連的碳原子一起形成3至6員碳環，所述的碳環任選進一步被0至6個選自F、Cl、Br、I、C1-4烷基或者C1-4烷氧基所取代；R6選自H或者C1-4烷基；R7選自H或者C1-4烷基。 An embodiment of the present invention includes a compound represented by the general formula (I), (Ia), or (Ib), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, or Prodrugs: wherein: R 1 , R 2 , R 2 ′ are each independently selected from H; R 3 , R 4 , R 4 ′, or R 5 are each independently selected from H, F, Cl, hydroxyl, or C 1-4 Alkyl; optionally, R 4 and R 4 ′ , R 4 and R 5 combine to form a double bond with the atoms to which they are connected, and the double bond is optionally further selected from 0 to 2 selected from F, Cl, C 1-4 alkyl or 3 to 6-membered carbocyclyl; optionally, R 4 and R 4 ′ may form a 3 to 6-membered carbocyclic ring with the carbon atom to which they are attached. Is further substituted with 0 to 6 selected from F, Cl, Br, I, C 1-4 alkyl or C 1-4 alkoxy; R 6 is selected from H or C 1-4 alkyl; R 7 is selected From H or C 1-4 alkyl.

本發明之一方案，包括通式(I)、(Ia)或者(Ib)所示的化合物，或者其所有的立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或前藥：其中：R3、R4、R4’或R5各自獨立地選自H、F、Cl、羥基、甲基、乙基、正丙基、異丙基、第三丁基；選擇性的，R4與R4’、R4與R5任意一組相結合與其相連的原子一起形成雙鍵，所述的雙鍵任選進一步被0至2個選自F、Cl、甲基、乙基、正丙基、異丙基、正丁基、第三丁基、環丙基、環丁基、環戊基或者環己基所取代；選擇性的，R4與R4’可與其相連的碳原子一起形成環丙基、環丁基、環戊基、環己基、氟代環丙基、2,2-二氟代環丙基、氟代環丁基、氟代環戊基、環丁基-2-烯基、環戊基-2-烯基、環己基-2-烯基；R6選自H、甲基、乙基、第三丁基；R7選自H、甲基、乙基、第三丁基。 An embodiment of the present invention includes a compound represented by the general formula (I), (Ia), or (Ib), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals, or Prodrug: wherein: R 3 , R 4 , R 4 ′ or R 5 are each independently selected from H, F, Cl, hydroxyl, methyl, ethyl, n-propyl, isopropyl, third butyl; select In nature, any combination of R 4 and R 4 ′ , R 4 and R 5 and its connected atoms form a double bond, and the double bond is optionally further selected from 0 to 2 selected from F, Cl, methyl , Ethyl, n-propyl, isopropyl, n-butyl, third butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally, R 4 and R 4 ′ may be substituted with The connected carbon atoms together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluorocyclopropyl, 2,2-difluorocyclopropyl, fluorocyclobutyl, fluorocyclopentyl, Cyclobutyl-2-enyl, cyclopentyl-2-enyl, cyclohexyl-2-enyl; R 6 is selected from H, methyl, ethyl, third butyl; R 7 is selected from H, methyl Group, ethyl, third butyl.

本發明之一方案，本發明關於化合物選自，但不限於： In one aspect of the present invention, the compound of the present invention is selected from, but not limited to:

本發明關於一種製備通式(I)、(Ia)或(Ib)所示的化合物或其立體異構物的中間體，該中間體選自如下通式(II)所示的化合物或其立體異構物： The present invention relates to an intermediate for preparing a compound represented by the general formula (I), (Ia) or (Ib) or a stereoisomer thereof, the intermediate is selected from the compound represented by the following general formula (II) or a stereo Isomers:

其中： Ra或Rb各自獨立地選自羥基或者C1-4烷基，所述的烷基任選進一步被0至2個選自硝基或者-COORx所取代；選擇性的，Ra與Rb相結合與其相連的原子一起形成雙鍵、C=O或者Ra、Rb與其相連的碳原子一起形成3至6員雜環基，所述的雙鍵任選進一步被0至2個選自F、C1-4烷基、硝基或者-COORx所取代，所述的雜環基含有1至2個選自N、O或者S的雜原子，且任選被0至2個=O所取代；Rc、Rd、Rd’或Re各自獨立地選自H、F、Cl、羥基或者C1-4烷基，所述的烷基任選進一步被0至2個選自F、羥基、-OMs、或者-COORx所取代；選擇性的，Rd與Rd’、Rd與Re任意一組相結合與其相連的原子一起形成雙鍵或者C=O，所述的雙鍵任選進一步被0至2個選自F、C1-4烷基或者-COORx所取代；選擇性的，Rd與Rd’可與其相連的碳原子一起形成3至6員碳環，所述的碳環任選進一步被0至6個選自F、Cl、Br、I、C1-4烷基或者C1-4烷氧基所取代；Rx選自H或者C1-4烷基。 Wherein: R a or R b are each independently selected from a hydroxyl group or a C 1-4 alkyl group, and the alkyl group is optionally further substituted by 0 to 2 selected from a nitro group or -COOR x ; optionally, R a and R b combine with the atom to which they are attached to form a double bond, C = O or R a , R b together with the carbon atom to which they are attached form a 3- to 6-membered heterocyclic group, said double bond optionally further being 0 to 2 selected from F, C 1-4 alkyl, nitro or -COOR x , said heterocyclic group containing 1 to 2 heteroatoms selected from N, O or S, and optionally from 0 to substituted 2 = O; R c, R d, Rd ' , or R e is independently selected from H, F, Cl, hydroxy or C 1-4 alkyl, said alkyl optionally further substituted by 0-2 a selected from F, hydroxy, -OMs, -COOR x or substituted; selective, R d and R d ', R d and R e group of a combination of any atoms which they are attached together form a double bond or C = O , Said double bond is optionally further substituted with 0 to 2 selected from F, C 1-4 alkyl or -COOR x ; optionally, R d and R d ' may form 3 together with the carbon atom to which they are attached To 6-membered carbocycles, which are optionally further selected from 0 to 6 selected from F, Cl, B R, I, C 1-4 alkyl or C 1-4 alkoxy; R x is selected from H or C 1-4 alkyl.

本發明之一方案，包括通式(II)所示的化合物，或者其所有的立體異構物：其中：Ra或Rb各自獨立地選自羥基、甲基、乙基、正丙基、正丁基或者第二丁基，所述的甲基、乙基、正丙基、正丁基或者第二丁基任選進一步被0至2個選自硝基、-COOH、-COOMe、-COOEt或者-COOtBu所取代；選擇性的，Ra與Rb相結合與其相連的原子一起形成雙鍵或者C=O，所 述的雙鍵任選進一步被0至2個選自F、甲基、乙基、正丙基、異丙基、正丁基、第二丁基、第三丁基、硝基、-COOEt或者-COOtBu所取代； 選擇性的，Ra、Rb與其相連的碳原子一起形成或者； Rc、Rd、Rd’或Re各自獨立地選自H、F、Cl、羥基、甲基、-CH2OH、-CH2COOEt、乙基、-CH2CH2OH、-CH2CH2OMs、正丙基、異丙基、正丁基、第二丁基或者第三丁基；選擇性的，Rd與Rd’、Rd與Re任意一組相結合與其相連的原子一起形成雙鍵或者C=O，所述的雙鍵任選進一步被0至2個選自F、甲基、乙基、正丙基、異丙基、正丁基、第二丁基、第三丁基、-CH2COOH或者-CH2COOEt所取代；選擇性的，Rd與Rd’可與其相連的碳原子一起形成環丙基、環丁基、環戊基、環己基、氟代環丙基、2,2-二氟代環丙基、氟代環丁基、氟代環戊基、環丁基-2-烯基、環戊基-2-烯基或者環己基-2-烯基；Rx選自H、甲基、乙基或者第三丁基。 An embodiment of the present invention includes a compound represented by the general formula (II), or all stereoisomers thereof: wherein: R a or R b are each independently selected from a hydroxyl group, a methyl group, an ethyl group, an n-propyl group, N-butyl or second butyl, said methyl, ethyl, n-propyl, n-butyl or second butyl is optionally further selected from 0 to 2 selected from nitro, -COOH, -COOMe,- COOEt or -COOtBu is substituted; optionally, R a and R b combine with the atom to which they are attached to form a double bond or C = O, and the double bond is optionally further selected from 0 to 2 selected from F, methyl , ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, nitro, -COOtBu substituted or -COOEt; selective, R a, R b carbon they are attached Atoms form together or ; R c, R d, R d ' , or R e is independently selected from H, F, Cl, hydroxy, methyl, -CH 2 OH, -CH 2 COOEt , ethyl, -CH 2 CH 2 OH, - CH 2 CH 2 OMs, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl; selective, R d and R d ', R d and R e group of a combination of any of its The connected atoms together form a double bond or C = O, and the double bond is optionally further selected from 0 to 2 selected from F, methyl, ethyl, n-propyl, isopropyl, n-butyl, and second butyl. Group, tertiary butyl, -CH 2 COOH or -CH 2 COOEt; optionally, Rd and Rd ' may form a cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, fluorocyclopropyl, 2,2-difluorocyclopropyl, fluorocyclobutyl, fluorocyclopentyl, cyclobutyl-2-enyl, cyclopentyl-2-enyl or ring hexyl-2-enyl; R x is selected from H, methyl, ethyl or tert-butyl.

本發明之一方案，本發明關於化合物選自，但不限於： In one aspect of the present invention, the compound of the present invention is selected from, but not limited to:

本發明提供通式(I)、(Ia)或者(Ib)所示化合物其藥學上可接受的鹽，所述的鹽為對甲苯磺酸鹽。 The present invention provides a pharmaceutically acceptable salt of a compound represented by the general formula (I), (Ia) or (Ib), wherein the salt is a p-toluenesulfonate.

本發明提供一種藥物組合物，所述的藥物組合物包括通式(I)、(Ia)或者(Ib)所述的化合物或其所有的立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或者前藥，和一種或者多種藥學上可接受的載體及/或賦形劑。 The invention provides a pharmaceutical composition, which comprises a compound described by the general formula (I), (Ia) or (Ib) or all stereoisomers, solvates, metabolites, pharmaceutically acceptable Accepted salts, co-crystals or prodrugs, and one or more pharmaceutically acceptable carriers and / or excipients.

本發明提供一種通式(I)、(Ia)或者(Ib)所示的化合物，或者其所有的立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或前藥或者其組合物，在製備治療及/或預防疼痛藥物中的用途，所述用途較佳為：治療皰疹後神經痛、三叉神經痛、偏頭痛、與骨關節炎或關節風濕病相關的疼痛、下背疼痛、坐骨神經痛、牙痛、由燒傷引起的疼痛、由糖尿病性神經病引起的疼痛、由化療誘導的神經病變引起的疼痛、與HIV相關的神經痛、與AIDS相關的神經痛、與癌症相關的神經痛或非神經痛、急性或慢性緊張性頭痛、手術後疼痛、纖維肌痛、癲癇、廣泛性焦慮症或者不寧腿症候群中的用途。 The present invention provides a compound represented by general formula (I), (Ia) or (Ib), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof, or The use of the composition in the preparation of a medicament for the treatment and / or prevention of pain, said use is preferably for the treatment of postherpetic neuralgia, trigeminal neuralgia, migraine, pain associated with osteoarthritis or joint rheumatism, Lower back pain, sciatica, toothache, pain caused by burns, pain caused by diabetic neuropathy, pain caused by chemotherapy-induced neuropathy, HIV-related neuralgia, AIDS-related neuralgia, cancer-related Of neuralgia or non-neuralgia, acute or chronic tension headache, postoperative pain, fibromyalgia, epilepsy, generalized anxiety or restless legs syndrome.

本發明關於一種治療及/或預防疼痛的方法，所述方法包括給予哺乳動物治療有效量的本發明的藥物組合物，或者本發明所述的化合物或其立 體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或者前藥。 The present invention relates to a method for treating and / or preventing pain, which method comprises administering to a mammal a therapeutically effective amount of a pharmaceutical composition of the present invention, or a compound of the present invention, or a compound thereof. Isomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs.

根據本發明所述的方法，所述的疼痛包括：皰疹後神經痛、三叉神經痛、偏頭痛、與骨關節炎或關節風濕病相關的疼痛、下背疼痛、坐骨神經痛、牙痛、由燒傷引起的疼痛、由糖尿病性神經病引起的疼痛、由化療誘導的神經病變引起的疼痛、與HIV相關的神經痛、與AIDS相關的神經痛、與癌症相關的神經痛或非神經痛、急性或慢性緊張性頭痛、手術後疼痛、纖維肌痛。 According to the method of the present invention, the pain includes: postherpetic neuralgia, trigeminal neuralgia, migraine, pain associated with osteoarthritis or joint rheumatism, lower back pain, sciatica, toothache, burns Caused pain, Pain caused by diabetic neuropathy, Pain caused by chemotherapy-induced neuropathy, HIV-related neuralgia, AIDS-related neuralgia, Cancer-related neuralgia or non-neuralgia, acute or chronic Tension headache, postoperative pain, fibromyalgia.

其中所述哺乳動物為人。 Wherein the mammal is human.

除非有相反的陳述，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.

本發明所述基團和化合物中所提及的碳、氫、氧、硫、氮或F、Cl、Br、I均包括它們的同位素情況，及本發明所述基團和化合物中所提及的碳、氫、氧、硫或氮任選進一步被一個或多個它們對應的同位素所替代，其中碳的同位素包括12C、13C和14C，氫的同位素包括氕(H)、氘(D，又叫重氫)、氚(T，又叫超重氫)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素包括17F和19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。 The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I mentioned in the groups and compounds of the present invention include their isotopes, and the groups and compounds mentioned in the present invention Carbon, hydrogen, oxygen, sulfur, or nitrogen is optionally further replaced by one or more of their corresponding isotopes, where carbon isotopes include 12 C, 13 C, and 14 C, and hydrogen isotopes include tritium (H), deuterium ( D, also known as heavy hydrogen), thorium (T, also called super heavy hydrogen), the isotopes of oxygen include 16 O, 17 O, and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S, and 36 S, and the isotopes of nitrogen Including 14 N and 15 N, isotopes of fluorine include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Cl, and isotopes of bromine include 79 Br and 81 Br.

「烷基」是指1至20個碳原子的直鏈或支鏈飽和脂肪族烴基，較佳為1至8個碳原子的烷基，更佳為1至6個碳原子的烷基，進一步較佳為1至4個碳原子的烷基。非限制性實施例包括甲基、乙基、正丙基、異丙基、正丁基、第二丁基、新丁基、第三丁基、正戊基、異戊基、新戊基、正己基及其各種支鏈異構物；所述的烷基可以任選進一步被0至6個選自F、Cl、Br、I、羥基、巰基、硝基、氰基、氨基、烷基氨基、醯胺基、烯基、炔 基、C1-6烷基、C1-6羥基烷基、C1-6烷氧基、3至8員碳環基、3至8員雜環基、3至8員碳環基氧基、3至8員雜環基氧基、羧基或者羧酸酯基的取代基所取代，本文中出現的烷基，其定義與本定義一致。 "Alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, further An alkyl group of 1 to 4 carbon atoms is preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, second butyl, neobutyl, third butyl, n-pentyl, isopentyl, neopentyl, N-hexyl and its various branched chain isomers; the alkyl group may optionally be further selected from 0 to 6 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, and alkylamino , Amido, alkenyl, alkynyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 3 to 8-membered carbocyclyl, 3 to 8-membered heterocyclyl, 3 to 8-membered carbocyclyloxy, 3 to 8-membered heterocyclyloxy, carboxyl, or carboxylate groups are substituted by the substituents, and the definition of alkyl in this text is consistent with this definition.

「烷氧基」是指-O-烷基。非限制性實施例包括甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、第二丁氧基、第三丁氧基、正戊氧基、正己氧基、環丙氧基和環丁氧基。所述的烷基可以任選進一步被0至5個選自F、Cl、Br、I、羥基、巰基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羥基烷基、烷氧基、碳環基、雜環基、碳環基氧基、雜環基氧基、羧基或者羧酸酯基的取代基所取代。本文中出現的烷氧基，其定義與本定義一致。 "Alkoxy" refers to -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, second butoxy, third butoxy, n-pentoxy, n-hexyloxy, Cyclopropoxy and cyclobutoxy. The alkyl group may be optionally further selected from 0 to 5 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, and hydroxyl The alkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylate substituents are substituted. The definition of alkoxy as used herein is consistent with this definition.

「硫烷基」是指-S-烷基。非限制性實施例包括甲硫基、乙硫基、正丙硫基、異丙硫基、正丁硫基、第二丁硫基、第三丁硫基、正戊硫基、正己硫基、環丙硫基和環丁硫基。所述的烷基可以任選進一步被0至5個選自F、Cl、Br、I、羥基、巰基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羥基烷基、烷氧基、碳環基、雜環基、碳環基氧基、雜環基氧基、羧基或者羧酸酯基的取代基所取代。本文中出現的硫烷基，其定義與本定義一致。 "Sulfanyl" refers to -S-alkyl. Non-limiting examples include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, second butylthio, third butylthio, n-pentylthio, n-hexylthio, Cyclopropylthio and cyclobutylthio. The alkyl group may be optionally further selected from 0 to 5 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, and hydroxyl The alkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylate substituents are substituted. As used herein, the definition of sulfanyl group is consistent with this definition.

「氨基」是指-NH2。 "Amino" means -NH 2 .

「氰基」是指。 `` Cyano '' means .

「羥基」是指-OH。 "Hydroxy" means -OH.

「巰基」是指-SH。 "Mercapto" refers to -SH.

「羧基」是指-COOH。 "Carboxy" means -COOH.

「烯基」是指含有1至3個碳-碳雙鍵，由2至20個碳原子組成的直鏈或者支鏈不飽和脂肪族烴基，較佳為2至12個碳原子的烯基，更佳為2至 8個碳原子的烯基，進一步較佳為2至6個碳原子的烯基。非限制性實施例包括乙烯基、丙烯-2-基、丁烯-2-基、戊烯-2-基、戊烯-4-基、己烯-2-基、己烯-3-基、庚烯-2-基、庚烯-3-基、庚烯-4-基、辛烯-3-基、壬烯-3-基、癸烯-4-基和十一烯-3-基。所述的烯基可以任選進一步被0至6個選自F、Cl、Br、I、烷基、烷氧基、直鏈烯基、直鏈炔基、氨基、硝基、氰基、巰基、醯胺基、碳環基或者雜環基的取代基所取代。 "Alkenyl" means a straight-chain or branched unsaturated aliphatic hydrocarbon group containing 1 to 3 carbon-carbon double bonds and composed of 2 to 20 carbon atoms, preferably an alkenyl group of 2 to 12 carbon atoms, More preferably 2 to An alkenyl group of 8 carbon atoms, more preferably an alkenyl group of 2 to 6 carbon atoms. Non-limiting examples include vinyl, propylene-2-yl, butene-2-yl, pentene-2-yl, pentene-4-yl, hexen-2-yl, hexene-3-yl, Hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and undecen-3-yl. The alkenyl may optionally be further selected from 0 to 6 selected from F, Cl, Br, I, alkyl, alkoxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, and mercapto , Amidino, carbocyclic or heterocyclic substituents.

「炔基」是指含有1至3個碳-碳參鍵，由2至20個碳原子組成的直鏈或者支鏈不飽和脂肪族烴基，較佳2至12個碳原子的炔基，更佳2至8個碳原子的炔基，進一步較佳2至6個碳原子的炔基。非限制性實施例包括乙炔基、丙炔-1-基、丙炔-2-基、丁炔-1-基、丁炔-2-基、丁炔-3-基、3,3-二甲基丁炔-2-基、戊炔-1-基、戊炔-2-基、己炔-1-基、1-庚炔-1-基、庚炔-3-基、庚炔-4-基、辛炔-3-基、壬炔-3-基、癸炔-4-基、十一炔-3-基、十二炔-4-基。所述的炔基可以任選進一步被0至4個選自F、Cl、Br、I、烷基、烷氧基、直鏈烯基、直鏈炔基、氨基、硝基、氰基、巰基、醯胺基、碳環基或者雜環基的取代基所取代。 "Alkynyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group containing 1 to 3 carbon-carbon reference bonds and composed of 2 to 20 carbon atoms, preferably an alkynyl group of 2 to 12 carbon atoms, more An alkynyl group of 2 to 8 carbon atoms is preferred, and an alkynyl group of 2 to 6 carbon atoms is more preferred. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl Butylacetyl-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4- , Octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl. The alkynyl may optionally be further selected from 0 to 4 selected from F, Cl, Br, I, alkyl, alkoxy, straight alkenyl, straight alkynyl, amino, nitro, cyano, and thiol , Amidino, carbocyclic or heterocyclic substituents.

「碳環基」是指飽和或者不飽和的非芳香環，非芳香環可以是3至8員的單環、4至12員稠合環或者10至15員三環體系，碳環基可以連接有橋環或者螺環，非限制性實施例包括環丙基、環丁基、環戊基、環己基、環 庚基、環辛基、環癸基和環十二烷基、環丁烯、環戊烯、環己烯、、 、、。所述的碳環基可以任選進一步被0至8個選自F、 Cl、Br、I、=O、羥基、巰基、硝基、氰基、氨基、烷基氨基、醯胺基、烯基、炔基、烷基、羥基烷基、烷氧基、碳環基、雜環基、碳環基氧基、雜環基氧基、羧基或者羧酸酯基所取代。本文中出現的碳環基，其定義與 本定義一致。 "Carbocyclyl" refers to a saturated or unsaturated non-aromatic ring. The non-aromatic ring can be a 3 to 8-membered monocyclic ring, a 4 to 12-membered fused ring, or a 10 to 15-membered tricyclic system. The carbocyclic group can be connected Bridged or spiro rings, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclobutene, Cyclopentene, cyclohexene, , , , . The carbocyclic group may optionally be further selected from 0 to 8 selected from F, Cl, Br, I, = 0, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amido, and alkenyl , Alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylate. The definition of carbocyclyl appearing in this text is consistent with this definition.

「雜環基」是指取代的或未取代的飽和或不飽和的芳香環或者非芳香環，芳香環或者非芳香環可以是3至8員的單環、4至12員雙環或者10至15員三環體系，且包含1至3個選自N、O或S的雜原子，較佳為3至8員雜環基，雜環基的環中選擇性取代的N、S可被氧化成各種氧化態。雜環基可以連接在雜原子或者碳原子上，雜環基可以連接有橋環或者螺環，非限制性實施例包括環氧乙基、氮雜環丙基、氧雜環丁基、氮雜環丁基、1,3-二氧戊環基、1,4-二氧戊環基、1,3-二氧六環基、氮雜環庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、噠嗪基、咪唑基、哌啶基、嗎啉基、硫代嗎啉基、1,3-二噻基、二氫呋喃基、二氫吡喃基、二噻戊環基、四氫呋喃基、四氫吡咯基、四氫咪唑基、四氫噻唑基、四氫吡喃基、苯並咪唑基、苯並吡啶基、吡咯並吡啶基、苯並二氫呋喃基、氮雜二環[3.2.1]辛烷基、氮雜二環[5.2.0]壬烷基、氧雜三環[5.3.1.1]十二烷基、氮雜金刚烷基和氧雜螺[3.3]庚烷基。所述的雜環基可以任選進一步被0至5個選自F、Cl、Br、I、=O、羥基、巰基、硝基、氰基、氨基、烷基氨基、醯胺基、烯基、炔基、烷基、羥基烷基、烷氧基、碳環基、雜環基、碳環基氧基、雜環基氧基、羧基或者羧酸酯基的取代基所取代。本文中出現的雜環基，其定義與本定義一致。 "Heterocyclyl" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring. The aromatic or non-aromatic ring may be a monocyclic ring of 3 to 8 members, a bicyclic ring of 4 to 12 members, or 10 to 15 members. Is a three-membered ring system and contains 1 to 3 heteroatoms selected from N, O or S, preferably 3 to 8 membered heterocyclic groups. The optionally substituted N and S in the ring of the heterocyclic group may be oxidized to Various oxidation states. The heterocyclic group may be attached to a heteroatom or a carbon atom, and the heterocyclic group may be attached to a bridged or spiro ring. Non-limiting examples include epoxyethyl, azetidinyl, oxetanyl, and aza Cyclobutyl, 1,3-dioxolyl, 1,4-dioxolyl, 1,3-dioxolyl, azacycloheptyl, pyridyl, furyl, thienyl, pyridine Ranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiayl, dihydrofuranyl , Dihydropyranyl, dithiapentyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridine Base, benzodihydrofuryl, azabicyclo [3.2.1] octyl, azabicyclo [5.2.0] nonanyl, oxatricyclo [5.3.1.1] dodecyl, nitrogen Heteradamantyl and oxaspiro [3.3] heptyl. The heterocyclic group may optionally be further selected from 0 to 5 selected from F, Cl, Br, I, = 0, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amido, and alkenyl Alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylate substituents. The definition of heterocyclyl appearing herein is consistent with this definition.

「氨基保護基」是指用於氨基保護的基團，該基團適用於保護氨基，使氨基不進行化學反應，但是在分子的其它部分完成所需化學反應之後該基團容易除去。非限制性實施例包括但不限於甲醯基、乙醯基、苯基醯基、甲氧基羰基、乙氧基羰基、2,2,2-三氯乙氧羰基、丙氧基羰基、第三丁氧基羰基、苄基氧基羰基、苯氧基羰基、9-芴基甲基氧基羰基、金剛烷基氧基羰 基、苄基氧基羰基、苄基羰基、苄基、苯甲基、三苯甲基、鄰苯二甲醯基。 "Amino protecting group" refers to a group for protecting an amino group. This group is suitable for protecting an amino group so that the amino group does not undergo a chemical reaction, but the group is easily removed after the other parts of the molecule have completed the required chemical reaction. Non-limiting examples include, but are not limited to, methylamyl, ethylamyl, phenylamyl, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, propoxycarbonyl, Tributoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, 9-fluorenylmethyloxycarbonyl, adamantyloxycarbonyl Group, benzyloxycarbonyl, benzylcarbonyl, benzyl, benzyl, trityl, phthalyl.

「羧基保護基」是指用於羧基保護的基團，該基團適用於保護羧基，使羧基不進行化學反應，但是在分子的其它部分完成所需化學反應之後該基團容易除去。非限制性實施例包括但不限於甲基、乙基、正丙基、異丙基、正丁基、第二丁基、新丁基、第三丁基、正戊基、異戊基、新戊基、正己基、三氯乙基、苄基、對硝基苄基、鄰硝基苄基、對甲氧基苄基、對第三丁基苄基、乙醯氧基甲基、丙醯氧基甲基、丁醯氧基甲基、異丁醯氧基甲基、戊氧基甲基、新戊醯氧基甲基、乙醯氧基乙基、乙醯氧基丙基、乙醯氧基丁基、丙醯氧基乙基、丙醯氧基丙基、丁醯氧基乙基、異丁醯氧基乙基、新戊醯氧基乙基、己醯氧基乙基、異丁醯氧基甲基、乙基丁醯氧基甲基、二甲基丁醯氧基甲基、戊醯氧基乙基、甲氧基羰氧基甲基、乙氧基羰氧基甲基、丙氧基羰氧基乙基、異丙氧基羰氧基乙基、第三丁氧基羰氧基甲基、甲氧基羰氧基乙基、乙氧基羰氧基乙基、異丙氧基羰氧基乙基、第三丁基二甲基甲矽烷基、三甲基甲矽烷基、甲氧基甲基、乙氧基甲基、丙氧基甲基、異丙氧基甲基、(2-甲基硫代)-乙基、3-甲基-2-丁烯基、5-茚滿基和3-2-苯並[C]呋喃酮亞基。 "Carboxy protecting group" refers to a group for protecting a carboxyl group. This group is suitable for protecting a carboxyl group so that the carboxyl group does not undergo a chemical reaction, but the group is easily removed after the other part of the molecule has completed the required chemical reaction. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, second butyl, neobutyl, third butyl, n-pentyl, isopentyl, neo Pentyl, n-hexyl, trichloroethyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, p-methoxybenzyl, p-tert-butylbenzyl, ethoxymethyl, propane Oxymethyl, butoxymethyl, isobutyloxymethyl, pentoxymethyl, neopentyloxymethyl, ethoxyethyl, ethoxypropyl, ethoxy Oxybutyl, propionyloxyethyl, propionyloxypropyl, butyryloxyethyl, isobutylpyroxyethyl, neopentyloxyethyl, hexamethyleneoxyethyl, isopropyl Butyloxymethyl, ethylbutyloxymethyl, dimethylbutyloxymethyl, pentyloxyethyl, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl , Propoxycarbonyloxyethyl, isopropoxycarbonyloxyethyl, third butoxycarbonyloxymethyl, methoxycarbonyloxyethyl, ethoxycarbonyloxyethyl, isopropyl Propoxycarbonyloxyethyl, tert-butyldimethylsilyl, trimethylsilyl Methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, (2-methylthio) -ethyl, 3-methyl-2-butenyl, 5- Indanyl and 3-2-benzo [C] furanone.

「藥學上可接受的鹽」或者「其藥學上可接受的鹽」是指本發明化合物保持游離酸或者游離鹼的生物有效性和特性，且所述的游離酸通過與無毒的無機鹼或者有機鹼，所述的游離鹼通過與無毒的無機酸或者有機酸反應獲得的鹽。所述的無機鹼的非限制性實施例包括Al、Ca、Li、Mg、K、Na和Zn；所述的有機鹼的非限制性實施例包括氨、異丙基胺、三甲基胺、二乙胺、三乙胺、三丙基胺、四甲基胺、二乙醇胺、乙醇胺、二甲基 乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二環己基胺、咖啡鹼、普鲁卡因、膽鹼、甜菜鹼、苯明青黴素、乙二胺、葡萄糖胺、N-甲基甲基葡糖胺、可可鹼、三乙醇胺、氨丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶和聚胺樹脂；所述的無機酸和有機酸的非限制性實施例包括硫酸、磷酸、硝酸、氫溴酸、鹽酸、甲酸、乙酸、丙酸、苯磺酸、苯甲酸、苯乙酸、水楊酸、褐藻酸、氨茴酸、樟腦酸、檸檬酸、乙烯磺酸、蟻酸、富馬酸、糠酸、葡萄糖酸、葡萄糖醛酸、谷胺酸、乙醇酸、羥乙磺酸、乳酸、馬來酸、蘋果酸、扁桃酸、黏液酸、雙羥萘酸、泛酸、硬脂酸、琥珀酸、磺胺酸、酒石酸、對甲苯磺酸、丙二酸、2-羥基丙酸、草酸、羥乙酸、葡萄糖醛酸、半乳糖醛酸、枸橼酸、賴胺酸、精胺酸、門冬胺酸、肉桂酸、對甲苯磺酸、甲磺酸、乙磺酸和三氟甲磺酸。 "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the compound of the present invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is passed through a non-toxic inorganic base or organic Base, the free base is a salt obtained by reacting with a non-toxic inorganic or organic acid. The non-limiting examples of the inorganic base include Al, Ca, Li, Mg, K, Na, and Zn; the non-limiting examples of the organic base include ammonia, isopropylamine, trimethylamine, Diethylamine, triethylamine, tripropylamine, tetramethylamine, diethanolamine, ethanolamine, dimethyl Ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, benzyl penicillin, ethylenediamine, glucosamine, N-formyl Methyl glucosamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins; non-limiting implementation of the inorganic and organic acids described Examples include sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, and ethylenesulfonic acid. Acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucinic acid, pamoic acid, Pantothenic acid, stearic acid, succinic acid, sulfamic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, lysine acid , Arginine, aspartic acid, cinnamic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, and trifluoromethanesulfonic acid acid.

「藥物組合物」是指一種或多種本發明所述化合物、其藥學上可接受的鹽或前藥和其它化學組分形成的混合物，其中，「其它化學組分」是指藥學上可接受的載體、賦形劑及/或一種或多種其它治療劑。 "Pharmaceutical composition" refers to a mixture of one or more compounds described in the present invention, a pharmaceutically acceptable salt or prodrug thereof, and other chemical components, wherein "other chemical components" means pharmaceutically acceptable A carrier, excipient, and / or one or more other therapeutic agents.

「載體」是指不會對生物體產生明顯刺激且不會消除所給予化合物的生物活性和特性的材料。 "Carrier" refers to a material that does not cause significant irritation to the organism and does not eliminate the biological activity and characteristics of the compound being administered.

「賦形劑」是指加入到藥物組合物中以促進化合物給藥的惰性物質。非限制性實施例包括碳酸鈣、磷酸鈣、糖、澱粉、纖維素衍生物(包括微晶纖維素)、明膠、植物油、聚乙二醇類、稀釋劑、成粒劑、潤滑劑、黏合劑和崩解劑。 "Excipient" means an inert substance added to a pharmaceutical composition to facilitate the administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulators, lubricants, binders And disintegrants.

「前藥」是指可羥體內代謝轉化為具有生物活性的本發明化合物。本發明的前藥通過修飾本發明化合物中的氨基或者羧基來製備，該修飾可以通過例行的操作或者在體內被除去，而得到母體化合物。當本發明的前藥被施予哺乳動物個體時，前藥被割裂形成游離的氨基或者羧基。 "Prodrug" refers to a compound of the present invention that can be metabolized in vivo to hydroxyl compounds. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by routine operations or in vivo to obtain the parent compound. When a prodrug of the invention is administered to a mammalian individual, the prodrug is cleaved to form a free amino or carboxyl group.

「共晶」是指活性藥物成分(API)和共晶形成物(CCF)在氫鍵或其他非共價鍵的作用下結合而成的晶體，其中API和CCF的純態在室溫下均為固體，並且各組分間存在固定的化學計量比。共晶是一種多組分晶體，既包含兩種中性固體之間形成的二員共晶，也包含中性固體與鹽或溶劑化物形成的多元共晶。非限定性實例包括丙胺酸、纈胺酸、亮胺酸、異亮胺酸、脯胺酸、***酸、色胺酸、蛋胺酸、甘胺酸、丝胺酸、苏胺酸、半胱胺酸、酪胺酸、天冬醯胺、谷氨醯胺、賴胺酸、精胺酸、組胺酸、天冬胺酸、門冬胺酸、谷胺酸、焦谷胺酸、硫酸、磷酸、硝酸、氫溴酸、鹽酸、甲酸、乙酸、丙酸、苯磺酸、苯甲酸、苯乙酸、水楊酸、褐藻酸、氨茴酸、樟腦酸、檸檬酸、乙烯磺酸、蟻酸、富馬酸、糠酸、葡萄糖酸、葡萄糖醛酸、谷胺酸、乙醇酸、羥乙磺酸、乳酸、馬來酸、蘋果酸、扁桃酸、黏液酸、雙羥萘酸、泛酸、硬脂酸、琥珀酸、磺胺酸、酒石酸、對甲苯磺酸、丙二酸、2-羥基丙酸、草酸、羥乙酸、葡萄糖醛酸、半乳糖醛酸、枸據酸、肉桂酸、對甲苯磺酸、甲磺酸、乙磺酸或三氟甲磺酸、氨、異丙基胺、三甲基胺、二乙胺、三乙胺、三丙基胺、二乙醇胺、乙醇胺、二甲基乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二環己基胺、咖啡鹼、普鲁卡因、膽鹼、甜菜鹼、苯明青黴素、乙二胺、葡萄糖胺、甲基葡糖胺、可可鹼、三乙醇胺、氨丁三醇、嘌呤、哌嗪、哌啶和N-乙基哌啶。 "Co-crystal" refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds.The pure states of API and CCF are both at room temperature. Is solid and there is a fixed stoichiometric ratio between the components. A eutectic is a multi-component crystal that includes both a two-member eutectic formed between two neutral solids and a multi-element eutectic formed by a neutral solid and a salt or solvate. Non-limiting examples include alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine Amino acid, tyrosine, asparagine, glutamine, lysine, arginine, histamine, aspartic acid, aspartic acid, glutamic acid, pyroglutamic acid, sulfuric acid, Phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, ethylenesulfonic acid, formic acid, Fumaric acid, furoic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucinic acid, pamoic acid, pantothenic acid, stearic acid Acid, succinic acid, sulfamic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, cinnamic acid, p-toluenesulfonic acid , Methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethyl Amine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, benzyl penicillin, ethylenediamine , Glucosamine, methylglucosamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, and N-ethylpiperidine.

「動物」是指包括哺乳動物，例如人、陪伴動物、動物園動物和家畜，較佳為人、馬或者犬。 "Animal" means mammals, such as humans, companion animals, zoo animals, and domestic animals, preferably humans, horses, or dogs.

「立體異構物」是指由分子中原子在空間上排列方式不同所產生的異構物，包括順反異構物、對映異構物和構象異構物。 "Stereoisomers" refer to isomers produced by the different arrangement of atoms in the molecule in space, including cis-trans isomers, enantiomers and conformers.

「任選」或「任選地」、「選擇性的」或「選擇性地」是指隨後所述的事件或狀況可以但未必發生，該描述包括其中發生該事件或狀況的情況及 其中未發生的情況。例如，「選擇性地被烷基取代的雜環基」是指該烷基可以但未必存在，該描述包括其中雜環基被烷基取代的情況，及其中雜環基未被烷基取代的情況。 "Optional" or "optionally", "optionally" or "optionally" means that the event or condition described later can, but does not necessarily occur, the description includes the situation in which the event or condition occurred and None of which happened. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but does not necessarily exist, and the description includes a case where the heterocyclic group is substituted with an alkyl group, and a heterocyclic group in which the heterocyclic group is not substituted with an alkyl group. Happening.

IC50(被測量的抑制劑的半抑制濃度)：通過測試受試化合物50%抑制加巴噴丁與鈣離子通道結合所需的濃度。 IC 50 (inhibitor measured half inhibitory concentration): Inhibition of gabapentin and calcium channel binding test required by the test compound concentration of 50%.

以下結合附圖及實施例詳細說明本發明的技術方案，但本發明的保護範圍包括但是不限於此。 The technical solutions of the present invention are described in detail below with reference to the drawings and embodiments, but the protection scope of the present invention includes but is not limited to this.

化合物的結構是通過核磁共振(NMR)或(和)質譜(MS)來確定的。NMR位移(δ)以10-6(ppm)的單位給出。NMR的測定是用(Bruker Avance III 400和Bruker Avance 300)核磁儀，測定溶劑為氘代二甲基亞碸(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，內標為四甲基矽烷(TMS)；MS的測定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；HPLC的測定使用Agilent 1260DAD高壓液相層析儀(Zorbax SB-C18 100×4.6mm,3.5μM)；薄層層析矽膠板使用烟台黃海HSGF254或青島GF254矽膠板，薄層層析法(TLC)使用的矽膠板採用的規格是0.15mm-0.20mm，薄層層析分離純化產品採用的規格是0.4mm-0.5mm；管柱層析一般使用烟台黃海矽膠200-300目矽膠為載體；本發明的已知起始原料可以採用或按照本領域已知的方法來合成，或可購買於泰坦科技、安耐吉化學、上海德默、成都科龍化工、韶遠化學科技、百靈威科技等公司； 氮氣氛是指反應瓶連接一個約1L容積的氮氣氣球；氫氣氛是指反應瓶連接一個約1L容積的氫氣氣球；氫化反應通常抽真空，充入氫氣，反復操作3次；若實施例中無特殊說明，反應在氮氣氛下進行；若實施例中無特殊說明，溶液是指水溶液；若實施例中無特殊說明，反應的溫度為室溫，室溫最適宜的反應溫度，為20℃-30℃；Et，乙基；tBu：第三丁基；Ms：甲磺醯基；PhSO3H：苯磺酸。 The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). NMR measurements were performed using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic analyzers. The solvents used for the determination were deuterated dimethylsulfinium (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD). ), The internal standard is tetramethylsilane (TMS); the determination of MS (Agilent 6120B (ESI) and Agilent 6120B (APCI)); HPLC measurement using Agilent 1260DAD high pressure liquid chromatography (Zorbax SB-C18 100 × 4.6mm, 3.5μM); thin-layer chromatography silica gel plate using Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, thin-layer chromatography (TLC) silica-gel plate used specifications are 0.15mm-0.20mm, thin-layer chromatography separation The specifications of the purified product are 0.4mm-0.5mm; column chromatography generally uses Yantai Huanghai Silicone 200-300 mesh silica gel as a carrier; the known starting materials of the present invention can be synthesized by or in accordance with methods known in the art, Or can be purchased from Titan Technology, Aniji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bellingway Technology and other companies; Nitrogen atmosphere refers to the reaction flask connected to a nitrogen balloon of about 1L volume; hydrogen atmosphere refers to The reaction flask is connected to a hydrogen balloon with a volume of about 1L; the hydrogenation reaction is usually pumped Vacuum, fill with hydrogen, repeat the operation 3 times; if there is no special instruction in the examples, the reaction is performed under a nitrogen atmosphere; if there is no special instructions in the examples, the solution refers to an aqueous solution; if there is no special instructions in the examples, the reaction temperature It is room temperature, and the optimum reaction temperature at room temperature is 20 ° C-30 ° C; Et, ethyl; tBu: third butyl; Ms: methanesulfonyl; PhSO 3 H: benzenesulfonic acid.

中間體1：(1aR,1a1r,3as,5aS)-八氫-1H-環丁烷[cd]戊搭烯-1-酮 Intermediate 1 : (1aR, 1a 1 r, 3as, 5aS) -octahydro-1H-cyclobutane [cd] pentaden-1-one

(1aR,1a1r,3as,5aS)-octahydro-1H-cyclobuta[cd]pentalen-1-one (1aR, 1a 1 r, 3as, 5aS) -octahydro-1H-cyclobuta [cd] pentalen-1-one

第一步：(1S,5R,7S)-7-(2-氯乙基)雙環[3.2.0]庚-2-烯-6-酮(1B) First step: (1S, 5R, 7S) -7- (2-chloroethyl) bicyclo [3.2.0] hept-2-en-6-one (1B)

(1S,5R,7S)-7-(2-chloroethyl)bicyclo[3.2.0]hept-2-en-6-one (1S, 5R, 7S) -7- (2-chloroethyl) bicyclo [3.2.0] hept-2-en-6-one

向反應瓶中加入1,3-環戊二烯(1A)(6.6g，0.1mol)，環己烷(350mL)，充氮氣保護，加入三乙胺(3.5g，35mmol)，加熱迴流下，滴加4-氯丁醯氯(4.9g，35.0mmol)的環己烷(25mL)溶液，加完迴流反應4小時。冷卻至室溫後將反應液抽濾，用環己烷洗滌(20mL×3)，合併濾液，依次用飽和氯化銨(150mL×3)和水(150mL×3)洗滌，有機相用無水硫酸鈉乾燥，過濾，將濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=80：1)得到淡黃色油狀液體(1S,5R,7S)-7-(2-氯乙基)雙環[3.2.0]庚-2-烯-6-酮(1B)(1.4g，產率：26%)。 Add 1,3-cyclopentadiene (1A) (6.6 g, 0.1 mol), cyclohexane (350 mL) to the reaction flask, protect with nitrogen, add triethylamine (3.5 g, 35 mmol), and heat and reflux. A solution of 4-chlorobutanechloromethane (4.9 g, 35.0 mmol) in cyclohexane (25 mL) was added dropwise, and the reaction was completed at reflux for 4 hours. After cooling to room temperature, the reaction solution was suction filtered, washed with cyclohexane (20 mL × 3), and the filtrates were combined, washed with saturated ammonium chloride (150 mL × 3) and water (150 mL × 3), and the organic phase was dried with anhydrous sulfuric acid. Sodium was dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 80: 1) to obtain a light yellow oily liquid (1S, 5R, 7S). -7- (2-chloroethyl) bicyclo [3.2.0] hept-2-en-6-one (1B) (1.4 g, yield: 26%).

1H NMR(400MHz,CDCl3)δ 5.95-5.85(m,1H),5.76(ddd,J=6,0,4,1,2.1Hz,1H),3.90-3.79(m,1H),3.74-3.52(m,4H),2.71-2.58(m,1H),2.48-2.33(m,1H),2.04(dq,J=14.3,6.3Hz,1H),1.91-1.77(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 5.95-5.85 (m, 1H), 5.76 (ddd, J = 6, 0, 4, 1, 2.1 Hz, 1H), 3.90-3.79 (m, 1H), 3.74- 3.52 (m, 4H), 2.71-2.58 (m, 1H), 2.48-2.33 (m, 1H), 2.04 (dq, J = 14.3, 6.3Hz, 1H), 1.91-1.77 (m, 1H).

第二步：(1aR,1a1r,3as,5aS)-八氫-1H-環丁烷[cd]戊搭烯-1-酮(中間體1) Second step: (1aR, 1a 1 r, 3as, 5aS) -octahydro-1H-cyclobutane [cd] pentaden-1-one ( intermediate 1 )

(1aR,1a1r,3as,5aS)-octahydro-1H-cyclobuta[cd]pentalen-1-one (1aR, 1a 1 r, 3as, 5aS) -octahydro-1H-cyclobuta [cd] pentalen-1-one

向反應瓶中加入(1S,5R,7S)-7-(2-氯乙基)雙環[3.2.0]庚-2-烯-6-酮(1B)(0.5g，3mmol)，充氮氣保護，加入甲苯(125mL)，加熱至迴流，緩慢滴加三正丁基氫化錫(1.7g，6mmol)和偶氮二異丁腈(0.1g，0.6mmol)的甲苯溶液(40mL)，加畢迴流下攪拌2小時。將反應液冷卻，用水(150mL×2)洗滌，有機相用無水硫酸鈉乾燥，過濾，將濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=100：1)得到無色油狀液體(1aR,1a1r,3as,5aS)-八氫-1H-環丁烷[cd]戊搭烯-1-酮(中間體1)(0.2g，產率： 50%)。 Add (1S, 5R, 7S) -7- (2-chloroethyl) bicyclo [3.2.0] hept-2-en-6-one ( 1B) (0.5g, 3mmol) to the reaction flask and protect with nitrogen. Toluene (125 mL) was added and heated to reflux. Tri-n-butyltin hydride (1.7 g, 6 mmol) and azobisisobutyronitrile (0.1 g, 0.6 mmol) in toluene solution (40 mL) were slowly added dropwise. Stir for 2 hours. The reaction solution was cooled, washed with water (150 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100: 1) A colorless oily liquid (1aR, 1a 1 r, 3as, 5aS) -octahydro-1H-cyclobutane [cd] pentaden-1-one ( intermediate 1 ) (0.2 g, product Rate: 50%).

1H NMR(400MHz,CDCl3)δ 3.53-3.38(m,2H),3.17(q,J=7.6Hz,1H),2.85(tt,J=12.5,6.2Hz,1H),2.00(ddd,J=13.0,7.9,2.3Hz,2H),1.93-1.70(m,4H),1.54(dt,J=11.8,6.6Hz,2H)。 1 H NMR (400MHz, CDCl 3 ) δ 3.53-3.38 (m, 2H), 3.17 (q, J = 7.6Hz, 1H), 2.85 (tt, J = 12.5, 6.2Hz, 1H), 2.00 (ddd, J = 13.0, 7.9, 2.3Hz, 2H), 1.93-1.70 (m, 4H), 1.54 (dt, J = 11.8, 6.6Hz, 2H).

實施例1Example 1

2-((1r,1aR,1a1r,3as,5aS)-1-(氨甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(化合物1) 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) octahydro-1H-cyclobutane [cd] pentadien-1-yl) acetic acid ( compound 1 )

2-((1r,1aR,1a1r,3as,5aS)-1-(aminomethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) octahydro-1H-cyclobuta [cd] pentalen-1-yl) acetic acid

第一步：(2-((1aR,1a1r,3as,5aS)-八氫-1H-環丁烷[cd]戊搭烯-1-亞基)乙酸乙酯(1C) The first step: (2-((1aR, 1a1r, 3as, 5aS) -octahydro-1H-cyclobutane [cd] pentalene-1-ylidene) acetate ( 1C )

Ethyl-2-((1aR,1a1r,3as,5aS)-octahydro-1H-cyclobuta[cd]pentalen-1-ylidene)acetate Ethyl-2-((1aR, 1a1r, 3as, 5aS) -octahydro-1H-cyclobuta [cd] pentalen-1-ylidene) acetate

向反應瓶中加入氫化鈉(60%，60mg，2.4mmol)和四氫呋喃(6mL)，冰水浴降至0℃，滴加三乙基磷醯乙酸酯(0.54g，2.4mmol)的四氫呋喃(2mL) 溶液，0℃反應1小時，滴加(1aR,1a1r,3as,5aS)-八氫-1H-環丁烷[cd]戊搭烯-1-酮(中間體1)(0.2g，1.5mmol)的四氫呋喃(2mL)溶液，升至室溫反應2小時。向反應液中加入水(10mL)和乙酸乙酯(10mL)，攪拌分液，水相用乙酸乙酯(10mL×2)萃取，合併有機相，用無水硫酸鈉乾燥，過濾，將濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=40：1)得到無色油狀液體(2-((1aR,1a1r,3as,5aS)-八氫-1H-環丁烷[cd]戊搭烯-1-亞基)乙酸乙酯(1C)(0.18g，產率：60%)。 Add sodium hydride (60%, 60mg, 2.4mmol) and tetrahydrofuran (6mL) to the reaction flask, reduce the temperature to 0 ° C in an ice-water bath, and dropwise add triethylphosphonium acetate (0.54g, 2.4mmol) in tetrahydrofuran (2mL). ) Solution, react at 0 ° C for 1 hour, and dropwise add (1aR, 1a 1 r, 3as, 5aS) -octahydro-1H-cyclobutane [cd] pentan-1-one ( intermediate 1 ) (0.2g, A 1.5 mmol) solution of tetrahydrofuran (2 mL) was warmed to room temperature and reacted for 2 hours. Water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, and the layers were stirred and separated. The aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed. Concentrated, the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 40: 1) to obtain a colorless oily liquid (2-((1aR, 1a1r, 3as, 5aS) -octahydro- 1H-cyclobutane [cd] pentalene-1-ylidene) acetate ( 1C ) (0.18 g, yield: 60%).

MS m/z(ES1)：207.3(M+1)。 MS m / z (ES1): 207.3 (M + 1).

1H NMR(400MHz,CDCl3)δ 5.56(t,J=2.2Hz,1H),4.22-4.08(q,2H),3.59-3.46(m,1H),3.27-3.12(m,1H),2.99(q,J=7.4Hz,1H),2.74-2.57(m,1H),1.87-1.48(m,8H),1.30-1.23(t,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 5.56 (t, J = 2.2Hz, 1H), 4.22-4.08 (q, 2H), 3.59-3.46 (m, 1H), 3.27-3.12 (m, 1H), 2.99 (q, J = 7.4Hz, 1H), 2.74-2.57 (m, 1H), 1.87-1.48 (m, 8H), 1.30-1.23 (t, 3H).

第二步：2-((1r,1aR,1a1r,3as,5aS)-1.-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸乙酯(1D) Second step: 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1 .- (nitromethyl) octahydro-1H-cyclobutane [cd] pentalen-1-yl) acetic acid Ethyl ester ( 1D )

ethyl-2-((1r,1aR,1a1r,3as,5aS)-1-(nitromethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetate ethyl-2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (nitromethyl) octahydro-1H-cyclobuta [cd] pentalen-1-yl) acetate

向反應瓶中加入(2-((1aR,1a1r,3as,5aS)-八氫-1H-環丁烷[cd]戊搭烯-1-亞基)乙酸乙酯(1C)(2.0g，10.0mmol)，硝基甲烷(30mL)和1,8-二氮雜雙環[5.4.0]十一碳-7-烯(1.5g，10.0mmol)，升溫至70℃反應8小時。向反應液中加入乙酸乙酯(30mL)和1M的鹽酸水溶液(20mL)，分液，水相用乙酸乙酯萃取(30mL×2)，合併有機相，用無水硫酸鈉乾燥，過濾，將濾液減壓濃 縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=40：1)，得到無色油狀液體2-((1r,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸乙酯(1D)(1.6g，產率：60%)。 To the reaction flask was added (2-((1aR, 1a1r, 3as, 5aS) -octahydro-1H-cyclobutane [cd] pentadiene-1-ylidene) acetate ( 1C ) (2.0g, 10.0 mmol), nitromethane (30 mL) and 1,8-diazabicyclo [5.4.0] undec-7-ene (1.5 g, 10.0 mmol), and the temperature was raised to 70 ° C for 8 hours. Into the reaction solution Ethyl acetate (30 mL) and 1M aqueous hydrochloric acid solution (20 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 40: 1) to obtain a colorless oily liquid 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1 -(Nitromethyl) octahydro-1H-cyclobutane [cd] pentalen-1-yl) ethyl acetate ( 1D ) (1.6 g, yield: 60%).

1H NMR(400MHz,CDCl3)δ 4.83(s,2H),4.13(q,J=7.1Hz,2H),2.97(q,J=7.9Hz,1H),2.65-2.45(m,5H),1.82-1.65(m,4H),1.64-1.53(m,2H),1.52-1.39(m,2H),1.26(dd,J=8.4,5.9Hz,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 4.83 (s, 2H), 4.13 (q, J = 7.1Hz, 2H), 2.97 (q, J = 7.9Hz, 1H), 2.65-2.45 (m, 5H), 1.82-1.65 (m, 4H), 1.64-1.53 (m, 2H), 1.52-1.39 (m, 2H), 1.26 (dd, J = 8.4, 5.9Hz, 3H).

第三步：2-((1r,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(1E) Third step: 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (nitromethyl) octahydro-1H-cyclobutane [cd] pentalen-1-yl) acetic acid ( 1E )

2-((1r,1aR,1a1r,3as,5aS)-1-(nitromethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (nitromethyl) octahydro-1H-cyclobuta [cd] pentalen-1-yl) acetic acid

向反應瓶中加入2-((1r,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸乙酯(1D)(1.5g，5.6mmol)，甲醇(18mL)，滴加氫氧化鈉(0.3g，5.6mmol)的水溶液(6mL)，60℃下反應5小時。冰浴下滴加1M的鹽酸至pH約為2，用乙酸乙酯(60mL×3)萃取，合併有機相，用水(60mL×3)洗滌，無水硫酸鈉乾燥，過濾，將濾液減壓濃縮，殘留物用矽膠柱層析分離純化(二氯甲烷/甲醇(v/v)=50：1)得到淡黃色油狀液體2-((1r,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(1E)(0.8g，產率：61%)。 To the reaction flask was added 2 - ((1r, 1aR, 1a 1 r, 3as, 5aS) -1- ( nitromethyl) cyclobutane octahydro -1H- [cd] pentalene-en-1-yl) acetic acid Ethyl acetate ( 1D ) (1.5 g, 5.6 mmol), methanol (18 mL), an aqueous solution (6 mL) of sodium hydroxide (0.3 g, 5.6 mmol) was added dropwise, and the mixture was reacted at 60 ° C for 5 hours. 1M hydrochloric acid was added dropwise to an pH of about 2 under an ice bath, and extracted with ethyl acetate (60 mL × 3). The organic phases were combined, washed with water (60 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 50: 1) to give a pale yellow oily liquid 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (Nitromethyl) octahydro-1H-cyclobutane [cd] pentalen-1-yl) acetic acid ( 1E ) (0.8 g, yield: 61%).

MS m/z(ESI)：262.1(M+23)。 MS m / z (ESI): 262.1 (M + 23).

1H NMR(400MHz,CDCl3)δ4.83(s,2H),2.98(q,J=7.9Hz,1H),2.66-2.46(m,5H),1.86-1.67(m,4H),1.66-1.53(m,2H),1.53-1.40(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ 4.83 (s, 2H), 2.98 (q, J = 7.9Hz, 1H), 2.66-2.46 (m, 5H), 1.86-1.67 (m, 4H), 1.66- 1.53 (m, 2H), 1.53-1.40 (m, 2H).

第四步：2-((1r,1aR,1a1r,3as,5aS)-1-(氨甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(化合物1) Fourth step: 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) octahydro-1H-cyclobutane [cd] pentaden-1-yl) acetic acid ( compound 1 )

2-((1r,1aR,1a1r,3as,5aS)-1-(aminomethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) octahydro-1H-cyclobuta [cd] pentalen-1-yl) acetic acid

向反應瓶中依次加入2-((1r,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(1E)(0.6g，2.5mmol)，甲醇(15mL)，鈀/碳(10%(w%)，0.6g)，氫氣換氣三次，35℃下氫化反應3小時，將反應液抽濾，甲醇(20mL×3)洗滌，合併濾液，將濾液減壓濃縮得到白色固體，將所得固體用二氯甲烷(50mL)打漿，抽濾，二氯甲烷(15mL×3)洗滌，乾燥，得到白色固體2-((1r,1aR,1a1r,3as,5aS)-1-(氨甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(化合物1)(0.22g，產率：46%)。 To the reaction flask were added 2 - ((1r, 1aR, 1a 1 r, 3as, 5aS) -1- ( nitromethyl) cyclobutane octahydro -1H- [cd] pentalene-en-1-yl) Acetic acid ( 1E ) (0.6g, 2.5mmol), methanol (15mL), palladium / carbon (10% (w%), 0.6g), hydrogen aeration three times, hydrogenation reaction at 35 ° C for 3 hours, and the reaction solution was suction filtered , Methanol (20mL × 3) was washed, the filtrates were combined, and the filtrates were concentrated under reduced pressure to obtain a white solid. The obtained solid was slurried with dichloromethane (50mL), suction filtered, washed with dichloromethane (15mL × 3), and dried to give white 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) octahydro-1H-cyclobutane [cd] pentaden-1-yl) acetic acid ( Compound 1 ) ( 0.22 g, yield: 46%).

MS m/z(ESI)：210.2(M+1)。 MS m / z (ESI): 210.2 (M + 1).

1H NMR(400MHz,CD3OD)δ 3.13(s,2H),3.05-2.93(m,2H),2.42(s,2H),2.37(dd,J=10.2,5.4Hz,2H),1.83-1.65(m,6H),1.58(qd,J=10.7,5.2Hz,2H)。 1H NMR (400MHz, CD 3 OD) δ 3.13 (s, 2H), 3.05-2.93 (m, 2H), 2.42 (s, 2H), 2.37 (dd, J = 10.2, 5.4Hz, 2H), 1.83-1.65 (m, 6H), 1.58 (qd, J = 10.7, 5.2Hz, 2H).

實施例2Example 2

2-((1s,1aR,1a1r,3as,5aS)-1-(氨基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(化合物2) 2-((1s, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) octahydro-1H-cyclobutane [cd] pentadien-1-yl) acetic acid ( compound 2 )

2-((1s,1aR,1a1r,3as,5aS)-1-(aminomethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid 2-((1s, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) octahydro-1H-cyclobuta [cd] pentalen-1-yl) acetic acid

第一步：(1aR,1a1r,3as,5aS)-1-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-醇(2B) The first step: (1aR, 1a 1 r, 3as, 5aS) -1- (nitromethyl) octahydro-1H-cyclobutane [cd] pentalen-1-ol ( 2B )

(1aR,1a1r,3as,5aS)-1-(nitromethyl)octahydro-1H-cyclobuta[cd]peutalen-1-ol (1aR, 1a 1 r, 3as, 5aS) -1- (nitromethyl) octahydro-1H-cyclobuta [cd] peutalen-1-ol

向反應瓶中依次加入(1aR,1a1r,3as,5aS)-八氫-1H-環丁烷[cd]戊搭烯-1-酮(中間體1)(9.7g，71.2mmol)，硝基甲烷(100mL)和1,8-二氮雜雙環[5.4.0]十一碳-7-烯(23.9g，157.0mmol)，室溫反應7小時。加入飽和氯化銨溶液(150mL)，用二氯甲烷(50mL×3)萃取，合併有機相，用無水硫酸鈉乾燥，過濾，將濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=100：1-10：1)得到無色油狀液體(1aR,1a1r,3as,5aS)-1-(硝基甲基)八氫 -1H-環丁烷[cd]戊搭烯-1-醇(2B)(5.8g，產率：41%)。 Add (1aR, 1a 1 r, 3as, 5aS) -octahydro-1H-cyclobutane [cd] pentaden-1-one ( Intermediate 1 ) (9.7g, 71.2mmol) to Methane (100 mL) and 1,8-diazabicyclo [5.4.0] undec-7-ene (23.9 g, 157.0 mmol) were reacted at room temperature for 7 hours. A saturated ammonium chloride solution (150 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum). Ether / ethyl acetate (v / v) = 100: 1-10: 1) to give a colorless oily liquid (1aR, 1a 1 r, 3as, 5aS) -1- (nitromethyl) octahydro-1H-cyclo Butane [cd] pentalen-1-ol ( 2B ) (5.8 g, yield: 41%).

MS m/z(ESI)：220.2(M+23)。 MS m / z (ESI): 220.2 (M + 23).

1H NMR(400MHz,CDCl3)δ 4.54(s,2H),2.75-2.67(m,1H),2.64(ddd,J=10.6,7.1,3.2Hz,1H),2.59-2.53(m,2H),1.97-1.88(m,2H),1.78-1.51(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ 4.54 (s, 2H), 2.75-2.67 (m, 1H), 2.64 (ddd, J = 10.6, 7.1, 3.2Hz, 1H), 2.59-2.53 (m, 2H) , 1.97-1.88 (m, 2H), 1.78-1.51 (m, 6H).

第二步：(1aR,1a1r,3as,5aS)-1-(硝基亞甲基)八氫-1H-環丁烷[cd]戊搭烯(2C) Second step: (1aR, 1a 1 r, 3as, 5aS) -1- (nitromethylene) octahydro-1H-cyclobutane [cd] pentadiene ( 2C )

(1aR,1a1r,3as,5aS)-1-(nitromethylene)octahydro-1H-cyclobuta[cd]pentalene (1aR, 1a 1 r, 3as, 5aS) -1- (nitromethylene) octahydro-1H-cyclobuta [cd] pentalene

向反應瓶中加入(1aR,1a1r,3as,5aS)-1-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-醇(2B)(8.5g，43.0mmol)，三乙胺(13.0g，130.0mmol)和二氯甲烷(215mL)，冷卻至0℃，滴加甲烷磺醯氯(15.0g，130.0mmol)，室溫反應2小時。向反應液中加入水(50mL)，分液，用二氯甲烷(50mL×2)萃取，合併有機相，用無水硫酸鈉乾燥，過濾，將濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=200：1)得到無色油狀液體(1aR,1a1r,3as,5aS)-1-(硝基亞甲基)八氫-1H-環丁烷[cd]戊搭烯(2C)(4.0g，產率：52%)。 To the reaction flask was added (1aR, 1a 1 r, 3as, 5aS) -1- (nitromethyl) octahydro-1H-cyclobutane [cd] pentadien-1-ol ( 2B ) (8.5g, 43.0 mmol), triethylamine (13.0 g, 130.0 mmol) and dichloromethane (215 mL), cooled to 0 ° C., methanesulfonyl chloride (15.0 g, 130.0 mmol) was added dropwise, and the mixture was reacted at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, the layers were separated, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography. Purification (petroleum ether / ethyl acetate (v / v) = 200: 1) gave a colorless oily liquid (1aR, 1a 1 r, 3as, 5aS) -1- (nitromethylene) octahydro-1H-cyclo Butane [cd] pentadiene ( 2C ) (4.0 g, yield: 52%).

MS m/z(ESI)：202.2(M+23)。 MS m / z (ESI): 202.2 (M + 23).

1H NMR(400MHz,CDCl3)δ 6.85(t,J=2.0Hz,1H),3.77-3.69(m,1H),3.32(td,J=7.8,2.0Hz,1H),3.10(q,J=7.3Hz,1H),2.75(dd,J=11.1,6.3Hz,1H),2.10(dtd,J=14.6,8.7,5.9Hz,1H),2.03-1.93(m,2H),1.91-1.75(m,2H), 1.68-1.52(m,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 6.85 (t, J = 2.0Hz, 1H), 3.77-3.69 (m, 1H), 3.32 (td, J = 7.8, 2.0Hz, 1H), 3.10 (q, J = 7.3Hz, 1H), 2.75 (dd, J = 11.1, 6.3Hz, 1H), 2.10 (dtd, J = 14.6, 8.7, 5.9Hz, 1H), 2.03-1.93 (m, 2H), 1.91-1.75 ( m, 2H), 1.68-1.52 (m, 3H).

第三步：2-((1s,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸乙酯(2D) Third step: 2-((1s, 1aR, 1a 1 r, 3as, 5aS) -1- (nitromethyl) octahydro-1H-cyclobutane [cd] pentalen-1-yl) acetic acid ethyl Esters ( 2D )

ethyl-2-((1s,1aR,1a1r,3as,5aS)-1-(nitromethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetate ethyl-2-((1s, 1aR, 1a 1 r, 3as, 5aS) -1- (nitromethyl) octahydro-1H-cyclobuta [cd] pentalen-1-yl) acetate

向反應瓶中加入雙(三甲矽基)氨基鋰(1.0mol/L，6.7g，40.0mmol)，冷卻至-78℃，滴加乙酸乙酯(3.5g，40.0mmol)的四氫呋喃(4mL)溶液，攪拌20分鐘，滴加(1aR,1a1r,3as,5aS)-1-(硝基亞甲基)八氫-1H-環丁烷[cd]戊搭烯(2C)(4.0g，22.0mmol)的四氫呋喃(15mL)溶液，-78℃下反應2小時，加入水(50mL)，用乙酸乙酯(30mL×3)萃取，合併有機相，用無水硫酸鈉乾燥，過濾，將濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=100：1)得到淡黃色油狀液體2-((1s,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸乙酯(2D)(4.0g，產率：67%)。 Add lithium bis (trimethylsilyl) amino (1.0 mol / L, 6.7 g, 40.0 mmol) to the reaction flask, cool to -78 ° C, and dropwise add a solution of ethyl acetate (3.5 g, 40.0 mmol) in tetrahydrofuran (4 mL). , Stirring for 20 minutes, (1aR, 1a 1 r, 3as, 5aS) -1- (nitromethylene) octahydro-1H-cyclobutane [cd] pentaene ( 2C ) (4.0g, 22.0) mmol) of tetrahydrofuran (15 mL) solution, reacted at -78 ° C for 2 hours, added water (50 mL), extracted with ethyl acetate (30 mL x 3), combined organic phases, dried over anhydrous sodium sulfate, filtered, and reduced the pressure of the filtrate Concentrated, the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100: 1) to give a pale yellow oily liquid 2-((1s, 1aR, 1a 1 r, 3as, 5aS) 1- (nitromethyl) octahydro-1H-cyclobutane [cd] pentalen-1-yl) ethyl acetate ( 2D ) (4.0 g, yield: 67%).

MS m/z(ESI)：290.1(M+23)。 MS m / z (ESI): 290.1 (M + 23).

1H NMR(400MHz,CDCl3)δ 4.68(s,2H),4.15(q,J=7.1Hz,2H),2.98(q,J=7.8Hz,1H),2.77(s,2H),2.65-2.56(m,1H),2.48(td,J=7.8,4.0Hz,2H),1.83-1.72(m,4H),1.72-1.61(m,2H),1.53-1.44(m,2H),1.26(dd,J=8.9,5.4Hz,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 4.68 (s, 2H), 4.15 (q, J = 7.1Hz, 2H), 2.98 (q, J = 7.8Hz, 1H), 2.77 (s, 2H), 2.65- 2.56 (m, 1H), 2.48 (td, J = 7.8, 4.0Hz, 2H), 1.83-1.72 (m, 4H), 1.72-1.61 (m, 2H), 1.53-1.44 (m, 2H), 1.26 ( dd, J = 8.9, 5.4 Hz, 3H).

第四步：2-((1s,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(2E) Fourth step: 2-((1s, 1aR, 1a 1 r, 3as, 5aS) -1- (nitromethyl) octahydro-1H-cyclobutane [cd] pentaden-1-yl) acetic acid ( 2E )

2-((1s,1aR,1a1r,3as,5aS)-1-(nitromethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid 2-((1s, 1aR, 1a 1 r, 3as, 5aS) -1- (nitromethyl) octahydro-1H-cyclobuta [cd] pentalen-1-yl) acetic acid

向反應瓶中加入2-((1s,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸乙酯(2D)(4.0g，15.0mmol)，甲醇(24mL)，滴加氫氧化鈉(0.9g，22.0mmol)的水溶液(8mL),60℃下反應5小時。冰浴下滴加1M的鹽酸至pH約為2，用乙酸乙酯(60mL×3)萃取，合併有機相，用水(60mL×3)洗滌，無水硫酸鈉乾燥，過濾，將濾液減壓濃縮，殘留物用矽膠柱層析分離純化(二氯甲烷/甲醇(v/v)=50：1)得到淡黃色油狀液體2-((1s,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(2E)(2.7g，產率：75%)。 Add 2-((1s, 1aR, 1a 1 r, 3as, 5aS) -1- (nitromethyl) octahydro-1H-cyclobutane [cd] pentalen-1-yl) acetic acid to the reaction flask Ethyl acetate ( 2D ) (4.0 g, 15.0 mmol), methanol (24 mL), an aqueous solution (8 mL) of sodium hydroxide (0.9 g, 22.0 mmol) was added dropwise, and the mixture was reacted at 60 ° C for 5 hours. 1M hydrochloric acid was added dropwise to an pH of about 2 under an ice bath, and extracted with ethyl acetate (60 mL × 3). The organic phases were combined, washed with water (60 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 50: 1) to give a pale yellow oily liquid 2-((1s, 1aR, 1a 1 r, 3as, 5aS) -1- (Nitromethyl) octahydro-1H-cyclobutane [cd] pentalen-1-yl) acetic acid ( 2E ) (2.7 g, yield: 75%).

MS m/z(ESI)：262.1(M+23)。 MS m / z (ESI): 262.1 (M + 23).

1H NMR(400MHz,CDCl3)δ 4.68(s,2H),3.00(q,J=7.8Hz,1H),2.87(s,2H),2.61(dt,J=15.6,6.0Hz,1H),2.49(dt,J=11.6,5.8Hz,2H),1.84-1.72(m,4H),1.71-1.61(m,2H),1.55-1.43(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ 4.68 (s, 2H), 3.00 (q, J = 7.8Hz, 1H), 2.87 (s, 2H), 2.61 (dt, J = 15.6, 6.0Hz, 1H), 2.49 (dt, J = 11.6, 5.8 Hz, 2H), 1.84-1.72 (m, 4H), 1.71-1.61 (m, 2H), 1.55-1.43 (m, 2H).

第五步：2-((1s,1aR,1a1r,3as,5aS)-1-(氨基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(化合物2) Step 5: 2-((1s, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) octahydro-1H-cyclobutane [cd] pentalen-1-yl) acetic acid ( compound 2 )

2-((1s,1aR,1a1r,3as,5aS)-1-(aminomethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid 2-((1s, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) octahydro-1H-cyclobuta [cd] pentalen-1-yl) acetic acid

向反應瓶中依次加入2-((1s,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(2E)(2.7g，11.3mmol)，甲醇(60mL)，鈀/碳(10%(w%)，2.7g)，氫氣換氣三次，35℃下氫化反應3小時，將反應液抽濾，甲醇(20mL×3)洗滌，將合併後的濾液減壓濃縮，所得的固體用二氯甲烷(60mL)打漿，抽濾，二氯甲烷(15mL×3)洗滌，乾燥，得到白色固體2-((1s,1aR,1a1r,3as,5aS)-1-(氨基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(化合物2)(1.0g，產率：42%)。 To the reaction flask were added 2 - ((1s, 1aR, 1a 1 r, 3as, 5aS) -1- ( nitromethyl) cyclobutane octahydro -1H- [cd] pentalene-en-1-yl) Acetic acid ( 2E ) (2.7 g, 11.3 mmol), methanol (60 mL), palladium / carbon (10% (w%), 2.7 g), hydrogen gas exchange three times, hydrogenation reaction at 35 ° C for 3 hours, and the reaction solution was suction filtered , Methanol (20mL × 3), the combined filtrate was concentrated under reduced pressure, the resulting solid was slurried with dichloromethane (60mL), suction filtered, washed with dichloromethane (15mL × 3), and dried to give a white solid 2- ((1s, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) octahydro-1H-cyclobutane [cd] pentalen-1-yl) acetic acid ( compound 2 ) (1.0 g, Yield: 42%).

MS m/z(ESI)：210.2(M+1)。 MS m / z (ESI): 210.2 (M + 1).

1H NMR(400MHz,CD3OD)δ 3.05(q,J=7.9Hz,1H),2.97(s,2H),2.69(s,2H),2.60(dt,J=11.4,5.4Hz,1H),2.44(td,J=7.9,3.9Hz,2H),1.85-1.72(m,4H),1.69-1.59(m,2H),1.59-1.51(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ 3.05 (q, J = 7.9Hz, 1H), 2.97 (s, 2H), 2.69 (s, 2H), 2.60 (dt, J = 11.4, 5.4Hz, 1H) , 2.44 (td, J = 7.9, 3.9 Hz, 2H), 1.85-1.72 (m, 4H), 1.69-1.59 (m, 2H), 1.59-1.51 (m, 2H).

實施例3Example 3

2-((1r,1aR,1a1r,3as,5aS)-1-(氨甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基乙酸 苯磺酸鹽(1：1)(化合物3) 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) octahydro-1H-cyclobutane [cd] pentalene-1-ylacetic acid benzenesulfonate (1: 1) ( Compound 3 )

2-((1r,1aR,1a1r,3as,5aS)-1-(aminomethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid benzene sulfonate(1：1) 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) octahydro-1H-cyclobuta [cd] pentalen-1-yl) acetic acid benzene sulfonate (1: 1)

第一步：2-((1r,1aR,1a1r,3as,5aS)-1-(氨甲基)八氫-1H-環丁烷[ed]戊搭烯-1-基)乙酸 苯磺酸鹽(1：1)(化合物3) First step: 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) octahydro-1H-cyclobutane [ed] pentalen-1-yl) benzenesulfonate Acid salt (1: 1) ( compound 3 )

2-((1r,1aR,1a1r,3as,5aS)-1-(aminomethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid benzene sulfonate(1：1) 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) octahydro-1H-cyclobuta [cd] pentalen-1-yl) acetic acid benzene sulfonate (1: 1)

向反應瓶中加入2-((1r,1aR,1a1r,3as,5aS)-1-(氨甲基)八氫-1H-環丁烷[ed]戊搭烯-1-基)乙酸(化合物1)(0.32g，1.53mmol)，甲醇(50mL)，攪拌至完全溶解，滴加苯甲磺酸(0.24g，1.53mmol)的甲醇(5mL)溶液，35℃下反應1小時，將反應液濃縮至乾，得到白色固體2-((1r,1aR,1a1r,3as,5aS)-1-(氨甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸 苯磺酸鹽(1：1)(化合物3)(0.55g，產率：99%)。 To the reaction flask was added 2 - ((1r, 1aR, 1a 1 r, 3as, 5aS) -1- ( aminomethyl) cyclobutane octahydro -1H- [ED] pentalene-en-1-yl) acetic acid ( Compound 1 ) (0.32g, 1.53mmol), methanol (50mL), stirred until completely dissolved, a solution of benzenesulfonic acid (0.24g, 1.53mmol) in methanol (5mL) was added dropwise, and the reaction was carried out at 35 ° C for 1 hour. It was concentrated to dryness to give a white solid 2 - ((1r, 1aR, 1a 1 r, 3as, 5aS) -1- ( aminomethyl) cyclobutane octahydro -1H- [cd] pentalene-en-1-yl ) Acetylbenzenesulfonate (1: 1) ( Compound 3 ) (0.55 g, yield: 99%).

1H NMR(400MHz,CD3OD)δ 7.91-7.79(m,2H),7.52-7.37(m,3H),3.33(s,2H),3.01(q,J=7.9Hz,1H),2.62(ddd,J=12.1,7.9,4.3Hz,1H),2.47(s,2H),2.39(td,J=7.7,3.9Hz,2H),1.86-1.63(m,6H),1.61-1.47(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ 7.91-7.79 (m, 2H), 7.52-7.37 (m, 3H), 3.33 (s, 2H), 3.01 (q, J = 7.9Hz, 1H), 2.62 ( ddd, J = 12.1,7.9,4.3Hz, 1H), 2.47 (s, 2H), 2.39 (td, J = 7.7,3.9Hz, 2H), 1.86-1.63 (m, 6H), 1.61-1.47 (m, 2H).

實施例4Example 4

2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(化合物4) 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) -3a-ethyloctahydro-1H-cyclobutane [cd] pentalen-1-yl) acetic acid ( Compound 4 )

2-((1r,1aR,1a1r,3as,5aS)-1-(aminomethyl)-3a-ethyloctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) -3a-ethyloctahydro-1H-cyclobuta [cd] pentalen-1-yl) acetic acid

第一步：(±)-(1S,5R,7S)-7-(2-溴乙基)雙環[3.2.0]庚-2-烯-6-酮(4B) First step: (±)-(1S, 5R, 7S) -7- (2-bromoethyl) bicyclo [3.2.0] hept-2-en-6-one ( 4B )

(1S,5R,7S)-7-(2-bromoethyl)bicyclo[3.2.0]hept-2-en-6-one (1S, 5R, 7S) -7- (2-bromoethyl) bicyclo [3.2.0] hept-2-en-6-one

向反應瓶中加入1,3-環戊二烯(1A)(26.4g，0.4mol)和環己烷(1200mL)，充氮氣保護，加入三乙胺(24.2g，0.24mol)，加熱至迴流，滴加4-溴丁醯氯(44.4g，0.24mol)的環己烷溶液(50mL，25mL/h)，加完迴流反應4小時，將反應液抽濾，用環己烷(100mL×3)洗滌濾渣，合併濾液，依次用飽和氯化銨(500mL×3)洗滌，水(500mL×3)洗，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=80：1)得到淡黃色油狀液體(±)-(1S,5R,7S)-7-(2-溴乙基)雙環[3.2.0]庚-2-烯-6-酮(4B)(12g，產率：24%)。 Add 1,3-cyclopentadiene (1A) (26.4g, 0.4mol) and cyclohexane (1200mL) to the reaction flask, protect with nitrogen, add triethylamine (24.2g, 0.24mol), and heat to reflux , A solution of 4-bromobutyrazine chloride (44.4 g, 0.24 mol) in cyclohexane (50 mL, 25 mL / h) was added dropwise, and the reaction was refluxed for 4 hours. The reaction solution was suction-filtered, and cyclohexane (100 mL × 3) ) The filter residue was washed, and the filtrates were combined, washed with saturated ammonium chloride (500 mL × 3), washed with water (500 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography ( Petroleum ether / ethyl acetate (v / v) = 80: 1) to obtain a light yellow oily liquid (±)-(1S, 5R, 7S) -7- (2-bromoethyl) bicyclo [3.2.0] heptane 2-en-6-one ( 4B ) (12 g, yield: 24%).

1H NMR(400MHz,CDCl3)δ 5.97-5.85(m,1H),5.80-5.70(m,1H),3.91-3.79(m,1H),3.67(dd,J=9.7,5.5Hz,2H),3.47(t,J=6.8Hz,2H),2.68(ddd,J=18.3,15.2,3.9Hz,1H),2.47-2.31(m,1H),2.13(dq,J=21.0,6.5Hz,1H),1.93(ddd,J=21.5,12.2,7.1Hz,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 5.97-5.85 (m, 1H), 5.80-5.70 (m, 1H), 3.91-3.79 (m, 1H), 3.67 (dd, J = 9.7, 5.5Hz, 2H) , 3.47 (t, J = 6.8Hz, 2H), 2.68 (ddd, J = 18.3, 15.2, 3.9Hz, 1H), 2.47-2.31 (m, 1H), 2.13 (dq, J = 21.0, 6.5Hz, 1H ), 1.93 (ddd, J = 21.5, 12.2, 7.1 Hz, 1H).

第二步：(±)-(1S,5R,7S)-7-(2-溴乙基)螺[雙環[3.2.0]庚-[2]烯-6,2'-[1,3]二噁戊烷](4C) Second step: (±)-(1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] hepta- [2] ene-6,2 '-[1,3] Dioxane) ( 4C )

(±)-(1S,5R,7S)-7-(2-bromoethyl)spiro[bicyclo[3.2.0]hept[2]ene-6,2'-[1,3]dioxolane] (±)-(1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] hept [2] ene-6,2 '-[1,3] dioxolane]

向反應瓶中依次加入(±)-(1S,5R,7S)-7-(2-溴乙基)雙環[3.2.0]庚-2-烯-6-酮(4B)(37g，0.173mol)，對甲苯磺酸一水合物(1.6g，8.6mmol)，乙二醇(42.9g，0.692mol)和甲苯(320mL)，加熱迴流分水5小時，冷卻後將反應 液倒入冰水中，加入碳酸氫鈉固體調節pH至中性，用乙酸乙酯(400mL×3)萃取，合併有機相，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(乙酸乙酯/石油醚=1：100)得到黃色油狀液體(±)-(1S,5R,7S)-7-(2-溴乙基)螺[雙環[3.2.0]庚-[2]烯-6,2'-[1,3]二噁戊烷](4C)(27.4g，產率：61%)。 (±)-(1S, 5R, 7S) -7- (2-bromoethyl) bicyclo [3.2.0] hept-2-en-6-one ( 4B ) (37g, 0.173mol) ), P-toluenesulfonic acid monohydrate (1.6 g, 8.6 mmol), ethylene glycol (42.9 g, 0.692 mol) and toluene (320 mL), heat and reflux for 5 hours, and after cooling, pour the reaction solution into ice water. Solid sodium bicarbonate was added to adjust the pH to neutral, and the mixture was extracted with ethyl acetate (400 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (acetic acid Ethyl ester / petroleum ether = 1: 100) to obtain a yellow oily liquid (±)-(1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] hepta- [2] ene -6,2 '-[1,3] dioxolane] ( 4C ) (27.4 g, yield: 61%).

1H NMR(400MHz,CDCl3)δ 5.94-5.83(m,1H),5.67-5.56(m,1H),3.95-3.75(m,4H),3.36-3.25(m,2H),3.23-3.12(m,1H),3.02(ddd,J=22.9,15.7,8.0Hz,2H),2.48-2.25(m,2H),1.99-1.78(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ 5.94-5.83 (m, 1H), 5.67-5.56 (m, 1H), 3.95-3.75 (m, 4H), 3.36-3.25 (m, 2H), 3.23-3.12 ( m, 1H), 3.02 (ddd, J = 22.9, 15.7, 8.0 Hz, 2H), 2.48-2.25 (m, 2H), 1.99-1.78 (m, 2H).

第三步：(±)-(1S,5R,7S)-7-(2-溴乙基)螺[雙環[3.2.0]庚-6,2'-[1,3]二氧戊烷]-2-醇(4D-1) The third step: (±)-(1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] hept-6,2 '-[1,3] dioxolane] -2-ol ( 4D-1 )

(±)-(1S,5R,7S)-7-(2-bromoethyl)spiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolan]-2-ol (±)-(1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] heptane-6,2 '-[1,3] dioxolan] -2-ol

(±)-(1S,5R,7S)-7-(2-溴乙基)螺[雙環[3.2.0]庚-6,2'-[1,3]二氧戊烷]-3-醇(4D-2) (±)-(1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] hept-6,2 '-[1,3] dioxolane] -3-ol ( 4D-2 )

(1S,5R,7S)-7-(2-bromoethyl)spiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolan]-3-ol (1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] heptane-6,2 '-[1,3] dioxolan] -3-ol

向反應瓶中加入(±)-(1S,5R,7S)-7-(2-溴乙基)螺[雙環[3.2.0]庚-[2]烯-6,2'-[1,3]二噁戊烷](4C)(27.4g，0.11mol)和四氫呋喃(330mL)，冰水浴下滴加硼烷二甲硫醚溶液(55mL，0.55mol)，加完0℃下反應2個小時，冰水 浴下滴加純化水(1.1mol)，3M的氫氧化鈉溶液(360mL)和雙氧水(含雙氧水1.1mol)，加完升至室溫反應3小時，用乙酸乙酯(500mL×3)萃取，合併有機相，用飽和碳酸氫鈉溶液(500mL×2)和水(500mL×2)洗滌，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到淡黃色油狀液體(±)-(1S,5R,7S)-7-(2-溴乙基)螺[雙環[3.2.0]庚-6,2'-[1,3]二氧戊烷]-2-醇(4D-1)和(±)-(1S,5R,7S)-7-(2-溴乙基)螺[雙環[3.2.0]庚-6,2'-[1,3]二氧戊烷]-3-醇(4D-2)的混合物(30g)，直接用於下一步反應。 Add (±)-(1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] hepta- [2] ene-6,2 '-[1,3] to the reaction flask ] Dioxolane ( 4C ) (27.4g, 0.11mol) and tetrahydrofuran (330mL), a borane dimethylsulfide solution (55mL, 0.55mol) was added dropwise in an ice water bath, and the reaction was completed at 0 ° C for 2 hours. , Purified water (1.1 mol), 3M sodium hydroxide solution (360 mL) and hydrogen peroxide (containing 1.1 mol of hydrogen peroxide) were added dropwise under an ice-water bath. After the addition, the temperature was raised to room temperature for 3 hours, and ethyl acetate (500 mL × 3) was added. Extraction, combined organic phases, washed with saturated sodium bicarbonate solution (500mL × 2) and water (500mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated the filtrate under reduced pressure to obtain a light yellow oily liquid (±)-(1S , 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] hepta-6,2 '-[1,3] dioxolane] -2-ol ( 4D-1 ) and (±)-(1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] hept-6,2 '-[1,3] dioxolane] -3-ol A mixture ( 4D-2 ) (30 g) was used directly in the next reaction.

第四步：(±)-(1S,5R,7S)-7-(2-溴乙基)螺[雙環[3.2.0]庚-6,2'-[1,3]二氧戊烷]-2-酮(4E-1) The fourth step: (±)-(1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] hept-6,2 '-[1,3] dioxolane] -2-one ( 4E-1 )

(±)-(1S,5R,7S)-7-(2-bromoethyl)spiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolan]-2-one (±)-(1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] heptane-6,2 '-[1,3] dioxolan] -2-one

(±)-(1S,5R,7S)-7-(2-溴乙基)螺[雙環[3.2.0]庚-6,2'-[1,3]二氧戊烷]-3-酮(4E-2) (±)-(1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] hept-6,2 '-[1,3] dioxolane] -3-one ( 4E-2 )

(±)-(1S,5R,7S)-7-(2-bromoethyl)spiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolan]-3-one (±)-(1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] heptane-6,2 '-[1,3] dioxolan] -3-one

向反應瓶中加入(±)-(1S,5R,7S)-7-(2-溴乙基)螺[雙環[3.2.0]庚-6,2'-[1,3]二氧戊烷]-2-醇(4D-1)和(±)-(1S,5R,7S)-7-(2-溴乙基)螺[雙環[3.2.0]庚-6,2'-[1,3]二氧戊烷]-3-醇(4D-2)的混合物(30g，0.11mol)和二氯甲烷(500mL)，冰水浴下分批加入戴斯馬丁氧化劑(70g，0.17mol)，室溫反應2小 時，向反應液中加入二氯甲烷(300mL)和2M的硫代硫酸鈉水溶液(500mL)，攪拌30分鐘，分液，水相用二氯甲烷(300mL×2)萃取，合併有機相，依次用2M的氫氧化鈉溶液(500mL×2)和水(500mL×2)洗滌，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=10：1)得到淡黃色油狀液體(±)-(1S,5R,7S)-7-(2-溴乙基)螺[雙環[3.2.0]庚-6,2'-[1,3]二氧戊烷]-2-酮(4E-1)(15g，產率：50.4%)和淡黃色油狀液體(±)-(1S,5R,7S)-7-(2-溴乙基)螺[雙環[3.2.0]庚-6,2'-[1,3]二氧戊烷]-3-酮(4E-2)(3.7g，產率：12.4%)。 Add (±)-(1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] hept-6,2 '-[1,3] dioxolane to the reaction flask ] -2-ol ( 4D-1 ) and (±)-(1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] heptan-6,2 '-[1, 3] A mixture of dioxolane-3-ol ( 4D-2 ) (30 g, 0.11 mol) and dichloromethane (500 mL). Dess Martin oxidant (70 g, 0.17 mol) was added in portions in an ice water bath. Warm for 2 hours, add dichloromethane (300mL) and 2M aqueous sodium thiosulfate solution (500mL) to the reaction solution, stir for 30 minutes, and separate the layers. The aqueous phase is extracted with dichloromethane (300mL × 2), and the organics are combined. The phases were sequentially washed with a 2M sodium hydroxide solution (500 mL × 2) and water (500 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / acetic acid). Ethyl ester (v / v) = 10: 1) to give a pale yellow oily liquid (±)-(1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] hept-6 , 2 '-[1,3] dioxolane] -2-one ( 4E-1 ) (15g, yield: 50.4%) and light yellow oily liquid (±)-(1S, 5R, 7S)- 7- (2-bromoethyl) spiro [bicyclo [3.2.0] hepta-6,2 '-[1,3] dioxolane] -3-one ( 4E-2 ) (3.7 g, yield: 12.4%).

4E-1：1H NMR(400MHz,CDCl3)δ 4.02-3.81(m,4H),3.40(dd,J=10.3,3.8Hz,2H),3.15(td,J=10.3,4.9Hz,2H),2.61(ddd,J=20.6,14.0,8.1Hz,2H)，2.27(ddt,J=18.9,9.6,1.8Hz,1H),2.12-2.00(m,1H),1.99-1.70(m,3H)。 4E-1 : 1 H NMR (400MHz, CDCl 3 ) δ 4.02-3.81 (m, 4H), 3.40 (dd, J = 10.3, 3.8Hz, 2H), 3.15 (td, J = 10.3, 4.9Hz, 2H) , 2.61 (ddd, J = 20.6,14.0,8.1Hz, 2H), 2.27 (ddt, J = 18.9,9.6,1.8Hz, 1H), 2.12-2.00 (m, 1H), 1.99-1.70 (m, 3H) .

4E-2：1H NMR(400MHz,CDCl3)δ 3.97-3.77(m,4H),3.30(dd,J=10.5,3.6Hz,2H),3.17(t,J=8.4Hz,1H),3.03(ddd,J=15.6,7.7,3.2Hz,1H),2.83(qd,J=8.8,6.2Hz,1H),2.34-2.24(m,3H),2.17(ddd,J=18.7,8.6,1.5Hz,1H),2.01(dt,J=14.2,7.1Hz,1H),1.91(dt,J=14.5,7.3Hz,1H)。 4E-2 : 1 H NMR (400MHz, CDCl 3 ) δ 3.97-3.77 (m, 4H), 3.30 (dd, J = 10.5, 3.6Hz, 2H), 3.17 (t, J = 8.4Hz, 1H), 3.03 (ddd, J = 15.6,7.7,3.2Hz, 1H), 2.83 (qd, J = 8.8,6.2Hz, 1H), 2.34-2.24 (m, 3H), 2.17 (ddd, J = 18.7,8.6,1.5Hz , 1H), 2.01 (dt, J = 14.2,7.1Hz, 1H), 1.91 (dt, J = 14.5,7.3Hz, 1H).

第五步：(±)-2-((1S,5R,7S)-7-(2-溴乙基)螺[雙環[3.2.0]庚烷-6,2'-[1,3]二氧戊環]-2-亞基)乙酸乙酯(4F) Step 5: (±) -2-((1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] heptane-6,2 '-[1,3] Oxolane] -2-ylidene) acetate ( 4F )

(±)-ethyl-2-((1S,5R,7S)-7-(2-bromoethyl)spiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolan]-2-ylidene)acetate (±) -ethyl-2-((1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] heptane-6,2 '-[1,3] dioxolan] -2-ylidene acetate

將氫化鈉(1.08g，16mmol)加入反應瓶中，加入四氫呋喃(30mL)，降 溫至0℃，滴加三乙基膦醯乙酸酯(5.4g，24mmol)的四氫呋喃溶液(10mL)，滴完，保溫反應1小時，得到淡黃色溶液備用；在另一反應瓶中加入(±)-(1S,5R,7S)-7-(2-溴乙基)螺[雙環[3.2.0]庚烷-6,2'-[1,3]二氧戊環]-2-酮(4E-1)(3.0g，11mmol)及四氫呋喃(20mL)，降溫至0℃，滴加上述製備好的淡黃色溶液，滴完升溫至10-15℃反應1小時。向反應液中加入水(100mL)和乙酸乙酯各(100mL)，攪拌分液，水相用乙酸乙酯(50mL×2)萃取，合併有機相，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(V/v)=50：1-20：1)得到淡黃色液體(±)-2-((1S,5R,7S)-7-(2-溴乙基)螺[雙環[3.2.0]庚烷-6,2'-[1,3]二氧戊環]-2-亞基)乙酸乙酯(4F)(1.5g，產率：40%)。 Sodium hydride (1.08 g, 16 mmol) was added to the reaction flask, tetrahydrofuran (30 mL) was added, the temperature was lowered to 0 ° C, and a tetrahydrofuran solution (10 mL) of triethylphosphinephosphonium acetate (5.4 g, 24 mmol) was added dropwise. , Holding the reaction for 1 hour to obtain a light yellow solution for future use; add (±)-(1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] heptane to another reaction flask) -6,2 '-[1,3] dioxolane] -2-one ( 4E-1 ) (3.0 g, 11 mmol) and tetrahydrofuran (20 mL), the temperature was lowered to 0 ° C, and the pale yellow color prepared above was added dropwise. The solution was heated to 10-15 ° C for 1 hour after the completion of dropping. Water (100 mL) and ethyl acetate (100 mL) were each added to the reaction solution, and the layers were stirred and separated. The aqueous phase was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed. Concentrated, the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / v) = 50: 1-20: 1) to obtain a light yellow liquid (±) -2-((1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] heptane-6,2 '-[1,3] dioxolane] -2-ylidene) acetate ( 4F ) (1.5 g, yield: 40%).

第六步：2-((1aR,1a1r,3as,5aS)-八氫螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊環]-3a-基)乙酸乙酯(4G) Step 6: 2-((1aR, 1a 1 r, 3as, 5aS) -octahydrospiro [cyclobutane [cd] pentadiene-1,2 '-[1,3] dioxolane] -3a -Yl) ethyl acetate ( 4G )

Ethyl-2-((1aR,1a1r,3as,5aS)-octahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolan]-3a-yl)acetate Ethyl-2-((1aR, 1a 1 r, 3as, 5aS) -octahydrospiro [cyclobuta [cd] pentalene-1,2 '-[1,3] dioxolan] -3a-yl) acetate

反應瓶中加入(±)-2-((1S,5R,7S)-7-(2-溴乙基)螺[雙環[3.2.0]庚烷-6,2'-[1,3]二氧戊環]-2-亞基)乙酸乙酯(4F)(0.5g，1.4mmol)，甲苯(50mL)，加熱至90℃，滴加三丁基錫氫(0.84g，2.9mmol)及偶氮二異丁腈(0.048g，0.29mmol)預先溶於甲苯(25mL)的混合溶液(12.5mL/h)，滴完於90℃反應3小時。將反應液冷卻至室溫，加入飽和氟化鉀水溶液(50mL)，攪拌後過濾，濾餅用乙酸乙酯(20mL×2)洗滌，將濾液分液，水相用乙酸乙酯(20mL×2) 萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=50：1-20：1)得到無色油狀液體2-((1aR,1a1r,3as,5aS)-八氫螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊環]-3a-基)乙酸乙酯(4G)(0.1g，產率：30%)。 (±) -2-((1S, 5R, 7S) -7- (2-bromoethyl) spiro [bicyclo [3.2.0] heptane-6,2 '-[1,3]) Oxopentan] -2-ylidene) acetate ( 4F ) (0.5 g, 1.4 mmol), toluene (50 mL), heated to 90 ° C, and tributyltin hydrogen (0.84 g, 2.9 mmol) and azobis were added dropwise. Isobutyronitrile (0.048 g, 0.29 mmol) was previously dissolved in a mixed solution (12.5 mL / h) of toluene (25 mL), and the reaction was completed at 90 ° C. for 3 hours. The reaction solution was cooled to room temperature, and a saturated potassium fluoride aqueous solution (50 mL) was added. After stirring, the filter cake was washed with ethyl acetate (20 mL × 2). The filtrate was separated, and the aqueous phase was ethyl acetate (20 mL × 2). ) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 50: 1-20: 1) to obtain Colorless oily liquid 2-((1aR, 1a 1 r, 3as, 5aS) -octahydrospiro [cyclobutane [cd] pentadiene-1,2 '-[1,3] dioxolane] -3a -Yl) ethyl acetate ( 4G ) (0.1 g, yield: 30%).

MS m/z(ESI)：289.3(M+23)。 MS m / z (ESI): 289.3 (M + 23).

1H NMR(400MHz,CDCl3)δ4.13(d,2H),3.85(d,4H),3.16(q,1H),2.81-2.70(m,1H),2.62-1.51(m,2H),2.37(s,2H),1.87-1.62(m,2H),1.51-1.44(m,3H),1.24(t,4H),0.82(t,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 4.13 (d, 2H), 3.85 (d, 4H), 3.16 (q, 1H), 2.81-2.70 (m, 1H), 2.62-1.51 (m, 2H), 2.37 (s, 2H), 1.87-1.62 (m, 2H), 1.51-1.44 (m, 3H), 1.24 (t, 4H), 0.82 (t, 1H).

第七步：2-((1aR,1a1r,3as,5aS)-八氫螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊環]-3a-基)乙醇(4H) Seventh step: 2-((1aR, 1a 1 r, 3as, 5aS) -octahydrospiro [cyclobutane [cd] pentadiene-1,2 '-[1,3] dioxolane] -3a -Yl) ethanol ( 4H )

2-((1aR,1a1r,3as,5aS)-octahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolan]-3a-yl)ethanol 2-((1aR, 1a 1 r, 3as, 5aS) -octahydrospiro [cyclobuta [cd] pentalene-1,2 '-[1,3] dioxolan] -3a-yl) ethanol

反應瓶中加入四氫鋁鋰(0.014g，0.38mmol)和四氫呋喃(2mL)，冰浴冷卻，滴加2-((1aR,1a1r,3as,5aS)-八氫螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊環]-3a-基)乙酸乙酯(4G)(0.1g，0.38mmol)的四氫呋喃溶液(1mL)，冰浴下反應1小時，向反應液中滴加水(1mL)，過濾，濾餅用乙酸乙酯(5mL×2)洗滌，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=5：1-3：1)得到無色油狀物2-((1aR,1a1r,3as,5aS)-八氫螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊環]-3a-基)乙醇(4H)(0.05g，產率：60%)。 Lithium tetrahydroaluminum (0.014 g, 0.38 mmol) and tetrahydrofuran (2 mL) were added to the reaction flask, and the solution was cooled in an ice bath, and 2-((1aR, 1a 1 r, 3as, 5aS) -octahydrospiro [cyclobutane [ cd] Pentadiene-1,2 '-[1,3] dioxolane] -3a-yl) ethyl acetate ( 4G ) (0.1g, 0.38mmol) in tetrahydrofuran solution (1mL), react under ice bath 1 hour, water (1 mL) was added dropwise to the reaction solution, and the filter cake was washed with ethyl acetate (5 mL x 2). The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate ( v / v) = 5: 1-3: 1) to obtain a colorless oil 2-((1aR, 1a 1 r, 3as, 5aS) -octahydrospiro [cyclobutane [cd] pentadiene- 1 , 2 '-[1,3] dioxolane] -3a-yl) ethanol ( 4H ) (0.05 g, yield: 60%).

MS m/z(ESI)：225.2(M+1)。 MS m / z (ESI): 225.2 (M + 1).

1H NMR(400MHz,CDCl3)δ 3.91-3.82(m,4H),3.74(t,2H),2.83-2.67(m, 1H),2.58-2.49(m,2H),1.76-1.26(m,9H),1.10(dd,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 3.91-3.82 (m, 4H), 3.74 (t, 2H), 2.83-2.67 (m, 1H), 2.58-2.49 (m, 2H), 1.76-1.26 (m, 9H), 1.10 (dd, 1H).

第八步：2-((1aR,1a1r,3as,5aS)-八氫螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊環]-3a-基)乙基甲磺酸酯(4I) Step 8: 2-((1aR, 1a 1 r, 3as, 5aS) -octahydrospiro [cyclobutane [cd] pentadiene-1,2 '-[1,3] dioxolane] -3a -Yl ) ethyl methanesulfonate ( 4I )

2-((1aR,1a1r,3as,5aS)-octahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolan]-3a-yl)ethylmethanesulfonate 2-((1aR, 1a 1 r, 3as, 5aS) -octahydrospiro [cyclobuta [cd] pentalene-1,2 '-[1,3] dioxolan] -3a-yl) ethylmethanesulfonate

向反應瓶中依次加入2-((1aR,1a1r,3as,5aS)-八氫螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊環]-3a-基)乙醇(4H)(1.80g，8.02mmol)，二氯甲烷(20mL)和三乙胺(1.62g，16.0mmol)，冰浴冷卻，滴加甲烷磺醯氯(1.38g，12.0mrnol)，室溫反應2小時，向反應液中加入二氯甲烷(10mL)和水(10mL)，攪拌分液，水層用二氯甲烷(10mL×2)萃取，合併有機相，用1M的鹽酸(10mL)洗滌，有機相用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=10：1-3：1)得到無色油狀物2-((1aR,1a1r,3as,5aS)-八氫螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊環]-3a-基)乙基甲磺酸酯(4I)(2.2g，產率：91%)。 Add 2-((1aR, 1a 1 r, 3as, 5aS) -octahydrospiro [cyclobutane [cd] pentadiene-1,2 '-[1,3] dioxolane] to the reaction bottle in order. -3a-yl) ethanol ( 4H ) (1.80g, 8.02mmol), dichloromethane (20mL) and triethylamine (1.62g, 16.0mmol), cooled in an ice bath, and added methanesulfonyl chloride (1.38g, 12.0) mrnol), react at room temperature for 2 hours, add dichloromethane (10mL) and water (10mL) to the reaction solution, stir and separate the layers, extract the aqueous layer with dichloromethane (10mL × 2), combine the organic phases, and use 1M The organic phase was washed with hydrochloric acid (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10: 1-3: 1 ) To give a colorless oil 2-((1aR, 1a 1 r, 3as, 5aS) -octahydrospiro [cyclobutane [cd] pentadiene-1,2 '-[1,3] dioxolane] -3a-yl) ethyl methanesulfonate ( 4I ) (2.2 g, yield: 91%).

1H NMR(400MHz,CDCl3)δ 4.32(t,2H),3.91-3.81(m,4H),3.00(s,3H),2.81-2.69(m,1H),2.65-2.44(m,2H),1.94-1.20(m,9H),1.11(dd,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 4.32 (t, 2H), 3.91-3.81 (m, 4H), 3.00 (s, 3H), 2.81-2.69 (m, 1H), 2.65-2.44 (m, 2H) , 1.94-1.20 (m, 9H), 1.11 (dd, 1H).

第九步：(1aR,1a1r,3as,5aS)-3a-乙基八氫螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊環](4J) Ninth step: (1aR, 1a 1 r, 3as, 5aS) -3a-ethyloctahydrospiro [cyclobutane [cd] pentadiene-1,2 '-[1,3] dioxolane] ( 4J )

(1aR,1a1r,3as,5aS)-3a-ethyloctahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolane] (1aR, 1a 1 r, 3as, 5aS) -3a-ethyloctahydrospiro [cyclobuta [cd] pentalene-1,2 '-[1,3] dioxolane]

向反應瓶中加入2-((1aR,1a1r,3as,5aS)-八氫螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊環]-3a-基)乙基甲磺酸酯(4I)(2.2g，7.3mmol)和四氫呋喃(35mL)，降溫至0℃，加入四氫鋁鋰(0.83g，22mmol)，加完升至室溫反應3小時，冰浴冷卻反應液，滴加水(1mL)，過濾，濾餅用乙酸乙酯(10mL×2)洗滌，將濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=200：1-100：1)得到無色油狀物(1aR,1a1r,3as,5aS)-3a-乙基八氫螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊環](4J)(1.3g，產率：86%)。 Add 2-((1aR, 1a1r, 3as, 5aS) -octahydrospiro [cyclobutane [cd] pentadiene-1,2 '-[1,3] dioxolane] -3a- to the reaction flask ) Ethyl mesylate ( 4I ) (2.2g, 7.3mmol) and tetrahydrofuran (35mL), the temperature was lowered to 0 ° C, lithium tetrahydroaluminum (0.83g, 22mmol) was added, and the temperature was raised to room temperature for 3 hours. The reaction solution was cooled in an ice bath, water (1 mL) was added dropwise, and filtered. The filter cake was washed with ethyl acetate (10 mL × 2). The filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate). (v / v) = 200: 1-100: 1) colorless oil (1aR, 1a 1 r, 3as, 5aS) -3a-ethyloctahydrospiro [cyclobutane [cd] pentaene-1 , 2 '-[1,3] dioxolane] (4J ) (1.3 g, yield: 86%).

1H NMR(400MHz,CDCl3)δ 3.91-3.82(m,4H),2.80-2.65(m,1H),2.57-2.50(m,2H),1.64-1.26(m,9H),1.02(dd,1H),0.88(t,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 3.91-3.82 (m, 4H), 2.80-2.65 (m, 1H), 2.57-2.50 (m, 2H), 1.64-1.26 (m, 9H), 1.02 (dd, 1H), 0.88 (t, 3H).

第十步：(1aR,1a1r,3as,5aS)-3a-乙基八氫-1氫-環丁烷[cd]戊搭烯-1-酮(4K) Step 10: (1aR, 1a 1 r, 3as, 5aS) -3a-ethyloctahydro-1hydro-cyclobutane [cd] pentaden-1-one ( 4K )

(1aR,1a1r,3as,5aS)-3a-ethyloctahydro-1H-cyclobuta[cd]pentalen-1-one (1aR, 1a 1 r, 3as, 5aS) -3a-ethyloctahydro-1H-cyclobuta [cd] pentalen-1-one

向反應瓶中加入(1aR,1a1r,3as,5aS)-3a-乙基八氫螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊環](4J)(1.3g，6.24mmol)，四氫呋喃(15mL)，水(5mL)和三氟醋酸(15mL)，升溫至50℃反應3小時，過濾，濾液減壓濃縮，加入乙酸乙酯(50mL)和水(50mL)，攪拌分液，水相用乙酸乙酯(20mL×2)萃取，合併有機相，用飽和碳酸氫鈉溶液(20mL)洗滌，有機相無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=100：1-50：1)得到無色油狀物(1aR,1a1r,3as,5aS)-3a-乙基八氫-1氫-環丁 烷[cd]戊搭烯-1-酮(4K)(1.0g，產率：97.6%)。 Add (1aR, 1a 1 r, 3as, 5aS) -3a-ethyloctahydrospiro [cyclobutane [cd] pentadiene-1,2 '-[1,3] dioxolane] to the reaction flask ( 4J ) (1.3g, 6.24mmol), tetrahydrofuran (15mL), water (5mL) and trifluoroacetic acid (15mL), heated to 50 ° C for 3 hours, filtered, the filtrate was concentrated under reduced pressure, and ethyl acetate (50mL) was added And water (50mL), stirred and separated. The aqueous phase was extracted with ethyl acetate (20mL × 2). The organic phases were combined, washed with saturated sodium bicarbonate solution (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed. Concentrated, the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100: 1-50: 1) to obtain a colorless oil (1aR, 1a 1 r, 3as, 5aS) -3a -Ethyloctahydro-1hydro-cyclobutane [cd] pentane-1-one ( 4K ) (1.0 g, yield: 97.6%).

MS m/z(ESI)：187.2(M+23)。 MS m / z (ESI): 187.2 (M + 23).

1H NMR(400MHz,CDCl3)δ 3.44-3.38(d,1H),3.28-3.07(m,1H),2.77(dd,1H),1.87-1.70(m,2H),1.62(ddd,1H),1.55-1.37(m,5H),1.31-1.23(m,2H),0.90(t,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 3.44-3.38 (d, 1H), 3.28-3.07 (m, 1H), 2.77 (dd, 1H), 1.87-1.70 (m, 2H), 1.62 (ddd, 1H) , 1.55-1.37 (m, 5H), 1.31-1.23 (m, 2H), 0.90 (t, 3H).

第十一步：2-((1aR,1a1r,3as,5aS)-3a-乙基八氫-1氫-環丁烷[cd]戊搭烯-1-亞基)乙酸第三丁酯(4L) Step 11: 2-((1aR, 1a 1 r, 3as, 5aS) -3a-ethyloctahydro-1hydro-cyclobutane [cd] pentadenene-1-ylidene) tert-butyl acetate ( 4L )

tert-butyl-2-((1aR,1a1r,3as,5aS)-3a-ethyloctahydro-1H-cyclobuta[cd]pentalen-1-ylidene)acetate tert-butyl-2-((1aR, 1a 1 r, 3as, 5aS) -3a-ethyloctahydro-1H-cyclobuta [cd] pentalen-1-ylidene) acetate

將氫化鈉(0.37g，9.1mmol，60%)和四氫呋喃(20mL)加入反應瓶中，降溫至0℃，滴加二乙基膦醯基乙酸第三丁酯(2.3g，9.1mmol)的四氫呋喃溶液(5mL)，0℃反應1小時，滴加(1aR,1a1r,3as,5aS)-3a-乙基八氫-1氫-環丁烷[cd]戊搭烯-1-酮(4K)(1.0g，6.1mmol)的四氫呋喃溶液(5mL)，滴完升至室溫反應1小時。向反應液中加入乙酸乙酯(20mL)和水(20mL)，攪拌分液，水相用乙酸乙酯(10mL×2)萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=200：1-100：1)，得到無色油狀物2-((1aR,1a1r,3as,5aS)-3a-乙基八氫-1氫-環丁烷[cd]戊搭烯-1-亞基)乙酸第三丁酯(4L)(1.3g，產率：81%)。 Sodium hydride (0.37 g, 9.1 mmol, 60%) and tetrahydrofuran (20 mL) were added to the reaction flask, the temperature was lowered to 0 ° C, and tetraethylfuran triethyl diethylphosphinofluorenylacetate (2.3 g, 9.1 mmol) was added dropwise. Solution (5mL), reacted at 0 ° C for 1 hour, and (1aR, 1a 1 r, 3as, 5aS) -3a-ethyloctahydro-1hydro-cyclobutane [cd] pentaden-1-one ( 4K ) (1.0 g, 6.1 mmol) in a tetrahydrofuran solution (5 mL), and the temperature was raised to room temperature for 1 hour. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction solution, and the layers were stirred and separated. The aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 200: 1-100: 1) to obtain a colorless oil 2-((1aR, 1a 1 r, 3as, 5aS) -3a-ethyloctahydro-1hydro-cyclobutane [cd] pentadiene-1-ylidene) acetic acid tert-butyl acetate ( 4L ) (1.3 g, yield: 81%).

第十二步：2-((1r,1aR,1a1r,3as,5aS)-3a-乙基-1-(硝基甲基)八氫-1氫-環丁烷[cd]戊搭烯-1-基)乙酸第三丁酯(4M) Step 12: 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -3a-ethyl-1- (nitromethyl) octahydro-1hydro-cyclobutane [cd] pentadiene 1-yl) tert-butyl acetate ( 4M )

tert-butyl-2-((1r,1aR,1a1r,3as,5aS)-3a-ethyl-1-(nitromethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetate tert-butyl-2-((1r, 1aR, 1a 1 r, 3as, 5aS) -3a-ethyl-1- (nitromethyl) octahydro-1H-cyclobuta [cd] pentalen-1-yl) acetate

向反應瓶中加入2-((1aR,1a1r,3as,5aS)-3a-乙基八氫-1氫-環丁烷[cd]戊搭烯-1-亞基)乙酸第三丁酯(4L)(1.3g，4.95mmol)，1,5-二氮雜二環[5.4.0]十一-5-烯(1.51g，9.91mmol)和硝基甲烷(20mL)，升溫至90℃反應8小時。將反應液降溫至室溫，加入二氯甲烷(50mL)及水(50mL)，攪拌分液，水相用二氯甲烷(20mL×2)萃取，合併有機相，用水(20mL×3)洗滌，有機相無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=200：1)得到無色油狀2-((1r,1aR,1a1r,3as,5aS)-3a-乙基-1-(硝基甲基)八氫-1氫-環丁烷[cd]戊搭烯-1-基)乙酸第三丁酯(4M)(0.8g，產率：50%)。 To the reaction flask was added 2-((1aR, 1a 1 r, 3as, 5aS) -3a-ethyloctahydro-1hydro-cyclobutane [cd] pentadiene-1-ylidene) tributyl acetate. ( 4L ) (1.3g, 4.95mmol), 1,5-diazabicyclo [5.4.0] undec-5-ene (1.51g, 9.91mmol) and nitromethane (20mL), warmed to 90 ° C The reaction took 8 hours. The reaction solution was cooled to room temperature, dichloromethane (50 mL) and water (50 mL) were added, and the solution was stirred and separated. The aqueous phase was extracted with dichloromethane (20 mL × 2). The organic phases were combined and washed with water (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 200: 1) to obtain a colorless oily 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -3a-ethyl-1- (nitromethyl) octahydro-1hydro-cyclobutane [cd] pentaden-1-yl) acetic acid tert-butyl ester ( 4M ) (0.8 g, yield: 50%).

1H NMR(400MHz,CDCl3)δ 4.82(s,2H),2.87(dt,1H),2.61-2.56(m,1H),2.51(q,2H),2.33(dt,1H),1.79-1.26(m,18H),1.08(dd,1H),0.88(t,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 4.82 (s, 2H), 2.87 (dt, 1H), 2.61-2.56 (m, 1H), 2.51 (q, 2H), 2.33 (dt, 1H), 1.79-1.26 (m, 18H), 1.08 (dd, 1H), 0.88 (t, 3H).

第十三步：2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸第三丁酯(4N) Step 13: 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) -3a-ethyloctahydro-1H-cyclobutane [cd] pentaene-1 -Yl ) tert- butyl acetate ( 4N )

tert-butyl-2-((1r,1aR,1a1r,3as,5aS)-1-(aminomethyl)-3a-ethyloctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetate tert-butyl-2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) -3a-ethyloctahydro-1H-cyclobuta [cd] pentalen-1-yl) acetate

向反應瓶中依次加入2-((1r,1aR,1a1r,3as,5aS)-3a-乙基-1-(硝基甲基)八氫-1氫-環丁烷[cd]戊搭烯-1-基)乙酸第三丁酯(4M)(1.25g，3.87mmol)，鐵粉 (1.08g，19.3mmol)，氯化銨(1.03g，19.3mmol)，乙醇(10mL)和水(5mL)，升溫至迴流反應6小時。過濾，濾餅用乙醇(10mL×3)洗滌，濾液減壓濃縮，加入乙酸乙酯(50mL)和水(50rmL)，攪拌分液，水相用乙酸乙酯(20mL×2)萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(二氯甲烷/甲醇(v/v)=20：1-15：1)得到無色糖漿狀2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸第三丁酯(4N)(1.1g，產率：97%)。 To the reaction flask were added 2 - ((1r, 1aR, 1a 1 r, 3as, 5aS) -3a- ethyl-1- (nitromethyl) -1H-octahydro - cyclobutane [cd] pentalene En-l-yl) tert-butyl acetate ( 4M ) (1.25 g, 3.87 mmol), iron powder (1.08 g, 19.3 mmol), ammonium chloride (1.03 g, 19.3 mmol), ethanol (10 mL), and water ( 5 mL), and heated to reflux for 6 hours. Filtered, washed the cake with ethanol (10 mL × 3), concentrated the filtrate under reduced pressure, added ethyl acetate (50 mL) and water (50 rmL), stirred and separated, the aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organics were combined The phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20: 1-15: 1) to give a colorless syrup 2- ( (1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) -3a-ethyloctahydro-1H-cyclobutane [cd] pentadenen-1-yl) tributyl acetate ( 4N ) (1.1 g, yield: 97%).

MS m/z(ESI)：294.2(M+1)。 MS m / z (ESI): 294.2 (M + 1).

1H NMR(400MHz,CDCl3)δ 3.29(d,2H),2.95-2.88(m,1H),2,67-2.40(m,3H),2.25(brs,1H),1.76-1.26(m,18H),1.06(dd,1H),0.87(t,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 3.29 (d, 2H), 2.95-2.88 (m, 1H), 2,67-2.40 (m, 3H), 2.25 (brs, 1H), 1.76-1.26 (m, 18H), 1.06 (dd, 1H), 0.87 (t, 3H).

第十四步：2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氫-1氫-環丁烷[cd]戊搭烯-1-基)乙酸(化合物4) Step Fourteen: 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) -3a-ethyloctahydro-1hydro-cyclobutane [cd] pentaene- 1-yl) acetic acid ( compound 4 )

2-((1r,1aR,1a1r,3as,5aS)-1-(aminomethyl)-3a-ethyloctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) -3a-ethyloctahydro-1H-cyclobuta [cd] pentalen-1-yl) acetic acid

向反應瓶中加入2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸第三丁酯(4N)(1.1g，3.75mmol)，三氟醋酸(7mL)和二氯甲烷(7mL)，室溫攪拌3小時，濾液減壓濃縮，加入二氯甲烷(20mL)，用三乙胺調節體系pH為8-9，過濾，濾餅用二氯甲烷(10mL×3)洗滌，得到白色固體2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氫-1氫-環丁烷[cd]戊搭烯-1-基)乙酸(化合物4)(0.7g，產率：79%)。 Add 2-((1r, 1aR, 1a1r, 3as, 5aS) -1- (aminomethyl) -3a-ethyloctahydro-1H-cyclobutane [cd] pentadien-1-yl to the reaction flask ) Third butyl acetate ( 4N ) (1.1 g, 3.75 mmol), trifluoroacetic acid (7 mL) and dichloromethane (7 mL), stirred at room temperature for 3 hours, the filtrate was concentrated under reduced pressure, and dichloromethane (20 mL) was added, The pH of the system was adjusted to 8-9 with triethylamine, filtered, and the filter cake was washed with dichloromethane (10 mL × 3) to obtain a white solid 2-((1r, 1aR, 1a1r, 3as, 5aS) -1- (aminomethyl) Yl) -3a-ethyloctahydro-1hydro-cyclobutane [cd] pentalen-1-yl) acetic acid ( Compound 4 ) (0.7 g, yield: 79%).

MS m/z(ESI)：238.3(M+1)。 MS m / z (ESI): 238.3 (M + 1).

1H NMR(400MHz,MeOD)δ 3.15(d,2H),2.89(dd,1H),2.59-2.46(m,3H),2.12-2.08(m,1H),1.77-1.31(m,9H),1.09(dd,1H),0.93(t,3H)。 1 H NMR (400MHz, MeOD) δ 3.15 (d, 2H), 2.89 (dd, 1H), 2.59-2.46 (m, 3H), 2.12-2.08 (m, 1H), 1.77-1.31 (m, 9H), 1.09 (dd, 1H), 0.93 (t, 3H).

實施例5Example 5

2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氫-1氫-環丁烷[cd]戊搭烯-1-基)乙酸 苯磺酸鹽(1：1)(化合物5) 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) -3a-ethyloctahydro-1hydro-cyclobutane [cd] pentaden-1-yl) acetic acid Benzenesulfonate (1: 1) ( Compound 5 )

2-((1r,1aR,1a1r,3as,5aS)-1-(aminomethyl)-3a-ethyloctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid benzene sulfonate(1：1) 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) -3a-ethyloctahydro-1H-cyclobuta [cd] pentalen-1-yl) acetic acid benzene sulfonate (1: 1)

第一步：2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氫-1氫-環丁烷[cd]戊搭烯-1-基)乙酸 苯磺酸鹽(1：1)(化合物5) First step: 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) -3a-ethyloctahydro-1hydro-cyclobutane [cd] pentadiene-1 -Yl) acetic acid benzenesulfonate (1: 1) ( compound 5 )

2-((1r,1aR,1a1r,3as,5aS)-1-(aminomethyl)-3a-ethyloctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid benzene sulfonate(1：1) 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) -3a-ethyloctahydro-1H-cyclobuta [cd] pentalen-1-yl) acetic acid benzene sulfonate (1: 1)

向反應瓶中加入2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氫-1氫-環丁烷[cd]戊搭烯-1-基)乙酸(化合物4)(0.4g，1.7mmol)，苯磺酸一水合物(0.45g，2.55mmol)和甲醇(8mL)，室溫攪拌30分鐘，過濾，濾液減壓濃縮，加入乙酸乙酯(10mL)打漿，過濾，濾餅用乙酸乙酯(5mL)洗滌，得到白色固體2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氫-1氫-環丁烷 [cd]戊搭烯-1-基)乙酸 苯磺酸鹽(1：1)(化合物5)(0.56g，產率：84%)。 To the reaction flask was added 2 - ((1r, 1aR, 1a 1 r, 3as, 5aS) -1- ( aminomethyl) -3a- ethyl octahydro-1H - cyclobutane [cd] pentalene - 1-yl) acetic acid ( compound 4 ) (0.4 g, 1.7 mmol), benzenesulfonic acid monohydrate (0.45 g, 2.55 mmol) and methanol (8 mL), stirred at room temperature for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure, added Ethyl acetate (10 mL) was slurried and filtered. The filter cake was washed with ethyl acetate (5 mL) to give a white solid 2-((1r, 1aR, 1a 1 r, 3as, 5aS) -1- (aminomethyl) -3a. -Ethyloctahydro-1hydro-cyclobutane [cd] pentalen-1-yl) acetic acid benzenesulfonate (1: 1) ( compound 5 ) (0.56 g, yield: 84%).

MS m/z(ESI)：238.3(M+1)。 MS m / z (ESI): 238.3 (M + 1).

1H NMR(400MHz,MeOD)δ 7.85(dd,2H),7.44(dd,3H),3.30(d,2H),2.91(dd,1H),2.68-2.41(m,3H),2.27-2.06(m,1H),1.85-1.37(d,9H),1.11(dd,1H),0.93(t,3H)。 1 H NMR (400MHz, MeOD) δ 7.85 (dd, 2H), 7.44 (dd, 3H), 3.30 (d, 2H), 2.91 (dd, 1H), 2.68-2.41 (m, 3H), 2.27-2.06 ( m, 1H), 1.85-1.37 (d, 9H), 1.11 (dd, 1H), 0.93 (t, 3H).

實施例6Example 6

(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨甲基)-3-亞甲基八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(化合物6) (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -3-methyleneoctahydro-1H-cyclobutane [cd] pentadiene-1 -Yl) acetic acid ( compound 6 )

(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(aminomethyl)-3-methyleneoctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -3-methyleneoctahydro-1H-cyclobuta [cd] pentalen-1-yl) acetic acid

第一步：(±)-(1aR,1a1R,3aR,5aS)-六氫螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊烷]-3(1a1H)-酮(6B) The first step: (±)-(1aR, 1a 1 R, 3aR, 5aS) -hexahydrospiro [cyclobutane [cd] pentadiene-1,2 '-[1,3] dioxolane]- 3 (1a 1 H) -one (6B)

(±)-(1aR,1a1R,3aR,5aS)-hexahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]d ioxolan]-3(1a1H)-one (±)-(1aR, 1a 1 R, 3aR, 5aS) -hexahydrospiro [cyclobuta [cd] pentalene-1,2 '-[1,3] d ioxolan] -3 (1a 1 H) -one

向反應瓶中加入第三丁醇鉀(0.58g，5.2mmol)和甲苯(40mL)，充氮氣保護，降溫至-15℃，滴加(±)-(1S,5R,7S)-7-(2-溴乙基)螺[雙環[3.2.0]庚-6,2'-[1,3]二氧戊烷]-3-酮(4E-2)(1.1g，4mmol)的甲苯(5mL)溶液，加完-15℃下攪拌1小時，升溫至0℃攪拌1小時，冰水浴下滴加飽和氯化銨溶液至pH為約為7，用乙酸乙酯(80mL×3)萃取，合併有機相，用水(80mL×2)洗滌，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=8：1)得到淡黃色油狀液體(±)-(1aR,1a1R,3aR,5aS)-六氫螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊烷]-3(1a1H)-酮(6B)(0.5g，產率：61%)。 Add potassium tert-butoxide (0.58g, 5.2mmol) and toluene (40mL) to the reaction flask, protect with nitrogen, cool to -15 ° C, and add (±)-(1S, 5R, 7S) -7- ( 2-bromoethyl) spiro [bicyclo [3.2.0] hepta-6,2 '-[1,3] dioxolane] -3-one ( 4E-2 ) (1.1 g, 4 mmol) in toluene (5 mL ) Solution, stirred at -15 ° C for 1 hour, heated to 0 ° C and stirred for 1 hour, and added a saturated ammonium chloride solution dropwise under ice-water bath to a pH of about 7, extracted with ethyl acetate (80mL × 3), combined The organic phase was washed with water (80 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 8: 1) to obtain Light yellow oily liquid (±)-(1aR, 1a 1 R, 3aR, 5aS) -hexahydrospiro [cyclobutane [cd] pentadiene-1,2 '-[1,3] dioxolane] -3 (1a 1 H) -one ( 6B ) (0.5 g, yield: 61%).

1H NMR(400MHz,CDCl3)δ 3.99-3.77(m,4H),3.30(t,J=7.1Hz,1H),3.17(t,J=8.4Hz,1H),3.09-2.96(m,1H),2.83(qd,J=8.8,6.3Hz,1H),2.34-2.24(m,3H),2.24-2.12(m,1H),2.02(dd,J=14.3,7.2Hz,1H),1.90(dd,J=14.6,7.4Hz,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 3.99-3.77 (m, 4H), 3.30 (t, J = 7.1Hz, 1H), 3.17 (t, J = 8.4Hz, 1H), 3.09-2.96 (m, 1H ), 2.83 (qd, J = 8.8, 6.3 Hz, 1H), 2.34-2.24 (m, 3H), 2.24-2.12 (m, 1H), 2.02 (dd, J = 14.3, 7.2 Hz, 1H), 1.90 ( dd, J = 14.6,7.4Hz, 1H).

第二步：(±)-(1aR,1a1R,3aR,5aS)-3-亞甲基八氫螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊烷](6C) The second step: (±)-(1aR, 1a 1 R, 3aR, 5aS) -3-methyleneoctahydrospiro [cyclobutane [cd] pentaene-1,2 '-[1,3] Oxypentane) ( 6C )

(±)-(1aR,1a1R,3aR,5aS)-3-methyleneoctahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolane] (±)-(1aR, 1a 1 R, 3aR, 5aS) -3-methyleneoctahydrospiro [cyclobuta [cd] pentalene-1,2 '-[1,3] dioxolane]

向反應瓶中加入三苯基甲基溴化膦(10.7g，30mmol)和四氫呋喃(60mL)，氮氣保護，降溫至0℃，分批加入第三丁醇鉀(3.4g，30mmol)，室溫攪拌30分鐘，冰水浴下滴加(±)-(1aR,1a1R,3aR,5aS)-六氫螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊烷]-3(1a1H)-酮(6B)(1.94g，10mmol)的四氫呋喃(10mL)溶液，加完升溫至室溫反應2小時，冰水浴下滴加飽和氯化銨溶液至pH約為7，用乙酸乙酯(100mL×3)萃取，合併有機相，用水(150mL×2)洗滌，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=10：1)得到淡黃色油狀液體(±)-(1aR,1a1R,3aR,5aS)-3-亞甲基八氫螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊烷](6C)(1.4g，產率：74%)。 Add triphenylmethylphosphine bromide (10.7g, 30mmol) and tetrahydrofuran (60mL) to the reaction flask, protect with nitrogen, lower the temperature to 0 ° C, and add potassium tert-butoxide (3.4g, 30mmol) in portions. Room temperature After stirring for 30 minutes, (±)-(1aR, 1a 1 R, 3aR, 5aS) -hexahydrospiro [cyclobutane [cd] pentaene-1,2 '-[1,3] A solution of oxypentane] -3 (1a 1 H) -one ( 6B ) (1.94 g, 10 mmol) in tetrahydrofuran (10 mL). The temperature was raised to room temperature for 2 hours, and a saturated ammonium chloride solution was added dropwise in an ice water bath to The pH was about 7, extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with water (150 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography ( Petroleum ether / ethyl acetate (v / v) = 10: 1) to obtain a light yellow oily liquid (±)-(1aR, 1a 1 R, 3aR, 5aS) -3-methyleneoctahydrospiro [cyclobutane [cd] Pentalene-1,2 '-[1,3] dioxolane] ( 6C ) (1.4 g, yield: 74%).

第三步：(±)-(1aR,1a1R,3aR,5aS)-3-亞甲基八氫-1H-環丁烷[cd]戊搭烯-1-酮(6D) The third step: (±)-(1aR, 1a 1 R, 3aR, 5aS) -3-methyleneoctahydro-1H-cyclobutane [cd] pentaden-1-one ( 6D )

(±)-(1aR,1a1R,3aR,5aS)-3-methyleneoctahydro-1H-cyclobuta[cd]pentalen-1-one (±)-(1aR, 1a 1 R, 3aR, 5aS) -3-methyleneoctahydro-1H-cyclobuta [cd] pentalen-1-one

向反應瓶中加入(±)-(1aR,1a1R,3aR,5aS)-3-亞甲基八氫螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊烷](6C)(0.77g，4mmol)，加入四氫呋喃(6mL)和水(2mL)，冰浴下滴加三氟醋酸(2mL)，50℃反應3小時，冰浴下滴加飽和碳酸 氫鈉溶液至pH約為7，用乙酸乙酯(60mL×3)萃取，合併有機相，用水(100mL×2)洗滌，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=100：1)得到白色固體(±)-(1aR,1a1R,3aR,5aS)-3-亞甲基八氫-1H-環丁烷[cd]戊搭烯-1-酮(6D)(0.54g，產率：90%)。 Add (±)-(1aR, 1a 1 R, 3aR, 5aS) -3-methyleneoctahydrospiro [cyclobutane [cd] pentaene-1,2 '-[1,3] to the reaction flask Dioxolane ( 6C ) (0.77 g, 4 mmol), tetrahydrofuran (6 mL) and water (2 mL) were added, and trifluoroacetic acid (2 mL) was added dropwise in an ice bath, and the reaction was carried out at 50 ° C for 3 hours. Sodium bicarbonate solution to pH about 7, extracted with ethyl acetate (60mL × 3), combined organic phases, washed with water (100mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to a silica gel column Chromatographic separation and purification (petroleum ether / ethyl acetate (v / v) = 100: 1) to obtain a white solid (±)-(1aR, 1a 1 R, 3aR, 5aS) -3-methylene octahydro-1H- Cyclobutane [cd] pental-1-one ( 6D ) (0.54 g, yield: 90%).

1H NMR(400MHz,CDCl3)δ 4.94(d,J=18.3Hz,2H),3.54-3.37(m,2H),3.15-3.02(m,1H),2.70(dd,J=8.6,5.7Hz,1H),2.22-2.07(m,1H),1.94-1.83(m,1H),1.62-1.46(m,2H),1.46-1.30(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ 4.94 (d, J = 18.3Hz, 2H), 3.54-3.37 (m, 2H), 3.15-3.02 (m, 1H), 2.70 (dd, J = 8.6, 5.7Hz , 1H), 2.22-2.07 (m, 1H), 1.94-1.83 (m, 1H), 1.62-1.46 (m, 2H), 1.46-1.30 (m, 2H).

第四步：(±)-2-((1aR,1a1R,3aR,5aS)-3-亞甲基八氫-1H-環丁烷[cd]戊搭烯-1-亞基)乙酸第三丁酯(6E) The fourth step: (±) -2-((1aR, 1a 1 R, 3aR, 5aS) -3-methyleneoctahydro-1H-cyclobutane [cd] pentalene-1-ylidene) acetic acid Tributyl ester ( 6E )

(±)-tert-butyl-2-((1aR,1a1R,3aR,5aS)-3-methyleneoctahydro-1H-cyclobuta[cd]penta len-1-ylidene)acetate (±) -tert-butyl-2-((1aR, 1a1R, 3aR, 5aS) -3-methyleneoctahydro-1H-cyclobuta [cd] penta len-1-ylidene) acetate

向反應瓶中加入氫化鈉(60%，0.13g，5.4mmol)和四氫呋喃(10mL)，降溫至0℃，滴加二乙基磷醯乙酸第三丁酯(1.2g，5.4mmol)的四氫呋喃(3mL)溶液，滴完0℃下反應20分鐘，滴加(±)-(1aR,1a1R,3aR,5aS)-3-亞甲基八氫-1H-環丁烷[cd]戊搭烯-1-酮(6D)(0.54g，3.6mmol)的四氫呋喃(2mL)溶液，升溫至室溫反應2小時，向反應液中加入水(50mL)和乙酸乙酯(50mL)，攪拌，分液，水相用乙酸乙酯(40mL×2)萃取，合併有機相，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=100：1)得到淡黃色油狀液體(±)-2-((1aR,1a1R,3aR,5aS)-3-亞甲 基八氫-1H-環丁烷[cd]戊搭烯-1-亞基)乙酸第三丁酯(6E)(0.65g，產率：81%)。 To the reaction flask were added sodium hydride (60%, 0.13 g, 5.4 mmol) and tetrahydrofuran (10 mL), the temperature was lowered to 0 ° C, and diethylphosphonium triacetate (1.2 g, 5.4 mmol) in tetrahydrofuran ( 3mL) solution, reacted at 0 ° C for 20 minutes, and (±)-(1aR, 1a 1 R, 3aR, 5aS) -3-methyleneoctahydro-1H-cyclobutane [cd] pentadiene was added dropwise. A solution of 1-one ( 6D ) (0.54 g, 3.6 mmol) in tetrahydrofuran (2 mL) was heated to room temperature and reacted for 2 hours. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate (40 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100: 1) A light yellow oily liquid was obtained (±) -2-((1aR, 1a 1 R, 3aR, 5aS) -3-methyleneoctahydro-1H-cyclobutane [cd] pentane Ene-1-ylidene) tert-butyl acetate ( 6E ) (0.65 g, yield: 81%).

1H NMR(400MHz,CDCl3)δ 5.49(dd,J=22.2,20.7Hz,1H),4.78(dd,J=14.8,13.6Hz,2H),3.83-3.62(m,1H),3.32-3.17(m,1H),3.09-2.98(m,1H),2.63(dd,J=8.3,6.0Hz,1H),2.15-1.89(m,2H),1.76(ddd,J=9.8,5.6,2.2Hz,1H),1.64-1.55(m,1H),1.53-1.41(m,11H)。 1 H NMR (400MHz, CDCl 3 ) δ 5.49 (dd, J = 22.2, 20.7Hz, 1H), 4.78 (dd, J = 14.8, 13.6Hz, 2H), 3.83-3.62 (m, 1H), 3.32-3.17 (m, 1H), 3.09-2.98 (m, 1H), 2.63 (dd, J = 8.3,6.0Hz, 1H), 2.15-1.89 (m, 2H), 1.76 (ddd, J = 9.8,5.6,2.2Hz , 1H), 1.64-1.55 (m, 1H), 1.53-1.41 (m, 11H).

第五步：(±)-2-((1R,1aR,1a1R,3aR,5aS)-3-亞甲基-1-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸第三丁酯(6F) Step 5: (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -3-methylene-1- (nitromethyl) octahydro-1H-cyclobutane [cd] Pentylene-1-yl) tert-butyl acetate ( 6F )

(±)-tert-butyl-2-((1R,1aR,1a1R,3aR,5aS)-3-methylene-1-(nitromethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetate (±) -tert-butyl-2-((1R, 1aR, 1a1R, 3aR, 5aS) -3-methylene-1- (nitromethyl) octahydro-1H-cyclobuta [cd] pentalen-1-yl) acetate

向反應瓶中加入(±)-2-((1aR,1a1R,3aR,5aS)-3-亞甲基八氫-1H-環丁烷[cd]戊搭烯-1-亞基)乙酸第三丁酯(6E)(3.2g，14.7mmol)，硝基甲烷(50mL)和1,8-二氮雜雙環[5.4.0]十一碳-7-烯(3.3g，22mmol)，升溫至70℃反應6小時。向反應液中加入乙酸乙酯(60mL)和1M的鹽酸溶液(60mL)，攪拌，分液，水相用乙酸乙酯(100mL×2)萃取，合併有機相，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=100：1)，得到無色油狀液體(±)-2-((1R,1aR,1a1R,3aR,5aS)-3-亞甲基-1-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸第三丁酯(6F)(3.5g，產率：85%)。 Add (±) -2-((1aR, 1a 1 R, 3aR, 5aS) -3-methyleneoctahydro-1H-cyclobutane [cd] pentalene-1-ylidene) acetic acid to the reaction flask Tertiary butyl ester ( 6E ) (3.2 g, 14.7 mmol), nitromethane (50 mL) and 1,8-diazabicyclo [5.4.0] undec-7-ene (3.3 g, 22 mmol), warm up The reaction was carried out at 70 ° C for 6 hours. Ethyl acetate (60 mL) and 1M hydrochloric acid solution (60 mL) were added to the reaction solution, and the mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100: 1) to obtain a colorless oily liquid (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -3-methylene-1- (nitromethyl) octahydro-1H-cyclobutane [cd] pentalen-1-yl) tributyl acetate ( 6F ) ( 3.5 g, yield: 85%).

1H NMR(400MHz,CDCl3)δ 4.91-4.70(m,4H),3.15-3.05(m,1H),2.75-2.60(m,3H),2.58(d,J=1.5Hz,2H),2.15(dt,J=13.7,9.0Hz,1H),1.94(dddd,J=15.4,9.0,6.3,1.5Hz,1H),1.81-1.52(m,4H),1.46(s,9H)。 1 H NMR (400MHz, CDCl 3 ) δ 4.91-4.70 (m, 4H), 3.15-3.05 (m, 1H), 2.75-2.60 (m, 3H), 2.58 (d, J = 1.5Hz, 2H), 2.15 (dt, J = 13.7, 9.0 Hz, 1H), 1.94 (dddd, J = 15.4, 9.0, 6.3, 1.5 Hz, 1H), 1.81-1.52 (m, 4H), 1.46 (s, 9H).

第六步：(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨甲基)-3-亞甲基八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸第三丁酯(6G) Step 6: (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -3-methyleneoctahydro-1H-cyclobutane [cd] pent Terten-1-yl) tert-butyl acetate ( 6G )

(±)-tert-butyl-2-((1R,1aR,1a1R,3aR,5aS)-1-(aminomethyl)-3-methyleneoctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetate (±) -tert-butyl-2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -3-methyleneoctahydro-1H-cyclobuta [cd] pentalen-1-yl) acetate

向反應瓶中加入(±)-2-((1R,1aR,1a1R,3aR,5aS)-3-亞甲基-1-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸第三丁酯(6F)(4g，13mmol)，乙醇(32mL)和水(16mL)，加入還原鐵粉(4.3g，78mmol)和氯化銨(4.1g，78mmol)，迴流反應6小時。將反應液冷卻後抽濾，用乙酸乙酯(50L×3)洗滌濾渣，收集濾液，減壓濃縮，水相用乙酸乙酯(10L×3)萃取，合併有機相，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(二氯甲烷/甲醇(v/v)=40：1-10：1)，得到白色固體(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨甲基)-3-亞甲基八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸第三丁酯(6G)(3.0g，產率：83%)。 Add (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -3-methylene-1- (nitromethyl) octahydro-1H-cyclobutane [cd ] Pentadien-1-yl) tert-butyl acetate ( 6F ) (4g, 13mmol), ethanol (32mL) and water (16mL), reduced iron powder (4.3g, 78mmol) and ammonium chloride (4.1g , 78 mmol), and refluxed for 6 hours. The reaction solution was cooled and suction filtered. The residue was washed with ethyl acetate (50 L × 3), and the filtrate was collected and concentrated under reduced pressure. The aqueous phase was extracted with ethyl acetate (10 L × 3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 40: 1-10: 1) to obtain a white solid (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -3-methyleneoctahydro-1H-cyclobutane [cd] pentaden-1-yl) acetic acid tert-butyl ester ( 6G ) (3.0 g, yield: 83%).

第七步：(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨甲基)-3-亞甲基八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(化合物6) Step 7: (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -3-methyleneoctahydro-1H-cyclobutane [cd] pent 1-Phen-1-yl) acetic acid ( Compound 6 )

(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(aminomethyl)-3-methyleneoctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -3-methyleneoctahydro-1H-cyclobuta [cd] pentalen-1-yl) acetic acid

向反應瓶中加入(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨甲基)-3-亞甲基八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸第三丁酯(6G)(0.28g，1mmol)，甲醇(3mL)和水(3mL)，加入氫氧化鈉(0.72g，18mmol)，迴流反應10小時，減壓濃縮以除去甲醇，用2M的鹽酸調節pH為7-8，有白色固體析出，抽濾，濾餅用水(20mL×3)和二氯甲烷(30mL×3)洗滌，烘乾，得到白色固體(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨甲基)-3-亞甲基八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(化合物6)(0.15g，產率：68%)。 Add (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -3-methyleneoctahydro-1H-cyclobutane [cd] to the reaction flask Pentylene-1-yl) tert-butyl acetate ( 6G ) (0.28g, 1mmol), methanol (3mL) and water (3mL), sodium hydroxide (0.72g, 18mmol) was added, and the reaction was refluxed for 10 hours, minus It was concentrated under pressure to remove methanol, and the pH was adjusted to 7-8 with 2M hydrochloric acid. A white solid was precipitated, filtered off with suction, the filter cake was washed with water (20 mL × 3) and dichloromethane (30 mL × 3), and dried to obtain a white solid (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -3-methyleneoctahydro-1H-cyclobutane [cd] pentadiene-1 -Yl) acetic acid ( Compound 6 ) (0.15 g, yield: 68%).

MS m/z(ESI)：222.3(M+1)。 MS m / z (ESI): 222.3 (M + 1).

1H NMR(400MHz,D2O)δ 4.82(d,J=1.7Hz,1H),4.74(d,J=1.6Hz,1H),3.31-3.19(m,2H),3.13-3.04(m,1H),2.65(t,J=6.9Hz,1H),2.53(dt,J=24.1,16.9Hz,3H),2.35(d,J=2.6Hz,1H),2.16-2.01(m,1H),1.91-1.79(m,1H),1.72(dt,J=13.7,9.5Hz,1H),1.60(d,J=13.9Hz,1H),1.57-1.37(m,2H)。 1 H NMR (400MHz, D 2 O) δ 4.82 (d, J = 1.7Hz, 1H), 4.74 (d, J = 1.6Hz, 1H), 3.31-3.19 (m, 2H), 3.13-3.04 (m, 1H), 2.65 (t, J = 6.9Hz, 1H), 2.53 (dt, J = 24.1, 16.9Hz, 3H), 2.35 (d, J = 2.6Hz, 1H), 2.16-2.01 (m, 1H), 1.91-1.79 (m, 1H), 1.72 (dt, J = 13.7, 9.5Hz, 1H), 1.60 (d, J = 13.9Hz, 1H), 1.57-1.37 (m, 2H).

實施例7Example 7

(±)-2-((1R,1aR,1a1R,3aS,5aS)-1-(氨甲基)-3-甲基八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(化合物7) (±) -2-((1R, 1aR, 1a 1 R, 3aS, 5aS) -1- (aminomethyl) -3-methyloctahydro-1H-cyclobutane [cd] pentadiene-1- Propyl) acetic acid ( Compound 7 )

(±)-2-((1R,1aR,1a1R,3aS,5aS)-1-(aminomethyl)-3-methyloctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid (±) -2-((1R, 1aR, 1a 1 R, 3aS, 5aS) -1- (aminomethyl) -3-methyloctahydro-1H-cyclobuta [cd] pentalen-1-yl) acetic acid

第一步：(±)-(1R,1aR,1a1R,3aR,5aS)-3-亞甲基八氫螺[環丁烷[cd]戊搭烯-1,3'-吡咯烷]-5'-酮(7B) The first step: (±)-(1R, 1aR, 1a 1 R, 3aR, 5aS) -3-methyleneoctahydrospiro [cyclobutane [cd] pentalene-1,3'-pyrrolidine]- 5'-one ( 7B )

(±)-(1R,1aR,1a1R,3aR,5aS)-3-methyleneoctahydrospiro[cyclobuta[cd]pentalene-1,3'-pyrrolidin]-5'-one (±)-(1R, 1aR, 1a 1 R, 3aR, 5aS) -3-methyleneoctahydrospiro [cyclobuta [cd] pentalene-1,3'-pyrrolidin] -5'-one

向反應瓶中加入(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨甲基)-3-亞甲基八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸第三丁酯(6G)(1.12g，4mmol)，甲醇(15mL)和水(15mL)，加入氫氧化鈉(0.72g，18mmol)，迴流反應1小時，冷卻後減壓濃縮以除去甲醇，用二氯甲烷(50mL×3)萃取，合併有機相，用無水硫酸鈉乾燥，減壓濃縮，得到灰白色固體(±)-(1R,1aR,1a1R,3aR,5aS)-3-亞甲基八氫螺[環丁烷[cd]戊搭烯-1,3'-吡咯烷]-5'-酮(7B)(0.5g，產率：61%)，直接用於下一步反應。 Add (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -3-methyleneoctahydro-1H-cyclobutane [cd] to the reaction flask Pentylene-1-yl) tert-butyl acetate ( 6G ) (1.12 g, 4 mmol), methanol (15 mL) and water (15 mL), sodium hydroxide (0.72 g, 18 mmol) was added, and the reaction was refluxed for 1 hour, and cooled Then concentrated under reduced pressure to remove methanol, extracted with dichloromethane (50 mL × 3), combined organic phases, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an off-white solid (±)-(1R, 1aR, 1a 1 R, 3aR , 5aS) -3-methyleneoctahydrospiro [cyclobutane [cd] pentadiene-1,3'-pyrrolidine] -5'-one ( 7B ) (0.5 g, yield: 61%), Used directly in the next reaction.

第二步：(±)-(1R,1aR,1a1R,3aR,5aS)-3-甲基八氫螺[環丁烷[cd]戊搭烯-1,3'-吡咯烷]-5'-酮(7C) Second step: (±)-(1R, 1aR, 1a 1 R, 3aR, 5aS) -3-methyloctahydrospiro [cyclobutane [cd] pentalene-1,3'-pyrrolidine] -5 '-Ketone ( 7C )

(±)-(1R,1aR,1a1R,3aS,5aS)-3-methyloctahydrospiro[cyclobuta[cd]pentalene-1,3'-pyrrolidin]-5'-one (±)-(1R, 1aR, 1a 1 R, 3aS, 5aS) -3-methyloctahydrospiro [cyclobuta [cd] pentalene-1,3'-pyrrolidin] -5'-one

向反應瓶中加入(±)-(1R,1aR,1a1R,3aR,5aS)-3-亞甲基八氫螺[環丁烷[cd]戊搭烯-1,3'-吡咯烷]-5'-酮(7B)(0.5g，2.46mmol)，甲醇(10mL)，和鈀/碳(10%(w%)，0.5g)，體系用氫氣置換三次，35℃下氫化3小時，將反應液抽濾，用甲醇(20mL×3)洗滌濾渣，合併濾液，將濾液減壓濃縮，殘留物用矽膠柱層析分離純化(二氯甲烷8甲醇(v/v)=40：1-10：1)，得到白色固體(±)-(1R,1aR,1a1R,3aR,5aS)-3-甲基八氫螺[環丁烷[cd]戊搭烯-1,3'-吡咯烷]-5'-酮(7C)(0.2g，產率：40%)。 Add (±)-(1R, 1aR, 1a 1 R, 3aR, 5aS) -3-methyleneoctahydrospiro [cyclobutane [cd] pentadiene-1,3'-pyrrolidine] to the reaction flask -5'-one ( 7B ) (0.5 g, 2.46 mmol), methanol (10 mL), and palladium / carbon (10% (w%), 0.5 g), the system was replaced with hydrogen three times, and hydrogenated at 35 ° C for 3 hours, The reaction solution was suction filtered, and the residue was washed with methanol (20 mL × 3). The filtrates were combined, and the filtrates were concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane 8 methanol (v / v) = 40: 1- 10: 1) to obtain (±)-(1R, 1aR, 1a 1 R, 3aR, 5aS) -3-methyloctahydrospiro [cyclobutane [cd] pentadiene-1,3'-pyrrole Alkyl] -5'-one ( 7C ) (0.2 g, yield: 40%).

1H NMR(400MHz,CDCl3)δ 3.56-3.37(m,2H),2.65-2.35(m,2H),2.22(dt,J=6.2,3.9Hz,2H),2.08-1.90(m,2H),1.88-1.75(m,2H),1.75-1.63(m,1H),1.51-1.22(m,3H),1.11(d,J=7.2Hz,3H),0.70(d,J=7.0Hz,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 3.56-3.37 (m, 2H), 2.65-2.35 (m, 2H), 2.22 (dt, J = 6.2, 3.9Hz, 2H), 2.08-1.90 (m, 2H) , 1.88-1.75 (m, 2H), 1.75-1.63 (m, 1H), 1.51-1.22 (m, 3H), 1.11 (d, J = 7.2Hz, 3H), 0.70 (d, J = 7.0Hz, 1H ).

第三步：(±)-2-((1R,1aR,1a1R,3aS,5aS)-1-(氨甲基)-3-甲基八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(化合物7) The third step: (±) -2-((1R, 1aR, 1a 1 R, 3aS, 5aS) -1- (aminomethyl) -3-methyloctahydro-1H-cyclobutane [cd] pentane En-1-yl) acetic acid ( compound 7 )

(±)-2-((1R,1aR,1a1R,3aS,5aS)-1-(aminomethyl)-3-methyloctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid (±) -2-((1R, 1aR, 1a 1 R, 3aS, 5aS) -1- (aminomethyl) -3-methyloctahydro-1H-cyclobuta [cd] pentalen-1-yl) acetic acid

向反應瓶中加入(±)-(1R,1aR,1a1R,3aR,5aS)-3-甲基八氫螺[環丁烷[cd]戊搭烯-1,3'-吡咯烷]-5'-酮(7C)(0.2g，0.97mmol)，甲醇(3mL)和水(3mL)，加入氫氧化鈉(0.72g，18mmol)，迴流反應6小時，減壓濃縮以除去甲醇， 加入水(10mL)，用二氯甲烷(30mL×3)萃取，水相用2M的鹽酸調節pH為7-8後用磺酸樹脂柱層析分離提純(水(50mL)-氨水(10%(v%)，100mL))，得到白色固體(±)-2-((1R,1aR,1a1R,3aS,5aS)-1-(氨甲基)-3-甲基八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(化合物7)(0.06g，產率：30%)。 Add (±)-(1R, 1aR, 1a 1 R, 3aR, 5aS) -3-methyloctahydrospiro [cyclobutane [cd] pentalene-1,3'-pyrrolidine]-to the reaction flask 5'-one ( 7C ) (0.2 g, 0.97 mmol), methanol (3 mL) and water (3 mL), sodium hydroxide (0.72 g, 18 mmol) was added, and the mixture was reacted at reflux for 6 hours, and concentrated under reduced pressure to remove methanol, and water was added (10mL), extracted with dichloromethane (30mL × 3), the aqueous phase was adjusted to pH 7-8 with 2M hydrochloric acid, and then purified by sulfonic resin column chromatography (water (50mL) -aqueous ammonia (10% (v% ), 100 mL)) to give a white solid (±) -2-((1R, 1aR, 1a 1 R, 3aS, 5aS) -1- (aminomethyl) -3-methyloctahydro-1H-cyclobutane [cd] Pentene-1-yl) acetic acid ( Compound 7 ) (0.06 g, yield: 30%).

MS m/z(ESI)：224.3(M+1)。 MS m / z (ESI): 224.3 (M + 1).

1H NMR(400MHz,D2O)δ 3.22(q,J=13.1Hz,2H),2.64-2.31(m,5H),2.01(dd,J=23.1,13.6Hz,3H),1.89-1.73(m,2H),1.72-1.62(m,1H),1.56-1.43(m,2H),1.33(dd,J=14.2,10.8Hz,1H),1.05(d,J=7.1Hz,3H),0.65(d,J=7.0Hz,1H)。 1 H NMR (400MHz, D 2 O) δ 3.22 (q, J = 13.1Hz, 2H), 2.64-2.31 (m, 5H), 2.01 (dd, J = 23.1, 13.6Hz, 3H), 1.89-1.73 ( m, 2H), 1.72-1.62 (m, 1H), 1.56-1.43 (m, 2H), 1.33 (dd, J = 14.2, 10.8Hz, 1H), 1.05 (d, J = 7.1Hz, 3H), 0.65 (d, J = 7.0Hz, 1H).

實施例8Example 8

(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨基甲基)-3,3-二氟八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(化合物8) (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -3,3-difluorooctahydro-1H-cyclobutane [cd] pentadiene- 1-yl) acetic acid ( compound 8 )

(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(aminomethyl)-3,3-difluorooctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -3,3-difluorooctahydro-1H-cyclobuta [cd] pentalen-1-yl) acetic acid

第一步：(±)-(1aR,1a1R,3aR,5aS)-3,3-二氟八氫螺螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊環](8B) The first step: (±)-(1aR, 1a 1 R, 3aR, 5aS) -3,3-difluorooctylspirospiro [cyclobutane [cd] pentalene-1,2 '-[1,3 ] Dioxolane] ( 8B )

(±)-(1aR,1a1R,3a.R,5aS)-3,3-difluorooctahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolane] (±)-(1aR, 1a 1 R, 3a.R, 5aS) -3,3-difluorooctahydrospiro [cyclobuta [cd] pentalene-1,2 '-[1,3] dioxolane]

向反應瓶中加入(±)-(1aR,1a1R,3aR,5aS)-六氫螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊烷]-3(1a1H)-酮(6B)(6.0g，31mmol)和乾燥的二氯甲烷(130mL)，充氮氣保護，冷卻至0℃，滴加二乙胺基三氟化硫(50g，310mmol)，加熱至迴流反應10小時，將冷至室溫的反應液滴加至冰冷的飽和碳酸氫鈉溶液(800mL)中，用二氯甲烷(150mL×3)萃取，合併有機相，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=50：1)得到黃色油狀液體(±)-(1aR,1a1R,3aR,5aS)-3,3-二氟八氫螺螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊環](8B)(5.2g，收率：78%)。 Add (±)-(1aR, 1a 1 R, 3aR, 5aS) -hexahydrospiro [cyclobutane [cd] pentadiene-1,2 '-[1,3] dioxolane] to the reaction flask -3 (1a 1 H) -one ( 6B ) (6.0 g, 31 mmol) and dry dichloromethane (130 mL), protected with nitrogen, cooled to 0 ° C, and added diethylamine sulfur trifluoride (50 g, (310mmol), heated to reflux for 10 hours, and the reaction solution cooled to room temperature was added dropwise to an ice-cold saturated sodium bicarbonate solution (800mL), and extracted with dichloromethane (150mL × 3). The organic phases were combined and dried with anhydrous It was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 50: 1) to obtain a yellow oily liquid (±)-(1aR, 1a 1 R, 3aR, 5aS) -3,3-difluorooctahydrospirospiro [cyclobutane [cd] pentaene-1,2 '-[1,3] dioxolane] ( 8B ) (5.2g , Yield: 78%).

MS m/z(ESI)：239.2(M+23)。 MS m / z (ESI): 239.2 (M + 23).

1H NMR(400MHz,CDCl3)δ 3.94-3.83(m,4H),2.85-2.78(m,1H),2.77-2.70(m,1H),2.63-2.52(m,1H),2.33-2.23(m,1H),2.21-2.09(m,1H),2.08-1.97(m,1H),1.85-1.72(m,1H),1.71-1.56(m,2H),1.55-1.44(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ 3.94-3.83 (m, 4H), 2.85-2.78 (m, 1H), 2.77-2.70 (m, 1H), 2.63-2.52 (m, 1H), 2.33-2.23 ( m, 1H), 2.21-2.09 (m, 1H), 2.08-1.97 (m, 1H), 1.85-1.72 (m, 1H), 1.71-1.56 (m, 2H), 1.55-1.44 (m, 1H).

19F NMR(376MHz,CDCl3)δ(-97.33)-(-97.93)(1F),(-118.13)-(-118.73)(1F)。 19 F NMR (376 MHz, CDCl 3 ) δ (-97.33)-(-97.93) (1F), (-118.13)-(-118.73) (1F).

第二步：(±)-(1aR,1a1R,3aR,5aS)-3,3-二氟八氫-1H-環丁烷[cd]戊搭烯 -1-酮(8C) Second step: (±)-(1aR, 1a 1 R, 3aR, 5aS) -3,3-difluorooctahydro-1H-cyclobutane [cd] pentaden-1-one ( 8C )

(±)-(1aR,1a1R,3aR,5aS)-3,3-difluorooctahydro-1H-cyclobuta[cd]pentalen-1-one (±)-(1aR, 1a 1 R, 3aR, 5aS) -3,3-difluorooctahydro-1H-cyclobuta [cd] pentalen-1-one

向反應瓶中加入(±)-(1aR,1a1R,3aR,5aS)-3,3-二氟八氫螺螺[環丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊環](8B)(3.0g，14mmol)，水(16mL)和四氫呋喃(28mL)，冷卻至0℃，滴加三氟乙酸(15mL)，加熱至90℃反應12小時，加入飽和碳酸氫鈉溶液調節pH至中性，用二氯甲烷(25mL×3)萃取，合併有機層，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=100：1)得到黃色固體(±)-(1aR,1a1R,3aR,5aS)-3,3-二氟八氫-1H-環丁烷[cd]戊搭烯-1-酮(8C)(1.7g，收率：71%)。 Add (±)-(1aR, 1a 1 R, 3aR, 5aS) -3,3-difluorooctylspiro [cyclobutane [cd] pentadiene-1,2 '-[1, 3] Dioxolane ( 8B ) (3.0 g, 14 mmol), water (16 mL) and tetrahydrofuran (28 mL), cooled to 0 ° C, trifluoroacetic acid (15 mL) was added dropwise, and the mixture was heated to 90 ° C for 12 hours and added Saturated sodium bicarbonate solution to adjust the pH to neutral, extracted with dichloromethane (25mL × 3), combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum Ether / ethyl acetate (v / v) = 100: 1) to give a yellow solid (±)-(1aR, 1a 1 R, 3aR, 5aS) -3,3-difluorooctahydro-1H-cyclobutane [cd ] Pentalen-1-one ( 8C ) (1.7 g, yield: 71%).

1H NMR(400MHz,CDCl3)δ 3.49(ddt,J=11.5,9.8,5.9Hz,2H),2.98-2.85(m,1H),2.47(tdd,J=8.2,6.0,1.9Hz,1H),2.39-2.17(m,2H),1.82-1.48(m,4H)。 1 H NMR (400MHz, CDCl3) δ 3.49 (ddt, J = 11.5, 9.8, 5.9Hz, 2H), 2.98-2.85 (m, 1H), 2.47 (tdd, J = 8.2, 6.0, 1.9Hz, 1H), 2.39-2.17 (m, 2H), 1.82-1.48 (m, 4H).

19F NMR(376MHz,CDCl3)δ(-96.18)-(-96.79)(1F),(-116.52)-(-117.13)(1F)。 19 F NMR (376 MHz, CDCl 3 ) δ (-96.18)-(-96.79) (1F), (-116.52)-(-117.13) (1F).

第三步：(±)-2-((1aR,1a1R,3aR,5aS)-3,3-二氟八氫-1H-環丁烷[cd]戊搭烯-1-亞基)乙酸第三丁酯(8D) The third step: (±) -2-((1aR, 1a 1 R, 3aR, 5aS) -3,3-difluorooctahydro-1H-cyclobutane [cd] pentalene-1-ylidene) acetic acid Tert-butyl ester ( 8D )

(±)-tert-butyl-2-((1aR,1a1R,3aR,5aS)-3,3-difluorooctahydro-1H-cyclobuta[cd]penta len-1-ylidene)acetate (±) -tert-butyl-2-((1aR, 1a 1 R, 3aR, 5aS) -3,3-difluorooctahydro-1H-cyclobuta [cd] penta len-1-ylidene) acetate

向反應瓶中加入氫化鈉(0.6g，13mmol)和四氫呋喃(10mL)，冷卻至0。℃，滴加二乙基膦醯基乙酸第三丁酯(2.9g，12mmol)溶於四氫呋喃(10mL)的溶液，0℃下攪拌30分鐘，滴加(±)-(1aR,1a1R,3aR,5aS)-3,3-二氟八氫-1H-環丁烷[cd]戊搭烯-1-酮(8C)(1.8g，10mmol)的四氫呋喃(10mL)溶液，升至室溫攪拌1.5小時，加入飽和氯化銨溶液(30mL)，用乙酸乙酯(50mL×3)萃取，合併有機相，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=200：1)，得到無色油狀液體(±)-2-((1aR,1a1R,3aR,5aS)-3,3-二氟八氫-1H-環丁烷[cd]戊搭烯-1-亞基)乙酸第三丁酯(8D)(2.0g，收率：71%)。 Add sodium hydride (0.6 g, 13 mmol) and tetrahydrofuran (10 mL) to the reaction flask and cool to zero. A solution of tert-butyl diethylphosphinofluorenylacetate (2.9g, 12mmol) in tetrahydrofuran (10mL) was added dropwise at ℃, stirred at 0 ° C for 30 minutes, and (±)-(1aR, 1a 1 R, 3aR, 5aS) -3,3-difluorooctahydro-1H-cyclobutane [cd] pentaden-1-one ( 8C ) (1.8g, 10mmol) in tetrahydrofuran (10mL), warm to room temperature and stir After 1.5 hours, a saturated ammonium chloride solution (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography. (Petroleum ether / ethyl acetate (v / v) = 200: 1) to obtain a colorless oily liquid (±) -2-((1aR, 1a 1 R, 3aR, 5aS) -3,3-difluorooctahydrogen -1H-cyclobutane [cd] pentalene-1-ylidene) acetic acid tert-butyl ester ( 8D ) (2.0 g, yield: 71%).

MS m/z(ESI)：293.2(M+23)。 MS m / z (ESI): 293.2 (M + 23).

1H NMR(400MHz,CDCl3)δ 5.53(dd,J=13.1,11.5Hz,1H),3.81-3.65(m,1H),3.35-3.18(m,1H),2.95-2.76(m,1H),2.41-2.16(m,3H),1.95-1.72(m,2H),1.73-1.61(m,1H),1.51-1.37(m,11H)。 1H NMR (400MHz, CDCl3) δ 5.53 (dd, J = 13.1,11.5Hz, 1H), 3.81-3.65 (m, 1H), 3.35-3.18 (m, 1H), 2.95-2.76 (m, 1H), 2.41 -2.16 (m, 3H), 1.95-1.72 (m, 2H), 1.73-1.61 (m, 1H), 1.51-1.37 (m, 11H).

第四步：(±)-2-((1R,1aR,1a1R,3aR,5aS)-3,3-二氟-1-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸第三丁酯(8E) Step 4: (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -3,3-difluoro-1- (nitromethyl) octahydro-1H-cyclobutane [cd ] Pentadien-1-yl) tributyl acetate ( 8E )

(±)-tert-butyl-2-((1R,1aR,1a1R,3aR,5aS)-3,3-difluoro-1-(nitromethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetate (±) -tert-butyl-2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -3,3-difluoro-1- (nitromethyl) octahydro-1H-cyclobuta [cd] pentalen-1-yl) acetate

向反應瓶中加入(±)-2-((1aR,1a1R,3aR,5aS)-3,3-二氟八氫-1H-環丁烷[cd]戊搭烯-1-亞基)乙酸第三丁酯(8D)(2.0g，7.4mmol)，硝基甲烷(65mL)和1,8-二氮雜二環十一碳-7-烯(5.6g，37mmol)，80℃反應7小時，冷卻至室溫，用2M的鹽酸調節溶液pH至中性，加入水(30mL)，用乙酸乙酯(30mL×3)萃取，合併有機相，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=400：1)，得到無色油狀液體(±)-2-((1R,1aR,1a1R,3aR,5aS)-3,3-二氟-1-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸第三丁酯(8E)(1.4g，收率：57%)。 Add (±) -2-((1aR, 1a 1 R, 3aR, 5aS) -3,3-difluorooctahydro-1H-cyclobutane [cd] pentadiene-1-subunit) to the reaction flask Tertiary butyl acetate ( 8D ) (2.0g, 7.4mmol), nitromethane (65mL) and 1,8-diazabicycloundec-7-ene (5.6g, 37mmol), react at 80 ° C for 7 Hour, cool to room temperature, adjust the pH of the solution to neutral with 2M hydrochloric acid, add water (30mL), extract with ethyl acetate (30mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and decompress the filtrate under reduced pressure Concentrated, the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 400: 1) to obtain a colorless oily liquid (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -3,3-difluoro-1- (nitromethyl) octahydro-1H-cyclobutane [cd] pentaden-1-yl) tert-butyl acetate ( 8E ) (1.4g , Yield: 57%).

MS m/z(ESI)：354.3(M+23)。 MS m / z (ESI): 354.3 (M + 23).

1H NMR(400MHz,CDCl3)δ 4.80(q,J=12.0Hz,2H),2.87(ddd,J=11.6,8.4,3.9Hz,1H),2.77-2.61(m,2H),2.54(q,J=17.6Hz,2H),2.44-2.17(m,3H),1.90-1.68(m,2H),1.62-1.53(m,1H),1.53-1.40(m,10H)。 1 H NMR (400MHz, CDCl 3 ) δ 4.80 (q, J = 12.0Hz, 2H), 2.87 (ddd, J = 11.6, 8.4, 3.9Hz, 1H), 2.77-2.61 (m, 2H), 2.54 (q , J = 17.6Hz, 2H), 2.44-2.17 (m, 3H), 1.90-1.68 (m, 2H), 1.62-1.53 (m, 1H), 1.53-1.40 (m, 10H).

19F NMR(376MHz,CDCl3)δ(-100.02)-(-100.63)(1F),(-121.03)-(-121.64)(1F)。 19 F NMR (376 MHz, CDCl 3 ) δ (-100.02)-(-100.63) (1F), (-121.03)-(-121.64) (1F).

第五步：(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨基甲基)-3,3-二氟八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸第三丁酯(8F) Step 5: (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -3,3-difluorooctahydro-1H-cyclobutane [cd] Pentylene-1-yl) tert-butyl acetate ( 8F )

(±)-tert-butyl-2-((1R,1aR,1a1R,3aR,5aS)-1-(aminomethyl)-3,3-difluorooctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetate (±) -tert-butyl-2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -3,3-difluorooctahydro-1H-cyclobuta [cd] pentalen-1-yl) acetate

向反應瓶中依次加入(±)-2-((1R,1aR,1a1R,3aR,5aS)-3,3-二氟-1-(硝基甲基)八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸第三丁酯(8E)(1.4g，4.2mmol)， 鐵粉(2.4g，32mmol)，氯化銨(0.9g，17mmol)，乙醇(32mL)和水(16mL)，加熱至90℃反應6小時，過濾，將濾液減壓濃縮，殘留物中加入飽和氯化鈉溶液(50mL)，用二氯甲烷(50mL×3)萃取，合併有機相，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(二氯甲烷/甲醇(v/v)=50：1-10：1)，得到白色固體(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨基甲基)-3,3-二氟八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸第三丁酯(8F)(1.2g，產率：94%)。 Add (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -3,3-difluoro-1- (nitromethyl) octahydro-1H-cyclobutane to the reaction bottle in order [cd] Pentadien-1-yl) tributyl acetate ( 8E ) (1.4g, 4.2mmol), iron powder (2.4g, 32mmol), ammonium chloride (0.9g, 17mmol), ethanol (32mL) And water (16 mL), heated to 90 ° C. for 6 hours, filtered, and the filtrate was concentrated under reduced pressure, a saturated sodium chloride solution (50 mL) was added to the residue, and extracted with dichloromethane (50 mL × 3), and the organic phases were combined, It was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 50: 1-10: 1) to obtain a white solid (±)- 2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -3,3-difluorooctahydro-1H-cyclobutane [cd] pentadien-1-yl) Tertiary butyl acetate ( 8F ) (1.2 g, yield: 94%).

MS m/z(ESI)：302.3(M+1)。 MS m / z (ESI): 302.3 (M + 1).

1H NMR(400MHz,CDCl3)δ 3.35(d,J=20.41-Hz,2H),2.87(tt,J=34.0,17.0Hz,1H),2.63(ddd,J=33.8,19.2,10.4Hz,4H),2.43-2.15(m,3H),1.90-1.65(m,2H),1.65-1.34(m,11H)。 1 H NMR (400MHz, CDCl 3 ) δ 3.35 (d, J = 20.41-Hz, 2H), 2.87 (tt, J = 34.0, 17.0 Hz, 1H), 2.63 (ddd, J = 33.8, 19.2, 10.4 Hz, 4H), 2.43-2.15 (m, 3H), 1.90-1.65 (m, 2H), 1.65-1.34 (m, 11H).

19F NMR(376MHz,CDCl3)δ(-99.71)-(-100.31)(1F),(-120.87)-(-121.48)(1F)。 19 F NMR (376 MHz, CDCl 3 ) δ (-99.71)-(-100.31) (1F), (-120.87)-(-121.48) (1F).

第六步：(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨基甲基)-3,3-二氟八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(化合物8) Step 6: (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -3,3-difluorooctahydro-1H-cyclobutane [cd] Pentenen-1-yl) acetic acid ( Compound 8 )

(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(aminomethyl)-3,3-difluorooctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -3,3-difluorooctahydro-1H-cyclobuta [cd] pentalen-1-yl) acetic acid

向反應瓶中加入(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨基甲基)-3,3-二氟八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸第三丁酯(8F)(1.2g，4.0mmol)，二氯甲烷(30mL)，滴加三氟乙酸(15mL)，室溫反應3小時，減壓濃縮，殘留物中 加入二氯甲烷(20mL)，加入三乙胺至溶液pH約為7，有固體析出，過濾。用二氯甲烷(20mL×3)洗滌濾餅，得到白色固體(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨基甲基)-3,3-二氟八氫-1H-環丁烷[cd]戊搭烯-1-基)乙酸(化合物8)(0.75g，產率：77%)。 Add (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -3,3-difluorooctahydro-1H-cyclobutane [cd ] Pentadien-1-yl) tert-butyl acetate ( 8F ) (1.2 g, 4.0 mmol), dichloromethane (30 mL), trifluoroacetic acid (15 mL) was added dropwise, the reaction was performed at room temperature for 3 hours, and concentrated under reduced pressure. To the residue was added dichloromethane (20 mL), and triethylamine was added until the solution had a pH of about 7, and a solid precipitated out, and filtered. The filter cake was washed with dichloromethane (20 mL × 3) to give a white solid (±) -2-((1R, 1aR, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -3,3-di Fluoroctahydro-1H-cyclobutane [cd] pentalen-1-yl) acetic acid ( Compound 8 ) (0.75 g, yield: 77%).

MS m/z(ESI)：246.3(M+1)。 MS m / z (ESI): 246.3 (M + 1).

1H NMR(400MHz,MeOD)δ 3.24-3.11(m,2H),2.92-2.80(m,1H),2.64-2.48(m,3H),2.47-2.10(m,4H),1.99-1.71(m,3H),1.66-1.55(m,1H)。 1 H NMR (400MHz, MeOD) δ 3.24-3.11 (m, 2H), 2.92-2.80 (m, 1H), 2.64-2.48 (m, 3H), 2.47-2.10 (m, 4H), 1.99-1.71 (m 3H), 1.66-1.55 (m, 1H).

19F NMR(376MHz,MeOD)δ(-100.62)-(-101.23)(1F),(-122.11)-(-122.72)(1F)。 19 F NMR (376 MHz, MeOD) δ (-100.62)-(-101.23) (1F), (-122.11)-(-122.72) (1F).

實施例9Example 9

(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基-1a,1a1,2,3,3a,5a-六氫-1H-環丁[cd]戊搭烯-1-基)乙酸 (±) -2-((1R, 1aS, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a-hexahydro- 1H-cyclobut [cd] pentalen-1-yl) acetic acid

(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(aminomethyl)-4-ethyl-1a,1a1,2,3,3a,5a-hexahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid (±) -2-((1R, 1aS, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a-hexahydro-1H-cyclobuta [ cd] pentalen-1-yl) acetic acid

第一步：(±)-2-((1aR,1a1R,3aR,5aS)-六氫螺環[環丁[cd]戊搭烯-1,2'-[1,3]二氧雜環戊烷]-3(1a1H)-亞基)乙酸乙酯(9B) The first step: (±) -2-((1aR, 1a 1 R, 3aR, 5aS) -hexahydrospiro [cyclobut [cd] pentadiene-1,2 '-[1,3] dioxane Cyclopentane] -3 (1a 1 H) -Subunit) ethyl acetate ( 9B )

(±)-ethyl-2-((1aR,1a1R,3aR,5aS)-hexahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolan]-3(1a1H)-ylidene)acetate (±) -ethyl-2-((1aR, 1a 1 R, 3aR, 5aS) -hexahydrospiro [cyclobuta [cd] pentalene-1,2 '-[1,3] dioxolan] -3 (1a 1 H) -ylidene acetate

將氫化鈉(2.1g，52.5mmol)加入乾燥的四氫呋喃(128mL)中，充氮氣保護，冷卻至0℃，滴加三乙氧基磷醯基乙酸酯(l0.8g，48.2mmol)，0℃下攪拌30分鐘，滴加(±)-(1aR,1a1R,3aR,5aS)-六氫螺環[環丁[cd]戊搭烯-1,2'-[1,3]二氧雜環戊烷]-3(1a1H)-酮(6B)(6.22g，32.0mmol)，自然升至室溫攪拌1.5 小時，冷卻至-5℃，滴加飽和氯化銨溶液(150mL)，用乙酸乙酯(150mL×3)萃取，有機相用飽和氯化鈉溶液(300mL)洗滌，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯=10：1)，得到無色液體(±)-2-((1aR,1a1R,3aR,5aS)-六氫螺環[環丁[cd]戊搭烯-1,2'-[1,3]二氧雜環戊烷]-3(1a1H)-亞基)乙酸乙酯(9B)(6.1g，產率：72%)。 Sodium hydride (2.1g, 52.5mmol) was added to dry tetrahydrofuran (128mL), protected with nitrogen, cooled to 0 ° C, and triethoxyphosphoranyl acetate (l0.8g, 48.2mmol) was added dropwise. After stirring at ℃ for 30 minutes, (±)-(1aR, 1a 1 R, 3aR, 5aS) -hexahydrospiro [cyclobut [cd] pentaene-1,2 '-[1,3] dioxy Heteropentane] -3 (1a 1 H) -one ( 6B ) (6.22 g, 32.0 mmol), naturally raised to room temperature and stirred for 1.5 hours, cooled to -5 ° C, and a saturated ammonium chloride solution (150 mL) was added dropwise. , Extracted with ethyl acetate (150mL × 3), the organic phase was washed with saturated sodium chloride solution (300mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / Ethyl acetate = 10: 1), a colorless liquid (±) -2-((1aR, 1a 1 R, 3aR, 5aS) -hexahydrospiro [cyclobut [cd] pentadiene-1,2'- [1,3] Dioxolane] -3 (1a 1 H) -ylidene) acetate ( 9B ) (6.1 g, yield: 72%).

第二步：(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-六氫螺環[環丁[cd]環戊二烯-1,2'-[1,3]二氧雜環戊烷]-4-基)乙酸乙酯(9C) Second step: (±) -2-((1aS, 1a 1 R, 3aR, 5aS) -1a, 1a 1 , 2,3,3a, 5a-hexahydrospiro [cyclobut [cd] cyclopentadiene -1,2 '-[1,3] dioxolane-4-yl) ethyl acetate ( 9C )

(±)-ethyl-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-hexahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolan]-4-yl)acetate (±) -ethyl-2-((1aS, 1a 1 R, 3aR, 5aS) -1a, 1a 1 , 2,3,3a, 5a-hexahydrospiro [cyclobuta [cd] pentalene-1,2 '-[1, 3] dioxolan] -4-yl) acetate

將(±)-2-((1aR,1a1R,3aR,5aS)-六氫螺環[環丁[cd]戊搭烯-1,2'-[1,3]二氧雜環戊烷]-3(1a1H)-亞基)乙酸乙酯(9B)(6.14g，23.2mmol)溶於硝基甲烷(80mL)，加入1,8-二氮雜二環[5.4.0]十一碳-7-烯(5.3g，35mmol)，升溫至70℃攪拌5小時，體系冷卻至室溫後冰水浴下滴加濃鹽酸至pH約為6，加入水(200mL)，用乙酸乙酯(200mL×3)萃取，合併有機相，用飽和氯化鈉溶液(400mL)洗滌，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=15：1)，得無色液體(±)--2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-六氫螺環[環丁[cd]環戊二烯-1,2'-[1,3]二氧雜環戊烷]-4-基)乙酸乙酯(9C)(4.5g，產率：73%)。 Put (±) -2-((1aR, 1a 1 R, 3aR, 5aS) -hexahydrospiro [cyclobut [cd] pentaene-1,2 '-[1,3] dioxolane ] -3 (1a1H) -Subunit) ethyl acetate ( 9B ) (6.14g, 23.2mmol) was dissolved in nitromethane (80mL), and 1,8-diazabicyclo [5.4.0] undecene was added -7-ene (5.3g, 35mmol), heated to 70 ° C and stirred for 5 hours. After the system was cooled to room temperature, concentrated hydrochloric acid was added dropwise to a pH of about 6 in an ice-water bath. Water (200mL) was added, and ethyl acetate (200mL) was used. × 3) extraction, the organic phases were combined, washed with saturated sodium chloride solution (400 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 15: 1), to obtain a colorless liquid (±)-2-((1aS, 1a 1 R, 3aR, 5aS) -1a, 1a 1 , 2,3,3a, 5a-hexahydrospiro [ Cyclobutene [cd] cyclopentadiene-1,2 '-[1,3] dioxolane] -4-yl) ethyl acetate ( 9C ) (4.5 g, yield: 73%).

MS M/Z(ESI)：265.1(M+1)；287.1(M+23)。 MS M / Z (ESI): 265.1 (M + 1); 287.1 (M + 23).

1H NMR(400MHz,CDCl3)δ 5.41(s,1H),4.18-4.12(m,2H),3.99-3.69(m,4H),3.47-3.07(m,1H),3.03-2.69(m,3H),1.88-1.48(m,6H),1.41-1.13(m,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 5.41 (s, 1H), 4.18-4.12 (m, 2H), 3.99-3.69 (m, 4H), 3.47-3.07 (m, 1H), 3.03-2.69 (m, 3H), 1.88-1.48 (m, 6H), 1.41-1.13 (m, 3H).

第三步：(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-六氫螺環[環丁[cd]戊搭烯-1,2'-[1,3]二氧雜環戊烷]-4-基)乙烷-1-醇(9D) The third step: (±) -2-((1aS, 1a 1 R, 3aR, 5aS) -1a, 1a 1 , 2,3,3a, 5a-hexahydrospiro [cyclobut [cd] pentalene- 1,2 '-[1,3] dioxolane-4-yl) ethane-1-ol ( 9D )

(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-hexahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolan]-4-yl)ethan-1-ol (±) -2-((1aS, 1a 1 R, 3aR, 5aS) -1a, 1a 1 , 2,3,3a, 5a-hexahydrospiro [cyclobuta [cd] pentalene-1,2 '-[1,3] dioxolan] -4-yl) ethan-1-ol

將(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-六氫螺環[環丁[cd]環戊二烯-1,2'-[1,3]二氧雜環戊烷]-4-基)乙酸乙酯(9C)(4.5g，17mmol)溶於四氫呋喃(50mL)中，降溫至0℃，分批加入四氫铝锂(1g，26.35mmol)，加畢後於0℃下攪拌1小時，依次滴加水(1mL)，氫氧化鈉溶液(15%(w%)，2mL)，水(2mL)，抽濾，用乙酸乙酯(5mL×3)洗滌濾渣，將濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=2：1)，得到無色液體(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-六氫螺環[環丁[cd]戊搭烯-1,2'-[1,3]二氧雜環戊烷]-4-基)乙烷-1-醇(9D)(2.8g，產率：74%)。 Put (±) -2-((1aS, 1a 1 R, 3aR, 5aS) -1a, 1a 1 , 2,3,3a, 5a-hexahydrospiro [cyclobut [cd] cyclopentadiene-1, 2 '-[1,3] dioxolane] -4-yl) ethyl acetate ( 9C ) (4.5 g, 17 mmol) was dissolved in tetrahydrofuran (50 mL), the temperature was lowered to 0 ° C, and tetrahydro was added in portions. Lithium aluminum (1g, 26.35mmol) was stirred at 0 ° C for 1 hour after the addition, and water (1mL), sodium hydroxide solution (15% (w%), 2mL), water (2mL), and suction filtration were added successively. The filter residue was washed with ethyl acetate (5 mL × 3), and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2: 1) to obtain a colorless liquid (± ) -2-((1aS, 1a 1 R, 3aR, 5aS) -1a, 1a 1 , 2,3,3a, 5a-Hexahydrospiro [cyclobut [cd] pentadenene-1,2 '-[ 1,3] dioxolane-4-yl) ethane-1-ol ( 9D ) (2.8 g, yield: 74%).

MS M/Z(ESI)：223.1(M+1)；245.2(M+23)。 MS M / Z (ESI): 223.1 (M + 1); 245.2 (M + 23).

1H NMR(400MHz,CDCl3)δ 5.32(s,1H),4.02-3.88(m,2H),3.88-3.70(m,4H),3.44-3.31(m,1H),3.19(t,J=6.5Hz,1H),3.00-2.86(m,1H),2.84-2.71(m,1H),2.46-2.33(m,1H),2.30-2.18(m,1H),1.86-1.54(m,4H)。 1 H NMR (400MHz, CDCl 3 ) δ 5.32 (s, 1H), 4.02-3.88 (m, 2H), 3.88-3.70 (m, 4H), 3.44-3.31 (m, 1H), 3.19 (t, J = 6.5Hz, 1H), 3.00-2.86 (m, 1H), 2.84-2.71 (m, 1H), 2.46-2.33 (m, 1H), 2.30-2.18 (m, 1H), 1.86-1.54 (m, 4H) .

第四步：(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-六氫螺環[環丁[cd] 戊搭烯-1,2'-[1,3]二氧雜環戊烷]-4-基)乙基甲磺酸酯(9E) The fourth step: (±) -2-((1aS, 1a 1 R, 3aR, 5aS) -1a, 1a 1 , 2,3,3a, 5a-hexahydrospiro [cyclobut [cd] pentenene- 1,2 '-[1,3] dioxolane] -4-yl) ethyl methanesulfonate ( 9E )

(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-hexahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolan]-4-yl)ethyl methanesulfonate (±) -2-((1aS, 1a 1 R, 3aR, 5aS) -1a, 1a 1 , 2,3,3a, 5a-hexahydrospiro [cyclobuta [cd] pentalene-1,2 '-[1,3] dioxolan] -4-yl) ethyl methanesulfonate

將(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-六氫螺環[環丁[cd]戊搭烯-1,2'-[1,3]二氧雜環戊烷]-4-基)乙烷-1-醇(9D)(2.8g，13mmol)溶於二氯甲烷(50mL)中，加入三乙胺(3.6mL)，冷卻至0℃，滴加甲基磺醯氯(1.73g，15.1mmol)，攪拌1小時，用濃鹽酸調節pH約為6，加入水(50mL)，用二氯甲烷(50mL×3)萃取，有機相用水(100mL)洗滌，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=2：1)，得無色油狀產物(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-六氫螺環[環丁[cd]戊搭烯-1,2'-[1,3]二氧雜環戊烷]-4-基)乙基甲磺酸酯(9E)(3.6g，產率：95%)。 Add (±) -2-((1aS, 1a 1 R, 3aR, 5aS) -1a, 1a 1 , 2,3,3a, 5a-hexahydrospiro [cyclobut [cd] pentadenene-1,2 '-[1,3] dioxolane] -4-yl) ethane-1-ol ( 9D ) (2.8 g, 13 mmol) was dissolved in dichloromethane (50 mL), and triethylamine (3.6 mL), cooled to 0 ° C, mesylsulfonyl chloride (1.73 g, 15.1 mmol) was added dropwise, and stirred for 1 hour, the pH was adjusted to about 6 with concentrated hydrochloric acid, water (50 mL) was added, and dichloromethane (50 mL × 3 ), The organic phase was washed with water (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2: 1), A colorless oily product (±) -2-((1aS, 1a 1 R, 3aR, 5aS) -1a, 1a 1 , 2,3,3a, 5a-hexahydrospiro [cyclobut [cd] pentaene -1,2 '-[1,3] dioxolane] -4-yl) ethyl methanesulfonate ( 9E ) (3.6 g, yield: 95%).

1H NMR(400MHz,CDCl3)δ 5.29(s,1H),4.37-4.28(m,2H),3.96-3.85(m,2H),3.85-3.70(m,2H),3.41-3.26(m,1H),3.16(t,J=6.3Hz,1H),2.99(s,3H),2.93-2.83(m,1H),2.82-2.67(m,1H),2.62-2.47(m,1H),2.43-2.29(m,1H),1.83-1.68(m,2H),1.67-1.50(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ 5.29 (s, 1H), 4.37-4.28 (m, 2H), 3.96-3.85 (m, 2H), 3.85-3.70 (m, 2H), 3.41-3.26 (m, 1H), 3.16 (t, J = 6.3Hz, 1H), 2.99 (s, 3H), 2.93-2.83 (m, 1H), 2.82-2.67 (m, 1H), 2.62-2.47 (m, 1H), 2.43 -2.29 (m, 1H), 1.83-1.68 (m, 2H), 1.67-1.50 (m, 2H).

第五步：(±)-(1aS,1a1R,3aR,5aS)-4-ethyl-1a,1a1,2,3,3a,5a-六氫螺環[環丁[cd]戊搭烯-1,2'-[1,3]二氧雜環戊烷](9F) The fifth step: (±)-(1aS, 1a 1 R, 3aR, 5aS) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a-hexahydrospiro [cyclobut [cd] pentalene -1,2 '-[1,3] dioxolane] ( 9F )

(±)-(1aS,1a1R,3aR,5aS)-4-ethyl-1a,1a1,2,3,3a,5a-hexahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolane] (±)-(1aS, 1a 1 R, 3aR, 5aS) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a-hexahydrospiro [cyclobuta [cd] pentalene-1,2 '-[1,3 ] dioxolane]

反應瓶中加入(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-六氫螺環[環丁[cd]戊搭烯-1,2'-[1,3]二氧雜環戊烷]-4-基)乙基甲磺酸酯(9E)(3.6g，12mmol)和四氫呋喃(60mL)，冷卻至0℃，分批加入四氫铝锂(1.4g，37mmol)，室溫下攪拌2小時，冷卻至0℃，依次滴加水(1.4mL)，氫氧化鈉溶液(15%(w%)，2.8mL)和水(2.8mL)，抽濾，用乙酸乙酯(10mL×3)洗滌濾渣，將濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=10：1)，得無色油狀(±)-(1aS,1a1R,3aR,5aS)-4-ethyl-1a,1a1,2,3,3a,5a-六氫螺環[環丁[cd]戊搭烯-1,2'-[1,3]二氧雜環戊烷](9F)(2g，產率：81%)。 (±) -2-((1aS, 1a 1 R, 3aR, 5aS) -1a, 1a 1 , 2,3,3a, 5a-hexahydrospiro [cyclobut [cd] pentadenene- 1,2 '-[1,3] dioxolane] -4-yl) ethyl methanesulfonate ( 9E ) (3.6 g, 12 mmol) and tetrahydrofuran (60 mL), cooled to 0 ° C, and batched Add lithium tetrahydroaluminum (1.4g, 37mmol), stir at room temperature for 2 hours, cool to 0 ° C, and add dropwise water (1.4mL), sodium hydroxide solution (15% (w%), 2.8mL), and water ( 2.8mL), suction filtration, washing the residue with ethyl acetate (10mL × 3), the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10: 1 ) To obtain a colorless oil (±)-(1aS, 1a 1 R, 3aR, 5aS) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a-hexahydrospiro [cyclobutyl [cd] pent Phenene-1,2 '-[1,3] dioxolane] ( 9F ) (2 g, yield: 81%).

1H NMR(400MHz,CDCl3)δ 5.18(s,1H),4.05-3.69(m,4H),3.50-3.25(m,1H),3.15(t,J=6.6Hz,1H),2.97-2.81(m,1H),2.81-2.63(m,1H),2.26-2.01(m,1H),2.01-1.84(m,1H),1.84-1.47(m,4H),1.07(t,J=7.4Hz,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 5.18 (s, 1H), 4.05-3.69 (m, 4H), 3.50-3.25 (m, 1H), 3.15 (t, J = 6.6Hz, 1H), 2.97-2.81 (m, 1H), 2.81-2.63 (m, 1H), 2.26-2.01 (m, 1H), 2.01-1.84 (m, 1H), 1.84-1.47 (m, 4H), 1.07 (t, J = 7.4Hz , 3H).

第六步：(±)-(1aS,1a1R,3aR,5aS)-4-乙基-1a,1a1,2,3,3a,5a-六氫-1H-環丁[cd]戊搭烯-1-酮(9G) Step 6: (±)-(1aS, 1a 1 R, 3aR, 5aS) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a-hexahydro-1H-cyclobutene [cd] penta En-1-one ( 9G )

(±)-(1aS,1a1R,3aR,5aS)-4-ethyl-1a,1a1,2,3,3a,5a-hexahydro-1H-cyclobuta[cd]pentalen-1-one (±)-(1aS, 1a 1 R, 3aR, 5aS) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a-hexahydro-1H-cyclobuta [cd] pentalen-1-one

將(±)-(1aS,1a1R,3aR,5aS)-4-ethyl-1a,1a1,2,3,3a,5a-六氫螺環[環丁[cd]戊搭烯-1,2'-[1,3]二氧雜環戊烷](9F)(1.1g，5.3mmol)溶於乙酸溶液(30%(w%)，30mL)中，升溫至70℃攪拌2小時，冷卻至室溫，加入水(30 mL)，用二氯甲烷(60mL×3)萃取，有機相用飽和氯化鈉溶液(200mL)洗滌，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=60：1)，得到無色油狀(±)-(1aS,1a1R,3aR,5aS)-4-乙基-1a,1a1,2,3,3a,5a-六氫-1H-環丁[cd]戊搭烯-1-酮(9G)(0.72g，產率：83%)。 Put (±)-(1aS, 1a 1 R, 3aR, 5aS) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a-hexahydrospiro [cyclobut [cd] pentadenene-1, 2 '-[1,3] dioxolane] ( 9F ) (1.1g, 5.3mmol) was dissolved in an acetic acid solution (30% (w%), 30mL), heated to 70 ° C and stirred for 2 hours, and cooled To room temperature, add water (30 mL), extract with dichloromethane (60 mL × 3), wash the organic phase with saturated sodium chloride solution (200 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Separation and purification by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 60: 1) to obtain (±)-(1aS, 1a 1 R, 3aR, 5aS) -4-ethyl-1a as a colorless oil. , 1a 1 , 2,3,3a, 5a-hexahydro-1H-cyclobut [cd] penta-1-enone ( 9G ) (0.72 g, yield: 83%).

1H NMR(400MHz,CDCl3)δ 5.09(s,1H),4.11-3.92(m,1H),3.57-3.36(m,2H),3.22-3.06(m,1H),2.13-1.84(m,4H),1.84-1.66(m,1H),1.63-1.45(m,1H),1.08(t,J=7.4Hz,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 5.09 (s, 1H), 4.11-3.92 (m, 1H), 3.57-3.36 (m, 2H), 3.22-3.06 (m, 1H), 2.13-1.84 (m, 4H), 1.84-1.66 (m, 1H), 1.63-1.45 (m, 1H), 1.08 (t, J = 7.4Hz, 3H).

第七步：(±)-2-((1aS,1a1R,3aR,5aS)-4-乙基-1a,1a1,2,3,3a,5a-六氫-1H-環丁[cd]戊搭烯-1-亞基)乙酸第三丁酯(9H) Step 7: (±) -2-((1aS, 1a 1 R, 3aR, 5aS) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a-hexahydro-1H-cyclobutane [cd ] Pentadiene-1-ylidene) tributyl acetate ( 9H )

(±)-tert-butyl-2-((1aS,1a1R,3aR,5aS)-4-ethyl-1a,1a1,2,3,3a,5a-hexahydro-1H-cyclo buta[cd]pentalen-1-ylidene)acetate (±) -tert-butyl-2-((1aS, 1a 1 R, 3aR, 5aS) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a-hexahydro-1H-cyclo buta [cd] pentalen -1-ylidene) acetate

將氫化鈉(0.22g，5.5mmol)加入到乾燥的四氫呋喃(15mL)中，冷卻至0℃，滴加二甲氧基磷醯基乙酸第三丁酯(1.17g，5.22mmol)，攪拌30分鐘，加入(±)-(1aS,1a1R,3aR,5aS)-4-乙基-1a,1a1,2,3,3a,5a-六氫-1H-環丁[cd]戊搭烯-1-酮(9G)(0.72g，4.4mmol)，加畢自然升溫，於室溫下攪拌1小時，冷卻至0℃，滴加飽和氯化銨溶液(50mL)，用乙酸乙酯(50mL×3)萃取，合併有機相，有機相用水(100mL)洗滌，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=10：1)，得到無色油狀(±)-2-((1aS,1a1R,3aR,5aS)-4-乙基-1a,1a1,2,3,3a,5a-六氫-1H-環丁[cd]戊 搭烯-1-亞基)乙酸第三丁酯(9H)(1g，產率：87%)。 Add sodium hydride (0.22g, 5.5mmol) to dry tetrahydrofuran (15mL), cool to 0 ° C, add dimethoxyphosphonium tributylacetate (1.17g, 5.22mmol) dropwise, and stir for 30 minutes Add (±)-(1aS, 1a 1 R, 3aR, 5aS) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a-hexahydro-1H-cyclobutene [cd] pentalene- 1-ketone ( 9G ) (0.72g, 4.4mmol). After heating, the mixture was naturally heated, stirred at room temperature for 1 hour, cooled to 0 ° C, saturated ammonium chloride solution (50mL) was added dropwise, and ethyl acetate (50mL × 3) Extraction, the organic phases are combined, the organic phases are washed with water (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10: 1) to obtain (±) -2-((1aS, 1a 1 R, 3aR, 5aS) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a-hexahydro-1H -Cyclobutene [cd] pentadiene-1-ylidene) acetic acid tert-butyl acetate ( 9H ) (1 g, yield: 87%).

第八步：(±)-2-((1R,1aS,1a1R,3aR,5aS)-4-乙基-1-(硝基甲基)-1a,1a1,2,3,3a,5a-六氫-1H-環丁[cd]戊搭烯-1-基)乙酸第三丁酯(9I) Step 8: (±) -2-((1R, 1aS, 1a 1 R, 3aR, 5aS) -4-ethyl-1- (nitromethyl) -1a, 1a 1 , 2,3,3a, 5a-hexahydro-1H-cyclobut [cd] pentalen-1-yl) tributyl acetate ( 9I )

(±)-tert-butyl-2-((1R,1aS,1a1R,3aR,5aS)-4-ethyl-1-(nitromethyl)-1a,1a1,2,3,3a,5a-hexa hydro-1H-cyclobuta[cd]pentalen-1-yl)acetate (±) -tert-butyl-2-((1R, 1aS, 1a 1 R, 3aR, 5aS) -4-ethyl-1- (nitromethyl) -1a, 1a 1 , 2,3,3a, 5a-hexa hydro -1H-cyclobuta [cd] pentalen-1-yl) acetate

將(±)-2-((1aS,1a1R,3aR,5aS)-4-乙基-1a,1a1,2,3,3a,5a-六氫-1H-環丁[cd]戊搭烯-1-亞基)乙酸第三丁酯(9H)(1g，3.84mmol)溶於硝基甲烷(15mL)中，加入1,8-二氮雜二環十一碳-7-烯(0.78g，5.1mmol)，加熱至70℃攪拌7小時，冷卻至0℃，用濃鹽酸調pH約為6，加入水(60mL)，用乙酸乙酯(60mL×3)萃取，合併有機相，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(石油醚/乙酸乙酯(v/v)=10：1)，得到無色油狀液體(±)-2-((1R,1aS,1a1R,3aR,5aS)-4-乙基-1-(硝基甲基)-1a,1a1,2,3,3a,5a-六氫-1H-環丁[cd]戊搭烯-1-基)乙酸第三丁酯(9I)(0.8g，產率：60%)。 Add (±) -2-((1aS, 1a 1 R, 3aR, 5aS) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a-hexahydro-1H-cyclobutene [cd] Ene-1-ylidene) tert-butyl acetate ( 9H ) (1g, 3.84mmol) was dissolved in nitromethane (15mL), and 1,8-diazabicycloundec-7-ene (0.78) was added g, 5.1 mmol), heated to 70 ° C. and stirred for 7 hours, cooled to 0 ° C., adjusted to pH 6 with concentrated hydrochloric acid, added water (60 mL), and extracted with ethyl acetate (60 mL × 3). The organic phases were combined with It was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10: 1) to obtain a colorless oily liquid (±) -2- ((1R, 1aS, 1a 1 R, 3aR, 5aS) -4-ethyl-1- (nitromethyl) -1a, 1a 1 , 2,3,3a, 5a-hexahydro-1H-cyclobutane [ cd] Pentadien-1-yl) tributyl acetate ( 9I ) (0.8 g, yield: 60%).

MS M/Z(ESI)：344.2(M+23)。 MS M / Z (ESI): 344.2 (M + 23).

1H NMR(400MHz,CDCl3)δ 5.17(s,1H),4.86(d,J=11.6Hz,1H),4.77(d,J=11.6Hz,1H),3.25-2.97(m,3H),2.59-2.45(m,1H),2.43(s,2H),2.21-2.04(m,1H),2.04-1.88(m,1H),1.88-1.79(m,1H),1.79-1.65(m,1H),1.65-1.47(m,1H),1.43(d,J=13.2Hz,9H),1.41-1.27(m,1H),1.08(t,J=7.4Hz,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 5.17 (s, 1H), 4.86 (d, J = 11.6Hz, 1H), 4.77 (d, J = 11.6Hz, 1H), 3.25-2.97 (m, 3H), 2.59-2.45 (m, 1H), 2.43 (s, 2H), 2.21-2.04 (m, 1H), 2.04-1.88 (m, 1H), 1.88-1.79 (m, 1H), 1.79-1.65 (m, 1H ), 1.65-1.47 (m, 1H), 1.43 (d, J = 13.2Hz, 9H), 1.41-1.27 (m, 1H), 1.08 (t, J = 7.4Hz, 3H).

第九步：(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基-1a,1a1,2,3,3a,5a-六氫-1H-環丁[cd]戊搭烯-1-基)乙酸第三丁酯(9J) Step 9: (±) -2-((1R, 1aS, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a -Hexahydro-1H-cyclobut [cd] pentalen-1-yl) tributyl acetate ( 9J )

(±)-tert-butyl-2-((1R,1aS,1a1R,3aR,5aS)-1-(aminomethyl)-4-ethyl-1a,1a1,2,3,3a,5a-hexahydro-1H-cyclobuta[cd]pentalen-1-yl)acetate (±) -tert-butyl-2-((1R, 1aS, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a-hexahydro- 1H-cyclobuta [cd] pentalen-1-yl) acetate

將(±)-2-((1R,1aS,1a1R,3aR,5aS)-4-乙基-1-(硝基甲基)-1a,1a1,2,3,3a,5a-六氫-1H-環丁[cd]戊搭烯-1-基)乙酸第三丁酯(9I)(0.8g，2mmol)溶於乙醇(10mL)中，加入水(5mL)，還原鐵粉(0.56g，10mmol)和氯化銨(0.22g，4.1mmol)，升溫至100℃，攪拌3小時，冷卻至室溫，加入水(50mL)，用乙酸乙酯(60mL×3)萃取，合併有機相，用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化(二氯甲烷/甲醇(v/v)=10：1)，得無色油狀(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基-1a,1a1,2,3,3a,5a-六氫-1H-環丁[cd]戊搭烯-1-基)乙酸第三丁酯(9J)(0.8g，產率：100%)。 Add (±) -2-((1R, 1aS, 1a 1 R, 3aR, 5aS) -4-ethyl-1- (nitromethyl) -1a, 1a 1 , 2,3,3a, 5a-hexa Hydrogen-1H-cyclobut [cd] pentadien-1-yl) tert-butyl acetate ( 9I ) (0.8g, 2mmol) was dissolved in ethanol (10mL), water (5mL) was added, and reduced iron powder (0.56 g, 10 mmol) and ammonium chloride (0.22 g, 4.1 mmol), warmed to 100 ° C, stirred for 3 hours, cooled to room temperature, added water (50 mL), extracted with ethyl acetate (60 mL × 3), and combined the organic phases , Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 10: 1) to obtain a colorless oil (±) -2- ((1R, 1aS, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a-hexahydro-1H-cyclobutane (cd ] Pentadien-1-yl) tributyl acetate ( 9J ) (0.8 g, yield: 100%).

1H NMR(400MHz,CDCl3)δ 5.19(s,1H),3.41(d,J=13.1Hz,1H),3.30(d,J=13.1Hz,1H),3.26-3.13(m,1H),3.11-2.94(m,2H),2.66-2.32(m,3H),2.20-2.01(m,1H),2.01-1.86(m,1H),1.85-1.65(m,2H),1.63-1.48(m,1H),13.4(s,9H),1.31-1.21(m,1H),1.07(t,J=7.4Hz,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 5.19 (s, 1H), 3.41 (d, J = 13.1Hz, 1H), 3.30 (d, J = 13.1Hz, 1H), 3.26-3.13 (m, 1H), 3.11-2.94 (m, 2H), 2.66-2.32 (m, 3H), 2.20-2.01 (m, 1H), 2.01-1.86 (m, 1H), 1.85-1.65 (m, 2H), 1.63-1.48 (m , 1H), 13.4 (s, 9H), 1.31-1.21 (m, 1H), 1.07 (t, J = 7.4Hz, 3H).

第十步：(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基-1a,1a1,2,3,3a,5a-六氫-1H-環丁[cd]戊搭烯-1-基)乙酸(化合物9) Step 10: (±) -2-((1R, 1aS, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a -Hexahydro-1H-cyclobut [cd] pentadien-1-yl) acetic acid (Compound 9)

(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(aminomethyl)-4-ethyl-1a,1a1,2,3,3a,5a-hexahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid (±) -2-((1R, 1aS, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a-hexahydro-1H-cyclobuta [ cd] pentalen-1-yl) acetic acid

反應瓶中加入(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基-1a,1a1,2,3,3a,5a-六氫-1H-環丁[cd]戊搭烯-1-基)乙酸第三丁酯(9J)(0.8g，3mmol)和二氯甲烷(14mL)，冰水浴冷卻，滴加三氟乙酸(7mL)，於室溫下攪拌4小時，減壓濃縮，殘留物中加入二氯甲烷(100mL)，逐滴加入三乙胺調節pH值7-8，抽濾，濾餅用二氯甲烷(5mL×3)洗滌，得到白色固體(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基-1a,1a1,2,3,3a,5a-六氫-1H-環丁[cd]戊搭烯-1-基)乙酸(化合物9)(0.42g，產率：70%)。 (±) -2-((1R, 1aS, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a -Hexahydro-1H-cyclobut [cd] pentalen-1-yl) acetic acid tert-butyl ester ( 9J ) (0.8g, 3mmol) and dichloromethane (14mL), cooled in an ice-water bath, and added trifluoroacetic acid dropwise (7 mL), stirred at room temperature for 4 hours, and concentrated under reduced pressure. Dichloromethane (100 mL) was added to the residue, and triethylamine was added dropwise to adjust the pH to 7-8. The filter cake was filtered with dichloromethane ( 5mL × 3) washing to obtain a white solid (±) -2-((1R, 1aS, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -4-ethyl-1a, 1a1,2,3 , 3a, 5a-hexahydro-1H-cyclobut [cd] pentalen-1-yl) acetic acid (Compound 9) (0.42 g, yield: 70%).

MS M/Z(ESI)：236.2(M+1)。 MS M / Z (ESI): 236.2 (M + 1).

1H NMR(400MHz,CD3OD)δ 5.27(s,1H),3.24-2.99(m,4H),2.86-2.72(m,1H),2.65-2.52(m,1H),2.49-2.29(m,2H),2.23-2.06(m,1H),2.06-1.90(m,1H),1.90-1.81(m,1H),1.80-1.67(m,1H),1.65-1.43(m,2H),1.09(t,J=7.4Hz,3H)。 1 H NMR (400MHz, CD 3 OD) δ 5.27 (s, 1H), 3.24-2.99 (m, 4H), 2.86-2.72 (m, 1H), 2.65-2.52 (m, 1H), 2.49-2.29 (m , 2H), 2.23-2.06 (m, 1H), 2.06-1.90 (m, 1H), 1.90-1.81 (m, 1H), 1.80-1.67 (m, 1H), 1.65-1.43 (m, 2H), 1.09 (t, J = 7.4Hz, 3H).

實施例10Example 10

(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基-1a,1a1,2,3,3a,5a-六氫-1H-環丁[cd]戊搭烯-1-基)乙酸 苯磺酸鹽(1：1)(化合物10) (±) -2-((1R, 1aS, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a-hexahydro- 1H-cyclobut [cd] pentalen-1-yl) acetic acid benzenesulfonate (1: 1) (Compound 10)

(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(aminomethyl)-4-ethyl-1a,1a1,2,3,3a,5a-hexahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid benzene sulfonate(1：1) (±) -2-((1R, 1aS, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a-hexahydro-1H-cyclobuta [ cd] pentalen-1-yl) acetic acid benzene sulfonate (1: 1)

第一步：(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基 -1a,1a1,2,3,3a,5a-六氫-1H-環丁[cd]戊搭烯-1-基)乙酸 苯磺酸鹽(1：1)(化合物10) First step: (±) -2-((1R, 1aS, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a -Hexahydro-1H-cyclobut [cd] pentalen-1-yl) acetic acid benzenesulfonate (1: 1) (Compound 10)

(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(aminomethyl)-4-ethyl-1a,1a1,2,3,3a,5a-hexahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid benzene sulfonate(1：1) (±) -2-((1R, 1aS, 1a 1 R, 3aR, 5aS) -1- (aminomethyl) -4-ethyl-1a, 1a 1 , 2,3,3a, 5a-hexahydro-1H-cyclobuta [ cd] pentalen-1-yl) acetic acid benzene sulfonate (1: 1)

反應瓶中加入(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基-1a,1a1,2,3,3a,5a-六氫-1H-環丁[cd]戊搭烯-1-基)乙酸(化合物9)(0.34g，1.4mmol)和甲醇(10mL)，加入苯磺酸1.5水合物(0.41g，2.1mmol)，攪拌30分鐘，減壓濃縮，殘留物中加入乙酸乙酯(10mL×3)打漿，抽濾，得到白色固體(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基-1a,1a1,2,3,3a,5a-六氫-1H-環丁[cd]戊搭烯-1-基)乙酸 苯磺酸鹽(化合物10)(1：1)(0.33g，產率：58%)。 (±) -2-((1R, 1aS, 1a1R, 3aR, 5aS) -1- (aminomethyl) -4-ethyl-1a, 1a1,2,3,3a, 5a-hexahydro -1H-cyclobut [cd] pentalen-1-yl) acetic acid ( Compound 9 ) (0.34 g, 1.4 mmol) and methanol (10 mL), benzenesulfonic acid 1.5 hydrate (0.41 g, 2.1 mmol) was added, and stirred 30 minutes, concentrated under reduced pressure, ethyl acetate (10mL × 3) was added to the residue for slurrying and suction filtration to obtain a white solid (±) -2-((1R, 1aS, 1a1R, 3aR, 5aS) -1- (amino) (Methyl) -4-ethyl-1a, 1a1,2,3,3a, 5a-hexahydro-1H-cyclobutene [cd] pentaden-1-yl) acetic acid benzene sulfonate ( compound 10 ) (1 : 1) (0.33 g, yield: 58%).

1H NMR(400MHz,CD3OD)δ 7.96-7.72(m,2H),7.51-7,32(m,3H),5.24(s,1H),3.43-3.22(m,2H),3.23-3.05(m,2H),2.96-2.82(m,1H),2.58-2.36(m,3H),2.25-2.09(m,1H),2.08-1.93(m,1H),1.93-1.83(m,1H),1.81-1.67(m,1H),1.66-1.48(m,1H),1.46-1.31(m,1H),1.10(t,J=7.4Hz,3H)。 1 H NMR (400MHz, CD 3 OD) δ 7.96-7.72 (m, 2H), 7.51-7, 32 (m, 3H), 5.24 (s, 1H), 3.43-3.22 (m, 2H), 3.23-3.05 (m, 2H), 2.96-2.82 (m, 1H), 2.58-2.36 (m, 3H), 2.25-2.09 (m, 1H), 2.08-1.93 (m, 1H), 1.93-1.83 (m, 1H) , 1.81-1.67 (m, 1H), 1.66-1.48 (m, 1H), 1.46-1.31 (m, 1H), 1.10 (t, J = 7.4Hz, 3H).

生物測試例Biological test cases

化合物對鈣離子通道蛋白Cavα2δ的競爭結合能力測試 Competitive binding ability of compounds to calcium channel protein Cavα2δ

取大鼠大腦皮質組織於10倍體積(w/v)冰冷的0.32M蔗糖/ mMTris-乙酸(pH 7.4)，匀漿後，蔗糖密度梯度離心法製備突觸質膜，保存於Tris-乙酸(pH 7.4)緩衝液，臨用前重新懸浮於10mM HEPES(pH 7.4)緩衝液。測試化合物溶於1%DMSO，並稀釋成梯度濃度(1nM-1000nM)，與20nM[3H]加巴噴丁一起加入突觸質膜懸浮液(約0.05-0.1mg總蛋白質)，25℃孵育30分鐘。反應結束後反應體系經真空濾過至Whatman GFB濾膜，濾膜以5mL 100mM冰冷的氯化鈉溶液洗3次，液體閃爍計數測定濾膜的放射性。非特異性結合以100M加巴噴丁封閉。計算化合物對放射標記加巴噴丁與突觸質膜的結合的抑制率，並計算化合物的IC50。實驗結果：見表1。 The rat cerebral cortex tissue was taken at 10 times the volume (w / v) of ice-cold 0.32M sucrose / mMTris-acetic acid (pH 7.4). After homogenization, the synaptic plasma membrane was prepared by sucrose density gradient centrifugation and stored in Tris-acetic acid (pH 7.4) buffer, resuspended in 10 mM HEPES (pH 7.4) buffer just before use. The test compound was dissolved in 1% DMSO and diluted to a gradient concentration (1 nM-1000 nM), and a synaptic plasma suspension (about 0.05-0.1 mg total protein) was added with 20 nM [3H] gabapentin, and incubated at 25 ° C for 30 minutes. After the reaction, the reaction system was vacuum filtered to a Whatman GFB filter. The filter was washed 3 times with 5 mL of 100 mM ice-cold sodium chloride solution, and the radioactivity of the filter was measured by liquid scintillation counting. Non-specific binding was blocked with 100M gabapentin. Compound binding inhibition rate calculated radiolabelled gabapentin synaptic plasma membrane and calculate IC 50 compound. Experimental results: see Table 1.

結論：本發明化合物具有較好的對鈣離子通道蛋白Cavα2δ的競爭結合能力。 Conclusion: The compound of the present invention has good competitive binding ability to the calcium channel protein Cavα2δ.

藥代動力學評價Pharmacokinetic evaluation

雄性SD大鼠(購自維通利華實驗動物有限公司)180-240g，禁食給水過夜，3隻大鼠口服灌胃10mg/kg，3隻大鼠靜脈注射5mg/kg。口服給藥組，受試化合物以0.5%甲基纖維素(MC)溶液配製成1.0mg/mL的混懸液，在給藥前和在給藥後30分鐘以及1、2、4、6、8、12和24小時採血各200μL；靜脈給藥組，化合物以生理鹽水配製成1.0mg/mL的溶液，在給藥前和在給藥後5、15和30分鐘以及1、2、4、8、12和24小時採血，採集的樣品均以肝素抗凝。血樣5500轉/分鐘離心10分鐘，收集血漿，於-20℃保存。取各時間點大鼠血漿10μL，加入含內標的乙腈溶液500μL混合後， 渦旋混合10分鐘，3700轉/分鐘離心18分鐘，取上清液50μL與100μL水混合，渦旋混合10分鐘，取混和液5μL進行LC-MS/MS分析，測定原形藥物的血藥濃度。主要藥代動力學參數用WinNonlin 6.3軟體非房室模型分析。試驗結果見表2。 Male SD rats (purchased from Weitong Lihua Experimental Animal Co., Ltd.) 180-240 g, fasted with water overnight, 3 rats were orally administered with 10 mg / kg, 3 rats were injected with 5 mg / kg intravenously. In the oral administration group, the test compound was prepared as a 1.0 mg / mL suspension in a 0.5% methylcellulose (MC) solution, before administration and 30 minutes after administration, and 1, 2, 4, and 6 200 μL blood samples were taken at 8, 8, 12, and 24 hours; in the intravenous administration group, the compound was formulated into a 1.0 mg / mL solution with physiological saline, before administration and at 5, 15, and 30 minutes after administration, and 1, 2, Blood was collected at 4, 8, 12, and 24 hours, and the collected samples were all anticoagulated with heparin. Blood samples were centrifuged at 5500 rpm for 10 minutes, and plasma was collected and stored at -20 ° C. Take 10 μL of rat plasma at each time point, add 500 μL of acetonitrile solution containing internal standard and mix. Vortex for 10 minutes, centrifuge at 3700 rpm for 18 minutes, take 50 μL of the supernatant and mix with 100 μL of water, vortex for 10 minutes, take 5 μL of the mixture for LC-MS / MS analysis, and determine the blood concentration of the original drug. The main pharmacokinetic parameters were analyzed using WinNonlin 6.3 software non-compartment model. The test results are shown in Table 2.

結論：本發明化合物表現出良好的藥代動力學性質。 Conclusion: The compounds of the invention show good pharmacokinetic properties.

雖然本發明以實施例說明如上，惟此些實施例並非用以限制本發明。本領域之通常知識者在不脫離本發明技藝精神的範疇內，當可對此些實施例進行等效實施或變更，故本發明的保護範圍應以其後所附之申請專利範圍為準。 Although the present invention has been described above by way of examples, these examples are not intended to limit the present invention. Those skilled in the art can perform equivalent implementations or changes to these embodiments without departing from the technical spirit of the present invention. Therefore, the scope of protection of the present invention shall be subject to the scope of patents attached thereafter.

Claims (13)

一種通式(I)所示的化合物，或者其立體異構物、溶劑化物、藥學上可接受的鹽或共晶：其中：R1、R2、R2’、R3、R4、R4’或R5各自獨立地選自H、F、Cl、Br、I、羥基、氰基、C1-6烷基、C1-6烷氧基、C1-6硫烷基、C2-6烯基、C2-6炔基或者3至6員碳環基，所述的烷基、烷氧基、硫烷基、烯基、炔基或者碳環基任選進一步被0至6個選自F、Cl、Br、I、羥基、C1-6烷基或者3至6員碳環基所取代；選擇性的，R1與R2、R2與R2’、R2與R3、R3與R4、R4與R4’、R4與R5任意一組相結合與其相連的原子一起形成雙鍵，所述的雙鍵任選進一步被0至2個選自F、Cl、Br、I、C1-6烷基、3至6員碳環基或者被1至3個鹵素取代的C1-6烷基所取代；所述的鹵素選自F、Cl或者Br；選擇性的，R2與R2’、R4與R4’任意一組與其相連的碳原子一起形成3至6員碳環，所述的碳環任選進一步被0至6個選自F、Cl、Br、I、C1-6烷基、C1-6烷氧基或者C1-6硫烷基所取代；R6選自H、C1-6烷基或氨基保護基；R7選自H、C1-6烷基或羧基保護基。A compound represented by general formula (I), or a stereoisomer, solvate, pharmaceutically acceptable salt, or co-crystal thereof: Wherein: R 1 , R 2 , R 2 ' , R 3 , R 4 , R 4 ′, or R 5 are each independently selected from H, F, Cl, Br, I, hydroxyl, cyano, and C 1-6 alkyl , C 1-6 alkoxy, C 1-6 sulfanyl, C 2-6 alkenyl, C 2-6 alkynyl or 3- to 6-membered carbocyclyl, said alkyl, alkoxy, sulfur Alkyl, alkenyl, alkynyl or carbocyclyl is optionally further substituted with 0 to 6 selected from F, Cl, Br, I, hydroxyl, C 1-6 alkyl or 3 to 6 membered carbocyclyl; select In nature, any one of R 1 and R 2 , R 2 and R 2 ' , R 2 and R 3 , R 3 and R 4 , R 4 and R 4' , and R 4 and R 5 combine with the atoms to which they are connected. Forms a double bond, which is optionally further substituted with 0 to 2 selected from F, Cl, Br, I, C 1-6 alkyl, 3 to 6 membered carbocyclyl, or 1 to 3 halogens C 1-6 alkyl substituted; said halogen is selected from F, Cl or Br; optionally, any group of R 2 and R 2 ′ , R 4 and R 4 ′ together form a carbon atom from 3 to 6-membered carbocyclic ring, said carbocyclic ring optionally further being 0 to 6 selected from F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 sulfanyl the substituent; R 6 is selected from H, C 1-6 alkyl or amino Protecting group; R 7 is selected from H, C 1-6 alkyl or a carboxy protecting group. 如申請專利範圍第1項所述的的化合物，或者其立體異構物、溶劑化物、藥學上可接受的鹽或共晶，其中該化合物選自通式(Ia)或者(Ib)所示的化合物：或者 The compound as described in item 1 of the scope of patent application, or a stereoisomer, solvate, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the group consisting of the general formula (Ia) or (Ib) Compound: or 如申請專利範圍第1至2項中任一項所述的化合物，或者其立體異構物、溶劑化物、藥學上可接受的鹽或共晶，其中：R1、R2、R2’各自獨立地選自H，或者R1與R2、R2與R2’任意一組相結合與其相連的原子一起形成雙鍵，所述的雙鍵任選進一步被0至2個選自F、Cl、C1-6烷基或者3至6員碳環基所取代；R3、R4、R4’或R5各自獨立地選自H、F、Cl、羥基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基或者3至6員碳環基，所述的烷基、烷氧基、烯基、炔基或者碳環基任選進一步被0至6個選自F、Cl、Br、羥基、C1-6烷基或者3至6員碳環基所取代；選擇性的，R4與R4’、R4與R5任意一組相結合與其相連的原子一起形成雙鍵，所述的雙鍵任選進一步被0至2個選自F、Cl、C1-6烷基或者3至6員碳環基所取代；選擇性的，R4與R4’可與其相連的碳原子一起形成3至6員碳環，所述的碳環任選進一步被0至6個選自F、Cl、Br、I、C1-6烷基、C1-6烷氧基或者C1-6硫烷基所取代；R6選自H或者C1-6烷基；R7選自H或者C1-6烷基。The compound according to any one of claims 1 to 2, or a stereoisomer, solvate, pharmaceutically acceptable salt, or co-crystal thereof, wherein: R 1 , R 2 , and R 2 ′ are each Independently selected from H, or any combination of R 1 and R 2 , R 2 and R 2 ′ to form a double bond together with the atom to which it is connected, said double bond optionally further being 0 to 2 selected from F, Cl, C 1-6 alkyl or 3 to 6-membered carbocyclyl; R 3 , R 4 , R 4 ′ or R 5 are each independently selected from H, F, Cl, hydroxyl, C 1-6 alkyl , C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl or 3- to 6-membered carbocyclyl, said alkyl, alkoxy, alkenyl, alkynyl or carbocyclyl Optionally further substituted by 0 to 6 selected from F, Cl, Br, hydroxyl, C 1-6 alkyl, or 3 to 6 membered carbocyclic groups; optionally, R 4 and R 4 ' , R 4 and R 5 Any group of atoms combined with its connected atom to form a double bond, said double bond is optionally further substituted by 0 to 2 selected from F, Cl, C 1-6 alkyl or 3 to 6 membered carbocyclyl ; selective, R 4 and R 4 'may form together with the carbon atoms they are attached 3-6 carbocyclic ring, said carbocyclic ring Selected from the group further substituted with 0-6 selected from F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 sulfanyl; R 6 is selected from H or C 1 -6 alkyl; R 7 is selected from H or C 1-6 alkyl. 如申請專利範圍第3項所述的化合物，或者其立體異構物、溶劑化物、藥學上可接受的鹽或共晶，其中：R1、R2、R2’各自獨立地選自H；R3、R4、R4’或R5各自獨立地選自H、F、Cl、羥基或者C1-4烷基；選擇性的，R4與R4’、R4與R5任意一組相結合與其相連的原子一起形成雙鍵，所述的雙鍵任選進一步被0至2個選自F、Cl、C1-4烷基或者3至6員碳環基所取代；選擇性的，R4與R4’可與其相連的碳原子一起形成3至6員碳環，所述的碳環任選進一步被0至6個選自F、Cl、Br、I、C1-4烷基或者C1-4烷氧基所取代；R6選自H或者C1-4烷基；R7選自H或者C1_4烷基。The compound as described in item 3 of the scope of patent application, or a stereoisomer, solvate, pharmaceutically acceptable salt or co-crystal thereof, wherein: R 1 , R 2 , and R 2 ′ are each independently selected from H; R 3 , R 4 , R 4 ′ or R 5 are each independently selected from H, F, Cl, hydroxyl or C 1-4 alkyl; optionally, any one of R 4 and R 4 ′ , R 4 and R 5 The group combines with the atom to which it is connected to form a double bond, and the double bond is optionally further substituted with 0 to 2 selected from F, Cl, C 1-4 alkyl or 3 to 6 membered carbocyclic groups; selectivity; R 4 and R 4 ′ may form a 3- to 6-membered carbocyclic ring together with the carbon atom to which they are attached. The carbocyclic ring is optionally further selected from 0 to 6 selected from F, Cl, Br, I, C 1-4 alkyl or substituted C 1-4 alkoxy; R 6 is selected from H or C 1-4 alkyl; R 7 is selected from H or C 1 _ 4 alkyl. 如申請專利範圍第4項所述的化合物，或者其立體異構物、溶劑化物、藥學上可接受的鹽或共晶，其中所述化合物選自以下結構之一： The compound as described in item 4 of the scope of patent application, or a stereoisomer, solvate, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from one of the following structures: 一種製備通式(I)、(Ia)或(Ib)所示的化合物或其立體異構物的中間體，該中間體選自如下通式(II)所示的化合物或其立體異構物：其中：Ra或Rb各自獨立地選自羥基或者C1-4烷基，所述的烷基任選進一步被0至2個硝基或者-COORx所取代；選擇性的，Ra與Rb相結合與其相連的原子一起形成雙鍵或者C=O，所述的雙鍵任選進一步被0至2個選自F、C1-4烷基、硝基或者-COORx所取代；Rc、Rd、Rd’或Re各自獨立地選自H、F、Cl、羥基或者C1-4烷基，所述的烷基任選進一步被0至2個選自F、羥基、-OMs、或者-COORx所取代；選擇性的，Rd與Rd’、Rd與Re任意一組相結合與其相連的原子一起形成雙鍵或者C=O，所述的雙鍵任選進一步被0至2個選自F、C1-4烷基或者-COORx所取代；選擇性的，Rd與Rd’可與其相連的碳原子一起形成3至6員碳環，所述的碳環任選進一步被0至6個選自F、Cl、Br、I、C1-4烷基或者C1-4烷氧基所取代；Rx選自H或者C1-4烷基。An intermediate for preparing a compound represented by the general formula (I), (Ia) or (Ib) or a stereoisomer thereof, the intermediate is selected from the compound represented by the following general formula (II) or a stereoisomer thereof : Wherein: R a or R b are each independently selected from a hydroxyl group or a C 1-4 alkyl group, and the alkyl group is optionally further substituted by 0 to 2 nitro groups or -COOR x ; optionally, R a and R R b combines with its connected atom to form a double bond or C = O, said double bond is optionally further substituted with 0 to 2 selected from F, C 1-4 alkyl, nitro or -COOR x ; R c, R d, R d ' , or R e is independently selected from H, F, Cl, hydroxy or C 1-4 alkyl, said alkyl optionally further substituted by 0-2 selected from F, hydroxy , -OMs, -COOR x or substituted; selective, R d and R d ', R d and R e group of a combination of any atoms which they are attached form a double bond C = O or together with the double bond Optionally further substituted by 0 to 2 selected from F, C 1-4 alkyl or -COOR x ; optionally, R d and R d ' may form a 3 to 6 membered carbocyclic ring together with the carbon atom to which they are attached, The carbocyclic ring is optionally further substituted by 0 to 6 selected from F, Cl, Br, I, C 1-4 alkyl or C 1-4 alkoxy; R x is selected from H or C 1-4 alkyl. 如申請專利範圍第6項所述的化合物或者其立體異構物，其中所述化合物選自以下結構之一： The compound or a stereoisomer thereof according to item 6 of the scope of patent application, wherein the compound is selected from one of the following structures: 如申請專利範圍第1、2、4或5中所述的化合物，或者其立體異構物、溶劑化物、藥學上可接受的鹽或共晶，其中所述的鹽為對甲苯磺酸鹽。The compound, or a stereoisomer, solvate, pharmaceutically acceptable salt or co-crystal thereof, as described in claim 1, 2, 4, or 5, wherein the salt is p-toluenesulfonate. 一種藥物組合物，所述藥物組合物包含如申請專利範圍第1至5項中任一項所述的化合物或其立體異構物、溶劑化物、藥學上可接受的鹽或共晶，及一種或者多種藥學上可接受的載體及/或賦形劑。A pharmaceutical composition comprising the compound or a stereoisomer, a solvate, a pharmaceutically acceptable salt or a co-crystal thereof according to any one of claims 1 to 5 of the scope of patent application, and a Or multiple pharmaceutically acceptable carriers and / or excipients. 一種如申請專利範圍第9項所述的藥物組合物在製備治療及/或預防疼痛之藥物的用途。The use of a pharmaceutical composition as described in item 9 of the scope of patent application for preparing a medicament for treating and / or preventing pain. 如申請專利範圍第10項的所述的用途，所述的疼痛包括：皰疹後神經痛、三叉神經痛、偏頭痛、與骨關節炎或關節風濕病相關的疼痛、下背疼痛、坐骨神經痛、牙痛、由燒傷引起的疼痛、由糖尿病性神經病引起的疼痛、由化療誘導的神經病變引起的疼痛、與HIV相關的神經痛、與AIDS相關的神經痛、與癌症相關的神經痛或非神經痛、急性或慢性緊張性頭痛、手術後疼痛、纖維肌痛。According to the use of claim 10, the pain includes: postherpetic neuralgia, trigeminal neuralgia, migraine, pain associated with osteoarthritis or joint rheumatism, lower back pain, sciatica , Toothache, pain caused by burns, pain caused by diabetic neuropathy, pain caused by chemotherapy-induced neuropathy, HIV-related neuralgia, AIDS-related neuralgia, cancer-related neuralgia or non-nerve Pain, acute or chronic tension headache, postoperative pain, fibromyalgia. 一種如申請專利範圍第1至5項中任一項所述的化合物或其立體異構物、溶劑化物、藥學上可接受的鹽或者共晶在製備治療及/或預防疼痛之藥物的用途。The use of a compound or a stereoisomer, a solvate, a pharmaceutically acceptable salt, or a co-crystal thereof according to any one of claims 1 to 5 of the scope of application for preparing a medicine for treating and / or preventing pain. 如申請專利範圍第12項所述的用途，所述的疼痛包括：皰疹後神經痛、三叉神經痛、偏頭痛、與骨關節炎或關節風濕病相關的疼痛、下背疼痛、坐骨神經痛、牙痛、由燒傷引起的疼痛、由糖尿病性神經病引起的疼痛、由化療誘導的神經病變引起的疼痛、與HIV相關的神經痛、與AIDS相關的神經痛、與癌症相關的神經痛或非神經痛、急性或慢性緊張性頭痛、手術後疼痛、纖維肌痛。According to the use of claim 12 in the scope of patent application, the pain includes: postherpetic neuralgia, trigeminal neuralgia, migraine, pain associated with osteoarthritis or joint rheumatism, lower back pain, sciatica, Toothache, pain caused by burns, pain caused by diabetic neuropathy, pain caused by chemotherapy-induced neuropathy, HIV-related neuralgia, AIDS-related neuralgia, cancer-related neuralgia or non-neuralgia , Acute or chronic tension headache, postoperative pain, fibromyalgia.
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