DE1138055B - Process for the preparation of N-substituted azepines and their salts - Google Patents
Process for the preparation of N-substituted azepines and their saltsInfo
- Publication number
- DE1138055B DE1138055B DEG25993A DEG0025993A DE1138055B DE 1138055 B DE1138055 B DE 1138055B DE G25993 A DEG25993 A DE G25993A DE G0025993 A DEG0025993 A DE G0025993A DE 1138055 B DE1138055 B DE 1138055B
- Authority
- DE
- Germany
- Prior art keywords
- carboxylic acid
- general formula
- salts
- azepine
- acid
- 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.)
- Pending
Links
- -1 N-substituted azepines Chemical class 0.000 title claims description 15
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 4
- 150000003839 salts Chemical class 0.000 title claims description 4
- 150000001414 amino alcohols Chemical class 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 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
- 150000001875 compounds Chemical class 0.000 description 3
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 2
- PYSGFFTXMUWEOT-UHFFFAOYSA-N 3-(dimethylamino)propan-1-ol Chemical compound CN(C)CCCO PYSGFFTXMUWEOT-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229960002887 deanol Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 230000002048 spasmolytic effect Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- DZCBKUAAGVVLOX-UHFFFAOYSA-N 1-morpholin-4-ylethanol Chemical compound CC(O)N1CCOCC1 DZCBKUAAGVVLOX-UHFFFAOYSA-N 0.000 description 1
- MADORZDTLHDDEN-UHFFFAOYSA-N 1-piperidin-1-ylethanol Chemical compound CC(O)N1CCCCC1 MADORZDTLHDDEN-UHFFFAOYSA-N 0.000 description 1
- POIVWEXWFKSJHL-UHFFFAOYSA-N 2-(dimethylamino)propan-2-ol Chemical compound CN(C)C(C)(C)O POIVWEXWFKSJHL-UHFFFAOYSA-N 0.000 description 1
- WKCYFSZDBICRKL-UHFFFAOYSA-N 3-(diethylamino)propan-1-ol Chemical compound CCN(CC)CCCO WKCYFSZDBICRKL-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- PLRXAFVBCHEMGD-UHFFFAOYSA-N 3-piperidin-1-ylpropan-1-ol Chemical compound OCCCN1CCCCC1 PLRXAFVBCHEMGD-UHFFFAOYSA-N 0.000 description 1
- ZMJQROKRSPSLFH-UHFFFAOYSA-N 3-pyrrolidin-1-ylpropan-1-ol Chemical compound OCCCN1CCCC1 ZMJQROKRSPSLFH-UHFFFAOYSA-N 0.000 description 1
- QCTOLMMTYSGTDA-UHFFFAOYSA-N 4-(dimethylamino)butan-1-ol Chemical compound CN(C)CCCCO QCTOLMMTYSGTDA-UHFFFAOYSA-N 0.000 description 1
- FYFJMRRHHBAMEH-UHFFFAOYSA-N 4-imino-3-(2-phenylethenyl)cyclohexa-1,5-diene-1-carbonyl chloride Chemical compound N=C1C=CC(C(=O)Cl)=CC1C=CC1=CC=CC=C1 FYFJMRRHHBAMEH-UHFFFAOYSA-N 0.000 description 1
- ZSMRRZONCYIFNB-UHFFFAOYSA-N 6,11-dihydro-5h-benzo[b][1]benzazepine Chemical group C1CC2=CC=CC=C2NC2=CC=CC=C12 ZSMRRZONCYIFNB-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- JXQSXIGQTATCAL-UHFFFAOYSA-N CC(C)(N(C)C)OC(C1=CC=CNC=C1)=O Chemical compound CC(C)(N(C)C)OC(C1=CC=CNC=C1)=O JXQSXIGQTATCAL-UHFFFAOYSA-N 0.000 description 1
- CBKSUTKPHWZMJP-UHFFFAOYSA-N CCN(CC)CCOC(C1=CC=CNC=C1)=O Chemical compound CCN(CC)CCOC(C1=CC=CNC=C1)=O CBKSUTKPHWZMJP-UHFFFAOYSA-N 0.000 description 1
- GDEIJMFEOIEOQM-UHFFFAOYSA-N CN(C)CCCOC(C1=CC=CNC=C1)=O Chemical compound CN(C)CCCOC(C1=CC=CNC=C1)=O GDEIJMFEOIEOQM-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- MOIPGXQKZSZOQX-UHFFFAOYSA-N carbonyl bromide Chemical compound BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- XBRDBODLCHKXHI-UHFFFAOYSA-N epolamine Chemical compound OCCN1CCCC1 XBRDBODLCHKXHI-UHFFFAOYSA-N 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
DEUTSCHESGERMAN
PATENTAMTPATENT OFFICE
G 25993 IVd/12 ρG 25993 IVd / 12 ρ
A NMELDE TA G: 19. DEZEMBER 1958 REPORTING DAY: DECEMBER 19, 1958
BEKANNTMACHUNG
DER ANMELDUNG
UNDAUSGABE DER
AUSLEGESCHRIFT: 18. OKTOBER 1962 NOTICE
THE REGISTRATION
AND ISSUE OF
EDITORIAL: OCTOBER 18, 1962
Die Erfindung betrifft ein Verfahren zur Herstellung von N-substituierten Azepinen der allgemeinen FormelThe invention relates to a process for the preparation of N-substituted azepines in general formula
COO-CnH2n-NCOO-C n H 2n -N
in der X die Äthylen- oder Vinylengruppe, Y und Z Wasserstoff- oder Halogenatome, η eine ganze Zahl von 2 bis 4, R1 und R2 niedermolekulare Alkylreste bedeuten und Rj und R2 zusammen mit dem Stickstoffatom auch zu einem gegebenenfalls ein Sauerstoffatom enthaltenden gesättigten heterocyclischen Ring verbunden sein können, und deren Salzen.in which X is the ethylene or vinylene group, Y and Z are hydrogen or halogen atoms, η is an integer from 2 to 4, R 1 and R 2 are low molecular weight alkyl radicals and Rj and R 2 together with the nitrogen atom also form an optionally containing an oxygen atom saturated heterocyclic ring, and their salts.
Es wurde nun gefunden, daß diese Verbindungen pharmakologisch wertvolle Eigenschaften, insbesondere spasmolytische und antiallergische Wirksamkeit, besitzen. Gegenüber dem aus der deutschen Patentschrift 935 546 bekannten 5-(a-D;methylaminopropionyl)-iminodibenzyl zeigen der erfindungsgemäß hergestellte Iminodibenzyl-5-carbonsäure-dimethylaminoäthylester und der Iminostilben-5-carbonsäure-dimethylaminoisopropylester eine stärkere spasmolytische Wirksamkeit, da von den neuen Verbindungen zur Erzielung derselben antagonistischen Wirkung gegenüber Histamin wie mit der bekannten Verbindung nur ein Siebentel bis ein Zehntel der Substanzmenge notwendig ist. Unter Berücksichtigung der Toxizitätswerte liegt der therapeutische Index bei den Verfahrensprodukten bedeutend höher als bei dem 5-(a-Dimethylaminopropionyl)-iminodibenzyl. Die N-substituierten Azepine der angegebenen allgemeinen Formel werden hergestellt, indem man in an sich bekannter Weise ein Azepin-5-carbonsäurehalogenid bzw. Dihydroazepin-5-carbonsäurehalogenid der allgemeinen Formel Verfahren zur Herstellung von N-substituierten Azepinen und deren SalzenIt has now been found that these compounds have pharmacologically valuable properties, in particular spasmolytic and antiallergic activity. Compared to the 5- (aD; methylaminopropionyl) -iminodibenzyl known from German patent specification 935 546, the dimethylaminoethyl iminodibenzyl-5-carboxylate and the dimethylaminoisopropyl iminostilbene-5-carboxylate produced according to the invention show a stronger spasmolytic activity, because of the new compounds to achieve the same antagonistic effect on histamine as with the known compound only one seventh to one tenth of the amount of substance is necessary. Taking into account the toxicity values, the therapeutic index of the process products is significantly higher than that of 5- (a-dimethylaminopropionyl) -iminodibenzyl. The N-substituted azepines of the general formula given are prepared by adding, in a manner known per se, an azepine-5-carboxylic acid halide or dihydroazepine-5-carboxylic acid halide of the general formula Process for the preparation of N-substituted azepines and their salts
Anmelder: J. R. Geigy A.-G., Basel (Schweiz)Applicant: J. R. Geigy A.-G., Basel (Switzerland)
Vertreter: Dr. F. Zumstein,Representative: Dr. F. Zumstein,
Dipl.-Chem. Dr. rer. nat. E. Assmann undDipl.-Chem. Dr. rer. nat. E. Assmann and
Dipl.-Chem. Dr. R. Koenigsberger, Patentanwälte,Dipl.-Chem. Dr. R. Koenigsberger, patent attorneys,
München 2, Bräuhausstr. 4Munich 2, Bräuhausstr. 4th
Beanspruchte Priorität: Schweiz vom 20. Dezember 1957 (Nr. 54 025)Claimed priority: Switzerland of December 20, 1957 (No. 54 025)
Dr. Walter Schindler, Riehen,Dr. Walter Schindler, Riehen,
und Dr. Franz Häfliger, Basel (Schweiz),and Dr. Franz Häfliger, Basel (Switzerland),
sind als Erfinder genannt wordenhave been named as inventors
in der Hai ein Chlor- oder Bromatom bedeutet, mit einem Aminoalkohol der allgemeinen Formelin which Hai means a chlorine or bromine atom, with an amino alcohol of the general formula
RiRi
HO-CnH271-NHO-C n H 271 -N
IIIIII
CO —HalCO —Hal
II umsetzt und gegebenenfalls die erhaltene Base mit einer anorganischen oder organischen Säure behandelt. II is reacted and, if appropriate, the base obtained is treated with an inorganic or organic acid.
Die Umsetzungen der Azepin- bzw. Dihydroazepin-5-carbonsäurehalogenide mit den Aminoalkoholen werden z. B. unter Erwärmen der Komponenten in einem inerten organischen Lösungsmittel, ζ. Β. Benzol oder Toluol, durchgeführt.The reactions of the azepine or dihydroazepine-5-carboxylic acid halides with the amino alcohols z. B. by heating the components in an inert organic solvent, ζ. Β. Benzene or toluene.
Die Ausgangsstoffe der allgemeinen Formel II können in an sich bekannter Weise aus 10,11-Dihydro - 5 - dibenzo [b,fj azepin, 5 - Dibenzo [b,f] azepin oder deren C-Substitutionsprodukten durch Behandeln mit Phosgen oder Kohlensäuredibromid in einem inerten organischen Lösungsmittel, z. B. Benzol oder Toluol, erhalten werden. Als BeispieleThe starting materials of the general formula II can be prepared in a manner known per se from 10,11-dihydro - 5 - dibenzo [b, fj azepine, 5 - dibenzo [b, f] azepine or their C-substitution products by treatment with phosgene or carbonic dibromide in an inert organic solvent, e.g. B. Benzene or toluene. As examples
209 677/306209 677/306
von Ausgangsstoffen seien neben den 5-Carbonsäurechloridderivaten des 10,ll-Dihydro-5-dibenzo[b,f]-azepins und des 5-Dibenzo[b,f]azepins, die auch als Iminodibenzyl-S-carbonsäurechlorid und Iminostilben-5-carbonsäurechlorid bezeichnet werden, diejenigen von 1,9-Dichlor- und 3,7-Dichlor-10,H-dihydro-5-dibenzo[b,f]azepin (1,9- bzw. 3,7-Dichloriminodibenzyl) sowie von 1,9-Dichlor- und 3,7-Dichlor-5-dibenzo[b,f]azepin (1,9-Dichlor- und 3,7-Dichlor-iminostilben) genannt.of starting materials are in addition to the 5-carboxylic acid chloride derivatives des 10, ll-dihydro-5-dibenzo [b, f] azepine and 5-dibenzo [b, f] azepine, which are also known as Iminodibenzyl-S-carboxylic acid chloride and iminostilbene-5-carboxylic acid chloride referred to are those of 1,9-dichloro- and 3,7-dichloro-10, H-dihydro-5-dibenzo [b, f] azepine (1,9- or 3,7-dichloriminodibenzyl) as well as 1,9-dichloro- and 3,7-dichloro-5-dibenzo [b, f] azepine (1,9-dichloro- and 3,7-dichloro-iminostilbene) called.
Geeignete Aminoalkohole der allgemeinen Formel III sind z. B. das Dimethylaminoäthanol, /J-Dimethylamino-propanol, y-Dimethylamino-propanol, ß-Dimethylamino-isopropanol, ö-Dimethylamino-butanol, Diäthylamino-äthanol, y-Diäthylamino - propanol, β - (Di - η - propylamino) - äthanol, ^-(N-Butyhnethylamino)-äthanol,Pyrrolidinoäthanol, y-Pyrrolidino-propanol, Piperidinoäthanol, y-Piperidino-propanol und Morpholinoäthanol.Suitable amino alcohols of the general formula III are, for. B. dimethylaminoethanol, / J-dimethylamino-propanol, γ-dimethylamino-propanol, ß-dimethylamino-isopropanol, δ-dimethylamino-butanol, diethylamino-ethanol, γ-diethylamino-propanol, β - (di - η - propylamino) - ethanol, ^ - (N-Butyhnethylamino) -ethanol, pyrrolidinoethanol, γ-pyrrolidino-propanol, piperidinoethanol, γ-piperidino-propanol and morpholinoethanol.
Mit anorganischen oder organischen Säuren, wie Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, Äthandisulfonsäure, Essigsäure, Bernsteinsäure, Fumarsäure, Maleinsäure, Äpfelsäure, Weinsäure, Zitronensäure, Benzoesäure und Phthalsäure bilden die tertiären basischen Ester Salze, welche zum Teil wasserlöslich sind.With inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, Phosphoric acid, methanesulfonic acid, ethane disulfonic acid, acetic acid, succinic acid, fumaric acid, maleic acid, Malic acid, tartaric acid, citric acid, benzoic acid and phthalic acid make up the tertiary ones basic ester salts, some of which are water-soluble.
Die nachfolgenden Beispiele sollen das Herstellungsverfahren der N-substituierten Azepine erläutern. Teile bedeuten darin Gewichtsteile.The following examples are intended to illustrate the manufacturing process explain the N-substituted azepines. Parts therein mean parts by weight.
12,2 Teile Immodibenzyl-S-carbonsäurechlorid (Schmp. 119 bis 1200C) werden in 50 Volumteilen absolutem Benzol gelöst und bei 60 bis 700C in eine Lösung von 10 Teilen Dimethyl-aminoäthanol in 50 Volumteilen absolutem Benzol eingetropft. Anschließend kocht man das Reaktionsgemisch 16 Stunden unter Rückfluß. Nach dem Abkühlen extrahiert man daraus die basischen Anteile mit 2 η-Salzsäure, macht die saure Lösung mit konzentrierter Natronlauge alkalisch und nimmt die ausgeschiedene Base in Petroläther auf. Nach dem Trocknen der Lösung mit Natriumsulfat engt man sie auf ein kleines Volumen ein, wobei der Iminodibenzyl - 5 - carbonsäure - dimethylaminoäthylester (lOJl-Dihydro-S-dibenzofbjfJazepin-S-carbonsäuredimethylaminoäthylester) vom Schmp. 76 bis 77°C auskristallisiert. Ausbeute 82% der Theorie.12.2 parts Immodibenzyl-S-carboxylic acid chloride (mp. 119-120 0 C) absolute benzene are dissolved in 50 parts by volume, and dimethyl-aminoethanol was added dropwise to 50 volumes of absolute benzene at 60 to 70 0 C in a solution of 10 parts. The reaction mixture is then refluxed for 16 hours. After cooling, the basic components are extracted therefrom with 2η hydrochloric acid, the acidic solution is made alkaline with concentrated sodium hydroxide solution and the base which has separated out is taken up in petroleum ether. After drying the solution with sodium sulfate, it is concentrated to a small volume, the iminodibenzyl-5-carboxylic acid-dimethylaminoethyl ester (10Jl-dihydro-S-dibenzofbjfjazepine-S-carboxylic acid dimethylaminoethyl ester) crystallizing out with a melting point of 76 to 77 ° C. Yield 82% of theory.
In analoger Weise erhält man, ausgehend von S^-Dichloriminodibenzyl-S-carbonsäurechlorid und y-Dimethylamino-propanol, den 3,7-Dichlor-iminodibenzyl-5-carbonsäure-y-dimethylaminopropylester (3,7-Dichlor-10,11 -dihydro-5-dibenzo [b,f]azepin-5 - carbonsäure - γ - dimethylamino - propylester); Kp.o,o5mm 1900C. Ausbeute 71% der Theorie.In an analogous manner, starting from S ^ -dichloriminodibenzyl-S-carboxylic acid chloride and γ-dimethylamino-propanol, the 3,7-dichloro-iminodibenzyl-5-carboxylic acid-γ-dimethylaminopropyl ester (3,7-dichloro-10.11 - dihydro-5-dibenzo [b, f] azepine-5 - carboxylic acid - γ - dimethylamino - propyl ester); Kp. O, Ø5mm 190 0 C. Yield 71% of theory.
12 Teile Iminostilben-S-carbonsäurechlorid werden in 50 Volumteilen absolutem Benzol gelöst, mit 15 Volumteilen Dimethylamino-isopropanol versetzt und 16 Stunden unter Rückfluß gekocht. Hierauf kühlt man die Reaktionslösung ab, extrahiert sie mit 2 η-Salzsäure, macht die salzsaure Lösung mit konzentrierter Natronlauge alkalisch und saugt die ausgeschiedene Base ab. Nach dem Umkristallisieren aus Alkohol schmilzt der Iminostilben- - carbonsäure - dimethylaminoisopropylester (5 - Dibenzo [b,f] azepin - 5 - carbonsäure - dimethylaminoisopropylester) bei 84° C. Ausbeute 85% der Theorie. Unter Verwendung von Diäthylaminoäthanol erhält man in analoger Weise den Iminostilben- - carbonsäure - diäthylaminoäthylester (5 - Dibenzo-[b,f] azepin - 5 - carbonsäure - diäthylaminoäthylester). Die rohe Base wird mit alkoholischer Salzsäure in das gut kristallisierende Hydrochlorid vom Schmp. 23O0C übergeführt. Ausbeute 65% der Theorie.12 parts of iminostilbene-S-carboxylic acid chloride are dissolved in 50 parts by volume of absolute benzene, 15 parts by volume of dimethylamino-isopropanol are added and the mixture is refluxed for 16 hours. The reaction solution is then cooled, it is extracted with 2η hydrochloric acid, the hydrochloric acid solution is made alkaline with concentrated sodium hydroxide solution and the base which has separated out is filtered off with suction. After recrystallization from alcohol, the iminostilbene carboxylic acid dimethylaminoisopropyl ester (5-dibenzo [b, f] azepine-5-carboxylic acid dimethylaminoisopropyl ester) melts at 84 ° C. Yield 85% of theory. Using diethylaminoethanol, the iminostilbene carboxylic acid diethylaminoethyl ester (5-dibenzo- [b, f] azepine-5-carboxylic acid diethylaminoethyl ester) is obtained in an analogous manner. The crude base is converted with alcoholic hydrochloric acid in the well-crystallized hydrochloride of mp. 23O 0 C. Yield 65% of theory.
In analoger Weise, wie in den vorangehenden Beispielen beschrieben, erhält man:In a manner analogous to that described in the preceding examples, one obtains:
Iminodibenzyl - 5 - carbonsäure -pyrrolidinoäthylester, Schmp. 860C;. Iminodibenzyl - 5 - carboxylic acid -pyrrolidinoäthylester, mp 86 0 C;
Iminostilben - 5 - carbonsäure -piperidinopropylester, Schmp. des Hydrochloride 240 bis 2420C;Iminostilbene - 5 - carboxylic acid -piperidinopropylester, mp of the hydrochloride 240-242 0 C.
Irmnostilben-5-carbonsäure-morpholinoäthylester,
Schmp. des Hydrochlorids 2020C; Iminodibenzyl-5-carbonsäure-morpholinoäthylester,
Schmp. des Hydrochlorids 248 0C (Umwandlung bei 2100C),
sowieIrmnostilbene-5-carboxylic acid morpholinoethyl ester, melting point of the hydrochloride 202 0 C; Iminodibenzyl-5-carboxylic acid morpholinoäthylester, mp. 248 0 C of the hydrochloride (conversion at 210 0 C),
as
Iminodibenzyl-5-carbonsäure-morpholinopropylester, Schmp. des Hydrochlorids 1800C.Iminodibenzyl-5-carboxylic acid morpholinopropylester, mp. Of the hydrochloride 180 0 C.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1138055X | 1957-12-20 |
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| Publication Number | Publication Date |
|---|---|
| DE1138055B true DE1138055B (en) | 1962-10-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEG25993A Pending DE1138055B (en) | 1957-12-20 | 1958-12-19 | Process for the preparation of N-substituted azepines and their salts |
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| Country | Link |
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| DE (1) | DE1138055B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2700091A1 (en) * | 1976-01-05 | 1977-07-14 | Searle & Co | 1- (SUBSTITUTE AMINO) ALKANOYL-2- (DIBENZOXAZEPINE-10-CARBONYL) -HYDRAZINE AND THEIR DERIVATIVES |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE935546C (en) * | 1951-07-11 | 1955-11-24 | Geigy Ag J R | Process for the preparation of N-acyl derivatives of iminodibenzyl |
-
1958
- 1958-12-19 DE DEG25993A patent/DE1138055B/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE935546C (en) * | 1951-07-11 | 1955-11-24 | Geigy Ag J R | Process for the preparation of N-acyl derivatives of iminodibenzyl |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2700091A1 (en) * | 1976-01-05 | 1977-07-14 | Searle & Co | 1- (SUBSTITUTE AMINO) ALKANOYL-2- (DIBENZOXAZEPINE-10-CARBONYL) -HYDRAZINE AND THEIR DERIVATIVES |
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