TWI628160B - Preparation method of 2-[1-cycloalkylethyl]phenol and intermediate - Google Patents

Abstract

The present invention relates to a method for preparing a 2-[1-cycloalkylethyl]phenol derivative, which is a method for preparing a compound represented by the formula (I) and an isomer thereof, and an intermediate thereof, which has a short reaction route. The raw materials are cheap and easy to obtain, and the yield is high. The structure of the compound of the formula (I) is shown below, and the definitions of R, R ¹ and n are in accordance with the definition of the specification.

Description

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

The present invention relates to a process for the preparation of 2-[1-cycloalkylethyl]phenol and an intermediate thereof.

The GABAA receptor is the major inhibitory neurotransmitter receptor in the central nervous system. The GABAA receptor consists of a pentamer of transmembrane protein subunits, and 19 different subunits make up a variety of different GABAA subtype receptors. GABAA receptors on the pathogenesis and diagnosis of a variety of diseases such as anesthesia, depression, anxiety, epilepsy, memory disorders, drug dependence.

WO2014180305 describes a class of phenol derivatives and their preparation and use in the field of central nervous system, and has good GABAA receptor agonistic activity, some compounds have stronger GABAA 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, higher in animal experiments The safety index, wider treatment range or low 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:

a:

b:

c:

The method has long route and harsh reaction conditions, which is not conducive to industrial production.

The object of the present invention is to solve the deficiencies and provide a novel preparation method with short reaction route and easier reaction.

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,

Wherein R is selected from H or a hydroxy protecting group; R ^{1 is} selected from methyl, ethyl or cyclopropyl; and n is selected from 1, 2 or 3.

According to a preferred embodiment of the present invention, there is provided a process for the preparation of a compound of the formula (I) and a stereoisomer thereof, wherein n is 1.

In a preferred embodiment of the present invention, there is provided a process for the preparation of a compound of the formula (I) and a stereoisomer thereof, which comprises the catalytic reduction of hydrogen by a compound of the formula (II) under the action of a catalyst, or the use of three Prepared by reduction reaction of methyl decane + acid, triethyl decane + acid, NH ₂ NH ₂ , B ₂ H ₆ + peroxyacid, KO ₂ CN=NCO ₂ K or Hans ester 1,4-dihydropyridine a compound of formula (I); said catalyst being selected from the group consisting of supported metal catalysts or metal complexes selected from the group consisting of Pt, Pd, Ni, Ru, Ir or Rh; said acid being selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, and trifluorocarbon Acetic acid or p-toluenesulfonic acid; the peroxyacid is selected from the group consisting of peroxybenzoic acid, m-CPBA or peracetic acid.

In a preferred embodiment of the present invention, there is provided a process for the preparation of a compound of 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. The reducing agent used in the reaction is hydrogen and the catalyst used is selected from a supported metal catalyst or metal complex selected from Pt, Pd, Ni, Ru, Ir or Rh; or the reducing agent is selected from trimethyl decane + Acid, triethyl decane + acid, NH ₂ NH ₂ , B ₂ H ₆ + peroxyacid, KO ₂ CN=NCO ₂ K or Hans ester 1,4-dihydropyridine; the acid is selected from the group consisting of hydrochloric acid and 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; the solvent used is selected from the group consisting of water, methanol, hexafluoroisopropanol, trifluoro Ethanol, ethanol, isopropanol, dioxane, chloroform, acetone, acetic acid, dimethyl hydrazine, dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, methyltetrahydrofuran, methyl third Butyl ether, diethyl ether, N,N-dimethylformamide, benzene, toluene, fluorinated benzene, 1,2-difluorobenzene, p-bromofluorobenzene, 2,3-difluorobromobenzene, hexafluorobenzene Any one or more mixtures of bromopentafluorobenzene, xylene, trimethylbenzene, tris(trifluoromethyl)benzene or trifluoromethylbenzene in any ratio.

In a preferred embodiment of the present invention, there is provided a process for the preparation of a compound of 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. The reducing agent used in the reaction is hydrogen and the catalyst used is selected from 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-t-butylphosphonium)ferrocene]ethyldi-(4-trifluoromethylphenyl)phosphine, [Rh(COD) ₂ ]O ₃ SCF ₃ /-(- )-1-[(S)-2-di-t-butylphosphonium)ferrocene]ethyldi-(4-trifluoromethylphenyl)phosphine or [Ru(COD)(OAc) ₂ ]/-( -)-1-[(S)-2-di-t-butylphosphine)ferrocene]ethyldi-(4-trifluoromethylphenyl)phosphine; the solvent used is selected from the group consisting of water, methanol, and hexafluoro Isopropanol, trifluoroethanol, ethanol, isopropanol, dioxane, chloroform, acetone, acetic acid, dimethyl hydrazine, 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- Any one or more of difluorobromobenzene, hexafluorobenzene, bromopentafluorobenzene, xylene, trimethylbenzene, 1,3,5-tris(trifluoromethyl)benzene or trifluoromethylbenzene Mixture ratio.

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 a compound of the formula (IV) and a stereoisomer thereof The coupling reaction is prepared, 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; 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 comprising, in addition to the hetero atom B, 0 to 4 hetero atoms selected from O, N or S, said ring being optionally 0 to 4 selected from H, C _1-6 Substituted by a substituent of an alkyl group or a C _1-6 alkoxy group; n is selected from 1, 2 or 3.

In a preferred embodiment of the present invention, there is provided a method for preparing a compound of the formula (II) and a stereoisomer thereof, which is a compound of the formula (III) or a compound of the formula (IV) And stereoisomer coupling reaction thereof, wherein X is selected from Br; the compound of formula (III) is selected from or ; the compound of formula (III`) is .

In a preferred embodiment of the present invention, there is provided a method for preparing a compound of the formula (II) and a stereoisomer thereof, which is a compound of the formula (III) or a compound of the formula (IV) And stereoisomer coupling reaction thereof, 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; a compound of formula (III) is selected from or ; the compound of formula (III`) is The reaction is carried out under the action of a catalyst selected from the group consisting of a supported metal catalyst or a metal complex selected from the group consisting of Pd, Ru, Ir, Rh or Ni; the catalyst preferably being a metal complex And the ligands thereof 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; Further preferred catalysts are Pd(OAc) ₂ , Pd(OAc) ₂ /S-Phos, Pd(OAc) ₂ /RuPhos, (PhCN) ₂ PdCl ₂ , Ni(cod) ₂ , NiCl ₂ -diglyme, PdCl ₂ - PEPPSI-iPr, PdCl ₂ /t-Bu ₃ P, PdCl ₂ /(Cy) ₃ P, Pd(dppf)Cl ₂ , Pd(PPh ₃ ) ₄ , Pd(PPh ₃ ) ₂ Cl ₂ or Pd ₂ (dba) ₃ /t-Bu ₃ P, more preferably Pd(dppf)Cl ₂ ; the solvent used in the reaction is selected from the group consisting of toluene, dioxane, tetrahydrofuran, dimethyl hydrazine, N,N-dimethylformamidine Any one or more mixtures of amine, water, methanol, ethanol, ethylene glycol dimethyl ether and dichloroethane in any ratio, preferably toluene, methanol, ethanol, dioxane, tetrahydrofuran, N, N- Any of dimethylformamide or ethylene glycol dimethyl ether a mixture of any ratio; the reaction is added to 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, phosphoric acid. a mixture of any one or more of potassium, triethylamine, potassium fluoride, tert-butylamine, N,N-diisopropylethylamine, tributylamine, and pyridine, preferably sodium carbonate, potassium carbonate, Potassium hydrogencarbonate, potassium acetate or potassium phosphate.

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 the group consisting of 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, a mixture of any one or more of water, methanol or ethanol in any ratio; the reaction is added to an alkaline agent selected from the group consisting of potassium acetate, sodium acetate, sodium butoxide or potassium t-butoxide. Any one or more of any mixture in any ratio.

The present invention provides a method for producing a compound represented by the formula (I) and a stereoisomer thereof, wherein a) reacting a general formula (V) with a boronic acid or a boronic acid ester to obtain a compound of the formula (III) or formula (III'); the boric acid or boric acid ester is selected from the group consisting of or And b) preparing a compound of the formula (II) by a coupling reaction of a compound of the formula (III) or a compound of the formula (III') with a compound of the formula (IV) and a stereoisomer thereof under the action of a catalyst and an alkaline reagent; a stereoisomer thereof, 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, the ligands of said metal complexes being independently One or more selected from 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 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 Preferably, Pd(dppf)Cl ₂ ; c) is obtained by reacting a compound of the formula (II) and a stereoisomer thereof with hydrogen under a catalyst to obtain a compound of the formula (I) and a stereoisomer thereof, or by a formula ( II) Compounds and their stereoisomers with trimethyldecane + acid, triethyl Silane acid _{+, NH 2 NH 2, B 2} H 6 + peroxyacid, KO ₂ CN = NCO ₂ K or Hans-1,4-dihydropyridine esters prepared by a reduction reaction of formula (I) compounds of the stereoisomer 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; Hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or p-toluenesulfonic acid; said peroxyacid selected from the group consisting of peroxybenzoic acid, m-CPBA or peroxyacetic acid X selected from the group consisting of Cl, Br or I, preferably Br; It 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)ethylamino a carbonyl group; R ^{1 is} selected from methyl, ethyl or cyclopropyl, preferably methyl; n is selected from 1, 2 or 3, n is preferably 1; and R ² and R ³ are each independently selected from H, OH, F, Cl, Br, or C _1-6 alkoxy; alternatively, R ² and R ³ may form a 4-10 membered ring, preferably a 5-membered ring or a 6-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 be as appropriate. 0-4 is selected from H, C _1-6 alkyl or C _1-6 alkoxy substituents; R ⁴ is F; R ⁵ is selected from H, OH, F, Cl, Br, or C _1-6 alkoxy group, preferably H, methoxy, ethoxy, propoxy or isopropoxy.

In a preferred embodiment of the present invention, there is provided a process for the preparation of a compound of the formula (I) and a stereoisomer thereof, wherein: a) the formula (V) and or The reaction gives a compound of the formula (III) or formula (III'); b) the solvent used in the reaction is selected from the group consisting of toluene, methanol, ethanol, dioxane, tetrahydrofuran, N,N-dimethylformamide or Any one or more mixtures of ethylene glycol dimethyl ether in any ratio, the alkaline reagent used in the reaction is selected from the group consisting of sodium carbonate, potassium carbonate, potassium hydrogencarbonate, potassium acetate or potassium phosphate; c) used in the reaction The solvent is selected from the group consisting of water, methanol, hexafluoroisopropanol, trifluoroethanol, ethanol, isopropanol, dioxane, chloroform, acetone, acetic acid, dimethyl hydrazine, dichloromethane, dichloroethane, tetrahydrofuran. , acetonitrile, ethyl acetate, 2-methyltetrahydrofuran, methyl tert-butyl ether, diethyl ether, N,N-dimethylformamide, benzene, toluene, fluorinated benzene, 1,2-difluorobenzene, Para-bromofluorobenzene, 2,3-difluorobromobenzene, hexafluorobenzene, bromopentafluorobenzene, xylene, trimethylbenzene, 1,3,5-tris(trifluoromethyl)benzene or trifluoromethylbenzene Any one or more mixtures in any ratio; the selected reducing agent is triethyl decane + acid, the catalyst is selected from a supported metal catalyst or a metal complex, the gold Is a genus 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; and n is selected from 1.

The present invention provides a compound represented by formula (II) or formula (IV) and a stereoisomer thereof, wherein

Formula (II): 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, and n is preferably 1.

Formula (IV): R is selected from S -(1-phenyl)ethylaminocarbonyl or R- (1-phenyl)ethylaminocarbonyl; R ^{1 is} selected from methyl, ethyl or cyclopropyl, preferably. It is a methyl group; X is selected from Cl, Br or I, preferably Br.

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. Alternatively, R ² and R ³ 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 be optionally selected from 0 to 4 selected from H, C _1-6 alkyl or C. Substituted by a substituent of the _1-6 alkoxy group; n is selected from 1, 2 or 3; 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, 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 may be selected from, but not limited to, the following structures: .

The compound represented by the formula (II) or the formula (IV) and the stereoisomer thereof provided by the present invention are selected from, but not limited to, one of the following structures:

The hydroxy protecting group is selected from an alkyl ether protecting group, an ester protecting group or an oxime ether protecting group, and the hydroxy protecting group includes, but not limited to, methyl, benzyl, p-methoxybenzyl, trityl, and third. Butyl, methoxymethyl ether, methoxyethoxymethyl, tetrahydrofuranyl, tert-butylcarbonyl, benzhydryl, ethyl hydrazino, chloromethylcarbonyl, tert-butoxycarbonyl, benzyloxy Carbonyl, trimethylsulfonyl, triethylsulfonyl, tert-butyldimethylhydrazino, tert-butyldiphenylfluorenyl, di-tert-butylhydroxyindenyl, S- (1-phenyl Ethylaminocarbonyl or R-(1-phenyl)ethylaminocarbonyl.

Unless otherwise stated, the nouns used in the specification and patent application have the following meanings:

When the compound of the formula referred to in the present invention has a palmitic center, the compound of the formula may be a racemate or an optical isomer, unless explicitly indicated.

When the present invention is referred to by a plurality of substituents, each substituent may be the same or different.

When the present invention refers to the inclusion of a plurality of heteroatoms, each heteroatom may be the same or different.

The elements mentioned in the groups and compounds of the present invention, carbon, hydrogen, oxygen, sulfur, nitrogen or halogen, include their isotopic conditions, namely the elements mentioned in the present invention and the elements mentioned in the compounds, carbon and hydrogen. , oxygen, sulfur or nitrogen are further replaced by 1 to 5 of their corresponding isotopes, wherein the carbon isotopes include ¹² C, ¹³ C and ¹⁴ C, and the hydrogen isotopes include 氕 (H), 氘 (D, also called Heavy hydrogen), strontium (T, also known as super heavy hydrogen), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, nitrogen isotopes include 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 an oxime ether protecting group, and the hydroxy protecting group includes, but not limited to, methyl, benzyl, p-methoxybenzyl, trityl, and third. Butyl, methoxymethyl ether, methoxyethoxymethyl, tetrahydrofuranyl, tert-butylcarbonyl, benzhydryl, ethyl hydrazino, chloromethylcarbonyl, tert-butoxycarbonyl, benzyloxy Carbonyl, trimethylsulfonyl, triethylsulfonyl, tert-butyldimethylhydrazino, tert-butyldiphenylfluorenyl, di-tert-butylhydroxyindenyl, S- (1-phenyl Ethylaminocarbonyl or R-(1-phenyl)ethylaminocarbonyl; alkyl ether protecting groups 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 alkaline conditions, including but not limited to sodium methoxide, potassium carbonate, Potassium hydroxide, sodium hydroxide, lithium aluminum hydride, pyridine or ammonia; the oxime ether protecting group can be removed under conditions of hydrogen fluoride, tetrabutylammonium fluoride and the like; Complex ", also known complexes, refers to a compound containing a coordinated unit. A complex molecule or ion formed by the combination of a central atom or ion with several ligand (ligand) molecules or ions with coordinate bonds, commonly referred to as 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, dppe, dba , BINAP, TDMPP, TMPP, TMSPP, P(O-o-methoxyphenyl) ₃ , P(O-p-methoxyphenyl) ₃ , pyridine, n -Bu ₃ P, t -Bu ₃ P, ( MeO) ₃ P, AsPh ₃ , P(OEt) ₃ . The metal complex may contain simple ions or simple ions in addition to the coordination unit, and the simple ions are 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) ruthenium (I) tetrakis(3,5-bis(trifluoromethyl)phenylborate, ( R )-Ru(OAc ₂ BINAP, (R)-(+)-[Ru(MeO-BIPHEP)(C ₆ H ₆ )Cl]Cl, (R)-(+)-[Ru(BIPHEP)(C ₆ H ₆ )Cl] Cl, ( R )-Ir(Tol-SDP)(COD)Cl, (R)-(+)-Ir(MeO-BIPHEP)(COD)Cl or from Pd(OAc) ₂ , PdCl ₂ and AsPh ₃ , n a catalytic system consisting of -Bu ₃ P, (MeO) ₃ P, Ph ₂ P(CH ₂ ) ₂ PPh ₂ (dppe), Ph ₂ P(CH ₂ ) ₃ PPh ₂ (dppp).

The "supported catalyst" is composed of a catalytically active component supported on the surface of the carrier. Commonly used carriers are alumina carrier, silicone carrier, activated carbon carrier 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 technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes but is not limited thereto.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The unit of NMR shift (δ) is 10 ^-6 (ppm). The NMR measurement was performed using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl hydrazine (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD). , deuterated acetonitrile (CD ₃ CN), internal standard is tetramethyl decane (TMS).

The measurement of MS was carried out (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).

The thin layer chromatography gelatin plate uses Yantai Huanghai HSGF254 or Qingdao GF254 gelatin plate. The specification of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.20mm. The specification for thin layer chromatography separation and purification is 0.4mm. ~0.5mm.

Pipe column chromatography generally uses Yantai Huanghai Tanji 200~300 mesh silicone as carrier.

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, Anike Chemical, Shanghai Demo, Chengdu Kelon Chemical, Suiyuan Chemical Technology, Belling Technology, etc. the company.

(Ph ₃ P) ₃ . RhCl: tris(triphenylphosphine) ruthenium chloride

(Ph ₃ P) ₃ . RuClH: tris(triphenylphosphine)hydroquinone

(Ph ₃ P) ₃ . IrH: tris(triphenylphosphine) hydrogenated ruthenium

( R )-Ru(OAc) ₂ BINAP: diacetate [(R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]anthracene

[(Ph) ₃ P] ₃ RuCl ₂ : tris(triphenylphosphine) antimony dichloride

[(Ph) ₃ P] ₃ Ru(CO)H ₂ : tris(triphenylphosphine)carbonyldihydroindole

PdCl ₂ : palladium dichloride

Pd(OAc) ₂ : palladium diacetate

PdCl ₂ (PPh ₃ ) ₂ : tris(triphenylphosphine)palladium dichloride

Pd(PPh ₃ ) ₄ : tetrakis(triphenylphosphine)palladium

PdCl ₂ (dppf): 1,1'-bis(diphenylphosphino)ferrocene palladium (II)

Pd(dba) ₂ : tris(dibenzylideneacetone)dipalladium

(dppp)NiCl ₂ : 1,3-bis(diphenylphosphino)propane nickel chloride

[Rh(NBD)Cl] ₂ : Chloro norbornadiene 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-t-butylphosphino)ferrocene]ethyldi-(4-trifluoromethylphenyl)phosphorus

[Rh(COD) ₂ ]O ₃ SCF ₃ : bis(1,5-cyclooctadiene)-trifluoromethanesulfonate

[Ru(COD)(OAc) ₂ ]: (1,5-cyclooctadiene)-acetic acid hydrazine

Pd(OAc) ₂ /S-Phos: palladium acetate/2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-diphenyl

m-CPBA: m-chloroperoxybenzoic acid

(PhCN) ₂ PdCl ₂ : bis(cyanobenzene) palladium dichloride

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 / tributylphosphonium

PdCl ₂ /(Cy) ₃ P: palladium dichloride / tricyclohexylphosphine

Pd(dppf)Cl ₂ :[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

Pd(PPh ₃ ) ₄ : tetrakis(triphenylphosphine)palladium

Pd(PPh ₃ ) ₂ Cl ₂ : bistriphenylphosphine palladium dichloride

Pd ₂ (dba) ₃ /t-Bu ₃ P: tris(dibenzylideneacetone)dipalladium/trit-butylphosphonium

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

Under a nitrogen atmosphere, anhydrous lithium chloride (4.66 g, 110 mmol), cuprous chloride (10.89 g, 110 mmol) and dry N,N-dimethylformamide (300 mL) were added to the reaction flask at room temperature. After stirring for 1 hour, potassium acetate (10.80 g, 110 mmol), bis(pinacolato diboron, 27.93 g, 110 mmol) and cyclopropylacetylene ( 1A ) (6.61 g, 100 mmol) were added in this order. The mixture was stirred for 20 hr. The mixture was washed with saturated brine (150 mL×3), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( petroleum ether) to give the desired product 2-(1-cyclopropyl) as a yellow liquid. Vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane ( Compound 1 ) (10.80 g, yield: 55.67%).

Method Two:

Under nitrogen protection, anhydrous tetrahydrofuran (30 mL) was added to the flask, and the nitrogen was purged with a water-flow pump for 10 min, and diisobutylaluminum hydride (DIBAL-H) was added dropwise (concentration in toluene was 1.5 M, 17.3 mL). , 26.0 mmol), added Bi in an ice-water bath was cooled to 0 deg.] C, was added dropwise cyclopropyl acetylene (1A) (1.322g, 20.0mmol) , warmed to room temperature after stirring for 2 hours, cooled to 0 deg.] C, was added iso Propyl alcohol pinacol borate (11.116g, 60.0mmol), after heating to 80 ° C for 4 hours, cooled to room temperature, added water (30mL), stirred for 30min, ethyl acetate extraction (30mL × 2), The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness, and the residue was purified by silica gel column chromatography ( petroleum ether) to give the desired product 2-(1-cyclopropylvinyl)-4 as a yellow liquid. 4,5,5-Tetramethyl-1,3,2-dioxaborane ( Compound 1 ) (530 mg, yield: 14%).

Method three:

Under a nitrogen atmosphere, anhydrous lithium chloride (4.66 g, 110 mmol), cuprous chloride (10.89 g, 110 mmol) and dry N,N-dimethylformamide (200 mL) were added to the reaction flask at room temperature. After stirring for 1 hour, potassium acetate (10.80 g, 110 mmol), pinacol borate (27.93 g, 110 mmol) and cyclopropylacetylene ( 1A ) (6.61 g, 100 mmol) were added in that order, and the mixture was heated to 40 ° C to continue stirring. The mixture was stirred for 10 minutes with saturated brine (200 mL), filtered, and filtered, filtered, ethyl acetate (50 mL). ×3) Washing, drying with anhydrous sodium sulfate, filtration, and concentrating the filtrate under reduced pressure. The residue was purified by silica gel column chromatography ( petroleum ether) to give the desired product 2-(1-cyclopropylvinyl)-4 as a yellow liquid. 4,5,5-tetramethyl-1,3,2-dioxaborane ( Compound 1 ) (11.64 g, yield: 60.02%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 5.64 (d, 1H), δ 5.49 (d, 1H), δ 1.54-1.48 (m, 1H), δ 1.26 (s, 12H) δ 0.70-0.65 (m, 2H) ), δ 0.60-0.57 (m, 2H).

Example 2

[2-(1-Cyclopropenyl)-6-isopropyl-phenyl] N -[(1 R )-1-phenylethyl]carbamate ( Compound 2 )

[2-(1-cyclopropylvinyl)-6-isopropyl-phenyl] N -[(1 R )-1-phenylethyl]carbamat

First step: 2-bromo-6-isopropylphenol ( 2B )

2-Bromo-6-isopropylphenol

To the reaction flask were added 2-isopropyl-phenol ( 2A ) (13.619 g, 100.0 mmol), N , N -diisopropylamine (1.012 g, 10.0 mmol) and dichloromethane (250 mL). To 0 ° C, N -bromosuccinimide (17.798g, 100.0mmol) was added in portions, and the ice water bath was removed after adding, and the mixture was naturally stirred to room temperature for 16 h, and quenched with sulfuric acid solution (80 mL, 2 mol/L). The reaction was separated, and the organic layer was separated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Purification (petroleum ether) gave the title compound 2-bromo-6-isopropylphenol ( 2B ) (17.851 g, yield: 83%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.29 (dd, J = 1.6, 8.0 Hz, 1H), δ 6.95 (dd, J = 1.6, 8.0 Hz, 1H), δ 6.77 (t, J = 8.0 Hz, 1H) ), δ 5.56 (s, 1H), δ 3.37-3.24 (m, 1H), δ 1.24 (d, J = 7.2 Hz, 6H).

The second step: (2-bromo-6-isopropyl-phenyl) N-[(1 R )-1-phenylethyl]carbamate ( 2C )

(2-bromo-6-isopropyl-phenyl) N -[(1 R )-1-phenylethyl]carbamate

2-bromo-6-isopropylphenol (2B) (172.15 g, 800 mmol), triethylamine (224 mL) and THF (800 mL) were added to the reaction flask, and the mixture was replaced with nitrogen three times. A solution of 1 R )-1-isocyanatoethyl]benzene (141.3 g, 960 mmol) in tetrahydrofuran (100 mL) was added dropwise over 30 min and stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced vacuol~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The title product (2-bromo-6-isopropyl-phenyl) N -[(1 R )-1-phenylethyl]carbamate (2C) (285.11) was obtained as white powdery solid. g, yield: 98.38%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.30-7.21 (m, 7H), δ 7.05 (t, 1H), δ 5.43 (s, 1H), δ 5.01-4.91 (m, 1H) δ 3.12-3.05 (m , 1H), δ 1.59 (d, 3H), δ 1.20 (d, 3H), δ 1.16 (d, 3H).

Step 3: [2-(1-Cyclopropenyl)-6-isopropyl-phenyl] N -[(1 R )-1-phenylethyl]carbamate ( Compound 2 )

[2-(1-cyclopropylvinyl)-6-isopropyl-phenyl] N -[(1 R )-1-phenylethyl]carbamate

method one:

To the reaction flask was added (2-bromo-6-isopropyl-phenyl)N-[(1 R )-1-phenylethyl]carbamate ( 2C ) (64.99 g, 180 mmol), 2- ( 1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane ( Compound 1 ) (34.95 g, 180 mmol), 4M K ₂ CO ₃ solution ( 315mL, 1260mmol) and toluene (1500mL), pumping with water at room temperature for 15min, then add Pd(dppf)Cl ₂ (7.35g, 9mmol), and then pumping again with water flow pumping 15min After the reaction was stirred for 9 h in an oil bath preheated to 90 ° C, the reaction was stopped, cooled to room temperature, and the reaction mixture was extracted with ethyl acetate (200 mL × 3). The mixture was washed with anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl ether: ethyl acetate = 10:1) to give the desired product as a yellow liquid. Propyl vinyl)-6-isopropyl-phenyl] N -[(1 R )-1-phenylethyl]carbamate ( Compound 2 ) (45.71 g, yield: 72.67%).

Method Two:

(2-Bromo-6-isopropyl-phenyl)N-[(1 R )-1-phenylethyl]carbamate ( 2C ) (2.17 g, 6.0 mmol), 2- (1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane ( Compound 1 ) (1.17 g, 6.0 mmol), 2M K ₃ PO ₄ The solution (12.0 mL, 24.0 mmol) and toluene (30 mL) were pumped with water at room temperature for 15 min, then Pd(PPh ₃ ) ₄ (1.04 g, 0.90 mmol) was added, and the water was again pumped with water. After pumping for 15 minutes, the reaction was stirred in an oil bath preheated to 80 ° C for 7 h, then the reaction was stopped, cooled to room temperature, and the reaction mixture was extracted with ethyl acetate (30 mL×3). The organic layer was washed with water (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (ethyl ether: ethyl acetate = 10:1) -(1-cyclopropenyl)-6-isopropyl-phenyl] N -[(1 R )-1-phenylethyl]carbamate ( Compound 2 ) (0.63 g, Yield: 30.12% ).

Method three:

(2-Bromo-6-isopropyl-phenyl)N-[(1 R )-1-phenylethyl]carbamate ( 2C ) (2.17 g, 6.0 mmol), 2- (1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane ( Compound 1 ) (1.17 g, 6.0 mmol), anhydrous Na ₂ CO ₃ (1.91 g, 18.0 mmol) and toluene/methanol (2:1, 30 mL). After pumping with water for 10 min at room temperature, Pd(PPh ₃ ) ₄ (0.27 g, 0.24 mmol) was added. After pumping with water for 15 min, the mixture was stirred for 15 h in an oil bath preheated to 90 ° C, the reaction was stopped, cooled to room temperature, and the reaction was concentrated under reduced pressure. (petroleum ether: ethyl acetate = 10:1) gave the desired product [2-(1-cyclopropenyl)-6-isopropyl-phenyl] N -[(1 R )-1- Phenylethyl]carbamate ( Compound 2 ) (0.51 g, yield: 24.30%).

Method four:

(2-Bromo-6-isopropyl-phenyl)N-[(1 R )-1-phenylethyl]carbamate ( 2C ) (2.17 g, 6.0 mmol), 2- (1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane ( Compound 1 ) (1.17 g, 6.0 mmol), anhydrous Cs ₂ CO ₃ (5.86g, 18.0mmol) and 1,4-dioxane (30mL), pumping with water at room temperature for 10min, then adding Pd(PPh ₃ ) ₄ (0.35g, 0.30mmol), add After pumping with water for 15 minutes, the mixture was preheated to 90 °C in an oil bath and stirred for 5 hours. The reaction was stopped, cooled to room temperature, and the reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. (petroleum ether: ethyl acetate = 10:1) gave the desired product [2-(1-cyclopropenyl)-6-isopropyl-phenyl] N -[(1 R )-1- Phenylethyl]carbamate ( Compound 2 ) (0.53 g, yield: 25.27%).

Method five:

(2-Bromo-6-isopropyl-phenyl)N-[(1 R )-1-phenylethyl]carbamate ( 2C ) (2.17 g, 6.0 mmol), 2- (1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane ( Compound 1 ) (1.17 g, 6.0 mmol), 2M Na ₂ CO ₃ The solution (9.0 mL, 18.0 mmol) and THF (18 mL) were pumped with water at room temperature for 10 min, then PdCl ₂ (PPh ₃ ) ₂ (0.11 g, 0.18 mmol) was added. After pumping for 15 minutes, the gas was pumped to reflux. After 7 h of reaction, the reaction was stopped, cooled to room temperature, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography ( petroleum ether: ethyl acetate = 10:1). The target product in the form of a yellow liquid [2-(1-cyclopropenyl)-6-isopropyl-phenyl] N -[(1 R )-1-phenylethyl]carbamate ( Compound 2 ) 0.43 g, yield: 20.50%).

Method six:

(2-Bromo-6-isopropyl-phenyl)N-[(1 R )-1-phenylethyl]carbamate ( 2C ) (2.17 g, 6.0 mmol), 2- (1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane ( Compound 1 ) (1.17 g, 6.0 mmol), 2M K ₃ PO ₄ The solution (9.0 mL, 18.0 mmol) and toluene (18 mL) were pumped with water at room temperature for 10 min, then P(dOAc) ₂ (0.067 g, 0.18 mmol) and Xantphos (0.21 g, 0.36 mmol) were added. After the addition, the pump was pumped with water for 15 minutes, and then placed in an oil bath preheated to 90 ° C for 6 hours. The reaction was stopped, cooled to room temperature, and the reaction solution was concentrated under reduced pressure. Chromatographic separation and purification (petroleum ether: ethyl acetate = 10:1) gave the desired product [2-(1-cyclopropenyl)-6-isopropyl-phenyl] N -[(1 R ) as a yellow liquid. 1-Benzylethyl]carbamate ( Compound 2 ) (0.66 g, yield: 31.53%).

Method seven:

(2-Bromo-6-isopropyl-phenyl)N-[(1 R )-1-phenylethyl]carbamate ( 2C ) (2.17 g, 6.0 mmol), 2- (1-Cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane ( Compound 1 ) (1.17 g, 6.0 mmol), K ₃ PO ₄ . 7H ₂ O (3.05g, 9.0mmol) and toluene (30 mL), at room temperature for 10min with a suction pump pumping water, was added _{Pd (dppf) Cl 2 (0.21g} , 0.30mmol), again with water addition was complete After pumping for 15 minutes, the pump was stirred in an oil bath preheated to 90 ° C for 6 h, then the reaction was stopped, cooled to room temperature, and the reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. : ethyl acetate = 10:1) to give the desired product [2-(1-cyclopropenyl)-6-isopropyl-phenyl] N -[(1 R )-1-phenylethyl as a yellow liquid. Carbamate ( Compound 2 ) (0.38 g, yield: 18.12%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.29-7.05 (m, 8H), δ 5.21 (s, 1H), δ 4.93-4.88 (m, 3H), δ 3.09-3.04 (m, 1H), δ 1.57- 1.50 (m, 4H), δ 1.21 (d, 3H), δ 1.17 (d, 3H), δ 0.66-0.64 (m, 2H) δ 0.46-0.44 (m, 2H).

Example 2-I: 2-(1-cyclopropylvinyl)-6-isopropylphenol ( Compound 2-I )

2-(1-cyclopropylvinyl)-6-isopropylphenol

method one:

2-bromo-6-isopropyl-phenol ( 2B ) (7.30 g, 33.94 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl- was added to the reaction flask. 1,3,2-dioxaborane ( Compound 1 ) (6.59 g, 33.94 mmmol), potassium carbonate solution (3 mol/L, 45 mL) and toluene (180 mL), pumping with water at room temperature After 15 minutes, 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride [PdCl ₂ (dppf)] (1.39 g, 17.03 mmol) was added, and after pumping for another 15 minutes, The reaction was stirred in an oil bath preheated to 90 ° C, and the reaction was stopped after 5 hours, cooled to room temperature, and the mixture was extracted with ethyl acetate (50 mL×3). Washing, drying over anhydrous sodium sulfate, filtration, concentrating the filtrate under reduced pressure, and purifying the residue by chromatography on silica gel ( petroleum ether) to give the desired product 2-(1-cyclopropylvinyl)-6- Propylphenol ( Compound 2-I ) (5.35 g, yield: 81%).

Method Two:

To the reaction flask was added 2-bromo-6-isopropyl-phenol ( 2B ) (215 mg, 1.0 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborane ( Compound 1 ) (388 mg, 2.0 mmol), potassium phosphate solution (3.0 mL, 2 mol/L) and 1,4-dioxane (10 mL), at room temperature After pumping for 10 minutes, the water was pumped for 10 minutes, followed by the addition of tri-tert-butylphosphine ( t -Bu ₃ P) (42 mg, 0.2 mmol) and tris(dibenzylideneacetone)dipalladium [Pd ₂ (dba) ₃ (46 mg, 0.05 mmol), after stirring for another 10 minutes, the reaction was stirred at room temperature for 20 hours, the reaction was stopped, the reaction was quenched with water (10 mL), ethyl acetate (10 mL×3) was extracted, and the organic layer was collected. The mixture was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( petroleum ether) to give the desired product 2-(1-cyclopropylvinyl) as a yellow liquid. - 6-isopropylphenol ( Compound 2-I ) (100 mg, yield: 50%).

Method three:

To the reaction flask was added 2-bromo-6-isopropyl-phenol ( 2B ) (215 mg, 1.0 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborane ( Compound 1 ) (291 mg, 1.5 mmol) and methanol/N,N-dimethylformamide (20 mL, v/v = 4:1) at room temperature After 10 minutes, potassium carbonate (414 mg, 3.0 mmol) and bistriphenylphosphine palladium dichloride [Pd(PPh ₃ ) ₂ Cl ₂ ] (35 mg, 0.05 mmol) were added in that order, and after pumping for another 10 minutes, The mixture was heated to 80 ° C and stirred. After 16 hours, the reaction was quenched. EtOAc (20 mL) was evaporated and evaporated. dried, filtered, and the filtrate was concentrated under reduced pressure, the residue was purified by silica gel to give a yellow liquid column chromatography (petroleum ether) with the desired product 2- (1-cyclopropyl-vinyl) -6-isopropyl-phenol (compound 2 -I ) (85 mg, yield: 42%).

Method four:

To the reaction flask was added 2-bromo-6-isopropyl-phenol ( 2B ) (215 mg, 1.0 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborane ( Compound 1 ) (388 mg, 2.0 mmol), potassium carbonate solution (1.3 mL, 3 mol/L) and N,N-dimethylformamide (6.5 mL), room Pumping for 10 minutes under temperature, adding 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride [Pd(dppf)Cl ₂ ] (82 mg, 0.1 mmol), and pumping again. After 10 minutes, the mixture was stirred at 90 ° C for 3 hours. The reaction was quenched, cooled to room temperature, diluted with ethyl acetate (20 mL), washed with water (20 mL×3), dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (peel ether) to give the desired product 2-(1-cyclopropylvinyl)-6-isopropylphenol ( Compound 2-I ) as a yellow liquid (78 mg, yield: 39%).

Method five:

To the reaction flask was added 2-bromo-6-isopropyl-phenol ( 2B ) (430 mg, 2.0 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborane ( Compound 1 ) (388 mg, 2.0 mmol), sodium carbonate (1.06 g, 5.0 mmol), water (5 mL) and 1,4-dioxane (5 mL), room After pumping with water for 10 minutes, the tetrakis(triphenylphosphine)palladium [Pd(PPh ₃ ) ₄ ] (116 mg, 0.1 mmol) was added, and the pump was pumped again for 10 minutes. The mixture was heated to 90 ° C for 5 hours, and cooled to room temperature. The reaction mixture was extracted with ethyl acetate (15 mL×3). The organic layer was washed with brine (30 mL) concentrated and the residue was purified by silica gel to give a yellow liquid column chromatography (petroleum ether) with the desired product 2- (1-cyclopropyl-vinyl) -6-isopropyl-phenol (compound 2-I) (79mg, yield :39%).

Method six:

To the reaction flask was added 2-bromo-6-isopropyl-phenol (2B) (430 mg, 2.0 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborane ( Compound 1 ) (388 mg, 2.0 mmol), potassium carbonate (4 mL, 3 mol/L) and toluene (8 mL), pumping with water at room temperature for 10 minutes After that, Pd(dppf)Cl ₂ (24 mg, 0.03 mmol) was added, and after further pumping for 10 minutes, the mixture was heated to 90 ° C for 5 hours, cooled to room temperature, and the reaction solution was extracted with ethyl acetate (15 mL×3). The organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( petroleum ether). Cyclopropylvinyl)-6-isopropylphenol ( Compound 2-I ) (330 mg, yield: 54%).

Method seven:

To the reaction flask was added 2-bromo-6-isopropyl-phenol ( 2B ) (1.291 g, 6.0 mmol), 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl -1,3,2-dioxaborane ( Compound 1 ) (1.165 g, 6.0 mmol), potassium carbonate (13 mL, 4 mol/L) and toluene (39 mL), pumping with water at room temperature After 10 minutes, 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride [Pd(dppf)Cl ₂ ] (245 mg, 0.3 mmol) was added, and after pumping for another 10 minutes, The mixture was heated to 90 ° C for 5 hours, and cooled to room temperature. The reaction mixture was extracted with ethyl acetate (30 mL×3). and concentrated to give a yellow liquid residue was purified by silica gel column chromatography (petroleum ether) with the desired product 2- (1-cyclopropyl-vinyl) -6-isopropyl-phenol (compound 2-I) (692mg, yield :57%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.12 (dd, 1H), δ 6.95 (dd, 1H), δ 6.84 (t, 1H), δ 5.67 (s, 1H), δ 5.30 (dd, 1H), δ 5.04(d,1H),δ 3.36-3.25(m,1H),δ 1.68-1.61(m,1H)δ 1.24(d,6H),δ 0.80-0.75(m,2H),δ 0.54-0.50(m , 2H).

Example 3

( R )-2-(1-Cyclopropylethyl)-6-isopropyl(1-phenylethyl)carbamate (Compound 3)

( R )-2-(1-cyclopropylethyl)-6-isopropylphenyl(1-phenylethyl)carbamate

( R )-2-(1-Cyclopropylvinyl)-6-isopropyl(1-phenylethyl)carbamate (Compound 2) (175 mg) in a 200 mL autoclave at room temperature , 0.5 mmol) and methanol (5 mL), then add the catalyst bis(1,5-cyclooctadiene) ruthenium (I) tetrafluoroborate (10 mg). After the addition, the autoclave device is tightly sealed and sealed in a cylinder. Hydrogen was replaced 3 times; hydrogen was charged, the pressure on the autoclave was about 10 atm, and the reaction was stirred at room temperature for 3 hours; methanol was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: acetic acid Ester (v/v) = 10:1) gave white solid ( R )-2-(1-cyclopropylethyl)-6-isopropyl(1-phenylethyl)carbamate (compound) 3,170 mg, yield 65%).

Example 3-I

2- (1-cyclopropylethyl) -6-isopropyl - phenol (Compound 3-I)

2-(1-cyclopropylethyl)-6-isopropyl-phenol

To the reaction flask was added 2-(1-cyclopropylvinyl)-6-isopropylphenol ( Compound 2-I ) (5 g, 24.72 mmol) and dichloromethane (50 mL). Decane (4.3 g, 37.08 mmol), trifluoroacetic acid (4.2 g, 37.08 mol) was added dropwise in a dry ice-ethanol bath, the temperature was controlled to be less than -30 °, and the temperature was maintained for 1 hour after the completion of the dropwise addition. ×1), a saturated sodium hydrogencarbonate solution (50 mL × 1) was washed. The organic phase was separated and placed in another reaction flask, tetrabutylammonium fluoride trihydrate (3.9 g, 12.36 mmol) was added, and the mixture was stirred at room temperature for 1 hour, followed by water (20 mL × 1), saturated brine (20 mL × 1) Washing, drying over anhydrous sodium sulfate, EtOAc (EtOAc m. Propylethyl)-6-isopropyl-phenol ( Compound 3 ) (4.7 g, yield: 94%).

MS m/z (ESI): 203.1 (M-1).

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.12 (dd, 1H), δ 7.07 (dd, 1H), 6.89 (t, 1H), 4.91 (s, 1H), 3.20-3.13 (m, 1H), 2.53- 2.46 (m, 1H), 1.30 (d, 6H), 1.27 (d, 3H), 1.08-1.03 (m, 1H), 0.58-0.56 (m, 1H), 0.47-0.46 (m, 1H), 0.22- 0.16 (m, 2H).

Example 5

1-(1-cyclopropylethyl)-3-isopropyl-2-methoxybenzene (compound 5)

1-(1-cyclopropylethyl)-3-isopropyl-2-methoxybenzene

First step: 1-bromo-3-isopropyl-2-methoxybenzene (5B)

1-bromo-3-isopropyl-2-methoxybenzene

2-Bromo-6-isopropylphenol (2.04 g, 9.48 mmol) and potassium carbonate (3.93 g, 28.5 mmol) were added In 20 mL of acetonitrile, nitrogen protection, reaction at 50 ° C for 10 minutes; dropwise addition of methyl iodide (1 mL, 16.0 mmol), after the completion of the dropwise addition, to 60 ° C, reaction for 4 hours; filtration, the filtrate was spun dry, the residue was used for the column Chromatography (petroleum ether: ethyl acetate (v/v) = 20:1) to give 1-bromo-3-isopropyl-2-methoxybenzene (5B) (2.17 g) as colorless liquid. The rate is 99.9%,).

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.38 (dd, 1H), 7.20 (dd, 1H), 6.96 (t, 1H), 3.83 (s, 3H), 3.32-3.39 (m, 1H), 1.23 (d , 6H).

Second step: 1-(1-cyclopropylvinyl)-3-isopropyl-2-methoxybenzene (5C)

1-(1-cyclopropylvinyl)-3-isopropyl-2-methoxybenzene

1-Bromo-3-isopropyl-2-methoxybenzene (5B) (2.06 g, 9.0 mmol), 2-(1-cyclohexylvinyl)-4,4,5,5-tetramethyl -1,3,2-dioxaborane (1.75 g, 9.0 mmol) and potassium carbonate aqueous solution (10 mL, 4 mol/L) were added to 30 mL of toluene, and then the catalyst [1,1'-bis(diphenyl) was added. Phosphyl)ferrocene]palladium dichloride (0.367g, 0.45mmol), packed in a condensing tube, pumped with water, pumped with nitrogen, replaced with nitrogen three times, protected with nitrogen, reacted at 90 °C for 6 hours, and solvent was removed. Column chromatography (petroleum ether: ethyl acetate (v/v) = 100:1-50:1) to give 1-(1-cyclopropylvinyl)-3-isopropyl-2-methoxy Benzene (5C) (1.10 g, yield 56.6%).

Third step: 1-(1-cyclopropylethyl)-2-isopropyl-2-methoxybenzene (compound 5)

1-(1-cyclopropylethyl)-3-isopropyl-2-methoxybenzene

1-(1-Cyclopropylvinyl)-3-isopropyl-2-methoxybenzene (5C) (108 mg, 2.02 mmol) and triethyldecane (0.47 g, 4.03 mmol) were added at room temperature To dichloromethane (10 mL), trifluoroacetic acid (0.46 g, 4.03 mmol) was then added dropwise at 0 ° C. The reaction was quenched by the addition of 20 mL of EtOAc EtOAc (EtOAc (EtOAc) After concentration under reduced pressure, the residue was purified to purified crystals eluted elution 2-isopropyl-2-methoxybenzene (Compound 5) (198 mg, yield 45%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.19-7.21 (m, 1H), 7.09-7.11 (m, 2H), 3.68 (s, 3H), 3.29-3.36 (m, 1H), 2.42-2.49 (m, 1H), 1.29 (d, 3H), 1.24 (d, 6H), 0.97-1.01 (m, 1H), 0.52-0.58 (m, 1H), 0.34-0.39 (m, 1H), 0.20-0.24 (m, 1H), 0.13-0.17 (m, 1H).

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

2-Bromo-6-((R)-1-cyclopropylethyl)phenyl((S)-1-phenylethyl)carbamate (6A) (3.2 g, 8.24 mmol), 2- (1-cyclohexylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (Compound 1) (3.2 g, 16.48 mmol) and aqueous potassium carbonate (10.5 ml) , 4 mol/L) was added to 50 ml of toluene, and then the catalyst [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.603 g, 0.824 mmol of petroleum ether: ethyl acetate (v) was added. /v)), replacing nitrogen three times, nitrogen protection, reaction at 90 ° C for 5 hours, solvent removal, residue column chromatography (petroleum ether: ethyl acetate (v / v) = 100:1-50:1) Purification of 2-((R)-1-cyclopropylethyl)-6-(1-cyclopropylvinyl)phenyl((S)-1-phenylethyl)carbamate as a yellow solid Compound 6) (0.9 g, yield 29.1%).

MS m/z (ESI): 376.1 [M+H] ⁺ .

Although the present invention has been described above by way of examples, the embodiments are not intended to limit the invention. It is to be understood by those of ordinary skill in the art that the invention may be practiced or modified without departing from the spirit and scope of the invention.

Claims (20)

A process for the preparation of a compound of the formula (I) and a stereoisomer thereof, characterized in that the compound of the formula (I) is obtained by a reduction reaction of a compound of the formula (II) and a stereoisomer thereof; Wherein R is selected from H or a hydroxy protecting group; R ^{1 is} selected from methyl, ethyl or cyclopropyl; and n is selected from 1, 2 or 3. The preparation method of claim 1, wherein n is 1. The preparation method according to claim 2, characterized in that the preparation method uses hydrogen to catalyze a reduction reaction under the action of a catalyst, or uses trimethyl decane + acid, triethyl decane + acid, NH ₂ Reduction reaction of NH ₂ , B ₂ H ₆ + peroxyacid, KO ₂ CN=NCO ₂ K or Hans ester 1,4-dihydropyridine; the catalyst is selected from a supported metal catalyst or a metal complex, The metal is selected from the group consisting of Pt, Pd, Ni, Ru, Ir or Rh; the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or p-toluenesulfonic acid; and the peroxyacid is selected from the group consisting of peroxybenzoic acid, m- CPBA or peracetic acid. The preparation method according to claim 3, wherein the solvent used in the preparation method is selected from the group consisting of water, methanol, hexafluoroisopropanol, trifluoroethanol, ethanol, isopropanol, and dioxane. Ring, chloroform, acetone, acetic acid, dimethyl hydrazine, dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, 2-methyltetrahydrofuran, methyl t-butyl ether, diethyl ether, N, N - dimethylformamide, benzene, toluene, fluorinated benzene, 1,2-difluorobenzene, p-bromofluorobenzene, 2,3-difluorobromobenzene, hexafluorobenzene, bromopentafluorobenzene, xylene, a mixture of any one or more of trimethylbenzene, 1,3,5-tris(trifluoromethyl)benzene and trifluoromethylbenzene in any ratio; and the catalyst is selected from the group consisting of palladium carbon, Raney nickel, [Rh ( NBD)Cl] ₂ /SL-W012-1, [Rh(NBD)Cl] ₂ /SL-W012-2[Rh(COD) ₂ ]O ₃ SCF ₃ /SL-W012-2,[Rh(COD) ₂ ]O ₃ SCF ₃ /SL-W012-1, [Rh(NBD)Cl] ₂ /-(-)-1-[(S)-2-di-t-butylphosphino)ferrocene]ethyldi- (4-Trifluoromethylphenyl)phosphorus, [Rh(COD) ₂ ]O ₃ SCF ₃ /-(-)-1-[(S)-2-di-t-butylphosphino)ferrocene]ethyl Di-(4-trifluoromethylphenyl)phosphine or [Ru(COD)(OAc) ₂ ]/-(-) 1-[(S)-2-di-t-butylphosphonium)ferrocene]ethylbis-(4-trifluoromethylphenyl)phosphine. A method for preparing a compound represented by the formula (II) and a stereoisomer thereof, characterized in that the compound of the formula (II) is a compound of the formula (III) or a compound of the formula (III'), and a formula (IV) a compound and a stereoisomer coupling reaction thereof, 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; R ^{1 is} selected from methyl, ethyl or cyclopropyl; R ² , R ³ , R ⁴ Each is independently selected from H, OH, F, Cl, Br or C _1-6 alkoxy, or R ² and R ² together with the atoms to which they are attached form a 4-10 membered ring, when R ² and R ³ form a ring The ring contains, in addition to the hetero atom B, 0 to 4 hetero atoms selected from O, N or S, and the ring is optionally 0 to 4 selected from H, C _1-6 alkyl or C ₁ Substituted by a substituent of _-6 alkoxy; and n is selected from 1, 2 or 3. The preparation method according to claim 5, wherein X is selected from Br; and the compound of formula (III) is selected from the group consisting of or And the compound of formula (III') is . The preparation method according to claim 6, wherein the coupling reaction is carried out under the action of a catalyst selected from the group consisting of a supported metal catalyst or a metal complex selected from the group consisting of Pd and Ru. , Ir, Rh or Ni; the solvent used in the coupling reaction is selected from the group consisting of toluene, dioxane, tetrahydrofuran, dimethyl hydrazine, N,N-dimethylformamide, water, methanol, ethanol, a mixture of any one or more of ethylene glycol dimethyl ether and dichloroethane in any ratio; and the coupling reaction is added to an alkaline agent 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, potassium fluoride, tert-butylamine, N,N-diisopropylethylamine, tributylamine And a mixture of any one or more of pyridine. The preparation method according to the seventh aspect of the invention, wherein R is H, S- (1-phenyl)ethylaminocarbonyl or R- (1-phenyl)ethylaminocarbonyl; The catalyst used in the coupling reaction is selected from the group consisting of Pd(OAc) ₂ , Pd(OAc) ₂ /S-Phos, Pd(OAc) ₂ /RuPhos, (PhCN) ₂ PdCl ₂ , Ni(cod) ₂ , NiCl ₂ - Diglymc, 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. A process for the preparation of a compound of the formula (III) or formula (III'), characterized in that: The formula (III) is prepared by reacting 1-cycloalkylacetylene, 1-cycloalkyl-1-(trifluoromethanesulfonyloxy)ethylene or 1-cycloalkyl-1-haloethylene with boric acid or boric acid ester. Or a compound of the formula (III'); wherein R ¹ , R ² , R ³ , R ⁴ , M, n are as described in item 5 of the scope of the patent application. The preparation method according to claim 9, wherein the boric acid or boric acid ester is selected from the group consisting of 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 a mixture of any one or more of any one of water, methanol or ethanol; the reaction is added to an alkaline agent selected from the group consisting of potassium acetate, sodium acetate, sodium butoxide or potassium t-butoxide. Any one or more of any mixture in any ratio. A method for preparing a compound represented by the formula (I) and a stereoisomer thereof, characterized in that: Step a: reacting a general formula (V) with a boronic acid or a boronic acid ester to obtain a compound of the formula (III) or formula (III'); the boronic acid or boric acid ester is selected from the group consisting of or ; Step b: the role of a catalyst and an alkaline reagent, by formula (III) or formula (III ^`), the coupling reaction was prepared isomeric compounds of general formula (IV) with its perspective of formula (II) a compound and a stereoisomer thereof, the catalyst used in the step b is selected from the group consisting of Pd(OAc) ₂ , Pd(OAc) ₂ /S-Phos, Pd(OAc) ₂ /RuPhos, (PhCN) ₂ PdCl ₂ , Ni (cod) ₂ , NiCl ₂ -diglyme, PdCl ₂ -PEPPSI-iPr, PdCl ₂ /t-Bu ₃ P, PdCl ₂ /(Cy) ₃ P, Pd(dppf)Cl ₂ , Pd(PPh ₃ ) ₄ , Pd (PPh ₃ ) ₂ Cl ₂ or Pd2(dba)3/t-Bu3P; Step c: preparing a compound of the formula (I) by reacting a compound of the formula (II) and a stereoisomer thereof with hydrogen under a catalyst Stereoisomers, or by the compound of formula (II) and its stereoisomers with trimethyldecane and acid, triethyldecane and acid, NH ₂ NH ₂ , B ₂ H ₆ and peroxyacid, KO ₂ CN =NCO ₂ K or Hans ester 1,4-dihydropyridine is subjected to a reduction reaction to obtain a compound of the formula (I) and a stereoisomer thereof, and the catalyst used in the step c is selected from a supported metal catalyst or a metal complex; The metal is selected from the group consisting of Pt, Pd, Ni, Ru, Ir or Rh; the acid 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; 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; and R ² and R ³ are each independently selected from H, OH, F , Cl, Br, or C _1-6 alkoxy, or R ² and R ³ together with the atom to which they are attached form a 4-10 membered ring, and when R ² and R ³ form a ring, the ring contains a hetero atom Further, it contains 0 to 4 hetero atoms selected from O, N or S, and the ring is optionally subjected to 0 to 4 substituents selected from H, C _1-6 alkyl or C _1-6 alkoxy groups. Substituted; R ⁴ is F; and R ^{5 is} selected from H, OH, F, Cl, Br, or C _1-6 alkoxy. The preparation method according to claim 11, wherein the step (a) and the formula (V) are or The reaction gives a compound of the formula (III') of the formula (III); the solvent used in the step b is selected from the group consisting of toluene, methanol, ethanol, dioxane, tetrahydrofuran, N,N-dimethylformamide or ethylene glycol. a mixture of any one or more of dimethyl ether in any ratio; the alkaline agent used is selected from the group consisting of sodium carbonate, potassium carbonate, potassium hydrogencarbonate, potassium acetate or potassium phosphate; the solvent used in step c is selected from the group consisting of water, methanol, Hexafluoroisopropanol, trifluoroethanol, ethanol, isopropanol, dioxane, chloroform, acetone, acetic acid, dimethyl hydrazine, dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, Methyltetrahydrofuran, methyl tert-butyl ether, diethyl ether, N,N-dimethylformamide, benzene, toluene, fluorinated benzene, 1,2-difluorobenzene, p-bromofluorobenzene, 2,3- Any one or more mixtures of difluorobromobenzene, hexafluorobenzene, bromopentafluorobenzene, xylene, trimethylbenzene, tris(trifluoromethyl)benzene or trifluoromethylbenzene in any ratio; selected reducing reagents triethyl + Silane acid; is R & lt H, S - (1- phenyl) ethyl aminocarbonyl or R - (1- phenyl) ethyl aminocarbonyl group; and X is selected from Br; M is selected from Na or K; n is 1. The preparation method according to claim 12, wherein R ¹ is a methyl group; and n is 1. a compound of the formula (II) or the formula (IV) and a stereoisomer thereof, wherein Formula (II): 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; Formula (IV): R is selected from S -(1- phenyl) ethyl aminocarbonyl or R - (1- phenyl) ethyl aminocarbonyl; R ¹ is selected from methyl, ethyl or cyclopropyl; X is selected Cl, Br or I. The compound of claim 14 and the stereoisomer thereof, wherein n is 1. A compound of the formula (III): Wherein R ² and R ³ are each independently selected from H, OH, F, Cl, Br or C _1-6 alkoxy, or R ² and R ³ together with the atom to which they are attached form a 4-10 membered ring, when R ² And when R ³ forms a ring, the ring further contains 0 to 4 hetero atoms selected from O, N or S in addition to the hetero atom B, and the ring is optionally selected from 0 to 4 selected from H, C _1- Substituted by a substituent of a ₆ alkyl group or a C _1-6 alkoxy group; n is selected from 1, 2 or 3. a compound represented by the formula (III'), wherein R ² and R ³ are as defined in claim 16, wherein R ⁴ is F; M is selected from Na, K or Li; and n is selected from 1, 2 or 3. The compound of claim 16, wherein the compound of the formula (III) is selected from one of the following structures: The compound of claim 17, wherein the compound of the formula (III') is selected from the group consisting of: The compound according to claim 14, wherein the compound represented by formula (II) or formula (IV) and stereoisomer thereof are selected from one of the following structures: