WO2013020938A1 - Method for the preparation of chlorinated pyridines - Google Patents
Method for the preparation of chlorinated pyridines Download PDFInfo
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- WO2013020938A1 WO2013020938A1 PCT/EP2012/065312 EP2012065312W WO2013020938A1 WO 2013020938 A1 WO2013020938 A1 WO 2013020938A1 EP 2012065312 W EP2012065312 W EP 2012065312W WO 2013020938 A1 WO2013020938 A1 WO 2013020938A1
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- WIPO (PCT)
- Prior art keywords
- formula
- compound
- group
- reaction
- metalcatalyst
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 150000003222 pyridines Chemical class 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 152
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 239000003054 catalyst Substances 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 26
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 21
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Inorganic materials [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 239000007800 oxidant agent Substances 0.000 claims description 9
- 230000001590 oxidative effect Effects 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- WXHIJDCHNDBCNY-UHFFFAOYSA-N palladium dihydride Chemical compound [PdH2] WXHIJDCHNDBCNY-UHFFFAOYSA-N 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 5
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 5
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 claims description 4
- RFSDQDHHBKYQOD-UHFFFAOYSA-N 6-cyclohexylmethyloxy-2-(4'-hydroxyanilino)purine Chemical compound C1=CC(O)=CC=C1NC1=NC(OCC2CCCCC2)=C(N=CN2)C2=N1 RFSDQDHHBKYQOD-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- CPRRHERYRRXBRZ-SRVKXCTJSA-N methyl n-[(2s)-1-[[(2s)-1-hydroxy-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CO)C[C@@H]1CCNC1=O CPRRHERYRRXBRZ-SRVKXCTJSA-N 0.000 claims description 4
- 238000006053 organic reaction Methods 0.000 claims description 4
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 4
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 229940117389 dichlorobenzene Drugs 0.000 claims description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 3
- 229950009390 symclosene Drugs 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 2
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims description 2
- 239000007792 gaseous phase Substances 0.000 claims description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims 2
- 229910006124 SOCl2 Inorganic materials 0.000 claims 1
- 230000006324 decarbonylation Effects 0.000 abstract description 7
- 238000006606 decarbonylation reaction Methods 0.000 abstract description 7
- -1 pyridine acyl halides Chemical class 0.000 abstract description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 229910052751 metal Inorganic materials 0.000 description 7
- 239000002184 metal Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 229910002666 PdCl2 Inorganic materials 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 150000001555 benzenes Chemical class 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 150000002739 metals Chemical class 0.000 description 5
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- MAKFMOSBBNKPMS-UHFFFAOYSA-N 2,3-dichloropyridine Chemical compound ClC1=CC=CN=C1Cl MAKFMOSBBNKPMS-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- 238000011437 continuous method Methods 0.000 description 4
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 4
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 4
- 239000008188 pellet Substances 0.000 description 4
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 3
- RBYGDVHOECIAFC-UHFFFAOYSA-L acetonitrile;palladium(2+);dichloride Chemical compound [Cl-].[Cl-].[Pd+2].CC#N.CC#N RBYGDVHOECIAFC-UHFFFAOYSA-L 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 3
- 239000012159 carrier gas Substances 0.000 description 3
- 239000003610 charcoal Substances 0.000 description 3
- 238000010924 continuous production Methods 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 229910001385 heavy metal Inorganic materials 0.000 description 3
- 229910001509 metal bromide Inorganic materials 0.000 description 3
- 229910001510 metal chloride Inorganic materials 0.000 description 3
- 239000010814 metallic waste Substances 0.000 description 3
- RXTRRIFWCJEMEL-UHFFFAOYSA-N 2-chloropyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1Cl RXTRRIFWCJEMEL-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- WXNOJTUTEXAZLD-UHFFFAOYSA-L benzonitrile;dichloropalladium Chemical compound Cl[Pd]Cl.N#CC1=CC=CC=C1.N#CC1=CC=CC=C1 WXNOJTUTEXAZLD-UHFFFAOYSA-L 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 150000001989 diazonium salts Chemical class 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 229910001511 metal iodide Inorganic materials 0.000 description 2
- 229910003455 mixed metal oxide Inorganic materials 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- 150000005759 2-chloropyridine Chemical class 0.000 description 1
- 150000003929 3-aminopyridines Chemical class 0.000 description 1
- CZGCEKJOLUNIFY-UHFFFAOYSA-N 4-Chloronitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C=C1 CZGCEKJOLUNIFY-UHFFFAOYSA-N 0.000 description 1
- 150000005761 4-chloropyridine Chemical class 0.000 description 1
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical class OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 description 1
- ROSCFXKNBQZLFC-UHFFFAOYSA-N 5,6-dichloropyridine-3-carbaldehyde Chemical compound ClC1=CC(C=O)=CN=C1Cl ROSCFXKNBQZLFC-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 229910052684 Cerium Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- 238000000297 Sandmeyer reaction Methods 0.000 description 1
- 229910021607 Silver chloride Inorganic materials 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical class ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- NYPWSMFKXAQMNP-UHFFFAOYSA-N carbonyl dichloride;2,3-dichloropyridine Chemical compound ClC(Cl)=O.ClC1=CC=CN=C1Cl NYPWSMFKXAQMNP-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids 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
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- PKMNZOFQIRXQDO-UHFFFAOYSA-N heptane;hexane Chemical compound CCCCCC.CCCCCCC PKMNZOFQIRXQDO-UHFFFAOYSA-N 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 229910052746 lanthanum Inorganic materials 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229910001512 metal fluoride Inorganic materials 0.000 description 1
- 229910001507 metal halide Inorganic materials 0.000 description 1
- 150000005309 metal halides Chemical class 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 229910052754 neon Inorganic materials 0.000 description 1
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- 150000002826 nitrites Chemical class 0.000 description 1
- MXQOYLRVSVOCQT-UHFFFAOYSA-N palladium;tritert-butylphosphane Chemical compound [Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C MXQOYLRVSVOCQT-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000011814 protection agent Substances 0.000 description 1
- PSAYJRPASWETSH-UHFFFAOYSA-N pyridine-2-carbonyl chloride Chemical class ClC(=O)C1=CC=CC=N1 PSAYJRPASWETSH-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/61—Halogen atoms or nitro radicals
Definitions
- XI is F, CI or Br; more preferably XI is Br or CI, even more preferably XI is CI, and Rl is selected from the group consisting of H, F, CI and Br, preferably of H, CI and Br.
- compound of formula (I) is compound of formula (1-12) and compound of formula (II) is compound of formula (11-22);
- catalyst (A) is Ru on a support (A), and support (A) is preferably charcoal.
- reaction (A) is done or carried out in a solvent (A).
- reaction (A) can be done in the presence of a reagent (A).
- Reagent (A) is a reagent that reacts with water to yield hydrogen chloride or reacts with carboxylic acids to yield acyl chlorides.
- reagent (A) is POCI 3 , oxalyl chloride or triphosgene.
- a glass tube (approximately 4 mm inner diameter) was charged with pellets (approx 2 mm diameter) of 0.5 weight% Pd on A1 2 0 3 (0.59 g, 3 mg Pd, 28 ⁇ Pd), placed vertically in an oven, flushed with nitrogen, and the oven was heated to 370 to 380 °C. Then, under a constant stream of nitrogen, a solution of compound of formula (201) (0.48 g, 2.75 mmol) and oxalyl chloride (0.19 ml, 2.23 mmol) in chlorobenzene (9.3 ml) was pumped into the upper part of the tube within 120 min. The lower part of the tube comprising the outlet of the tube was immersed in cold (0 °C) acetonitrile (70 ml).
- a glass tube (approximately 4 mm inner diameter) was charged with catalyst CAT (7) as defined in example 3 (2 mol-% Pd, the mol-% based on the molar amount of compound of formula (201)), placed vertically in an oven, the lower part of the tube was immersed in cold (0 °C) acetonitrile (70 ml), the tube was flushed with nitrogen, and the oven was heated to 385 °C.
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Abstract
The invention discloses a method for the preparation of halogenated pyridines by decarbonylation of pyridine acyl halides.
Description
Method for the preparation of chlorinated pyridines
The invention discloses a method for the preparation of halogenated pyridines by
decarbonylation of pyridine acyl halides.
Chlorinated pyridines are widely used as synthetic intermediates for the preparation of insecticides, herbicides, fungicides, other crop protection agents, pharmaceuticals, and fine chemicals. US 2010/0160641 A discloses a method for producing 2,3-dihalopyridines, wherein the process comprises halogenating 3-aminopyridines with an halogenating agent in presence of ferric chloride, to obtain crude 3-amino-2-halopyridines, diazotizing the 3-amino-2- halopyridines with a nitrite salt to obtain diazonium salts, reacting the diazonium salt with halo acid in presence of a copper (I) catalyst to form crude mass of 2,3-dihalopyridines, and isolating the desired products 2,3-dihalopyridines.
This multistep synthesis proceeds under high dilution, comprises a Sandmeyer reaction and generates large amounts of inorganic and heavy metal waste; the process can not or only inadequately, dissatisfactorily and with difficulties be adapted to a continuous process technology.
Verbicky et al, Tetrahedron Letters, 1982, 23, 371-372, discloses the preparation of p- substituted chlorobenzenes by decarbonylation of p-substituted benzoyl chlorides in the gas phase at elevated temperatures with Pd on carbon as catalyst. The p-nitro substituted benzoyl chloride provides p-nitro chlorobenzene in 7% yield.
Graf R., Journal fur praktische Chemie, 1932, 134, 177-187, discloses a decarbonylation of 5,6-dichloro pyridine carbonyl chloride to 5,6-dichloro-pyridine-3-aldehyde. 2,3- dichloropyridine was observed as side product via cleavage of HCl and CO. But no chlorine was bound to the carbon previously substituted by COC1.
Pyridines are less electron rich than benzenes, and do not usually undergo reactions as those reported for benzenes. Thus, while benzenes may be chlorinated under mild conditions and with high regioselectivity, pyridines can usually only be chlorinated under harsh conditions,
as reported e.g. by Pearson et al, J. Org. Chem., 1961, 26, 789-792; often yielding mixtures of isomers and poly chlorinated pyridines. Benzenes undergo Friedel-Crafts acylation under mild conditions, while pyridines can not usually be acylated with acyl halides, as reported by Jephcott et al, J. Am. Chem. Soc, 1928, 50, 1189-1192. Therefore, it is not to be generally expected that pyridines will react in the same way as benzenes.
There was a need for a method for preparation chlorinated pyridines with a method having few steps, without generating large amounts of inorganic or heavy metal waste, with good yields and the potential to implement a continuous process.
Surprisingly, it was found, that chlorinated pyridines can be prepared from pyridine carboxylic acid chlorides by catalyzed decarbonylation.
The following abbreviations are used, if not otherwise stated:
halogen means F, CI, Br or I, preferably CI, Br or I, more preferably CI or Br;
metal halide means metal fluoride, metal chloride, metal bromide or metal iodide, preferably metal chloride, metal bromide or metal iodide, more preferably metal chloride or metal bromide;
alkyl or alkane means linear, branched alkyl or alkane or cycloalkyl or cycloalkane. Subject of the invention is a method (A) for the preparation of a compound of formula (I),
XI is F, CI or Br; catalyst (A) is selected from the group consisting of metalcatalyst (A), metalcatalyst (A) on a support (A) and mixtures thereof;
metalcatalyst (A) is a substance derived from Pd(0), Pd (I), Pd(II), Ni(0), Ni(I), Ni(II), Pt(0),
Pt(I), Pt(II), Co(0), Ru(0), lr(0), Rh(0), Rh(I), Rh(III), Ag(0), Ag(I), Cu(0), Cu(I) or
Cu(II);
support (A) is a support conventionally used for supporting metalcatalysts, which are used in organic reactions.
Reaction (A) is a decarbonylation. The contact of compound of formula (II) with catalyst (A) at a temperature (A) provides for the decarbonylation. In other words, in reaction (A) compound of formula (II) is decarbonylated at a temperature (A) in the presence of a catalyst (A).
Preferably, Rl and R2 are identical or different and independently from each other selected from the group consisting of H, halogen, Ci_4 alkyl, CN, CF3, Ci_4 alkoxy and Ci_4 alkoxycarbonyl; more preferably, Rl and R2 are identical or different and independently from each other selected from the group consisting of H, F, CI,
Br, Ci_4 alkyl, CN and CF3; even more preferably, Rl and R2 are identical or different and independently from each other selected from the group consisting of H, CI, Br, Ci_4 alkyl, CN and CF3.
Especially, R2 is H and Rl is selected from the group consisting of H, halogen, Ci_4 alkyl,
CN, CF3, Ci_4 alkoxy and Ci_4 alkoxycarbonyl; more especially Rl is selected from the group consisting of H, F, CI, Br, Ci_4 alkyl, CN and CF3; even more especially Rl is selected from the group consisting of H, CI, Br, Ci_4 alkyl, CN and CF3.
In particular, R2 is H and Rl is selected from the group consisting of H, F, CI, Br, methyl, ethyl, CN, CF3; more in particular Rl is selected from the group consisting of H, F, CI, Br. Preferably, XI is Br or CI, more preferably XI is CI.
Specifically, XI is Br or CI, more preferably XI is CI, and R2 is H, and Rl is selected from the group consisting of H, F, CI and Br, preferably of H, CI and Br.
Preferably,
compound of formula (I) is compound of formula (1-1) and compound of formula (II) is
compound of formula (II- 1), or
compound of formula (I) is compound of formula (1-2) and compound of formula (II) is
compound of formula (II-2);
compound of formula (I) is compound of formula (1-5) and compound of formula (II) is
compound of formula (Π-5), or
compound of formula (I) is compound of formula (1-6) and compound of formula (II) is
compound of formula (II-6);
(1-5) (II-5)
(1-6) (II-6) wherein Rl is as defined herein, also with all its preferred embodiments. Even more preferably,
compound of formula (I) is compound of formula (1-5) and compound of formula (II) is compound of formula (Π-5), or
compound of formula (I) is compound of formula (1-6) and compound of formula (II) is compound of formula (II-6);
(1-6) (II-6)
XI is F, CI or Br; more preferably XI is Br or CI, even more preferably XI is CI, and Rl is selected from the group consisting of H, F, CI and Br, preferably of H, CI and Br.
Especially,
compound of formula (I) is compound of formula (I- 10) and compound of formula (II) is compound of formula (11-20), or
compound of formula (I) is compound of formula (I- 11) and compound of formula (II) is compound of formula (11-21), or
compound of formula (I) is compound of formula (1-12) and compound of formula (II) is compound of formula (11-22);
(1-10) (11-20)
(i-i i) (11-21)
(1-12) (11-22) wherein Rl is as defined herein, also with all its preferred embodiments. More especially,
compound of formula (I) is compound of formula (I- 10) and compound of formula (II) is compound of formula (11-20), or
compound of formula (I) is compound of formula (1-11) and compound of formula (II) is compound of formula (11-21), or
compound of formula (I) is compound of formula (1-12) and compound of formula (II) is compound of formula (11-22);
In particular,
compound of formula (I) is compound of formula (101) and compound of formula (II) is compound of formula (201), or
compound of formula (I) is compound of formula (102) and compound of formula (II) is compound of formula (202), or
compound of formula (I) is compound of formula (103) and compound of formula (II) is compound of formula (203), or
compound of formula (I) is compound of formula (104) and compound of formula (II) is compound of formula (204).
(101) (201)
(102) (202)
(103) (203)
(104) (204)
More in particular,
compound of formula (I) is compound of formula (101) and compound of formula (II) is compound of formula (201).
Preferably, metalcatalyst (A) is a substance derived from Pd(0), Pd (I), Pd(II), Ni(0), Ni(I),
Ni(II), Ru(0), Ag(0), Ag(I), Cu(0), Cu(I) or Cu(II).
More preferably, metalcatalyst (A) is a substance derived from Pd(0), Pd (I), Pd(II), Ni(0),
Ni(I), Ni(II), Ru(0), Ag(0) or Ag(I).
Even more preferably, metalcatalyst (A) is a substance derived from Pd(0), Pd (I), Pd(II) or
Preferably, support (A) is a support conventionally used for supporting metalcatalysts, which are used in heterogeneously catalyzed organic reactions.
More preferably, support (A) is carbon or an inorganic substance conventionally used for supporting metalcatalysts, which are used in heterogeneously catalyzed organic reactions.
More preferably, support (A) is selected from the group consisting of carbon, of oxides,
sulfates and carbonates of metals, said metals are selected from the group consisting of alkaline earth metals, Al, Si, Ce, Zr, La, Ti and Zn, of mixed metal oxides of said metals, of mixed metal carbonates of said metals, of mixed metal oxides carbonates of said metals and of mixtures thereof,
Preferably, mixed metallic oxides are alumosilicates, more preferably zeolithes.
Even more preferably, support (A) is selected from the group consisting of carbon, A1203, BaS04, Si02, alumosilicate and mixtures thereof.
Especially, support (A) is carbon, BaS04 or A1203.
More especially, support (A) is BaS04 or A1203.
If Pd on a support is used as catalyst (A), the support (A) is preferably A1203, BaS04 or charcoal, more preferably A1203 or BaS04.
Preferably, if metalcatalyst (A) is derived from Pd(0), Pd(I) or Pd(II), then metalcatalyst (A) is selected from the group consisting of
PdCl2, Pd(OAc)2, PdCl2(PhCN)2, PdCl2(MeCN)2, PdCl2(PPh3)2,
Pd, Pd(dba)2, Pd2(dba)3, Pd(P(tBu)3)2, Pd2(P(tBu)3)3, Pd(P(l-adamantyl)3)2, Pd2(P(l- adamantyl)3)3, Pd(PPh3)4, Pd on charcoal, on A1203, or on BaS04,
and mixtures thereof;
more preferably selected from the group consisting of
Pd, PdCl2, Pd(OAc)2, Pd(dba)2, Pd2(dba)3, PdCl2(PhCN)2, PdCl2(MeCN)2, Pd on charcoal, on A1203, or on BaS04, and mixtures thereof;
even more preferably selected from the group consisting of
Pd, PdCl2, Pd(OAc)2, Pd(dba)2, Pd2(dba)3, PdCl2(MeCN)2, Pd on charcoal, on A1203, or on BaS04, and mixtures thereof;
especially selected from the group consisting of Pd, PdCl2, Pd(OAc)2, Pd2(dba)3 and Pd on charcoal, on A1203, or on BaS04;
more especially selected from the group consisting of Pd, PdCl2, Pd(OAc)2 and Pd on
charcoal, on A1203, or on BaS04. Preferably, if metalcatalyst (A) is derived from Ru(0), then catalyst (A) is Ru on a support (A), and support (A) is preferably charcoal.
Preferably, if metalcatalyst (A) is derived from Ni(0), Ni(I) or Ni(II), then catalyst (A) is Ni on a support (A), and support (A) is preferably Si02, or NiCl2
Preferably, if metalcatalyst (A) is derived from Cu(0), Cu(I) or Cu(II), then metalcatalyst (A) is selected from the group consisting of Cu, CuCl and CuCl2.
Preferably, if metalcatalyst (A) is derived from Ag(0) or Ag(I), then metalcatalyst (A) is selected from the group consisting of Ag and AgCl.
Preferably, metalcatalyst (A) is Pd, more preferably Pd(0).
Preferably, catalyst (A) is a metalcatalyst (A) on a support (A), wherein the metalcatalyst (A) is Pd(0) or Ru(0), and the support (A) is selected from the group consisting of carbon,
A1203, BaS04, Si02, alumosilicate and mixtures thereof.
More preferably, catalyst (A) is a metalcatalyst (A) on a support (A), wherein the
metalcatalyst (A) is Pd(0) or Ru(0), and the support (A) is selected from the group consisting of carbon, A1203 and BaS04.
Even more preferably, catalyst (A) is a metalcatalyst (A) on a support (A), wherein the metalcatalyst (A) is Pd and the support (A) is AI2O3.
Especially, catalyst (A) is a metalcatalyst (A) on a support (A), wherein the metalcatalyst (A) is Pd(0) and the support (A) is AI2O3.
Preferably, the amount of metalcatalyst (A) is from 0.001 to 1000 mol%, more preferably from 0.001 to 100 mol%, even more preferably 0.5 to 100 mol%, the mol% being based on the molar amount of compound of formula (II). In another preferred embodiment, the amount of metalcatalyst (A) is from 0.001 to 10 mol%, more preferably from 0.05 to 5 mol%, even more preferably from 0.1 to 2 mol%, the mol% being based on the molar amount of compound of formula (II).
Preferably, when catalyst (A) comprises a support (A), the amount of support (A) is from 20% to 99.99% weight%, more preferably from 40% to 99.9% weight%, even more preferably from 70%> to 99.5%>, the % being weight%> and are based on the total weight of catalyst (A).
Preferably, reaction (A) is done at a temperature (A) of 200 to 500 °C, more preferably of 250 to 500 °C, even more preferably of 300 to 500 °C, in another even more preferred
embodiment of 250 to 400 °C.
Preferably, reaction (A) is done in gaseous phase. Preferably, reaction (A) is done at a pressure of 0.001 to 10 bar, more preferably of 0.01 to 5 bar, even more preferably of 0.5 to 2 bar.
Preferably, the reaction time of reaction (A) is from 5 min to 24 h, more preferably from 10 min to 12 h, even more preferably from 1 h to 6 h.
In one embodiment, reaction (A) is done or carried out without a solvent.
In another embodiment, reaction (A) is done or carried out in a solvent (A).
Preferably, solvent (A) is selected from the group consisting of chlorobenzene,
dichlorobenzene, toluene, xylene, trimethylbenzene, benzene, mono-, di- and tri- fluorinated
benzene, chloroform, carbon tetrachloride, dichloromethane, acetonitrile, C5_i2 alkanes and mixtures thereof.
C5_i2 alkanes are preferably selected from the group consisting of pentane, hexane, heptane and methy Icy clo hexane.
More preferably, solvent (A) is selected from the group consisting of chlorobenzene, dichlorobenzene, toluene, xylene, benzene, chloroform, carbon tetrachloride,
dichloromethane, acetonitrile, pentan, hexane heptane and methy Icy clo hexane and mixtures thereof.
Even more preferably, solvent (A) is chlorobenzene, chloroform and acetonitrile.
Preferably, the amount of solvent (A) is from 0.5 to 200 fold, more preferably from 2 to 100 fold, even more preferably from 5 to 50 fold, especially from 10 to 30 fold, of the weight of compound of formula (II).
Compound of formula (II) can be added to the reactor either as a melt or as a solution in solvent (A). Optionally, reaction (A) can be done in the presence of a reagent (A). Reagent (A) is a reagent that reacts with water to yield hydrogen chloride or reacts with carboxylic acids to yield acyl chlorides.
Preferably, reagent (A) is selected from the group consisting of oxalyl chloride, POCI3, PCI5, SOCI2, phosgene, diphosgene, triphosgene, Ci_4 carboxylic acid chloride, carbon tetrachloride and mixtures thereof.
A Ci_4 carboxylic acid chloride is preferably acetyl chloride.
More preferably, reagent (A) is POCI3, oxalyl chloride or triphosgene.
Even more preferably, reagent (A) is oxalyl chloride. Preferably, the molar amount of reagent (A) is from 1 to 200 %, more preferably from 5 to 150 %, even more preferably from 10 to 100 %, the % being based on the molar amount of compound of formula (II).
Optionally, reaction (A) can be done in the presence of an oxidant (A).
Preferably, oxidant (A) is selected from the group consisting of air, 02, Cl2, Br2, 12, N20, N02, sulfuryl chloride, cyanogene chloride, Ν,Ν,Ν-trichloroisocyanuric acid and mixtures thereof. More preferably, oxidant (A) is selected from the group consisting of 02, Cl2, N20, N02, cyanogene chloride and mixtures thereof.
Preferably, the molar amount of oxidant (A) is from 1 to 200 %, more preferably from 20 to 150 %, the % being based on the molar amount of compound of formula (II).
Reaction (A) can be done under inert atmosphere. Preferably, the inert atmosphere is made from a gas (A) selected from the group consisting of nitrogen, helium, neon, argon, carbon dioxide and mixtures thereof.
More preferably, gas (A) is nitrogen or carbon dioxide.
Preferably, the method (A) is done continuously, i.e. the reaction (A) is done in a continuous way, in a reactor for continuous reactions. Preferably, a melt or a mixture, preferably a solution, of compound of formula (II) in solvent (A) is continuously added into the reactor for continuous reactions, such as a tube reactor or a micro reactor, the continuous reactor is charged with catalyst (A) and heated to the desired temperature (A), and the product is removed at the other end of the reactor for continuous reactions. Preferably, the whole zone of the continuous reactor, where the catalyst (A) is located, is heated to the desired temperature (A). The time of contact of compound of formula (II) with the catalyst (A) will depend on the concentration of compound of formula (II), on the addition rate of compound of formula (A) into the continuous reactor, on the flow rate (A) of compound of formula (A) and optionally on the flow rate of an optional gas (A).
In case of a continuous method (A), the process parameters can be adjusted in such a way, that a high conversion of compound of formula (II) into compound of formula (I) is attained, but the amount of byproducts is kept low. In another embodiment, a continuous method (A) can be done in such a way, that only a low, preferably equal or below 40 %, conversion rate of compound of formula (II) into compound of formula (I) is attained, the conversion rate in % are weight % of compound of formula (I) based on the weight of compound of formula (II).
Optionally in case of a continuous method (A), the crude product mixture comprising compound of formula (I) and compound of formula (II) can be fed again into the continuous reactor and subjected again to the conditions of reaction (A). Such a technique would be suitable for a continuous loop reactor set-up.
A continuous method (A) or reaction (A) has the advantage, that residence time of the product at the elevated temperature (A) and optionally in the solvent (A) can be minimized, thereby side reaction can be avoided or at least minimized. Compound of formula (I) and compound of formula (II) can be separated by conventional separation techniques, such as distillation or crystallization.
The compound of formula (I) can be isolated, purified, and analyzed using conventional techniques, well known to those skilled in the art. For instance, the gases leaving a reactor can be cooled, and the products of the reaction can be collected in a freezing trap. Alternatively, the gases leaving a reactor can be conveyed into a cold inert solvent, such as solvent (A) or dichloromethane, preferably dichloromethane, acetonitrile or toluene. The resulting solution or mixture can be distilled.
Compound of formula (I) can be purified, preferably by distillation, optionally under reduced pressure, or by crystallization.
The condensed crude products from reaction (A) can be treated with water, optionally water comprising a base, i.e. of alkaline pH, in order to hydrolyze the unreacted compound of formula (II), and compound of formula (I) can be isolated by phase separation and distillation.
Further subject of the invention is a method (A), with the method (A) as defined above, also with all its preferred embodiments,
wherein after reaction (A) a reaction (REG) is done;
wherein in reaction (REG) catalyst (A) is contacted with oxidant (REG) at a temperature
(REG) of 300 to 1000 °C;
oxidant (REG) is selected from the group consisting of air, 02, Cl2, Br2, 12, N20, N02, sulfuryl chloride, cyanogene chloride, Ν,Ν,Ν-trichloroisocyanuric acid and mixtures thereof; with catalyst (A) as defined above, also with all its preferred embodiments.
Preferably, oxidant (REG) is selected from the group consisting of air, 02 and N20.
Preferably, temperature (REG) is from 400 to 900 °C. The method of the present can be performed continuously, what provides a more constant product quality than batchwise processes. A continuous process is also more convenient for the large scale production of compounds, because fewer complex operations and fewer operators are required, because no dangerous accumulation of starting materials occurs, and because the process is easier to control.
A further important andvantage of the process of the present invention is, that no inorganic or heavy metal waste but only carbon monoxide is produced as byproduct, and no large amounts of solvents and water are required. The absence of water in the process of the present invention enables the complete recycling of the unreacted compound of formula (II), and provides for dry compound of formula (I). Some of the compounds of formula (I), in particular 2- and 4-chloropyridines are water sensitive, and can react with water to form the corresponding 2- or 4-hydroxypyridines. For this reason, the absence of water in the current, new process is a further valuable feature.
Examples
List of Abbreviations and Raw materials
hexanes mixture of isomeric hexanes
THF tetrahydrofuran
quant. quantitative, i.e. 100% yield
GC Method
column: ZS-G00011 1, HP-5 ms, 30 m x 0.25 mm x 0.25 μιη
initial temperature: 60 °C
initial time: 1.0 min
number of ramps: 1
rate: 20 K/min
final temperature: 280 °C
GC-MS Method
For the GC part of GC-MS, the same above listed parameter as for GC alone were used.
GC-MS analysis of the crude product mixture of example 1 and 2 gave three main peaks. The crude product of example 1 gave the following result:
3.63 min (33% area, M+ 112, PhCl);
5.67 min (30% area, M+ 147/149, 2,3-dichloropyridine)
7.08 min (33% area, M+ 175/177, 2-chloronicotinoyl chloride)
These three peaks accounted for 96% of total peak area. None of the additional peaks accounted for more than 1.2% of the total peak area.
The identity of the peak at 5.67 min was ascertained by analyzing a commercial sample of 2,3-dichloropyridine (Aldrich) using the same GC-method as above. Retention time and mass spectrum were identical to those of crude product.
NMR Method
The molar ratio of compound of formula (II) to compound of formula (I) was determined by 1H-NMR in CDCI3 chloroform using commercially available reference substances.
Example 1
A glass tube (approximately 4 mm inner diameter) was charged with pellets (approx 2 mm diameter) of 0.5 weight% Pd on A1203 (0.59 g, 3 mg Pd, 28 μιηοΐ Pd), placed vertically in an oven, flushed with nitrogen, and the oven was heated to 370 to 380 °C. Then, under a constant stream of nitrogen, a solution of compound of formula (201) (0.48 g, 2.75 mmol) and oxalyl chloride (0.19 ml, 2.23 mmol) in chlorobenzene (9.3 ml) was pumped into the upper part of the tube within 120 min. The lower part of the tube comprising the outlet of the tube was immersed in cold (0 °C) acetonitrile (70 ml).
When the addition was finished, a sample of the acetonitrile solution was concentrated to dryness, and the residue analyzed by 1H NMR, GC and GC-MS. 1H NMR indicated the product to be essentially a mixture of compound of formula (201) and compound of formula (101) in a molar ratio of 0.80 : 0.20 of compound of formula (201) : compound of formula (101). 1H NMR (400 MHz, CDC13)
2-chloronicotinic acid chloride: delta 7.46 (dd, J = 4 Hz, 6 Hz, 0.8 H), 8.41 (dd, J = 2 Hz, 6 Hz, 0.8H), 8.61 (dd, J = 2 Hz, 4 Hz, 0.8H)
2,3-dichloropyridine: delta 7.23 (dd, J = 4 Hz, 6 Hz, 0.2 H), 7.79 (dd, J = 2 Hz, 6 Hz, 0.2 H), 8.31 (dd, J = 2 Hz, 4 Hz, 0.2H)
Example 2
Example 1 was repeated with the sole difference, that the solution of compound of formula (201) and oxalyl chloride in chlorobenzene (9.3 ml) was pumped into the upper part of the tube within 30 min (and not with 120 min).
The resulting molar ratio of compound of formula (201) to compound of formula (101), as determined by 1H NMR, was 0.89 : 0.11.
NMR, GC-retention times, and MS data were equivalent to example 1. Examples 3
Example 3-1 to 3-19 were carried out with the general procedure was as follows:
A glass tube (approximately 4 mm inner diameter) was charged with catalyst CAT in an amount as given in table (1), wherein the amount is given in table (1) as mol-% of the metal of the catalyst, the mol-% being based on the molar amount of compound of formula (201); in
case that CAT was in form of pellets, the diameter of the pellets was approx 2 mm; placed vertically in an oven, the lower part of the tube comprising the outlet was immersed in cold (0 °C) acetonitrile (70 ml), the tube was flushed with nitrogen, and the oven was heated to the first temperature TEMP given in table (1). Then, under a constant stream of nitrogen as a carrier gas, wherein only in example 3-12 the carrier gas C02 instead of nitrogen was used, a solution of compound of formula (201) (0.5 g; except for example 3-19, where 200 mg were used instead of 0.5 g) and oxalyl chloride (0.83 mol equivalents, the mol equivalents based on the molar amount of compound of formula (201); except for examples 3-5, 3-15 and 3-19, where no oxalyl chloride was used, and except for example 3-6, where 0.28 mol equivalents of triphosgene was used, the mol equivalents based on the molar amount of compound of formula (201)) in the solvent chlorobenzene, wherein only in example 3-5 the solvent chloroform instead of chlorobenzene was used, was pumped into the upper part of the tube within dosing time DOS. The temperature during dosing was in the range of the first temperature TEMP to the second temperature TEMP as given in table (1).
The concentration of compound of formula (201) with respect to solvent was 5 % by weight of compound of formula (201), the % by weight based on the weight of the combined amount of compound of formula (201) and solvent; except for example 3-5, where 10 % by weight were used, and except for example 3-19, where 16 % by weight were used, instead of said 5 % by weight.
The effluent condensed in said acetonitrile.
Further details of examples 3-1 to 3-19 are given in table (1).
Table (1)
Ex Catalyst DOS TEMP Ratio yield
CAT Amount (10) (11)
[mol-%] [min] [°C] [%]
3-1 (5) 1 120 375, 380 1:0.24 nd
3-2 (5) 1 30 375, 385 1:0.13 nd
3-3 (8) 2 60 380, 395 1:0.83 43
3-4 (9) 2 60 380, 390 1:0.21, 1:0.13 7
3-5 (14) 2 60 390, 405 1:0.04 3.5
3-6 (8) 2 60 380, 400 1:0.8, 1:3.57, 1:2.38 20
3-7 (8) 2 60 450, 475 1:25, 1:3.6, 1:1.3 41
3-8 (8) 2 60 300, 315 1:0.58, 1:0.451:0.26 16
3-9 (8) 2 60 380, 396 1:52, 1:8, 1:2.4 42
3-10 (5) 1 60 377, 390 1:0.06, 1:0.11, 1:0,11 8
3-11 (5) 1 60 375, 395 1:0.12, 1:0.12, 1:0.14 6
3-12 (8) 2 60 376, 390 1:2.8, 1:1.5, 1:0.91 36
3-13 (13) 2 60 374, 390 1:0.006, 1:0.001, 1:0.01 0.4
3-14 (?) 0.5 60 370, 390 1:0.46, 1:0.20, 1:0.46 24
3-15 (8) 1 60 340, 380 1:0.45, 1:0.12 9
3-16 (V) 5 60 374, 380 1:38, 1:23 nd
3-17 (5) 5 60 374, 387 1:0.25, 1:0.33, 1:0.59 nd
3-18 (?) 2 60 379, 387 1:0.55, 1:0.36, 1:0.30, nd
1:0.14, 1:0.13
3-19 (8) 3 25 395, 400 1:0.79 nd not determined
0.5 % by weight, the % by weight being based on the total weight of the catalyst, of Pd on A1203, as pellets
0.5 % by weight, the % by weight being based on the total weight of the catalyst, of Pd on AI2O3, as powder
10 % by weight, the % by weight being based on the total weight of the catalyst, of Pd on C, as powder
(9) 5 % by weight, the % by weight being based on the total weight of the catalyst, of Ru on C, as powder
(10) A sample of the condensate was concentrated to dryness, and the residue analyzed by 1H NMR. Table (1) gives the molar ratio of compound of formula (201) : compound of formula (101).
If one ratio is given, the sample was taken when the dosing was finished.
If two ratios are given, the first sample giving the first ratio was taken when the dosing was half finished, the second sample giving the second ratio was taken when the dosing was finished.
If three ratios are given, the first sample giving the first ratio was taken when the
dosing was one third half finished, the second sample giving the second ratio was taken when the dosing was two third finished, and the third sample giving the third ratio was taken when the dosing was finished.
If five ratios are given, a total of five samples were taken after one fifth, after two fifth, after three fifth, after four fifth and at the end of the dosing time.
(11) a sample of the final condensate, after dosing was finished, was used to determine the yield of compound of formula (101) by 1H NMR with an internal standard, the yield is given in mol-%, the mol-% being based on the molar amount of compound of formula (201)
(13) 10 % by weight, the % by weight being based on the total weight of the catalyst, of Pd on BaS04, as powder
(14) PdCl2 as powder
In example 3-19 compound of formula (202) was used instead of compound of formula (201), and compound of formula (102) was the product instead of compound of formula (101), the therefore any molar amounts are based on compound of formula (202) and not on compound of formula (201).
Examples 4
For a first dosing, a glass tube (approximately 4 mm inner diameter) was charged with catalyst CAT (7) as defined in example 3 (2 mol-% Pd, the mol-% based on the molar amount of compound of formula (201)), placed vertically in an oven, the lower part of the tube was immersed in cold (0 °C) acetonitrile (70 ml), the tube was flushed with nitrogen, and the oven was heated to 385 °C. Then, under a constant stream of nitrogen as a carrier gas, a solution of compound of formula (201) (0.5 g, 2.8 mmol) and oxalyl chloride (0.83 mol equivalents, the
mol equivalents based on the molar amount of compound of formula (201)) in the solvent chlorobenzene was pumped into the upper part of the tube within 60 min. The temperature during dosing was from 385 to 394 °C.
The concentration of compound of formula (201) with respect to the solvent was 5 % by weight of compound of formula (201), the % by weight based on the weight of the combined amount of compound of formula (201) and solvent.
The effluent condensed in said acetonitrile.
After this first dosing the catalyst was heated to 450 °C and was contacted with air at 450°C. Then a second dosing was done in analogy to the first dosing with the sole difference, that the temperature range during the second dosing was from 380 to 396 °C.
The ratios in analogy to example 3 (10) were for the first dosing 1 : 3.8, 1 : 1.55, 1 :0.60, and for the second dosing 1 :3.8, 1 :0.60, 1 :0.30.
Claims
1. A method (A) for the preparation of a compound of formula (I),
method (A) comprises a reaction (A), wherein a compound of formula (II)
XI is F, CI or Br; catalyst (A) is selected from the group consisting of metalcatalyst (A), metalcatalyst (A) on a support (A) and mixtures thereof;
metalcatalyst (A) is a substance derived from Pd(0), Pd (I), Pd(II), Ni(0), Ni(I), Ni(II), Pt(0),
Pt(I), Pt(II), Co(0), Ru(0), lr(0), Rh(0), Rh(I), Rh(III), Ag(0), Ag(I), Cu(0), Cu(I) or
Cu(II);
support (A) is a support conventionally used for supporting metalcatalysts, which are used in organic reactions.
2. Method (A) according to claim 1 , wherein Rl and R2 are identical or different and independently from each other selected from the group consisting of H, halogen, Ci_4 alkyl, CN, CF3, Ci_4 alkoxy and Ci_4 alkoxycarbonyl.
3. Method (A) according to claim 1 or 2, wherein
XI is CI or Br.
4. Method (A) according to one or more of claims 1 or 3, wherein
compound of formula (I) is compound of formula (1-1) and compound of formula (II) is compound of formula (II- 1), or
compound of formula (I) is compound of formula (1-2) and compound of formula (II) is compound of formula (Π-2).
5. Method (A) according to one or more of claims 1 or 3, wherein
compound of formula (I) is compound of formula (1-5) and compound of formula (II) is compound of formula (Π-5), or
compound of formula (I) is compound of formula (1-6) and compound of formula (II) is compound of formula (Π-6). 
(1-5) (II-5)
(1-6) (II-6)
6. Method (A) according to one or more of claims 1 to 5, wherein
metalcatalyst (A) is a substance derived from Pd(0), Pd (I), Pd(II), Ni(0), Ni(I), Ni(II), Ru(0), Ag(0), Ag(I), Cu(0), Cu(I), Cu(II).
7. Method (A) according to one or more of claims 1 to 6, wherein
catalyst (A) is a metalcatalyst (A) on a support (A), wherein the metalcatalyst (A) is Pd(0) or Ru(0), and the support (A) is selected from the group consisting of carbon, A1203, BaS04, Si02, alumosilicate and mixtures thereof.
8. Method (A) according to one or more of claims 1 to 7, wherein
reaction (A) is done at a temperature (A) of 200 to 500 °C.
9. Method (A) according to one or more of claims 1 to 8, wherein
reaction (A) is done in gaseous phase.
10. Method (A) according to one or more of claims 1 to 9, wherein
reaction (A) is done in a solvent (A); solvent (A) is selected from the group consisting of chlorobenzene, dichlorobenzene, toluene, xylene, trimethylbenzene, benzene, mono-, di- and tri- fluorinated benzene, chloroform, carbon tetrachloride, dichloromethane, acetonitrile, C5_i2 alkanes and mixtures thereof.
1 1. Method (A) according to claim 10, wherein
solvent (A) is chlorobenzene, chloroform and acetonitrile.
12. Method (A) according to one or more of claims 1 to 1 1 , wherein
reaction (A) is done in the presence of a reagent (A), reagent (A) is selected from the group consisting of oxalyl chloride, POCI3, PCI5, SOCl2, phosgene, diphosgene, triphosgene, Ci_4 carboxylic acid chloride, carbon tetrachloride and mixtures thereof.
13. Method (A) according to claim 12, wherein
reagent (A) is POCI3, oxalyl chloride or triphosgene.
14. Method (A) according to one or more of claims 1 to 13, wherein
method (A) is done continuously.
15. Method (A) according to one or more of claims 1 to 14, wherein
wherein after reaction (A) a reaction (REG) is done;
wherein in reaction (REG) catalyst (A) is contacted with oxidant (REG) at a temperature
(REG) of 300 to 1000 °C; wherein
oxidant (REG) is selected from the group consisting of air, 02, Cl2, Br2, 12, N20, N02, sulfuryl chloride, cyanogene chloride, Ν,Ν,Ν-trichloroisocyanuric acid and mixtures thereof.
Applications Claiming Priority (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161521038P | 2011-08-08 | 2011-08-08 | |
| EP11006494.6 | 2011-08-08 | ||
| EP11006494 | 2011-08-08 | ||
| US61/521,038 | 2011-08-08 | ||
| EP11007996 | 2011-09-30 | ||
| EP11007996.9 | 2011-09-30 | ||
| EP12150364 | 2012-01-06 | ||
| EP12150364.3 | 2012-01-06 | ||
| EP12152623.0 | 2012-01-26 | ||
| EP12152623 | 2012-01-26 |
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| Publication Number | Publication Date |
|---|---|
| WO2013020938A1 true WO2013020938A1 (en) | 2013-02-14 |
Family
ID=47667909
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2012/065312 WO2013020938A1 (en) | 2011-08-08 | 2012-08-06 | Method for the preparation of chlorinated pyridines |
Country Status (2)
| Country | Link |
|---|---|
| TW (1) | TW201321354A (en) |
| WO (1) | WO2013020938A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0239905A1 (en) * | 1986-03-31 | 1987-10-07 | Makhteshim Chemical Works Limited | Vapor phase production of Chlorinated pyridines from alpha-picoline |
| US5247093A (en) * | 1992-12-15 | 1993-09-21 | Reilly Industries, Inc. | Chlorination process |
| US20100160641A1 (en) | 2008-12-19 | 2010-06-24 | Jubilant Organosys Ltd. | Process for producing dihalopyridines |
-
2012
- 2012-08-06 WO PCT/EP2012/065312 patent/WO2013020938A1/en active Application Filing
- 2012-08-07 TW TW101128401A patent/TW201321354A/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0239905A1 (en) * | 1986-03-31 | 1987-10-07 | Makhteshim Chemical Works Limited | Vapor phase production of Chlorinated pyridines from alpha-picoline |
| US5247093A (en) * | 1992-12-15 | 1993-09-21 | Reilly Industries, Inc. | Chlorination process |
| US20100160641A1 (en) | 2008-12-19 | 2010-06-24 | Jubilant Organosys Ltd. | Process for producing dihalopyridines |
Non-Patent Citations (6)
| Title |
|---|
| GRAF R., JOURNAL FURPRAKTISCHE CHEMIE, vol. 134, 1932, pages 177 - 187 |
| J. W. VERBICKY ET. AL.: "Palladium catalyzed decarbonylation of aromatic acyl chlorides", TETRAHEDRON LETTERS, vol. 23, no. 4, 1 March 1982 (1982-03-01), pages 371 - 372, XP002666350 * |
| JEPHCOTT ET AL., J. AM. CHEM. SOC., vol. 50, 1928, pages 1189 - 1192 |
| PEARSON ET AL., J. ORG. CHEM., vol. 26, 1961, pages 789 - 792 |
| R. GRAF: "Die Rosenmundsche Aldehydsynthese in der Pyridinreihe", JOURNAL FÜR PRAKTISCHE CHEMIE, vol. 134, 1 July 1932 (1932-07-01), pages 177 - 187, XP001026824 * |
| VERBICKY ET AL., TETRAHEDRON LETTERS, vol. 23, 1982, pages 371 - 372 |
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