WO2022077851A1 - 1,4-二氢吡啶类手性杂合氢化试剂及其制备方法和应用 - Google Patents

1,4-二氢吡啶类手性杂合氢化试剂及其制备方法和应用 Download PDF

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WO2022077851A1
WO2022077851A1 PCT/CN2021/079229 CN2021079229W WO2022077851A1 WO 2022077851 A1 WO2022077851 A1 WO 2022077851A1 CN 2021079229 W CN2021079229 W CN 2021079229W WO 2022077851 A1 WO2022077851 A1 WO 2022077851A1
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dihydropyridine
hydrogenation
substituted
carbon atoms
group
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French (fr)
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徐亮
刘艳
蒙发明
徐伟平
卢汉彬
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中山奕安泰医药科技有限公司
佛山奕安赛医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B35/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving a change in the type of bonding between two carbon atoms already directly linked
    • C07B35/02—Reduction
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/56—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and doubly-bound oxygen atoms bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/62—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by hydrogenation of carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
    • C07C47/228—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing six-membered aromatic rings, e.g. phenylacetaldehyde
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
    • C07C47/228—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing six-membered aromatic rings, e.g. phenylacetaldehyde
    • C07C47/23—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing six-membered aromatic rings, e.g. phenylacetaldehyde polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
    • C07C47/24—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/48—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings
    • 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
    • C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—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 two 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 directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the invention relates to the technical field of asymmetric catalysis, in particular to a 1,4-dihydropyridine chiral hybrid hydrogenation reagent and a preparation method and application thereof.
  • Asymmetric catalytic hydrogenation is an important direction in modern synthetic chemistry.
  • NADH reduced nicotinamide adenine dinucleotide
  • NADPH nicotinamide adenine dinucleotide phosphate
  • lactate dehydrogenase LDH can reduce carbonyl to alcohol through NADH transfer hydrogenation.
  • the transfer hydrogenation of HEHs is inspired by the molecular structure of NADH, and the reaction driving force is to obtain the aromatic pyridine ring product.
  • the realization of asymmetric transfer hydrogenation of HEHs requires the help of other chiral catalysts.
  • the hybridization of the two systems is usually difficult to control, requiring a large amount of chiral catalyst, and the chiral catalyst is difficult to recover and recycle. Therefore, the design and development of non-metallic green catalysts to avoid residual transition metals; the development of single-molecule high-efficiency hydrogen transfer catalysts to avoid the use of high-pressure hydrogen and realize the recycling of catalysts are the hotspots of today's asymmetric catalytic hydrogenation.
  • 1,4-dihydropyridine-based chiral catalysts can be used as a hydrogen source by themselves, which can avoid the use of high-pressure hydrogen, and are gradually favored by researchers.
  • the researchers introduced a chiral center at the 3,5 position of 1,4-dihydropyridine to control the chiral configuration of the product, but such reagents usually require several steps to obtain the desired
  • the target product of the configuration requires column separation and purification, and the industrial index cost is relatively high, and because this type of hydrogenation reagent itself participates in the reaction, the amount added in the reaction is relatively high, so the cost is relatively high, which is not conducive to widespread use.
  • the 1,4-dihydropyridine-based chiral hybrid hydrogenation reagent has better asymmetric properties
  • the conversion rate is high, the preparation and synthesis are simple, the production cost can be effectively reduced, and it is suitable for industrial production and application.
  • a 1,4-dihydropyridine chiral hybrid hydrogenation reagent having the structure shown in formula (I):
  • R 1 and R 2 are each independently selected from C 1-4 alkyl.
  • R 1 is ethyl and R 2 is methyl.
  • the preparation method of the above-mentioned 1,4-dihydropyridine chiral hybrid hydrogenation reagent comprises the following steps:
  • the solvent is dichloromethane.
  • An asymmetric catalysis method comprising the following steps:
  • the substrate is mixed with the above-mentioned 1,4-dihydropyridine chiral hybrid hydrogenation reagent, and an asymmetric hydrogenation reaction is performed to obtain the target compound of the desired configuration.
  • the substrate has a structure represented by formula (II-1):
  • R 3 is selected from: substituted or unsubstituted straight-chain alkyl with 1-20 carbon atoms, substituted or unsubstituted branched alkyl with 3-20 carbon atoms, substituted or unsubstituted with 3 - a cycloalkyl group of 20 carbon atoms, a substituted or unsubstituted heterocyclyl group with 3-20 ring atoms, a substituted or unsubstituted aryl group with 6-20 ring atoms, or a substituted or unsubstituted group with Heteroaryl groups of 5-20 ring atoms;
  • R 4 is selected from: a substituted or unsubstituted straight-chain alkyl group having 1-20 carbon atoms, or a substituted or unsubstituted branched-chain alkyl group having 3-20 carbon atoms.
  • R 3 is an aryl group with 6-10 ring atoms, or R a is substituted for an aryl group with 6-10 ring atoms; R a is selected from: cyano, nitro, halogen, tris Fluoromethyl or difluoromethyl;
  • R 4 is selected from: straight-chain alkyl having 1-4 carbon atoms, or branched-chain alkyl having 3-6 carbon atoms.
  • the step of mixing the substrate and the above-mentioned 1,4-dihydropyridine-based chiral hybrid hydrogenation reagent, and performing the asymmetric hydrogenation reaction includes the following steps:
  • the substrate is mixed with the above-mentioned 1,4-dihydropyridine chiral hybrid hydrogenation reagent, protic acid and organic solvent, and after the reaction is completed, separation and purification are performed to obtain the target compound of the desired configuration.
  • the organic solvent is selected from one or more of dioxane, chloroform, dichloromethane, ether, toluene, tetrahydrofuran and acetonitrile;
  • the protic acid is selected from one or more of trifluoroacetic acid, acetic acid, benzoic acid, sulfonic acid, hydrochloric acid and phosphoric acid.
  • the molar ratio of the substrate to the protic acid is 1:(0.2-0.4).
  • the above-mentioned 1,4-dihydropyridine chiral hybrid hydrogenation reagent realizes the control of the steric configuration in the transfer hydrogenation reaction by adopting the salt formed by the 1,4-dihydropyridine derivative and ⁇ -hydroxyphenylacetic acid, so as to ensure the hydrogenation Transfer efficiency and improve asymmetric conversion rate; at the same time, the above-mentioned hydrogenation reagents only need to undergo a simple salt-forming reaction to be prepared, and because the product is in the form of a salt, the separation and purification is relatively simple, and there is no need to use complex column separation, etc.
  • the method can greatly reduce the preparation difficulty, thereby achieving the purpose of reducing the preparation cost.
  • the 1,4-dihydropyridine-based chiral hybrid hydrogenation reagent realizes asymmetric hydrogenation based on the hydrogenation transfer of the reagent itself, so it is safe and reliable to avoid using high-pressure hydrogen gas with harsh conditions as the hydrogen source.
  • the above-mentioned hydrogenation reagent does not need to use transition metal catalyst, can avoid the transition metal residue caused by the use of transition metal, reduce the pollution of transition metal, especially toxic heavy metals, is green and environmentally friendly, and is especially suitable for industrial production applications.
  • substituted or unsubstituted means that the defined group may or may not be substituted.
  • a defined group is substituted, it is understood to be optionally substituted with art-accepted groups, including but not limited to: alkyl groups having 1-20 carbon atoms, heterocyclic groups having 3-20 ring atoms Cyclic, aryl with 5-20 ring atoms, heteroaryl with 5-20 ring atoms, silyl, carbonyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, haloformyl, methyl acyl, -SO2R ', -NR'R", cyano, isocyano, isocyanate, thiocyanate, isothiocyanate, hydroxy, trifluoromethyl, nitro or halogen, and
  • the above-mentioned groups can also be further substituted by substituents acceptable in the art; it is understood that R' and R" in -SO 2 R'
  • alkyl refers to a saturated hydrocarbon containing primary (normal) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof. Phrases containing this term, for example, "C 1-9 alkyl” and “alkyl having 1 to 9 carbon atoms” have the same meaning, and each occurrence may independently be C 1 alkyl, C 2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl or C9 alkyl .
  • Suitable examples include, but are not limited to: methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n - propyl, -CH2CH2CH ) 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ) , 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 ) )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 ) CH 2 CH 2 CH 3 ), 2-p
  • cycloalkyl refers to a non-aromatic hydrocarbon containing ring carbon atoms, which may be monocycloalkyl, or spirocycloalkyl, or bridged cycloalkyl. Phrases containing this term, for example, "C3- C9 cycloalkyl” refers to a cycloalkyl group containing 3 to 9 carbon atoms, each occurrence of which may independently be C3 cycloalkyl, C4 Cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl, C8 cycloalkyl or C9 cycloalkyl.
  • Suitable examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Additionally, "cycloalkyl” may also contain one or more double bonds, and representative examples of cycloalkyl groups containing double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl, and cyclobutadienyl .
  • alkoxy refers to a group having an -O-alkyl group, ie an alkyl group as defined above is attached to the core structure via an oxygen atom. Phrases containing this term, for example, "C 1-9 alkoxy” means that the alkyl moiety contains 1 to 9 carbon atoms, and each occurrence may independently be C 1 alkoxy, C 4 alkoxy group, C 5 alkoxy, C 6 alkoxy, C 7 alkoxy, C 8 alkoxy or C 9 alkoxy.
  • Suitable examples include, but are not limited to: methoxy (-O- CH3 or -OMe), ethoxy (-O- CH2CH3 or -OEt) and tert-butoxy (-OC( CH3 ) 3 or -OtBu).
  • Aryl refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing one hydrogen atom, which can be a single-ring aryl group, a fused-ring aryl group, or a polycyclic aryl group. For polycyclic ring species, at least One is an aromatic ring system.
  • C 5-20 aryl refers to an aryl group containing 5 to 20 carbon atoms, and each occurrence may independently be a C 5 aryl group, a C 6 aryl group, a C 10 aryl group, a C 14 aryl group.
  • Aryl, C 18 aryl or C 20 aryl Suitable examples include, but are not limited to, benzene, biphenyl, naphthalene, anthracene, phenanthrene, perylene, triphenylene, and derivatives thereof.
  • Heteroaryl means that on the basis of an aryl group, at least one carbon atom is replaced by a non-carbon atom, and the non-carbon atom can be N atom, O atom, S atom and the like.
  • C 3-10 heteroaryl refers to a heteroaryl group containing 3 to 10 carbon atoms, and each occurrence may independently be C 3 heteroaryl, C 4 heteroaryl, C 5 heteroaryl Aryl, C6heteroaryl , C7heteroaryl , or C8heteroaryl .
  • Suitable examples include, but are not limited to: furan, benzofuran, thiophene, benzothiophene, pyrrole, pyrazole, triazole, imidazole, oxazole, oxadiazole, thiazole, tetrazole, indole, carbazole, pyrrolo Imidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furopyrrole, furanofuran, thienofuran, benzisoxazole, benziisothiazole, benzimidazole, pyridine, pyrazine, pyridazine, pyrimidine , triazine, quinoline, isoquinoline, naphthalene, quinoxaline, phenanthridine, primary pyridine, quinazoline and quinazolinone.
  • Heterocyclyl means that at least one carbon atom is replaced by a non-carbon atom on the basis of a cycloalkyl group, and the non-carbon atom can be N atom, O atom, S atom, etc., and can be a saturated ring or a partially unsaturated ring.
  • C 4 -C 9 heterocyclyl refers to a heterocyclyl group containing 4 to 9 carbon atoms, each occurrence of which may independently be C 4 heteroalkyl, C 6 Heteroalkyl, C7heteroalkyl , C8heteroalkyl or C9heteroalkyl .
  • Suitable examples include, but are not limited to: dihydropyridyl, tetrahydropyridyl (piperidinyl), tetrahydrothienyl, sulfur-oxidized tetrahydrothienyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinoline base, indoline.
  • Halogen or halo refers to F, Cl, Br or I.
  • One embodiment of the present invention provides a 1,4-dihydropyridine chiral hybrid hydrogenation reagent, which has the structure shown in formula (I):
  • R 1 and R 2 are each independently selected from C 1-4 alkyl.
  • R 1 is methyl, ethyl, propyl or isopropyl; further, R 1 is methyl or ethyl; further, R 2 is methyl, ethyl, propyl or isopropyl ; Further, R 2 is methyl or isopropyl; further, R 1 is ethyl, and R 2 is methyl.
  • the above-mentioned 1,4-dihydropyridine chiral hybrid hydrogenation reagent realizes the control of the steric configuration in the transfer hydrogenation reaction by adopting the salt formed by the 1,4-dihydropyridine derivative and ⁇ -hydroxyphenylacetic acid, so as to ensure the hydrogenation Transfer efficiency and improve asymmetric conversion rate; at the same time, the above-mentioned hydrogenation reagents only need to undergo a simple salt-forming reaction to be prepared, and because the product is in the form of a salt, the separation and purification is relatively simple, and there is no need to use complex column separation, etc.
  • the method can greatly reduce the preparation difficulty, thereby achieving the purpose of reducing the preparation cost.
  • the present invention also provides a method for preparing the above-mentioned 1,4-dihydropyridine chiral hybrid hydrogenation reagent, comprising the following steps:
  • the solvent in step S101 is not particularly limited, and conventional solvents in the field can be used.
  • the preferred solvent is dichloromethane to improve the yield;
  • the mixing temperature of each reagent is not particularly limited, and can be stirred at room temperature for a predetermined time That is all; further, the preferred mixing temperature is 15°C-45°C; further, the mixing temperature is 20°C-30°C.
  • the reaction solution can be directly concentrated and removed. If the purity needs to be improved, the concentration of the reaction solution can be made to have solid precipitation, and the desired product can be obtained by filtration, washing and drying after the solid precipitation is completed.
  • the preparation method of the above-mentioned 1,4-dihydropyridine chiral hybrid hydrogenation reagent is relatively simple and easy to operate. Compound molecules with chiral centers, the difficulty of synthesis is greatly reduced, and the difficulty of post-processing is also greatly reduced.
  • the above-mentioned preparation method does not require complicated equipment and operation skills, and the raw materials are cheap and easy to obtain, which is especially suitable for industrial production applications.
  • the substrate for asymmetric hydrogenation is a substrate containing an unsaturated double bond; preferably, the double bond to be reduced in the substrate is conjugated with a carbonyl group; in one embodiment, the substrate is an ⁇ , ⁇ -unsaturated aldehyde; In one embodiment, the substrate is a conjugated N-alkene, and N is greater than or equal to 2; in one embodiment, the substrate is a cyclic conjugated alkene; The alkyl group of the electron withdrawing group is attached. In one embodiment, the substrate contains an E-type unsaturated double bond.
  • the present invention also provides an asymmetric catalysis method, comprising the following steps:
  • S201 provide a substrate containing an unsaturated bond
  • the unsaturated bond in step S201 should be understood according to the common practice in the art, including but not limited to: carbon-carbon double bond, carbon-oxygen double bond, carbon-nitrogen double bond, etc.; the specific substrate is as described above, and will not be repeated here.
  • the substrate in step S201 has the structure shown in formula (II-1):
  • R 3 is selected from: substituted or unsubstituted straight-chain alkyl with 1-20 carbon atoms, substituted or unsubstituted branched alkyl with 3-20 carbon atoms, substituted or unsubstituted with 3 - a cycloalkyl group of 20 carbon atoms, a substituted or unsubstituted heterocyclyl group with 3-20 ring atoms, a substituted or unsubstituted aryl group with 6-20 ring atoms, or a substituted or unsubstituted group with Heteroaryl groups of 5-20 ring atoms;
  • R 4 is selected from: a substituted or unsubstituted straight-chain alkyl group having 1-20 carbon atoms, or a substituted or unsubstituted branched-chain alkyl group having 3-20 carbon atoms.
  • R 3 is a substituted or unsubstituted aryl group with 6-10 ring atoms, or a substituted or unsubstituted heteroaryl group with 5-10 ring atoms; further, R 3 is a 6- Aryl with 10 ring atoms, heteroaryl with 5-10 ring atoms, electron-withdrawing group substituted for aryl with 6-10 ring atoms, or electron-withdrawing group substituted for aryl with 6-10 ring atoms base.
  • R 3 is an aryl group with 6-10 ring atoms, or R a is substituted for an aryl group with 6-10 ring atoms;
  • R a is selected from: cyano, nitro, halogen, trifluoromethyl Or difluoromethyl;
  • R 3 is phenyl or naphthyl;
  • R 4 is selected from: straight-chain alkyl with 1-16 carbon atoms, or branched alkyl with 3-10 carbon atoms; further, R 4 is selected from: methyl, ethyl, propyl radical or isopropyl;
  • the substrate is mixed with the above-mentioned 1,4-dihydropyridine chiral hybrid hydrogenation reagent, and an asymmetric hydrogenation is carried out to obtain the target compound of the desired configuration.
  • the obtained target compound is a compound containing an S chiral center
  • the substrate is the compound of the structure shown in formula (II-2); further, the double bond to be reduced in the compound of the structure shown in formula (II-2) is E configuration; the obtained target product contains S hand Sex centers, such as:
  • S202 includes the following steps: mixing the substrate, the above-mentioned 1,4-dihydropyridine-based chiral hybrid hydrogenation reagent, a protic acid and an organic solvent to obtain a target compound with a desired configuration.
  • the organic solvent is selected from one or more of dioxane, chloroform, dichloromethane, ether, toluene, tetrahydrofuran and acetonitrile; further, the organic solvent is selected from dioxane.
  • the protonic acid is selected from one or more of trifluoroacetic acid, acetic acid, benzoic acid, sulfonic acid, hydrochloric acid and phosphoric acid; further, the protonic acid is selected from trifluoroacetic acid.
  • step S202 the reaction temperature is 40°C-80°C; further, the organic solvent is dioxane, and the reaction temperature is 50°C.
  • step S202 for every 1 mol of the double bond to be reduced in the substrate, add (1.1-2) mol of hydrogenation reagent; further, for every 1 mol of double bond to be reduced, add (1.1-1.5) mol of hydrogenation reagent.

Abstract

一种1,4-二氢吡啶类手性杂合氢化试剂及其制备方法和应用，所述1,4-二氢吡啶类手性杂合氢化试剂具有式(I)所示结构。R 1和R 2各自独立地选自C 1-4烷基。该1,4-二氢吡啶类手性杂合氢化试剂具有较优的不对称转化率，且制备合成简单，能够有效地降低生产成本，适宜工业生产应用。

Description

1,4-二氢吡啶类手性杂合氢化试剂及其制备方法和应用 技术领域
本发明涉及不对称催化技术领域，特别涉及1,4-二氢吡啶类手性杂合氢化试剂及其制备方法和应用。
背景技术
不对称催化氢化是现代合成化学的重要方向。自然界中，还原态烟酰胺腺嘌呤二核苷酸(NADH)和烟酰胺腺嘌呤二核苷酸磷酸(NADPH)借助其独特的二氢吡啶结构能够实现负氢转移。其中，乳酸脱氢酶LDH就是通过NADH转移氢化能够将将羰基还原为醇。据此，有机化学家仿生开发出转移氢化试剂Hantzsch ester(HEHs)，并成功应用到各种转移氢化和不对称转移氢化反应中。HEHs实现转移氢化，正是受NADH分子结构的启示，以得到芳香化的吡啶环产物为反应推动力。然而，HEHs实现不对称转移氢化反应需要借助其他手性催化剂，共同作用。而两体系杂合作用通常难以控制，需要的手性催化剂用量较大，且手性催化剂难以回收和循环利用。因此，设计开发非金属的绿色催化剂以避免过渡金属的残留；开发单分子高效氢转移催化剂，以避免高压氢气的使用，实现催化剂的循环利用，是当今不对称催化氢化的热点。
目前，由于1,4-二氢吡啶类手性催化剂自身能够作为氢源，可以避免高压氢气的使用，逐渐受到广大研究者的青睐。为了实现不对称氢化，研究者通过在1,4-二氢吡啶的3,5位上引入手性中心，来实现产物手性构型的控制，但该类试剂通常需要数歩才能获得所需构型的目标产物，且需要柱分离提纯，工业指标成本相对较高，且由于该类氢化试剂本身参与反应，故在反应中添加量较高，因此成本相对较高，不利于广泛使用。
发明内容
基于此，有必要提供一种1,4-二氢吡啶类手性杂合氢化试剂及其制备方法和应用，该1,4-二氢吡啶类手性杂合氢化试剂具有较优的不对称转化率，且制 备合成简单，能够有效地降低生产成本，适宜工业生产应用。
一种1,4-二氢吡啶类手性杂合氢化试剂，具有式(I)所示结构：
Figure PCTCN2021079229-appb-000001
R 1和R 2各自独立地选自C 1-4烷基。
在其中一实施例中，R 1为乙基，R 2为甲基。
上述1,4-二氢吡啶类手性杂合氢化试剂的制备方法，包括以下步骤：
将式(I-1)所示结构化合物、式(I-2)所示结构化合物和溶剂混合，获得式(I)所示结构的1,4-二氢吡啶类手性杂合氢化试剂；
Figure PCTCN2021079229-appb-000002
在其中一实施例中，所述溶剂为二氯甲烷。
一种不对称催化方法，包括以下步骤：
提供含有不饱和键的底物；
将所述底物和上述1,4-二氢吡啶类手性杂合氢化试剂混合，进行不对称氢化反应，制得所需构型的目标化合物。
在其中一实施例中，所述底物具有式(II-1)所示结构：
Figure PCTCN2021079229-appb-000003
其中，R 3选自：取代或未取代的具有1-20个碳原子的直链烷基、取代或未取代的具有3-20个碳原子的支链烷基、取代或未取代的具有3-20个碳原子的环烷基、取代或未取代的具有3-20个环原子的杂环基、取代或未取代的具有6-20个环原子的芳基、或取代或未取代的具有5-20个环原子的杂芳基；
R 4选自：取代或未取代的具有1-20个碳原子的直链烷基、或取代或未取代的具有3-20个碳原子的支链烷基。
在其中一实施例中，R 3为具有6-10个环原子的芳基、或R a取代具有6-10个环原子的芳基；R a选自：氰基、硝基、卤素、三氟甲基或二氟甲基；
R 4选自：具有1-4个碳原子的直链烷基、或具有3-6个碳原子的支链烷基。
在其中一实施例中，将所述底物和上述1,4-二氢吡啶类手性杂合氢化试剂混合，进行不对称氢化反应的步骤包括以下步骤：
将所述底物和上述1,4-二氢吡啶类手性杂合氢化试剂、质子酸和有机溶剂混合，反应完全后，分离提纯，获得所需构型的目标化合物。
在其中一实施例中，所述有机溶剂选自：二氧六环、氯仿、二氯甲烷、乙醚、甲苯、四氢呋喃和乙腈中的一种或多种；
所述质子酸选自：三氟乙酸、醋酸、苯甲酸、磺酸、盐酸和磷酸中的一种或多种。
在其中一实施例中，所述底物中每1mol待还原双键，加入(1.1-2)mol的氢化试剂；
所述底物和所述质子酸的摩尔比为1：(0.2-0.4)。
有益效果：
上述1,4-二氢吡啶类手性杂合氢化试剂通过采用1,4-二氢吡啶衍生物和α-羟基苯乙酸形成的盐来实现转移氢化反应中对立体构型的控制，保证氢化转移效率，提高不对称转化率；与此同时，上述氢化试剂仅需进行简单的成盐反应即可制得，且由于产物是盐的形式，故分离纯化较为简单，无需采用复杂的柱分离等手段，能够大幅度降低制备难度，进而达到降低制备成本的目的。
且该类1,4-二氢吡啶类手性杂合氢化试剂是基于试剂本身的氢化转移来实现不对称氢化，故可以避免使用条件苛刻的高压氢气作为氢源，安全可靠。且上述氢化试剂无需使用过渡金属催化剂，可以避免因使用过渡金属而引起过渡金属残留，减少过渡金属尤其是有毒重金属的污染，绿色环保，特别适用于工业生产应用。
具体实施方式
为了便于理解本发明，下面将对本发明进行更全面的描述，并给出了本发明的较佳实施例。但是，本发明可以以许多不同的形式来实现，并不限于本文所描述的实施例。相反地，提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
术语解释
除非另外说明或存在矛盾之处，本文中使用的术语或短语具有以下含义：
本发明中，“取代或未取代”表示所定义的基团可以被取代，也可以不被取代。当所定义的基团被取代时，应理解为任选被本领域可接受的基团所取代，包括但不限于：具有1-20个碳原子的烷基、具有3-20个环原子的杂环基、具有5-20个环原子的芳基、具有5-20个环原子的杂芳基、硅烷基、羰基、烷氧基羰基、芳氧基羰基、氨基甲酰基、卤甲酰基、甲酰基、-SO 2R′、-NR′R″、氰基、异氰基、异氰酸酯基、硫氰酸酯基、异硫氰酸酯基、羟基、三氟甲基、硝基或卤素，且上述基团也可以进一步被本领域可接受取代基取代；可理解的，-SO 2R′、-NR′R″中的R′和R″各自独立地为本领域可接受的基团所取代，包括但不限于H、C 1-6烷基、具有3-8个环原子的环烷基、具有3-8个环原子的杂环基、具有5-20个环原子的芳基或含有5-10个环原子的杂芳基；所述C 1-6烷基、具有3-8个环原子的环烷基、具有3-8个环原子的杂环基、具有5-20个环原子的芳基或含有5-10个环原子的杂芳基任选进一步被一个或多个以下基团取代：C 1-6烷基、具有3-8个环原子的环烷基、具有3-8个环原子的杂环基、卤素、羟基、硝基或氨基。
术语“烷基”是指包含伯(正)碳原子、或仲碳原子、或叔碳原子、或季碳原子、或其组合的饱和烃。包含该术语的短语，例如，“C 1-9烷基”和“有1～9个碳原子的烷基”具有相同的含义，每次出现时，可以互相独立地为C 1烷基、C 2烷基、C 3烷基、C 4烷基、C 5烷基、C 6烷基、C 7烷基、C 8烷基或C 9烷基。合适的 实例包括但不限于：甲基(Me、-CH 3)、乙基(Et、-CH 2CH 3)、1-丙基(n-Pr、n-丙基、-CH 2CH 2CH 3)、2-丙基(i-Pr、i-丙基、-CH(CH 3) 2)、1-丁基(n-Bu、n-丁基、-CH 2CH 2CH 2CH 3)、2-甲基-1-丙基(i-Bu、i-丁基、-CH 2CH(CH 3) 2)、2-丁基(s-Bu、s-丁基、-CH(CH 3)CH 2CH 3)、2-甲基-2-丙基(t-Bu、t-丁基、-C(CH 3) 3)、1-戊基(n-戊基、-CH 2CH 2CH 2CH 2CH 3)、2-戊基(-CH(CH3)CH2CH2CH3)、3-戊基(-CH(CH 2CH 3) 2)、2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)、3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)、3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)、2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)、1-己基(-CH 2CH 2CH 2CH 2CH 2CH 3)、2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)、3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))、2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)、3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)、4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)、3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)、2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)、2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)、3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3和辛基(-(CH 2) 7CH 3)。
术语“环烷基”是指包含环碳原子的非芳香族烃，可以为单环烷基、或螺环烷基、或桥环烷基。包含该术语的短语，例如，“C 3～C 9环烷基”是指包含3～9个碳原子的环烷基，每次出现时，可以互相独立地为C 3环烷基、C 4环烷基、C 5环烷基、C 6环烷基、C 7环烷基、C 8环烷基或C 9环烷基。合适的实例包括但不限于：环丙基、环丁基、环戊基、环己基和环庚基。另外，“环烷基”还可含有一个或多个双键，含有双键的环烷基的代表性实例包括环戊烯基、环己烯基、环己二烯基和环丁二烯基。
术语“烷氧基”是指具有-O-烷基的基团，即如上所定义的烷基经由氧原子连接至母核结构。包含该术语的短语，例如，“C 1-9烷氧基”是指烷基部分包含1～9个碳原子，每次出现时，可以互相独立地为C 1烷氧基、C 4烷氧基、C 5烷氧基、C 6烷氧基、C 7烷氧基、C 8烷氧基或C 9烷氧基。合适的实例包括但不限于：甲氧基(-O-CH 3或-OMe)、乙氧基(-O-CH 2CH 3或-OEt)和叔丁氧基(-O-C(CH 3) 3或-OtBu)。
“芳基”是指在芳香环化合物的基础上除去一个氢原子衍生的芳族烃基，可以为单环芳基、或稠环芳基、或多环芳基，对于多环的环种，至少一个是芳族环 系。例如，“C 5～20芳基”是指包含5～20个碳原子的芳基，每次出现时，可以互相独立地为C 5芳基、C 6芳基、C 10芳基、C 14芳基、C 18芳基或C 20芳基。合适的实例包括但不限于：苯、联苯、萘、蒽、菲、二萘嵌苯、三亚苯及其衍生物。
“杂芳基”是指在芳基的基础上至少一个碳原子被非碳原子所替代，非碳原子可以为N原子、O原子、S原子等。例如，“C 3～10杂芳基”是指包含3～10个碳原子的杂芳基，每次出现时，可以互相独立地为C 3杂芳基、C 4杂芳基、C 5杂芳基、C 6杂芳基、C 7杂芳基或C 8杂芳基。合适的实例包括但不限于：呋喃、苯并呋喃、噻吩、苯并噻吩、吡咯、吡唑、三唑、咪唑、噁唑、噁二唑、噻唑、四唑、吲哚、咔唑、吡咯并咪唑、吡咯并吡咯、噻吩并吡咯、噻吩并噻吩、呋喃并吡咯、呋喃并呋喃、噻吩并呋喃、苯并异噁唑、苯并异噻唑、苯并咪唑、吡啶、吡嗪、哒嗪、嘧啶、三嗪、喹啉、异喹啉、邻二氮萘、喹喔啉、菲啶、伯啶、喹唑啉和喹唑啉酮。
“杂环基”是指在环烷基的基础上至少一个碳原子被非碳原子所替代，非碳原子可以为N原子、O原子、S原子等，可以为饱和环或部分不饱和环。包含该术语的短语，例如，“C 4～C 9杂环基”是指包含4～9个碳原子的杂环基，每次出现时，可以互相独立地为C 4杂烷基、C 6杂烷基、C 7杂烷基、C 8杂烷基或C 9杂烷基。合适的实例包括但不限于：二氢吡啶基、四氢吡啶基(哌啶基)、四氢噻吩基、硫氧化的四氢噻吩基、四氢呋喃基、四氢喹啉基、四氢异喹啉基、二氢吲哚基。
“卤素”或“卤基”是指F、Cl、Br或I。
详细解释
本发明一实施方式提供了一种1,4-二氢吡啶类手性杂合氢化试剂，具有式(I)所示结构：
Figure PCTCN2021079229-appb-000004
R 1和R 2各自独立地选自C 1-4烷基。
进一步地，R 1为甲基、乙基、丙基或异丙基；更进一步地，R 1为甲基或乙基；进一步地，R 2为甲基、乙基、丙基或异丙基；更进一步地，R 2为甲基或异丙基；进一步地，R 1为乙基，R 2为甲基。
上述1,4-二氢吡啶类手性杂合氢化试剂通过采用1,4-二氢吡啶衍生物和α-羟基苯乙酸形成的盐来实现转移氢化反应中对立体构型的控制，保证氢化转移效率，提高不对称转化率；与此同时，上述氢化试剂仅需进行简单的成盐反应即可制得，且由于产物是盐的形式，故分离纯化较为简单，无需采用复杂的柱分离等手段，能够大幅度降低制备难度，进而达到降低制备成本的目的。
本发明还提供了上述1,4-二氢吡啶类手性杂合氢化试剂的制备方法，包括以下步骤：
S101：将式(I-1)所示结构化合物、式(I-2)所示结构化合物和溶剂混合，获得式(I)所示结构的1,4-二氢吡啶类手性杂合氢化试剂；
Figure PCTCN2021079229-appb-000005
其中，步骤S101中的溶剂无特别限定，可以采用本领域常规的溶剂，进一步地，优选溶剂为二氯甲烷，以提高产率；各试剂混合的温度无特别限定，可以在室温下搅拌预定时间即可；进一步地，优选混合温度为15℃-45℃；更进一步地，混合温度为20℃-30℃。反应结束后，直接浓缩除去反应液即可，若需要提高纯度，可以将反应液浓度到有固体析出，静置待固体析出完毕，过滤，洗涤、干燥即可获得所需产物。
上述1,4-二氢吡啶类手性杂合氢化试剂的制备方法操作较为简便，相比于将α-羟基苯乙酸通过偶联的方法与1,4-二氢吡啶衍生物反应，制备含手性中心的化合物分子，合成难度大幅度降低，且后处理难度也大幅度降低。且上述制备方法无需复杂仪器设备和操作技巧，原料廉价易得，特别适用于工业生产应用。
本发明还提供上述氢化试剂在不对称氢化中的应用。可理解的，不对称氢化的底物为含有不饱和双键的底物；优选底物中待还原双键与羰基共轭；在一 实施例中，底物为α，β-不饱和醛；在一实施例中，底物为共轭N烯烃，N大于或等于2；在一实施例中，底物为环状共轭烯烃；在一实施例中，底物中待还原双键与含吸电子基团的烷基相连。在一实施例中，底物中包含有E型不饱和双键。
本发明还提供了一种不对称催化方法，包括以下步骤：
S201:提供含有不饱和键的底物；
步骤S201中的不饱和键应该按本领域的常规理解，包括但不限于：碳碳双键、碳氧双键、碳氮双键等；具体地底物如上所述，在此不再进行赘述。
进一步地，步骤S201中的底物具有式(II-1)所示结构：
Figure PCTCN2021079229-appb-000006
其中，R 3选自：取代或未取代的具有1-20个碳原子的直链烷基、取代或未取代的具有3-20个碳原子的支链烷基、取代或未取代的具有3-20个碳原子的环烷基、取代或未取代的具有3-20个环原子的杂环基、取代或未取代的具有6-20个环原子的芳基、或取代或未取代的具有5-20个环原子的杂芳基；
R 4选自：取代或未取代的具有1-20个碳原子的直链烷基、或取代或未取代的具有3-20个碳原子的支链烷基。
进一步地，R 3为取代或未取代的具有6-10个环原子的芳基、或取代或未取代的具有5-10个环原子的杂芳基；更进一步地，R 3为具有6-10个环原子的芳基、具有5-10个环原子的杂芳基、吸电子基团取代具有6-10个环原子的芳基或吸电子基团取代具有6-10个环原子的芳基。
更进一步地，R 3为具有6-10个环原子的芳基、或R a取代具有6-10个环原子的芳基；R a选自：氰基、硝基、卤素、三氟甲基或二氟甲基；更进一步地，R 3为苯基或萘基；
进一步地，R 4选自：具有1-16个碳原子的直链烷基、或具有3-10个碳原子的支链烷基；进一步地，R 4选自：甲基、乙基、丙基或异丙基；
S202:将底物和上述1,4-二氢吡啶类手性杂合氢化试剂混合，进行不对称氢 化反应，制得所需构型的目标化合物。
进一步地，步骤S202中，所得到的目标化合物为含有S手性中心的化合物；
进一步地，底物为式(II-2)所示结构的化合物；进一步地，式(II-2)所示结构的化合物中待还原的双键为E构型；获得的目标产物含有S手性中心，例如：
Figure PCTCN2021079229-appb-000007
进一步地，S202包括以下步骤：将底物、上述1,4-二氢吡啶类手性杂合氢化试剂、质子酸和有机溶剂混合，获得所需构型的目标化合物。
进一步地，步骤S202中，有机溶剂选自：二氧六环、氯仿、二氯甲烷、乙醚、甲苯、四氢呋喃和乙腈中的一种或多种；进一步地，有机溶剂选自二氧六环。
进一步地，步骤S202中，质子酸选自：三氟乙酸、醋酸、苯甲酸、磺酸、盐酸和磷酸中的一种或多种；进一步地，质子酸选自三氟乙酸。
进一步地，步骤S202中反应温度为40℃-80℃；进一步地，有机溶剂为二氧六环，反应温度为50℃。
进一步地，步骤S202中，底物中每1mol待还原双键，加入(1.1-2)mol的氢化试剂；更进一步地，每1mol待还原双键，加入(1.1-1.5)mol的氢化试剂。
下面列举不同实施例来对本发明进行说明。
实施例1
将(S)-α-羟基苯乙酸(152.1mg,1mmol)与2,6-二甲基-3,5-二酸甲酯-1,4-二氢吡啶(253.3mg,1mmol)溶于二氯甲烷中，在常温下反应2h，减压除去溶剂，定量得白色1,4-二氢吡啶类手性杂合氢化试剂，即Catalyst I。
实施例2
不对称转移氢化制备(S)-3-苯基丁醛的反应式：
Figure PCTCN2021079229-appb-000008
不对称转移氢化制备(S)-3-苯基丁醛的方法：将(E)-3-苯基-2-烯丁醛(1.0equiv)、Catalyst I(1.2equiv)、TFA(30mol％),溶于二氧六环(1mL)中，在50℃的条件下剧烈搅拌24小时，加水淬灭反应后，用乙酸乙酯萃取。有机相浓缩后，经柱层析纯化后，得(S)-3-苯基丁醛，产率为80％，ee值为65％。
实施例3
不对称转移氢化制备(S)-3-(4-氰基苯基)丁醛的反应式：
Figure PCTCN2021079229-appb-000009
不对称转移氢化制备(S)-3-(4-氰基苯基)丁醛的方法：将(E)-3-(4-氰基苯基)-2-烯丁醛(1.0equiv)、Catalyst I(1.2equiv)、TFA(30mol％),溶于二氧六环(1mL)中，在50℃的条件下剧烈搅拌24小时，加水淬灭反应后，用乙酸乙酯萃取。有机相浓缩后，经柱层析纯化后，得(S)-3-(4-氰基苯基)丁醛，产率为85％，ee值为70％。
实施例4
不对称转移氢化制备(S)-3-(4-硝基苯基)丁醛的反应式：
Figure PCTCN2021079229-appb-000010
不对称转移氢化制备(S)-3-(4-硝基苯基)丁醛的方法：将(E)-3-(4-硝基苯基)-2-烯丁醛(1.0equiv)、Catalyst I(1.2equiv)、TFA(30mol％),溶于二氧六环(1mL)中，在50℃的条件下剧烈搅拌24小时，加水淬灭反应后，用乙酸乙酯萃取。有机相浓缩后，经柱层析纯化后，得(S)-3-(4-硝基苯基)丁醛，产率为90％，ee值为83％。
实施例5
不对称转移氢化制备(S)-3-(4-三氟甲基苯基)丁醛的反应式：
Figure PCTCN2021079229-appb-000011
不对称转移氢化制备(S)-3-苯基丁醛的方法：将(E)-3-(4-三氟甲基苯基)-2-烯丁醛(1.0equiv)、Catalyst I(1.2equiv)、TFA(30mol％),溶于二氧六环(1mL)中，在50℃的条件下剧烈搅拌24小时，加水淬灭反应后，用乙酸乙酯萃取。有机相浓缩后，经柱层析纯化后，得(S)-3-(4-三氟甲基苯基)丁醛，产率为92％，ee值为81％。
实施例6
不对称转移氢化制备(S)-3-萘基丁醛的反应式：
Figure PCTCN2021079229-appb-000012
不对称转移氢化制备(S)-3-萘基丁醛的方法：将(E)-3-萘基-2-烯丁醛(1.0equiv)、Catalyst I(1.2equiv)、TFA(30mol％),溶于二氧六环(1mL)中，在50℃的条件下剧烈搅拌24小时，加水淬灭反应后，用乙酸乙酯萃取。有机相浓缩后，经柱层析纯化后，得(S)-3-萘基丁醛，产率为86％，ee值为70％。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (10)

  1. 一种1,4-二氢吡啶类手性杂合氢化试剂，其特征在于，具有式(I)所示结构：
    Figure PCTCN2021079229-appb-100001
    R 1和R 2各自独立地选自C 1-4烷基。
  2. 根据权利要求1所述的1,4-二氢吡啶类手性杂合氢化试剂，其特征在于，R 1为乙基，R 2为甲基。
  3. 权利要求1或2所述的1,4-二氢吡啶类手性杂合氢化试剂的制备方法，其特征在于，包括以下步骤：
    将式(I-1)所示结构化合物、式(I-2)所示结构化合物和溶剂混合，获得式(I)所示结构的1,4-二氢吡啶类手性杂合氢化试剂；
    Figure PCTCN2021079229-appb-100002
  4. 根据权利要求3所述的制备方法，其特征在于，所述溶剂为二氯甲烷。
  5. 一种不对称催化方法，其特征在于，包括以下步骤：
    提供含有不饱和键的底物；
    将所述底物和权利要求1或2所述的1,4-二氢吡啶类手性杂合氢化试剂混合，进行不对称氢化反应，制得所需构型的目标化合物。
  6. 根据权利要求5所述的不对称氢化方法，其特征在于，所述底物具有式(II-1)所示结构：
    Figure PCTCN2021079229-appb-100003
    Figure PCTCN2021079229-appb-100004
    其中，R 3选自：取代或未取代的具有1-20个碳原子的直链烷基、取代或未取代的具有3-20个碳原子的支链烷基、取代或未取代的具有3-20个碳原子的环烷基、取代或未取代的具有3-20个环原子的杂环基、取代或未取代的具有6-20个环原子的芳基、或取代或未取代的具有5-20个环原子的杂芳基；
    R 4选自：取代或未取代的具有1-20个碳原子的直链烷基、或取代或未取代的具有3-20个碳原子的支链烷基。
  7. 根据权利要求6所述的不对称氢化方法，其特征在于，R 3为具有6-10个环原子的芳基、或R a取代具有6-10个环原子的芳基；R a选自：氰基、硝基、卤素、三氟甲基或二氟甲基；
    R 4选自：具有1-4个碳原子的直链烷基、或具有3-6个碳原子的支链烷基。
  8. 根据权利要求7所述的不对称氢化方法，其特征在于，将所述底物和权利要求1或2所述的1,4-二氢吡啶类手性杂合氢化试剂混合，进行不对称氢化反应的步骤包括以下步骤：
    将所述底物和权利要求1或2所述的1,4-二氢吡啶类手性杂合氢化试剂、质子酸和有机溶剂混合，反应完全后，分离提纯。
  9. 根据权利要求8所述的不对称氢化方法，其特征在于，所述有机溶剂选自：二氧六环、氯仿、二氯甲烷、乙醚、甲苯、四氢呋喃和乙腈中的一种或多种；
    所述质子酸选自：三氟乙酸、醋酸、苯甲酸、磺酸、盐酸和磷酸中的一种或多种。
  10. 根据权利要求8所述的不对称氢化方法，其特征在于，所述底物中每1mol待还原双键，对应加入(1.1-2)mol所述的1,4-二氢吡啶类手性杂合氢化试剂；
    所述底物和所述质子酸的摩尔比为1：(0.2-0.4)。
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