USRE41898E1 - Process for halomethyl ethers of hydroxyiminomethyl quaternary pyridinium salts - Google Patents
Process for halomethyl ethers of hydroxyiminomethyl quaternary pyridinium salts Download PDFInfo
- Publication number
- USRE41898E1 USRE41898E1 US12/274,133 US27413308A USRE41898E US RE41898 E1 USRE41898 E1 US RE41898E1 US 27413308 A US27413308 A US 27413308A US RE41898 E USRE41898 E US RE41898E
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- US
- United States
- Prior art keywords
- pyridino
- formula
- oxapropane
- bis
- pyridinealdoxime
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000000034 method Methods 0.000 title claims abstract description 49
- -1 halomethyl ethers Chemical class 0.000 title claims abstract description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims description 17
- MTFJSAGADRTKCI-UHFFFAOYSA-N N-(pyridin-2-ylmethylidene)hydroxylamine Chemical compound ON=CC1=CC=CC=N1 MTFJSAGADRTKCI-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 17
- MTFJSAGADRTKCI-VMPITWQZSA-N chembl77510 Chemical compound O\N=C\C1=CC=CC=N1 MTFJSAGADRTKCI-VMPITWQZSA-N 0.000 claims description 12
- 150000003222 pyridines Chemical class 0.000 claims description 11
- 150000001450 anions Chemical class 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 238000005342 ion exchange Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 238000013019 agitation Methods 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 150000002500 ions Chemical class 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 2
- 239000000729 antidote Substances 0.000 abstract description 8
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 229920000642 polymer Polymers 0.000 abstract description 8
- 229940075522 antidotes Drugs 0.000 abstract description 7
- 238000000746 purification Methods 0.000 abstract description 4
- 231100000167 toxic agent Toxicity 0.000 abstract description 4
- 239000003440 toxic substance Substances 0.000 abstract description 4
- 239000002516 radical scavenger Substances 0.000 abstract description 3
- 229910021645 metal ion Inorganic materials 0.000 abstract description 2
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical class COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 0 C1=CC=[N+](COC[N+]2=CC=CC=C2)C=C1.[1*]C.[2*]C.[3*]C.[4*]C Chemical compound C1=CC=[N+](COC[N+]2=CC=CC=C2)C=C1.[1*]C.[2*]C.[3*]C.[4*]C 0.000 description 16
- CQVKMVQRSNNAGO-UHFFFAOYSA-N 2-[4-formyl-3-methyl-n-(2-methylsulfonyloxyethyl)anilino]ethyl methanesulfonate Chemical class CC1=CC(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)=CC=C1C=O CQVKMVQRSNNAGO-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 239000000543 intermediate Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000002002 slurry Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 150000003841 chloride salts Chemical class 0.000 description 9
- HKYGSMOFSFOEIP-UHFFFAOYSA-N dichloro(dichloromethoxy)methane Chemical compound ClC(Cl)OC(Cl)Cl HKYGSMOFSFOEIP-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- RYKLZUPYJFFNRR-UHFFFAOYSA-N 3-hydroxypiperidin-2-one Chemical compound OC1CCCNC1=O RYKLZUPYJFFNRR-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 230000002000 scavenging effect Effects 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229940075894 denatured ethanol Drugs 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WMQUKDQWMMOHSA-UHFFFAOYSA-N CC(=O)C1=CC=NC=C1 Chemical compound CC(=O)C1=CC=NC=C1 WMQUKDQWMMOHSA-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 239000000835 fiber Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 239000003456 ion exchange resin Substances 0.000 description 3
- 229920003303 ion-exchange polymer Polymers 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- KKVTYAVXTDIPAP-UHFFFAOYSA-M sodium;methanesulfonate Chemical compound [Na+].CS([O-])(=O)=O KKVTYAVXTDIPAP-UHFFFAOYSA-M 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 150000003871 sulfonates Chemical class 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZCQINGMEELDDLT-VQSZBRBVSA-N C.C/C=N/O.C1=CC=NC=C1 Chemical compound C.C/C=N/O.C1=CC=NC=C1 ZCQINGMEELDDLT-VQSZBRBVSA-N 0.000 description 2
- JVXZJEUVAOVXIX-UHFFFAOYSA-N C1=CC=NC=C1.CC(C)=O Chemical compound C1=CC=NC=C1.CC(C)=O JVXZJEUVAOVXIX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 244000265913 Crataegus laevigata Species 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- FOIXSVOLVBLSDH-UHFFFAOYSA-N Silver ion Chemical compound [Ag+] FOIXSVOLVBLSDH-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical group NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 description 2
- 125000005358 mercaptoalkyl group Chemical group 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 238000002411 thermogravimetry Methods 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- ABZJDNLKVWSLPM-UHFFFAOYSA-N 2-sulfanylethyl prop-2-enoate Chemical group SCCOC(=O)C=C ABZJDNLKVWSLPM-UHFFFAOYSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- BMNJFCVJILLIIU-UHFFFAOYSA-P NC(=O)C1=CC=[N+](COC[N+]2=CC=CC=C2/C=N/O)C=C1.O=S(=O)=O.[CH2-]OS([CH2-])(=O)=O Chemical compound NC(=O)C1=CC=[N+](COC[N+]2=CC=CC=C2/C=N/O)C=C1.O=S(=O)=O.[CH2-]OS([CH2-])(=O)=O BMNJFCVJILLIIU-UHFFFAOYSA-P 0.000 description 1
- FJZDLOMCEPUCII-UHFFFAOYSA-P NC(=O)C1=CC=[N+](COC[N+]2=CC=CC=C2/C=N/O)C=C1.[Cl-].[Cl-] Chemical compound NC(=O)C1=CC=[N+](COC[N+]2=CC=CC=C2/C=N/O)C=C1.[Cl-].[Cl-] FJZDLOMCEPUCII-UHFFFAOYSA-P 0.000 description 1
- SCSOEIFDGFLGIL-UHFFFAOYSA-O O/N=C/C1=[N+](COCCl)C=CC=C1.[Cl-] Chemical compound O/N=C/C1=[N+](COCCl)C=CC=C1.[Cl-] SCSOEIFDGFLGIL-UHFFFAOYSA-O 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- UHGKYJXJYJWDAM-UHFFFAOYSA-N Propylthiourea Chemical group CCCNC(N)=S UHGKYJXJYJWDAM-UHFFFAOYSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical group [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- BWEYVLQUNDGUEC-UHFFFAOYSA-L calcium;methanesulfonate Chemical compound [Ca+2].CS([O-])(=O)=O.CS([O-])(=O)=O BWEYVLQUNDGUEC-UHFFFAOYSA-L 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000004970 halomethyl group Chemical group 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000012263 liquid product Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 150000001455 metallic ions Chemical class 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003958 nerve gas Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 229920000098 polyolefin Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- MLKQJVFHEUORBO-UHFFFAOYSA-M silver;methanesulfonate Chemical compound [Ag+].CS([O-])(=O)=O MLKQJVFHEUORBO-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000010626 work up procedure Methods 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/53—Nitrogen atoms
-
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
Definitions
- This invention resides in the field of process chemistry for the N-alkylation of pyridinealdoximes.
- this invention addresses processes for the preparation of intermediates for the synthesis of asymmetrical dipyridinomethyl ethers.
- the bis-quaternary salts of certain dipyridinomethyl ethers are known to be effective antidotes for toxic agents that are known in the military as nerve gases as well as for certain insecticides. These antidotes are thus useful to the military, the agricultural industry, and the home gardener, and in general any location or application where there is a risk of exposure to the toxic agents.
- the most potent of the antidotes in this class are those with asymmetrical structures, i.e., those in which one or more substituents are present on one of the two pyridine rings and not the other, or the substituent(s) on one of the two pyridine rings differ in either structure or position from those on the other.
- antidotes with asymmetrical structures are difficult to manufacture, with known synthesis routes tending to produce low yields and high levels of undesired.
- An illustration of the difficulty is found in U.S. Pat. No. 5,130,438 (Hsiao, L. Y. Y, et al., Jul. 14, 1992, entitled “Bis-Methylene Ether Pyridinium Compound Preparation”).
- the product mixtures in this patent include the desired asymmetrical ether together with symmetrical ethers and quaternary salts of the pyridinium compounds that are used as starting materials.
- One of the most potent compounds disclosed in the patent is 1-(2-hydroxyiminomethyl-1-pyridino)-3-(4-carbamoyl-1-pyridino)-2-oxapropane (commonly known as “HI-6”), shown as both the dichloride and dimethanesulfonate salts.
- HI-6 1-(2-hydroxyiminomethyl-1-pyridino)-3-(4-carbamoyl-1-pyridino)-2-oxapropane
- This compound is only one of four reaction products in the product mixture, however, and recovery of the desired compound requires a lengthy isolation procedure involving multiple recrystallizations and resulting in a low yield.
- Other disclosures of potential relevance to this invention are U.S. Pat.
- This procedure is distinct from that of the prior art, particularly the disclosures of Hagedorn cited above, in which a reverse addition procedure is used, i.e., the bis-halomethylether is added to the pyridinealdoxime, and this invention achieves a significant and surprising improvement in both product yield and product purity.
- This invention thus resides in a process for the preparation of salts of asymmetrical 1,3-di-(1-pyridino)-2-oxapropanes, as well as a process for the preparation of the intermediates. Further objects, advantages, and aspects of this invention will be apparent from the descriptions that follow.
- dimethanesulfonate salts of 1,3-di-(1-pyridino)-2-oxapropanes can be purified to a particularly high degree from a product mixture containing metallic methanesulfonate salts by contacting a liquid solution of said product mixture with an insoluble mercaptoalkyl-functionalized polymer.
- the resulting purity is unexpectedly greater than the purity achieved by the use of other purifying media.
- the symbol R 1 represents —CH ⁇ NOH
- the symbols R 2 , R 3 , and R 4 independently represent either H, lower alkyl, —C(O)—O-(lower alkyl), —C(O)—NH 2 , or —CH ⁇ NOH, provided that the selection of the substituents, their arrangement on the pyridine rings, or both, result in an asymmetric structure.
- asymmetric in this specification and the appended claims denotes that the substituents are such that the two pyridino rings differ from each other, either because one is substituted and the other is not, or because a substituent appears on one that does not appear on the other, or the ring vertices to which the various substituents are bonded differ between the two rings, or a combination of these differences.
- independently selected is used herein to denote that R 2 , R 3 , and R 4 can be all the same, all different, or two the same and the third different.
- the alkyl groups are either linear or branched, and preferred lower alkyls are C 1 -C 3 alkyl, preferably linear, and most preferably CH 3 .
- Preferred among the R 1 groups are —C(O)—O-(lower alkyl), —C(O)—NH 2 , and —CH ⁇ NOH other than 2-CH ⁇ NOH.
- Also preferred are lower alkyl, —C(O)—O-(lower alkyl), —C(O)—NH 2 in the 4-position (i.e., the para-position) on the pyridine ring. More preferred are —C(O)—O-(lower alkyl) and —C(O)—NH 2 , and the most preferred is —C(O)—NH 2 , particularly 4-C(O)—NH 2 .
- X represents any atom or group capable of forming a pharmaceutically acceptable anion.
- Preferred examples are halides, hydrocarbyl sulfonates, and halohydrocarbyl sulfonates, of the generic formula R 5 SO 3 ⁇ .
- halides Br and Cl are preferred, and Cl is the most preferred.
- sulfonates aliphatic and aromatic sulfonates are included, with preferred sulfonates being those in which R 5 is C 1 —C 4 alkyl, halo(C 1 —C 4 alkyl), cyclohexyl, or phenyl, and the most preferred is that in which R 5 is methyl or halomethyl.
- the sulfonate in which R 5 is methyl is referred to herein as methanesulfonate.
- the intermediate of interest in this invention is a 1-(hydroxyiminomethyl-1-pyridino)-3-(halomethyl)-2-oxapropane, halide salt, whose formula is wherein X is a halogen atom. Conversion of this intermediate to the antidote of Formula (I) will result in a product in which the anion X is the same halogen atom. This anion can be exchanged for other anions, including dimethanesulfonate and the other pharmaceutically acceptable anions, by ion exchange, as will be demonstrated below.
- Addition of the pyridinealdoxime to bis-halomethylether is achieved such that the unreacted bis-halomethylether remains in stoichiometric excess for most, if not all, of the addition.
- This is preferably achieved by adding the pyridinealdoxime to a body of the bis-halomethylether at a slow rate with continuous agitation. Dropwise addition is one means of accomplishing this result.
- the excess of unreacted bis-halomethylether is preferably maintained for at least until 75% of the pyridinealdoxime has been added, more preferably until at least 90% has been added, and most preferably throughout the entire addition.
- the bis-halomethylethers are known compounds, commercially available and disclosed for example in the Hsiao et al. and Hagedorn patents cited above, as well as U.S. Pat. No. 3,137,702 (Lüttringhaus, A., et al., Jun. 6, 1964, entitled “Preparation of Bis-Quaternary Pyridinium Salts”).
- Bis-chloromethylether for example can be prepared by reaction of paraformaldehyde with hydrochloric acid and chlorosulfonic acid.
- the bis-halomethylether is in the liquid phase during the addition of the pyridinealdoxime, and this can be achieved by using the ether in neat form since it is a liquid at ambient temperature and any elevated temperatures at which the reaction might be performed, or the ether can be dissolved in a solvent. If a solvent is used, any conventional solvent that is inert to the reaction will suffice. Examples are tetrahalomethanes, dimethylformamide, trihalomethanes, dihalomethanes, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, acetonitrile, dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran.
- a particularly preferred pyridinealdoxime is 2-pyridinealdoxime, whose formula is
- a third is that represented by the formula
- a particularly preferred substituted pyridine is 4-carbamoylpyridine of the formula
- Both reactions can be conducted in batch-wise or continuous manner, provided that the reaction to form the intermediate (II) is performed with a continuous excess of the bis-halomethyl ether for most, if not all, of the duration of the reaction.
- the reaction to form the intermediate (II) is preferably accompanied by agitation, and can be performed at ambient temperature but is preferably performed at an elevated temperature of from about 30° C. to about 100° C., or most preferably from about 35° C. to about 60° C.
- the reaction between the intermediate (II) and the substituted pyridine (III) can likewise be performed at ambient temperature but is preferably performed at an elevated temperature within the same ranges. Both reactions can be performed at atmospheric pressure or slightly above or below. Both reactions can be performed in air or in an inert atmosphere such as nitrogen or argon.
- Reaction products at either stage can be isolated by conventional means. Liquid products can thus be recovered by conventional phase separation, including decantation and centrifugation, and solid products can be recovered by filtration or centrifugation. Conversion of the chloride salts to salts of other anions, including methanesulfonate (which is also referred to as “mesylate”), can be achieved by ion exchange.
- the ion exchange may be performed with metallic salts such as silver methanesulfonate, sodium methanesulfonate, and calcium methanesulfonate, or common ion exchange resins, all of which are commercially available.
- one of the products that can be synthesized by the methods of this invention is 1-(2-hydroxyiminomethyl-1-pyridino)-3-(4-carbamoyl-1-pyridino)-2-oxapropane (commonly known as “HI-6”) methanesulfonate salt, a highly effective anti-nerve agent.
- HI-6 1-(2-hydroxyiminomethyl-1-pyridino)-3-(4-carbamoyl-1-pyridino)-2-oxapropane
- HI-6 1-(2-hydroxyiminomethyl-1-pyridino)-3-(4-carbamoyl-1-pyridino)-2-oxapropane
- functionalized polymers and notably mercaptoalkyl-functionalized polymers, have been found to be a particularly effective class of metal scavenging media for the isolation of dimethanesulfonate salts of 1,3-di-(1-pyridino)-2-oxapropanes from metallic methanesulfonate salts.
- This quality makes these polymers particularly useful in product purification procedures following the conversion of dihalide salts of the 1,3-di-(1-pyridino)-2-oxapropanes to dimethylsulfonate form.
- Examples of these polymers are silica gels, polyolefins, polystyrene, polyvinyl alcohol, poly-epichlorohydrin, polyoxetane, and crosslinked polyalkyl fiber, all functionalized with mercaptoalkyl groups.
- Preferred among the mercaptoalkyl functional groups are mercapto-(C 1 -C 5 alkyl) groups, more preferred are mercapto-(C 2 -C 4 alkyl) groups, and the most preferred is mercaptopropyl.
- the metal ions that these polymers are effective in removing include Ag + , Hg ++ , Pd ++ , and Pt 4+ ions.
- the polymers are of particular interest in removing Ag + ions.
- Mercaptopropyl-functionalized silica gel is one example.
- Other silica gels that are efficient Ag + ion scavengers and can be used herein are silica gels bonded with triaminetetraacetic acid groups (SiliaBond TAAcOH) and propylthiourea groups (SiliaBond Thiourea), both of which are commercially available from Silicycle, Inc., Quebec, Canada.
- Examples of functionalized polyalkyl fibers that are known to be effective in removing Ag + ion are polyalkyl fibers functionalized with benzylthio groups (SMOPEX®-111x), isothionium groups (SMOPEX®-112x) and mercaptoethyl acrylate groups (SMOPEX®-234x), all of which are commercially available from Johnson Matthey plc., United Kingdom.
- the metal scavenging can be performed either by stirring the scavenger medium in the reaction mixture or by pumping the reaction mixture through one or several columns packed with the scavenger medium, with the columns connected either in series or in parallel.
- the metal scavenging can be performed in a continuous manner using a scavenging unit similar to a continuous catalytic reactor. Metal scavenging can be performed at any temperature within the range of 0° C. to 150° C., using conventional heating or microwave heating. Metal scavenging can also be enhanced in certain cases by the use of ultrasound.
- the dimethanesulfonate salts of 1,3-di-(1-pyridino)-2-oxapropanes that are purified in this manner include salts of both substituted and unsubstituted 1,3-di-(1-pyridino)-2-oxapropanes, symmetrical and asymmetrical, and the preferred 1,3-di-(1-pyridino)-2-oxapropanes are those listed above as preferred embodiments for the synthesis reactions described herein.
- bis-chloromethylether was prepared by first cooling a mixture of paraformaldehyde (21.1 g, 0.7 mole) and 37% hydrochloric acid (16.7 g ) to 10° C., then slowly adding chlorosulfonic acid (55.1 g, 0.6 mole) and stirring overnight. The phases were then separated to obtain bis-chloromethylether as the neat liquid.
- the procedure used for this paragraph is described in Buc, S. R., Organic Syntheses, Collective Volume IV: pp. 101-103, 1963.
- the product was identified by proton NMR as 1-(2-hydroxyiminomethyl-1-pyridino)-3-(chloromethyl)-2-oxapropane, chloride salt, plus the bis-impurity 1,3-di-(2-hydroxyiminomethyl-1-pyridino)-2-oxapropane.
- the bis-chloromethylether (28.7 g, 0.250 mole) prepared as described above was added to pyridine-2-aldoxime (28.3 g, 0.227 mole) in dropwise manner over a period of 30 minutes (by adding one drop of bis-chloromethylether approximately every 0.5 second) at 45° C. with continuous stirring. Once the addition was complete, stirring was continued for three hours at the same temperature. The reaction mixture was then cooled to 18° C., and the product was filtered, washed with chloroform (66 g), and vacuum dried at 40° C.
- the product was again identified by proton NMR as 1-(2-hydroxyiminomethyl-1-pyridino)-3-(chloromethyl)-2-oxapropane, chloride salt, with 1,3-di-(2-hydroxyiminomethyl-1-pyridino)-2-oxapropane as an impurity (referred to herein as the “bis-impurity”).
- the yield was 56.4%, and from the NMR analysis, the product purity was 52.6%, with the bis-impurity as the remainder.
- This example illustrates the conversion of 1-(2-hydroxyiminomethyl-1-pyridino)-3-(chloromethyl)-2-oxapropane, chloride salt, to 1-(2-hydroxyiminomethyl-1-pyridino)-3-(4-carbamoyl-1-pyridino)-2-oxapropane, dichloride salt.
- the structure of the latter is as follows:
- the salt was then dissolved in 50 mL water, and the insolubles were filtered off and washed with 20 mL water.
- the combined filtrates were distilled under reduced pressure and solvent exchanged to ethanol. After water was removed, a slurry of tan color was formed and then chilled to 0-5° C.
- the solid was isolated by filtration, then washed with two 10-mL portions of denatured ethanol and dried to give 8.24 g (86.1% yield) of the dimethanesulfonate as a tan-colored solid.
- ion exchange resin Via ion exchange resin: The ion exchange resin, AMBERLYST® (Dow Chemical Co., Midland, Mich., USA) A-26 (OH form) (6.0 g) was placed in a 125-mL Erlenmeyer flask and treated with 35 mL 1M methanesulfonic acid aqueous solution. The mixture was poured into a glass column 3 ⁇ 4-inch in diameter. The solution was drained and the resin was rinsed with deionized water until the pH was 4.15.
- AMBERLYST® Low Chemical Co., Midland, Mich., USA
- the dichloride salt of 1-(2-hydroxy-iminomethyl-1-pyridino)-3-(4-carbamoyl-1-pyridino)-2-oxapropane (1.0 g, 2.78 mmoles) was dissolved in water 6.5 g and the solution was passed through the resin bed at least five times. The resin bed was then eluted with 30 mL 0.5 mM methanesulfonic acid aqueous solution. After elution, the combined eluate was decolorized with 0.35 g activated charcoal, filtered through a bed of CELITE® (diatomaceous earth, product of Celite Corporation, Lompoc, Calif., USA), and distilled with ethanol under reduced pressure to remove water.
- CELITE® diatomaceous earth
- Example 3 prepared by silver methanesulfonate 8.23 g was suspended in 60 mL of water in a 125-mL Erlenmeyer flask, where it was agitated with a mechanical stirrer. Insolubles were present, and charcoal (0.28 g) was added while stirring continued for 5 minutes. The resulting slurry was then filtered through a CELITE bed which was subsequently washed with two 10-mL portions of water. The filtrate was clear yellow in color and was distilled under reduced pressure. The solvent was then replaced with ethanol, and the resulting white slurry was chilled to 0-5° C.
- Example 4 In a parallel procedure to that of Example 4, 1.0 g of the product of Example 3, which was prepared by silver methanesulfonate and found to contain 1.0% residues (as silver ion) was dissolved in 9.6 mL of water in a 50-mL flask, where it was agitated with a mechanical stirrer. To the solution was added 1.0 g of 3-mercaptopropyl-functionalized silica gel (SiliCycle Inc., Quebec City, Quebec, Canada, and Sigma-Aldrich Corporation, St. Louis, Mo., USA). The resulting mixture was heated to 50-55° C. for three hours and filtered. After filtration, the silica gel was washed with 10 mL water.
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Abstract
Description
wherein X is a halogen atom. Conversion of this intermediate to the antidote of Formula (I) will result in a product in which the anion X is the same halogen atom. This anion can be exchanged for other anions, including dimethanesulfonate and the other pharmaceutically acceptable anions, by ion exchange, as will be demonstrated below.
in which R3 and R4 are as defined above. This reaction is likewise performed in a liquid reaction medium, and a solvent can be used if desired. The solvents listed above are examples of solvents that can be used in this reaction as well.
Claims (22)
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3137702A (en) * | 1960-08-13 | 1964-06-16 | Merck E | Preparation of bis-quaternary pyridinium salts |
US3773775A (en) * | 1968-08-27 | 1973-11-20 | Merck Patent Gmbh | Bis-quaternary pyridinium salts |
US3852294A (en) * | 1968-08-27 | 1974-12-03 | Merck Patent Gmbh | Bis-quaternary pyridinium salts |
US4128651A (en) * | 1976-04-14 | 1978-12-05 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Bis-quaternary pyridinium-2-aldoxime salts and a process for their preparation |
US4677204A (en) * | 1965-12-07 | 1987-06-30 | The United States Of America As Represented By The Secretary Of The Army | Chemical agents |
US5130438A (en) * | 1985-11-20 | 1992-07-14 | The United States Of America As Represented By The Secretary Of The Army | Bis-methylene ether pyridinium compound preparation |
US20060183777A1 (en) * | 2005-02-17 | 2006-08-17 | Aerojet Fine Chemicals Llc, A Delaware Limited Liability Company | Process for halomethyl ethers of hydroxyiminomethyl quaternary pyridinium salts |
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Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3137702A (en) * | 1960-08-13 | 1964-06-16 | Merck E | Preparation of bis-quaternary pyridinium salts |
US4677204A (en) * | 1965-12-07 | 1987-06-30 | The United States Of America As Represented By The Secretary Of The Army | Chemical agents |
US3773775A (en) * | 1968-08-27 | 1973-11-20 | Merck Patent Gmbh | Bis-quaternary pyridinium salts |
US3852294A (en) * | 1968-08-27 | 1974-12-03 | Merck Patent Gmbh | Bis-quaternary pyridinium salts |
US4128651A (en) * | 1976-04-14 | 1978-12-05 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Bis-quaternary pyridinium-2-aldoxime salts and a process for their preparation |
US5130438A (en) * | 1985-11-20 | 1992-07-14 | The United States Of America As Represented By The Secretary Of The Army | Bis-methylene ether pyridinium compound preparation |
US20060183777A1 (en) * | 2005-02-17 | 2006-08-17 | Aerojet Fine Chemicals Llc, A Delaware Limited Liability Company | Process for halomethyl ethers of hydroxyiminomethyl quaternary pyridinium salts |
Non-Patent Citations (8)
Title |
---|
Dirks et al, 1970, Arneim. Forsch. vol. 20, No. 1, pp. 55-62. * |
Dirks, E. et al.; "Beziehung zwischen chemischer Struktur und Cholinesterase-reaktivierender Wirkung bei einer Reihe neuer unsymmetrischer Pyridinumsalze"; 1970, Arneim Forsch, vol. 20, No. 1, pp. 55-62. |
Eyer et al., 1992, Arch Toxicol, vol. 66, No. 9, pp. 603-621. * |
Eyer, P. et al.; "HLo7 dimethanesulfonate, a potent bispyridinium-dioxime against anticholinesterases"; 1992, Arch Toxicol, vol. 66, No. 9, pp. 603-621. |
Hagedorn et al., 1978, Arzneim-Forsch., vol. 28, No. 11, pp. 2055-2057. * |
Hagedorn, Von I. et al.; "Reaktivierung phosphorylierter Acetylcholin-Esterase"; 1978, Arzneim-Forsch., vol. 28, No. 11, pp. 2055-2057. |
Yang et al., 2003, Bull, Korean Chem. Soc., vol. 24, No. 9, pp. 1368-1370. * |
Yang, Garp Yeol et al.; "Synthesis of Bis-pyridinium Oxime Anti-dotes Using Bis(methylsulfonoxymethyl) Ether for Organophosphate Nerve Agents"; 2003, Bull. Korean Chem. Soc., vol. 24, No. 9, pp. 1368-1370. |
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