CN1038452A - 吡咯嗪衍生物的制备方法 - Google Patents
吡咯嗪衍生物的制备方法 Download PDFInfo
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- CN1038452A CN1038452A CN89103741A CN89103741A CN1038452A CN 1038452 A CN1038452 A CN 1038452A CN 89103741 A CN89103741 A CN 89103741A CN 89103741 A CN89103741 A CN 89103741A CN 1038452 A CN1038452 A CN 1038452A
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- piperazine
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- 238000002360 preparation method Methods 0.000 title claims description 14
- 125000002152 1H-pyrrolizinyl group Chemical class C1(C=CN2C=CC=C12)* 0.000 title abstract description 4
- 238000000034 method Methods 0.000 claims abstract description 35
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 60
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 229910021529 ammonia Inorganic materials 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- HCFAJYNVAYBARA-UHFFFAOYSA-N 4-heptanone Chemical compound CCCC(=O)CCC HCFAJYNVAYBARA-UHFFFAOYSA-N 0.000 claims description 6
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- -1 lithium aluminum hydride Chemical compound 0.000 description 12
- 238000000605 extraction Methods 0.000 description 11
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 10
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229960001701 chloroform Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- SNKQZROJNVIEFC-UHFFFAOYSA-N perchloric acid;piperazine Chemical compound OCl(=O)(=O)=O.C1CNCCN1 SNKQZROJNVIEFC-UHFFFAOYSA-N 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000012670 alkaline solution Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
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- 238000009835 boiling Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000012434 nucleophilic reagent Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- HUAUNKAZQWMVFY-UHFFFAOYSA-M sodium;oxocalcium;hydroxide Chemical compound [OH-].[Na+].[Ca]=O HUAUNKAZQWMVFY-UHFFFAOYSA-M 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- MWFMGBPGAXYFAR-UHFFFAOYSA-N 2-hydroxy-2-methylpropanenitrile Chemical class CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-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
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 125000005219 aminonitrile group Chemical group 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 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
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 235000014666 liquid concentrate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000000803 paradoxical effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 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 1
- 239000000376 reactant Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000007669 thermal treatment Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pyrrole Compounds (AREA)
Abstract
公开了一种制备下式所示的吡咯嗪衍生物及其盐类的方法式中R为-CN或-CH2NH2。
Description
本发明涉及一种制备吡咯嗪衍生物的方法,更具体地说,涉及一种制备用作7a-氨甲基-2,3,5,6,7,7a-六氢-1H-吡咯嗪合成的中间体的7a-氰基-2,3,5,6,7,7a-六氢-1H-吡咯嗪及其盐的方法和制备7a-氨甲基-2,3,5,6,7,7a-六氢-1H-吡咯嗪及其盐的方法。
已知用下面的式1-B和式1-A表示的7a-氨甲基-2,3,5,6,7,7a-六氢-1H-吡咯嗪和7a-氰基-2,3,5,6,7,7a-六氢-1H-吡咯嗪由于其结构中具有生物碱的骨架,因此可用于制备各种医药和农药
此外,该两种化合物可用作合成头孢菌素衍生物〔日本专利Sho62-16487(A)〕和合成有机铂络合物〔日本专利Sho61-229893(A)〕、2-氧吡咯烷类化合物及其盐〔日本专利Sho61-254587(A)号〕的原料。
就7a-氨甲基-2,3,5,6,7,7a-六氢-1H-吡咯嗪的合成而论,迄今只有一种方法是已知的,该方法是用氢化铝锂使7a-氰基-2,3,5,6,7,7a-六氢-1H-吡咯嗪还原〔Miyano等人“Abstract on the 97th Annual Lecture of the Pharmaceutical Society of Japan”,P.223(1978)〕。在该情况下,制备原料7a-氰基-2,3,5,6,7,7a-六氢-1H-吡咯嗪的方法是先使γ-丁内酯与KOCN反应,接着在碱石灰的存在下对生成的γ-(N-2-吡咯烷酮基)丁酸〔γ-(N-2-Pyrrolid-inonyl)butyric acid〕进行热处理,并使热处理后生成的2,3,5,6-四氢-1H-吡咯嗪与高氯酸反应,然后再使反应生成的1,2,3,5,6,7-六氢吡咯嗪高氯酸盐与氰化钾反应〔Miyano等人“Synthesis”,P.701(1978)〕。这种方法也可用来制备所述的γ-(N-2-吡咯烷酮基)丁酸,即将γ-丁内酯加入2-吡咯烷酮与钠的反应混合物中〔Miyano等人:“J.Heterocyclic Chem”,Vol.19,P.1465(1982)〕。
此外,还知道有这样一种制备7a-取代的-2,3,5,6,7,7a-六氢-1H-吡咯嗪衍生物的方法,即使上述的1,2,3,5,6,7-六氢吡咯嗪高氯酸盐与一种亲核试剂反应,或使上述7a-氰基-2,3,5,6,7,7a-六氢-1H-吡咯嗪中的氰基进行化学改性。
现将用化学式表示的所述的有关技术归纳如下:
但上述常用的制备7a-氨甲基-2,3,5,6,7,7a-六氢-1H-吡咯嗪的方法有以下缺点。
在第一步即使γ-丁内酯与KOCN反应以合成γ-(N-2-吡咯烷酮基)丁酸的过程中存在的问题是进行反应所需的温度较高(约200℃),且反应产物的产率较低(约40%)。这种方法发展成的另一种或独立的方法,即将γ-丁内酯加入2-吡咯烷酮与钠的反应产物中以合成γ-(N-2-吡咯烷酮基)丁酸,也有其问题,即有可能引起爆炸等反常反应。
在第二步即在碱石灰的存在下将γ-(N-2-吡咯烷酮基)丁酸进行热处理以合成2,3,5,6-四氢-1H-吡咯嗪的过程中存在问题是进行反应所需的温度较高(约250~300℃)且所生成的化合物较不稳定。
此外,在最后一步即使7a-氰基-2,3,5,6-四氢-1H-吡咯嗪还原以合成7a-氨甲基-2,3,5,6,7,7a-六氢-1H-吡咯嗪的过程中存在的问题是需要用昂贵的氢化铝锂作还原剂,且反应必须在无水溶剂中进行。
使1,2,3,5,6,7-六氢吡咯嗪高氯酸盐与亲核试剂反应或使7a-氰基-2,3,5,6,7,7a-六氢-1H-吡咯嗪中的氰基进行化学改性的这两种方法都存在着这样的缺点,即其原材料的制备很难。
因此,本发明的主要目标是创立一种制备可用于药物的化合物7a-氨甲基-2,3,5,6,7,7a-六氢-1H-吡咯嗪及其盐的方法,该方法的合成操作容易、保证工作非常安全、不需要使用昂贵的反应物、产率高且适合于工业生产。
本发明的具体目标首先是提供一种新颖的制备7a-氰基-2,3,5,6,7,7a-六氢-1H-吡咯嗪的方法,其次是提供一种将该化合物转化为从经济角度和其他方面来看更为有利的7a-氨甲基-2,3,5,6,7,7a-六氢-1H-吡咯嗪的方法。
根据本发明,第一个具体目标的是一种制备7a-氰基-2,3,5,6,7,7a-六氢-1H-吡咯嗪及其盐的方法,该方法包括使下面式(Ⅱ)的1,7-二取代的-4-庚酮与式(Ⅲ)的氰化物和氨反应:
式中X为卤原子或R1-SO3基,其中R1为烃基,
式中R2和R3可同可不同,各为氢原子或烃基,R4为羟基或氨基,
如有必要,还可使所生成的7a-氰基-2,3,5,6,7,7a-六氢-1H-吡咯嗪转化为其盐。
达到本发明的第二个具体目标的是一种制备式(Ⅰ-B)的7a-氨甲基-2,3,5,6,7,7a-六氢-1H-吡咯嗪及其盐的方法,该方法包括使上面所得的式(Ⅰ-A)的7a-氰基-2,3,5,6,7,7a-六氢-1H-吡咯嗪或其盐在金属催化剂的存在下与氢反应,
如有必要,还可使所生成的式(Ⅰ-B)的化合物转化为其盐。
上述Ⅰ-A和Ⅰ-B化合物的盐的例子有:氢氯化物、氢溴化物、氢碘化物、高氯化物等氢卤化物;硫酸盐、硝酸盐、磷酸盐等无机酸盐;醋酸盐、丙酸盐、甘醇酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、乳酸盐、苯甲酸盐、肉桂酸盐等有机羧酸盐;甲磺酸盐等烷基磺酸盐;苯磺酸盐、对甲苯磺酸盐等芳基磺酸盐;环己烷磺酸盐等环烷基磺酸盐。
在化合物(Ⅱ)中,卤原子可以是氯、溴或碘原子。取代基R1的烃基系选自烷基或芳基,烷基的例子有甲基、乙基、正丙基、正丁基、正戊基、正己基、正癸基等含1~10个碳原子的直链烷基;异丙基、异丁基、仲丁基、叔丁基、异戊基等支链烷基;环丙基、环丁基、环戊基、环己基、环庚基等含3个或3个以上碳原子的环烷基;芳基的例子有苯基、甲苯基、二甲苯基、 基等。
在化合物(Ⅲ)中,取代基R2和R3的烃基都与上述取代基R1的相同。
合成化合物(Ⅰ-A)时,在每1当量化合物(Ⅱ)中加入1~10当量化合物(Ⅲ)和3~10当量氨,溶剂可加可不加,然后在20~50℃下搅拌该混合物,使反应在12~48小时内完成。此后加碱溶液,使所得的反应混合物呈碱性,并用有机溶剂萃取。萃取液浓缩后,将所得的残余物进行真空蒸馏以分离出所需的7a-氰基-2,3,5,6,7,7a-六氢-1H-吡咯嗪(化合物Ⅰ-A)。用已知的方法使该化合物与一种酸反应便得到其盐。
在上述操作中,加氨可采用任何方法。即可将所需的全部氨溶于溶剂后加入反应体系;或每隔一定时间通氨气,使氨在反应体系中的量保持在0.5~3当量的水平;或使该反应在氨气氛中进行;或采用以上各种方法的任何组合。溶剂的例子有甲醇、乙醇、正丙醇、异丙醇等醇;N,N-二甲基甲酰胺、乙醚、四氢呋喃、二噁烷等醚。用于使反应混合物呈碱性的碱的例子有氢氧化钠、氢氧化钾、碳酸钠、碳酸钾等。萃取溶剂的例子有二氯甲烷、三氯甲烷、乙醚、醋酸乙酯等。
下面谈谈原料,式Ⅱ所示的1,7-二取代的-4-庚酮易于用容易得到的γ-丁内酯按照H.Hart等人所公开的方法〔“J.Am.Chem.Soc.,”Vol.78,p.112(1956)〕合成而得。在式Ⅲ所示的化合物中,氰醇衍生物(R4∶OH)易于用Cox等人所公开的方法〔“Org Syn.”Coll.11,P.7(1946)〕合成而得。而氨基腈衍生物(R4∶NH2)则易于用R.A.Jecobson等人所公开的方法〔“J.Am.Chem.Soc.,”Vol.68,P.2628(1946)〕和日本专利Sho54-79232(A)和Sho61-87658(A)所公开的方法制备。
本发明的由式Ⅰ-A所示的7a-氰基-2,3,5,6,7,7a-六氢-1H-吡咯嗪制备成式Ⅰ-B所示的7a-氨甲基-2,3,5,6,7,7a-六氢-1H-吡咯嗪的方法是使化合物Ⅰ-A或其盐及一种金属催化剂(如阮内镍、氧化珀、披钯碳等)在适当的溶剂中溶解或悬浮,然后在例如20℃的温度下在氢气氛下搅拌6~24小时,直至反应完成。可用作溶剂的有甲醇、乙醇、正丙醇、异丙醇等醇;醋酸、丙酸等有机酸;盐酸、硫酸、硝酸、高氯酸等含水无机酸;水或其混合物。反应完成后,滤去反应混合物中的不溶物质,将滤液浓缩和蒸馏,或者如有必要在滤去不溶物质后,将滤液进行真空浓缩,并加碱溶液使其呈碱性,用有机溶剂萃取,并将萃取液浓缩,然后进行真空蒸馏以获得式Ⅰ-B所示的7a-氨甲基-2,3,5,6,7,7a-六氢-1H-吡咯嗪这样所要求的化合物。可用于使反应混合物呈碱性的碱有氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠等。可用的萃取溶剂有二氯甲烷、三氯甲烷、乙醚、醋酸乙酯等。
下面用实施例进一步对本发明作详细的说明。
实施例1
7a-氰基-2,3,5,6,7,7a-六氢-1H-吡咯嗪
在20℃下将1,7-二氯-4-庚酮(0.50克,2.7毫摩尔)滴加到为氨所饱和的丙酮合氰化氢(2.3克,27毫摩尔)溶液中。将所得的溶液在氨气氛下在20℃下搅拌48小时。然后在反应混合物中加入0.1N的NaOH,并用二氯甲烷萃取。用无水硫酸钠使萃取液干燥,进行真空浓缩和蒸馏,获得0.33克所需化合物(产率:89%)。
沸点:70~74℃(3毫米汞柱)
1H-NMR谱(CDCl3-)δppm
IR谱(ν净 最大)Cm-1
2960,2860,2810(C-H),2225(C-H)
MS谱(E1/D1)m/z
136(M+)
实施例2
7a-氰基-2,3,5,6,7,7a-六氢-1H-吡咯嗪
将2-氨基-2-甲基丙腈(2-amino-2-methyl propane nitrile)(41.4克,492毫摩尔)与1,7-二氯-4-庚酮(30.0克,164毫摩尔)在220毫升16%NH3/MeOH溶液中的混合溶液在20℃下搅拌24小时。将所得的反应混合物进行真空浓缩以脱除其中的MeOH,在残余物中加入0.1N的NaOH,并用二氯甲烷萃取,萃取液用无水硫酸钠干燥,然后进行浓缩和真空蒸馏,获得18.1克所需的化合物(产率:82%)。
该化合物的物理数据与实施例1的相同。
实施例3
7a-氨甲基-2,3,5,6,7,7a-六氢-1H-吡咯嗪
将7a-氰基-2,3,5,6,7,7a-六氢-1H-吡咯嗪(300毫克,2.20毫摩尔,实施例1中制得)和氧化铂(30毫克)加入8.5毫升已通入氯化氢气体(400毫克,11.0毫摩尔)的醋酸中,并在氢气氛下在20℃下搅拌24小时。滤去反应混合物中的不溶物质,浓缩滤液,加0.5N的NaOH(10毫升),用三氯甲烷萃取,然后用无水硫酸钠干燥萃取液,再将萃取液浓缩和真空蒸馏,得188毫克所需的化合物(产率:61%)
沸点:46~49℃(3毫米汞柱)
1H NMR谱(CDCl3)δppm
1.40 (2H,br.s,NH2),
2.53 (2H,s,CH2NH2),
2.93-3.02(2H,m,
1R谱(ν净 最大)Cm-1:
3380(N-H),2950(C-H),1460,1100,840。
MS谱(E1/D1)m/z:
110(基峰)。
MS谱〔C1/D1(i-Bu)〕m/z:
141〔(M+1)+〕。
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