US20070142681A1 - Process for chlorinating tertiary alcohols - Google Patents
Process for chlorinating tertiary alcohols Download PDFInfo
- Publication number
- US20070142681A1 US20070142681A1 US11/704,257 US70425707A US2007142681A1 US 20070142681 A1 US20070142681 A1 US 20070142681A1 US 70425707 A US70425707 A US 70425707A US 2007142681 A1 US2007142681 A1 US 2007142681A1
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- US
- United States
- Prior art keywords
- process according
- tertiary
- thionyl chloride
- reaction
- group
- 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.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 38
- 150000003509 tertiary alcohols Chemical class 0.000 title claims description 9
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 46
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 40
- 150000002894 organic compounds Chemical class 0.000 claims abstract description 19
- 239000002904 solvent Substances 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims abstract description 12
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims abstract description 9
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims abstract description 8
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 229940078552 o-xylene Drugs 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 27
- 239000011541 reaction mixture Substances 0.000 claims description 7
- 238000004821 distillation Methods 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 239000012320 chlorinating reagent Substances 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000005984 hydrogenation reaction Methods 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 239000007795 chemical reaction product Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- JEJFFMUJOCTNHU-KUARMEPBSA-N 1-[(1s,2s)-2-chloro-2-(3-methoxyphenyl)cyclohexyl]-n,n-dimethylmethanamine;hydrochloride Chemical compound Cl.COC1=CC=CC([C@@]2(Cl)[C@@H](CCCC2)CN(C)C)=C1 JEJFFMUJOCTNHU-KUARMEPBSA-N 0.000 description 5
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 5
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 5
- 229930182817 methionine Natural products 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 230000000202 analgesic effect Effects 0.000 description 4
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 4
- 238000005661 deetherification reaction Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000004291 sulphur dioxide Substances 0.000 description 4
- 235000010269 sulphur dioxide Nutrition 0.000 description 4
- UTXIQBQAEVCBPH-UHFFFAOYSA-N COC1=CC=CC(C2(Cl)CCCCC2CN(C)C)=C1 Chemical compound COC1=CC=CC(C2(Cl)CCCCC2CN(C)C)=C1 UTXIQBQAEVCBPH-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- PIWJOWRKZFCXSQ-DMLYUBSXSA-N 1-[(1r,2r)-2-(3-methoxyphenyl)cyclohexyl]-n,n-dimethylmethanamine;hydrochloride Chemical compound Cl.COC1=CC=CC([C@H]2[C@@H](CCCC2)CN(C)C)=C1 PIWJOWRKZFCXSQ-DMLYUBSXSA-N 0.000 description 2
- SLOIWIHZXQWWIY-SLHAJLBXSA-N 3-[(1r,2r)-2-[(dimethylamino)methyl]cyclohexyl]phenol;hydrochloride Chemical compound Cl.CN(C)C[C@@H]1CCCC[C@H]1C1=CC=CC(O)=C1 SLOIWIHZXQWWIY-SLHAJLBXSA-N 0.000 description 2
- TVYLLZQTGLZFBW-UHFFFAOYSA-N COC1=CC=CC(C2(O)CCCCC2CN(C)C)=C1 Chemical compound COC1=CC=CC(C2(O)CCCCC2CN(C)C)=C1 TVYLLZQTGLZFBW-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- VTXTVLAQPBIPPF-UHFFFAOYSA-N [H]C1(C2=CC(OC)=CC=C2)CCCCC1CN(C)C Chemical compound [H]C1(C2=CC(OC)=CC=C2)CCCCC1CN(C)C VTXTVLAQPBIPPF-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 230000000536 complexating effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000007210 heterogeneous catalysis Methods 0.000 description 2
- 229940102396 methyl bromide Drugs 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- TVYLLZQTGLZFBW-GOEBONIOSA-N (S,S)-tramadol Chemical compound COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- PPKXEPBICJTCRU-KUARMEPBSA-N (S,S)-tramadol hydrochloride Chemical compound Cl.COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-KUARMEPBSA-N 0.000 description 1
- 0 *CC(CCCC1)C1c1cccc(O)c1 Chemical compound *CC(CCCC1)C1c1cccc(O)c1 0.000 description 1
- QLMHVJYCCMDWGV-LMRHVHIWSA-N 1-[(1r,2r)-2-(2-methoxyphenyl)cyclohexyl]-n,n-dimethylmethanamine;hydrochloride Chemical compound Cl.COC1=CC=CC=C1[C@H]1[C@H](CN(C)C)CCCC1 QLMHVJYCCMDWGV-LMRHVHIWSA-N 0.000 description 1
- PIWJOWRKZFCXSQ-KUARMEPBSA-N 1-[(1r,2s)-2-(3-methoxyphenyl)cyclohexyl]-n,n-dimethylmethanamine;hydrochloride Chemical compound Cl.COC1=CC=CC([C@@H]2[C@@H](CCCC2)CN(C)C)=C1 PIWJOWRKZFCXSQ-KUARMEPBSA-N 0.000 description 1
- UTXIQBQAEVCBPH-GOEBONIOSA-N 1-[(1s,2s)-2-chloro-2-(3-methoxyphenyl)cyclohexyl]-n,n-dimethylmethanamine Chemical compound COC1=CC=CC([C@@]2(Cl)[C@@H](CCCC2)CN(C)C)=C1 UTXIQBQAEVCBPH-GOEBONIOSA-N 0.000 description 1
- WBUIRWUUSPTUQK-ARASBNDYSA-N 3-[(1R,2R)-2-[(dimethylamino)methyl]cyclohexyl]phenol dihydrate hydrochloride Chemical compound O.O.Cl.CN(C)C[C@@H]1CCCC[C@H]1c1cccc(O)c1 WBUIRWUUSPTUQK-ARASBNDYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- JLGWTGKOSOABRI-UHFFFAOYSA-N B.[Zn] Chemical class B.[Zn] JLGWTGKOSOABRI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- GXSUPXHFASOJQS-KYSPHBLOSA-N [(1r,2r)-2-(3-methoxyphenyl)cyclohexyl]methanamine;n-methylmethanamine Chemical compound CNC.COC1=CC=CC([C@H]2[C@@H](CCCC2)CN)=C1 GXSUPXHFASOJQS-KYSPHBLOSA-N 0.000 description 1
- YUDRVAHLXDBKSR-UHFFFAOYSA-N [CH]1CCCCC1 Chemical compound [CH]1CCCCC1 YUDRVAHLXDBKSR-UHFFFAOYSA-N 0.000 description 1
- JIRYWFYYBBRJAN-UHFFFAOYSA-N [H]C1(C2=CC(O)=CC=C2)CCCCC1CN(C)C Chemical compound [H]C1(C2=CC(O)=CC=C2)CCCCC1CN(C)C JIRYWFYYBBRJAN-UHFFFAOYSA-N 0.000 description 1
- PMXVXALPUUNTBF-UHFFFAOYSA-N [H]C1(CN(C)C)CCCCC1(Cl)C1=CC=CC(OC)=C1.[H]C1(CN(C)C)CCCCC1(O)C1=CC=CC(OC)=C1.[H]C1(CN(C)C)CCCCC1([H])C1=CC=CC(O)=C1.[H]C1(CN(C)C)CCCCC1([H])C1=CC=CC(OC)=C1 Chemical compound [H]C1(CN(C)C)CCCCC1(Cl)C1=CC=CC(OC)=C1.[H]C1(CN(C)C)CCCCC1(O)C1=CC=CC(OC)=C1.[H]C1(CN(C)C)CCCCC1([H])C1=CC=CC(O)=C1.[H]C1(CN(C)C)CCCCC1([H])C1=CC=CC(OC)=C1 PMXVXALPUUNTBF-UHFFFAOYSA-N 0.000 description 1
- DIKPSLUEBJDRLR-UHFFFAOYSA-N [H]C1(CN(C)C)CCCCC1(O)C1=CC=CC(C)=C1.[H]C1(CN(C)C)CCCCC1(O)C1=CC=CC(OC)=C1 Chemical compound [H]C1(CN(C)C)CCCCC1(O)C1=CC=CC(C)=C1.[H]C1(CN(C)C)CCCCC1(O)C1=CC=CC(OC)=C1 DIKPSLUEBJDRLR-UHFFFAOYSA-N 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical class O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B39/00—Halogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the present invention relates to a process for converting a tertiary OH group of an organic compound into a tertiary C1 group of the organic compound.
- EP 0 753 506 A1 discloses a process for producing the compound of formula (I) starting from a compound of general formula (II), the production of which is known from the literature (K. Flick et al., Arzneim.-Forsch./Drug Res. 28 (1), issue 1a (1978)), wherein, to convert the tertiary alcohol function on the cyclohexyl radical into a C-substitution with retention on the carbon atom marked by *, thionyl chloride is used as the chlorination reagent and as the solvent.
- the invention relates to a process for producing a compound of general formula (I) and, more precisely, in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in the illustrated form or in the form of its salts, in particular the physiologically acceptable salts, particularly preferably in the form of the hydrochloride, or in the form of its solvates, in particular the hydrates.
- the object is achieved by a process for converting a tertiary OH group of an organic compound into a tertiary C1 group of the organic compound, characterized in that the tertiary alcohol is suspended or dissolved in a solvent, selected from the group comprising toluene, o-xylene, m-xylene, p-xylene and mixtures thereof, thionyl chloride being added to the resultant suspension or solution and then the resultant organic compound comprising the tertiary C1 group is separated from the further reaction components.
- a solvent selected from the group comprising toluene, o-xylene, m-xylene, p-xylene and mixtures thereof, thionyl chloride being added to the resultant suspension or solution and then the resultant organic compound comprising the tertiary C1 group is separated from the further reaction components.
- the organic compound comprising the tertiary C1 group can be isolated, after the reaction has taken place, by distilling off (distillation of) the further reaction components with the solvent. Distilling off (distillation of) is also taken to mean the partial removal of the solvent with the further reaction components by supplying heat under vacuum. It is also possible, after the reaction has taken place, to obtain the organic compound comprising the tertiary C1 group as a solid by cooling to below ambient temperature and to then dry it at temperatures between 35° C. and 75° C., preferably under vacuum.
- the halogenated organic compound is preferably obtained in the form of its hydrochloride.
- This process according to the invention allows synthesis of organic compounds comprising a tertiary C1 group, starting from the corresponding tertiary alcohol while retaining the stereochemistry at the stereogenic center in high yields of more than 70% and while reducing the quantity of thionyl chloride to be used.
- the process according to the invention has proven to be particularly advantageous for producing a compound of formula (I) in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in the illustrated form or in the form of its salts, in particular physiologically acceptable salts, particularly preferably in the form of the hydrochloride, and/or in the form of its solvates, in particular the hydrates; wherein the process is characterized in that a compound of formula (II) in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in the illustrated form or in the form of its salts, in particular physiologically acceptable salts, particularly preferably in the form of the hydrochloride, and/or
- reaction product of formula (I) is separated (c) by distilling off (distillation of) the solvent with the further reaction components.
- Distilling off (distillation) includes, without limitation, the partial removal of the solvent with the further reaction components by supplying heat under vacuum.
- separation (c) can take place by precipitating the reaction product of formula (I) by means of cooling the reaction mixture to below ambient temperature and then drying the reaction product at temperatures between 35° C. and 75° C., preferably under vacuum.
- Toluene is preferred as the solvent or solubilizer.
- the use of other non-polar solvents as toluene and/or xylene, for example THF, heptane, hexane and cyclohexane, has not proven to be advantageous, as the reaction is then carried out with the formation of numerous by-products, i.e. not sufficiently selectively.
- 1 to 2 equivalents in particular 1.5 to 1.7 equivalents, particularly preferably 1.6 equivalents of thionyl chloride—based on the compound of formula (II)—are used. This represents a drastic reduction in the quantity of thionyl chloride to be used compared with the process known from EP 0 753 506 A1. Much higher yields, which are greater than 70% of the theoretical yield, are also achieved with complete conversion of the starting compound (II).
- the compound (II) is preferably reacted at elevated temperature, in particular at a temperature of 30 to 50° C., preferably 35 to 45° C., for 1 to 4 hours, preferably 2 to 3 hours, though the reaction time can also be longer or shorter than this.
- the starting compound (II) is generally used in the form of its hydrochloride. It is suspended in the inert or non-polar solubilizer, toluene, in which it does not dissolve at either low or high temperature.
- a further advantage is that it is possible to separate the desired reaction product from the solubilizer and the further reaction components and as the solubilizer, preferably toluene, is distilled off, preferably under vacuum; the sulphur dioxide that has formed and the hydrogen chloride are also removed in the process.
- the compounds of formula (I) have an analgesic effect and can be used as intermediate compounds to produce further analgesically active cyclohexyl compounds.
- a compound of formula (I), produced by the process according to the invention by (d) catalytic hydrogenation into a compound of formula (III):
- Hydrogenation is preferably carried out by heterogeneous catalysis with palladium on activated carbon, of which the quantity can be varied within a wide range between 1% through 5% to 10% palladium on activated carbon.
- Suitable solvents include alkyl alcohols, in particular methanol and ethanol.
- the compound (I) is conventionally used as the hydrochloride.
- the hydrogenation step (d) is preferably carried out with retention of the stereochemistry on the carbon atom marked by an asterisk (*) in formula (I) or (III).
- the optionally formed quantity of compound (III) with inverted stereochemistry on the carbon*atom is so low that it can easily be separated during conventional working up. This process is therefore eminently suitable, starting from the enantiomer with the absolute configuration (IIa), via the corresponding enantiomer of compound (Ia) for producing the compound (III) as the enantiomer with the absolute configuration (IIIa) (The compound (IIIb) mirror-inverted to (IIa) can be correspondingly produced, starting from the optical antipode (IIb) via (Ib)).
- the compound of formula (III) is also accessible by hydrogenation with complex zinc-boron hydrides of (I), as described in EP 0 753 506 A1.
- the compound of formula (III), preferably produced by the process according to the invention, can also be converted by methyl ether cleavage in a further step (e) into the compound of formula (IV):
- Aqueous hydrobromic acid was formerly used for this methyl ether cleavage (EP 0 753 506 A1).
- these reaction conditions have various drawbacks. To achieve satisfactory yields therefore a high excess of acid has to be used, and, after the reaction has taken place, has to be laboriously distilled off and destroyed.
- methyl bromide is formed as the reaction product when HBr is used is particularly serious.
- Methyl bromide is a toxic, highly flammable gas with a boiling point of 4° C., which, it is suspected, damages the ozone layer of the earth's atmosphere and for which a production ban in the European Union is therefore being considered.
- the compound (III), preferably in the form of the hydrochloride, is suspended in a mixture of a large excess of methane sulphonic acid, conventionally between 5 and 40 equivalents, in particular 10 to 30 equivalents, particularly preferably about 20 equivalents, and 1 to 2, equivalents preferably about 1.1 to 1.3 equivalents of methionine, and then heated for 1 to 12 hours, preferably 3 to 8 hours, in particular 5 hours, to temperatures of 50 to 100° C., preferably 70 to 90° C.
- reaction products were identified and the chemical and optical purity analysed by NMR spectroscopy and HPLC chromatography.
- the reaction mixture was cooled to 2° C. and stirred for 4 hours.
- the precipitate formed was centrifuged off and dried in a drying cabinet for 17 hours at 40° C. and under a vacuum of ⁇ 150 mbar.
- the product thus obtained could be used for subsequent hydrogenation.
- the yield was 2.55 kg (80 % of theoretical) (1S,2S)-[2-chloro-2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine hydrochloride.
- Identification was effected by comparing the analytical data of the product obtained in variant A or B and the compound known from EP 0 753 506 A1, which exhibited identity.
- the chemical and optical purity was analysed by HPLC on a Nucleosil 100-5 C8 HD column (250 ⁇ 3 mm) by gradient elution with acetonitrile/water. Detection was effected using a UV spectrometer at 210 nm.
- Identification was effected by comparing the analytical data of the product obtained and the compound known from EP 0 753 506 A1, which exhibited identity.
- the chemical and optical purity was analysed by HPLC on a Nucleosil 100-5 C8 HD column (250 ⁇ 3 mm) by gradient elution with acetonitrile/water. Detection was effected using a UV spectrometer at 210 nm.
- Identification was effected by comparing the analytical data of the product obtained and the compound known from EP 0 753 506 A1, which exhibited identity.
- the chemical and optical purity was analysed by HPLC on a Nucleosil 100-5 C8 HD column (250 ⁇ 3 mm) by gradient elution with acetonitrile/water. Detection was effected using a UV spectrometer at 210 nm.
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Abstract
The present invention relates to a process for converting a tertiary OH group of an organic compound into a tertiary C1 group of the organic compound by using a solvent selected from the group comprising toluene, o-xylene, m-xylene, p-xylene and mixtures thereof, and thionyl chloride as the chlorinating agent.
Description
- This application is a continuation of co-pending U.S. patent application Ser. No. 10/972,773, filed Oct. 26, 2004, now U.S. Pat. No.______, which in turn was a continuation of international patent application no. PCT/EP03/04213, filed Apr. 23, 2003, designating the United States of America, and published in German as WO 03/091199 A1, the entire disclosure of which is incorporated herein by reference. Priority is claimed based on German patent application no. 102 18 862.9, filed Apr. 26, 2002.
- The present invention relates to a process for converting a tertiary OH group of an organic compound into a tertiary C1 group of the organic compound.
- As is known from EP 0 753 506 A1, the compound of formula (I) (below) has an analgesic effect and is also used as an intermediate product to produce further analgesic substances. EP 0 753 506 A1 discloses a process for producing the compound of formula (I) starting from a compound of general formula (II),
the production of which is known from the literature (K. Flick et al., Arzneim.-Forsch./Drug Res. 28 (1), issue 1a (1978)), wherein, to convert the tertiary alcohol function on the cyclohexyl radical into a C-substitution with retention on the carbon atom marked by *, thionyl chloride is used as the chlorination reagent and as the solvent. This process therefore requires large quantities of thionyl chloride. The subsequent working up while expelling the excess thionyl chloride with a stream of nitrogen gas or by distillation is stressful for humans, the environment and operating equipment. Furthermore, only poor yields (maximum of 55% of theoretical) are achieved. - In particular the invention relates to a process for producing a compound of general formula (I)
and, more precisely, in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in the illustrated form or in the form of its salts, in particular the physiologically acceptable salts, particularly preferably in the form of the hydrochloride, or in the form of its solvates, in particular the hydrates. - It is therefore an object of the invention to provide a process with which an organic compound comprising a tertiary OH group, in particular a compound of formula (II), is converted into a corresponding organic compound comprising a tertiary C1 group, in particular into a compound of formula (I), in a high yield. It is also desirable to reduce the quantity of chlorinating agent to be used, compared to the process known from the literature, using this process.
- The object is achieved by a process for converting a tertiary OH group of an organic compound into a tertiary C1 group of the organic compound, characterized in that the tertiary alcohol is suspended or dissolved in a solvent, selected from the group comprising toluene, o-xylene, m-xylene, p-xylene and mixtures thereof, thionyl chloride being added to the resultant suspension or solution and then the resultant organic compound comprising the tertiary C1 group is separated from the further reaction components.
- It is preferred in this case that at least 1 equivalent but not more than 3 equivalents of thionyl chloride is/are used. The preferred solvent is toluene.
- Separation of the resultant organic compound comprising the tertiary C1 group can be effected in different ways. Thus, the organic compound comprising the tertiary C1 group can be isolated, after the reaction has taken place, by distilling off (distillation of) the further reaction components with the solvent. Distilling off (distillation of) is also taken to mean the partial removal of the solvent with the further reaction components by supplying heat under vacuum. It is also possible, after the reaction has taken place, to obtain the organic compound comprising the tertiary C1 group as a solid by cooling to below ambient temperature and to then dry it at temperatures between 35° C. and 75° C., preferably under vacuum. The halogenated organic compound is preferably obtained in the form of its hydrochloride.
- This process according to the invention allows synthesis of organic compounds comprising a tertiary C1 group, starting from the corresponding tertiary alcohol while retaining the stereochemistry at the stereogenic center in high yields of more than 70% and while reducing the quantity of thionyl chloride to be used.
- The process according to the invention has proven to be particularly advantageous for producing a compound of formula (I)
in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in the illustrated form or in the form of its salts, in particular physiologically acceptable salts, particularly preferably in the form of the hydrochloride, and/or in the form of its solvates, in particular the hydrates; wherein the process is characterized in that a compound of formula (II)
in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in the illustrated form or in the form of its salts, in particular physiologically acceptable salts, particularly preferably in the form of the hydrochloride, and/or in the form of its solvates, in particular the hydrates; - (a) is suspended in a solvent, which is selected from the group comprising toluene, o-xylene, m-xylene, p-xylene and mixtures thereof;
- (b) thionyl chloride is added to the resultant suspension; and
- (c) the reaction product comprising the tertiary C1 group of formula (I) is separated from the further reaction components.
- It is advantageous here that the reaction product of formula (I) is separated (c) by distilling off (distillation of) the solvent with the further reaction components. Distilling off (distillation) includes, without limitation, the partial removal of the solvent with the further reaction components by supplying heat under vacuum. Alternatively, separation (c) can take place by precipitating the reaction product of formula (I) by means of cooling the reaction mixture to below ambient temperature and then drying the reaction product at temperatures between 35° C. and 75° C., preferably under vacuum.
- Toluene is preferred as the solvent or solubilizer. The use of other non-polar solvents as toluene and/or xylene, for example THF, heptane, hexane and cyclohexane, has not proven to be advantageous, as the reaction is then carried out with the formation of numerous by-products, i.e. not sufficiently selectively. It is also preferred that 1 to 2 equivalents, in particular 1.5 to 1.7 equivalents, particularly preferably 1.6 equivalents of thionyl chloride—based on the compound of formula (II)—are used. This represents a drastic reduction in the quantity of thionyl chloride to be used compared with the process known from EP 0 753 506 A1. Much higher yields, which are greater than 70% of the theoretical yield, are also achieved with complete conversion of the starting compound (II).
- The compound (II) is preferably reacted at elevated temperature, in particular at a temperature of 30 to 50° C., preferably 35 to 45° C., for 1 to 4 hours, preferably 2 to 3 hours, though the reaction time can also be longer or shorter than this.
- It has been found that the reaction according to the invention of (II) to (I) in the presence of catalysts, for example dimethyl formamide, does not result in higher conversion rates or improved yields; however, these catalysts do not disturb the course of the reaction either.
- The starting compound (II) is generally used in the form of its hydrochloride. It is suspended in the inert or non-polar solubilizer, toluene, in which it does not dissolve at either low or high temperature. The addition of the thionyl chloride, which for its part is relatively non-polar, should not make any difference but during the course of the reaction it will be seen that the educt (II) dissolves completely. It is also surprising, and advantageous to process management as a whole, that—in contrast to what is conventional in reactions with thionyl chloride, such as in the process of EP 0 753 506 A1 known from the literature, no sulphur dioxide gas and no hydrogen chloride gas develops during heating. It is possible that the educt of formula (II) and/or the product of formula (I) go into a complex comprising sulphur dioxide and hydrogen chloride, so the compounds (I) and (II) remain in solution and SO2 and HCl are not released as gases. The complexing of amines with SO2 in organic solvents is known in the literature (see for example J. Grundnes, S. D. Christian, J. Am. Chem. Soc. (1968) 90, 2239-2245), the teachings of which are incorporated by reference, while the—hypothetical—complexing with HCl has not previously been observed.
- Irrespective of whether the hypothesis of complexing applies, the surprising circumstance whereby the reactants of the reaction remain in a homogeneous solution has proven to be advantageous with respect to yield and reaction. A further advantage is that it is possible to separate the desired reaction product from the solubilizer and the further reaction components and as the solubilizer, preferably toluene, is distilled off, preferably under vacuum; the sulphur dioxide that has formed and the hydrogen chloride are also removed in the process.
- It is also advantageous to achieve separation of the product (I) by cooling the reaction mixture to a temperature below ambient temperature, preferably to 0 to 10° C., in particular to about 2 to 4° C., which leads to precipitation of the crude product. Subsequent treatment in a drying cabinet at elevated temperatures of preferably 35 to 75° C., in particular 40° C., and preferably under vacuum, in particular at a pressure of 1 to 300 mbar, preferably 50 to 180 mbar, most particularly preferably 50 to 150 mbar, yields the pure product, preferably as hydrochloride.
- It is particularly preferred to carry out the process according to the invention with the stereoisomers of compound (II) which have the configuration (IIa) and/or (IIb):
The reaction according to the invention with thionyl chloride leads, as expected with retention of the stereochemistry at the center of the reaction, to the corresponding stereoisomers of compound (I). It is also preferred to use the compound (II) in the process according to the invention as the enantiomer with the absolute configuration (Ia), i.e. as (1S,2S)-2-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexanol, in particular as the hydrochloride. (1 S,2S)-[2-chloro-2-(3-methoxyphenyl)-cyclohexylmethyl]-dimethylamine, in particular in the form of the HCl salt, is obtained as the product here. - As known from EP 753 506 A1, the compounds of formula (I) have an analgesic effect and can be used as intermediate compounds to produce further analgesically active cyclohexyl compounds.
- It is therefore also preferred to convert a compound of formula (I), produced by the process according to the invention by (d) catalytic hydrogenation, into a compound of formula (III):
Hydrogenation is preferably carried out by heterogeneous catalysis with palladium on activated carbon, of which the quantity can be varied within a wide range between 1% through 5% to 10% palladium on activated carbon. Suitable solvents include alkyl alcohols, in particular methanol and ethanol. The compound (I) is conventionally used as the hydrochloride. - The hydrogenation step (d) is preferably carried out with retention of the stereochemistry on the carbon atom marked by an asterisk (*) in formula (I) or (III). The optionally formed quantity of compound (III) with inverted stereochemistry on the carbon*atom is so low that it can easily be separated during conventional working up. This process is therefore eminently suitable, starting from the enantiomer with the absolute configuration (IIa), via the corresponding enantiomer of compound (Ia)
for producing the compound (III) as the enantiomer with the absolute configuration (IIIa)
(The compound (IIIb) mirror-inverted to (IIa) can be correspondingly produced, starting from the optical antipode (IIb) via (Ib)). - As an alternative to hydrogenation by means of heterogeneous catalysis, the compound of formula (III) is also accessible by hydrogenation with complex zinc-boron hydrides of (I), as described in EP 0 753 506 A1.
- The compound of formula (III), preferably produced by the process according to the invention, can also be converted by methyl ether cleavage in a further step (e) into the compound of formula (IV):
Aqueous hydrobromic acid was formerly used for this methyl ether cleavage (EP 0 753 506 A1). However, these reaction conditions have various drawbacks. To achieve satisfactory yields therefore a high excess of acid has to be used, and, after the reaction has taken place, has to be laboriously distilled off and destroyed. The fact that methyl bromide is formed as the reaction product when HBr is used is particularly serious. Methyl bromide is a toxic, highly flammable gas with a boiling point of 4° C., which, it is suspected, damages the ozone layer of the earth's atmosphere and for which a production ban in the European Union is therefore being considered. - A process is therefore required which allows the desired methyl ether cleavage while avoiding the use of HBr and at the same time guarantees high yields of the product (IV).
- It has accordingly been found that due to the simultaneous use of methionine and methane sulphonic acid, the methyl ether cleavage of (III) to (IV) can be carried out extremely easily and with high yields of more than 70%. (The use of methionine/methane sulphonic acid to produce phenols has been described by N. Fujii et al., J. Chem. Soc. Perkin I (1977) 2288-2298, but they do not convert any amine-substituted compounds). Here the compound (III), preferably in the form of the hydrochloride, is suspended in a mixture of a large excess of methane sulphonic acid, conventionally between 5 and 40 equivalents, in particular 10 to 30 equivalents, particularly preferably about 20 equivalents, and 1 to 2, equivalents preferably about 1.1 to 1.3 equivalents of methionine, and then heated for 1 to 12 hours, preferably 3 to 8 hours, in particular 5 hours, to temperatures of 50 to 100° C., preferably 70 to 90° C. After cooling and conventional working up, the desired phenol (IV) is obtained in high yields without by-products and at most very small quantities of unreacted starting material (III), preferably as hydrochloride; by recrystallisation from water, (IV) is obtained in the form of hydrochloride hydrates. It is surprising in this connection that the dimethylamino group otherwise very unstable in an acid medium proves to be stable compared with the large excess of methane sulphonic acid present.
- An efficient process for producing the analgesic compound known from EP 0 753 506 A1 with the absolute configuration (IVa), starting from the tertiary alcohol (II) with the absolute configuration (IIa), is thus provided which can also be carried out on an industrial scale. The synthesis sequence is shown in diagram I. (The same applies to the optical antipode of (IVa) with (1S,2S) configuration.
Diagram 1 - The invention will be described hereinafter by examples, without being limited thereto.
- The syntheses were carried out using commercially available reagents and substances or with compounds that had been produced by processes known from the literature.
- The reaction products were identified and the chemical and optical purity analysed by NMR spectroscopy and HPLC chromatography.
- 3 kg (10 mol) (1S,2S)-2-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexanol hydrochloride were suspended in 10 l toluene and heated to 30° C. 1.9 kg (16 mol) thionyl chloride were added within 10 min. The mixture was heated to 35° to 45° C. A clear solution was produced after 2 to 3 hours. Further processing was effected according to variant A or B.
- Variant A:
- 3 kg toluene were distilled off under vacuum via a gas washer. Hydrogen chloride gas and sulphur dioxide escaped as the toluene was distilled off. The mixture was then cooled to 2° C. and stirred for 2 hours at this temperature. The precipitate was centrifuged off and thoroughly rewashed with toluene. The product could be used directly or after drying for subsequent hydrogenation. The yield was 2.87 kg (90% of theoretical) (1S,2S)-[2-chloro-2-(3-methoxyphenyl)-cyclohexylmethyl]-dimethylamine hydrochloride.
- Variant B:
- The reaction mixture was cooled to 2° C. and stirred for 4 hours. The precipitate formed was centrifuged off and dried in a drying cabinet for 17 hours at 40° C. and under a vacuum of <150 mbar. The product thus obtained could be used for subsequent hydrogenation. The yield was 2.55 kg (80 % of theoretical) (1S,2S)-[2-chloro-2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine hydrochloride.
- Identification was effected by comparing the analytical data of the product obtained in variant A or B and the compound known from EP 0 753 506 A1, which exhibited identity. The chemical and optical purity was analysed by HPLC on a Nucleosil 100-5 C8 HD column (250×3 mm) by gradient elution with acetonitrile/water. Detection was effected using a UV spectrometer at 210 nm.
- 3.18 kg (10 mol) (1S,2S)-[2-chloro-2-(3-methoxy-phenyl)-cyclohexylmethyl] dimethylamine hydrochloride (from Example 1) were dissolved in 15 l methanol, and 350 g palladium on activated carbon 5% were added. Hydrogen was introduced at normal pressure and ambient temperature until hydrogenation was complete. The catalyst was suction filtered, the solvent concentrated to a small volume and the base liberated using aqueous sodium hydroxide solution. After shaking out the aqueous phase using ethyl acetate and distilling off the organic solvent 2.47 kg (100% of theoretical) (1R,2R)-[2-(3-methoxyphenyl)-cyclohexylmethylamine]-dimethylamine as a slightly yellow colored oil remained.
- The oil was dissolved in acetone and the hydrochloride precipitated using hydrochloric acid gas. 2.27 kg (80% of theoretical) (1R,2R)-[2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine hydrochloride were obtained as a colorless powder with a content of <10% of (1R,2S)-[2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine hydrochloride, which was removed from 2-propanol by recrystallisation.
- Identification was effected by comparing the analytical data of the product obtained and the compound known from EP 0 753 506 A1, which exhibited identity. The chemical and optical purity was analysed by HPLC on a Nucleosil 100-5 C8 HD column (250×3 mm) by gradient elution with acetonitrile/water. Detection was effected using a UV spectrometer at 210 nm.
- 2.83 kg (10 mol) (1R,2R)-[2-(3-methoxyphenyl)-cyclohexyl-methyl]-dimethylamine hydrochloride were suspended in a mixture of 8.70 l methane sulphonic acid and 1.50 kg (D,L) methionine and heated for 5 hours to 70° to 90° C. The mixture was cooled to 30° C. and adjusted using 32% aqueous sodium hydroxide solution to a pH of 12 to 14. The base was extracted with ethyl acetate. After concentrating the organic solvent and precipitation in acetone with hydrochloric acid gas (or aqueous hydrochloric acid) 1.86 kg (80%) (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol hydrochloride with a content of <1% of the starting product (1R,2R)-[2-(methoxyphenyl)-cyclohexyl-methyl]-dimethylamine hydrochloride.
- Recrystallisation from water produced colorless crystals (1.5 kg, 80%) of (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol hydrochloride dihydrate.
- Identification was effected by comparing the analytical data of the product obtained and the compound known from EP 0 753 506 A1, which exhibited identity. The chemical and optical purity was analysed by HPLC on a Nucleosil 100-5 C8 HD column (250×3 mm) by gradient elution with acetonitrile/water. Detection was effected using a UV spectrometer at 210 nm.
- The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the describe embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.
Claims (12)
1. A process for converting a tertiary OH group of an organic compound into a tertiary C1 group of the organic compound, said process comprising the steps of:
suspending or dissolving the tertiary alcohol in a solvent selected from the group consisting of toluene, o-xylene, m-xylene, p-xylene and mixtures thereof;
adding thionyl chloride to the resultant suspension or solution to form a reaction mixture without the presence of any catalyst in the reaction mixture, and separating the resultant organic compound comprising the tertiary C1 group from the reaction mixture.
2. A process according to claim 1 , wherein the step of separating the organic compound comprising the tertiary C1 group involves distillation of the reaction mixture.
3. A process according to claim 1 , wherein the organic compound comprising the tertiary C1 group is obtained as a solid after the reaction has taken place by cooling to below ambient temperature and drying at temperatures between 35° C. and 75° C.
4. A process according to claim 3 , wherein the drying step is performed under vacuum.
5. A process according to claim 1 , wherein the solvent is toluene.
6. A process according to claim 1 , wherein 1 to 2 equivalents of thionyl chloride, based on the amount of the tertiary alcohol, are added.
7. A process according to claim 6 , wherein 1.5 to 1.7 equivalents of thionyl chloride, based on the amount of the tertiary alcohol, are added.
8. A process according to claim 6 , wherein 1.6 equivalents of thionyl chloride, based on the amount of the tertiary alcohol, are added.
9. A process according to claim 1 , wherein a reaction is carried out with thionyl chloride at a temperature of 30 to 50° C.
10. A process according to claim 1 , wherein a reaction is carried out with thionyl chloride at a temperature of 35 to 45° C.
11. A process according to claim 1 , wherein a reaction is carried out with thionyl chloride for 1 to 4 hours.
12. A process according to claim 1 , wherein a reaction is carried out with thionyl chloride for 2 to 3 hours.
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US11/704,257 US20070142681A1 (en) | 2002-04-26 | 2007-02-09 | Process for chlorinating tertiary alcohols |
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DE10218862A DE10218862A1 (en) | 2002-04-26 | 2002-04-26 | Process for the chlorination of tertiary alcohols |
DE10218862.9 | 2002-04-26 | ||
PCT/EP2003/004213 WO2003091199A1 (en) | 2002-04-26 | 2003-04-23 | Method for chlorinating tertiary alcohols |
US10/972,773 US7235693B2 (en) | 2002-04-26 | 2004-10-26 | Process for chlorinating tertiary alcohols |
US11/704,257 US20070142681A1 (en) | 2002-04-26 | 2007-02-09 | Process for chlorinating tertiary alcohols |
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EP (1) | EP1499582B1 (en) |
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DE102005034973A1 (en) * | 2005-07-22 | 2007-02-15 | Grünenthal GmbH | Salt of dimethylaminomethyl-phenyl-cyclohexane and its crystalline forms |
EP2336103A3 (en) * | 2005-07-22 | 2011-07-20 | Grünenthal GmbH | HCL-polymorphs of 3-[2-(Dimethylamino)methyl-(cyclohex-1-yl)]phenol |
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US20040054203A1 (en) * | 2002-08-19 | 2004-03-18 | Bohling James Charles | Resin functionalization method |
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GB8525954D0 (en) * | 1985-10-21 | 1985-11-27 | Mcneilab Inc | Chlorination of carbohydrates &c alcohols |
DE19525137C2 (en) * | 1995-07-11 | 2003-02-27 | Gruenenthal Gmbh | 6-Dimethylaminomethyl-1-phenyl-cyclohexane compounds as intermediates for the preparation of pharmaceutical agents |
IL119121A (en) * | 1996-08-22 | 2000-11-21 | Chemagis Ltd | Process for the purification of (RR-SS)-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol hydrochloride |
DE19941062A1 (en) * | 1999-08-28 | 2001-03-01 | Aventis Pharma Gmbh | Pure methyl 2-acetamido-3-chloropropionate preparation for use as intermediate for hypotensive agent ramipril, from methyl serinate hydrochloride by chlorination, acetylation and purification |
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CN100338027C (en) | 2007-09-19 |
US20050119349A1 (en) | 2005-06-02 |
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IL164807A (en) | 2012-10-31 |
DE10218862A1 (en) | 2003-11-06 |
SI1499582T1 (en) | 2011-02-28 |
ES2354355T3 (en) | 2011-03-14 |
IL164807A0 (en) | 2005-12-18 |
US7235693B2 (en) | 2007-06-26 |
CN1662486A (en) | 2005-08-31 |
ATE491681T1 (en) | 2011-01-15 |
AU2003229715A1 (en) | 2003-11-10 |
EP1499582A1 (en) | 2005-01-26 |
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DE50313325D1 (en) | 2011-01-27 |
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