NL8201208A - NEW PROCESS FOR THE PREPARATION OF IMIDAZOBENZODIAZEPINES AND THEIR SALTS. - Google Patents
NEW PROCESS FOR THE PREPARATION OF IMIDAZOBENZODIAZEPINES AND THEIR SALTS. Download PDFInfo
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- NL8201208A NL8201208A NL8201208A NL8201208A NL8201208A NL 8201208 A NL8201208 A NL 8201208A NL 8201208 A NL8201208 A NL 8201208A NL 8201208 A NL8201208 A NL 8201208A NL 8201208 A NL8201208 A NL 8201208A
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- methylene chloride
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- 150000003839 salts Chemical class 0.000 title claims description 12
- 238000000034 method Methods 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- -1 phenylpiperazin-1-yl Chemical group 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 150000007522 mineralic acids Chemical class 0.000 claims description 5
- 150000007524 organic acids Chemical class 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 235000005985 organic acids Nutrition 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 8
- 239000000047 product Substances 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229940049706 benzodiazepine Drugs 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 2
- VFTOHJFKIJLYKN-UHFFFAOYSA-N 7-nitro-9h-fluoren-2-ol Chemical group [O-][N+](=O)C1=CC=C2C3=CC=C(O)C=C3CC2=C1 VFTOHJFKIJLYKN-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- KLNFAMGHSZQYHR-UHFFFAOYSA-N imidazo[4,5-i][1,2]benzodiazepine Chemical class C1=CC=NN=C2C3=NC=NC3=CC=C21 KLNFAMGHSZQYHR-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- XTKDAFGWCDAMPY-UHFFFAOYSA-N azaperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCN(C=2N=CC=CC=2)CC1 XTKDAFGWCDAMPY-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical class OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
_____________________________________ .· ....... ...... ... *·.._ t' _ -* .823015/Ar/th_____________________________________. · ....... ...... ... * · .._ t '_ - * .823015 / Ar / th
Korte aanduiding: Nieuwe werkwijze voor de bereiding van imidazoben- zodiazepinen en hun zouten.Short designation: Novel process for the preparation of imidazobenzodiazepines and their salts.
De uitvinding heeft betrekking op een nieuwe werkwijze voor de bereiding van imidazobenzodiazepinen en hun additiezouten met zuren.The invention relates to a new process for the preparation of imidazobenzodiazepines and their addition salts with acids.
De uitvinding heeft meer in het bijzonder betrekking op een nieuwe werkwijze voor de bereiding van de verbindingen met de alge-5 mene formule 1 van het formuleblad, waarin fi^ een waterstofatoom, een halogeenatoom, een nitrogroep of een trifluormethylgroep en R^ een waterstofatoom of een halogeenatoom voorstelt, en Rj en B^ te zamen met het stikstofatoom, waaraan zij gebonden zijn, een 4-alkyl-pipera-zin-1-yl-, Vcycloalkyl-alkylpiperazin-1-yl-, 4-fenylpiperazin-1-yl-10 of piperidinogroep vormen, en hun additiezouten met anorganische of organische zuren.The invention more particularly relates to a new process for the preparation of the compounds of the general formula 1 of the formula sheet, wherein fi ^ a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group and R1 a hydrogen atom or a halogen atom, and R 1 and B 4 together with the nitrogen atom to which they are attached, a 4-alkyl-pipera-1-yl-, V-cycloalkyl-alkyl-piperazin-1-yl-, 4-phenyl-piperazin-1-yl -10 or piperidino group, and their addition salts with inorganic or organic acids.
Wanneer in formule 1 en het hierna volgende B.^ een halogeenatoom voorstelt, is dit bij voorkeur een fluor-, chloor- of broomatoom en in het bijzonder een chlooratoom, wanneer Bg een halogeenatoom voor-15 stelt, is dit bij voorkeur een fluor-, chloor- of broomatoom en in het bijzonder een fluor- of chlooratoom, terwijl bovendien, wanneer Β^ een halogeenatoom is, dit zich bij voorkeur op de ortho-plaats bevindt, wanneer B^ en B^ te zamen met het stikstofatoom, waaraan zij gebonden zijn, een 4-alkylpiperazin-1-ylgroep vormen, is dit bij voor-20 keur een 4-methylpiperazin-1-yl 4-ethyl-piperazin-1-yl- of 4-propyl-piperazin-1-ylgroep en in het bijzonder de ^-methylpiperazin-1-yl-groep, wanneer B^ en B^ te zamen met het stikstofatoom, waaraan zij gebonden zijn, een ^-cycloalkyl-alkylpiperazin-l-ylgroep vormen, is dit bij voorkeur een cycloalkylgroep met 3-6 koolstofatomen zoals 25 de cyclopropyl-, cyclobutyl- of cyclopentylgroep. Van de 4-cycloalkyl-alkylpiperazin-1-ylgroepen kan in het bijzonder de 4-cyclopropylmethyl-piperazin-1-ylgroep genoemd worden.When in formula 1 and the following B. ^ represents a halogen atom, this is preferably a fluorine, chlorine or bromine atom and in particular a chlorine atom, when Bg represents a halogen atom, it is preferably a fluorine atom , chlorine or bromine atom and in particular a fluorine or chlorine atom, while moreover, when Β ^ is a halogen atom, it is preferably in the ortho position, when B ^ and B ^ together with the nitrogen atom to which they bonded, form a 4-alkylpiperazin-1-yl group, this is preferably a 4-methylpiperazin-1-yl 4-ethyl-piperazin-1-yl or 4-propyl-piperazin-1-yl group and in especially the 1-methylpiperazin-1-yl group, when B 1 and B 2 together with the nitrogen atom to which they are bonded form a 1-cycloalkyl-alkylpiperazin-1-yl group, this is preferably a 3-cycloalkyl group -6 carbon atoms such as the cyclopropyl, cyclobutyl or cyclopentyl group. Of the 4-cycloalkyl-alkylpiperazin-1-yl groups, the 4-cyclopropylmethyl-piperazin-1-yl group may be mentioned in particular.
De additiezouten met anorganische of organische zuren kunnen bij voorbeeld de zouten met zoutzuur, broorawaterstofzuur, ioodwaterstof-30 zuur, salpeterzuur, zwavelzuur, fosforzuur, propionzuur, azijnzuur, mierezuur, benzoezuur, maleinezuur, fumarzuur, barnsteenzuur, wijnsteenzuur, citroenzuur, oxaalzuur, glyoxylzuur, asparaginezuur, alkaansulfonzuren zoals methaansulfonzuur en arylsufonzuren zoals benzeensulfonzuur zijn.The addition salts with inorganic or organic acids can include, for example, the salts with hydrochloric, hydrochloric, hydrochloric, acid, nitric, sulfuric, phosphoric, propionic, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic acids aspartic acid, alkane sulfonic acids such as methanesulfonic acid and aryl sulfonic acids such as benzenesulfonic acid.
35 De produkten met de algemene formule 1 en hun zouten alsmede een werkwijze voor de bereiding daarvoor zijn beschreven in het Franse 8201208 * Λ '9 - 2 - octrooischrift no. 2300 569 ten name van aanvraagster· Zoals vermeld is in dit octrooischrift, bezitten de produkt cabinet de algemene formule 1 belangwekkende sedatieve, hypnotische, anxiolytische, tranquil-liserende, krampwerende en myorelaxerende eigenschappen.The products of the general formula I and their salts as well as a process for the preparation thereof are described in French 8201208 * 9-2 - Patent No. 2300 569 in the name of the applicant. As stated in this patent, the product cabinet the general formula 1 interesting sedative, hypnotic, anxiolytic, tranquilizing, antispasmodic and myorelaxing properties.
5 De nieuwe werkwijze volgens de uitvinding maakt het mogelijk om de produkten met formule 1 te bereiden met goede opbrengsten in een geringer aantal trappen dan bij de in het eerder genoemde Franse octrooischrift beschreven werkwijzen.The new process according to the invention makes it possible to prepare the products of formula 1 with good yields in a smaller number of steps than in the processes described in the aforementioned French patent.
De aanvrage heeft derhalve betrekking op een nieuwe werkwijze 10 voor de bereiding van verbindingen met de algemene formulé 1 en hun additiezouten met anorganische of organische zuren, die daardoor gekenmerkt is, dat men een verbinding met formule 2 van het formuleblad, waarin R^ en R^ de eerder genoemde betekenissen bezitten, laat reageren met een amine met de formule 3 van'het formuleblad, waarin 15 alc een alkylgroep met 1-3 koolstofatomen voorstelt en R^ en R^ de eerdergenoemde betekenissen bezitten, in een organisch oplosmiddel ter vorming van het gewenste produkt met formule 1, dat men eventueel om kan zetten in een zout. Onder voorkeursuitvoeringsomstandigheden van de werkwijze der uitvinding wordt de reactie van de verbinding 20 met formule 2 met de verbinding met formule 3 uitgevoerd in een organisch oplosmiddel zoals methyleenchloride en in aanwezigheid van een amine zoals triethylamine.The application therefore relates to a new process for the preparation of compounds of the general formula 1 and their addition salts with inorganic or organic acids, characterized in that a compound of formula 2 of the formula sheet, wherein R 1 and R Having the aforementioned meanings, react with an amine of the formula III of the formula sheet wherein 15 alc represents an alkyl group having 1 to 3 carbon atoms and R 1 and R 2 having the aforementioned meanings in an organic solvent to form the desired product of formula 1, which can optionally be converted into a salt. Under preferred operating conditions of the process of the invention, the reaction of the compound of formula 2 with the compound of formula 3 is carried out in an organic solvent such as methylene chloride and in the presence of an amine such as triethylamine.
De additiezouten van de verbindingen met formule 1 met zuren kunnen bereid worden door de verbindingen met formule 1 te laten reageren 23 met een stoechiometrische hoeveelheid van een anorganiech of organisch zuur. De reactie wordt bij voorkeur uitgevoerd in een organisch oplosmiddel of een mengsel van organische oplosmiddelen zoals alkanolen, bij voorbeeld methanol of ethanol, of alkylhalogeniden, bij voorbeeld methyleenchloride.The addition salts of the compounds of formula 1 with acids can be prepared by reacting the compounds of formula 1 with a stoichiometric amount of an inorganic or organic acid. The reaction is preferably carried out in an organic solvent or a mixture of organic solvents such as alkanols, for example methanol or ethanol, or alkyl halides, for example methylene chloride.
30 Zoals vermeld in het Franse octrooischrift 2.3ΟΟ.569 kunnen de verbindingen met formule 2 bereid wordea uit een verbinding met formule 4 van het formuleblad, waarin R^ en R^ de eerdergenoemde betekenissen bezitten, door reactie met glycine ter vorming van een verbinding met formule 5 van het formuleblad, waarin en R^ de eerder-35 genoemde betekenissen bezitten, die men dehydrateert ter vorming van de gewenste verbinding met formule 2.As disclosed in French Pat. No. 2,3ΟΟ,569, the compounds of formula II may be prepared from a compound of formula IV of the formula sheet wherein R 1 and R 2 have the aforementioned meanings by reaction with glycine to form a compound of formula 5 of the formula sheet, wherein and R 4 have the aforementioned meanings, which are dehydrated to form the desired compound of formula 2.
De dehydratatie kan met voordeel uitgevoerd worden met behulp van een carbodiimide zoals dicyclohexylcarbodiimide.Dehydration can advantageously be carried out using a carbodiimide such as dicyclohexylcarbodiimide.
8201208 - 3 -8201208 - 3 -
Wanneer de verbindingen met formule 3 niet bekend zijn, kunnen ze bereid worden door reactie .van een verbinding met formule 6 van bet formuleblad, waarin en R^ de eerdergenoemde betekenissen bezitten, met een alkylketaal van dimethylformamide. Een voorbeeld van 5 een dergelijke bereiding wordt in het experimentele gedeelte gegeven.When the compounds of formula III are not known, they can be prepared by reacting a compound of formula VI of the formula sheet, wherein and R1 have the aforementioned meanings, with an alkyl ketal of dimethylformamide. An example of such a preparation is given in the experimental part.
De uitvinding zal nu toegelicht worden door een niet beperkend voorbeeld.The invention will now be illustrated by a non-limiting example.
Voorbeeld: 8-nitro, 1,2-dihydro 2-(N-acthyl-piperazin-1-yl)fflethyleen 6-(o-chloorfenyl? 1H, 4H-imldazo /ï,2-a7/Ï,^7 benzodiazepin-1-on.Example: 8-nitro, 1,2-dihydro 2- (N-acthyl-piperazin-1-yl) -flethylene 6- (o-chlorophenyl? 1H, 4H-imldazo / 1,2-a7 /, 7-benzodiazepine 1-on.
10 Trag Aj: 2-carboxjmethjlamino-7-nitro_5“(o-chloorfenyl23H-/Ïj,^7; benzodiazegin.10 Trag Aj: 2-carboxymethylamino-7-nitro_5 "(o-chlorophenyl23H-] / 7, benzodiazin.
In drie liter gedemineraliseerd water brengt men 1,360 kg glycine en vervolgens geleidelijk 1,^50 kg natriumbicarbonaat. Men roert 30 minuten bij kamertemperatuur, voegt 15 liter ethanol toe en ver-15 volgens in ongeveer vijf minuten 3 kg 7-nitro, 1,3-dihydro-5-(o-chloorfenyl)-2H-/“l ,A7-henzodiazepin-2-thion. Men kookt een uur en 30 minuten onder terugvloeikoeling, destilleert onder verminderde druk, voegt in twee keer 15 liter gedemineraliseerd water toe en vervolgens 7,5 liter methyleenchloride én scheidt de fasen.1.360 kg of glycine and then 1.50 kg of sodium bicarbonate are gradually introduced into three liters of demineralized water. The mixture is stirred for 30 minutes at room temperature, 15 liters of ethanol are added, and then 3 kg of 7-nitro, 1,3-dihydro-5- (o-chlorophenyl) -2H- / 1, 7-henzodiazepin in about five minutes. -2-thion. It is refluxed for an hour and 30 minutes, distilled under reduced pressure, 15 liters of demineralized water are added in two times, then 7.5 liters of methylene chloride and the phases are separated.
20 Men extraheert de waterige fase met drie maal 6 liter methyleenchloride, wast de methyleenchloride-fasen met water en verzamelt de waterige fasen. Men voegt 18 liter methyleenchloride toe en vervolgns bij 0°, +5°C 1,3 liter zoutzuur van 22°Be. Men verkrijgt een oplossing van 2-carboxymethylamine 7-nitro 5-(o-chloorfenyl) 3H-/Ï,kj 25 benzodiazepine in methyleenchloride, die men in de volgende trap toepast.The aqueous phase is extracted with three times 6 liters of methylene chloride, the methylene chloride phases are washed with water and the aqueous phases are collected. 18 liters of methylene chloride are added, followed by 1.3 liters of hydrochloric acid at 22 ° C at + 5 ° C. A solution of 2-carboxymethylamine 7-nitro 5- (o-chlorophenyl) 3H- / l, benzodiazepine in methylene chloride is obtained, which is used in the next step.
Trag B: 8-nitro_1,2-dihydro^6-(o-chloorfenyl)lH,_^H-imidazo/Ï^2-a7 /1, ^^benzodiazegin^ 1-on.Trag B: 8-nitro-1,2-dihydro ^ 6- (o-chlorophenyl) 1H, ^ H-imidazo / 2-a7 / 1, ^ benzodiazin ^ 1-one.
Aan de in de voorafgaande trap verkregen oplossing van 2-carboxy 30 methylamino'7-nitro 5-(o-chloorfenyl) 3H-/Ï,^-benzodiazepine in methyleenchloride voegt men bij +5°C in ongeveer twee minuten een oplossing van 1,865 kg dicyclohexylcarbodiimide in drie liter methyleenchloride toe en roert vervolgens 30 minuten.To the solution of 2-carboxy methylamino-7-nitro 5- (o-chlorophenyl) 3H- / -, - benzodiazepine in methylene chloride obtained in the previous step, a solution of 1,865 is added in about two minutes at + 5 ° C. kg of dicyclohexylcarbodiimide in three liters of methylene chloride and then stir for 30 minutes.
Men laat een nacht staan en zuigt vervolgens af. Men wast twee 35 maal met drie liter methyleenchloride en wint de oplossing van 8-nitro 1,2-dihydro 6-(o-chloorfenyl) iH^fl-imidazo /ï,2-a7 /1,^7 benzodiazepin-1-on in methyleenchloride, die men in de volgende trap toepast.It is left overnight and then vacuumed. It is washed twice with three liters of methylene chloride and the solution of 8-nitro 1,2-dihydro 6- (o-chlorophenyl) 1H-fl-imidazo / 1,2-a7 / 1, 7-benzodiazepin-1-one is recovered in methylene chloride, which is used in the next step.
8201208 * v· .·· ?£2E-.£i.--r5ii£2-.l2^r-iè?-£2-.Jriiir22i-ïirPiE5£2zin”1,,‘ïl^metilyleen8201208 * v. ··? £ 2E-. £ i .-- r5ii £ 2-.l2 ^ r-iè? - £ 2-.Jriiir22i-ïirPiE5 £ 2zin "1 ,," l ^ metilylene
Aan de in de voorafgaande trap verkregen oplossing van 8-nitro 1,2-dihydro 6-(o-chloorfenyl) lH,4H-imidazo /^,2-5/ /1,47 benzodia-5 zepin-1-on in methyleenchloride voegt men in ongeveer 5 minuten en bij kamertemperatuur 650 gram triethylamine en vervolgens 2,4 kg van een oplossing van het dimethylketaal van N-formyl N-methylpipe-razine toe» waarvan de bereiding hierna is beschreven.To the solution of 8-nitro 1,2-dihydro 6- (o-chlorophenyl) 1H, 4H-imidazo / 2-5 / / 1.47 benzodia-5-zepin-1-one in methylene chloride obtained in the previous step 650 grams of triethylamine and then 2.4 kg of a dimethyl ketal solution of N-formyl N-methylpiperazine, the preparation of which is described below, are added in about 5 minutes and at room temperature.
Men roert 1 uur en 30 minuten, concentreert tot droog onder ver-10 minderde druk en voegt 6 liter ethanol toe. Men destilleert onder handhaving van een constant niveau door toevoeging van ethanol tot dampen bij 78° C worden verkregen, koelt vervolgens tot 0° + 2°C, roert 2 uur en zuigt af. Men wast met ethanol en wint 4,260 kg ruw produkt, dat men zuivert door behandeling met actieve kool en ver» 15 volgens met ethanol.It is stirred for 1 hour and 30 minutes, concentrated to dryness under reduced pressure and 6 liters of ethanol are added. Distillation is maintained while maintaining a constant level by adding ethanol until vapors are obtained at 78 ° C, then cooled to 0 ° + 2 ° C, stirred for 2 hours and filtered off. It is washed with ethanol and 4,260 kg of crude product is recovered, which is purified by treatment with activated carbon and then with ethanol.
Men verkrijgt ten slotte 3,362 kg 8-nitro 1,2-dihydro 2-(N-methyl piperazin-1-yl) methyleen 6-(o-chloorfenyl) 1H,4H-imidazo /1,2-a7 /1, 47 benzodiazepin-1-on.Finally, 3.362 kg of 8-nitro 1,2-dihydro 2- (N-methyl piperazin-1-yl) methylene 6- (o-chlorophenyl) 1H, 4H-imidazo / 1,2-a7 / 1,47 benzodiazepin are obtained -1-on.
Het verkregen produkt is identiek aan het in voorbeeld 30 van het 20 eerder genoemde Franse oct!*ooischrift beschreven produkt.The product obtained is identical to the product described in Example 30 of the aforementioned French Patent Specification.
De oplossing van het dimethylketaal van N-formyl N-methyl piperazine kan als volgt worden bereid:The dimethyl ketal solution of N-formyl N-methyl piperazine can be prepared as follows:
Men brengt in 2 kg van het dimethylketaal van dimethylformaoide 3,3 kg N-methyl piperazine en kookt 15 uur onder terugvloeikoeling.3.3 kg of N-methyl piperazine are added to 2 kg of the dimethyl ketal of dimethylformaoide and the mixture is refluxed for 15 hours.
25 Men destilleert het niet omgezette N-methylpiperazine onder verminderde druk af, roert 1 uur onder verminderde druk bij 115-120°C en koelt vervolgens tot 20°C. Men verkrijgt 3,920 kg van een bruine oplossing van het dimethylketaal van N-formyl N-methylpiperazine.The unreacted N-methylpiperazine is distilled off under reduced pressure, stirred under reduced pressure at 115-120 ° C for 1 hour and then cooled to 20 ° C. 3.920 kg of a brown solution of the dimethyl ketal of N-formyl N-methylpiperazine are obtained.
82012088201208
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8106171 | 1981-03-27 | ||
| FR8106171A FR2502621B1 (en) | 1981-03-27 | 1981-03-27 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NL8201208A true NL8201208A (en) | 1982-10-18 |
| NL193246B NL193246B (en) | 1998-12-01 |
| NL193246C NL193246C (en) | 1999-04-02 |
Family
ID=9256708
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NL8201208A NL193246C (en) | 1981-03-27 | 1982-03-23 | Process for the preparation of imazobenzodiazepines and their salts. |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS57169483A (en) |
| AU (1) | AU549222B2 (en) |
| CA (1) | CA1175823A (en) |
| CH (1) | CH651565A5 (en) |
| DE (1) | DE3211243A1 (en) |
| DK (1) | DK153404C (en) |
| ES (1) | ES509284A0 (en) |
| FI (1) | FI71152C (en) |
| FR (1) | FR2502621B1 (en) |
| GB (1) | GB2095674B (en) |
| HU (1) | HU185092B (en) |
| IT (1) | IT1147917B (en) |
| MA (1) | MA19416A1 (en) |
| NL (1) | NL193246C (en) |
| PT (1) | PT74669B (en) |
| SE (2) | SE8200271L (en) |
| ZA (1) | ZA821141B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3872090A (en) * | 1972-07-12 | 1975-03-18 | Boehringer Sohn Ingelheim | 3-(amino-methylene)-5-phenyl-1,4-benzodiazepin-2-ones |
| IL48888A (en) * | 1975-02-15 | 1979-03-12 | Roussel Uclaf | 2-aminomethylene-1,2-dihydro-6-phenyl-1h-imidazo(1,2-a)(1,4) benzodiazepin-1-ones, process for their preparation andpharmaceutical compositions incorporating them |
-
1981
- 1981-03-27 FR FR8106171A patent/FR2502621B1/fr not_active Expired
-
1982
- 1982-01-19 SE SE8200271D patent/SE8200271L/en not_active Application Discontinuation
- 1982-01-19 SE SE8200271A patent/SE448731B/en not_active IP Right Cessation
- 1982-02-03 ES ES509284A patent/ES509284A0/en active Granted
- 1982-02-22 ZA ZA821141A patent/ZA821141B/en unknown
- 1982-02-26 AU AU80947/82A patent/AU549222B2/en not_active Expired
- 1982-03-18 MA MA19621A patent/MA19416A1/en unknown
- 1982-03-19 IT IT48036/82A patent/IT1147917B/en active
- 1982-03-23 NL NL8201208A patent/NL193246C/en not_active IP Right Cessation
- 1982-03-24 JP JP57045728A patent/JPS57169483A/en active Pending
- 1982-03-25 FI FI821058A patent/FI71152C/en not_active IP Right Cessation
- 1982-03-26 DE DE19823211243 patent/DE3211243A1/en active Granted
- 1982-03-26 PT PT74669A patent/PT74669B/en unknown
- 1982-03-26 CA CA000399537A patent/CA1175823A/en not_active Expired
- 1982-03-26 CH CH1896/82A patent/CH651565A5/en not_active IP Right Cessation
- 1982-03-26 GB GB8208933A patent/GB2095674B/en not_active Expired
- 1982-03-26 DK DK138682A patent/DK153404C/en not_active IP Right Cessation
- 1982-03-26 HU HU82939A patent/HU185092B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| PT74669B (en) | 1985-01-08 |
| DE3211243C2 (en) | 1993-05-19 |
| FR2502621A1 (en) | 1982-10-01 |
| MA19416A1 (en) | 1982-10-01 |
| ES8302712A1 (en) | 1983-01-16 |
| AU549222B2 (en) | 1986-01-23 |
| DK153404B (en) | 1988-07-11 |
| IT8248036A0 (en) | 1982-03-19 |
| FI71152C (en) | 1986-11-24 |
| ES509284A0 (en) | 1983-01-16 |
| CH651565A5 (en) | 1985-09-30 |
| ZA821141B (en) | 1983-01-26 |
| CA1175823A (en) | 1984-10-09 |
| DE3211243A1 (en) | 1982-10-07 |
| FI821058L (en) | 1982-09-28 |
| HU185092B (en) | 1984-11-28 |
| GB2095674A (en) | 1982-10-06 |
| FR2502621B1 (en) | 1983-10-28 |
| SE448731B (en) | 1987-03-16 |
| DK138682A (en) | 1982-09-28 |
| AU8094782A (en) | 1982-09-30 |
| FI821058A0 (en) | 1982-03-25 |
| SE8200271L (en) | 1982-09-28 |
| FI71152B (en) | 1986-08-14 |
| NL193246C (en) | 1999-04-02 |
| GB2095674B (en) | 1984-10-10 |
| DK153404C (en) | 1988-11-21 |
| IT1147917B (en) | 1986-11-26 |
| PT74669A (en) | 1982-04-01 |
| JPS57169483A (en) | 1982-10-19 |
| NL193246B (en) | 1998-12-01 |
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| Date | Code | Title | Description |
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| A85 | Still pending on 85-01-01 | ||
| BA | A request for search or an international-type search has been filed | ||
| BB | A search report has been drawn up | ||
| BC | A request for examination has been filed | ||
| CNR | Transfer of rights (patent application after its laying open for public inspection) |
Free format text: HOECHST MARION ROUSSEL |
|
| BK | Erratum |
Free format text: PAT. BUL. 06/99, HEADING P, SECTION 2, PAGE 761 PATENT NUMBER 193246: THE TITLE OF THE INVENTION SHOULD READ; WERKWIJZE VOOR DE BEREIDING VAN IMIDAZOBENZODIAZEPINEN EN HUN ZOUTEN. |
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| V4 | Discontinued because of reaching the maximum lifetime of a patent |
Free format text: 20020323 |
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| V4 | Discontinued because of reaching the maximum lifetime of a patent |
Effective date: 20020323 |