CN114516774A - Preparation method of chiral bromo-1, 4-dihydropyridine compound - Google Patents
Preparation method of chiral bromo-1, 4-dihydropyridine compound Download PDFInfo
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- CN114516774A CN114516774A CN202210068642.XA CN202210068642A CN114516774A CN 114516774 A CN114516774 A CN 114516774A CN 202210068642 A CN202210068642 A CN 202210068642A CN 114516774 A CN114516774 A CN 114516774A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- -1 bromo-1, 4-dihydropyridine compound Chemical class 0.000 title claims description 34
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims abstract description 19
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 5
- 150000002500 ions Chemical class 0.000 claims abstract description 4
- COYVQCYYXQLWBS-UHFFFAOYSA-N 1-bromo-4H-pyridine Chemical class BrN1C=CCC=C1 COYVQCYYXQLWBS-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical group BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 41
- 239000000758 substrate Substances 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- MARXMDRWROUXMD-UHFFFAOYSA-N 2-bromoisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(Br)C(=O)C2=C1 MARXMDRWROUXMD-UHFFFAOYSA-N 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- 238000004809 thin layer chromatography Methods 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- JUIKUQOUMZUFQT-UHFFFAOYSA-N 2-bromoacetamide Chemical compound NC(=O)CBr JUIKUQOUMZUFQT-UHFFFAOYSA-N 0.000 claims description 2
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 4
- 238000005893 bromination reaction Methods 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000004071 biological effect Effects 0.000 abstract description 2
- 230000031709 bromination Effects 0.000 abstract description 2
- 230000003287 optical effect Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 46
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 239000003480 eluent Substances 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 5
- 229960000528 amlodipine Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- HTIQEAQVCYTUBX-KRWDZBQOSA-N (S)-amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-KRWDZBQOSA-N 0.000 description 2
- JCLJZOQVXKOUSW-UHFFFAOYSA-N dimethyl 2,6-dimethyl-4-(2-methylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1C JCLJZOQVXKOUSW-UHFFFAOYSA-N 0.000 description 2
- KUTGAPTWYPKOSN-UHFFFAOYSA-N dimethyl 2,6-dimethyl-4-(4-methylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=C(C)C=C1 KUTGAPTWYPKOSN-UHFFFAOYSA-N 0.000 description 2
- IGYRGGMXQGVOTC-UHFFFAOYSA-N dimethyl 2-(bromomethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(CBr)=C(C(=O)OC)C1C1=CC=CC=C1Cl IGYRGGMXQGVOTC-UHFFFAOYSA-N 0.000 description 2
- JBKYBXKWAKFJQI-UHFFFAOYSA-N dimethyl 2-(bromomethyl)-6-methyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(NC(=C(C1C1=CC=CC=C1)C(=O)OC)C)CBr JBKYBXKWAKFJQI-UHFFFAOYSA-N 0.000 description 2
- FFQZJXYLJQZVPJ-UHFFFAOYSA-N dimethyl 4-(2,4-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=C(Cl)C=C1Cl FFQZJXYLJQZVPJ-UHFFFAOYSA-N 0.000 description 2
- REIGLQUFMMOAFU-UHFFFAOYSA-N dimethyl 4-(2-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl REIGLQUFMMOAFU-UHFFFAOYSA-N 0.000 description 2
- JPWHOMRZIVPQOM-UHFFFAOYSA-N dimethyl 4-(3-bromophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC(Br)=C1 JPWHOMRZIVPQOM-UHFFFAOYSA-N 0.000 description 2
- IPYNBIWYHLDEGY-UHFFFAOYSA-N dimethyl 4-(4-bromophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=C(Br)C=C1 IPYNBIWYHLDEGY-UHFFFAOYSA-N 0.000 description 2
- IAXDEFZXLVTHLU-UHFFFAOYSA-N dimethyl 4-(4-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=C(OC)C=C1 IAXDEFZXLVTHLU-UHFFFAOYSA-N 0.000 description 2
- 229950008554 levamlodipine Drugs 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000003257 anti-anginal effect Effects 0.000 description 1
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002429 anti-coagulating effect Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- GPGILZSNELVEAP-UHFFFAOYSA-N dimethyl 4-(2-bromophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Br GPGILZSNELVEAP-UHFFFAOYSA-N 0.000 description 1
- KALSHWKRMSJLAB-UHFFFAOYSA-N dimethyl 4-(2-fluorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1F KALSHWKRMSJLAB-UHFFFAOYSA-N 0.000 description 1
- TZIWGKSUBLFVGQ-UHFFFAOYSA-N dimethyl 4-(2-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1OC TZIWGKSUBLFVGQ-UHFFFAOYSA-N 0.000 description 1
- ZDYBFSOIKXOITC-UHFFFAOYSA-N dimethyl 4-(4-fluorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=C(F)C=C1 ZDYBFSOIKXOITC-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a preparation method of chiral bromo-1, 4-dihydropyridine compounds, which is characterized in that under the catalysis of chiral phosphoric acid, compounds in a formula I react with bromine sources II of different types to obtain compounds in a formula III:
wherein R is1、R2Alkyl and aryl are independently selected, II is various bromine sources capable of providing bromine positive ions, and the chiral III compound is obtained in an asymmetric bromination mode under the catalysis of chiral phosphoric acid. The method of the invention can easily prepare high optical purity (ee value)>99%) of chiral 1, 4-dihydropyridine derivatives. The 1, 4-dihydropyridine compounds have wide biological activity, so the invention lays a foundation for developing chiral drugs and has economic practicability and industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of preparation methods of 1, 4-dihydropyridine compounds in organic synthesis directions, and particularly relates to a preparation method of chiral 1, 4-dihydropyridine compounds.
Background
1, 4-dihydropyridines are an important class of nitrogen-containing heterocyclic compounds. The structural skeleton of the compound is widely present in natural products, medicines and molecules with biological and medicinal activities. The 1, 4-dihydropyridines themselves also possess a number of biological activities, such as hypotensive, antianginal, antiatherosclerotic, antidiabetic, antituberculotic, anticoagulant, antioxidant, antiviral, antibacterial and anti-inflammatory effects and tumour multidrug resistance reversal and antitumour activity. Among them, the most important of the pharmaceutical functions of 1, 4-dihydropyridine is as a calcium channel blocker. It is a first-line medicine with highest clinical specificity and strongest action. Meanwhile, the main chemical substance of the racemic amlodipine with pharmacological activity is levorotatory amlodipine which is levorotatory enantiomer, and the calcium ion antagonism of the levorotatory amlodipine is about 1000 times that of dextrorotatory enantiomer and 2 times that of racemic modification. Further research shows that the levamlodipine can avoid the side effects of acral edema, headache, dizziness and the like caused by racemic amlodipine, so that the levamlodipine is clinically used for treating angina and hypertension, the curative effect is superior to that of racemic amlodipine, and the side effect caused by dextroamlodipine is avoided. The main current way is obtained by a resolution mode, so that the chiral 1, 4-dihydropyridine compounds are synthesized by starting from cheap and easily available raw materials 1, 4-dihydropyridine in a catalytic asymmetric mode, and the synthesis of the required drug molecules by derivatization is of great significance. The following are examples of the class of 1, 4-dihydropyridines:
there have been many reports of methods for the synthesis of racemic 1, 4-dihydropyridines, and relatively few asymmetric syntheses of chiral 1, 4-dihydropyridines. The chiral 1, 4-dihydropyridine ring (Gong, Angew. chem. int. Ed.2008,47, 2458-Astro 2462; Rodriguez, Angew. chem. int. Ed.2016,55, 1401-Astro 1405) is constructed mainly by a catalytic asymmetric synthesis mode. The major disadvantage of this approach is the limitation to the specific substrate. Therefore, the method has important research value for obtaining the symmetrical 1, 4-dihydropyridine through a simple and easily obtained substrate and obtaining the chiral 1, 4-dihydropyridine through a catalytic asymmetric bromination mode. And the obtained chiral bromo-1, 4-dihydropyridine is easy to be derived to synthesize different types of 1, 4-dihydropyridine derivatives.
Disclosure of Invention
The invention aims to provide a preparation method of a chiral bromo-1, 4-dihydropyridine compound. The corresponding chiral bromo-1, 4-dihydropyridine compound is obtained by taking simple and easily obtained symmetric 1, 4-dihydropyridine as a raw material and performing asymmetric bromination reaction under the catalysis of chiral phosphoric acid, thereby overcoming the defects in the prior art.
The preparation method of the chiral bromo-1, 4-dihydropyridine compound is characterized by comprising the following steps:
in an air environment, taking a symmetrical 1, 4-dihydropyridine compound I as a reaction substrate, adding a bromine source II capable of providing bromine positive ions and chiral phosphoric acid which is 0.02-0.15 equivalent of the compound of the formula I as a catalyst into an organic solvent according to a molar ratio of 1: 1-1: 2, reacting for 2-24 hours at-78-25 ℃, determining a reaction end point by using a thin-layer chromatography, and then obtaining the chiral bromo-1, 4-dihydropyridine compound of the formula III by using a silica gel column chromatography. The method has the advantages of easily-obtained and easily-obtained raw materials, and is convenient for synthesis, and the chiral product is obtained in a desymmetry mode.
Chiral 1, 4-dihydropyridine compounds of the formula III in which R is a substituent1、R2Each independently selected from alkyl and aryl, and formula II is a variety of bromine sources capable of providing bromine cations.
The organic solvent is benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, acetone, acetonitrile, 1, 4-dioxane, tetrahydrofuran, 1, 2-dichloroethane, diethyl ether, n-butyl ether and ethyl acetate.
The bromine source is bromosuccinimide, dibromohydantoin, bromoacetamide, N-bromophthalimide and N-bromophthalimide.
Detailed Description
EXAMPLE 1 preparation of dimethyl 2-bromomethyl-6-methyl-4-phenyl-1, 4-dihydropyridine-3, 5-dicarboxylate (3a)
1a (0.1mmol), CPA (5 mol%), and toluene (2mL) were added at room temperature, stirred for 10min, and then placed in a constant temperature stirring bath, and 2a (0.1mmol) was added with stirring. And then observing the disappearance of the raw material 1a by thin layer chromatography, stopping stirring, and directly separating by silica gel column chromatography to obtain the target product 3 a.
3a pale yellow solid; the yield is 72%; 92% ee;1H-NMR(400MHz,CDCl3)δ7.18–7.02(m,5H),6.20(s,1H),5.00(s,1H),4.86(d,J＝11.4Hz,1H),4.61(d,J＝11.4Hz,1H),3.70(d,J＝12.5Hz,6H),2.39(s,3H)；13C-NMR(101MHz,CDCl3)δ167.65,167.62,149.23,142.7,13.80,13.59,13.30,125.59,124.60,106.98,104.14,52.30,39.92,36.12,27.34,19.54.HPLC analysis:(Daicel Chiralcel IC,eluent,hexane 95％,i-propanol 5％,flow rate 1.0mL/min,30℃,254nm,tR1:16.4min and tR2:17.3min)。
example 2: preparation of 2-bromomethyl-6-methyl-4- (2-methylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester (3b)
Dimethyl 2, 6-dimethyl-4- (2-methylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (1b) was reacted with N-bromosuccinimide (2a) as a starting substrate to prepare the objective product 3b, in the same manner as in example 1.
3b light yellow solid, yield 68%; 90% ee;1H-NMR(400MHz,CDCl3)δ8.15(s,1H),7.18–7.02(m,4H),5.08(s,1H),4.52(s,2H),3.54(s,3H),2.61(s,3H),2.36(s,3H)；13C-NMR(101MHz,CDCl3)δ167.65,167.62,149.23,142.7,13.80,13.59,13.30,125.59,124.60,106.98,104.14,52.30,39.92,36.12,27.34,19.54；HRMS(m/z,ESI):Calcd.For C18H21BrNO4 +[M+H+]:394.0648,found:394.0644；HPLC analysis:(Daicel Chiralcel IC,eluent,hexane 95％,i-propanol 5％,flow rate 1.0mL/min,30℃,254nm,tR1:12.9min and tR2:15.5min)。
example 3: preparation of 2-bromomethyl-6-methyl-4- (4-methylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester (3c)
Dimethyl 2, 6-dimethyl-4- (4-methylphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (1c) was reacted with N-bromosuccinimide (2a) as a starting substrate to prepare the objective product 3c in the same manner as in example 1.
A light yellow solid; the yield is 68 percent; 82% ee;1H-NMR(400MHz,CDCl3)δ7.17(d,J＝7.9Hz,2H),7.06(d,J＝7.9Hz,2H),6.20(s,1H),5.00(s,1H),4.86(d,J＝11.4Hz,1H),4.61(d,J＝11.4Hz,1H),3.70(d,J＝12.5Hz,6H),2.39(s,3H),2.30(s,3H)；13C-NMR(101MHz,CDCl3)δ167.25,167.20,149.20,142.73,141.43,135.42,129.02,128.88,107.02,104.10,52.33,42.42,36.12,21.35,19.06；HRMS(m/z,ESI):Calcd.For C18H21BrNO4+[M+H+]:394.0648,found:394.0645；HPLC analysis:(Daicel Chiralcel IC,eluent,hexane 95％,i-propanol 5％,flow rate 1.0mL/min,30℃,254nm,tR1:14.4min and tR2:15.6min)。
example 4: preparation of 2-bromomethyl-6-methyl-4- (2-chlorophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester (3d)
Dimethyl 2, 6-dimethyl-4- (2-chlorophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (1d) was reacted with N-bromosuccinimide (2a) as a starting substrate to prepare the objective product 3d in the same manner as in example 1.
A light yellow solid; the yield is 68 percent; 90% ee;1H-NMR(400MHz,CDCl3)δ7.23(s,1H),7.19–7.13(m,3H),6.24(s,1H),5.03(s,1H),4.87(d,J＝11.4Hz,1H),4.62(d,J＝11.4Hz,1H),3.71(d,J＝11.9Hz,6H),2.40(s,3H)；13C-NMR(101MHz,CDCl3)δ167.30,166.88,148.98,143.71,141.54,131.42,128.75,127.06,126.58,126.47,107.07,104.13,52.35,37.34,35.08,19.12；HPLC analysis:(Daicel Chiralcel IC,eluent,hexane 95％,i-propanol 5％,flow rate 1.0mL/min,30℃,254nm,tR1:10.3min and tR2:12.3min)。
example 5: preparation of dimethyl 2-bromomethyl-6-methyl-4- (3-bromophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (3e)
Dimethyl 2, 6-dimethyl-4- (3-bromophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (1e) was reacted with N-bromosuccinimide (2a) as a starting substrate to prepare the objective product 3e, in the same manner as in example 1.
A light yellow solid; the yield is 64 percent; 86% ee;1H-NMR(400MHz,CDCl3)δ7.39(s,1H),7.32(s,1H),7.21(d,J＝7.8Hz,1H),7.13(d,J＝7.8Hz,1H),6.19(s,1H),5.02(s,1H),4.88(d,J＝11.5Hz,1H),4.63(d,J＝11.5Hz,1H),3.71(d,J＝11.7Hz,6H),2.41(s,3H)；13C-NMR(101MHz,CDCl3)δ167.23,166.89,150.21,144.43,142.73,133.87,129.41,128.61,126.70,123.01,107.01,104.13,52.17,51.98,41.72,36.10,19.20；HPLC analysis:(Daicel Chiralcel IC,eluent,hexane 95％,i-propanol 5％,flow rate 1.0mL/min,30℃,254nm,tR1:11.4min and tR2:13.4min)。
example 6: preparation of dimethyl 2-bromomethyl-6-methyl-4- (4-bromophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (3f)
Dimethyl 2, 6-dimethyl-4- (4-bromophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (1f) was reacted with N-bromosuccinimide (2a) as a starting substrate to prepare the objective product 3f, in the same manner as in example 1.
A light yellow solid; the yield is 60 percent; 90% ee;1H-NMR(400MHz,CDCl3)δ7.37(d,J＝8.4Hz,2H),7.16(d,J＝8.4Hz,2H),6.21(s,1H),4.99(s,1H),4.80(d,J＝11.4Hz,1H),4.66(d,J＝11.4Hz,1H),3.69(d,J＝11.8Hz,6H),2.39(s,3H)；13C-NMR(101MHz,CDCl3)δ167.50,166.79,145.47,144.50,142.14,131.37(d,J＝15.9Hz),129.50,120.44,105.40,103.37,51.66,51.23,39.26,27.34,19.54；HRMS(m/z,ESI):Calcd.For[C17H17Br2NO4+H]+＝457.9597；found:457.9595.HPLC analysis:(Daicel Chiralcel IC,eluent,hexane 95％,i-propanol 5％,flow rate 1.0mL/min,30℃,254nm,tR1:11.5min and tR2:14.7min)。
example 7: preparation of dimethyl 2-bromomethyl-6-methyl-4- (2-methoxyphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (3g)
Dimethyl 2, 6-dimethyl-4- (2-methoxyphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (1g) was reacted with N-bromosuccinimide (2a) as a starting substrate to prepare the objective product (3g), in the same manner as in example 1.
A light yellow solid; the yield is 65%; 60% ee;1H-NMR(400MHz,CDCl3)δ6.85(dd,J＝13.0,6.3Hz,4H),5.29(s,1H),5.23(s,1H),4.68(d,J＝17.4Hz,2H),3.83(d,J＝9.7Hz,6H),3.64(s,3H),2.35(s,3H).13C-NMR(101MHz,CDCl3)δ167.78,166.89,158.62,149.20,142.73,130.02,126.75,121.03,129.97,112.24,107.03,104.12,56.10,52.33,52.27,36.58,36.10,19.20；HRMS(m/z,ESI):Calcd.For[C17H17Br2NO4+H]+＝457.9597；found:457.9595；HPLC analysis:(Daicel Chiralcel IC,eluent,hexane 95％,i-propanol 5％,flow rate 1.0mL/min,30℃,254nm,tR1:14.2min and tR2:18.6min)。
example 8: preparation of 2-bromomethyl-6-methyl-4- (4-methoxyphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester (3h)
Dimethyl 2, 6-dimethyl-4- (4-methoxyphenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (1h) was reacted with N-bromosuccinimide (2a) as a starting substrate to prepare the objective product 3h in the same manner as in example 1.
A light yellow solid; the yield is 62 percent; 91% ee;1H-NMR(400MHz,CDCl3)δ7.21–7.18(m,2H),6.78(d,J＝8.6Hz,2H),6.22(s,1H),4.97(s,1H),4.83(d,J＝11.3Hz,1H),4.62(d,J＝11.3Hz,1H),3.70(d,J＝12.3Hz,6H),2.38(s,3H)；13C-NMR(101MHz,CDCl3)δ167.58,167.48,157.60,149.22,142.73,136.72,130.02,114.26,167.26,104.11,55.80,53.02,52.80,42.46,36.10,19.02；HPLC analysis:(Daicel Chiralcel IC,eluent,hexane 95％,i-propanol 5％,flow rate 1.0mL/min,30℃,254nm,tR1:15.1min and tR2:19.5min)。
example 9: preparation of dimethyl 2-bromomethyl-6-methyl-4- (2-bromophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (3i)
Dimethyl 2, 6-dimethyl-4- (2-bromophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (1i) was reacted with N-bromosuccinimide (2a) as a starting substrate to prepare the objective product 3i in the same manner as in example 1.
A light yellow solid; the yield is 72 percent;82％ee；1H-NMR(400MHz,CDCl3)δ7.46(d,J＝7.9Hz,1H),7.39(dd,J＝7.8,1.4Hz,1H),7.22(t,J＝7.6Hz,1H),7.00(dd,J＝10.8,4.4Hz,1H),6.16(s,1H),5.41(s,1H),4.73(q,J＝11.4Hz,2H),3.68(d,J＝13.8Hz,6H),2.38(s,3H)；13C-NMR(101MHz,CDCl3)δ168.10,167.88,149.22,142.72,141.04,132.60,131.25,127.90,127.68,124.05,107.04,104.15,53.10,52.94,38.60,36.12,19.06；HPLC analysis:(Daicel Chiralcel IC,eluent,hexane 95％,i-propanol 5％,flow rate 1.0mL/min,30℃,254nm,tR1:15.6min and tR2:19.2min)。
example 10: preparation of dimethyl 2-bromomethyl-6-methyl-4-phenethyl-1, 4-dihydropyridine-3, 5-dicarboxylate (3j)
Dimethyl 2, 6-dimethyl-4- (4-phenylethyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (1j) was reacted with N-bromosuccinimide (2a) as a starting substrate to prepare the objective product 3j, in the same manner as in example 1.
A light yellow solid; the yield is 65%; 60% ee;1H-NMR(400MHz,CDCl3)δ7.25(d,J＝7.1Hz,2H),7.15(d,J＝7.8Hz,3H),6.17(s,1H),4.82(d,J＝11.3Hz,1H),4.61(d,J＝11.3Hz,1H),4.08(t,J＝5.8Hz,1H),3.77(d,J＝11.8Hz,6H),2.60–2.53(m,2H),2.37(s,3H),1.69(ddd,J＝11.1,5.6,2.7Hz,2H)；HPLC analysis:(Daicel Chiralcel IC,eluent,hexane 95％,i-propanol 5％,flow rate1.0mL/min,30℃,254nm,tR1:13.9min and tR2:15.5min)。
example 11: preparation of dimethyl 2-bromomethyl-6-methyl-4- (2, 4-dichlorophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (3k)
Dimethyl 2, 6-dimethyl-4- (2, 4-dichlorophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (1k) was reacted with N-bromosuccinimide (2a) as a starting substrate to prepare the objective product 3k in the same manner as in example 1.
A light yellow solid; the yield is 65%; 92% ee;1H-NMR(400MHz,CDCl3)δ7.31(d,J＝8.4Hz,1H),7.28(d,J＝2.0Hz,1H),7.17–7.12(m,1H),6.39(s,1H),5.39(s,1H),4.70(d,J＝2.7Hz,2H),3.65(d,J＝13.2Hz,6H),2.36(s,3H)；HPLC analysis:(Daicel Chiralcel IC,eluent,hexane 95％,i-propanol 5％,flow rate 1.0mL/min,30℃,254nm,tR1:11.3min and tR2:14.8min)。
example 12: preparation of dimethyl 2-bromomethyl-6-methyl-4- (4-fluorophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (3l)
Dimethyl 2, 6-dimethyl-4- (4-fluorophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (1l) was reacted with N-bromosuccinimide (2a) as a starting substrate to prepare the objective product 3l in the same manner as in example 1.
A light yellow solid; the yield is 65%; 92% ee;1H-NMR(400MHz,CDCl3)δ7.24(dd,J＝8.3,5.6Hz,2H),6.93(t,J＝8.7Hz,2H),6.13(s,1H),5.01(s,1H),4.83(d,J＝11.5Hz,1H),4.67(d,J＝11.5Hz,1H),3.70(d,J＝11.9Hz,6H),2.40(s,3H)；HPLC analysis:(Daicel Chiralcel IC,eluent,hexane 95％,i-propanol 5％,flow rate 1.0mL/min,30℃,254nm,tR1:11.9min and tR2:15.9min)。
example 13: preparation of dimethyl 2-bromomethyl-6-methyl-4- (2-fluorophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (3m)
Dimethyl 2, 6-dimethyl-4- (2-fluorophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate (1m) was reacted with N-bromosuccinimide (2a) as a starting substrate to prepare the objective product 3m by the same procedure as in example 1.
A light yellow solid; the yield is 65%; 92% ee;1H-NMR(400MHz,CDCl3)δ7.31(dd,J＝7.6,1.6Hz,1H),7.18–7.11(m,1H),7.04(dd,J＝10.8,4.2Hz,1H),6.99–6.92(m,1H),6.24(s,1H),5.28(s,1H),4.82(d,J＝11.4Hz,1H),4.65(d,J＝11.4Hz,1H),3.66(d,J＝13.1Hz,6H),2.38(s,3H).HPLC analysis:92％ee(Daicel Chiralcel IC,eluent,hexane 95％,i-propanol 5％,flow rate 1.0mL/min,30℃,254nm,tR1:16.0min and tR2:21.3min)。
example 14: preparation of dimethyl 2-bromomethyl-6-methyl-4-styryl-1, 4-dihydropyridine-3, 5-dicarboxylate (3n)
Dimethyl 2, 6-dimethyl-4-styryl-1, 4-dihydropyridine-3, 5-dicarboxylate (1N) was reacted with N-bromosuccinimide (2a) as a starting substrate to prepare the objective product 3N in the same manner as in example 1.
A light yellow solid; the yield is 70%; 82% ee;1H-NMR(400MHz,CDCl3)δ7.34(d,J＝7.4Hz,2H),7.27(s,1H),7.20(t,J＝7.0Hz,1H),6.20(dt,J＝16.0,11.0Hz,3H),4.90(d,J＝11.4Hz,1H),4.66(d,J＝6.1Hz,1H),4.62(d,J＝11.4Hz,1H),3.78(d,J＝11.5Hz,6H),2.40(s,3H)；HPLC analysis:(Daicel Chiralcel IC,eluent,hexane 95％,i-propanol 5％,flow rate 1.0mL/min,30℃,254nm,tR1:15.7min and tR2:18.9min)。
Claims (3)
1. a preparation method of chiral bromo-1, 4-dihydropyridine compounds is characterized by comprising the following steps:
in an air environment, taking a symmetrical 1, 4-dihydropyridine compound I as a reaction substrate, adding a bromine source II capable of providing bromine positive ions and chiral phosphoric acid which is 0.02-0.15 equivalent of the compound of the formula I as a catalyst into an organic solvent according to a molar ratio of 1: 1-1: 2, reacting for 2-24 hours at-78-25 ℃, determining a reaction end point by using a thin-layer chromatography, and then obtaining a chiral bromo-1, 4-dihydropyridine compound of the formula III by using silica gel column chromatography;
chiral 1, 4-dihydropyridine compounds of the formula III in which R is a substituent1、R2Alkyl and aryl are independently selected, and formula II is various bromine sources capable of providing bromine positive ions.
2. The method of claim 1, wherein the organic solvent is benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, acetone, acetonitrile, 1, 4-dioxane, tetrahydrofuran, 1, 2-dichloroethane, diethyl ether, n-butyl ether, ethyl acetate.
3. The method of claim 1, wherein the bromine source is bromosuccinimide, dibromohydantoin, bromoacetamide, N-bromophthalimide, or N-bromophthalimide.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4567268A (en) * | 1984-04-03 | 1986-01-28 | Merck & Co., Inc. | Process for preparation of certain tetrahydrofuro[3,4-b]pyridines |
| JPH0859618A (en) * | 1994-08-22 | 1996-03-05 | Amano Pharmaceut Co Ltd | Optically active 1,4-dihydropyridine compound and production of the same |
| WO2000024741A2 (en) * | 1998-10-28 | 2000-05-04 | Abbott Laboratories | Dihydropyridine compounds and their use as potassium channel openers |
| CN109721587A (en) * | 2018-12-29 | 2019-05-07 | 南京远淑医药科技有限公司 | A kind of method and its application preparing phthalyl Amlodipine |
-
2022
- 2022-01-20 CN CN202210068642.XA patent/CN114516774A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4567268A (en) * | 1984-04-03 | 1986-01-28 | Merck & Co., Inc. | Process for preparation of certain tetrahydrofuro[3,4-b]pyridines |
| JPH0859618A (en) * | 1994-08-22 | 1996-03-05 | Amano Pharmaceut Co Ltd | Optically active 1,4-dihydropyridine compound and production of the same |
| WO2000024741A2 (en) * | 1998-10-28 | 2000-05-04 | Abbott Laboratories | Dihydropyridine compounds and their use as potassium channel openers |
| CN109721587A (en) * | 2018-12-29 | 2019-05-07 | 南京远淑医药科技有限公司 | A kind of method and its application preparing phthalyl Amlodipine |
Non-Patent Citations (3)
| Title |
|---|
| HAN, MIN，等: "Chiral Phosphoric Acid Catalyzed Enantioselective Desymmetrization of 1,4-Dihydropyridines by C(sp3)-H Bromination", ANGEWANDTE CHEMIE * |
| PETROVA, MARINA,等: "Experimental and Theoretical Studies of Bromination of Diethyl 2,4,6-Trimethyl-1,4-dihydropyridine-3,5-dicarboxylate", HETEROATOM CHEMISTRY * |
| 刘雨畅: "手性磷酸催化螺环吲哚生物碱的不对称合成研究", 中国优秀硕士学位论文全文数据库 工程科技I辑 * |
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