CN116535418A - Synthesis method and application of chiral N- (1-substituted-allyl) amine - Google Patents

Synthesis method and application of chiral N- (1-substituted-allyl) amine Download PDF

Info

Publication number
CN116535418A
CN116535418A CN202211703066.8A CN202211703066A CN116535418A CN 116535418 A CN116535418 A CN 116535418A CN 202211703066 A CN202211703066 A CN 202211703066A CN 116535418 A CN116535418 A CN 116535418A
Authority
CN
China
Prior art keywords
allyl
chiral
amine
substituted
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202211703066.8A
Other languages
Chinese (zh)
Inventor
可汗
希德
王钰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xian Jiaotong University
Original Assignee
Xian Jiaotong University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Xian Jiaotong University filed Critical Xian Jiaotong University
Priority to CN202211703066.8A priority Critical patent/CN116535418A/en
Publication of CN116535418A publication Critical patent/CN116535418A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a synthesis method and application of chiral N- (1-substituted-allyl) amine, which successfully realizes asymmetric allylic ammonification reaction catalyzed by molybdenum, avoids the use of complex chiral phosphine ligands which are difficult to synthesize, and has the advantages of wide substrate range, specific stereoselectivity, specific chemical reaction sites, easily obtained raw materials, simple and convenient operation, mild reaction conditions and the like. The method provides more options for green synthesis of chiral allylamine, can be applied to total synthesis of natural products, and simultaneously performs practical operation on total synthesis of the drug clopidogrel for inhibiting platelet aggregation.

Description

Synthesis method and application of chiral N- (1-substituted-allyl) amine
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method and application of chiral N- (1-substituted-allyl) amine.
Background
Asymmetric amination reactions of transition metal catalyzed allylic nucleophiles are one of the most common and powerful strategies used industrially and academia to prepare chiral a-branched allylic amines. However, overwhelmingly predominance in this area of research is palladium catalysis, as well as the manner in which iridium, rhodium, and ruthenium add chiral phosphine ligands, and cobalt and nickel catalysis (chem. Soc. Rev.2020, 49, 6141.). The use of chiral phosphine ligands, which are costly and require multi-step syntheses, makes the above reactions uneconomical and practical. Thus, the development of metal catalyzed approaches that do not require phosphine ligands is a strong need for asymmetric amination processes.
Molybdenum is gradually becoming a substitute for palladium, rhodium and iridium in transition metal catalysis due to the characteristics of low cost, environmental friendliness, abundant stock and the like. However, molybdenum catalyzes asymmetric allylic nucleophile heteroatom substitution remains a great challenge because there is no suitable chiral ligand.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide a synthesis method and application of chiral N- (1-substituted-allyl) amine, so as to solve the technical problem that asymmetric allylic ammonification reaction cannot be realized due to no verified chiral ligand in the prior art molybdenum catalysis process.
In order to achieve the above purpose, the invention is realized by adopting the following technical scheme:
the invention discloses a synthetic method of chiral N- (1-substituted-allyl) amine, which comprises the following steps: stirring allyl carbonate and amine under the action of Schiff base ligand and metallic molybdenum catalyst for reaction, standing the stirred mixture at 30 ℃ for 24 hours, removing reaction solvent, and separating and purifying by column chromatography to obtain chiral N- (1-substituted-allyl) amine; wherein:
the structural formula of the reactant allyl carbonate is as follows:
R 1 is alkyl, aryl or aryl;
the structural formula of the reactant amine is as follows:
R 2 is aryl or aryl; r is R 3 Is H or alkyl;
the structural formula of the chiral N- (1-substituted-allyl) amine of the product is as follows:
preferably, the metallic molybdenum catalyst is selected (C 7 H 8 )Mo(CO) 3 。
Preferably, the molar ratio of metallic molybdenum catalyst to schiff base ligand is l:1.5.
preferably, the molar ratio of allyl carbonate to amine is 1:1.2.
preferably, the reaction solvent is selected from dichloromethane.
The invention also discloses application of the synthesis method of chiral N- (1-substituted-allyl) amine, which is used for realizing total synthesis of clopidogrel.
Preferably, it comprises: stirring and reacting an allyl carbonate compound shown in the following formula I and an amine compound shown in the formula II under the action of a Schiff base ligand and a metal molybdenum catalyst, standing the stirred and generated mixture at 30 ℃ for 24 hours, removing a reaction solvent, and separating and purifying by column chromatography to obtain an intermediate compound shown in the following formula III;
the intermediate compound is converted into chiral drug clopidogrel in two steps;
the chiral drug clopidogrel has the following structural formula:
preferably, the two-step conversion reaction comprises:
the first step: in sodium iodide and RuCl 3 .H 2 Under the action of O, the compound III is dissolved in CCl4, meCN and DCM, stirred at room temperature for 6H, and the reaction solution is poured into DCM/H 2 Separating in O, and drying an organic layer to obtain a crude reaction product;
and a second step of: adding TMSCHN into the crude reaction product 2 Stirring at room temperature for 2h, and purifying by silica gel column chromatography to obtain (S) -clopidogrel.
Compared with the prior art, the invention has the following beneficial effects:
the invention successfully realizes the asymmetric allylic ammonification reaction catalyzed by molybdenum, avoids the use of complex chiral phosphine ligands which are difficult to synthesize, and has the advantages of wide substrate range, specific stereoselectivity, specific chemical reaction sites, easily obtained raw materials, simple and convenient operation, mild reaction conditions and the like. The method provides more options for green synthesis of chiral allylamine, can be applied to total synthesis of natural products, and simultaneously performs practical operation on total synthesis of the drug clopidogrel for inhibiting platelet aggregation.
Detailed Description
In order that the manner in which the invention may be better understood, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings. All other embodiments, which can be made by those skilled in the art based on the embodiments of the present invention without making any inventive effort, shall fall within the scope of the present invention.
It should be noted that the terms "and" having "and any variations thereof in the description and claims of the present invention are intended to cover a non-exclusive inclusion, such that a process, method, system, article, or apparatus that comprises a list of steps or elements is not necessarily limited to those steps or elements that are expressly listed or inherent to such process, method, article, or apparatus.
The invention discloses a series of chiral N- (1-substituted allyl) aryl and alkylamine reaction equations as follows:
specifically, general synthetic examples:
magnetic stirring is arranged in the dried reaction tube, and then the metal catalyst (C7H is added in turn 8 )Mo(CO) 3 (912mg,10 mol%), schiff base (imine) ligand (S, S) -L2 (16.4 mg,15 mol%), allyl carbonate 1 (0.2 mmol) and amine 2 (0.24 mmol). The reaction tube is sealed by a rubber interlayer, and then vacuumized and backfilled with nitrogen. Anhydrous CH is added into a syringe 2 Cl 2 (0.5 mL). The resulting mixture was stirred and left at 30℃for 24 hours (under a nitrogen balloon). The reaction mixture was transferred to a 50ml round bottom flask and the solvent was removed in vacuo with the aid of a rotary evaporator. Purifying the residue by silica gel column chromatography to obtain the product allylamine 3 with high purity.
The invention also discloses a method for fully synthesizing the chiral drug clopidogrel based on the synthesis principle, which comprises the following two steps of reactions:
the first step: asymmetric synthesis of clopidogrel intermediate 3dm by using the catalytic route of the invention
(R) -5- (1- (2-chlorophenyl) allyl) -4,5,6, 7-tetrahydrothiophene [3,2-c ] pyridine (3 dm)
The reaction equation is as follows:
magnetic stirring is arranged in the dried reaction tube, and then the metal catalyst (C 7 H 8 )Mo(CO) 3 (16.3 mg,10 mol%), schiff base (imine) ligand (S, S) -L2 (49.2 mg,15 mol%), allyl carbonate 1d (161.2 mg,0.6 mmol) and amine 2m (100.2 mg,0.72 mmol). The reaction tube is sealed by a rubber interlayer, and then vacuumized and backfilled with nitrogen. Anhydrous CH is added into a syringe 2 Cl 2 (1.5 mL). The resulting mixture was stirred and left at 30 ℃ for 24 hours (under nitrogen sphere). The reaction mixture was transferred to a 50ml round bottom flask and the solvent was removed in vacuo with the aid of a rotary evaporator. The residue was purified by silica gel column chromatography to give 3dm 161.7mg of colorless oily liquid in 97% yield and ee > 99%.
Characterization data: [ alpha ]] 25 D ＝217.4(c＝0.14，CHCl 3 ).Lit.data：[α] 20 D ＝41.3(c＝1.0，CHCl 3 )； 1 H NMR(400MHz，CDCl 3 )δ7.66(dd，J＝1.8，7.8Hz，1H)，7.36(dd，J＝1.8，7.8Hz，1H)，7.28(ddd，J＝1.2，7.4，15.0Hz，1H)，7.17(ddd，J＝1.7，7.9，15.2Hz，1H)，7.06(d，J＝5.2Hz，1H)，6.69(d，J＝5.2Hz，1H)，5.895.80(m，1H)，5.40(dd，J＝17.1，1.4Hz，1H)，5.12(dd，J＝10.0，1.5Hz，1H)，4.50(d，J＝8.8Hz，1H)，3.71(d，J＝14.6Hz，1H)，3.45(d，J＝14.6Hz，1H)，2.892.77(m，4H)； 13 C NMR(100MHz，CDCl 3 )δ139.5，139.0，134.0，133.7，133.6，129.7，129.0，128.0，127.3，125.4，122.6，116.8，68.8，51.6，48.7，25.5；HRMS(ESI-MS)：Calcd.for C16H 16 ClNS[M+H]+：290.0765，Found：290.0765；HPLC conditions：Chiralcel OJ-H column，254nm，flow rate：1ml/min，i-PrOH/hexanes＝5/95，t minor ＝5.05min，t major ＝6.15min；＞99％ee.
And a second step of: the intermediate 3dm is converted into chiral drug clopidogrel 7 by two steps
(S) -methyl 2- (2-chlorophenyl) -2- (6, 7-dihydrothiophene [3,2-c ] -5 (4H) -pyridine) acetate (7)
The reaction equation is as follows:
sodium iodide (642.0 mg,3.0mmol,10.0 equiv) and RuCl were added to a 10ml dry reaction tube equipped with a stirring bar 3 .H 2 O (6.8 mg,10 mol%) was sealed with a rubber septum to fill N 2 And (3) air. Compound (R-3 dm) (87 mg,0.3 mmol) was dissolved in CCl 4 (1.5 mL), meCN (1.0 mL) and DCM (1.0 mL) were added to the reaction tube and stirred at room temperature for 6 hours. The reaction solution was poured into 1:1 DCM/H 2 O (10 m 1). The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over anhydrous MgSO 4 Drying, filtering and concentrating in vacuum. TMSCHN2 (342.6 mg,0.3mmol,10.0 equiv) was added to the crude product and the reaction was stirred at room temperature for 2h. After the concentration reaction, purification was performed on silica gel by flash column chromatography,the viscous oil product with the purity of (S) -clopidogrel is obtained, 60.8mg of target product 7 is obtained by separation, and the yield is 63% by combining the two steps. Characterization of data: [ alpha ]] 25 D ＝+89.9(c＝1.1，CHCl 3 ).Lit.data：[α] 25 D＝+89.9(c＝1.1，CHCl 3 )； 1 H NMR(400MHz，CDCl3)δ7.70(d，J＝7.1Hz，1H)，7.41(d，J＝7.1Hz，1H)，7.31 7.23(m，2H)，7.05(d，J＝5.0Hz，1H)，6.67(d，J＝5.0Hz，1H)，4.92(s，1H)，3.76(d，J＝14.4Hz，1H)，3.72(s，3H)，3.63(d，J＝14.4Hz，1H)，2.28(s，4H)； 13 C NMR(100MHz，CDCl 3 )δ171.3，134.6，133.7，133.2，133.1，129.9，129.7，129.4，127.1，125.2，122.7，67.8，52.1，50.6，48.2，25.4；HRMS(ESI-MS)：Calcd.for C 16 H 17 ClNO 2 S[M+H]+：322.0663，Found：322.0665.
General embodiment a:
magnetic stirring is arranged in the dried reaction tube, and then the metal catalyst (C 7 H 8 )Mo(CO) 3 (9.12 mg,10 mole 1%), schiff base (imine) ligand (S, S) -L2 (16.4 mg,15 mole%), allyl carbonate 1 (0.2 mmol) and amine 2 (0.24 mmol). The reaction tube is sealed by a rubber interlayer, and then vacuumized and backfilled with nitrogen. Anhydrous CH is added into a syringe 2 Cl 2 (0.5 mL). The resulting mixture was stirred and left at 30℃for 24 hours (under a nitrogen balloon). The reaction mixture was transferred to a 50ml round bottom flask and the solvent was removed in vacuo with the aid of a rotary evaporator. Purifying the residue by silica gel column chromatography to obtain the product allylamine 3 with high purity.
Example 1 preparation of (R) -4-methoxy-N- (1-phenylallyl) aniline (3 aa)
From allyl la and p-methoxyaniline 2a as reaction substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=50: 1, 44mg (R) -4-methoxy-N- (1-phenylallyl) aniline (3 aa) were isolated in 92% yield.
Characterization of data:
[α] 25 D ＝+24.3(c＝0.72，CHCl3).Lit.data(S-isomer)：[α] 25 D ＝16.7(c＝1.0，CHCl 3 )； 1 H NMR(400MHz，CDCl 3 )δ7.397.32(m，4H)，7.287.24(m，lH)，6.756.71(m，2H)，6.586.54(m，2H)，6.075.99(m，1H)，5.27(dt，J＝17.1，1.3Hz，1H)，5.2l(dt，J＝10.2，1.3Hz，1H)，4.85(d，J＝6.0Hz，1H)，3.84(brs，1H)，3.72(s，3H)； 13 C NMR(100MHz，CDCl 3 )δ152.1，124.1，141.4，139.5，128.7，127.3，127.1，115.8，114.8，114.7，61.7，55.7；HRMS(ESI-MS)：Calcd.for C 16 H 1 7NO[M] + ：239.13，Found：239.1311；HPLC conditions：Chiralcel OD-H column，254nm，flow rate：1 ml/min，j-PrOH/hexanes＝1/19，t ma jor＝6.93min，t min or＝8.39min；96％ee.
the structural formula of (R) -4-methoxy-N- (1-phenylallyl) aniline (3 aa) is as follows:
example 2 preparation of (R) -4-methoxy-N- (1- (4-methoxyphenyl) allyl) aniline (3 ba)
From p-methoxyallylbenzene 1b and p-methoxyaniline 2a as reaction substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=40: 1. 50mg of (R) -4-methoxy-N- (1- (4-methoxyphenyl) allyl) aniline (3 ba) was isolated in 93% yield.
Characterization data: [ alpha ]] 25 D ＝+128.9(c＝0.23，CHCl 3 )； 1 H NMR(400MHz，CDCl 3 )δ7.31 7.27(m，2H)，6.896.86(m，2H)，6.756.71(m，2H)，6.586.54(m，2H)，6.055.97(m，1H)，5.25(dt，J＝17.2，1.2Hz，1H)，5.19(dt，J＝10.2，1.2Hz，1H)，4.80(d，J＝6.0Hz，1H)，3.80(s，3H)，3.78(brs，1H)，3.72(s，3H)； 13 C NMR(100MHz，CDCl 3 )δ158.8，152.1，141.5，139.6，134.2，128.2，115.5，114.8，114.7，114.0，61.1，55.7，55.3；HRMS(ESI-MS)：Calcd.for C 17 H 19 NO 2 [M+H] + ：270.1489，Found：270.1488；HPLC conditions：Chiralcel OD-H column，254nm，flow rate：1ml/min，i-PrOH/hexanes＝1/19，t minor ＝10.11min，t major ＝12.37min；92％ee.
(R) -4-methoxy-N- (1- (4-methoxyphenyl) allyl) aniline (3 ba) has the following structural formula:
EXAMPLE 3 preparation of (R) -N- (1- (4-chlorophenyl) allyl) -4-methoxyaniline (3 ca)
The crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=50: 1. 44.9mg was isolated in 82% yield.
Characterization of data: [ alpha ]] 25 D ＝+132.3(c＝0.2，CHCl 3 )； 1 H NMR(400MHz，CDCl 3 )δ7.30(s，4H)，6.746.70(m，2H)，6.546.50(m，2H)，6.035.94(m，1H)，5.23(dt，J＝17.2，1.3Hz，1H)，5.20(dt，J＝10.2，1.3Hz，1H)，4.82(d，J＝6.0Hz，1H)，3.71(s，3H)；13C NMR(100MHz，CDCl 3 )δ152.4，140.9，140.6，139.0，133.0，128.8，128.5，116.4，115.0，114.7，61.3，55.7；HRMS(ESI-MS)：Calcd.for C 16 H 16 ClNO[M+H] + ：274.0993，Found：274.0975；HPLC conditions：Chiralcel OD-H column，254nm，flow rate：1ml/min，i-PrOH/hexanes＝1/19，t ma jor＝7.78min，tminor＝10.87min；91％ee.
The structural formula of (R) -N- (1- (4-chlorophenyl) allyl) -4-methoxyaniline (3 ca) is as follows:
example 4 preparation of (R) -N- (1- (2-chlorophenyl) allyl) -4-methoxyaniline (3 da)
From allyl benzene 1d and p-methoxyaniline 2a as reaction substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=50: 1. isolation gave 49.8mg, 91% yield.
Characterization of data: [ alpha ]]25D＝+157.8(c＝0.3，CHCl3)；1H NMR(400MHz，CDCl3)δ7.45(dd，J＝2.0，7.2Hz，1H)，7.38(dd，J＝2.0，8.4Hz，1H)，7.247.16(m，2H)，6.736.69(m，2H)，6.526.48(m，2H)，6.075.99(m，1H)，5.33(d，J＝5.6Hz，1H)，5.235.18(m，2H)，3.69(s，3H)；13C NMR(100MHz，CDCl3)δ152.3，140.8，139.0，137.6，133.4，129.7，128.4，128.1，127.2，116.6，114.7，114.6，57.7，55.6；HRMS(ESI-MS)：Calcd.for C 16 H 16 ClNO[M+Na] + ：296.0812，Found：296.0836；HPLC conditions：Chiralcel OJ-H column，254nm，flow rate：1ml/min，i-PrOH/hexanes＝3/97，t ma jo r ＝21.1min，t min or＝27.01min；92％ee.
The structural formula of (R) -N- (1- (2-chlorophenyl) allyl) -4-methoxyaniline (3 da) is as follows:
example 5 preparation of (R) -4-methoxy-N- (1- (m-tolyl) allyl) aniline (3 ea)
From m-methallyl benzene 1e and p-methoxyaniline 2a as reaction substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=50: 1. isolation gave 43.5mg, 86% yield.
Characterization of data: [ alpha ]] 25 D ＝+222.1(c＝0.12，CHCl 3 )； 1 H NMR(400MHz，CDC1 3 )δ7.257.16(m，3H)，7.08(d，J＝7.6Hz，1H)，6.756.71(m，2H)，6.586.54(m，2H)，6.055.97(m，1H)，5.27(dt，J＝17.2，1.2Hz，1H)，5.19(dt，J＝10.0，1.6Hz，1H)，4.80(d，J＝6.0Hz，1H)，3.71(s，3H)，2.34(s，3H)； 13 C NMR(100MHz，CDCl 3 )δ152.1，142.1，141.5，139.6，138.3，128.6，128.1，127.8，124.1，115.6，114.8，114.7，61.8，55.7，21.4；HRMS(ESI-MS)：Calcd.forC 17 H 19 NO[H] + ：253.1467，Found：253.1461；HPLC conditions：Chiralcel OJ-H column，254nm，flow rate：1ml/min，i-PrOH/hexanes＝3/97，tmajor＝24.37min，t minor ＝26.28min；92％ee.
The structural formula of (R) -4-methoxy-N- (1- (m-tolyl) allyl) aniline (3 ea) is as follows:
EXAMPLE 6 preparation of (R) -N- (1- (3, 4-dimethoxyphenyl) allyl) -4-methoxyaniline (3 fa)
From 3, 4-dimethoxyallylbenzene 1f and p-methoxyaniline 2a as reaction substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=40: 1. 54.5mg was isolated in 91% yield.
Characterization of data: [ alpha ]] 25 D ＝+108.6(c＝0.24，CHCl 3 )； 1 H NMR(400MHz，CDCl 3 )δ6.946.90(m，2H)，6.84(d，J＝8.0Hz，1H)，6.766.72(m，2H)，6.596.55(m，2H)，6.065.97(m，1H)，5.27(dt，J＝17.2，1.2Hz，1H)，5.20(dt，J＝10.0，1.2Hz，1H)，4.79(d，J＝6.0Hz，1H)，3.87(s，3H)，3.86(s，3H)，3.72(s，3H)；13C NMR(100MHz，CDCl 3 )δ152.2，149.1，148.2，141.5，139.5，136.9，134.7，115.7，114.9，114.7，111.2，110.2，61.5，55.9，55.8，55.7；HRMS(ESI-MS)：Calcd.for C 18 H 21 NO 3 [M+Na]：322.1419，Found：322.1439；HPLC conditions：Chiralcel OJ-H column，254nm，flowrate：1ml/min，i-PrOH/hexanes＝5/95，t major ＝24.4min，t minor ＝29.26min；93％ee.
The structural formula of (R) -N- (1- (3, 4-dimethoxyphenyl) allyl) -4-methoxyaniline (3 fa) is as follows:
EXAMPLE 7 preparation of (R) -4-methoxy-N- (1- (2-naphthyl) allyl) aniline (3 ga)
From 1g of 2-allylnaphthalene and p-methoxyaniline 2a as reaction substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=50: 1. isolation gave 48mg, 83% yield.
Characterization of data: [ alpha ]] 25 D ＝+168.6(c＝0.12，CHCl 3 )； 1 H NMR(400MHz，CDCl 3 )δ7.837.79(m，4H)，7.507.42(m，3H)，6.736.69(m，2H)，6.61 6.57(m，2H)，6.146.06(m，1H)，5.30(dt，J＝17.2，1.2Hz，1H)，5.24(dt，J＝10.0，1.2Hz，1H)，5.01(d，J＝6.0Hz，1H)，3.69(s，3H)； 13 C NMR(100MHz，CDCl 3 )δ152.3，141.3，139.5，139.3，133.5，132.9，128.5，127.9，127.6，126.1，125.8，125.7，125.4，116.2，115.0，114.7，62.0，55.7；HRMS(ESI-MS)：Calcd.for C 20 H 19 NO[M+H] + ：290.1539，Found：290.1518；HPLC conditions：Chiralcel OD-H column，254nm，flow rate：1 ml/min，i-PrOH/hexanes＝5/95，t major ＝10.40min，t minor ＝13.03min；94％ee.
The structural formula of (R) -4-methoxy-N- (1- (2-naphthyl) allyl) aniline (3 ga) is as follows:
example 8 preparation of (R) -4-methoxy-N- (1- (3-pyridyl) allyl) aniline (3 ha)
From 3-allylpyridine 1h and p-methoxyaniline 2a as reaction substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=20: 1. isolation gave 39.4mg, 82% yield.
Characterization of data: [ alpha ]] 25 D ＝+34.1(c＝0.68，CHCl 3 )； 1 H NMR(400MHz，CDCl 3 )δ8.64(d，J＝2.0Hz，1H)，8.53(dd，J＝2.4，4.8Hz，1H)，7.71 7.69(m，1H)，7.307.27(m，1H)，6.756.71(m，2H)，6.566.52(m，2H)，6.075.98(m，1H)，5.292.24(m，2H)，4.92(d，J＝6.0Hz，1H)，3.72(s，3H)； 13 C NMR(100MHz，CDCl 3 )δ152.5，149.2，148.8，140.7，138.5，137.5，134.6，123.6，117.0，115.1，114.8，59.5，55.7；HRMS(ESI-MS)：Calcd.for C 15 H l6 N 2 O[M+H] + ：241.1335，Found：241.1334；HPLC conditions：Chiralcel IC column，254nm，flow rate：lml/min，i-PrOH/hexanes＝20/80，t major ＝7.68min，t minor ＝8.30min：91％ee.
The structural formula of (R) -4-methoxy-N- (1- (3-pyridyl) allyl) aniline (3 ha) is as follows:
EXAMPLE 9 Synthesis of (R) -4-methoxy-N- (1- (2-thienyl) allyl) aniline (3 ia)
From 2-allylthiophene 1i and p-methoxyaniline 2a as reaction substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=50: 1. isolation gave 37.2mg, 76% yield.
Characterization of data: [ alpha ]] 25 D ＝+66.4(c＝0.48，CHCl 3 )； 1 H NMR(400MHz，CDCl 3 )δ7.24(dd，J＝1.6，4.8Hz，1H)，7.006.96(m，2H)，6.786.74(m，2H)，6.656.61(m，2H)，6.096.01(m，1H)，5.35(dt，J＝16.8，1.2Hz，1H)，5.25(dt，J＝10.4，1.2Hz，1H)，5.13(d，J＝6.0Hz，1H)，3.82(brs，1H)，3.74(s，3H)； 13 C NMR(100MHz，CDCl 3 )δ152.2，140.4，138.2，134.3，127.4，126.0，124.1，123.3，114.8，114.5，59.2，55.4；HRMS(ESI-MS)：Calcd.for C 14 H 15 NOS[M+NH4] + ：263.1213，Found：263.1234；HPLC conditions：Chiralcel OD-H column，254nm，flow rate：1 ml/min，i-PrOH/hexanes＝5/95，t major ＝7.04min，t minor ＝8.39min；92％ee.
The structural formula of (R) -4-methoxy-N- (1- (2-thienyl) allyl) aniline (3 ia) is as follows:
example 10 preparation of (S) -4-methoxy-N- (1-phenylallyl) aniline (3 ja)
From the reaction substrates of the allylbenzene 1i and p-methoxyaniline 2a, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=60: 1. 49.2mg was isolated in 92% yield.
Characterization of data: [ α ] 25d= +51.6 (c=0.52, chcl 3). Lit.data (R-enantiomcr), [ α ] 25d=10.7 (c=1.0, chcl 3); 1H NMR (400 mhz, cdcl 3) δ 7.307.17 (m, 5H), 6.796.72 (m, 2H), 6.546.50 (m, 2H), 5.795.71 (m, 1H), 5.20 (dt, j=17.2, 1.2hz, 1H), 5.25 (dt, j=10.4, 1.2hz, 1H), 3.783.74 (m, 1H), 3.73 (s, 3H), 3.37 (brs, 1H), 2.74 (t, j=7.6 hz, 2H), 1.921.86 (m, 2H); 13C NMR (100 MHz, CDCl 3) delta 152.0, 141.7, 141.6, 140.1, 128.5, 128.4, 125.9, 115.4, 114.8, 114.7, 56.3, 55.8, 37.3, 32.2; HRMS (ESI-MS): calcd.for C18H21NO [ M+H ] +:268.1696, found:268.1695; HPLC conditions: chiralcel OJ-H column,254nm, flow rate:1ml/min, i-PrOH/hexanes=1/99, tminor=31.84 min, tmajor= 33.97min;94% ee.
The structural formula of (S) -4-methoxy-N- (1-phenyl-allyl) aniline (3 ja) is as follows:
example 11 preparation of (S) -4-methoxy-N- (1, 12-dienyltridecyl) aniline (3 ka)
From 1, 12-dientridecane 1k and p-methoxyaniline 2a as reaction substrates, through general embodiment a, the crude product obtained was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=100: 1. isolation gave 51.2mg, 85% yield.
Characterization of data: [ alpha ]] 25 D ＝+36.78(c＝0.77，CHCl 3 )；1H NMR(400MHz，CDC1 3 )δ6.776.73(m，2H)，6.58(d，J＝8.8Hz，2H)，5.865.67(m，2H)，5.17(dt，J＝17.2，1.2Hz，1H)，5.10(dt，J＝10.4，1.2Hz，1H)，5.024.91(m，2H)，3.73(s，3H)，3.733.68(m，1H)，2.062.01(m，2H)，1.641.50(m，2H)，1.431.35(m，4H)，1.331.26(m，8H)； 13 C NMR(100MHz，CDCl 3 )δ152.1，140.4，139.2，115.2，115.1，115.0，114.7，114.1，57.2，55.8，35.7，33.8，29.5，29.4，29.3，29.1，28.9，25.9；HRMS(ESI-MS)：Calcd.for C 20 H 31 NO[M+H] + ：302.2478，Found：302.2476；HPLC conditions：Chiralcel OJ-H column，254nm，flow rate：1 ml/min，i-PrOH/hexanes＝1/99，tmajor＝22.10min，t minor ＝27.17min；91％ee.
(S) -4-methoxy-N- (1, 12-dienyltridecyl) aniline (3 ka) having the structural formula:
EXAMPLE 12 preparation of (S) -N- (8-chloroheptene) -4-methoxyaniline (3 la)
The crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate = 100:1. isolation gave 36.5mg, 72% yield.
Characterization of data: [ alpha ]] 25D ＝+110.3(c＝0.27，CHCl 3 )； 1 H NMR(400MHz，CDCl 3 )δ6.956.91(m，2H)，6.826.78(m，2H)，5.785.69(m，1H)，5.01 4.96(m，2H)，3.82(brt，1H)，3.76(s，3H)，3.123.07(m，1H)，2.972.92(m，lH)，1.861.82(m，1H)，1.761.66(m，4H)，1.551.48(m，1H)； 13 C NMR(100MHz，CDCl 3 )δ154.2，145.7，139.2，121.8，115.7，114.0，61.5，55.4，50.8，32.2，26.2，21.7；HRMS(ESI-MS)：Calcd.for C 14 H 20 ClNO[M]：253.1233，Found：253.1232；HPLC conditionns：Chiralcel OJ-H column，254nm，flow rate：1ml/min，i-PrOH/hexanes＝5/95，t ma jor＝8.03min，t minor ＝11.10min；93％ee.
The structural formula of the (S) -N- (8-chloroheptene) -4-methoxyaniline (31 a) is as follows:
EXAMPLE 13 preparation of (R) -N- (1-cyclohexylallyl) -4-methoxyaniline (3 ma)
From cyclohexylpropene 1m and p-methoxyaniline 2a as reaction substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=100: 1. isolation gave 41.2mg, 64% yield. [ alpha ]]25 D ＝+37.7(c＝0.6，CHCl 3 ).Lit.data(S-enantiomer)，[α] 25 D ＝12.2(c＝1.0，CHCl 3 )；1H NMR(400MHz，CDCl 3 )δ6.766.74(m，2H)，6.575.54(m，2H)，5.745.65(m，1H)，5.165.12(m，2H)，3.73(s，3H)，3.55(t，J＝6.0Hz，1H)，3.45(brs，1H)，1.851.64(m，5H)，1.521.47(m，1H)，1.271.03(m，5H)； 13 C NMR(100MHz，CDCl 3 )δ152.1，142.5，139.1，116.1，115.1，114.8，62.3，56.1，42.9，29.8，29.6，26.8，26.6，26.5；HRMS(ESI-MS)：Calcd.for C 16 H 23 NO[M+H] + ：246.1852，Found：246.1833；HPLC connditionns：Chiralcel OJ-H columm，254nm，flow rate：1ml/min，i-PrOH/hexanes＝1/99，tmajor＝23.93min，tminor＝33.81min；91％ee.
The structural formula of (R) -N- (1-cyclohexylallyl) -4-methoxyaniline (3 ma) is as follows:
EXAMPLE 14 preparation of (R) -N- (1-phenylvinyl) aniline (3 ab)
From allylbenzene 1a and 2b as reaction substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=100: 1. the isolation gave 35.2mg, 84% yield.
Characterization of data: [ alpha ]] 25 D ＝+62(c＝0.77，CHCl 3 ).Lit.dataforS-enantiomer)，[α] 25 D ＝9.1(c＝1.0，CHCl 3 ).(R-enantiomer)，[α] 25 D ＝6.5(c＝1.0，CHCl 3 )； 1 H NMR(400MHz，CDCl 3 )δ7.41 7.34(m，5H)，7.177.12(m，2H)，6.726.68(m，1H)，6.626.59(m，2H)，6.096.01(m，1H)，5.29(dt，J＝17.1，1.4Hz，1H)，5.24(dt，J＝10.2，1.3Hz，1H)，4.95(d，J＝6.0Hz，1H)，4.05(brs，1H)； 13 C NMR(100MHz，CDCl 3 )δ147.2，141.8，139.0，129.1，128.7，127.4，127.1，117.6，116.0，113.5，60.8；HRMS(ESI-MS)：Calcd.for C 15 H 15 N[M+H] + ：210.1277，Found：210.1280；HPLC conditions：Chiralcel OJ-H column，254nm，flow rate：1ml/min，i-PrOH/hexanes＝1/99，tmajor＝17.79min，t minor ＝19.22min；94％ee.
(R) -N- (1-phenylvinyl) aniline (3 ab) has the formula:
EXAMPLE 15 preparation of (R) -4-bromo-N- (1-phenylallyl) aniline (3 ac)
From allyl la and 2c as reaction substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=100: 1. isolation gave 50.1mg, 87% yield.
Characterization of data: [ alpha ]] 25 D ＝+132.3(c＝0.16，CHCl 3 )；1H NMR(400MHz，CDCl 3 )δ7.377.32(m，5H)，7.227.18(m，2H)，6.486.45(m，2H)，6.055.97(m，1H)，5.26(dt，J＝17.1，1.2Hz，1H)，5.23(dt，J＝10.2，1.2Hz，1H)，4.88(d，J＝6.0Hz，1H)，4.06(brs，1H)；13C NMR(100MHz，CDCl 3 )δ141.3，138.6，132.8，131.8，128.8，128.3，127.6，127.1，116.3，115.1，60.8；HRMS(ESI-MS)：Calcd.for C 15 H 14 BrN[M] + ：287.0304，Found：287.0271；HPLC conditions：Chiralcel OD-H columm，254nm，flow rate：1 ml/min，i-PrOH/hexanes＝5/95，t ma jor＝7.83min，tminor＝8.87min；93％ee.
The structural formula of (R) -4-bromo-N- (1-phenylallyl) aniline (3 ac) is as follows:
EXAMPLE 16 preparation of (R) -4-methyl-N- (1-phenylvinyl) aniline (3 ad)
From allylbenzene 1a and 2d as substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=100: 1. isolation gave 41.9mg, 94% yield.
Characterization of data: [ alpha ]]25 D ＝+291.1(c＝0.12，CHCl 3 )；1H NMR(400MHz，CDCl 3 )δ7.387.31(m，5H)，6.956.92(m，2H)，6.536.50(m，2H)，6.065.98(m，1H)，5.26(dt，J＝16.8，1.6Hz，1H)，5.21(dt，J＝10.0，1.2Hz，1H)，4.89(d，J＝6.0Hz，1H)，3.91(brs，1H)，2.21(s，3H)； 13 C NMR(100MHz，CDCl 3 )δ144.9，142.0，139.3，129.6，128.7，127.3，127.1，126.8，115.9，113.7，61.1，20.3；HRMS(ESI-MS)：Calcd.for C 16 H 17 N[M+H]+：224.1433，Found：224.1419；HPLC conditions：Chiralcel OJ-H column，254nm，flow rate：1 ml/min，i-PrOH/hexanes＝2/98，tmajor＝14.88min，t minor ＝17.00min；92％ee.
The structural formula of (R) -4-methyl-N- (1-phenylvinyl) aniline (3 ad) is as follows:
EXAMPLE 17 preparation of (R) -N- (3- ((1-phenylvinyl) amino) phenyl) acetamide (3 ae)
From allylbenzene 1a and 2 e As a reaction substrate, by general embodiment a, the crude product obtained was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate = 100:1. isolation gave 39.4mg, 74% yield.
Characterization of data: [ alpha ]]25D＝+33.2(c＝0.92，CHCl 3 )；1H NMR(400MHz，CDCl3)δ7.367.27(m，5H)，7.097.01(m，2H)，6.65(d，J＝7.6Hz，1H)，6.32(dd，J＝1.6，7.6Hz，1H)，6.055.96(m，1H)，5.26(d，J＝17.8Hz，1H)，5.21(d，J＝10.6Hz，1H)，4.92(d，J＝6.0Hz，1H)，4.11(brs，1H)，2.10(s，3H)，1.73(brs，1H)；13C NMR(100MHz，CDCl 3 )δ168.3，147.9，141.7，138.8，138.7，129.5，128.7，127.4，127.1，116.1，109.4，108.9，105.0，60.7，28.3；HRMS(ESI-MS)：Calcd.forC 17 H 18 N 2 O[M+H]+：267.1492，Found：267.1483；HPLC conditionS：Chiralcel IC column，254nm，flow rate：1ml/min，i-PrOH/hexanes＝20/80，tmajor＝8.86min，tminor＝10.48min；90％ee.
(R) -N- (3- ((1-phenylvinyl) amino) phenyl) acetamide (3 ae) has the formula:
EXAMPLE 18 preparation of (R) -N- (1-phenylallyl) naphthalen-2-amine (3 af)
From allylbenzene 1a and 2f as substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=100: 1. 46.2mg was isolated in 89% yield.
Characterization of data: [ alpha ]]25D＝+255.8(c＝0.12，CHCl 3 )；1H NMR(400MHz，CDCl3)δ7.64(d，J＝8.0Hz，1H)，7.60(d，J＝8.8Hz，1H)，7.53(d，J＝8.4Hz，1H)，7.437.31(m，5H)，7.297.27(m，1H)，7.197.15(m，1H)，6.91(dd，J＝2.4，8.8Hz，1H)，6.77(d，J＝2.0Hz，1H)，6.136.04(m，1H)，5.32(dt，J＝17.2，1.2Hz，1H)，5.26(dt，J＝10.0，1.2Hz，1H)，5.07(d，J＝6.0Hz，1H)，4.24(brt，1H)； 13 C NMR(100MHz，CDCl 3 )δ144.7，141.6，138.8，135.0，128.8，128.6，127.6，127.5，127.2，126.2，126.1，126.0，122.1，118.1，116.2，105.9，60.8；HRMS(ESI-MS)：Calcd.for C 19 H 17 N[M+H] + ：260.1434，Found：260.1435；HPLC conditions：Chiralcel OD-H column，254nm，flow rate：1 ml/min，i-PrOH/hexanes＝2/98，tmajor＝12.53min，t min or＝15.76min；95％ee.
The structural formula of (R) -N- (1-phenylallyl) naphthalenyl-2-amine (3 af) is as follows:
EXAMPLE 19 preparation of (R) -5-methyl-N- (1-phenylallyl) pyridinyl-2-amine (3 ag)
From allylbenzene 1a and 2g as reaction substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=100: 1. isolation gave 33.6mg, 75% yield.
Characterization of data: [ alpha ]]25D＝+241.3(c＝0.13，CHCl 3 )；1H NMR(400MHz，CDCl 3 )δ7.92(d，J＝2.0Hz，1H)，7.387.31(m，5H)，7.21(dd，J＝1.6，8.4Hz，1H)，6.27(d，J＝8.4Hz，1H)，6.106.02(m，1H)，5.285.20(m，3H)，4.83(brs，1H)，2.15(s，3H)； 13 C NMR(100MHz，CDCl 3 )δ161.8，156.0，147.6，138.7，138.6，128.7，127.4，127.1，122.1，115.7，106.7，58.8，17.4；HRMS(ESI-MS)：Calcd.for C 15 H 16 N2[M+H] + ：225.1386，Found：225.1386；HPLC conditions：Chiralcel OD-H column，254nm，flow rate：1ml/min，i-PrOH/hexanes＝20/80，tminor＝5.89min，tmajor＝8.29min；90％ee.
The structural formula of (R) -5-methyl-N- (1-phenylallyl) pyridinyl-2-amine (3 ag) is as follows:
EXAMPLE 20 preparation of (R) -N-benzyl-1- (phenylallyl) -amine (3 ah)
From allylbenzene 1a and 2h as substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=100: 1. 14.3mg was isolated in 32% yield.
Characterization of data: [ alpha ]] 25 D ＝+84.8(c＝0.39，CHCl 3 ).Lit.data：[α] 25 D ＝(c＝0.5，CHCl 3 )；1H NMR(400MHz，CDCl3)δ7.397.27(m，10H)，5.995.91(m，1H)，5.23(dt，J＝17.1，1.6Hz，1H)，5.13(dt，J＝10.1，1.6Hz，1H)，4.23(d，J＝7.1Hz，lH)，3.753.69(m，2H)； 13 C NMR(100MHz，CDCl3)δ142.8，141.0，140.4，128.5，128.4，128.2，127.3，127.2，126.9，115.2，65.1，51.3；HRMS(ESI-MS)：Calcd.for C 16 H 17 N[M+Na] + ：246.1253，Found：246.1264；HPLC conditions：Chiralcel OJ-H column，254nm，flow rate：1 ml/min，i-PrOH/hexanes＝2/98，tmajor＝12.58min，t minor ＝15.46min；92％ee.
The structural formula of (R) -N-benzyl-1- (phenylallyl) -amine (3 ah) is as follows:
example 21 preparation of (R) -1- (1-phenylallyl) pyrrole (3 ai)
From allylbenzene 1a and 2i as substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=50: 1. 34.5mg was isolated in 92% yield.
Characterization of data: [ alpha ]] 25 D＝+261.1(c＝0.11，CHCl 3 ).Lit.data：[α] 25 D ＝(c＝1.0，CHCl 3 )；1H NMR(400MHz，CDCl 3 )δ7.377.29(m，4H)，7.257.21(m，1H)，6.086.00(m，1H)，5.21(dd，J＝16.8，1.2Hz，1H)，5.00(dd，J＝10.0，1.6Hz，1H)，3.58(d，J＝8.8Hz，1H)，2.532.74(m，2H)，2.402.35(m，2H)，1.811.73(m，4H)； 13 C NMR(100MHz，CDCl 3 )δ143.0，141.3，128.5，127.6，127.1，115.0，75.2，53.0，23.3；HRMS(ESI-MS)：Calcd.for C 13 H17N[M+H]+：188.1434，Found：188.1439；HPLC conditions：Chiralcel OJ-H column，254nm，flow rate：1ml/min，i-PrOH/hexanes＝1/99，tminor＝6.74min，t ma jor＝7.83min；90％ee.
The structural formula of (R) -1- (1-phenylallyl) pyrrole (3 ai) is as follows:
example 22 preparation of (R) -1- (1-phenylallyl) azepane (3 aj)
From allylbenzene 1a and 2j as substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=50: 1. isolation gave 41mg in 95% yield.
Characterization of data: [ alpha ]]25D＝+179.8(c＝0.17，CHCl 3 ).Lit.data：[α] 25 D＝(c＝13.8，CHCl 3 )；1H NMR(400MHz，CDCl 3 )δ7.407.37(m，2H)，7.327.28(m，2H)，7.247.19(m，1H)，5.995.90(m，1H)，5.17(dd，J＝17.2，1.6Hz，1H)，5.11(dd，J＝10.0，2.4Hz，1H)，4.04(d，J＝8.4Hz，1H)，2.682.55(m，4H)，1.641.50(m，8H)； 13 C NMR(100MHz，CDC1 3 )δ143.1，139.9，128.2，127.9，126.8，115.9，73.5，52.9，28.8，27.0；HRMS(ESI-MS)：Calcd.for C 15 H 21 N[M+H]：216.1752，Found：216.1747；HPLC conditions：Chiralcel OJ-H column，254nm，flow rate：0.5ml/min，i-PrOH/hexanes＝l/99，t min or＝8.45min，t ma jo r ＝9.93min；93％ee.
The structural formula of (R) -l- (1-phenylallyl) azepane (3 aj) is as follows:
EXAMPLE 23 preparation of (R) -4- (1-phenylallyl) morpholin (3 ak)
From allylbenzene 1a and 2k as substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=50: 1. isolation gave 38.2mg, 94% yield.
Characterization of data: [ alpha ]]25 D ＝+232.1(c＝0.13，CHCl 3 ).Lit.data：[α] 20 D ＝(c＝1.022，CHCl 3 )；1H NMR(400MHz，CDCl 3 )δ7.367.30(m，4H)，7.257.22(m，1H)，5.955.86(m，1H)，5.24(dd，J＝17.2，1.6Hz，1H)，5.11(dd，J＝10.0，1.6Hz，1H)，3.723.66(m，4H)，3.62(d，J＝8.8Hz，1H)，2.482.30(m，4H)； 13 C NMR(100MHz，CDCl 3 )δ143.5，139.7，128.6，127.9，127.2，116.7，75.5，67.1，52.0；HRMS(ESI-MS)：Calcd.for C 13 H 17 NO[M+H]：204.1388，Found：204.1390；HPLC conditions：Chiralcel OJ-H column，254nm，flow rate：1ml/min，i-PrOH/hexanes＝1/99，tminor＝7.40min，t ma jor＝8.35min；92％ee.
The structural formula of (R) -4- (1-phenylallyl) morpholine (3 ak) is as follows:
EXAMPLE 24 preparation of (R) -4- (1-phenylallyl) thiomorpholine (3 al)
From allylbenzene 1a and 21 as reaction substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=50: 1. 42.1mg was isolated in 96% yield.
Characterization of data: [ alpha ]]25 D ＝+278.6(c＝0.10，CHCl 3 )；1H NMR(400MHz，CDCl 3 )δ7.347.30(m，4H)，7.257.22(m，1H)，5.945.85(m，1H)，5.2l(dd，J＝17.2，1.6Hz，1H)，5.15(dd，J＝10.0，1.6Hz，1H)，3.81(d，J＝8.4Hz，1H)，2.812.74(m，2H)，2.692.62(m，6H)； 13 C NMR(100MHz，CDCl 3 )δ143.5，139.0，128.5，127.9，127.1，116.9，74.5，52.8，28.1；HRMS(ESI-MS)：Calcd.for C 13 H 17 NS[M+H] + ：220.1155，Found：220.1158；HPLC conditionS：Chiralcel OJ-H column，254nm，flow rate：1 ml/min，i-PrOH/hexanes＝2/98，t min o r ＝6.61min，t ma jor＝7.19min；93％ee.
The structural formula of (R) -4- (1-phenylallyl) thiomorpholine (3 a 1) is as follows:
EXAMPLE 25 preparation of (R) -5- (1-phenylallyl) -4,5,6, 7-tetrahydrothienyl [3,2-c ] pyridine (3 am)
From allylbenzene 1a and 2m as substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=50: l. Isolation gave 30.7mg, 92% yield.
Characterization of data: [ alpha ]]25D＝+97.4(c＝0.36，CHCl 3 )；1H NMR(400MHz，CDCl 3 )δ7.41 7.39(m，2H)，7.357.32(m，2H)，7.287.24(m，1H)，7.06(d，J＝5.2Hz，1H)，6.68(d，J＝5.2Hz，1H)，6.065.97(m，1H)，5.28(dd，J＝17.2，1.2Hz，lH)，5.14(dd，J＝10.0，1.6Hz，1H)，3.91(d，J＝9.6Hz，1H)，2.67(d，J＝14.4Hz，1H)，3.45(d，J＝14.8Hz，1H)，2.862.77(m，4H)；13C NMR(100MHz，CDCl 3 )δ142.0，140.0，134.0，133.5，128.6，127.8，127.3，125.4，122.6，116.4，73.9，51.5，48.3，25.4；HRMS(ESI-MS)：Calcd.for C 16 H 17 NS[M+H] + ：256.1155，Found：256.1161；HPLC conditions：Chiralcel OJ-H column，254nm，flow rate：1 ml/min，i-PrOH/hexanes＝5/95，t min or＝9.57min，t ma jor＝11.44min；90％ee.
The structural formula of (R) -5- (1-phenylallyl) -4,5,6, 7-tetrahydrothienyl [3,2-c ] pyridine (3 am) is as follows:
EXAMPLE 26 preparation of (R) -1-benzhydryl-4- (1-phenylallyl) piperazine (3 an)
From allylbenzene 1a and 2n as substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=50: 1. isolation gave 66.3mg, 90% yield. [ alpha ]]25 D ＝+56.6(c＝0.52，CHCl 3 )；1H NMR(400MHz，CDCl 3 )δ7.41 7.36(m，4H)，7.31 7.20(m，9H)，7.187.10(m，2H)，5.965.87(m，1H)，5.20(dd，J＝17.2，1.3Hz，1H)，5.06(dd，J＝10.0，1.6Hz，1H)，4.21(s，1H)，3.64(d，J＝8.8Hz，1H)，2.38(s，8H)； 13 C NMR(100MHz，CDCl 3 )δ142.8，142.7，141.8，140.0，128.4，128.3，127.9，127.1，126.8，126.7，116.2，76.2，75.1，52.0，51.6；HRMS(ESI-MS)：Calcd.forC 26 H 28 N 2 [M+H] + ：369.2325，Found：369.2323；HPLC conditions：Chiralcel OJ-H column，254nm，flow rate：1ml/min，i-PrOH/hexanes＝5/95，t min or＝7.80min，t ma jor＝9.09min；94％ee.
The structural formula of (R) -1-benzhydryl-4- (1-phenylallyl) piperazine (3 an) is as follows:
EXAMPLE 27 preparation of (R) -N-methyl-N- (1-phenylallyl) aniline (3 ao)
From allylbenzene 1a and 2o as substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=100: 1. isolation gave 15.6mg, 35% yield. [ alpha ]]25 D ＝+53.6(c＝0.62，CHCl 3 ).Lit.data：[α]35D＝(c＝1.0，CHCl3)；1H NMR(400MHz，CDCl 3 )δ7.37-7.22(m，7H)，6.85(d，J＝8.0Hz，2H)，6.73(t，J＝7.2Hz，1H)，6.19-6.10(m，1H)，5.49(d，J＝6.0Hz，1H)，5.35(dd，J＝10.0，1.6Hz，1H)，5.21(dt，J＝17.2，1.6Hz，1H)，2.74(s，3H)； 13 C NMR(100MHz，CDCl 3 )δ140.4，135.6，129.1，128.5，127.9，127.2，118.0，116.9，113.3，65.1，33.7；HRMS(ESI-MS)：Calcd.forC 16 H 17 N[M]+：223.1352，Found：223.1359；HPLC conditions：Chiralcel OD-H column，254nm，flow rate：1ml/min，i-PrOH/hexanes＝5/95，t min or＝7.89min，tmajor＝8.90min；96％ee.
The structural formula of (R) -N-methyl-N- (1-phenylallyl) aniline (3 ao) is as follows:
EXAMPLE 28 preparation of (R) -4- (4-chlorophenyl) -1- (1-phenylallyl) piperidin-4-ol (3 ap)
From allylbenzene 1a and 2p as substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=30: 1. the isolation gave 56.4mg, 86% yield. [ alpha ]]25D＝+186.1(c＝0.16，CHCl 3 )；1H NMR(400MHz，CDCl 3 )δ7.457.24(m，9H)，6.01 5.92(m，1H)，5.24(d，J＝17.2Hz，1H)，5.11(d，J＝10.4Hz，1H)，4.00(brs，1H)，3.75(d，J＝8.8Hz，1H)，2.432.27(m，2H)，2.161.85(m，4H)，1.751.60(m，2H)； 13 C NMR(100MHz，CDCl 3 )δ139.9，136.9，132.6，128.5，128.3，127.8，126.2，123.7，121.1，116.4，74.9，71.1，74.4，38.5；HRMS(ESI-MS)：Calcd.for C 20 H 22 ClNO[M+H] + ：328.1436，Found：328.1462；HPLC conditions：Chiralcel OJ-H column，254nm，flow rate：1 ml/min，i-PrOH/hexanes＝10/90，tmajor＝16.67min，tminor＝20.86min；90％ee.
The structural formula of (R) -4- (4-chlorophenyl) -1- (1-phenylallyl) piperidin-4-ol (3 ap) is as follows:
EXAMPLE 29 preparation of (R) -4- (4-aminophenoxy) -N- (1-phenylvinyl) aniline (3 aq)
From allylbenzene 1a and 2 q As a reaction substrate, by general embodiment a, the crude product obtained was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate = 50:1. 42.3mg was isolated in 67% yield.
Characterization of data: [ alpha ]]25 D ＝+69.3(c＝0.43，CHCl 3 )；1H NMR(400MHz，CDCl 3 )δ7.397.34(m，5H)，6.846.77(m，4H)，6.646.60(m，2H)，6.576.53(m，2H)，6.075.99(m，1H)，5.27(dt，J＝17.1，1.3Hz，1H)，5.22(dt，J＝10.4，1.3Hz，1H)，4.87(d，J＝6.0Hz，1H)，3.91 3.89(m，3H)； 13 C NMR(100MHz，CDCl 3 )δ149.2，148.6，139.2，137.0，128.7，127.1，126.3，123.7，120.3，114.5，114.0，61.4；HRMS(ESI-MS)：Calcd.for C 21 H 20 N 2 O[M+H] + ：317.1648，Found：317.1621；HPLC conditionns：Chiralcel OD-H column，254nm，flow rate：1ml/min，i-PrOH/hexanes＝2/98，t ma jor＝30.23min，t minor ＝38.83min；92％ee.
The structural formula of (R) -4- (4-aminophenoxy) -N- (1-phenylvinyl) aniline (3 aq) is as follows:
EXAMPLE 30 preparation of (R) -butyl-4- ((1-phenylallyl) amino) benzoate (3 ar)
From allylbenzene 1a and 2r as substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=50: 1. isolation gave 50.2mg, 84% yield.
Characterization of data: [ alpha ]]25 D ＝+132.1(c＝0.38，CHCl 3 )；1H NMR(400MHz，CDCl 3 )δ7.857.81(m，2H)，7.367.30(m，4H)，7.31 7.27(m，1H)，6.576.54(m，2H)，6.07-5.99(m，1H)，5.295.24(m，2H)，5.01(brt，1H)，4.48(d，J＝3.6Hz，1H)，4.24(t，J＝6.5Hz，2H)，1.731.66(m，2H)，1.491.40(m，2H)，0.95(t，J＝7.3Hz，3H)； 13 C NMR(100MHz，CDCl 3 )δ166.8，150.7，140.8，138.0，131.3，128.8，127.7，127.1，119.1，116.6，112.3，64.1，60.2，30.9，19.3，13.8；HRMS(ESI-MS)：Calcd.for C 20 H 23 NO 2 [M+H] + ：310.1802，Found：310.1800；HPLC connditionns：Chiralcel OD-H column，254nm，flow rate：1ml/min，i-PrOH/hexanes＝3/97，t ma jor＝17.77min，t min or＝28.61 min；＞99％ee.
(R) -butyl-4- ((1-phenylallyl) amino) benzoate (3 ar) has the formula:
example 31 preparation of (R) -1- (2- ((2, 4-dimethylphenylsulfanyl) phenyl) -4- (1-phenylallyl) piperazine (3 as)
From allylbenzene 1a and 2s as substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=50: 1. isolation gave 67.1mg, 81% yield.
Characterization of data: [ alpha ]] 25 D ＝+201.0(c＝0.16，CHCl 3 )；1H NMR(400MHz，CDCl 3 )δ7.337.28(m，5H)，7.207.15(m，1H)，7.087.02(1H)，6.966.92(m，3H)，6.796.74(m，1H)，6.41(d，J＝8.1Hz，1H)，5.975.88(m，1H)，5.19(d，J＝17.2Hz，1H)，5.04(d，J＝10.2Hz，1H)，3.87(d，J＝8.8Hz，1H)，3.022.92(m，4H)，2.652.47(m，4H)，2.28(s，3H)，2.22(s，3H)； 13 C NMR(100MHz，CDCl 3 )δ149.3，142.5，142.1，140.2，139.1，136.3，134.6，131.6，128.6，128.1，128.0，127.7，127.1，126.0，125.4，124.2，119.7，116.4，75.3，51.8，51.7，21.2，20.6；HRMS(ESI-MS)：Calcd.for C 27 H 30 N 2 S[M+H]+：415.2203，Found：415.2203；HPLC conditions：Chiralcel OJ-H column，254nm，flow rate：1ml/min，i-PrOH/hexanes＝10/90，tmajor＝10.17min，tminor＝12.26min；95％ee.
The structural formula of (R) -1- (2- ((2, 4-dimethylbenzenesulfonyl) phenyl) -4- (1-phenylallyl) piperazine (3 as) is as follows:
EXAMPLE 32 preparation of (R) -8-chloro-11- (1- (1-phenylallyl) piperidin-4-ene) -6, 11-dihydro-5H-benzo [5,6] seven membered cyclo [1,2-b ] pyridine (3 at)
From allylbenzene 1a and 2t as substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=20: 1. 67.4mg was isolated in 79% yield.
Characterization of data: [ alpha ]]25D＝+285.6(c＝0.12，CHCl 3 )；1H NMR(400MHz，CDC1 3 )δ8.41 8.35(m，1H)，7.447.38(m，1H)，7.367.29(m，4H)，7.237.18(m，1H)，7.147.04(4H)，5.995.90(m，1H)，5.17(dt，J＝17.2，1.6Hz，1H)，5.07(dt，J＝10.2，1.6Hz，1H)，3.69(d，J＝8.7Hz，1H)，3.433.31(m，2H)，2.922.86(m，1H)，2.842.75(m，2H)，2.652.59(m，1H)，2.522.27(m，4H)，2.13(m，2H)；13C NMR(100MHz，CDCl 3 )δ157.6，146.5，139.5，137.8，137.1，133.4，132.5，130.8，130.6，128.9，128.8，128.4，127.8，127.1，125.9，1258，122.2，122.0，116.2，74.5，52.9，52.7，31.8，31.4，30.9，30.7；HRMS(ESI-MS)：Calcd.for C 28 H 27 ClN 2 [M+H]+：427.1936，Found：427.1927；HPLC conditions：Chiralcel OJ-H column，254nm，flow rate：lml/min，j-PrOH/hexanes＝10/90，t m inor＝18.77min，tmajor＝25.95min；93％ee.
The structural formula of (R) -8-chloro-11- (1- (1-phenylallyl) piperidin-4-ene) -6, 11-dihydro-5H-benzo [5,6] heptamembered ring [1,2-b ] pyridine (3 at) is as follows:
example 333 preparation of- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -5- (1- (1- ((R) -1-phenylallyl) 4-piperidinyl) -1H-4-pyrazolyl) -2-pyridylamine (3 au)
From allylbenzene 1a and 2u as reaction substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=10: 1. isolation gave 35.1mg, 62% yield.
Characterization of data: 1H NMR (400 MHz, CDC 1) 3 )δ7.76(d，J＝1.8Hz，1H)，7.55(s，1H)，7.51(s，1H)，7.387.29(m，6H)，7.077.02(m，1H)，6.87(d，J＝1.6Hz，1H)，6.08(dd，J＝6.7，13.4Hz，1H)，6.005.91(m，1H)，5.27(dd，J＝17.2，1.0Hz，1H)，5.07(dd，J＝10.2，1.5Hz，1H)，4.76(s，2H)，4.134.07(m，1H)，3.76(d，J＝8.7Hz，1H)，3.283.23(m，lH)，2.91 2.87(m，1H)，2.172.00(m，6H)，1.86(d，J＝6.7Hz，3H)；13C NMR(100MHz，CDCl 3 )δ165.1，148.8，139.8，139.7，136.9，135.6，135.4，128.6，127.8，127.2，122.5，119.8，119.3，116.8，116.5，115.0，74.4，72.4，59.7，50.5，29.4，22.7；HRMS(ESI-MS)：Calcd.for C 30 H 30 Cl 2 N 2 [M+H] + ：566.1884，Found：566.1883.
The structural formula of 3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -5- (1- (1- ((R) -1-phenylallyl) 4-piperidinyl) -lH-4-pyrazolyl) -2-pyridylamine (3 au) is as follows:
example 343 preparation of- ((R) -1-phenylallyl) -1,2,3,4,5, 6-hexahydro-8H-1, 5-methanopyrido [1,2-alI1,5] diazo-8-one (3 av)
From allylbenzene 1a and 2v as substrates, the crude product obtained by general embodiment a was passed through a silica gel column, buffer polar petroleum ether/ethyl acetate=20: 1. 46.5mg was isolated in 76% yield.
Characterization of data: 1H NMR (400 MHz, CDCl) 3 )δ7.297.15(m，5H)，6.936.9l(m，lH)，6.52(dd，J＝1.4，9.0Hz，lH)，5.84(dd，J＝1.2，6.8Hz，lH)，5.745.65(m，1H)，5.1l(dd，J＝17.2，1.2Hz，1H)，5.04(dd，J＝10.2，1.2Hz，1H)，4.15(d，J＝15.4Hz，1H)，3.933.88(m，1H)，3.67(d，J＝8.4Hz，1H)，3.223.18(m，lH)，2.882.85(m，lH)，2.792.74(m，1H)，2.482.46(m，1H)，2.32(d，J＝10.4Hz，1H)，2.15(dd，J＝10.8，1.3Hz，1H)，1.931.87(m，1H)，1.801.75(m，1H)；13C NMR(100MHz，CDCl 3 )δ164.4，151.4，141.5，139.5，138.5，128.4，127.5，127.1，116.5，116.3，104.7，73.5，58.3，57.5，50.2，35.6，28.3，26.2；HRMS(ESI-MS)：Calcd.for C 20 H 22 N 2 O[M+H]+：307.1805，Found：307.1802.
3- ((R) -1-phenylallyl) -1,2,3,4,5, 6-hexahydro-8H-1, 5-methanopyrido [1,2-a ] [1,5] diazin-8-one (3 av) has the structural formula:
in summary, the asymmetric ammonification of the molybdenum-catalyzed allylic nucleophiles of the present invention produces a series of chiral N- (1-substituted allyl) aryl and alkylamines. Through condition screening, a proper non-phosphine chiral ligand is found to be matched with metal molybdenum, and an asymmetric allylic ammonification reaction is realized. The method has mild reaction conditions, high catalytic activity and excellent stereoselectivity, has important application prospect, provides a new path for the total synthesis of a plurality of natural products, and simultaneously realizes the total synthesis preparation of the clopidogrel inhibiting platelet aggregation medicine by applying the catalytic conditions.
The above is only for illustrating the technical idea of the present invention, and the protection scope of the present invention is not limited by this, and any modification made on the basis of the technical scheme according to the technical idea of the present invention falls within the protection scope of the claims of the present invention.

Claims (8)

1. The synthesis method of chiral N- (1-substituted-allyl) amine is characterized by comprising the following steps: stirring allyl carbonate and amine under the action of Schiff base ligand and metallic molybdenum catalyst for reaction, standing the stirred mixture at 30 ℃ for 24 hours, removing reaction solvent, and separating and purifying by column chromatography to obtain chiral N- (1-substituted-allyl) amine; wherein:
the structural formula of the reactant allyl carbonate is as follows:
R 1 is alkyl, aryl or aryl;
the structural formula of the reactant amine is as follows:
R 2 is aryl or aryl; r is R 3 Is H or alkyl;
the structural formula of the chiral N- (1-substituted-allyl) amine of the product is as follows:
2. the method for synthesizing chiral N- (1-substituted-allyl) amine according to claim 1, wherein the metal molybdenum catalyst is selected from (C 7 H 8 )Mo(CO) 3 。
3. The method for synthesizing chiral N- (1-substituted-allyl) amine according to claim 1, wherein the molar ratio of the metal molybdenum catalyst to the schiff base ligand is 1:1.5.
4. The method for synthesizing chiral N- (1-substituted-allyl) amine according to claim 1, wherein the molar ratio of allyl carbonate to amine is 1:1.2.
5. The method for synthesizing chiral N- (1-substituted-allyl) amine according to claim 1, wherein the reaction solvent is dichloromethane.
6. Use of the synthetic method of chiral N- (1-substituted-allyl) amine according to claim 1, characterized in that the total synthesis of clopidogrel is achieved.
7. The use according to claim 6, comprising: stirring and reacting an allyl carbonate compound shown in the following formula I and an amine compound shown in the formula II under the action of a Schiff base ligand and a metal molybdenum catalyst, standing the stirred and generated mixture at 30 ℃ for 24 hours, removing a reaction solvent, and separating and purifying by column chromatography to obtain an intermediate compound shown in the following formula III;
the intermediate compound is converted into chiral drug clopidogrel in two steps;
the chiral drug clopidogrel has the following structural formula:
8. the use of claim 7, wherein the two-step conversion reaction comprises:
the first step: in sodium iodide and RuCl 3 .H 2 Under the action of O, dissolving the compound III in CCl 4 The reaction was stirred at room temperature in MeCN and DCM for 6H, and the reaction mixture was poured into DCM/H 2 Separating in O, and drying an organic layer to obtain a crude reaction product;
and a second step of: adding TMSCHN into the crude reaction product 2 Stirring at room temperature for 2h, and purifying by silica gel column chromatography to obtain (S) -clopidogrel.
CN202211703066.8A 2022-12-27 2022-12-27 Synthesis method and application of chiral N- (1-substituted-allyl) amine Pending CN116535418A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202211703066.8A CN116535418A (en) 2022-12-27 2022-12-27 Synthesis method and application of chiral N- (1-substituted-allyl) amine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202211703066.8A CN116535418A (en) 2022-12-27 2022-12-27 Synthesis method and application of chiral N- (1-substituted-allyl) amine

Publications (1)

Publication Number Publication Date
CN116535418A true CN116535418A (en) 2023-08-04

Family

ID=87449402

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202211703066.8A Pending CN116535418A (en) 2022-12-27 2022-12-27 Synthesis method and application of chiral N- (1-substituted-allyl) amine

Country Status (1)

Country Link
CN (1) CN116535418A (en)

Similar Documents

Publication Publication Date Title
CN113372184B (en) Method for synthesizing C-N axis chiral phenanthridinone compound based on chiral transfer strategy
CN113087691B (en) Method for synthesizing chiral aryl tertiary alcohol and benzopyran compound based on kinetic resolution strategy
CN114478337A (en) Axial chiral sulfur-containing diaryl derivative and synthesis method thereof
EP2139853A1 (en) Process for preparing precursors of carbenes of caac type and use thereof for preparing said carbenes
KR19980701747A (en) 4, 6-dichloro-pyrimidine preparation method
CN116535418A (en) Synthesis method and application of chiral N- (1-substituted-allyl) amine
CN110590644B (en) Chiral 1, 2-dihydropyridine compound, preparation method and application thereof
JP3598277B2 (en) Method for producing ethanesulfonylpiperidine derivative
CN110003105B (en) Axial chiral pyridine compound, and preparation method and application thereof
CN112500419A (en) Epoxy fused 2-methylene pyrrolidine compound and preparation method thereof
WO2021015108A1 (en) Method for producing morphinan derivative
CN1037896A (en) The preparation method of aromatic substance of 5-member heterocyclic ring containing nitrogen
KR101153713B1 (en) Preparation method of itopride and intermediate compound
CN111454217A (en) Preparation method of apltinib intermediate
CN113072486A (en) Amino alcohol-boron-binaphthol complex and preparation method of optically active amino alcohol derivative using same
CN114671816B (en) Preparation method of axial chiral aryl triazole compound
CN106831522B (en) Lactam compound and preparation method thereof
MXPA05004793A (en) Novel 2,3-dihydro-4(1h)-pyridinone derivatives, method for production thereof and pharmaceutical composition comprising the same.
CN111471020B (en) Preparation method of apltinib intermediate
Ruano et al. Synthesis of enantiomerically pure acyclic α-sulfinyl ketimines
CN111499558B (en) Asymmetric reduction method of chiral spiro-bis-boron catalytic substituted pyridine and application thereof
CN112624963B (en) Silver-catalyzed serial cyclization reaction for constructing chiral 4-amino tetrahydrocarbazole
TW201217325A (en) Diastereoselective preparation of bicyclo[2.2.2]octan-2-one compounds
CN109180406B (en) Synthesis method of (4R, 5R) -5-benzyl-4-hydroxy-2-cyclopentene-1-ketone compound
CN115073521A (en) 1-phospha norbornene-oxazole chiral phosphine ligand, synthetic method and application thereof, and monocyclic compound

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination