DK141726B - Process for the preparation of s-triazolo (4,3-a) (1,4) -benzodiazepine derivatives. - Google Patents
Process for the preparation of s-triazolo (4,3-a) (1,4) -benzodiazepine derivatives. Download PDFInfo
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- DK141726B DK141726B DK520370A DK520370A DK141726B DK 141726 B DK141726 B DK 141726B DK 520370 A DK520370 A DK 520370A DK 520370 A DK520370 A DK 520370A DK 141726 B DK141726 B DK 141726B
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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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- 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
- C07D243/20—Nitrogen atoms
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Description
(11) FREMLÆGGELSESSKRIFT 141726 DANMARK (B1) lnt C| 3 c 07 D 487/04 §(21) Ansøgning nr. 5203/70 (22) Indleveret den 14. Okt. 1970 (23) Løbedag 14. Okt. 1970 (44) Ansøgningen fremlagt og fremleggetoesskriftet offentliggjort den 2 · Jun. 1 980 DIREKTORATET FOR __ ___.(11) PRESENTATION 141726 DENMARK (B1) lnt C | 3 c 07 D 487/04 (21) Application No. 5203/70 (22) Filed on 14 Oct. 1970 (23) Race day 14 Oct. 1970 (44) The application submitted and the petition published on 2 · Jun. 1 980 DIRECTORATE FOR __ ___.
PATENT-OG VAREMÆRKEVÆSENET (30) Prioritet begaret fra denPATENT AND TRADE MARKET (30) Priority granted from it
23. Okt. 1969, 84870/69, JPOct 23 1969, 84870/69, JP
(71) TAKEDA CHEMICAL INDUSTRIES LTD., 27, Doshomachl 2-chome, Hi gas hi-ku, Osaka, JP.(71) TAKEDA CHEMICAL INDUSTRIES LTD., 27, Doshomachl 2-chome, Hi gas hi-ku, Osaka, JP.
(72) Opfinder: Kanji Meguro, 4-51, Hirai-aza-higashi-shiroraaru, Takarazuka, Hyogo, JP: Yutaka Kuwada, 4-3, Maeda-cho, Ashiya, Huogo, JP.(72) Inventor: Kanji Meguro, 4-51, Hirai-aza-higashi-shiroraaru, Takarazuka, Hyogo, JP: Yutaka Kuwada, 4-3, Maeda-cho, Ashiya, Huogo, JP.
(74) Fuldmagtig under sagens behandling:(74) Proxy during the proceedings:
Kontor for Industriel Eneret ved Svend Schønning.Office for Industrial Excellence by Svend Schønning.
(54) Fremgangsmåde til fremstilling af s-triazolo(4,3-a)(l,4)-henzodiaze“ pinderivater. 5 i . .(54) Process for the preparation of s-triazolo (4,3-a) (1,4) -henzodiaze 'stick derivatives. 5 i. .
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af s-triazolo[4,3-a][1,4J-benzodiazepin-derivater med den almene formel B1—_*The present invention relates to a particular process for the preparation of s-triazolo [4,3-a] [1,4J-benzodiazepine derivatives of the general formula B1 -
Ί 2 3 NΊ 2 3 N
N- ^ 7 A. 6 */N- ^ 7 A. 6 * /
B IB I
U1726 2 hvor R^ er et hydrogenatom, en alkylgruppe med op til 6 kulstof- 2 atomer, en benzylgruppe eller en fenylgruppe, R er et hydrogenatom eller en alkylgruppe med op til 6 kulstofatomer, og hvor ringene A og B hver uafhængigt af hinanden er usubstitue-ret eller substitueret med en nitrogruppe, en trifluormetyl-gruppe, en alkylgruppe med op til 3 kulstofatomer, en alkoxy-gruppe med op til 2 kulstofatomer eller et halogenatom, og hvor nitrogenatomet i 5-stillingen kan være i form af N-oxydet.U1726 is R 2 is a hydrogen atom, an alkyl group of up to 6 carbon atoms, a benzyl group or a phenyl group, R is a hydrogen atom or an alkyl group of up to 6 carbon atoms, and wherein the rings A and B are each independently unsubstituted or substituted by a nitro group, a trifluoromethyl group, an alkyl group of up to 3 carbon atoms, an alkoxy group of up to 2 carbon atoms or a halogen atom and the nitrogen atom at the 5-position may be in the form of the N-oxide .
Det er kendt fra DK patentansøgning nr. 5836/69 at fremstille de omhandlede forbindelser med den almene formel I ved omsætning af et 2-hydrazino-l,4-benzodiazepinderivat med den almene formel NHNH_It is known from DK Patent Application No. 5836/69 to prepare the subject compounds of general formula I by reacting a 2-hydrazino-1,4-benzodiazepine derivative of the general formula NHNH
A | \-R VA | \ -R V
^ i med en karboxylsyre med formlen R1COOH eller dens reaktive derivat. Disse forbindelser har vist sig at være nyttige som mu-skelafslappende midler, anti-konvulsiviske midler, sedative og beroligende midler.with a carboxylic acid of the formula R1COOH or its reactive derivative. These compounds have been found to be useful as muscle relaxants, anticonvulsants, sedatives and sedatives.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved at et 2-aminobenzodiazepinderivat med den almene formel Λ_^NH2 \ 2The process according to the invention is characterized in that a 2-aminobenzodiazepine derivative of the general formula Λ
* I. */~R* I. * / ~ R
\ N\ N
B | 3 141726 omsættes med et acylhydrazinderivat med den almene formelB | No. 3 141726 is reacted with an acylhydrazine derivative of the general formula
NH^NHCOR1 IIINH4 NHCOR1 III
hvor R1 er defineret som ovenfor, hvorved der vindes en forbindelse med formlen NHNHCOR1wherein R 1 is defined as above to give a compound of formula NHNHCOR1
CC
A I \_E2 IVA I \ _E2 IV
B IB I
sy hvor symboler og substituenter i formel II og IV har samme betydning som i formel I, idet således nitrogenatomet i 4-stillingen kan være i form af N-oxydet, hvorefter den fremstillede forbindelse med formel IV ringsluttes.sew where symbols and substituents of formulas II and IV have the same meaning as in formula I, thus the nitrogen atom at the 4-position can be in the form of the N-oxide, after which the compound of formula IV is terminated.
Ved anvendelse af denne metode kan forbindelserne med formel I med fordel fremstilles i industriel skala, idet de vindes i højt udbytte under anvendelse af let tilgængelige udgangsmaterialer med lave omkostninger og på simpel måde.By using this method, the compounds of formula I can advantageously be prepared on an industrial scale, obtained in high yield using readily available low cost starting materials and in a simple manner.
Ved at benytte fremgangsmåden ifølge opfindelsen kan man ud fra en forbindelse med den almene formel II fremstille en forbindelse med den almene formel I ved anvendelse af kun 2 trin, trin A og trin D, hvorimod der ved den fremgangsmåde, der er kendt fra DK patentansøgning nr. 5836/69, kræves 3 trin, trin B, trin C og trin D, jvf. følgende reaktionsskema: 4 141726By using the process according to the invention, a compound of the general formula II can be prepared from a compound of the general formula I using only 2 steps, step A and step D, whereas in the method known from DK patent application No. 5836/69, 3 steps, step B, step C and step D are required, according to the following reaction scheme: 4 141726
CMCM
PiPi
χ%=/γγHχ =% / γγH
PS / \ '-'PS / \ "-"
/K/ K
CiC
•H• H
MM
H -PH -P
PS O O KPS O O K
Z CM K PSZ CM K PS
yk - Syk - S
I I f \ > o u / V -5I I f \> o u / V -5
/ \ \ Pi 4J/ \ \ Pi 4J
V/ \V / \
SS
Z CMZ CM
t “1t “1
k VAk VA
h K z HPS rfj K. J <\ ® ,) > O fi . Γ» Γ==Γ\ X Ί » -H w / \ W—* SCM 4J CM /. rf! \ g g /7 \_y ./ P3 CM CM / k ps X g VS - zWx/a v} 141726 5h K z HPS rfj K. J <\ ®,)> O fi. Γ »Γ == Γ \ X Ί» -H w / \ W— * SCM 4J CM /. rf! \ g g / 7 \ _y ./ P3 CM CM / k ps X g VS - zWx / a v} 141726 5
En væsentlig forskel mellem fremgangsmåden ifølge opfindelsen og den fremgangsmåde, der kendes fra DK patentansøgning nr. 5836/69, ligger således i at man ved den førstnævnte fremstiller en forbindelse med formel IV ved direkte at omsætte en forbindelse med formel II irød acylhydrazin med formlen III, hvorimod man ved sidstnævnte først fremstiller en forbindelse med den almene formel V ved at omsætte forbindelsen med formel II irød hydrazin, hvorefter den vundne forbindelse omdannes til en forbindelse med formel IV ved omsætning med en karboxylsyre med formlen VI.A major difference between the process according to the invention and the method known from DK patent application 5836/69 lies in the fact that in the former a compound of formula IV is prepared by directly reacting a compound of formula II with acylhydrazine of formula III whereas, in the latter, a compound of general formula V is first prepared by reacting the compound of formula II with irradiated hydrazine, after which the compound obtained is converted to a compound of formula IV by reaction with a carboxylic acid of formula VI.
Ved en sammenligning kan følgende siges om fremstillingen af en forbindelse med den almene formel IV. I trin A ifølge opfindelsen, hvor en forbindelse med formel II omsættes med et acylhydrazin med formel III er det overraskende, at der opnås en så effektiv udskiftning af 2-aminogruppen i forbindelsen med formel II med acylhydrazinet III, idet acylhydra-zins basiske karakter er noget svagere end for hydrazinet selv. Det har imidlertid overraskende vist sig, at der i trin A ikke sker dannelse af en dimer af forbindelsen med formel II repræsenteret med formlen /øf^· \By comparison, the following can be said about the preparation of a compound of general formula IV. In step A of the invention, where a compound of formula II is reacted with an acylhydrazine of formula III, it is surprising that such an effective replacement of the 2-amino group of the compound of formula II with the acylhydrazine III is achieved, the basic nature of the acyl hydrazine being somewhat weaker than for the hydrazine itself. However, it has surprisingly been found that in step A, a dimer of the compound of formula II represented by the formula / formula
S/jpN IS / jpN I
& l og der iagttages intet fald i udbyttet af forbindelsen med formel IV idet dette biprodukt ikke dannes, og der kræves således heller ikke besværlige procedurer til fjernelse af dette biprodukt.& l and no decrease in the yield of the compound of formula IV is observed since this by-product is not formed, and thus no cumbersome procedures are required for removal of this by-product.
I modsætning hertil er der ved den kendte fremgangsmådes trin B en tendens til dannelsen af den ovennævnte dimer som biprodukt, hvilket resulterer i et fald i udbytte samt besværlige procedurer til at fraskille dette biprodukt.In contrast, in step B of the known process, there is a tendency for the formation of the above dimer as a by-product, which results in a decrease in yield as well as cumbersome procedures for separating this by-product.
6 141726 X følgende tabel ses en sammenligning af udbytterne ved fremstillingen af forbindelser med formel IV ved anvendelse af trin A (fremgangsmåden ifølge opfindelsen) eller ved anvendelse af trin B og trin C (dansk patentansøgning nr. 5836/69).The following table shows a comparison of the yields in the preparation of compounds of formula IV using Step A (the process of the invention) or using Step B and Step C (Danish Patent Application No. 5836/69).
TABELTABLE
NHNHCOR1 C6H5NHNHCOR1 C6H5
......in i ·ι . " - " i " " 1 1 ..... I...... in i · ι. "-" i "" 1 1 ..... I
Forbindelse Fremgangsmåden Dansk patentans. nr.Connection Procedure Danish Patent. no.
iflg. opfindelser 5836/69 R1 Trin Eks.nr. Trin Eks. Trin Eks. Samlet A B nr. C nr. udbytte __%___%___%___%_ CH3- 84 4a) 81 25 78x81=63acc. Inventions 5836/69 R1 Step Ex. Step Ex. Step Ex. Total A B No. C No. Yield __% ___% ___% ___% _ CH3- 84 4a) 81 25 78x81 = 63
CgH5- 89 8a) 78 1 89 34 78x89=69CgH5- 89 8a) 78 1 89 34 78x89 = 69
CgH5CH2- 90 10 a) 90 38 78x90=70 141726 7 I den almene formel I kan gruppen betegnet R1 fx være en alkylgruppe med op til 6 kulstofatomer (fx metyl, ætyl, propyl, isopropyl, butyl, s-butyl, t-butyl, amyl og hexyl), en benzylgruppe eller en fenylgruppe. Eksempler på en alkyl- 2 gruppe repræsenteret ved R er metyl, ætyl, propyl, isopropyl, butyl, s-butyl, t-butyl, amyl og hexyl. Begge ringene A og B kan være usubstitueret eller substitueret med hver højst en substituent, som kan være ens eller forskellige for de to ringe, og som fx er nitro, trifluormetyl, alkyl såsom metyl, ætyl eller propyl eller alkoxy såsom metoxy eller ætoxy, eller halogen (såsom klor, fluor, brom eller jod).CgH5CH2- 90 10 a) 90 38 78x90 = 70 141726 7 In the general formula I, for example, the group denoted R1 may be an alkyl group of up to 6 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl , amyl and hexyl), a benzyl group or a phenyl group. Examples of an alkyl group represented by R are methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, amyl and hexyl. Both rings A and B may be unsubstituted or substituted with at most one substituent which may be the same or different for the two rings and which are, for example, nitro, trifluoromethyl, alkyl such as methyl, ethyl or propyl or alkoxy such as methoxy or ethoxy, or halogen (such as chlorine, fluorine, bromine or iodine).
Til fremstilling af forbindelserne med den almene formel IV omsættes forbindelserne med formel II med forbindelserne med formel III. Denne omsætning udføres fortrinsvis i nærværelse af ét opløsningsmiddel samt en syre. Det anvendte opløsningsmiddel er fortrinsvis polært, såsom metanol, ætanol, pyridin og dimetylformamid. Den anvendte syre kan være uorganisk (fx saltsyre, svovlsyre og hydrogenbromid), organiske karboxylsyrer (fx eddikesyre, propionsyre og smørsyre) eller organiske sulfonsyrer (fx p-toluensulfonsyre og benzensulfon-syre). Disse syrer kan sættes direkte til reaktionssystemet eller tilsættes i form af et passende syresalt med baser (fx pyridin, triætylamin og 2-metylimidazol). Syren kan også tilsættes i form af et sålt med forbindelsen II eller med forbindelsen III. Syren anvendes sædvanligvis i mængder på 1-2 mol pr. mol af forbindelsen II.For the preparation of the compounds of general formula IV, the compounds of formula II are reacted with the compounds of formula III. This reaction is preferably carried out in the presence of one solvent and one acid. The solvent used is preferably polar, such as methanol, ethanol, pyridine and dimethylformamide. The acid used may be inorganic (e.g. hydrochloric, sulfuric and hydrogen bromide), organic carboxylic acids (e.g. acetic, propionic and butyric) or organic sulfonic acids (e.g. p-toluenesulfonic acid and benzenesulfonic acid). These acids can be added directly to the reaction system or added in the form of a suitable acid salt with bases (e.g., pyridine, triethylamine and 2-methylimidazole). The acid may also be added in the form of a screen with compound II or with compound III. The acid is usually used in amounts of 1-2 moles per day. mole of compound II.
Den anvendte mængde af acylhydrazinet (III) er sædvanligvis mere end 1 mol og fortrinsvis 3-5 mol pr. mol af forbindelsen II. Omsætningen foregår almindeligvis ved stuetemperatur, men kan udføres under afkøling eller opvarmning, hvis det ønskes. Acylhydrazinobenzodiazepinderivaterne (IV) fremstillet som beskrevet ovenfor ringsluttes i enhver passende form, fx i selve reaktionsblandingen eller i isoleret form med passende renhedsgrad.The amount of acylhydrazine (III) used is usually more than 1 mole and preferably 3-5 moles per ml. mole of compound II. The reaction is usually carried out at room temperature, but can be carried out under cooling or heating if desired. The acylhydrazinobenzodiazepine derivatives (IV) prepared as described above are cyclized in any suitable form, for example, in the reaction mixture itself or in isolated form of appropriate purity.
Isoleringen af forbindelsen IV kan udføres på konventionel måde, fx ved inddampning af opløsningsmidlet fra reaktionsblandingen.The isolation of compound IV can be carried out in a conventional manner, for example by evaporation of the solvent from the reaction mixture.
Ringslutningsreaktionen udføres sædvanligvis ved opvarm- 8 141726 ning af forbindelsen IV, eventuelt i nærværelse af et opløsningsmiddel. Selv om de nødvendige temperaturer til cyklode-hydreringen varierer afhængigt af arten af forbindelsen II, ligger den sædvanligvis mellem 100 og 250°C. Der kan anvendes opløsningsmidler med et kogepunkt inden for dette område, og eksempler herpå er toluen, xylen, pyridin, kollidin, dimetyl-formamid og tetralin. Når der ikke anvendes et opløsningsmiddel, udføres cyklodehydreringen blot ved opvarmning af forbindelsen IV ved dens smeltepunkt. Tilsætningen af syrer (fx saltsyre, svovlsyre, eddikesyre og p-toluensulfonsyre) eller Lewis-syre (fx zinkklorid og aluminiumklorid) eller anvendelsen af dehydrerende midler (fx fosforoxyklorid, fosforpentoxyd, tionylklorid, polyfosforsyre og polyfosfatester) kan accelerere omsætningen, og cyklodehydreringen kan udføres ved en lavere temperatur (mellem 20 og 180°C). I disse tilfælde kan der derfor også anvendes opløsningsmidler med lave kogepunkter, såsom kloroform, metanol, ætanol, tetrahydrofuran og benzen.The cyclization reaction is usually carried out by heating the compound IV, optionally in the presence of a solvent. Although the temperatures required for the cyclode hydration vary depending on the nature of the compound II, it is usually between 100 and 250 ° C. Solvents having a boiling point in this range can be used, and examples are toluene, xylene, pyridine, collidine, dimethylformamide and tetralin. When no solvent is used, the cyclodehydration is carried out simply by heating the compound IV at its melting point. The addition of acids (e.g. hydrochloric, sulfuric, acetic, and p-toluenesulfonic) or Lewis acid (e.g., zinc chloride and aluminum chloride) or the use of dehydrating agents (e.g., phosphorus oxychloride, phosphorus pentoxide, thionyl chloride, polyphosphoric acid and polyphosphoric acid at a lower temperature (between 20 and 180 ° C). Therefore, in these cases, low boiling solvents such as chloroform, methanol, ethanol, tetrahydrofuran and benzene can also be used.
Den længere omsætning mellem forbindelsen II og forbindelsen III i nærværelse af syre bevirker også dannelsen af forbindelsen med formlen I.The longer reaction between compound II and compound III in the presence of acid also causes the formation of the compound of formula I.
De omhandlede forbindelser med formel I kan isoleres på konventionel måde, fx ved inddampning af opløsningsmidlet fra reaktio nsblandingen.The present compounds of formula I can be isolated in conventional manner, for example by evaporation of the solvent from the reaction mixture.
Forbindelserne med formel I kan danne salte med en passende syre, som fx kan være uorganisk, såsom saltsyre og svovlsyre, eller organisk, såsom eddikesyre, malonsyre, fumarsyre, vinsyre og citronsyre.The compounds of formula I may form salts with an appropriate acid which may be, for example, inorganic, such as hydrochloric acid and sulfuric acid, or organic, such as acetic acid, malonic acid, fumaric acid, tartaric acid and citric acid.
Fremgangsmåden ifølge opfindelsen skal forklares nærmere ved et antal udførelseseksempler, hvor forholdet mellem vægtdele og rumfangsdele svarer til forholdet mellem gram og milliliter.The process according to the invention will be explained in more detail by a number of exemplary embodiments in which the ratio of parts by weight to volumes corresponds to the ratio between grams and milliliters.
Eksempel 1Example 1
En blanding af 2,7 vægtdele 2-amino-7-klor-5-fenyl-3H- 1,4-benzodiazepin, 2,4 vægtdele formylhydrazin, 50 rumfangsdele metanol og 1,2 rumfangsdele iseddikesyre opvarmes under tilbagesvalirig i 1 1/2 time. De små mængder uopløste materialer 9 141726 frafiltreres, og filtratet koncentreres, hvorpå der tilsættes vand. De således dannede krystaller udvindes ved filtrering, hvorved der vindes krystallinsk 8-klor-6-fenyl-4H-s-tria-zolo[4,3-a][1/4]-benzodiazepin. Omkrystallisation ud fra ætylacetat giver farveløse flager der smelter ved 225-227°C.A mixture of 2.7 parts by weight of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine, 2.4 parts by weight of formylhydrazine, 50 parts by volume of methanol and 1.2 parts by volume of glacial acetic acid is heated under reflux for 1 1/2 hour. The small amounts of undissolved materials are filtered off and the filtrate is concentrated and water is added. The crystals thus formed are recovered by filtration to give crystalline 8-chloro-6-phenyl-4H-s-triazolo [4,3-a] [1/4] benzodiazepine. Recrystallization from ethyl acetate gives colorless flakes melting at 225-227 ° C.
Eksempel 2 a) En blanding af 2,7 vægtdele 7-klor-2-amino-5-fenyl-3H- 1.4- benzodiazepin, 2,4 vægtdele formylhydrazin, 50 rumfangsdele metanol og 1,2 vægtdele iseddikesyre omrøres ved stuetemperatur, hvorpå krystallerne opløses gradvis, hvorefter der dannes nye krystaller. Omrøringen fortsættes i to timer, og de nye krystaller opsamles ved filtrering. Der vindes krystallinsk 7-klor-2-(2-formylhydrazino)-5-fenyl-3H-l,4-benzodiazepin. Ved omkrystallisation ud fra kloroform/meta-nol vindes farveløse prismer som smelter ved 161-162°C (under skumning). Dette produkt er et additionsprodukt indeholdende 1/2 mol metanol.Example 2 a) A mixture of 2.7 parts by weight of 7-chloro-2-amino-5-phenyl-3H-1,4-benzodiazepine, 2.4 parts by weight of formylhydrazine, 50 parts by volume of methanol and 1.2 parts by weight of glacial acetic acid is stirred at room temperature whereupon the crystals dissolves gradually, after which new crystals form. Stirring is continued for two hours and the new crystals are collected by filtration. Crystalline 7-chloro-2- (2-formylhydrazino) -5-phenyl-3H-1,4-benzodiazepine is obtained. By recrystallization from chloroform / methanol colorless prisms melt at 161-162 ° C (under foaming). This product is an addition product containing 1/2 mole of methanol.
b) 3,3 vægtdele 7-klor-2-(2-formylhydrazino)-5-fenyl-3H- 1.4- benzodiazepin fremstillet som i eksempel 2a) opvarmes på et oliebad ved 180°C, hvorefter krystallerne smeltes under skumning og derpå størknes. Skummet synker til bunds i løbet af 10 minutter. Derefter omkrystalliseres det faste produkt ud fra acetone/n-hexan, hvilket giver 8-klor-6-fenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepin som farveløse flager der smelter ved 226-227°C. Dette produkt er identisk med forbindelsen fremstillet ifølge eksempel 1.b) 3.3 parts by weight of 7-chloro-2- (2-formylhydrazino) -5-phenyl-3H-1,4-benzodiazepine prepared as in Example 2a) are heated on an oil bath at 180 ° C, then the crystals are melted under foaming and then solidified . The foam sinks to the bottom in 10 minutes. Then, the solid product is recrystallized from acetone / n-hexane to give 8-chloro-6-phenyl-4H-s-triazolo [4,3-a] [1,4] -benzodiazepine as colorless flakes melting at 227 ° C. This product is identical to the compound of Example 1.
Eksempel 3Example 3
En opløsning af 3,3 vægtdele 7-klor-2-(2-formylhydra-zino)-5-fenyl-3H-l,4-benzodiazepin fremstillet ved metoden ifølge eksempel 2a) i 10 rumfangsdele pyridin opvarmes under tilbagesvaling i 30 minutter. Opløsningsmidlet fjernes ved destillation under reduceret tryk, hvorpå der tilsættes vand.A solution of 3.3 parts by weight of 7-chloro-2- (2-formylhydrazino) -5-phenyl-3H-1,4-benzodiazepine prepared by the method of Example 2a) in 10 volumes of pyridine is heated at reflux for 30 minutes. The solvent is removed by distillation under reduced pressure, to which water is added.
141726 ίο141726 ίο
De således dannede krystaller udvindes ved filtrering. På denne måde vindes 8-klor-6-fenyl-4H-s-triazolo[4,3-a][1,4]-benzo-diazepin som krystaller. Ved omkrystallisation ud fra acetone vindes farveløse flager der smelter ved 226-227°C. Dette produkt er identisk med forbindelserne fremstillet i eksemplerne 1 og 2.The crystals thus formed are recovered by filtration. In this way, 8-chloro-6-phenyl-4H-s-triazolo [4,3-a] [1,4] -benzo-diazepine is obtained as crystals. By recrystallization from acetone, colorless flakes are melted at 226-227 ° C. This product is identical to the compounds prepared in Examples 1 and 2.
Eksempel 4 a) En blanding af 2,7 vægtdele 2-amino-7-klor-5-fenyl-3H- 1.4- benzodiazepin, 3 vægtdele acetylhydrazin, 50 rumfangsdele metanol og 1,2 rumfangsdele iseddikesyre omrøres ved stuetemperatur. Krystallerne opløses i løbet af 30 minutter, hvorpå der dannes nye krystaller. Efter 1 1/2 times forløb udvindes de nye krystaller ved filtrering. Der opnås 2-(2-acetylhydra-zino)-7-klor-5-fenyl-3H-l,4-benzodiazepin som krystaller. Omkrystallisation ud fra metanol giver pulverformede krystaller der smelter ved 202-204°C (under opskumning).Example 4 a) A mixture of 2.7 parts by weight of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine, 3 parts by weight of acetylhydrazine, 50 parts by volume of methanol and 1.2 parts by volume of glacial acetic acid is stirred at room temperature. The crystals dissolve within 30 minutes, forming new crystals. After 1 1/2 hours, the new crystals are recovered by filtration. 2- (2-Acetylhydrazino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine is obtained as crystals. Recrystallization from methanol gives powdery crystals melting at 202-204 ° C (during foaming).
b) 3,3 vægtdele 2-(2-acetylhydrazino)-7-klor-5-fenyl-3H- 1.4- benzodiazepin fremstillet ved metoden ifølge eksempel 4a) smeltes ved opvarmning til 215°C i 10 minutter ved et ringe undertryk. Efter afkøling omkrystalliseres den smeltede substans ud fra ætylacetat, hvorved der vindes 8-klor-l-metyl- 6-fenyl-4H-s-triazolo[4,3-a][l,4]-benzodiazepin som farveløse nåle der smelter ved 225-226°C.b) 3.3 parts by weight of 2- (2-acetylhydrazino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine prepared by the method of Example 4a) are melted by heating to 215 ° C for 10 minutes under low pressure. After cooling, the molten substance is recrystallized from ethyl acetate to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4] -benzodiazepine as colorless needles which melt at 225-226 ° C.
Eksempel 5Example 5
En blanding af 3,3 vægtdele 2-(2-acetylhydrazino)-7-klor-5-fenyl-3H-l,4-benzodiazepin fremstillet ved metoden ifølge eksempel 4a) og 20 rumfangsdele pyridin opvarmes under tilbagesvaling i 2 timer. Opløsningsmidlet fjernes ved destillation under reduceret tryk. Omkrystallisation af remanensen ud fra acetone/n-hexan giver 8-klor-l-metyl-6-fenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepin som farveløse nåle. Smp.: 225-225°C. Dette produkt er identisk med forbindelsen fremstillet i eksempel 4.A mixture of 3.3 parts by weight of 2- (2-acetylhydrazino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine prepared by the method of Example 4a) and 20 volumes of pyridine is heated at reflux for 2 hours. The solvent is removed by distillation under reduced pressure. Recrystallization of the residue from acetone / n-hexane affords 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4] -benzodiazepine as colorless needles. Mp: 225-225 ° C. This product is identical to the compound prepared in Example 4.
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Eksempel 6 a) En blanding af 2,7 vægtdele 2-amino-7-klor-5-fenyl-3H- 1,4-benzodiazepin, 5,8 vægtdele enantylhydrazin, 50 rumfangs-dele metanol og 1,2 rumfangsdele iseddikesyre omrøres ved stuetemperatur i 5 timer. De således fremstillede krystaller udvindes ved filtrering, hvorpå 7-klor-2-(2-enantylhydrazino)- 5-fenyl-3H-l,4-benzodiazepin vindes som krystaller. Omkrystal-lisation ud fra dimetylformamid og vand giver farveløse nåle der smelter ved 224-225°C (med skumning).Example 6 a) A mixture of 2.7 parts by weight of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine, 5.8 parts by weight of enantylhydrazine, 50 parts by volume of methanol and 1.2 parts by volume of glacial acetic acid is stirred. room temperature for 5 hours. The crystals thus obtained are recovered by filtration, and 7-chloro-2- (2-enantylhydrazino) -5-phenyl-3H-1,4-benzodiazepine is obtained as crystals. Recrystallization from dimethylformamide and water gives colorless needles melting at 224-225 ° C (with foaming).
b) En blanding af 30 vægtdele polyfosforsyre og 1,98 vægtdele 7-klor-2-(2-enantylhydrazino)-5-fenyl-3H-l,4-benzodiazepin fremstillet ved den i eksempel 6a) angivne metode opvarmes ved 170-180°C i to timer. Efter afkøling tilsættes 200 rumfangsdele isvand. Den resulterende opløsning neutraliseres med koncentreret vandig ammoniak under afkøling med is og ekstra-heres med kloroform. Kloroformlaget vaskes med vand og tørres over NajSO^. Opløsningsmidlet fjernes ved destillering, hvorved der vindes 8-klor-l-hexyl-6-fenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepin. Qmkrystallisation ud fra vandig acetone giver farveløse flager der smelter ved 75-78°C (blødgøringspunkt). Krystallerne indeholder 2 mol kryetalvand. Tørring under reduceret tryk giver ét 1/4-hydrat (smp.: 61-63°€ (blødgørings-punkt)).b) A mixture of 30 parts by weight of polyphosphoric acid and 1.98 parts by weight of 7-chloro-2- (2-enantylhydrazino) -5-phenyl-3H-1,4-benzodiazepine prepared by the method of Example 6a) is heated at 170-180 ° C for two hours. After cooling, add 200 volumes of ice water. The resulting solution is neutralized with concentrated aqueous ammonia under cooling with ice and extracted with chloroform. The chloroform layer is washed with water and dried over Na 2 SO 4. The solvent is removed by distillation to give 8-chloro-1-hexyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4] -benzodiazepine. Crystallization from aqueous acetone gives colorless flakes melting at 75-78 ° C (softening point). The crystals contain 2 moles of crystal water. Drying under reduced pressure gives one 1/4 hydrate (mp: 61-63 ° € (softening point)).
Eksempel 7Example 7
En blanding af 4 vægtdele 7-klor-2-(2-enantylhydrazino)- 5-fenyl-3H-l,4-benzodiazepin og 20 rumfangsdele pyridin opvarmes under tilbagesvaling i ca. 3 timer. Pyridinet fjernes ved destillation under reduceret tryk, hvorefter der tilsættes vand. Bundfaldet udvindes ved filtrering, hvorpå der vindes 8-klor-l-hexyl-6-fenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepin som krystaller. Omkrystallisation ud fra vandig acetone giver farveløse flager der smelter ved 75-78°C (blødgøringspunktet).A mixture of 4 parts by weight of 7-chloro-2- (2-enantylhydrazino) -5-phenyl-3H-1,4-benzodiazepine and 20 parts by volume of pyridine is heated at reflux for approx. 3 hours. The pyridine is removed by distillation under reduced pressure and then water is added. The precipitate is recovered by filtration to give 8-chloro-1-hexyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine as crystals. Recrystallization from aqueous acetone gives colorless flakes that melt at 75-78 ° C (softening point).
Dette produkt er identisk med forbindelsen fremstillet i eksempel 6.This product is identical to the compound prepared in Example 6.
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Eksempel 8 a) En blanding af 2,7 vægtdele 2-amino-7-klor-5-fenyl-3H- 1.4- benzodiazepin, 5,4 vægtdele benzoylhydrazin, 100 rumfangsdele metanol og 1,2 rumfangsdele iseddikesyre omrøres ved stuetemperatur i 5 timer, hvorpå krystallerne straks opløses og der dannes nye krystaller. De nye krystaller udvindes ved filtrering. Der opnås 2-(2-benzoylhydrazino)-7-klor-5-fenyl-3H- 1.4- benzodiazepin som krystaller. Omkrystallisation ud fra kloroform/metanol giver hvide nåle der smelter ved 207-208°C (skumning).Example 8 a) A mixture of 2.7 parts by weight of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine, 5.4 parts by weight of benzoylhydrazine, 100 parts by volume of methanol and 1.2 parts by volume of glacial acetic acid is stirred at room temperature for 5 hours. , whereupon the crystals immediately dissolve and new crystals are formed. The new crystals are recovered by filtration. 2- (2-Benzoylhydrazino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine is obtained as crystals. Recrystallization from chloroform / methanol gives white needles melting at 207-208 ° C (foam).
b) En blanding af 400 vægtdele polyfosforsyre og 38,8 vægtdele 2-(2-benzoylhydrazino)-7-klor-5-fenyl-3H-l,4-benzodiaze-pin fremstillet ved den i eksempel 8a) beskrevne metode opvarmes ved 150°C i 1 1/2 time. Reaktionsblandingen behandles på samme måde som i eksempel 6b, hvilket giver 8-klor~l,6-difenyl-4H-s-triazolo-[4,3-a][1,4]-benzodiazepin som krystaller. Omkrystallisation ud fra ætylacetat giver farveløse nåle med smp. ved 191-192°C.b) A mixture of 400 parts by weight of polyphosphoric acid and 38.8 parts by weight of 2- (2-benzoylhydrazino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine prepared by the method described in Example 8a) is heated at 150 ° C for 1 1/2 hours. The reaction mixture is treated in the same manner as in Example 6b to give 8-chloro-1,6-diphenyl-4H-s-triazolo- [4,3-a] [1,4] -benzodiazepine as crystals. Recrystallization from ethyl acetate gives colorless needles with m.p. at 191-192 ° C.
Eksempel 9 3,9 vægtdele 2-(2-benzoylhydrazino)-7-klor-5-fenyl-3H- 1.4- benzodiazepin fremstillet som beskrevet i eksempel 8a) smeltes ved opvarmning ved 215°C i ca. 15 minutter under reduceret tryk. Efter afkøling omkrystalliseres det faste produkt ud fra ætylacetat, hvilket giver 8-klor-l,6-difenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepin som farveløse nåle der smelter ved 193-194°C. Dette produkt er 'Identisk med forbindelsen fremstillet i eksempel 8.Example 9 3.9 parts by weight of 2- (2-benzoylhydrazino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine prepared as described in Example 8a) are melted by heating at 215 ° C for approx. 15 minutes under reduced pressure. After cooling, the solid product is recrystallized from ethyl acetate to give 8-chloro-1,6-diphenyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine as colorless needles melting at 193-194 ° C. This product is identical to the compound prepared in Example 8.
Eksempel 10 a) En blanding af 1,35 vægtdele 2-amino-7-klor-5-fenyl-3H- 1.4- benzodiazepin, 3 vægtdele fenylacetylhydrazin, 50 rumfangsdele metanol og 0,6 rumfangsdele iseddikesyre omrøres ved stuetemperatur i 5 timer. De dannede krystaller udvindes ved filtrering. Der vindes 7-klor-2-(2-fenylacetylhydrazino)-5-fenyl- 141726 13 3H-l,4-benzodiazepin sqiu krystaller. Omkrystallisation ud fra diraetylformamid/vand giver farveløse prismer der smelter ved 224-225°C (skumning).Example 10 a) A mixture of 1.35 parts by weight of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine, 3 parts by weight of phenylacetylhydrazine, 50 parts by volume of methanol and 0.6 parts by volume of acetic acid is stirred at room temperature for 5 hours. The crystals formed are recovered by filtration. 7-Chloro-2- (2-phenylacetylhydrazino) -5-phenyl-3H-1,4-benzodiazepine silica crystals are obtained. Recrystallization from diraethylformamide / water gives colorless prisms melting at 224-225 ° C (foaming).
b) En blanding af 50 vægtdele polyfosforsyre og 4 vægtdele 7-klor-2-(2-fenylacetylhydrazino)-5-fenyl-3H-l,4-benzo-diazepin fremstillet i eksempel 10 a) opvarmes ved 180°C i to timer og behandles derefter på samme m&de som i eksempel 6b).b) A mixture of 50 parts by weight of polyphosphoric acid and 4 parts by weight of 7-chloro-2- (2-phenylacetylhydrazino) -5-phenyl-3H-1,4-benzodiazepine prepared in Example 10 a) is heated at 180 ° C for two hours. and then treated in the same manner as in Example 6b).
Der vindes herved l-benzyl-8-klor-6-fenyl-4H-s-triazolo-[4,3-a][l,4]-benzodiazepin. Omkrystallisation ud fra ætylacetat giver farveløse søjler der smelter ved 190-192°C, mens omkrystallisation ud fra metanol giver farveløse nåle der smelter ved 101-103°C (skumning). Sistnævnte krystaller indeholder 1 mol krystallisationsmetanol.There is thus obtained 1-benzyl-8-chloro-6-phenyl-4H-s-triazolo [4,3-a] [1,4] -benzodiazepine. Recrystallization from ethyl acetate gives colorless columns melting at 190-192 ° C, while recrystallization from methanol gives colorless needles melting at 101-103 ° C (foaming). The latter crystals contain 1 mole of crystallization methanol.
Eksempel 11 4 vægtdele 7-klor-2-(2-fenylacetylhydrazino)-5-fenyl-3H-l,4-benzodiazepin fremstillet i eksempel 10 a) smeltes ved opvarmning ved 230°C i ca. 10 minutter under reduceret tryk.Example 11 4 parts by weight of 7-chloro-2- (2-phenylacetylhydrazino) -5-phenyl-3H-1,4-benzodiazepine prepared in Example 10 a) are melted by heating at 230 ° C for approx. 10 minutes under reduced pressure.
Efter afkøling omkrystalliseres det fremstillede faste produkt ud fra ætylacetat, hvilket giver l-benzyl,*8-klor-6-fenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepin som farveløse prismer. Smp.: 191-192°C. Dette produkt er identisk med forbindelsen fremstillet i eksempel 10 b).After cooling, the solid product prepared is recrystallized from ethyl acetate to give 1-benzyl, * 8-chloro-6-phenyl-4H-s-triazolo [4,3-a] [1,4] -benzodiazepine as colorless prisms. Mp: 191-192 ° C. This product is identical to the compound prepared in Example 10 b).
Eksempel 12 a) En blanding af 2,86 vægtdele 2-amino-7-klor-5-fenyl-3H- l,4-benzodiazepin-4N-oxyd, 2,96 vægtdele acetylhydrazin, 50 rumfangsdele metanol og 1,2 rumfangsdele iseddikesyre omrøres ved stuetemperatur, hvorpå krystallerne gradvis opløses, hvorefter der dannes nye krystaller. Efter 6 timers forløb udvindes krystallerne ved filtrering. 2-(2-Acetylhydrazino)-7-klor-5-fenyl-3H-l,4«benzodiazepin-4N-oxyd vindes som krystaller. Omkrystallisation ud fra dimetylformamid/vand giver farveløse fine nåle der smelter ved 256-258°C.Example 12 a) A mixture of 2.86 parts by weight of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine-4N-oxide, 2.96 parts by weight of acetylhydrazine, 50 parts by volume of methanol and 1.2 parts by volume of acetic acid is stirred at room temperature, whereupon the crystals gradually dissolve, after which new crystals are formed. After 6 hours, the crystals are recovered by filtration. 2- (2-Acetylhydrazino) -7-chloro-5-phenyl-3H-1,4, benzodiazepine-4N-oxide is obtained as crystals. Recrystallization from dimethylformamide / water gives colorless fine needles that melt at 256-258 ° C.
14 141726 b) En opløsning af 3,4 vægtdele 2-(2-acetylhydrazino)-7-klør-5-fenyl-3H-l,4-benzodiazepin-4N-oxyd i 30 rumfangsdele pyridin opvarmes under tilbagesvaling i 4 timer. Pyridinet fjernes ved destillation, og remanensen omkrystalliseres ud fra metanol, og der vindes 8-klor-l-metyl-6-fenyl-4H-s-tria-zolo[4,3-a][l,4]-benzodiazepin-5N-oxvd som farveløse nåle, smp.: 272-274°C (sønderdeling).B) A solution of 3.4 parts by weight of 2- (2-acetylhydrazino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine-4N-oxide in 30 volumes of pyridine is heated at reflux for 4 hours. The pyridine is removed by distillation and the residue is recrystallized from methanol to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4] -benzodiazepine-5N -oxvd as colorless needles, mp: 272-274 ° C (dec.).
Eksempel 13Example 13
En blanding af 2,8 vægtdele 2-amino-7-nitro-5-fenyl-3H- 1.4- benzodiazepin, 2,4 vægtdele formylhydrazin, 50 rumfangsdele metanol og 1,2 rumfangsdele iseddikesyre opvarmes under tilbagesvaling i 2 timer. De små mængder bundfald filtreres, og filtratet koncentreres og afkøles. De dannede krystaller udvindes ved filtrering. Der 'vindes 8-nitro-6-fenyl-4H-s-triazolo[4,3-a][l,4]-benzodiazepin som krystaller. Omkrystallisation ud fra kloroform/metanol giver svagt gule nåle der smelter ved 268-270°C.A mixture of 2.8 parts by weight of 2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepine, 2.4 parts by weight of formylhydrazine, 50 parts by volume of methanol and 1.2 parts by volume of glacial acetic acid is heated under reflux for 2 hours. The small amounts of precipitate are filtered and the filtrate is concentrated and cooled. The crystals formed are recovered by filtration. 8-Nitro-6-phenyl-4H-s-triazolo [4,3-a] [1,4] -benzodiazepine is obtained as crystals. Recrystallization from chloroform / methanol gives slightly yellow needles melting at 268-270 ° C.
Eksempel 14 a) En blanding af 5,6 vægtdele 2-amino-7-nitro-5-fenyl-3H-l,4-benzodiazepin, 7,4 vægtdele acetylhydrazin, 100 rumfangsdele ætanol og 2,4 rumfangsdele iseddikesyre omrøres ved stuetemperatur i 4 timer, hvorpå krystallerne gradvis opløses og nye krystaller dannes. De nye krystaller udvindes ved filtrering. Der vindes 2-(2-acetylhydrazino)-7-nitro-5-fenyl-3H- 1.4- benzodiazepin som krystaller. Omkrystallisation ud fra dimetylformamid/vand giver gule fine nåle der smelter ved 184-185°C (skumning). Disse krystaller indeholder 1/2 mol krystalvand.Example 14 a) A mixture of 5.6 parts by weight of 2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepine, 7.4 parts by weight of acetylhydrazine, 100 parts by volume of ethanol and 2.4 parts by volume of glacial acetic acid is stirred at room temperature. 4 hours, after which the crystals gradually dissolve and new crystals are formed. The new crystals are recovered by filtration. 2- (2-Acetylhydrazino) -7-nitro-5-phenyl-3H-1,4-benzodiazepine is obtained as crystals. Recrystallization from dimethylformamide / water gives yellow fine needles that melt at 184-185 ° C (foaming). These crystals contain 1/2 mol of crystal water.
b) 3,37 vægtdele 2-(2-acetylhydrazino)-7-nitro-5-fenyl-3H- 1.4- benzodiazepin fremstillet ved metoden ifølge eksempel 14 a) opvarmes ved 195°C under et svagt reduceret tryk, hvorpå krystallerne smelter under opskumning. Opvarmningen fortsættes i ca. 30 minutter indtil skummet går til bunds. Omkrystallisa 141726 15 tion af den smeltede substans ud fra acetone giver 1-metyl-8-nitro-6-fenyl-4H-s-triazolo[4,3-a][l,4]-benzodiazepin som gule prismer. Smp.: 23Q-231°C.b) 3.37 parts by weight of 2- (2-acetylhydrazino) -7-nitro-5-phenyl-3H-1,4-benzodiazepine prepared by the method of Example 14 a) are heated at 195 ° C under a slight reduced pressure, and the crystals melt below foaming. Heating continues for approx. 30 minutes until the foam settles to the bottom. Recrystallization of the molten substance from acetone gives 1-methyl-8-nitro-6-phenyl-4H-s-triazolo [4,3-a] [1,4] -benzodiazepine as yellow prisms. Mp: 23Q-231 ° C.
Eksempel 15Example 15
Til en opløsning af 3,37 vægtdele 2-(2-acetylhydrazino)- 7-nitro-5-fenyl-3H-l,4-benzodiazepin fremstillet ved metoden ifølge eksempel 14 a) i 50 rumfangsdele vandfrit pyridin tilsættes 3 vægtdele fosforoxyklorid. Blandingen opvarmes på et kogende vandbad i 1 time, hvorpå opløsningsmidlet fjernes ved destillation under reduceret tryk. Til remanensen sættes isvand, hvorpå der ekstraheres med kloroform. Kloroformlaget vaskes med en mættet vandig natriumbikarbonatopløsning og tørres over Na2SO^. Derefter fjernes kloroformen ved destillation, hvorved der vindes l-metyl-8-nitro-6-fenyl-4H-s-triazolo-[4,3-a][l,4]-benzodiazepin. Omkrystallisation ud fra acetone giver gule prismer der smelter ved 228-230°C. Dette produkt er identisk med forbindelsen fremstillet i eksempel 14.To a solution of 3.37 parts by weight of 2- (2-acetylhydrazino) -7-nitro-5-phenyl-3H-1,4-benzodiazepine prepared by the method of Example 14 a) in 50 parts by volume of anhydrous pyridine is added 3 parts by weight of phosphorus oxychloride. The mixture is heated on a boiling water bath for 1 hour, then the solvent is removed by distillation under reduced pressure. To the residue is added ice water and then extracted with chloroform. The chloroform layer is washed with a saturated aqueous sodium bicarbonate solution and dried over Na 2 SO 4. The chloroform is then removed by distillation to give 1-methyl-8-nitro-6-phenyl-4H-s-triazolo- [4,3-a] [1,4] -benzodiazepine. Recrystallization from acetone gives yellow prisms melting at 228-230 ° C. This product is identical to the compound prepared in Example 14.
Eksempel 16Example 16
Samme omsætning som i eksempel 15 udføres i vandfrit tetrahydrofuran i stedet for i pyridin. Der vindes samme forbindelse, nemlig l-metyl-8-nitro-6-fenyl-4H-s-triazolo[4,3-a]- [l,4]-benzodiazepin som gule prismer.The same reaction as in Example 15 is carried out in anhydrous tetrahydrofuran instead of in pyridine. The same compound is obtained, namely 1-methyl-8-nitro-6-phenyl-4H-s-triazolo [4,3-a] - [1,4] -benzodiazepine as yellow prisms.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8487069 | 1969-10-23 | ||
| JP8487069A JPS4927880B1 (en) | 1969-10-23 | 1969-10-23 |
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| Publication Number | Publication Date |
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| DK141726B true DK141726B (en) | 1980-06-02 |
| DK141726C DK141726C (en) | 1980-10-27 |
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| DK520370A DK141726B (en) | 1969-10-23 | 1970-10-14 | Process for the preparation of s-triazolo (4,3-a) (1,4) -benzodiazepine derivatives. |
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| Country | Link |
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| JP (1) | JPS4927880B1 (en) |
| AT (1) | AT299958B (en) |
| CH (1) | CH550810A (en) |
| DK (1) | DK141726B (en) |
| ES (2) | ES384814A1 (en) |
| FI (1) | FI51699C (en) |
| NL (1) | NL7015430A (en) |
| SE (1) | SE383348B (en) |
| YU (1) | YU34881B (en) |
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| US3879406A (en) * | 1972-07-13 | 1975-04-22 | Hoffmann La Roche | Preparation of triazolobenzodiazepines |
| US4155913A (en) * | 1973-02-08 | 1979-05-22 | Hoffmann-La Roche Inc. | Thienotriazolodiazepine derivatives |
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1969
- 1969-10-23 JP JP8487069A patent/JPS4927880B1/ja active Pending
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1970
- 1970-10-14 DK DK520370A patent/DK141726B/en not_active IP Right Cessation
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- 1970-10-21 YU YU257470A patent/YU34881B/en unknown
- 1970-10-22 SE SE1428570A patent/SE383348B/en unknown
- 1970-10-22 FI FI285070A patent/FI51699C/en active
- 1970-10-22 ES ES384814A patent/ES384814A1/en not_active Expired
- 1970-10-23 AT AT957570A patent/AT299958B/en not_active IP Right Cessation
- 1970-10-23 CH CH1571270A patent/CH550810A/en not_active IP Right Cessation
-
1973
- 1973-03-31 ES ES413244A patent/ES413244A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| YU257470A (en) | 1979-10-31 |
| FI51699B (en) | 1976-11-30 |
| AT299958B (en) | 1972-07-10 |
| YU34881B (en) | 1980-04-30 |
| DK141726C (en) | 1980-10-27 |
| SE383348B (en) | 1976-03-08 |
| ES384814A1 (en) | 1973-09-01 |
| ES413244A1 (en) | 1976-01-01 |
| FI51699C (en) | 1977-03-10 |
| JPS4927880B1 (en) | 1974-07-22 |
| NL7015430A (en) | 1971-04-27 |
| CH550810A (en) | 1974-06-28 |
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| Date | Code | Title | Description |
|---|---|---|---|
| PUP | Patent expired |