WO2022077852A1 - 3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂及其制备方法和应用 - Google Patents

3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂及其制备方法和应用 Download PDF

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WO2022077852A1
WO2022077852A1 PCT/CN2021/079232 CN2021079232W WO2022077852A1 WO 2022077852 A1 WO2022077852 A1 WO 2022077852A1 CN 2021079232 W CN2021079232 W CN 2021079232W WO 2022077852 A1 WO2022077852 A1 WO 2022077852A1
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carbon atoms
hydrogenation
substituted
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dihydropyridine
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PCT/CN2021/079232
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French (fr)
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徐亮
刘艳
蒙发明
李佑智
徐伟平
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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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Publication of WO2022077852A1 publication Critical patent/WO2022077852A1/zh

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/44—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by —CHO groups
    • 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
    • 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 hydrogenation, in particular to a 3,5-dicarboxylate-1,4-dihydropyridine hydrogenation reagent and a preparation method and application thereof.
  • Asymmetric catalytic hydrogenation is an important direction in modern synthetic chemistry.
  • hydrogen is used as the reducing agent and a chiral catalyst based on transition metals is used to carry out asymmetric catalytic hydrogenation.
  • Isopropanol and formic acid are commonly used hydrogen sources in asymmetric transfer catalytic hydrogenation.
  • the catalytic process of these transition metals shows good reactivity and selectivity, however, the reaction still has great limitations, such as: the type of substrate is limited, that is, the substrate range is narrow, and the use of high-pressure hydrogen is difficult to control , there is a big security risk.
  • the typical 1,4-dihydropyridine chiral catalyst is based on the characteristics that 1,4-dihydropyridine derivatives can realize transfer hydrogenation, so as to avoid the use of 1,4-dihydropyridine derivatives.
  • High-pressure hydrogen gas with harsh conditions was used as the hydrogen source, and chiral tetrahydropyrrole derivatives were introduced on 1,4-dihydropyridine derivatives to realize the construction of chiral centers, such as:
  • the above-mentioned hydrogenation reagents are chiral proline derivatives.
  • the hydrogenation reagents have high hydrogenation efficiency and can obtain target products with higher ee values.
  • the preparation of such hydrogenation reagents is relatively complicated, and in order to construct the pyrrole ring, high-pressure hydrogen reduction is required.
  • the method has low safety and high cost in the industrial production process.
  • 1,4-dihydropyridine derivatives are different from general hydrogenation catalysts, they themselves need to participate in the reaction, so the amount of addition is usually relatively large and the cost is relatively high, so obtaining a kind of low production cost and high cost
  • the hydrogenation reagent of hydrogenation efficiency is particularly important.
  • the 3,5-dicarboxylate-1,4-dihydropyridine hydrogenation reagent has better hydrogenation efficiency, simple synthesis method and mild reaction conditions, which can effectively reduce production cost and improve production safety.
  • a 3,5-dicarboxylate-1,4-dihydropyridine hydrogenation reagent having the structure shown in formula (I):
  • R is selected from: a hydrogen atom, a straight-chain alkyl group having 1-20 carbon atoms, a branched-chain alkyl group having 3-10 carbon atoms, a cycloalkyl group having 3-10 carbon atoms, or a substituted or unsubstituted benzene base.
  • R is selected from: H, straight chain alkyl having 1-4 carbon atoms or branched alkyl having 3-8 carbon atoms.
  • the above-mentioned hydrogenation reagent is selected from any of the following compounds:
  • the preparation method of the above-mentioned 3,5-dicarboxylate-1,4-dihydropyridine hydrogenation reagent comprises the following steps:
  • the molar ratio of the compound represented by the formula (I-1) and the 2,2,6-trimethyl-1,3-dioxin-4-one is 1:(0.5 ⁇ 2); the reaction solvent is Toluene; the reaction temperature is 50°C ⁇ 180°C;
  • the molar ratio of the compound represented by the formula (I-2), the hexamethylenetetramine and the ammonium acetate is 1:(0.5 ⁇ 2):(0.5 ⁇ 2); the reaction temperature is 50°C ⁇ 180 °C.
  • An asymmetric hydrogenation method comprising the following steps:
  • the substrate is mixed with the above-mentioned 3,5-dicarboxylate-1,4-dihydropyridine hydrogenation reagent, and an asymmetric hydrogenation reaction is carried out to obtain the target compound of the desired configuration.
  • the substrate has a structure represented by formula (II-1):
  • R 1 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 2 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 1 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 2 is selected from: straight-chain alkyl having 1-4 carbon atoms, or branched-chain alkyl having 3-8 carbon atoms.
  • the substrate is mixed with the above-mentioned 3,5-dicarboxylate-1,4-dihydropyridine hydrogenation reagent, and the step of performing asymmetric hydrogenation includes the following steps:
  • 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 above-mentioned 3,5-dicarboxylate-1,4-dihydropyridine hydrogenation reagents are introduced into chiral ⁇ -hydroxybenzenecarboxylate derivatives on 1,4-dihydropyridine derivatives to achieve transfer hydrogenation reaction
  • the control of the stereo configuration ensures the hydrogenation transfer efficiency and improves the asymmetric conversion rate; at the same time, the above hydrogenation reagents only need to convert the corresponding intermediates of ⁇ -hydroxybenzenecarboxylate and 1,4-dihydropyridine derivatives
  • the desired hydrogenation reagent can be obtained by coupling, the operation is simple, the reaction conditions are mild, and the raw materials are relatively cheap and easily available.
  • the above-mentioned 3,5-dicarboxylate-1,4-dihydropyridine hydrogenation reagent is based on the hydrogenation transfer of the reagent itself to achieve asymmetric hydrogenation, so it is safe and reliable to avoid using high-pressure hydrogen with harsh conditions as a hydrogen source.
  • the above-mentioned 3,5-dicarboxylate-1,4-dihydropyridine hydrogenation reagents do not need to use transition metal catalysts, can avoid transition metal residues caused by the use of transition metals, reduce the pollution of transition metals, especially toxic heavy metals, green Environmentally friendly, 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 ring 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 3,5-dicarboxylate-1,4-dihydropyridine hydrogenation reagent, which has the structure shown in formula (I):
  • R is selected from: a hydrogen atom, a straight-chain alkyl group having 1-20 carbon atoms, a branched-chain alkyl group having 3-10 carbon atoms, a cycloalkyl group having 3-10 carbon atoms, or a substituted or unsubstituted benzene base.
  • R is selected from: a hydrogen atom, a straight-chain alkyl group having 1-6 carbon atoms, a branched-chain alkyl group having 3-8 carbon atoms, a cycloalkyl group having 3-8 carbon atoms, - Heterocyclyl of 8 ring atoms or substituted or unsubstituted phenyl.
  • phenyl group when the phenyl group is further substituted, it is selected from the following substituents: straight-chain alkyl groups with 1-6 carbon atoms, branched-chain alkyl groups with 3-8 carbon atoms, and branched-chain alkyl groups with 3-8 carbon atoms cycloalkyl, alkoxy or halogen with 1-6 carbon atoms;
  • R is selected from: methyl, ethyl, 1-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl;
  • R is selected from: methyl, ethyl, isopropyl or tert-butyl;
  • the above-mentioned hydrogenation reagent is selected from any of the following compounds:
  • the above-mentioned 3,5-dicarboxylate-1,4-dihydropyridine hydrogenation reagents are introduced into chiral ⁇ -hydroxybenzenecarboxylate derivatives on 1,4-dihydropyridine derivatives to achieve transfer hydrogenation reaction
  • the control of the stereo configuration ensures the hydrogenation transfer efficiency and improves the asymmetric conversion rate; at the same time, the above hydrogenation reagents only need to convert the corresponding intermediates of ⁇ -hydroxybenzenecarboxylate and 1,4-dihydropyridine derivatives
  • the desired hydrogenation reagent can be obtained by coupling, the operation is simple, the reaction conditions are mild, and the raw materials are relatively cheap and easily available.
  • the above-mentioned 3,5-dicarboxylate-1,4-dihydropyridine hydrogenation reagent is based on the hydrogenation transfer of the reagent itself to achieve asymmetric hydrogenation, so it is safe and reliable to avoid using high-pressure hydrogen with harsh conditions as a hydrogen source. Moreover, 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.
  • the present invention also provides a method for preparing the above-mentioned 3,5-dicarboxylate-1,4-dihydropyridine hydrogenation reagent, comprising the following steps:
  • a solvent acceptable in the art can be used in step S101, and the reaction temperature can be selected according to the type of solvent, which is not particularly limited here; preferably, toluene is used as the solvent in step S101, and the reaction temperature is 50°C-180°C. °C;
  • step S101 the molar ratio of the compound represented by formula (I-1) and 2,2,6-trimethyl-1,3-dioxin-4-one is 1:(0.5-2); Further, the molar ratio of the compound represented by formula (I-1) and 2,2,6-trimethyl-1,3-dioxin-4-one is 1:1;
  • the reaction solvent is dioxane, and the reaction temperature is 50°C-180°C; further, the reaction temperature is 80°C-120°C;
  • step S102 the molar ratio of the compound represented by formula (I-2), hexamethylenetetramine and ammonium acetate is 1:(0.5-2):(0.5-2); further, step S102 wherein, the molar ratio of the compound represented by formula (I-2), hexamethylenetetramine and ammonium acetate is 1:(1 ⁇ 2):(0.5 ⁇ 1);
  • the above preparation method is by reacting the compound represented by formula (I-1) with 2,2,6-trimethyl-1,3-dioxin-4-one, and introducing ⁇ -hydroxybenzene carboxylate containing a chiral center 3,5-dicarboxylate-1,4-dihydropyridine hydrogenation reagent of formula (I) is formed by cyclization reaction with hexamethylenetetramine, only two steps are required
  • the target product can be obtained by the reaction, and the reaction conditions in each step are mild, the operation is simple, the yield is high, and the raw material sources are wide, 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.
  • the present invention also provides an asymmetric hydrogenation 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 1 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 2 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 1 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 1 is a 6- Aryl having 10 ring atoms, heteroaryl having 5-10 ring atoms, electron withdrawing group substituted for aryl having 6-10 ring atoms, or electron withdrawing group substituted for heteroaryl having 6-10 ring atoms Aryl.
  • R 1 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; further, R 1 is phenyl or naphthyl.
  • R 2 is selected from: a straight-chain alkyl group having 1-6 carbon atoms, or a branched alkyl group having 3-10 carbon atoms; further, R 2 is selected from: having 1-4 carbon atoms A straight-chain alkyl group of atoms, or a branched-chain alkyl group with 3-8 carbon atoms; further, R 2 is selected from: methyl, ethyl or isopropyl;
  • the obtained target compound is a compound containing an S chiral center
  • the substrate is a compound of the structure shown in formula (II-2); for example:
  • S202 includes the following steps: mixing the substrate, the above-mentioned hydrogenation reagent, the protonic acid and the organic solvent, reacting for a predetermined time, separating and purifying 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; 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.

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Abstract

3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂及其制备方法和应用，所述氢化试剂具有式(I)所示结构，具有较优的氢化效率，且合成方法简单，反应条件温和，能够有效地降低生产成本和提高生产安全性。

Description

3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂及其制备方法和应用 技术领域
本发明涉及不对称氢化技术领域，特别涉及3,5-二羧酸酯-1,4-二氢吡啶类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。传统的不对称催化氢化反应，是以氢气为还原剂，并基于过渡金属的手性催化剂，进行不对称催化氢化。不对称转移催化氢化反应中，异丙醇和甲酸是常用的氢源。虽然这些过渡金属的催化过程显示出较好的反应活性和选择性，然而，反应仍有较大的局限，如：底物类型受限，即底物范围较窄，且高压氢气的使用难以控制，存在较大安全隐患。
基于此开发了一系列氢化试剂，目前较为典型的是1,4-二氢吡啶类手性催化剂，其原理是基于1,4-二氢吡啶类衍生物能够实现转移氢化的特点，以避免使用条件苛刻的高压氢气作为氢源，同时在1,4-二氢吡啶衍生物上引入手性四氢吡咯衍生物，以实现手性中心的构建，例如：
Figure PCTCN2021079232-appb-000001
上述氢化试剂为手性脯氨酸衍生物，该氢化试剂氢化效率较高，能够获得较高ee值的目标产物，但该类氢化试剂制备较为复杂，且为了构建吡咯环，需要采用高压氢气还原的方法，在工业生产过程中安全性较低，且成本较高。此外，由于1,4-二氢吡啶类衍生物不同于一般的氢化催化剂，其本身需要参与反应，故添加量通常比较大，成本相对较高，故获得一种生产成本较低且具有较高氢化效率的氢化试剂显得尤为重要。
发明内容
基于此，有必要提供一种3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂及其制备方法和应用，该3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂具有较优的氢化效率，且合成方法简单，反应条件温和，能够有效地降低生产成本和提高生产安全性。
一种3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂，具有式(I)所示结构：
Figure PCTCN2021079232-appb-000002
R选自：氢原子、具有1-20个碳原子直链烷基、具有3-10个碳原子的支链烷基、具有3-10个碳原子的环烷基、或取代或未取代苯基。
在其中一实施例中，R选自：H、具有1-4个碳原子的直链烷基或具有3-8个碳原子的支链烷基。
在其中一实施例中，上述氢化试剂选自以下任一化合物：
Figure PCTCN2021079232-appb-000003
上述3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂的制备方法，包括以下步骤：
将式(I-1)所示化合物和2，2，6-三甲基-1，3-二噁英-4-酮进行反应，制得式(I-2)所示化合物；
将所述式(I-2)所示化合物、六次甲基四胺和醋酸铵反应，制得式(I)所示结构的氢化试剂；
Figure PCTCN2021079232-appb-000004
在其中一实施例中，将式(I-1)所示化合物和2，2，6-三甲基-1，3-二噁英-4-酮进行反应的步骤中：
所述式(I-1)所示化合物和所述2，2，6-三甲基-1，3-二噁英-4-酮的摩尔比为1:(0.5～2)；反应溶剂为甲苯；反应温度为50℃～180℃；
将式(I-2)所示化合物、六次甲基四胺和醋酸铵反应的步骤中：
所述式(I-2)所示化合物、所述六次甲基四胺和所述醋酸铵的摩尔比为1：(0.5～2):(0.5～2)；反应温度为50℃～180℃。
一种不对称氢化方法，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3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂混合，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 PCTCN2021079232-appb-000005
其中，R 1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 2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 1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 2选自：具有1-4个碳原子的直链烷基、或具有3-8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3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂混合，进行不对称氢化反应的步骤包括以下步骤：
将所述底物、所述3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂、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。
有益效果
上述3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂通过在1，4-二氢吡啶衍生物上引入手性α-羟基苯羧酸酯衍生物，以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，上述氢化试剂仅需将α-羟基苯羧酸酯和1，4-二氢吡啶衍生物的相应中间体进行偶联即可获得所需氢化试剂，操作简单，反应条件温和，且原料相对廉价易得，相比于传统的手性脯氨酸偶联1,4-二氢吡啶类氢化试剂，可以大幅度缩短合成路线，且制备过程中能够避免高压氢气的使用，提高生产安全性的同时，降低生产成本，更利于工业生产应用。
上述3,5-二羧酸酯-1,4-二氢吡啶类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3,5-二羧酸酯-1,4-二氢吡啶类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C1-6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个环原子的杂环基，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3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂，具有式(I)所示结构：
Figure PCTCN2021079232-appb-000006
R选自：氢原子、具有1-20个碳原子直链烷基、具有3-10个碳原子的支链烷基、具有3-10个碳原子的环烷基、或取代或未取代苯基。
进一步地，R选自：氢原子、具有1-6个碳原子的直链烷基、具有3-8个碳 原子的支链烷基、具有3-8个碳原子的环烷基、具有3-8个环原子的杂环基或取代或未取代苯基。
进一步地，当苯基被进一步取代时，选自以下取代基：具有1-6个碳原子的直链烷基、具有3-8个碳原子的支链烷基、具有3-8个碳原子的环烷基、具有1-6个碳原子的烷氧基或卤素；
进一步地，R选自：甲基、乙基、1-丙基、异丙基、正丁基、异丁基、或叔丁基；
进一步地，R选自：甲基、乙基、异丙基或叔丁基；
进一步地，上述氢化试剂选自以下任一化合物：
Figure PCTCN2021079232-appb-000007
上述3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂通过在1，4-二氢吡啶衍生物上引入手性α-羟基苯羧酸酯衍生物，以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，上述氢化试剂仅需将α-羟基苯羧酸酯和1，4-二氢吡啶衍生物的相应中间体进行偶联即可获得所需氢化试剂，操作简单，反应条件温和，且原料相对廉价易得，相比于传统的手性脯氨酸偶联1,4-二氢吡啶类氢化试剂，可以大幅度缩短合成路线，且制备过程中能够避免高压氢气的使用，提高生产安全性的同时，降低生产成本，更利于工业生产应用。
上述3,5-二羧酸酯-1,4-二氢吡啶类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。
本发明还提供了上述3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂的制备方法，包括以下步骤：
S101：将式(I-1)所示化合物和2，2，6-三甲基-1，3-二噁英-4-酮进行反应，制得式(I-2)所示化合物；
Figure PCTCN2021079232-appb-000008
其中，R的定义如上所述，在此不再进行赘述。
可理解的，步骤S101中可以采用本领域中可接受的溶剂，反应温度可以根据溶剂的种类进行选择，在此不进行特别限定；优选步骤S101中以甲苯作为溶剂，反应温度为50℃-180℃；
进一步地，步骤S101中，式(I-1)所示化合物和2，2，6-三甲基-1，3-二噁英-4-酮的摩尔比为1:(0.5～2)；更进一步地，式(I-1)所示化合物和2，2，6-三甲基-1，3-二噁英-4-酮的摩尔比为1：1；
S102：将式(I-2)所示化合物、六次甲基四胺和醋酸铵反应，制得式(I)所示结构的氢化试剂；
Figure PCTCN2021079232-appb-000009
进一步地，步骤S102中反应溶剂为二氧六环，反应温度为50℃-180℃；更进一步地，反应温度为80℃-120℃；
进一步地，步骤S102中，式(I-2)所示化合物、六次甲基四胺和醋酸铵的摩尔比为1:(0.5～2):(0.5～2)；更进一步地，步骤S102中，式(I-2)所示化合物、 六次甲基四胺和醋酸铵的摩尔比为1:(1～2):(0.5～1)；
上述制备方法通过将式(I-1)所示化合物和2，2，6-三甲基-1，3-二噁英-4-酮进行反应，引入含手性中心的α-羟基苯羧酸酯，然后通过与六次甲基四胺进行环化反应，形成式(I)所示结构的3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂，仅需两步反应即可获得目标产物，且各步骤中反应条件温和，操作简单，收率较高，且原料来源广泛，特别适用于工业生产应用。
本发明还提供上述3,5-二羧酸酯-1,4-二氢吡啶类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。
本发明还提供了一种不对称氢化方法，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 PCTCN2021079232-appb-000010
其中，R 1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 2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 1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 1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个环原子的杂芳基。
更进一步地，R 1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 1为苯基或萘基。
进一步地，R 2选自：具有1-6个碳原子的直链烷基、或具有3-10个碳原子的支链烷基；更进一步地，R 2选自：具有1-4个碳原子的直链烷基、或具有3-8个碳原子的支链烷基；更进一步地，R 2选自：甲基、乙基或异丙基；
S202：将底物和上述3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂混合，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；例如：
Figure PCTCN2021079232-appb-000011
进一步地，S202包括以下步骤：将底物、上述氢化试剂、质子酸和有机溶剂混合，反应预定时间，分离提纯，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。
下面列举具体实施例来对本发明进行说明。
实施例1
(1)将2，2，6-三甲基-1，3-二噁英-4-酮(142.2mg,1mmol)滴加到(S)-α-羟基苯乙酸甲酯(166.2mg,1mmol)的甲苯(0.5mL)的溶液中。搅拌回流过夜，待反应完全后，将反应液冷却至50℃，真空除去溶剂。粗产品经硅胶柱层析纯化分离纯化得到212.6mg白色固体化合物，(S)-2-methoxy-2-oxo-1-phenylethyl 3-oxobutanoate，产率85％。
Figure PCTCN2021079232-appb-000012
(2)将(S)-2-methoxy-2-oxo-1-phenylethyl 3-oxobutanoate(500.0mg,2mmol)、醋酸铵(77.1mg,1mmol)、六次甲基四胺(140.2mg)和二氧六环(5mL)混合，在100℃的条件下反应30分钟，反应完成后，冷却，加水，用二氯甲烷萃取，萃取三次后，合并有机相，浓缩，经硅胶柱层析纯化，得400mg淡黄色目标物，Catalyst I，产率81％。
Figure PCTCN2021079232-appb-000013
实施例2
(1)将2，2，6-三甲基-1，3-二噁英-4-酮(142.2mg,1mmol)滴加到(S)-α-羟基苯乙酸乙酯(180.2mg,1mmol)的甲苯(0.5mL)的溶液中。搅拌回流过夜，待反应完全后，将反应液冷却至50℃，真空除去溶剂。粗产品经硅胶柱层析纯化，分离纯化得到243.0mg白色固体化合物，(S)-2-ethoxy-2-oxo-1-phenylethyl 3-oxobutanoate产率92％.
Figure PCTCN2021079232-appb-000014
(2)将(S)-2-ethoxy-2-oxo-1-phenylethyl 3-oxobutanoate(528mg,2mmol)、醋酸铵(77.1mg,1mmol)、六次甲基四胺(140.2mg)和二氧六环(5mL)混合，在100℃的条件下反应30分钟，反应完全后，冷却，加水，用二氯甲烷萃取用二氯甲烷萃取，萃取三次后，合并有机相，浓缩，经硅胶柱层析纯化，得443mg淡黄色目标物，Catalyst II，产率85％。
Figure PCTCN2021079232-appb-000015
实施例3
(1)将2，2，6-三甲基-1，3-二噁英-4-酮(142.2mg,1mmol)滴加到(S)-α-羟基苯乙酸异丙酯(194.2mg,1mmol)的甲苯(0.5mL)的溶液中。搅拌回流过夜，待反应完全后，将反应液冷却至50℃，真空除去溶剂。粗产品经硅胶柱层析纯化分离纯化，得到217.3mg淡黄色固体化合物，(S)-2-isopropoxy-2-oxo-1-phenylethyl 3-oxobutanoate，产率78％.
Figure PCTCN2021079232-appb-000016
(2)将(S)-2-isopropoxy-2-oxo-1-phenylethyl 3-oxobutanoate(556mg,2mmol)、醋酸铵(77.1mg,1mmol)、六次甲基四胺(140.2mg)和二氧六环(5mL)混合，在100℃的条件下反应30分钟，反应完成后，冷却，加水，用二氯甲烷萃取，萃取三次后，合并有机相，浓缩，经硅胶柱层析纯化，得390mg淡黄色目标物，Catalyst III，产率71％。
Figure PCTCN2021079232-appb-000017
实施例4
不对称转移氢化制备(S)-3-苯基丁醛的反应式：
Figure PCTCN2021079232-appb-000018
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)和TFA(30mol％)溶于二氧六环(1mL)中，在50℃的条件下剧烈搅拌，反应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85％。
实施例5
不对称转移氢化制备(S)-3-(4-氰基苯基)丁醛的反应式：
Figure PCTCN2021079232-appb-000019
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)和TFA(30mol％),溶于二氧六环(1mL)中，在50℃的条件下，剧烈搅拌反应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85％，ee值为90％。
实施例6
不对称转移氢化制备(S)-3-(4-硝基苯基)丁醛的反应式：
Figure PCTCN2021079232-appb-000020
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)和TFA(30mol％)溶于二氧六环(1mL)中，在50℃的条件下，剧烈搅拌反应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89％，ee值为93％。
实施例7
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 PCTCN2021079232-appb-000021
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)和TFA(30mol％)溶于二氧六环(1mL)中，在50℃的条件下，剧烈搅拌反应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92％，ee值为91％。
实施例8
不对称转移氢化制备(S)-3-萘基丁醛的反应式：
Figure PCTCN2021079232-appb-000022
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)和TFA(30mol％)溶于二氧六环(1mL)中，在50℃的条件下，剧烈搅拌反应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86％，ee值为90％。
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3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂，其特征在于，具有式(I)所示结构：
    Figure PCTCN2021079232-appb-100001
    R选自：氢原子、具有1-20个碳原子直链烷基、具有3-10个碳原子的支链烷基、具有3-10个碳原子的环烷基、或取代或未取代的苯基。
  2. 根据权利要求1所述的3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂，其特征在于，R选自：H、具有1-4个碳原子的直链烷基或具有3-8个碳原子的支链烷基。
  3. 根据权利要求1所述的3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂，其特征在于，选自以下任一化合物：
    Figure PCTCN2021079232-appb-100002
  4. 权利要求1-3任一项所述的3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂的制备方法，其特征在于，包括以下步骤：
    将式(I-1)所示化合物和2，2，6-三甲基-1，3-二噁英-4-酮进行反应，制得式(I-2)所示化合物；
    将所述式(I-2)所示化合物、六次甲基四胺和醋酸铵反应，制得式(I)所示结构的3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂；
    Figure PCTCN2021079232-appb-100003
  5. 根据权利要求4所述的制备方法，其特征在于，将式(I-1)所示化合物和2，2，6-三甲基-1，3-二噁英-4-酮进行反应的步骤中：
    所述式(I-1)所示化合物和所述2，2，6-三甲基-1，3-二噁英-4-酮的摩尔比为1:(0.5～2)；反应溶剂为甲苯；反应温度为50℃～180℃；
    将式(I-2)所示化合物、六次甲基四胺和醋酸铵反应的步骤中：
    所述式(I-2)所示化合物、所述六次甲基四胺和所述醋酸铵的摩尔比为1：(0.5～2):(0.5～2)；反应温度为50℃～180℃。
  6. 一种不对称氢化方法，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1-3任一项所述的3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂混合，进行不对称氢化反应，制得所需构型的目标化合物。
  7. 根据权利要求6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 PCTCN2021079232-appb-100004
    其中，R 1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 2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。
  8. 根据权利要求7所述的不对称氢化方法，其特征在于，R 1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 2选自：具有1-4个碳原子的直链烷基、或具有3-8个碳原子的支链烷基。
  9. 根据权利要求6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1-3任一项所述的3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂混合，进行不对称氢化反应的步骤包括以下步骤：
    将所述底物、所述3,5-二羧酸酯-1,4-二氢吡啶类氢化试剂、质子酸和有机溶剂混合，反应完全后，分离提纯。
  10. 根据权利要求9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。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102348685A (zh) * 2009-03-11 2012-02-08 格林代克斯联合股份公司 5-氟尿嘧啶和1，4-二氢吡啶衍生物的药物组合及其在治疗癌症中的用途
EP2578218A1 (en) * 2011-10-06 2013-04-10 Grindeks, A Joint Stock Company Antiviral efficacy of disodium 2,6-dimethyl-1,4-dihydropyridine-3,5-bis(carbonyloxyacetate) and its derivatives
CN109824652A (zh) * 2019-03-04 2019-05-31 广西九圣新材料有限公司 一种1，4-二氢吡啶类双官能手性催化剂及其制备方法和应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111170949B (zh) * 2018-11-09 2021-07-27 中国科学院大连化学物理研究所 一种不对称转移氢化合成3,4-二氢嘧啶酮化合物的方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102348685A (zh) * 2009-03-11 2012-02-08 格林代克斯联合股份公司 5-氟尿嘧啶和1，4-二氢吡啶衍生物的药物组合及其在治疗癌症中的用途
EP2578218A1 (en) * 2011-10-06 2013-04-10 Grindeks, A Joint Stock Company Antiviral efficacy of disodium 2,6-dimethyl-1,4-dihydropyridine-3,5-bis(carbonyloxyacetate) and its derivatives
CN109824652A (zh) * 2019-03-04 2019-05-31 广西九圣新材料有限公司 一种1，4-二氢吡啶类双官能手性催化剂及其制备方法和应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE Registry ANONYMOUS : "- 3,5-Pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-, 3,5-bis(2-ethoxy-2-oxo-1-phenylethyl) ester (CA INDEX NAME)", XP055921814, Database accession no. STN *
LI GUANGXUN, CHEN RONG, WU LEI, FU QINGQUAN, ZHANG XIAOMEI, TANG ZHUO: "Alkyl Transfer from CC Cleavage", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, VERLAG CHEMIE, vol. 52, no. 32, 5 August 2013 (2013-08-05), pages 8432 - 8436, XP055921831, ISSN: 1433-7851, DOI: 10.1002/anie.201303696 *
NISHIYAMA, KAZUYOSHI ET AL.: "Asymmetric Reduction of α-Ketoesters with Hantzsch Esters (Dialkoxycarbonyldihydropyridines)", J.C.S.CHEM.COMM., 1 January 1976 (1976-01-01), XP055211399, ISSN: 0022-4936, DOI: 10.1039/C39760000101 *

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