WO2016119757A1 - Procédé de préparation de 2-[1-cycloalkyléthyl]phénol et de son intermédiaire - Google Patents

Procédé de préparation de 2-[1-cycloalkyléthyl]phénol et de son intermédiaire 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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formula
compound
reaction
acid
group
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Chinese (zh)
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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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Priority to CN201680003442.9A priority Critical patent/CN107108483B/zh
Publication of WO2016119757A1 publication Critical patent/WO2016119757A1/fr

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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
    • 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

Definitions

  • the present invention relates to a process for the preparation of 2-[1-cycloalkylethyl]phenol and an intermediate thereof.
  • 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 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:
  • a method for preparing a 2-[1-cycloalkylethyl]phenol derivative is also disclosed, as follows:
  • the method has a long route and is harsh in reaction, which is not conducive to industrial production.
  • 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.
  • the present invention provides a process for preparing a 2-(1-cycloalkylethyl)phenol derivative.
  • the present invention provides a process for preparing a 2-(1-cycloalkylvinyl)phenol derivative.
  • 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,
  • R is selected from H or a hydroxy protecting group
  • R 1 is selected from methyl, ethyl or cyclopropyl
  • n is selected from 1, 2 or 3.
  • a preferred embodiment of the present invention a method of producing a compound of the formula (I) and a stereoisomer thereof, wherein Is 1.
  • 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.
  • 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.
  • 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
  • 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
  • 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,
  • X is selected from Cl, Br or I; M is selected from Na, K or Li; R is H or a hydroxy protecting group;
  • R 1 is selected from methyl, ethyl or cyclopropyl; n is selected from 1, 2 or 3;
  • 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 is selected from 1, 2 or 3.
  • 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 is selected from Br
  • the compound of formula (III) is selected from or
  • 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 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 or
  • 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)
  • 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;
  • 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.
  • 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, tributyl
  • the present invention provides a process for the preparation of a compound of the formula (III) or formula (III'), wherein
  • 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');
  • R 1 , R 2 , R 3 , R 4 , M, n are as described above.
  • the present invention provides a process for the preparation of a compound of the formula (III) or formula (III'), wherein
  • the boric acid or boric acid ester is selected from or
  • R 5 is selected from H, OH, F, Cl, Br, or C 1-6 alkoxy
  • 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;
  • 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.
  • 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.
  • the present invention provides a method for producing a compound represented by the formula (I) and a stereoisomer thereof, wherein
  • 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.
  • 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 ;
  • 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;
  • the acid is selected from 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
  • 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;
  • R 1 is selected from methyl, ethyl or cyclopropyl, preferably methyl; n is selected from 1, 2 or 3, and n is preferably 1;
  • 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;
  • R 4 is F
  • R 5 is selected from H, OH, F, Cl, Br, or C 1-6 alkoxy, preferably H, methoxy, ethoxy, propoxy or isopropoxy.
  • 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.
  • 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;
  • 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-
  • 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 is H, S-(1-phenyl)ethylaminocarbonyl or R-(1-phenyl)ethylaminocarbonyl;
  • the present invention provides a compound represented by the formula (II) and a stereoisomer thereof, wherein
  • 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.
  • the present invention provides a compound represented by the formula (III), wherein
  • R 2 and R 3 are each independently selected from H, OH, F, Cl, Br or C 1-6 alkoxy.
  • 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 is selected from 1, 2 or 3; preferably n is 1.
  • the present invention provides a compound represented by the formula (III'), wherein
  • R 1 and R 2 are as defined above, and R 4 is F;
  • M is selected from Na, K or Li, preferably K; n is selected from 1, 2 or 3, preferably 1.
  • the compound of the formula (III) provided by the present invention is selected from, but not limited to, one of the following structures:
  • the compound of the formula (III') provided by the present invention is selected from, but not limited to, the following structure:
  • 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.
  • the compound of the formula may be a racemate or an optical isomer unless explicitly indicated.
  • the present invention relates to the substitution of a plurality of substituents, which may be the same or different.
  • the present invention relates to the inclusion of a plurality of heteroatoms, each of which may be the same or different.
  • 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).
  • 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.
  • 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;
  • 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;
  • 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;
  • 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.
  • 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,
  • 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) ⁇ (I
  • 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.
  • “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.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) 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).
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • CD 3 CN deuterated acetonitrile
  • TMS tetramethylsilane
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).
  • 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.
  • 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.
  • RhCl tris(triphenylphosphine) ruthenium chloride
  • PdCl 2 (PPh 3 ) 2 tris(triphenylphosphine)palladium dichloride
  • Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium
  • SL-J011-1 R-(-)-1-[(S)-2-di-tert-butylphosphine)ferrocene]ethyldi-(4-trifluoromethylphenyl)phosphorus
  • Ni(cod) 2 bis-(1,5-cyclooctadiene) nickel
  • NiCl 2 -diglyme diglyme, nickel dichloride
  • PdCl 2 -PEPPSI-iPr ([1,3-bis(2,6-diisopropylbenzene)imidazole- 2- ylide](3-chloropyridine)palladium dichloride
  • PdCl 2 /t-Bu 3 P palladium dichloride / tri-tert-butyl phosphate
  • Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium
  • Pd(PPh 3 ) 2 Cl 2 bistriphenylphosphine palladium dichloride
  • 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.
  • potassium acetate (10.80 g, 110 mmol)
  • pinacol borate 27.93 g, 110 mmol
  • cyclopropylacetylene (1A) (6.61 g, 100 mmol
  • 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.
  • potassium acetate (10.80 g, 110 mmol)
  • pinacol borate 27.93 g, 110 mmol
  • 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.

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

Abstract

La présente invention concerne un procédé de préparation d'un dérivé de 2-[1-cycloalkyléthyl]phénol, c'est-à-dire un procédé de préparation d'un composé tel que représenté dans la formule (I) et d'un isomère de celui-ci ainsi qu'un intermédiaire, et le procédé présente les avantages d'une voie réactionnelle courte, bon marché et de matières premières disponibles, un rendement élevé et analogue. La structure du composé de formule générale (I) est telle que représentée ci-dessous, les définitions de R, R1 et n étant cohérent avec les définitions dans la description.
PCT/CN2016/073091 2015-01-30 2016-02-01 Procédé de préparation de 2-[1-cycloalkyléthyl]phénol et de son intermédiaire WO2016119757A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101151234A (zh) * 2005-03-31 2008-03-26 三共农业株式会社 环丙基苯酚衍生物的制造方法
WO2009140275A1 (fr) * 2008-05-12 2009-11-19 Pharmacofore, Inc. Analogues de propofol, leur préparation et leur utilisation comme anesthésiques
WO2014180305A1 (fr) * 2013-05-09 2014-11-13 四川海思科制药有限公司 Dérivé du phénol, et son procédé de préparation et son utilisation en médecine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101151234A (zh) * 2005-03-31 2008-03-26 三共农业株式会社 环丙基苯酚衍生物的制造方法
WO2009140275A1 (fr) * 2008-05-12 2009-11-19 Pharmacofore, Inc. Analogues de propofol, leur préparation et leur utilisation comme anesthésiques
WO2014180305A1 (fr) * 2013-05-09 2014-11-13 四川海思科制药有限公司 Dérivé du phénol, et son procédé de préparation et son utilisation en médecine

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