CN113214299A - Gamma-biphenyldicarboxylate intermediate, synthetic method thereof and gamma-biphenyldicarboxylate synthetic method - Google Patents
Gamma-biphenyldicarboxylate intermediate, synthetic method thereof and gamma-biphenyldicarboxylate synthetic method Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title description 7
- YDFLNALWZZTEJM-UHFFFAOYSA-N COC(C(C=C1OC)=C(B(O)O)C2=C1OCO2)=O Chemical group COC(C(C=C1OC)=C(B(O)O)C2=C1OCO2)=O YDFLNALWZZTEJM-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000001308 synthesis method Methods 0.000 claims abstract description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 108
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 87
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 69
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 59
- 239000000243 solution Substances 0.000 claims description 50
- 239000002904 solvent Substances 0.000 claims description 50
- LBTTXOWOLNELBG-UHFFFAOYSA-N methyl 4-bromo-7-methoxy-1,3-benzodioxole-5-carboxylate Chemical compound COC(=O)C1=CC(OC)=C2OCOC2=C1Br LBTTXOWOLNELBG-UHFFFAOYSA-N 0.000 claims description 44
- 239000011259 mixed solution Substances 0.000 claims description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 43
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 38
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 38
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 34
- 229960000583 acetic acid Drugs 0.000 claims description 34
- HEVFTQCHIUGKGA-UHFFFAOYSA-N methyl 6-bromo-7-methoxy-1,3-benzodioxole-5-carboxylate Chemical compound COC1=C(Br)C(C(=O)OC)=CC2=C1OCO2 HEVFTQCHIUGKGA-UHFFFAOYSA-N 0.000 claims description 34
- 239000012362 glacial acetic acid Substances 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 28
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 27
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 26
- 229910052794 bromium Inorganic materials 0.000 claims description 26
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 26
- 239000003208 petroleum Substances 0.000 claims description 25
- 238000004440 column chromatography Methods 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 21
- 239000007788 liquid Substances 0.000 claims description 20
- 238000000926 separation method Methods 0.000 claims description 18
- 229910052786 argon Inorganic materials 0.000 claims description 17
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 16
- 239000011777 magnesium Substances 0.000 claims description 16
- 229910052749 magnesium Inorganic materials 0.000 claims description 16
- 239000007789 gas Substances 0.000 claims description 15
- 230000001681 protective effect Effects 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 230000002194 synthesizing effect Effects 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- 239000012074 organic phase Substances 0.000 claims description 13
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 13
- 239000011230 binding agent Substances 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000004327 boric acid Substances 0.000 claims description 11
- -1 boric acid compound Chemical class 0.000 claims description 11
- 239000010410 layer Substances 0.000 claims description 10
- 239000012044 organic layer Substances 0.000 claims description 10
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 10
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical group BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000003999 initiator Substances 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 238000002390 rotary evaporation Methods 0.000 claims description 7
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 6
- 230000005587 bubbling Effects 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 229960001701 chloroform Drugs 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- 239000011698 potassium fluoride Substances 0.000 claims description 3
- 235000003270 potassium fluoride Nutrition 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 claims description 3
- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 description 29
- 230000015572 biosynthetic process Effects 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 18
- 239000000047 product Substances 0.000 description 10
- 230000001276 controlling effect Effects 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 230000008878 coupling Effects 0.000 description 6
- 238000010168 coupling process Methods 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000006887 Ullmann reaction Methods 0.000 description 5
- 239000004305 biphenyl Substances 0.000 description 5
- 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 description 4
- 238000011914 asymmetric synthesis Methods 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical class OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 150000001642 boronic acid derivatives Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- CHIHQLCVLOXUJW-UHFFFAOYSA-N benzoic anhydride Chemical class C=1C=CC=CC=1C(=O)OC(=O)C1=CC=CC=C1 CHIHQLCVLOXUJW-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000005619 boric acid group Chemical group 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 229910000435 bromine oxide Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- CQRYARSYNCAZFO-UHFFFAOYSA-N salicyl alcohol Chemical compound OCC1=CC=CC=C1O CQRYARSYNCAZFO-UHFFFAOYSA-N 0.000 description 1
- YEFOAORQXAOVJQ-RZFZLAGVSA-N schisandrol a Chemical compound C1[C@H](C)[C@@](C)(O)CC2=CC(OC)=C(OC)C(OC)=C2C2=C1C=C(OC)C(OC)=C2OC YEFOAORQXAOVJQ-RZFZLAGVSA-N 0.000 description 1
- YEFOAORQXAOVJQ-UHFFFAOYSA-N wuweizischun A Natural products C1C(C)C(C)(O)CC2=CC(OC)=C(OC)C(OC)=C2C2=C1C=C(OC)C(OC)=C2OC YEFOAORQXAOVJQ-UHFFFAOYSA-N 0.000 description 1
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a gamma-biphenyldicarboxylate intermediate, a synthesis method and a gamma-biphenyldicarboxylate synthesis method, wherein the gamma-biphenyldicarboxylate intermediate is 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid, and based on the gamma-biphenyldicarboxylate intermediate, the invention also provides a novel gamma-biphenyldicarboxylate synthesis method.
Description
Technical Field
The invention relates to the field of drug synthesis, and mainly relates to a gamma-biphenyldicarboxylate intermediate, a synthesis method and a gamma-biphenyldicarboxylate synthesis method.
Background
Gamma-biphenyldicarboxylate (gamma-DDB), alpha-biphenyldicarboxylate (alpha-DDB) and beta-biphenyldicarboxylate (beta-DDB) are all medical intermediates of artificial schisandrin and important drugs for liver diseases. The alpha-biphenyldicarboxylate and the beta-biphenyldicarboxylate are both symmetrical structures, and the gamma-biphenyldicarboxylate is an asymmetrical structure. Wherein the chemical name of the gamma-biphenyldicarboxylate is as follows: 6,4 '-dimethoxy-4, 5,5',6 '-dimethyldioxy-2, 2' -dimethoxycarbonylbiphenyl, CAS 79279-07-5, alpha-biphenyldicarboxylate, beta-biphenyldicarboxylate and gamma-biphenyldicarboxylate have the following structures, respectively:
in the prior art, various methods for obtaining the gamma-biphenyldicarboxylate generally adopt indirect methods, but have the defects of complex process, high separation difficulty, insufficient purity, low yield and the like, and are difficult to realize industrialization.
For example: xijingxian et al (the pharmaceutical science, 1982(1), 23-27) report that gallic acid is used as a starting material, and the intermediate 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester and 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester are obtained through esterification, etherification and bromination, and the intermediate is subjected to Ullmann coupling reaction to prepare a mixture of three isomers of alpha-biphenyldicarboxylate, beta-biphenyldicarboxylate and gamma-biphenyldicarboxylate, and then the mixture is subjected to column chromatography separation to obtain the gamma-biphenyldicarboxylate. In the synthesis method, the gamma-biphenyldicarboxylate is only obtained as a byproduct and a large amount of alpha-biphenyldicarboxylate and beta-biphenyldicarboxylate are generated when the gamma-biphenyldicarboxylate is generated, so that the yield is low and the process is complicated. The synthetic route is shown as the following formula:
chang et al (Bioorganic & medicinal chemistry letters, 2004, 14(9): 2131-2136) acidylates the intermediates 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester and 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester to prepare acyl chloride intermediates, bridges the two acyl chloride intermediates with salicyl alcohol to obtain a bridge, and then the bridge is subjected to Ullmann coupling reaction to prepare a gamma-biphenyl diester derivative, which is hydrolyzed with methanol to obtain gamma-biphenyl bibenzoic acid, and then esterified to obtain gamma-biphenyl diester. The method uses auxiliary bridging to prepare an intermediate, and then performs coupling, hydrolysis and esterification to obtain a product, isomers cannot appear, but two molecule intermediate couplings rather than only intramolecular couplings appear, so that the yield is improved, but the steps are multiple and the separation is complex. The synthetic route is shown as the following formula:
song et al (Bioorganic & Medicinal Chemistry Letters, 2010, 20(7): 2297-2298.) acidylates intermediates 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester and 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester to prepare an acyl chloride intermediate and a carboxylic acid intermediate, directly prepares a benzoic anhydride derivative from the two intermediates, prepares gamma-biphenyl dicarboxylic acid through Ullmann coupling reaction and hydrolysis of the derivative, and then esterifies to obtain gamma-biphenyl diester. The method also uses auxiliary bridging to prepare an intermediate, and then couples, hydrolyzes and esterifies the intermediate to obtain a product, so isomers do not appear, two-molecule intermediate coupling also appears instead of intramolecular coupling, the yield is still low, the synthesis steps are still multiple, and the separation is complex. The synthetic route is shown as the following formula:
accordingly, the prior art is yet to be improved and developed.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a gamma-biphenyldicarboxylate intermediate, a synthesis method and a gamma-biphenyldicarboxylate synthesis method, wherein a Suzuki-Miyaura reaction is introduced as a key step of asymmetric synthesis, so that the synthesis is simple, isomers are not generated, the preparation process is optimized and upgraded, reaction steps are reduced, and reaction conditions are optimized, and the problem that the reaction route of the existing gamma-biphenyldicarboxylate is too complex is solved.
The technical scheme of the invention is as follows:
the gamma-biphenyldicarboxylate intermediate is 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid, and has a molecular structural formula as follows:
a method for synthesizing the gamma-biphenyldicarboxylate intermediate, which comprises the following steps:
adding magnesium strips and a solvent in the protective gas atmosphere, dripping an initiator to initiate reaction, after bubbling is started, controlling the temperature to be 45-55 ℃, dripping a solution prepared by 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester and the solvent, and keeping the temperature and stirring for 0.5-2 hours after dripping is finished; cooling in ice salt water to an internal temperature below 0 ℃, dripping a solution prepared from a boric acid compound and a solvent, stirring for 1-3 hours after dripping, dripping hydrochloric acid, stirring for 20-50 minutes, extracting with an extraction solvent, and carrying out rotary evaporation on an organic layer to obtain a white solid; separating the white solid by a chromatographic column to obtain the 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonyl phenylboronic acid.
The synthesis method of the gamma-biphenyldicarboxylate intermediate comprises the following steps of (1) preparing a protective gas, wherein the protective gas is argon or nitrogen;
the solvent is tetrahydrofuran, diethyl ether, toluene, n-hexane, dichloromethane or 2-methyltetrahydrofuran;
the initiator is 1, 2-dibromoethane, iodine, dichloroethane or methyl iodide;
the boric acid compound is trimethyl borate, triethyl borate or tributyl borate;
the extraction solvent is dichloromethane, trichloromethane, dichloroethane or carbon tetrachloride;
the column chromatography solvent adopted in the separation process of the chromatographic column is a mixed solution of ethyl acetate and petroleum ether or a mixed solution of ethyl acetate and n-hexane.
The synthesis method of the gamma-biphenyldicarboxylate intermediate comprises the following steps of (1) mixing magnesium strips with 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester in a mass ratio of 0.1-0.15: 1;
the mass ratio of the initiator to the 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester is (0.005-0.01): 1;
the mass ratio of the boric acid compound to the 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester is 0.3-0.5: 1;
the hydrochloric acid is 0.5-2M hydrochloric acid, and the mass ratio of the hydrochloric acid to 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester is 1-10: 1;
when the column chromatography solvent is a mixed solution of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1 (1-4); when the column chromatography solvent is a mixed solution of ethyl acetate and n-hexane, the volume ratio of the ethyl acetate to the n-hexane is 1 (1-4);
in the magnesium strip and the solvent, the weight ratio of the solvent to the magnesium strip is 30-70: 1; in a solution prepared by 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester and a solvent, the weight ratio of the solvent to the 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester is 2-5: 1; in a solution prepared from a boric acid compound and a solvent, the weight ratio of the solvent to the boric acid compound is 5-10: 1; in the synthesis method, the weight ratio of the whole addition amount of the solvent to the 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester is 10-15: 1.
A method for synthesizing gamma-biphenyldicarboxylate comprises the following steps:
adding a mixed solution of 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester, triphenylphosphine, palladium acetate, 1, 4-dioxane and an acid-binding agent solution under the atmosphere of protective gas, heating to 50-70 ℃ while stirring, preserving heat for 10-50min, adding a mixed solution of 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid and 1, 4-dioxane as claimed in claim 1, and continuously heating to 90-110 ℃ for refluxing for 24-72 hours; after the reaction is finished, carrying out suction filtration, separating liquid while the liquid is hot, extracting a water layer by using 1, 4-dioxane, combining organic phases and carrying out rotary evaporation until the organic phases are dried to obtain oily liquid; separating the oily liquid by a chromatographic column to obtain the gamma-biphenyldicarboxylate.
The synthesis method of the gamma-biphenyldicarboxylate comprises the following steps of (1) using argon or nitrogen as a protective gas;
the acid-binding agent is potassium carbonate, cesium carbonate, potassium tert-butoxide, potassium phosphate or potassium fluoride;
the column chromatography solvent adopted in the separation process of the chromatographic column is a mixed solution of ethyl acetate and petroleum ether or a mixed solution of ethyl acetate and n-hexane.
The synthesis method of the gamma-biphenyldicarboxylate comprises the following steps of, by mass, 1-2% of 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester and 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid: 1;
the concentration range of the acid-binding agent solution is 1.5-3M; when the concentration of the acid-binding agent solution is 2M, the mass ratio of triphenylphosphine, the acid-binding agent solution, palladium acetate and 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid is (0.05-0.15): 8-12): 0.02-0.03): 1;
in a mixed solution of 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester, triphenylphosphine, palladium acetate, 1, 4-dioxane and a potassium carbonate solution, the mass ratio of the 1, 4-dioxane to the 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester is 5-10: 1; in the mixed solution of 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid and 1, 4-dioxane, the mass ratio of 1, 4-dioxane to 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid is in the range of 2-6: 1; when the 1, 4-dioxane is used for extracting the water layer, the mass ratio of the 1, 4-dioxane to the 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid is 2-10: 1;
when the column chromatography solvent is a mixed solution of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1 (5-15); when the column chromatography solvent is a mixed solution of ethyl acetate and n-hexane, the volume ratio of the ethyl acetate to the n-hexane is 1 (5-15).
The method for synthesizing the gamma-biphenyldicarboxylate is characterized in that 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid is prepared by the method for synthesizing the gamma-biphenyldicarboxylate intermediate as claimed in any one of claims 2 to 4.
The synthesis method of the gamma-biphenyldicarboxylate comprises the following steps:
dissolving bromine in glacial acetic acid to prepare a bromine glacial acetic acid solution; controlling the temperature at 20-23 ℃, dripping a bromine glacial acetic acid solution into a mixed solution of methyl-7-methoxybenzo [ d ] [1,3] dioxo-5-carboxylic acid and glacial acetic acid, and continuing stirring after dripping; then adjusting the pH to be =7 by using a sodium hydroxide solution with the mass concentration of 40%; extracting the system with dichloromethane, combining organic phases, performing rotary evaporation to obtain brown oily matter, and separating the oily matter through a chromatographic column to obtain 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester; continuously separating to obtain 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester.
The synthesis method of the gamma-biphenyldicarboxylate comprises the following steps of, by mass, 1-3: 1;
in a bromine glacial acetic acid solution, the mass ratio of glacial acetic acid to bromine is 5-10: 1;
in the mixed solution of methyl-7-methoxybenzo [ d ] [1,3] dioxo-5-carboxylic acid and glacial acetic acid, the mass ratio of the glacial acetic acid to the methyl-7-methoxybenzo [ d ] [1,3] dioxo-5-carboxylic acid is 5-10: 1;
the mass ratio of the dichloromethane to the methyl-7-methoxybenzo [ d ] [1,3] dioxo-5-carboxylic acid is 10-20: 1;
the column chromatography solvent adopted in the separation of the chromatographic column is a mixed solvent of dichloromethane and petroleum ether with the volume ratio of 1-4: 1.
Has the advantages that: the preparation method of the gamma-biphenyldicarboxylate provided by the invention has the following advantages that the key steps are replaced on the basis of the prior art: 1. reaction steps are reduced, loss is reduced, and production efficiency is improved; 2. the direct asymmetric synthesis removes the possibility of isomer generation; 3. the post-treatment is simple and the direct separation is realized; 4. the reaction condition is mild, the high-temperature reaction is eliminated, and the requirement on equipment is not high; 5. high yield and high quality.
Drawings
FIG. 1 is a scheme of the synthesis method of gamma-biphenyldicarboxylate of the present invention.
Detailed Description
The invention provides a gamma-biphenyldicarboxylate intermediate, a synthetic method thereof and a gamma-biphenyldicarboxylate synthetic method, and the invention is further described in detail below in order to make the purpose, technical scheme and effect of the invention clearer and clearer. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The invention provides a gamma-biphenyldicarboxylate intermediate, which is 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid and has the following molecular structural formula:
the invention also provides a synthetic method of the gamma-biphenyldicarboxylate intermediate, which comprises the following steps:
adding magnesium strips and dry tetrahydrofuran into a flask in a protective gas atmosphere, dripping 1, 2-dibromoethane to initiate reaction, dripping a solution prepared from 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester and tetrahydrofuran into the flask when bubbling begins in a three-neck flask, controlling the temperature to be 45-55 ℃, preserving the temperature and stirring for 0.5-2 hours after dripping; cooling in brine ice to below 0 deg.C, adding dropwise solution prepared from trimethyl borate and tetrahydrofuran, stirring for 1-3 hr, adding dropwise hydrochloric acid, stirring for 20-50 min, extracting with dichloromethane, and rotary evaporating organic layer to obtain white solid; separating the white solid by a chromatographic column to obtain the 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonyl phenylboronic acid.
The protective gas may be argon, nitrogen, or the like.
The mass ratio of the magnesium strips to the 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester is 0.1-0.15: 1.
the mass ratio of the 1, 2-dibromoethane to the 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester is (0.005-0.01): 1. In the process of the present invention, 1, 2-dibromoethane functions as an initiator, and iodine, dichloroethane, methyl iodide, etc. may be used in place of 1, 2-dibromoethane.
The mass ratio of trimethyl borate to 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester is 0.3-0.5: 1. trimethyl borate is a boric acid compound which has the function of providing boron and substituting bromine on a benzene ring to generate boric acid group, and in the invention, triethyl borate and tributyl borate can be used for replacing the trimethyl borate.
The hydrochloric acid can be 0.5-2M hydrochloric acid, and the mass ratio of the hydrochloric acid to 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester is 1-10: 1. In the method, 1M hydrochloric acid is taken as an example, and the mass ratio of the 1M hydrochloric acid to the 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester is 2-5: 1. The hydrochloric acid has the functions of quenching reaction and regulating acidity, so that the product is more easily dissolved in an organic layer and is convenient to extract.
The weight ratio of the dried tetrahydrofuran to the magnesium strips is 30-70: 1; in a solution prepared from methyl 2-bromo-3, 4-methylenedioxy-5-methoxybenzoate and tetrahydrofuran, the weight ratio of the tetrahydrofuran to the methyl 2-bromo-3, 4-methylenedioxy-5-methoxybenzoate is 2-5: 1; in a solution prepared from trimethyl borate and tetrahydrofuran, the weight ratio of tetrahydrofuran to trimethyl borate is 5-10: 1; in the synthesis method, the weight ratio of the whole tetrahydrofuran to methyl 2-bromo-3, 4-methylenedioxy-5-methoxybenzoate is 10-15: 1. In the method of the present invention, tetrahydrofuran functions as a solvent, and in addition to tetrahydrofuran, diethyl ether, toluene, n-hexane, dichloromethane, 2-methyltetrahydrofuran, and the like may be used instead.
The mass ratio of the dichloromethane to the 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester is 10-15: 1. Methylene chloride is used as an extraction solvent, and in the present invention, chloroform, dichloroethane, carbon tetrachloride, and the like may be used instead of methylene chloride.
In the preparation method, a column chromatography solvent adopted in a chromatographic column separation process can be a mixed solution of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1 (1-4), in the invention, the column chromatography solvent can also be replaced by a mixed solution of ethyl acetate and n-hexane, and the volume ratio of the ethyl acetate to the n-hexane is 1 (1-4).
In the synthesis method, argon protection is preferably adopted, and the argon protection is more suitable for being used as protective gas to isolate air because the argon protection has higher density than nitrogen or air. Magnesium strips and 2-bromo-3, 4-methylenedioxy-5-methoxy methyl benzoate are used for generating a Grignard reagent, the Grignard reagent and trimethyl borate are used for generating a borate derivative, and finally, the borate derivative is hydrolyzed under an acidic condition to generate 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonyl phenylboronic acid, and meanwhile, unreacted magnesium is continuously reacted by hydrochloric acid to generate inorganic salt. In column chromatography, unreacted starting materials can be separated off first and the product can be separated off.
Based on the gamma-biphenyldicarboxylate intermediate 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid, the invention also provides a novel gamma-biphenyldicarboxylate synthesis method, which does not adopt Ullmann reaction, but introduces Suzuki-Miyaura reaction as a key step of asymmetric synthesis so that the synthesis is simple and no isomer appears, optimizes and upgrades the preparation process, reduces the reaction steps and optimizes the reaction conditions.
Specifically, the method for synthesizing the gamma-biphenyldicarboxylate comprises the following steps:
adding a mixed solution of 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester, triphenylphosphine, palladium acetate, 1, 4-dioxane and a potassium carbonate solution into a flask under the atmosphere of protective gas, starting stirring while heating to 50-70 ℃, keeping the temperature for 10-50min, adding a mixed solution of 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid and 1, 4-dioxane, and continuously heating to 90-110 ℃ for refluxing for 24-72 h. After the reaction, the mixture was immediately filtered by suction and the liquid was separated while hot, the aqueous layer was extracted with 1, 4-dioxane, and the organic phases were combined and rotary-evaporated to dryness to give an oily liquid. Separating the oily liquid by a chromatographic column to obtain the gamma-biphenyldicarboxylate.
The protective gas may be argon, nitrogen, or the like, and preferably is argon.
The mass ratio of the 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester to the 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid is 1-2: 1.
the concentration range of the potassium carbonate solution can be 1.5-3M. When the concentration of the potassium carbonate solution is 2M, the mass ratio of triphenylphosphine, the potassium carbonate solution, palladium acetate and 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid is (0.05-0.15): 8-12): 0.02-0.03): 1. In the present invention, potassium carbonate acts as an acid-binding agent, and cesium carbonate, potassium tert-butoxide, potassium phosphate, potassium fluoride, or the like may be used instead.
In a mixed solution of 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester, triphenylphosphine, palladium acetate, 1, 4-dioxane and a potassium carbonate solution, the mass ratio of the 1, 4-dioxane to the 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester is 5-10: 1. In the mixed solution of 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid and 1, 4-dioxane, the mass ratio of 1, 4-dioxane to 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid is in the range of 2-6: 1. when the aqueous layer is extracted by 1, 4-dioxane, the mass ratio of 1, 4-dioxane to 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid can be 2-10: 1.
In the preparation method, a column chromatography solvent adopted in the separation process of the chromatographic column can be a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1 (5-15). In the invention, the column chromatography solvent can also be replaced by a mixed solution of ethyl acetate and n-hexane, and the volume ratio of the ethyl acetate to the n-hexane is 1 (5-15).
In the synthesis method, argon is used as protective gas, so that the influence of catalyst poisoning on the reaction process can be prevented. Triphenylphosphine and palladium acetate are added firstly to form a triphenylphosphine palladium complex in a solvent, the complex is a Suzuki-Miyaura reaction catalyst, and potassium carbonate is an acid-binding agent. 1, 4-dioxane is selected as a solvent for reaction, and the post-treatment is convenient due to low boiling point. After heat preservation, a mixed solution of 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid and 1, 4-dioxane is added, so that the triphenylphosphine palladium complex can be better prepared, and the catalytic effect is promoted. The catalyst and insoluble substances are removed by filtration while the solution is hot, and the 1, 4-dioxane and water can be separated when the solution is hot, and the solution can be separated if the solution is cooled, so that the miscibility is increased and the solution is not separated well. And the aqueous layer is extracted by 1, 4-dioxane, so that the product loss can be reduced, and the yield is improved. Separating unreacted raw materials in a column chromatography mode, separating a reaction by-product triphenylphosphine oxide, and finally separating the product gamma-biphenyldicarboxylate, wherein if the product and the triphenylphosphine oxide are mixed together, the secondary column chromatography separation can be carried out.
Further, the invention also provides a preferable synthesis method of the gamma-biphenyldicarboxylate, as shown in fig. 1, comprising the following steps:
(1) synthesis of methyl 2-bromo-3, 4-methylenedioxy-5-methoxybenzoate (I) with methyl 6-bromo-3, 4-methylenedioxy-5-methoxybenzoate (II):
dissolving bromine in glacial acetic acid to prepare a bromine glacial acetic acid solution, adding a mixed solution of methyl-7-methoxybenzo [ d ] [1,3] dioxo-5-carboxylic acid (CAS:22934-58-3) and glacial acetic acid into a flask, controlling the temperature in the flask to be 20-23 ℃, dropwise adding the bromine glacial acetic acid solution, and continuing stirring after dropwise adding; then adjusting the pH to be =7 by using a sodium hydroxide solution with the mass concentration of 40%; extracting with dichloromethane, mixing organic phases, and rotary evaporating to obtain brown oil, separating with chromatographic column to obtain methyl 2-bromo-3, 4-methylenedioxy-5-methoxybenzoate (CAS: 81474-46-6); continuously separating to obtain 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester (CAS: 81474-47-7).
In the step (1), the mass ratio of the bromine to the methyl-7-methoxybenzo [ d ] [1,3] dioxo-5-carboxylic acid is 1-3: 1;
in a bromine glacial acetic acid solution, the mass ratio of glacial acetic acid to bromine is 5-10: 1;
in the mixed solution of methyl-7-methoxybenzo [ d ] [1,3] dioxo-5-carboxylic acid and glacial acetic acid, the mass ratio of the glacial acetic acid to the methyl-7-methoxybenzo [ d ] [1,3] dioxo-5-carboxylic acid is 5-10: 1;
the mass ratio of the dichloromethane to the methyl-7-methoxybenzo [ d ] [1,3] dioxo-5-carboxylic acid is 10-20: 1;
the column chromatography solvent adopted in the separation of the chromatographic column is a mixed solvent of dichloromethane and petroleum ether in a volume ratio of 1-4: 1.
In the invention, two blank sites on the benzene ring of methyl-7-methoxybenzo [ d ] [1,3] dioxo-5-carboxylic acid (CAS:22934-58-3) can be brominated to generate two isomers of methyl 2-bromo-3, 4-methylenedioxy-5-methoxybenzoate (CAS:81474-46-6) and methyl 6-bromo-3, 4-methylenedioxy-5-methoxybenzoate (CAS:81474-47-7), and the two isomers can be obtained only by simple separation, and the main structures of the two isomers just meet the synthesis requirement of gamma-biphenyl diester, so that the two isomers do not need to be synthesized respectively. Bromine is added dropwise to prevent the explosive reaction temperature from being uncontrollable, and is added all at once, two blank sites on the benzene ring of methyl-7-methoxybenzo [ d ] [1,3] dioxo-5-carboxylic acid (CAS:22934-58-3) are likely to be brominated simultaneously to generate impurities. The method is characterized in that a sodium hydroxide solution is used for neutralization and then dichloromethane is used for extraction, the aim is to generate sodium bromide by redundant bromine and sodium hydroxide, and simultaneously, a solvent glacial acetic acid can be removed, so that the problem that redundant bromine and acetic acid are not well separated in the following steps is avoided. The product is dissolved in dichloromethane, and the dichloromethane is easy to remove, so the dichloromethane is selected to extract the product.
(2) 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid (III) synthesis:
under the protection of argon, adding magnesium strips and dry tetrahydrofuran into a flask, dropwise adding 1, 2-dibromoethane to initiate a reaction, controlling the temperature to be 45-55 ℃ when bubbling begins in a three-necked flask, dropwise adding a solution prepared from 2-bromo-3, 4-methylenedioxy-5-methoxy methyl benzoate and tetrahydrofuran, stirring while keeping the temperature after dropwise adding, placing in ice brine to reduce the temperature to be below 0 ℃, dropwise adding a solution prepared from trimethyl borate and tetrahydrofuran, stirring while dropwise adding hydrochloric acid, extracting with dichloromethane, carrying out rotary evaporation on an organic layer until the organic layer is dried to obtain a white solid, and separating the solid by a chromatographic column to obtain 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid.
The phenylboronic acid derivatives can be prepared from both methyl 2-bromo-3, 4-methylenedioxy-5-methoxybenzoate and methyl 6-bromo-3, 4-methylenedioxy-5-methoxybenzoate, but the yield of methyl 2-bromo-3, 4-methylenedioxy-5-methoxybenzoate in step (1) is higher, and after a part of the produced phenylboronic acid derivative is continuously prepared later, the molar amount of the phenylboronic acid derivative is closer to 1:1 than that of methyl 6-bromo-3, 4-methylenedioxy-5-methoxybenzoate synthesized in step (1), so that the cost is saved in industrialization.
(3) Synthesis of gamma-biphenyldicarboxylate (gamma-DDB):
under the protection of argon, 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester, triphenylphosphine, palladium acetate, 1, 4-dioxane and potassium carbonate solution are added into a flask, stirring is started, the temperature is raised to 60 ℃, after heat preservation, a mixed solution of 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid and 1, 4-dioxane is added, and the temperature is continuously raised to reflux. After the reaction, the mixture was immediately filtered by suction and the liquid was separated while hot, the aqueous layer was extracted with 1, 4-dioxane, and the organic phases were combined and rotary-evaporated to dryness to give an oily liquid. Separating the oily liquid by a chromatographic column to obtain the gamma-biphenyldicarboxylate.
The preparation method of the gamma-biphenyldicarboxylate provided by the invention upgrades and reforms the key steps on the basis of the prior art, and has the following advantages: 1. the auxiliary bridge is banned, and the asymmetric synthesis is directly carried out, so that the synthesis difficulty is reduced; 2. by replacing the main reaction method, the byproducts are greatly reduced; 3. the post-treatment difficulty is reduced, and the quality and the yield are ensured; 4. by replacing auxiliary raw materials, the reaction temperature is optimized, the ultra-high temperature harsh reaction is eliminated, and the dependence on equipment is reduced; 5. the intermediate is not required to be refined after being separated, and the finished product reaction can be continuously carried out, so that the reaction efficiency is improved.
The present invention is further illustrated by the following specific examples.
Example 1
(1) Synthesis of methyl 2-bromo-3, 4-methylenedioxy-5-methoxybenzoate (I) with methyl 6-bromo-3, 4-methylenedioxy-5-methoxybenzoate (II):
dissolving 21g of bromine in 150g of glacial acetic acid to prepare a bromine glacial acetic acid solution, adding a mixed solution of 21g of methyl-7-methoxybenzo [ d ] [1,3] dioxo-5-carboxylic acid and 150g of glacial acetic acid into a flask, controlling the temperature in the flask to be 20-23 ℃, dropwise adding the bromine glacial acetic acid solution, and continuing stirring for 5 hours after dropwise adding; adjusting the pH to be =7 by using 40% sodium hydroxide solution; the system was extracted three times with 300g of dichloromethane and the combined organic phases were rotary evaporated to give a brown oil which was purified by column [ V (dichloromethane): v (petroleum ether) = 2: 1 ] separating to obtain 15.8g of 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester, wherein the yield of the step is 54.6%, the melting point is 103-105 ℃, and the 1HNMR (CDCl3) delta is 3.90(3H, s, -OCH 3),3.91(3H, s, -COOCH 3),6.11(2H, s, -OCH 2O-), 7.16(H, s, ArH); continuously separating to obtain 10.6 g of 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester, wherein the yield is 36.8%, the melting point is 83-84 ℃, and the ratio of 1HNMR (CDCl3) delta to 3.83(3H, s, -OCH 3),3.90(3H, s, -COOCH 3),6.12(2H, s, -OCH 2O-), 7.15(H, s, ArH).
(2) 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid (III) synthesis:
under the protection of argon, adding 1.6g of magnesium strip and 100g of dry tetrahydrofuran into a flask, dropwise adding 0.1g of 1, 2-dibromoethane to initiate a reaction, controlling the temperature to be 45-55 ℃ when bubbling begins in a three-necked flask, dropwise adding a solution prepared from 15.8g of methyl 2-bromo-3, 4-methylenedioxy-5-methoxybenzoate and 50g of tetrahydrofuran, preserving the temperature and stirring for 1 hour after dropwise adding, placing in ice brine to cool to the internal temperature of below 0 ℃, dropwise adding a solution prepared from 5.7g of trimethyl borate and 50g of tetrahydrofuran, stirring for 2 hours after dropwise adding, dropwise adding 40mL of 1M hydrochloric acid, stirring for 30 minutes, extracting with 200g of dichloromethane, and rotationally steaming an organic layer until the organic layer is dried to obtain a white solid, wherein the solid is subjected to chromatography column [ V (ethyl acetate): v (petroleum ether) = 1: 2 ] separating to obtain 11.7g of 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid, wherein the yield of the step is 84.3%, and 1HMR (CDCl3) delta is 3.84(3H, s, -OCH 3),3.92(3H, s, -COOCH 3),6.10(2H, s, -OCH 2O-), 6.5(2H, s, -OH) and 7.13(H, s, ArH).
(3) Synthesis of gamma-biphenyldicarboxylate (gamma-DDB):
under the protection of argon, 10.4g of 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester, 0.95g of triphenylphosphine, 0.2g of palladium acetate, 100g of 1, 4-dioxane and 90g of 2M potassium carbonate solution are added into a flask, stirring is started, the temperature is raised to 60 ℃, after 20 minutes of heat preservation, a mixed solution of 9.2g of 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid and 50g of 1, 4-dioxane is added, and the temperature is raised to 100 ℃ continuously and refluxed for 48 hours. After the reaction, the mixture was immediately filtered by suction and the liquid was separated while hot, the aqueous layer was extracted with 3X 20g of 1, 4-dioxane, and the organic phases were combined and rotary-evaporated to dryness to give an oily liquid. The oily liquid was passed through a chromatography column [ V (ethyl acetate): v (petroleum ether) = 1: 9 ] separating to obtain 11.2g of gamma-biphenyldicarboxylate with the purity of 98.2 percent and the yield of 74.4 percent, the melting point of 150-151 ℃ and the yield of 1HMR (CDCl3) delta of 3.62(3H, s-OCH 3), 3.64(3H, s-OCH 3),3.82(3H, s-COOCH 3),3.88(3H, s-COOCH 3), 6.02(2H, s-OCH 2O-), 6.11(2H, s-OCH 2O-), 7.16(H, s, ArH),7.22(H, s, ArH) FT-IR (KBr, cm-1): 1, 1623, 1578, 1185, 821, 752 and 752.
Example 2
(1) Synthesis of methyl 2-bromo-3, 4-methylenedioxy-5-methoxybenzoate (I) with methyl 6-bromo-3, 4-methylenedioxy-5-methoxybenzoate (II):
dissolving 40g of bromine in 200g of glacial acetic acid to prepare a bromine glacial acetic acid solution, adding a mixed solution of 20g of methyl-7-methoxybenzo [ d ] [1,3] dioxo-5-carboxylic acid and 200g of glacial acetic acid into a flask, controlling the temperature in the flask to be 20-23 ℃, dropwise adding the bromine glacial acetic acid solution, continuing stirring for 5 hours after the dropwise adding is finished, and then adjusting the pH to be =7 by using 40% of sodium hydroxide solution. The system was extracted three times with 360g of dichloromethane and the combined organic phases were rotary evaporated to give a brown oil which was purified by column [ V (dichloromethane): v (petroleum ether) = 3: 1 ] to obtain 15.3g of methyl 2-bromo-3, 4-methylenedioxy-5-methoxybenzoate with the yield of 55.6 percent. The separation was continued to obtain 9.19 g of methyl 6-bromo-3, 4-methylenedioxy-5-methoxybenzoate in a yield of 33.4%.
(2) 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid (III) synthesis:
under the protection of argon, adding 2.1g of magnesium strip and 80g of dry tetrahydrofuran into a flask, dropwise adding 0.1g of 1, 2-dibromoethane to initiate a reaction, controlling the temperature to be 45-55 ℃ when bubbling begins in a three-necked flask, dropwise adding a solution prepared from 15.3g of methyl 2-bromo-3, 4-methylenedioxy-5-methoxybenzoate and 40g of tetrahydrofuran, preserving the temperature and stirring for 1 hour after dropwise adding, placing in ice brine to cool to the internal temperature of below 0 ℃, dropwise adding a solution prepared from 6.1g of trimethyl borate and 40g of tetrahydrofuran, stirring for 2 hours after dropwise adding, dropwise adding 50mL of 1M hydrochloric acid, stirring for 30 minutes, extracting with 160g of dichloromethane, and rotationally steaming an organic layer until the organic layer is dried to obtain a white solid, wherein the solid is subjected to chromatography column [ V (ethyl acetate): v (petroleum ether) = 1: 3] separating to obtain 11.3g of 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid, wherein the yield of the step is 83.8%.
(3) Synthesis of gamma-biphenyldicarboxylate (gamma-DDB):
under the protection of argon, a mixed solution of 9.10g of 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester, 0.90g of triphenylphosphine, 0.23g of palladium acetate, 70g of 1, 4-dioxane and 100g of 2M potassium carbonate solution is added into a flask, stirring is started, the temperature is raised to 60 ℃, after 20 minutes of heat preservation, a mixed solution of 9.0g of 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid and 40g of 1, 4-dioxane is added, and the temperature is raised to 100 ℃ continuously and the mixture is refluxed for 48 hours. After the reaction, the mixture was immediately filtered by suction and the liquid was separated while hot, the aqueous layer was extracted with 3X 20g of 1, 4-dioxane, and the organic phases were combined and rotary-evaporated to dryness to give an oily liquid. The oily liquid was passed through a chromatography column [ V (ethyl acetate): v (petroleum ether) = 1: 12 ] separation to obtain 10.05g of gamma-biphenyldicarboxylate, the purity is 98.3 percent, and the yield in the step is 76.3 percent.
As can be seen from the above examples, the overall yield of the synthesis of the method using the Suzuki-Miyaura reaction is 25.5%, which is much higher than the synthesis by Ullmann coupling reaction or coupling by bridging. The gamma-biphenyldicarboxylate prepared by the method has the purity as high as 98.2%, can be applied to chemical analysis, and can also be used for biological property research or further synthesis as a medical intermediate.
It is to be understood that the invention is not limited to the examples described above, but that modifications and variations may be effected thereto by those of ordinary skill in the art in light of the foregoing description, and that all such modifications and variations are intended to be within the scope of the invention as defined by the appended claims.
Claims (10)
1. The gamma-biphenyldicarboxylate intermediate is 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid, and has a molecular structural formula as follows:
2. a method of synthesizing the γ -biphenyldicarboxylate intermediate according to claim 1, comprising the steps of:
adding magnesium strips and a solvent in the protective gas atmosphere, dripping an initiator to initiate reaction, after bubbling is started, controlling the temperature to be 45-55 ℃, dripping a solution prepared by 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester and the solvent, and keeping the temperature and stirring for 0.5-2 hours after dripping is finished; cooling in ice salt water to an internal temperature below 0 ℃, dripping a solution prepared from a boric acid compound and a solvent, stirring for 1-3 hours after dripping, dripping hydrochloric acid, stirring for 20-50 minutes, extracting with an extraction solvent, and carrying out rotary evaporation on an organic layer to obtain a white solid; separating the white solid by a chromatographic column to obtain the 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonyl phenylboronic acid.
3. The method for synthesizing the gamma-biphenyldicarboxylate intermediate according to claim 2, wherein the protective gas is argon or nitrogen;
the solvent is tetrahydrofuran, diethyl ether, toluene, n-hexane, dichloromethane or 2-methyltetrahydrofuran;
the initiator is 1, 2-dibromoethane, iodine, dichloroethane or methyl iodide;
the boric acid compound is trimethyl borate, triethyl borate or tributyl borate;
the extraction solvent is dichloromethane, trichloromethane, dichloroethane or carbon tetrachloride;
the column chromatography solvent adopted in the separation process of the chromatographic column is a mixed solution of ethyl acetate and petroleum ether or a mixed solution of ethyl acetate and n-hexane.
4. The synthesis method of the gamma-biphenyldicarboxylate intermediate according to claim 2, wherein the mass ratio of the magnesium strips to the methyl 2-bromo-3, 4-methylenedioxy-5-methoxybenzoate ranges from 0.1 to 0.15: 1;
the mass ratio of the initiator to the 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester is (0.005-0.01): 1;
the mass ratio of the boric acid compound to the 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester is 0.3-0.5: 1;
the hydrochloric acid is 0.5-2M hydrochloric acid, and the mass ratio of the hydrochloric acid to 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester is 1-10: 1;
when the column chromatography solvent is a mixed solution of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1 (1-4); when the column chromatography solvent is a mixed solution of ethyl acetate and n-hexane, the volume ratio of the ethyl acetate to the n-hexane is 1 (1-4);
in the magnesium strip and the solvent, the weight ratio of the solvent to the magnesium strip is 30-70: 1; in a solution prepared by 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester and a solvent, the weight ratio of the solvent to the 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester is 2-5: 1; in a solution prepared from a boric acid compound and a solvent, the weight ratio of the solvent to the boric acid compound is 5-10: 1; in the synthesis method, the weight ratio of the whole addition amount of the solvent to the 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester is 10-15: 1.
5. The synthesis method of gamma-biphenyldicarboxylate is characterized by comprising the following steps:
adding a mixed solution of 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester, triphenylphosphine, palladium acetate, 1, 4-dioxane and an acid-binding agent solution under the atmosphere of protective gas, heating to 50-70 ℃ while stirring, preserving heat for 10-50min, adding a mixed solution of 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid and 1, 4-dioxane as claimed in claim 1, and continuously heating to 90-110 ℃ for refluxing for 24-72 hours; after the reaction is finished, carrying out suction filtration, separating liquid while the liquid is hot, extracting a water layer by using 1, 4-dioxane, combining organic phases and carrying out rotary evaporation until the organic phases are dried to obtain oily liquid; separating the oily liquid by a chromatographic column to obtain the gamma-biphenyldicarboxylate.
6. The method for synthesizing gamma-biphenyldicarboxylate according to claim 5, wherein the protective gas is argon or nitrogen;
the acid-binding agent is potassium carbonate, cesium carbonate, potassium tert-butoxide, potassium phosphate or potassium fluoride;
the column chromatography solvent adopted in the separation process of the chromatographic column is a mixed solution of ethyl acetate and petroleum ether or a mixed solution of ethyl acetate and n-hexane.
7. The method for synthesizing gamma-biphenyldicarboxylate as claimed in claim 5, wherein the mass ratio of methyl 6-bromo-3, 4-methylenedioxy-5-methoxybenzoate to 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid is in the range of 1 to 2: 1;
the concentration range of the acid-binding agent solution is 1.5-3M; when the concentration of the acid-binding agent solution is 2M, the mass ratio of triphenylphosphine, the acid-binding agent solution, palladium acetate and 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid is (0.05-0.15): 8-12): 0.02-0.03): 1;
in a mixed solution of 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester, triphenylphosphine, palladium acetate, 1, 4-dioxane and a potassium carbonate solution, the mass ratio of the 1, 4-dioxane to the 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester is 5-10: 1; in the mixed solution of 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid and 1, 4-dioxane, the mass ratio of 1, 4-dioxane to 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid is in the range of 2-6: 1; when the 1, 4-dioxane is used for extracting the water layer, the mass ratio of the 1, 4-dioxane to the 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid is 2-10: 1;
when the column chromatography solvent is a mixed solution of ethyl acetate and petroleum ether, the volume ratio of the ethyl acetate to the petroleum ether is 1 (5-15); when the column chromatography solvent is a mixed solution of ethyl acetate and n-hexane, the volume ratio of the ethyl acetate to the n-hexane is 1 (5-15).
8. The method for synthesizing γ -biphenyldicarboxylate according to claim 5, wherein 4-methoxy-5, 6-methylenedioxy-2-methoxycarbonylphenylboronic acid is prepared by the method for synthesizing γ -biphenyldicarboxylate intermediate according to any one of claims 2 to 4.
9. The method for synthesizing gamma-biphenyldicarboxylate according to claim 6, wherein the method for synthesizing gamma-biphenyldicarboxylate further comprises the steps of:
dissolving bromine in glacial acetic acid to prepare a bromine glacial acetic acid solution; controlling the temperature at 20-23 ℃, dripping a bromine glacial acetic acid solution into a mixed solution of methyl-7-methoxybenzo [ d ] [1,3] dioxo-5-carboxylic acid and glacial acetic acid, and continuing stirring after dripping; then adjusting the pH to be =7 by using a sodium hydroxide solution with the mass concentration of 40%; extracting the system with dichloromethane, combining organic phases, performing rotary evaporation to obtain brown oily matter, and separating the oily matter through a chromatographic column to obtain 2-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester; continuously separating to obtain 6-bromo-3, 4-methylenedioxy-5-methoxybenzoic acid methyl ester.
10. The method for synthesizing γ -biphenyldicarboxylate according to claim 9, wherein the mass ratio of bromine to methyl-7-methoxybenzo [ d ] [1,3] dioxo-5-carboxylic acid is in the range of 1 to 3: 1;
in a bromine glacial acetic acid solution, the mass ratio of glacial acetic acid to bromine is 5-10: 1;
in the mixed solution of methyl-7-methoxybenzo [ d ] [1,3] dioxo-5-carboxylic acid and glacial acetic acid, the mass ratio of the glacial acetic acid to the methyl-7-methoxybenzo [ d ] [1,3] dioxo-5-carboxylic acid is 5-10: 1;
the mass ratio of the dichloromethane to the methyl-7-methoxybenzo [ d ] [1,3] dioxo-5-carboxylic acid is 10-20: 1;
the column chromatography solvent adopted in the separation of the chromatographic column is a mixed solvent of dichloromethane and petroleum ether with the volume ratio of 1-4: 1.
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