DK162980B - Fremgangsmaade til fremstilling af sekundaere aminer - Google Patents
Fremgangsmaade til fremstilling af sekundaere aminer Download PDFInfo
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- DK162980B DK162980B DK188384A DK188384A DK162980B DK 162980 B DK162980 B DK 162980B DK 188384 A DK188384 A DK 188384A DK 188384 A DK188384 A DK 188384A DK 162980 B DK162980 B DK 162980B
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- hours
- mole
- methanol
- fluoro
- ethyl
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- 238000000034 method Methods 0.000 title claims abstract description 8
- 150000003335 secondary amines Chemical class 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- -1 2-fluoro-3,4-dimethoxyphenyl Chemical group 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 7
- 150000003568 thioethers Chemical class 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- HEQLIFTUXWOFFR-UHFFFAOYSA-N 1-methylsulfanylethanamine Chemical compound CSC(C)N HEQLIFTUXWOFFR-UHFFFAOYSA-N 0.000 claims 1
- WRGMAUWWSLMQIR-UHFFFAOYSA-N 2-(2-fluoro-3,4-dimethoxyphenyl)ethanamine Chemical compound COC1=CC=C(CCN)C(F)=C1OC WRGMAUWWSLMQIR-UHFFFAOYSA-N 0.000 claims 1
- FMTOTEXFFQUHHC-UHFFFAOYSA-N 2-[2-(2-fluoro-3,4-dimethoxyphenyl)ethylamino]-1-(4-methoxyphenyl)ethanol Chemical compound C1=CC(OC)=CC=C1C(O)CNCCC1=CC=C(OC)C(OC)=C1F FMTOTEXFFQUHHC-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000002002 slurry Substances 0.000 claims 1
- 239000012265 solid product Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 17
- YTKGUKHQYUHYTQ-UHFFFAOYSA-N 2-(2-chloro-3,4-dimethoxyphenyl)ethanamine Chemical compound COC1=CC=C(CCN)C(Cl)=C1OC YTKGUKHQYUHYTQ-UHFFFAOYSA-N 0.000 abstract description 5
- 239000000543 intermediate Substances 0.000 abstract description 5
- 125000000217 alkyl group Chemical group 0.000 abstract description 4
- LNZBSIXPXJKKDF-UHFFFAOYSA-N 2-(4-methoxyphenyl)-2-oxoacetaldehyde Chemical compound COC1=CC=C(C(=O)C=O)C=C1 LNZBSIXPXJKKDF-UHFFFAOYSA-N 0.000 abstract description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000003638 chemical reducing agent Substances 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 238000001311 chemical methods and process Methods 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- PQRXADLRQKVLHQ-UHFFFAOYSA-N 2-[2-(2-chloro-3,4-dimethoxyphenyl)ethylamino]-1-(4-methoxyphenyl)ethanol Chemical compound C1=CC(OC)=CC=C1C(O)CNCCC1=CC=C(OC)C(OC)=C1Cl PQRXADLRQKVLHQ-UHFFFAOYSA-N 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229940117803 phenethylamine Drugs 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical group N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 description 1
- LXTNZWGUMORTKT-UHFFFAOYSA-N 1-phenyl-2-(2-phenylethylamino)ethanol Chemical class C=1C=CC=CC=1C(O)CNCCC1=CC=CC=C1 LXTNZWGUMORTKT-UHFFFAOYSA-N 0.000 description 1
- PMTBLRKLMNAJQI-UHFFFAOYSA-N 2-(2-chloro-3,4-dimethoxyphenyl)ethanamine;hydrochloride Chemical compound Cl.COC1=CC=C(CCN)C(Cl)=C1OC PMTBLRKLMNAJQI-UHFFFAOYSA-N 0.000 description 1
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 description 1
- ARHIWOBUUAPVTB-UHFFFAOYSA-N 2-(4-methoxyphenyl)oxirane Chemical compound C1=CC(OC)=CC=C1C1OC1 ARHIWOBUUAPVTB-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- RCKHJBKVFQNBOW-UHFFFAOYSA-N 2-[2-(2-chloro-3,4-dimethoxyphenyl)ethylamino]-1-(4-methoxyphenyl)-2-methylsulfanylethanone Chemical compound C1=CC(OC)=CC=C1C(=O)C(SC)NCCC1=CC=C(OC)C(OC)=C1Cl RCKHJBKVFQNBOW-UHFFFAOYSA-N 0.000 description 1
- CGKRFDXHYBJWPO-UHFFFAOYSA-N C(C)[AlH]CC.[Na] Chemical compound C(C)[AlH]CC.[Na] CGKRFDXHYBJWPO-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000246358 Thymus Species 0.000 description 1
- 235000007303 Thymus vulgaris Nutrition 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 description 1
- 150000005215 alkyl ethers Chemical group 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- JUGGGTWXNOOGNX-UHFFFAOYSA-N dichloromethane;methanesulfonic acid Chemical compound ClCCl.CS(O)(=O)=O JUGGGTWXNOOGNX-UHFFFAOYSA-N 0.000 description 1
- USLKCMBGQFYUFI-UHFFFAOYSA-N dichloromethane;tribromoborane Chemical compound ClCCl.BrB(Br)Br USLKCMBGQFYUFI-UHFFFAOYSA-N 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 229940005501 dopaminergic agent Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 150000003947 ethylamines Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- WLGDAKIJYPIYLR-UHFFFAOYSA-N octane-1-sulfonic acid Chemical compound CCCCCCCCS(O)(=O)=O WLGDAKIJYPIYLR-UHFFFAOYSA-N 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 description 1
- QLUZJFBPDLVUQW-UHFFFAOYSA-K sodium zinc trihydroxide Chemical compound [OH-].[OH-].[OH-].[Na+].[Zn++] QLUZJFBPDLVUQW-UHFFFAOYSA-K 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- QGXFDKHOSNJQKE-UHFFFAOYSA-N sulfuric acid;2,2,2-trifluoroacetic acid Chemical compound OS(O)(=O)=O.OC(=O)C(F)(F)F QGXFDKHOSNJQKE-UHFFFAOYSA-N 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000001585 thymus vulgaris Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- 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
-
- G—PHYSICS
- G05—CONTROLLING; REGULATING
- G05B—CONTROL OR REGULATING SYSTEMS IN GENERAL; FUNCTIONAL ELEMENTS OF SUCH SYSTEMS; MONITORING OR TESTING ARRANGEMENTS FOR SUCH SYSTEMS OR ELEMENTS
- G05B2219/00—Program-control systems
- G05B2219/30—Nc systems
- G05B2219/50—Machine tool, machine tool null till machine tool work handling
- G05B2219/50103—Restart, reverse, return along machined path, stop
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
i
DK 162980 B
Opfindelsen angår en hidtil ukendt kemisk fremgangsmåde til fremstilling af sekundære aminer. Mere specifikt angår fremgangsmåden fremstillingen af N-(2-hydroxy-2-phenylethyl)-2-phenylethylaminer, f.eks. N-[2-hydroxy-2-(p-methoxyophenyl)-S ethy1]-2-(2-halogen-3,4-dimethoxypheny1)ethy1aminer. Disse sidste er kemiske mellemprodukter til fremstilling af 6-halo-gen-7,8-dihydroxy-l-(p-hydroxyopheny1)-2,3,4,5-tetrahydro-lH- 3-benzazepiner, der er dopaminergi ske midler, der kan anvendes til behandling af forhøjet blodtryk eller nyredysfunk-10 ti on.
US patentskrift nr. 4.197.297 beskriver to fremgangsmåder til fremstilling af N - [ 2-hydroxy-2-(p-methoxypheny1)ethyl]-2-(2-chlor-3,4-dimethoxyphenyl)ethylamin. Den første involverer om-15 sætning af 2-chlor-3,4-dimethoxyphenethy1amin med p-methoxy-styrenoxid, og den anden kondensation af 2-brom-l-t-butoxy-l-(p-methoxypheny1)ethan og 2-ch1or-3,4-dimethoxyphenethylamin efterfulgt af fjernelse af den beskyttende t-butylgruppe.
20 Den kemiske fremgangsmåde ifølge opfindelsen illustreres ved følgende reaktionsskema: R1
0 S-R I
ίΧΤ ^Η~°~Η + CH2-CH2-NH2 -» 25 “^© CB3oJ^j @ R1 0 S_R [ C - CH - NH - CHZ—CH2.~—— OCH3 30 I I —* ch-o—s. — och3 __ v V _ R1 °H Ϊ ... C \>)—CH- CH 0 -NH-CH ~ -CH 0 /vr OCH, q ty- °ch3 2
DK 162980 B
hvori R er en lavere alkylgruppe med 1-4 carbonatomer, fortrinsvis methyl, og Ri er chlor eller fluor.
Den kemiske fremgangsmåde ifølge opfindelsen omfatter den før-5 ste reaktion mellem hemimercaptalen med formlen 1 og phenethyl-aminen med formlen 2 i et organisk opløsningsmiddel, der er inert over for reaktanterne, og i hvilket reaktanterne er næsten fuldstændig opløselige, indtil koblingen er fuldstændig.
Et overskud af hvert af udgangsmaterialerne kan eventuelt være 10 til stede, men sædvanligvis anvendes støkiometriske mængder. Faktisk kan et overskud af den primære amin i visse reaktioner give bedre udbytte af det isolerede thioethermellemprodukt med formlen 3. Egnede opløsningsmidler udvælges fra de foretrukne lavere alkoholer, såsom methanol, ethanol, propanol eller iso-15 propanol, ethere, såsom tetrahydrofuran, dimethylsulfoxid, dimethyl formamid, dimethylacetamid, aromatiske forbindelser, såsom benzen, toluen eller xylen, estere, såsom ethylacetat, ha-1ogenhydrocarboner, såsom chloroform, carbontetrachlorid, ethylendichlorid, methylenchlorid eller blandinger deraf. Me-20 thanol eller vandige blandinger af methanol foretrækkes.
Reaktionen udføres hensigtsmæssigt ved stuetemperatur, indtil den er fuldstændig, sædvanligvis 1-12 timer. Såfremt phen-ethylamin anvendes i form af et syreadditionssalt, såsom hy-25 drochloridet eller hydrobromidet, tilsættes en ækvivalent mængde af et syrebindende middel, såsom et lavere alkalimetal-alkoxid, -hydroxid eller -carbonat, for at danne basen in situ.
30 Højere temperaturer, op til tilbageløbstemperaturen af reaktionsblandingen, kan eventuelt anvendes, f.eks. når opløseligheden af udgangsmaterialet er et problem. Såfremt methanol anvendes som opløsningsmiddel, separeres mellemproduktet med formlen 3, f.eks. N-[2-(2-chlor-3,4-dimethoxyphenyl)ethyl]-2-35 keto-2-(p-methoxyphenyl)-1-methy1-thioethylamin, nemt fra reaktionsblandingen ved bundfældning. Thioethermellemprodukterne med formlen 3 er hidtil ukendte forbindelser.
3
DK 162980 B
Laboranten kan eventuelt isolere a-thiomel1emproduktet med formlen 3, eller vedkommende kan fortsætte med det næste trin af reaktionsskemaet A uden isolering, α-thioforbindelsen behandles med et reducerende middel, der er i stand til at om-5 danne en ketogruppe til en hydroxygruppe. Uventet fjerner denne reaktion samtidigt α-alkylthoigruppen i form af et lavere alkylmercaptanbiprodukt. Reducerende midler omfatter de traditionelle, der anvendes inden for området, til at omdanne en ketogruppe til en hydroxygruppe. Eksempler er metalsyre, såsom 10 zinkstøv-eddikesyre eller jern og eddikesyre, zink-natriumhydroxid i ethanol eller en Meerwein-reduktion. Spaltning af en ring-methoxysubstituent under reduktionen er ikke uacceptabel, men der bør tages hensyn til at anvende et reducerende middel, der ikke angriber halogensubstituenter.
15
Bedre egnede reduktionsmidler, specielt da et halogen er til stede på en af phenylringen af forbindelse 3, er borhydridreduktionsmi dier. De bedst egnede af disse er alkalimetal borhy-drider, såsom natrium- eller kaliumborhydrid. Andre indbefat-20 ter alkali metaltri al kyl borhydrider, såsom lithium- eller kal i -umtriisoamy1borhydrider og lithium- eller kaliumtri-sek.-bu-tylborhydrider, alkalimethaltrialkoxyborhydrider, såsom natrium- eller kaliumtriisopropoxyborhydrider. De tilsvarende hy-drider, såsom 1ithiumaluminiumhydrid, natriumaluminiumhydrid, 25 diisobutulaluminiumhydrid, natriumdiethylaluminiumhydrid eller natrium-bis-(2-methoxyethoxy)aluminiumhydrid kan også anvendes .
Organiske opløsningsmidler, der sædvanligvis anvendes i hy-30 drid- eller borhydridreaktioner, vil vise sig at være egnede til denne reaktion, f.eks. lavere alkoholer, tetrahydrofuran, glycolmethylether, diethylenglycolmethylether, dimethyl formamid og sul fol an.
35 Mest hensigtsmæssigt udføres den anden reaktion ved at anvende mindst to ækvivalenter natriumborhydrid i methanol, indtil reaktionen er fuldstændig, og ved først at holde temperaturen 4
DK 162980 B
under 20°C og derefter tillade den at nå op på stuetemperatur. Det totale udbytte af den i én beholder foregående totrinsreaktion varierer fra 50 til 80¾ af produktet, der isoleres ud fra standardkemiske fremgangsmåder. Såfremt den totale to-5 tri nsreakt ion med reakti onsskema A forløber uden isolering af thioetheren, må opløsningsmidlet udvælges således, at det tilpasses det reducerende middel.
De sekundære aminer med formlen 4 omdannes til biologisk ak-10 tive slutprodukter ifølge kendt teknik. Den sekundære amin behandles f.eks. med koncentreret svovlsyre-trifluoreddikesyre eller methansulfonsyre-methylenchlorid til dannelse af benza-zepinringen. Beskyttende grupper som alkylethere spaltes, såfremt de er til stede, ved at anvende bortribromidmethylen-15 chlorid eller 48%'s hydrogenbromidsyre til opnåelse af det ønskede slutprodukt.
De følgende eksempler skal illustrere udøvelsen af opfindelsen. Alle temperaturer er i °C. Andre variationer af disse ek-20 sempler vil være nærliggende for fagmanden inden for området.
Eksempel 1
En 22 1 kolbe blev påfyldt 526,6 g (2,48 mol) p-methoxyphenyl-25 glyoxalmethylhemimercaptal og 626,3 g (2,48 mol) 2-chlor-3,4-dimethoxyphenethylaminhydrochlorid efterfulgt af 7,4 1 methanol og 535,8 g (2,48 mol) 25Vs natriummethoxid/methanol . Blandingen blev omrørt ved stuetemperatur i 3 timer og derefter afkølet til 0°C. Natriumborhydrid (200 g, 5,26 mol) blev 30 tilsat med en sådan hastighed, at reaktionstemperaturen blev holdt under 20°C. Blandingen blev omrørt i 8 timer, medens reaktionsblandingen fik lov til at blive opvarmet til stuetemperatur. Methanolen blev fjernet under vakuum ved mindre end 50°C. Der blev tilsat ca. 2,5 1 10%'s saltsyre til opnåelse af 35 en pH-værdi på 1. Methylenchlorid (2,25 1) blev tilsat. Det organiske moderekstrakt kombineret med 2 1 supplerende ekstrakter blev nedbragt til det halve volumen, hvorefter der 5
DK 162980 B
blev tilsat 5,6 1 ethyl acetat. Efter omrøring, indtil det ønskede produkt var udskilt fuldstændigt, blev der genvundet 505,19 g (50,8%) N-[2-hydroxy-2-(p-methoxyphenyl)ethyl]-2-(2-chlor-3,4-dimethoxyphenyl)ethylamin ved filtrering, vask med 1 5 1 ethylacetat og ovntørring. Dette materiale var identisk med det, der er beskrevet ifølge kendt teknik ved hjælp af NMR.
Eksempel 2.
10 A. En blanding af 3,6 g (0,017 mol) p-methoxyphenylglyoxalme-thy1hemimercapta 1, 4,61 g (0,0213 mol) 2-ch1or-3,4-dimethoxy- phenethy1amin og 70 ml methanol blev omrørt ved stuetemperatur i 3 timer. Det bundfældede faste stof blev fraskilt ved filtrering, vasket med propanol og lufttørret til opnåelse af 15 5,53 g (79%) N-[ 2-(2-ch1or-3,4-dimethoxypheny1)ethy1]-2-keto- 2-(p-methoxyphenyl)-l-methylthioethylamin, smeltepunkt 75-78°C.
Analyse: C2oH24NS04c^: Beregnet: C 58,60, H 5,90, N 3,42, S 7,82, Cl 8,65.
20 Fundet: C 58,47, H 5,98, N 3,43, S 8,01, Cl 9,00.
B. En blanding af 3,40 g (16 mmol) p-methoxyphenylglyoxalme-thylhemimercaptal, 3,46 g (16 mmol) 2-chlor-3,4-dimethoxyphen-25 ethylamin og 90 ml methanol blev omrørt ved stuetemperatur i 72 timer. Methanol blev fjernet til dannelse af en olie. Methanol (20 ml) blev tilsat uden nogen krystallisation ved afkøling. 2 ml cyclohexan blev tilsat. Ved afkøling fraskiltes 1,86 g thioether.
30
En del af thioetheren (0,3 g, 0,73 mmol) i methanol blev omsat med 0,06 g (1,46 mmol) natriumborhydrid. Efter 1 time var alle reaktanterne gået i opløsning. Højtryksvæskekromatografisk omvendt faseanalyse (HPLC) (over silica ved 60:40 met hano 1/vand 35 med eddikesyre som puffer og octansulfonsyre som mobil fase) viste næsten kvantitativ omsætning til N - [ 2-hydroxy-2-(p-me-thoxyphenyl)-ethyl]-2-(2-chlor-3,4-dimethoxyphenyl)ethylamin.
7
DK 162980 B
R1 .. 0H Jl j -ch-ch2-nh-ch2-ch2—"j — och3 5 ch3o —i0CH3 hvori R1 er.chlor eller fluor, kendetegnet ved, at en forbindelse med formlen: 10 R1 CH30 -— CH2"CH2"NH2 ch3° - 15 ” hvori Ri er som ovenfpr defineret, omsættes med en p-methoxy- phenylglyoxal-lavere alkylhemimercaptal til fremstilling af en thioforbindelse med formlen: 20 r1
O S-R I
|^Γ- ί-έΗ-ΝΗ-€Η2-ΟΗ2-γρ^ρ ^ CH30 - °CH3 25 hvori R er en lavere alkylgruppe, og Ri er som ovenfor defineret, og at nævnte thioforbindelse omsættes med et reducerende middel til dannelse af den i kravets indledning omhandlede sekundære amin.
30 2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at R er methyl og det reducerende middel et borhydrid.
3. Fremgangsmåde ifølge krav 1, kendetegnet ved, 35 at reaktionerne udføres i methanol ved anvendelse af natrium- borhydrid som det reducerende middel.
Claims (6)
10 En blanding af 185 g (0,93 mol) 2-f 1 uor-3,4-dimethoxyphen-ethylamin, 340 g (0,97 mol) p-methoxyg1yoxa1 methy1hemimercap-tal og 3 1 methanol blev omsat ved stuetemperatur i 15 timer. En kort opkoncentrering og afkøling af en lille prøve gav N-[2-(2-f1uor-3,4-dimethoxyphenyl)ethyl]-2-keto-2-(p-methoxyphe-15 ny 1)-l-methy1thioethy1amin. Størsteparten af reaktionsblandingen blev afkølet til 8eC, hvorefter 72 g (1,86 mol) 98¾ natriumborhydrid blev tilsat over en periode på 2 timer og ved at fastholde temperaturen 20 under 20°C. Den gule opslæmning blev omrørt ved omgivelsernes temperatur i 1,5 time og derefter afkølet i 12 1 i s/vand (0 -8°C). Efter 30 minutters omrøring blev det faste produkt fraskilt, smeltepunkt 99 - loi°c.
25 Produktet blev rekrystal1iseret fra isopropanol til opnåelse af 225 g (78¾) hvidt fast stof af N-[2-hydroxy-2-(p-methoxy-phenyl)ethyl]-2-(2-fluor-3,4-dimethoxyphenyl)-ethylamin, smeltepunkt 106 - 107°C.
30 Analyse: Cigf^FNO^ Beregnet: C 65,92, H 6,92, N 4,01. Fundet: C 65,46, H 7,06, N 3,98. Patentkrav. 35
1. Fremgangsmåde til fremstilling af en sekundær amin med formlen: DK 162980 B
4. Fremgangsmåde ifølge krav 1, kendetegnet ved, at de to trin forløber uden isolering af thioethermellemproduktet .
5. Fremgangsmåde ifølge ethvert af kravene 1-4, kende tegnet ved, at R er methyl, og Ri er fluor. 10 15 20 25 30 35
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US48965483 | 1983-04-28 | ||
| US06/489,654 US4540819A (en) | 1983-04-28 | 1983-04-28 | Process for preparing secondary amines |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK188384D0 DK188384D0 (da) | 1984-04-11 |
| DK188384A DK188384A (da) | 1984-10-29 |
| DK162980B true DK162980B (da) | 1992-01-06 |
| DK162980C DK162980C (da) | 1992-06-01 |
Family
ID=23944726
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK188384A DK162980C (da) | 1983-04-28 | 1984-04-11 | Fremgangsmaade til fremstilling af sekundaere aminer |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4540819A (da) |
| EP (1) | EP0125053B1 (da) |
| JP (1) | JPS59206339A (da) |
| AT (1) | ATE22285T1 (da) |
| AU (1) | AU573209B2 (da) |
| CA (1) | CA1210780A (da) |
| DE (1) | DE3460757D1 (da) |
| DK (1) | DK162980C (da) |
| ES (1) | ES8506584A1 (da) |
| GR (1) | GR81490B (da) |
| IE (1) | IE57250B1 (da) |
| PT (1) | PT78470B (da) |
| ZA (1) | ZA842474B (da) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4579972A (en) * | 1983-04-28 | 1986-04-01 | Smithkline Beckman Corporation | Intermediates for preparing secondary amines |
| US4781173A (en) * | 1985-06-28 | 1988-11-01 | Juha Ven | Evaporating device and electric supply station provided with such an evaporating device |
| EP1725517A2 (en) * | 2005-01-24 | 2006-11-29 | Sicor Inc. | Process for the preparation of fenoldopam mesylate |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3345416A (en) * | 1963-09-04 | 1967-10-03 | Dept Of Chemistry | Preparation and rearrangement of beta-ketosulfoxides |
| AT338242B (de) * | 1975-09-25 | 1977-08-10 | Tanabe Seiyaku Co | Verfahren zur herstellung neuer racemischer und optisch aktiver 1-hydroxyphenyl-2-(3',4'-dimethoxyphenathyl)aminoathanole-(1) |
| US4197297A (en) * | 1976-11-17 | 1980-04-08 | Smithkline Corporation | 6-Halo-7,8-dihydroxy-1-(hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepines |
| CH637383A5 (en) * | 1978-01-01 | 1983-07-29 | Smithkline Beckman Corp | Trisubstituted 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines, and their salts |
| IT1148741B (it) * | 1980-11-28 | 1986-12-03 | Zambeletti Spa L | Procedimento per la preparazione dell'1-(3,5-dimetossi-4-idrossifenil)-2-(n-metilammino)etanolo cloridrato |
-
1983
- 1983-04-28 US US06/489,654 patent/US4540819A/en not_active Expired - Fee Related
-
1984
- 1984-04-03 ZA ZA842474A patent/ZA842474B/xx unknown
- 1984-04-10 AU AU26680/84A patent/AU573209B2/en not_active Ceased
- 1984-04-11 CA CA000451717A patent/CA1210780A/en not_active Expired
- 1984-04-11 DK DK188384A patent/DK162980C/da active
- 1984-04-13 AT AT84302552T patent/ATE22285T1/de active
- 1984-04-13 EP EP84302552A patent/EP0125053B1/en not_active Expired
- 1984-04-13 DE DE8484302552T patent/DE3460757D1/de not_active Expired
- 1984-04-23 PT PT78470A patent/PT78470B/pt not_active IP Right Cessation
- 1984-04-25 JP JP59085080A patent/JPS59206339A/ja active Granted
- 1984-04-26 IE IE1022/84A patent/IE57250B1/en not_active IP Right Cessation
- 1984-04-26 GR GR74516A patent/GR81490B/el unknown
- 1984-04-27 ES ES531975A patent/ES8506584A1/es not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| AU2668084A (en) | 1984-11-01 |
| ZA842474B (en) | 1985-04-24 |
| JPS59206339A (ja) | 1984-11-22 |
| CA1210780A (en) | 1986-09-02 |
| PT78470A (en) | 1984-05-01 |
| ATE22285T1 (de) | 1986-10-15 |
| EP0125053B1 (en) | 1986-09-17 |
| ES531975A0 (es) | 1985-08-01 |
| PT78470B (en) | 1986-08-28 |
| GR81490B (da) | 1984-12-11 |
| JPH0472818B2 (da) | 1992-11-19 |
| IE841022L (en) | 1984-10-28 |
| US4540819A (en) | 1985-09-10 |
| DE3460757D1 (en) | 1986-10-23 |
| ES8506584A1 (es) | 1985-08-01 |
| DK162980C (da) | 1992-06-01 |
| DK188384A (da) | 1984-10-29 |
| IE57250B1 (en) | 1992-06-17 |
| AU573209B2 (en) | 1988-06-02 |
| EP0125053A1 (en) | 1984-11-14 |
| DK188384D0 (da) | 1984-04-11 |
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