US3822322A - Intermediates for tricyclic amines - Google Patents
Intermediates for tricyclic amines Download PDFInfo
- Publication number
- US3822322A US3822322A US00330931A US33093173A US3822322A US 3822322 A US3822322 A US 3822322A US 00330931 A US00330931 A US 00330931A US 33093173 A US33093173 A US 33093173A US 3822322 A US3822322 A US 3822322A
- Authority
- US
- United States
- Prior art keywords
- dibenzo
- cycloheptene
- formula
- methyl
- ether
- 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
Links
- 150000001412 amines Chemical class 0.000 title description 10
- 239000000543 intermediate Substances 0.000 title description 5
- 230000001430 anti-depressive effect Effects 0.000 abstract description 3
- 239000000935 antidepressant agent Substances 0.000 abstract description 3
- 150000001933 cycloheptenes Chemical class 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 72
- 150000001875 compounds Chemical class 0.000 description 45
- -1 such as Chemical group 0.000 description 41
- 239000000243 solution Substances 0.000 description 37
- 239000011541 reaction mixture Substances 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 238000010992 reflux Methods 0.000 description 16
- 125000003342 alkenyl group Chemical group 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 11
- 239000011777 magnesium Substances 0.000 description 10
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 9
- 150000002576 ketones Chemical class 0.000 description 9
- 229910052749 magnesium Inorganic materials 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 239000005457 ice water Substances 0.000 description 8
- 239000000155 melt Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 7
- 125000004969 haloethyl group Chemical group 0.000 description 7
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 7
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 7
- 229910052753 mercury Inorganic materials 0.000 description 7
- 238000006053 organic reaction Methods 0.000 description 7
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- 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 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 230000018044 dehydration Effects 0.000 description 6
- 238000006297 dehydration reaction Methods 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 125000001118 alkylidene group Chemical group 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 125000001033 ether group Chemical group 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 235000012222 talc Nutrition 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 150000001450 anions Chemical class 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- WWBGONGKRSWMGE-UHFFFAOYSA-N cycloheptene Chemical compound [CH]1CCCC=CC1 WWBGONGKRSWMGE-UHFFFAOYSA-N 0.000 description 3
- 239000012259 ether extract Substances 0.000 description 3
- 230000001747 exhibiting effect Effects 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- CEVMYGZHEJSOHZ-UHFFFAOYSA-N 1-bromo-3-methoxypropane Chemical compound COCCCBr CEVMYGZHEJSOHZ-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- OIKCNTYPPSMVEU-UHFFFAOYSA-N 9'-bromospiro[1,3-dioxolane-2,2'-tricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,9,11,13-heptaene] Chemical compound C1OC2(C3=C(C(=CC4=C2C=CC=C4)Br)C=CC=C3)OC1 OIKCNTYPPSMVEU-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- 206010001497 Agitation Diseases 0.000 description 2
- 208000020401 Depressive disease Diseases 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 235000019759 Maize starch Nutrition 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000001294 propane Substances 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- BQLHMMQUVJCTAN-UHFFFAOYSA-N 1-chloro-3-methoxypropane Chemical compound COCCCCl BQLHMMQUVJCTAN-UHFFFAOYSA-N 0.000 description 1
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 description 1
- JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- WYAFINWXANSYGR-UHFFFAOYSA-N 5-bromodibenzo[1,2-a:1',2'-e][7]annulen-11-one Chemical compound BrC1=CC2=CC=CC=C2C(=O)C2=CC=CC=C12 WYAFINWXANSYGR-UHFFFAOYSA-N 0.000 description 1
- WZYKEKVYFKGLDP-UHFFFAOYSA-N 5-methyl-11h-dibenzo[2,1-a:2',1'-e][7]annulene Chemical compound CC1=CC2=CC=CC=C2CC2=CC=CC=C12 WZYKEKVYFKGLDP-UHFFFAOYSA-N 0.000 description 1
- DZYYOPLEVZBXSP-UHFFFAOYSA-N 7-methyltricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,9,11,13-heptaene Chemical compound CC1=CC=CC=2CC3=C(C=CC21)C=CC=C3 DZYYOPLEVZBXSP-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- YETNECSXMSQLDF-UHFFFAOYSA-N N-methyl-3-(9-methyl-2-tricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,9,11,13-heptaenylidene)propan-1-amine Chemical compound CNCCC=C1C2=C(C(=CC3=C1C=CC=C3)C)C=CC=C2 YETNECSXMSQLDF-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241000696021 Taophila mars Species 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000001449 anionic compounds Chemical class 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- RWNDHBXQGJICCE-UHFFFAOYSA-K calcium magnesium octadecanoate carbonate Chemical compound C([O-])([O-])=O.[Mg+2].C(CCCCCCCCCCCCCCCCC)(=O)[O-].[Ca+2] RWNDHBXQGJICCE-UHFFFAOYSA-K 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 230000020335 dealkylation Effects 0.000 description 1
- 238000006900 dealkylation reaction Methods 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 201000003104 endogenous depression Diseases 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 229910001412 inorganic anion Inorganic materials 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- DQEUYIQDSMINEY-UHFFFAOYSA-M magnesium;prop-1-ene;bromide Chemical compound [Mg+2].[Br-].[CH2-]C=C DQEUYIQDSMINEY-UHFFFAOYSA-M 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002891 organic anions Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical class CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/31—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by at least three rings
- C07C211/32—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by at least three rings containing dibenzocycloheptane or dibenzocycloheptene ring systems or condensed derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
- C07C2603/32—Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes
Definitions
- Patent No. 3,736,351 which is a division of application Ser. No. 620,241, Mar. 3, 1967, now Patent No. 3,527,806. Divided and this application Feb. 9, 1973, Ser. No. 330,931
- alkyl is to be understood to mean a straight or branched chain lower alkyl group, preferably one having from l-4 carbon atoms, such as, methyl, ethyl, propyl and butyl.
- alkylene is to be understood to mean lower alkylene having from 1-5 carbon atoms.
- alkylidene is to be understood to mean a lower alkylidene, preferably one having from 1-4 carbon atoms, such as, methylidene.
- alkenyl is to be understood to mean a straight or branched chain lower alkenyl group, preferably one having from 2-4 carbon atoms, such as, allyl.
- aralkylidene is to be understood to mean a lower aralkylidene group having from 7-10 carbon atoms, such as, benzylidene.
- halogen and halo include chlorine, bromine, fluorine and iodine; chlorine and bromine being preferred.
- R and R taken together with the attached nitrogen atom represent a 5-6 ring atom heterocyclic radical, for example, l-pyrrolidinyl, l-piperidyl, l-piperazinyl and 4- morpholinyl.
- anion is to be understood to mean an anion of an organic acid or inorganic acid, such as, chloride, sulfate, acetate, p-toluene-sulfonate and the like.
- compounds characterized by the formula wherein R R R and R are as previously described can be prepared by dehydrating a compound selected from the group consisting of compounds of the formulas wherein R R R and R are as previously described, R is selected from the group consisting of alkylidene and aralkylidene, A is an anion selected from the group consisting of organic and inorganic anions, and X is hydrogen when Y is hydroxyl, and Y is hydrogen when X is hydroxyl.
- the dehydration of compounds of Formulas II and III is conveniently carried out with an anhydrous or hydrous hydrohalic acid.
- a preferred dehydrating agent is an alcoholic hydrohalic acid.
- other dehydrating agents such as phosphorus oxychloride, p-toluenesulfonyl chloride, sulfuric acid, zinc chloride or potassium bisulfate, for example, in an inert organic solvent such as, chloroform or methylene chloride, are also useful.
- the dehydration can be accelerated by heating the reaction mixture.
- the alkylidene and aralkylidene substituents present in the compounds of Formula III are saponified under the conditions given for the dehydration.
- Another embodiment for the preparation of compounds of Formula I comprises reacting a compound of the formula wherein R and R are as previously described, and B is selected from the group consisting of vinyl and haloethyl,
- Examples of amines covered by Formula V are: methylamine, dimethylamine, ethylamine, diethylamine, and the like.
- Examples of heterocyclic compounds covered by Formula V are: pyrrolidine, piperidine, piperazine, morpholine and the like.
- the preferred compounds of Formula V are the monoand di-substituted amines.
- the reaction of the haloethyl compounds of Formula IV with compounds of Formula V can be conveniently carried out in the presence of inert organic solvents, such as, benzene, toluene or the like.
- the reaction is conducted conveniently at elevated temperatures in the range of 50 to 150 C., preferably of the boiling temperature of the reaction mixture.
- Readily volatile amines are expediently brought to reaction in a closed system at a temperature of about 100 C.
- the reaction of the two components is conducted in the presence of an acid-binding agent, such as, anhydrous potassium carbonate. It is especially convenient to utilize as the acid-binding agent a compound of Formula V. Under the latter condition, it is sufiicient to employ an excess of the amine of Formula V in the reaction with a compound of Formula IV.
- amines of Formula V to the vinyl compounds of Formula IV is conveniently carried out in the presence of a metal, such as, lithium or sodium; a metal amide, such as, sodium or potassium amide; or a metalorganic compound, such as, a Grignard compound, preferably at a temperature in the range of 50 to 150 C.
- a metal such as, lithium or sodium
- a metal amide such as, sodium or potassium amide
- a metalorganic compound such as, a Grignard compound
- the compounds of Formula I, wherein R and R are alkyl, obtained by dehydration of compounds of Formulas II and III or by amination of compounds of Formula IV, can be dealkylated in a manner similar to those previously utilized for compounds having a secondary amino group.
- the dealkylation can, for example, be carried out by allowing a cyanogen halide, such as, cyanogen bromide or a haloformate, preferably ethyl chloroformate to act on the dialkylamino group of a compound of Formula I.
- a cyanogen halide such as, cyanogen bromide or a haloformate, preferably ethyl chloroformate
- the compounds of Formula I can be converted into acid addition salts with organic or inorganic acids.
- they 4 form pharmaceutically acceptable acid addition salts with organic acids, such as, acetic acid, oxalic acid, citric acid, lactic acid, and the like, as well as with inorganic acids, such as, hydrochloric acid, hydrobromic acid, sulfuric acid, and the like.
- the tricyclic amines obtained in accordance with the invention consist of an isomer mixture, caused by cistrans-isomerism and, insofar as they are substituted in the aromatic rings, by position isomerism. Separation of the isomers can be accomplished utilizing methods such as fractional crystallization based on the difiYerent solubilities of the bases or acid addition salts. It is advantageous with ring-substituted compounds to separate the isomeric starting compounds prior to further processing.
- the compounds of Formula I and the pharmaceutically acceptable acid addition salts thereof obtained in accordance with the invention exhibit multiple actions on the nervous system.
- the compounds are useful as antidepressants. They are useful in that they reverse either endogenous or exogenous depression of the central nervous system. Preferred for its antidepressive action is S-(dimethylamino-propylidene -10-allyl-dibenzo[a,d] cycloheptene.
- the compounds of Formula I and their pharmaceutically acceptable acid addition salts can be administered orally or parenterally with dosage adjusted to individual requirements. They can be administered therapeutically, for example, orally or parenterally, by incorporating a therapeutic dosage in a conventional dosage form, such as tablets, capsules, elixirs, suspensions, solutions or the like. They can be administered in mixture with conventional pharmaceutical carriers or excipients, such as, for example, corn starch, calcium stearate magnesium carbonate, calcium silicate, dicalcium phosphate, talc, lactose, and the like.
- the dosage forms can, if desired, be subjected to conventional pharmaceutical expedients such as, for example, sterilization.
- conventional pharmaceutical expedients such as, for example, sterilization.
- the dosage can be adjusted to individual requirements. They can also contain other therapeutically valuable substances.
- the quantity of active medicament which is present in any of the above-described dosage forms is variable. It is preferred, however, to provide capsules or tablets containing from about 5 mg. to about 50 mg. of the Formula I base or an equivalent amount of a medicinally acceptable acid addition salt thereof. For parenteral administration, it is preferred to provide a solution containing from about 10 mg./ml. to about 20 mg./ml. of the Formula I base, or an equivalent quantity of a salt thereof.
- any such dosage form will be administered to a patient will vary, depending upon the quantity of active medicament present therein and the needs and requirements of the patient, as diagnosed by the prescribing physician. Under ordinary circumstances, however, up to about 3 mg./kg. of the compound can be administered orally daily in several dosages. It is to be understood, however, that the dosages set forth therein are exemplary only and that they do not, to any extent, limit the scope or practice of this invention.
- a ketal of 10-bromo-dibenzo[a,d]cycloheptene-5-one is reacted utilizing a metal-organic reaction with an alkyl, alkenyl or benzyl halide to yield the corresponding 10- alkyl, alkenyl or benzyl derivative which, by splitting off the protecting group, can be converted into the 10-alkyl, alkenyl or benzyl-dibenzo[a,d]cyclohepten-5-one, a key intermediate for the starting compounds represented by Formulas HI and IV.
- the ketone can be linked utilizing a metal-organic reaction to an N-monoor N-disubstituted 3-amino-propyl halide and transformed by hydrolysis into the desired 5- hydroxy-S-(N-monoor N-disubstituted 3-aminopropyl) derivative.
- Another process for preparing the compounds of Formula II comprises reacting a -alkyl, alkenyl or benzyldibenzo[a,d]cyclohepten-S-one with an N-mono or N- disubstituted 3-aminopropyl halide in the presence of 2 gram atoms of sodium per mole of ketone and hydrolyzing the reaction mixture.
- the ketone named above is reacted utilizing a metalorganic reaction 'with an ethyl halide and is thereafter hydrolyzed.
- the carbinol formed is converted by dehydration into the corresponding ethylidene compound having a semicyclic double bond.
- the ethylidene group is subsequently transformed into the acetyl group by the action of oxidation agents and treatment of the oxidation product with aqueous mineral acid.
- the S-acetyl derivative obtained is thereupon reacted with a monoor di-substituted amine in the presence of formaldehyde to give the corresponding S-amino-ethylcarbonyl compound and reduced to the desired carbinol of Formula H.
- the starting materials of Formula III can be prepared by reacting, for example, the above-mentioned IO-alkyl, alkenyl or benzyl-dibenzo[a,d]cyclohepten-S-one, as previously described, in the presence of 2 gram atoms of sodium per mole of ketone with a l-substituted 3-amino propyl halide, and hydrolyzing the reaction product to the corresponding S-hydroxy-S-amino propyl derivative.
- the starting compounds of Formula 1V in which B represents a haloethyl group can be prepared from a 10- or 1l-halodibenzo[a,d]cyclohepten-S-one as follows:
- Bromo-dibenzo[a,d]cyclohepten-S-one is reacted utilizing a metal-organic reaction with a propyl halide exhibiting an ether function such as, 3-methoxypropyl bromide and is thereafter converted by hydrolysis into the corresponding tertiary carbinol.
- the bromine atom of the S-hydroxy-5-methoxy-propyl- IO-bromo-dibenzo [a,d]cycloheptene obtained can, after dehydration of the carbinol has been effected, be replaced by the alkyl, alkenyl or benzyl residue by reaction with an alkyl, alkenyl or benzyl halide utilizing a metal-organic reaction.
- the ether function of the S-methoxy-propylidene compound thus obtained is replaced by bromine or chlorine by treatment with a hydrohalic acid, such as, an aqueous, concentrated solution of hydrobromic acid or a solution of hydrogen bromide in glacial acetic, or also by treatment with phosphorus oxychloride, or, preferably, by treatment with boron trifluoride in chloroform.
- a hydrohalic acid such as, an aqueous, concentrated solution of hydrobromic acid or a solution of hydrogen bromide in glacial acetic, or also by treatment with phosphorus oxychloride, or, preferably, by treatment with boron trifluoride in chloroform.
- the 5-(halo-propylidene)-10-alkyl, alkenyl or benzyldibenzo[a,d]cycloheptene obtained in this manner is a starting compound of the present process corresponding to Formula IV, wherein B is haloethyl.
- the same compound is also accessible from the 10- alkyl, alkenyl or benzyl-dibenzo[a,d]cyclohepten-S-one.
- the ketone is reacted, as previously described, utilizing a metal-organic reaction either with a propyl halide exhibiting an ether function, such as, 3-methoxy-propyl bromide or with a corresponding propyne-( 1) derivative, such as, 3-methoxy-propyne-(1).
- the 5-hydroxy-S-methoxy-propyl-10-alkyl, alkenyl or benzyldibenzo [a,d]cycloheptene formed after hydrolysis has taken place can be converted as previously described into the desired S-halo-propylidene compound of Formula IV.
- a further route to the compound of Formula IV, wherein B is haloethyl likewise begins with the 10-alkyl, alkenyl or benzyl-dibenzo[a,d]cyclohepten-S-one.
- the ketone is reacted utilizing metal-organic reaction with a cyclopropyl halide.
- the 5-hydroxy-5-cyclopropy1 derivative obtained by hydrolysis can be converted into the desired 5-bromopropy'lidene compound of Formula IV by the action of a concentrated hydrohalic acid, such as, hydrobromic acid.
- Starting compounds of Formula IV in which B represents the vinyl group can likewise be manufactured from the 10-alkyl, alkenyl or benzyl-dibenzo [a,d]cyclohepten- 5-one.
- the ketone is reacted, for example, with the help of a metal-organic reaction, with a l-propenyl halide, such as, l-propenyl bromide.
- a l-propenyl halide such as, l-propenyl bromide.
- the 5-hydroxy-5-propen-(1)-yl derivative formed can be converted into the corresponding 5-propenylidene compound of Formula IV by the action of dehydrating agents.
- EXAMPLE 1 15.8 g. of 5-(3-chloro-propylidene)-10-allyl-dibenzo [a,d]cycloheptene, 75 ml. of dry toluene and 50 ml. of dimethylamine are heated at for 20 hours in a pressure vessel. After expelling the excess dimethylamine, the reaction mixture is diluted with ether. The etherealsolution is washed with water and subsequently extracted with dilute hydrochloric acid. The aqueous acidic extract is made alkaline with potassium carbonate.
- the 5-(3-dimethylamino-propylidene) 10 allyldibenzo[a,d]cycloheptene which separates as an oil is taken up in ether. After the ether is removed by evaporation, the product is removed by distillation and has a b.p. of 155/ 0.01 mm. of mercury.
- the 5 (3 chloro propyli-dene)-10-allyl-dibenzo[a,d] cycloheptene employed above as starting material can be prepared as follows:
- the resulting light-brown solution is cooled to 10- treated with a solution of 7.65 g. of allyl bromide in 25 ml. of dry peroxide-free tetrahydrofuran, stirred under reflux conditions for a period of 90 minutes, cooled with ice-water, and treated with a cold saturated aqueous ammonium chloride solution.
- the tetrahydrofuran is subsequently evaporated under reduced pressure, and the residue is taken up in ether.
- the ethereal solution is washed with water, dried and evaporated.
- the residual 5 (3 methoxy-propylidene)-10-allyl-dibenzo[a,d]cycloheptene boils at 160/0.06 mm. of mercury.
- EXAMPLE 2 18 g. of 5-hydroxy-5-(3-dimethylamino-propyl)-10- methyl-dibenzo[a,d]cycloheptene and 180 ml. of 3 percent alcoholic hydrochloric acid are heated on a steam-bath under reflux conditions for a period of 2 hours and subsequently evaporated to dryness. The residual 5-(3-dimethylamino propylidene) 10 methyl-dibenzo [a,d]cycloheptene boils at 165-170/0.03 mm. of pressure.
- the 5-hydroxy-5-(3 dimethylamino-propyl)-10-methyl-dibenzo[a,d]cycloheptene employed above as starting material can be prepared as follows:
- the resulting light-brown solution is cooled with icewater, treated with a solution of 34 g. of methyl iodide in 50 ml. of dry, peroxide-free tetrahydrofuran, stirred under reflux conditions for a period of 2 hours, again cooled with ice-water and treated with a cold saturated ammonium chloride solution.
- the tetrahydrofuran is evaporated under reduced pressure and the residue is taken up in chloroform.
- the chloroform solution is Washed with water and evaporated.
- the residual 5,5- ethylenedioxy-lO-methyl dibenzo[a,d]cycloheptene may be recrystallized from methanol.
- the reaction mixture is subsequently stirred at 40 under reflux conditions for a period of 6 hours, then cooled with ice-water and treated with a cold, saturated ammonium chloride solution.
- the organic layer is separated.
- the aqueous phase is shaken out twice with 100 ml. portions of ether.
- the ether extracts are combined, dried over sodium sulfate and evaporated.
- the residual 5 -hydroxy-5- 3-dimethylamino-pro pyl -10-methyl-dibenzo[a,d]cycloheptene can be processed as previously set out without further purification.
- EXAMPLE 3 A Grignard compound prepared from 13.2 g. of bromobenzene, 2 g. of magnesium and 50 ml. of absolute ether is treated with 13.9 g. of 5-propenylidene-IO-methyl-dibenzo[a,d]cycloheptene. The mixture is charged into a moisture-free autoclave. The ether is removed by evaporation with slight heating. The reaction mixture is cooled, charged with 50 ml. of anhydrous methylamine, and heated at 80 for a period of 10 hours. The reaction mixture is thereafter cooled and taken up in ether. The excess methylamine is removed by distillation. The dispersed magnesium hydroxide is precipitated with 25 ml. of water.
- the supernatant ether solution is removed by decantation and the residue is shaken out twice with ether.
- the combined ether fractions are concentrated under reduced pressure and subsequently dried over sodium sulfate.
- the ditficulty soluble 5-(3-methylaminopropylidene)-10-methyl-dibenzo[a,d]cycloheptene acetate which is precipitated from an ethereal solution by addition of 3 g. of glacial acetic is treated with dilute ammonia.
- the free base which separates is extracted with ether.
- the resulting ethereal solution is dried and treated with ethanolic hydrochloric acid.
- S-propenylidene-IO-methyl dibenzo[a,d]cycloheptene employed as the starting material can be prepared as follows:
- the S-hydroxy-S-allyl-IO-methyl-dibenzo[a,d]cycloheptene (20 g.) which separates as a yellow oil is stirred and heated at 90 with 10 g. of acetic acid anhydride and 10 ml. of absolute toluene. 0.5 m1. of acetyl chloride are introduced when the internal temperature reaches 85. The internal temperature thereupon rises to 100. Thereafter, the reaction mixture is cooled, diluted with ether, washed with aqueous ammonia and dried. The residual S-propenylidene 10-methyl dibenzo[a,d]cycloheptene, after evaporation of the ether, is a yellow-brown oil.
- EXAMPLE 4 11.8 g. of -(3-chloropropylidene)-10-methyl-dibenzo [a,d]cycloheptene, 50 ml. of toluene and 50 ml. of methylamine are heated at 120 for 20 hours in a pressure vessel. The excess methylamine is subsequently driven off under reduced pressure. Thereafter, the reaction mixture is diluted with ether, washed with water and extracted with dilute hydrochloric acid. This aqueous acidic solution is made alkaline with potassium carbonate. The oil which separates is shaken out with ether.
- the 5 (3-chloro-propylidene)-l0-methyl-dibenzo[a,d] cycloheptene employed as the starting material can be prepared as follows:
- EXAMPLE 5 13.2 g. of crude N-benzylidene-N-[3-(5-hydroxy-10- methyl-dibenzo[a,d] cycloheptene 5-yl)-propyl]-N-methyl-ammonium-p-toluenesulfonate are dissolved in 100 ml. 1/N hydrochloric acid and warmed for 15 minutes on a water bath, cooled and alkalized by the addition of potassium carbonate. The precipitated oil is extracted with ether. The extract is dried and treated with ethanolic hydrochloric acid. After recrystallization from ethanolether, the precipitated 5 (3-methylamino-propylidene)- IO-methyI-dibenzo[a,d]cycloheptene hydrochloride melts at 200-202.
- N-benzylidene-N-[S (5 hydroxy-lO-methyl-dibenzo[a,d]cycloheptene 5 yl)-propyl]-N-methyl-ammonium-p-toluenesulfonate utilized as the starting material can be prepared according to the following:
- the active substance is homogeneously mixed with the talcum and mannitol, sieved, again thoroughly mixed and filled into No. 4 gelatin capsules.
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Abstract
5-(AMINOPROPYLIDENE)-DIBENZO(A,D)CYCLOHEPTENES HAVING ANTI-DEPRESSANT ACTIVITY.
Description
United States Patent Oflice 3,822,322 INTERMEDIATES FOR TRICYCLIC AMINES Gerald Rey-Ballet and Hans Spiegelherg, Basel, Switzerland, assignors to Holfmann-La Roche Inc., Nutley,
No Drawing. Application Apr. 23, 1970, Ser. No. 31,397,
now Patent No. 3,736,351, which is a division of application Ser. No. 620,241, Mar. 3, 1967, now Patent No. 3,527,806. Divided and this application Feb. 9, 1973, Ser. No. 330,931
Int. Cl. C07c 25/18, 25/22 US. Cl. 260-649 R 2 Claims ABSTRACT OF THE DISCLOSURE -(Aminopropylidene)-dibenzo[a,d]cycloheptenes having anti-depressant activity.
This is a division of application Ser. No. 31,397 filed Apr. 23, 1970, now Pat. No. 3,736,351, which in turn is a division of application Ser. No. 620,241, filed Mar. 3, 1967, now US. Pat. No. 3,527,806.
BRIEF SUMMARY OF THE INVENTION This invention relates to novel intermediates and to compounds characterized by the formula AR (no and pharmaceutically acceptable acid addition salts there- DETAILED DESCRIPTION As used herein, the term alkyl is to be understood to mean a straight or branched chain lower alkyl group, preferably one having from l-4 carbon atoms, such as, methyl, ethyl, propyl and butyl.
The term alkylene is to be understood to mean lower alkylene having from 1-5 carbon atoms.
The term alkylidene is to be understood to mean a lower alkylidene, preferably one having from 1-4 carbon atoms, such as, methylidene.
The term alkenyl is to be understood to mean a straight or branched chain lower alkenyl group, preferably one having from 2-4 carbon atoms, such as, allyl.
The term aralkylidene is to be understood to mean a lower aralkylidene group having from 7-10 carbon atoms, such as, benzylidene.
The terms halogen and halo include chlorine, bromine, fluorine and iodine; chlorine and bromine being preferred.
R and R taken together with the attached nitrogen atom, represent a 5-6 ring atom heterocyclic radical, for example, l-pyrrolidinyl, l-piperidyl, l-piperazinyl and 4- morpholinyl.
The term anion is to be understood to mean an anion of an organic acid or inorganic acid, such as, chloride, sulfate, acetate, p-toluene-sulfonate and the like.
Patented July 2, 1974 Examples of compounds of this invention corresponding to Formula I are:
5-(3-Dimethylamino-propylidene)-10-allyl-dibenzo [a,d] cycloheptene;
5-(3-Dimethylamino-propylidene)-10-methy1-dibenzo [a,d]cycloheptene;
5-(3-Methylamino-propylidene)-IO-methyl-dibenzo [a,d]cycloheptene; and the like.
In accordance with this invention, compounds characterized by the formula wherein R R R and R are as previously described, can be prepared by dehydrating a compound selected from the group consisting of compounds of the formulas wherein R R R and R are as previously described, R is selected from the group consisting of alkylidene and aralkylidene, A is an anion selected from the group consisting of organic and inorganic anions, and X is hydrogen when Y is hydroxyl, and Y is hydrogen when X is hydroxyl.
Compounds of Formula II are exemplified by:
5-Hydroxy-5-(3 dimethylamino propyl)-lO-methyl-di benzo[a,d]cycloheptene, and the like.
Compounds of Formula III are exemplified by:
N-benzylidene-N-[3-(5-hydroxy-l0-methyl dibenzo[a,d]
cycloheptene-S-yl)-propyl] N methyl-ammonium-ptoluenesulfonate, and the like.
The dehydration of compounds of Formulas II and III is conveniently carried out with an anhydrous or hydrous hydrohalic acid. A preferred dehydrating agent is an alcoholic hydrohalic acid. However, other dehydrating agents, such as phosphorus oxychloride, p-toluenesulfonyl chloride, sulfuric acid, zinc chloride or potassium bisulfate, for example, in an inert organic solvent such as, chloroform or methylene chloride, are also useful. The dehydration can be accelerated by heating the reaction mixture. The alkylidene and aralkylidene substituents present in the compounds of Formula III are saponified under the conditions given for the dehydration.
Another embodiment for the preparation of compounds of Formula I comprises reacting a compound of the formula wherein R and R are as previously described, and B is selected from the group consisting of vinyl and haloethyl,
with a compound of the formula wherein R and R are as previously described.
Compounds of Formula IV are exemplified by:
Examples of amines covered by Formula V are: methylamine, dimethylamine, ethylamine, diethylamine, and the like. Examples of heterocyclic compounds covered by Formula V are: pyrrolidine, piperidine, piperazine, morpholine and the like. The preferred compounds of Formula V are the monoand di-substituted amines.
The compounds of Formula IV, wherein B represented haloethyl, can be aminated by simple reaction with a compound of Formula V.
The compounds of Formula IV wherein B denotes vinyl can be aminated by addition of the appropriate monoor di-substituted amine of Formula V.
The reaction of the haloethyl compounds of Formula IV with compounds of Formula V can be conveniently carried out in the presence of inert organic solvents, such as, benzene, toluene or the like. The reaction is conducted conveniently at elevated temperatures in the range of 50 to 150 C., preferably of the boiling temperature of the reaction mixture. Readily volatile amines are expediently brought to reaction in a closed system at a temperature of about 100 C. Advantageously, the reaction of the two components is conducted in the presence of an acid-binding agent, such as, anhydrous potassium carbonate. It is especially convenient to utilize as the acid-binding agent a compound of Formula V. Under the latter condition, it is sufiicient to employ an excess of the amine of Formula V in the reaction with a compound of Formula IV.
The addition of amines of Formula V to the vinyl compounds of Formula IV is conveniently carried out in the presence of a metal, such as, lithium or sodium; a metal amide, such as, sodium or potassium amide; or a metalorganic compound, such as, a Grignard compound, preferably at a temperature in the range of 50 to 150 C.
The compounds of Formula I, wherein R and R are alkyl, obtained by dehydration of compounds of Formulas II and III or by amination of compounds of Formula IV, can be dealkylated in a manner similar to those previously utilized for compounds having a secondary amino group. Thus, the dealkylation can, for example, be carried out by allowing a cyanogen halide, such as, cyanogen bromide or a haloformate, preferably ethyl chloroformate to act on the dialkylamino group of a compound of Formula I. In this reaction, one of the two alkyl groups on the nitrogen atom is exchanged for the cyano or alkoxycarbonyl residue and then, in turn, is itself replaced by hydrogen by saponification.
The compounds of Formula I can be converted into acid addition salts with organic or inorganic acids. Thus, they 4 form pharmaceutically acceptable acid addition salts with organic acids, such as, acetic acid, oxalic acid, citric acid, lactic acid, and the like, as well as with inorganic acids, such as, hydrochloric acid, hydrobromic acid, sulfuric acid, and the like.
The tricyclic amines obtained in accordance with the invention consist of an isomer mixture, caused by cistrans-isomerism and, insofar as they are substituted in the aromatic rings, by position isomerism. Separation of the isomers can be accomplished utilizing methods such as fractional crystallization based on the difiYerent solubilities of the bases or acid addition salts. It is advantageous with ring-substituted compounds to separate the isomeric starting compounds prior to further processing.
The compounds of Formula I and the pharmaceutically acceptable acid addition salts thereof obtained in accordance with the invention exhibit multiple actions on the nervous system. The compounds are useful as antidepressants. They are useful in that they reverse either endogenous or exogenous depression of the central nervous system. Preferred for its antidepressive action is S-(dimethylamino-propylidene -10-allyl-dibenzo[a,d] cycloheptene.
The compounds of Formula I and their pharmaceutically acceptable acid addition salts can be administered orally or parenterally with dosage adjusted to individual requirements. They can be administered therapeutically, for example, orally or parenterally, by incorporating a therapeutic dosage in a conventional dosage form, such as tablets, capsules, elixirs, suspensions, solutions or the like. They can be administered in mixture with conventional pharmaceutical carriers or excipients, such as, for example, corn starch, calcium stearate magnesium carbonate, calcium silicate, dicalcium phosphate, talc, lactose, and the like. Moreover, they can be administered in the presence of buffers, or agents used to adjust to isotinicity, and the pharmaceutical dosage forms can, if desired, be subjected to conventional pharmaceutical expedients such as, for example, sterilization. As stated above, the dosage can be adjusted to individual requirements. They can also contain other therapeutically valuable substances.
The quantity of active medicament which is present in any of the above-described dosage forms is variable. It is preferred, however, to provide capsules or tablets containing from about 5 mg. to about 50 mg. of the Formula I base or an equivalent amount of a medicinally acceptable acid addition salt thereof. For parenteral administration, it is preferred to provide a solution containing from about 10 mg./ml. to about 20 mg./ml. of the Formula I base, or an equivalent quantity of a salt thereof.
The frequency with which any such dosage form will be administered to a patient will vary, depending upon the quantity of active medicament present therein and the needs and requirements of the patient, as diagnosed by the prescribing physician. Under ordinary circumstances, however, up to about 3 mg./kg. of the compound can be administered orally daily in several dosages. It is to be understood, however, that the dosages set forth therein are exemplary only and that they do not, to any extent, limit the scope or practice of this invention.
The compounds of Formulas II, HI and IV are new and are useful intermediates for the preparation of compounds of Formula I.
Compounds of Formula II, in which X represents hydroxyl and Y represents hydrogen can be prepared from a 10- to 11 halo-dibenzo[a,d]cycl0hepten-5-one, as follows:
A ketal of 10-bromo-dibenzo[a,d]cycloheptene-5-one is reacted utilizing a metal-organic reaction with an alkyl, alkenyl or benzyl halide to yield the corresponding 10- alkyl, alkenyl or benzyl derivative which, by splitting off the protecting group, can be converted into the 10-alkyl, alkenyl or benzyl-dibenzo[a,d]cyclohepten-5-one, a key intermediate for the starting compounds represented by Formulas HI and IV.
The ketone can be linked utilizing a metal-organic reaction to an N-monoor N-disubstituted 3-amino-propyl halide and transformed by hydrolysis into the desired 5- hydroxy-S-(N-monoor N-disubstituted 3-aminopropyl) derivative.
It is also possible to react the ketone under the same conditions with an N-monoor N-disubstituted 3-aminopropyne-( 1) and to hydrogenate the triple bond of the .S-hydroxy-S-(N-monoor N-disubstituted 3 amino-propyne-( l) derivative obtained after hydrolysis to the single bond propane. Both processes lead to a S-(N-monoor N- disubstituted 3-aminopropyl)-10-alkyl, alkenyl or benzyldibenzo[a,d]cycloheptene of Formula II.
Another process for preparing the compounds of Formula II comprises reacting a -alkyl, alkenyl or benzyldibenzo[a,d]cyclohepten-S-one with an N-mono or N- disubstituted 3-aminopropyl halide in the presence of 2 gram atoms of sodium per mole of ketone and hydrolyzing the reaction mixture.
The starting compounds of Formula II werein X represents hydrogen and Y represents hydroxyl can also be synthesized as follows:
The ketone named above is reacted utilizing a metalorganic reaction 'with an ethyl halide and is thereafter hydrolyzed. The carbinol formed is converted by dehydration into the corresponding ethylidene compound having a semicyclic double bond. The ethylidene group is subsequently transformed into the acetyl group by the action of oxidation agents and treatment of the oxidation product with aqueous mineral acid. The S-acetyl derivative obtained is thereupon reacted with a monoor di-substituted amine in the presence of formaldehyde to give the corresponding S-amino-ethylcarbonyl compound and reduced to the desired carbinol of Formula H.
The starting materials of Formula III can be prepared by reacting, for example, the above-mentioned IO-alkyl, alkenyl or benzyl-dibenzo[a,d]cyclohepten-S-one, as previously described, in the presence of 2 gram atoms of sodium per mole of ketone with a l-substituted 3-amino propyl halide, and hydrolyzing the reaction product to the corresponding S-hydroxy-S-amino propyl derivative. This is reacted with an aliphatic or araliphatic aldehyde, preferably with acetaldehyde or benzaldehyde and the resulting Schiffs base is quaternized through the action of an alkylating substance, particularly, through the treatment with an alkyl halide or an alkyltoluene sulfonate.
The starting compounds of Formula 1V in which B represents a haloethyl group can be prepared from a 10- or 1l-halodibenzo[a,d]cyclohepten-S-one as follows:
10 Bromo-dibenzo[a,d]cyclohepten-S-one is reacted utilizing a metal-organic reaction with a propyl halide exhibiting an ether function such as, 3-methoxypropyl bromide and is thereafter converted by hydrolysis into the corresponding tertiary carbinol.
It is also possible to react the ketone under the same conditions with a propyne-(l) exhibiting an ether function, such as, 3-methoxy-propyne-(1) and to hydrogenate up to the single bond the triple bond of the S-hydroxy- S-methoxy-propyne derivative obtained by hydrolysis.
The bromine atom of the S-hydroxy-5-methoxy-propyl- IO-bromo-dibenzo [a,d]cycloheptene obtained can, after dehydration of the carbinol has been effected, be replaced by the alkyl, alkenyl or benzyl residue by reaction with an alkyl, alkenyl or benzyl halide utilizing a metal-organic reaction.
The ether function of the S-methoxy-propylidene compound thus obtained is replaced by bromine or chlorine by treatment with a hydrohalic acid, such as, an aqueous, concentrated solution of hydrobromic acid or a solution of hydrogen bromide in glacial acetic, or also by treatment with phosphorus oxychloride, or, preferably, by treatment with boron trifluoride in chloroform.
The 5-(halo-propylidene)-10-alkyl, alkenyl or benzyldibenzo[a,d]cycloheptene obtained in this manner is a starting compound of the present process corresponding to Formula IV, wherein B is haloethyl.
The same compound is also accessible from the 10- alkyl, alkenyl or benzyl-dibenzo[a,d]cyclohepten-S-one. For example, the ketone is reacted, as previously described, utilizing a metal-organic reaction either with a propyl halide exhibiting an ether function, such as, 3-methoxy-propyl bromide or with a corresponding propyne-( 1) derivative, such as, 3-methoxy-propyne-(1). The 5-hydroxy-S-methoxy-propyl-10-alkyl, alkenyl or benzyldibenzo [a,d]cycloheptene formed after hydrolysis has taken place can be converted as previously described into the desired S-halo-propylidene compound of Formula IV.
A further route to the compound of Formula IV, wherein B is haloethyl, likewise begins with the 10-alkyl, alkenyl or benzyl-dibenzo[a,d]cyclohepten-S-one.
The ketone is reacted utilizing metal-organic reaction with a cyclopropyl halide. The 5-hydroxy-5-cyclopropy1 derivative obtained by hydrolysis can be converted into the desired 5-bromopropy'lidene compound of Formula IV by the action of a concentrated hydrohalic acid, such as, hydrobromic acid.
Starting compounds of Formula IV in which B represents the vinyl group can likewise be manufactured from the 10-alkyl, alkenyl or benzyl-dibenzo [a,d]cyclohepten- 5-one.
The ketone is reacted, for example, with the help of a metal-organic reaction, with a l-propenyl halide, such as, l-propenyl bromide. The 5-hydroxy-5-propen-(1)-yl derivative formed can be converted into the corresponding 5-propenylidene compound of Formula IV by the action of dehydrating agents.
The compounds of Formula IV, wherein B represents the vinyl group can be transformed by addition of hydrogen halide into compounds of Formula III in which B denotes the haloethyl group.
The following examples are presented to further illusstrate the invention. All temperatures are in degrees Centigrade, unless otherwise mentioned.
EXAMPLE 1 15.8 g. of 5-(3-chloro-propylidene)-10-allyl-dibenzo [a,d]cycloheptene, 75 ml. of dry toluene and 50 ml. of dimethylamine are heated at for 20 hours in a pressure vessel. After expelling the excess dimethylamine, the reaction mixture is diluted with ether. The etherealsolution is washed with water and subsequently extracted with dilute hydrochloric acid. The aqueous acidic extract is made alkaline with potassium carbonate. The 5-(3-dimethylamino-propylidene) 10 allyldibenzo[a,d]cycloheptene which separates as an oil is taken up in ether. After the ether is removed by evaporation, the product is removed by distillation and has a b.p. of 155/ 0.01 mm. of mercury.
The 5 (3 chloro propyli-dene)-10-allyl-dibenzo[a,d] cycloheptene employed above as starting material can be prepared as follows:
15 g. of magnesium shavings are overlaid with 50 ml. of dry ether and treated with 0.5 ml. of methyl iodide. After the vigorous initial reaction has subsided somewhat, a solution of 54.6 g. of 1-chloro-3-methoxy-propane in 300 ml. of dry ether is added dropwise and the temperature of the reaction mixture is maintained at its boiling. The mixture is subsequently heated at 45 under reflux conditions for a period of 3 hours, cooled with ice-water,
' treated dropwise over a 1 hour period with a solution of 69.2 g. of 10-bromo-di-benzo [a,d]cyclohepten-S-one in 500 ml. of dry ether and again heated at 45 under reflux conditions for 16 hours. The reaction mixture is again cooled with ice-water and treated with a cold, saturated solution of ammonium chloride. The organic layer is removed and the aqueous phase is shaken out with two ml. portions of ether. The combined ether extracts were dried over sodium sulfate and evaporated. The residual 5-hydroxy 5 (3-methoxy-propyl) l brorno-dibenzo[a,d] cycloheptene, after recrystallization from petroleum ether, melts at 82-84".
50 g. of -hydroxy-5-(3-methoxy-propyl)-10-bromodibenzo[a,d]cycloheptene and 500 ml. of a 3 percent alcoholic hydrochloric acid solution are heated on a steambath under reflux conditions for a period of 3 hours. After the alcohol is driven off, the residue is taken up in ether. The ethereal solution is successively washed with water, bicarbonate solution, and water, dried over sodium sulfate and evaporated. The residual 5-(3-methoxy-propylidene)- -bromo-dibenzo[a,d]cycloheptene, after recrystallization from petroleum ether, boils at 155 /0.05 mm. of mercury and melts at 113-115".
2 g. of magnesium shavings are treated with a few drops of methyl iodide. As soon as the reaction commences, a solution of 22.7 g. of 5-(3-methoxy-propylidene)-l0-bromo-dibenzo[a,d]cycloheptene in 100 ml. of dry, peroxide-free tetrahydrofuran is added dropwise and the internal temperature is maintained at 50 to 55. The reaction mixture is subsequently boiled under reflux conditions for an additional 3 hours, whereby substantially all of the magnesium is consumed.
The resulting light-brown solution is cooled to 10- treated with a solution of 7.65 g. of allyl bromide in 25 ml. of dry peroxide-free tetrahydrofuran, stirred under reflux conditions for a period of 90 minutes, cooled with ice-water, and treated with a cold saturated aqueous ammonium chloride solution. The tetrahydrofuran is subsequently evaporated under reduced pressure, and the residue is taken up in ether. The ethereal solution is washed with water, dried and evaporated. The residual 5 (3 methoxy-propylidene)-10-allyl-dibenzo[a,d]cycloheptene boils at 160/0.06 mm. of mercury.
16 g. of 5-(3-methoxy-propylidene)-10-allyl-dibenzo [a,d]cycloheptene are dissolved in 100 ml. of dry chloroform, cooled to 10 and treated dropwise with a solu tion of 6.5 g. of boron trichloride in 30 ml. of chloroform. After standing at room temperature for a period of 16 hours, the reaction mixture is successively washed with water, a sodium bicarbonate solution and water, dried and evaporated. The residual 5-(3-chloropropylidene)-10- allyl-dibenzo[a,d]cycloheptene boils at 145l50/0.0l mm. of mercury.
EXAMPLE 2 18 g. of 5-hydroxy-5-(3-dimethylamino-propyl)-10- methyl-dibenzo[a,d]cycloheptene and 180 ml. of 3 percent alcoholic hydrochloric acid are heated on a steam-bath under reflux conditions for a period of 2 hours and subsequently evaporated to dryness. The residual 5-(3-dimethylamino propylidene) 10 methyl-dibenzo [a,d]cycloheptene boils at 165-170/0.03 mm. of pressure.
The 5-hydroxy-5-(3 dimethylamino-propyl)-10-methyl-dibenzo[a,d]cycloheptene employed above as starting material can be prepared as follows:
50 g. of IO-bromo-dibenzo[a,d]cyclohepten-5-one in 150 ml. of ethylene glycol are saturated with hydrochloric acid gas with vigorous stirring. The temperature of the reaction mixture rises to 85 The temperature of the reaction mixture is subsequently maintained at 100 on a steam-bath for a period of 1 hour, then cooled and poured into excess ice-cold caustic soda; The precipitated 5,5-ethylenedioxy-10-bromo dibenzo [a,d] cycloheptene, after recrystallization from petroleum ether, melts at 171-172".
9 g. of magnesium shavings are treated with a few drops of methyl iodide. As soon as reaction takes place, a solution of 78.6 g. of 5,5-ethylenedioxy-10-bromo-dibenzo[a,d]cycloheptene in 450 ml. of dry, peroxide-free tetrahydrofuran is added dropwise and the internal temperature maintained between 40 and 42. The reaction mixture is subsequently heated under reflux conditions for an additional 3 hours, whereby substantially all of the magnesium is consumed.
The resulting light-brown solution is cooled with icewater, treated with a solution of 34 g. of methyl iodide in 50 ml. of dry, peroxide-free tetrahydrofuran, stirred under reflux conditions for a period of 2 hours, again cooled with ice-water and treated with a cold saturated ammonium chloride solution. The tetrahydrofuran is evaporated under reduced pressure and the residue is taken up in chloroform. The chloroform solution is Washed with water and evaporated. The residual 5,5- ethylenedioxy-lO-methyl dibenzo[a,d]cycloheptene may be recrystallized from methanol.
25 g. of 5,5-ethylenedioxy-IO-methyl-dibenzo[a,d]cycloheptene, 25 ml. of concentrated hydrochloric acid and 250 ml. of acetone are heated under reflux conditions on the steam-bath for a period of 1 hour. The solvent is subsequently removed by evaporation. The residue is taken up in methylene chloride, washed with a sodium bicarbonate solution and water, and evaporated. The residual IO-methyl-dibenzo[a,d]cyclohepen-5-one may be recrystallized from methanol.
8 g. of Gilman alloy are overlaid with 20 ml. of dry ether and treated with 0.5 m1. of methyl iodide. After the vigorous initial reaction has subsided, 30 g. of l-chloro- 3-dimethylamino-propane in ml. of dry ether are added dropwise and the temperautre of the reaction mixture is maintained at its boiling. The mixture is heated at 45 under reflux conditions for an additional period of 4 hours, then cooled with ice-water, and treated dropwise over a period of 1 hour with a solution of 20 g. of IO-methyl-dibenzo[a,d]cyclohepten-5-one in ml. of ether. The reaction mixture is subsequently stirred at 40 under reflux conditions for a period of 6 hours, then cooled with ice-water and treated with a cold, saturated ammonium chloride solution. The organic layer is separated. The aqueous phase is shaken out twice with 100 ml. portions of ether. The ether extracts are combined, dried over sodium sulfate and evaporated. The residual 5 -hydroxy-5- 3-dimethylamino-pro pyl -10-methyl-dibenzo[a,d]cycloheptene can be processed as previously set out without further purification.
EXAMPLE 3 A Grignard compound prepared from 13.2 g. of bromobenzene, 2 g. of magnesium and 50 ml. of absolute ether is treated with 13.9 g. of 5-propenylidene-IO-methyl-dibenzo[a,d]cycloheptene. The mixture is charged into a moisture-free autoclave. The ether is removed by evaporation with slight heating. The reaction mixture is cooled, charged with 50 ml. of anhydrous methylamine, and heated at 80 for a period of 10 hours. The reaction mixture is thereafter cooled and taken up in ether. The excess methylamine is removed by distillation. The dispersed magnesium hydroxide is precipitated with 25 ml. of water. The supernatant ether solution is removed by decantation and the residue is shaken out twice with ether. In order to remove the last of the remaining methylamine, the combined ether fractions are concentrated under reduced pressure and subsequently dried over sodium sulfate. The ditficulty soluble 5-(3-methylaminopropylidene)-10-methyl-dibenzo[a,d]cycloheptene acetate which is precipitated from an ethereal solution by addition of 3 g. of glacial acetic is treated with dilute ammonia. The free base which separates is extracted with ether. The resulting ethereal solution is dried and treated with ethanolic hydrochloric acid. The 5-(3-methylaminopropylidene) -10-methyl-dibenzo [a,d] cycloheptene hydrochloride which is formed after recrystallization from ethanol/ethyl ether melts at 200-202".
The S-propenylidene-IO-methyl dibenzo[a,d]cycloheptene employed as the starting material can be prepared as follows:
6.45 g. of magnesium shavings are treated with 21.6 g. of allyl bromide in ml. of absolute ether to form an allyl magnesium bromide solution. To this are added dropwise 16.7 g. of IO-methyl-dibenzo[a,dJcyclohepten- S-one in 100 ml. of absolute ether and 50 ml. of absolute benzene over a period of 1 hour. The reaction mixture is subsequently heated under reflux conditions for a period of 1 hour and thereafter treated with a saturated ammonium chloride solution. The organic layer is separated. The aqueous phase is extracted with ether. The combined ether extracts are evaporated. The S-hydroxy-S-allyl-IO-methyl-dibenzo[a,d]cycloheptene (20 g.) which separates as a yellow oil is stirred and heated at 90 with 10 g. of acetic acid anhydride and 10 ml. of absolute toluene. 0.5 m1. of acetyl chloride are introduced when the internal temperature reaches 85. The internal temperature thereupon rises to 100. Thereafter, the reaction mixture is cooled, diluted with ether, washed with aqueous ammonia and dried. The residual S-propenylidene 10-methyl dibenzo[a,d]cycloheptene, after evaporation of the ether, is a yellow-brown oil.
EXAMPLE 4 11.8 g. of -(3-chloropropylidene)-10-methyl-dibenzo [a,d]cycloheptene, 50 ml. of toluene and 50 ml. of methylamine are heated at 120 for 20 hours in a pressure vessel. The excess methylamine is subsequently driven off under reduced pressure. Thereafter, the reaction mixture is diluted with ether, washed with water and extracted with dilute hydrochloric acid. This aqueous acidic solution is made alkaline with potassium carbonate. The oil which separates is shaken out with ether. The residual, oily 5 (3-methylamino-propylidene)-l0-methyl-dibenzo [a,d]cycloheptene, after evaporation of the solvent, boils at 160/ 0.01 mm. of mercury. The hydrochloride addition salt thereof melts at 201-203 after recrystallization from ethanol/ether.
The 5 (3-chloro-propylidene)-l0-methyl-dibenzo[a,d] cycloheptene employed as the starting material can be prepared as follows:
4 g. of magnesium shavings are treated with a few drops of methyl iodide. As soon as reaction commences, 45.5 g. of 5 (3 methoxy-propylidene)--bromo-dibenzo[a,d] cycloheptene in 200 ml. of dry, peroxide-free tetrahydrofuran are added dropwise and the internal temperature of the reaction mixture is maintained between 50 and 55. The reaction mixture is subsequently heated under reflux conditions for an additional 3 hours, whereby substantially all of the magnesium is consumed.
The resulting brown solution is cooled to 10-15, treated with a solution of 17.95 g. of methyl iodide in 50 ml. of dry, peroxide-free tetrahydrofuran, stirred under reflux conditions for 90 minutes, cooled with ice-water and treated with a cold saturated aqueous ammonium chloride solution. The tetrahydrofuran is removed by evaporation under reduced pressure and the residue is taken up in ether. The ethereal solution is washed with water, dried over sodium sulfate and evaporated. After recrystallization from alcohol, the residual 5-(3-methoxypropylidene) 10-methyl-dibenzo[a,d]cycloheptene melts at 125-428".
11 g. of 5-(3-methoxy-propylidene)-IO-methyl dibenzo [a,d]cycloheptene are dissolved in 100 ml. of methylene chloride, cooled to --10 C., and treated dropwise with a solution of 6 g. of boron trichloride in 30 ml. of methylene chloride. After standing at room temperature for 15 hours, the reaction mixture is washed with water, with a sodium bicarbonate solution and again with water, dried and evaporated. The residual 5-(3-chloro-propylidene)- 10 methyl-dibenzo[a,d]cycloheptene boils at 155-158 and 0.03 mm. of mercury.
EXAMPLE 5 13.2 g. of crude N-benzylidene-N-[3-(5-hydroxy-10- methyl-dibenzo[a,d] cycloheptene 5-yl)-propyl]-N-methyl-ammonium-p-toluenesulfonate are dissolved in 100 ml. 1/N hydrochloric acid and warmed for 15 minutes on a water bath, cooled and alkalized by the addition of potassium carbonate. The precipitated oil is extracted with ether. The extract is dried and treated with ethanolic hydrochloric acid. After recrystallization from ethanolether, the precipitated 5 (3-methylamino-propylidene)- IO-methyI-dibenzo[a,d]cycloheptene hydrochloride melts at 200-202.
The N-benzylidene-N-[S (5 hydroxy-lO-methyl-dibenzo[a,d]cycloheptene 5 yl)-propyl]-N-methyl-ammonium-p-toluenesulfonate utilized as the starting material can be prepared according to the following:
6.7 g. of 10-methyl-dibenzo[a,d]cyclohepten-S-one, prepared according to the procedure of Example 2, are dissolved in 20 ml. of toluene and added dropwise with agita tion to 30 ml. of liquid ammonia previously dried over sodium chips, 1.4 g. of sodium are added to the reaction mixture piece by piece over a period of 30 minutes. The mixture is agitated for an additional hour and then reacted with 3.5 g. of freshly distilled l-chloro-3-amin0- propane (free base) in 20 ml. of toluene. The reaction mixture is carefully treated with water after 12 hours of agitation. The organic phase is separated and treated with 4 g. of benzaldehyde. The toluene and the liberated water are removed by distillation under reduced pressure. The residual benzylidene compound is mixed with 5.0 g. of the methyl-p-toluenesulfonate, slowly heated to and maintained at for 30 minutes, whereby the desired N- benzylidenc N [3-(S-hydroxy-lO-metbyl-dibenzo[a,d] cycloheptene 5 yl)-propyl]-N-methyl-ammonium-ptoluenesulfonate is formed.
EXAMPLE '6 25 g. of ethyl chloroformate in 80 ml. of dry benzene are slowly dropped into a solution of 20 g. of 5-(3-dimethylaminopropylidene) IO-methyl-dibenzo[a,d]cycloheptene in 80 m1. of dry benzene. The reaction mixture is heated under reflux conditions over a period of 20 hours, then cooled, washed with three 200 ml. portions of 3-N hydrochloric acid and with water, dried and subsequently evaporated. The residual oily 5 (3-methyl-carbethoxyamino-propylidene) l0 methyl-dibenzo[a,d]cycloheptene boils at 175 /0.01 mm. of mercury.
17.8 g. of 5-(3-methyl-carbethoxyamino-propylidene)- l0-methyl-dibenzo[a,d]cycloheptene, 20 g. of potassium hydroxide and 200 ml. of n-butanol are heated under reflux conditions in a nitrogen atmosphere with stirring for a period of 17 hours. The butanol is subsequently removed by distillation under reduced pressure. The residue is taken up in 170 ml. of sulfuric acid, heated at 70 for a brief time, then washed with two 200 ml. portions of hexane and made alkaline with caustic soda. The oil which separates is extracted with ether. The ethereal solution is washed with water, dried and evaporated. The residual oily 5 (3-methyl-propylidene)-10-methyl-dibenzo[a,d] cycloheptene boils at /0.01 mm. of pressure. After recrystallization from ethanol/petroleum ether, the compound melts at 201-203".
The active substance is homogeneously mixed with the talcum and mannitol, sieved, again thoroughly mixed and filled into No. 4 gelatin capsules.
11 EXAMPLE 8 Drages are formulated as follows:
Mg. 5-(Methylamino-propylidene)-10-methyl-dibenzo- [a,d]cycloheptene 25 Mannitol 100 Maize starch 20 Talcum 5 A 10 percent aqueous paste prepared from the maize starch is homogeneously mixed with the mannitol, the talcum and the active substance, granulated and pressed to kernels which can be coated with a sugar layer in the usual manner.
From the foregoing description and examples, it will be apparent to those skilled in the art that various modifications are possible without departing from the scope of the invention and, therefore, said description and examples are not to be construed as limiting the invention except as defined by the appended claims.
12 1 We claim: 1. A compound of the formula 7 References Cited UNITED STATES PATENTS 9/ 1966 Hotfsommer et al. 260646 R 3/1968 Engelhardt 260649 R HOWARD T. MARS, Primary Examiner UNITED STATES PATENT OFFICE a QERTIFICATE OF CORRECTION .Patent No. 3,822,322 Dated I J121y2, 1974 Inventor(s)- 2 Gerald Rey-Bellet and Hans Spiegelberg It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
Column l, line 10, after "Ser. No. 330,931" insert --C1aims priority, application Switzerland, March 17, 1966,
No, sew/sa Signed and sealed this 21st day of January 1975.
(SEAL) Attest:
MCCOY M. GIBSON JR. c. MARSHALL DANN Attescing Officer] Commissioner of Patents
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US20180370887A1 (en) * | 2015-12-21 | 2018-12-27 | Dsm Ip Assets B.V. | Intermolecular reaction of propargyl ethers with dimethylfuran in the presence of gold(i) complexes |
US10815178B2 (en) | 2015-12-21 | 2020-10-27 | Dsm Ip Assets B.V. | Intermolecular reaction of propargyl ethers with dimethylfuran in the presence of gold(I) complexes |
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