SE435285B - PROCEDURE FOR PREPARING 6-PHENYL-4H-S-TRIAZOLO (4,3-A) (1,4) BENZODIAZEPINES - Google Patents
PROCEDURE FOR PREPARING 6-PHENYL-4H-S-TRIAZOLO (4,3-A) (1,4) BENZODIAZEPINESInfo
- Publication number
- SE435285B SE435285B SE8107017A SE8107017A SE435285B SE 435285 B SE435285 B SE 435285B SE 8107017 A SE8107017 A SE 8107017A SE 8107017 A SE8107017 A SE 8107017A SE 435285 B SE435285 B SE 435285B
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- Prior art keywords
- triazol
- methyl
- chloro
- benzophenone
- hydroxymethyl
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- 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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
8107017-9 I lll där A är utvald från den grupp som består av 0 \ 0 där Rl betecknar väte, alkyl med l-3 kolatomer, fenyl, bensyl eller COOR' där R' betecknaralkyl med l-3 kolatomer och där R2, R3, R4 och RS betecknar väte, alkyl med 1-3 kolatomer, halogen, nitro, cyano, trifluormetyløch alkoxi, alkyltio, alkylsulfinfyl, alkyl- sulfonyl, alkylamino eller dialkylamino där alkylgrupperna inne- håller l-3 kolatomer. 8-107017-9 Förfarandet enligt föreliggande uppfinning består i behandling av en 2- 3-(hydroximetyl)-4H-l,2,4-triazol-4-yl7 bensofenon (1) med ftalimid och trifenylfosin i närvaro av en vâteacceptor, t ex die-' tylazodikarboxylat, varvid erhålles en förening med formeln II där A betecknar ' O 0 \ / behandlas med hydrazinhydrat i en lägre alkanol (1 till 3 kolatomer) under l-4 timmar vid 25-l00°C, varvid motsvarande förening med for- meln III erhålles. 1111 where A is selected from the group consisting of 0 \ 0 where R 1 represents hydrogen, alkyl having 1-3 carbon atoms, phenyl, benzyl or COOR 'where R' represents alkyl having 1-3 carbon atoms and where R 2, R 3 , R 4 and R 5 represent hydrogen, alkyl of 1-3 carbon atoms, halogen, nitro, cyano, trifluoromethyl and alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino or dialkylamino where the alkyl groups contain 1-3 carbon atoms. The process of the present invention consists in treating a 2- 3- (hydroxymethyl) -4H-1,2,4-triazol-4-yl7-benzophenone (1) with phthalimide and triphenylphosin in the presence of a hydrogen acceptor, t ex diethyl azodicarboxylate to give a compound of formula II wherein A represents O 2 is treated with hydrazine hydrate in a lower alkanol (1 to 3 carbon atoms) for 1-4 hours at 25-100 ° C, the corresponding compound having formula III is obtained.
Alkaligrupper med 1-3 kolatomer innefattar metyl, etyl, propyl och isopropyl.Alkali groups having 1-3 carbon atoms include methyl, ethyl, propyl and isopropyl.
Gruppen innehållande en kolkedja i alkoxi, alkyltio, alkylsulfinyl, alkylsulfonyl, diakylamino med l-3 kolatomer innefattar de lägre alkylgrupper som definierats i föregående stycke.The group containing a carbon chain in alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, diakylamino having 1 to 3 carbon atoms includes the lower alkyl groups as defined in the preceding paragraph.
Alkyanoylaminogruppen med l-3 kolatomer utgöres av formamido O _ H (-NH-C-H), accetamido och propionamido.The alkanoylamino group having 1-3 carbon atoms consists of formamido O-H (-NH-C-H), accetamido and propionamido.
Uttrycket halogen betecknar fluor, klor och brom. 8107017-9 Föreningarna med formeln II är mellanprodukter i den nya syntensen av föreningar enligt formeln III, 6-fenyl-4H-s-triazolo»[ä,3-av [l,4l7-bensodiazepiner, Föreningarna med formeln III är en typ av mycket effektiva sedativa och lugnande medel, vilka nyligen upp- täckts och beskrivits i detalj av Hester och medarbetare i J. _ Medical Chemistry l4, 1078 (1971) och i kanandensiska patentskrif- ten 905 954.The term halogen denotes fluorine, chlorine and bromine. The compounds of formula II are intermediates in the novel synthesis of compounds of formula III, 6-phenyl-4H-s-triazolo »[α, 3-of [1,4,17-benzodiazepines. The compounds of formula III are a type of highly effective sedatives and sedatives, which have recently been discovered and described in detail by Hester and co-workers in J. _ Medical Chemistry 14, 1078 (1971) and in Canadian Patents 905 954.
Utgångsföreningarna med formeln I enligt föreliggande uppfinning syntetiseras på det sätt som anges i framställningsexemplen nedan.The starting compounds of formula I according to the present invention are synthesized in the manner set forth in the preparation examples below.
Mellanprodukten och formeln II_utgöres av ett ftalimidoderivat består förfarandet i att behandla utgângsmaterialet i ett lösnings- medel med ftalimid i ungefär ekvimolekylär mängd eller företrädes- vis i ett litet överskott på 5-20 % av den beräknade mängden och en ekvimolekylär mängdätrifenylfosin och en vätskeaoceptor, exempelvis ett dialkylazodikarboxylat, företrädesvis dietylazodikarboxylat.The intermediate and formula II are a phthalimido derivative, the process consisting of treating the starting material in a solvent with phthalimide in an approximately equimolar amount or preferably in a small excess of 5-20% of the calculated amount and an equimolecular amount of triphenylphosphine and e.g. a dialkyl azodicarboxylate, preferably diethyl azodicarboxylate.
Reaktionen genomföres vid temperaturer mellan O och l00°C. Enligt en föredragen utföringsform av föreliggande reaktion användes tempe- raturer mellan 20 dch 4000 och omröring mellan 2 och 36 timmar för fullständig reaktion. Företrädesvis användes som lösningsmedel vat- tenfri tetrahydrofuran, dioxan, 1,2-dümâoxümfifinf eter, kloroform, metylenklorid och liknande. Vid reaktionens slut utvinnes produkten med formeln II och renas på konventionellt sätt, t ex genom koncent- ration av reaktionsblandningen, extraktion, kromatografi och om- kristallisation.The reaction is carried out at temperatures between 0 and 100 ° C. According to a preferred embodiment of the present reaction, temperatures between 20 dch 4000 and stirring between 2 and 36 hours were used for complete reaction. Preferably, anhydrous tetrahydrofuran, dioxane, 1,2-dimoxomphene, chloroform, methylene chloride and the like are used as solvents. At the end of the reaction, the product of formula II is recovered and purified in a conventional manner, for example by concentration of the reaction mixture, extraction, chromatography and recrystallization.
Produkten behandlas därefter med hydrazinhydrat i en lägre alkanol, t ex metanol, etanol, l-propanol, eller 2-propanol vid en tempera- tur av 25-l00°C under l-5 timmar. Företrädesvis hâlles temperaturen mellan.65-l00°C. Produkten med formeln III utvinnes och renas på konventionellt sätt, t ex genom extraktion, kromatografisk kristal- lisation och liknande.The product is then treated with hydrazine hydrate in a lower alkanol, eg methanol, ethanol, 1-propanol, or 2-propanol at a temperature of 25-100 ° C for 1-5 hours. Preferably the temperature is kept between 65-100 ° C. The product of formula III is recovered and purified in a conventional manner, for example by extraction, chromatographic crystallization and the like.
Följande framställningsexempel och exempel belyser förfarandet en- ligt föreliggande uppfinning. 8107017-9 Framställning l 2'-bensoyl-4'-kloracetanilid Acetylklorid (8l,3 g, 1,037 mol) sättes till en omrörd lösning av 2-amino-5-klorbensofenon (200,0 g, 0,864 mol) och pyridin (68,4 g, 0,864 mol) i torr eter (4 11. Blandningen hölls vid omgivningens temperatur under 2 timmar och behandlades med 500nfl.vatten. Faserna separerades och eterfasen torkades över vattenfritt natriumsulfat och koncentrerades. Kristallisation av återstoden ur etylacetat- Skellysolve B-hexaner gav 124,0 g 2'-bensoyl-4'-kloracetanilid med en smältpunkt på ll4-ll5°C. Två satser 2'-bensoyl-4'-kloracetanilid erhölls: 67,8 g med en smältpunkt på 113,5-ll4,5°C och 33,0 g med en smältpunkt av 113-ll4°C.The following preparation examples and examples illustrate the process of the present invention. Preparation 1 2'-Benzoyl-4'-chloroacetanilide Acetyl chloride (81.3 g, 1.037 mol) is added to a stirred solution of 2-amino-5-chlorobenzophenone (200.0 g, 0.864 mol) and pyridine (68 .4 g, 0.864 mol) in dry ether (4 11. The mixture was kept at ambient temperature for 2 hours and treated with 500n vatten of water. The phases were separated and the ether phase was dried over anhydrous sodium sulfate and concentrated. Crystallization of the residue from ethyl acetate- Skellysolve B-hexanes gave 124.0 g of 2'-benzoyl-4'-chloroacetanilide with a melting point of 14-115 ° C. Two batches of 2'-benzoyl-4'-chloroacetanilide were obtained: 67.8 g with a melting point of 113.5-114 , 5 ° C and 33.0 g with a melting point of 113-114 ° C.
Framställning 2 6-klor-4-fenyl-2(lH)-kinolin Förfarandet (reaktion mellan 2'bensoyl-5'-kloracetanilid och natrium- hydroxid) enligt A.B. Drukker och C.I. Judd, J., Heterocyclic Chem. 3, 359 (1966) användes för denna framställning. Utbytet var 77 %.Preparation 2 6-Chloro-4-phenyl-2 (1H) -quinoline The procedure (reaction between 2'benzoyl-5'-chloroacetanilide and sodium hydroxide) according to A.B. Drukker and C.I. Judd, J., Heterocyclic Chem. 3, 359 (1966) was used for this preparation. The yield was 77%.
Två andra framställningar beskrives i S.C. Bell, T.S. Sulkowski, C. Gochmann och S.J. Childress, J. Org. Chem 27, 562 (1962) samt G.A. Reynolds och C.R. Hauser, J. Amer. Chem. Soc. 72, 1852 (1950).Two other representations are described in S.C. Bell, T.S. Sulkowski, C. Gochmann, and S.J. Childress, J. Org. Chem 27, 562 (1962) and G.A. Reynolds and C.R. Hauser, J. Amer. Chem. Soc. 72, 1852 (1950).
Framställning 3 2,6-diklor-4-fenylkinolin Förfarandet enligt A.E.Drukker och C.I. Judd, J. Heterocyclic Chem.3, 359 (1966) användes för denna framställning. Utbytet var 62 %.Preparation 3 2,6-Dichloro-4-phenylquinoline The procedure of A.E.Drukker and C.I. Judd, J. Heterocyclic Chem.3, 359 (1966) was used for this preparation. The yield was 62%.
Framställning 4 6-klor-2-hydrazino-4-fenylkinolin En omrörd blandning av 2,6-diklor-4-fenylkinolin (2,7 g, 0,01 mol) och hydrazinhydrat (6,8 g) kokades under återflöde i kväveatmosfär under l timme och koncentrerades i vakuum. Återstoden suspendera- des i varmt vatten och det fasta materialet uppsamlades genom filt- rering, torkades och omkristalliserades ur etylacetat-Skellysolve B-hexanef, varvid erhölls 1,81 g (67 %) utbyte av 6-klor-2-hydra- zino-4-fenylkinolin med en smältpunkt på 156,5-l57°C. 8107017-9 Analys: Beräknat för CISHIZCIN3 c 66.79; H 4.49; cL 13.15; N 1s.sa.Preparation 4 6-Chloro-2-hydrazino-4-phenylquinoline A stirred mixture of 2,6-dichloro-4-phenylquinoline (2.7 g, 0.01 mol) and hydrazine hydrate (6.8 g) was refluxed under a nitrogen atmosphere. for 1 hour and concentrated in vacuo. The residue was suspended in hot water and the solid was collected by filtration, dried and recrystallized from ethyl acetate-Skellysolve B-hexanef to give 1.81 g (67%) yield of 6-chloro-2-hydrazino. 4-phenylquinoline, m.p. 156.5-167 ° C. 8107017-9 Analysis: Calculated for CISHIZCIN3 c 66.79; H 4.49; cL 13.15; N 1s.sa.
Erhâlletf C 67.15; H 4.65; Cl 13.19; N 15.32.Obtained C 67.15; H 4.65; Cl 13.19; N 15.32.
Framställning 5 7-klor-l-metyl-5-fenyl-s-triazolo ÅFW3-gjkinolin En omrörd blandning av 6-klor-2-hydrazino-4-fenylkinolin (1,4 g, 0,0052 mol) trietylortoacetat (0,925 g, 0,005? mol) och xylen (100 ml) kokades under_återflöde i kvaveatmosfär under 2 timmar och 40 minuter. Under denna period avlägsnades den vid reaktionen bilda- de etanolen genom dèstillation genom en kort, glasringpackad kolonn.Preparation 5 7-Chloro-1-methyl-5-phenyl-s-triazolo ÅFW3-gquinoline A stirred mixture of 6-chloro-2-hydrazino-4-phenylquinoline (1.4 g, 0.0052 mol) triethyl orthoacetate (0.925 g 0.005 mol) and xylene (100 ml) were refluxed under a nitrogen atmosphere for 2 hours and 40 minutes. During this period, the ethanol formed in the reaction was removed by distillation through a short, glass ring packed column.
Blandningen koncentrerades till torrhet i vakuum och återstoden kristalliserades ur metanol-etylacetat, varvid erhölls 1,28 g 7-klor-l-metyl-S-fenyl-s-triazolo [4,3-a_] kinolin med en smältpunkt på 253,5 - 255°C. (33,9 % utbyte) Ett analytiskt prov kristallise- rade ur metylenklorid: metanol och hade en smältpunkt på 252,5 - zs3,s°c.The mixture was concentrated to dryness in vacuo and the residue was crystallized from methanol-ethyl acetate to give 1.28 g of 7-chloro-1-methyl-5-phenyl-s-triazolo [4,3-a] quinoline, m.p. 255 ° C. (33.9% yield) An analytical sample crystallized from methylene chloride: methanol and had a melting point of 252.5 - zs3, s ° c.
Analys Beräknat för C17Hl2ClN3: c 69.50; -H ¿_l2; c1 12.o7;l N 14.31 Erhåliet c 69:38; H 4.02; c1 12.10; N 14.49 ,Framställning 6 5-klor-2-(3-metyl-4H-l,2,4,triazol-4-yl)- bensofenon (oxidation av 7-klor-l-metyl-5-fenyl-s-triazolo 4,3-a;7- kinolin) En omrörd suspension av 7-klor-l-metyl-S-fenyl-s-triazolo [LIS-a]- kinolin (2,94 g, 0,01 mol) i aceton (ll0 ml) kyldes på ett isbad och behandlades långsamt med en lösning framställd genom tillsats av natriumperiodat (2 g) till en omrörd suspension av rutenium- dioxid (200 mg) i vatten (35 ml). Blandningen blev mörk. Ytterli- gare natriumperjodat (8 g) tillsattes under de efterföljande 15 minuterna. Isbadet avlägsnades och blandningen omrördes under 45 minuter. Ytterligare natriumperjodat (4 g) tillsattes och bland- ningen omrördes vid omgivningens temperatur under 18 timar och filtrerades. Det fasta materialet tvättades med aceton och de sam- manslagna filtraten koncentrerades i vakuum. Aterstoden suspen- 8107017-9 derades i vatten och extraherades med metylenklorid. Extraktet tor- kades över vattenfritt kaliumkarbonat och koncentrerades. Atersto- den kromatograferades på kiselgel (100 g) med 10 % metanol. (90 %' etylacetat; varvid fraktioner på 50 ml uppsamlades)IProdukten elue- rades i fraktionerna 10-20 och kristalliserade ur etylacetat, var- vid erhölls 0,405 g med en smältpunkt på 168-l69,5°C och 0,291 g med en emältpunkt på 167,5-1s9°c (23,4 % utbyte; ev s-k1er-2-<3- metyl-4H-1,2,4-triazol-4-yl)bensofenon. Det analytiska provet hade en smältpunkt på l68°C.Analysis Calculated for C 17 H 12 ClN 3: c 69.50; -H ¿_l2; c1 12.o7; l N 14.31 Erhåliet c 69:38; H 4.02; c1 12.10; N 14.49, Preparation 6 5-chloro-2- (3-methyl-4H-1,2,4, triazol-4-yl) -benzophenone (oxidation of 7-chloro-1-methyl-5-phenyl-s-triazolo 4,3-a; 7-quinoline) A stirred suspension of 7-chloro-1-methyl-5-phenyl-s-triazolo [LIS-a] quinoline (2.94 g, 0.01 mol) in acetone ( 10 ml) was cooled on an ice bath and treated slowly with a solution prepared by adding sodium periodate (2 g) to a stirred suspension of ruthenium dioxide (200 mg) in water (35 ml). The mixture became dark. Additional sodium periodate (8 g) was added over the next 15 minutes. The ice bath was removed and the mixture was stirred for 45 minutes. Additional sodium periodate (4 g) was added and the mixture was stirred at ambient temperature for 18 hours and filtered. The solid was washed with acetone and the combined filtrates were concentrated in vacuo. The residue was suspended in water and extracted with methylene chloride. The extract was dried over anhydrous potassium carbonate and concentrated. The residue was chromatographed on silica gel (100 g) with 10% methanol. (90% ethyl acetate; 50 ml fractions were collected) The product was eluted in fractions 10-20 and crystallized from ethyl acetate to give 0.405 g with a melting point of 168-169.5 ° C and 0.291 g with a melting point. at 167.5-1s9 ° C (23.4% yield; optionally s-chlor-2- <3-methyl-4H-1,2,4-triazol-4-yl) benzophenone. The analytical sample had a melting point of 168 ° C.
Analys: Beräknat för Cl6Hl2ClN30: C 64.54; H 4.06; C1 11.91; N 14.11 Erhâllet: C 64.56; H 4.35; Cl 11.97; 11.93; N 14.29.Analysis: Calculated for C 16 H 12 ClN 3 O: C 64.54; H 4.06; C1 11.91; N 14.11 Found: C 64.56; H 4.35; Cl 11.97; 11.93; N 14.29.
Framställning 7 5-klor-2- ÅB-(hydroximetyl)-5-metyl-4H-l,2,4-tria- zol-4-yl] bensofenon En omrörd blandning av 5-klor-2-(3-metyl-4H-1,2,4,-triazolo-4-yl)- bensofenon (2,98 g, 0,01 mol) paraformaldehyd (3 g) och xylen (100 ml) värmdes i kväveatmosfär på ett bad, som hölls vid l25°C under 7 timmar. Blandningen koncentrerades i vakuum. Återstoden kro- motograferades på kiselgel (150 g) med 3 % metanol-97 % kloroform.Preparation 7 5-Chloro-2- [1B- (hydroxymethyl) -5-methyl-4H-1,2,4-triazol-4-yl] benzophenone A stirred mixture of 5-chloro-2- (3-methyl- 4H-1,2,4, -triazolo-4-yl) -benzophenone (2.98 g, 0.01 mol) paraformaldehyde (3 g) and xylene (100 ml) were heated in a nitrogen atmosphere in a bath maintained at 125 ° C for 7 hours. The mixture was concentrated in vacuo. The residue was chromatographed on silica gel (150 g) with 3% methanol-97% chloroform.
Fraktioner på 50 ml uppsamlades. Produkten eluerades i fraktioner -44. Fraktionerna koncentrerades och återstoden kristalliserades ur etanol-etyl-acetat, varvid erhölls 1,64 g 5~klor-2-[ä-(hydroxi- metyl)-5-metyl-4H-1,2,4-triazol-4-yl] bensofenon med en smältpunkt på 138-142°c; o,31e g med en emältpunkt på 138,5-141°c een 0,431 g med en smältpunkt på 139-l4l°C (72,8 % utbyte). Ett analytiskt prov hade en smältpunkt på 138-l39°C.50 ml fractions were collected. The product eluted in fractions -44. The fractions were concentrated and the residue was crystallized from ethanol-ethyl acetate to give 1.64 g of 5-chloro-2- [α- (hydroxymethyl) -5-methyl-4H-1,2,4-triazol-4-yl ] benzophenone with a melting point of 138-142 ° C; 0.3e g with a melting point of 138.5-141 ° C and 0.431 g with a melting point of 139-114 ° C (72.8% yield). An analytical sample had a melting point of 138-139 ° C.
Analys: Beräknat för Cl7Hl4ClN3O2: C 62.30; H 4.30; Cl 10.81; N 12.82 Erhållet: C 62.23; H 4.22; C1 10.82; N 11.73. 8107017-9 Framställning 8, 2'-(o-klorbensoyl)-4'-kloracetanilid På det sätt som\angavs;i framställning l fick 2-amino-2',5-dik1or- _ bensofenon, acetylklorid och pyridin reagera i eter, varvid erhölls 2'-(o-klorbensoyl)-4”-kloracetanilid.Analysis: Calculated for C 17 H 14 ClN 3 O 2: C 62.30; H 4.30; Cl 10.81; N 12.82 Found: C 62.23; H 4.22; C1 10.82; N 11.73. Preparation 8, 2 '- (o-chlorobenzoyl) -4'-chloroacetanilide As indicated in Preparation 1, 2-amino-2', 5-dichlorobenzophenone, acetyl chloride and pyridine were reacted in ether , whereby 2 '- (o-chlorobenzoyl) -4 "-chloroacetanilide was obtained.
Framställning 9 6-klor-4-(o-klorfeny1}Q-(lHI-kinolon Förfarandet enligt framställning 2 användes, varvid 2'-(o-klorben- soyl)-4”-kloracetanilid fick reagera med natriumhydroxid, varvid erhölls e-k1°r-4-(<>-k1orfeny1)-2 (m) -kino1an.Preparation 9 6-Chloro-4- (o-chlorophenyl) Q- (1HI-quinolone The procedure of Preparation 2 was used, whereby 2 '- (o-chlorobenzoyl) -4 "-chloroacetanilide was reacted with sodium hydroxide to give e- k1 ° r-4 - (<> - chlorophenyl) -2 (m) -quinoline.
Framställning 10 2,6-diklor-4-(o-klorfenylïkinolin Förfarandet eligt A.E. Drukker och C.l. Judd, J. Heterocyclic. Chem. 3, 339 (1966) användes, varvid 6-klor-4-(o-klorfenyl)-2(lH)-kinolin klorerades, varvid erhölls 2,6-diklor-4-(o-klorfenyl)kinolin.Preparation 10 2,6-Dichloro-4- (o-chlorophenylquinoline The procedure of AE Drukker and Cl Judd, J. Heterocyclic. Chem. 3, 339 (1966) using 6-chloro-4- (o-chlorophenyl) -2 (1H) -quinoline was chlorinated to give 2,6-dichloro-4- (o-chlorophenyl) quinoline.
Framställning ll 6-klor-2-hydrazino-4-(o-klorfenyl)-kinolin På det sätt som angavs i framställning 4 upphettades 2,6-diklor- 4-(o-klorfenylfkinolin med hydrazinhydrat, varvid erhölls (6-klor- 2-hydrazino-4-(o-klorfenyl¥kinolin.Preparation 11 6-Chloro-2-hydrazino-4- (o-chlorophenyl) -quinoline As indicated in Preparation 4, 2,6-dichloro-4- (o-chlorophenylphinoline was heated with hydrazine hydrate to give (6-chlorophenyl). 2-hydrazino-4- (o-chlorophenyl) quinoline.
Framställning 12 7-klor-l-metyl-5*(o-klorfenyl)-s-triazo1r>Lß,3-a]- kinolin På det sätt som angavs i framställning 5 kokades 6-klor-2-hydrazino- 4-(o-klorfenylykinolin och trietyl-ortoacetat i xylen under åter- flöde, varvid erhölls 7-klor-l-metyl-t-(o-klorfenyl)-s-triazolo ß , s-aj- kinolin. ' Framställning 13 2',5-diklor-2-(3-metyl-4H-1,2,4-triazol-4-yl)ben- sofenon Pâ det sätt som angavs i framställning 6 oxiderades 7-klor-l-metyl- -(o-klorfenyl)-s-triazolotä,3-alkinolin i aceton med natriumper- jodat och ruteniumdioxid, varvid erhölls 2',5-diklor-2-(3-metyl- 43-1,2,4,-triazolo-4-yl)bensofenon med en smältpunkt på 147,5- 14s,s°c. 81070179 Analys: Beräknat för Cl6HllCl2N30= C 57.85; H 3.34; Cl 21.35; N 12.65.Preparation 12 7-Chloro-1-methyl-5 * (o-chlorophenyl) -s-triazolyl> β, 3-α] quinoline As described in Preparation 5, 6-chloro-2-hydrazino-4- ( o-chlorophenylyquinoline and triethyl orthoacetate in xylene under reflux to give 7-chloro-1-methyl-t- (o-chlorophenyl) -s-triazolo ß, s-aj-quinoline. 'Preparation 13 2', 5 dichloro-2- (3-methyl-4H-1,2,4-triazol-4-yl) benzophenone In the manner set forth in Preparation 6, 7-chloro-1-methyl- (o-chlorophenyl) was oxidized. -s-triazolotha, 3-alkynoline in acetone with sodium periodate and ruthenium dioxide to give 2 ', 5-dichloro-2- (3-methyl-43-1,2,4, -triazolo-4-yl) benzophenone with mp 147.5-14s, s ° C. 81070179 Analysis: Calculated for C 16 H 11 Cl 2 N 3 O = C 57.85; H 3.34; Cl 21.35; N 12.65.
Erhållet: C 57.70; H 3.21; Cl 21.58; N 12.47.' Framställning 14 2',5-diklor-2-¿'3-(hydroximetyll-5-metyl-4H- 1,2,4,triazol-4-yl]bensofenon På det sätt som angavs 1 framställning 7 behandlades 2',5-diklor- 2-(3-metyl-4H-l,2,4-triazol-4-yl)bensofenon vid l25oC i yxlen med paraformaldehyd, varvid erhölls 2“,5-diklor-2-[š-(hydroximetyl)-5- metyl-4H-triazol-4-ylybensofenon med en smältpunkt på 193,5 - 195°c.Found: C 57.70; H 3.21; Cl 21.58; N 12.47. ' Preparation 14 2 ', 5-Dichloro-2- [3- (hydroxymethyl-5-methyl-4H-1,2,4, triazol-4-yl] benzophenone In the manner set forth in Preparation 7, 2', 5 -dichloro- 2- (3-methyl-4H-1,2,4-triazol-4-yl) benzophenone at 125 DEG C. in the exchange with paraformaldehyde to give 2 ", 5-dichloro-2- [.alpha .- (hydroxymethyl) - 5-Methyl-4H-triazol-4-ylybenzophenone with a melting point of 193.5-195 ° C.
På samma sätt somëflgäVS i föregående framställningar kan andra ut- gångsföreningar med formeln I framställas. Representativa föreningar erhållna på detta sätt innefattar: 2'~klor-5-nitrc-2-'[3-(hydroximetyl)-5-metyl-4H-l,2,4,-triazol- 4-yljbensofenon; -klor-2-ŧ-(hydroximetyl)-5-etyl-4H-1,2,4-triazol-4-yl]bensofenon; -k10r-2-[§-(hyaroximetyl)-5-fenyl-4H-1,2,4-triazol-4-yr]- bensofenon; . -klor~2-Äš-(hydroximetyl)-5-bensyl-4H-1,2,4-triazol-4-yl]- bensofenon; 2“ , 6 '-difluor- 5- (metyltio) -2- E- (hydroximetylfinopyl-S ~4H-l , 2 , 4- triazol-4-ylybensofenon; -brom-2'-klor-2-[š-(hydroximetyl)4H-l,2,4-triazol-4-yli- bensofenon; 2'-khnP5-fluor-2-Zš-(hydroximetyl)-4H-l,2,4-triazol-4-yl7bensO_ fenon; I 2'-klor-6-cyano-2-Åš-(hydroximetyl)-5-karbometoxi-4H-l,2,4-triazol- 4-yl]bensofenon; 2'-klor-4-dietylamino-2-lg-(hydroximetyl)-5-metyl-4H-1,2,4-triazol- 4-yl7bensofenon; 2'-klor-5-(metyltio)-2-l§-(hydroximetyl)-5-metyl-4H-l,2,4,-triazol- 4-ylybensofenon; 2'-klor-3-formamido=2-lä-(hydroximetyl)-5-etyl~4H-1,2,4-triazol- 4-ylybensofenon; 81107017-9 2'-k1°r-4-cety1su1finy1)-2- [§-(nyaroxrmetylx-5-fenyl-4H-1,2,4- triazol-4-yl]bensofenon; 2'-klor-5-(propylsulfonyl1-2-¿ë-(hydroximetylï-5-karbopropoxi- 4H-l,2,4-triazol-4-yl]bensofenon; 6-metyl-3'-(propyltio)-2-[š-(hydroximetyl)-4H-1,2,4-triazol-4- ylybensofenon; 2"-(dimetylamíno)-4-isopro;@1- 2 -~Åš-(hydroximetyl)-4H-l,2,4- triazol-4-yl]bensofenon; 2'-klor-4,5-dicyano-2-l§-(hydroxímetyl)-5-metyl-4H-l,2,4-triazol- 4-yl]bensofenon; * 3'-(etylsulfinyl)-3,5-dipropyl-2- 3-(hydroximetyl)-5-metyl-4H- l,2,4-triazol-4-ylybensofenon; -klor-2'-acetamido-2- 3-(hydroximetyl)-5-metyl-4H-1,2,4-triazol- 4-yl]bensofenon; S-klor-2- Érflßiübxümfiäl)-M%-1,2,4-triazol-4-ylybensofenon; 2'-klor-2-ŧ-(hydroximetyl)-4H-l,2,4-triazol-4-yl]bensofenon; 2',5-diklor-2-lä-(hydroximetyl)-4H-1,2,4,-triazol-4-ylibensofenon; 2-[š-(hyaroximety1>-4H-1,2,4-triazol-4-yijbensørenon; 2-L;-(hydroximetyl)-5-metyl-4H-l,2,4-triazo1-4-yl7bensofenon; och liknande.In the same way as in previous presentations, other starting compounds of formula I can be prepared. Representative compounds thus obtained include: 2 '- chloro-5-nitrc-2 -' [3- (hydroxymethyl) -5-methyl-4H-1,2,4, -triazol-4-yl] benzophenone; -chloro-2-α- (hydroxymethyl) -5-ethyl-4H-1,2,4-triazol-4-yl] benzophenone; -k10r-2- [§- (hyaroxymethyl) -5-phenyl-4H-1,2,4-triazol-4-yl] -benzophenone; . -chloro-2-š- (hydroxymethyl) -5-benzyl-4H-1,2,4-triazol-4-yl] -benzophenone; 2 ', 6' -difluoro-5- (methylthio) -2- E- (hydroxymethyl-monopyl-S-4H-1,2,2-triazol-4-ylybenzophenone; -bromo-2'-chloro-2- (hydroxymethyl) 4H-1,2,4-triazol-4-yl-benzophenone; 2'-quinP5-fluoro-2-Zš- (hydroxymethyl) -4H-1,2,4-triazol-4-yl7-benzo-phenone; 2'-chloro-6-cyano-2-Ås- (hydroxymethyl) -5-carbomethoxy-4H-1,2,4-triazol-4-yl] benzophenone; 2'-chloro-4-diethylamino-2-Ig (hydroxymethyl) -5-methyl-4H-1,2,4-triazol-4-yl7benzophenone; 2'-chloro-5- (methylthio) -2-1- (hydroxymethyl) -5-methyl-4H-1, 2,4, -triazol-4-ylybenzophenone; 2'-chloro-3-formamido = 2-la- (hydroxymethyl) -5-ethyl-4H-1,2,4-triazol-4-ylybenzophenone; 81107017-9 2 '-k1 ° r-4-cetylsulfinyl) -2- [§- (nyaroxymethylx-5-phenyl-4H-1,2,4-triazol-4-yl] benzophenone; 2'-chloro-5- (propylsulfonyl1-2) -Β- (hydroxymethyl-5-carbopropoxy-4H-1,2,4-triazol-4-yl] benzophenone; 6-methyl-3 '- (propylthio) -2- [β- (hydroxymethyl) -4H-1 , 2,4-triazol-4-ylybenzophenone; 2 "- (dimethylamino) -4-isopro; 1-2 - 2- [2- (hydroxymethyl) -4H-1,2,4-triazol-4-yl] benzophenone; 2'-chloro-4,5-dicyano-2- [1- (hydroxymethyl) -5-methyl-4H-1,2,4- triazol-4-yl] benzophenone; * 3 '- (ethylsulfinyl) -3,5-dipropyl-2- 3- (hydroxymethyl) -5-methyl-4H-1,2,4-triazol-4-ylybenzophenone; -chloro-2'-acetamido-2- 3- (hydroxymethyl) -5-methyl-4H-1,2,4-triazol-4-yl] benzophenone; S-chloro-2- (β-β-β-β) -M% -1,2,4-triazol-4-ylybenzophenone; 2'-chloro-2-N- (hydroxymethyl) -4H-1,2,4-triazol-4-yl] benzophenone; 2 ', 5-dichloro-2-la- (hydroxymethyl) -4H-1,2,4, -triazol-4-yl-benzophenone; 2- [β- (hyaroxymethyl) -4H-1,2,4-triazol-4-ylbenzenerenone; 2-L ;-( hydroxymethyl) -5-methyl-4H-1,2,4-triazol-4-yl] benzophenone; and similar.
Exemgel l 5-klor-2- 3-(ftalimidometyl)-5-metyl-4H-1,2,4-triazol- 4-yl)bensofenon En omrörd blandning av 5-klor-2-Zš-(hydroximetyl)-5-metyl-4H-1,2,4- triazøl-4-y§]bensQfenon (o,sss g, o;ooz mo1)afta1imia (o,324 g, 0,0022 mol), trifenylfosfin (0,576 9, 0,0022 mol) och torr tetra- hydrofuran (20 ml) i kväveatmosfär behandlades med dietylazokar- boxylat (0,383 g, 0,0022 mol) och omrördes vid omgivningens tempe- ratur under 23 timmar. Blandningen koncentrerades i vakuum och åter- stoden kromatograferades på kiselgel (75 g) med 1,5 % metanol, 98,5 % kloroform, varvid fraktioner på 10 ml uppsamlades. Produkten eluerades i fraktionerna 31-57 och kristalliserade' ur metanol- etylacetat, varvid erhölls 0,148 g 5-klor-2-ß-(ftalimidometyl)-5- metyl-4H-l,2,4-twiazo11~4-yljbensofenon med en smältpunkt pâ 217,5- 219°c;'o,2s7 g av en produkt med en smältpunkt på 219-22oPc; 0,189 g med en smältpunkt på 218,5-220°C; 0,082 g med en smältpunkt på 219-220,5°C av 5-klor-2-ŧ-(ftalimido-metyl)-5-metyl-4H-l,2,4- trialzol-4-yl)bensofenon. 8107017-'9 ll Ett analytiskt prov hade en smältpunkt på 219-22l°C.Example 1 5-chloro-2- 3- (phthalimidomethyl) -5-methyl-4H-1,2,4-triazol-4-yl) benzophenone A stirred mixture of 5-chloro-2-Zš- (hydroxymethyl) -5 -methyl-4H-1,2,4-triazol-4-yl] benzophenone (o, sss g, o; ooz mol) phthalate (o, 324 g, 0.0022 mol), triphenylphosphine (0.576 9, 0, 0022 mol) and dry tetrahydrofuran (20 ml) in a nitrogen atmosphere were treated with diethyl azocarboxylate (0.383 g, 0.0022 mol) and stirred at ambient temperature for 23 hours. The mixture was concentrated in vacuo and the residue was chromatographed on silica gel (75 g) with 1.5% methanol, 98.5% chloroform to collect 10 ml fractions. The product was eluted in fractions 31-57 and crystallized from methanol-ethyl acetate to give 0.148 g of 5-chloro-2-β- (phthalimidomethyl) -5-methyl-4H-1,2,4-thiazol-4-yl] benzophenone with a melting point of 217.5-219 ° C; 0.2s7 g of a product having a melting point of 219-222 ° C; 0.189 g with a melting point of 218.5-220 ° C; 0.082 g with a melting point of 219-220.5 ° C of 5-chloro-2-α- (phthalimidomethyl) -5-methyl-4H-1,2,4-trialzol-4-yl) benzophenone. An analytical sample had a melting point of 219-222 ° C.
Analys: Beräknat för C25Hl7ClN4Q3 C 65.72; H 3.75; Cl 7.76; N 12.26.Analysis: Calculated for C 25 H 17 ClN 4 Q 3 C 65.72; H 3.75; Cl 7.76; N 12.26.
Erhållet: C 65.86; H 3.83; Cl 7.72; N 12.63.Found: C 65.86; H 3.83; Cl 7.72; N 12.63.
Alternativa 2-lš~(ftälimiå0metyD-4H-1,2,4-triazol-4-ylybensofenoner med formeln II, där A betecknar: ftp k / kan framställas ur 3-amino-3,4-dihydro-4-hydroxi-4-fenylkinazoliner med formeln IV genom att tillåta en förening med formeln IV reagera med ett aktiverat derivat av ftaloylglycin, t ex syrakloriden, blanda- dade anhydrider eller imidazolid, varefter den erhållna produkten värmesi ättíksyra, varvid erhålles en förening med formeln II, där 0 A betecknar: 0 ny, \ % / 0 3-amino-3,4-dihydro-4-hydroxi-4-fenylkinazoliner (IV) kan framstäl- las på det sätt som beskrives i litteraturen för en framställning av 3-amino-6-klor-3,4-dihydro-4-hydroxi-4-fenylkinazoliner av M.E.Alternative 2- [1- [Phthilimethylmethyl-4H-1,2,4-triazol-4-ylybenzophenones of the formula II, wherein A represents: ftp k / can be prepared from 3-amino-3,4-dihydro-4-hydroxy-4 -phenylquinazolines of the formula IV by allowing a compound of the formula IV to react with an activated derivative of phthaloylglycine, for example the acid chloride, mixed anhydrides or imidazolide, after which the product obtained is heated in acetic acid to give a compound of the formula II in which denotes: 0 new, \% / 0 3-amino-3,4-dihydro-4-hydroxy-4-phenylquinazolines (IV) can be prepared in the manner described in the literature for a preparation of 3-amino-6- chloro-3,4-dihydro-4-hydroxy-4-phenylquinazolines of ME
Derieg och medarbetare, Ü. Org. Chem. 36, 782 (1971): 8107017-9 där Rl, R2, R3, R4 och R5 tidigare definierats och där X betecknar klor, brom, 0 u -O-C-OC2H5 eller 81--07017-9 13 och där A betecknar Exempel 2 5-klor-2-[B-(ftalimidometyl)-5-metyl-4H-l,2,4,-triazol- 4-yllbensofenon En omrörd lösning av ftaloylglycin (2,26 g, 0,01 mol) i torr tetra- hydrofuran (20 ml) i käveatmomsfär kyldes på ett isbad och behandla- des med karbonyldiimidazol. Blandningen hölls vid omgivningens tempe- ratur (22-24°C) under 1,5 timmar, kyldes på ett isbad och behandla- des med en blandning av 3-amino-6-klor-3,4-dihydro-4-hydroxi-4- fenylkinazolin (2,88 g, 0,01 mol) i tetrahydrofuran (25 ml). Bland- ningen hölls vid omgivningens temperatur under 42 timmar och koncent- rerades i vakuum. Återstoden blandades med utspädd natriumbikarbonat- lösning och extraherades med metylenklorid. Extrakten tvättades med mättad natriumkloridlösning, torkades över vattenfritt natriumsulfat och koncentrerades, varvid erhölls en oren olja. Denna olja blanda- des med ättiksyra (50 ml) och värmdes på ett oljebad till l20°C under en timme.Ättiksyränkoncentrerades i vakuum och återstoden blandades med vatten, neutraliserades med natrlumbikarbonat och extra- herades med metylenklorid. Extraktet tvâttades med vatten, torkades över vattenfritt natrhmmulfat och koncentrerades. Återstoden kromato- graferades över kiselgel (400 g) med 2,5 % metanol - 97,5 % kloro- form. Den erhâllna produkten från kolonnen kristalliserades ur me- tylenklorid-etylacetat, varvid erhölls 0,24 g 5-klor-2-¿§-ftalimido- metyl)-S-metyl-4H-l,2,4,-triazol-4-ylybensofenon med en smältpunkt på 21s-21s°c. ytterligare 0,135 g ev denna produkt erhölls :med en sfaltpunkt på 216-2l8,5°C vid upparbetning av moderlutarna¿ 8107017-9 14 Exempel 3 8-k1or-l-metyl-S-fenyl-llii-s-triaåoloE!ß-aj- [1,ë7bensodiazepin En omrörd blandning av Sfi-klor-Z- ß- (ftàlinxidometyl) -S-metyl-LIH- 1,2,4-trdazol-4-ylibensofenon (0,257g,0)562 mmoll och absolut etanol (3 mll behandlades med hydrazin (0,05 ml, 1,04 mmol) och- värmdes på ett oljebad till 739C under 80 minuter. (Ur lösningen fälldes ett fastnmterialefter 30 minuterï. Den kylda blandningen blandades med vatten och extraherades med kloroform. Extraktet tvättades med koksalt, torkades över vattenfritt natriumsulfat och «koncentrerades. Återstoden kromatograferades på kiselgel (42 g) med 2 % metanol-98 % kloroform, varvid fraktioner pa 10 ml uppsamlades.Derieg and co-workers, Ü. Org. Chem. 36, 782 (1971): 8107017-9 where R1, R2, R3, R4 and R5 have been previously defined and where X represents chlorine, bromine, 0 u -OC-OC2H5 or 81--07017-9 13 and where A represents Example 2 5-Chloro-2- [B- (phthalimidomethyl) -5-methyl-4H-1,2,4, -triazol-4-ylbenzophenone A stirred solution of phthaloylglycine (2.26 g, 0.01 mol) in dry tetra hydrofuran (20 ml) in a nitrogen atmosphere was cooled in an ice bath and treated with carbonyldiimidazole. The mixture was kept at ambient temperature (22-24 ° C) for 1.5 hours, cooled in an ice bath and treated with a mixture of 3-amino-6-chloro-3,4-dihydro-4-hydroxy. 4-phenylquinazoline (2.88 g, 0.01 mol) in tetrahydrofuran (25 ml). The mixture was kept at ambient temperature for 42 hours and concentrated in vacuo. The residue was mixed with dilute sodium bicarbonate solution and extracted with methylene chloride. The extracts were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give a crude oil. This oil was mixed with acetic acid (50 ml) and heated on an oil bath to 120 ° C for one hour. Acetic acid was concentrated in vacuo and the residue was mixed with water, neutralized with sodium lumbicarbonate and extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel (400 g) with 2.5% methanol - 97.5% chloroform. The product obtained from the column was crystallized from methylene chloride-ethyl acetate to give 0.24 g of 5-chloro-2-((6-phthalimidomethyl) -S-methyl-4H-1,2,4, -triazole-4- ylybenzophenone with a melting point of 21s-21s ° c. an additional 0.135 g, if any, of this product was obtained: with an asphalt point of 216-218.5 ° C when working up the mother liquors Example 3 8-chloro-1-methyl-S-phenyl-llii-s-triazolol aj- [1,7-benzodiazepine A stirred mixture of S fi-chloro-Z- ß- (phthalinxidomethyl) -S-methyl-LIH-1,2,4-trdazol-4-ylibenzophenone (0.257g, 0) 562 mmol and absolute ethanol (3 ml) was treated with hydrazine (0.05 ml, 1.04 mmol) and heated on an oil bath to 73 DEG C. for 80 minutes. (From the solution a solid was precipitated after 30 minutes). The cooled mixture was mixed with water and extracted with chloroform. washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel (42 g) with 2% methanol-98% chloroform to collect 10 ml fractions.
Produkten eluerades ur fraktionerna 33+57 och kristalliserades ur etylacetat, varvid erhölls 77 mg med en smältpunkt på 229-230°C och ze mg med en smältpunkt på 22a-229i,s°c av s-kior-i-metyl-e-fenyl- 4H-s-triazölolä,3-ay¿l,¶]bensodiazepin.The product was eluted from fractions 33 + 57 and crystallized from ethyl acetate to give 77 mg with a melting point of 229-230 ° C and ze mg with a melting point of 22a-229i, s ° c of s-chloro-i-methyl-e- phenyl-4H-s-triazolola, 3-ayl, ¶] benzodiazepine.
Analys; Beräknat för Cl7H13C1N4: C 66.13; H 4.24; Cl 11.48; N 18.15.Analysis; Calculated for C 17 H 13 ClN 4: C 66.13; H 4.24; Cl 11.48; N 18.15.
Erhâlletz C 66.05; H 4.13; Cl 11.34; N 18.00.Maintenance C 66.05; H 4.13; Cl 11.34; N 18.00.
Exempel 4 8-nitro-l-metyl-6-(o-klorfenyl)-4H-s-triazo1o¿;,3-ål_ Ål,4]bensodiazepin På samma sätt som i exempel 1 behandlades enblandningav 5-nitro- 2'-klor-2- ß- (hydroximetyl) -S-metyl- 4H-l, 2 , 4 , -triazol-fll-yfl benso- fenon, ftalimid och trifenylfosrin i tetrahydrofuran med dietylazo- karboxylat, varvid erhölls 5~nitro-2'-klor-2-[§-(ftalimidometyl)-5- metyl-4H-1,2,4,-triazol-4-y1]bensofenon.Example 4 8-Nitro-1-methyl-6- (o-chlorophenyl) -4H-s-triazolo [3,3-eel] Al, 4] benzodiazepine In the same manner as in Example 1, a mixture of 5-nitro-2'- chloro-2β- (hydroxymethyl) -S-methyl-4H-1,2,4,4-triazol-1-yl benzophenone, phthalimide and triphenylphosrine in tetrahydrofuran with diethyl azocarboxylate to give 5-nitro-2 ' -chloro-2- [§- (phthalimidomethyl) -5-methyl-4H-1,2,4, -triazol-4-yl] benzophenone.
Pâ det sätt som angavs i exempel 2 upphettades 5-nitro-2”-klor-2- Lä-(ftalimidometyl)-5-metyl-4H-1,2,4,-triazol-4-y17bensofenon i etanol med hydrazinhydrat, varvid erhölls 8-nitro-1-mety1-6-(o- klorfenyl)-4H-s-triazolo¿Ä,3-a?Ål,Q]hensodiazepin. 8107017-9 Exempel 5 8-f1uor-l-etyl-6-!;-(propylsulfinyl)fenyá7-4H-s-triazolo- [Ä,3-a]Äl,4 bensodiazepin På det sätt som angavs i exempel 1 behandlades en blandning av 5- fluor-4'-(propylsulfinyl)-2-l§-(hydroximetyfl-5-etyl-4H-1,2,4-triazol- 4~yl]bensofenon, ftalimid och trifenylfosfin i dioxan med dietyl- azodikarboxylat, varvid erhölls 5-fluor-4'**(propylsulfinyl)-2- [E-(ftalimidometyl)-5-etyl-4H-l,2,4-triazol-4-yi7bensofenon.In the manner set forth in Example 2, 5-nitro-2 "-chloro-2- (1- (phthalimidomethyl) -5-methyl-4H-1,2,4, -triazol-4-yl] benzophenone in ethanol was heated with hydrazine hydrate, there was obtained 8-nitro-1-methyl-6- (o-chlorophenyl) -4H-s-triazolo [3-a] al, Q] hensodiazepine. Example 5 8-Fluoro-1-ethyl-6 - [(propylsulfinyl) phenyl] -4H-s-triazolo- [N, 3-a] Al, 4 benzodiazepine In the manner set forth in Example 1, a mixture of 5-fluoro-4 '- (propylsulfinyl) -2-1- (hydroxymethyl-5-ethyl-4H-1,2,4-triazol-4-yl] benzophenone, phthalimide and triphenylphosphine in dioxane with diethyl azodicarboxylate to give 5-fluoro-4 '** (propylsulfinyl) -2- [E- (phthalimidomethyl) -5-ethyl-4H-1,2,4-triazol-4-yl] benzophenone.
Pâ det sätt som angavs i exempel 3 upphettades 5-fluor-4“-(propyl- sulfinyl)-2-¿§-(ftalimidometyl)-5-etyl-AH-l,2,4-triazol-4-yl7benso- fenon i etanol med hydrazinhydrat, varvid erhölls 8-fluor~l-etyl- 6-lš-(propylsulfinyl)fenyll-4H-s-triazolold,3-a)Ål,¶]bensodiazepin.In the manner set forth in Example 3, 5-fluoro-4 "- (propylsulfinyl) -2-N- (phthalimidomethyl) -5-ethyl-AH-1,2,4-triazol-4-yl7benzophenone was heated. in ethanol with hydrazine hydrate to give 8-fluoro-1-ethyl-6-1β- (propylsulfinyl) phenyl-4H-s-triazolold, 3-a) eel, ¶] benzodiazepine.
Exempel 6 8-metyltio-l-metyl-6-(o-klorfenyl)-4H-s-triazoloÄ¿,3-a7- [l,4]bensodiazepin Pâ samma sätt som i exempel 3 behandlades en blandning av 5-metyltio- 2-klor-2-lå(hydroximetyl)-5-metyl-4H-l,2,4-triazol-4-ylybensofenon, ftalimid och trifenylfosfin i tetrahydrofuran med dietylazodikarbo- xylat, varvid erhölls 5-metyltio-2“-klor-2Lš-(fcalimidometyl)-5- metyl-4H-1,2,4-triazol-4-ylybensofenon.Example 6 8-Methylthio-1-methyl-6- (o-chlorophenyl) -4H-s-triazolo [3,3-a7- [1,4] benzodiazepine In the same manner as in Example 3, a mixture of 5-methylthio- 2-Chloro-2-la (hydroxymethyl) -5-methyl-4H-1,2,4-triazol-4-ylybenzophenone, phthalimide and triphenylphosphine in tetrahydrofuran with diethyl azodicarboxylate to give 5-methylthio-2 "-chloro- 2Lš- (phcalimidomethyl) -5-methyl-4H-1,2,4-triazol-4-ylybenzophenone.
På det sätt som angavs i exempel 5 upphettades 5-metyltio-2'-klor-2- 3-(ftalimiåometyl)-5-metyl-4H-1,2,4-triazol-4-ylybensofenon i eta- nol med hydrazinhydrat, varvid erhölls 8-metyltio-l-metyl-6-(o-klor- fenyl)-4H-s-triazolo[%,3-a] l,¶7bensodiazepin.In the manner of Example 5, 5-methylthio-2'-chloro-2- (3- (phthalimylmethyl) -5-methyl-4H-1,2,4-triazol-4-ylybenzophenone in ethanol was heated with hydrazine hydrate. to give 8-methylthio-1-methyl-6- (o-chlorophenyl) -4H-s-triazolo [%, 3-a] 1,7-benzodiazepine.
Exempel 7 l-fenyl-9-etoxi-8~isopropyl-6-Åm-(metyltio)-fenyl?4H- s-triazolo ß, 3-a7ß.,4]bensodiazepin På det sätt som angavs i exempel 3 behandlades en blandning av 4-etoxi-5-isopropyl-3'-metyltio-2-tš-(hydroximetyl)-5-fenyl-4H- 1,2,4-triazol-4-yl7bensofenon, ftalimid och trifenylfosfin i tetra- hydrofuran med dietylazodikarboxylat, varvid erhölls 4-etoxi-5-iso- propyl-3'-metyltio-2-Zš-(ftalimidometyl)-5-fenyl-4H-1,2,4-triazol- 4-yl bensofenon. 8107017-9 16 På det sätt som angavs i exempel 3 upphettades 4-etoxi-5-isopropyl- ar-metyltio-z- s-(ftainumaometyn -s-fenyi-fzn-i, z , 4-triazøi-4-yfl ben- sofenon i etanol med hydrazinhydrat, varvid erhölls l-fenyl-9-etoxis 8-isopropyl-G-[u-(metyltio) fenyl] -llffi-s-triazoløßi , 3-:37 [lnljbensodia- zepin.Example 7 1-Phenyl-9-ethoxy-8-isopropyl-6-Nα- (methylthio) -phenyl-4H-s-triazolo β, 3-α7β, 4] benzodiazepine In the manner of Example 3, a mixture was treated of 4-ethoxy-5-isopropyl-3'-methylthio-2-tis- (hydroxymethyl) -5-phenyl-4H-1,2,4-triazol-4-yl7benzophenone, phthalimide and triphenylphosphine in tetrahydrofuran with diethyl azodicarboxylate, to give 4-ethoxy-5-isopropyl-3'-methylthio-2-Z- (phthalimidomethyl) -5-phenyl-4H-1,2,4-triazol-4-yl benzophenone. In the manner set forth in Example 3, 4-ethoxy-5-isopropyl-ar-methylthio-z- s- (phthalumaomethyl-5-phenyl-phenyl-z, 4-triazo-4-yl) sophenone in ethanol with hydrazine hydrate to give 1-phenyl-9-ethoxy 8-isopropyl-G- [.alpha .- (methylthio) phenyl] -11β-s-triazolose, 3-:37 [.alpha.-benzodiazepine.
Exemgel 8 l-propyl-8-isopropylsulfonyl-6-(o-flüorfenyl)-4H-s-tria- zolo[§,3-ayllsåzbensodiazepin Pâ det sätt som angavs i exempel l behandlades en blandning av S-isopro- pylsulfonyl-2'-fluor-2lå-(hydroximetyl)-5-propyl-4H-1,2,4-triazo1- 4-yljbensofenon, ftalimid och trifenylfosfin i tetrahydrofuran med dietylazodikarboxylat, varvid erhålles 5-isopropylsulfonyl-2'-fluor- 2-[š-(ftalimidometyl)-5-propyl-4H-l,2,4-triazol-4-yl7bensofenon.Example 8 1-propyl-8-isopropylsulfonyl-6- (o-fluorophenyl) -4H-s-triazolo [§, 3-ayl] benzodiazepine In the manner set forth in Example 1, a mixture of S-isopropylsulfonyl-2 was treated. '-fluoro-2α- (hydroxymethyl) -5-propyl-4H-1,2,4-triazol-4-yl] benzophenone, phthalimide and triphenylphosphine in tetrahydrofuran with diethyl azodicarboxylate to give 5-isopropylsulfonyl-2'-fluoro-2- [ š- (phthalimidomethyl) -5-propyl-4H-1,2,4-triazol-4-yl7benzophenone.
Pâ samma sätt som angavs i exempel-3 upphettades en lösning av -isopropylsulfonyl-2'-fluor-2-ZE-(ftalímidometyb-5-propyl-4H- l,2,4-triazol-4-yl)bensofenon i metanol med hydrazinhydrat, varvid erhölls l-propyl-8-isopropy1sulfonyl-6-(o-fluorfeny1%4H-s-triazolo- [g,3-a]¿l,d]bensodiazepin.In the same manner as in Example 3, a solution of -isopropylsulfonyl-2'-fluoro-2-ZE- (phthalimidomethyb-5-propyl-4H-1,2,4-triazol-4-yl) benzophenone in methanol was heated with hydrazine hydrate to give 1-propyl-8-isopropylsulfonyl-6- (o-fluorophenyl% 4H-s-triazolo- [g, 3-a] β, d] benzodiazepine.
Exemgel 9 l-bensyl-7-formamido-6-(o-klorfenyl)-4H-s-triazolo 4,3-Éy- l:l,{]bensodiazepin På det satt som angavs i exempel l behandlades enßlandningav 6- formamido-2'-klor-2-[-3-(hydroximetyl)-5-bensyl-4H-1,2,4-triazol- 4-yl]bensofenon, ftalimid och trifenylfosfin i tetrahydrofuran Och dietylazodikarboxylat, varvid erhölls 6-formamido-2'-klor-2-¿š1?ta- limidometyl)-5-bensyl-4H-l,2,4-triazol-4-ylybensofenon.Example 9 1-Benzyl-7-formamido-6- (o-chlorophenyl) -4H-s-triazolo 4,3-Eyl-1,1, {] benzodiazepine In the manner set forth in Example 1, a mixture of 6-formamido- 2'-chloro-2 - [- 3- (hydroxymethyl) -5-benzyl-4H-1,2,4-triazol-4-yl] benzophenone, phthalimide and triphenylphosphine in tetrahydrofuran And diethyl azodicarboxylate to give 6-formamido-2 (1-chloro-2-(1-thalamidolomethyl) -5-benzyl-4H-1,2,4-triazol-4-ylybenzophenone.
På det sätt som angavs i exempel 3 upphettades 6-formamido-2'-klor- 2- [š- (ftalimiaometyl) -s-bensy1-4n-1 , 2, 4-triaz01-4-yflbensofenon 1 etanol med hydrazinhydrat, varvid erhölls l-bensyl-7-formamido-6- (o-klorfenyl)-4H-s-triazollâ,3-a7Ål,é]bensodiazepin. 8107017-9 17 Exemßel 10 8-klor-l-metyl-6-(o-klorfenyli-4H-s-triazolZTÄ,3-a;_ [l,ê7bensødiazepin Pâ det sätt som angavs i exempel 1 behandlades enßflandningav 2',5- diklor-2-Åš-(hydroximetyll-5-metyl-4H-1,2,4-triazol-4-yl7bensofénon, ftalimid och trifenylfosfin i tetrahydrofuran med dietylazodikar- boxylat, varvid erhölls 2',5-diklor-2-Z§-(ftalimidometyl)-5-metyl~ 4H-l,2,4-triazol-4-yl7bensofenon med en Smältpunktpå 262-265°C. 2sH16°l2N4°3* Analys: Beräknat för C C 61.11; H 3.28; Cl 14.43; N 11.40.In the manner set forth in Example 3, 6-formamido-2'-chloro-2- [š- (phthalimylmethyl) -s-benzyl-4n-1,2,4-triazol-4-yl] benzophenone 1 ethanol was heated with hydrazine hydrate, 1-Benzyl-7-formamido-6- (o-chlorophenyl) -4H-s-triazolα, 3-α7α1, e] benzodiazepine was obtained. Example 10 8-Chloro-1-methyl-6- (o-chlorophenyl-4H-s-triazolZTA, 3-a; _ [1,7] benzodiazepine In the manner set forth in Example 1, a breath of 2 ', 5 dichloro-2-Åš- (hydroxymethyl-5-methyl-4H-1,2,4-triazol-4-yl] benzophenone, phthalimide and triphenylphosphine in tetrahydrofuran with diethyl azodicarboxylate to give 2 ', 5-dichloro-2-Z §- (phthalimidomethyl) -5-methyl-4H-1,2,4-triazol-4-yl7benzophenone with a melting point of 262-265 ° C.25H16 ° 12N4 ° 3 * Analysis: Calculated for CC 61.11; H 3.28; Cl 14.43 ; N 11.40.
Erhâllet: C 60.77; H 3.26; Cl 14.49; N 11.45.Found: C, 60.77; H 3.26; Cl 14.49; N 11.45.
Pâ det sätt søm angavs i exempel 2 upphettades 2",5-diklor-2-¿š- (ftalimidometyl)-5-metyl-4H-1,2,4-triazol-4-yâïbensofenon i etanol med hydrazinhydrat, varvid erhölls 8-klor-l-metyl-6-(o-klorfenyl)- 4H-s-triazololå,3-a]¿d,4] bensodiazepin med en smältpunkt på 223- 22s°c.As indicated in Example 2, 2 ", 5-dichloro-2-β- (phthalimidomethyl) -5-methyl-4H-1,2,4-triazol-4-ylbenzophenone in ethanol was heated with hydrazine hydrate to give 8 -chloro-1-methyl-6- (o-chlorophenyl) -4H-s-triazololo, 3-a] ¿d, 4] benzodiazepine with a melting point of 223-222 ° C.
Claims (5)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33237773A | 1973-02-14 | 1973-02-14 |
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| Publication Number | Publication Date |
|---|---|
| SE8107017L SE8107017L (en) | 1981-11-25 |
| SE435285B true SE435285B (en) | 1984-09-17 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE7401858A SE423546B (en) | 1973-02-14 | 1974-02-12 | PROCEDURE FOR PREPARING 6-PHENYL-4H-S-TRIAZOLO (4,3-A) (1,4) BENZODIAZEPINES |
| SE8107017A SE435285B (en) | 1973-02-14 | 1981-11-25 | PROCEDURE FOR PREPARING 6-PHENYL-4H-S-TRIAZOLO (4,3-A) (1,4) BENZODIAZEPINES |
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| SE7401858A SE423546B (en) | 1973-02-14 | 1974-02-12 | PROCEDURE FOR PREPARING 6-PHENYL-4H-S-TRIAZOLO (4,3-A) (1,4) BENZODIAZEPINES |
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| Country | Link |
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| JP (1) | JPS49110699A (en) |
| AU (1) | AU471038B2 (en) |
| BE (1) | BE811025A (en) |
| CA (1) | CA999000A (en) |
| CH (2) | CH587263A5 (en) |
| DE (1) | DE2402363A1 (en) |
| DK (1) | DK140803B (en) |
| ES (2) | ES422941A1 (en) |
| FR (1) | FR2217335B1 (en) |
| GB (3) | GB1454684A (en) |
| HU (1) | HU168136B (en) |
| IL (3) | IL44068A (en) |
| NL (1) | NL7400958A (en) |
| PH (2) | PH10784A (en) |
| SE (2) | SE423546B (en) |
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| US3709898A (en) * | 1971-02-09 | 1973-01-09 | Upjohn Co | Process for the production of triazolobenzodiazepines and intermediates |
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1974
- 1974-01-14 CH CH1421978A patent/CH587263A5/xx not_active IP Right Cessation
- 1974-01-14 CH CH48574A patent/CH586704A5/xx not_active IP Right Cessation
- 1974-01-14 CA CA190,079A patent/CA999000A/en not_active Expired
- 1974-01-18 DE DE2402363A patent/DE2402363A1/en not_active Withdrawn
- 1974-01-22 ZA ZA740466A patent/ZA74466B/en unknown
- 1974-01-23 AU AU64786/74A patent/AU471038B2/en not_active Ceased
- 1974-01-24 NL NL7400958A patent/NL7400958A/xx not_active Application Discontinuation
- 1974-01-24 IL IL44068A patent/IL44068A/en unknown
- 1974-01-24 IL IL49503A patent/IL49503A/en unknown
- 1974-01-30 PH PH15460A patent/PH10784A/en unknown
- 1974-02-04 JP JP49013786A patent/JPS49110699A/ja active Pending
- 1974-02-05 ES ES422941A patent/ES422941A1/en not_active Expired
- 1974-02-07 GB GB2340276A patent/GB1454684A/en not_active Expired
- 1974-02-07 GB GB2340176A patent/GB1454683A/en not_active Expired
- 1974-02-12 SE SE7401858A patent/SE423546B/en not_active IP Right Cessation
- 1974-02-13 FR FR7404855A patent/FR2217335B1/fr not_active Expired
- 1974-02-13 DK DK73974AA patent/DK140803B/en not_active IP Right Cessation
- 1974-02-14 HU HUUO99A patent/HU168136B/hu not_active IP Right Cessation
- 1974-02-14 BE BE140902A patent/BE811025A/en not_active IP Right Cessation
- 1974-04-07 GB GB576474*[A patent/GB1454682A/en not_active Expired
-
1976
- 1976-03-08 ES ES445860A patent/ES445860A1/en not_active Expired
- 1976-04-30 IL IL49503A patent/IL49503A0/en unknown
-
1977
- 1977-04-05 PH PH19633A patent/PH11789A/en unknown
-
1981
- 1981-11-25 SE SE8107017A patent/SE435285B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IL44068A (en) | 1977-05-31 |
| CA999000A (en) | 1976-10-26 |
| GB1454682A (en) | 1976-11-03 |
| GB1454684A (en) | 1976-11-03 |
| DE2402363A1 (en) | 1974-08-22 |
| AU471038B2 (en) | 1976-04-08 |
| HU168136B (en) | 1976-02-28 |
| DK140803C (en) | 1980-04-21 |
| CH586704A5 (en) | 1977-04-15 |
| AU6478674A (en) | 1975-07-24 |
| DK140803B (en) | 1979-11-19 |
| FR2217335B1 (en) | 1977-06-10 |
| ES445860A1 (en) | 1977-05-01 |
| NL7400958A (en) | 1974-08-16 |
| PH11789A (en) | 1978-07-05 |
| GB1454683A (en) | 1976-11-03 |
| IL49503A0 (en) | 1976-06-30 |
| JPS49110699A (en) | 1974-10-22 |
| CH587263A5 (en) | 1977-04-29 |
| SE423546B (en) | 1982-05-10 |
| SE8107017L (en) | 1981-11-25 |
| IL49503A (en) | 1977-05-31 |
| ES422941A1 (en) | 1976-09-16 |
| FR2217335A1 (en) | 1974-09-06 |
| BE811025A (en) | 1974-08-14 |
| PH10784A (en) | 1977-09-06 |
| ZA74466B (en) | 1974-12-24 |
| IL44068A0 (en) | 1974-05-16 |
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| NUG | Patent has lapsed |
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