CN107108483B - Preparation method and intermediate of 2- [ 1-cycloalkylethyl ] phenol - Google Patents

Preparation method and intermediate of 2- [ 1-cycloalkylethyl ] phenol Download PDF

Info

Publication number
CN107108483B
CN107108483B CN201680003442.9A CN201680003442A CN107108483B CN 107108483 B CN107108483 B CN 107108483B CN 201680003442 A CN201680003442 A CN 201680003442A CN 107108483 B CN107108483 B CN 107108483B
Authority
CN
China
Prior art keywords
compound
acid
reaction
general formula
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201680003442.9A
Other languages
Chinese (zh)
Other versions
CN107108483A (en
Inventor
秦琳琳
王伟
王文晶
刘国亮
任磊
万松林
罗新峰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tibet Haisike Pharmaceutical Co ltd
Original Assignee
Sichuan Haisco Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sichuan Haisco Pharmaceutical Co Ltd filed Critical Sichuan Haisco Pharmaceutical Co Ltd
Publication of CN107108483A publication Critical patent/CN107108483A/en
Application granted granted Critical
Publication of CN107108483B publication Critical patent/CN107108483B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • 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
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07C41/20—Preparation of ethers by reactions not forming ether-oxygen bonds by hydrogenation of carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/21—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a 2- [ 1-cycloalkylethyl group]The preparation method of the phenol derivative, namely the preparation method and the intermediate of the compound shown in the formula (I) and the isomer thereof, has the advantages of short reaction route, cheap and easily obtained raw materials, high yield and the like. The structure of the compound of the general formula (I) is shown as R, R1And n is as defined in the specification.

Description

Preparation method and intermediate of 2- [ 1-cycloalkylethyl ] phenol
Technical Field
The invention relates to a preparation method of 2- [ 1-cycloalkyl ethyl ] phenol and an intermediate thereof.
Background
GABAAReceptors are the major inhibitory neurotransmitter receptors in the central nervous system. GABAAThe receptor is composed of a pentamer of transmembrane polypeptide subunits, with 19 different subunits constituting a variety of different GABA' sAThe receptor subtype. GABAAThe receptor is involved in the pathogenesis and diagnosis and treatment of various diseases such as anesthesia, depression, anxiety, epilepsy, dysmnesia, drug dependence and the like.
WO2014180305 describes a class of phenol derivatives, preparation methods and uses thereof in the central nervous field, and has good GABAAReceptor agonistic activity, some compounds have stronger GABA than commercial propofolAThe agonistic activity, especially some 2- (1-cyclopropylethyl) phenol derivatives (such as 2- (1-cyclopropylethyl) -6-isopropylphenol) and isomers thereof, have shown in animal experiments a greater therapeutic index, a higher safety index, a broader therapeutic window or a corresponding low free concentration of the aqueous phase in the formulation, which is predictive of avoiding pain upon injectionThe composition has good clinical application prospect, and the general structure is as follows:
Figure GPA0000228092730000021
also discloses a preparation method of the 2- [ 1-cycloalkyl ethyl ] phenol derivative, which comprises the following steps:
Figure GPA0000228092730000022
Figure GPA0000228092730000031
the method has long route and harsh reaction, and is not beneficial to industrial production.
The invention aims to solve the defects and provide a novel preparation method which is short in route and easy to react.
Disclosure of Invention
The invention provides a method for preparing a 2- (1-cycloalkylethyl) phenol derivative.
The invention provides a method for preparing a 2- (1-cycloalkylvinyl) phenol derivative.
The invention provides a preparation method of a compound shown in a general formula (I) and a stereoisomer thereof, wherein the compound is prepared by reduction reaction of a compound shown in a general formula (II) and a stereoisomer thereof,
Figure GPA0000228092730000032
wherein R is selected from H or a hydroxy protecting group; r1Selected from methyl, ethyl or cyclopropyl; n is selected from 1,2 or 3.
In a preferred embodiment of the present invention, the present invention relates to a method for preparing a compound represented by the general formula (I) and a stereoisomer thereof, wherein n is 1.
In a preferred embodiment of the present invention, a method for preparing a compound represented by the general formula (I) and a stereoisomer thereof is provided, wherein the compound represented by the general formula (II)Catalyzing hydrogen to perform reduction reaction under the action of a catalyst, or using trimethylsilane + acid, triethylsilane + acid and NH2NH2、B2H6+ Peroxyacid, KO2CN＝NCO2K or hanster 1, 4-dihydropyridine is subjected to reduction reaction to prepare a compound shown in the formula (I); the catalyst is selected from a supported metal catalyst or a metal complex, and the metal is selected from Pt, Pd, Ni, Ru, Ir or Rh; the acid is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or p-toluenesulfonic acid; the peroxy acid is selected from peroxybenzoic acid, m-CPBA or peroxyacetic acid.
In a preferred embodiment of the present invention, the compound represented by the general formula (I) and the stereoisomer thereof are prepared by a reduction reaction of the compound represented by the general formula (II) and the stereoisomer thereof using a reducing agent of hydrogen and a catalyst selected from a supported metal catalyst or a metal complex, wherein the metal is selected from Pt, Pd, Ni, Ru, Ir or Rh; or the reducing agent is selected from trimethylsilane + acid, triethylsilane + acid, NH2NH2、B2H6+ Peroxyacid, KO2CN＝NCO2K or hanster 1, 4-dihydropyridine; the acid is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or p-toluenesulfonic acid; the peroxy acid is selected from peroxybenzoic acid, m-CPBA or peroxyacetic acid; the solvent used is selected from any one or a mixture of any several 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-dimethylformamide, benzene, toluene, fluorinated benzene, 1, 2-difluorobenzene, p-bromofluorobenzene, 2, 3-difluorobromobenzene, hexafluorobenzene, bromopentafluorobenzene, xylene, trimethylbenzene, tris (trifluoromethyl) benzene or trifluoromethylbenzene.
In a preferred embodiment of the present invention, there is provided a process for producing a compound represented by the general formula (I) or a stereoisomer thereof, which comprises reducing a compound represented by the general formula (II) or a stereoisomer thereof with hydrogen as a reducing agentThe catalyst used is selected from palladium on carbon, Raney nickel, [ 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-di-tert-butylphosphino) ferrocene]Ethyl bis- (4-trifluoromethylphenyl) phosphonium, [ Rh (COD) ]2]O3SCF3(-) -1- [ (S) -2-di-tert-butylphosphino) ferrocene]Ethyl bis- (4-trifluoromethylbenzene) phosphorus or [ Ru (COD) (OAc)2](-) -1- [ (S) -2-di-tert-butylphosphino) ferrocene]Ethyl bis- (4-trifluoromethylphenyl) phosphonium; the solvent used is selected from any one or mixture of any several 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-dimethylformamide, benzene, toluene, fluorinated benzene, 1, 2-difluorobenzene, p-bromofluorobenzene, 2, 3-difluorobromobenzene, hexafluorobenzene, bromopentafluorobenzene, xylene, trimethylbenzene, 1,3, 5-tri (trifluoromethyl) benzene or trifluoromethyl benzene.
The invention provides a preparation method of a compound shown in a formula (II) and a stereoisomer thereof, wherein the compound is prepared by coupling reaction of a general formula (III) or a general formula (III') with a general formula (IV) and the stereoisomer thereof,
Figure GPA0000228092730000051
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;
R1selected from methyl, ethyl or cyclopropyl; n is selected from 1,2 or 3;
R2、R3、R4each independently selected from H, OH, F, Cl, Br or C1-6An alkoxy group; alternatively, R2And R3May be taken together with the atoms to which they are attached to form a 4-10 membered ring containing, in addition to heteroatom B, 0 to 4 heteroatoms selected from O, N or S, andsaid ring may optionally be substituted by 0 to 4 substituents selected from H, C1-6Alkyl or C1-6Substituted by a substituent of alkoxy;
n is selected from 1,2 or 3.
The invention preferably relates to a preparation method of the compound shown in the formula (II) and the stereoisomer thereof, which is characterized in that the compound is prepared by the coupling reaction of the general formula (III) or the general formula (III') with the compound shown in the general formula (IV) and the stereoisomer thereof, wherein
X is selected from Br;
the compound of formula (III) is selected from
Figure GPA0000228092730000052
The compound of the formula (III') is
Figure GPA0000228092730000053
In a preferred embodiment of the present invention, the compound represented by formula (II) and the stereoisomer thereof are prepared by coupling reaction of a compound represented by general formula (III) or general formula (III'):
x is selected from Br;
r is H or a hydroxy protecting group, preferably H, S- (1-phenyl) ethylaminocarbonyl or R- (1-phenyl) ethylaminocarbonyl;
the compound of formula (III) is selected from
Figure GPA0000228092730000061
The compound of the formula (III') is
Figure GPA0000228092730000062
The reaction is carried out under the action of a catalyst, the catalyst used in the reaction is selected from a supported metal catalyst or a metal complex, and the metal is selected from Pd, Ru, Ir, Rh or Ni; the catalyst is preferably: the ligands of the metal complex are respectively and independently selected from Phos, PhCN, COD, diglyme, PEPSI-iPr and t-Bu3P、(Cy)3P、dppf、PPh3Dba, OAc; the catalyst is further preferably 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)2Cl2Or Pd2(dba)3/t-Bu3P, more preferably Pd (dppf) Cl2；
The solvent used in the reaction is selected from any one or a mixture of any several of toluene, dioxane, tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide, water, methanol, ethanol, ethylene glycol dimethyl ether and dichloroethane, preferably any one or a mixture of any several of toluene, methanol, ethanol, dioxane, tetrahydrofuran, N-dimethylformamide or ethylene glycol dimethyl ether;
and adding an alkaline reagent into the reaction, wherein the alkaline reagent is selected from any one or a mixture of any more of sodium carbonate, sodium bicarbonate, sodium acetate, sodium phosphate, cesium carbonate, potassium bicarbonate, potassium acetate, potassium phosphate, triethylamine, potassium fluoride, tert-butylamine, N-diisopropylethylamine, tributylamine and pyridine, and preferably the sodium carbonate, the potassium bicarbonate, the potassium acetate or the potassium phosphate.
The invention provides a method for preparing a compound shown in a general formula (III) or a general formula (III'), wherein
Figure GPA0000228092730000063
Preparing a compound of a general formula (III) or a general formula (III') through reaction of 1-naphthenic acetylene, 1-naphthenic base-1- (trifluoromethanesulfonyloxy) ethylene or 1-naphthenic base-1-halogenated ethylene and boric acid or boric acid ester;
R1、R2、R3、R4m, n are as described above.
The invention provides a method for preparing a compound shown in a general formula (III) or a general formula (III'), wherein
The boric acid or boric acid ester is selected from
Figure GPA0000228092730000071
R5Selected from H, OH, F, Cl, Br, or C1-6An alkoxy group;
the solvent used in the reaction is any one or a mixture of any several of toluene, dichloromethane, N-dimethylformamide, tetrahydrofuran, water, methanol or ethanol in any proportion;
and adding an alkaline reagent into the reaction, wherein the alkaline reagent is selected from any one of potassium acetate, sodium tert-butoxide or potassium tert-butoxide or a mixture of any several of the potassium acetate, the sodium tert-butoxide or the potassium tert-butoxide in any proportion.
The invention provides a compound shown in a general formula (I) and a preparation method of a stereoisomer thereof, wherein
Figure GPA0000228092730000072
a) Reacting the general formula (V) with boric acid or boric acid ester to obtain a compound of a general formula (III) or a general formula (III'); the boric acid or boric acid ester is selected from
Figure GPA0000228092730000073
b) Under the action of a catalyst and an alkaline reagent, a compound of a general formula (III) or a compound of a general formula (III') and a compound of a formula (IV) and a stereoisomer thereof are subjected to coupling reaction to prepare a compound of a formula (II) and the stereoisomer thereof, the catalyst used in the reaction is selected from a supported metal catalyst or a metal complex, the metal is selected from Pd, Ru, Ir, Rh or Ni, and the ligands of the metal complex are respectively and independently selected from Phos, PhCN, COD, diglyme, PEPSI-iPr and t-Bu3P、(Cy)3P、dppf、PPh3Dba, OAc; the catalyst is preferably 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)2Cl2Or Pd2(dba)3/t-Bu3P, more preferably Pd (dppf) Cl2；
c) The compound of formula (I) and the stereoisomer thereof are prepared by the reduction reaction of the compound of formula (II) and the stereoisomer thereof with hydrogen under the action of a catalyst, or the compound of formula (II) and the stereoisomer thereof with trimethylsilane + acid, triethylsilane + acid and NH2NH2、B2H6+ Peroxyacid, KO2CN＝NCO2K or hanster 1, 4-dihydropyridine is subjected to reduction reaction to prepare a compound shown in the formula (I) and a stereoisomer thereof;
the catalyst is selected from a supported metal catalyst or a metal complex, and the metal is selected from Pt, Pd, Ni, Ru, Ir or Rh; preferably palladium carbon, raney nickel;
the acid is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or p-toluenesulfonic acid;
said peroxy acid is selected from peroxybenzoic acid, m-CPBA or peroxyacetic acid
X is selected from Cl, Br or I, preferably Br; m is selected from Na, K or Li, preferably K;
r is H or a hydroxy protecting group, preferably H, S- (1-phenyl) ethylaminocarbonyl or R- (1-phenyl) ethylaminocarbonyl;
R1selected from methyl, ethyl or cyclopropyl, preferably methyl; n is selected from 1,2 or 3, n is preferably 1;
R2and R3Each independently selected from H, OH, F, Cl, Br, or C1-6An alkoxy group; alternatively, R1And R2Can be taken together with the atoms to which they are attached to form a 4-to 10-membered, preferably a 5-or 6-membered ring, which ring contains, in addition to the heteroatom B, 0 to 4 heteroatoms selected from O, N or S, and which ring can optionally be substituted by 0 to 4 heteroatoms selected from H, C1-6Alkyl or C1-6Substituent of alkoxyGeneration;
R4is F;
R5selected from H, OH, F, Cl, Br, or C1-6Alkoxy, preferably H, methoxy, ethoxy, propoxy or isopropoxy.
In a preferred embodiment of the present invention, a method for producing a compound represented by the general formula (I) and a stereoisomer thereof, wherein:
a) general formula (V) and
Figure GPA0000228092730000081
reacting to obtain a compound of a general formula (III) or a general formula (III');
b) the solvent used in the reaction is any one or a mixture of any several of toluene, methanol, ethanol, dioxane, tetrahydrofuran, N-dimethylformamide or ethylene glycol dimethyl ether in any proportion, and the alkaline reagent used in the reaction is selected from sodium carbonate, potassium bicarbonate, potassium acetate or potassium phosphate;
c) the solvent used in the reaction is selected from any one or a mixture of any proportion 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-dimethylformamide, benzene, toluene, fluorinated benzene, 1, 2-difluorobenzene, p-bromofluorobenzene, 2, 3-difluorobromobenzene, hexafluorobenzene, bromopentafluorobenzene, xylene, trimethylbenzene, 1,3, 5-tris (trifluoromethyl) benzene or trifluoromethylbenzene; the selected reduction reagent is triethyl silicane plus acid,
the catalyst is selected from a supported metal catalyst or a metal complex, and the metal is selected from Pt, Pd, Ni, Ru, Ir or Rh; preferably palladium carbon, raney nickel;
r is H, S- (1-phenyl) ethylaminocarbonyl or R- (1-phenyl) ethylaminocarbonyl;
x is selected from Br; m is selected from Na or K; n is selected from 1.
The invention provides a compound shown as a formula (II) and a stereoisomer thereof, wherein
Figure GPA0000228092730000091
R is selected from H or a hydroxy protecting group, preferably R- (1-phenyl) ethylaminocarbonyl; r1Selected from methyl, ethyl or cyclopropyl, preferably methyl; n is selected from 1,2 or 3, n preferably being 1.
The invention provides a compound shown as a formula (III), wherein
Figure GPA0000228092730000092
R2And R3Each independently selected from H, OH, F, Cl, Br or C1-6Alkoxy, alternatively, R1And R2Can be taken together with the atoms to which they are attached to form a 4-10 membered ring containing from 0 to 4 heteroatoms selected from O, N or S in addition to heteroatom B, which ring can optionally be substituted with from 0 to 4 heteroatoms selected from H, C1-6Alkyl or C1-6Substituted by a substituent of alkoxy;
n is selected from 1,2 or 3; preferably n is 1.
The invention provides a compound shown as a formula (III'), wherein
Figure GPA0000228092730000093
R1And R2As defined above, R4Is F;
m is selected from Na, K or Li, preferably K; n is selected from 1,2 or 3, preferably 1.
The compounds of formula (III) provided by the present invention are selected from, but not limited to, one of the following structures:
Figure GPA0000228092730000094
the compounds of formula (III') provided by the present invention are selected from, but not limited to, the following structures:
Figure GPA0000228092730000095
the hydroxyl protecting group is selected from alkyl ether protecting group, ester protecting group or silicon ether protecting group, and the hydroxyl protecting group includes but is not limited to methyl, benzyl, p-methoxybenzyl, trityl, tert-butyl, methoxy methyl ether, methoxyethoxymethyl, tetrahydrofuryl, 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.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
When the compound of the general formula exists in a chiral center, the compound of the general formula can be a racemate or an optical isomer except for a clear mark.
When the present invention relates to a compound substituted with a plurality of substituents, each substituent may be the same or different.
When the present invention relates to a compound containing a plurality of hetero atoms, the hetero atoms may be the same or different.
The elemental carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention all include their isotopes, and the elemental carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally further replaced by 1 to 5 of their corresponding isotopes, wherein isotopes of carbon include12C、13C and14c, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), isotopes of oxygen including16O、17O and18isotopes of O, sulfur including32S、33S、34S and36isotopes of S, nitrogen include14N and15isotopes of N, F19Isotopes of F, chlorine including35Cl and37cl, isotopes of bromine including79Br and81Br。
the hydroxyl protecting group is selected from alkyl ether protecting group, ester protecting group or silicon ether protecting group, and the hydroxyl protecting group includes but is not limited to methyl, benzyl, p-methoxybenzyl, trityl, tert-butyl, methoxy methyl ether, methoxyethoxymethyl, tetrahydrofuryl, 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;
the alkyl ether protecting group may 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;
the ester protecting group may be removed under basic conditions, including but not limited to sodium methoxide, potassium carbonate, potassium hydroxide, sodium hydroxide, lithium aluminum hydride, pyridine, or ammonia;
the silicon ether protecting group can be removed under the conditions of hydrogen fluoride, tetrabutyl ammonium fluoride and the like; "Complex," also known as a complex, refers to a compound containing a coordination unit. Complex molecules or ions formed by the coordinative bonding of a central atom or ion to several ligand molecules or ions are often referred to as coordination units.
"Metal complex" means that the coordination unit is composed of a metal and a ligand, and when a 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-valent compounds of Co, Ni, Ru, Pd, Ir, or Rh; non-limiting examples of the ligand include 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-O-methoxyphenyl)3P (O-P-methoxyphenyl)3Pyridine, n-Bu3P、t-Bu3P、(MeO)3P、AsPh3、P(OEt)3. The metal complexes may contain, in addition to the coordination units, simple ions selected from Cl, or may be absent-、BF4 -、PF6 -、CF3SO3 -、B(C6F5)4 -、B(C6H5)4 -、Al(OC(CF3)3)4 -Or [ B [3, 5- (CF)3)2C6H3]4]-. Non-limiting examples of metal complexes include 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)3RhCl, ((4R, 5R) - (+) -O- [ 1-benzyl-1- (5-methyl-2-phenyl-4, 5-dihydrooxazol-4-yl) -2-phenylethyl](dicyclohexylphosphine sulfite) (1, 5-COD) Iridium (I) tetrakis (3, 5-bis (trifluoromethyl) phenylboronate, (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 or from Pd (OAc)2、PdCl2With AsPh3、n-Bu3P、(MeO)3P、Ph2P(CH2)2PPh2(dppe)、Ph2P(CH2)3PPh2(dppp) in the presence of a catalyst system.
The "supported catalyst" is prepared by supporting catalytic active components on the surface of a carrier, and commonly used carriers include alumina carriers, silica gel carriers, activated carbon carriers and certain natural products such as pumice, diatomite and the like.
"supported metal catalyst" refers to a supported catalyst whose catalytically active component is a metal selected from the group consisting of transition metals, non-limiting examples including but not limited to Co, Ni, Ru, Pd, Ir, or Rh; non-limiting examples of supported metal catalysts include, but are not limited to, palladium on carbon, raney nickel, and the like.
Detailed Description
The technical solutions of the present invention are described in detail below with reference to the drawings and the embodiments, but the scope of the present invention includes but is not limited thereto.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), deuterated acetonitrile (CD)3CN), internal standard Tetramethylsilane (TMS).
MS was measured by Agilent 6120B (ESI) and Agilent 6120B (APCI).
HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6 mm).
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.20 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Tatan technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical, Shaoshan far chemical technology, and Bailingwei technology.
(Ph3P)3RhCl: tris (triphenylphosphine) rhodium chloride
(Ph3P)3RuClH: tris (triphenylphosphine) ruthenium chlorohydrate
(Ph3P)3IrH: tris (triphenylphosphine) iridium hydride
(R)-Ru(OAc)2BINAP: diacetic acid [ (R) - (+) -2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl group]Ruthenium (II)
[(Ph)3P]3RuCl2: tris (triphenylphosphine) ruthenium dichloride
[(Ph)3P]3Ru(CO)H2: tris (triphenylphosphine) carbonyldihydroruthenium (III)
PdCl2: palladium dichloride
Pd(OAc)2: palladium diacetate
PdCl2(PPh3)2: tris (triphenylphosphine) palladium dichloride
Pd(PPh3)4: tetrakis (triphenylphosphine) palladium
PdCl2(dppf): 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride
Pd(dba)2: tris (dibenzylideneacetone) dipalladium
(dppp)NiCl2: 1, 3-bis (diphenylphosphino) propane nickel chloride
[Rh(NBD)Cl]2: chloronorbornadiene rhodium dimer
SL-W012-1: s- (-) -1- [ (S) -2-di-t-butylphosphino) ferrocene ] ethyl-2- [2- (diphenylphosphino) benzene ]
SL-W012-2: r- (-) -1- [ (S) -2-di-t-butylphosphino) ferrocene ] ethyl-2- [2- (diphenylphosphino) benzene ]
SL-J011-1: r- (-) -1- [ (S) -2-di-tert-butylphosphino) ferrocene ] ethylbis- (4-trifluoromethylphenyl) phosphine
[Rh(COD)2]O3SCF3: bis (1, 5-cyclooctadiene) -rhodium trifluoromethanesulfonate
[Ru(COD)(OAc)2]: (1, 5-cyclooctadiene) -acetic acid ruthenium salt
Pd(OAc)2(ii) S-Phos: palladium acetate/2-dicyclohexylphosphine-2 ', 6 ' -dimethoxy-1, 1 ' -biphenyl
m-CPBA: meta-chloroperoxybenzoic acid
(PhCN)2PdCl2: bis (cyanophenyl) palladium dichloride
Ni(cod)2: bis- (1, 5-cyclooctadiene) nickel
NiCl2-diglyme: diethylene glycol dimethyl ether nickel dichloride
PdCl2-PEPPSI-iPr: ([1, 3-bis (2, 6-diisopropylbenzene) imidazole-2-ylidene)](3-Chloropyridine) Palladium dichloride
PdCl2/t-Bu3P: palladium dichloride/tri-tert-butylphosphine
PdCl2/(Cy)3P: palladium dichloride/tricyclohexylphosphorus
Pd(dppf)Cl2: [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride
Pd(PPh3)4: tetrakis (triphenylphosphine) palladium
Pd(PPh3)2Cl2: bis (triphenylphosphine) palladium dichloride
Pd2(dba)3/t-Bu3P: tris (dibenzylideneacetone) dipalladium/tri-tert-butylphosphine
Example 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-dioxaborolane
Figure GPA0000228092730000131
Under nitrogen protection, anhydrous lithium chloride (4.66g, 110mmol), cuprous chloride (10.89g, 110mmol) and dry N, N-dimethylformamide (300mL) were added to a reaction flask, and after stirring at room temperature for 1 hour, potassium acetate (10.80g, 110mmol), pinacol diboron ester (27.93g, 110mmol) and cyclopropylacetylene (1A) (6.61g, 100mmol) were added in this order, stirring was continued at room temperature for 20 hours, saturated saline (200mL) was added and stirred for 10 minutes, suction filtration was performed, the cake was washed with ethyl acetate (50mL), the filtrate was extracted with ethyl acetate (150 mL. times.3), the collected organic layer was washed with saturated saline (150 mL. times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain the objective product 2- (1-cyclopropylvinyl) -4 as a yellow liquid, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (Compound 1) (10.80g, yield: 55.67%).
The second method comprises the following steps:
adding anhydrous tetrahydrofuran (30mL) into a two-neck flask under the protection of nitrogen, replacing nitrogen for 10min by a water pump, dropwise adding diisobutylaluminum hydride (DIBAL-H) (the concentration in toluene is 1.5M, 17.3mL and 26.0mmol), cooling to 0 ℃ in an ice-water bath after adding, dropwise adding cyclopropylacetylene (1A) (1.322g and 20.0mmol), heating to room temperature and stirring for 2 hours, cooling to 0 ℃, adding isopropanol pinacol borate (11.116g and 60.0mmol), heating to 80 ℃ and stirring for 4 hours after adding, cooling to room temperature, adding water (30mL) and stirring for 30min, extracting with ethyl acetate (30mL multiplied by 2), combining organic phases and drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, separating and purifying the residue by silica gel column chromatography (petroleum ether) to obtain the target product 2- (1-cyclopropylvinyl) -4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (compound 1) (530mg, yield: 14%).
The third method comprises the following steps:
under nitrogen protection, anhydrous lithium chloride (4.66g, 110mmol), cuprous chloride (10.89g, 110mmol) and dry N, N-dimethylformamide (200mL) were added to a reaction flask, and after stirring at room temperature for 1 hour, potassium acetate (10.80g, 110mmol), pinacol diboron ester (27.93g, 110mmol) and cyclopropylacetylene (1A) (6.61g, 100mmol) were added in this order, heating was continued at 40 ℃ for 5 hours, saturated saline (200mL) was added and stirred for 10 minutes, suction filtration was performed, the cake was washed with ethyl acetate (50mL), the filtrate was extracted with ethyl acetate (150 mL. times.3), the collected organic layer was washed with saturated saline (150 mL. times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain the objective product 2- (1-cyclopropylvinyl) -4 as a yellow liquid, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (compound 1) (11.64g, 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)。
Example 2
[2- (1-Cyclopropylethenyl) -6-isopropyl-phenyl ] N- [ (1R) -1-phenylethyl ] carbamate (Compound 2)
[2-(1-cyclopropylvinyl)-6-isopropyl-phenyl]N-[(1R)-1-phenylethyl]carbamat
Figure GPA0000228092730000141
The first step is as follows: 2-bromo-6-isopropylphenol (2B)
2-Bromo-6-isopropylphenol
Figure GPA0000228092730000142
2-isopropyl-phenol (2A) (13.619g, 100.0mmol), N-diisopropylamine (1.012g, 10.0mmol) and dichloromethane (250mL) were added to a reaction flask, an ice-water bath was cooled to 0 deg.C, N-bromosuccinimide (17.798g, 100.0mmol) was added several times, the ice-water bath was removed after the addition, the mixture was naturally warmed to room temperature and stirred for 16 hours, a sulfuric acid solution (80mL, 2mol/L) was added to quench the reaction, the organic phase was separated, dichloromethane was extracted (50 mL. times.3) to obtain an aqueous phase, the combined organic phases were washed with a saturated saline solution (200mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain 2-bromo-6-isopropylphenol (2B) as a colorless liquid as the objective product (17.851g, yield: 83%).
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)。
The second step is that: (2-bromo-6-isopropyl-phenyl) N- [ (1R) -1-phenylethyl ] carbamate (2C)
(2-bromo-6-isopropyl-phenyl)N-[(1R)-1-phenylethyl]carbamate
Figure GPA0000228092730000151
2-bromo-6-isopropylphenol (2B) (172.15g, 800mmol), triethylamine (224mL) and THF (800mL) were added to the reaction flask, the mixture was purged with nitrogen 3 times, and a solution of [ (1R) -1-isocyanatoethyl ] benzene (141.3g, 960mmol) in tetrahydrofuran (100mL) was added dropwise with stirring at room temperature, and after dropping for about 30 minutes, the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give a crude product as a white solid, to which petroleum ether (200mL) was added and, after stirring at room temperature for 1 hour, it was filtered with a Buchner funnel under suction, and the filter cake was washed with petroleum ether (200mL) and dried at 50 ℃ to give the objective product (2-bromo-6-isopropyl-phenyl) N- [ (1R) -1-phenylethyl ] carbamate (2C) (285.11g, yield: 98.38%) as a white powdery solid.
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)。
The third step: [2- (1-Cyclopropylethenyl) -6-isopropyl-phenyl ] N- [ (1R) -1-phenylethyl ] carbamate (Compound 2)
[2-(1-cyclopropylvinyl)-6-isopropyl-phenyl]N-[(1R)-1-phenylethyl]carbamate
Figure GPA0000228092730000152
The method comprises the following steps:
to the reaction flask was added (2-bromo-6-isopropyl-phenyl) N- [ (1R) -1-phenylethyl]Carbamate (2C) (64.99g, 180mmol), 2- (1-cyclopropylvinyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (Compound 1) (34.95g, 180mmol), 4M K2CO3The solution (315mL, 1260mmol) and toluene (1500mL) were pumped down at room temperature for 15min, followed by addition of Pd (dppf) Cl2(7.35g, 9mmol), pumping off again for 15min after the addition, placing in oil bath preheated to 90 ℃ and stirring for reaction for 9h to stop the reaction, cooling to room temperature, extracting the reaction solution with ethyl acetate (200mL × 3), collecting the organic layer, washing with saturated saline (200mL × 3), and removing waterDrying over sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the residue by silica gel column chromatography (petroleum ether: ethyl acetate: 10: 1) to obtain the desired product [2- (1-cyclopropylvinyl) -6-isopropyl-phenyl ] -phenyl ester as a yellow liquid]N- [ (1R) -1-phenylethyl group]Carbamate (Compound 2) (45.71g, yield: 72.67%).
The second method comprises the following steps:
to the reaction flask was added (2-bromo-6-isopropyl-phenyl) N- [ (1R) -1-phenylethyl]Carbamate (2C) (2.17g, 6.0mmol), 2- (1-cyclopropylvinyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (Compound 1) (1.17g, 6.0mmol), 2M K3PO4The solution (12.0mL, 24.0mmol) and toluene (30mL) were pumped down at room temperature for 15min, after which Pd (PPh) was added3)4(1.04g, 0.90mmol), after the addition, pumping off again for 15min with a water pump, placing in an oil bath preheated to 80 ℃ for stirring reaction for 7h to stop the reaction, cooling to room temperature, extracting the reaction solution with ethyl acetate (30 mL. times.3), collecting the organic layer, washing with saturated saline (50 mL. times.2), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the residue by silica gel column chromatography (petroleum ether: ethyl acetate: 10: 1) to obtain the target product [2- (1-cyclopropylvinyl) -6-isopropyl-phenyl ] as a yellow liquid]N- [ (1R) -1-phenylethyl group]Carbamate (Compound 2) (0.63g, yield: 30.12%).
The third method comprises the following steps:
to the reaction flask was added (2-bromo-6-isopropyl-phenyl) N- [ (1R) -1-phenylethyl]Carbamate (2C) (2.17g, 6.0mmol), 2- (1-cyclopropylvinyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (Compound 1) (1.17g, 6.0mmol), anhydrous Na2CO3(1.91g, 18.0mmol) and toluene/methanol (2: 1, 30mL) were pumped at room temperature for 10min, followed by addition of Pd (PPh)3)4(0.27g, 0.24mmol), pumping off again for 15min after the addition, placing in oil bath preheated to 90 ℃ for stirring reaction for 5h to stop the reaction, cooling to room temperature, concentrating the reaction solution under reduced pressure, separating and purifying the residue by silica gel column chromatography (petroleum ether: ethyl acetate: 10: 1) to obtain the target product [2- (1-cyclopropylvinyl) -6-isopropyl-phenyl ] as yellow liquid]N- [ (1R) -1-phenylethyl group]Carbamate ester(s) ((s))Compound 2) (0.51g, yield: 24.30%).
The method four comprises the following steps:
to the reaction flask was added (2-bromo-6-isopropyl-phenyl) N- [ (1R) -1-phenylethyl]Carbamate (2C) (2.17g, 6.0mmol), 2- (1-cyclopropylvinyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (Compound 1) (1.17g, 6.0mmol), anhydrous Cs2CO3(5.86g, 18.0mmol) and 1, 4-dioxane (30mL) were pumped at room temperature for 10min, followed by addition of Pd (PPh)3)4(0.35g, 0.30mmol), pumping off again for 15min after the addition, placing in oil bath preheated to 90 ℃ for stirring reaction for 5h to stop the reaction, cooling to room temperature, concentrating the reaction solution under reduced pressure, separating and purifying the residue by silica gel column chromatography (petroleum ether: ethyl acetate: 10: 1) to obtain the target product [2- (1-cyclopropylvinyl) -6-isopropyl-phenyl ] as yellow liquid]N- [ (1R) -1-phenylethyl group]Carbamate (Compound 2) (0.53g, yield: 25.27%).
The method five comprises the following steps:
to the reaction flask was added (2-bromo-6-isopropyl-phenyl) N- [ (1R) -1-phenylethyl]Carbamate (2C) (2.17g, 6.0mmol), 2- (1-cyclopropylvinyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (Compound 1) (1.17g, 6.0mmol), 2M Na2CO3The solution (9.0mL, 18.0mmol) and THF (18mL) were pumped down at room temperature for 10min, after which PdCl was added2(PPh3)2(0.11g, 0.18mmol), extracting with water again for 15min after the addition, heating to reflux, stopping the reaction after 7h, cooling to room temperature, concentrating the reaction solution under reduced pressure, and separating and purifying the residue with silica gel column chromatography (petroleum ether: ethyl acetate: 10: 1) to obtain the target product [2- (1-cyclopropylvinyl) -6-isopropyl-phenyl ] as a yellow liquid]N- [ (1R) -1-phenylethyl group]Carbamate (Compound 2) (0.43g, yield: 20.50%).
The method six:
to the reaction flask was added (2-bromo-6-isopropyl-phenyl) N- [ (1R) -1-phenylethyl]Carbamate (2C) (2.17g, 6.0mmol), 2- (1-cyclopropylvinyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (Compound 1) (1.17g, 6.0mmol), 2M K3PO4Solution (9.0 m)L, 18.0mmol) and toluene (18mL) were pumped down at room temperature for 10min, then P (dOAc) was added2(0.067g, 0.18mmol) and Xantphos (0.21g, 0.36mmol), pumping for 15min, placing in oil bath preheated to 90 ℃, stirring for reaction for 6h, stopping reaction, cooling to room temperature, concentrating the reaction solution under reduced pressure, and separating and purifying the residue by silica gel column chromatography (petroleum ether: ethyl acetate: 10: 1) to obtain the target product [2- (1-cyclopropylvinyl) -6-isopropyl-phenyl ] as yellow liquid]N- [ (1R) -1-phenylethyl group]Carbamate (Compound 2) (0.66g, yield: 31.53%).
The method comprises the following steps:
to the reaction flask was added (2-bromo-6-isopropyl-phenyl) N- [ (1R) -1-phenylethyl]Carbamate (2C) (2.17g, 6.0mmol), 2- (1-cyclopropylvinyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (Compound 1) (1.17g, 6.0mmol), K3PO4·7H2O (3.05g, 9.0mmol) and toluene (30mL) were pumped at room temperature for 10min, and Pd (dppf) Cl was added2(0.21g, 0.30mmol), pumping off again for 15min after the addition, placing in oil bath preheated to 90 ℃ for stirring reaction for 6h to stop the reaction, cooling to room temperature, concentrating the reaction solution under reduced pressure, separating and purifying the residue by silica gel column chromatography (petroleum ether: ethyl acetate: 10: 1) to obtain the target product [2- (1-cyclopropylvinyl) -6-isopropyl-phenyl ] as yellow liquid]N- [ (1R) -1-phenylethyl group]Carbamate (Compound 2) (0.38g, 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)。
Example 2-I: 2- (1-Cyclopropylvinyl) -6-isopropylphenol (Compound 2-I)
2-(1-cyclopropylvinyl)-6-isopropylphenol
Figure GPA0000228092730000181
The method comprises the following steps:
reaction of2-bromo-6-isopropyl-phenol (2B) (7.30g, 33.94mmol), 2- (1-cyclopropylvinyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (compound 1) (6.59g, 33.94mmol), a potassium carbonate solution (3mol/L, 45mL) and toluene (180mL) were charged to a flask, and after 15 minutes of suction with a water pump at room temperature, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) [ PdCl (II) ] was added2(dppf)](1.39g, 17.03mmol), after the addition of which air was again removed for 15 minutes, the reaction mixture was placed in an oil bath preheated to 90 ℃ and stirred, after 5 hours the reaction was stopped, cooled to room temperature, the reaction mixture was extracted with ethyl acetate (50 mL. times.3), the collected organic layer was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, 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 (compound 2-I) (5.35g, yield: 81%) as a yellow liquid.
The second method comprises the following steps:
2-bromo-6-isopropyl-phenol (2B) (215mg, 1.0mmol), 2- (1-cyclopropylvinyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (Compound 1) (388mg, 2.0mmol), a potassium phosphate solution (3.0mL, 2mol/L) and 1, 4-dioxane (10mL) were charged into a reaction flask, and after evacuating with a water pump at room temperature for 10 minutes, tri-tert-butylphosphine (t-Bu) was added in this order3P) (42mg, 0.2mmol) and tris (dibenzylideneacetone) dipalladium [ Pd2(dba)3](46mg, 0.05mmol), after the addition was again evacuated for 10 minutes, the reaction was stopped after stirring at room temperature for 20 hours, the reaction was quenched with water (10mL), extracted with ethyl acetate (10 mL. times.3), the collected organic layer was washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, 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 (compound 2-I) as a yellow liquid (100mg, yield: 50%).
The third method comprises the following steps:
to a reaction flask were added 2-bromo-6-isopropyl-phenol (2B) (215mg, 1.0mmol), 2- (1-cyclopropylvinyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (compound 1) (291mg, 1.5mmol), and methanol/N, N-dimethylformamide (20mL, v/v ═ 4: 1) and the mixture was evacuated at room temperature for 10 minutesThereafter, potassium carbonate (414mg, 3.0mmol) and bis (triphenylphosphine) palladium dichloride [ Pd (PPh) were added successively3)2Cl2](35mg, 0.05mmol), after the addition of the reaction solution and further extraction of air for 10 minutes, the reaction solution was heated to 80 ℃ and stirred, after 16 hours the reaction was stopped, water (20mL) was added to quench the reaction, ethyl acetate (20 mL. times.3) was extracted, the collected organic layer was washed with saturated brine (30 mL. times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain the objective 2- (1-cyclopropylvinyl) -6-isopropylphenol (compound 2-I) as a yellow liquid (85mg, yield: 42%).
The method four comprises the following steps:
to a reaction flask were added 2-bromo-6-isopropyl-phenol (2B) (215mg, 1.0mmol), 2- (1-cyclopropylvinyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (compound 1) (388mg, 2.0mmol), potassium carbonate solution (1.3mL, 3mol/L) and N, N-dimethylformamide (6.5mL), and evacuated at room temperature for 10 minutes, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) [ Pd (dppf) Cl ] was added2](82mg, 0.1mmol), after the addition was again evacuated for 10 minutes, the reaction was stopped after heating to 90 ℃ and stirring for 3 hours, cooled to room temperature, diluted with ethyl acetate (20mL), washed with water (20 mL. times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, 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 (compound 2-I) as a yellow liquid (78mg, yield: 39%).
The method five comprises the following steps:
2-bromo-6-isopropyl-phenol (2B) (430mg, 2.0mmol), 2- (1-cyclopropylvinyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (Compound 1) (388mg, 2.0mmol), sodium carbonate (1.06g, 5.0mmol), water (5mL) and 1, 4-dioxane (5mL) were added to a reaction flask, and after 10 minutes of pumping with a water pump at room temperature, tetrakis (triphenylphosphine) palladium [ Pd (PPh)3)4](116mg, 0.1mmol), pumping again for 10min after the addition, heating to 90 deg.C for reaction for 5 hr, cooling to room temperature, extracting the reaction solution with ethyl acetate (15 mL. times.3), collecting the organic layer, washing with saturated brine (30mL), drying over anhydrous sodium sulfate, filtering, and separatingThe filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give the objective 2- (1-cyclopropylvinyl) -6-isopropylphenol (compound 2-I) as a yellow liquid (79mg, yield: 39%).
The method six:
2-bromo-6-isopropyl-phenol (2B) (430mg, 2.0mmol), 2- (1-cyclopropylvinyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (Compound 1) (388mg, 2.0mmol), potassium carbonate (4mL, 3mol/L) and toluene (8mL) were charged into a reaction flask, and after 10 minutes of suction with a water pump at room temperature, Pd (dppf) Cl was added2(24mg, 0.03mmol), after the addition of which air was again withdrawn for 10 minutes, the mixture was heated to 90 ℃ to react for 5 hours, cooled to room temperature, the reaction solution was extracted with ethyl acetate (15 mL. times.3), the collected organic layer was washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, 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 (compound 2-I) as a yellow liquid (330mg, yield: 54%).
The method comprises the following steps:
2-bromo-6-isopropyl-phenol (2B) (1.291g, 6.0mmol), 2- (1-cyclopropylvinyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (Compound 1) (1.165g, 6.0mmol), potassium carbonate (13mL, 4mol/L) and toluene (39mL) were added to a reaction flask, and after 10 minutes of pump evacuation at room temperature, 1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) [ Pd (dppf) Cl ] was added2](245mg, 0.3mmol), after the addition of which air was again withdrawn for 10 minutes, the reaction mixture was heated to 90 ℃ for 5 hours, cooled to room temperature, extracted with ethyl acetate (30 mL. times.3), the collected organic layer was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, 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 (compound 2-I) as a yellow liquid (692mg, 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)。
Example 3
(R) -2- (1-Cyclopropylethyl) -6-isopropyl (1-phenylethyl) carbamate (Compound 3)
(R)-2-(1-cyclopropylethyl)-6-isopropylphenyl(1-phenylethyl)carbamate
Figure GPA0000228092730000201
Figure GPA0000228092730000211
(R) -2- (1-Cyclopropylvinyl) -6-isopropyl (1-phenylethyl) carbamate (compound 2) (175mg, 0.5mmol) and methanol (5mL) were added to a 200mL autoclave at room temperature, followed by the addition of the catalyst bis (1, 5-cyclooctadiene) rhodium (I) tetrafluoroborate (10mg), after which the autoclave apparatus was screwed tight and sealed and replaced with hydrogen in a steel cylinder 3 times; filling hydrogen into the autoclave, wherein the upper pressure of the autoclave is about 10atm, and stirring and reacting the mixture for 3 hours at room temperature; methanol was removed by distillation under the reduced pressure, and the residue was purified by column chromatography (eluent petroleum ether: ethyl acetate (v/v) ═ 10: 1) to give (R) -2- (1-cyclopropylethyl) -6-isopropyl (1-phenylethyl) carbamate (compound 3, 170mg, yield 65%) as a white solid.
Example 3-I
2- (1-Cyclopropylethyl) -6-isopropyl-phenol (Compound 3-I)
2-(1-cyclopropylethyl)-6-isopropyl-phenol
Figure GPA0000228092730000212
2- (1-Cyclopropylvinyl) -6-isopropylphenol (Compound 2-I) (5g, 24.72mmol) and methylene chloride (50mL) were charged into a reaction flask, triethylsilane (4.3g, 37.08mmol) was added with stirring, trifluoroacetic acid (4.2g, 37.08mol) was added dropwise into a dry ice-ethanol bath, the temperature was controlled to be less than-30 ℃ and the reaction was maintained at this temperature for 1 hour after completion of the addition, and the reaction solution was washed with water (50 mL. times.1) and a saturated sodium bicarbonate solution (50 mL. times.1) in this order. The organic phase was separated and placed in another reaction flask, tetrabutylammonium fluoride trihydrate (3.9g, 12.36mmol) was added, stirred at room temperature for 1 hour, washed successively with water (20mL × 1), saturated brine (20mL × 1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 100: 1) to give 2- (1-cyclopropylethyl) -6-isopropyl-phenol (compound 3) (4.7g, yield: 94%) as a yellow oil.
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)。
Example 5
1- (1-Cyclopropylethyl) -2-isopropyl-2-methoxybenzene (Compound 5)
1-(1-cyclopropylethyl)-3-isopropyl-2-methoxybenzene
Figure GPA0000228092730000221
The first step is as follows: 1-bromo-3-isopropyl-2-methoxybenzene (5B)
1-bromo-3-isopropyl-2-methoxybenzene
Figure GPA0000228092730000222
Adding 2-bromo-6-isopropylphenol (2.04g, 9.48mmol) and potassium carbonate (3.93g, 28.5mmol) into 20mL of acetonitrile, and reacting at 50 ℃ for 10 minutes under the protection of nitrogen; dropwise adding methyl iodide (1mL, 16.0mmol), heating to 60 ℃ after dropwise adding, and reacting for 4 hours; after filtration and spin-drying of the filtrate, the residue was purified by column chromatography (petroleum ether: ethyl acetate (v/v) ═ 20: 1) to give 1-bromo-3-isopropyl-2-methoxybenzene (5B) (2.17g, 99.9% yield) 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)。
The second step is that: 1- (1-Cyclopropylvinyl) -3-isopropyl-2-methoxybenzene (5C)
1-(1-cyclopropylvinyl)-3-isopropyl-2-methoxybenzene
Figure GPA0000228092730000223
1-bromo-3-isopropyl-2-methoxybenzene (5B) (2.06g, 9.0mmol), 2- (1-cyclohexylvinyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (1.75g, 9.0mmol) and an aqueous potassium carbonate solution (10mL, 4mol/L) were added to 30mL of toluene, followed by addition of a catalyst [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (0.367g, 0.45mmol), a condenser tube was installed, a water pump was used to pump off the gas, nitrogen was replaced three times, nitrogen was protected, reaction was carried out at 90 ℃ for 6 hours, the solvent was removed by rotation, column chromatography (petroleum ether: ethyl acetate (v/v): 100: 1-50: 1) was carried out to purify 1- (1-cyclopropylvinyl) -3-isopropyl-2-methoxybenzene (5C) (1.10g, yield 56.6%).
The third step: 1- (1-Cyclopropylethyl) -2-isopropyl-2-methoxybenzene (Compound 5)
1-(1-cyclopropylethyl)-3-isopropyl-2-methoxybenzene
Figure GPA0000228092730000231
1- (1-Cyclopropylvinyl) -3-isopropyl-2-methoxybenzene (5C) (108mg, 2.02mmol) and triethylsilane (0.47g, 4.03mmol) were added to dichloromethane (10mL) at room temperature, and trifluoroacetic acid (0.46g, 4.03mmol) was added dropwise at 0 deg.C, and after dropping, the mixture was stirred at room temperature for 5 hours under a nitrogen balloon. The reaction was quenched by addition of 20mL of saturated sodium bicarbonate solution, extracted with dichloromethane (20mL × 2), the organic phases were combined, washed with water (20mL × 1), washed with saturated sodium chloride (20mL × 1), dried over anhydrous sodium sulfate for 10 minutes, concentrated under reduced pressure, and the concentrated residue was purified by column chromatography (petroleum ether: ethyl acetate (v/v) ═ 50: 1 to 10: 1) to give 1- (1-cyclopropylethyl) -2-isopropyl-2-methoxybenzene (compound 5) as a pale yellow liquid (198mg, 45% yield).
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)。
Example 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)carbamate
Figure GPA0000228092730000232
2-bromo-6- ((R) -1-cyclopropylethyl) phenyl ((S) -1-phenylethyl) carbamate (6A) (3.2g, 8.24mmol), 2- (1-cyclohexylvinyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane (compound 1) (3.2g, 16.48mmol) and an aqueous potassium carbonate solution (10.5ml, 4mol/L) were added to 50ml of toluene, followed by addition of a catalyst [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (0.603g, 0.824mmol of petroleum ether: ethyl acetate (v/v)), nitrogen was replaced three times, nitrogen protection was performed at 90 ℃ for 5 hours, the solvent was removed by spinning, and the residue was purified by column chromatography (petroleum ether: ethyl acetate (v/v) ═ 100: 1 to 50: 1) to give a yellow 2- ((R) -1-cyclic solid Propylethyl) -6- (1-cyclopropylvinyl) phenyl ((S) -1-phenylethyl) carbamate (compound 6) (0.9g, 29.1% yield).
MS m/z(ESI)：376.1[M+H]+。

Claims (15)

1. A preparation method of a compound shown in a general formula (I) and a stereoisomer thereof is characterized in that the compound is prepared by reduction reaction of a compound shown in a general formula (II) and a stereoisomer thereof;
Figure FDA0002263872070000011
wherein R isSelected from H or a hydroxy protecting group; r1Selected from methyl, ethyl or cyclopropyl;
n is selected from 1,2 or 3.
2. The method of claim 1, wherein n is 1.
3. The method of claim 2, wherein:
in the reaction, hydrogen is used for catalyzing and carrying out reduction reaction under the action of a catalyst, or trimethylsilane + acid, triethylsilane + acid and NH are used2NH2、B2H6+ Peroxyacid, KO2CN＝NCO2K or hanster 1, 4-dihydropyridine is subjected to reduction reaction;
the catalyst is selected from a supported metal catalyst or a metal complex, and the metal is selected from Pt, Pd, Ni, Ru, Ir or Rh;
the acid is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or p-toluenesulfonic acid;
the peroxy acid is selected from peroxybenzoic acid, m-CPBA or peroxyacetic acid.
4. The production method according to claim 3, characterized in that:
the solvent used in the reaction is selected from any one or a mixture of any proportion 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-dimethylformamide, benzene, toluene, fluorinated benzene, 1, 2-difluorobenzene, p-bromofluorobenzene, 2, 3-difluorobromobenzene, hexafluorobenzene, bromopentafluorobenzene, xylene, trimethylbenzene, 1,3, 5-tris (trifluoromethyl) benzene or trifluoromethylbenzene;
the catalyst is selected from palladium carbon, Raney nickel, [ 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-di-tert-butylphosphino) ferrocene]Ethyl bis- (4-trifluoromethylphenyl) phosphonium, [ Rh (COD) ]2]O3SCF3(-) -1- [ (S) -2-di-tert-butylphosphino) ferrocene]Ethyl bis- (4-trifluoromethylbenzene) phosphorus or [ Ru (COD) (OAc)2](-) -1- [ (S) -2-di-tert-butylphosphino) ferrocene]Ethyl bis- (4-trifluoromethylphenyl) phosphonium.
5. A method for preparing a compound shown in a general formula (II) and a stereoisomer thereof is characterized in that the compound is prepared by coupling reaction of a compound shown in a general formula (III) or a compound shown in a general formula (III'), a compound shown in a formula (IV) and a stereoisomer thereof,
Figure FDA0002263872070000021
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;
R1selected from methyl, ethyl or cyclopropyl;
R2、R3、R4each independently selected from H, OH, F, Cl, Br or C1-6Alkoxy, alternatively, R2And R3Can be taken together with the atoms to which they are attached to form a 4-10 membered ring containing from 0 to 4 heteroatoms selected from O, N or S in addition to heteroatom B, which ring can optionally be substituted with from 0 to 4 heteroatoms selected from H, C1-6Alkyl or C1-6Substituted by a substituent of alkoxy;
n is selected from 1,2 or 3.
6. The method of claim 5, wherein:
x is selected from Br;
the compound of formula (III) is selected from
Figure FDA0002263872070000022
The compound of the formula (III') is
Figure FDA0002263872070000023
7. The method of claim 6, wherein:
the reaction is carried out under the action of a catalyst, the catalyst used in the reaction is selected from a supported metal catalyst or a metal complex, and the metal is selected from Pd, Ru, Ir, Rh or Ni;
the solvent used in the reaction is any one or a mixture of any several of toluene, dioxane, tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide, water, methanol, ethanol, ethylene glycol dimethyl ether and dichloroethane in any proportion;
and adding an alkaline reagent into the reaction, wherein the alkaline reagent is selected from any one or a mixture of any more of sodium carbonate, sodium bicarbonate, sodium acetate, sodium phosphate, cesium carbonate, potassium bicarbonate, potassium acetate, potassium phosphate, triethylamine, potassium fluoride, tert-butylamine, N-diisopropylethylamine, tributylamine and pyridine.
8. The method of claim 7, wherein:
r is H, S- (1-phenyl) ethylaminocarbonyl or R- (1-phenyl) ethylaminocarbonyl;
the catalyst used in the reaction is selected from 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)2Cl2Or Pd2(dba)3/t-Bu3P。
9. The method according to any one of claims 5 to 8, wherein the method for producing the compound represented by the general formula (III) or the general formula (III') comprises:
preparing a compound of formula (III) or a general formula (III') through the reaction of 1-naphthenic acetylene, 1-naphthenic base-1- (trifluoromethanesulfonyloxy) ethylene or 1-naphthenic base-1-halogenated ethylene and boric acid or boric acid ester;
R1、R2、R3、R4m, n is as claimed in claim 5.
10. The method of claim 9, wherein:
the boric acid or boric acid ester is selected from
Figure FDA0002263872070000031
R5Selected from H, OH, F, Cl, Br, or C1-6An alkoxy group;
the solvent used in the reaction is any one or a mixture of any several of toluene, dichloromethane, N-dimethylformamide, tetrahydrofuran, water, methanol or ethanol in any proportion;
and adding an alkaline reagent into the reaction, wherein the alkaline reagent is selected from any one of potassium acetate, sodium tert-butoxide or potassium tert-butoxide or a mixture of any several of the potassium acetate, the sodium tert-butoxide or the potassium tert-butoxide in any proportion.
11. A method for preparing a compound shown in a general formula (I) and a stereoisomer thereof, which is characterized in that:
Figure FDA0002263872070000041
a) reacting the general formula (V) with boric acid or boric acid ester to obtain a compound of a general formula (III) or a general formula (III'); the boric acid or boric acid ester is selected from
Figure FDA0002263872070000042
b) Under the action of catalyst and alkaline reagent, the compound of formula (II) is prepared by coupling reaction of the compound of formula (III) or the compound of formula (III') and the compound of formula (IV) and stereoisomer thereofA compound and a stereoisomer thereof, wherein the catalyst used in the reaction is selected from 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)2Cl2Or Pd2(dba)3/t-Bu 3P;
c) the compound of formula (I) and the stereoisomer thereof are prepared by the reduction reaction of the compound of formula (II) and the stereoisomer thereof with hydrogen under the action of a catalyst, or the compound of formula (II) and the stereoisomer thereof with trimethylsilane + acid, triethylsilane + acid and NH2NH2、B2H6+ Peroxyacid, KO2CN＝NCO2K or hanster 1, 4-dihydropyridine is subjected to reduction reaction to prepare a compound shown in the formula (I) and a stereoisomer thereof;
the catalyst is selected from a supported metal catalyst or a metal complex, and the metal is selected from Pt, Pd, Ni, Ru, Ir or Rh;
the acid is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or p-toluenesulfonic acid;
the peroxy acid is selected from peroxybenzoic acid, m-CPBA or peroxyacetic acid;
x is selected from Cl, Br or I;
m is selected from Na, K or Li;
r is H or a hydroxy protecting group;
R1selected from methyl, ethyl or cyclopropyl; n is selected from 1,2 or 3;
R2and R3Each independently selected from H, OH, F, Cl, Br, or C1-6Alkoxy, alternatively, R1And R2Can be taken together with the atoms to which they are attached to form a 4-10 membered ring containing from 0 to 4 heteroatoms selected from O, N or S in addition to heteroatom B, which ring can optionally be substituted with from 0 to 4 heteroatoms selected from H, C1-6Alkyl or C1-6Substituted by a substituent of alkoxy;
R4is F;
R5selected from H, OH, F, Cl, Br, or C1-6An alkoxy group.
12. The method of claim 11, wherein:
a) general formula (V) and
Figure FDA0002263872070000051
reacting to obtain a compound of a general formula (III) and a general formula (III');
b) the solvent used in the reaction is any one or a mixture of any several of toluene, methanol, ethanol, dioxane, tetrahydrofuran, N-dimethylformamide or ethylene glycol dimethyl ether in any proportion, and the alkaline reagent used in the reaction is selected from sodium carbonate, potassium bicarbonate, potassium acetate or potassium phosphate;
c) the solvent used in the reaction is selected from any one or a mixture of any several 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-dimethylformamide, benzene, toluene, fluorinated benzene, 1, 2-difluorobenzene, p-bromofluorobenzene, 2, 3-difluorobromobenzene, hexafluorobenzene, bromopentafluorobenzene, xylene, trimethylbenzene, tri (trifluoromethyl) benzene or trifluoromethylbenzene; the selected reducing agent is triethylsilane and acid;
r is H, S- (1-phenyl) ethylaminocarbonyl or R- (1-phenyl) ethylaminocarbonyl;
x is selected from Br; m is selected from Na or K; n is 1.
13. The method of manufacturing according to claim 12, wherein:
R1is methyl; n is 1.
14. A compound represented by the formula (II) and a stereoisomer thereof,
Figure FDA0002263872070000052
r is selected from H or a hydroxyl protecting group; r1Selected from methyl, ethyl or cyclopropyl; n is selected from 1,2 or 3.
15. A compound according to claim 14 wherein n is 1 and stereoisomers thereof.
CN201680003442.9A 2015-01-30 2016-02-01 Preparation method and intermediate of 2- [ 1-cycloalkylethyl ] phenol Active CN107108483B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN201510050297 2015-01-30
CN2015100502977 2015-01-30
PCT/CN2016/073091 WO2016119757A1 (en) 2015-01-30 2016-02-01 Method for preparing 2-[1-cycloalkylethyl] phenol and intermediate thereof

Publications (2)

Publication Number Publication Date
CN107108483A CN107108483A (en) 2017-08-29
CN107108483B true CN107108483B (en) 2020-05-22

Family

ID=56542476

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201680003442.9A Active CN107108483B (en) 2015-01-30 2016-02-01 Preparation method and intermediate of 2- [ 1-cycloalkylethyl ] phenol

Country Status (2)

Country Link
CN (1) CN107108483B (en)
WO (1) WO2016119757A1 (en)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200714579A (en) * 2005-03-31 2007-04-16 Sankyo Agro Co Ltd A process for preparing a cyclopropylphenol derivative
US20120283335A1 (en) * 2008-05-12 2012-11-08 Jenkins Thomas E Analogs of Propofol, Preparation Thereof and Use as Anesthetics
PT2995604T (en) * 2013-05-09 2019-10-11 Sichuan Haisco Pharmaceutical Co Ltd Phenol derivative and preparation method and use in medicine thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Nanogold-Catalyzed cis-Silaboration of Alkynes with Abnormal Regioselectivity;Charis Gryparis and Manolis Stratakis;《Org.Lett》;20141231;第5卷(第16期);第1430-1431，表1 *

Also Published As

Publication number Publication date
CN107108483A (en) 2017-08-29
WO2016119757A1 (en) 2016-08-04

Similar Documents

Publication Publication Date Title
CN107108416B (en) Preparation method of 1, 2-dicyclopropylethylphenol and optical isomer thereof
WO2018115362A1 (en) Process for preparing 4-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-5-yl)oxy]benzonitrile (crisaborole)
CN103415495A (en) Cyclopolyarylene compound and method of manufacturing same
CN107108483B (en) Preparation method and intermediate of 2- [ 1-cycloalkylethyl ] phenol
CN107074675B (en) Preparation method of chiral 2- [ 1-cyclopropylethyl ] -6-isopropyl-phenol
JP6686050B2 (en) Borane complex and method for producing the same
TWI628160B (en) Preparation method of 2-[1-cycloalkylethyl]phenol and intermediate
CN112062697A (en) M-benzene polyphenol derivative and preparation method thereof
CN104860975B (en) A kind of preparation method of bortezomib synthetic intermediate
CN108456172B (en) Chiral N-heterocyclic carbene precursor compound with benzimidazole skeleton and preparation method and application thereof
WO2021002407A1 (en) Fluoroalkyl group-containing compound and production method therefor
CN107690436B (en) Method for forming complexes, complexes and use thereof
CN105837406B (en) A kind of preparation method of 2- (1- cycloalkylethyls) phenol derivatives
JP2021535927A (en) GABAA receptor allosteric enhancing compound and its preparation and application
KR102600309B1 (en) Salt compound and producing method of the same and alkylating reagent comprising the same
CN111517932B (en) Preparation method and intermediate of fused tricyclic derivative
CN103030662B (en) 2,2 '-functionalized chirality aryl-linking compound, preparation method and its usage
KR102050066B1 (en) New 1,1-diboryl-1-metalic alkyl compounds, preparation method thereof and preparation method of 1,1,-diboronate ester compounds using the same
US10889599B2 (en) 1,1-diborylalkyl-1-metal compounds, preparation method thereof, and their applications toward synthesis of 1,1-diboronate ester compounds
KR100976966B1 (en) Bisdiphenylvinylarene compound
CN117700456A (en) Arylamine photocatalyst and preparation method thereof, defluorinated mono-bridged ring propeller compound, preparation method and application thereof
CN108137637B (en) Method for producing ruthenium complex
KR101370803B1 (en) Development of a Novel Method to access bath (R)- and (S)-3,3'-diaryl BINOL Derivatives via Diastereomeric Resolution of rasemic-BINOL with a chiral Boron Ligand followed by suzuki Reaction of the resulting (R)- and (S)-BINOL boronic acids
JP6281877B2 (en) Method for synthesizing catalyst precursor and asymmetric chain compound
JP2014148475A (en) Method for producing optically active 2-arylpiperidinium salt

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right

Effective date of registration: 20231219

Address after: 856099 Xingfu Jiayuan Economic Development Zone, Gyerba, Nedong District, Shannan City, Tibet Autonomous Region

Patentee after: Tibet Haisike Pharmaceutical Co.,Ltd.

Address before: 611130 Sichuan Chengdu Wenjiang District Science and Technology Park cross strait Bailey Road 136

Patentee before: SICHUAN HAISCO PHARMACEUTICAL Co.,Ltd.

TR01 Transfer of patent right