IL43505A - Process for bromination of nitrogen-containing heterocyclic compounds - Google Patents
Process for bromination of nitrogen-containing heterocyclic compoundsInfo
- Publication number
- IL43505A IL43505A IL43505A IL4350573A IL43505A IL 43505 A IL43505 A IL 43505A IL 43505 A IL43505 A IL 43505A IL 4350573 A IL4350573 A IL 4350573A IL 43505 A IL43505 A IL 43505A
- Authority
- IL
- Israel
- Prior art keywords
- nitrogen
- pyrimidine
- hydrochloride
- solvent
- containing heterocyclic
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 32
- -1 nitrogen-containing heterocyclic compounds Chemical class 0.000 title claims description 23
- 238000005893 bromination reaction Methods 0.000 title claims description 6
- 230000031709 bromination Effects 0.000 title claims description 4
- 239000000203 mixture Substances 0.000 claims description 39
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 35
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 35
- 229910052794 bromium Inorganic materials 0.000 claims description 35
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 27
- 229910000039 hydrogen halide Inorganic materials 0.000 claims description 25
- 239000012433 hydrogen halide Substances 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 13
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 12
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 12
- GYCPLYCTMDTEPU-UHFFFAOYSA-N 5-bromopyrimidine Chemical compound BrC1=CN=CN=C1 GYCPLYCTMDTEPU-UHFFFAOYSA-N 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 8
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 8
- SDPYFZLDWYNXJF-UHFFFAOYSA-N 5-bromo-4-phenylpyrimidine Chemical compound BrC1=CN=CN=C1C1=CC=CC=C1 SDPYFZLDWYNXJF-UHFFFAOYSA-N 0.000 claims description 7
- 239000011541 reaction mixture Substances 0.000 claims description 7
- IDXKTTNFXPPXJY-UHFFFAOYSA-N pyrimidin-1-ium;chloride Chemical group Cl.C1=CN=CN=C1 IDXKTTNFXPPXJY-UHFFFAOYSA-N 0.000 claims description 5
- VSOSXKMEQPYESP-UHFFFAOYSA-N 1,6-naphthyridine Chemical compound C1=CN=CC2=CC=CN=C21 VSOSXKMEQPYESP-UHFFFAOYSA-N 0.000 claims description 4
- CFBYEGUGFPZCNF-UHFFFAOYSA-N 2-nitroanisole Chemical compound COC1=CC=CC=C1[N+]([O-])=O CFBYEGUGFPZCNF-UHFFFAOYSA-N 0.000 claims description 4
- PLAZTCDQAHEYBI-UHFFFAOYSA-N 2-nitrotoluene Chemical compound CC1=CC=CC=C1[N+]([O-])=O PLAZTCDQAHEYBI-UHFFFAOYSA-N 0.000 claims description 4
- ZGIKWINFUGEQEO-UHFFFAOYSA-N 3-bromoquinoline Chemical compound C1=CC=CC2=CC(Br)=CN=C21 ZGIKWINFUGEQEO-UHFFFAOYSA-N 0.000 claims description 4
- SCRBSGZBTHKAHU-UHFFFAOYSA-N 4-bromoisoquinoline Chemical compound C1=CC=C2C(Br)=CN=CC2=C1 SCRBSGZBTHKAHU-UHFFFAOYSA-N 0.000 claims description 4
- MKLQPIYLZMLAER-UHFFFAOYSA-N 4-phenylpyrimidine Chemical compound C1=CC=CC=C1C1=CC=NC=N1 MKLQPIYLZMLAER-UHFFFAOYSA-N 0.000 claims description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 4
- GOZNZGWCQSNZFX-UHFFFAOYSA-N 1,6-naphthyridine;hydrochloride Chemical compound Cl.C1=CN=CC2=CC=CN=C21 GOZNZGWCQSNZFX-UHFFFAOYSA-N 0.000 claims description 3
- DCHUYAXTJQCCRX-UHFFFAOYSA-N 4-phenylpyrimidine;hydrochloride Chemical compound Cl.C1=CC=CC=C1C1=CC=NC=N1 DCHUYAXTJQCCRX-UHFFFAOYSA-N 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000011874 heated mixture Substances 0.000 claims description 3
- PSXRWZBTVAZNSF-UHFFFAOYSA-N hydron;quinoline;chloride Chemical compound Cl.N1=CC=CC2=CC=CC=C21 PSXRWZBTVAZNSF-UHFFFAOYSA-N 0.000 claims description 3
- IEJBHGRSGHMNTB-UHFFFAOYSA-N 4-phenylpyrimidine hydrobromide Chemical compound Br.C1(=CC=CC=C1)C1=NC=NC=C1 IEJBHGRSGHMNTB-UHFFFAOYSA-N 0.000 claims description 2
- UGSBNWMMAHCMON-UHFFFAOYSA-N 4-phenylpyrimidine hydroiodide Chemical compound I.C1(=CC=CC=C1)C1=NC=NC=C1 UGSBNWMMAHCMON-UHFFFAOYSA-N 0.000 claims description 2
- FXMQMXNRMSLCKG-UHFFFAOYSA-N [I-].c1c[nH+]c2ccncc2c1 Chemical compound [I-].c1c[nH+]c2ccncc2c1 FXMQMXNRMSLCKG-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- BATMYWDOUUWCJE-UHFFFAOYSA-N pyrimidin-1-ium;bromide Chemical compound Br.C1=CN=CN=C1 BATMYWDOUUWCJE-UHFFFAOYSA-N 0.000 claims description 2
- ZSIALBZCWCLSOG-UHFFFAOYSA-N pyrimidine;hydroiodide Chemical compound I.C1=CN=CN=C1 ZSIALBZCWCLSOG-UHFFFAOYSA-N 0.000 claims description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims 4
- SHLPPXXKRFINFY-UHFFFAOYSA-N isoquinolin-2-ium;bromide Chemical compound Br.C1=NC=CC2=CC=CC=C21 SHLPPXXKRFINFY-UHFFFAOYSA-N 0.000 claims 1
- GHESMRYCQSFSSF-UHFFFAOYSA-N isoquinolin-2-ium;iodide Chemical compound [I-].C1=[NH+]C=CC2=CC=CC=C21 GHESMRYCQSFSSF-UHFFFAOYSA-N 0.000 claims 1
- LQNUZADURLCDLV-IDEBNGHGSA-N nitrobenzene Chemical group [O-][N+](=O)[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 LQNUZADURLCDLV-IDEBNGHGSA-N 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 39
- 239000007787 solid Substances 0.000 description 23
- 239000000047 product Substances 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000007795 chemical reaction product Substances 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000002002 slurry Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 239000012259 ether extract Substances 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000003822 preparative gas chromatography Methods 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 239000002026 chloroform extract Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 150000002391 heterocyclic compounds Chemical class 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
- 239000011343 solid material Substances 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- YKPXUVTWLVHJBM-UHFFFAOYSA-N 1,1,1,3-tetraethoxypropane Chemical compound CCOCCC(OCC)(OCC)OCC YKPXUVTWLVHJBM-UHFFFAOYSA-N 0.000 description 2
- WGDHEJVNOWBUCH-UHFFFAOYSA-N 5-bromopyrimidine;hydrobromide Chemical compound Br.BrC1=CN=CN=C1 WGDHEJVNOWBUCH-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 230000000855 fungicidal effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000005648 plant growth regulator Substances 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- KVJHGPAAOUGYJX-UHFFFAOYSA-N 1,1,3,3-tetraethoxypropane Chemical compound CCOC(OCC)CC(OCC)OCC KVJHGPAAOUGYJX-UHFFFAOYSA-N 0.000 description 1
- QGRPVMLBTFGQDQ-UHFFFAOYSA-N 1-chloro-2-methoxybenzene Chemical compound COC1=CC=CC=C1Cl QGRPVMLBTFGQDQ-UHFFFAOYSA-N 0.000 description 1
- FFPZTTQEXPMQBS-UHFFFAOYSA-N 4-amino-n-isoquinolin-1-ylbenzenesulfonamide Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC2=CC=CC=C12 FFPZTTQEXPMQBS-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 241000272517 Anseriformes Species 0.000 description 1
- 241000123650 Botrytis cinerea Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 241001045770 Trichophyton mentagrophytes Species 0.000 description 1
- GDKWFLJNGDCPDY-UHFFFAOYSA-N [Br-].c1cnc2cc[nH+]cc2c1 Chemical compound [Br-].c1cnc2cc[nH+]cc2c1 GDKWFLJNGDCPDY-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 230000000935 anti-streptococcal effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 244000000004 fungal plant pathogen Species 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 229910001867 inorganic solvent Inorganic materials 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- IYRMNDOLPONSCJ-UHFFFAOYSA-N isoquinolin-2-ium;chloride Chemical compound Cl.C1=NC=CC2=CC=CC=C21 IYRMNDOLPONSCJ-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000013489 large scale run Methods 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- TYRDEZUMAVRTEO-UHFFFAOYSA-N pyrimidin-5-ylmethanol Chemical class OCC1=CN=CN=C1 TYRDEZUMAVRTEO-UHFFFAOYSA-N 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/30—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B39/00—Halogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/18—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Quinoline Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
BROMINATION I PROCESS OF NITROGEN CONTAINING HETEROCYCLIC COMPOUNDS »¾»p»srnon man 3 in © n'si'sna i*->nn ΤΡ3Π n »30n The present invention relates to a process for brominating nitrogen-containing heterocycles which comprises reacting bromine at an elevated temperature with the hydrogen halide addition salt of the nitrogen-containing heterocycle in a solvent substantially inert to the action of bromine under the conditions of the process. A product of this process, 5-bromopyrimidine, has proven to be a valuable intermediate in the synthesis of several new agricultural products, particularly those which have interesting plant growth regulator and plant fungicidal properties.
The importance of these products led to a search for a more facile synthesis of the important intermediate, 5-bromopyrimidine.
In the prior art, Bredereck et al^ , Chem. Ber. 91, 2832 at 3848 (1958) , teach the reaction of pyrimidine hydrochloride with bromine by heating a mixture of the two in an oil bath for about 3 hours at a temperature of about 160°C, to form a solid mass, the reaction product mixture. The temperature of the oil bath was then raised to 250°C, and the 5-bromopyrimidine hydrobromide was sublimed out of the solid reaction product mixture under vacuum. The 5-bromopyrimidine hydrobromide was taken up in sodium bisulfite solution, the solution made alkaline with potassium hydroxide, and extracted with chloroform. The chloroform was distilled to leave behind pure 5-bromopyrimidine.
An alternate approach to the synthesis of 5-bromopyrimidine is also reported by Bredereck et al^. , Chem. Ber. 95, 803 at 807 and 808 (1962). 2-Bromo-l,l,3,3-tetraethoxy-propane was prepared by brominating 1,1,3,3-tetraethoxypropane in carbon tetrachloride. The 2-bromo-l,l,3, 3-tetraethoxypro- pane was then condensed with formamide, in the presence of ammonium formate and water, to give 5-bromopyrimidine.
The preparation of 4-bromoisoguinoline is taught by Gilman et al . , J. Am. Chem. Soc. 69 , 1946 (1947). Isoguino-line perbromide hydrobromide was subjected to prolonged heating, yielding a solid mass. Excess agueous sodium hydroxide solution was added to the solid mass and the liberated 4-bromoisoguinoline was recovered by steam distillation. The crude product was purified by recrystallization from petroleum ether.
The preparation of 5-bromo-4-phenylpyrimidine via a six-step synthetic process is reported by van der Plas, Rec. Trav. Chim. 84, 1101 (1965) , who stated that the direct bromination method of Bredereck et aJL. , supra , did not seem suitable for the synthesis of 5-bromo-4-phenylpyrimidine, the phenyl group being vulnerable to the attack of brominating agents.
The preparation of 3-bromoguinoline by the pyrolysis of guinoline hydrobromide perbromide at 180-200°C. is reported by Eisch, J. Org. Chem. 27, 1318 (1962) .
This invention relates to a process for brominating nitrogen-containing heterocycles . More particularly, this invention relates to a process for brominating a nitrogen-containing heterocyclic compound selected from the group consisting of pyrimidine, 4-phenylpyrimidine, guinoline, iso-guinoline, and 1,6-naphthyridine. The process comprises adding bromine at a uniform rate over a period of time to a heated mixture of the nitrogen-containing heterocycle in the form of its hydrogen halide salt and a solvent which is substantially inert to the action of bromine under the con- ditions of the reaction.
This invention makes available a process for preparing bromo-substituted, nitrogen-containing heterocycles , for example, 5-bromopyrimidine, in good yield, which process is adaptable to commercial use. The process has been found generally applicable to nitrogen-containing heterocycles.
The preparation of the bromo-substituted, nitrogen-containing heterocyclic compound is conveniently carried out utilizing a hydrogen halide addition salt of the particular nitrogen-containing heterocycle. Suitable hydrogen halide addition salts include those formed with hydrogen chloride, hydrogen bromide, or hydrogen iodide, for example, pyrimidine hydrochloride, pyrimidine hydrobromide, pyrimidine hydriodide, guinoline hydrochloride, guinoline hydrobromide, guinoline hydriodide, isoguinoline hydrobromide, isoguinoline hydrochloride, isoguinoline hydriodide, 4-phenylpyrimidine hydrobromide, 4-phenylpyrimidine hydrochloride, 4-phenylpyrimidine hydriodide, 1, 6-naphthyridine hydrobromide, 1,6-naphthyridine hydrochloride and 1,6-naphthyridine hydriodide. Of these hydrogen halide salts, the hydrogen chloride salts are preferred for use in the claimed bromination reaction.
The nitrogen-containing heterocycle hydrogen halide is suspended or dissolved in a suitable reaction solvent, the mixture heated, and bromine is added thereto. The bromine and the nitrogen-containing heterocycle hydrogen halide appear to first form a complex, which complex is soluble in the reaction solvent. The solvent selected is substantially inert to the action of bromine under the conditions of the reaction. A suitable solvent is one in which the starting nitrogen-containing heterocycle hydrogen halide addition salt is insoluble the complex formed between the bromine and the nitrogen-containing heterocycle hydrogen halide salt is quite soluble, and in which the hydrogen halide addition salt of the bromo-substituted nitrogen-containing heterocycle, the product, is substantially insoluble. Suitable solvents include thionyl chloride and phosphorus oxychloride, both of which are inorganic solvents, as well as organic solvents such as carbon tetrachloride, nitrobenzene, ortho-dichlorobenzene , chloro-benzene, ortho-nitrotoluene, benzonitrile, ortho-nitroanisole, and ortho-chloroanisole. All of these solvents are substantially inert to the action of bromine under the conditions of the novel process. While any of the above-mentioned solvents aid in obtaining better yields of the desired bromo-substi-tuted, nitrogen-containing heterocyclic compound, the organic solvents are more desirable because of their ease of handling and possibilities for recycling; Thus, the organic solvents benzonitrile, o-nitrotoluene , o-dichlorobenzene, o-nitro-anisole, and nitrobenzene are particularly helpful in obtaining better yields. Of these organic solvents, o-dichlorobenzene and nitrobenzene are preferred, with nitrobenzene being the solvent of choice.
The solvent plays an important part in this novel process. The solvent assists in controlling the temperature of the reaction mixture, and allows better mixing of the bromine and the nitrogen-containing heterocycle hydrogen halide addition salt. The solvent permits the reaction mixture to be stirred throughout the duration of the reaction, and makes it possible to obtain a higher yield of product than that obtained in the absence of a solvent. This reaction product mixture which can be stirred is in marked contrast to those described in the prior art where the reaction product mixtures set up as solid masses as the reaction proceeded.
The presence of the solvent also makes isolation of the bromo-substituted nitrogen-containing heterocycle easier. With the inert solvent present, the reaction product mixture is present in the reaction vessel as a slurry instead of a solid mass at the completion of the reaction, and the crude product can be filtered off from the solvent. This is more convenient, especially on a large-scale run, than isolating the product either by sublimation or by chiseling it out of the reaction vessel. The presence of the inert solvent thus greatly aids in making large-scale preparations feasible.
The bromination reaction is carried out by suspending the hydrogen halide addition salt of the nitrogen-containing heterocyclic compound in the inert solvent, for example, nitrobenzene, and heating the mixture to a suitable temperature. The suitable temperature varies with the heterocyclic reactant, from about 125°C. (pyrimidine) to about 200°C. (guinoline) .
The bromine is added to the heated mixture over a period of from about 30 to about 90 minutes. The addition is preferably carried out at such a rate that a smooth and controlled reaction of bromine with the nitrogen-containing heterocyclic compound is accomplished. The addition of the bromine over the period of from 30 to 90 minutes can preferably be accomplished dropwise in the laboratory. It is preferred that addition of the bromine be accomplished in equal portions at evenly spaced intervals of time, but addition of unequal portions of bromine may also be accomplished at unequal intervals of time.
As the bromine is added, hydrogen halide is evolved from the reaction mixture. The rate of evolution of the hydrogen halide is regulated by the rate of addition of the bromine. Control of the rate of evolution of the hydrogen halide is important in one aspect in that too rapid evolution of hydrogen halide may produce entrainment of the bromine being added. Such entrainment can cause loss of bromine, and cut down the yield of product, while raising the cost of production. Control of the rate of evolution of the hydrogen halide is important in another aspect in that the effluent gas from the reaction is desirably put through a scrubber to remove the hydrogen halide. Such removal is desirable in maintaining the atmosphere as free from noxious gases as possible. Thus, whether the reaction is being carried out on a laboratory scale or a commercial scale, the addition of the bromine is preferably accomplished at a rate which permits control of the rate of evolution of hydrogen halide to prevent the entrainment and loss of bromine, and which allows the efficient removal of hydrogen halide from the effluent gases produced by the reaction.
When addition of the bromine is complete, the reaction product mixture is heated for an additional period of time, about two to about six hours, to complete the reaction. Longer heating times tend to lower the yield of desired product and for that reason are to be avoided. Heating times also depend on the heterocyclic compound being brominated.
At the end of the additional heating period, the reaction product mixture is ready for work-up. The reaction product mixture is worked up by methods well known to those skilled in the art. Thus, the reaction product mixture is partially cooled, and a solvent, for example, benzene, added thereto. Other solvents which can be used include hexane, ether, toluene and xylene. The added solvent aids in diluting the inert reaction solvent and in separating the product from such inert solvent. After addition of the diluting solvent, the whole mixture is further cooled to about room temperature. The mixture is filtered to separate the solid which has precipitated upon cooling. The precipitated solid is the hydrogen halide salt of the bromo-substituted, nitrogen-containing heterocycle. The bromo-substituted, nitrogen-containing heterocyclic free base is obtained by suspending the salt in water, adjusting the pH to approximately pH 8 to 10 with strong base, and steam distilling. Suitable strong bases include sodium hydroxide, potassium hydroxide, and sodium carbonate. The product is filtered from the cooled distillate. Alternatively, the product can be recovered by extraction of the basic mixture with chloroform or ether.
The chloroform or ether extract is dried and the solvent distilled in vacuo, to yield the bromo-substituted, nitrogen-containing heterocycle.
The following examples serve to illustrate the invention, but are not to be regarded as limiting the scope thereof. Example 1 5-Bromopyrimidine A slurry of 29.0 g. (0.25 mole) of pyrimidine hydrochloride in 30 ml. of nitrobenzene, contained in a 250 ml. three-neck round-bottom flask equipped with a paddle stirrer, condenser, dropping funnel, and thermometer, was heated to about 130°C, and 44.0 g. (0.275 mole) of bromine was added dropwise through the dropping funnel over a period of 30 minutes. Heating and stirring was continued at about 130°C, for an additional two hours. At the end of that time, the reaction product mixture was cooled to about 80°C, and 150 ml. of benzene was added. The resulting slurry was filtered. The solid collected on the filter was washed with 100 ml. of benzene, and sucked dry. The dry, tan solid, which weighed 61.0 g., was placed in 200 ml. of water. The aqueous mixture was adjusted to pH 8 with a saturated solution of sodium carbonate and steam distilled. The distillate was cooled and the white solid filtered therefrom and air-dried overnight. The aqueous filtrate was extracted three times with 100 ml . portions of ethyl ether. The combined ether extracts were dried, filtered, and evaporated to yield additional product which was combined with the previously recovered product. The product had a melting point of about 73-75°C. and weighed 35 g. (88 percent of theory). It was identified by n.m.r. spectra and elemental analyses as 5-bromopyrimidine.
Other solvents were used in the reaction as set forth in the following table.
Example Compound Solvent Temp. 2 Pyrimidine *HC1 benzonitrile 125-128eC. 3 Pyrimidine *HC1 o-nitrotoluene 130eC. 4 Pyrimidine *HC1 o-dichlorobenzene 130°C. 5 Pyrimidine *HC1 o-nitroanisole 130°C.
Example 6 3-Bromoquinoline Λ slurry of 33.3 g. (0.20 mole) of quinoline hydrochloride in 50 ml. of nitrobenzene, contained in a 250 ml. three-neck round-bottom flask equipped with a paddle stirrer, condenser, dropping funnel, and thermometer, was heated to 177-180°C., and 35.2 g. (0.22 mole) of bromine was added drop wise via the dropping funnel over a period of 1 and 1/2 hours The temperature was maintained at about 180°C, and the mixture stirred for an additional 3 hours and 20 minutes, at which time the evolution of hydrogen chloride had ceased.
Heating was stopped, the reaction product mixture was cooled to room temperature, and 200 ml. of benzene was added. The mixture was filtered, and the solid on the filter was washed with 100 ml. of benzene, and sucked dry on the filter. In this manner, 48.7 g. of crude product was obtained. This crude product was added to 200 ml. of water and the mixture made basic with saturated aqueous sodium carbonate solution. The basic mixture was extracted four times with 200 ml. portions of ether. The combined ether extracts were dried, and the solvent was removed in vacuo, leaving 35.1 g. of a pale yellow oil which solidified on standing in the refrigerator. The solid had a melting point of about 12-13°C, and was identified as 3-bromoquinoline. Yield, 84.5 percent of theory; VPC purity, 97 percent.
Example 7 4-Bromoisoquinoline The same general procedure set forth in Example 1 above was followed. In a flask equipped with a reflux condenser, dropping funnel, thermometer, and stirrer was placed 1 33.3 g. (0.20 mole) of isoquinoline hydrochloride, together with 50 ml. of nitrobenzene, and the mixture was stirred and heated to about 180°C. to give a clear yellow solution. To this solution was added dropwise, via the dropping funnel, over a period of 1 hour and 13 minutes, 35.2 g. (0.22 mole) of bromine. The evolution of hydrogen chloride was smooth from the start to the completion of the addition of the bromine. After all the bromine had been added, the reaction mixture was of a single phase, amber red in color. Heating at about 180°C. and stirring were continued after addition of the bromine had been completed. An hour later, a few crystals of a solid material started to collect in the flask near the condenser. After 3 hours and 15 minutes of heating and stirring a very thin slurry of crystals had begun to form and hydrogen chloride evolution had become very slow. After 4 hours and 45 minutes of heating and stirring, the evolution of hydrogen chloride had practically ceased.
The heat source was shut off and the almost clear amber solution was allowed to cool slowly. At about 150°C, crystallization became very rapid. At about 90 °C, 200 ml. of benzene was added to the slurry, and the mixture was stirred for about 15 minutes. The mixture was then cooled to about 20°C. and filtered to yield fine cottony needles which were washed with 100 ml. of benzene, then reslurried with 200 ml. of benzene, filtered off, and dried. The product, which weighed 46.6 g., was placed in 200 ml. of water and the mixture made basic by the addition of a saturated solution of sodium bicarbonate. The basic mixture was extracted four times with 200 ml. portions of ether. The combined ether extracts were dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the ether was evaporated, to yield 33.6 g. of a pale yellow oil, which crystallized on standing. Using vapor-phase chromatography, this crude material was shown to contain 93.5 percent of 4-bromoisoquinoline. The overall yield of 4-bromoisoquinoline was about 80.5 percent. A sample of the crude material was recrystallized from petroleum ether to yield product having a melting point of about 41-42°C.
Example 8 5-Bromo-4-phenylpyrimidine Following the same general procedure set forth above, a mixture of 11.0 g. (0.0572 mole) of 4-phenylpyrimidine hydrochloride in 30 ml. of nitrobenzene, contained in a three-neck flask equipped with stirrer, thermometer, condenser, and dropping funnel, was stirred and heated in an oil bath at about 150°C, and 9.2 g. (0.0575 mole) of bromine was added over a period of 35 minutes. Evolution of hydrogen chloride began immediately. The reaction mixture was heated and stirred about 5.5 hours at 150°C. after addition of the bromine .
At the end of that time the reaction product mixture was cooled to about 105°C. and 100 ml. of benzene was added. Cooling was continued and at about 47 °C. a brown solid separated and a slurry formed. The mixture was stirred for about 20 minutes while cooling to room temperature. The solid material which separated was filtered off, and the filtrate, a mixture of nitrobenzene and benzene, was saved for further work-up. The gummy solid on the Buchner funnel was then suspended in water and the mixture made basic by the addition of 4.2 g. of 50 percent aqueous sodium hydroxide. The basic aqueous mixture was extracted with chloroform. The chloroform extracts were combined, dried over anhydrous magnesium sulfate, and evaporated, to give 6.1 g. of a gummy solid.
By vapor-phase chromatography assay, the gummy solid was shown to consist of 71 percent of 4-phenylpyrimidine and 29 percent of the desired product, 4-phenyl-5-bromopyrimidine. An additional 5.9 g. of solid was recovered from the filtrate, referred to above, the combined benzene and nitrobenzene from the beginning work-up of the reaction product mixture. This additional solid material was assayed by vapor-phase chromatography and was determined to contain 39 percent starting 4-phenylpyrimidine and 61 percent 5-bromo-4-phenylpyrimidine . Example 9 3 , 8-Dibromo-l , 6-naphthyridine Following the same general procedure set forth in Example 1, a mixture of 9.8 g. (0.0589 mole) of 1, 6-naphthyridine hydrochloride and 20 ml. of nitrobenzene was heated to 180°C. and bromine (10.36 g., 10 percent molar excess) was added dropwise over a period of about 50 minutes . When the addition of the bromine was complete, the reaction mixture was heated and stirred at about 178-180 °C. for an additional three and one-half hours. The reaction product mixture was then cooled to about 90°C. and 100 ml. of benzene added thereto. A tan solid separated which was filtered off and washed with ether and benzene. The solid weighed about 15 g. This tan solid was added to about 100 ml. of water. The pH of the mixture was adjusted to about 8, using solid sodium carbonate, and the basic mixture extracted four times with 200 ml. portions of chloroform. The combined chloroform extracts were dried and were evaporated to dryness to yield 8.7 g. of a tan solid. Vapor-phase chromatography showed two major components, one of which was the free base of the starting 1,6-naphthyridine and the other appeared to be desired product. The crude product was chromatographed on grade 3 alumina using 5 percent ethyl acetate in carbon tetrachloride as solvent. By this procedure, there was obtained 4.4 g. of product which was identified by n.m.r. spectra as 3, 8-dibromo-l,6-naphthyridine. This material was recrystal-lized from commercial absolute ethanol to yield 3.8 g. of needle-like crystals having a melting point of about 186-188°C.
The bromo-substituted nitrogen-containing hetero-cycles, prepared as set forth above, are useful intermediates in the preparation of compounds having interesting pharmaceutical, veterinary, and agricultural chemical utilities. Thus, for example, the 5-bromopyrimidine is used jin the synthesis of certain substituted 5-pyrimidinemethanols, which are useful either as fungicides for the control of numerous plant pathogenic fungi, or as plant growth regulators. As taught in Belgian Patent 714,003, referred to supra , the synthesis of the 5-substituted pyrimidinemethanols is accomplished by reaction of a ketone with 5-bromopyrimidine in the presence of n-butyllithium at the low temperature of a Dry Ice-acetone cooling bath.
The 4-bromoisoguinoline can be used in the preparation of 4-sulfanilamidoisoquinoline, useful for its antistrep-tococcal properties, as reported by Craig and Cass, J. Am.
Chem. Soc. 64, 783 (1942).
The 3-bromoquinoline can be used in the preparation of a- (2-piperidyl) -3-quinolinemethanol , as reported by Seibert et al. , J. Am. Chem. Soc. 68, 2721 at 2722 (1946). The gulnollnemethanol is reported to possess activity against Lophurae malaria in ducks. See Wiselogle, A_ Survey of Antimalarial Drugs, 1941-1945, Volume 1, page 149, Table 17, (Published by J. W. Edwards, Ann Arbor, Michigan, 1946) .
The 5-bromo-4-phenylpyrimidine has fungicidal activity against Trichophyton mentagrophytes and against Botrytis cinerea .
Claims (12)
1. A process for brominating a nitrogen-containing heterocyclic compound selected from the group consisting of pyrimidine, quinoline, isoquinoline, 4-phenylpyrimidine, and 1,6-naphthyridine which comprises commingling the nitrogen-containing heterocyclic compound in the form of its hydrogen halide addition salt with a solvent substantially inert to the action of bromine under the conditions of the bromination process, heating and maintaining the mixture at a temperature in the range of from about 125°C. to about 200°C, adding bromine to the heated mixture over a period of time of from about 30 minutes to about 90 minutes, and maintaining the reaction mixture at a temperature of from about 125°C. to about 200°C. for an additional period of time of from about two to about six hours.
2. The process of Claim 1 wherein the solvent is selected from the group consisting of nitrobenzene, o-dichlorobenzene, o-nitroanisole, o-nitrotoluene, and benzonitrile.
3. The process of Claims 1 or 2 wherein the solvent is nitrobenzene.
4. The process of Claims 1 or 2 wherein the solvent is o-dichlorobenzene.
5. The process of any of Claims 1 to 4 wherein the nitrogen-containing heterocyclic compound is pyrimidine.
6. The process of any of Claims 1 to 4 wherein the nitrogen-containing heterocyclic compound is quinoline.
7. The process of any of Claims 1 to 4 wherein the nitrogen-containing heterocyclic compound is isoquinoline.
8. The process of any of Claims 1 to 4 wherein the nitrogen-containing heterocycle hydrogen halide is pyrimidine hydrochloride, pyrimidine hydrobromide , pyrimidine hydriodide, quinoline hydrochloride, guinoline hydrobromide, guinoline hydriodide, isoquinoline hydro-bromide, isoguinoline hydrochloride, isoquinoline hydriodide, 4-phenylpyrimidine hydrobromide, 4-phenylpyrimidine hydrochloride, 4-phenylpyrimidine hydriodide, 1,6-naphthyri-dine hydrobromide, 1,6-naphthyridine hydrochloride or 1,6-naphthyridine hydriodide.
9. The process of any of Claims 1 to 5 or 8 wherein the nitrogen-containing heterocycle hydrogen halide is pyrimidine hydrochloride.
10. The process of any of Claims 1 to 4, 6 or 8 wherein the nitrogen-containing heterocycle hydrogen halide is quinoline hydrochloride.
11. The compounds 5-bromopyrimidine, 3-bromoquinoline , 4-bromoisoquinoline, 5-bromo-4-phenyl-pyrimidine, 3,8-dibromo-l,6-naphthyridine whenever prepared by the process of any of Claims 1 to 10.
12. The process of brominating a nitrogen-containing heterocyclic compound as defined in Claim 1, substantially as hereinbefore described with particular reference to the Examples. S. HOROWITZ & CO. AGENTS FOR APPLICANTS
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US30838972A | 1972-11-21 | 1972-11-21 |
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IL43505A true IL43505A (en) | 1977-04-29 |
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IL43505A IL43505A (en) | 1972-11-21 | 1973-10-29 | Process for bromination of nitrogen-containing heterocyclic compounds |
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BE (1) | BE807525A (en) |
CH (1) | CH584205A5 (en) |
DE (1) | DE2356358C2 (en) |
FR (1) | FR2207100B1 (en) |
GB (1) | GB1439682A (en) |
IL (1) | IL43505A (en) |
IT (1) | IT1001824B (en) |
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DE2221808C2 (en) * | 1972-05-04 | 1985-06-20 | Sandoz-Patent-GmbH, 7850 Lörrach | Hydrazinopyridazine derivatives, their acid addition salts, processes for their preparation and medicines |
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1973
- 1973-10-29 IL IL43505A patent/IL43505A/en unknown
- 1973-10-30 GB GB5046973A patent/GB1439682A/en not_active Expired
- 1973-11-06 CH CH1558773A patent/CH584205A5/xx not_active IP Right Cessation
- 1973-11-12 DE DE2356358A patent/DE2356358C2/en not_active Expired
- 1973-11-16 IT IT31462/73A patent/IT1001824B/en active
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- 1973-11-20 BE BE1005515A patent/BE807525A/en not_active IP Right Cessation
- 1973-11-21 FR FR7341410A patent/FR2207100B1/fr not_active Expired
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NL184058B (en) | 1988-11-01 |
FR2207100A1 (en) | 1974-06-14 |
IT1001824B (en) | 1976-04-30 |
DE2356358A1 (en) | 1974-05-30 |
BE807525A (en) | 1974-05-20 |
IL43505A0 (en) | 1974-01-14 |
NL184058C (en) | 1989-04-03 |
JPS596854B2 (en) | 1984-02-15 |
FR2207100B1 (en) | 1981-06-19 |
DE2356358C2 (en) | 1984-12-06 |
NL7315788A (en) | 1974-05-24 |
JPS4981375A (en) | 1974-08-06 |
CH584205A5 (en) | 1977-01-31 |
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