CN104557583A - Method for synthesizing gamma-aminobutyric acid chiral compound - Google Patents
Method for synthesizing gamma-aminobutyric acid chiral compound Download PDFInfo
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- CN104557583A CN104557583A CN201510053178.7A CN201510053178A CN104557583A CN 104557583 A CN104557583 A CN 104557583A CN 201510053178 A CN201510053178 A CN 201510053178A CN 104557583 A CN104557583 A CN 104557583A
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- Prior art keywords
- compound
- aminobutyric acid
- catalyst
- nitroolefin
- phenyl
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- 238000000034 method Methods 0.000 title claims abstract description 44
- 150000001875 compounds Chemical class 0.000 title claims abstract description 42
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 230000002194 synthesizing effect Effects 0.000 title abstract description 6
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 title abstract description 5
- 229960003692 gamma aminobutyric acid Drugs 0.000 title abstract description 5
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical class C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 claims abstract description 40
- 239000003054 catalyst Substances 0.000 claims abstract description 17
- 239000000654 additive Substances 0.000 claims abstract description 12
- 230000000996 additive effect Effects 0.000 claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 12
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 238000007259 addition reaction Methods 0.000 claims abstract description 7
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 238000006722 reduction reaction Methods 0.000 claims abstract description 4
- 230000009435 amidation Effects 0.000 claims abstract description 3
- 238000007112 amidation reaction Methods 0.000 claims abstract description 3
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 20
- 238000010520 demethylation reaction Methods 0.000 claims description 19
- 229960001404 quinidine Drugs 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- -1 substituted-phenyl Chemical group 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 11
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical group [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 claims description 7
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 230000000694 effects Effects 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
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical group [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 229940093916 potassium phosphate Drugs 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 11
- 239000003814 drug Substances 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 7
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 6
- 230000008569 process Effects 0.000 abstract description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 5
- 239000003513 alkali Substances 0.000 abstract description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 238000012512 characterization method Methods 0.000 description 19
- LDCRTTXIJACKKU-ARJAWSKDSA-N dimethyl maleate Chemical compound COC(=O)\C=C/C(=O)OC LDCRTTXIJACKKU-ARJAWSKDSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 11
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 11
- 239000003208 petroleum Substances 0.000 description 11
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 9
- 229960000794 baclofen Drugs 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- CZGCEKJOLUNIFY-UHFFFAOYSA-N 4-Chloronitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C=C1 CZGCEKJOLUNIFY-UHFFFAOYSA-N 0.000 description 7
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 6
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229940009697 lyrica Drugs 0.000 description 4
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 4
- 229950005741 rolipram Drugs 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 0 *C(*)[C@@](*)C[N+]([O-])=O Chemical compound *C(*)[C@@](*)C[N+]([O-])=O 0.000 description 3
- IEPRKVQEAMIZSS-UHFFFAOYSA-N Di-Et ester-Fumaric acid Natural products CCOC(=O)C=CC(=O)OCC IEPRKVQEAMIZSS-UHFFFAOYSA-N 0.000 description 3
- IEPRKVQEAMIZSS-WAYWQWQTSA-N Diethyl maleate Chemical compound CCOC(=O)\C=C/C(=O)OCC IEPRKVQEAMIZSS-WAYWQWQTSA-N 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 239000001961 anticonvulsive agent Substances 0.000 description 3
- 238000004296 chiral HPLC Methods 0.000 description 3
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 235000001258 Cinchona calisaya Nutrition 0.000 description 2
- 230000003556 anti-epileptic effect Effects 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229960000948 quinine Drugs 0.000 description 2
- 210000002027 skeletal muscle Anatomy 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- AYXYPKUFHZROOJ-UHFFFAOYSA-N CC(C)CC(CC(O)=O)CN Chemical compound CC(C)CC(CC(O)=O)CN AYXYPKUFHZROOJ-UHFFFAOYSA-N 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- QBSUYTACQGNNPR-BYPYZUCNSA-N S(=O)(=O)(O)N1[C@@H](CCC1)C(=O)N Chemical compound S(=O)(=O)(O)N1[C@@H](CCC1)C(=O)N QBSUYTACQGNNPR-BYPYZUCNSA-N 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- HBTLXHOUELJMKV-LMOVPXPDSA-N [Si].C1(=CC=CC=C1)[C@@]1(N(CCC1)C1=CC=CC=C1)CO Chemical compound [Si].C1(=CC=CC=C1)[C@@]1(N(CCC1)C1=CC=CC=C1)CO HBTLXHOUELJMKV-LMOVPXPDSA-N 0.000 description 1
- 230000000049 anti-anxiety effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002557 soporific effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a method for synthesizing a gamma-aminobutyric acid chiral compound. The method comprises the following steps of: adding nitroolefin and malonate to a solvent in the presence of a catalyst A and an additive; carrying out conjugate addition reaction on nitroolefin and malonate to selectively obtain a compound V; carrying out hydrogenation reduction reaction on the compound V under the action of a catalyst B and hydrogen, decarboxylation and amidation to obtain a compound II; carrying out acidolysis on the compound II to obtain a compound I. According to the method, a gamma-aminobutyric acid chiral drug prepared by taking a low-cost easily-prepared quinidine derivative as a catalyst and alkali as an additive is high in yield and high in enantioselectivity. The method disclosed by the invention is moderate in reaction condition and easy to operate and is a green synthesis process for synthesizing gamma-aminobutyric acid chiral drugs.
Description
Technical field
The invention belongs to organic synthesis field, be specifically related to a kind of method of synthesizing γ-aminobutyric acid class chipal compounds.
Background technology
The chirality γ-aminobutyric acid of beta substitution and lactam derivatives thereof have physiologically active widely, clinical in tranquilizing soporific, antidepressant, skeletal muscle solution spasm, anti-senile dementia and antiepileptic etc.Wherein, representational medicine comprises skeletal muscle relaxation reconciliation anticonvulsant drug baclofen, anti-epileptic, anxiety and neuralgia pharmaceutical pregabaline, anxiety and the non-Buddhist nun's Boot of insomnia drug, antidepressant drug rolipram.
For the synthesis of this kind of chiral drug, existing main method has: 1) chiral separation (WO9638405, WO2009147528; WO2010061403; CN101362696A); 2) from chiral raw material synthesis (Tetrahedron:Asymmetry 2008,19,651; J.Org.Chem.2007,72,7390; CN101585778A); 3) chiral auxiliary(reagent) synthesis (Heterocycles 2005,66,385 is adopted; Tetrahedron:Asymmetry 2004,15,2039; Synlett 2006,1589); 4) transition metal-catalyzed asymmetric synthesis (WO2001055090; J.Am.Chem.Soc.2003.125,10219; J.Am.Chem.Soc.2004,126,9920).These methods also exist the defects such as cost is high, complex synthetic route, waste discharge amount are large.
Recent years, several research group also reports method (J.Am.Chem.Soc.2004,126,9906 by organic catalysis method synthesis γ-aminobutyric acid class chiral drug; J.Am.Chem.Soc.2005,127,119; Org.Lett.2007,9,5307; Org.Lett.2010,12,1280; Org.Lett.2012,14,1516; CN101333168A and CN102701987A), wherein the asymmetric conjugated reaction of Nitromethane 99Min. and olefine aldehydr is the committed step building chiral centre, and the catalyzer that these methods adopt is price Thiourea catalyzer costly, diphenylprolinol silicon ether catalyst and sulfo-prolineamide type catalyzer.
McQuade and Kataja group reports respectively reacts by the asymmetric conjugated reaction of nitroolefin and malonic ester the method preparing baclofen and lyrica, have employed Ni (II) catalyzer (J.Am.Chem.Soc.2007 of chirality, 129,9216; ARKIVOC 2010, ii, 205).Thereafter, Takemoto group adopts the derivative thiourea catalyst of quinine to complete this reaction, obtains good enantioselectivity (J.Am.Chem.Soc.2005,127,119).But the Thiourea catalyzer price that Ni (II) catalyzer of chirality and quinine derive all costly, reduces the industrial application value of this route.
Summary of the invention
The object of the present invention is to provide a kind of method of synthesizing γ-aminobutyric acid class chipal compounds, the method employs additive on the basis of existing technology, by follow-up a few step reactions, obtain a series of γ-aminobutyric acid class chipal compounds with the productive rate of excellence and enantioselectivity.
Object of the present invention is achieved through the following technical solutions:
Synthesize a method for γ-aminobutyric acid class chipal compounds, comprise the following steps:
Under catalyst A and additive exist, nitroolefin (compound III) and malonic ester (compounds Ⅳ) are added in solvent, nitroolefin and malonic ester generation conjugate addition reaction, optionally obtain compound V, compound V obtains Compound II per there is hydro-reduction reaction, decarboxylation, amidation under the effect of catalyst B and hydrogen after, and Compound II per acidolysis can obtain Compound I;
Reaction process is shown below:
In Compound I, II, III, V, R
1for straight chain or the branched-chain alkyl of phenyl, substituted-phenyl, naphthyl, thienyl, furyl, pyridyl, benzofuryl, benzothienyl, quinolyl, C1-C6; Described substituted-phenyl is for containing 1-3 substituent phenyl, and substituting group is selected from fluorine, chlorine, bromine, the straight chain of C1-C6 or branched-chain alkyl, the straight chain of C1-C6 or branched alkoxy, nitro, trifluoromethyl, phenyl;
γ-aminobutyric acid class chipal compounds of the present invention comprises Compound I and II, and common γ-aminobutyric acid class chipal compounds is as follows:
In compounds Ⅳ, V, R
2for methyl, ethyl, sec.-propyl, n-propyl, butyl, isobutyl-, the tertiary butyl;
Catalyst A has following general structure:
Wherein R
3for hydrogen, allyl group, benzyl, trimethyl silicon based, triethyl is silica-based, benzoyl, ethanoyl or p-toluenesulfonyl;
Catalyst A is 6 '-demethylation Quinidine, 9-O-allyl group-6 '-demethylation Quinidine or 9-benzoyl-6 '-demethylation Quinidine preferably;
Described additive is sodium carbonate, salt of wormwood, potassiumphosphate, triethylamine, N, N-diisopropylethylamine, piperidines, 1,4-diazabicylo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene, 4-dimethylamino pyridine, N-Methylimidazole, preferred DIPEA;
Described solvent is ether, dipropyl ether, Di Iso Propyl Ether, tetrahydrofuran (THF), t-butyl methyl ether, dioxane, methylene dichloride, ethylene dichloride, chloroform, normal hexane, methyl alcohol, ethanol, Virahol, toluene, water, preferred tetrahydrofuran (THF);
Described catalyst B is Raney's nickel, palladium carbon or platinum carbon, preferred Raney's nickel;
In described conjugate addition reaction, the mol ratio of nitroolefin III and malonic ester IV is 1:1 ~ 1:5, preferred 1:3; The mol ratio of catalyst A and nitroolefin III is 1:2 ~ 1:20, preferred 1:10;
Conjugate addition reaction can carry out at 0-60 DEG C, preferably carries out at 25 DEG C;
In described hydro-reduction reaction, hydrogenation pressure is 1-20 normal atmosphere, is preferably 3 normal atmosphere; Temperature is 0-120 DEG C, is preferably 80 DEG C.
The present invention has following advantage and effect relative to prior art:
The inventive method adopts quinidine derivative cheap and easy to get to be catalyzer, and alkali is additive, and obtained γ-aminobutyric acid class chiral drug yield is high, enantioselectivity is high; The inventive method reaction conditions is gentle, simple to operate, is the green synthesis process of a synthesis γ-aminobutyric acid class chiral drug.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.
Embodiment 1
Synthesize a method for baclofen, comprise the following steps:
(1) by parachloronitrobenzene ethene (3.66g, 20.0mmol), dimethyl malonate (7.92g, 60.0mmol), 6 '-demethylation Quinidine (0.62g, 10mol%) and N, N-diisopropylethylamine (0.52g, 20mol%) be dissolved in THF (100mL), stir 24 hours under normal temperature, react complete concentrated, column chromatography (ethyl acetate/petroleum ether=1/10) purifying, obtain (R)-2-(1-(4-chlorobenzene)-2-nitro-ethyl) dimethyl maleate (6.00g, yield 95%, ee 94%).
The structural characterization data of product are as follows:
1h NMR (400MHz, CDCl
3): δ 7.31 (d, J=8.4Hz, 2H), 7.18 (d, J=8.4Hz, 2H), 4.91 (dd, J=4.8,12.8Hz, 1H), 4.85 (dd, J=8.4,13.6Hz, 1H), 4.23 (dt, J=4.8,9.2Hz, 1H), 3.83 (d, J=9.2Hz, 1H), 3.77 (s, 3H), 3.60 (s, 3H);
13c NMR (100MHz, CDCl
3): δ 167.6,167.0,134.6,134.4,129.3,129.2,77.1,54.4,53.0,52.9,42.3.chiral HPLC:Daicel chiralcel OD-H Column, Hexane/2-propanol=80/20,0.8mL/min, λ 220nm, t
r(major)=14.7min, t
r(minor)=16.0min. determines that product is (R)-2-(1-(4-chlorobenzene)-2-nitro-ethyl) dimethyl maleate, and structure is as follows:
(2) inside hydrogenation reaction kettle, add (R)-2-(1-(4-chlorobenzene)-2-nitro-ethyl) dimethyl maleate (3.15g, 10.0mmol), Raney's nickel (2.0mg) and ethanol (10mL), with hydrogen exchange three times, react 18 hours under 80 DEG C and three normal atmosphere.By washing with alcohol after reaction solution diatomite filtration, obtain lactam compound (1.81g, yield 93%).
The structural characterization data of product are as follows:
M.P.109-111 DEG C; [α]
d 30– 39.0 (c 1.00, CHCl
3);
1h NMR (400MHz, CDCl
3) δ 7.32 (d, J=7.9Hz, 2H), 7.19 (t, J=8.2Hz, 2H), 6.15 (s, 1H), 3.79 (t, J=8.9Hz, 1H), 3.68 (m, 1H), 3.38 (t, J=8.4Hz, 1H), (2.74 dd, J=9.0,16.9Hz, 1H), (2.45 dd, J=8.6,16.8Hz, 1H);
13c NMR (100MHz, CDCl
3) δ 177.5,140.7,132.9,129.0,128.1,49.3,39.6,37.8; MS (ESI): 196 (MH
+). determine that the structure of product is as follows:
(3) get lactam compound (1.17g, 6.0mmol), add the HCl (20mL) of 5M, react 18 hours at 90 DEG C, cool rear ethyl acetate (4 × 50mL) extraction, aqueous phase concentrates to obtain yellow solid (1.43g, yield 95%).
The structural characterization data of product are as follows:
M.P.188-189 DEG C; [α]
d 25– 3.79 (c 0.65, H
2o);
1h NMR (400MHz, DMSO-d
6) δ 12.26 (s, 1H), 8.13 (s, 3H), 7.57-7.13 (m, 4H), (3.15-3.07 m, 1H), 3.04-2.92 (m, 1H), 2.85 (dd, J=5.5,16.2Hz, 1H), 2.56 (dd, J=9.5,16.5Hz, 1H);
13c NMR (100MHz, DMSO-d
6) δ 172.5,139.5,131.9,130.0,128.7,128.6,128.0,43.1,39.1,37.8; MS (ESI): 214 (MH
+). determine that the structure of product is as follows:
Comparative example 1
Synthesize a method for baclofen, comprise the following steps:
(1) by parachloronitrobenzene ethene (3.66g, 20.0mmol), dimethyl malonate (7.92g, 60.0mmol) and 6 '-demethylation Quinidine (0.62g, 20mol%) be dissolved in THF (100mL), stir 36 hours under normal temperature, react complete concentrated, column chromatography (ethyl acetate/petroleum ether=1/10) purifying, obtain (R)-2-(1-(4-chlorobenzene)-2-nitro-ethyl) dimethyl maleate (6.13g, yield 97%, ee 78%).The structural characterization data consistent with Example 1 of product.
(2) this step is with embodiment 1.
(3) this step is with embodiment 1.
Embodiment 1 and the difference of comparative example 1 are to prepare to be had additive-free in the process of compound V, the yield of both obtained compound V is close, but embodiment 1 is deposited in case there being additive, and the ee value of compound V significantly improves.
Embodiment 2
Synthesize a method for baclofen, comprise the following steps:
(1) by parachloronitrobenzene ethene (3.66g, 20.0mmol), dimethyl malonate (7.92g, 60.0mmol), 9-O-allyl group-6 '-demethylation Quinidine (0.67g, 10mol%) and N, N-diisopropylethylamine (0.52g, 20mol%) be dissolved in THF (100mL), stir 24 hours under normal temperature, react complete concentrated, column chromatography (ethyl acetate/petroleum ether=1/10) purifying, obtain (R)-2-(1-(4-chlorobenzene)-2-nitro-ethyl)) dimethyl maleate (6.13g, yield 97%, ee 97%).The structural characterization data consistent with Example 1 of product.
(2) this step is with embodiment 1.
(3) this step is with embodiment 1.
Embodiment 3
Synthesize a method for baclofen, comprise the following steps:
(1) by parachloronitrobenzene ethene (3.66g; 20.0mmol), dimethyl malonate (7.92g; 60.0mmol), 9-benzoyl-6 '-demethylation Quinidine (0.82g; 2.0mmol) with 4-dimethylamino pyridine (0.26g; 2.0mmol) be dissolved in THF (100mL); stir 24 hours under normal temperature; react complete concentrated; column chromatography (ethyl acetate/petroleum ether=1/10) purifying; obtain (R)-2-(1-(4-chlorobenzene)-2-nitro-ethyl) dimethyl maleate (5.87g; yield 93%, ee 88%).The structural characterization data consistent with Example 1 of product.
(2) this step is with embodiment 1.
(3) this step is with embodiment 1.
Embodiment 4
Synthesize a method for baclofen, comprise the following steps:
(1) by parachloronitrobenzene ethene (3.66g, 20.0mmol), dimethyl malonate (7.92g, 60.0mmol), 9-O-allyl group-6 '-demethylation Quinidine (0.67g, 2.0mmol) and N, N-diisopropylethylamine (0.52g, 20mol%) be dissolved in t-butyl methyl ether (100mL), stir 24 hours under normal temperature, react complete concentrated, column chromatography (ethyl acetate/petroleum ether=1/10) purifying, obtain (R)-2-(1-(4-chlorobenzene)-2-nitro-ethyl dimethyl maleate (5.81g, yield 92%, ee 85%).The structural characterization data consistent with Example 1 of product.
(2) this step is with embodiment 1.
(3) this step is with embodiment 1.
Embodiment 5
Synthesize a method for baclofen, comprise the following steps:
(1) by parachloronitrobenzene ethene (3.66g, 20.0mmol), dimethyl malonate (7.92g, 60.0mmol), 9-O-allyl group-6 '-demethylation Quinidine (0.67g, 10mol%) and N, N-diisopropylethylamine (0.52g, 20mol%) be dissolved in ether (100mL), stir 24 hours under normal temperature, react complete concentrated, column chromatography (ethyl acetate/petroleum ether=1/10) purifying, obtain (R)-2-(1-(4-chlorobenzene)-2-nitro-ethyl) dimethyl maleate (5.81g, yield 92%, ee 84%).The structural characterization data consistent with Example 1 of product.
(2) this step is with embodiment 1.
(3) this step is with embodiment 1.
Embodiment 6
Synthesize a method for baclofen, comprise the following steps:
(1) by parachloronitrobenzene ethene (3.66g, 20.0mmol), dimethyl malonate (7.92g, 60.0mmol), 9-O-allyl group-6 '-demethylation Quinidine (0.67g, 10mol%) and N-Methylimidazole (0.33g, 20mol%) be dissolved in THF (100mL), stir 24 hours under normal temperature, react complete concentrated, column chromatography (ethyl acetate/petroleum ether=1/10) purifying, obtain (R)-2-(1-(4-chlorobenzene)-2-nitro-ethyl) dimethyl maleate (5.87g, yield 93%, ee 85%).The structural characterization data consistent with Example 1 of product.
(2) this step is with embodiment 1.
(3) this step is with embodiment 1.
Embodiment 7
Synthesize a method for lyrica, comprise the following steps:
(1) by 4-methyl nitro amylene (2.58g, 20.0mmol), dimethyl malonate (7.92g, 60.0mmol), 9-O-allyl group-6 '-demethylation Quinidine (0.67g, 10mol%) and N, N-diisopropylethylamine (0.52g, 10mol%) be dissolved in THF (100mL), stir 24 hours under normal temperature, post-treating method is with the step (1) of embodiment 1, obtain (R)-2-(4-methyl nitro amyl group) dimethyl maleate (4.80g, yield 92%, ee 92%).
The structural characterization data of product are as follows:
1h NMR (400MHz, CDCl
3) δ 4.70-4.63 (m, 1H), 4.53-4.46 (m, 1H), 3.77 (s, 3H), 3.76 (s, 3H), 3.63-3.61 (m, 1H), 2.98-2.92 (m, 1H), 1.67-1.61 (m, 1H), 1.31-1.26 (m, 2H), 0.91-0.87 (m, 6H);
13c NMR (100MHz, CDCl
3) δ 168.6,168.4,76.9,53.1,52.9,52.5,39.1,35.1,25.3,22.6,22.4. determines that product is (R)-2-(4-methyl nitro amyl group) dimethyl maleate, structure is as follows:
(2) inside hydrogenation reaction kettle, add (R)-2-(4-methyl nitro amyl group) dimethyl maleate (2.60g, 10.0mmol), Raney's nickel (2.0mg) and ethanol (10mL), with hydrogen exchange three times, react 18 hours under 80 DEG C and three normal atmosphere.By washing with alcohol after reaction solution diatomite filtration, obtain (S)-4-isobutyl-pyrroles-2-ketone (1.27g, yield 90%).
The structural characterization data of product are as follows:
1h NMR (400MHz, CDCl
3) δ: 6.56 (br, 1H), 3.41 (t, J=8.7Hz, 1H), 2.92 (dd, J=9.3,7.2Hz, 1H), 2.47 (m, 1H), 2.34 (dd, J=16.5,8.4Hz, 1H), 1.91 (dd, J=16.2,8.4Hz, 1H), 1.51 (d, J=7.2Hz, 1H), 1.28 (t, J=7.5Hz, 2H), 0.84 (d, J=6.6Hz, 3H), 0.82 (d, J=6.6Hz, 3H);
13c NMR (100MHz, CDCl
3) δ: 22.4,22.6,26.1,32.9,36.9,43.8,48.3,178.6. determine that the structure of product is as follows:
(3) (S)-4-isobutyl-pyrroles-2-ketone (1.13g, 8.0mmol), add the HCl (20mL) of 5M, react 18 hours at 90 DEG C, cool rear ethyl acetate (4 × 50mL) extraction, aqueous phase concentrates to obtain hydrochloric acid lyrica (1.17g, yield 92%).
The structural characterization data of product are as follows:
[α]
d 25=+9.6 (c=1.0, H
2o).
1h NMR (400MHz, CD
3oD) δ 2.95-2.92 (d, J=6.0Hz, 2H), 2.34 (dd, J=7.0,6.4Hz, 2H), 2.21-2.16 (m, 1H), 1.68-1.61 (m, 1H), 1.24-1.20 (m, 2H), 0.96-0.89 (m, 6H);
13c NMR (100MHz, CD
3oD) δ 175.8,44.5,41.9,37.1,32.5,26.1,23.2,22.4. determines that the structure of product is as follows:
Comparative example 2
Synthesize a method for lyrica, comprise the following steps:
(1) by 4-methyl nitro amylene (2.58g, 20.0mmol), dimethyl malonate (7.92g, 60.0mmol) and 9-O-allyl group-6 '-demethylation Quinidine (0.67g, 10mol%) be dissolved in THF (100mL), stir 24 hours under normal temperature, post-treating method is with the step (1) of embodiment 7, obtain (R)-2-(4-methyl nitro amyl group) dimethyl maleate (4.28g, yield 82%, ee 74%).The structural characterization data consistent with Example 7 of product.
(2) this step is with embodiment 7.
(3) this step is with embodiment 7.
Embodiment 7 and the difference of comparative example 2 are to prepare to be had additive-free in the process of compound V, the yield of both obtained compound V is close, but embodiment 7 is deposited in case there being additive, and the ee value of compound V significantly improves.
Embodiment 8
Synthesize a method for non-Buddhist nun's Boot, comprise the following steps:
(1) by nitrostyrolene (2.98g, 20.0mmol), dimethyl malonate (7.92g, 60.0mmol), 9-O-allyl group-6 '-demethylation Quinidine (0.67g, 10mol%) and N, N-diisopropylethylamine (0.52g, 20mol%) be dissolved in THF (100mL), stir 24 hours under normal temperature, react complete concentrated, column chromatography (ethyl acetate/petroleum ether=1/10) purifying, obtain (R)-2-(2-nitro-1-phenylethyl) dimethyl maleate (5.34g, yield 95%, ee 96%).
The structural characterization data of product are as follows:
1h NMR (400MHz, CDCl
3): δ 7.37 – 7.27 (m, 3H), 7.23 (dd, J=7.7,1.8Hz, 2H), 4.97 – 4.83 (m, 2H), 4.25 (td, J=8.7,5.6Hz, 1H), 3.87 (d, J=9.1Hz, 1H), 3.76 (s, 3H), 3.56 (s, 3H);
13c NMR (100MHz): δ 167.9,167.3,136.2,129.1,128.5,127.9,77.5,54.8,53.1,53.0,43.0,29.8; Chiral HPLC (Daicel Chiralcel OD-H) hexane/2-propanol=90/10, flow rate:1.00mL/min; λ=254nm; t
r(minor)=24.0min, t
r(major)=28.0min. determines that the structure of product is as follows:
(2) inside hydrogenation reaction kettle, add (R)-2-(2-nitro-1-styroyl) dimethyl maleate (2.81g, 10.0mmol), Raney's nickel (2.0mg) and ethanol (20mL), with hydrogen exchange three times, react 18 hours under 80 DEG C and three normal atmosphere.By washing with alcohol after reaction solution diatomite filtration, obtain non-Buddhist nun's Boot (1.81g, yield 93%).
The structural characterization data of product are as follows:
[α]
d 20+ 22 (c 0.5, MeOH); M.P.98 – 99 DEG C;
1h NMR (400MHz, CDCl
3): 7.34-7.29 (m, 2H), 7.25-7.21 (m, 3H), 3.75 (dd, J=8.8,8.4Hz, 1H), 3.65 (q, 1H), 3.38 (dd, J=6.8,8.4Hz, 1H), 2.71 (dd, J=8.8,16.8Hz, 1H), 2.48 (dd, J=6.8,16.8Hz, 1H);
13c NMR (100MHz, CDCl
3): 178.0,142.1,128.8,127.1,126.7,49.6,40.3,38.0. determines that the structure of product is as follows:
Comparative example 3
Synthesize a method for non-Buddhist nun's Boot, comprise the following steps:
(1) by nitrostyrolene (2.98g, 20.0mmol), dimethyl malonate (7.92g, 60.0mmol) and 9-O-allyl group-6 '-demethylation Quinidine (0.67g, 10mol%) be dissolved in THF (100mL), stir 24 hours under normal temperature, react complete concentrated, column chromatography (ethyl acetate/petroleum ether=1/10) purifying, obtain (R)-2-(2-nitro-1-phenylethyl) dimethyl maleate (5.28g, yield 94%, ee 76%).The structural characterization data consistent with Example 8 of product.
(2) this step is with embodiment 8.
Embodiment 8 and the difference of comparative example 3 are to prepare to be had additive-free in the process of compound V, the yield of both obtained compound V is close, but embodiment 8 is deposited in case there being additive, and the ee value of compound V significantly improves.
Embodiment 9
Synthesize a method for rolipram, comprise the following steps:
(1) by 2-cyclopentyloxy-1-methoxyl group-4-nitroethylene base benzene (5.26g, 20.0mmol), diethyl malonate (9.60g, 60.0mmol), 9-O-allyl group-6 '-demethylation Quinidine (0.67g, 2mmol) and N, N-diisopropylethylamine (0.52g, 2.0mmol) be dissolved in THF (100mL), stir 24 hours under normal temperature, react complete concentrated, column chromatography (ethyl acetate/petroleum ether=1/10) purifying, obtain 2-(1-(3-cyclopentyloxy)-4-p-methoxy-phenyl-2-nitro-ethyl) ethyl maleate (7.61g, yield 90%, ee 90%).
The structural characterization data of product are as follows:
M.P.94.5 – 95.5 DEG C; [α]
d 30– 9.4 (c 1.15, CHCl
3);
1h NMR (CDCl
3=400MHz) δ 6.81-6.72 (m, 3H), 4.90 (d, J=12.9Hz, 1H), 4.82 (d, J=12.9Hz, 1H), 4.73-4.69 (m, 1H), 4.29-4.14 (m, 3H), 4.05-4.07 (m, 2H), 3.76 (s, 3H), 3.79-3.80 (m, 1H), 2.02-1.79 (m, 5H), 1.64-1.59 (m, 3H), 1.29-1.30 (m, 3H), 0.91-0.93 (m, 3H); ESI m/z441 (M+NH
4); Chiral HPLC (Daicel Chiralcel AD) hexane/2-propanol=95/5, flowrate:1.00mL/min; λ=254nm; t
r(minor)=20.0min, t
r(major)=26.0min. determines that the structure of product is as follows:
(2) inside hydrogenation reaction kettle, add 2-(1-(3-cyclopentyloxy)-4-p-methoxy-phenyl)-2-nitro-ethyl) ethyl maleate (4.23g, 10.0mmol), Raney's nickel (2.0mg) and ethanol (10mL), with hydrogen exchange three times, react 18 hours under 80 DEG C and three normal atmosphere.By washing with alcohol after reaction solution diatomite filtration, obtain rolipram (2.80g, yield 93%).
The structural characterization data of product are as follows:
[α]
d 27-31.0 (c 1.00MeOH) for 94%ee. [lit.:[α]
d 25-33.9 (c 1.09, MeOH) for99%ee in the R-isomer; J.Am.Chem.Soc.2002,13394.].
1h NMR (400MHz, CDCl
3): δ 6.76-6.84 (m, 3H); 6.56 (br s, 1H), 4.75-4.78 (m, 1H), 3.83 (s, 3H), 3.77-3.73 (m, 1H), 3.66-3.58 (m, 1H), 3.38 (dd, J=7.6,8.8Hz, 1H), 2.71 (dd, J=8.8,16.8Hz, 1H), 2.47 (dd, J=8.8,16.8Hz, 1H), 1.94-1.81 (m, 6H), 1.63-1.59 (m, 2H);
13c NMR (100MHz, CDCl
3): δ 178.0,149.2,147.9,134.6,118.8,113.9,112.3,80.6,56.1,49.8,39.9,38.2,32.8,24.0.EI-MS m/z (%): 275 (14.69, M
+), 207 (68.55), 150 (100). determine that the structure of product is as follows:
Comparative example 4
Synthesize a method for rolipram, comprise the following steps:
(1) by 2-cyclopentyloxy-1-methoxyl group-4-nitroethylene base benzene (5.26g, 20.0mmol), diethyl malonate (9.60g, 60.0mmol) and 9-O-allyl group-6 '-demethylation Quinidine (0.67g, 10mol%) be dissolved in THF (100mL), stir 24 hours under normal temperature, react complete concentrated, column chromatography (ethyl acetate/petroleum ether=1/10) purifying, obtain 2-(1-(3-cyclopentyloxy)-4-p-methoxy-phenyl-2-nitro-ethyl) ethyl maleate (8.03g, yield 95%, ee 76%).The structural characterization data consistent with Example 9 of product.
(2) this step is with embodiment 9.
Embodiment 9 and the difference of comparative example 4 are to prepare to be had additive-free in the process of compound V, the yield of both obtained compound V is close, but embodiment 9 is deposited in case there being additive, and the ee value of compound V significantly improves.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (5)
1. synthesize a method for γ-aminobutyric acid class chipal compounds, it is characterized in that comprising the following steps:
Under catalyst A and additive exist, nitroolefin (compound III) and malonic ester (compounds Ⅳ) are added in solvent, nitroolefin and malonic ester generation conjugate addition reaction, optionally obtain compound V, compound V obtains Compound II per there is hydro-reduction reaction, decarboxylation, amidation under the effect of catalyst B and hydrogen after, and Compound II per acidolysis can obtain Compound I;
In Compound I, II, III, V, R
1for straight chain or the branched-chain alkyl of phenyl, substituted-phenyl, naphthyl, thienyl, furyl, pyridyl, benzofuryl, benzothienyl, quinolyl, C1-C6; Described substituted-phenyl is for containing 1-3 substituent phenyl, and substituting group is selected from fluorine, chlorine, bromine, the straight chain of C1-C6 or branched-chain alkyl, the straight chain of C1-C6 or branched alkoxy, nitro, trifluoromethyl, phenyl;
In compounds Ⅳ, V, R
2for methyl, ethyl, sec.-propyl, n-propyl, butyl, isobutyl-, the tertiary butyl;
Catalyst A has following general structure:
Wherein R
3for hydrogen, allyl group, benzyl, trimethyl silicon based, triethyl is silica-based, benzoyl, ethanoyl or p-toluenesulfonyl;
Described additive is sodium carbonate, salt of wormwood, potassiumphosphate, triethylamine, N, N-diisopropylethylamine, piperidines, 1,4-diazabicylo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene, 4-dimethylamino pyridine, N-Methylimidazole;
Described catalyst B is Raney's nickel, palladium carbon or platinum carbon.
2. the method for synthesis γ-aminobutyric acid class chipal compounds according to claim 1, is characterized in that: catalyst A is 6 '-demethylation Quinidine, 9-O-allyl group-6 '-demethylation Quinidine or 9-benzoyl-6 '-demethylation Quinidine.
3. the method for synthesis γ-aminobutyric acid class chipal compounds according to claim 1, is characterized in that: described solvent is ether, dipropyl ether, Di Iso Propyl Ether, tetrahydrofuran (THF), t-butyl methyl ether, dioxane, methylene dichloride, ethylene dichloride, chloroform, normal hexane, methyl alcohol, ethanol, Virahol, toluene, water.
4. the method for synthesis γ-aminobutyric acid class chipal compounds according to claim 1, is characterized in that: in described conjugate addition reaction, and the mol ratio of nitroolefin and malonic ester is 1:1 ~ 1:5.
5. the method for synthesis γ-aminobutyric acid class chipal compounds according to claim 1, it is characterized in that: in described conjugate addition reaction, the mol ratio of catalyst A and nitroolefin is 1:2 ~ 1:20.
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| WO2019232708A1 (en) * | 2018-06-06 | 2019-12-12 | 浙江华海药业股份有限公司 | Method for preparing pregabalin |
| CN112608267A (en) * | 2020-12-23 | 2021-04-06 | 南京艾斯特医药科技有限公司 | Synthetic method of 4-phenyl-2-pyrrolidone |
| CN116655482A (en) * | 2023-06-05 | 2023-08-29 | 贵州大学 | Preparation method of gamma-aminobutyric acid derivatives |
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| CN101869846A (en) * | 2010-06-18 | 2010-10-27 | 中国科学院上海有机化学研究所 | Catalyst of first category bi-quinine or bi-quinidine, synthesis method and application |
| WO2013189920A1 (en) * | 2012-06-19 | 2013-12-27 | Ucb Pharma S.A. | New compound based on cinchona alkaloïds for use in asymmetric michael addition |
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| DAVID M. BARNES ET AL.: "Development of a Catalytic Enantioselective Conjugate Addition of 1,3-Dicarbonyl Compounds to Nitroalkenes for the Synthesis of Endothelin-A Antagonist ABT-546. Scope,Mechanism, and Further Application to the Synthesis of the Antidepressant Rolipram", 《J. AM. CHEM. SOC.》 * |
Cited By (7)
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| WO2019232708A1 (en) * | 2018-06-06 | 2019-12-12 | 浙江华海药业股份有限公司 | Method for preparing pregabalin |
| US11919835B2 (en) | 2018-06-06 | 2024-03-05 | Zhejiang Huahai Pharmaceutical Co., Ltd | Method for preparing pregabalin |
| CN109315493A (en) * | 2018-11-19 | 2019-02-12 | 徐州工程学院 | A kind of fermentation chickpea milk produces GABA experiment of single factor and response phase method optimization method |
| CN112608267A (en) * | 2020-12-23 | 2021-04-06 | 南京艾斯特医药科技有限公司 | Synthetic method of 4-phenyl-2-pyrrolidone |
| CN112608267B (en) * | 2020-12-23 | 2022-10-25 | 赣州中能实业有限公司 | Synthetic method of 4-phenyl-2-pyrrolidone |
| CN116655482A (en) * | 2023-06-05 | 2023-08-29 | 贵州大学 | Preparation method of gamma-aminobutyric acid derivatives |
| CN116655482B (en) * | 2023-06-05 | 2024-06-04 | 贵州大学 | Preparation method of gamma-aminobutyric acid derivatives |
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| CN104557583B (en) | 2016-06-29 |
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