CS223447B1 - Method of preparation of the new 2-/s-hydrindacen-4-ylamino/-2,imidazoline - Google Patents
Method of preparation of the new 2-/s-hydrindacen-4-ylamino/-2,imidazoline Download PDFInfo
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- CS223447B1 CS223447B1 CS255782A CS255782A CS223447B1 CS 223447 B1 CS223447 B1 CS 223447B1 CS 255782 A CS255782 A CS 255782A CS 255782 A CS255782 A CS 255782A CS 223447 B1 CS223447 B1 CS 223447B1
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- CS
- Czechoslovakia
- Prior art keywords
- hydrindacen
- ylamino
- imidazoline
- preparation
- formula
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 4
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 title 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 5
- 238000009835 boiling Methods 0.000 claims description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 2
- CPEKAXYCDKETEN-UHFFFAOYSA-N benzoyl isothiocyanate Chemical compound S=C=NC(=O)C1=CC=CC=C1 CPEKAXYCDKETEN-UHFFFAOYSA-N 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- SOIFLUNRINLCBN-UHFFFAOYSA-N ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 208000001953 Hypotension Diseases 0.000 description 1
- 230000002908 adrenolytic effect Effects 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000005792 cardiovascular activity Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000007360 debenzoylation reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Vynález se týká způsobu přípravy nového 2- (s-hydrindacen-4-ylamino) -2-imidazolinu vzorce IThe invention relates to a process for the preparation of the novel 2- (s-hydrindacen-4-ylamino) -2-imidazoline of formula I
2=2 =
Látka vzorce I je meziproduktem výroby léčiv, speciálně léčiv s kardiovaskulární účinností (hypotenzívní, adrenolytickou).The compound of formula I is an intermediate in the manufacture of medicaments, especially medicaments with cardiovascular activity (hypotensive, adrenolytic).
Podstatou způsobu přípravy nového 2-(s-hydrindacen-4-ylam-ino)-2-imidazolinu podle tohoto- vynálezu je převedení známéhoThe process for the preparation of the novel 2- (s-hydrindacen-4-ylamino) -2-imidazoline according to the invention is based on the conversion of the known
4-amino-s-hydrindacenu (Z. J. Vejdělek, M. Bartošová, M. Protiva, Collect. Czech. Chem. Commun. 42, 1992, 1977) přes tři meziprodukty (látky vzorců II, III a IV), z nichž první dva lze izolovat v čistém stavu a třetí není nutné izolovat.4-amino-s-hydrindacene (ZJ Vejdelek, M. Bartosova, M. Protiva, Collect. Czech. Chem. Commun. 42, 1992, 1977) via three intermediates (compounds of formulas II, III and IV), the first two can be insulated in a clean state and the third does not need to be insulated.
Při postupu podle vynálezu se nejprve provede reakce jmenovaného 4-amlno-s-hydrindacenu s benzoylisothiokyanátem, připraveným „in sítu“ reakcí amoniumthiokyanátu s benzoylchloridem v acetonu (R. L. Frank, Ρ. V. Smith, Org. Syn., Coll. Vol. 3, 735, 1955), kterou vzniká l-benzoyl-3-(s-hydrindacen-4-yl)thiomočovina vzorce II. V druhém stupni se látka vzorce II podrobí debenzoylaci mírnou alkalickou hydrolýzou (krátkodobý var s 10% roztokem hydroxidu sodného), přičemž se získá N-(s-hydrindacen-4-yl)thiomočovina vzorce III. Na tuto se působí methyljodidem v methanolu, přičemž vznikne isothiuroniová sůl vzorce IV, která se neizoluje a v surovém stavu se podrobí zahřívání s přebytečným ethylendiamlnem. Přitom se získá žádaná látka vzorce I jako solvát s nestechiometrickým množstvím benzenu, jejíž identita byla zajištěna pomocí spekter.In the process according to the invention, the 4-amino-s-hydrindacene is first reacted with benzoyl isothiocyanate prepared in situ by reacting the ammonium thiocyanate with benzoyl chloride in acetone (RL Frank, V. Smith, Org. Syn., Coll. Vol. 3). , 735, 1955) to give 1-benzoyl-3- (s-hydrindacen-4-yl) thiourea of formula II. In the second step, the compound of formula II is subjected to debenzoylation by mild alkaline hydrolysis (short boiling with 10% sodium hydroxide solution) to give N- (s-hydrindacen-4-yl) thiourea of formula III. This is treated with methyl iodide in methanol to give the isothiuronium salt of formula IV, which is not isolated and is subjected to heating with excess ethylenediamine in the crude state. In this case, the desired compound of the formula I is obtained as a solvate with a non-stoichiometric amount of benzene, the identity of which is ensured by means of spectra.
Meziprodukty vzorců II a III jsou krystalické látky s charakteristickými teplotami tání. Všechny nové látky ve vynálezu popisované (meziprodukty vzorců II a III a konečný produkt vzorce I) byly po stránce identity zajištěny pomocí analýz a všech běžných spekter.The intermediates of formulas II and III are crystalline substances with characteristic melting points. All novel substances described in the invention (intermediates of formulas II and III and the final product of formula I) were assured in terms of identity by means of analyzes and all conventional spectra.
PříkladExample
K míchanému roztoku 6,0 g amoniumthiokyanátu v 25 ml acetonu se během 15 min. přikape 9,4 g benzoylchloridu. Směs se vaří 5 min. pod zpětným chladičem, potom se zahřívání přeruší a pomalu se přidá teplý roztok 11,5 g 4-amino-s-hydrindacenu v 35 ml acetonu; protože je reakce exotermní, reakční směs setrvává v mírném varu pod zpětným chladičem. Směs se potom míchá ještě 10 min. a nalije se do 500 ml studené vody. Po 1 hodině stání se vyloučené žluté krystaly odfiltrují, promyjí se vodou a vysuší ve vakuu. Ve výtěžku 20,0 g (90 %) se získá surová l-benzoyl-3-(s-hydrindacen-4-yljthiomočovina (II) tající při 177 až 179 °C. Krystalizací z ethanolu se získá analytický produkt tající při 194 až 195 °C.To a stirred solution of 6.0 g of ammonium thiocyanate in 25 ml of acetone was added within 15 min. 9.4 g of benzoyl chloride are added dropwise. The mixture is boiled for 5 min. at reflux, then stop heating and slowly add a warm solution of 11.5 g of 4-amino-s-hydrindacene in 35 ml of acetone; since the reaction is exothermic, the reaction mixture remains at a gentle reflux. The mixture was then stirred for a further 10 min. and pour into 500 ml of cold water. After 1 hour of standing, the precipitated yellow crystals are filtered off, washed with water and dried in vacuo. Yield: 20.0 g (90%) of crude 1-benzoyl-3- (s-hydrindacen-4-yl) -thiourea (II) melting at 177-179 ° C. Deň: 32 ° C.
Směs 14,6 g předešlého produktu (II) a 150 ml 10% roztoku hydroxidu sodného se míchá a vaří 20 min. pod zpětným chladičem. Po ochlazení se vyloučený produkt zfiltruje, promyje se vodou a vysuší ve vakuu. Získá se 13,2 g (96 %) surové N-(s-hydrindacen-4-yl)thiomočoviny (III) tající při 205 až 208 °C. Krystalizací z ethanolu se získá analyticky čistý produkt tající při 229 až 230 °C.A mixture of 14.6 g of the preceding product (II) and 150 ml of 10% sodium hydroxide solution is stirred and boiled for 20 min. under reflux. After cooling, the precipitated product is filtered, washed with water and dried in vacuo. 13.2 g (96%) of crude N- (s-hydrindacen-4-yl) thiourea (III) are obtained, melting at 205-208 ° C. Crystallization from ethanol gave an analytically pure product, melting at 229-230 ° C.
Směs 13,0 g předešlé látky III, 6,5 ml methyljodidu a 200 ml methanolu se vaří 3 hodiny pod zpětným chladičem, čímž vznikne čirý roztok. Odpaří se za sníženého tlaku při teplotě 70 °C do sucha a amorfní zbytek (20,7 g, 99 %) představuje surovou isothiuroniovou sůl vzorce IV. Přidá se 6,5 ml bezvodého ethylendiaminu a směs se zahřívá 1 hodinu pod zpětným chladičem v lázní na 135 až 145 °C. Po ochlazení se směs zředí roztokem 45 ml kyseliny octové ve 230 ml vody a získaná suspenze se zalkalizuje 20% roztokem hydroxidu sodného. Vyloučená pevná látka se zfiltruje, promyje vodou a extrahuje etherem. Nerozpuštěná hmota se odhodí a extrakt se odpaří. Zbytek se krystaluje ze směsi hexanu, benzenu a ethanolu; získá se 3,8 g látky tající při 89 až 90 CC, která je výchozím 4-amino-s-hydrindacenem (citovaná literatura pro něj uvádí t. t. 87 až 88 °C). Matečný louh se chromatografuje na sloupci 400 g neutrálního kysličníku hlinitého (aktivita II). Chloroformem s 5 % ethanolu se nejdříve eluuje 2,1 g dalšího 4-amino-s-hydrindacenu (t. t. 87 až 90 °C). Elucí chloroformem s 15 % ethanolu se potom získá další substance, která krystaluje ze směsi etheru a hexanu a potom z benzenu, t. t. 210 až 211 °Celsla. Podle analýzy, hmotnostního spektra, infračerveného spektra a XH NMR spektra jde o žádaný 2-(s-hydrindacen-4-ylamino)-2-imidazolin vzorce I, solvatovaný 1/3 molekuly benzenu.A mixture of 13.0 g of the preceding compound III, 6.5 ml of methyl iodide and 200 ml of methanol was heated under reflux for 3 hours to give a clear solution. Evaporate to dryness under reduced pressure at 70 ° C and the amorphous residue (20.7 g, 99%) is the crude isothiuronium salt of formula IV. Anhydrous ethylenediamine (6.5 ml) was added and the mixture was refluxed in a bath at 135-145 ° C for 1 hour. After cooling, the mixture is diluted with a solution of 45 ml of acetic acid in 230 ml of water and the suspension obtained is made alkaline with 20% sodium hydroxide solution. The precipitated solid was filtered, washed with water and extracted with ether. The undissolved matter is discarded and the extract is evaporated. The residue was crystallized from a mixture of hexane, benzene and ethanol; 3.8 g of compound melting at 89-90 [ deg.] C., starting from 4-amino-s-hydrindacene (cited in the literature, mp 87-88 [deg.] C.), were obtained. The mother liquor is chromatographed on a column of 400 g of neutral alumina (activity II). Chloroform with 5% ethanol first eluted 2.1 g of additional 4-amino-s-hydrindacene (mp 87-90 ° C). Elution with chloroform with 15% ethanol gave an additional substance which crystallized from ether / hexane and then benzene, mp 210-211 ° C. According to the analysis, mass spectra, infrared spectra and X H NMR spectra in terms of the desired 2- (S-hydrindacen-4-ylamino) -2-imidazoline of formula I, 03.01 solvated molecules of benzene.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS255782A CS223447B1 (en) | 1982-04-09 | 1982-04-09 | Method of preparation of the new 2-/s-hydrindacen-4-ylamino/-2,imidazoline |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS255782A CS223447B1 (en) | 1982-04-09 | 1982-04-09 | Method of preparation of the new 2-/s-hydrindacen-4-ylamino/-2,imidazoline |
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| Publication Number | Publication Date |
|---|---|
| CS223447B1 true CS223447B1 (en) | 1983-10-28 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS255782A CS223447B1 (en) | 1982-04-09 | 1982-04-09 | Method of preparation of the new 2-/s-hydrindacen-4-ylamino/-2,imidazoline |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS223447B1 (en) |
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1982
- 1982-04-09 CS CS255782A patent/CS223447B1/en unknown
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