WO2016119757A1 - Method for preparing 2-[1-cycloalkylethyl] phenol and intermediate thereof - Google Patents

Method for preparing 2-[1-cycloalkylethyl] phenol and intermediate thereof Download PDF

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WO2016119757A1
WO2016119757A1 PCT/CN2016/073091 CN2016073091W WO2016119757A1 WO 2016119757 A1 WO2016119757 A1 WO 2016119757A1 CN 2016073091 W CN2016073091 W CN 2016073091W WO 2016119757 A1 WO2016119757 A1 WO 2016119757A1
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acid
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秦琳琳
王伟
王文晶
刘国亮
任磊
万松林
罗新峰
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四川海思科制药有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/44—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
    • C07C37/18—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms by condensation involving halogen atoms of halogenated compounds
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    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
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    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
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    • C07F5/04—Esters of boric acids
    • 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
    • Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention relates to a method for preparing a 2-[1-cycloalkylethyl] phenol derivative, i.e. a method for preparing a compound as shown in formula (I) and an isomer thereof, and an intermediate, and the method has the advantages of short reaction route, inexpensive and available raw materials, high yield and the like. The structure of the compound of general formula (I) is as shown below, with the definitions of R, R1 and n being consistent with the definitions in the description.

Description

一种2-[1-环烷基乙基]苯酚的制备方法及其中间体Preparation method of 2-[1-cycloalkylethyl]phenol and intermediate thereof 技术领域Technical field
本发明涉及一种2-[1-环烷基乙基]苯酚的制备方法及其中间体。The present invention relates to a process for the preparation of 2-[1-cycloalkylethyl]phenol and an intermediate thereof.
背景技术Background technique
GABAA受体是中枢神经系统中主要的抑制性神经递质受体。GABAA受体由跨膜多肽亚基的五聚体构成，19种不同的亚基组成了多种不同的GABAA受体亚型。GABAA受体涉及麻醉、抑郁、焦虑、癫痫、记忆障碍、药物依赖等多种疾病的发病机制和诊断治疗。The GABA A receptor is the major inhibitory neurotransmitter receptor in the central nervous system. The GABA A receptor consists of a pentamer of transmembrane polypeptide subunits, and 19 different subunits make up a variety of different GABA A receptor subtypes. GABA A receptors are involved in the pathogenesis and diagnosis and treatment of various diseases such as anesthesia, depression, anxiety, epilepsy, memory disorders, and drug dependence.
WO2014180305描述了一类苯酚衍生物及其制备方法和在中枢神经领域的用途，并具有良好的GABAA受体激动活性，有些化合物具有比市售丙泊酚更强的GABAA激动活性，尤其是一些2-(1-环丙基乙基)苯酚衍生物(如2-(1-环丙基乙基)-6-异丙基苯酚)及其异构体在动物实验上显示更大治疗指数、更高安全指数、更宽的治疗窗或对应制剂中水相的游离浓度低，可预测有避免注射痛的效果，具有良好的临床应用前景，其通式结构如下：WO2014180305 describes a class of phenol derivatives, their preparation and use in the field of central nervous system, and has good GABA A receptor agonistic activity, some compounds have stronger GABA A agonistic activity than commercially available propofol, especially Some 2-(1-cyclopropylethyl)phenol derivatives (such as 2-(1-cyclopropylethyl)-6-isopropylphenol) and their isomers show greater therapeutic index in animal experiments The higher the safety index, the wider therapeutic window or the lower free concentration of the aqueous phase in the corresponding preparation, can predict the effect of avoiding injection pain, and has good clinical application prospects. The general structure is as follows:
Figure PCTCN2016073091-appb-000001
Figure PCTCN2016073091-appb-000001
同时也公开了2-[1-环烷基乙基]苯酚衍生物的制备方法，具体如下：A method for preparing a 2-[1-cycloalkylethyl]phenol derivative is also disclosed, as follows:
a：a:
Figure PCTCN2016073091-appb-000002
Figure PCTCN2016073091-appb-000002
b：b:
Figure PCTCN2016073091-appb-000003
Figure PCTCN2016073091-appb-000003
c：c:
Figure PCTCN2016073091-appb-000004
Figure PCTCN2016073091-appb-000004
该方法路线长，反应苛刻，不利于工业生产。The method has a long route and is harsh in reaction, which is not conducive to industrial production.
本发明的目的在于解决其不足之处，提供一种新的路线短的、反应更易的制备方法。The object of the present invention is to solve the deficiencies and provide a new preparation method which is short in route and easier to react.
发明内容Summary of the invention
本发明提供了一种制备2-(1-环烷基乙基)苯酚衍生物的方法。The present invention provides a process for preparing a 2-(1-cycloalkylethyl)phenol derivative.
本发明提供了一种制备2-(1-环烷基乙烯基)苯酚衍生物的方法。The present invention provides a process for preparing a 2-(1-cycloalkylvinyl)phenol derivative.
本发明提供了一种通式(I)所示的化合物及其立体异构体的制备方法，其中是通过通式(II)化合物及其立体异构体进行还原反应制得，The present invention provides a method for preparing a compound represented by the formula (I) and a stereoisomer thereof, which is obtained by a reduction reaction of a compound of the formula (II) and a stereoisomer thereof,
Figure PCTCN2016073091-appb-000005
Figure PCTCN2016073091-appb-000005
其中，R选自H或者羟基保护基；R1选自甲基、乙基或环丙基；n选自1、2或3。Wherein R is selected from H or a hydroxy protecting group; R 1 is selected from methyl, ethyl or cyclopropyl; and n is selected from 1, 2 or 3.
本发明优选方案，一种通式(I)所示的化合物及其立体异构体的制备方法，其中n 为1。A preferred embodiment of the present invention, a method of producing a compound of the formula (I) and a stereoisomer thereof, wherein Is 1.
本发明优选方案，一种通式(I)所示的化合物及其立体异构体的制备方法，其中通过通式(II)化合物在催化剂作用下催化氢气进行还原反应，或者使用三甲基硅烷+酸、三乙基硅烷+酸、NH2NH2、B2H6+过氧酸、KO2CN＝NCO2K或汉斯酯1,4-二氢吡啶进行还原反应制得式(I)化合物；所述催化剂选自负载型金属催化剂或金属配合物，所述金属选自Pt、Pd、Ni、Ru、Ir或Rh；所述的酸选自盐酸、硫酸、醋酸、三氟乙酸或对甲苯磺酸；所述的过氧酸选自过氧苯甲酸、m-CPBA或过氧乙酸。Preferred Embodiments of the Invention The present invention provides a process for the preparation of a compound of the formula (I) and a stereoisomer thereof, wherein a compound of the formula (II) is used to catalyze the reduction of hydrogen under the action of a catalyst, or a trimethylsilane is used. + (acid, triethylsilane + acid, NH 2 NH 2 , B 2 H 6 + peroxyacid, KO 2 CN = NCO 2 K or Hans ester 1,4-dihydropyridine to carry out the reduction reaction to obtain the formula (I a compound; the catalyst is selected from a supported metal catalyst or a metal complex selected from the group consisting of Pt, Pd, Ni, Ru, Ir or Rh; and the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or P-toluenesulfonic acid; the peroxyacid is selected from the group consisting of peroxybenzoic acid, m-CPBA or peracetic acid.
本发明优选方案，一种通式(I)所示的化合物及其立体异构体的制备方法，其中是通过通式(II)化合物及其立体异构体进行还原反应制得的反应中使用的还原剂为氢气且使用的催化剂选自负载型金属催化剂或金属配合物，所述金属选自Pt、Pd、Ni、Ru、Ir或Rh；或者还原剂选自三甲基硅烷+酸、三乙基硅烷+酸、NH2NH2、B2H6+过氧酸、KO2CN＝NCO2K或汉斯酯1,4-二氢吡啶；所述的酸选自盐酸、硫酸、醋酸、三氟乙酸或对甲苯磺酸；所述的过氧酸选自过氧苯甲酸、m-CPBA或过氧乙酸；所使用的溶剂选自水、甲醇、六氟异丙醇、三氟乙醇、乙醇、异丙醇、二氧六环、氯仿、丙酮、乙酸、二甲基亚砜、二氯甲烷、二氯乙烷、四氢呋喃、乙腈、乙酸乙酯、甲基四氢呋喃、甲基叔丁基醚、乙醚、N,N-二甲基甲酰胺、苯、甲苯、氟化苯、1,2-二氟苯、对溴氟苯、2,3-二氟溴苯、六氟苯、溴五氟苯、二甲苯、三甲苯、三(三氟甲基)苯或三氟甲基苯中的任一种或任几种任意比例的混合物。A preferred embodiment of the present invention, a method for producing a compound represented by the formula (I) and a stereoisomer thereof, which is produced by a reaction obtained by a reduction reaction of a compound of the formula (II) and a stereoisomer thereof The reducing agent is hydrogen and the catalyst used is selected from a supported metal catalyst or a metal complex selected from Pt, Pd, Ni, Ru, Ir or Rh; or the reducing agent is selected from the group consisting of trimethylsilane + acid, three Ethylsilane + acid, NH 2 NH 2 , B 2 H 6 + peroxyacid, KO 2 CN=NCO 2 K or Hans ester 1,4-dihydropyridine; the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid , trifluoroacetic acid or p-toluenesulfonic acid; the peroxyacid is selected from the group consisting of peroxybenzoic acid, m-CPBA or peroxyacetic acid; the solvent used is selected from the group consisting of water, methanol, hexafluoroisopropanol, trifluoroethanol , ethanol, isopropanol, dioxane, chloroform, acetone, acetic acid, dimethyl sulfoxide, dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, methyltetrahydrofuran, methyl t-butyl Ether, diethyl ether, N,N-dimethylformamide, benzene, toluene, fluorinated benzene, 1,2-difluorobenzene, p-bromofluorobenzene, 2,3-difluorobromobenzene, Any one or a mixture of any of hexafluorobenzene, bromopentafluorobenzene, xylene, trimethylbenzene, tris(trifluoromethyl)benzene or trifluoromethylbenzene in any ratio.
本发明优选方案，一种通式(I)所示的化合物及其立体异构体的制备方法，其特在于是通过通式(II)化合物及其立体异构体进行还原反应制得的反应中使用的还原剂为氢气且使用的催化剂选自钯碳、雷尼镍、[Rh(NBD)Cl]2/SL-W012-1、[Rh(NBD)Cl]2/SL-W012-2[Rh(COD)2]O3SCF3/SL-W012-2、[Rh(COD)2]O3SCF3/SL-W012-1、[Rh(NBD)Cl]2/-(-)-1-[(S)-2-二叔丁基磷)二茂铁]乙基二-(4-三氟甲基苯)磷、[Rh(COD)2]O3SCF3/-(-)-1-[(S)-2-二叔丁基磷)二茂铁]乙基二-(4-三氟甲基苯)磷或[Ru(COD)(OAc)2]/-(-)-1-[(S)-2-二叔丁基磷)二茂铁]乙基二-(4-三氟甲基苯)磷；所使用的溶剂选自水、甲醇、六氟异丙醇、三氟乙醇、乙醇、异丙醇、二氧六环、氯仿、丙酮、乙酸、二甲基亚砜、二氯甲烷、二氯乙烷、四氢呋喃、乙腈、乙酸乙酯、2-甲基四氢呋喃、甲基叔丁基醚、乙醚、N,N-二甲基甲酰胺、苯、甲苯、氟化苯、1,2-二氟苯、对溴氟苯、2,3-二氟溴苯、六氟苯、溴五氟苯、二甲苯、三甲苯、1,3,5-三(三氟甲基)苯或三氟甲基苯中的任一种或任几种任意比例的混合物。 A preferred embodiment of the present invention, a method for producing a compound represented by the formula (I) and a stereoisomer thereof, which is characterized in that the reaction is carried out by a reduction reaction of a compound of the formula (II) and a stereoisomer thereof The reducing agent used is hydrogen and the catalyst used is selected from the group consisting of palladium carbon, Raney nickel, [Rh(NBD)Cl] 2 /SL-W012-1, [Rh(NBD)Cl] 2 /SL-W012-2 [ Rh(COD) 2 ]O 3 SCF 3 /SL-W012-2, [Rh(COD) 2 ]O 3 SCF 3 /SL-W012-1, [Rh(NBD)Cl] 2 /-(-)-1 -[(S)-2-di-tert-butylphosphine)ferrocene]ethylbis-(4-trifluoromethylphenyl)phosphine, [Rh(COD) 2 ]O 3 SCF 3 /-(-)- 1-[(S)-2-di-tert-butylphosphine)ferrocene]ethyldi-(4-trifluoromethylphenyl)phosphine or [Ru(COD)(OAc) 2 ]/-(-)- 1-[(S)-2-di-tert-butylphosphine)ferrocene]ethyldi-(4-trifluoromethylphenyl)phosphine; the solvent used is selected from the group consisting of water, methanol, hexafluoroisopropanol, Trifluoroethanol, ethanol, isopropanol, dioxane, chloroform, acetone, acetic acid, dimethyl sulfoxide, dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, 2-methyltetrahydrofuran, Methyl tert-butyl ether, diethyl ether, N,N-dimethylformamide, benzene, toluene, fluorinated benzene, 1,2 -difluorobenzene, p-bromofluorobenzene, 2,3-difluorobromobenzene, hexafluorobenzene, bromopentafluorobenzene, xylene, trimethylbenzene, 1,3,5-tris(trifluoromethyl)benzene or three Any one or a mixture of any of fluoromethylbenzene in any ratio.
本发明提供一种式(II)所示的化合物及其立体异构体的制备方法，其中是通过通式(III)或通式(III`)与通式(IV)化合物及其立体异构体偶联反应制备得到，The present invention provides a method for preparing a compound represented by the formula (II) and a stereoisomer thereof, which is a compound of the formula (III) or the formula (III) and a stereoisomer thereof Prepared by a bulk coupling reaction,
Figure PCTCN2016073091-appb-000006
Figure PCTCN2016073091-appb-000006
其中，X选自Cl、Br或I；M选自Na、K或Li；R为H或者羟基保护基；Wherein X is selected from Cl, Br or I; M is selected from Na, K or Li; R is H or a hydroxy protecting group;
R1选自甲基、乙基或环丙基；n选自1、2或3；R 1 is selected from methyl, ethyl or cyclopropyl; n is selected from 1, 2 or 3;
R2、R3、R4各自独立的选自H、OH、F、Cl、Br或C1-6烷氧基；作为选择，R2和R3可以与其相连的原子一起形成4-10元环，所述环除含有杂原子B外，还含有0至4个选自O、N或S的杂原子，所述的环可以任选被0至4个选自H、C1-6烷基或C1-6烷氧基的取代基所取代；R 2 , R 3 , R 4 are each independently selected from H, OH, F, Cl, Br or C 1-6 alkoxy; alternatively, R 2 and R 3 may form 4-10 together with the atom to which they are attached. a ring which, in addition to the hetero atom B, contains from 0 to 4 heteroatoms selected from O, N or S, said ring may optionally be from 0 to 4 selected from H, C 1-6 alkane Substituted with a substituent of a C 1-6 alkoxy group;
n选自1、2或3。n is selected from 1, 2 or 3.
本发明优选方案，一种式(II)所示的化合物及其立体异构体的制备方法，其特在于是通过通式(III)或通式(III`)与通式(IV)化合物及其立体异构体偶联反应制备得到，其中A preferred embodiment of the present invention, a method for producing a compound represented by the formula (II) and a stereoisomer thereof, which is characterized in that the compound of the formula (III) or the formula (III) and the compound of the formula (IV) The stereoisomer coupling reaction is prepared, wherein
X选自Br；X is selected from Br;
式(III)化合物选自
Figure PCTCN2016073091-appb-000007
或
Figure PCTCN2016073091-appb-000008
The compound of formula (III) is selected from
Figure PCTCN2016073091-appb-000007
or
Figure PCTCN2016073091-appb-000008
式(III`)化合物为
Figure PCTCN2016073091-appb-000009
The compound of formula (III`) is
Figure PCTCN2016073091-appb-000009
本发明优选方案，一种式(II)所示的化合物及其立体异构体的制备方法，其特在于是通过通式(III)或通式(III`)与通式(IV)化合物及其立体异构体偶联反应制备得到，其中：A preferred embodiment of the present invention, a method for producing a compound represented by the formula (II) and a stereoisomer thereof, which is characterized in that the compound of the formula (III) or the formula (III) and the compound of the formula (IV) Its stereoisomer coupling reaction is prepared, wherein:
X选自Br；X is selected from Br;
R为H或者羟基保护基，优选H、S-(1-苯基)乙基氨基羰基或者R-(1-苯基)乙基氨基羰基； R is H or a hydroxy protecting group, preferably H, S-(1-phenyl)ethylaminocarbonyl or R-(1-phenyl)ethylaminocarbonyl;
式(III)化合物选自
Figure PCTCN2016073091-appb-000010
或
Figure PCTCN2016073091-appb-000011
The compound of formula (III) is selected from
Figure PCTCN2016073091-appb-000010
or
Figure PCTCN2016073091-appb-000011
式(III`)化合物为
Figure PCTCN2016073091-appb-000012
The compound of formula (III`) is
Figure PCTCN2016073091-appb-000012
反应在催化剂作用下进行，反应中所使用的催化剂选自负载型金属催化剂或金属配合物，所述的金属选自Pd、Ru、Ir、Rh或Ni；所述催化剂优选：所述金属配合物的配体各自独立的选自Phos、PhCN、COD、diglyme、PEPPSI-iPr、t-Bu3P、(Cy)3P、dppf、PPh3、dba、OAc中的一种或多种；所述催化剂进一步优选Pd(OAc)2、Pd(OAc)2/S-Phos、Pd(OAc)2/RuPhos、(PhCN)2PdCl2、Ni(cod)2、NiCl2-diglyme、PdCl2-PEPPSI-iPr、PdCl2/t-Bu3P、PdCl2/(Cy)3P、Pd(dppf)Cl2、Pd(PPh3)4、Pd(PPh3)2Cl2或Pd2(dba)3/t-Bu3P，更优选Pd(dppf)Cl2；The reaction is carried out under the action of a catalyst selected from a supported metal catalyst or a metal complex selected from the group consisting of Pd, Ru, Ir, Rh or Ni; the catalyst preferably: the metal complex The ligands are each independently selected from one or more of the group consisting of Phos, PhCN, COD, diglyme, PEPPSI-iPr, t-Bu 3 P, (Cy) 3 P, dppf, PPh 3 , dba, OAc; The catalyst is further preferably Pd(OAc) 2 , Pd(OAc) 2 /S-Phos, Pd(OAc) 2 /RuPhos, (PhCN) 2 PdCl 2 , Ni(cod) 2 , NiCl 2 -diglyme, PdCl 2 -PEPPSI- iPr, PdCl 2 /t-Bu 3 P, PdCl 2 /(Cy) 3 P, Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 or Pd 2 (dba) 3 / t-Bu 3 P, more preferably Pd(dppf)Cl 2 ;
反应中所使用的溶剂选自甲苯、二氧六环、四氢呋喃、二甲基亚砜、N,N-二甲基甲酰胺、水、甲醇、乙醇、乙二醇二甲醚、二氯乙烷中的任一种或任几种任意比例的混合物，优选甲苯、甲醇、乙醇、二氧六环、四氢呋喃、N,N-二甲基甲酰胺或乙二醇二甲醚中的任一种或任几种任意比例的混合物；The solvent used in the reaction is selected from the group consisting of toluene, dioxane, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, water, methanol, ethanol, ethylene glycol dimethyl ether, dichloroethane. Any one or any mixture of any ratio, preferably any one of toluene, methanol, ethanol, dioxane, tetrahydrofuran, N,N-dimethylformamide or ethylene glycol dimethyl ether or Any mixture of any ratio;
所述的反应加入碱性试剂，所述的碱性试剂选自碳酸钠、碳酸氢钠、醋酸钠、磷酸钠、碳酸铯、碳酸钾、碳酸氢钾、醋酸钾、磷酸钾、三乙胺、氟化钾、叔丁基胺、N,N-二异丙基乙胺、三丁胺、吡啶中的任一种或任几种的混合物，优选碳酸钠、碳酸钾、碳酸氢钾、醋酸钾或磷酸钾。The reaction is added with an alkaline reagent selected from the group consisting of sodium carbonate, sodium hydrogencarbonate, sodium acetate, sodium phosphate, cesium carbonate, potassium carbonate, potassium hydrogencarbonate, potassium acetate, potassium phosphate, triethylamine, a mixture of any one or any of potassium fluoride, tert-butylamine, N,N-diisopropylethylamine, tributylamine, pyridine, preferably sodium carbonate, potassium carbonate, potassium hydrogencarbonate, potassium acetate Or potassium phosphate.
本发明提供一种通式(III)或通式(III`)所示的化合物的制备方法，其中The present invention provides a process for the preparation of a compound of the formula (III) or formula (III'), wherein
Figure PCTCN2016073091-appb-000013
Figure PCTCN2016073091-appb-000013
通过1-环烷基乙炔、1-环烷基-1-(三氟甲磺酰氧基)乙烯或1-环烷基-1-卤代乙烯与硼酸或硼酸酯反应制备得到通式(III)或通式(III`)化合物；The general formula is prepared by reacting 1-cycloalkylacetylene, 1-cycloalkyl-1-(trifluoromethanesulfonyloxy)ethylene or 1-cycloalkyl-1-haloethylene with boric acid or boric acid ester ( III) or a compound of the formula (III');
R1、R2、R3、R4、M、n如上文所述。R 1 , R 2 , R 3 , R 4 , M, n are as described above.
本发明提供一种通式(III)或通式(III`)所示的化合物的制备方法，其中 The present invention provides a process for the preparation of a compound of the formula (III) or formula (III'), wherein
所述的硼酸或硼酸酯选自
Figure PCTCN2016073091-appb-000014
或
Figure PCTCN2016073091-appb-000015
The boric acid or boric acid ester is selected from
Figure PCTCN2016073091-appb-000014
or
Figure PCTCN2016073091-appb-000015
R5选自H、OH、F、Cl、Br、或C1-6烷氧基；R 5 is selected from H, OH, F, Cl, Br, or C 1-6 alkoxy;
反应中所使用溶剂选自甲苯、二氯甲烷、N,N-二甲基甲酰胺、四氢呋喃、水、甲醇或乙醇中的任一种或任几种任意比例的混合物；The solvent used in the reaction is selected from the group consisting of toluene, dichloromethane, N,N-dimethylformamide, tetrahydrofuran, water, methanol or ethanol, or a mixture of any of them in any ratio;
所述的反应加入碱性试剂，所述的碱性试剂选自醋酸钾、醋酸钠、叔丁醇钠或叔丁醇钾中的任一种或任几种任意比例的混合物。The reaction is carried out by adding an alkaline agent selected from the group consisting of potassium acetate, sodium acetate, sodium t-butoxide or potassium t-butoxide, or a mixture of any of them in any ratio.
本发明提供一种通式(I)所示的化合物及其立体异构体的制备方法，其中The present invention provides a method for producing a compound represented by the formula (I) and a stereoisomer thereof, wherein
Figure PCTCN2016073091-appb-000016
Figure PCTCN2016073091-appb-000016
a)通式(V)与硼酸或硼酸酯反应得到通式(III)或通式(III`)化合物；所述的硼酸或硼酸酯选自
Figure PCTCN2016073091-appb-000017
或
Figure PCTCN2016073091-appb-000018
a) reacting a general formula (V) with a boronic acid or a boronic acid ester to obtain a compound of the formula (III) or formula (III'); the boric acid or boric acid ester is selected from the group consisting of
Figure PCTCN2016073091-appb-000017
or
Figure PCTCN2016073091-appb-000018
b)在催化剂和碱性试剂作用下，通过通式(III)化合物或通式(III`)化合物与式(IV)化合物及其立体异构体偶联反应制备得到式(II)化合物及其立体异构体，反应中所使用的催化剂选自负载型金属催化剂或金属配合物，所述的金属选自Pd、Ru、Ir、Rh或Ni，所述金属配合物的配体各自独立的选自Phos、PhCN、COD、diglyme、PEPPSI-iPr、t-Bu3P、(Cy)3P、dppf、PPh3、dba、OAc中的一种或多种；所述催化剂优选Pd(OAc)2、Pd(OAc)2/S-Phos、Pd(OAc)2/RuPhos、(PhCN)2PdCl2、Ni(cod)2、NiCl2-diglyme、PdCl2-PEPPSI-iPr、PdCl2/t-Bu3P、PdCl2/(Cy)3P、Pd(dppf)Cl2、Pd(PPh3)4、Pd(PPh3)2Cl2或Pd2(dba)3/t-Bu3P，进一步优选Pd(dppf)Cl2；b) preparing a compound of the formula (II) by a coupling reaction of a compound of the formula (III) or a compound of the formula (III') with a compound of the formula (IV) and a stereoisomer thereof under the action of a catalyst and an alkaline reagent a stereoisomer, the catalyst used in the reaction is selected from a supported metal catalyst or a metal complex selected from the group consisting of Pd, Ru, Ir, Rh or Ni, and the ligands of the metal complex are independently selected. One or more of Phos, PhCN, COD, diglyme, PEPPSI-iPr, t-Bu 3 P, (Cy) 3 P, dppf, PPh 3 , dba, OAc; the catalyst is preferably Pd(OAc) 2 , Pd(OAc) 2 /S-Phos, Pd(OAc) 2 /RuPhos, (PhCN) 2 PdCl 2 , Ni(cod) 2 , NiCl 2 -diglyme, PdCl 2 -PEPPSI-iPr, PdCl 2 /t-Bu 3 P, PdCl 2 /(Cy) 3 P, Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 or Pd 2 (dba) 3 /t-Bu 3 P, further preferred Pd(dppf)Cl 2 ;
c)通过式(II)化合物及其立体异构体在催化剂作用下与氢气还原反应制得式(I)化合物及其立体异构体，或者通过式(II)化合物及其立体异构体与三甲基硅烷+酸、三乙基硅烷+酸、NH2NH2、B2H6+过氧酸、KO2CN＝NCO2K或汉斯酯1,4-二氢吡啶进行还原反应制得式(I)化合物及其立体异构体； c) obtaining a compound of the formula (I) and a stereoisomer thereof by a reaction of a compound of the formula (II) and a stereoisomer thereof with hydrogen under the action of a catalyst, or by a compound of the formula (II) and a stereoisomer thereof Reduction reaction of trimethylsilane+acid, triethylsilane+acid, NH 2 NH 2 , B 2 H 6 +peroxyacid, KO 2 CN=NCO 2 K or Hans ester 1,4-dihydropyridine a compound of the formula (I) and a stereoisomer thereof;
所述催化剂选自负载型金属催化剂或金属配合物，所述金属选自Pt、Pd、Ni、Ru、Ir或Rh；优选钯碳、雷尼镍；The catalyst is selected from a supported metal catalyst or a metal complex selected from the group consisting of Pt, Pd, Ni, Ru, Ir or Rh; preferably palladium carbon, Raney nickel;
所述的酸选自盐酸、硫酸、醋酸、三氟乙酸或对甲苯磺酸；The acid is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or p-toluenesulfonic acid;
所述的过氧酸选自过氧苯甲酸、m-CPBA或过氧乙酸The peroxyacid is selected from the group consisting of peroxybenzoic acid, m-CPBA or peracetic acid
X选自Cl、Br或I，优选Br；M选自Na、K或Li，优选K；X is selected from Cl, Br or I, preferably Br; M is selected from Na, K or Li, preferably K;
R为H或者羟基保护基，优选H、S-(1-苯基)乙基氨基羰基或者R-(1-苯基)乙基氨基羰基；R is H or a hydroxy protecting group, preferably H, S-(1-phenyl)ethylaminocarbonyl or R-(1-phenyl)ethylaminocarbonyl;
R1选自甲基、乙基或环丙基，优选甲基；n选自1、2或3，n优选为1；R 1 is selected from methyl, ethyl or cyclopropyl, preferably methyl; n is selected from 1, 2 or 3, and n is preferably 1;
R2和R3各自独立的选自H、OH、F、Cl、Br、或C1-6烷氧基；作为选择，R1和R2可以与其相连的原子一起形成4-10元环，优选5元环或6元环，所述环除含有杂原子B外，还含有0至4个选自O、N或S的杂原子，所述的环可以任选被0至4个选自H、C1-6烷基或C1-6烷氧基的取代基所取代；R 2 and R 3 are each independently selected from H, OH, F, Cl, Br, or C 1-6 alkoxy; alternatively, R 1 and R 2 may form a 4-10 membered ring together with the atom to which they are attached, A 5-membered or 6-membered ring is preferred, which contains, in addition to the hetero atom B, 0 to 4 heteroatoms selected from O, N or S, said ring optionally being selected from 0 to 4 Substituted by a substituent of H, C 1-6 alkyl or C 1-6 alkoxy;
R4为F；R 4 is F;
R5选自H、OH、F、Cl、Br、或C1-6烷氧基，优选H、甲氧基、乙氧基、丙氧基或异丙氧基。R 5 is selected from H, OH, F, Cl, Br, or C 1-6 alkoxy, preferably H, methoxy, ethoxy, propoxy or isopropoxy.
本发明优选方案，一种通式(I)所示的化合物及其立体异构体的制备方法，其中：According to a preferred embodiment of the present invention, there is provided a method of producing a compound of the formula (I) and a stereoisomer thereof, wherein:
a)通式(V)与
Figure PCTCN2016073091-appb-000019
或
Figure PCTCN2016073091-appb-000020
反应得到通式(III)或通式(III`)化合物；a) General formula (V) and
Figure PCTCN2016073091-appb-000019
or
Figure PCTCN2016073091-appb-000020
The reaction gives a compound of the formula (III) or formula (III');
b)反应中所使用的溶剂选自甲苯、甲醇、乙醇、二氧六环、四氢呋喃、N,N-二甲基甲酰胺或乙二醇二甲醚中的任一种或任几种任意比例的混合物，反应中所使用的碱性试剂选自碳酸钠、碳酸钾、碳酸氢钾、醋酸钾或磷酸钾；b) The solvent used in the reaction is selected from any one or any of a ratio of toluene, methanol, ethanol, dioxane, tetrahydrofuran, N,N-dimethylformamide or ethylene glycol dimethyl ether. a mixture, the alkaline reagent used in the reaction is selected from the group consisting of sodium carbonate, potassium carbonate, potassium hydrogencarbonate, potassium acetate or potassium phosphate;
c)反应中所使用的溶剂选自水、甲醇、六氟异丙醇、三氟乙醇、乙醇、异丙醇、二氧六环、氯仿、丙酮、乙酸、二甲基亚砜、二氯甲烷、二氯乙烷、四氢呋喃、乙腈、乙酸乙酯、2-甲基四氢呋喃、甲基叔丁基醚、乙醚、N,N-二甲基甲酰胺、苯、甲苯、氟化苯、1,2-二氟苯、对溴氟苯、2,3-二氟溴苯、六氟苯、溴五氟苯、二甲苯、三甲苯、1,3,5-三(三氟甲基)苯或三氟甲基苯中的任一种或任几种任意比例的混合物；所选用的还原试剂为三乙基硅烷+酸，c) The solvent used in the reaction is selected from the group consisting of water, methanol, hexafluoroisopropanol, trifluoroethanol, ethanol, isopropanol, dioxane, chloroform, acetone, acetic acid, dimethyl sulfoxide, dichloromethane , dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, 2-methyltetrahydrofuran, methyl tert-butyl ether, diethyl ether, N,N-dimethylformamide, benzene, toluene, fluorinated benzene, 1,2 -difluorobenzene, p-bromofluorobenzene, 2,3-difluorobromobenzene, hexafluorobenzene, bromopentafluorobenzene, xylene, trimethylbenzene, 1,3,5-tris(trifluoromethyl)benzene or three Any one or a mixture of any one of fluoromethylbenzene; the reducing agent selected is triethylsilane + acid,
所述催化剂选自负载型金属催化剂或金属配合物，所述金属选自Pt、Pd、Ni、Ru、Ir或Rh；优选钯碳、雷尼镍；The catalyst is selected from a supported metal catalyst or a metal complex selected from the group consisting of Pt, Pd, Ni, Ru, Ir or Rh; preferably palladium carbon, Raney nickel;
R为H、S-(1-苯基)乙基氨基羰基或者R-(1-苯基)乙基氨基羰基； R is H, S-(1-phenyl)ethylaminocarbonyl or R-(1-phenyl)ethylaminocarbonyl;
X选自Br；M选自Na或者K；n选自1。X is selected from Br; M is selected from Na or K; and n is selected from 1.
本发明提供一种式(II)所示的化合物及其立体异构体，其中The present invention provides a compound represented by the formula (II) and a stereoisomer thereof, wherein
Figure PCTCN2016073091-appb-000021
Figure PCTCN2016073091-appb-000021
R选自H或者羟基保护基，优选R-(1-苯基)乙基氨基羰基；R1选自甲基、乙基或环丙基，优选甲基；n选自1、2或3，n优选为1。R is selected from H or a hydroxy protecting group, preferably R-(1-phenyl)ethylaminocarbonyl; R 1 is selected from methyl, ethyl or cyclopropyl, preferably methyl; n is selected from 1, 2 or 3, n is preferably 1.
本发明提供一种式(III)所示的化合物，其中The present invention provides a compound represented by the formula (III), wherein
Figure PCTCN2016073091-appb-000022
Figure PCTCN2016073091-appb-000022
R2和R3各自独立的选自H、OH、F、Cl、Br或C1-6烷氧基，作为选择，R1和R2可以与其相连的原子一起形成4-10元环，所述环除含有杂原子B外，还含有0至4个选自O、N或S的杂原子，所述的环可以任选被0至4个选自H、C1-6烷基或C1-6烷氧基的取代基所取代；R 2 and R 3 are each independently selected from H, OH, F, Cl, Br or C 1-6 alkoxy. Alternatively, R 1 and R 2 may form a 4-10 membered ring together with the atom to which they are attached. The ring contains, in addition to the hetero atom B, 0 to 4 hetero atoms selected from O, N or S, and the ring may optionally be 0 to 4 selected from H, C 1-6 alkyl or C. Substituted by a substituent of 1-6 alkoxy;
n选自1、2或3；优选n为1。n is selected from 1, 2 or 3; preferably n is 1.
本发明提供一种式(III`)所示的化合物，其中The present invention provides a compound represented by the formula (III'), wherein
Figure PCTCN2016073091-appb-000023
Figure PCTCN2016073091-appb-000023
R1和R2的定义如上文所述，R4为F；R 1 and R 2 are as defined above, and R 4 is F;
M选自Na、K或Li，优选K；n选自1、2或3，优选1。M is selected from Na, K or Li, preferably K; n is selected from 1, 2 or 3, preferably 1.
本发明提供的通式(III)化合物选自，但不限于如下结构之一：The compound of the formula (III) provided by the present invention is selected from, but not limited to, one of the following structures:
Figure PCTCN2016073091-appb-000024
或
Figure PCTCN2016073091-appb-000025
Figure PCTCN2016073091-appb-000024
or
Figure PCTCN2016073091-appb-000025
本发明提供的通式(III`)化合物选自，但不限于如下结构：
Figure PCTCN2016073091-appb-000026
The compound of the formula (III') provided by the present invention is selected from, but not limited to, the following structure:
Figure PCTCN2016073091-appb-000026
羟基保护基选自烷基醚类保护基、酯类保护基或硅醚类保护基，羟基保护基包括但 不限于甲基、苄基、对甲氧基苄基、三苯甲基、叔丁基、甲氧基甲醚、甲氧乙氧基甲基、四氢呋喃基、叔丁基羰基、苯甲酰基、乙酰基、氯甲基羰基、叔丁氧基羰基、苄氧基羰基、三甲基硅基、三乙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、二叔丁基羟基硅基、S-(1-苯基)乙基氨基羰基或R-(1-苯基)乙基氨基羰基。The hydroxy protecting group is selected from an alkyl ether protecting group, an ester protecting group or a silyl protecting group, and the hydroxy protecting group includes Not limited to methyl, benzyl, p-methoxybenzyl, trityl, tert-butyl, methoxymethyl ether, methoxyethoxymethyl, tetrahydrofuranyl, tert-butylcarbonyl, benzoyl, Acetyl, chloromethylcarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, di Tert-butylhydroxysilyl, S-(1-phenyl)ethylaminocarbonyl or R-(1-phenyl)ethylaminocarbonyl.
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Terms used in the specification and claims have the following meanings unless stated to the contrary.
本发明涉及的通式化合物存在手性中心时，除明确标示外，通式化合物可以是消旋体，也可以是旋光异构体。When a chiral center of the compound of the present invention is present, the compound of the formula may be a racemate or an optical isomer unless explicitly indicated.
本发明涉及到被多个取代基取代时，各取代基可以相同或不相同。The present invention relates to the substitution of a plurality of substituents, which may be the same or different.
本发明涉及到含有多个杂原子时，各杂原子可以相同或不相同。The present invention relates to the inclusion of a plurality of heteroatoms, each of which may be the same or different.
本发明所述基团和化合物中所涉及的元素碳、氢、氧、硫、氮或卤素均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的元素碳、氢、氧、硫或氮任选进一步被1至5个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，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19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。The elements carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopic conditions, and the elements, carbon, hydrogen and oxygen involved in the groups and compounds of the present invention. Sulfur or nitrogen is optionally further replaced by 1 to 5 of their corresponding isotopes, including 12 C, 13 C and 14 C. The isotopes of hydrogen include helium (H) and helium (D, also known as heavy hydrogen). ), 氚 (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes including 14 N and 15 N The fluorine isotope 19 F, the chlorine isotope includes 35 Cl and 37 Cl, and the bromine isotopes include 79 Br and 81 Br.
羟基保护基选自烷基醚类保护基、酯类保护基或硅醚类保护基，羟基保护基包括但不限于甲基、苄基、对甲氧基苄基、三苯甲基、叔丁基、甲氧基甲醚、甲氧乙氧基甲基、四氢呋喃基、叔丁基羰基、苯甲酰基、乙酰基、氯甲基羰基、叔丁氧基羰基、苄氧基羰基、三甲基硅基、三乙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、二叔丁基羟基硅基、S-(1-苯基)乙基氨基羰基或R-(1-苯基)乙基氨基羰基；The hydroxy protecting group is selected from an alkyl ether protecting group, an ester protecting group or a silyl protecting group, and the hydroxy protecting group includes, but not limited to, methyl, benzyl, p-methoxybenzyl, trityl, tert-butyl. , methoxymethyl ether, methoxyethoxymethyl, tetrahydrofuranyl, tert-butylcarbonyl, benzoyl, acetyl, chloromethylcarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, trimethyl Silyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, di-tert-butylhydroxysilyl, S-(1-phenyl)ethylaminocarbonyl or R- (1-phenyl)ethylaminocarbonyl;
烷基醚类保护基可以在碱性或酸性条件下脱除，所述碱或酸包括但不限于氢化钠、甲醇钠、碳酸钾、氢氧化钾、氢氧化钠、吡啶、三氟乙酸、盐酸、甲酸或乙酸；The alkyl ether protecting group can be removed under basic or acidic conditions including, but not limited to, sodium hydride, sodium methoxide, potassium carbonate, potassium hydroxide, sodium hydroxide, pyridine, trifluoroacetic acid, hydrochloric acid. , formic acid or acetic acid;
酯类保护基可以在碱性条件下脱除，所述碱包括但不限于甲醇钠、碳酸钾、氢氧化钾、氢氧化钠、氢化铝锂、吡啶或氨；The ester protecting group can be removed under basic conditions including, but not limited to, sodium methoxide, potassium carbonate, potassium hydroxide, sodium hydroxide, lithium aluminum hydride, pyridine or ammonia;
硅醚类保护基可以在氟化氢、四丁基氟化氨等条件下脱除；“配合物”也称络合物，是指含有配位单元的化合物。由中心原子或离子与几个配体分子或离子以配位键相结合而形成的复杂分子或离子，通常称为配位单元。The silyl ether protecting group can be removed under conditions of hydrogen fluoride, tetrabutylammonium fluoride, etc. "Complex", also referred to as a complex, refers to a compound containing a coordination unit. A complex molecule or ion formed by the combination of a central atom or ion with several ligand molecules or ions with coordinate bonds, commonly referred to as a coordination unit.
“金属配合物”是指配位单元是由金属和配体构成，当金属与多个配体结合时，配体可以相同，也可以不相同。所述金属选自过渡金属，非限制性实例包括Co、Ni、Ru、Pd、Ir或Rh的零价或高价化合物；所述配体的非限制性实例包括Cl-、OAc-、CN-、COD、 PPh3、P(i-Pr)3、PCy3、P(o-MeOPh)3、P(p-MeOPh)3、Ph2P(CH2)3PPh2、Ph2P(CH2)2PPh2、Ph2P(CH2)4PPh2、Ph2P(CH2)2PPh2(dppe)、Ph2P(CH2)3PPh2(dppp)、dppp、dppb、dppe、dba、BINAP、TDMPP、TMPP、TMSPP、P(O-邻甲氧基苯基)3、P(O-对甲氧基苯基)3、吡啶、n-Bu3P、t-Bu3P、(MeO)3P、AsPh3、P(OEt)3。除配位单元外金属配合物可以含有简单离子，也可以缺省，所述的简单离子选自Cl-、BF4 -、PF6 -、CF3SO3 -、B(C6F5)4 -、B(C6H5)4 -、Al(OC(CF3)3)4 -或[B[3,5-(CF3)2C6H3]4]-。金属配合物的非限制性实例包括Pd(OAc)2、PdCl2(PPh3)2、Pd(PPh3)4、PdCl2(dppf)、Pd(dba)2、(dppp)NiCl2、(R)-Ru(OAc)2BINAP、(Ph3P)3·RuClH、[(Ph)3P]3RuCl2、[(Ph)3P]3Ru(CO)H2、Ph3P)3·IrH、Ir(dppe)2、Ph3P)3·RhCl、((4R,5R)-(+)-O-[1-苯甲基-1-(5-甲基-2-苯基-4,5-二氢恶唑-4-基)-2-苯基乙基](二环己基膦亚盐)(1,5-COD)铱(I)四(3,5-二(三氟甲基)苯基硼酸盐、(R)-Ru(OAc)2BINAP、(R)-(+)-[Ru(MeO-BIPHEP)(C6H6)Cl]Cl、(R)-(+)-[Ru(BIPHEP)(C6H6)Cl]Cl、(R)-Ir(Tol-SDP)(COD)Cl、(R)-(+)-Ir(MeO-BIPHEP)(COD)Cl或由Pd(OAc)2、PdCl2与AsPh3、n-Bu3P、(MeO)3P、Ph2P(CH2)2PPh2(dppe)、Ph2P(CH2)3PPh2(dppp)组成的催化体系。"Metal complex" means that the coordination unit is composed of a metal and a ligand. When the metal is combined with a plurality of ligands, the ligands may be the same or different. The metal is selected from transition metals, non-limiting examples include zero or high valence compounds of Co, Ni, Ru, Pd, Ir or Rh; non-limiting examples of such ligands include Cl - , OAc - , CN - , COD, PPh 3 , P(i-Pr) 3 , PCy 3 , P(o-MeOPh) 3 , P(p-MeOPh) 3 , Ph 2 P(CH 2 ) 3 PPh 2 , Ph 2 P(CH 2 ) 2 PPh 2 , Ph 2 P(CH 2 ) 4 PPh 2 , Ph 2 P(CH 2 ) 2 PPh 2 (dppe), Ph 2 P(CH 2 ) 3 PPh 2 (dppp), dppp, dppb, dppe, dba , BINAP, TDMPP, TMPP, TMSPP, P(O-o-methoxyphenyl) 3 , P(O-p-methoxyphenyl) 3 , pyridine, n-Bu 3 P, t-Bu 3 P, ( MeO) 3 P, AsPh 3 , P(OEt) 3 . The metal complex may contain a simple ion in addition to the coordination unit, or may be, by default, the simple ion selected from the group consisting of Cl - , BF 4 - , PF 6 - , CF 3 SO 3 - , B(C 6 F 5 ) 4 - , B(C 6 H 5 ) 4 - , Al(OC(CF 3 ) 3 ) 4 - or [B[3,5-(CF 3 ) 2 C 6 H 3 ] 4 ] - . Non-limiting examples of metal complexes include Pd(OAc) 2 , PdCl 2 (PPh 3 ) 2 , Pd(PPh 3 ) 4 , PdCl 2 (dppf), Pd(dba) 2 , (dppp)NiCl 2 , (R )-Ru(OAc) 2 BINAP, (Ph 3 P) 3 ·RuClH, [(Ph) 3 P] 3 RuCl 2 , [(Ph) 3 P] 3 Ru(CO)H 2 , Ph 3 P) 3 · IrH, Ir(dppe) 2 , Ph 3 P) 3 · RhCl, ((4R, 5R)-(+)-O-[1-benzyl-1-(5-methyl-2-phenyl-4) ,5-dihydrooxazol-4-yl)-2-phenylethyl](dicyclohexylphosphine subsalt)(1,5-COD)铱(I)tetrakis(3,5-di(trifluoromethyl) Phenylborate, (R)-Ru(OAc) 2 BINAP, (R)-(+)-[Ru(MeO-BIPHEP)(C 6 H 6 )Cl]Cl, (R)-(+ )-[Ru(BIPHEP)(C 6 H 6 )Cl]Cl,(R)-Ir(Tol-SDP)(COD)Cl,(R)-(+)-Ir(MeO-BIPHEP)(COD)Cl Or from Pd(OAc) 2 , PdCl 2 and AsPh 3 , n-Bu 3 P, (MeO) 3 P, Ph 2 P(CH 2 ) 2 PPh 2 (dppe), Ph 2 P(CH 2 ) 3 PPh 2 (dppp) consists of a catalytic system.
“负载型催化剂”是由催化活性组分担载在载体表面上组成的，常用的载体有氧化铝载体、硅胶载体、活性炭载体及某些天然产物如浮石、硅藻土等。The "supported catalyst" is composed of a catalytically active component supported on the surface of the support. The usual supports are alumina support, silica gel support, activated carbon support and certain natural products such as pumice, diatomaceous earth and the like.
“负载型金属催化剂”是指催化活性成分为金属的负载型催化剂，所述金属选自过渡金属，非限制性实例包括但不限于Co、Ni、Ru、Pd、Ir或Rh；负载型金属催化剂非限制性实例包括但不限于钯碳、雷尼镍等。"Supported metal catalyst" means a supported catalyst in which the catalytically active component is a metal selected from transition metals, non-limiting examples including, but not limited to, Co, Ni, Ru, Pd, Ir or Rh; supported metal catalysts Non-limiting examples include, but are not limited to, palladium carbon, Raney nickel, and the like.
具体实施方式detailed description
以下结合附图及实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes but is not limited thereto.
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，氘代乙腈(CD3CN)，内标为四甲基硅烷(TMS)。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). The NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD). ), deuterated acetonitrile (CD 3 CN), internal standard is tetramethylsilane (TMS).
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。The measurement of MS was carried out (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4 mm～0.5mm。Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.20mm. The specification for thin layer chromatography separation and purification is 0.4. Mm ~ 0.5mm.
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
(Ph3P)3·RhCl：三(三苯基膦)氯化铑(Ph 3 P) 3 · RhCl: tris(triphenylphosphine) ruthenium chloride
(Ph3P)3·RuClH：三(三苯基膦)氯氢化钌(Ph 3 P) 3 ·RuClH: tris(triphenylphosphine)hydroquinone
(Ph3P)3·IrH：三(三苯基膦)氢化合铱(Ph 3 P) 3 ·IrH: tris(triphenylphosphine) hydrogenated ruthenium
(R)-Ru(OAc)2BINAP：二乙酸根[(R)-(+)-2,2'-二(二苯基膦基)-1,1'-联萘基]钌(R)-Ru(OAc) 2 BINAP: diacetate [(R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]anthracene
[(Ph)3P]3RuCl2：三(三苯基膦)二氯化钌[(Ph) 3 P] 3 RuCl 2 : tris(triphenylphosphine) antimony dichloride
[(Ph)3P]3Ru(CO)H2：三(三苯基膦)羰基二氢钌[(Ph) 3 P] 3 Ru(CO)H 2 : tris(triphenylphosphine)carbonyldihydroindole
PdCl2：二氯化钯PdCl 2 : palladium dichloride
Pd(OAc)2：二醋酸钯Pd(OAc) 2 : palladium diacetate
PdCl2(PPh3)2：三(三苯基膦)二氯化钯PdCl 2 (PPh 3 ) 2 : tris(triphenylphosphine)palladium dichloride
Pd(PPh3)4：四(三苯基膦)钯Pd(PPh 3 ) 4 : tetrakis(triphenylphosphine)palladium
PdCl2(dppf)：1,1'-二(二苯膦基)二茂铁二氯化钯(II)PdCl 2 (dppf): 1,1'-bis(diphenylphosphino)ferrocene palladium (II)
Pd(dba)2：三(二亚苄基丙酮)二钯Pd(dba) 2 : tris(dibenzylideneacetone)dipalladium
(dppp)NiCl2：1,3-双(二苯基膦)丙烷氯化镍(dppp)NiCl 2 : 1,3-bis(diphenylphosphino)propane nickel chloride
[Rh(NBD)Cl]2：氯降冰片二烯铑二聚体[Rh(NBD)Cl] 2 : Chloro norbornadiene dimer
SL-W012-1：S-(-)-1-[(S)-2-二叔丁基磷)二茂铁]乙基-2-[2-(二苯基磷基)苯]SL-W012-1: S-(-)-1-[(S)-2-di-tert-butylphosphine)ferrocene]ethyl-2-[2-(diphenylphosphino)benzene]
SL-W012-2：R-(-)-1-[(S)-2-二叔丁基磷)二茂铁]乙基-2-[2-(二苯基磷基)苯]SL-W012-2: R-(-)-1-[(S)-2-di-tert-butylphosphine)ferrocene]ethyl-2-[2-(diphenylphosphino)benzene]
SL-J011-1：R-(-)-1-[(S)-2-二叔丁基磷)二茂铁]乙基二-(4-三氟甲基苯)磷SL-J011-1: R-(-)-1-[(S)-2-di-tert-butylphosphine)ferrocene]ethyldi-(4-trifluoromethylphenyl)phosphorus
[Rh(COD)2]O3SCF3：双(1,5-环辛二烯)-三氟甲磺酸铑[Rh(COD) 2 ]O 3 SCF 3 : bis(1,5-cyclooctadiene)-trifluoromethanesulfonate
[Ru(COD)(OAc)2]：(1,5-环辛二烯)-乙酸钌[Ru(COD)(OAc) 2 ]: (1,5-cyclooctadiene)-acetic acid hydrazine
Pd(OAc)2/S-Phos：醋酸钯/2-双环己基膦-2',6'-二甲氧基-1,1'-二联苯Pd(OAc) 2 /S-Phos: palladium acetate/2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-diphenyl
m-CPBA：间氯过氧苯甲酸m-CPBA: m-chloroperoxybenzoic acid
(PhCN)2PdCl2：二(氰基苯)二氯化钯(PhCN) 2 PdCl 2 : bis(cyanobenzene) palladium dichloride
Ni(cod)2：双-(1，5-环辛二烯)镍Ni(cod) 2 : bis-(1,5-cyclooctadiene) nickel
NiCl2-diglyme：二甘醇二甲醚二氯化镍NiCl 2 -diglyme: diglyme, nickel dichloride
PdCl2-PEPPSI-iPr：([1,3-双(2,6-二异丙基苯)咪唑-2-叉](3-氯吡啶)二氯化钯PdCl 2 -PEPPSI-iPr: ([1,3-bis(2,6-diisopropylbenzene)imidazole- 2- ylide](3-chloropyridine)palladium dichloride
PdCl2/t-Bu3P：二氯化钯/三叔丁基磷 PdCl 2 /t-Bu 3 P: palladium dichloride / tri-tert-butyl phosphate
PdCl2/(Cy)3P：二氯化钯/三环己磷PdCl 2 /(Cy) 3 P: palladium dichloride / tricyclohexylphosphine
Pd(dppf)Cl2：[1,1'-双(二苯基膦基)二茂铁]二氯化钯Pd(dppf)Cl 2 :[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
Pd(PPh3)4：四(三苯基磷)钯Pd(PPh 3 ) 4 : tetrakis(triphenylphosphine)palladium
Pd(PPh3)2Cl2：双三苯基磷二氯化钯Pd(PPh 3 ) 2 Cl 2 : bistriphenylphosphine palladium dichloride
Pd2(dba)3/t-Bu3P：三(二亚苄基丙酮)二钯/三叔丁基磷Pd 2 (dba) 3 /t-Bu 3 P: tris(dibenzylideneacetone)dipalladium/tri-tert-butylphosphine
实施例1Example 1
2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (Compound 1)
2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Figure PCTCN2016073091-appb-000027
Figure PCTCN2016073091-appb-000027
氮气保护下，向反应瓶中加入无水氯化锂(4.66g,110mmol)、氯化亚铜(10.89g，110mmol)和干燥的N,N-二甲基甲酰胺(300mL)，室温下搅拌1小时后，依次加入醋酸钾(10.80g，110mmol)、联硼酸频那醇酯(27.93g，110mmol)和环丙基乙炔(1A)(6.61g，100mmol)，室温下继续搅拌20小时，加入饱和食盐水(200mL)搅拌10分钟，抽滤，滤饼用乙酸乙酯(50mL)洗，滤液用乙酸乙酯(150mL×3)萃取，收集的有机层用饱和食盐水(150mL×3)洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚)得到黄色液体状的目标产物2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(10.80g，产率：55.67％)。Under a nitrogen atmosphere, anhydrous lithium chloride (4.66 g, 110 mmol), cuprous chloride (10.89 g, 110 mmol) and dry N,N-dimethylformamide (300 mL) were added to the reaction flask and stirred at room temperature. After 1 hour, potassium acetate (10.80 g, 110 mmol), pinacol borate (27.93 g, 110 mmol) and cyclopropylacetylene (1A) (6.61 g, 100 mmol) were added successively, and stirring was continued for 20 hours at room temperature, and then added. The mixture was stirred with EtOAc (EtOAc) (EtOAc) (EtOAc) Drying with anhydrous sodium sulfate, filtration, and concentrating the filtrate under reduced pressure. The residue was purified by silica gel column chromatography ( petroleum ether) to give the desired product 2-(1-cyclopropylvinyl)-4,4 as a yellow liquid. 5,5-Tetramethyl-1,3,2-dioxaborane (Compound 1) (10.80 g, yield: 55.67%).
方法二：Method Two:
氮气保护下，向两口瓶中加入无水四氢呋喃(30mL)，用水泵置换氮气10min，滴加二异丁基氢化铝(DIBAL-H)(在甲苯中浓度为1.5M，17.3mL，26.0mmol)，加毕于冰水浴中冷却至0℃后，滴加环丙基乙炔(1A)(1.322g，20.0mmol)，升至室温搅拌2小时后，却至0℃，加入异丙醇频哪醇硼酸酯(11.116g，60.0mmol)，加毕升至80℃搅拌4小时后，冷却至室温，加入水(30mL)搅拌30min，乙酸乙酯萃取(30mL×2)，合并 有机相用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚)得到黄色液体状的目标产物2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(530mg，产率：14％)。Under nitrogen, add anhydrous tetrahydrofuran (30 mL) to a two-necked flask, replace the nitrogen with a water pump for 10 min, and add diisobutylaluminum hydride (DIBAL-H) (concentration in toluene: 1.5 M, 17.3 mL, 26.0 mmol) After adding to the ice water bath and cooling to 0 ° C, cyclopropyl acetylene (1A) (1.322 g, 20.0 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours, but then at 0 ° C, isopropanol pinacol was added. The boric acid ester (11.116g, 60.0mmol) was added to the mixture after stirring to 80 ° C for 4 hours, then cooled to room temperature, added with water (30 mL), stirred for 30 min, ethyl acetate (30 mL × 2), combined The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 4,5,5-Tetramethyl-1,3,2-dioxaborane (Compound 1) (530 mg, yield: 14%).
方法三：Method three:
氮气保护下，向反应瓶中加入无水氯化锂(4.66g,110mmol)、氯化亚铜(10.89g，110mmol)和干燥的N,N-二甲基甲酰胺(200mL)，室温下搅拌1小时后，依次加入醋酸钾(10.80g，110mmol)、联硼酸频那醇酯(27.93g，110mmol)和环丙基乙炔(1A)(6.61g，100mmol)，加热至40℃继续搅拌5小时，加入饱和食盐水(200mL)搅拌10分钟，抽滤，滤饼用乙酸乙酯(50mL)洗，滤液用乙酸乙酯(150mL×3)萃取，收集的有机层用饱和食盐水(150mL×3)洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚)得到黄色液体状的目标产物2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(11.64g，产率：60.02％)。Under a nitrogen atmosphere, anhydrous lithium chloride (4.66 g, 110 mmol), cuprous chloride (10.89 g, 110 mmol) and dry N,N-dimethylformamide (200 mL) were added to the reaction flask, and stirred at room temperature. After 1 hour, potassium acetate (10.80 g, 110 mmol), pinacol borate (27.93 g, 110 mmol) and cyclopropylacetylene (1A) (6.61 g, 100 mmol) were added in sequence, and the mixture was heated to 40 ° C and stirred for 5 hours. After adding saturated brine (200 mL), the mixture was stirred for 10 minutes, and filtered with suction. The filter cake was washed with ethyl acetate (50 mL), and the filtrate was extracted with ethyl acetate (150 mL×3). The mixture was washed with anhydrous sodium sulfate and filtered, and the filtrate was evaporated to dryness, and the residue was purified by silica gel column chromatography ( petroleum ether) to give the desired product 2-(1-cyclopropylvinyl)-4 as a yellow liquid. 4,5,5-Tetramethyl-1,3,2-dioxaborane (Compound 1) (11.64 g, Yield: 60.02%).
1HNMR(400MHz,CDCl3)：δ5.64(d,1H),δ5.49(d,1H),δ1.54-1.48(m,1H),δ1.26(s,12H)δ0.70-0.65(m,2H),δ0.60-0.57(m,2H)。1H NMR (400MHz, CDCl3): δ 5.64 (d, 1H), δ 5.49 (d, 1H), δ 1.54-1.48 (m, 1H), δ 1.26 (s, 12H) δ 0.70-0.65 ( m, 2H), δ 0.60-0.57 (m, 2H).
实施例2Example 2
[2-(1-环丙乙烯基)-6-异丙基-苯基]N-[(1R)-1-苯乙基]氨基甲酸酯(化合物2)[2-(1-Cyclopropenyl)-6-isopropyl-phenyl]N-[(1R)-1-phenylethyl]carbamate (Compound 2)
[2-(1-cyclopropylvinyl)-6-isopropyl-phenyl]N-[(1R)-1-phenylethyl]carbamat[2-(1-cyclopropylvinyl)-6-isopropyl-phenyl]N-[(1R)-1-phenylethyl]carbamat
Figure PCTCN2016073091-appb-000028
Figure PCTCN2016073091-appb-000028
第一步：2-溴-6-异丙基苯酚(2B)First step: 2-bromo-6-isopropylphenol (2B)
2-Bromo-6-isopropylphenol2-Bromo-6-isopropylphenol
Figure PCTCN2016073091-appb-000029
Figure PCTCN2016073091-appb-000029
向反应瓶中加入2-异丙基-苯酚(2A)(13.619g，100.0mmol)、N,N-二异丙基胺(1.012g，10.0mmol)和二氯甲烷(250 mL)，冰水浴冷却至0℃，分数次加入N-溴代丁二酰亚胺(17.798g，100.0mmol)，加毕撤去冰水浴，自然升至室温搅拌16h，加入硫酸溶液(80mL， 2mol/L)淬灭反应，分离有机相，二氯甲烷萃取(50mL×3)水相，合并有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚)得到无色液体状的目标产物2-溴-6-异丙基苯酚(2B)(17.851g，产率：83％)。To the reaction flask were added 2-isopropyl-phenol (2A) (13.619 g, 100.0 mmol), N,N-diisopropylamine (1.012 g, 10.0 mmol) and dichloromethane (250 mL). After cooling to 0 ° C, N-bromosuccinimide (17.798 g, 100.0 mmol) was added in portions. After the addition, the ice water bath was removed, and the mixture was naturally stirred at room temperature for 16 h, and sulfuric acid solution (80 mL, 2 mol/L), the reaction was quenched, the organic phase was separated, EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (EtOAc) toield
1HNMR(400MHz,CDCl3)：δ7.29(dd,J＝1.6,8.0Hz,1H),δ6.95(dd,J＝1.6,8.0Hz,1H),δ6.77(t,J＝8.0Hz,1H),δ5.56(s,1H),δ3.37-3.24(m,1H),δ1.24(d,J＝7.2Hz,6H)。 1 H NMR (400 MHz, CDCl 3 ): δ 7.29 (dd, J = 1.6, 8.0 Hz, 1H), δ 6.95 (dd, J = 1.6, 8.0 Hz, 1H), δ 6.77 (t, J = 8.0) Hz, 1H), δ 5.56 (s, 1H), δ 3.37-3.24 (m, 1H), δ 1.24 (d, J = 7.2 Hz, 6H).
第二步：(2-溴-6-异丙基-苯基)N-[(1R)-1-苯乙基]氨基甲酸酯(2C)Second step: (2-bromo-6-isopropyl-phenyl) N-[(1R)-1-phenylethyl]carbamate (2C)
(2-bromo-6-isopropyl-phenyl)N-[(1R)-1-phenylethyl]carbamate(2-bromo-6-isopropyl-phenyl)N-[(1R)-1-phenylethyl]carbamate
Figure PCTCN2016073091-appb-000030
Figure PCTCN2016073091-appb-000030
向反应瓶中加入2-溴-6-异丙基苯酚(2B)(172.15g,800mmol)、三乙胺(224mL)和THF(800mL)，氮气置换3次，室温搅拌下滴加[(1R)-1-异氰酸基乙基]苯(141.3g，960mmol)的四氢呋喃(100mL)溶液，约30分钟滴毕，在室温下搅拌4小时。减压浓缩反应液得到白色固体粗产物，向此粗产物加入石油醚(200mL)，室温下搅拌1小时后，用布氏漏斗抽滤，滤饼用石油醚(200mL)洗涤，于50度下烘干后得到白色粉末状固体的目标产物(2-溴-6-异丙基-苯基)N-[(1R)-1-苯乙基]氨基甲酸酯(2C)(285.11g，产率：98.38％)。2-bromo-6-isopropylphenol (2B) (172.15 g, 800 mmol), triethylamine (224 mL) and THF (800 mL) were added to the reaction flask, and the mixture was replaced with nitrogen three times, and the mixture was stirred at room temperature [(1R) A solution of 1-isocyanatoethyl]benzene (141.3 g, 960 mmol) in tetrahydrofuran (100 mL) was added dropwise over 30 minutes and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced vacuol~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ After drying, the title product (2-bromo-6-isopropyl-phenyl)N-[(1R)-1-phenylethyl]carbamate (2C) (285.11 g) was obtained. Rate: 98.38%).
1HNMR(400MHz,CDCl3)：δ7.30-7.21(m,7H),δ7.05(t,1H),δ5.43(s,1H),δ5.01-4.91(m,1H)δ3.12-3.05(m,1H),δ1.59(d,3H),δ1.20(d,3H),δ1.16(d,3H)。 1 H NMR (400 MHz, CDCl 3 ): δ 7.30-7.21 (m, 7H), δ 7.05 (t, 1H), δ 5.43 (s, 1H), δ 5.01-4.91 (m, 1H) δ 3. 12-3.05 (m, 1H), δ 1.59 (d, 3H), δ 1.20 (d, 3H), δ 1.16 (d, 3H).
第三步：[2-(1-环丙乙烯基)-6-异丙基-苯基]N-[(1R)-1-苯乙基]氨基甲酸酯(化合物2)Third step: [2-(1-cyclopropenyl)-6-isopropyl-phenyl]N-[(1R)-1-phenylethyl]carbamate (Compound 2)
[2-(1-cyclopropylvinyl)-6-isopropyl-phenyl]N-[(1R)-1-phenylethyl]carbamate[2-(1-cyclopropylvinyl)-6-isopropyl-phenyl]N-[(1R)-1-phenylethyl]carbamate
Figure PCTCN2016073091-appb-000031
Figure PCTCN2016073091-appb-000031
方法一：method one:
向反应瓶中加入(2-溴-6-异丙基-苯基)N-[(1R)-1-苯乙基]氨基甲酸酯(2C)(64.99g，180mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(34.95g，180mmol)、4M K2CO3溶液(315mL，1260mmol)和甲苯(1500mL)，室温下用水泵抽气15 min后，加入Pd(dppf)Cl2(7.35g，9mmol)，加毕再次用水泵抽气15min后，置于已预热到90℃油浴中搅拌反应9h后停止反应，冷却至室温，反应液用乙酸乙酯(200mL×3)萃取，收集有机层用饱和食盐水(200mL×3)洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯＝10:1)得到黄色液体状的目标产物[2-(1-环丙乙烯基)-6-异丙基-苯基]N-[(1R)-1-苯乙基]氨基甲酸酯(化合物2)(45.71g，产率：72.67％)。(2-Bromo-6-isopropyl-phenyl)N-[(1R)-1-phenylethyl]carbamate (2C) (64.99 g, 180 mmol), 2-(1) -cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (Compound 1) (34.95 g, 180 mmol), 4M K 2 CO 3 solution (315 mL) , 1260mmol) and toluene (1500mL), pumped with water pump for 15 min at room temperature, then add Pd(dppf)Cl 2 (7.35g, 9mmol), after pumping again with water pump for 15min, placed in preheated to 90 After the reaction was stirred for 9 h in an EtOAc EtOAc EtOAc (EtOAc) (EtOAc) The filtrate was concentrated under reduced pressure, and the residue was purified (jjjjjjjjjjj -Phenyl]N-[(1R)-1-phenethyl]carbamate (Compound 2) (45.71 g, yield: 72.67%).
方法二：Method Two:
向反应瓶中加入(2-溴-6-异丙基-苯基)N-[(1R)-1-苯乙基]氨基甲酸酯(2C)(2.17g，6.0mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(1.17g，6.0mmol)、2M K3PO4溶液(12.0mL，24.0mmol)和甲苯(30mL)，室温下用水泵抽气15min后，加入Pd(PPh3)4(1.04g，0.90mmol)，加毕再次用水泵抽气15min后，置于已预热到80℃油浴中搅拌反应7h后停止反应，冷却至室温，反应液用乙酸乙酯(30 mL×3)萃取，收集有机层用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯＝10:1)得到黄色液体状的目标产物[2-(1-环丙乙烯基)-6-异丙基-苯基]N-[(1R)-1-苯乙基]氨基甲酸酯(化合物2)(0.63g，产率：30.12％)。To the reaction flask was added (2-bromo-6-isopropyl-phenyl)N-[(1R)-1-phenethyl]carbamate (2C) (2.17 g, 6.0 mmol), 2- ( 1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (Compound 1) (1.17 g, 6.0 mmol), 2M K 3 PO 4 solution (12.0mL, 24.0mmol) and toluene (30mL), pumped with water pump for 15min at room temperature, then added Pd(PPh 3 ) 4 (1.04g, 0.90mmol), after pumping again with water pump for 15min, placed in the After preheating to 80 ° C in an oil bath, the reaction was stirred for 7 h, the reaction was stopped, and the mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate (30 mL×3), and the organic layer was washed with saturated brine (50 mL×2). The sodium was dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( petroleum ether: ethyl acetate = 10:1) to give the desired product [2-(1-cyclopropenyl) 6-Isopropyl-phenyl]N-[(1R)-1-phenethyl]carbamate (Compound 2) (0.63 g, yield: 30.12%).
方法三：Method three:
向反应瓶中加入(2-溴-6-异丙基-苯基)N-[(1R)-1-苯乙基]氨基甲酸酯(2C)(2.17g，6.0mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(1.17g，6.0mmol)、无水Na2CO3(1.91g，18.0mmol)和甲苯/甲醇(2:1,30mL)，室温下用水泵抽气10min后，加入Pd(PPh3)4(0.27g，0.24mmol)，加毕再次用水泵抽气15min后，置于已预热到90℃油浴中搅拌反应5h后停止反应，冷却至室温，反应液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯＝10:1)得到黄色液体状的目标产物[2-(1-环丙乙烯基)-6-异丙基-苯基]N-[(1R)-1-苯乙基]氨基甲酸酯(化合物2)(0.51g，产率：24.30％)。To the reaction flask was added (2-bromo-6-isopropyl-phenyl)N-[(1R)-1-phenethyl]carbamate (2C) (2.17 g, 6.0 mmol), 2- ( 1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (Compound 1) (1.17 g, 6.0 mmol), anhydrous Na 2 CO 3 (1.91g, 18.0mmol) and toluene/methanol (2:1, 30mL), pumped with water pump for 10min at room temperature, then add Pd(PPh 3 ) 4 (0.27g, 0.24mmol), and pump again with water pump After 15 minutes, the reaction was stirred in an oil bath preheated to 90 ° C for 5 h, the reaction was stopped, the reaction was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( petroleum ether: ethyl acetate = 10:1) The target product [2-(1-cyclopropenyl)-6-isopropyl-phenyl]N-[(1R)-1-phenylethyl]carbamate (Compound 2) was obtained as a yellow liquid. (0.51 g, yield: 24.30%).
方法四：Method four:
向反应瓶中加入(2-溴-6-异丙基-苯基)N-[(1R)-1-苯乙基]氨基甲酸酯(2C)(2.17g，6.0mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(1.17g，6.0mmol)、无水Cs2CO3(5.86g，18.0mmol)和1,4-二氧六环(30mL)，室温下用水泵抽气10min后，加入Pd(PPh3)4(0.35g，0.30mmol)，加毕再次用水泵抽气15min后，置于已预热到90℃油浴中搅拌反应5h后停止反应，冷却至室温，反应液减压浓缩，残留物用硅胶柱色谱分 离提纯(石油醚:乙酸乙酯＝10:1)得到黄色液体状的目标产物[2-(1-环丙乙烯基)-6-异丙基-苯基]N-[(1R)-1-苯乙基]氨基甲酸酯(化合物2)(0.53g，产率：25.27％)。To the reaction flask was added (2-bromo-6-isopropyl-phenyl)N-[(1R)-1-phenethyl]carbamate (2C) (2.17 g, 6.0 mmol), 2- ( 1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (Compound 1) (1.17 g, 6.0 mmol), anhydrous Cs 2 CO 3 (5.86g, 18.0mmol) and 1,4-dioxane (30mL), pumped with water pump for 10min at room temperature, then add Pd(PPh 3 ) 4 (0.35g, 0.30mmol), and pump again with water pump After 15 minutes, the mixture was placed in an oil bath which had been preheated to 90 ° C for 5 hours, and the reaction was stopped. The reaction was cooled to room temperature. The reaction mixture was concentrated under reduced pressure. 1) The target product [2-(1-cyclopropenyl)-6-isopropyl-phenyl]N-[(1R)-1-phenylethyl]carbamate (Compound 2) was obtained as a yellow liquid. (0.53 g, yield: 25.27%).
方法五：Method five:
向反应瓶中加入(2-溴-6-异丙基-苯基)N-[(1R)-1-苯乙基]氨基甲酸酯(2C)(2.17g，6.0mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(1.17g，6.0mmol)、2M Na2CO3溶液(9.0mL，18.0mmol)和THF(18mL)，室温下用水泵抽气10min后，加入PdCl2(PPh3)2(0.11g，0.18mmol)，加毕再次用水泵抽气15min后，升温至回流，反应7h后停止反应，冷却至室温，反应液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯＝10:1)得到黄色液体状的目标产物[2-(1-环丙乙烯基)-6-异丙基-苯基]N-[(1R)-1-苯乙基]氨基甲酸酯(化合物2)(0.43g，产率：20.50％)。To the reaction flask was added (2-bromo-6-isopropyl-phenyl)N-[(1R)-1-phenethyl]carbamate (2C) (2.17 g, 6.0 mmol), 2- ( 1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (Compound 1) (1.17 g, 6.0 mmol), 2M Na 2 CO 3 solution (9.0mL, 18.0mmol) and THF (18mL), pumped with water pump for 10min at room temperature, then added PdCl 2 (PPh 3 ) 2 (0.11g, 0.18mmol), after pumping again with water pump for 15min, then warm up to After refluxing, the reaction was quenched for 7 h, cooled to room temperature, and the mixture was evaporated to dryness. -cyclopropenyl)-6-isopropyl-phenyl]N-[(1R)-1-phenylethyl]carbamate (Compound 2) (0.43 g, yield: 20.50%).
方法六：Method six:
向反应瓶中加入(2-溴-6-异丙基-苯基)N-[(1R)-1-苯乙基]氨基甲酸酯(2C)(2.17g，6.0mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(1.17g，6.0mmol)、2MK3PO4溶液(9.0mL，18.0mmol)和甲苯(18mL)，室温下用水泵抽气10min后，加入P(dOAc)2(0.067g，0.18mmol)和Xantphos(0.21g，0.36mmol)，加毕再次用水泵抽气15min后，置于已预热到90℃油浴中搅拌反应6h后停止反应，冷却至室温，反应液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯＝10:1)得到黄色液体状的目标产物[2-(1-环丙乙烯基)-6-异丙基-苯基]N-[(1R)-1-苯乙基]氨基甲酸酯(化合物2)(0.66g，产率：31.53％)。To the reaction flask was added (2-bromo-6-isopropyl-phenyl)N-[(1R)-1-phenethyl]carbamate (2C) (2.17 g, 6.0 mmol), 2- ( 1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (Compound 1) (1.17 g, 6.0 mmol), 2MK 3 PO 4 solution ( 9.0 mL, 18.0 mmol) and toluene (18 mL) were pumped with a water pump for 10 min at room temperature, then P(dOAc) 2 (0.067 g, 0.18 mmol) and Xantphos (0.21 g, 0.36 mmol) were added. After 15 minutes, the mixture was stirred in an oil bath preheated to 90 ° C for 6 h, and the reaction was stopped. The reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( petroleum ether: ethyl acetate = 10: 1) The target product [2-(1-cyclopropenyl)-6-isopropyl-phenyl]N-[(1R)-1-phenylethyl]carbamate (Compound 2) was obtained as a yellow liquid. (0.66 g, yield: 31.53%).
方法七：Method seven:
向反应瓶中加入(2-溴-6-异丙基-苯基)N-[(1R)-1-苯乙基]氨基甲酸酯(2C)(2.17g，6.0mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(1.17g，6.0mmol)、K3PO4·7H2O(3.05g，9.0mmol)和甲苯(30mL)，室温下用水泵抽气10min后，加入Pd(dppf)Cl2(0.21g，0.30mmol)，加毕再次用水泵抽气15min后，置于已预热到90℃油浴中搅拌反应6h后停止反应，冷却至室温，反应液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯＝10:1)得到黄色液体状的目标产物[2-(1-环丙乙烯基)-6-异丙基-苯基]N-[(1R)-1-苯乙基]氨基甲酸酯(化合物2)(0.38g，产率：18.12％)。To the reaction flask was added (2-bromo-6-isopropyl-phenyl)N-[(1R)-1-phenethyl]carbamate (2C) (2.17 g, 6.0 mmol), 2- ( 1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (Compound 1) (1.17 g, 6.0 mmol), K 3 PO 4 ·7H 2 O (3.05g, 9.0mmol) and toluene (30mL), pumped with water pump for 10min at room temperature, then added Pd (dppf) Cl 2 (0.21g, 0.30mmol), after pumping again with water pump for 15min, set After the reaction was stirred in an oil bath of 90 ° C for 6 h, the reaction was stopped, and the reaction was cooled to room temperature. The reaction mixture was evaporated. [2-(1-Cyclopropenyl)-6-isopropyl-phenyl]N-[(1R)-1-phenylethyl]carbamate (Compound 2) (0.38 g, Yield: 18.12%).
1HNMR(400MHz,CDCl3)：δ7.29-7.05(m,8H),δ5.21(s,1H),δ4.93-4.88(m,3H),δ3.09-3.04(m,1H),δ1.57-1.50(m,4H),δ1.21(d,3H),δ1.17(d,3H),δ0.66-0.64(m,2H)δ0.46-0.44(m,2H)。 1 H NMR (400 MHz, CDCl 3 ): δ 7.29-7.05 (m, 8H), δ 5.21 (s, 1H), δ 4.93-4.88 (m, 3H), δ 3.09-3.04 (m, 1H) , δ1.57-1.50 (m, 4H), δ1.21 (d, 3H), δ 1.17 (d, 3H), δ 0.66-0.64 (m, 2H) δ 0.46-0.44 (m, 2H) .
实施例2-I：2-(1-环丙基乙烯基)-6-异丙基苯酚(化合物2-I)Example 2-I: 2-(1-Cyclopropylvinyl)-6-isopropylphenol (Compound 2-I)
2-(1-cyclopropylvinyl)-6-isopropylphenol2-(1-cyclopropylvinyl)-6-isopropylphenol
Figure PCTCN2016073091-appb-000032
Figure PCTCN2016073091-appb-000032
方法一：method one:
反应瓶中加入2-溴-6-异丙基-苯酚(2B)(7.30g，33.94mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(6.59g，33.94mmol)、碳酸钾溶液(3mol/L，45mL)和甲苯(180mL)，室温下用水泵抽气15分钟后，加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)[PdCl2(dppf)](1.39g，17.03mmol)，加毕再次抽气15分钟后，置于已预热到90℃油浴中搅拌反应，5小时后停止反应，冷却至室温，反应液用乙酸乙酯(50mL×3)萃取，收集的有机层用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚)得到黄色液体状的目标产物2-(1-环丙基乙烯基)-6-异丙基苯酚(化合物2-I)(5.35g，产率：81％)。2-bromo-6-isopropyl-phenol (2B) (7.30 g, 33.94 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl- was added to the reaction flask. 1,3,2-dioxaborane (Compound 1) (6.59 g, 33.94 mmol), potassium carbonate solution (3 mol/L, 45 mL) and toluene (180 mL), pumped at room temperature for 15 minutes, then added 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride [PdCl 2 (dppf)] (1.39 g, 17.03 mmol), after being pumped again for 15 minutes, placed in the pre-prepared The reaction was stirred in an oil bath of 90 ° C. After 5 hours, the reaction was stopped, and the mixture was cooled to room temperature. The mixture was extracted with ethyl acetate (50 mL×3), and the collected organic layer was washed with saturated brine (100 mL) Drying, filtration, and concentrating the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography ( petroleum ether) to give the desired product 2-(1-cyclopropylvinyl)-6-isopropylphenol as a yellow liquid. -I) (5.35 g, yield: 81%).
方法二：Method Two:
向反应瓶中加入2-溴-6-异丙基-苯酚(2B)(215mg，1.0mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(388mg，2.0mmol)、磷酸钾溶液(3.0mL,2mol/L)和1,4-二氧六环(10mL)，室温下用水泵抽气10分钟后，依次加入三叔丁基膦(t-Bu3P)(42mg，0.2mmol)和三(二亚苄基丙酮)二钯[Pd2(dba)3](46mg，0.05mmol)，加毕再次抽气10分钟后，室温搅拌反应20小时后停止反应，加水(10mL)淬灭反应，乙酸乙酯(10mL×3)萃取，收集的有机层用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚)得到黄色液体状的目标产物2-(1-环丙基乙烯基)-6-异丙基苯酚(化合物2-I)(100mg，产率：50％)。To the reaction flask was added 2-bromo-6-isopropyl-phenol (2B) (215 mg, 1.0 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborane (Compound 1) (388 mg, 2.0 mmol), potassium phosphate solution (3.0 mL, 2 mol/L) and 1,4-dioxane (10 mL), water pump at room temperature After pumping for 10 minutes, tri-tert-butylphosphine (t-Bu 3 P) (42 mg, 0.2 mmol) and tris(dibenzylideneacetone) dipalladium [Pd 2 (dba) 3 ] (46 mg, 0.05 mmol) were added in that order. After the mixture was pumped again for 10 minutes, the reaction was stirred at room temperature for 20 hours, the reaction was stopped, the reaction was quenched with water (10 mL), ethyl acetate (10 mL×3) was extracted, and the collected organic layer was washed with brine (30 mL) Drying with anhydrous sodium sulfate, filtration, and concentrating the filtrate under reduced pressure. The residue was purified by silica gel column chromatography ( petroleum ether) to give the desired product 2-(1-cyclopropylvinyl)-6-isopropyl as a yellow liquid. Phenol (Compound 2-I) (100 mg, yield: 50%).
方法三： Method three:
向反应瓶中加入2-溴-6-异丙基-苯酚(2B)(215mg，1.0mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(291mg，1.5mmol)和甲醇/N，N-二甲基甲酰胺(20mL,v/v＝4:1)室温下抽气10分钟后，依次加入碳酸钾(414mg，3.0mmol)和双三苯基磷二氯化钯[Pd(PPh3)2Cl2](35mg，0.05mmol)，加毕再次抽气10分钟后，加热到80℃搅拌，16小时后停止反应，加水(20mL)淬灭反应，乙酸乙酯(20mL×3)萃取，收集有机层用饱和食盐水(30mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚)得到黄色液体状的目标产物2-(1-环丙基乙烯基)-6-异丙基苯酚(化合物2-I)(85mg，产率：42％)。To the reaction flask was added 2-bromo-6-isopropyl-phenol (2B) (215 mg, 1.0 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborane (Compound 1) (291 mg, 1.5 mmol) and methanol/N,N-dimethylformamide (20 mL, v/v = 4:1) were pumped for 10 min at room temperature After that, potassium carbonate (414 mg, 3.0 mmol) and bistriphenylphosphine palladium dichloride [Pd(PPh 3 ) 2 Cl 2 ] (35 mg, 0.05 mmol) were added in that order, and after pumping for another 10 minutes, it was heated to The mixture was stirred at 80 ° C, and the reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography ( petroleum ether) to give the desired product 2-(1-cyclopropylvinyl)-6-isopropylphenol as a yellow liquid. I) (85 mg, yield: 42%).
方法四：Method four:
向反应瓶中加入2-溴-6-异丙基-苯酚(2B)(215mg，1.0mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(388mg，2.0mmol)、碳酸钾溶液(1.3mL,3mol/L)和N,N-二甲基甲酰胺(6.5mL)，室温下抽气10分钟，加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)[Pd(dppf)Cl2](82mg，0.1mmol)，加毕再次抽气10分钟后，加热到90℃搅拌3小时后停止反应，冷却至室温，加入乙酸乙酯(20mL)稀释，水洗(20mL×3)，无水硫酸钠干燥有机相，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚)得到黄色液体状的目标产物2-(1-环丙基乙烯基)-6-异丙基苯酚(化合物2-I)(78mg，产率：39％)。To the reaction flask was added 2-bromo-6-isopropyl-phenol (2B) (215 mg, 1.0 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborane (Compound 1) (388 mg, 2.0 mmol), potassium carbonate solution (1.3 mL, 3 mol/L) and N,N-dimethylformamide (6.5 mL) at room temperature After pumping for 10 minutes, add 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride [Pd(dppf)Cl 2 ] (82 mg, 0.1 mmol), and pump again for 10 minutes. After heating to 90 ° C for 3 hours, the reaction was stopped, cooled to room temperature, diluted with ethyl acetate (20 mL), washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered and evaporated. The product was purified by silica gel column chromatography (chrome ether) to give the desired product 2-(1-cyclopropylvinyl)-6-isopropylphenol (Compound 2-I) (78 mg, yield: 39%) ).
方法五：Method five:
向反应瓶中加入2-溴-6-异丙基-苯酚(2B)(430mg，2.0mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(388mg，2.0mmol)、碳酸钠(1.06g，5.0mmol)，水(5mL)和1,4-二氧六环(5mL)，室温下用水泵抽气10分钟后，加入四(三苯基膦)钯[Pd(PPh3)4](116mg，0.1mmol)，加毕再次泵抽气10分钟，加热至90℃反应5小时，冷却至室温，反应液用乙酸乙酯(15mL×3)萃取，收集有机层用饱和食盐水(30 mL)洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚)得到黄色液体状的目标产物2-(1-环丙基乙烯基)-6-异丙基苯酚(化合物2-I)(79mg，产率：39％)。To the reaction flask was added 2-bromo-6-isopropyl-phenol (2B) (430 mg, 2.0 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborane (Compound 1) (388 mg, 2.0 mmol), sodium carbonate (1.06 g, 5.0 mmol), water (5 mL) and 1,4-dioxane (5 mL), room temperature After pumping for 10 minutes with a water pump, tetrakis(triphenylphosphine)palladium [Pd(PPh 3 ) 4 ] (116 mg, 0.1 mmol) was added, pumped again for 10 minutes, and heated to 90 ° C for 5 hours. The mixture was cooled to room temperature, and the mixture was evaporated and evaporated. The title product 2-(1-cyclopropylvinyl)-6-isopropylphenol (Compound 2-I) (yield: 39%) was obtained from the title product (yield: 39%).
方法六：Method six:
向反应瓶中加入2-溴-6-异丙基-苯酚(2B)(430mg，2.0mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(388mg，2.0mmol)、碳酸钾(4mL，3mol/L)和甲苯(8mL)，室温下用水泵抽气10分钟后，加入Pd(dppf)Cl2(24mg，0.03 mmol)，加毕再次抽气10分钟后，加热至90℃反应5小时，冷却至室温，反应液用乙酸乙酯(15mL×3)萃取，收集有机层用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚)得到黄色液体状的目标产物2-(1-环丙基乙烯基)-6-异丙基苯酚(化合物2-I)(330mg，产率：54％)。To the reaction flask was added 2-bromo-6-isopropyl-phenol (2B) (430 mg, 2.0 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborane (Compound 1) (388 mg, 2.0 mmol), potassium carbonate (4 mL, 3 mol/L) and toluene (8 mL), and pumped for 10 minutes at room temperature, then added Pd ( Dppf)Cl 2 (24 mg, 0.03 mmol), after further pumping for 10 minutes, heating to 90 ° C for 5 hours, cooling to room temperature, extracting the reaction mixture with ethyl acetate (15 mL × 3), collecting the organic layer with saturated The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. 6-isopropylphenol (Compound 2-I) (330 mg, yield: 54%).
方法七：Method seven:
向反应瓶中加入2-溴-6-异丙基-苯酚(2B)(1.291g，6.0mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(1.165g，6.0mmol)、碳酸钾(13mL，4mol/L)和甲苯(39mL)，室温下用水泵抽气10分钟后，加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)[Pd(dppf)Cl2](245mg，0.3mmol)，加毕再次抽气10分钟后，加热至90℃反应5小时，冷却至室温，反应液用乙酸乙酯(30 mL×3)萃取，收集有机层用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯(石油醚)得到黄色液体状的目标产物2-(1-环丙基乙烯基)-6-异丙基苯酚(化合物2-I)(692mg，产率：57％)。To the reaction flask was added 2-bromo-6-isopropyl-phenol (2B) (1.291 g, 6.0 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl -1,3,2-dioxaborane (Compound 1) (1.165 g, 6.0 mmol), potassium carbonate (13 mL, 4 mol/L) and toluene (39 mL), pumped at room temperature for 10 minutes, then added 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride [Pd(dppf)Cl 2 ] (245 mg, 0.3 mmol), after pumping for another 10 minutes, heating to 90 ° C The reaction mixture was stirred for 5 hours, and the mixture was evaporated to dryness. The title product 2-(1-cyclopropylvinyl)-6-isopropylphenol (Compound 2-I) was obtained (yield: 57%). .
1HNMR(400MHz,CDCl3)：δ7.12(dd,1H),δ6.95(dd,1H),δ6.84(t,1H),δ5.67(s,1H),δ5.30(dd,1H),δ5.04(d,1H),δ3.36-3.25(m,1H),δ1.68-1.61(m,1H)δ1.24(d,6H),δ0.80-0.75(m,2H),δ0.54-0.50(m,2H)。 1 H NMR (400 MHz, CDCl 3 ): δ 7.12 (dd, 1H), δ 6.95 (dd, 1H), δ 6.84 (t, 1H), δ 5.67 (s, 1H), δ 5.30 (dd, 1H), δ5.04(d,1H), δ3.36-3.25(m,1H), δ1.68-1.61(m,1H)δ1.24(d,6H),δ0.80-0.75(m, 2H), δ 0.54-0.50 (m, 2H).
实施例3Example 3
(R)-2-(1-环丙基乙基)-6-异丙基(1-苯基乙基)氨基甲酸酯(化合物3)(R)-2-(1-cyclopropylethyl)-6-isopropyl(1-phenylethyl)carbamate (Compound 3)
(R)-2-(1-cyclopropylethyl)-6-isopropylphenyl(1-phenylethyl)carbamate(R)-2-(1-cyclopropylethyl)-6-isopropylphenyl(1-phenylethyl)carbamate
Figure PCTCN2016073091-appb-000033
Figure PCTCN2016073091-appb-000033
Figure PCTCN2016073091-appb-000034
Figure PCTCN2016073091-appb-000034
室温下在200mL的高压反应釜中加入(R)-2-(1-环丙基乙烯基)-6-异丙基(1-苯基乙基)氨基甲酸酯(化合物2)(175mg,0.5mmol)和甲醇(5mL)，然后加入催化剂二(1,5-环辛二烯)四氟硼酸铑(I)(10mg)，加完后将高压釜装置拧紧密封，用钢瓶中的氢气置换3次；充入氢气，高压釜上压力约为10atm，室温下搅拌反应3个小时；减压蒸馏除去甲醇，残留物用柱层析纯化(洗脱剂为石油醚:乙酸乙酯(v/v)＝10:1)，得白色固体(R)-2-(1-环丙基乙基)-6-异丙基(1-苯基乙基)氨基甲酸酯(化合物3,170mg,产率65％)。(R)-2-(1-Cyclopropylvinyl)-6-isopropyl(1-phenylethyl)carbamate (Compound 2) (175 mg, in a 200 mL autoclave at room temperature 0.5 mmol) and methanol (5 mL), then the catalyst bis(1,5-cyclooctadiene) ruthenium (I) tetrafluoroborate (10 mg) was added. After the addition, the autoclave device was tightly sealed and replaced with hydrogen in a cylinder. 3 times; charged with hydrogen, the pressure in the autoclave was about 10 atm, and the reaction was stirred at room temperature for 3 hours; methanol was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent petroleum ether: ethyl acetate (v/) v) = 10:1) gave (R)-2-(1-cyclopropylethyl)-6-isopropyl(1-phenylethyl)carbamate as a white solid (Compound 3, 170 mg, yield Rate 65%).
实施例3-IExample 3-I
2-(1-环丙基乙基)-6-异丙基-苯酚(化合物3-I)2-(1-cyclopropylethyl)-6-isopropyl-phenol (Compound 3-I)
2-(1-cyclopropylethyl)-6-isopropyl-phenol2-(1-cyclopropylethyl)-6-isopropyl-phenol
Figure PCTCN2016073091-appb-000035
Figure PCTCN2016073091-appb-000035
向反应瓶中加入2-(1-环丙基乙烯基)-6-异丙基苯酚(化合物2-I)(5g，24.72mmol)和二氯甲烷(50mL)，搅拌条件下加入三乙基硅烷(4.3g，37.08mmol)，干冰-乙醇浴下滴加三氟乙酸(4.2g，37.08mol)，控制温度小于-30度，滴完后保持此温度反应1小时，反应液依次用水(50mL×1)、饱和碳酸氢钠溶液(50mL×1)洗涤。有机相分出置于另一个反应瓶中，加入四丁基氟化铵三水合物(3.9g，12.36mmol)，室温搅拌1小时，依次用水(20mL×1)、饱和食盐水(20mL×1)洗涤，无水硫酸钠干燥，减压浓缩，残留物用柱层析分离(石油醚/乙酸乙酯(v/v)＝100:1)得到谈黄色油状的2-(1-环丙基乙基)-6-异丙基-苯酚(化合物3)(4.7g，产率：94％)。To the reaction flask was added 2-(1-cyclopropylvinyl)-6-isopropylphenol (Compound 2-I) (5 g, 24.72 mmol) and dichloromethane (50 mL). Silane (4.3 g, 37.08 mmol), trifluoroacetic acid (4.2 g, 37.08 mol) was added dropwise in a dry ice-ethanol bath, and the temperature was controlled to be less than -30 degrees. After the completion of the dropwise addition, the temperature was maintained for 1 hour, and the reaction liquid was sequentially washed with water (50 mL). ×1), a saturated sodium hydrogencarbonate solution (50 mL × 1) was washed. The organic phase was separated and placed in another reaction flask, and tetrabutylammonium fluoride trihydrate (3.9 g, 12.36 mmol) was added, and the mixture was stirred at room temperature for 1 hour, followed by water (20 mL × 1), saturated brine (20 mL × 1) Washed, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl ether / ethyl acetate (v/v) = 100:1) to give 2-(1-cyclopropyl) as a yellow oil. Ethyl)-6-isopropyl-phenol (Compound 3) (4.7 g, yield: 94%).
MS m/z(ESI):203.1(M-1)。 MS m/z (ESI): 203.1 (M-1).
1HNMR(400MHz,CDCl3)：δ7.12(dd，1H)，δ7.07(dd，1H)，6.89(t，1H)，4.91(s,1H),3.20-3.13(m，1H)，2.53-2.46(m，1H)，1.30(d，6H)，1.27(d，3H)，1.08-1.03(m，1H)，0.58-0.56(m，1H)，0.47-0.46(m，1H)，0.22-0.16(m，2H)。 1 H NMR (400 MHz, CDCl 3 ): δ 7.12 (dd, 1H), δ 7.07 (dd, 1H), 6.89 (t, 1H), 4.91 (s, 1H), 3.20-3.13 (m, 1H), 2.53-2.46 (m, 1H), 1.30 (d, 6H), 1.27 (d, 3H), 1.08-1.03 (m, 1H), 0.58-0.56 (m, 1H), 0.47-0.46 (m, 1H), 0.22-0.16 (m, 2H).
实施例5Example 5
1-(1-环丙基乙基)-2-异丙基-2-甲氧基苯(化合物5)1-(1-cyclopropylethyl)-2-isopropyl-2-methoxybenzene (compound 5)
1-(1-cyclopropylethyl)-3-isopropyl-2-methoxybenzene1-(1-cyclopropylethyl)-3-isopropyl-2-methoxybenzene
Figure PCTCN2016073091-appb-000036
Figure PCTCN2016073091-appb-000036
第一步:1-溴-3-异丙基-2甲氧基苯(5B)First step: 1-bromo-3-isopropyl-2-methoxybenzene (5B)
1-bromo-3-isopropyl-2-methoxybenzene1-bromo-3-isopropyl-2-methoxybenzene
Figure PCTCN2016073091-appb-000037
Figure PCTCN2016073091-appb-000037
将2-溴-6-异丙基苯酚(2.04g,9.48mmol)和碳酸钾(3.93g,28.5mmol)加入到20mL乙腈中，氮气保护，50℃反应10分钟；滴加碘甲烷(1mL,16.0mmol)，滴完后升至60℃，反应4个小时；过滤,滤液旋干后，残留物用柱层析纯化(石油醚:乙酸乙酯(v/v)＝20:1),得无色液体状的1-溴-3-异丙基-2甲氧基苯(5B)(2.17g,产率99.9％,)。Add 2-bromo-6-isopropylphenol (2.04 g, 9.48 mmol) and potassium carbonate (3.93 g, 28.5 mmol) to 20 mL of acetonitrile, protect with nitrogen, react at 50 ° C for 10 min; add methyl iodide (1 mL, 16.0 mmol), after the completion of the dropwise addition, the temperature was raised to 60 ° C, and the reaction was carried out for 4 hours; after filtration, the filtrate was evaporated to dryness, and the residue was purified by column chromatography ( petroleum ether: ethyl acetate (v/v) = 20:1). 1-Bromo-3-isopropyl-2-methoxybenzene (5B) (2.17 g, yield 99.9%) as a colorless liquid.
1HNMR(400MHz,CDCl3):δ7.38(dd,1H),7.20(dd,1H),6.96(t,1H),3.83(s,3H),3.32-3.39(m,1H),1.23(d,6H)。 1 HNMR (400MHz, CDCl 3) : δ7.38 (dd, 1H), 7.20 (dd, 1H), 6.96 (t, 1H), 3.83 (s, 3H), 3.32-3.39 (m, 1H), 1.23 ( d, 6H).
第二步:1-(1-环丙基乙烯基)-3-异丙基-2-甲氧基苯(5C)Second step: 1-(1-cyclopropylvinyl)-3-isopropyl-2-methoxybenzene (5C)
1-(1-cyclopropylvinyl)-3-isopropyl-2-methoxybenzene1-(1-cyclopropylvinyl)-3-isopropyl-2-methoxybenzene
Figure PCTCN2016073091-appb-000038
Figure PCTCN2016073091-appb-000038
将1-溴-3-异丙基-2甲氧基苯(5B)(2.06g,9.0mmol)，2-(1-环己基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(1.75g,9.0mmol)和碳酸钾水溶液(10mL,4mol/L)加入到30mL甲苯中，然后加入催化剂[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.367g,0.45mmol)，装好 冷凝管，水泵抽气,置换氮气三次，氮气保护，90℃反应6个小时，旋除溶剂，柱层析(石油醚:乙酸乙酯(v/v)＝100:1-50:1)纯化得1-(1-环丙基乙烯基)-3-异丙基-2-甲氧基苯(5C)(1.10g,产率56.6％)。1-Bromo-3-isopropyl-2-methoxybenzene (5B) (2.06 g, 9.0 mmol), 2-(1-cyclohexylvinyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborane (1.75 g, 9.0 mmol) and potassium carbonate aqueous solution (10 mL, 4 mol/L) were added to 30 mL of toluene, and then the catalyst [1,1'-bis(diphenylphosphine) was added. Base) ferrocene] palladium dichloride (0.367 g, 0.45 mmol), packed Condensate tube, pump pumping, replacing nitrogen three times, nitrogen protection, reaction at 90 ° C for 6 hours, solvent removal, column chromatography (petroleum ether: ethyl acetate (v / v) = 100:1-50:1) purification 1-(1-Cyclopropylvinyl)-3-isopropyl-2-methoxybenzene (5C) (1.10 g, yield 56.6%).
第三步:1-(1-环丙基乙基)-2-异丙基-2-甲氧基苯(化合物5)Third step: 1-(1-cyclopropylethyl)-2-isopropyl-2-methoxybenzene (compound 5)
1-(1-cyclopropylethyl)-3-isopropyl-2-methoxybenzene1-(1-cyclopropylethyl)-3-isopropyl-2-methoxybenzene
Figure PCTCN2016073091-appb-000039
Figure PCTCN2016073091-appb-000039
室温下将1-(1-环丙基乙烯基)-3-异丙基-2-甲氧基苯(5C)(108mg，2.02mmol)和三乙基硅烷(0.47g,4.03mmol)加入到二氯甲烷(10mL)，然后0℃下滴加三氟乙酸(0.46g,4.03mmol)，滴完后氮气球保护，室温搅拌5小时。加入20mL饱和碳酸氢钠溶液淬灭反应，用二氯甲烷萃取(20mL×2)，合并有机相，水洗(20mL×1)，饱和氯化钠洗(20mL×1)，无水硫酸钠干燥10分钟后减压浓缩，浓缩残留物柱层析纯化(石油醚:乙酸乙酯(v/v)＝50:1-10:1)得淡黄色液体1-(1-环丙基乙基)-2-异丙基-2-甲氧基苯(化合物5)(198 mg,产率45％)。1-(1-Cyclopropylvinyl)-3-isopropyl-2-methoxybenzene (5C) (108 mg, 2.02 mmol) and triethylsilane (0.47 g, 4.03 mmol) were added at room temperature Dichloromethane (10 mL) was added dropwise trifluoroacetic acid (0.46 g, 4.03 mmol) at 0 ° C. The reaction was quenched by the addition of 20 mL of EtOAc EtOAc (EtOAc) After a few minutes, it was concentrated under reduced pressure. EtOAcjjjjjjjjj 2-isopropyl-2-methoxybenzene (Compound 5) (198 mg, yield 45%).
1HNMR(400MHz,CDCl3):δ7.19-7.21(m,1H),7.09-7.11(m,2H),3.68(s,3H),3.29-3.36(m,1H),2.42-2.49(m,1H),1.29(d,3H),1.24(d,6H),0.97-1.01(m,1H),0.52-0.58(m,1H),0.34-0.39(m,1H),0.20-0.24(m,1H),0.13-0.17(m,1H)。 1 H NMR (400 MHz, CDCl 3 ): δ 7.19-7.21 (m, 1H), 7.09-7.11 (m, 2H), 3.68 (s, 3H), 3.29-3.36 (m, 1H), 2.42-2.49 (m) , 1H), 1.29 (d, 3H), 1.24 (d, 6H), 0.97-1.01 (m, 1H), 0.52-0.58 (m, 1H), 0.34-0.39 (m, 1H), 0.20-0.24 (m) , 1H), 0.13-0.17 (m, 1H).
实施例6Example 6
2-((R)-1-环丙基乙基)-6-(1-环丙基乙烯基)苯基((S)-1-苯乙基)氨基甲酸酯(化合物6)2-((R)-1-cyclopropylethyl)-6-(1-cyclopropylvinyl)phenyl((S)-1-phenylethyl)carbamate (Compound 6)
2-((R)-1-cyclopropylethyl)-6-(1-cyclopropylvinyl)phenyl((S)-1-phenylethyl)carbamate2-((R)-1-cyclopropylethyl)-6-(1-cyclopropylvinyl)phenyl((S)-1-phenylethyl)carbamate
Figure PCTCN2016073091-appb-000040
Figure PCTCN2016073091-appb-000040
将2-溴-6-((R)-1-环丙基乙基)苯基((S)-1-苯乙基)氨基甲酸酯(6A)(3.2g,8.24mmol)，2-(1-环己基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(3.2g,16.48mmol)和碳酸钾水溶液(10.5ml,4mol/L)加入到50ml甲苯中，然后加入催化剂[1,1'-双(二苯基膦基) 二茂铁]二氯化钯(0.603g,0.824mmol石油醚:乙酸乙酯(v/v))，置换氮气三次，氮气保护，90℃反应5个小时，旋除溶剂，残余物柱层析(石油醚：乙酸乙酯(v/v)＝100:1-50:1)纯化得黄色固体状2-((R)-1-环丙基乙基)-6-(1-环丙基乙烯基)苯基((S)-1-苯乙基)氨基甲酸酯(化合物6)(0.9g,产率29.1％)。2-Bromo-6-((R)-1-cyclopropylethyl)phenyl((S)-1-phenylethyl)carbamate (6A) (3.2 g, 8.24 mmol), 2- (1-cyclohexylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (Compound 1) (3.2 g, 16.48 mmol) and aqueous potassium carbonate (10.5 ml) , 4 mol/L) was added to 50 ml of toluene, and then the catalyst [1,1'-bis(diphenylphosphino) was added. Ferrocene] palladium dichloride (0.603 g, 0.824 mmol petroleum ether: ethyl acetate (v/v)), replacing nitrogen three times, nitrogen protection, reaction at 90 ° C for 5 hours, solvent removal, residue column chromatography (Petroleum ether: ethyl acetate (v/v) = 100:1 - 50:1) purified to give 2-((R)-1-cyclopropylethyl)-6-(1-cyclopropyl) as a yellow solid. Vinyl)phenyl((S)-1-phenylethyl)carbamate (Compound 6) (0.9 g, yield 29.1%).
MS m/z(ESI):376.1[M+H]+。 MS m/z (ESI): 376.1 [M+H] + .

Claims (19)

  1. 一种通式(I)所示的化合物及其立体异构体的制备方法，其特征在于是通过通式(II)化合物及其立体异构体进行还原反应制得；A method for preparing a compound represented by the formula (I) and a stereoisomer thereof, which is obtained by a reduction reaction of a compound of the formula (II) and a stereoisomer thereof;
    Figure PCTCN2016073091-appb-100001
    Figure PCTCN2016073091-appb-100001
    其中，R选自H或者羟基保护基；R1选自甲基、乙基或环丙基；Wherein R is selected from H or a hydroxy protecting group; and R 1 is selected from methyl, ethyl or cyclopropyl;
    n选自1、2或3。n is selected from 1, 2 or 3.
  2. 根据权利要求1所述的制备方法，其中n为1。The production method according to claim 1, wherein n is 1.
  3. 根据权利要求2述的制备方法，其特征在于：The preparation method according to claim 2, characterized in that:
    反应中使用氢气在催化剂作用下催化进行还原反应，或者使用三甲基硅烷+酸、三乙基硅烷+酸、NH2NH2、B2H6+过氧酸、KO2CN＝NCO2K或汉斯酯1,4-二氢吡啶进行还原反应；The reaction uses hydrogen to catalyze the reduction reaction under the action of a catalyst, or uses trimethylsilane + acid, triethylsilane + acid, NH 2 NH 2 , B 2 H 6 + peroxyacid, KO 2 CN=NCO 2 K Or Hans ester 1,4-dihydropyridine for reduction;
    所述催化剂选自负载型金属催化剂或金属配合物，所述金属选自Pt、Pd、Ni、Ru、Ir或Rh；The catalyst is selected from a supported metal catalyst or a metal complex selected from Pt, Pd, Ni, Ru, Ir or Rh;
    所述的酸选自盐酸、硫酸、醋酸、三氟乙酸或对甲苯磺酸；The acid is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or p-toluenesulfonic acid;
    所述的过氧酸选自过氧苯甲酸、m-CPBA或过氧乙酸。The peroxyacid is selected from the group consisting of peroxybenzoic acid, m-CPBA or peracetic acid.
  4. 根据权利要求3所述的制备方法，其特征在于：The preparation method according to claim 3, wherein:
    反应中所使用的溶剂选自水、甲醇、六氟异丙醇、三氟乙醇、乙醇、异丙醇、二氧六环、氯仿、丙酮、乙酸、二甲基亚砜、二氯甲烷、二氯乙烷、四氢呋喃、乙腈、乙酸乙酯、2-甲基四氢呋喃、甲基叔丁基醚、乙醚、N,N-二甲基甲酰胺、苯、甲苯、氟化苯、1,2-二氟苯、对溴氟苯、2,3-二氟溴苯、六氟苯、溴五氟苯、二甲苯、三甲苯、1,3,5-三(三氟甲基)苯或三氟甲基苯中的任一种或任几种任意比例的混合物；The solvent used in the reaction is selected from the group consisting of water, methanol, hexafluoroisopropanol, trifluoroethanol, ethanol, isopropanol, dioxane, chloroform, acetone, acetic acid, dimethyl sulfoxide, dichloromethane, and Ethyl chloride, tetrahydrofuran, acetonitrile, ethyl acetate, 2-methyltetrahydrofuran, methyl tert-butyl ether, diethyl ether, N,N-dimethylformamide, benzene, toluene, fluorinated benzene, 1,2-di Fluorobenzene, p-bromofluorobenzene, 2,3-difluorobromobenzene, hexafluorobenzene, bromopentafluorobenzene, xylene, trimethylbenzene, 1,3,5-tris(trifluoromethyl)benzene or trifluoromethyl Any one or a mixture of any of a number of bases in any ratio;
    所述催化剂选自钯碳、雷尼镍、[Rh(NBD)Cl]2/SL-W012-1、[Rh(NBD)Cl]2/SL-W012-2[Rh(COD)2]O3SCF3/SL-W012-2、[Rh(COD)2]O3SCF3/SL-W012-1、[Rh(NBD)Cl]2/-(-)-1-[(S)-2-二叔丁基磷)二茂铁]乙基二-(4-三氟甲基苯)磷、[Rh(COD)2]O3SCF3/-(-)-1-[(S)-2-二叔丁基磷)二茂铁]乙基二-(4-三氟甲基苯)磷或[Ru(COD)(OAc)2]/-(-)-1-[(S)-2-二叔丁基磷)二茂铁]乙基二-(4-三氟甲基苯)磷。 The catalyst is selected from the group consisting of palladium carbon, Raney nickel, [Rh(NBD)Cl] 2 /SL-W012-1, [Rh(NBD)Cl] 2 /SL-W012-2[Rh(COD) 2 ]O 3 SCF 3 /SL-W012-2, [Rh(COD) 2 ]O 3 SCF 3 /SL-W012-1, [Rh(NBD)Cl] 2 /-(-)-1-[(S)-2- Di-tert-butylphosphine)ferrocene]ethyldi-(4-trifluoromethylphenyl)phosphine, [Rh(COD) 2 ]O 3 SCF 3 /-(-)-1-[(S)-2 -di-tert-butylphosphine)ferrocene]ethyldi-(4-trifluoromethylphenyl)phosphine or [Ru(COD)(OAc) 2 ]/-(-)-1-[(S)-2 -di-tert-butylphosphine)ferrocene]ethylbis-(4-trifluoromethylphenyl)phosphine.
  5. 一种通式(II)所示的化合物及其立体异构体的制备方法，其特征在于是通过通式(III)化合物或通式(III`)化合物与式(IV)化合物及其立体异构体偶联反应制备得到，A method for preparing a compound represented by the formula (II) and a stereoisomer thereof, which is characterized by a compound of the formula (III) or a compound of the formula (III') and a compound of the formula (IV) The structure coupling reaction is prepared,
    Figure PCTCN2016073091-appb-100002
    Figure PCTCN2016073091-appb-100002
    其中，X选自Cl、Br或I；M选自Na、K或Li；Wherein X is selected from Cl, Br or I; M is selected from Na, K or Li;
    R为H或者羟基保护基；R is H or a hydroxy protecting group;
    R1选自甲基、乙基或环丙基；R 1 is selected from methyl, ethyl or cyclopropyl;
    R2、R3、R4各自独立的选自H、OH、F、Cl、Br或者C1-6烷氧基，作为选择，R2和R3可以与其相连的原子一起形成4-10元环，所述环除含有杂原子B外，还含有0至4个选自O、N或S的杂原子，所述的环可以任选被0至4个选自H、C1-6烷基或C1-6烷氧基的取代基所取代；R 2 , R 3 , and R 4 are each independently selected from H, OH, F, Cl, Br or C 1-6 alkoxy. Alternatively, R 2 and R 3 may form 4-10 members together with the atoms to which they are attached. a ring which, in addition to the hetero atom B, contains from 0 to 4 heteroatoms selected from O, N or S, said ring may optionally be from 0 to 4 selected from H, C 1-6 alkane Substituted with a substituent of a C 1-6 alkoxy group;
    n选自1、2或3。n is selected from 1, 2 or 3.
  6. 根据权利要求5所述的制备方法，其特征在于：The preparation method according to claim 5, wherein:
    X选自Br；X is selected from Br;
    式(III)化合物选自
    Figure PCTCN2016073091-appb-100003
    The compound of formula (III) is selected from
    Figure PCTCN2016073091-appb-100003
    式(III`)化合物为
    Figure PCTCN2016073091-appb-100004
    The compound of formula (III`) is
    Figure PCTCN2016073091-appb-100004
  7. 根据权利要求6所述的制备方法，其特征在于：The preparation method according to claim 6, wherein:
    反应在催化剂作用下进行，反应中所使用的催化剂选自负载型金属催化剂或金属配合物，所述的金属选自Pd、Ru、Ir、Rh或Ni；The reaction is carried out under the action of a catalyst, wherein the catalyst used in the reaction is selected from a supported metal catalyst or a metal complex selected from the group consisting of Pd, Ru, Ir, Rh or Ni;
    反应中所使用的溶剂选自甲苯、二氧六环、四氢呋喃、二甲基亚砜、N,N-二甲基甲酰胺、水、甲醇、乙醇、乙二醇二甲醚、二氯乙烷中的任一种或任几种任意比例的混合物； The solvent used in the reaction is selected from the group consisting of toluene, dioxane, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, water, methanol, ethanol, ethylene glycol dimethyl ether, dichloroethane. Any one or any mixture of any ratio;
    所述的反应加入碱性试剂，所述的碱性试剂选自碳酸钠、碳酸氢钠、醋酸钠、磷酸钠、碳酸铯、碳酸钾、碳酸氢钾、醋酸钾、磷酸钾、三乙胺、氟化钾、叔丁基胺、N,N-二异丙基乙胺、三丁胺、吡啶中的任一种或任几种的混合物。The reaction is added with an alkaline reagent selected from the group consisting of sodium carbonate, sodium hydrogencarbonate, sodium acetate, sodium phosphate, cesium carbonate, potassium carbonate, potassium hydrogencarbonate, potassium acetate, potassium phosphate, triethylamine, Any one or a mixture of any of potassium fluoride, tert-butylamine, N,N-diisopropylethylamine, tributylamine, pyridine.
  8. 根据权利要求7所述的制备方法，其特征在于：The preparation method according to claim 7, wherein:
    R为H、S-(1-苯基)乙基氨基羰基或R-(1-苯基)乙基氨基羰基；R is H, S-(1-phenyl)ethylaminocarbonyl or R-(1-phenyl)ethylaminocarbonyl;
    反应中所使用的催化剂选自Pd(OAc)2、Pd(OAc)2/S-Phos、Pd(OAc)2/RuPhos、(PhCN)2PdCl2、Ni(cod)2、NiCl2-diglyme、PdCl2-PEPPSI-iPr、PdCl2/t-Bu3P、PdCl2/(Cy)3P、Pd(dppf)Cl2、Pd(PPh3)4、Pd(PPh3)2Cl2或Pd2(dba)3/t-Bu3P。The catalyst used in the reaction is selected from the group consisting of Pd(OAc) 2 , Pd(OAc) 2 /S-Phos, Pd(OAc) 2 /RuPhos, (PhCN) 2 PdCl 2 , Ni(cod) 2 , NiCl 2 -diglyme, PdCl 2 -PEPPSI-iPr, PdCl 2 /t-Bu 3 P, PdCl 2 /(Cy) 3 P, Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 or Pd 2 (dba) 3 /t-Bu 3 P.
  9. 一种通式(III)或通式(III`)所示的化合物的制备方法，其特征在于：A process for the preparation of a compound of the formula (III) or formula (III'), characterized in that:
    通过1-环烷基乙炔、1-环烷基-1-(三氟甲磺酰氧基)乙烯或1-环烷基-1-卤代乙烯与硼酸或硼酸酯反应制备得到式(III)或通式(III`)化合物；The formula (III) is prepared by reacting 1-cycloalkylacetylene, 1-cycloalkyl-1-(trifluoromethanesulfonyloxy)ethylene or 1-cycloalkyl-1-haloethylene with boric acid or boric acid ester. Or a compound of the formula (III');
    R1、R2、R3、R4、M、n如权利要求5所述。R 1 , R 2 , R 3 , R 4 , M, n are as defined in claim 5.
  10. 根据权利要求9所述的制备方法，其特征在于：The preparation method according to claim 9, wherein:
    所述的硼酸或硼酸酯选自
    Figure PCTCN2016073091-appb-100005
    The boric acid or boric acid ester is selected from
    Figure PCTCN2016073091-appb-100005
    R5选自H、OH、F、Cl、Br、或C1-6烷氧基；R 5 is selected from H, OH, F, Cl, Br, or C 1-6 alkoxy;
    反应中所使用溶剂选自甲苯、二氯甲烷、N,N-二甲基甲酰胺、四氢呋喃、水、甲醇或乙醇中的任一种或任几种任意比例的混合物；The solvent used in the reaction is selected from the group consisting of toluene, dichloromethane, N,N-dimethylformamide, tetrahydrofuran, water, methanol or ethanol, or a mixture of any of them in any ratio;
    所述的反应加入碱性试剂，所述的碱性试剂选自醋酸钾、醋酸钠、叔丁醇钠或叔丁醇钾中的任一种或任几种任意比例的混合物。The reaction is carried out by adding an alkaline agent selected from the group consisting of potassium acetate, sodium acetate, sodium t-butoxide or potassium t-butoxide, or a mixture of any of them in any ratio.
  11. 一种通式(I)所示的化合物及其立体异构体的制备方法，其特征在于：A method for preparing a compound represented by the formula (I) and a stereoisomer thereof, characterized in that:
    Figure PCTCN2016073091-appb-100006
    Figure PCTCN2016073091-appb-100006
    a)通式(V)与硼酸或硼酸酯反应得到通式(III)或通式(III`)化合物；所述的硼酸 或硼酸酯选自
    Figure PCTCN2016073091-appb-100007
    a) reacting a general formula (V) with a boronic acid or a boronic acid ester to obtain a compound of the formula (III) or formula (III'); the boric acid or boric acid ester is selected from the group consisting of
    Figure PCTCN2016073091-appb-100007
    b)在催化剂和碱性试剂作用下，通过通式(III)化合物或通式(III`)与通式(IV)化合物及其立体异构体偶联反应制备得到式(II)化合物及其立体异构体，反应中所使用的催化剂选自Pd(OAc)2、Pd(OAc)2/S-Phos、Pd(OAc)2/RuPhos、(PhCN)2PdCl2、Ni(cod)2、NiCl2-diglyme、PdCl2-PEPPSI-iPr、PdCl2/t-Bu3P、PdCl2/(Cy)3P、Pd(dppf)Cl2、Pd(PPh3)4、Pd(PPh3)2Cl2或Pd2(dba)3/t-Bu3P；b) preparing a compound of the formula (II) by a coupling reaction of a compound of the formula (III) or a compound of the formula (III) with a compound of the formula (IV) and a stereoisomer thereof under the action of a catalyst and an alkaline reagent a stereoisomer, the catalyst used in the reaction is selected from the group consisting of Pd(OAc) 2 , Pd(OAc) 2 /S-Phos, Pd(OAc) 2 /RuPhos, (PhCN) 2 PdCl 2 , Ni(cod) 2 , NiCl 2 -diglyme, PdCl 2 -PEPPSI-iPr, PdCl 2 /t-Bu 3 P, PdCl 2 /(Cy) 3 P, Pd(dppf)Cl 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 or Pd2(dba)3/t-Bu3P;
    c)通过式(II)化合物及其立体异构体在催化剂作用下与氢气还原反应制得式(I)化合物及其立体异构体，或者通过式(II)化合物及其立体异构体与三甲基硅烷+酸、三乙基硅烷+酸、NH2NH2、B2H6+过氧酸、KO2CN＝NCO2K或汉斯酯1,4-二氢吡啶进行还原反应制得式(I)化合物及其立体异构体；c) obtaining a compound of the formula (I) and a stereoisomer thereof by a reaction of a compound of the formula (II) and a stereoisomer thereof with hydrogen under the action of a catalyst, or by a compound of the formula (II) and a stereoisomer thereof Reduction reaction of trimethylsilane+acid, triethylsilane+acid, NH 2 NH 2 , B 2 H 6 +peroxyacid, KO 2 CN=NCO 2 K or Hans ester 1,4-dihydropyridine a compound of the formula (I) and a stereoisomer thereof;
    所述催化剂选自负载型金属催化剂或金属配合物，所述金属选自Pt、Pd、Ni、Ru、Ir或Rh；The catalyst is selected from a supported metal catalyst or a metal complex selected from Pt, Pd, Ni, Ru, Ir or Rh;
    所述的酸选自盐酸、硫酸、醋酸、三氟乙酸或对甲苯磺酸；The acid is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or p-toluenesulfonic acid;
    所述的过氧酸选自过氧苯甲酸、m-CPBA或过氧乙酸；The peroxyacid is selected from the group consisting of peroxybenzoic acid, m-CPBA or peracetic acid;
    X选自Cl、Br或I；X is selected from Cl, Br or I;
    M选自Na、K或Li；M is selected from Na, K or Li;
    R为H或者羟基保护基；R is H or a hydroxy protecting group;
    R1选自甲基、乙基或环丙基；n选自1、2或3；R 1 is selected from methyl, ethyl or cyclopropyl; n is selected from 1, 2 or 3;
    R2和R3各自独立的选自H、OH、F、Cl、Br、或C1-6烷氧基，作为选择，R1和R2可以与其相连的原子一起形成4-10元环，所述环除含有杂原子B外，还含有0至4个选自O、N或S的杂原子，所述的环可以任选被0至4个选自H、C1-6烷基或C1-6烷氧基的取代基所取代；R 2 and R 3 are each independently selected from H, OH, F, Cl, Br, or C 1-6 alkoxy. Alternatively, R 1 and R 2 may form a 4-10 membered ring together with the atom to which they are attached. The ring contains, in addition to the hetero atom B, 0 to 4 hetero atoms selected from O, N or S, and the ring may optionally be 0 to 4 selected from H, C 1-6 alkyl or Substituted by a substituent of a C 1-6 alkoxy group;
    R4为F；R 4 is F;
    R5选自H、OH、F、Cl、Br、或C1-6烷氧基。R 5 is selected from H, OH, F, Cl, Br, or C 1-6 alkoxy.
  12. 根据权利要求11所述的制备方法，其特征在于：The preparation method according to claim 11, wherein:
    a)通式(V)与
    Figure PCTCN2016073091-appb-100008
    反应得到通式(III)通式(III`)化合物；    a) General formula (V) and
    Figure PCTCN2016073091-appb-100008
    The reaction gives a compound of the formula (III) of the formula (III);
    b)反应中所使用的溶剂选自甲苯、甲醇、乙醇、二氧六环、四氢呋喃、N,N-二甲基 甲酰胺或乙二醇二甲醚中的任一种或任几种任意比例的混合物，反应中所使用的碱性试剂选自碳酸钠、碳酸钾、碳酸氢钾、醋酸钾或磷酸钾；b) The solvent used in the reaction is selected from the group consisting of toluene, methanol, ethanol, dioxane, tetrahydrofuran, N,N-dimethyl Any one or a mixture of any of a plurality of formamide or ethylene glycol dimethyl ether, and the alkaline agent used in the reaction is selected from the group consisting of sodium carbonate, potassium carbonate, potassium hydrogencarbonate, potassium acetate or potassium phosphate;
    c)反应中所使用的溶剂选自水、甲醇、六氟异丙醇、三氟乙醇、乙醇、异丙醇、二氧六环、氯仿、丙酮、乙酸、二甲基亚砜、二氯甲烷、二氯乙烷、四氢呋喃、乙腈、乙酸乙酯、甲基四氢呋喃、甲基叔丁基醚、乙醚、N,N-二甲基甲酰胺、苯、甲苯、氟化苯、1,2-二氟苯、对溴氟苯、2,3-二氟溴苯、六氟苯、溴五氟苯、二甲苯、三甲苯、三(三氟甲基)苯或三氟甲基苯中的任一种或任几种任意比例的混合物；所选用的还原试剂为三乙基硅烷+酸；c) The solvent used in the reaction is selected from the group consisting of water, methanol, hexafluoroisopropanol, trifluoroethanol, ethanol, isopropanol, dioxane, chloroform, acetone, acetic acid, dimethyl sulfoxide, dichloromethane , dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, methyltetrahydrofuran, methyl tert-butyl ether, diethyl ether, N,N-dimethylformamide, benzene, toluene, fluorinated benzene, 1,2-di Any of fluorobenzene, p-bromofluorobenzene, 2,3-difluorobromobenzene, hexafluorobenzene, bromopentafluorobenzene, xylene, trimethylbenzene, tris(trifluoromethyl)benzene or trifluoromethylbenzene Or any mixture of any ratio; the selected reducing agent is triethylsilane + acid;
    R为H、S-(1-苯基)乙基氨基羰基或者R-(1-苯基)乙基氨基羰基；R is H, S-(1-phenyl)ethylaminocarbonyl or R-(1-phenyl)ethylaminocarbonyl;
    X选自Br；M选自Na或者K；n为1。X is selected from Br; M is selected from Na or K; n is 1.
  13. 根据权利要求12所述的制备方法，其特征在于：The preparation method according to claim 12, wherein:
    R1为甲基；n为1。R 1 is a methyl group; n is 1.
  14. 一种式(II)所示的化合物及其立体异构体，其中，a compound represented by the formula (II) and a stereoisomer thereof, wherein
    Figure PCTCN2016073091-appb-100009
    Figure PCTCN2016073091-appb-100009
    R选自H或者羟基保护基；R1选自甲基、乙基或环丙基；n选自1、2或3。R is selected from H or a hydroxy protecting group; R 1 is selected from methyl, ethyl or cyclopropyl; and n is selected from 1, 2 or 3.
  15. 根据权利要求14所述的化合物及其立体异构体，其中n为1。The compound according to claim 14 and a stereoisomer thereof, wherein n is 1.
  16. 一种通式(III)所示的化合物，其中，a compound represented by the formula (III), wherein
    Figure PCTCN2016073091-appb-100010
    Figure PCTCN2016073091-appb-100010
    R2和R3各自独立的选自H、OH、F、Cl、Br或C1-6烷氧基，作为选择，R1和R2可以与其相连的原子一起形成4-10元环，所述环除含有杂原子B外，还含有0至4个选自O、N或S的杂原子，所述的环可以任选被0至4个选自H、C1-6烷基或C1-6烷氧基的取代基所取代；n选自1、2或3。R 2 and R 3 are each independently selected from H, OH, F, Cl, Br or C 1-6 alkoxy. Alternatively, R 1 and R 2 may form a 4-10 membered ring together with the atom to which they are attached. The ring contains, in addition to the hetero atom B, 0 to 4 hetero atoms selected from O, N or S, and the ring may optionally be 0 to 4 selected from H, C 1-6 alkyl or C. Substituted by a substituent of the 1-6 alkoxy group; n is selected from 1, 2 or 3.
  17. 一种通式(III`)所示的化合物，其中， a compound represented by the formula (III'), wherein
    Figure PCTCN2016073091-appb-100011
    Figure PCTCN2016073091-appb-100011
    R2和R3的定义如权利要求16所述，R4为F；R 2 and R 3 are as defined in claim 16, R 4 is F;
    M选自Na、K或Li；n选自1、2或3。M is selected from Na, K or Li; n is selected from 1, 2 or 3.
  18. 根据权利要求16所述的化合物，其中通式(III)化合物选自如下结构之一：The compound according to claim 16, wherein the compound of the formula (III) is selected from one of the following structures:
    Figure PCTCN2016073091-appb-100012
    Figure PCTCN2016073091-appb-100012
  19. 根据权利要求17所述的化合物，其中通式(III`)化合物选自：The compound according to claim 17, wherein the compound of the formula (III') is selected from the group consisting of:
    Figure PCTCN2016073091-appb-100013
    Figure PCTCN2016073091-appb-100013
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101151234A (en) * 2005-03-31 2008-03-26 三共农业株式会社 Process for producing cyclopropylphenol derivative
WO2009140275A1 (en) * 2008-05-12 2009-11-19 Pharmacofore, Inc. Analogs of propofol, preparation thereof and use as anesthetics
WO2014180305A1 (en) * 2013-05-09 2014-11-13 四川海思科制药有限公司 Phenol derivative and preparation method and use in medicine thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101151234A (en) * 2005-03-31 2008-03-26 三共农业株式会社 Process for producing cyclopropylphenol derivative
WO2009140275A1 (en) * 2008-05-12 2009-11-19 Pharmacofore, Inc. Analogs of propofol, preparation thereof and use as anesthetics
WO2014180305A1 (en) * 2013-05-09 2014-11-13 四川海思科制药有限公司 Phenol derivative and preparation method and use in medicine thereof

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