US3856795A - Process for preparation of secondary amines from tertiary amines - Google Patents
Process for preparation of secondary amines from tertiary amines Download PDFInfo
- Publication number
- US3856795A US3856795A US00247438A US24743872A US3856795A US 3856795 A US3856795 A US 3856795A US 00247438 A US00247438 A US 00247438A US 24743872 A US24743872 A US 24743872A US 3856795 A US3856795 A US 3856795A
- Authority
- US
- United States
- Prior art keywords
- oxide
- amine
- tertiary amine
- process according
- amines
- 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.)
- Expired - Lifetime
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- 238000000034 method Methods 0.000 title claims abstract description 44
- 150000003512 tertiary amines Chemical class 0.000 title claims abstract description 32
- 150000003335 secondary amines Chemical class 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title description 6
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 22
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 14
- 150000001340 alkali metals Chemical class 0.000 claims abstract description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 12
- -1 1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3 -benzazocine-8-methanol Chemical group 0.000 claims description 23
- ARXJGSRGQADJSQ-UHFFFAOYSA-N 1-methoxypropan-2-ol Chemical group COCC(C)O ARXJGSRGQADJSQ-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 150000004967 organic peroxy acids Chemical class 0.000 claims description 5
- OXELMKYUIJQOJR-QWHCGFSZSA-N (1r,2s)-2-benzylcyclohexan-1-ol Chemical compound O[C@@H]1CCCC[C@H]1CC1=CC=CC=C1 OXELMKYUIJQOJR-QWHCGFSZSA-N 0.000 claims description 3
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 2
- 150000004965 peroxy acids Chemical class 0.000 abstract description 4
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000012267 brine Substances 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 238000003776 cleavage reaction Methods 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 230000007017 scission Effects 0.000 description 8
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 229910052744 lithium Inorganic materials 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- GLVYLTSKTCWWJR-UHFFFAOYSA-N 2-carbonoperoxoylbenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1C(O)=O GLVYLTSKTCWWJR-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000000746 allylic group Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- CKUAXEQHGKSLHN-UHFFFAOYSA-N [C].[N] Chemical compound [C].[N] CKUAXEQHGKSLHN-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 150000001555 benzenes Chemical class 0.000 description 2
- 125000001743 benzylic group Chemical group 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 229910017464 nitrogen compound Inorganic materials 0.000 description 2
- 150000002830 nitrogen compounds Chemical class 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- QMGVPVSNSZLJIA-FVWCLLPLSA-N strychnine Chemical compound O([C@H]1CC(N([C@H]2[C@H]1[C@H]1C3)C=4C5=CC=CC=4)=O)CC=C1CN1[C@@H]3[C@]25CC1 QMGVPVSNSZLJIA-FVWCLLPLSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000002348 vinylic group Chemical group 0.000 description 2
- POTIYWUALSJREP-DTWKUNHWSA-N (4as,8ar)-1,2,3,4,4a,5,6,7,8,8a-decahydroquinoline Chemical compound N1CCC[C@@H]2CCCC[C@H]21 POTIYWUALSJREP-DTWKUNHWSA-N 0.000 description 1
- 150000003970 1-benzazocines Chemical class 0.000 description 1
- KYGMSGYKSGNPHM-UHFFFAOYSA-N 1-prop-2-enylpiperidine Chemical compound C=CCN1CCCCC1 KYGMSGYKSGNPHM-UHFFFAOYSA-N 0.000 description 1
- ASLUVGUEPYXPRF-UHFFFAOYSA-N 1h-1-benzazonine Chemical class N1C=CC=CC=CC2=CC=CC=C21 ASLUVGUEPYXPRF-UHFFFAOYSA-N 0.000 description 1
- SMOHMDMTVAYPAI-UHFFFAOYSA-N 2,3,6,7-tetrahydro-1h-azepine Chemical compound C1CC=CCCN1 SMOHMDMTVAYPAI-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- MLFIYYDKLNZLAO-UHFFFAOYSA-N 2-aminoethane-1,1-diol Chemical compound NCC(O)O MLFIYYDKLNZLAO-UHFFFAOYSA-N 0.000 description 1
- DMGLUDJTJZXMMG-UHFFFAOYSA-N 3-benzazocine Chemical compound C1=CN=CC=CC2=CC=CC=C21 DMGLUDJTJZXMMG-UHFFFAOYSA-N 0.000 description 1
- SSSYOIPHXANRMO-UHFFFAOYSA-N 4h-benzo[a]quinolizine Chemical class C1=CC=C2C3=CC=CCN3C=CC2=C1 SSSYOIPHXANRMO-UHFFFAOYSA-N 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- QMGVPVSNSZLJIA-UHFFFAOYSA-N Nux Vomica Natural products C1C2C3C4N(C=5C6=CC=CC=5)C(=O)CC3OCC=C2CN2C1C46CC2 QMGVPVSNSZLJIA-UHFFFAOYSA-N 0.000 description 1
- 241001279009 Strychnos toxifera Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 230000003569 amebicidal effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000010504 bond cleavage reaction Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003874 central nervous system depressant Substances 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- OAIVIYSBZFEOIU-UHFFFAOYSA-N chloroform;propan-2-one Chemical compound CC(C)=O.ClC(Cl)Cl OAIVIYSBZFEOIU-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 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
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 1
- 229940035422 diphenylamine Drugs 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 235000008216 herbs Nutrition 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- AHKJGIUKIBGOKH-UHFFFAOYSA-N morpholine;piperidine Chemical compound C1CCNCC1.C1COCCN1 AHKJGIUKIBGOKH-UHFFFAOYSA-N 0.000 description 1
- GBCKRQRXNXQQPW-UHFFFAOYSA-N n,n-dimethylprop-2-en-1-amine Chemical compound CN(C)CC=C GBCKRQRXNXQQPW-UHFFFAOYSA-N 0.000 description 1
- YLFDIUNVGXCCPV-UHFFFAOYSA-N n-benzyl-n-propylpropan-1-amine Chemical compound CCCN(CCC)CC1=CC=CC=C1 YLFDIUNVGXCCPV-UHFFFAOYSA-N 0.000 description 1
- NYLGUNUDTDWXQE-UHFFFAOYSA-N n-phenyl-n-prop-2-enylaniline Chemical compound C=1C=CC=CC=1N(CC=C)C1=CC=CC=C1 NYLGUNUDTDWXQE-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- HBMUMVMGBLMQJT-UHFFFAOYSA-N pyrrolo[2,1-a]isoquinoline Chemical class C12=CC=CC=C2C=CN2C1=CC=C2 HBMUMVMGBLMQJT-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- AGRTUYYPROFOFX-ZMUQRAOQSA-N strychnidine Chemical compound O([C@H]1CCN2C=3C4=CC=CC=3)CC=C3CN5CC[C@]64[C@@H]2[C@H]1[C@H]3C[C@H]56 AGRTUYYPROFOFX-ZMUQRAOQSA-N 0.000 description 1
- 229960005453 strychnine Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/023—Preparation; Separation; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/64—Preparation of compounds containing amino groups bound to a carbon skeleton by disproportionation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
- C07D215/60—N-oxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/26—Benzomorphans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
- C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- One aspect of the present invention relates to a novel process for the protection and preparation of secondary amines from tertiary amines through the preparation of an intermediate N-oxide which is converted to the secondary amine.
- a further aspect of the present invention is to convert tertiary amines wherein the nitrogen is substituted with a benzyl, allyl or propargyl group to the corresponding secondary amine by the cleavage of such group.
- Yet another aspect of the present invention relates to an improved process for scission of a benzylic type bridgehead carbon-nitrogen bond in a ring system to convert the tertiary nitrogen to a secondary amine.
- An additional aspect of the present invention relates to converting compounds containing ring systems, such as appropriate benzquinolizines (including emetines), benzindolizines, indolquinolizines and indolindolizines to secondary amines at the carbon-nitrogen bridgehead, in yields higher than heretofore obtainable with prior art processes.
- benzquinolizines including emetines
- benzindolizines including emetines
- indolquinolizines and indolindolizines to secondary amines at the carbon-nitrogen bridgehead
- the process of the present invention comprises reacting a tertiary amine with an oxidizing agent such as a peracid to form the N-oxide of the selected tertiary amine and then reacting the N- oxide with an alkali metal in the presence of liquid ammonia to form the secondary amine.
- an oxidizing agent such as a peracid
- the tertiary amines that are particularly useful in the process of the present invention are those having either (a) a substituent linked directly to the N-atom selected from the class consisting of allyl, dimetyl allyl, propargyl, benzyl or substituted benzyl or (b) a benzylic type bridgehead carbon-nitrogen structure.
- the preferred secondary amines obtained by the process of the present invention have the following structural formula:
- R and R are selected from the class consisting of an aliphatic radical and an alicyclic radical, which radicals are not subject to cleavage from the nitrogen to which it is linked under the process conditions of the present invention and which radicals do not undergo any change in chemical structure under the process conditions for converting the tertiary amine to a secondary amine and/or obtaining a substituted aralkyl compound;
- R plus R may be joined to form with the N atom a non-aromatic type heterocyclic moiety having up to nine carbom atoms in the ring which may optionally include one additional hetero atom in the ring selected from the class consisting of oxygen and nitrogen.
- the hetero ring is either saturated or it may contain a non-allylic double bond; n is a whole number which is l or 2; A represents a fused benzene nucleus or fused indole nucleus attached through its 2-3 position to the nitrogen containing ring; X represents one or more substitutents selected from the group consisting of hydrogen, (lower)alkyl, lower alkoxy, methylene radical are piperidino, pyrrolidino, piperazino, morpholino, hexamethylenimino, decahydroquinoline, benzazocine, 2,3,6,7-tetrahydro-lH-azepine, etc.
- aliphatic radicals defined by R and R are straight or branch chain alkyl groups havingl to 12 carbon atoms, an non-allylic alkenyl group having 4 to 12 carbon atoms (e.g. S-pentenyl) or a non-allylic, nonconjugated alkadienyl group having 6 to 12 carbon atoms (e.g. 3,6-decadienyl).
- lllustrative of alicyclic radicals are cycloalkyl groups having four through ten ring carbon atoms (e.g.
- cyclobutyl cyclopentyl, cyclohexyl, cyclooctyl
- non-allylic cycloalkenyl groups having seven through ten ring carbon atoms e.g. 4- cycloheptenyl
- an aryl radical having from six to ten ring carbon atoms (e.g. phenyl, naphthyl), an aryl(lower)alkyl radical (e.g. ,B-phenylethyl, a-phenylpropyl).
- the foregoing radicals may contain one or more substituents such as hydroxy, (lower)alkoxy.
- the process of the present invention is carried out by treating compound [II with a peracid at a temperature between +32 and 40C. to produce the corresponding N-oxide which is then treated with an alkali metal in liquid ammonialto produce the secondary amine as shown in the following equations:
- R is selected from the group consisting of allyl, dimethyl allyl, propargyl and unsubstituted or substituted benzyl.
- the treatment of Illa is preferably carried out in the presence of a proton donor.
- the formation ofl is via N-OH intermediate.
- a proton donor i.e. an alcohol
- the reaction of Illa with the alkali metal in liquid ammonia leads to the formation of a mixture of Illb and I.
- the product isolated by CHCl extraction is purified by filtration in ether through a short column of Woelm A1 0 Grade 1 basic.
- the hydrochloride is obtained by addition of isopropanolic hydrogen chloride to the eluate and recrystallized from acetonehexane to give 1.2 g. of the title compound, m.p. -126C. identical with an authentic sample [J. P. Yardley, R. W. Rees and H. Smith, J. Med. Chem., 10, 1088 (1967)].
- Example 4 Using the compound of Example 1 as a starting material, Example 3 was repeated except that the 1- methoxy-Z-propanol was omitted and the reaction time is reduced from 6 minutes to 2 h minutes. There is obtained after dilution with warm water and CHCl extraction a crystalline residue, m.p. -143C. shown by glc. to be a mixture of two major components. Column silicone (Floro) QF-l linear program l80-250, 5 minutes at then at 8lmin. 59% mixture retention time after 4.6 minutes and 14 minutes 36% mixture (N-OH compound).
- the ether layer is washed with water (twice), brine, and dried (Na SO
- the product is filtered in ether through a Woelm A1 0 (Grade 1 basic) column and eluted with the same solvent.
- Treatment of the eluate with an excess of isopropanolic hydrogen chloride and recrystallization of the precipitate from acetone-hexane gives 14 g. of the title compound m.p. l33l35C.
- the free base (clear oil) is regenerated from 8 g. of the hydrochloride by treatment with aqueous K CO solution extraction into ether, washing with brine and drying (Na SO NMR (CDCl shows a complex vinylic resonance (3H) in the range 4.9-6.35 ppm.
- N-allyl trans decahydroquinoline (5.0 g., 2.8 X 10' moles) is placed in methanol ml.) and is treated, dropwise at 20C. during 1 hour with 94 ml.
- EXAMPLE 8 N-allyl decahydroquinoline N-oxide (2.0 g., 1 X 10' moles) prepared in accordance with the procedure of Example 7 is placed in NH (1 L) containing 1- methoxy-2-propanol, 4 ml. (4 X 10 moles), is treated with lithium (360 mg, 5.2 X 10" moles) following by a further 6 ml. (6 X 10 moles) of the alcohol. This mixture is stirred until white (ca.
- reaction mixture is filtered througha Woelm basic A1203 column (Grade 1) built in CHCl and eluted with chloroformmethanol (3:1) to give 45 g. of white solid (mass spectrum shows an M 1 ion at 321 for a bis N-oxide), 4.4 g of the above product as a vigorously stirred suspen sion in THF"(4'O'riil.)liquid”ammonia (filter) is treated with excess lithium (230 mg., 3.3 X 10 moles). The mixture is quenched with acetone 30 seconds after the appearance of a uniform blue color. Solvent is removed on the steam bath and the residue acidified with an ice-hydrochloric acid mixture.
- the secondary'amines of the present invention are useful intermediates in the preparation of pharmacologically active compounds, such as tertiary amines.
- pharmacologically active compounds such as tertiary amines.
- the compound of Example 6 has been reported to have amebicidal activity [.I. P. Yardley, R. W. Rees and H. Smith, J. Med. Chem., 10, 1088 (1967)].
- the benzazocines and benzazonines described herein belong to a class of compounds that exhibit diuretic activity and central nervous system depressant activity.
- R1 wherein R and R are each a radical selected from the class consisting of an alkyl group of 1 through 12 carbon atoms, a cycloalkyl group having 4 through ring carbon atoms, phenyl, naphthyl and phenyl(lower)alkyl; R and R when joined together form with the N- atom a member selected from the class consisting of piperidino, pyrrolidino, piperazino, morpholino, hexamethylenimino, decahydroquinolino, and 1.2.3.456- hexahydro-6,1 l-dimethyl-2,6-methano-3-benzazocino- 8-methanol, said groups defined by R and R being optionally substituted with a member selected from the class consisting of hydroxy and (lower)-alkoxy; and R is a member selected from the group consisting of allyl, dimethyl allyl, propargyl and benzyl; to a secondary amine of
- NII R! which comprises reacting said tertiary amine with an organic peracid to form the N-oxide of said tertiary amine and reacting said N-oxide with an alkali metal in the presence of liquid ammonia to form the corresponding secondary amine by cleavage of said R group from said tertiary amine, the reaction of said tertiary amine with said organic peracid being carried out at a temperature between about 40C. and about +32C. l5 2.
- a process according to claim 1 wherein said reaction of said N-oxide with said alkali metal in liquid ammonia is carried out in the presence of a proton donor.
- A represents a fused benzene nucleus or fused indolc nucleus attached through its 2-3 position to the nitrogen containing ring;
- X represents one or more 0 substituents selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, hydroxy, hydroxy (lower)alkyl, lower alkoxyisoquinolinylmethyl, 2-(lower)alkyl-isoquinolinylmethyl;
- Z or Z are se- 5 lected from the class consisting of hydrogen and (lower)alkyl;
- n is a number selected from 1 to 2; to a secondary amine of the formula:
- 10.Apr0cess which comprises reacting trans-Z-[athe presence of liquid ammonia to cleave off (4-methyl-l-piperazinyl)benzyl]cycl0hexanol with an trans-2-benzylcycl0hexan0l.
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Abstract
A process of converting tertiary amines to secondary amines is described comprising reacting the tertiary amine with a peracid to form the N-oxide which is converted to the secondary amine in the presence of an alkali metal and liquid ammonia.
Description
ilnited States Patent [191 [111 3,856,795 Yardley Dec. 24, 1974 PROCESS FOR PREPARATION OF [56] References Cited SECONDARY AMINES FROM TERTIARY OTHER PUBLICATIONS 1 AMINES Smith, Open Chain Nitrogen Compounds, Vol. 2, (W. [7 Inventor: J P- ard y, K ng of Prus a, A. Benjamin, Inc, New York, 1966), pages 15, 23-24,
Pa. 27, QD412N156. [73] Assignee: American Hom P du t Herbs! et al., J. Med. Chem, Vol, 9, pages 864-868 Corporation, New York, NY. (1969) R515- [22] Filed: 1972 Primary ExaminerAlton D. Rollins [21] App]. No.: 247,438
[57] ABSTRACT [52] US. CL. 260/283 SY, 260/239 B, 260/239 BB, A process of converting tertiary amines to secondary 260/247, 260/268 SY, 260/283 SY, 260/286 amines is described comprising reacting the tertiary R, 260/288 R, 260/288 E, 260/293.51, amine with a peracid to form the N-oxide which is 260/293.53, 260/293.54, 260/326.5 B, converted to the secondary amine in the presence of g 1 260/326.8, 260/326.81 an alkali metal and liquid ammonia. [51] lint. Cl...... C07b 1/00, 'C07b 3/00, C07d 41/08 [58] Field of Search.... 260/239 BB, 239 BE, 239 B,
260/286 R, 288 R, 288 E, 340.5, 326.5 B, 326.8, 326.81, 287 E, 283 SY, 247, 293.51, 293.53, 293.54, 293.62, 583 R, 583 D, 583
H, 563 R, 563 C, 584 R, 584 C, 570.8 R, 570.9, 574, 576, 577, 268 SY, 618 C 10 Claims, N0 Drawings PROCESS FOR PREPARATION OF SECONDARY AMINES FROM TERTIARY AMINES This invention relates to a novel process for producing secondary amines from tertiary amines.
One aspect of the present invention relates to a novel process for the protection and preparation of secondary amines from tertiary amines through the preparation of an intermediate N-oxide which is converted to the secondary amine.
A further aspect of the present invention is to convert tertiary amines wherein the nitrogen is substituted with a benzyl, allyl or propargyl group to the corresponding secondary amine by the cleavage of such group.
Yet another aspect of the present invention relates to an improved process for scission of a benzylic type bridgehead carbon-nitrogen bond in a ring system to convert the tertiary nitrogen to a secondary amine.
An additional aspect of the present invention relates to converting compounds containing ring systems, such as appropriate benzquinolizines (including emetines), benzindolizines, indolquinolizines and indolindolizines to secondary amines at the carbon-nitrogen bridgehead, in yields higher than heretofore obtainable with prior art processes.
These and other aspects of the present invention will be apparent from the following description.
In its broadest aspect, the process of the present invention comprises reacting a tertiary amine with an oxidizing agent such as a peracid to form the N-oxide of the selected tertiary amine and then reacting the N- oxide with an alkali metal in the presence of liquid ammonia to form the secondary amine.
The tertiary amines that are particularly useful in the process of the present invention are those having either (a) a substituent linked directly to the N-atom selected from the class consisting of allyl, dimetyl allyl, propargyl, benzyl or substituted benzyl or (b) a benzylic type bridgehead carbon-nitrogen structure. The preferred secondary amines obtained by the process of the present invention have the following structural formula:
wherein R and R are selected from the class consisting of an aliphatic radical and an alicyclic radical, which radicals are not subject to cleavage from the nitrogen to which it is linked under the process conditions of the present invention and which radicals do not undergo any change in chemical structure under the process conditions for converting the tertiary amine to a secondary amine and/or obtaining a substituted aralkyl compound; R plus R may be joined to form with the N atom a non-aromatic type heterocyclic moiety having up to nine carbom atoms in the ring which may optionally include one additional hetero atom in the ring selected from the class consisting of oxygen and nitrogen. The hetero ring is either saturated or it may contain a non-allylic double bond; n is a whole number which is l or 2; A represents a fused benzene nucleus or fused indole nucleus attached through its 2-3 position to the nitrogen containing ring; X represents one or more substitutents selected from the group consisting of hydrogen, (lower)alkyl, lower alkoxy, methylene radical are piperidino, pyrrolidino, piperazino, morpholino, hexamethylenimino, decahydroquinoline, benzazocine, 2,3,6,7-tetrahydro-lH-azepine, etc. lllustrative of aliphatic radicals defined by R and R are straight or branch chain alkyl groups havingl to 12 carbon atoms, an non-allylic alkenyl group having 4 to 12 carbon atoms (e.g. S-pentenyl) or a non-allylic, nonconjugated alkadienyl group having 6 to 12 carbon atoms (e.g. 3,6-decadienyl). lllustrative of alicyclic radicals are cycloalkyl groups having four through ten ring carbon atoms (e.g. cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl), non-allylic cycloalkenyl groups having seven through ten ring carbon atoms (e.g. 4- cycloheptenyl), an aryl radical having from six to ten ring carbon atoms (e.g. phenyl, naphthyl), an aryl(lower)alkyl radical (e.g. ,B-phenylethyl, a-phenylpropyl). The foregoing radicals may contain one or more substituents such as hydroxy, (lower)alkoxy.
The process of the present invention is carried out by treating compound [II with a peracid at a temperature between +32 and 40C. to produce the corresponding N-oxide which is then treated with an alkali metal in liquid ammonialto produce the secondary amine as shown in the following equations:
wherein R is selected from the group consisting of allyl, dimethyl allyl, propargyl and unsubstituted or substituted benzyl. The treatment of Illa is preferably carried out in the presence of a proton donor. The formation ofl is via N-OH intermediate. In the absence of a proton donor (i.e. an alcohol) the reaction of Illa with the alkali metal in liquid ammonia leads to the formation of a mixture of Illb and I.
In the same manner the secondary amines defined by formula II are prepared by starting with a bridgehead nitrogen compound shown in the following formula:
(2 llquldmnmoniii l (1 alkali metal Formula 11 (T EXAMPLE 1 1,3,4,6,7,11b-Hexahydro-9,l0-Dimethoxy-2H- Benzo[a]Quinalizine -Oxide Hydrochloride The compound 1,3,4,6,7,1 1b-hexahydro-9,l0- dimethoxy-2H-benzo[alquinolizine (R. Child and F. Lee Pyman, JCS 36 [1931]) (5 g. 2.07 X moles) in MeOH (40 ml) is treated, dropwise, at l0C. with ethereal monoperphthalic acid solution (38 ml., 0.65 molar, 2.47 X 10 moles) and the resultant solution is stored at 0C. overnight. Excess 10% NaOH solution is added which results in formation of two layers. The upper ethereal layer is washed with water and discarded. The aqueous layer is extracted with CHCl three times. The extracts are washed with brine, dried K CO and stripped. The residue, a pale green oil is treated in tetrahydrofuran with a slight excess of isopropanolic hydrogen chloride to give a crystalline precipitate of the product. Recrystallization from chloroform-acetone provides 4.5 g. of the titled product, m.p. 205-212C. decomposition.
Analysis: Calculated for C H NO HCl: C, 60.09;
H, 7.40;N, 4.67; Cl, 11.83 Found: C, 59.84; H, 7.26; N, 4.65; Cl, 11.82
EXAMPLE 2 l ,2,3,5,6,10b-Hexahydro-8,9-Dimethoxypyrrolo[2,la] lsoquinoline-4-Oxide, Hydrochloride Using the method of Example 1, l,2,3,5,6,10bhexahydro-8,9-dimethoxypyrrolol2,1-a]isoquinoline [R. Child and F. Lee Pyman, JCS 36 (1931)] is converted to the title compound, m.p. l88.5-192C. decomposition.
Analysis: Calculated for C H NO HCl'. C, 58.84;
H, 7.05; N, 4.90; Cl, 12.41 Found: C, 58.93; H, 7.07; N, 5.14; CI, 12.45
EXAMPLE 3 1,2,3,4,5,6,7,8-Octahydro-l0,1l-Dimethoxy-3- Benzazecine Hydrochloride The compound prepared in Example 1 (2 g., 7.6 X 10 moles) in THF (20 ml.) is added toa stirred solution of NH (500 ml.) containing 1-methoxy-2- propanol (3 ml., 3 X 10 moles) Lithium (260 mg.. 3.7 X 10 moles) is added portionwise and the deep blue solution vigorously during a further 6 minutes after completion of the addition. Excess lithium is decomposed by water and the reaction mixture diluted cautiously with warm water. The product isolated by CHCl extraction is purified by filtration in ether through a short column of Woelm A1 0 Grade 1 basic. The hydrochloride is obtained by addition of isopropanolic hydrogen chloride to the eluate and recrystallized from acetonehexane to give 1.2 g. of the title compound, m.p. -126C. identical with an authentic sample [J. P. Yardley, R. W. Rees and H. Smith, J. Med. Chem., 10, 1088 (1967)].
EXAMPLE 4 Using the compound of Example 1 as a starting material, Example 3 was repeated except that the 1- methoxy-Z-propanol was omitted and the reaction time is reduced from 6 minutes to 2 h minutes. There is obtained after dilution with warm water and CHCl extraction a crystalline residue, m.p. -143C. shown by glc. to be a mixture of two major components. Column silicone (Floro) QF-l linear program l80-250, 5 minutes at then at 8lmin. 59% mixture retention time after 4.6 minutes and 14 minutes 36% mixture (N-OH compound). Mass spectograph indicates a mixture with molecular ions at 249 (title compound of Example 3) and 265 (/NOH compound of Example 3 EXAMPLE 5 2,3,4,5,6,7-Hexahydro-9,l0-Dimethoxy-1H-3- Benzazonine Hydrochloride Using the method of Example 3, 1,2,3,5,6,10bhexahydro-8,9-dimethoxypyrrolo[2,1-a]isoquinoline- 3-oxide is converted to the title compound. Identity is established by comparison with an authentic sample [1. P. Yardley et al. J. Med. Chem, 10, 1088 (1967)]. The starting N-oxide was prepared in accordance with the procedure of Example 1.
EXAMPLE 6 1,2-Secoemetine Benzyloxycarbonylemetine [J. P. Yardley et al. J. Med. Chem., 10, 1088 (1967)] 14.3 g. (2.32 X 10'2 moles) in methanol (60 ml.) is treated, dropwise, at 10C. with 58.5 ml. ethereal monoperphthalic acid (0.585 molar 3.5 X 10 moles) and the mixture is kept at 05C. overnight. This mixture is basified strongly with 10% aqueous NaOH solution and extracted with CHCl (five times). The CHCl extracts are washed with brine, dried (K Co and evaporated to give the crude oily N-oxide (12 g.). The oily N-oxide (5 g., 7.7 X 10* moles) is placed in tetrahydrofuran (25 ml.) and added to NH (1.5 L) containing 1-methoxy-2- propanol (4.8 ml., 419 X 10 moles). Lithium (260 mg., 3.7 X 10' moles) is added portionwise to a permanent blue coloration. Acetic acid (2.22 g., 2.1 ml.
3.5 X moles) is added and the solution again titrated to a permanent blue coloration. 200 mg. of lithium is added, after 6 minutes the reaction mixture is diluted with hot water and extracted with CHCl The chloroform extracts are washed with brine, dried (Na S0 and the stripped residuein ether is charcoaled (Norite) and treated with an excess of isopropanolic hydrogen chloride. The precipitate crystallizes from acetone to give 3 g. l',2'secoemetinehydrochloride, m.p. 234-237C.
Conversion ofa portion to the bis hydroiodide [cf. J. P. Yardley et al., J. Med Chem, 10, 1088 (1967)] confirmed its identity.
EXAMPLE 7 N-Allyl trans Decahydroquinoline Hydrochloride Trans decahydroquinoline g., 1.44 X 10 moles), allyl chloride (16 ml., 1.96 X 10 moles), triethylamine (18 ml., 1.96 X 10 moles) and acetonitrile (200 ml.) are stirred at room temperature under nitro- 7 gen overnight. The reaction mixture is evaporated in vacuo and the residue distributed between ether and saturated NaHCO- solution. The ether layer is washed with water (twice), brine, and dried (Na SO The product is filtered in ether through a Woelm A1 0 (Grade 1 basic) column and eluted with the same solvent. Treatment of the eluate with an excess of isopropanolic hydrogen chloride and recrystallization of the precipitate from acetone-hexane gives 14 g. of the title compound m.p. l33l35C.
Analysis: Calculated for C H NClz C, 66.79; H,
10.28; N, 6.49; Cl, 16.43
Found: C, 66.71; H, 10.16; N, 6.45; Cl, 16.15
The free base (clear oil) is regenerated from 8 g. of the hydrochloride by treatment with aqueous K CO solution extraction into ether, washing with brine and drying (Na SO NMR (CDCl shows a complex vinylic resonance (3H) in the range 4.9-6.35 ppm.
The N-allyl trans decahydroquinoline (5.0 g., 2.8 X 10' moles) is placed in methanol ml.) and is treated, dropwise at 20C. during 1 hour with 94 ml.
0.65N monoperphthalic acid solution in ether (3.05 X 10 moles). After one further hour during which the reaction mixture is allowed to warm to room temperature, excess aqueous 10% NaOH is added. The ether layer is separated, washed with water, and discarded. The combined aqueous layers are extracted (three times) with CHCl washed with brine, dried (Na SO and stripped at 20C. to give N-allyl trans dodecahydroquinoline N-oxide, a solid crystalline product (4.5 g.). The NMR shows a complex vinylic resonance (3H) in the range 5.2-6.5 ppm.
EXAMPLE 8 N-allyl decahydroquinoline N-oxide (2.0 g., 1 X 10' moles) prepared in accordance with the procedure of Example 7 is placed in NH (1 L) containing 1- methoxy-2-propanol, 4 ml. (4 X 10 moles), is treated with lithium (360 mg, 5.2 X 10" moles) following by a further 6 ml. (6 X 10 moles) of the alcohol. This mixture is stirred until white (ca. 20 minutes), then diluted with hot water and extracted with CHCl (twice), washed with brine, dried (Na SO.,) and stripped; the residue is filtered in ether through Woelm A1 0 l 0 g.) and eluted with ether to give trans decahydroquinoline (l g.), m.p. -47C. (70% yield) identical with an authentic sample.
EXAMPLE 9 l,2,3,4,5,6-Hexahydro-6a,8,l l-Trimethyl-2,6- Methano-3-Benzazocine Dl-l ,2,3,4,5,6-Hexahydro-cis-6,l l-dimethyl-3-(3- methyl-2-butenyl)-2,6-methnano-3benzazocine-8- methanol (700 mg, 2.34 X 10' moles) is placed in methanol (7 ml.) and stirred at 20C. during the dropwise addition of ethereal monoperphthalic acid (6 ml.,
0.46 molar, 2.76 X 10' moles). The mixture is stirred for a further 3 hours during which time the reaction mixture is allowed to attain room temperature. The mixture is then basified with 10% NaOH solution, washed with ether and the ether layer, after a water backwash, discarded. The aqueous layers are extracted (thrice), the organic layers washed with brine, filtered to clarify thesolution and stripped to give a residue of the crude N-oxide (600 mg).
The crude product (500 mg.) in THF (30 ml.) is added to a freshly distilled NH (180 ml.), treated with l-methoxy-Z-propanol, followed by an excess of lithium. After 8 minutes the mixture is diluted with hot water and extracted with CHCI (twice). The organic layer is washed with brine, stripped and filtered in ether through a column of Woelm A1 0 Elution with ether afforded 200 mg. colorless oil homogeneous by thin layer chromatography (tlc) (SiO system CHCl saturated NH;,) and R, identical with that of 1,2,3,4,5,- 6-hexahydro-6a,8,1 ltrimethyl-2,6-methano-3- benzazocine prepared by an alternative route. The crystalline hydrochlorine m.p. 23 l-232C. was identical with an authentic sample by mixed m.p., IR, Mass spectograph and NMR.
EXAMPLE l0 Trans-2Benzylcyclohexanol from Trans-2-[a-(4- Methyl-l-Piperazinyl) Benzyl]Cyclohexanol Trans-2-[a-(4-methyl-l-piperazinyl)benzl]cyclohexarol (4.0g, 1.39 X 10 moles) in THF (60 ml.) is added at 0-5C to a solution ofmonochloroperbenzoic acid 5.7 g., 2.8 X 10' moles) during 10 minutes and the solution stored at 5C. overnight. The reaction mixture is filtered througha Woelm basic A1203 column (Grade 1) built in CHCl and eluted with chloroformmethanol (3:1) to give 45 g. of white solid (mass spectrum shows an M 1 ion at 321 for a bis N-oxide), 4.4 g of the above product as a vigorously stirred suspen sion in THF"(4'O'riil.)liquid"ammonia (filter) is treated with excess lithium (230 mg., 3.3 X 10 moles). The mixture is quenched with acetone 30 seconds after the appearance of a uniform blue color. Solvent is removed on the steam bath and the residue acidified with an ice-hydrochloric acid mixture. A crystalline solid separates at this stage and is extracted into ether. The ether phase is washed with water, brine and dried (Na SO The residue crystallizes from pentane to give 2.0 g. trans 2-benzylcyclohexanol, m.p. 77C. (lit. 77, P. B. Russell, J. Chem. $06., 1771, [1951]).
Found C, 81.67; H, 9.76. C H O requires: C, 82.06;
EXAMPLE 1 1 l,2,4,5,6,7,8,9-Octahydro-3H-Azecino [5,4-b]lndole Using the methods of Examples 1 and 3, l,2,3,4,6,7,--
l2,12b-octahydroindolo-(2,3-a) quinolizine was converted to the title product.
EXAMPLE 12 When the following tertiary amines are employed in the process of the present invention in Examples 1 and 3;
. dimethyl allyl amine dihydroxyethyl allylamine dimethyl benzyl amine N-allyl piperidine N-propargyl morpholine diphenyl allyl amine dipropyl benzyl amine N-benzyl-2,3,6,7-tetrahydro-lH-azepine N-methyLN-[3-pentenyl]-benzylamine 10. N-benzyLN-methyl-3,6-decadienylamine the following corresponding secondary amines are produced:
. dimethyl amine dihydroxyethyl amine dimethyl amine piperidine morpholine diphenyl amine dipropyl amine 2,3,6,7-tetrahydro-lH-azepine N-methyl-3-pentenylamine lv N-methyl-3,6-decadienylamine The secondary'amines of the present invention are useful intermediates in the preparation of pharmacologically active compounds, such as tertiary amines. For example, the compound of Example 6 has been reported to have amebicidal activity [.I. P. Yardley, R. W. Rees and H. Smith, J. Med. Chem., 10, 1088 (1967)]. The benzazocines and benzazonines described herein belong to a class of compounds that exhibit diuretic activity and central nervous system depressant activity.
One of the advantages of the process of the present invention is that it affords a simple and convenient method of cleavage of allylic tertiary amines. The previous claim in the literature by Clemo et al. J. Chem.
$00., 1661 (1948) for allyl amine cleavage in strychnine and strychnidine has been disproved by R. Rees et al. J. Med. Chem., 10, 624 (1967), while E. M. Perry Dissertation Abstracts 16, 1587-1588 (1956), (CA. 51, 2532g) reports The best catalytic method of cleaving allylic amines is with a platinum catalyst in methyl alcohol solution. Nevertheless, the extent of cleavage even by this catalytic method is small since hydrogenation of the double bond competes with the cleavage reaction; the saturated amine is resistant to cleavage by this method."
What is claimed is: 1. A process of converting a tertiary amine of the formula:
R1 wherein R and R are each a radical selected from the class consisting of an alkyl group of 1 through 12 carbon atoms, a cycloalkyl group having 4 through ring carbon atoms, phenyl, naphthyl and phenyl(lower)alkyl; R and R when joined together form with the N- atom a member selected from the class consisting of piperidino, pyrrolidino, piperazino, morpholino, hexamethylenimino, decahydroquinolino, and 1.2.3.456- hexahydro-6,1 l-dimethyl-2,6-methano-3-benzazocino- 8-methanol, said groups defined by R and R being optionally substituted with a member selected from the class consisting of hydroxy and (lower)-alkoxy; and R is a member selected from the group consisting of allyl, dimethyl allyl, propargyl and benzyl; to a secondary amine of the formula:
NII R! which comprises reacting said tertiary amine with an organic peracid to form the N-oxide of said tertiary amine and reacting said N-oxide with an alkali metal in the presence of liquid ammonia to form the corresponding secondary amine by cleavage of said R group from said tertiary amine, the reaction of said tertiary amine with said organic peracid being carried out at a temperature between about 40C. and about +32C. l5 2. A process according to claim 1 wherein said reaction of said N-oxide with said alkali metal in liquid ammonia is carried out in the presence of a proton donor.
3. A process according to claim 1 wherein R and R are joined together to form decahydroquinolyl.
4. A process according to claim 1 wherein said tertiary amine is l,2,3,4,5,6-hexahydro-6,l l-dimethyl-3- (3-methyl-2-butenyl)-2,6-methano-3-benzazocine-8- methanol.
5. Aprocess according to claim 1 wherein said tertiary amine is'N-allyl dodecahydroquinoline.
6. A process of converting a tertiary amine of the formula:
wherein:
A represents a fused benzene nucleus or fused indolc nucleus attached through its 2-3 position to the nitrogen containing ring; X represents one or more 0 substituents selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, hydroxy, hydroxy (lower)alkyl, lower alkoxyisoquinolinylmethyl, 2-(lower)alkyl-isoquinolinylmethyl; Z or Z are se- 5 lected from the class consisting of hydrogen and (lower)alkyl; n is a number selected from 1 to 2; to a secondary amine of the formula:
q 6 5 iii- (011.1.
which comprises reacting said tertiary amine with an organic peracid to form the corresponding N-oxide of said tertiary amine, said reaction being carried out be- 0 tween -40C. and about 0C., and reacting said N- oxide with an alkali metal in the presence of liquid ammonia to form said secondary amine.
7. A process according to claim 6 wherein said reaction of said N-oxide with said alkali metal is carried out in the presence ofa proton donor.
8. A process according to claim 7 wherein said proton donor is l-methoxy-Z-propanol.
9. A process according to claim 6 wherein said tertiary amine is benzyloxycarbonylemetine and the secondary amine obtained is l,2,2' -secoemetine.
Z-acetylisoquinolinylmethyl,
10.Apr0cess which comprises reacting trans-Z-[athe presence of liquid ammonia to cleave off (4-methyl-l-piperazinyl)benzyl]cycl0hexanol with an trans-2-benzylcycl0hexan0l.
organic peracid to form an N-oxide of said tertiary amine and reacting said N-oxide with an alkali metal in gig UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION p t N 3,856,795 Dated December 24, 1974 Invenmfl John P. Yardley It is certified that error appears in the above-identified patent; and that said Letters Patent are hereby corrected as shown below:
Column 3, change formula IVb from Column 8 line |-6, change "1 b0 2" to ----1 and 2--.
Signed and sealed this 8th day of April 1975.
SEAL) Attest:
C. Z-IARSHALL DANN RUTH C. MASON I Commissioher of Pat n nttestlng Officer 7 and Trademarks ts
Claims (10)
1. A PROCESS OF CONVERTING A TERTIARY AMINE OF THE FORMULA:
2. A process according to claim 1 wherein said reaction of said N-oxide with said alkali metal in liquid ammonia is carried out in the presence of a proton donor.
3. A process according to claim 1 wherein R1 and R2 are joined together to form decahydroquinolyl.
4. A process according to claim 1 wherein said tertiary amine is 1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3 -benzazocine-8-methanol.
5. A PROCESS ACCORDING TO CLAIM I WHEREIN SAID TERTIARY AMINE IS N-ALLYL DODECAHYDROQUINOLINE.
6. A process of converting a tertiary amine of the formula:
7. A process according to claim 6 wherein said reaction of said N-oxide with said alkali metal is carried out in the presence of a proton donor.
8. A process according to claim 7 wherein said proton donor is 1-methoxy-2-propanol.
9. A PROCESS ACCORDING TO CLAIM 6 WHEREIN SAID TERTIARY AMINE IS BENZYLOXYCARBONYLEMETINE AND THE SECONDARY AMINE OBTAINED IS 1'',2'',2'' -SECOEMETINE.
10. A process which comprises reacting trans-2-( Alpha -(4-methyl-1-piperazinyl)benzyl)cyclohexanol with an organic peracid to form an N-oxide of said tertiary amine and reacting said N-oxide with an alkali metal in the presence of liquid ammonia to cleave off trans-2-benzylcyclohexanol.
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US4264776A (en) * | 1976-01-02 | 1981-04-28 | Monsanto Company | Production of secondary amines |
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