DK141604B - Process for preparing 1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one derivatives. - Google Patents
Process for preparing 1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one derivatives. Download PDFInfo
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- DK141604B DK141604B DK372871AA DK372871A DK141604B DK 141604 B DK141604 B DK 141604B DK 372871A A DK372871A A DK 372871AA DK 372871 A DK372871 A DK 372871A DK 141604 B DK141604 B DK 141604B
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- tetrahydro
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- benzodiazepin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
- C07D243/28—Preparation including building-up the benzodiazepine skeleton from compounds containing no hetero rings
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
( I ***»' i \Ra/ (11) FREMUEGGELSESSKRIFr 141604 DANMARK <«> Intel,’ 0 07 0,243/28 «(21) Ansøgning nr. 272Q/71 (22) IncHsverst dsn 29· Jul. 1971 (23) Løbsdag 29· Jul. 1971 (44) Ansøgningen fremlagt og . q.(I *** »'i \ Ra / (11) PROGRESSION NOTICE 141604 DENMARK <«> Intel,' 0 07 0.243 / 28 '(21) Application No. 272Q / 71 (22) IncHsverst dsn 29 · Jul. 1971 (23 ) Race Day 29 · Jul. 1971 (44) The application submitted and. Q.
fremlaggelsessfcrlftst offenaggjort dsn 0· Π®*) lyoUthe presentation is disclosed dsn 0 · Π® *) lyoU
DI REKTORATET FOR ^ ^DI RECTORATE FOR ^^
PATENT- OG VAREMÆRKEVÆSENET (3°> 1^^0,, HITHE PATENT AND TRADEMARKET SYSTEM (3 °> 1 ^^ 0 ,, HI
(71) RICHTER GEDEON VEGYESZETI GYAR RT, Budapest X., Gyoemroei ut 21, HU, (72) Opfinder: La Job Klsfaludy, Budapest II, Riado u. 6/a, HU: Istvan Lza= kolczay, Budapest HI, Dereglye u. 4, HU: Juliana Roehricht, Budapest VII, Majakovszki j u. 105, HU: Ferenc Korenczki, Budapest X, Halom u. 35/t, HU.(71) RICHTER GEDEON VEGYESZETI GYAR RT, Budapest X., Gyoumroei ut 21, HU, (72) Inventor: La Job Klsfaludy, Budapest II, Riado u. 6 / a, HU: Istvan Lza = kolczay, Budapest HI, Dereglye u 4, HU: Juliana Roehricht, Budapest VII, Majakovszki j u. 105, HU: Ferenc Korenczki, Budapest X, Halom u. 35 / h, HU.
(74) Fuldmegtig under sagens behandling:(74) Plenipotentiary:
Kontor for Industriel Eneret ved Svend Schønning.Office for Industrial Excellence by Svend Schønning.
(64) Fremgangsmåde til fremstilling af 1,5,4,5-tetrahydro-2H-1,4-benzodia* zepin-2-on-derivater.(64) Process for preparing 1,5,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one derivatives.
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af l,3,4,5-tetrahydro-2H-l,4-benzodiazepin- 2-on-derivater med den almene formelThe present invention relates to a particular process for the preparation of 1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one derivatives of the general formula
RR
r^X-"N-cvr ^ X "N-cv
x-h (Γ Λ Ix-h (Γ Λ I
CH-NH"^ C6H5 hvor R er hydrogen eller en alkylgruppe med 1-5 kulstofatomer 141604 og X er hydrogen, halogen eller amino.Wherein R is hydrogen or an alkyl group having 1 to 5 carbon atoms and X is hydrogen, halogen or amino.
Det er kendt, at tetrahydro-benzodiazepin-2-on-derivater er værdifulde beroligende og sedativt virkende forbindelser og endvidere er vigtige mellemprodukter ved fremstilling af dihydro-benzodiazepin-2-on-derivater ved oxydation. Fra litteraturen kendes forskellige fremgangsmåder til fremstilling af tetrahydro-benzodiazepin-2-on-derivater. Ifølge GB-PS 1.037.375 omdannes N-benzhydrylglycin-derivater ved varmebehandling i de tilsvarende tetrahydro-1,4-benzodiazepin-2-on-derivater. Ifølge DE-AS 1 199 776 vindes tetrahydro-1,4-benzodiazepin-2-on-derivater ved katalytisk hydrogenering af dihydro-1,4-benzodiazepin-2-on-derivater. I HU-PS 155 251 beskrives en fremgangsmåde til fremstilling af l,3,4,5-tetrahydro-2H-l,4-benzodiazepin-2-on-forbindelser, hvor man ud fra benzhydrolderivater, ved selektiv N-acylering og efterfølgende hydrogenering vinder det ønskede slutprodukt.It is known that tetrahydro-benzodiazepine-2-one derivatives are valuable tranquilizers and sedatively acting compounds and are also important intermediates in the preparation of dihydro-benzodiazepin-2-one derivatives by oxidation. Various methods are known from the literature for the preparation of tetrahydro-benzodiazepine-2-one derivatives. According to GB-PS 1,037,375, N-benzhydrylglycine derivatives are converted by heat treatment into the corresponding tetrahydro-1,4-benzodiazepin-2-one derivatives. According to DE-AS 1 199 776 tetrahydro-1,4-benzodiazepin-2-one derivatives are obtained by catalytic hydrogenation of dihydro-1,4-benzodiazepin-2-one derivatives. HU-PS 155 251 discloses a process for preparing 1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one compounds using benzhydrol derivatives by selective N-acylation and subsequent hydrogenation wins the desired final product.
Fra DK-PS 107.168 kendes en fremgangsmåde til fremstilling af 5-aryl-3H-l,4-benzodiazepin-2(lH)-oner ved omsætning af en 2-karbobenzoxyglycylamido-benzofenon i nærværelse af eddikesyre med et hydrogenhalogenid, hvorefter den vundne 2-glycylamido-benzofenon ved vandfraspaltning ringsluttes til den ønskede forbindelse i neutralt eller alkalisk medium.DK-PS 107,168 discloses a process for preparing 5-aryl-3H-1,4-benzodiazepine-2 (1H) -ones by reacting a 2-carbobenzoxyglycylamido-benzophenone in the presence of acetic acid with a hydrogen halide, whereupon the obtained 2 -glycylamido-benzophenone by water cleavage is cyclized to the desired compound in neutral or alkaline medium.
Fra DK-PS 118.953 er det kendt at fremstille 1,3,4,5-tetra-hydro-2H-l,4-benzodiazepin-2-oner ved omsætning af et 2-amino-benzhydrolderivat og en beskyttet aminosyre, hvorefter beskyttelsesgruppen fraspaltes fra det dannede benzhydrolderivat og hydroxylgruppen eventuelt udskiftes med et halogenatom, hvorefter den vundne forbindelse, især et 2-substitueret benzhydryl-halogenid, ringsluttes i alkalisk medium.From DK-PS 118,953, it is known to prepare 1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-ones by reaction of a 2-amino-benzhydrol derivative and a protected amino acid, whereupon the protecting group is cleaved. optionally, the benzhydrol derivative formed and the hydroxyl group are optionally replaced with a halogen atom, after which the compound obtained, especially a 2-substituted benzhydryl halide, is cyclized in alkaline medium.
Fra de ovennævnte danske patentskrifter samt desuden fra G.A. Archer og R.H. Sternbach, Chem. Rev. 68, 747, 1968, er det således kendt at 1,4-benzodiazepiner fremstilles ved ringslutning ved en pH-værdi på over 7. Ifølge litteraturen (se A. Stempel und F.W. Landgraf, J. Org. Chem. 27, 4675, 1962) kan endvidere den selektive fjernelse af karbobenzoxygruppen af med karbobenzoxy-aminosyrer acylerede 2-amino-benzofenon-derivater kun udføres ved behandling med brombrintesyre. Ved katalytisk hydrogenering af disse forbindelser i surt medium i nærværelse af palladium-aktiv kul reduceres benzofenons karbonylgruppe samtidig med fraspaltning af karbobenzoxygruppen.From the above mentioned Danish patents and also from G.A. Archer and R.H. Sternbach, Chem. Rev. 68, 747, 1968, it is thus known that 1,4-benzodiazepines are produced by cyclization at a pH greater than 7. According to the literature (see A. Stempel und FW Landgraf, J. Org. Chem. 27, 4675, 1962 ), furthermore, the selective removal of the carbobenzoxy group of 2-amino-benzophenone derivatives acylated with carbobenzoxy amino acids can only be effected by treatment with hydrobromic acid. By catalytic hydrogenation of these compounds in acidic medium in the presence of palladium-activated carbon, the carbonyl group of benzophenone is reduced simultaneously with cleavage of the carbobenzoxy group.
Det var således ikke, ifølge dette litteratursted, muligt 3 141604 at gennemføre en ringslutning ved reduktion i surt medium, idet der tværtimod optrådte bireaktioner, som gjorde ringslutningen umulig.Thus, according to this literature site, it was not possible to effect a cyclization by reduction in acidic medium, on the contrary, side reactions occurred which made the cyclization impossible.
Det har nu overraskende vist sig, at der sker reduktiv intra-molekylær ringslutning ved katalytisk hydrogenering af 2-(N-karbo-benzoxyglycyl)-amino-benzofenonderivater med den almene formelIt has now surprisingly been found that reductive intra-molecular cyclization occurs by catalytic hydrogenation of 2- (N-carbo-benzoxyglycyl) amino-benzophenone derivatives of the general formula
RR
✓Tss^^N-C0-CH2-NH-C0-0-CH2-C6H5✓Tss ^^ N-C 0-CH2-NH-C0-0-CH2-C6H5
X·-C |T IIX · -C | T II
-CO-C6H5 hvor X' er hydrogen, halogen, nitro eller amino og R har den ovenfor angivne betydning, i surt medium i nærværelse af palladium og/eller platinoxyd som katalysator, under dannelse af et l,3,4,5-tetrahydro-2H-l,4-benzodiazepin-2-on-derivat med den almene formel I, idet der sker fraspaltning af karbobenzoxybe-skyttelsesgruppen samtidig med ringslutningsreaktionen. Ved anvendelse af en udgangsforbindelse, med formel II, hvor X' er en nitrogruppe, kan denne reduktive ringslutning foregå i en mineralsyre eller i en organisk syre med opnåelse af udbytter på over 80 vægt%. Ringslutning af forbindelser med formel II, hvor X' er halogen kan med fordel gennemføres i eddikesyre.-CO-C6H5 wherein X 'is hydrogen, halogen, nitro or amino and R is as defined above, in acidic medium in the presence of palladium and / or platinum oxide as catalyst, to form a 1,3,4,5-tetrahydro -2H-1,4-benzodiazepine-2-one derivative of the general formula I, wherein the carbobenzoxy protecting group is cleaved off simultaneously with the cyclization reaction. Using an starting compound of formula II, where X 'is a nitro group, this reductive cyclization can take place in a mineral acid or in an organic acid, with yields in excess of 80% by weight. The cyclization of compounds of formula II wherein X 'is halogen can advantageously be carried out in acetic acid.
Fremgangsmåde ifølge opfindelsen er ejendommelig ved det i kravets kendetegnende del angivne.The process according to the invention is characterized by the characterizing part of the claim.
I de ved fremgangsmåden ifølge opfindelsen fremstillede tetrahydro-l,4-benzodiazepin-derivater med den almene formel I er R fortrinsvis hydrogen. Forbindelser med den almene formel I, hvor X er en aminogruppe, er hidtil ukendte.In the tetrahydro-1,4-benzodiazepine derivatives of the general formula I prepared by the process of the invention, R is preferably hydrogen. Compounds of general formula I wherein X is an amino group are novel.
I forbindelserne med den almene formel II er karbobenzoxy-gruppen en ved den katalytiske hydrogenering fraspaltelig beskyttelsesgruppe. Hvis der befinder sig en nitrogruppe i X1-stillingen i disse forbindelser, vil denne ligeledes reduceres ved den katalytiske hydrogenering.In the compounds of the general formula II, the carbobenzoxy group is a protecting group which is cleavable by the catalytic hydrogenation. If a nitro group is in the X1 position of these compounds, it will also be reduced by the catalytic hydrogenation.
Med særlig fordel hydrogeneres forbindelserne med den almene formel II, især hvis X' = N02~, i ætanolisk opløsning i nærværelse af eddikesyre og palladium på aktiv kul.With particular advantage, the compounds of general formula II, especially if X '= NO2 ~, are hydrogenated in ethanolic solution in the presence of acetic acid and palladium on activated carbon.
Isoleringen af slutproduktet sker på meget simpel måde:The final product is insulated in a very simple way:
Efter frafiltrering af katalysatoren inddampes filtratet under nedsat tryk til tørhed, og remanensen omkrystalliseres, fx ud fra benzen. I almindelighed kan der allerede ved en enkelt omkrystallisation vindes et kromatografisk rent produkt.After filtration of the catalyst, the filtrate is evaporated under reduced pressure to dryness and the residue is recrystallized, for example from benzene. In general, a single chromatographic pure product can already be obtained by a single recrystallization.
4 14160Λ4 14160Λ
Den reduktive ringslutning af forbindelserne med den almene formel II, hvor X' er en nitrogruppe, kan udføres både i ren eddikesyre eller i fortyndet mineralsyre og i nærværelse af mineralsyre i organiske opløsningsmidler med samme gode resultat.The reductive cyclization of the compounds of the general formula II, wherein X 'is a nitro group, can be carried out both in pure acetic acid or in dilute mineral acid and in the presence of mineral acid in organic solvents with the same good result.
Forbindelser med formel I, hvor X er en 7-aminogruppe, kan fremstilles ud fra det tilsvarende 2-acylamino-5-nitro- eller -5-amino-benzofenonderivat, idet der som syre kan anvendes såvel organiske syrer som mineralsyrer.Compounds of formula I, wherein X is a 7-amino group, can be prepared from the corresponding 2-acylamino-5-nitro or -5-amino-benzophenone derivative, using both organic acids and mineral acids as acid.
Til fremstilling af en forbindelse med formel I, hvor X er 7-klor og R er metyl foretages den katalytiske ringslutning med fordel i nærværelse af en organisk syre.To prepare a compound of formula I wherein X is 7-chloro and R is methyl, the catalytic ring closure is advantageously made in the presence of an organic acid.
Fremgangsmåden ifølge opfindelsen gennemføres med fordel i et opløsningsmiddel. Som katalysator anvendes fx palladium på aktivt kul eller en blandingskatalysator af palladium på aktivt kul og platinoxyd.Advantageously, the process of the invention is carried out in a solvent. As a catalyst, for example, palladium is used on activated carbon or a mixture catalyst of palladium on activated carbon and platinum oxide.
Fremgangsmåden ifølge opfindelsen skal forklares nærmere ved hjælp af et antal udføreiseseksempler. De i eksemplerne angivne smeltepunkter bestemmes ved hjælp af Tottolis apparat. De tyndtlagskromatografiske undersøgelser udføres på "kiselgel G efter Stahl" i systemet bestående af eddikesyreester-pyridin-iseddike-vand i forholdet 30:2,5:0,76:1,4. Fremkaldelsen Sker med klor og tolidin. De fremstillede forbindelsers struktur efterprøves ved IR-spektroskopi.The process according to the invention will be explained in more detail by means of a number of examples. The melting points indicated in the examples are determined by means of Tottoli apparatus. The thin-layer chromatographic studies are performed on "silica gel G after Stahl" in the system of acetic acid ester-pyridine glacial acetic acid water in a ratio of 30: 2.5: 0.76: 1.4. The development occurs with chlorine and tolidine. The structure of the compounds produced is verified by IR spectroscopy.
Eksempel 1 1,3,4,5-Tetrahydro-5-fenyl-7-amino-2H-l,4-benzodiazepin-2-on.Example 1 1,3,4,5-Tetrahydro-5-phenyl-7-amino-2H-1,4-benzodiazepin-2-one.
a) 4,6 g palladium-aktivt kul (10 vægt%) forhydrogeneres i 50 ml ætanol, hvorpå en suspension bestående af 17,0 g (39 mmol) 2-(N-karbobenzoxyglycyl)-amino-5-nitro-benzofenon i 380 ml ætanol og 9,2 ml iseddike tilsættes. Hydrogeneringen udføres ved atmosfæretryk ved tilledning af hydrogen til reaktionsblandingen natten over, hvorefter reaktionsblandingen frafiltreres og filtratet inddampes under nedsat tryk til tørhed. Remanensen opløses i 500 ml kloroform, opløsningen vaskes med 14% vandig ammoniak-opløsning og derpå med vand og tørres og inddampes under formindsket tryk. Der vindes 9,8 g råt 1,3,4,5-tetrahydro-5-fenyl- 7-amino-2H-l,4-benzodiazepin-2-on som remanens. Efter omkrystallisation ud fra benzen vindes 8,4 g rent produkt (84,7 vægt% af det teoretiske udbytte); smp. 182-184°C; R^ = 0,49.a) 4.6 g of palladium-activated charcoal (10% by weight) is dehydrogenated in 50 ml of ethanol, upon which a suspension consisting of 17.0 g (39 mmol) of 2- (N-carbobenzoxyglycyl) amino-5-nitro-benzophenone in 380 ml of ethanol and 9.2 ml of glacial acetic acid are added. The hydrogenation is carried out at atmospheric pressure by adding hydrogen to the reaction mixture overnight, after which the reaction mixture is filtered off and the filtrate is evaporated under reduced pressure to dryness. The residue is dissolved in 500 ml of chloroform, the solution is washed with 14% aqueous ammonia solution and then with water and dried and evaporated under reduced pressure. 9.8 g of crude 1,3,4,5-tetrahydro-5-phenyl-7-amino-2H-1,4-benzodiazepin-2-one are obtained as residue. After recrystallization from benzene, 8.4 g of pure product are obtained (84.7% by weight of theoretical yield); mp. 182-184 ° C; R f = 0.49.
5 1416045 141604
Beregnet: C 71,2 H 6,0 N 16,6Calculated: C 71.2 H 6.0 N 16.6
Fundet: 71,3 5,6 16,4% b) Man går frem som beskrevet under afsnit a), Idet der dog anvendes 1,1 g 2-(N-karbobenzoxyglycyl)-aminp-5-nitro-benzofenon og 0,3 g palladium-aktivt kul i 40 ml ætanol, og i stedet for iseddike tilsættes 0,5 ml saltsyre. På denne måde vindes 0,5 g (78% af det teoretiske udbytte) rent l,3,4,5-tetrahydro-5-fenyl- 7-amino-2H-l,4-benzodiazepin-2-on af samme kvalitet som den, der blev opnået ved anvendelse af metode a).Found: 71.3 5.6 16.4% b) Proceed as described in section a) However, using 1.1 g of 2- (N-carbobenzoxyglycyl) amine-5-nitrobenzophenone and 0, 3 g of palladium-activated charcoal in 40 ml of ethanol and 0.5 ml of hydrochloric acid are added in place of glacial acetic acid. In this way, 0.5 g (78% of theoretical yield) of pure 1,3,4,5-tetrahydro-5-phenyl-7-amino-2H-1,4-benzodiazepin-2-one is obtained of the same quality as that obtained by using method a).
Eksempel 2 7-Klor-5-fenyl-l~metyl-l,3,4,5-tetrahydro-2H-l,4-benzodiaze-pin-2-on.____ 0,15 g palladium-aktiv kul (10 vægt%) og 0,15 g platinoxyd suspenderes i 5 ml iseddike og forhydrogeneres, hvorpå der til denne katalysator-suspension sættes 1,1 g (2,4 mmol) 2-(karbo-benzoxyglycyl-N-metylamino)-5-klor-benzofenon i 5 ml iseddike. Blandingen hydrogeneres ved stuetemperatur og ved atmosfæretryk i 5 timer. Efter to timers forløb tilsættes yderligere samme mængde af ovennævnte katalysatorblanding. Efter hydrogeneringens afslutning filtreres blandingen fra og filtratet inddampes til tørhed. Remanensen opløses i kloroform, og opløsningen udrystes ved fjernelse af spor af eddikesyre med en 8% vandig natrium-bikarbonatopløsning. Den adskilte kloroformfase tørres og inddampes til tørhed. Som remanens vindes 0,65 g råt produkt, som ved behandling med 2N saltsyre omdannes til hydrokloridet, fra-filtreres og behandles med en 8% vandig natriumbikarbonatop-løsning. På denne måde vindes 0,55 g (79 vægt% af det teoretiske udbytte) 7-klor-l-metyl-5-fenyl-l,3,4,5-tetrahydro-2H- 1,4-benzodiazepin-2-on. Det ud fra isopropanol omkrystalliserede rene produkt smelter ved 142-145°C; Rf = 0,15 (hexan-iseddike-kloroform 1:1:8).Example 2 7-Chloro-5-phenyl-1-methyl-1,3,4,5-tetrahydro-2H-1,4-benzodiaze-pin-2-one. 0.15 g palladium-activated carbon (10 wt. %) and 0.15 g of platinum oxide are suspended in 5 ml of glacial acetic acid and prehydrogenated, and to this catalyst suspension are added 1.1 g (2.4 mmol) of 2- (carbo-benzoxyglycyl-N-methylamino) -5-chloroacetic acid. benzophenone in 5 ml glacial acetic acid. The mixture is hydrogenated at room temperature and at atmospheric pressure for 5 hours. After two hours, the same amount of the above catalyst mixture is added. After hydrogenation is complete, the mixture is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in chloroform and the solution is shaken off by removing traces of acetic acid with an 8% aqueous sodium bicarbonate solution. The separated chloroform phase is dried and evaporated to dryness. As the residue, 0.65 g of crude product which, by treatment with 2N hydrochloric acid, is recovered into the hydrochloride is filtered off and treated with an 8% aqueous sodium bicarbonate solution. In this way, 0.55 g (79% by weight of theoretical yield) of 7-chloro-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one is obtained. . The pure product recrystallized from isopropanol melts at 142-145 ° C; Rf = 0.15 (hexane glacial acetic chloroform 1: 1: 8).
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HURI000403 | 1970-07-30 | ||
HURI000403 | 1970-07-30 |
Publications (2)
Publication Number | Publication Date |
---|---|
DK141604B true DK141604B (en) | 1980-05-05 |
DK141604C DK141604C (en) | 1980-10-06 |
Family
ID=11000846
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK372871AA DK141604B (en) | 1970-07-30 | 1971-07-29 | Process for preparing 1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one derivatives. |
Country Status (10)
Country | Link |
---|---|
JP (1) | JPS5432792B1 (en) |
AT (1) | AT311356B (en) |
CH (1) | CH558370A (en) |
CS (1) | CS171708B2 (en) |
DK (1) | DK141604B (en) |
ES (1) | ES393521A1 (en) |
NL (1) | NL7110356A (en) |
PL (1) | PL70872B1 (en) |
SE (1) | SE385888B (en) |
SU (1) | SU461503A3 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HU187262B (en) * | 1979-08-16 | 1985-12-28 | Richter Gedeon Vegyeszet | Process for preparing new tetrahydro-1,4-benzodiazepin-2-ones |
-
1971
- 1971-07-20 CH CH1068871A patent/CH558370A/en not_active IP Right Cessation
- 1971-07-22 ES ES393521A patent/ES393521A1/en not_active Expired
- 1971-07-26 CS CS5453A patent/CS171708B2/cs unknown
- 1971-07-27 AT AT654571A patent/AT311356B/en not_active IP Right Cessation
- 1971-07-27 NL NL7110356A patent/NL7110356A/xx unknown
- 1971-07-28 PL PL1971149707A patent/PL70872B1/pl unknown
- 1971-07-28 SE SE7109699A patent/SE385888B/en unknown
- 1971-07-29 DK DK372871AA patent/DK141604B/en unknown
- 1971-07-29 SU SU1688515A patent/SU461503A3/en active
- 1971-07-29 JP JP5711071A patent/JPS5432792B1/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
NL7110356A (en) | 1972-02-01 |
PL70872B1 (en) | 1974-04-30 |
DK141604C (en) | 1980-10-06 |
ES393521A1 (en) | 1973-08-16 |
SU461503A3 (en) | 1975-02-25 |
CS171708B2 (en) | 1976-10-29 |
SE385888B (en) | 1976-07-26 |
CH558370A (en) | 1975-01-31 |
AT311356B (en) | 1973-11-12 |
JPS5432792B1 (en) | 1979-10-16 |
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