CS268487B1 - Method of 4,5-dihydroimidazole derivative and its maleate preparation - Google Patents
Method of 4,5-dihydroimidazole derivative and its maleate preparation Download PDFInfo
- Publication number
- CS268487B1 CS268487B1 CS887632A CS763288A CS268487B1 CS 268487 B1 CS268487 B1 CS 268487B1 CS 887632 A CS887632 A CS 887632A CS 763288 A CS763288 A CS 763288A CS 268487 B1 CS268487 B1 CS 268487B1
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- maleate
- biphenylyloxy
- preparation
- dihydroimidazole
- substance
- Prior art date
Links
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 title claims abstract description 9
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 title claims abstract description 5
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical class C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 title claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims abstract description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims abstract description 5
- FWWOWPGPERBCNJ-UHFFFAOYSA-N 2-hydroxy-4-(2-hydroxyethoxy)-4-oxobutanoic acid Chemical compound OCCOC(=O)CC(O)C(O)=O FWWOWPGPERBCNJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- KDFRZOHGRSVOKN-UHFFFAOYSA-N 4-(2-phenylphenoxy)butanenitrile Chemical compound N#CCCCOC1=CC=CC=C1C1=CC=CC=C1 KDFRZOHGRSVOKN-UHFFFAOYSA-N 0.000 claims description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 239000011976 maleic acid Substances 0.000 claims description 3
- 238000006386 neutralization reaction Methods 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- PJZVKROJSJCOQU-UHFFFAOYSA-N 2-[3-(2-phenylphenoxy)propyl]-4,5-dihydro-1h-imidazole Chemical compound N=1CCNC=1CCCOC1=CC=CC=C1C1=CC=CC=C1 PJZVKROJSJCOQU-UHFFFAOYSA-N 0.000 abstract description 2
- BLGXFZZNTVWLAY-CCZXDCJGSA-N Yohimbine Natural products C1=CC=C2C(CCN3C[C@@H]4CC[C@@H](O)[C@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-CCZXDCJGSA-N 0.000 abstract description 2
- 230000000845 anti-microbial effect Effects 0.000 abstract description 2
- BLGXFZZNTVWLAY-UHFFFAOYSA-N beta-Yohimbin Natural products C1=CC=C2C(CCN3CC4CCC(O)C(C4CC33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-UHFFFAOYSA-N 0.000 abstract description 2
- 238000013016 damping Methods 0.000 abstract description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- BLGXFZZNTVWLAY-SCYLSFHTSA-N yohimbine Chemical compound C1=CC=C2C(CCN3C[C@@H]4CC[C@H](O)[C@@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-SCYLSFHTSA-N 0.000 abstract description 2
- 229960000317 yohimbine Drugs 0.000 abstract description 2
- AADVZSXPNRLYLV-UHFFFAOYSA-N yohimbine carboxylic acid Natural products C1=CC=C2C(CCN3CC4CCC(C(C4CC33)C(O)=O)O)=C3NC2=C1 AADVZSXPNRLYLV-UHFFFAOYSA-N 0.000 abstract description 2
- 239000002253 acid Substances 0.000 abstract 2
- 239000004599 antimicrobial Substances 0.000 abstract 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- YRULSMJTKCEWAX-UHFFFAOYSA-N 1-(3-bromopropoxy)-2-phenylbenzene Chemical group BrCCCOC1=CC=CC=C1C1=CC=CC=C1 YRULSMJTKCEWAX-UHFFFAOYSA-N 0.000 description 1
- -1 2-biphenyloxy Chemical group 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000588767 Proteus vulgaris Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 231100000460 acute oral toxicity Toxicity 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000001977 ataxic effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- KJOPBRFBPVOFSV-UHFFFAOYSA-N ethyl 4-(2-phenylphenoxy)butanimidate Chemical compound CCOC(=N)CCCOC1=CC=CC=C1C1=CC=CC=C1 KJOPBRFBPVOFSV-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940007042 proteus vulgaris Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Řešeni spadá do oboru synthesy té- - čiv. Jeho předmětem je způsob přípravy 2-/3-/2-bifenylyloxy/propyl/-4,5-dihydroimidazolu /1/ a jeho maleinátu. Látka I je meziproduktem synthesy farnakodynamicky účinných látek a její maleinát vykazuje mirnou centrálně tlumivou účinnost, mírně potencuje jedovatost yohimbinu a má. mírnou anti mikrobiálni účinnost. Způsob přípravy látky I podle řešeni spočívá v dvoustupňové synthese z 4-/2-bifenytyloxy/butyronitritu, který se reakci s ethanolen a chlorovodíkem převede na hydrochlorid /ethyl/4-/2-bifenylyloxy/butyrimidátu, který reakci s ethylendiaminem poskytuje žádanou látku I. Jeji neutralisac1 kyselinou malelnovou se získá krystalický hydrogenmaleinát.The solution falls within the field of čiv. His subject is a method of preparation 2- [3- (2-Biphenylyloxy) propyl] -4,5-dihydroimidazole And its maleate. Substance I is an intermediate of farnakodynamic synthesis and the maleate thereof mild central damping efficiency it slightly potentiates the toxicity of yohimbine and has. mild anti-microbial efficacy. Way the preparation of the substance I according to the solution consists in two-stage synthesis from 4- (2-biphenytyloxy) butyronitrile, which is reacted with ethanolene and converted to the hydrochloride with hydrogen chloride (ethyl) 4- (2-biphenylyloxy) butyrimidate, which reacts with ethylenediamine provides the desired compound I. Its neutralization1 malelic acid gives a crystalline acid hydrogen maleate.
Description
Vynález se týká způsobu přípravy 4,5-dihydroimidazolového derivátu vzorce I o/ch2/3 The invention relates to a process for preparing 4,5-dihydroimidazolového derivative of the formula I O / CH 2/3
H /1/ a jeho maleinátu.H / 1 / and its maleate.
Látka vzorce I, tj. 2-/3-/2-bi feny lytoxy/propyl/-4,5-dihydro 1 mldazol, je meziproduktem synthesy farmakodynamicky účinných látek. Ve formě svého maleinátu vykazuje sama o sobě některé použitelné biologické účinky. Její akutní toxicita u myši při orálním podáni je 187 mg/kg. V testu rotujici tyčky u myši má ataxický účinek vycházející zřejmě z jejího mírného centrálně tlumivého působení; ΕΡ^θ i* 50 mg/kg p.o. Mírně potencuje jedovatost yohimbinu u myši; orální dávka 50 mg/kg je účinná u 20 % zvířat. Má mírnou anti mikrobiálni účinnost v testech in vitro vůči kokům. Pseudomonas aeruginosa, Escherichia colí a Proteus vulgaris.The compound of formula I, i.e. 2- [3- (2-biphenyloxy) propyl] -4,5-dihydro-1-billionazole, is an intermediate in the synthesis of pharmacodynamically active substances. In the form of its maleate, it itself has some useful biological effects. Its acute oral toxicity in mice is 187 mg / kg. In the rotating rod test in mice, it has an ataxic effect apparently based on its mild central damping effect; ΕΡ ^ θ i * 50 mg / kg p.o. Slightly potentiates the toxicity of yohimbine in mice; an oral dose of 50 mg / kg is effective in 20% of animals. It has mild anti-microbial activity in in vitro tests against cocci. Pseudomonas aeruginosa, Escherichia coli and Proteus vulgaris.
Látka vzorce I se připraví podle vynálezu dvoustupňovým postupem z 4-/2-bifenylyloxy/butyronitrilu. Tento nitril se v prvním stupni reakci s chlorovodíkem a ethanolem v etheru a chloroformu převede na hydrochlorid /ethyl/4-/2-bifenylyloxy/-butyrimidátu, který ve druhém stupni reakci s ethylendiaminem v ethanolu poskytne žádanou látku vzorce I. Tato se získá jako krystalická báze, která neutralizací kyselinou maleinovou poskytne krystalický hydrogenmaleinát. Výchozí 4-/2-bifenylyloxy/butyronitril je látkou nivou a jeho příprava je v přikladu popsána. Všechny látky zde popsané jsou nové a jejich identita byla zajištěna analytickými a spektrálními metodami. Přiklad je pouze ilustraci možností vynálezu a neni jeho úkolem uvádět všechny možnosti.The compound of formula I is prepared according to the invention in a two-step process from 4- (2-biphenylyloxy) butyronitrile. This nitrile is converted in the first step by reaction with hydrogen chloride and ethanol in ether and chloroform to the hydrochloride of (ethyl) 4- (2-biphenylyloxy) -butyrimidate, which in the second step in reaction with ethylenediamine in ethanol gives the desired compound of formula I. This is obtained as a crystalline base which, upon neutralization with maleic acid, gives a crystalline hydrogen maleate. The starting 4- (2-biphenylyloxy) butyronitrile is a blue substance and its preparation is described in the example. All substances described here are new and their identity has been ensured by analytical and spectral methods. The example is only an illustration of the possibilities of the invention and is not intended to list all possibilities.
PřikladExample
K roztoku 4,7 g 4-/2-bifenylyloxy/butyronitrilu ve směsi 30 ml etheru a 20 ml chloroformu se přidá 1,5 ml ethanolu a směs se nasytí chlorovodíkem /příbytek na váze 2,3 g/. Ponechá se v klidu přes noc při 0 °C, zředí se etherem a vyloučený krystalický hydrochlorid /ethyl/4-/2-bifenylyloxy/butyrimidátu /5,9 g, 94 %/ se isoluje filtraci.To a solution of 4.7 g of 4- (2-biphenylyloxy) butyronitrile in a mixture of 30 ml of ether and 20 ml of chloroform was added 1.5 ml of ethanol, and the mixture was saturated with hydrogen chloride (weight 2.3 g). It is left to stand overnight at 0 DEG C., diluted with ether and the precipitated crystalline hydrochloride (ethyl) 4- (2-biphenylyloxy) butyrimidate (5.9 g, 94%) is isolated by filtration.
Směs 14,3 g předešlého hydrochloridu, 4,5 g ethylendiaminu a 15 ml ethanolu se udí— zuje po dobu 30 h při teplotě 65 až 70 °C. Rozpouštědlo se potom odpaří ve vakuu, zbytek se rozloží vodným amoniakem a base se isoluje extrakci směsi etheru a benzenu. Zpracováním extraktu se získá 10,1 g /98 %/ žádaného 2-/3-/2-bifenylyloxy/propyl/-4,5-dihydroimidazolu /1/. Tato base krystalizuje z acetonu a taje pří 99 až 101 °C. Neutralizací kyselinou maleinovou ve směsi acetonu a etheru se ziská krystalický hydrogenmaleinát tající při 81 až 84 °C.A mixture of 14.3 g of the preceding hydrochloride, 4.5 g of ethylenediamine and 15 ml of ethanol is fed for 30 hours at 65-70 ° C. The solvent was then evaporated in vacuo, the residue quenched with aqueous ammonia and the base isolated by extraction with a mixture of ether and benzene. Work-up of the extract gave 10.1 g (98%) of the desired 2- (3- (2-biphenylyloxy) propyl) -4,5-dihydroimidazole (1). This base crystallizes from acetone and melts at 99-101 ° C. Neutralization with maleic acid in a mixture of acetone and ether gives crystalline hydrogen maleate melting at 81-84 ° C.
Použitý výchozi 4-/2-bifenylyloxy/butyronitrii se připraví takto: K míchanému roztoku 2,2 g kyanidu sodného ve 20 ml dimethylsulfoxidu se při 55 až 60 °C během 10 min přidá 11,6 g 2-/3-brompropoxy/bifenylu /Wilbur J. M., Jr., J. Med. Chem. 21, 1168 /1978/7. Směs se mfchá 45 min při 75 až 80 °C, po ochlazeni se zředí 100 ml vody a extrahuje se benzenem. Extrakt se promyje 6M HCl a vodou, vysuší se síranem hořečnatým a odpaří za sníženého tlaku. Zbytek se předestiluje ve vakuu. Ziská se 7,8 g /83 %/ žádaného nitrilu vroucího při 210 až 212 °C/2,1kPa. Zcela čistá látka se ziská chroniatografii vzorku na silikagelu a .ředestitací; t.v. 174 °C/1,9 kpa.The starting 4- (2-biphenylyloxy) butyronitrile used is prepared as follows: To a stirred solution of 2.2 g of sodium cyanide in 20 ml of dimethyl sulfoxide at 55-60 ° C is added 11.6 g of 2- (3-bromopropoxy) biphenyl over 10 minutes. / Wilbur JM, Jr., J. Med. Chem. 21, 1168 (1978) 7. The mixture is stirred at 75 DEG-80 DEG C. for 45 minutes,, after cooling, diluted with 100 ml of water and extracted with benzene. The extract was washed with 6M HCl and water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is distilled in vacuo. 7.8 g (83%) of the desired nitrile boiling at 210 DEG-212 DEG C. (2.1 kPa) are obtained. Completely pure material is obtained by chroniatography of the sample on silica gel and distillation; t.v. 174 ° C / 1.9 kpa.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS887632A CS268487B1 (en) | 1988-11-21 | 1988-11-21 | Method of 4,5-dihydroimidazole derivative and its maleate preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS887632A CS268487B1 (en) | 1988-11-21 | 1988-11-21 | Method of 4,5-dihydroimidazole derivative and its maleate preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS763288A1 CS763288A1 (en) | 1989-08-14 |
| CS268487B1 true CS268487B1 (en) | 1990-03-14 |
Family
ID=5425822
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS887632A CS268487B1 (en) | 1988-11-21 | 1988-11-21 | Method of 4,5-dihydroimidazole derivative and its maleate preparation |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS268487B1 (en) |
-
1988
- 1988-11-21 CS CS887632A patent/CS268487B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CS763288A1 (en) | 1989-08-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Mennicke et al. | Metabolism of some naturally occurring isothiocyanates in the rat | |
| JPS63150237A (en) | Catechol derivative | |
| NO128869B (en) | ||
| McKay et al. | Amino Acids. II. Synthesis of Cyclic Guanidino Acids1 | |
| US3445518A (en) | P-acylphenylethylamines | |
| KR900006127B1 (en) | Method for preparing aminoalkadiene derivative | |
| HU195486B (en) | Process for preparing new pyridine derivatives | |
| US4008232A (en) | 3-Amino-5,6-diaryl-1,2,4-triazines | |
| SU1169538A3 (en) | Method of obtaining tricyclic compounds | |
| O'BRIEN et al. | Amino derivatives of Kojic acid | |
| JPS6168473A (en) | Benzimidazole derivative | |
| CS268487B1 (en) | Method of 4,5-dihydroimidazole derivative and its maleate preparation | |
| EP0079810B1 (en) | Derivatives of 4-phenyl-quinazoline active on the central nervous system | |
| US3979516A (en) | Anti-inflammatory 3-amino-5,6-diaryl-1,2,4-triazines | |
| Mathis et al. | Synthesis of high specific activity 125I‐and 123I‐labelled enantiomers of 2, 5‐dimethoxy‐4‐iodophenylisopropylamine (DOI) | |
| Kelly et al. | 2-Cyanomethyl-1, 1, 3, 3-tetracyanopropene, a Self-Condensation Product of Malononitrile | |
| AU651608B2 (en) | Substituted naphthoxazines useful as dopaminergics | |
| Hunter et al. | The A New Sympatholytic Agent | |
| Naveen et al. | Green Synthesis, Biological Evaluation of Newer Benzothiazole Derivatives | |
| Cohen et al. | Analgesic activity of novel spiro heterocycles. 2-Amino-7-oxa-3-thia-1-azaspiro [5.5] undec-1-enes and related compounds | |
| Walter | 4, 4', 4 ″-Trinitrotriphenylamine1 | |
| Wolinsky et al. | The reaction of 3-propylindole with aldehydes preparation of 2-(α-aminoalkyl) indoles | |
| KR820001082B1 (en) | Process for preparing moranoline derivatives | |
| RU911881C (en) | N-(p-sulfamoylphenyl)-n-(2-oxyethyl)succinamide possessing antinelammatory activity | |
| KR820001081B1 (en) | Process for preparing moranoline derivatives |