DK145892B - Fremgangsmaade til fremstilling af pyrazinamidderivater - Google Patents
Fremgangsmaade til fremstilling af pyrazinamidderivater Download PDFInfo
- Publication number
- DK145892B DK145892B DK429268AA DK429268A DK145892B DK 145892 B DK145892 B DK 145892B DK 429268A A DK429268A A DK 429268AA DK 429268 A DK429268 A DK 429268A DK 145892 B DK145892 B DK 145892B
- Authority
- DK
- Denmark
- Prior art keywords
- diamino
- alkyl
- alkoxyphenyl
- mol
- phenyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 7
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical class NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 4
- -1 alkoxymethylalkyl Chemical group 0.000 claims description 27
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000005036 alkoxyphenyl group Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 4
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000005059 halophenyl group Chemical group 0.000 claims description 3
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims 4
- 229910052739 hydrogen Inorganic materials 0.000 claims 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims 1
- 125000004663 dialkyl amino group Chemical group 0.000 claims 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 125000001326 naphthylalkyl group Chemical group 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 239000000203 mixture Substances 0.000 description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000001953 recrystallisation Methods 0.000 description 13
- OCSQJDAUOOHJEI-UHFFFAOYSA-N 3,5-diamino-6-chloropyrazine-2-carboxylic acid Chemical compound NC1=NC(N)=C(C(O)=O)N=C1Cl OCSQJDAUOOHJEI-UHFFFAOYSA-N 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- MPSXGPCFLAGJOM-UHFFFAOYSA-M 2-tert-butyl-5-methyl-1,2-oxazol-2-ium;perchlorate Chemical compound [O-]Cl(=O)(=O)=O.CC1=CC=[N+](C(C)(C)C)O1 MPSXGPCFLAGJOM-UHFFFAOYSA-M 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- GWFPKLISOBTNHW-UHFFFAOYSA-N (3-amino-3-oxoprop-1-en-2-yl) pyrazine-2-carboxylate Chemical compound N1=C(C=NC=C1)C(=O)OC(C(=O)N)=C GWFPKLISOBTNHW-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 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 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- FPLIWXBQBNLRRH-UHFFFAOYSA-N 3,5-diamino-6-chloro-n-ethylpyrazine-2-carboxamide Chemical compound CCNC(=O)C1=NC(Cl)=C(N)N=C1N FPLIWXBQBNLRRH-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- CUDVNBSIZQTLLL-UHFFFAOYSA-N NC(=N)N.O.O.Cl Chemical compound NC(=N)N.O.O.Cl CUDVNBSIZQTLLL-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-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
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- LTKVFMLMEYCWMK-UHFFFAOYSA-N amiloride hydrochloride dihydrate Chemical compound [H+].O.O.[Cl-].NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N LTKVFMLMEYCWMK-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229960000789 guanidine hydrochloride Drugs 0.000 description 2
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- JJGGIYYGVKGMQZ-UHFFFAOYSA-N 1,2,4-triazole-3,4,5-triamine Chemical compound NC1=NN=C(N)N1N JJGGIYYGVKGMQZ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- GIUTUZDGHNZVIA-UHFFFAOYSA-N 2-(ethylamino)acetic acid;hydrochloride Chemical compound Cl.CCNCC(O)=O GIUTUZDGHNZVIA-UHFFFAOYSA-N 0.000 description 1
- HAHCPVYIYQRMBZ-UHFFFAOYSA-N 2-(propan-2-ylideneamino)guanidine Chemical compound CC(C)=NN=C(N)N HAHCPVYIYQRMBZ-UHFFFAOYSA-N 0.000 description 1
- DWKNOLCXIFYNFV-HSZRJFAPSA-N 2-[[(2r)-1-[1-[(4-chloro-3-methylphenyl)methyl]piperidin-4-yl]-5-oxopyrrolidine-2-carbonyl]amino]-n,n,6-trimethylpyridine-4-carboxamide Chemical compound CN(C)C(=O)C1=CC(C)=NC(NC(=O)[C@@H]2N(C(=O)CC2)C2CCN(CC=3C=C(C)C(Cl)=CC=3)CC2)=C1 DWKNOLCXIFYNFV-HSZRJFAPSA-N 0.000 description 1
- USXDSOBKRLJYJU-UHFFFAOYSA-N 2-hydroxyguanidine;sulfuric acid;hydrate Chemical compound O.NC(N)=NO.OS(O)(=O)=O USXDSOBKRLJYJU-UHFFFAOYSA-N 0.000 description 1
- WWHZKHHZRIJLEM-UHFFFAOYSA-N 2-phenylmethoxyguanidine Chemical compound NC(N)=NOCC1=CC=CC=C1 WWHZKHHZRIJLEM-UHFFFAOYSA-N 0.000 description 1
- CVHZLHNTGDMEQJ-UHFFFAOYSA-N 3,5-diamino-6-chloro-n-(diaminomethylideneamino)pyrazine-2-carboxamide Chemical compound NC(N)=NNC(=O)C1=NC(Cl)=C(N)N=C1N CVHZLHNTGDMEQJ-UHFFFAOYSA-N 0.000 description 1
- RGZPQVVHAHPFOS-UHFFFAOYSA-N 3,5-diamino-6-chloro-n-phenylpyrazine-2-carboxamide Chemical compound N1=C(Cl)C(N)=NC(N)=C1C(=O)NC1=CC=CC=C1 RGZPQVVHAHPFOS-UHFFFAOYSA-N 0.000 description 1
- KSEHSAXZBNRCCY-UHFFFAOYSA-N 3-chloropyrazine-2,6-diamine Chemical compound NC1=CN=C(Cl)C(N)=N1 KSEHSAXZBNRCCY-UHFFFAOYSA-N 0.000 description 1
- UXHQLGLGLZKHTC-CUNXSJBXSA-N 4-[(3s,3ar)-3-cyclopentyl-7-(4-hydroxypiperidine-1-carbonyl)-3,3a,4,5-tetrahydropyrazolo[3,4-f]quinolin-2-yl]-2-chlorobenzonitrile Chemical compound C1CC(O)CCN1C(=O)C1=CC=C(C=2[C@@H]([C@H](C3CCCC3)N(N=2)C=2C=C(Cl)C(C#N)=CC=2)CC2)C2=N1 UXHQLGLGLZKHTC-CUNXSJBXSA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 101100516563 Caenorhabditis elegans nhr-6 gene Proteins 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- MCRWZBYTLVCCJJ-DKALBXGISA-N [(1s,3r)-3-[[(3s,4s)-3-methoxyoxan-4-yl]amino]-1-propan-2-ylcyclopentyl]-[(1s,4s)-5-[6-(trifluoromethyl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]methanone Chemical compound C([C@]1(N(C[C@]2([H])C1)C(=O)[C@@]1(C[C@@H](CC1)N[C@@H]1[C@@H](COCC1)OC)C(C)C)[H])N2C1=CC(C(F)(F)F)=NC=N1 MCRWZBYTLVCCJJ-DKALBXGISA-N 0.000 description 1
- FKCBLVCOSCZFHV-UHFFFAOYSA-N acetonitrile;ethanol Chemical compound CCO.CC#N FKCBLVCOSCZFHV-UHFFFAOYSA-N 0.000 description 1
- UGBKOURNNQREPE-UHFFFAOYSA-N azepan-1-amine Chemical compound NN1CCCCCC1 UGBKOURNNQREPE-UHFFFAOYSA-N 0.000 description 1
- LZCZIHQBSCVGRD-UHFFFAOYSA-N benzenecarboximidamide;hydron;chloride Chemical compound [Cl-].NC(=[NH2+])C1=CC=CC=C1 LZCZIHQBSCVGRD-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- ZGNIYAPHJAPRMA-UHFFFAOYSA-N chlorine azide Chemical compound ClN=[N+]=[N-] ZGNIYAPHJAPRMA-UHFFFAOYSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-O hydron;1,2-oxazole Chemical compound C=1C=[NH+]OC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-O 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical class C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 1
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
- 239000002833 natriuretic agent Substances 0.000 description 1
- LWMPFIOTEAXAGV-UHFFFAOYSA-N piperidin-1-amine Chemical compound NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- QDGHXQFTWKRQTG-UHFFFAOYSA-N pyrimidin-2-ylhydrazine Chemical compound NNC1=NC=CC=N1 QDGHXQFTWKRQTG-UHFFFAOYSA-N 0.000 description 1
- SBMSLRMNBSMKQC-UHFFFAOYSA-N pyrrolidin-1-amine Chemical compound NN1CCCC1 SBMSLRMNBSMKQC-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
(19) DANMARK (®)
|p (12) FREMLÆGGELSESSKRIFT on 145892 B
DIREKTORATET FOR PATENT- OG VAREMÆRKEVÆSENET
(21) Ansøgning nr. 4292/68 (51) IntCI.3 C 07 D 2 Λ1 / 2 6 (22) Indleveringsdag 6. s ep. 1968 C 07 D A01/12 (24) Løbedag 6. sep. 1968 C 07 D A03/12 (41) Aim. tilgængelig 8. mar. 1969 (44) Fremlagt 5 · apr · 1 9^5 (86) International ansøgning nr. -(86) International indleveringsdag (85) Videreførelsesdag -(62) Stamansøgning nr. -
(30) Prioritet 7. sep. 1967, 666004, US 21. mar. 1968, 718976, US
(71) Ansøger MERCK & CO. INC., Rahway, US.
(72) Opfinder Edward Jethro Cragoe Jr., US: Kenneth Leroy Shepard, US.
(74) Fuldmægtig Ingeniørfirmaet Hofman-Bang & Boutard.
(54) Fremgangsmåde til fremstilling af pyrazinamidderivater.
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af pyrazinamidderivater med den i indledningen til krav 1 angivne almene formel. Denne formel omfatter både kendte og hidtil ukendte forbindelser, der kan benyttes som aktive diure-tiske og natriuretiske midler.
Hidtil ukendte er forbindelserne med den angivne almene formel, hvori halo betyder chlor, brom eller iod, R° er alkyl, alkoxymeth-^ yl-alkyl, cyano-alkyl, alkoxycarbonylalkyl, phenylalkyl, 2-(2- Π imidazolinyl)-aminomethylalkyl, alkenyl, alkynyl, phenyl, halogen- ° phenyl, alkylphenyl, alkoxyphenyl, amino, di(alkyl)amino, (alkyl- t phenylalkyl)amino, pyridylamino, pyrimidinylamino, quinolinylamino, 4 m
J
2 145892 1-pyrrolidinyl, 1-piperidino, 1-hexahydro-l-azepinyl, 4-morph-olino eller 4- ( 3,5-diamino-l,2,4-triazolyl).
Ved fremgangsmåden ifølge opfindelsen, der er ejendommelig ved det i den kendetegnende del af krav 1 anførte, benyttes et hidtil ukendt mellemprodukt, nemlig et pyrazinoyloxyacrylamid, der med høj omsætningsgrad reagerer med primære aminer. Denne reaktion kan anskueliggøres ved følgende reaktionsskema: R1 R1^
Ργν"2 S YT
halo^ ^ \-0-C=C-C-NHR5+HoNR6 -^ halo /^N'\,_NHR6 o r¥o o
I II III
i hvilke formler R1, R^, R^, r\ R^, og halo har den i krav 1 angivne betydning.
Det er tidligere foreslået at fremstille forbindelser svarende til de ovennævnte pyrazinamider (III) ved omsætning af den pågældende aminoforbindelse og et alkylpyrazinoat. Det har dog vist sig, at disse estere ikke eller kun langsomt reagerer. Hvis man forsøger at fremme reaktionen ved anvendelse af kraftigere reaktionsbetingelser, bliver bireaktionerne dominerende. Derfor har der været et behov for mere reaktionsdygtige derivater af pyrazinsyrer. Det har ifølge opfindelsen overraskende vist sig, at de omhandlede py-razinoyloxyacrylamider er yderst reaktionsdygtige derivater. Reaktionen forløber særlig glat og i højt udbytte ved de i krav 2 karakteriserede reaktionsbetingelser.
Udgangsmaterialerne er let tilgængelige, idet de kan fremstilles i overensstemmelse med følgende reaktionsskema: 145892 3 R1 r3 K v. η n N m0 4 R\ * TI ♦ A κξ, .^γ·γ*! „„/ «-' ο» „>y · „„ΛΑ L· £~°~9 = 9-coNHR5 R 8 i3 I4
IV V I
12345 hvori R,R,R,R,R og halo har den ovennævnte betydning..
Omkring ækvivalente mængder pyrazinsyre IV, et isoxazoliumsait V og en tertiær amin opløses i et opløsningsmiddel og omrøres. Eksempler på en egnet amin er en trialkylamin, såsom trimethylamin, triethylamin eller tripropylamin. Som opløsningsmiddel kan hensigtsmæssigt benyttes dimethylformamid, dimethylsulfoxid, dimet-hylsulfon, acetonitril eller tetrahydrofuran, idet dimethylformamid og acetonitril foretrækkes. Først opløses pyrazinsyren og den tertiære amin, idet opløsningen omrøres i et tidsrum mellem 5 minutter og flere timer. Derefter tilsættes isoxazoliumsaltet, og blandingen omrøres i 1 - 4 timer, f.eks. 2 timer ved stuetemperatur, men blandingen kan dog om ønsket opvarmes til 50° C. Produkt I er sædvanligvis så stabilt, at det kan isoleres og renses. Isoleringen sker simpelt ved tilsætning af vand til reaktionsblandingen, hvorved pyrazinoyloxyacrylamid udfældes. I stedet kan produkt (i) fås ved inddampning af reaktionsblandingen. De dannede produkter kan omkrystalliseres, sædvanligvis af et polært organisk opløsningsmiddel, såsom acetonitril eller isopropanol.
Det er undertiden en fordel at tandlade at isolere mellemprodukterne, pyrazinoyloxyacrylamiderne, men derimod omdanne dem in situ til de ønskede substituerede pyrazinamider (III). I så tilfælde kan man ca. 1 time efter blandingen af reagenserne IV og V og den tertiære amin tilsætte 1-10 ækvivalenter af aminen (II), og reaktionsblandingen omrøres ved en temperatur fra stuetemperatur indtil 150° C i 2 - 24 timer. Det dannede amid isoleres ved fortynding af reaktionsblandingen med vand eller i nogle tilfælde med en alkohol, såsom ethanol eller isopropylalkohol, som udfælder det ønskede substituerede amid.
145892 4
Hvis det er hensigtsmæssigt først af isolere pyra”inoyloxyacryl-amiderne (I), udføres reaktionen som ovenfor beskrevet med den ændring, at det forud dannede mellemprodukt (i) og aminoforbin-delsen (II) blandes i et molært forhold på mellem 1:1 og 1:10 i et opløsningsmiddel, såsom dimethylformamid, dioxan, dichlor-methan, tetrahydrofuran, acetonitril eller t-butanol, fortrinsvis tetrahydrofuran eller acetonitril, og blandingen omrøres fra 2 til 24 timer mellem stuetemperatur og kogepunktet. Reaktionstid og -temperatur afhænger af reagensernes art.
Pyrazinsyrerne kan fremstilles ved hydrolyse af de tilsvarende methylestere (VI) som vist nedenfor. Hydrolysen kan udføres med en vandig base, såsom natriumhydroxid eller kaliumhydroxid, og et opløsningsmiddel, såsom isopropanol eller ethanol, og blandingen koges i 1 - 10 timer. Pyrazinsyren isoleres derefter ved afkøling og tilsætning af syre, såsom saltsyre eller svovlsyre.
NS\ ^
halo C00CH, halo/ C00H
3
VI IV
Fremgangsmåden ifølge opfindelsen illustreres ved de følgende eksempler.
EKSEMPEL_1 N-Ethvl-3.5-diamino-6-chlorpyrazinamid N-(t-Butyl)-3-methyl-3-(3,5-diamino-6-chlorpyrazinoyloxy)acryl-amid (0,10 g, 0,3 mol) opløses i et minimum af tetrahydrofuran.
En 70 $ vandig ethylaminopløsning (1,0 ml) tilsættes, og opløsningen koges i 4 minutter. Opløsningen inddampes under reduceret tryk, og remanensen behandles med vand (5 ml). Ved henstand udkrystalliserer et fast stof, der opsamles og tørres, 0,05 g (769é)., smp: 204 - 6° C. Ved omkrystallisation af benzen fås N-ethyl- 3,5-diamino-6-chlorpyrazinamid, der smelter ved 205 - 206° C.
5 U5832
Analyse beregnet for CyH^øClN^O: C 38,98, Η 4,67, N 32,48.
Fundet: C 38,65, H 4,60, N 33,28.
EKSEMPEL_2 N-Ethoxycarbonylmethvl-5,5-diamino-6-chlorpyrazinamid
Ethylglycinat-hydrochlorid (5,60 g, 0,04 mol) opløses i en blanding af vand (50 ml) og natriumbicarbonat (5,0 g, 0,06 mol). En opløsning af N-(t-butyl)-3-methyl-3-(3,5-diamino-6-chlorpyrazin-oyloxy)acrylamid (3,27 g, 0,01 mol) i tetrahydrofuran (100 ml) tilsættes, og blandingen opvarmes på dampbad i 2 timer. Vand (500 ml) tilsættes, og opløsningen afkøles. Det faste bundfald opsamles og tørres, 2,17 g (80 %), smp: 172 - 174°C. Efter omkrystallisation af isopropanol smelter N-ethoxycarbonylmethyl-3,5-diamino-6-chlorpyrazinamidet ved 174 - 175° C.
Analyse beregnet for CgH12ClN503: C 39,49, H 4,42, N 25,59.
Fundet: C 39,77, H 4,38, N 25,45.
EKSEMPEL_3 N-(2-Morpholinoethyl)-3,5-diamino-6-chlorpyrazinamid
En opløsning af N-(t-butyl)-3-methyl-3-(3,5-diamino-6-chlorpyra-zinoyloxy)acrylamid (3,27 g, 0,01 mol) og 2-morpholinoethylamin, (1,50 g, 0,0115 m), i tetrahydrofuran koges i 2 timer. Tetrahy-drofuranet afdampes under reduceret tryk, og remanensen suspenderes i hexan (40 ml) og filtreres, 3,0 g (100 %), smp: 153 -166°C. Ved omkrystallisation af N-(2-morpholin'oethyl)-3,5-dia-mino-6-chlorpyrazinamidet af absolut ethanol hæves smeltepunktet til 178 - 180°c.
Analyse beregnet for cnHi7C1N6°2: c ^3,93, H 5,70, N 27,95.
Fundet: C 44,22, H 5,68, N 27,84.
... 6 '· 145892 - EKSEMPEL 4 N-Phenvl-5.5-diamino-6-chlorpyrazinamid
En blanding af N- (t-butyl)-3-methyl-3- (3,5-diamino-6-chlorpyra-zinoyloxy)acrylamid (3,27 g, 0,01 mol),, anilin (4,65 g, 0,05 mol) og n-amylalkohol (20 ml) opvarmes til reflux. Den dannede opløsning koges i 24 timer og filtreres varmt til fjernelse af noget uopløseligt stof. Filtratet inddampes under reduceret tryk, og den olieagtige remanens opløses i dichlormethan (50 ml). Denne opløsning ekstrahere s med 1 n saltsyre (to 20 ml portioner), dichlor-methanen tørres over vandfrit magnesiumsulfat og inddampes derefter under reduceret tryk. Remanensen udrives med butylchlorid, hvorved fås 0,30 g N-phenyl-3,5-diamino-6-chlorpyrazinamid, smp: 193 1970C. Efter omKrystallisation af cyclohexan smelter produk tet ved 198 - 202° C.
Analyse beregnet for C^H^qCIN^O: C 50,10, H 3,82, N 26,56.
Fundet: C 49,98, H 3,84, N 26,39.
EKSEMPEL 5 3.5-Diamino-6-chlorpyrazinsyre. 2.2-tetramethylenhydrazid
En blanding af 1-aminopyrrolidin (2,15 g, 0,025 mol), N-(t-butyl)- 3-methyl-3-(3,5-diamino-6-chlorpyrazinoyloxy)acrylamid (6,56 g, 0,02 mol) og acetonitril (100 ml) opvarmes under reflux i 2 timer.
Det udfældede stof opsamles og tørres, 3,45 g (67 %), smp. 222 -224,5°C. Ved omkrystallisation af acetonitril fås 3,5-diamino-6-chlor-pyrazinsyre, 2,2-tetramethylenhydrazid, smp: 224 - 225,5°c.
Analyse beregnet for C^H-^ClNgO: C 42,11, H 5,10, N 32,74.
Fundet: C 42,44, H 4,88, N 32,38.
EKSEMPEL_6 7 145892 3.5- Diamino-6-chlorpyrazinsyre. 2-(2-pyridvl)hvdrazid
En blanding af 2-hydrazinpyridin (2,18 g, 0,02 mol), N-(t-butyl)- 3-methyl-3-(3,5-diamino-6-chlorpyrazinoyloxy)acrylamid (3.39 g, 0,01 mol) og acetonitril (75 ml) opvarmes under reflux i 3 timer.
Det udfældede stof opsamles og tørres, 2,21 g (79 %), smp: 283 -286°C, dek. Denne prøve renses yderligere ved opløsning af fortyndet methansulfonsyre og genudfældning ved tilsætning af 10 % natriumhydroxid-opløsning, hvorved fås 3,5-diamino-6-chlor-py-razinsyre, 2-(2-pyridyl)hydrazid, smp: 286 - 290°C, dek..
Analyse beregnet for cioH10C1N70: C 42,94, H 3,60, N 35,00.
Pundet: C 42,74, H 3,96, N 34,75.
EKSEMPEL 7 3.5- Diamino-6-chlorpyrazinsyre,2-(2-pyrimidinyl)-hydrazidhvdrat
En blanding af 3,5-diamino-6-chlorpyrazinsyre (l,90 g, 0,01 mol) og triethylamin (1,0 g, 0,01 mol) i dimethylformamid (20 ml) omrøres i 10 minutter. Til denne opløsning sættes N-(t-butyl)-5-methylisoxazolium-perchlorat (2,40 g, 0,01 mol), og den dannede opløsning omrøres i 1 time. En opløsning af 2-hydrazinopyrimidin (4,40 g, 0,04 mol) i dimethylformamid (20 ml) tilsættes, opløsningen omrøres i 4 timer og opvarmes derefter på dampbad i 3 timer. Vand (200 ml) tilsættes, og det udfældede stof opsamles og tørres. Udbyttet er 2,25 g (80,5 %), smp: 257 - 260° C. Omkrystallisation af 80 % acetonitril giver lysegule krystaller, smp: 262 -263°C af 3,5-diamino-6-chlorpyrazinsyre, 2-(2-pyrimidinyljhydrazid-hydrat.
Analyse beregnet for C^H^dN^O.HgO: C 36,19, H 3,71, N 37,52.
Pundet: C 36,18, H 3,75, N 37,74.
EKSEMPEL 8 5♦5-Diamlno-6-chlorpyrazinsyre. 2,2-hexamethvlenhydrazid 8 145892
En opløsning af 1-aminohomopiperidin (4,56 g, 0,04 mol) og N-(t-butyl)-3-methyl-3-(3,5-diamino-6-chlorpyrazinoyloxy)acrylamid (3,28 g, 0,01 mol) i tetrahydrofuran (50 ml) koges i 24 timer. Opløsningsmidlet afdampes under reduceret tryk, og den olieag-tige remanens opløses i isopropanol (100 ml). Ved afkøling udskilles et stof, som opsamles og tørres, 1,06 g (37%), smp: 181 ” 1S0°C. Ved omkrystallisation af acetonitril fås 3,5-dia-mino-6-chlorpyrazinsyre, 2,2-hexamethylenhydrazid, smp: 190 -192° C.
Analyse beregnet for C^E^ClNgO: C 46,39, H 6,02, N 29,52.
Pundet: C 46,80, H 5,85, N 29,96.
EKSEMPEL 9 3.5- Diamino-6-chlorpyrazinsvre. 2.2-pentamftt.h vi pnhvrtr-* ? -i ή
En blanding af 3,5-diamino-6-chlorpyrazinsyre (3,80 g, 0,02 mol) og triethylamin (2,0 g, 0,02 mol) i dimethylformamid (40 ml) omrøres i 10 minutter. Til denne opløsning sættes N-(t-butyl)-5-methylisoxazolium-perchlorat (4,80 g, 0,02 mol), og den dannede opløsning omrøres i 1 time. 1-Aminopiperidin (5,2 g, 0,52 mol) tilsættes, og opløsningen opvarmes på dampbad i 4 timer. Isopropanol (25Ο ml) tilsættes, og det faste stof, som fraskilles ved afkøling og tørres, 2,22 g (41 %), smp: 238 - 243°C. Ved omkrystallisation af acetonitril fås gule krystaller af 3,5-diami-no-6-chlorpyrazinsyre, 2,2-pentamethylenhydrazid, smp: 244 - 245°c.
Analyse beregnet for C^QH^ClNgO: C 44,36, H 5,59, N 31,05.
Fundet: C 44,52, H 5,28, N 31,37.
EKSEMPEL_12 3.5- Diamino-4-(3,5-diamino-6-chlorpyrazinamido)-4H-l,2,4-triazol-hemihydrat 9 146892
En blanding af 3,5-diamino-6-chlorpyrazinsyre (1,90 g, 0,01 mol) og triethylamin (1,0 g, 0,01 mol) i dimethylformamid (20 ml) omrøres i 10 minutter. Til denne opløsning sættes N-(t-butyl)-5-methylisoxazolium-perchlorat (2,40 g, 0,01 mol), og den dannede opløsning omrøres i 1 time. En blanding af 3,4,5-triamino-4H-1,2,4-triazol (3,06 g, 0,03 mol) og dimethylformamid (10 ml) tilsættes, og reaktionsblandingen opvarmes på dampbad i 16 timer.
Vand (200 ml) tilsættes, og det dannede bundfald opsamles og tørres; udbytte 1,50 g (51 %), gradvis dekomposition over 200° C.
Ved omkrystallisation af vand fås brune krystaller af 3,5-diami-no-4-(3,5“diamino-6-chlorpyrazinamido)-4H-1,2,4-triazol-hemihy-drat, smp: 275 - 280°c, dek..
Analyse beregnet for C7HgClN1()0.l/2H20: C 28,63, H 3,43, N 47,70. Fundet: C 28,58, H 3,37, N 47,45.
EKSEMPEL_11 N-(3.5-Diamino-6-chlorpyrazinoyl)benzamidin
Natriumhydroxid (1,20 g, 0,03 mol) opløses i vand (30 ml), og benzamidin-hydrochlorid (5,60 g, 0,036 mol) tilsættes. Denne opløsning omrøres i to minutter, N-(t-butyl)-3-methyl-3-(3,5-dia-mino-6-chlorpyrazinoyloxy)acrylamid (3,28 g, 0,01 mol) tilsættes, og blandingen omrøres i 2 timer. Bundfaldet opsamles, tørres og omkrystalliseres af acetonitril, hvorved fås 0,83 g (29 %) smp: 220 - 224°C, dek.. Ved omkrystallisation af ethanol-acetoni-tril fås N-(3,5-diamino-6-chlorpyrazinoyl)benzamidin, smp: 221 -224° C, dek..
Analyse beregnet for C^gH^ClNgO: C 49,57, H 3,81, N 28,91*
Fundet: C 49,95, H 3,90, N 29,12.
EKSEMPEL 12 (3.5-Diamino-6-chlorpvrazinovl)guanidin-hydrochlorid-dihvdrat
En blanding af 3,5-diamino-6-chlorpyrazinsyre (1,90 g, 0,01 mol) og triethylamin (1,0 g, 0,01 mol) i dimethylformamid (20 ml) om- 10 1Λ5892 røres i 10 minutter. N-(t-butyl)-5Hnethylisoxazolium-perchlorat (2,40 g, 0,01 mol) tilsættes, og den dannede opløsning omrøres i 1 time.
Natrium (1,15 g, 0,05 mol) opløses i absolut ethanol (50 ml). Guanidin-hydrochlorid (4,75 g, 0,05 mol) tilsættes, og blandingen omrøres i l/2 time. Blandingen filtreres, og filtratet inddampes under reduceret tryk. Remanensen opløses i dimethylform-amid (10 ml) og sættes til ovennævnte opløsning. Denne reaktionsblanding omrøres i 24 timer, hældes i vand (100 ml) og afkøles. Bundfaldet opsamles og tørres. Udbyttet er 0,88 g, smp: 229 -233° C,dek..
Produktet opløses i en blanding af vand (15 ml) og methansulfon-syre (2 ml) ved opvarmning, koncentreret saltsyre (4 ml) tilsættes, og opløsningen henstilles. Det udfældede stof opsamles og tørres. Udbyttet af (3,5-diamino-6-chlorpyrazinoyl)gUanidin-hy-drochloriddihydrat er 36 %, smp: 295° C, (dek.). Dette stof opfører sig på samme måde ved kromatografiske undersøgelser, har samme infrarøde spektra som en på anden måde fremstillet prøve, samt udviser ingen frysepunktsdepression med en sådan prøve.
EKSEMPEL_13 3.5-Diamino-6-chlorpYrazinoylguanidin-hydrochlorid-dihydrat
Natrium (0,09 g, 0,004 mol) opløses i absolut ethanol (10 ml), og guanidin-hydrochlorid (0,382 g, 0,004 mol) tilsættes. Denne blanding omrøres l/2 time, N-(t-butyl)-3-methyl-3-(3,5-diamino- 6-chlorpyrazinoyloxy)acrylamid (0,300 g, 0,0009 mol) tilsættes, og blandingen koges i 1 time. Reaktionsblandingen afkøles, fortyndes med vand (25 ml) og gøres sur med fortyndet saltsyre. Ved henstand udskilles et bundfald, som opsamles og tørres, hvorved fås 0,15 g (60 %), (3>5-diamino-6-chlorpyrazinoyl)guanidin-hy-drochlorid-dihydrat smp: 295° C (dek.).
1-(5.5-Diamino-6-chlorpyrazinovl)-5-isopropylidenaminoguanidin EKSEMPEL 14 11 US892
En blanding af 3,5-diamino-6-chlorpyrazinsyre (3,80 g, 0,02 mol) og triethylamin (2,0 g, 0,02 mol) i dimethylformamid (40 ml) omrøres i 10 minutter. Til denne opløsning sættes N-(t-butyl)-5-methylisoxazolium-perchlorat (4,80 g, 0,02 mol), og den dannede opløsning omrøres i 1 time. En opløsning af isopropylidenamino-guanidin (9,12 g, 0,08 mol) i dimethylformamid (20 ml) tilsættes, og reaktionsblandingen omrøres ved stuetemperatur i 18 timer.
Vand (250 ml) tilsættes, og det udfældede stof opsamles og tørres. Udbyttet af l-(3,5-diamino-6-chlorpyrazinoyl)3-isopropyli-denaminoguanidin er 4,35 g (76 %); smp: 171 - 178°c. Ved omkry-stallisation af acetonitril fås lysegule krystaller, smp: 183 -186°C.
Analyse beregnet for CgH^ClNgO: C 37,96, H 4,60, N 39,36.
Fundet: C 38,01, H 4,65, N 39,15.
EKSEMPEL 15 l-(5.5-Diamino-6-chlorpyrazinoyl)-3-hydroxyguanidin
Natrium (1,0 g, 0,044 mol) opløses i kogende isopropanol (200 ml). Hydroxyguanidin-sulfat-hydrat (6,38 g, 0,024 mol) tilsættes, og denne blanding koges i 1 time. N-(t-butyl)-3-methyl-3-(3,5-di-amino-6-chlorpyrazinoyloxy)acrylamid (6,54 g, 0,02 mol) tilsættes, kogningen fortsættes i 1 time, hvorefter blandingen afkøles og filtreres. Det gule stof vaskes med vand og isopropanol og tørres, hvorved fås 2,75 g (56 %), l-(3,5-diamino-6-chlorpyrazinoyl)- 3-hydroxyguanidin, smp: 188 - 200° C (effervescens). Ved omkrystallisation af dimethylformamid-vand fås et produkt med smp: 200 - 202° C (dek.).
Analyse beregnet for CgHgClNy02: C 29,34, H 3,28, N 39,92.
Fundet: C 29,42, H 3,25, N 40,01.
12 1-(3,5-Diamino-6-chlorpyrazinoyl)-5-benzyloxyguanldin
EKSEMPELVIS
145892
En opløsning af N-(t-butyl)-3-methyl-3-(3,5-diamino-6-chlorpyra-zinoyloxy)acrylamid (1,08 g, 0,0033 mol) og benzyloxyguanidin (1,1 g, 0,0067 mol) i tetrahydrofuran (30 ml) koges i 48 timer. Opløsningen inddampes under reduceret tryk, og isopropanol (20 ml) sættes til remanensen. Det faste stof opsamles og tørres, 0,95 g, smp: 105 - 110° C, stivner atter og smelter igen ved ca.
160° C. Ved omkrystallisation af benzen fås lysegule krystaller af l-(3,5-diamino-6-chlorpyrazinoyl)-3-benzyloxyguanidin, smp: 163 -166°C.
Analyse beregnet for C^^H^ClN^Og: C 46,50, H 4,20, N 29,21.
Pundet: C 46,72, H 4,23, N 29,45.
Ved fremgangsmåden ifølge ovennævnte eksempler kan fremstilles følgende forbindelser: 1_(3,5-diamino-6-chlorpyrazinamido)guanidin, smp: 281 - 282 °c, l-(3,5-diamino-6-chlorpyrazinamido)-3-benzylguanidin, der bliver flydende ved 120 - 130° C, stivner igen red 200° C, og derpå har et smeltepunkt på 243 - 246°C (delt.), 1-(3,5-diamino-6~chlorpyrazinamido)-3-aminoguanidin-hydrat, smp: 196- 200 °C under opbrusning, og 1-(3,5-diamino-6-chlorpyrazinamido)-2,3-ethylenguanidin, smp: 250 - 251 °C, (dek.).
Claims (2)
1. Fremgangsmåde til fremstilling af pyrazinamidderivater med den almene formel: R1 XX e halo^ “ CONHR° hvori R^ er hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkylalkyl), dialkylaminoalkyl, hydroxyalkylmethyl, poly-hydroxyalkylmethyl ,iw, \}J, U/-trif luoralkyl, phenylalkyl, halogen-phenylalkyl, furylalkyl, phenyl, halogenphenyl, alkoxy eller amino; 0 R er hydrogen eller alkyl; eller 1
2 R og R kan tilsammen danne en azacyclisk ri'ng med det tilknyttede nitrogenatom; halo er chlor, brom eller iod; R® er alkyl, alkoxymethylalkyl, cyanoalkyl, alkoxycarbonylalkyl, phenylalkyl, dialkylaminomethylalkyl, 2-(2-imidazolinyl)amino- methylalkyl, 1-pyrrolidinylalkyl, piperidinoalkyl, hexahydro- 1-azeoinylalkyl, morpholinoalkyl, 4-alkyl-l-piperazinylalkyl, alkenyl, alkynyl, phenyl, halogenphenyl, alkylphenyl, alkoxy- phenyl, amino, dialkylamino, alkylphenylalkylamino, pyridylamino, pyrimidinylamino, quinolinylamino, 1-pyrrolidinyl, 1-piperidino, 1-hexahydro-1-azepinyl, 4-morpholino, 4-(3,5-diamino-l,2,4-tria-7 7 zolyl), -OR / hvor R er alkyl, phenyl, halogen- Ih phenyl, alkylphenyl eller alkoxyphenyl; 9 10 8 -C-NR R , hvor R er hydrogen eller alkyl; t8 g R er hydrogen, alkyl, hydroxyalkyl, phenylalkyl, halogenphenyl-alkyl, alkylphenylalkyl, naphthylalkyl, pyridylalkyl, morpholinoalkyl, furylalkyl, alkoxyalkyl, alkenyl, alkylidenamino, phenyl-alkylidenamino, hydroxy, phenyl, alkylphenyl, alkoxyphenyl, halogenphenyl, alkoxyphenylalkyl, alkoxy, phenylalkoxy;
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US66600467A | 1967-09-07 | 1967-09-07 | |
| US66600467 | 1967-09-07 | ||
| US71897668A | 1968-03-21 | 1968-03-21 | |
| US71897668 | 1968-03-21 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK145892B true DK145892B (da) | 1983-04-05 |
| DK145892C DK145892C (da) | 1983-09-12 |
Family
ID=27099350
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK429268A DK145892C (da) | 1967-09-07 | 1968-09-06 | Fremgangsmaade til fremstilling af pyrazinamidderivater |
Country Status (15)
| Country | Link |
|---|---|
| AT (1) | AT289123B (da) |
| BE (1) | BE720233A (da) |
| CA (1) | CA939345A (da) |
| CH (1) | CH534168A (da) |
| DK (1) | DK145892C (da) |
| ES (1) | ES357877A1 (da) |
| FI (1) | FI50975C (da) |
| FR (1) | FR8490M (da) |
| GB (2) | GB1214408A (da) |
| IL (1) | IL30634A0 (da) |
| NL (1) | NL6812003A (da) |
| NO (1) | NO125678B (da) |
| OA (1) | OA02886A (da) |
| SE (1) | SE355811B (da) |
| YU (2) | YU205268A (da) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013064450A1 (en) | 2011-11-02 | 2013-05-10 | Boehringer Ingelheim International Gmbh | Heterocyclic compounds, medicaments containing said compounds, use thereof and processes for the preparation thereof |
| CA2854221A1 (en) * | 2011-11-02 | 2013-05-10 | Boehringer Ingelheim International Gmbh | Novel process for the preparation of acylguanidines and acylthioureas |
| US8859559B2 (en) | 2011-12-20 | 2014-10-14 | Boehringer Ingelheim International Gmbh | Substituted pyrazines and their use in the treatment of disease |
| WO2013174757A1 (en) | 2012-05-25 | 2013-11-28 | Boehringer Ingelheim International Gmbh | Tertiary amines, medicaments containing said amines, use thereof and processes for the preparation thereof |
| WO2014044849A1 (en) | 2012-09-24 | 2014-03-27 | Boehringer Ingelheim International Gmbh | Heterocyclic compounds, medicaments containing said compounds, use thereof and processes for the preparation thereof |
-
1968
- 1968-08-22 NL NL6812003A patent/NL6812003A/xx unknown
- 1968-08-26 IL IL30634A patent/IL30634A0/xx unknown
- 1968-08-28 FI FI682412A patent/FI50975C/fi active
- 1968-08-30 BE BE720233D patent/BE720233A/xx unknown
- 1968-08-31 CA CA028,994A patent/CA939345A/en not_active Expired
- 1968-09-02 YU YU02052/68A patent/YU205268A/xx unknown
- 1968-09-03 GB GB41777/68A patent/GB1214408A/en not_active Expired
- 1968-09-03 GB GB53830/69A patent/GB1214409A/en not_active Expired
- 1968-09-04 OA OA53362A patent/OA02886A/xx unknown
- 1968-09-05 SE SE11956/68A patent/SE355811B/xx unknown
- 1968-09-05 ES ES357877A patent/ES357877A1/es not_active Expired
- 1968-09-06 AT AT872468A patent/AT289123B/de not_active IP Right Cessation
- 1968-09-06 CH CH1340268A patent/CH534168A/de not_active IP Right Cessation
- 1968-09-06 DK DK429268A patent/DK145892C/da active
- 1968-09-06 NO NO3467/68A patent/NO125678B/no unknown
- 1968-12-06 FR FR176992A patent/FR8490M/fr not_active Expired
-
1969
- 1969-09-02 YU YU2052/68A patent/YU34082B/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NL6812003A (da) | 1969-03-11 |
| OA02886A (fr) | 1970-12-15 |
| BE720233A (da) | 1969-02-28 |
| CH534168A (de) | 1973-02-28 |
| YU205268A (en) | 1978-06-30 |
| YU34082B (en) | 1978-12-31 |
| FI50975C (fi) | 1976-09-10 |
| NO125678B (da) | 1972-10-16 |
| FI50975B (da) | 1976-05-31 |
| SE355811B (da) | 1973-05-07 |
| ES357877A1 (es) | 1970-05-01 |
| FR8490M (da) | 1973-07-27 |
| CA939345A (en) | 1974-01-01 |
| GB1214409A (en) | 1970-12-02 |
| GB1214408A (en) | 1970-12-02 |
| AT289123B (de) | 1971-04-13 |
| IL30634A0 (en) | 1968-10-24 |
| DK145892C (da) | 1983-09-12 |
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