CN102718695A - Method for synthesizing aza-bicyclo octane [3.3.0] derivatives - Google Patents
Method for synthesizing aza-bicyclo octane [3.3.0] derivatives Download PDFInfo
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- CN102718695A CN102718695A CN2012102118757A CN201210211875A CN102718695A CN 102718695 A CN102718695 A CN 102718695A CN 2012102118757 A CN2012102118757 A CN 2012102118757A CN 201210211875 A CN201210211875 A CN 201210211875A CN 102718695 A CN102718695 A CN 102718695A
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- 238000000034 method Methods 0.000 title abstract description 21
- QUIJMHDIAFOPRK-UHFFFAOYSA-N 1-cyclooctylazocane Chemical compound C1CCCCCCC1N1CCCCCCC1 QUIJMHDIAFOPRK-UHFFFAOYSA-N 0.000 title abstract description 6
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 125000006239 protecting group Chemical group 0.000 claims abstract description 20
- CIFFBTOJCKSRJY-UHFFFAOYSA-N 3α,4,7,7α-tetrahydro-1h-isoindole-1,3(2h)-dione Chemical compound C1C=CCC2C(=O)NC(=O)C21 CIFFBTOJCKSRJY-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 5
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 3
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000003786 synthesis reaction Methods 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- 238000010511 deprotection reaction Methods 0.000 claims description 9
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical class CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 230000002378 acidificating effect Effects 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 238000001308 synthesis method Methods 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
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- 150000003335 secondary amines Chemical class 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 239000000010 aprotic solvent Substances 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 4
- GAKIJEPUVBHWCK-UHFFFAOYSA-N 2-methoxy-2-(3,4,5-trimethoxyphenyl)ethanamine Chemical compound COC(CN)C1=CC(OC)=C(OC)C(OC)=C1 GAKIJEPUVBHWCK-UHFFFAOYSA-N 0.000 claims description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- GQNZGCARKRHPOH-RQIKCTSVSA-N miocamycin Chemical compound C1[C@](OC(C)=O)(C)[C@@H](OC(=O)CC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](OC(=O)CC)CC(=O)O[C@H](C)C/C=C/C=C/[C@H](OC(C)=O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C GQNZGCARKRHPOH-RQIKCTSVSA-N 0.000 claims description 3
- 239000012286 potassium permanganate Substances 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 150000003949 imides Chemical class 0.000 claims description 2
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 claims 2
- 229910010082 LiAlH Inorganic materials 0.000 claims 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims 1
- 230000003647 oxidation Effects 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 3
- 238000006722 reduction reaction Methods 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- 238000004949 mass spectrometry Methods 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000012230 colorless oil Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 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 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 230000008034 disappearance Effects 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 229910010084 LiAlH4 Inorganic materials 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 2
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- KQVNCFJZEZPYOS-UHFFFAOYSA-N O=C(C1C2CC=CC1)N(Cc1ccccc1)C2=O Chemical compound O=C(C1C2CC=CC1)N(Cc1ccccc1)C2=O KQVNCFJZEZPYOS-UHFFFAOYSA-N 0.000 description 1
- WGJFDSIODDVPRB-UHFFFAOYSA-N O=C(N(C1)CC2C1CC=CC2)Cl Chemical compound O=C(N(C1)CC2C1CC=CC2)Cl WGJFDSIODDVPRB-UHFFFAOYSA-N 0.000 description 1
- 238000006647 Pauson-Khand annulation reaction Methods 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- -1 Trimethylsilyl (TMS) Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000001142 dicarboxylic acid group Chemical group 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- GQKZBCPTCWJTAS-UHFFFAOYSA-N methoxymethylbenzene Chemical compound COCC1=CC=CC=C1 GQKZBCPTCWJTAS-UHFFFAOYSA-N 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- LFQULJPVXNYWAG-UHFFFAOYSA-N sodium;phenylmethanolate Chemical compound [Na]OCC1=CC=CC=C1 LFQULJPVXNYWAG-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing aza-bicyclo octane [3.3.0] derivatives shown as a formula (I). 1,2,3,6-tetrahydrophthalimide (V) is used as an initial raw material; and the aza-bicyclo octane [3.3.0] derivatives shown as the formula (I) are obtained by protective group addition, reduction reaction, protective group removing reaction, oxidation reaction and cyclization decarboxylation reaction sequentially. The method is mild in reaction conditions, readily available and cheap in raw materials, simple in synthetic route and high in yield; and the aza-bicyclo octane [3.3.0] derivatives serving as important medicinal intermediates are widely applied to industrialized large-scale production.
Description
Technical Field
The invention belongs to the technical field of organic compound process application, and particularly relates to a synthesis method of an azabicyclo [3.3.0] octane derivative.
Background
Azabicyclo [3.3.0]Octane derivative (aza-bicyclooctane [ 3.3.0)]derivatives) are very important chemical intermediates, and have very high medical application value. Some of the new drugs reported in recent years, such as serine protease dipeptidylpeptidase (DDP-4) inhibitors for the treatment of diabetes (Bioorganic and Medicinal Chemistry Letters,2010,20,3565-]Octane structure. Azabicyclo [3.3.0] s of the prior art]The synthesis method of the octane derivative mainly comprises the following steps: method of producing a composite materialOne is represented by the formula (a) of (7S,8R) -1,4-dioxaspiro [4.4 ]]non-7, 8-dicarboxylic acid dimethyl ester was obtained by blocking reaction with a secondary amine at 190 ℃ for 16 hours (J.org.chem.1989,54,5115-5122 and WO 2004/087142). The method has harsh conditions and is difficult to realize in industrial scale-up production. Another method is that dimethyl 2-allyl-2- (prop-2-ynyl) malonate is cyclized by Pauson-Khand reaction under metal catalysis, and then olefinic bond is reduced, as shown in equation (b) (organic letters,2002,4,3983-2(CO)8Is a potential hazard for catalysts.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a synthetic method of aza-bicyclo [3.3.0] octane derivatives (aza-bicyclo octane [3.3.0] derivatives) with high yield and simple operation, which is suitable for industrial scale production.
The invention provides a synthesis method of an azabicyclo [3.3.0] octane derivative, which is characterized in that 1,2,3, 6-tetrahydrophthalimide of a compound shown in a formula (V) is used as a raw material, and the azabicyclo [3.3.0] octane derivative shown in the formula (I) is obtained by sequentially carrying out protecting group adding, reducing reaction, protecting group removing reaction, oxidizing reaction and cyclization decarboxylation reaction;
the reaction route is as follows:
wherein,
when A is O, R is C1～C8An alkyl substituent of (a), or an aryl group;
when A is N, R is hydrogen, C1～C8An alkyl group, or an aryl group;
PG is Ph3C. Tert-butyl, MOM, BOM, TMS, naphthylmethyl,
Wherein X is H, F, Cl, Br, I, NO2、CH3、CH3CH2、OCH3Or OCH or3CH2。
Wherein, the protecting group reaction is to take 1,2,3, 6-tetrahydrophthalimide of a compound shown in a formula (V) as a raw material to perform a halogenated protecting group reaction under an alkaline condition to generate a compound shown in a formula (IV).
The base used in the protecting group-attaching reaction is K2CO3，KHCO3，KOH，KOMe，KOEt，KOtBu，KOPr，KOiPr，Na2CO3，NaHCO3，NaOH，NaOMe，NaOEt，NaOPr，NaOiPr，NaH，KH，CaH2Pyridine, triethylamine or diisopropylethylamine.
Wherein the reduction reaction is to reduce carbonyl on imide of the compound shown in the formula (IV) into methylene by a reducing agent in an aprotic solvent to generate the compound shown in the formula (III).
The aprotic solvent is tetrahydrofuran, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, benzene, toluene or ethylbenzene.
The reducing agent is LiAlH4。
The high yield of the compound of formula (III) through the deprotection reaction to produce the compound of formula (II) is one of the determinants of the present invention.
Wherein, when PG is Ph3C. When the compound is tert-butyl, methyl ether (MOM), benzyl methyl ether (BOM), Trimethylsilyl (TMS) or naphthylmethyl, the deprotection reaction is to remove the protecting group of the compound shown in the formula (III) under acidic or alkaline conditions to form secondary amine, and then the secondary amine is reacted with haloformate or haloformamide under alkaline conditions to generate the compound shown in the formula (II).
In the compound of formula (III), the N atom of the five-membered ring is connected with a common Protecting Group (PG), the protecting group is removed under acidic or basic conditions, and then a protecting group containing an ester group or an amide group is connected to the N atom, so that the five-membered ring is not damaged when another five-membered ring is constructed.
The alkali used in the deprotection reaction is NaOH, KOH or Na2CO3，K2CO3，NaHCO3Or KHCO3。
The acid used for the deprotection reaction is HCl, HBr and H2SO4，H3PO4，AcOH，CF3COOH or TsOH.
Wherein, when PG isThe deprotection agent reaction is to react a compound shown in a formula (III) with phosgene or triphosgene under the catalysis of catalyst alkali, and then react with corresponding alcohol or amine to generate a compound shown in a formula (II); wherein X is H, F, Cl, Br, I, NO2、CH3、CH3CH2、OCH3Or OCH or3CH2。
When PG is
When the structure of the compound of the formula (III) is shown as the formula (III'). In the formula (III'), X is H, F, Cl, Br, I, NO2、CH3、CH3CH2、OCH3Or OCH or3CH2. The compound of formula (III') reacts with phosgene or triphosgene under the catalysis of catalyst base to generate acyl chloride compound with the structure shown in formula (III "), and then the acyl chloride compound reacts with corresponding alcohol or amine to obtain the compound of formula (II). The reaction is synthesized by a one-pot method, and an intermediate product does not need to be separated, so that the loss caused by operation can be avoided, the efficiency and the yield are improved, and the cost is saved.
The catalyst base is any one of triethylamine, trimethylamine, diisopropylethylamine, diethylamine, dipropylamine, dibutylamine, pyridine or DMAP.
Wherein the oxidation reaction is to oxidize the compound of the formula (II) into a dicarboxylic acid structure by an oxidant; preferably, the oxidizing agent is a strong oxidizing agent. Preferably, the oxidant is H2O2，O3，KMnO4Or K2Cr2O7。
Wherein the cycloddecarboxylation reaction is carried out after the oxidation reaction and is a cycloddecarboxylation in an acidic solvent to produce the compound of formula (I); wherein the acidic solvent is acetic acid, acetic anhydride or propionic acid.
The reaction route of the invention is shown as follows:
the synthesis method has the advantages of mild conditions, easily available and cheap raw materials, simple synthesis route and higher yield, and the product of the compound shown in the formula (I) is used as an important medical intermediate and is widely suitable for industrial mass production. The synthesis method improves the yield of key reaction (reduction reaction with highest cost) of the whole route through protection of the protecting group, and has the advantages of simple impurity removal and cost saving. Without accompanying losses in terms of yield of the final product, but rather increased.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples, but the present invention is not limited to the following examples. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected. The procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited. The data given in the examples below include specific operating and reaction conditions and products. The purity of the product was identified by nuclear magnetism.
Example 1
1,2,3, 6-Tetrahydrophthalimide V (4540.0mg,30.0mmol), K was weighed out2CO3(12440.0mg,90.0mmol), TBAB (970.0mg,3.0mmol) in a 250mL round bottom flask was dissolved by adding 50.0mL DMF. Benzyl chloride (4940.0mg,39.0mmol) was weighed out and added dropwise slowly to the reaction flask with stirring. After the reaction was completed for 5 hours, 50.0mL of water was added to quench the reaction. Then, 100.0mL of ethyl acetate was added for extraction, and after separation, the organic phase was washed with saturated brine (40.0 mL. times.5) and dried over anhydrous sodium sulfate overnight. The sodium sulfate was removed by filtration and the ethyl acetate was removed by rotary evaporation to give a crude white solid. Recrystallization from ethyl acetate/n-hexane gave 5740.0mg of the title compound in 79.3% yield. Mass Spectrometry MS (ESI, m/s): 241.
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.30~7.27(m,5H),5.88~5.87(t,2H),4.62(s,2H),3.10~3.08(t,2H),2.63~2.58(m,2H),2.25~2.19(m,2H)。
Example 2
The procedure is as in example 1. Yield: 81.3% of white solid. Mass Spectrometry MS (ESI, m/s): 393.
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.29~7.04(m,15H),5.84~5.83(t,2H),2.96~2.94(m,2H),2.50~2.46(m,2H),2.11~2.06(m,2H)。
Example 3
A60% NaH (96.0mg) was weighed into a 50mL round bottom flask and freshly distilled THF was added. 1,2,3, 6-Tetrahydrophthalimide V (302.3mg) was weighed out and dissolved in 5.0mL THF and slowly added to the reaction flask until no air bubbles were formed. MOMCl (193.0mg) was slowly added dropwise to the reaction solution, KI (32.2mg) was added thereto, and the reaction was stirred for 3 hours. Adding water to quench and react. Then, ethyl acetate was added thereto for extraction, and after separation, the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. A crude colorless liquid was obtained and column chromatography gave 321.3mg of the title compound in 82.3% yield. Mass Spectrometry MS (ESI, M/s)196(M + H).
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)5.92~5.90(t,2H),4.84(s,2H),3.29(s,2H),3.14~3.13(t,2H),2.66~2.61(m,2H),2.27~2.21(m,2H)。
Example 4
Weighing LiAlH4(380.0mg) in a 100mL two-necked flask with reflux condenser, the nitrogen was purged and 20.0mL of THF was added. Compound IV (a) (1206.5mg) was weighed out and dissolved in 15.0mL of THF, and slowly added dropwise to the flask. After the dropwise addition, the mixture was heated under reflux and the starting material was substantially disappeared by TLC detection. After cooling to room temperature, the reaction was quenched with water, then diluted with additional THF and dried over anhydrous sodium sulfate. A crude product was obtained as a colorless oil. The product is pure enough and is directly put into the next reaction without purification. Mass Spectrometry MS (ESI, M/s):214(M + H).
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.31~7.19(m,5H),5.81~5.80(t,2H),3.60(s,2H),2.93~2.89(m,2H),2.38~2.37(m,2H),2.20~2.11(m,4H),1.87~1.83(d,2H)。
Example 5
The procedure was as in example 4. Yield: 72.3% white solid. Mass Spectrometry MS (ESI, m/s): 365.
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.37~7.10(m,15H),5.52~5.46(t,2H),3.46~2.45(m,2H),2.79~2.70(m,2H),2.23~2.10(m,4H),2.05~1.97(m,2H),1.86~1.79(m,2H)。
Example 6
The procedure was as in example 4. Yield: 83.2% colorless oil. Mass Spectrometry MS (ESI, M/s):138(M + H).
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)5.81~5.79(t,2H),2.87~2.83(m,2H),2.41~2.37(m,2H),2.31(s,2H),2.16~2.10(m,4H),1.86~1.81(m,2H)。
Example 7
Triphosgene (98.0mg) and DMAP (6.1mg) were weighed into a reaction flask, 3.0mL of dichloromethane was added, and the mixture was placed in a ice-salt bath. Then, 4.0mL of a dichloromethane solution of the compound III' (a) was added, and after completion of the dropwise addition, the mixture was reacted at this temperature for 2 hours. TLC monitored the disappearance of starting material. Performing flash column chromatography to obtain 99.6mg of target product. Yield: 54.6% of colorless oily liquid. Mass spectrometry MS (ESI, m/s): 185.
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)5.67~5.61(t,2H),3.67~3.53(m,2H),3.37~3.28(m,2H),2.43~2.23(m,4H),1.93~1.86(m,2H)。
Example 8
Compound III "(18.6 mg) was weighed out and dissolved in 1.0mL of dichloromethane and added to a nitrogen-exchanged test tube reaction tube, and 1.0mL of NaOMe in methanol (0.12 mol/L) was added dropwise slowly to the reaction tube, and a colorless solid formed immediately. After 5h TLC was used to monitor the disappearance of starting material and water was added to quench the reaction. The mixture was extracted with dichloromethane 3 times, and the organic layers were combined and dried over anhydrous sodium sulfate. The crude product was obtained as a colorless oil, which was subjected to column chromatography to give 17.5mg of the objective compound. Yield: 96.6% as colorless oily liquid.
The compound II '(a) can be prepared by adding a methanol solution of sodium methoxide directly to the compound III' (a) without separation after the reaction for preparing the compound III ″. Mass Spectrometry MS (ESI, m/s): 181.
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)5.66~5.61(t,2H),3.68(s,3H),3.49~2.39(m,2H),3.23~3.10(m,2H),2.31~2.19(m,4H),1.92~1.88(m,2H)。
Example 9
The procedure is as in example 8. Yield: 83.2% colorless oil. Mass Spectrometry MS (ESI, m/s): 195.
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)5.63~5.58(t,2H),4.10~4.07(m,2H),3.45~3.37(m,2H),3.19~3.07(m,2H),2.32~2.16(m,4H),1.89~1.84(m,2H),1.24~1.20(t,3H)。
Example 10
The procedure is as in example 8. NaOBn was prepared from BnOH with NaH in THF solution. Yield: 82.3% colorless oil. Mass Spectrometry MS (ESI, m/s): 257.
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.37~7.29(m,5H),5.64(s,2H),5.16~5.09(m,2H),3.50~3.47(m,2H),3.26~3.16(m,2H),2.32~2.20(m,4H),1.93~1.88(m,2H)。
Example 11
Compound III "(18.6 mg) was weighed out and dissolved in 1.0mL of dichloromethane and added to a test tube reaction tube purged with nitrogen, and 0.5mL of 33% dimethylamine in water was slowly added dropwise to the reaction tube. After 5h TLC monitored the disappearance of starting material and 2.0mL of water was added to quench the reaction. Extraction with dichloromethane was performed 3 times, and the organic layers were combined and dried over anhydrous sodium sulfate to give a crude colorless oil. Column chromatography gave 14.6mg of the expected compound II (d). Yield: 75.4% of colorless oily liquid.
The compound II (d) can also be prepared by adding sodium methoxide in methanol solution to react without separation when the compound III '(a) is used to prepare the compound III'. Mass spectrometry MS (ESI, m/s): 194.
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)5.64~5.58(t,2H),3.42~3.38(m,2H),3.16~3.12(m,2H),2.79(s,6H),2.25~2.16(m,4H),1.90~1.86(m,2H)。
Example 12
The procedure is as in example 11. Yield: 80.3% colorless oil. Mass Spectrometry MS (ESI, M/s):223(M + H).
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)5.67~5.60(t,2H),3.43~3.39(m,2H),3.21~3.11(m,6H),2.29~2.18(m,4H),1.91~1.87(m,2H),1.12~1.09(t,6H)。
Example 13
The procedure is as in example 11. Yield: 79.4% colorless oil. Mass Spectrometry MS (ESI, m/s): 278.
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)5.66~5.59(t,2H),3.41~3.37(m,2H),3.15~3.09(m,6H),2.28~2.17(m,4H),1.90~1.86(m,2H),1.50~1.44(m,4H),1.29~1.24(m,4H),0.91~0.87(t,6H)。
Example 14
The procedure is as in example 11. Yield: 65.3% colorless oil. Mass spectrometry MS (ESI, M/s):255 (M-H).
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.33~7.27(m,5H),5.67~5.61(t,2H),4.44(s,2H),3.42~3.41(m,2H),3.18~3.17(m,2H),2.37~2.21(m,4H),1.94~1.89(m,2H)。
Example 15
Compound V (302.3mg) was weighed into a 50mL two-necked flask with a reflux condenser, purged with nitrogen, and added with 8.0mL of triethylamine. TMSCl (434.6mg) was added slowly dropwise with a syringe and a large amount of solid formed immediately. Heating to 90 deg.C, reacting for 4 hr, adding n-hexane, and rapidly filtering. The filtrate was removed by rotary evaporation to give 450.0mg of crude product.
Weighing LiAlH4(152.0mg,) in a 50.0mL neck flask, 10.0mL of freshly distilled THF was added, and the 450.0mg of crude product from the previous step was diluted with 3.0mL of THF and added dropwise to the flask, which was then heated to reflux for 5 hours. Cooled to room temperature and 10.0mL THF/H was added2The reaction was quenched with a mixture of O (10:1), dried over anhydrous sodium sulfate. Adding K into the filtrate2CO3(276.4mg), CbzCl (375.0mg) was slowly added dropwise thereto, and the reaction was stirred for 2 hours to substantially complete the reaction. The reaction solution was rotary-drained, 20.0mL of water was added, extraction was performed 4 times with ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and column chromatography was performed to obtain 255.0mg of the objective compound ii (c). Yield: 49.6 percent.
Example 16
Compound II (a), (158.7mg) and TBAB (28.0mg) were weighed into a 50mL single-necked flask, dissolved in 10.0mL of dichloromethane, and slowly added dropwise to 10.0mL of KMnO4(415.2mg,2.63mmol) of aqueous solution. The reaction was stirred at room temperature for 2 hours and TLC monitored for disappearance of starting material. 1200.0mg of sodium sulfite and 1.0mL of concentrated hydrochloric acid were added to the reaction mixture, and after rotary evaporation of methylene chloride obtained in the reaction mixture, the mixture was extracted with ethyl acetate 4 times. The ethyl acetate were combined and dried over anhydrous sodium sulfate to give 199.2mg of a crude white foamy solid. Directly putting into the next reaction.
Sodium acetate (107.8mg) was weighed into the above crude product, 4.0mL of acetic anhydride was added, and the reaction was completed by heating to 120 ℃ for 2 hours. After cooling to room temperature, 10.0mL of water was added and solid sodium carbonate was added in portions. Extraction with dichloromethane, combination of organic layers, drying over anhydrous sodium sulfate, column chromatography gave 108.5mg of the desired product. Yield: 67.7% as a colorless oily liquid. Mass Spectrometry MS (ESI, m/s): 183.
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)3.63~3.58(m,5H),3.25~3.14(m,2H),2.89~2.85(m,2H),2.46~2.39(m,2H),2.20~2.06(m,2H)。
Example 17
The operation is the same as in example 16. Yield 72.7%, colorless oily liquid. Mass Spectrometry MS (ESI, M/s):198(M + H).
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)4.14~4.08(q,2H),3.72~3.64(m,2H),3.30~3.18(m,2H),2.93~2.92(m,2H),2.51~2.44(m,2H),2.17~2.11(m,2H),1.26～1.22(t,3H)。
Example 18
The procedure is as in example 16. Yield 70.0%, light color solid. Mass spectrometry MS (ESI, m/s): 259.
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)7.37~7.30(m,5H),5.13(s,2H),3.77~3.71(m,2H),3.35~3.25(m,2H),2.96.~2.94(m,2H),2.53~2.47(m,2H),2.19~2.13(m,2H)。
Example 19
The procedure is as in example 16. Yield 56.3%, colorless liquid. Mass Spectrometry MS (ESI, m/s): 196.
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)3.71~3.66(m,2H),3.28~3.23(m,2H),3.06~2.88(m,4H),2.83(s,6H),2.51~2.44(m,2H),2.19~2.13(m,2H)。
Example 20
The procedure is as in example 16. Yield 59.0%, colorless liquid. Mass Spectrometry MS (ESI, M/s):225(M + H).
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)3.68~3.64(d,2H),3.23~3.15(m,6H),2.94~2.85(m,2H),2.50~2.44(m,2H),2.17~2.11(m,2H),1.12~1.09(t,6H)。
Example 21
The procedure is as in example 16. Yield 61.6% as colorless liquid. Mass Spectrometry MS (ESI, M/s):281(M + H).
1H-NMR(CDCl3/TMS,400MHz):δ(ppm)3.67~3.63(d,2H),3.23~3.20(m,2H),3.14~3.10(t,4H),2.94~2.85(m,2H),2.51~2.44(m,2H),2.17~2.11(m,2H),1.52~1.45(m,4H),1.32~1.22(m,4H),0.92~0.88(t,6H)。
Claims (12)
1. A synthesis method of an azabicyclo [3.3.0] octane derivative is characterized in that 1,2,3, 6-tetrahydrophthalimide of a compound shown in a formula (V) is used as a raw material, and the azabicyclo [3.3.0] octane derivative shown in the formula (I) is obtained by sequentially carrying out protecting group adding, reducing reaction, protecting group removing reaction, oxidizing reaction and cyclization decarboxylation reaction;
the reaction route is as follows:
wherein,
when A is O, R is C1～C8An alkyl substituent of (a), or an aryl group;
when A is N, R is hydrogen, C1～C8An alkyl group, or an aryl group;
PG is Ph3C. Tert-butyl, MOM, BOM, TMS, naphthylmethyl,
Wherein X is H, F, Cl, Br, I, NO2、CH3、CH3CH2、OCH3Or OCH or3CH2。
2. The synthesis of claim 1, wherein the protecting group-up reaction is a reaction of the compound of formula (V) with a halogenated protecting group under basic conditions to produce the compound of formula (IV).
3. The synthesis reaction of claim 2, wherein the base used in the protecting group-up reaction is K2CO3，KHCO3，KOH，KOMe，KOEt，KOtBu，KOPr，KOiPr，Na2CO3，NaHCO3，NaOH，NaOMe，NaOEt，NaOPr，NaOiPr，NaH，KH，CaH2Pyridine, triethylamine or diisopropylethylamine.
4. The synthesis reaction of claim 1, wherein the reduction is a reduction of the carbonyl group on the imide of the compound of formula (IV) to a methylene group with a reducing agent in an aprotic solvent to produce the compound of formula (III).
5. A synthesis reaction according to claim 4, characterised in that the aprotic solvent is tetrahydrofuran, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, benzene, toluene or ethylbenzene; the reducing agent is LiAlH 4.
6. A synthesis reaction according to claim 1, characterised in that when PG is Ph3C. When the compound is tert-butyl, MOM, BOM, TMS or naphthylmethyl, the deprotection reaction is to remove the protecting group of the compound in the formula (III) under acidic or alkaline conditions to obtain secondary amine, and then the secondary amine is reacted with haloformate or haloformamide under alkaline conditions to generate the compound in the formula (II).
7. The synthesis reaction of claim 6, wherein the base used in the deprotection reaction is NaOH, KOH, Na2CO3，K2CO3，NaHCO3Or KHCO3。
8. The synthesis reaction of claim 6, wherein the acid used for the deprotection reaction is HCl, HBr, H2SO4，H3PO4，AcOH，CF3COOH or TsOH.
9. A synthesis reaction according to claim 1, characterised in that when PG is
The deprotection reaction is to react a compound shown in a formula (III) with phosgene or triphosgene under the catalysis of alkali and then react with corresponding alcohol or amine to obtain a compound with a structural general formula (II); wherein X is the same as X is H, F, Cl, Br, I, NO2、CH3、CH3CH2、OCH3Or OCH or3CH2。
10. The synthesis reaction of claim 9, wherein the catalyst base is any one of triethylamine, trimethylamine, diisopropylethylamine, diethylamine, dipropylamine, dibutylamine, pyridine or DMAP.
11. The synthesis reaction of claim 9, wherein the oxidation reaction is oxidation of the compound of formula (II) to a dicarboxylic acid via an oxidizing agent; wherein the oxidant is H2O2，O3，KMnO4Or K2Cr2O7。
12. The synthesis reaction of claim 1, wherein the cycloddecarboxylation reaction is a cycloddecarboxylation in an acidic solvent to produce a compound of formula (I); wherein the acidic solvent is acetic acid, acetic anhydride or propionic acid.
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