CN114989072A - 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 PDFInfo
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Abstract
The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for asymmetrically catalyzing and synthesizing a chiral 1, 4-dihydropyridine compound and application thereof. The method comprises the steps of reacting a 2-substituted-3-oxobutyrate and 3-aminocrotonate serving as raw materials in an organic solvent by using a complex formed by chiral amine oxide and a metal compound as a catalyst to obtain a chiral 1, 4-dihydropyridine compound; 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 can be used to construct chiral 1, 4-dihydropyridine drug molecules such as: nitrendipine, nimodipine, isradipine, amlodipine, nisoldipine, barnidipine, azinidipine, benidipine, cilnidipine, felodipine, and the like; provides a novel asymmetric catalysis method with high efficiency and high selectivity for synthesizing a series of chiral 1, 4-dihydropyridine drug molecules.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for asymmetrically catalyzing and synthesizing a chiral 1, 4-dihydropyridine compound and application thereof.
Background
1, 4-dihydropyridine compounds are widely used as a highly effective calcium channel blocker for clinical treatment of cardiovascular diseases, and currently, commercially available 1, 4-dihydropyridine drug molecules for treating hypertension include: felodipine, amlodipine, nitrendipine, nimodipine, nisoldipine and the like, and the pharmacological activity of the structure is greatly influenced by the stereochemistry of the C-4 substituent of the drug molecule. Therefore, the synthesis of optically pure 1, 4-dihydropyridine drug molecules is beneficial to enhancing the clinical treatment effect of the drug molecules. Strategies for the chiral induction, resolution, and asymmetric catalytic synthesis of such chiral drug molecules have been disclosed.
Splitting:
dollee et al performed a resolution reaction of the calcium channel antagonist S11568 using chiral High Performance Liquid Chromatography (HPLC) to give the product in two configurations in 50% yield, respectively (bioorg. med. chem.1997,5,749); yingmei and ximilux et al achieve chiral resolution of 1, 4-dihydropyridine drug molecules using chiral Supercritical Fluid Chromatography (SFC), and achieve resolution of nimodipine, amlodipine, azelnidipine, benidipine, cilnidipine, nisoldipine, and felodipine drug molecules by adjusting flow rates and solvents (j.ofsupercritical fluidids2016, 107, 129).
Sonavine et al used (+) -L-tartrate to resolve amlodipine drug molecules (org. process res. dev.2010,14,640). In this reaction, (S) -amlodipine and (+) -L-tartrate are precipitated in the form of a co-crystal with DMF/water (v/v 85:15) as a mixed solvent, and (R) -amlodipine is dissolved in a DMF/water mixed solution. Then (S) -amlodipine and benzenesulfonic acid in the mixed solvent of isopropanol/water can be converted into chiral drug molecule (S) -amlodipine besylate at room temperature.
Rebolledo et al achieved kinetic resolution of 1, 4-dihydropyridine drug molecule derivatives using lipase (Tetrahedron2015,71,3976). The product gave an enantioselective hydrolysate in 58-98% ee with a conversion of 34-51%.
Chiral induction:
s. Sundell topic group uses chiral alcohol as raw material, and sequentially undergoes six steps of protecting group adding, esterification, addition dehydration tandem reaction, protecting group removing, hydrolysis and esterification, and chiral felodipine drug molecules are obtained with a yield of 37% (Tetrahedron Lett.1989,30,6423).
H. Lee et al, using chiral glycidol as starting material, also undergo multi-step derivatization, finally obtaining (S) -felodipine (Tetrahedron2011,67,10222) in an overall yield of 22%.
Asymmetric catalysis:
gong column et al used chiral binaphthyl phosphate as catalyst and benzonitrile as solvent, reacted at 50 deg.C for 24h to obtain a series of chiral 1, 4-dihydropyridine compounds with 31-93% yield and 66-98% ee enantioselectivity (Angew. chem. int. Ed.2008,47,2458). However, such 1, 4-dihydropyridine products are difficult to convert into 3, 5-dicarboxylate-substituted chiral 1, 4-dihydropyridine drug molecules.
Bressy, x.bugaut and j.rodriguez et al, using thiourea derivatives as chiral organic small molecule catalysts and dichloromethane as reaction solvent, reacted at 37 ℃ for 24h, to finally obtain chiral 1, 4-dihydropyridine compounds with 25-71% yield and enantioselectivity of 58-96% ee, which were also difficult to convert into 3, 5-dicarboxylate substituted chiral 1, 4-dihydropyridine drug molecules (angew.chem.int.ed.2016,55,1401). Under the action of an oxidant, the 1, 4-dihydropyridine structure is oxidized into pyridine, so that the conversion from central chirality to axial chirality is realized.
Wu builds a subject group and utilizes chiral small molecule catalyst derived from cinchona alkaloid to realize asymmetric construction of nitrendipine molecules (advanced materials research,2012,518-523, 3943). Because two end substituents of the chiral center of the product are methyl ester and ethyl ester with smaller differentiation respectively, the chiral control of the product is poorer, nitrendipine can be obtained only with enantioselectivity of 41% ee, and the asymmetric synthesis of other 1, 4-dihydropyridine drug families with similar structures to the product is not involved.
In summary, current strategies for the direct synthesis of chiral 1, 4-dihydropyridine drug molecules and their derivatives rely primarily on resolution and chiral induction. However, the highest resolution can only achieve 50% yield, and the atom economy is poor; and chiral induction requires advanced preparation of a substrate, and has the disadvantages 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 at present, the 1, 4-dihydropyridine compounds have special structures and are difficult to convert into real chiral 1, 4-dihydropyridine drug molecules. Only one example of the catalytic asymmetric synthesis of chiral 1, 4-dihydropyridine drug molecules is reported, but the chiral control is poor and is only limited to the synthesis of nitrendipine drug molecules. Therefore, there is a need for a method for synthesizing chiral 1, 4-dihydropyridine compounds and pharmaceutical molecules thereof, which is simple, efficient, environmentally friendly, and has good substrate universality.
Disclosure of Invention
The invention aims to construct a 1, 4-dihydropyridine compound in one step through asymmetric 1, 4-addition/nucleophilic addition/dehydration tandem reaction of 2-substituted-3-oxobutyrate 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 purpose 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 for forming 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:
in the formula, R 1 Is aryl, heterocyclic aryl or alkyl;
R 2 is aryl, heterocyclic aryl or alkyl;
R 3 is aryl, heterocyclic aryl or alkyl;
R 4 is aryl, heterocyclic aryl or alkyl;
R 5 is aryl, heterocyclic aryl or alkyl;
R 1 ，R 2 ，R 3 ，R 4 ，R 5 wherein said aryl, heteroaryl or alkyl is each independently substituted with one or more R x Substituted with the substituent(s); said R is x Is one or more of hydrogen atom, halogen, alkyl, fluorine substituent, nitro, cyano, ester group, alkenyl, alkynyl, alkoxy, substituted amino, aryl, hydroxyl, amino, amido and sulfonamide;
the structural formula of the chiral amine oxide is as follows:
wherein R is alkyl, aryl or heterocycle, said alkyl, aryl and heterocycle being each independently substituted with one or more R y Substituted; the R is y Is one or more of hydrogen atom, alkyl, alkoxy, ester group, aryl and halogen; m is 0-6; preferably, the chiral amine oxide is m ═ 1, and R is 2,3,4,5,6-Me 5 C 6 Is marked as L 3 -PiMe 5 (ii) a Preferably, the chiral amine oxide is m ═ 1, and R is 2,6-Et 2 C 6 H 3 Is marked as L 3 -PeEt 2 ；
The metal compound is: magnesium trifluoromethanesulfonate [ Mg (OTf) 2 ]Magnesium perchlorate [ Mg (ClO) 4 ) 2 ]Bis (trifluoromethylsulfonyl) imide magnesium [ Mg (NTf) 2 ) 2 ]Scandium trifluoromethanesulfonate [ Sc (OTf) ] 3 ]Ferrous triflate [ Fe (OTf) ] 2 ]And iron trifluoromethanesulfonate [ Fe (OTf) 3 ]Nickel trifluoromethanesulfonate [ 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 trifluoromethanesulfonate [ Cu (OTf) ] 2 ]Copper bis (trifluoromethylsulfonyl) imide [ Cu (NTf) 2 ) 2 ]Zinc trifluoromethanesulfonate [ Zn (OTf) ] 2 ]Yttrium trifluoromethanesulfonate [ Y (OTf) 3 ]Lanthanum trifluoromethanesulfonate [ La (OTf) ] 3 ]Cerium trifluoromethanesulfonate [ Ce (OTf) ] 3 ]Praseodymium trifluoromethanesulfonate [ Pr (OTf) 3 ]Neodymium trifluoromethanesulfonate [ Nd (OTf) ] 3 ]Samarium trifluoromethanesulfonate [ Sm (OTf) ] 3 ]Europium trifluoromethanesulfonate [ Eu (OTf) 3 ]Gadolinium trifluoromethanesulfonate [ Gd (OTf) 3 ]Terbium trifluoromethanesulfonate [ Tb (OTf) 3 ]Dysprosium trifluoromethanesulfonate [ Dy (OTf) 3 ]Holmium trifluoromethanesulfonate [ Ho (OTf) 3 ]Erbium triflate [ Er (OTf) 3 ]Thulium trifluoromethanesulfonate [ Tm (OTf) ] 3 ]Ytterbium trifluoromethanesulfonate [ Yb (OTf) 3 ]Lutetium trifluoromethanesulfonate [ Lu (OTf) 3 ]Cobalt trifluoromethanesulfonate [ Co (OTf) ] 2 ]And bis (trifluoromethylsulfonyl) cobaltous [ Co (NTf) 2 ) 2 ]Aluminum trifluoromethanesulfonate [ Al (OTf) ] 3 ]Indium trifluoromethanesulfonate [ in (OTf) ] 3 ]Gallium trifluoromethanesulfonate [ Ga (OTf) ] 3 ]One or more of (a).
Further, in the formula (I),
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- (methylisulfonyl) -benzyl, 2- (methylisulfonyl) -benzyl or 3- (methylisulfonyl) -benzyl;
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-(Methylsulfonyl) -benzyl, 2- (Methylsulfonyl) -benzyl or 3- (Methylsulfonyl) -benzyl.
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 said compound I and compound II are reacted, and R 1 When not 2-Ar, an additive NaBAr is also used 4 F (ii) a 2-Ar has the meaning of an aryl group substituted in the 2-position, i.e.
Wherein N represents a substituent.
Further, NaBAr was used 4 F The functions of the method are as follows: no additive NaBAr is added in standard reaction 4 F Can also react, has better chiral control, and only has higher ee value of the product after adding the additive. NaBAr 4 F May mainly play a role of counter ion exchange, which can help the catalyst to form a better chiral environment, better shield one side of the reaction and realize better chiral control of the product.
The compound I and an additive NaBAr 4 F In a molar ratio of 1:0.01-1, preferably said compound I and additive NaBAr 4 F Is 1: 0.1.
Further, when R is 1 When the metal compound is 2-Ar, the metal compound is neodymium trifluoromethanesulfonate [ Nd (OTf) 3 ]The chiral amine oxide is L 3 -PeEt 2 The catalyst is L 3 -PeEt 2 And neodymium trifluoromethanesulfonate [ Nd (OTf) 3 ]The complex formed; when R is 1 When not 2-Ar, the metal compoundIs nickel trifluoromethanesulfonate [ Ni (OTf) 2 ]The chiral amine oxide is L 3 -PiMe 5 The catalyst is L 3 -PiMe 5 And nickel trifluoromethanesulfonate [ Ni (OTf) ] 2 ]The complex formed.
Further, the kinds of the organic solvent include: dichloromethane, trichloromethane, 1, 2-dichloroethane, 1, 2-trichloroethane, 1,2, 2-tetrachloroethane, toluene, ethylbenzene, cumene, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, ethyl acetate or isopropyl acetate.
Further, when R is 1 In the case of 2-Ar, the organic solvent is ethyl acetate. When R is 1 When not 2-Ar, the organic solvent is dichloromethane.
And/or the molar ratio of the organic solvent to the compound I is as follows: 1:0.01-1.
Further, the reaction temperature is 0-100 ℃, and/or the reaction time is 2-240 h; preferably, the temperature of the reaction is 10-30 ℃, and/or the time of the reaction is 72-96 h.
The invention also provides 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, azinidipine, benidipine, cilnidipine and felodipine.
Further, the method for synthesizing nitrendipine comprises the following steps: selecting the compound I as
The compound II is
The nitrendipine can be synthesized;
further, the method for synthesizing nitrendipine comprises the following steps: taking nickel trifluoromethanesulfonate, chiral amine oxide, 2-substituted-3-oxobutyrate and NaBAr 4 F And twoPerforming activation reaction on chloromethane, and adding 3-amino ethyl crotonate for reaction to obtain nitrendipine;
furthermore, the synthesis method specifically comprises the following steps: taking nickel trifluoromethanesulfonate [ Ni (OTf) 2 ](0.01mmol), chiral amine oxide L 3 -PiMe 5 (0.01mmol), 2-substituted-3-oxobutanoic acid ester (0.10mmol) and NaBAr 4 F (0.10 mmol); adding 2.0mL of dichloromethane, activating at 30 ℃ for 30min, transferring the reaction to 20 ℃, and continuing stirring for 10 min; slowly adding 3-aminocrotonic acid ethyl ester (0.12mmol) at 20 ℃, continuously reacting for 72h at 20 ℃, separating and purifying by petroleum ether/ethyl acetate column chromatography to obtain a product Nitrendipine Nitrendipine, and measuring the enantiomeric excess of the product by using a high performance liquid chromatography (Daicel chiralcel IG, V n-hexane: V isopropanol: 95:5, flow rate of 1.0 mL/min);
the reaction formula is as follows:
further, the method for synthesizing nimodipine comprises the following steps: selecting a compound I as
The compound II is
The nimodipine can be synthesized;
further, the method for synthesizing nimodipine comprises the following steps: taking nickel trifluoromethanesulfonate, chiral amine oxide, 2-substituted-3-oxobutyrate and NaBAr 4 F Carrying out activation reaction with dichloromethane, and then adding 3-amino isopropyl crotonate for reaction to obtain the nimodipine;
furthermore, the synthesis method specifically comprises the following steps: taking nickel trifluoromethanesulfonate [ Ni (OTf) 2 ](0.01mmol), chiral amine oxide L 3 -PiMe 5 (0.01mmol), 2-substituted-3-oxobutanoic acid ester (0.10mmol) and NaBAr 4 F (0.10 mmol); dichloromethane 2.0 is addedmL, activating at 30 ℃ for 30min, slowly adding 3-aminocrotonic acid isopropyl ester (0.12mmol), continuously reacting at 30 ℃ for 96h, separating and purifying by petroleum ether/ethyl acetate column chromatography to obtain Nimodipine, and measuring the enantiomeric excess of the Nimodipine by using a high performance liquid chromatography (Daicel chiralcel IF, V n-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 the compound I as
The compound II is
The felodipine can be synthesized;
further, the synthesis method of felodipine comprises the following steps: taking neodymium trifluoromethanesulfonate and chiral amine oxide L 3 -PeEt 2 Carrying out activation reaction on the 2-substituted-3-oxobutyrate and ethyl acetate, and then adding 3-aminocrotonic acid ethyl ester for reaction to obtain felodipine;
furthermore, the synthesis method specifically comprises the following steps: taking neodymium trifluoromethanesulfonate [ Nd (OTf) 3 ](0.01mmol), chiral amine oxide L 3 -PeEt 2 (0.01mmol) and 2-substituted-3-oxobutanoate 1d (0.10 mmol); adding 2.0mL of ethyl acetate, activating at 30 ℃ for 30min, transferring the reaction to 20 ℃, and continuing stirring for 10 min; adding 3-aminocrotonic acid ethyl ester 2a (0.12mmol) at 20 ℃, continuously reacting for 72h at 20 ℃, separating and purifying by petroleum ether/ethyl acetate column chromatography to obtain Felodipine, and measuring the enantiomeric excess of the Felodipine by using high performance liquid chromatography (Daicel chiralcel IC, V n-hexane: V isopropanol: 95:5, flow rate of 1.0 mL/min);
the reaction formula is as follows:
the invention has the beneficial effects that:
1. the chiral amine oxide-nickel trifluoromethanesulfonate/neodymium trifluoromethanesulfonate complex is used for catalyzing the asymmetric 1, 4-addition/nucleophilic addition/dehydration tandem reaction of the 2-substituted-3-oxobutyrate and the 3-aminocrotonate, so that the 1, 4-dihydropyridine compound and the pharmaceutical molecules thereof can be constructed in one step with high yield and high enantioselectivity, and the substrate universality is good;
2. the product of the invention is easy to separate from the catalyst and the raw material;
3. the reaction system is simple and clean, and accords with the economy of green chemical atoms;
4. by using the method, a series of chiral 1, 4-dihydropyridine compounds with potential biological activity, such as nitrendipine, nimodipine, isradipine, amlodipine, nisoldipine, barnidipine, azinidipine, benidipine or felodipine, can be constructed in one step with high yield and corresponding selection, and particularly chiral drug molecules, such as felodipine, nitrendipine and nimodipine.
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;
figure 3 is a nuclear magnetic spectrum of felodipine prepared in example 5.
Detailed Description
For better understanding of the present invention, the following description is given with reference to specific examples, but the present invention is not limited to the specific embodiments.
Example 1 comparison of the effects of different Metal Compounds
Respectively adding metal salt [ 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 (0.01mmol), 2-substituted-3-oxobutanoate 1a (0.1mmol), stirrer and 1, 2-dichloroethane (1.0mL) are stirred at 30 ℃ for 30min, substrate 2a (0.12mmol) is added at 30 ℃ and the reaction is continued at this temperature for 24h, purified by petroleum ether/ethyl acetate column chromatography and 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 structure is as follows:
a standard reaction conditions 1.0mL of dichloromethane was used as the reaction solvent.
Example 2 comparison of the Effect of different chiral amine oxides
Adding nickel trifluoromethanesulfonate [ Ni (OTf) ]into a reaction bottle 2 ](0.01mmol), chiral amine oxide (0.01mmol), NaBAr 4 F (0.01mmol), 2-substituted-3-oxobutyrate 1a (0.1mmol), stirrer and dichloromethane (2.0mL) were activated at 30 ℃ for 30min, the reaction was transferred to 20 ℃ and stirring was continued for 10min, substrate 2a (0.12mmol) was added and reacted at this temperature for 48 h. After the reaction was completed, the product was separated and purified by a petroleum ether/ethyl acetate column chromatography, and the enantiomeric excess of the product was measured by high performance liquid chromatography (Daicelchiralcel IC, V-hexane: V-isopropanol: 95:5, flow rate 1.0 mL/min). The reaction formula and the chiral amine oxide ligand structure are as follows:
a the reaction was carried out at 10 ℃ for 72 h.
Example 3 Synthesis of the chiral drug molecule Nitrendipine (Nitrendipine)
Adding nickel trifluoromethanesulfonate [ Ni (OTf) ]into a reaction bottle 2 ](0.01mmol), chiral amine oxide L 3 -PiMe 5 (0.01mmol), 2-substituted-3-oxobutanoic acid ester 1b (0.10mmol) and NaBAr 4 F (0.10 mmol); adding 2.0mL of dichloromethane, activating at 30 ℃ for 30min, transferring the reaction to 20 ℃, and continuing stirring for 10 min; ethyl 3-aminocrotonate 2a (0.12mmol) was added slowly at 20 ℃ and allowed to react for a further 72h at 20 ℃ 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 n-hexane: V isopropanol 95:5, flow rate 1.0 mL/min).
Example 4 Synthesis of the chiral drug molecule Nimodipine (Nimodipine)
Adding nickel trifluoromethanesulfonate [ Ni (OTf) ]into a reaction bottle 2 ](0.01mmol), chiral amine oxide L 3 -PiMe 5 (0.01mmol), 2-substituted-3-oxobutanoic acid ester 1c (0.10mmol) and NaBAr 4 F (0.10 mmol); adding dichloromethane 2.0mL, activating at 30 deg.C for 30min, adding isopropyl 3-aminocrotonate 2b (0.12mmol) at the temperature, reacting at 30 deg.C for 96h, separating and purifying by petroleum ether/ethyl acetate column chromatography to obtain Nimodipine (75% yield,87% ee) and the enantiomeric excess of the product was determined by high performance liquid chromatography (Daicel chiralcel IF, V n-hexane: V isopropanol 95:5, flow rate 1.0 mL/min).
Example 5: synthesis of chiral drug molecule Felodipine (Felodipine)
Adding neodymium trifluoromethanesulfonate [ Nd (OTf) ]into a reaction bottle 3 ](0.01mmol), chiral amine oxide L 3 -PeEt 2 (0.01mmol) and 2-substituted-3-oxobutanoate 1d (0.10 mmol); adding 2.0mL of ethyl acetate, activating at 30 ℃ for 30min, transferring the reaction to 20 ℃, and continuing stirring for 10 min; ethyl 3-aminocrotonate 2a (0.12mmol) was added at 20 ℃ and the reaction was continued for 72h at 20 ℃ and purified by petroleum ether/ethyl acetate column chromatography to give the product Felodipine (65% yield, 91% ee) with enantiomeric excess determined by high performance liquid chromatography (Daicel chiralcel IC, V n-hexane: V isopropanol 95:5, flow rate 1.0 mL/min).
The foregoing is illustrative of the preferred embodiments of this invention, and it is to be understood that the invention is not limited to the precise form disclosed herein and that various other combinations, modifications, and environments may be resorted to, falling within the scope of the concept as disclosed herein, either as described above or as apparent to those skilled in the relevant art. And that modifications and variations may be effected by those skilled in the art without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. A method for asymmetrically catalyzing and synthesizing chiral 1, 4-dihydropyridine compound is characterized by comprising the following steps:
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 to obtain the chiral 1, 4-dihydropyridine compound;
the reaction formula is as follows:
in the formula, R 1 Is aryl, heterocyclic aryl or alkyl;
R 2 is aryl, heterocyclic aryl or alkyl;
R 3 is aryl, heterocyclic aryl or alkyl;
R 4 is aryl, heterocyclic aryl or alkyl;
R 5 is aryl, heterocyclic aryl or alkyl;
R 1 ，R 2 ，R 3 ，R 4 ，R 5 wherein said aryl, heteroaryl or alkyl is independently substituted with one or more R x Substituted with a substituent of (1); the R is x Is one or more of hydrogen atom, halogen, alkyl, fluorine substituent, nitro, cyano, ester group, alkenyl, alkynyl, alkoxy, substituted amino, aryl, hydroxyl, amino, amido and sulfonamide;
the structural formula of the chiral amine oxide is as follows:
wherein R is alkyl, aryl or heterocycle, said alkyl, aryl and heterocycle being each independently substituted with one or more R y Substituted; the R is y Is one or more of hydrogen atom, alkyl, alkoxy, ester group, aryl and halogen; m is 0-6;
the metal compound is: magnesium trifluoromethanesulfonate [ Mg (OTf) 2 ]Magnesium perchlorate [ Mg (ClO) 4 ) 2 ]Bis (trifluoromethylsulfonyl) imide magnesium [ Mg (NTf) 2 ) 2 ]Scandium trifluoromethanesulfonate [ Sc (OTf) ] 3 ]Iron (II) trifluoromethanesulfonate [ Fe (O) ]Tf) 2 ]Iron trifluoromethanesulfonate [ Fe (OTf) ] 3 ]Nickel trifluoromethanesulfonate [ 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 trifluoromethanesulfonate [ Cu (OTf) ] 2 ]Copper bis (trifluoromethylsulfonyl) imide [ Cu (NTf) 2 ) 2 ]Zinc trifluoromethanesulfonate [ Zn (OTf) ] 2 ]Yttrium trifluoromethanesulfonate [ Y (OTf) 3 ]Lanthanum triflate [ La (OTf) 3 ]Cerium trifluoromethanesulfonate [ Ce (OTf) ] 3 ]Praseodymium trifluoromethanesulfonate [ Pr (OTf) 3 ]Neodymium trifluoromethanesulfonate [ Nd (OTf) 3 ]Samarium trifluoromethanesulfonate [ Sm (OTf) ] 3 ]Europium trifluoromethanesulfonate [ Eu (OTf) 3 ]Gadolinium trifluoromethanesulfonate [ Gd (OTf) 3 ]Terbium trifluoromethanesulfonate [ Tb (OTf) 3 ]Dysprosium trifluoromethanesulfonate [ Dy (OTf) 3 ]Holmium trifluoromethanesulfonate [ Ho (OTf) 3 ]Erbium triflate [ Er (OTf) 3 ]Thulium trifluoromethanesulfonate [ Tm (OTf) ] 3 ]Ytterbium trifluoromethanesulfonate [ Yb (OTf) 3 ]Lutetium trifluoromethanesulfonate [ Lu (OTf) 3 ]Cobalt trifluoromethanesulfonate [ Co (OTf) ] 2 ]And bis (trifluoromethylsulfonyl) cobaltous [ Co (NTf) 2 ) 2 ]Aluminum trifluoromethanesulfonate [ Al (OTf) ] 3 ]Indium trifluoromethanesulfonate [ in (OTf) ] 3 ]Gallium trifluoromethanesulfonate [ Ga (OTf) ] 3 ]One or more of (a).
2. The method according to claim 1, wherein in 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- (Methylsulfonyl) -benzyl, 2- (Methylsulfonyl) -benzyl or 3- (Methylsulfonyl) -benzyl;
and/or, R 5 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- (Methylsulfulfonyl) -benzyl, 2- (Methylsulfulfonyl) -benzyl or 3- (Methylsulfulfonyl) -benzyl.
3. The method according to claim 2, wherein the molar ratio of the compound I to the compound II is 1: 0.5-5;
and/or the molar ratio of the compound I to the catalyst is 1: 0.01-1;
and/or the molar ratio of the chiral amine oxide to the metal compound is 0.5-2: 1.
4. A process according to any one of claims 1 to 3, wherein when said compound I and compound II are reacted, and R is 1 When not 2-Ar, an additive NaBAr is also used 4 F (ii) a The compound I and an additive NaBAr 4 F The molar ratio of (A) to (B) is 1: 0.01-1.
5. The method of claim 4, wherein when R is 1 When it is 2-Ar, the metal compound is neodymium trifluoromethanesulfonate [ Nd (OTf) 3 ]Wherein m is 1 and R is 2,6-Et in the chiral amine oxide 2 C 6 H 3 (ii) a When R is 1 When not 2-Ar, the metal compound is nickel trifluoromethanesulfonate [ Ni (OTf) 2 ]Wherein m is 1 and R is 2,3,4,5,6-Me in the chiral amine oxide 5 C 6 。
6. The method according to any one of claims 1 to 3, wherein the kind of the organic solvent includes: dichloromethane, trichloromethane, 1, 2-dichloroethane, 1, 2-trichloroethane, 1,2, 2-tetrachloroethane, toluene, ethylbenzene, cumene, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, ethyl acetate or isopropyl acetate.
And/or the molar ratio of the organic solvent to the compound I is as follows: 1:0.01-1.
7. A process according to any one of claims 1 to 3, wherein the reaction temperature is between 0 ℃ and 100 ℃ and/or the reaction time is between 2 and 240 h.
8. Use of a method according to any one of claims 1 to 7 for the synthesis of said chiral 1, 4-dihydropyridine compound.
9. The use of claim 8, wherein the chiral 1, 4-dihydropyridine compound comprises one or more of nitrendipine, nimodipine, isradipine, amlodipine, nisoldipine, barnidipine, azinidipine, benidipine, cilnidipine, and felodipine.
10. Use according to claim 9,
the synthetic method of nitrendipine comprises the following steps: selecting the compound I as
The compound II is
The nitrendipine can be synthesized;
and/or the synthetic method of the nimodipine comprises the following steps: selecting a compound I as
The compound II is
The nimodipine can be synthesized;
and/or the synthetic method of the felodipine comprises the following steps: selecting the compound I as
The compound II is
The felodipine can be synthesized.
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