CN114989072B - Method for asymmetric catalytic synthesis of chiral 1, 4-dihydropyridine compound and application thereof - Google Patents

Method for asymmetric catalytic synthesis of chiral 1, 4-dihydropyridine compound and application thereof Download PDF

Info

Publication number
CN114989072B
CN114989072B CN202210586317.2A CN202210586317A CN114989072B CN 114989072 B CN114989072 B CN 114989072B CN 202210586317 A CN202210586317 A CN 202210586317A CN 114989072 B CN114989072 B CN 114989072B
Authority
CN
China
Prior art keywords
compound
chiral
otf
triflate
dihydropyridine
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.)
Active
Application number
CN202210586317.2A
Other languages
Chinese (zh)
Other versions
CN114989072A (en
Inventor
冯小明
胡欣月
刘小华
陈龙
曹伟地
董顺喜
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.)
Sichuan University
Original Assignee
Sichuan 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 Sichuan University filed Critical Sichuan University
Priority to CN202210586317.2A priority Critical patent/CN114989072B/en
Publication of CN114989072A publication Critical patent/CN114989072A/en
Application granted granted Critical
Publication of CN114989072B publication Critical patent/CN114989072B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • 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
    • Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
    • 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
    • Y02P20/584—Recycling of catalysts

Landscapes

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

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for asymmetric catalytic synthesis of chiral 1, 4-dihydropyridine compounds and application thereof. The invention takes 2-substituted-3-oxo-butyrate and 3-aminocrotonate as raw materials, a complex formed by chiral amine oxide and a metal compound is taken as a catalyst, and the chiral 1, 4-dihydropyridine compound is obtained by reaction in an organic solvent; the method has the advantages of mild reaction conditions, simple operation, convenient product purification, high yield and enantioselectivity and good substrate universality. Chiral 1, 4-dihydropyridine compounds chiral 1, 4-dihydropyridine drug molecules can be built in one step by 1, 4-addition/nucleophilic addition/dehydration tandem reactions such as: nitrendipine, nimodipine, isradipine, amlodipine, nisoldipine, barnidipine, azetidine, benidipine, cilnidipine, felodipine, and the like; provides a novel efficient and high-selectivity asymmetric catalysis method for synthesizing a series of chiral 1, 4-dihydropyridine drug molecules.

Description

Method for asymmetric catalytic synthesis of chiral 1, 4-dihydropyridine compound and application thereof
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for asymmetric catalytic synthesis of chiral 1, 4-dihydropyridine compounds and application thereof.
Background
1, 4-dihydropyridine compounds are widely used as a potent calcium channel blocker in the clinical treatment of cardiovascular diseases, and 1, 4-dihydropyridine drug molecules currently on the market for the treatment of hypertension include: felodipine, amlodipine, nitrendipine, nimodipine, nisoldipine and the like, and the stereochemistry of a C-4 substituent of the medicine molecule greatly influences the pharmacological activity of the structure. Therefore, the synthesis of optically pure 1, 4-dihydropyridine drug molecules would be beneficial to enhancing the clinical therapeutic effect of such drug molecules. At present, strategies for chiral induction, resolution and asymmetric catalytic synthesis of such chiral drug molecules have been disclosed.
Splitting:
the resolution of the calcium channel antagonist S11568 was achieved by chiral High Performance Liquid Chromatography (HPLC) by Doll et al, which gave the product in both configurations in 50% yield (Bioorg. Med. Chem.1997,5,749), respectively; yin Yongmei and imago et al achieve chiral resolution of 1, 4-dihydropyridine drug molecules using chiral Supercritical Fluid Chromatography (SFC), and complete resolution of nimodipine, amlodipine, azelnidipine, benidipine, cilnidipine, nisoldipine and felodipine drug molecules by adjustment of flow rates and solvents (j.ofsuperficialilfluidis 2016,107, 129).
Amlodipine drug molecules were resolved by s.p. sonawane et al using (+) -L-tartrate (org.process res.dev.2010,14,640). In this reaction, (S) -amlodipine and (+) -L-tartrate are precipitated in a co-crystalline form using DMF/water (v/v=85:15) as a mixed solvent, and (R) -amlodipine is dissolved in a DMF/water mixed solution. And then the (S) -amlodipine can be converted into chiral drug molecules (S) -amlodipine besylate at room temperature by the mixed solvent of isopropanol/water and benzenesulfonic acid.
Rebolledo et al achieved kinetic resolution of 1, 4-dihydropyridine drug molecule derivatives using lipases (Tetrahedron 2015,71,3976). The product gave a 58-98% ee enantioselective hydrolysate at 34-51% conversion.
Chiral induction:
s, using chiral alcohol as a raw material, sequentially carrying out six-step reactions of protecting group loading, esterification, addition dehydration series reaction, protecting group removal and hydrolysis reesterification to obtain chiral felodipine drug molecules with 37% yield (Tetrahedron Lett.1989,30,6423).
H. Lee et al use chiral glycidol as starting material, also undergo multi-step derivatization, ultimately giving (S) -felodipine (Tetrahedron 2011,67,10222) in 22% overall yield.
Asymmetric catalysis:
liuzhu et al reacted at 50℃for 24 hours using chiral binaphthyl phosphate as a catalyst and benzonitrile as a solvent to give a series of chiral 1, 4-dihydropyridine compounds (Angew. Chem. Int. Ed.2008,47,2458) in 31-93% yield and enantioselectivity of 66-98% ee. However, such 1, 4-dihydropyridine products are difficult to convert into 3, 5-dicarboxylate group-substituted chiral 1, 4-dihydropyridine drug molecules.
C.Bressy, X.Bugaut and J.Rodriguez et al reacted at 37℃for 24 hours using thiourea derivatives as chiral small organic molecule catalysts and methylene chloride as reaction solvent to finally give chiral 1, 4-dihydropyridine compounds in 25-71% yield and enantioselectivity of 58-96% ee, which are also difficult to convert to 3, 5-dicarboxylate substituted chiral 1, 4-dihydropyridine drug molecules (Angew. Chem. Int. Ed.2016,55,1401). Under the action of oxidant, the 1, 4-dihydropyridine structure is oxidized into pyridine to realize the conversion from central chirality to axial chirality.
Wu Jian an object group utilizes cinchona-derived chiral small molecule catalysts to achieve asymmetric construction of nitrendipine molecules (advanced materials research,2012,518-523,3943). Because the substituents at two ends of the chiral center of the product are methyl ester and ethyl ester with smaller differentiation degree respectively, the chiral control of the product is poor, nitrendipine can be obtained only with the enantioselectivity of 41%ee, and the asymmetric synthesis of other 1, 4-dihydropyridine drug families similar to the structure of the product is not involved.
In summary, current strategies for direct synthesis of chiral 1, 4-dihydropyridine drug molecules and derivatives thereof rely primarily on resolution and chiral induction. However, the resolution can only achieve 50% yield at maximum, and the atomic economy is poor; the chiral induction requires the preparation of a substrate in advance, and has the advantages of long steps, low yield and poor atom economy. Although some small molecule catalysts can realize asymmetric construction of 1, 4-dihydropyridine compounds and have good chiral control, the 1, 4-dihydropyridine compounds have special structures and are difficult to convert into true chiral 1, 4-dihydropyridine drug molecules. There are only one example of catalytic asymmetric synthesis of chiral 1, 4-dihydropyridine drug molecules, but chiral control is poor and limited to synthesis of nitrendipine drug molecules. Therefore, there is a need for developing a simple, efficient, environmentally friendly method for synthesizing chiral 1, 4-dihydropyridine compounds and pharmaceutical molecules thereof with good substrate universality.
Disclosure of Invention
The invention aims to construct a 1, 4-dihydropyridine compound by one-step construction of asymmetric 1, 4-addition/nucleophilic addition/dehydration tandem reaction of 2-substituted-3-oxo-butyrate and 3-aminocrotonate, and provides a novel efficient and high-selectivity asymmetric catalysis method for synthesizing a series of chiral 1, 4-dihydropyridine drug molecules.
The aim of the invention is realized by the following technical scheme:
a method for asymmetric catalytic synthesis of chiral 1, 4-dihydropyridine compounds, comprising the steps of:
taking a compound I and a compound II as raw materials, taking a complex formed by chiral amine oxide and a metal compound as a catalyst, stirring the chiral amine oxide and the metal compound in an organic solvent to form the complex, wherein the preferable stirring time is 10-60min, and reacting in the organic solvent to obtain the chiral 1, 4-dihydropyridine compound;
the reaction formula is as follows:
wherein R is 1 Is aryl, heteroaryl or alkyl;
R 2 is aryl, heteroaryl or alkyl;
R 3 is aryl, heteroaryl or alkyl;
R 4 is aryl, heteroaryl or alkyl;
R 5 is aryl, heteroaryl or alkyl;
R 1 ，R 2 ，R 3 ，R 4 ，R 5 wherein each of said aryl, heteroaryl or alkyl groups is independently substituted with one or more R x Is substituted by a substituent of (a); the R is x Is one or more of hydrogen atom, halogen, alkyl, fluoro substituent, nitro, cyano, ester group, alkenyl, alkynyl, alkoxy, substituted amino, aryl, hydroxy, amino, amido and sulfonamide;
the structural formula of the chiral amine oxide is as follows:
one or more of the following;
wherein R is an alkyl group, an aryl group or a heterocyclic ring, each of which is independently one or more R y Substituted; the R is y Is one or more of hydrogen atom, alkyl group, alkoxy group, ester group, aryl group and halogen; m=0 to 6; preferably, the chiral amine oxide is m=1, r is 2,3,4,5,6-Me 5 C 6 Denoted as L 3 -PiMe 5 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, the chiral amine oxide is m=1, r is 2,6-Et 2 C 6 H 3 Denoted as L 3 -PeEt 2 ；
The metal compound is as follows: magnesium triflate [ Mg (OTf) 2 ]Magnesium perchlorate [ Mg (ClO) 4 ) 2 ]Magnesium bis (trifluoromethylsulfonyl) imide [ Mg (NTf) 2 ) 2 ]Scandium triflate [ Sc (OTf) 3 ]Ferrous triflate [ Fe (OTf) 2 ]Ferric triflate [ Fe (OTf) 3 ]Nickel triflate [ Ni (OTf) 2 ]Nickel bis (trifluoromethylsulfonyl) imide [ Ni (NTf) 2 ) 2 ]Nickel tetrafluoroborate hexahydrate [ Ni (BF) 4 ) 2 ]·6H 2 O, nickel perchlorate hexahydrate [ Ni (ClO) 4 ) 2 ]·6H 2 O, copper triflate [ Cu (OTf) 2 ]Copper bis (trifluoromethylsulfonyl) imide [ Cu (NTf) 2 ) 2 ]Zinc triflate [ Zn (OTf) 2 ]Yttrium triflate [ Y (OTf) 3 ]Lanthanum triflate [ La (OTf) 3 ]Cerium triflate [ Ce (OTf) 3 ]Praseodymium triflate [ Pr (OTf) 3 ]Neodymium triflate [ Nd (OTf) 3 ]Samarium triflate [ Sm (OTf) 3 ]Europium triflate [ Eu (OTf) 3 ]Gadolinium triflate [ Gd (OTf) 3 ]Terbium triflate [ Tb (OTf) 3 ]Dysprosium triflate [ Dy (OTf) 3 ]Holmium triflate [ Ho (OTf) 3 ]Erbium triflate [ Er (OTf) 3 ]Thulium triflate [ Tm (OTf) 3 ]Ytterbium triflate [ Yb (OTf) 3 ]Lutetium triflate [ Lu (OTf) 3 ]Cobalt triflate [ Co (OTf) 2 ]And bis (trifluoromethylsulfonyl) cobaltous (Co (NTf) 2 ) 2 ]Aluminum triflate [ Al (OTf) 3 ]Indium triflate [ In (OTf) 3 ]Gallium triflate [ Ga (OTf) 3 ]One or more of the following.
Further, in the formula, the compound of the formula,
R 1 is C 6 H 5 ，2F-C 6 H 4 ，3F-C 6 H 4 ，4F-C 6 H 4 ，2CF 3 -C 6 H 4 ，2CF 3 -C 6 H 4 ，2CF 3 -C 6 H 4 ，2Cl-C 6 H 4 ，3Cl-C 6 H 4 ，4Cl-C 6 H 4 ，2BrC 6 H 4 ，3BrC 6 H 4 ，4BrC 6 H 4 ，2Me-C 6 H 4 ，3Me-C 6 H 4 ，4Me-C 6 H 4 ，2OMe-C 6 H 4 ，3OMe-C 6 H 4 ，4OMe-C 6 H 4 ，2NO 2 -C 6 H 4 ，3NO 2 -C 6 H 4 ，4NO 2 -C 6 H 4 ，4OEt-C 6 H 4 ，4Ph-C 6 H 4 ，2CN-C 6 H 4 ，3CN-C 6 H 4 ，4CN-C 6 H 4 ，2CO 2 Me-C 6 H 4 ，3CO 2 Me-C 6 H 4 ，4CO 2 Me-C 6 H 4 ，3,4-Me 2 -C 6 H 3 ，3Cl-4F-C 6 H 3 ，2-Thienyl，3-Thienyl，Piperonyl，2-Naphthyl，1-Naphthyl，2,3-Cl 2 -C 6 H 3 ，2NMe 2 C 6 H 4 ，3NMe 2 C 6 H 4 ，4NMe 2 C 6 H 4 ，4-(Methylsulfonyl)-benzenyl，2-(Methylsulfonyl)-benzenyl，
3-(Methylsulfonyl)-benzenyl，Me，Et，Isopropyl，Tertiarybutyl，Isobutyl，Cyclopropyl，Cyclopentyl，Cyclohexyl，Cycloheptyl，
And/or R 2 Is CH 3 ，Et，Isopropyl，Tertiarybutyl，Isobutyl，C 6 H 5 ,2F-C 6 H 4 ，3F-C 6 H 4 ，4F-C 6 H 4 ，2CF 3 -C 6 H 4 ，2CF 3 -C 6 H 4 ，2CF 3 -C 6 H 4 ，2Cl-C 6 H 4 ，3Cl-C 6 H 4 ，4Cl-C 6 H 4 ，2BrC 6 H 4 ，3BrC 6 H 4 ，4BrC 6 H 4 ，2Me-C 6 H 4 ，3Me-C 6 H 4 ，4Me-C 6 H 4 ，2OMe-C 6 H 4 ，3OMe-C 6 H 4 ，4OMe-C 6 H 4 ，2NO 2 -C 6 H 4 ，3NO 2 -C 6 H 4 ，4NO 2 -C 6 H 4 ，4OEt-C 6 H 4 ，4Ph-C 6 H 4 ，2CN-C 6 H 4 ，3CN-C 6 H 4 ，4CN-C 6 H 4 ，2CO 2 Me-C 6 H 4 ，3CO 2 Me-C 6 H 4 ，4CO 2 Me-C 6 H 4 ，3,4-Me 2 -C 6 H 3 ，3Cl-4F-C 6 H 3 ，2-Thienyl，3-Thienyl，Piperonyl，2-Naphthyl，1-Naphthyl，2,3-Cl 2 -C 6 H 3 ，2NMe 2 C 6 H 4 ，3NMe 2 C 6 H 4 ，4NMe 2 C 6 H 4 ，4-(Methylsulfonyl)-benzenyl，2-(Methylsulfonyl)-benzenyl，3-(Methylsulfonyl)-benzenyl，Cyclopropyl，Cyclopentyl，Cyclohexyl，Cycloheptyl，CH 2 CO 2 n Pr，C 2 H 4 OMe，
And/or R 3 Is CH 3 ，Et，Isopropyl，Tertiarybutyl，Isobutyl，C 2 H 4 OMe，C 6 H 5 ,2F-C 6 H 4 ，3F-C 6 H 4 ，4F-C 6 H 4 ，2CF 3 -C 6 H 4 ，2CF 3 -C 6 H 4 ，2CF 3 -C 6 H 4 ，2Cl-C 6 H 4 ，3Cl-C 6 H 4 ，4Cl-C 6 H 4 ，2BrC 6 H 4 ，3BrC 6 H 4 ，4BrC 6 H 4 ，2Me-C 6 H 4 ，3Me-C 6 H 4 ，4Me-C 6 H 4 ，2OMe-C 6 H 4 ，3OMe-C 6 H 4 ，4OMe-C 6 H 4 ，2NO 2 -C 6 H 4 ，3NO 2 -C 6 H 4 ，4NO 2 -C 6 H 4 ，4OEt-C 6 H 4 ，4Ph-C 6 H 4 ，2CN-C 6 H 4 ，3CN-C 6 H 4 ，4CN-C 6 H 4 ，2CO 2 Me-C 6 H 4 ，3CO 2 Me-C 6 H 4 ，4CO 2 Me-C 6 H 4 ，3,4-Me 2 -C 6 H 3 ，3Cl-4F-C 6 H 3 ，2-Thienyl，3-Thienyl，Piperonyl，2-Naphthyl，1-Naphthyl，2,3-Cl 2 -C 6 H 3 ，2NMe 2 C 6 H 4 ，3NMe 2 C 6 H 4 ，4NMe 2 C 6 H 4 ，4-(Methylsulfonyl)-benzenyl，2-(Methylsulfonyl)-benzenyl，3-(Methylsulfonyl)-benzenyl，Cyclopropyl，Cyclopentyl，Cyclohexyl，Cycloheptyl，
And/or R 4 Is CH 3 ，Et，Isopropyl，Tertiarybutyl，Isobutyl，Cyclopropyl，Cyclopentyl，Cyclohexyl，Cycloheptyl，C 6 H 5 ,2F-C 6 H 4 ，3F-C 6 H 4 ，4F-C 6 H 4 ，2CF 3 -C 6 H 4 ，2CF 3 -C 6 H 4 ，2CF 3 -C 6 H 4 ，2Cl-C 6 H 4 ，3Cl-C 6 H 4 ，4Cl-C 6 H 4 ，2BrC 6 H 4 ，3BrC 6 H 4 ，4BrC 6 H 4 ，2Me-C 6 H 4 ，3Me-C 6 H 4 ，4Me-C 6 H 4 ，2OMe-C 6 H 4 ，3OMe-C 6 H 4 ，4OMe-C 6 H 4 ，2NO 2 -C 6 H 4 ，3NO 2 -C 6 H 4 ，4NO 2 -C 6 H 4 ，4OEt-C 6 H 4 ，4Ph-C 6 H 4 ，2CN-C 6 H 4 ，3CN-C 6 H 4 ，4CN-C 6 H 4 ，2CO 2 Me-C 6 H 4 ，3CO 2 Me-C 6 H 4 ，4CO 2 Me-C 6 H 4 ，3,4-Me 2 -C 6 H 3 ，3Cl-4F-C 6 H 3 ，2-Thienyl，3-Thienyl，Piperonyl，2-Naphthyl，1-Naphthyl，2,3-Cl 2 -C 6 H 3 ，2NMe 2 C 6 H 4 ，3NMe 2 C 6 H 4 ，4NMe 2 C 6 H 4 4- (methyl-methyl) -benzenyl,2- (methyl-methyl) -benzenyl or 3- (methyl-benzenyl);
and/or R 5 Is CH 3 ，Et，Isopropyl，Tertiary butyl，Isobutyl，Cyclopropyl，Cyclopentyl，Cyclohexyl，Cycloheptyl，C 6 H 5 ,2F-C 6 H 4 ，3F-C 6 H 4 ，4F-C 6 H 4 ，2CF 3 -C 6 H 4 ，2CF 3 -C 6 H 4 ，2CF 3 -C 6 H 4 ，2Cl-C 6 H 4 ，3Cl-C 6 H 4 ，4Cl-C 6 H 4 ，2BrC 6 H 4 ，3BrC 6 H 4 ，4BrC 6 H 4 ，2Me-C 6 H 4 ，3Me-C 6 H 4 ，4Me-C 6 H 4 ，2OMe-C 6 H 4 ，3OMe-C 6 H 4 ，4OMe-C 6 H 4 ，2NO 2 -C 6 H 4 ，3NO 2 -C 6 H 4 ，4NO 2 -C 6 H 4 ，4OEt-C 6 H 4 ，4Ph-C 6 H 4 ，2CN-C 6 H 4 ，3CN-C 6 H 4 ，4CN-C 6 H 4 ，2CO 2 Me-C 6 H 4 ，3CO 2 Me-C 6 H 4 ，4CO 2 Me-C 6 H 4 ，3,4-Me 2 -C 6 H 3 ，3Cl-4F-C 6 H 3 ，2-Thienyl，3-Thienyl，Piperonyl，2-Naphthyl，1-Naphthyl，2,3-Cl 2 -C 6 H 3 ，2NMe 2 C 6 H 4 ，3NMe 2 C 6 H 4 ，4NMe 2 C 6 H 4 4- (methyl-methyl) -benzenyl,2- (methyl-methyl) -benzenyl or 3- (methyl-benzenyl).
Further, the molar ratio of the compound I to the compound II is 1:0.5-5; preferably, the molar ratio of the compound I to the compound II is 1:1.2;
and/or the molar ratio of the compound I to the catalyst is 1:0.01-1; preferably, the molar ratio of the compound I to the catalyst is 1:0.1;
and/or the molar ratio of the chiral amine oxide to the metal compound is 0.5-2:1; preferably, the molar ratio of the chiral amine oxide to the metal compound is 1:1.
Further, when the compound I and the compound II are reacted, and R 1 If not 2-Ar, naBAr with additive is also used 4 F The method comprises the steps of carrying out a first treatment on the surface of the 2-Ar means aryl having a substituent at the 2-position, i.eWherein N represents a substituent.
Further, naBAr is used 4 F The functions of (1) are as follows: standard reaction without additive NaBAr 4 F Can also react, has better chiral control, and has higher ee value after the additive is added. NaBAr 4 F The addition of (2) may act mainly as counter ion exchange, which may help the promoter to form a better chiral environment, better shield one of the faces of the reaction, and achieve better chiral control of the product.
The compound I and an additive NaBAr 4 F In a molar ratio of 1:0.01 to 1, preferably said compound I and additive NaBAr 4 F The molar ratio of (2) is 1:0.1.
Further, when R 1 In the case of 2-Ar, the metal compound is neodymium triflate [ Nd (OTf) 3 ]The chiral amine oxide is L 3 -PeEt 2 The catalyst is L 3 -PeEt 2 And neodymium triflate [ Nd (OTf) 3 ]A complex formed; when R is 1 When the metal compound is not 2-Ar, the metal compound is nickel triflate [ Ni (OTf) 2 ]The chiral amine oxide is L 3 -PiMe 5 The catalyst is L 3 -PiMe 5 And nickel triflate [ Ni (OTf) 2 ]The complex formed.
Further, the types of the organic solvents include: dichloromethane, chloroform, 1, 2-dichloroethane, 1, 2-trichloroethane, 1, 2-tetrachloroethane, toluene, ethylbenzene, cumene, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, ethyl acetate or isopropyl acetate.
Further, when R 1 In the case of 2-Ar, the organic solvent is ethyl acetate. When R is 1 And when the organic solvent is not 2-Ar, the organic solvent is dichloromethane.
And/or, the molar ratio of the organic solvent to the compound I is: 1:0.01-1.
Further, the temperature of the reaction is 0-100 ℃, and/or the time of the reaction is 2-240h; preferably, the temperature of the reaction is 10-30 ℃ and/or the time of the reaction is 72-96 hours.
The invention also provides an application of the method in synthesizing the chiral 1, 4-dihydropyridine compound.
Further, the chiral 1, 4-dihydropyridine compound comprises one or more of nitrendipine, nimodipine, isradipine, amlodipine, nisoldipine, barnidipine, azetidine, benidipine, cilnidipine and felodipine.
Further, the synthesis method of nitrendipine comprises the following steps: selecting Compound I asCompound II is->Synthesizing the nitrendipine;
further, the synthesis method of nitrendipine comprises the following steps: taking nickel triflate, chiral amine oxide, 2-substituted-3-oxo-butyrate and NaBAr 4 F Activating with dichloromethane, adding 3-ethyl aminocrotonate, and reacting to obtain nitrendipine;
further, the synthesis method specifically includes: nickel triflate [ Ni (OTf) 2 ](0.01 mmol), chiral amine oxide L 3 -PiMe 5 (0.01 mmol), 2-substituted-3-oxobutanoic acid ester (0.10 mmol) and NaBAr 4 F (0.10 mmol); 2.0mL of dichloromethane is added, after activation is carried out for 30min at 30 ℃, the reaction is transferred to 20 ℃ and stirring is continued for 10min; slowly adding 3-aminocrotonate (0.12 mmol) at 20 ℃, continuously reacting for 72 hours at 20 ℃, separating and purifying by petroleum ether/ethyl acetate column chromatography to obtain a product Nitrendipine, wherein the enantiomeric excess of the product is determined by high performance liquid chromatography (Daicel chiralcel IG, V-hexane: V-isopropanol=95:5, flow rate 1.0 mL/min);
the reaction formula is as follows:
further, the synthesis method of nimodipine comprises the following steps: selecting Compound I asCompound II is->Synthesizing the nimodipine;
further, the synthesis method of nimodipine comprises the following steps: taking nickel triflate, chiral amine oxide, 2-substituted-3-oxo-butyrate and NaBAr 4 F Carrying out an activation reaction with dichloromethane, and then adding 3-aminocrotonic acid isopropyl ester for reaction to obtain nimodipine;
further, the synthesis method specifically includes: nickel triflate [ Ni (OTf) 2 ](0.01 mmol), chiral amine oxide L 3 -PiMe 5 (0.01 mmol), 2-substituted-3-oxobutanoic acid ester (0.10 mmol) and NaBAr 4 F (0.10 mmol); 2.0mL of methylene chloride was added, and after activation at 30℃for 30min, isopropyl 3-aminocrotonate (0.12 mmol) was slowly added and the reaction was continued at 30℃for 96h, via petroleum ether/acetic acidSeparating and purifying by ethyl ester column chromatography to obtain Nimodipine, and measuring the enantiomeric excess of the Nimodipine by high performance liquid chromatography (Daicel chiralcel IF, V-hexane: V-isopropanol=95:5, flow rate 1.0 mL/min);
the reaction formula is as follows:
further, the synthesis method of felodipine comprises the following steps: selecting Compound I asCompound II is->Synthesizing the felodipine;
further, the synthesis method of felodipine comprises the following steps: taking neodymium triflate and chiral amine oxide L 3 -PeEt 2 2-substituted-3-oxo-butyrate and ethyl acetate are subjected to an activation reaction, and then 3-amino ethyl crotonate is added for reaction, so that felodipine is obtained;
further, the synthesis method specifically includes: neodymium triflate [ Nd (OTf) 3 ](0.01 mmol), chiral amine oxide L 3 -PeEt 2 (0.01 mmol) and 2-substituted-3-oxobutanoic acid ester 1d (0.10 mmol); adding 2.0mL of ethyl acetate, activating at 30 ℃ for 30min, transferring the reaction to 20 ℃ and continuously stirring for 10min; adding 3-aminocrotonate ethyl ester 2a (0.12 mmol) at 20 ℃, continuously reacting for 72 hours at 20 ℃, separating and purifying by petroleum ether/ethyl acetate column chromatography to obtain a product Felodipine, wherein the enantiomeric excess of the product is determined by high performance liquid chromatography (Daicel chiralcel IC, V-n-hexane: V-isopropanol=95:5, flow rate 1.0 mL/min);
the reaction formula is as follows:
the beneficial effects of the invention are as follows:
1. the invention uses chiral amine oxide-nickel triflate/neodymium triflate complex to catalyze asymmetric 1, 4-addition/nucleophilic addition/dehydration tandem reaction of 2-substituted-3-oxo-butyrate and 3-aminocrotonate, realizes one-step construction of 1, 4-dihydropyridine compound and drug molecules thereof with high yield and high enantioselectivity, and has good substrate universality;
2. the product of the invention is easy to separate from the catalyst and the raw materials;
3. the reaction system is simple and clean, and accords with the economy of green chemical atoms;
4. the method can realize one-step construction of a series of chiral 1, 4-dihydropyridine compounds with potential bioactivity, such as nitrendipine, nimodipine, isradipine, amlodipine, nisoldipine, barnidipine, azelnidipine, benidipine, cilnidipine or felodipine, in particular chiral drug molecules felodipine, nitrendipine and nimodipine, with high yield and corresponding selection.
Drawings
FIG. 1 is a nuclear magnetic spectrum of nitrendipine prepared in example 3;
FIG. 2 is a nuclear magnetic spectrum of nimodipine prepared in example 4;
fig. 3 is a nuclear magnetic spectrum of felodipine prepared in example 5.
Detailed Description
For a better understanding of the present invention, reference will now be made to the following specific examples, which are not intended to limit the scope of the invention.
Example 1 comparison of effects of different Metal Compounds
The reaction flask was filled with metal salts [ Al (OTf) 3 、In(OTf) 3 、Zn(OTf) 2 、Sc(OTf) 3 、Fe(OTf) 3 、Fe(OTf) 2 、La(OTf) 3 、Y(OTf) 3 、Cu(OTf) 2 、Mg(OTf) 2 、Ni(OTf) 2 、Co(OTf) 2 (0.01mmol)]Chiral amine oxide L 3 -PiEt 2 (0.01 mmol), 2-substituted-3-oxobutanoic acid ester 1a (0.1 mmol), stirrer and 1, 2-dichloroethane (1.0 mL), stirring at 30℃for 30min, adding substrate 2a (0.12 mmol) at 30℃and continuing to react at this temperature for 24h, separating and purifying by petroleum ether/ethyl acetate column chromatography, and determining the enantiomeric excess of the product by high performance liquid chromatography (Daicel chiralcelIC, V-n-hexane: V-isopropanol=95:5, flow rate 1.0 mL/min). The reaction structure is as follows:
a 1.0mL of methylene chloride was used as the reaction solvent under standard reaction conditions.
Example 2 comparison of the effects of different chiral amine oxides
Nickel triflate [ Ni (OTf) was added to the reaction flask 2 ](0.01 mmol), chiral amine oxide (0.01 mmol), naBAr 4 F (0.01 mmol), 2-substituted-3-oxobutanoate 1a (0.1 mmol), stirrer and dichloromethane (2.0 mL) were activated at 30℃for 30min, the reaction was transferred to 20℃with continued stirring for 10min, substrate 2a (0.12 mmol) was added and reacted at this temperature for 48h. After the reaction was completed, the product was separated and purified by petroleum ether/ethyl acetate column chromatography, and the enantiomeric excess of the product was determined by high performance liquid chromatography (Daicelchiralcel IC, V-n-hexane: V-isopropanol=95:5, flow rate 1.0 mL/min). The structures of the reactive and chiral amine oxide ligands are as follows:
a the reaction was carried out at 10℃for 72h.
EXAMPLE 3 Synthesis of chiral drug molecule Nitrendipine (Nitrendipine)
Nickel triflate [ Ni (OTf) was added to the reaction flask 2 ](0.01 mmol), chiral amine oxide L 3 -PiMe 5 (0.01 mmol), 2-substituted-3-oxobutanoic acid ester 1b (0.10 mmol) and NaBAr 4 F (0.10 mmol); 2.0mL of dichloromethane is added, after activation is carried out for 30min at 30 ℃, the reaction is transferred to 20 ℃ and stirring is continued for 10min; 3-aminocrotonate ethyl ester 2a (0.12 mmol) was slowly added at 20℃and the reaction was continued at 20℃for 72h, separated and purified by petroleum ether/ethyl acetate column chromatography to give the product Nitrendipine (98% yield,92% ee), the enantiomeric excess of which was determined by high performance liquid chromatography (Daicel chiralcel IG, V-hexane: V-isopropanol=95:5, flow rate 1.0 mL/min).
EXAMPLE 4 Synthesis of the chiral drug molecule Nimodipine (Nimodipine)
Nickel triflate [ Ni (OTf) was added to the reaction flask 2 ](0.01 mmol), chiral amine oxide L 3 -PiMe 5 (0.01 mmol), 2-substituted-3-oxobutanoic acid ester 1c (0.10 mmol) and NaBAr 4 F (0.10 mmol); 2.0mL of methylene dichloride is added, after activation is carried out for 30min at 30 ℃, 3-aminocrotonate isopropyl ester 2b (0.12 mmol) is added at the temperature, the reaction is continued for 96h at 30 ℃, the product Nimodipine (75% yield,87% ee) is obtained after separation and purification by petroleum ether/ethyl acetate column chromatography, and the enantiomeric excess of the product is measured by high performance liquid chromatography (Daicel chiralcel IF, V-hexane: V-isopropanol=95:5 and the flow rate is 1.0 mL/min)And (5) setting.
Example 5: synthesis of chiral drug molecule Felodipine
Neodymium triflate [ Nd (OTf) was added to the reaction flask 3 ](0.01 mmol), chiral amine oxide L 3 -PeEt 2 (0.01 mmol) and 2-substituted-3-oxobutanoic acid ester 1d (0.10 mmol); adding 2.0mL of ethyl acetate, activating at 30 ℃ for 30min, transferring the reaction to 20 ℃ and continuously stirring for 10min; ethyl 3-aminocrotonate 2a (0.12 mmol) was added at 20 ℃ and the reaction was continued at 20 ℃ for 72h, separated and purified by petroleum ether/ethyl acetate column chromatography to give the product Felodipine (65% yield,91% ee), the enantiomeric excess of which was determined by high performance liquid chromatography (Daicel chiralcel IC, V-hexane: V-isopropanol=95:5, flow rate 1.0 mL/min).
The foregoing is merely a preferred embodiment of the invention, and it is to be understood that the invention is not limited to the form disclosed herein but is not to be construed as excluding other embodiments, but is capable of numerous other combinations, modifications and environments and is capable of modifications within the scope of the inventive concept, either as taught or as a matter of routine skill or knowledge in the relevant art. And that modifications and variations which do not depart from the spirit and scope of the invention are intended to be within the scope of the appended claims.

Claims (10)

1. A method for asymmetric catalytic synthesis of chiral 1, 4-dihydropyridine compounds, comprising the steps of:
the chiral 1, 4-dihydropyridine compound is obtained by taking a compound I and a compound II as raw materials, taking a complex formed by chiral amine oxide and a metal compound as a catalyst and reacting in an organic solvent;
the reaction formula is as follows:
wherein R is 1 Is phenyl, R 1 Wherein the phenyl is substituted by one or more hydrogen atoms, halogen and nitro groups which are independent;
R 2 is methyl or
R 3 Is methyl;
R 4 ethyl or isopropyl;
R 5 is methyl;
the structural formula of the chiral amine oxide is as follows:
one or more of the following;
wherein R is phenyl, and the phenyl is substituted by one or more independent hydrogen atoms, methyl, ethyl, isopropyl and tert-butyl; m=0 to 6;
the metal compound is as follows: aluminum triflate [ Al (OTf) 3 ]Indium triflate [ In (OTf) 3 ]Zinc triflate [ Zn (OTf) 2 ]Scandium triflate [ Sc (OTf) 3 ]Ferric triflate [ Fe (OTf) 3 ]Ferrous triflate [ Fe (OTf) 2 ]Lanthanum triflate [ La (OTf) 3 ]Yttrium triflate [ Y (OTf) 3 ]Copper triflate [ Cu (OTf) 2 ]Magnesium triflate [ Mg (OTf) 2 ]Nickel triflate [ Ni (OTf) 2 ]Cobalt triflate [ Co (OTf) 2 ]One or more of the following.
2. The method according to claim 1, wherein the molar ratio of compound i to compound ii is 1:0.5-5;
the molar ratio of the compound I to the catalyst is 1:0.01-1;
the molar ratio of the chiral amine oxide to the metal compound is 0.5-2:1.
3. The process according to claim 1 or 2, wherein, when the compound i and the compound ii are reacted, and R 1 When the phenyl group is not substituted at the 2-position, naBAr which is an additive is also used 4 F The method comprises the steps of carrying out a first treatment on the surface of the The compound I and an additive NaBAr 4 F The molar ratio of (2) is 1:0.01-1.
4. A method according to claim 3, wherein when R 1 In the case of phenyl having a substituent at the 2-position, the metal compound is neodymium triflate [ Nd (OTf) 3 ]M=1, r is 2,6-Et in the chiral amine oxide 2 C 6 H 3 The method comprises the steps of carrying out a first treatment on the surface of the When R is 1 In the case of phenyl group having a substituent other than the 2-position, the metal compound is nickel triflate [ Ni (OTf) 2 ]M=1, r is 2,3,4,5,6-Me in the chiral amine oxide 5 C 6 。
5. The method according to claim 1 or 2, wherein the kind of the organic solvent comprises: dichloromethane, chloroform, 1, 2-dichloroethane, 1, 2-trichloroethane, 1, 2-tetrachloroethane, toluene, ethylbenzene, cumene, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, ethyl acetate or isopropyl acetate;
the molar ratio of the organic solvent to the compound I is as follows: 1:0.01-1.
6. The method according to claim 1 or 2, wherein the temperature of the reaction is 0-100 ℃ and the time of the reaction is 2-240h.
7. Use of the method according to any one of claims 1-6 for the synthesis of said chiral 1, 4-dihydropyridine compound, said chiral 1, 4-dihydropyridine compound being one of nitrendipine, nimodipine, felodipine.
8. The use according to claim 7, wherein the method for synthesizing nitrendipine comprises: selecting Compound I asCompound II is->The nitrendipine can be synthesized.
9. The use according to claim 7, wherein the method for synthesizing nimodipine comprises: selecting Compound I asCompound II is->The nimodipine can be synthesized.
10. The use according to claim 7, characterized in that the synthesis method of felodipine comprises: selecting Compound I asCompound II is->The felodipine can be synthesized.
CN202210586317.2A 2022-05-27 2022-05-27 Method for asymmetric catalytic synthesis of chiral 1, 4-dihydropyridine compound and application thereof Active CN114989072B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210586317.2A CN114989072B (en) 2022-05-27 2022-05-27 Method for asymmetric catalytic synthesis of chiral 1, 4-dihydropyridine compound and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210586317.2A CN114989072B (en) 2022-05-27 2022-05-27 Method for asymmetric catalytic synthesis of chiral 1, 4-dihydropyridine compound and application thereof

Publications (2)

Publication Number Publication Date
CN114989072A CN114989072A (en) 2022-09-02
CN114989072B true CN114989072B (en) 2023-07-21

Family

ID=83029797

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210586317.2A Active CN114989072B (en) 2022-05-27 2022-05-27 Method for asymmetric catalytic synthesis of chiral 1, 4-dihydropyridine compound and application thereof

Country Status (1)

Country Link
CN (1) CN114989072B (en)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999025688A1 (en) * 1997-11-14 1999-05-27 A/S Gea Farmaceutisk Fabrik Process for the preparation of 1,4-dihydropyridines and compounds used in this process
CN1305995A (en) * 1999-12-10 2001-08-01 辉瑞大药厂 Method for preparing 1,4-dihydropyridine compound
CN104926813A (en) * 2015-05-15 2015-09-23 四川大学 Method for asymmetric catalytic synthesis of spirocyclic tetrahydrocarbazoline compound
CN105017132A (en) * 2015-06-19 2015-11-04 绍兴文理学院 1,4-dihydropyridine compound and preparation method thereof
CN109824652A (en) * 2019-03-04 2019-05-31 广西九圣新材料有限公司 A kind of Isosorbide-5-Nitrae-dihydropyridines difunctionality chiral catalyst and its preparation method and application
CN110590644A (en) * 2019-07-19 2019-12-20 华东师范大学 Chiral 1, 2-dihydropyridine compounds and preparation method and application thereof
CN114349687A (en) * 2020-10-13 2022-04-15 中山奕安泰医药科技有限公司 3, 5-dicarboxylic ester-1, 4-dihydropyridine hydrogenation reagent and preparation method and application thereof
CN114349686A (en) * 2020-10-13 2022-04-15 中山奕安泰医药科技有限公司 1, 4-dihydropyridine chiral hybrid hydrogenation reagent and preparation method and application thereof

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999025688A1 (en) * 1997-11-14 1999-05-27 A/S Gea Farmaceutisk Fabrik Process for the preparation of 1,4-dihydropyridines and compounds used in this process
CN1305995A (en) * 1999-12-10 2001-08-01 辉瑞大药厂 Method for preparing 1,4-dihydropyridine compound
CN104926813A (en) * 2015-05-15 2015-09-23 四川大学 Method for asymmetric catalytic synthesis of spirocyclic tetrahydrocarbazoline compound
CN105017132A (en) * 2015-06-19 2015-11-04 绍兴文理学院 1,4-dihydropyridine compound and preparation method thereof
CN109824652A (en) * 2019-03-04 2019-05-31 广西九圣新材料有限公司 A kind of Isosorbide-5-Nitrae-dihydropyridines difunctionality chiral catalyst and its preparation method and application
CN110590644A (en) * 2019-07-19 2019-12-20 华东师范大学 Chiral 1, 2-dihydropyridine compounds and preparation method and application thereof
CN114349687A (en) * 2020-10-13 2022-04-15 中山奕安泰医药科技有限公司 3, 5-dicarboxylic ester-1, 4-dihydropyridine hydrogenation reagent and preparation method and application thereof
CN114349686A (en) * 2020-10-13 2022-04-15 中山奕安泰医药科技有限公司 1, 4-dihydropyridine chiral hybrid hydrogenation reagent and preparation method and application thereof

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
1,4-二氢吡啶的合成研究进展;鲁玲玲,等;有机化学;第36卷(第12期);第2858-2879页 *
Catalyzing Synthesis of Chiral Nitrendipine;Jianyi Wu,等;Advanced Materials Research;第518-523卷;第3943-3946页 *
Enantioselective Catalytic Hantzsch Dihydropyridine Synthesis;Xinyue Hu, 等;ACS Catalysis;第13卷(第10期);第6675-6682页 *
含氮杂环化合物的研究进展;张进;等;石油化工;第40卷(第06期);第579-584页 *
手性合成手性识别手性拆分及在医药学中应用;张来新;等;化学工程师;第30卷(第07期);第53-56页 *
手性有机小分子催化最新进展;李楠;等;化学进展;第22卷(第07期);第1362-1379页 *

Also Published As

Publication number Publication date
CN114989072A (en) 2022-09-02

Similar Documents

Publication Publication Date Title
CN108276287B (en) Synthesis method of 4-oxo acrylate derivative catalyzed by visible light
CN112898192B (en) Preparation method of N-acyl indole compound
CN113549062B (en) Chiral quaternary ammonium salt phase transfer catalyst with high steric hindrance derived from cinchona alkaloid and synthesis method thereof
CN111646964B (en) Novel method for synthesizing 2H-pyran-2-one derivative by base catalysis
CN114989072B (en) Method for asymmetric catalytic synthesis of chiral 1, 4-dihydropyridine compound and application thereof
JP2017530956A (en) Asymmetric catalytic synthesis of nitropyrazole amide compounds
CN107915653B (en) Method for preparing amide by catalyzing ester and amine to react
CN111087417A (en) Synthesis method of methyl diphenyl silane compound containing C-Si bond
CN113527367B (en) Chiral diphosphine ligand rhodium complex containing tetra (3, 5-bistrifluoromethylphenyl) boron anion and preparation method and application thereof
CN112694430B (en) Preparation method of 1, 5-dihydro-2H-pyrrole-2-ketone compound
CN113444040A (en) Method for synthesizing chiral alpha-unnatural amino acid derivative under drive of visible light
CN110655485A (en) Preparation method of N-substituted indolone
CN111675650A (en) Preparation method of aromatic vinyl bromide derivative
CN101602681A (en) The preparation method of β-enamine ketone, ester derivative
CN115304557B (en) Enamine derivative and preparation method thereof
CN102924206B (en) Water-phase green preparation method of 1,3-disubstituted-3-aryl allyl compound and application of 1,3-disubstituted-3-aryl allyl compound
CN112430212B (en) Method for synthesizing asymmetric N-diarylmethyl substituted heterocyclic compound catalyzed by recyclable bismuth complex
CN109833908A (en) A kind of chirality high price iodine catalyst and its preparation method and application
CN114057717B (en) Quinoline-substituted bisoxazoline ligand, and synthetic method and application thereof
CN113429323B (en) Preparation method of sulfonyl substituted styrene type axial chiral compound
CN112028800B (en) Cysteine derivative and synthesis method thereof
CN115504946B (en) Method for synthesizing alpha-ketoamide compound
CN112778199B (en) Compound containing nitrate functional group and synthetic method thereof
CN111732541B (en) Method for efficiently synthesizing 6-alkenyl phenanthridine derivative through ruthenium-catalyzed C-H activation/cyclization reaction
CN117185952A (en) Alpha-arylamine compound and preparation method and application thereof

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
GR01 Patent grant
GR01 Patent grant