CN1041627C - (s)-2,2,2-三氯-n-(2-氯环己-2-烯基)-乙酰胺和(s)-2-氯环己-2-烯胺 - Google Patents
(s)-2,2,2-三氯-n-(2-氯环己-2-烯基)-乙酰胺和(s)-2-氯环己-2-烯胺 Download PDFInfo
- Publication number
- CN1041627C CN1041627C CN94194207A CN94194207A CN1041627C CN 1041627 C CN1041627 C CN 1041627C CN 94194207 A CN94194207 A CN 94194207A CN 94194207 A CN94194207 A CN 94194207A CN 1041627 C CN1041627 C CN 1041627C
- Authority
- CN
- China
- Prior art keywords
- oxo
- acid
- dioxo
- dihydro
- pyridine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title description 14
- 239000000460 chlorine Substances 0.000 claims description 51
- 229910052801 chlorine Inorganic materials 0.000 claims description 51
- 150000001875 compounds Chemical class 0.000 claims description 28
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 24
- -1 1-oxo-2(S)-acetylthio-3-phenylpropyl Chemical group 0.000 abstract description 19
- 150000003839 salts Chemical class 0.000 abstract description 13
- 239000000543 intermediate Substances 0.000 abstract description 11
- 238000002360 preparation method Methods 0.000 abstract description 10
- 102000003729 Neprilysin Human genes 0.000 abstract description 3
- 108090000028 Neprilysin Proteins 0.000 abstract description 3
- 239000003112 inhibitor Substances 0.000 abstract description 3
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 abstract 1
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 abstract 1
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 55
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 48
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 44
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 239000000047 product Substances 0.000 description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 26
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 19
- 238000000605 extraction Methods 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 239000002253 acid Substances 0.000 description 15
- 235000010290 biphenyl Nutrition 0.000 description 15
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- 238000007738 vacuum evaporation Methods 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 238000001953 recrystallisation Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000003513 alkali Substances 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 229960005190 phenylalanine Drugs 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000003638 chemical reducing agent Substances 0.000 description 6
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 150000004702 methyl esters Chemical class 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 4
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 208000032825 Ring chromosome 2 syndrome Diseases 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 229910000085 borane Inorganic materials 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 150000001261 hydroxy acids Chemical class 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000003797 solvolysis reaction Methods 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- KSILMCDYDAKOJD-UHFFFAOYSA-N 2-aminoisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(N)C(=O)C2=C1 KSILMCDYDAKOJD-UHFFFAOYSA-N 0.000 description 2
- PMNLUUOXGOOLSP-UHFFFAOYSA-N 2-mercaptopropanoic acid Chemical compound CC(S)C(O)=O PMNLUUOXGOOLSP-UHFFFAOYSA-N 0.000 description 2
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 2
- VYIBCOSBNVFEIW-UHFFFAOYSA-N 3-phenylpropanamide Chemical compound NC(=O)CCC1=CC=CC=C1 VYIBCOSBNVFEIW-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 108090000279 Peptidyltransferases Proteins 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- ATBZEYWJVINAKW-UHFFFAOYSA-N [B].O1C=NC=C1 Chemical compound [B].O1C=NC=C1 ATBZEYWJVINAKW-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 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 description 2
- 239000000376 reactant Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000011916 stereoselective reduction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000003809 water extraction Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- NQBWNECTZUOWID-UHFFFAOYSA-N (E)-cinnamyl (E)-cinnamate Natural products C=1C=CC=CC=1C=CC(=O)OCC=CC1=CC=CC=C1 NQBWNECTZUOWID-UHFFFAOYSA-N 0.000 description 1
- VOXXWSYKYCBWHO-QMMMGPOBSA-N (S)-3-phenyllactic acid Chemical compound OC(=O)[C@@H](O)CC1=CC=CC=C1 VOXXWSYKYCBWHO-QMMMGPOBSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- PKRSYEPBQPFNRB-UHFFFAOYSA-N 2-phenoxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1OC1=CC=CC=C1 PKRSYEPBQPFNRB-UHFFFAOYSA-N 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 1
- VOXXWSYKYCBWHO-UHFFFAOYSA-N HO-Phe-OH Natural products OC(=O)C(O)CC1=CC=CC=C1 VOXXWSYKYCBWHO-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 229910001038 basic metal oxide Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- NQBWNECTZUOWID-QSYVVUFSSA-N cinnamyl cinnamate Chemical compound C=1C=CC=CC=1\C=C/C(=O)OC\C=C\C1=CC=CC=C1 NQBWNECTZUOWID-QSYVVUFSSA-N 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006392 deoxygenation reaction Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical compound C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- ZILHAPDUURXFDN-UHFFFAOYSA-N ethyl 2-ethyl-2h-quinoline-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OCC)C(CC)C=CC2=C1 ZILHAPDUURXFDN-UHFFFAOYSA-N 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ketene group Chemical group C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
- C07C211/40—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing only non-condensed rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
- C07C233/14—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本发明涉及(S)-1-[2(S)-(1,3-二氢-1,3-二氧代-异吲哚-2-基)-1-氧代-3-苯基丙基]-1,2,3,4-四氢-2-吡啶甲酸甲酯的立体有择制备方法,所述化合物是制备[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(S)-硫代-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1-a][2]苯并吖庚因-4-甲酸和[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(S)-乙酰硫代-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1-a][2]苯并吖庚因-4-甲酸及其可药用盐的中间体,后者适于用作脑啡肽酶和血管紧张肽转移酶的抑制剂;本发明还涉及制备该化合物的新中间体(S)-2,2,2-三氯-N-(2-氯环己-2-烯基)-乙酰胺和(S)-2-氯环己-2-烯胺。
Description
本发明涉及(S)-1-[2(S)-(1,3-二氢-1,3-二氧代-异吲哚-2-基)-1-氧代-3-苯基丙基]-1,2,3,4-四氢-2-吡啶甲酸甲酯的新的制备方法,所述化合物是制备[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(S)-硫代-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1-a][2]苯并吖庚因-4-甲酸和[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(S)-乙酰硫代-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1-a][2]苯并吖庚因-4-甲酸及其可药用盐的有用的中间体,后者适于用作脑啡肽酶和血管紧张肽转移酶的抑制剂[EP 0 481 522A1,1992年4月22日公开],本发明还涉及所制备化合物的新的中间体。
本发明的方法和中间体为制备(S)-1-[2(S)-(1,3-二氢-1,3-二氧代-异吲哚-2-基)-1-氧代-3-苯基丙基]-1,2,3,4-四氢-2-吡啶甲酸甲酯提供了新的对映特征方法。
本发明提供了(S)-1-[2(S)-(1,3-二氢-1,3-二氧代-异吲哚-2-基)-1-氧代-3-苯基丙基]-1,2,3,4-四氢-2-吡啶甲酸甲酯的新的制备方法,该方法包括下列步骤:
(a)将环己酮依次与合适的氯化剂和合适的碱反应,得到2-氯环己-2-烯-1-酮;
(b)将2-氯环己-2-烯-1-酮与合适的手性助剂和合适的还原剂反应,得到(R)-2-氯环己-2-烯醇;
(c)将(R)-2-氯环己-2-烯醇与三氯乙腈反应,得到(R)-2,2,2-三氯-1-(2-氯环己-2-烯基氧基)-亚乙基胺;
(d)将(R)-2,2,2-三氯-1-(2-氯环己-2-烯基氧基)-亚乙基胺加热反应,得到(S)-2,2,2-三氯-N-(2-氯环已-2-烯基)-乙酰胺;
(e)将(S)-2,2,2-三氯-N-(2-氯环己-2-烯基)-乙酰胺与合适的溶剂分解试剂反应,得到(S)-2-氯环己-2-烯胺;
(f)将(S)-2-氯环已-2-烯胺与邻苯二甲酰亚氨基-L-苯丙氨酸衍生物反应,得到(S)-N-(2-氯环己-2-烯基)-2-[2(S)-1,3-二氢-1,3-二氧代-异吲哚-2-基)-3-苯基-丙酰胺;
(g)在甲醇存在下,将(S)-N-(2-氯环己-2-烯基)-2-[2(S)-1,3-二氢-1,3-二氧代-异吲哚-2-基)-3-苯基-丙酰胺与臭氧反应,经还原处理后,得到N-[2(S)-[(6-氧代)-己酸甲酯]]-2-[2(S)-1,3-二氢-1,3-二氧代-异吲哚-2-基)-3-苯基-丙酰胺甲酯;
(h)将N-[2(S)-[(6-氧代)-己酸甲酯]]-2-[2(S)-1,3-二氢-1,3-二氧代-异吲哚-2-基)-3-苯基-丙酰胺与合适的环化酸反应。
其中R是氢或三氯乙酰基。
术话“可药用酸加成盐”是指适用于任何[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(S)-硫代-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,l-a][2]苯并吖庚因-4-甲酸或[4S-[4α,7α(R*),12b β]]-7-[(1-氧代-2(S)-乙酰硫代-3-苯基丙基)氨基]-l,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1-a][2]苯并吖庚因-4-甲酸或任何其中间体的无毒有机或无机酸加成盐。形成合适的盐的典型的无机酸包括盐酸、氢溴酸、硫酸和磷酸以及酸式金属盐例如正磷酸一氢钠和硫酸氢钾。形成合适的盐的典型的有机酸包括一元羟酸、二元羟酸和三元羟酸。典型的这些酸是例如乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、羟墓马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水扬酸、2-苯氧基苯甲酸和磺酸例如对甲苯磺酸、甲磺酸和2-羟基乙磺酸。这些盐可以以水合物或基本无水的形式存在。
术语“可药用的碱加成盐”是指适用于任何[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(S)-硫代-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1-a][2]苯并吖庚因-4-甲酸或[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(S)-乙酰硫代-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1-a][2]苯并吖庚因-4-甲酸或任何其中间体的无毒有机或无机碱加成盐。形成合适的盐的典型的碱包括碱金属或碱土金属氢氧化物,例如氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁、或氢氧化钡;氨和脂族胺、环胺或芳族有机胺,例如甲胺、二甲胺、三甲胺、三乙胺、二乙胺、异丙基二乙胺、吡啶和甲基吡啶。
正如本领域的普通专业人员所如,本申请所公开的方法可用于制备(S)-1-[2(S)-(1,3-二氢-1,3-二氧代-异吲哚-2-基)-1-氧代-3-苯基丙基]-1,2,3,4-四氢-2-吡啶甲酸甲酯的所有对映体和所有的非对映体,从而由其产生脑啡肽酶和血管紧张肽转移酶的对映体和非对映体的抑制剂。由本发明形成的(S)-1-[2(S)-(1,3-二氢-1,3-二氧代-异吲哚-2-基)-1-氧代-3-苯基丙基]-1,2,3,4-四氢-2-吡啶甲酸甲酯的立体异构体取决于2-氯-环己-2-烯胺的立体化学和邻苯二甲酰氨基-苯丙氨酸衍生物的立体化学。
一般合成方法列于反应方案A中。在反应方案A中,除非另外指明,所有的取代基均如前所述。反应方案A所用的原料、试剂、技术和方法均是本领域普通专业人员公知的和显而易见的。
在反应方案A步骤a中,将环己酮依次与合适的氯化剂和合适的碱反应,得到2-氯环己-2-烯-1-酮。
合适的氯化剂是可以提供所需的2,3-二氯环己-1-酮中间体,而不致使过氯化产物的量过分升高的化合物。2,3-二氯环己-1-酮是该技术步骤a所需的中间体。本发明不受该技术建议的2,3-二氯环己-1-酮作为步骤a的中间体的的限制。
合适的碱是有助于消去3-位氯而不形成亲核反应副产物的化合物。
例如,将环己酮与等摩尔量的合适的氯化剂反应。反应在合适的溶剂例如二氯甲烷中进行。在氯化过程中使用位阻碱例如2,6-二甲基吡啶有利于防止过氧化产物的形成。该反应在-40℃至20℃、优选-5℃至0℃的温度下进行。通过本领域公知的萃取和蒸发,可以将产物从反应区中分离。产物可以采用本领域公知的技术例如色谱和重结晶进行纯化。
在反应方案A步骤b中,将2-氯环己-2-烯-1-酮与合适的手性助剂和合适的还原剂反应,得到(R)-2-氯环己-2-烯醇。
合适的手性助剂是使2-氯环己-2-烯-1-酮立体有择还原的化合物。
合适的还原剂是参与与合适的手性助剂形成手性配合物,从而产生立体选择性还原产物的化合物。合适的还原剂是本领域公知的,并且包括但不限于硼烷四氢呋喃配合物和硼烷二甲硫醚配合物,优选硼烷二甲硫醚配合物。
例如,将2-氯环己-2-烯-1-酮与分数摩尔量的合适的手性助剂(例如(S)-四氢-1-甲基-3,3-二苯基-1H,3H-吡咯并[1,2C][1,3,2]噁唑硼[D.J.Mathre等,J.Org.Chem.56,751-762(1991)])和略微摩尔过量的合适的还原剂反应。合适的手性助剂的量取决于所用的手性助剂,其范围在0.05-0.5摩尔当量。该反应在不使烯酮官能团过分还原并且使手性助剂配合物对映选择还原的温度下进行。反应在合适的溶剂例如四氢呋喃或乙醚中进行。通过用质子传递溶剂例如甲醇终止反应并进行萃取可以将产物从反应区中分离。该产物无需进一步纯化即可使用,或者可以采用本领域公知的方法例如色谱和重结晶纯化该产物。
在反应方案A步骤c中,将(R)-2-氯环己-2-烯醇与三氯乙腈反应,得到(R)-2,2,2-三氯-1-(2-氯环己-2-烯基氧基)-亚乙基胺。
例如,将(R)-2-氯环己-2-烯醇与摩尔过量的三氯乙腈反应。该反应在催化量的碱例如氢化钠存在下进行。催化量在0.05至0.20摩尔当量的范围内变化。该反应在合适的溶剂例如四氢呋喃或乙醚存在下进行。反应在-20℃至20℃的温度范围内进行,优选0℃。通过蒸发或萃取从反应区中分离产物,并且该产物无需进一步纯化即可使用,或者可以采用本领域公知的方法例如色谱和重结晶纯化该产物。
在反应方案A步骤d中,将(R)-2,2,2-三氯-1-(2-氯环己-2-烯基氧基)-亚乙基胺加热,得到(S)-2,2,2-三氯-N-(2-氯环己-2-烯基)-乙酰胺。
例如,将(R)-2,2,2-三氯-1-(2-氯环己-2-烯基氧基)-亚乙基胺在130℃至150℃的温度下加热。反应在合适的溶剂例如氯苯中进行。通过蒸发或萃取从反应区中分离产物,并且可以采用本领域公知的方法例如色谱和重结晶纯化该产物。
在反应方案A步骤e中,用合适的溶剂分解试剂处理(S)-2,2,2-三氯-N-(2-氯环己-2-烯基)-乙酰胺,得到(S)-2-氯环己-2-烯胺。
合适的溶剂分解试剂是本领域公知的,例如甲醇、乙醇和水。例如,将(S)-2,2,2-三氯-N-(2-氯环己-2-烯基)-乙酰胺与水反应,得到(S)-2-氯环己-2-烯胺。该反应可以在合适的溶剂例如乙醇、甲醇、水、甲醇/水混合物或乙醇/水混合物中进行。通过加入合适的碱例如碳酸钾可以促进该反应。该反应在50℃至90℃的温度下进行,优选70℃。产物可以直接使用。当使用甲醇/水混合物或乙醇/水混合物时,在除去醇溶剂后产物可以直接使用。通过蒸发或萃取从反应区中分离产物,并且该产物无需进一步纯化即可使用,或者可以采用本领域公知的方法例如色谱和成盐以及重结晶纯化该产物。
在反应方案A步骤f中,将(S)-2-氯环己-2-烯胺与合适的邻苯二甲酰亚氨基-L-苯丙氨酸衍生物反应,得到(S)-N-(2-氯环已-2-烯基)-2-[2(S)-1,3-二氢-1,3-二氧代-异吲哚-2-基)-3-苯基丙酰胺。
合适的邻苯二甲酰亚氨基-L-苯丙氨酸衍生物是指转移邻苯二甲酰氨基-L-苯丙氨酸基团的化合物,例如邻苯二甲酰氨基-L-苯丙氨酸、邻苯二甲酰亚氨基-L-苯丙氨酸酐、邻苯二甲酰亚氨基-L-苯丙氨酸混合酸酐、邻苯二甲酰亚氨基-L-苯丙氨酰氯或邻苯二甲酰氨基-L-苯丙氨酸N-羟基琥珀酰亚胺。
例如,将(S)-2-氯环己-2-烯胺与合适的邻苯二甲酰亚氨基-L-苯丙氨酸衍生物反应。邻苯二甲酰亚氨基-L苯丙氨酸的反应是在有助于酸和胺偶合的试剂存在下进行的,这种试剂的例子是1,3-二环己基碳化二亚胺或2-乙基-1-乙氧基羰基-1,2-二氢喹啉。当合适的邻苯二甲酰亚氨基-L-苯丙氨酸衍生物是邻苯二甲酰亚氨基-L-苯丙氨酸时,该反应在有助于酸与胺偶合的试剂例如1,3-二环己基碳化二亚胺或2-乙基-1-乙氧羰基-1,2-二氢喹啉存在下进行。当合适的邻苯二甲酰亚氨基-L-苯丙氨酸衍生物是邻苯二甲酰亚氨基-L-苯丙氨酸酐、邻苯二甲酰亚氨基-L-苯丙氨酸混合酸酐、邻苯二甲酰亚氨基-L-苯丙氨酰氯或邻苯二甲酰亚氨基-L-苯丙氨酸N-羟基琥珀酰亚胺时,该反应在碱例如碳酸钠、碳酸钾、三乙胺或碳酸氢钾存在下进行,以中和反应过程中释放出的酸。该反应在合适的溶剂例如水、四氢呋喃、乙酸乙酯或乙酸乙酯/水的混合物中进行。反应在-20℃至40℃的温度下进行,优选0℃。通过本领域公知的萃取和蒸发,可以将产物从反应区中分离。产物可以采用本领域公知的技术例如色谱和重结晶进行纯化。
在反应方案A步骤g中,在甲醇存在下,将(S)-N-(2-氯环己-2-烯基)-2-[2(S)-1,3-二氢-1,3-二氧代-异吲哚-2-基)-3-苯基-丙酰胺与臭氧反应,经还原处理后,得到N-[2(S)-[(6-氧代)-己酸甲酯]]-2-[2(S)-1,3-二氢-1,3-二氧代-异吲哚-2-基)-3-苯基-丙酰胺甲酯。
例如,在甲醇存在下,将(S)-N-(2-氯环己-2-烯基)-2-[2(S)-1,3-二氢-1,3-二氧代-异吲哚-2-基)-3-苯基-丙酰胺与臭氧反应。该反应在合适溶剂例如二氯甲烷中进行。反应在-100℃至-60℃温度下进行,优选-70℃。通过加入合适的还原剂例如三丁基膦或二甲硫使反应物进行还原处理。通过萃取可以将产物从反应区中分离,并且该产物无需进一步纯化即可使用。该产物可以采用本领域公知的技术例如色谱和重结晶进行纯化。
在反应方案A步骤h中,将N-[2(S)-[(6-氧代)-己酸甲酯]]-2-[2(S)-1,3-二氢-1,3-二氧代-异吲哚-2-基)-3-苯基-丙酰胺与合适的环化酸反应,得到(S)-1-[2(S)-(1,3-二氢-1,3-二氧代-异吲哚-2-基)-1-氧代-3-苯基丙基]-1,2,3,4-四氢-2-吡啶甲酸甲酯。
例如,将N-[2(S)-[(6-氧代)-己酸甲酯]]-2-[2(S)-1,3-二氢-1,3-二氧代-异吲哚-2-基)-3-苯基-丙酰胺与合适的环化酸例如三氟乙酸反应。该反应在合适的非质于传递溶剂例如二氯甲烷中进行。反应在溶剂的回流温度下进行。该反应可以以如下的方式进行,即在干燥过程中形成回流物(refluxate),例如使用迪安-斯榻克分水器,或者使回流物通过3埃或4埃的分子筛床。可以通过蒸发分离产物,并且可以采用本领域公知的技术例如色谱或重结晶纯化该产物。
下列实施例说明了反应方案A所述的典型合成方法。应该理解,这些实施例仅仅用于说明,而非以任何方式限制本发明的范围。下列实施例中所用的下列术语含义如下:“g”指克,“mg”指毫克,“mmol”指毫摩尔,“mL”指毫升,“μL”指微升,“℃”指摄氏度,“Rf”指保留因子,“mp”指熔点,“dec”指分解,“[α]2D0”指在1分米池中得到的在20℃钠D线的比旋光度,“c”指浓度,“M”指摩尔,“L”指升,“MeOH”指甲醇,“2-PrOH”指异丙醇,“DIAD”指二异丙基偶氮二甲酸,“TLC”指薄层色谱。
实施例1反应方案A步骤a:2-氯环己酮
将环己酮(19.2g,200mmol)与二氯甲烷(75ml)混合。在惰性气氛下放置。将溶液冷却至-10℃。制备硫酰氯(17.0mL,200mmol)在二氯甲烷(30ml)中的溶液。向上述冷却的溶液中加入3毫升硫酰氯溶液。加入2,6-二甲基吡啶(1.0mL,10mmol)。以保持反应混合物的温度为-10℃至0℃的速度加入剩余的硫酰氯溶液。在硫酰氯加完后,在-10℃搅拌15分钟。加入在二氯甲烷(20mL)中的三乙胺(30mL,215mmol),同时保持反应混合物的温度低于0℃。温热至0℃并搅拌30分钟。用二氯甲烷(200mL)稀释,并用10%盐酸溶液、饱和碳酸氢钠溶液和饱和氯化钠溶液萃取。用MgSO4干燥分离的有机层,过滤并真空蒸发,得到固体。该固体从己烷中重结晶,得到固体状标题化合物:熔点70-72℃。
实施例2反应方案A步骤b:(R)-2-氯环己-2-烯醇
在四氢呋喃(150mL)中将2-氯环己酮(20.77g,160mmol)和(S)-四氢-1-甲基-3,3-二苯基-1H,3H-吡咯并[1,2C][1,3,2]噁唑硼(13mmol)[按照D.J.Mathre等,J.Org.Chem.56,751-762(1991)的方法制备]混合。冷却至5℃,用30分钟加入硼烷二甲硫配合物(50mL,2M,在四氢呋喃中,100mmol)。在-5℃搅拌该溶液3小时。加入甲醇(5mL)并搅拌,直到气体发生停止。加入甲醇(100mL)并在室温搅拌12小时。残余物在二氯甲烷和10%盐酸溶液之间分配。分离有机层,用饱和碳酸氢钠萃取。用MgSO4干燥分离的有机层,过滤并真空蒸发,得到油状标题化合物,该化合物无需进一步纯化即可使用。
实施例3反应方案A步骤c:(R)-2,2,2-三氯-1-(2-氯环已-2-烯基氧基)-亚乙基胺
将氢化钠(0.50g,60%,在油中,12mmol)与乙醚(50mL)混合,并冷却至0℃。用15分钟加入(R)-2-氯环己-2-烯醇(23.0g,160mmol)在乙醚(40mL)中的溶液。搅拌,直到气体发生停止。加入三氯乙腈(20mL,200mmol)在乙醚(30mL)中的溶液。在0℃搅拌30分钟,然后用1.5小时温热至室温。将反应混合物真空蒸发,得到标题化合物。
实施例4反应方案A步骤d:(S)-2,2,2-三氯-N-(2-氯环己-2-烯基)-乙酰胺
将上述得到的(R)-2,2,2-三氯-1-(2-氯环己-2-烯基氧基)-亚乙基胺与氯苯(200mL)混合,并加热至140℃。8小时后,真空蒸发得到残余物。在硅胶上进行色谱,依次用30%二氯甲烷/己烷、50%二氯甲烷/己烷、70%二氯甲烷/己烷和二氯甲烷洗脱。蒸发含有产物的馏分,得到固体。将该固体从二氯甲烷/己烷中重结晶,得到固体状标题化合物:熔点78-79℃。比旋光度[α]2D0=-77.30°(c=0.920,CHCl3)。
实施例5反应方案A步骤e:(S)-2-氯环己-2-烯胺
在1/1水/甲醇(40mL)中,将(S)-2,2,2-三氯-N-(2-氯环己-2-烯基)-乙酰胺(5.55g,20mmol)与碳酸钾(5.60g,40mmol)混合。在70℃搅拌48小时。真空除去甲醇,得到标题化合物的水溶液。
实施例6反应方案A步骤f:(S)-N-(2-氯环己-2-烯基)-2-[2(S)-1,3-二氢-1,3-二氧代-异吲哚-2-基)-3-苯基-丙酰胺
将上述得到的(S)-2-氯环已-2-烯胺的水溶液冷却至0℃。加入邻苯二甲酰氨基-L-苯丙氨酰氯(23mL,27%,在乙酸乙酯中,20.5mmol)。用1小时温热至室温。将反应混合物倒入二氯甲烷中,并用1M盐酸和饱和碳酸氢钠萃取。分离有机层,用MgSO4干燥,过滤并真空蒸发,得到固体。从二氯甲烷/己烷中重结晶,得到固体状标题化合物:熔点189-190℃。比旋光度[α]2D0=-147.30°(c=0.983,CHCl3)。元素分析C23H20ClN2O3,计算值:C,67.56;H,5.81;N.6.85。实测值:C,67.68;H,5.13;N,6.83。
实施例7反应方案A步骤g:N-[2(S)-[(6-氧代)-已酸甲酯]]-2-[2(S)-1,3-二氢-1,3-二氧代-异吲哚-2-基)-3-苯基-丙酰胺甲酯
将在二氯甲烷(30mL)中的(S)-N-(2-氯环己-2-烯基)-2-[2(S)-1,3-二氢-1,3-二氧代-异吲哚-2-基)-3-苯基-丙酰胺(0.818g,2.0mmol)与甲醇(20mL)混合。将该溶液冷却至-78℃。使臭氧气流通过该溶液,直到获得持久稳固的蓝色溶液。向该溶液中通入氮气流直到该溶液无色。加入三丁基膦(1.05mL,4.0mmol)并在-70℃搅拌30分钟。温热至室温并搅拌5小时。真空蒸发,得到无色油状标题化合物。
实施例8反应方案A步骤h:(S)-1-[2(S)-(1,3-二氢-1,3-二氧代-异吲哚-2-基)-1-氧代-3-苯基丙基]-1,2,3,4-四氢-2-吡啶甲酸甲酯
将上述得到的无色油状N-[2(S)-[(6-氧代)-己酸甲酯]]-2-[2(S)-1,3-二氢-1,3-二氧代-异吲哚-2-基)-3-苯基-丙酰胺甲酯、二氯甲烷(70mL)和三氟乙酸(200μL)混合。加热至回流,使用迪安-斯榻克分水器干燥回流物。2小时后,真空蒸发。在硅胶上进行色谱,得到固体状标题化合物:熔点145-146℃。制备[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(S)-硫代-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1-a][2]苯并吖庚因-4-甲酸和[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(S)-乙酰硫代-3-本基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1-a][2]苯并吖庚因-4-甲酸
实施例9[4S-[4α,7α(R*),12bβ]]-7-[(1,3-二氢-1,3-二氧代-2H-异吲哚-2-基)]-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸二苯基甲酯
将三氟甲磺酸(500g,3.33mole)与三氟乙酸酐(74.8mL,0.53mole)混合,并置于氮气氛下。在冷却的同时,搅拌并以保持罐温低于35℃的速度加入在二氯甲烷(1L)中的(S)-1-[2(S)-(1,3-二氢-1,3-二氧代-异吲哚-2-基)-1-氧代-3-苯基丙基]-1,2,3,4-四氢-2-吡啶甲酸甲酯(200g,0.48mole)。在室温搅拌2天。倒入剧烈搅拌着的冰水(5L)中,并搅拌30分钟。用乙酸乙酯(3×1L)萃取,合并有机层并用水(3×500mL)萃取。真空蒸发得到残余物。将残余物溶于乙酸乙酯(4L)中,用1/4饱和的碳酸氢钾(1L)萃取,然后用1/3饱和的碳酸氢钾(7×1L)萃取。合并含水萃取物,用乙酸乙酯(2L)稀释。搅拌所得的混合物并冷却到5-10℃。用浓盐酸(约750mL)调节pH为2。
分离有机层,用乙酸乙酯(3×1L)萃取水相。合并乙酸乙酯层,用水(3×1L)萃取,然后用饱和氯化钠(0.8L)萃取,并干燥(MgSO4),过滤并用乙酸乙酯(3×200mL)洗涤。真空蒸发,得到无色泡沫状的[4S-[4α,7α(R*),12bβ]]-7-[(1,3-二氢-1,3-二氧代-2H-异吲哚-2-基)]-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸。
将[4S-[4α,7α(R*),12bβ]]-7-[(1,3-二氢-1,3-二氧代-2H-异吲哚-2-基)]-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸(113.9g,0.28mole)溶于二氯甲烷中,并用无水MgSO4(60g)干燥。过滤并用二氯甲烷(3×200mL)洗涤。真空蒸发得到残余物。将残余物溶于无水二甲基甲酰胺(860mL)中,并置于氮气氛下。一次加入碳酸铯(98.9g,0.3mole)。在室温搅拌45分钟。加入溴二苯基甲烷(164.8g,0.67mole)。在室温搅拌所得混合物18小时。用乙酸乙酯(2.464L)和水(630mL)终止反应。分离有机相并用水(7×625mL)、1/4饱和碳酸氢钾(625mL)、水(625mL)和饱和氯化钠(625mL)洗涤。干燥(MgSO4)、过滤并真空蒸发,得到214.4g油。用乙酸乙酯(3×500mL)萃取合并的含水洗涤物,用水(4×300mL)萃取并干燥(MgSO4)。过滤并真空蒸发,得到另外一份油状物,为20.2g。
将粗产物(234.6g)溶于二氯甲烷(200mL)中,经213g硅胶过滤,用二氯甲烷(2L)洗脱。煮沸除去溶剂并用己烷置换(3L),罐温最高达65℃。冷却至室温,倾析出沉淀的油和结晶(9A乙醇)得到标题化合物;熔点153-155℃。
实施例10[4S-[4α,7α(R*),12bβ]]-7-(氨基)-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸二苯基甲酯
在氮气氛下,将[4S-[4α,7α(R*),12bβ]]-7-[(1,3-二氢1,3-二氧代-2H-并吲哚-2-基)]-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸二苯基甲酯(170.9g,0.3mole)、一水合肼(34.4g,0.68mole)和甲醇(3.4L)混合。加热回流5小时。冷却至室温并过滤,以除去邻苯二甲酰肼。真空蒸发滤液得到残余物,并将该残余物在二氯甲烷(600mL)中制成匀浆。过滤除去不溶性邻苯二甲酰肼,用氯仿(4×210mL)洗涤。用水(4×429mL)萃取滤液,干燥(MgSO4)并过滤。蒸发滤液,得到标题化合物的固体残余物。
实施例11[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(S)-乙酰氧基-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸二苯基甲酯
将(S)-3-苯基乳酸(11.17g,67.2mmol)与硫酸(0.3mL,在乙酸中的10%溶液)混合。用10分钟加入乙酸酐(6.34mL,67.2mmol)。在搅拌的同时温热至90℃,保持45分钟。将其冷却,倒入乙醚中,用水萃取三次。分离有机层,干燥(MgSO4)并真空浓缩,得到白色油状的(S)-3-苯基-2-乙酰氧基丙酸。
在二氯甲烷(50mL)中将(S)-3-苯基-2-乙酰氧基丙酸(3.6g,17mmol)与[4S-[4α,7α(R*),12bβ]]-7-(氨基)-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸二苯基甲酯(7.6g,17mmol)混合。加入EEDQ(4.3g,17mmol)。在室温和氩气氛下搅拌18小时。用2N盐酸萃取,分离有机层,用水萃取,然后用饱和碳酸氢钠萃取。干燥(MgSO4)并真空浓缩,得到米色泡沫。经硅胶色谱(30%、然后是40%,然后是50%乙酸乙酯/己烷)纯化,得到标题化合物。
实施例12[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(S)-羟基-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸二苯基甲酯
将[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(S)-乙酰氧基-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸二苯基甲酯(11.0g,17.4mmol)溶于乙醇(75mL)和四氢呋喃(40mL)中,并加入氢氧化锂(22mL,在水中的1M溶液,22mmol)。搅拌反应混合物2小时。在35℃真空除去溶剂,并在乙酸乙酯和1M盐酸之间分配残余物。分离有机相,干燥(MgSO4)并真空浓缩。经硅胶色谱(1∶1/四氢呋喃∶己烷)纯化,得到标题化合物。元素分析C37H36N2O5,计算值:C,75.49;H,6.16;N,4.76;实测值:C,75.30;H,6.44;N,4.54。
实施例13[4S-[4α,7α)(R*),12bβ]]-7-[(1-氧代-2(R)-乙酰氧基-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸二苯基甲酯
将[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(S)-羟基-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸二苯基甲酯(59mg,0.1mmol)、三苯膦(39mg,0.15mmol)和乙酸(8.7μL,0.15mmol)溶于无水四氢呋喃(3mL)中。在0℃用DIAD(32mg,0.15mmol)处理。在0℃搅拌5分钟,然后在室温搅拌45分钟。真空除去挥发性物质,并通过硅胶色谱法(3∶1/己烷∶四氢呋喃)纯化残余物,得到标题化合物。
实施例14[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(R)-羟基-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸二苯基甲酯
将[4S-[4α,7α(R*),12bβ ]]-7-[(1-氧代-2(R)-乙酰氧基-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸二苯基甲酯(366mg,0.58mmol)溶于甲醇(5mL)和四氢呋喃(5mL)中,并加入氢氧化锂(0.8mL,在水中的1M溶液,0.8mmol)。搅拌反应混合物2小时,真它除去溶剂。酸化并在二氯甲烷和水之间分配。分离有机相,干燥(MgSO4)并真空浓缩,得到白色泡沫。
另一种方法是,将[4S-[4α,7α(R*),12bβ ]]-7-[(1-氧代-2(R)-乙酰氧基-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸二苯基甲酯(100mg,0.16mmol)溶于甲醇(5mL)和四氢呋喃(5mL)中,并加入氢氧化锂(0.2mL,在水中的1M溶液,0.2mmol)。搅拌反应混合物1小时,用水(500mL)稀释,酸化并用乙醚(50mL)萃取。分离有机相,用水(2×50mL)萃取,干燥(MgSO4)并真空浓缩。
将两种方法得到的物质合并,经硅胶色谱法(30%,然后是50%四氢呋喃/己烷)纯化,得到白色泡沫状标题化合物。
实施例15[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(S)-乙酰硫代-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸二苯基甲酯
将DIAD(31mg,0.15mmol)、三苯膦(39mg,0.16mmol)和无水四氢呋喃(2mL)混合。冷却至0℃,并在氩气氛下搅拌30分钟。加入固体[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(R)-羟基-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸二苯基甲酯(59mg,0.1mmol),然后立即加入硫代乳酸(11μL,0.15mmol)。使反应物温热至室温并搅拌过夜。真空除去溶剂,经硅胶色谱法(40%乙酸乙酯/己烷,然后是50%乙酸乙酯/己烷)纯化残余物,得到标题化合物。
实施例16[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(S)-乙酰硫代-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸
在氩气氛和室温下,将[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(S)-乙酰硫代-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸二苯基甲酯(51mg,0.079mmol)溶于茴香醚(4滴)和三氟乙酸(1mL)中。放置45分钟,真空除去三氟乙酸,经硅胶色谱法(50mL 40%乙酸乙酯/已烷,然后是50mL加有5%乙酸的40%乙酸乙酯/己烷)纯化,得到标题化合物。
实施例17制备[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(S)-硫代-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸
将[4S-[4α,7α(R*),12bβ]]-7-[(1-氧代-2(S)-乙酰硫代-3-苯基丙基)氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代吡啶并[2,1-a][2]苯并吖庚因-4-甲酸(57mg,0.12mmol)溶于含有氢氧化锂(0.25mL,1M水溶液,0.25mmol)的脱氧合甲醇(3mL)中。在氩气氛和室温下搅拌30分钟。真空使体积减少至1.5mL,然后将其滴加至快速搅拌着的2M盐酸(2mL)溶液中。收集所得的沉淀,用水洗涤,在真空干燥器中干燥1小时。在35℃干燥过夜,得到白色静电粉末状标题化合物。
Claims (2)
1.化合物(S)-2,2,2-三氯-N-(2-氯环己-2-烯基)-乙酰胺。
2.化合物(S)-2-氯环己-2-烯胺。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15597293A | 1993-11-19 | 1993-11-19 | |
US08155,972 | 1993-11-19 | ||
US08/155972 | 1993-11-19 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1135217A CN1135217A (zh) | 1996-11-06 |
CN1041627C true CN1041627C (zh) | 1999-01-13 |
Family
ID=22557529
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN94194207A Expired - Fee Related CN1041627C (zh) | 1993-11-19 | 1994-10-20 | (s)-2,2,2-三氯-n-(2-氯环己-2-烯基)-乙酰胺和(s)-2-氯环己-2-烯胺 |
Country Status (20)
Country | Link |
---|---|
US (2) | US5502253A (zh) |
EP (1) | EP0729456B1 (zh) |
JP (1) | JP3547749B2 (zh) |
KR (1) | KR100310592B1 (zh) |
CN (1) | CN1041627C (zh) |
AT (1) | ATE161251T1 (zh) |
AU (1) | AU683956B2 (zh) |
CA (1) | CA2177044C (zh) |
DE (1) | DE69407430T2 (zh) |
DK (1) | DK0729456T3 (zh) |
ES (1) | ES2112034T3 (zh) |
FI (1) | FI962045A0 (zh) |
GR (1) | GR3025899T3 (zh) |
HU (1) | HU220895B1 (zh) |
IL (1) | IL111656A (zh) |
NO (1) | NO309269B1 (zh) |
NZ (1) | NZ275939A (zh) |
TW (1) | TW321638B (zh) |
WO (1) | WO1995014663A2 (zh) |
ZA (1) | ZA949030B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8049732B2 (en) * | 2007-01-03 | 2011-11-01 | Apple Inc. | Front-end signal compensation |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0249223A2 (en) * | 1986-06-13 | 1987-12-16 | Merrell Dow Pharmaceuticals Inc. | Novel antihypertensive agent |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4608082A (en) * | 1985-02-19 | 1986-08-26 | Union Carbide Corporation | Herbicidal cycloalkenyl acetamides |
US4973585A (en) * | 1986-06-13 | 1990-11-27 | Merrell Dow Pharmaceuticals | Tricyclic lactams active as antihypertensive agents |
US4824832A (en) * | 1987-12-30 | 1989-04-25 | Merrell Dow Pharmaceuticals Inc. | Sulfhydryl containing tricyclic lactams and their pharmacological methods of use |
US5430145A (en) * | 1990-10-18 | 1995-07-04 | Merrell Dow Pharmaceuticals Inc. | Mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace |
-
1994
- 1994-10-20 HU HU9601335A patent/HU220895B1/hu not_active IP Right Cessation
- 1994-10-20 CA CA002177044A patent/CA2177044C/en not_active Expired - Fee Related
- 1994-10-20 KR KR1019960702648A patent/KR100310592B1/ko not_active IP Right Cessation
- 1994-10-20 DK DK95900385.6T patent/DK0729456T3/da active
- 1994-10-20 JP JP51506295A patent/JP3547749B2/ja not_active Expired - Fee Related
- 1994-10-20 WO PCT/US1994/011941 patent/WO1995014663A2/en active IP Right Grant
- 1994-10-20 EP EP95900385A patent/EP0729456B1/en not_active Expired - Lifetime
- 1994-10-20 DE DE69407430T patent/DE69407430T2/de not_active Expired - Lifetime
- 1994-10-20 NZ NZ275939A patent/NZ275939A/en not_active IP Right Cessation
- 1994-10-20 AT AT95900385T patent/ATE161251T1/de active
- 1994-10-20 AU AU81225/94A patent/AU683956B2/en not_active Ceased
- 1994-10-20 ES ES95900385T patent/ES2112034T3/es not_active Expired - Lifetime
- 1994-10-20 CN CN94194207A patent/CN1041627C/zh not_active Expired - Fee Related
- 1994-11-14 ZA ZA949030A patent/ZA949030B/xx unknown
- 1994-11-15 TW TW083110598A patent/TW321638B/zh not_active IP Right Cessation
- 1994-11-16 IL IL11165694A patent/IL111656A/xx not_active IP Right Cessation
-
1995
- 1995-03-30 US US08/415,028 patent/US5502253A/en not_active Expired - Lifetime
-
1996
- 1996-03-30 US US08/413,649 patent/US5508411A/en not_active Expired - Lifetime
- 1996-05-14 FI FI962045A patent/FI962045A0/fi unknown
- 1996-05-15 NO NO961999A patent/NO309269B1/no not_active IP Right Cessation
-
1998
- 1998-01-14 GR GR980400072T patent/GR3025899T3/el unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0249223A2 (en) * | 1986-06-13 | 1987-12-16 | Merrell Dow Pharmaceuticals Inc. | Novel antihypertensive agent |
Non-Patent Citations (1)
Title |
---|
J,AM,CHEM,SUE,109(18) 1987.1.1 E.J.CORY等人,HIGH ENANTISELEEFIVE BORANE REDACFION OF KEFONES CATALGYE EL BES CATALGYEEL B * |
Also Published As
Publication number | Publication date |
---|---|
NO961999L (no) | 1996-05-15 |
JPH09505583A (ja) | 1997-06-03 |
WO1995014663A2 (en) | 1995-06-01 |
HU9601335D0 (en) | 1996-07-29 |
IL111656A0 (en) | 1995-01-24 |
GR3025899T3 (en) | 1998-04-30 |
HUT74326A (en) | 1996-12-30 |
TW321638B (zh) | 1997-12-01 |
NZ275939A (en) | 1997-04-24 |
US5508411A (en) | 1996-04-16 |
AU683956B2 (en) | 1997-11-27 |
CA2177044A1 (en) | 1995-06-01 |
EP0729456B1 (en) | 1997-12-17 |
DK0729456T3 (da) | 1998-03-30 |
CA2177044C (en) | 1999-06-01 |
DE69407430D1 (de) | 1998-01-29 |
ES2112034T3 (es) | 1998-03-16 |
NO309269B1 (no) | 2001-01-08 |
KR100310592B1 (ko) | 2002-05-13 |
US5502253A (en) | 1996-03-26 |
ATE161251T1 (de) | 1998-01-15 |
HU220895B1 (en) | 2002-06-29 |
NO961999D0 (no) | 1996-05-15 |
WO1995014663A3 (en) | 1995-08-17 |
AU8122594A (en) | 1995-06-13 |
FI962045A (fi) | 1996-05-14 |
ZA949030B (en) | 1995-07-18 |
FI962045A0 (fi) | 1996-05-14 |
CN1135217A (zh) | 1996-11-06 |
EP0729456A1 (en) | 1996-09-04 |
IL111656A (en) | 1999-06-20 |
DE69407430T2 (de) | 1998-04-09 |
JP3547749B2 (ja) | 2004-07-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1072218C (zh) | 1-(巯甲基)环丙烷乙酸的制备工艺 | |
KR100426030B1 (ko) | 락톤계 당화합물에서의 키랄성 전환방법 | |
CN1134702A (zh) | 咪唑并(1,2-a)吡啶类的氨基甲酸烷氧基烷基酯 | |
CN1048727C (zh) | 制备2-(1-氮杂双环[2.2.2]辛-3-基)-2,4,5,6-四氢-1h-苯并[de]异喹啉-1-酮及其中间产物的方法 | |
CN1041627C (zh) | (s)-2,2,2-三氯-n-(2-氯环己-2-烯基)-乙酰胺和(s)-2-氯环己-2-烯胺 | |
CN1015714B (zh) | 制备7-氨基-3-丙烯基头孢菌素酸及其脂类的方法 | |
CN101374812A (zh) | 合成瑞芬太尼的方法 | |
CN1311788A (zh) | (1H)-苯并[c]喹嗪-3-酮衍生物的合成方法 | |
CN1310884C (zh) | 对映体纯的n-甲基-n-[(1s)-1-苯基-2-((3s)-3-羟基吡咯烷-1-基)乙基]-2,2-二苯基乙酰胺的制备方法 | |
CN115215814A (zh) | 异恶唑烷类化合物的合成方法 | |
CN1252788A (zh) | 制备药用化合物的方法 | |
Kato et al. | Total synthesis of uracil polyoxin C | |
CN1175943A (zh) | 氨基四氢萘酮衍生物及其制备方法 | |
CN1278253A (zh) | 取代的烷基胺或其盐的生产方法 | |
CN1304356C (zh) | 还原脱卤方法 | |
US5380849A (en) | Process for optically pure decahydroisoqiunolines | |
WO2012098563A2 (en) | One-pot preparation of cyclobenzaprine hydrochloride | |
CN108640861B (zh) | 炔酰胺介导的“一锅法”制备大环内酯 | |
Mandville et al. | A New Stereo-and Enantioselective Approach to the N-Terminal Amino Acid Moiety of Nikkomycins B and BX | |
CN1121383C (zh) | 地尔硫䓬合成的废产物的再利用方法 | |
CN1515561A (zh) | 生产手性琥珀酸衍生物的方法 | |
CN1104641A (zh) | 制备n-叔丁基酰胺的方法 | |
CN112939848B (zh) | 一种布比卡因及其中间体(s)-2-哌啶甲酸的制备方法 | |
CN1047387C (zh) | 一种半抗原化合物、合成方法及其用途 | |
JP4374088B2 (ja) | 新規な4,4−ジフルオロベンゾアゼピンケタール誘導体、およびそれを経由する4,4−ジフルオロベンゾアゼピン−5−オン誘導体の製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 19990113 Termination date: 20121020 |