DK141846B - Analogous process for preparing 1-oxo- or 1-thioxo-s-triazolo (4,3-a) (1,4) benzodiazepine derivatives. - Google Patents
Analogous process for preparing 1-oxo- or 1-thioxo-s-triazolo (4,3-a) (1,4) benzodiazepine derivatives. Download PDFInfo
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- DK141846B DK141846B DK582970AA DK582970A DK141846B DK 141846 B DK141846 B DK 141846B DK 582970A A DK582970A A DK 582970AA DK 582970 A DK582970 A DK 582970A DK 141846 B DK141846 B DK 141846B
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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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
(11) FREMLÆGGELSESSKRIFT 1 k 1 846 DANMARK ('” lni c|3 c 07 D 487/04 §(21) Ansøgning nr. 5829/70 (22) Indleveret døn 17· nov. 1970 (23) Løbedeg 17· HOV · 1970 (44) Ansøgningen fremlagt og ,n . 1 aftn fremlaggeisesskriftet offentliggjort den -2U * Jun * -7(11) PUBLICATION WRITING 1 k 1 846 DENMARK ('”lni c | 3 c 07 D 487/04 § (21) Application no. 5829/70 (22) Filed in d. 17 · Nov. 1970 (23) Runway 17 · HOV · 1970 (44) The application presented and, n. 1 evening, the submission document was published on -2U * Jun * -7
DIREKTORATET FORDIRECTORATE OF
PATENT-OG VAREMÆRKEVÆSENET (30) Prioritet begæret fra denPATENT AND TRADE MARKET (30) Priority requested from it
18. nov. 1969, 92566/69, JPNov 18 1969, 92566/69, JP
(71) TAK~F.HA CHEMICAL INDUSTRIES LTD., 27, Doshomachi 2-chome, Higashi-Icu, Osaka, JP.(71) TAK ~ F.HA CHEMICAL INDUSTRIES LTD., 27, Doshomachi 2-chome, Higashi-Icu, Osaka, JP.
(72) Opfinder: Kanji Me guro, 2-5, Takagihigashimachi, Nishinomiya, Hyogo, JP: Yutaka Kuwada, 4-5, Maedacho, Ashiya, Hyogo, JP.(72) Inventor: Kanji Me guro, 2-5, Takagihigashimachi, Nishinomiya, Hyogo, JP: Yutaka Kuwada, 4-5, Maedacho, Ashiya, Hyogo, JP.
(74) Fuldmægtig under sagens behandling:(74) Plenipotentiary in the proceedings:
Kontor for Industriel Eneret ved Svend Schønning.Office for Industrial Excellence by Svend Schønning.
(54) Analogifremgangsmåde til fremstilling af 1-oxo- eller 1-thioxo-s-triazolo(4,5-a)(1,4)benzodiazepinderivater.(54) Analogous process for the preparation of 1-oxo- or 1-thioxo-s-triazolo (4,5-a) (1,4) benzodiazepine derivatives.
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte 1-oxo- eller 1-ti-oxo-s-triazolo^4,3-§7Zl,47benzodiazepinderivater med den almene formel 141846 2The present invention relates to an analogous process for the preparation of novel 1-oxo- or 1-ti-oxo-5-triazolo-4,3-§7Zl, 47-benzodiazepine derivatives of the general formula
/H/ H
X-^ N.X- ^ N.
- i z\- i z \
/VK/ VK
I!& I >>-R IVI! & I >> - R IV
^Aj^vAi ^ ^ v
“ I“I
hvor ringene A og B uafhængigt af hinanden hver er usub-stitueret eller substitueret med et halogenatom, en nitrogruppe, en trifluormetylgruppe, en alkylgruppe med op til 6 kulstofatomer eller en alkoxygruppe med op til 4 kulstofatomer, R er et hydrogenatom eller en alkylgruppe med op til 6 kulstofatomer og X er oxygen eller svovl, og hvor nitrogenatomet i 5-stillingen eventuelt er forbundet med oxygen, eller farmaceutisk acceptable salte heraf.wherein rings A and B are each independently unsubstituted or substituted by a halogen atom, a nitro group, a trifluoromethyl group, an alkyl group of up to 6 carbon atoms or an alkoxy group of up to 4 carbon atoms, R is a hydrogen atom or an alkyl group of up to to 6 carbon atoms and X is oxygen or sulfur and wherein the nitrogen atom at the 5-position is optionally linked to oxygen, or pharmaceutically acceptable salts thereof.
Som eksempler på substituenter på ringene A og B i formlen IV kan nævnes: halogen (såsom fluor, klor, brom og jod), nitro-, trifluormetyl-, alkylgrupper med op til 6 kulstofatomer (såsom metyl-, ætyl-, propyl-, isopropyl-, butyl-,s-butyl-, t-butyl-, pentyl-, hexyl- og cyklohexyl-grupper), og alkoxygrupper med op til 4 kulstofatomer (såsom metoxy-, ætoxy-, propoxy-, butoxy-, s-butoxy- og t-butoxygrupper). En alkylgruppe repræsenteret ved R i formel IV indeholder op til 6 kulstofatomer og er f.eks. metyl-, ætyl-, propyl-, isopropyl-, butyl-, s-butyl-t-butyl-, amyl- og hexylgrupper).Examples of substituents on the rings A and B of formula IV include: halogen (such as fluorine, chlorine, bromine and iodine), nitro, trifluoromethyl, alkyl groups of up to 6 carbon atoms (such as methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, hexyl and cyclohexyl groups), and alkoxy groups with up to 4 carbon atoms (such as methoxy, ethoxy, propoxy, butoxy, s butoxy and t-butoxy groups). An alkyl group represented by R in formula IV contains up to 6 carbon atoms and is e.g. methyl, ethyl, propyl, isopropyl, butyl, s-butyl-t-butyl, amyl and hexyl groups).
Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i kravets kendetegnende del angivne.The process according to the invention is characterized by the characterizing part of the claim.
1-Oxo- eller l-tioxo-s-triazolo/4,3-§7^1»47benzo-diazepinderivater med formel IV fremstilles således som vist i følgende reaktionsskemaer, hvor trin 1 viser fremstillingen af den som udgangsmateriale anvendte forbindelse med den almene formel II og trin 2 viser fremgangsmåden ifølge opfindelsen.Thus, 1-Oxo or 1-thioxo-5-triazolo [4,3-a] 47 benzodiazepine derivatives of formula IV are prepared as shown in the following reaction schemes, wherein step 1 shows the preparation of the starting compound used with the general formula II and step 2 show the process of the invention.
141846 3 NH-NH-NH-NH-
Λ β-AΛ β-A
\ „ ι \ π trin 1 a ι y—R _\\ "Ι \ π Step 1 a ι y — R _ \
_*/ R'NCX_ * / R'NCX
XIXI
B ιB ι
XX
NN
NH-NHC-NHR' A I \—R' trin 2 \/ \ fl/ —;-> ^ w -R'NH2NH-NHC-NHR 'A I \ -R' Step 2 \ / \ fl / -; -> ^ w -R'NH2
IIIIII
AA
X-—-NX --- N
— i1 2>- i1 2>
,ΑΑΑ* 'C, ΑΑΑ * 'C
U^Xe s ™ ^-yrr— n/ B j hvor X og R er defineret ovenfor og ringene A og B er usubstitueret eller substitueret som ovenfor anført, R' er en karbonhydridgruppe, og nitrogenaternet i 4-stillingen i formlen I og III og i 5-stillingen i formlen IV eventuelt er forbundet med oxygen.Wherein X and R are defined above and rings A and B are unsubstituted or substituted as indicated above, R 'is a hydrocarbon group, and the nitrogen atom at the 4-position of formulas I and III and optionally associated with oxygen at the 5-position of formula IV.
141846 4141846 4
Som eksempler på karbonhydridgrupper repræsenteret ved R' i formlerne II og III kan nævnes alkylgrupper, såsom metyl-, ætyl-, propyl-, isopropyl-, butyl-, s-butyl-, t-butyl-, hexyl-, cyklohexyl- og oktylgrupper, arylgrup-per, såsom fenyl- og naftylgrupper, og aralkylgrupper, såsom benzyl- og fenætylgrupper. De aromatiske ringe i disse aryl- og aralkylgrupper kan indeholde substituen-ter, ifald disse ikke indvirker på reaktionen.Examples of hydrocarbon groups represented by R 'in formulas II and III include alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, hexyl, cyclohexyl and octyl groups , aryl groups such as phenyl and naphthyl groups, and aralkyl groups such as benzyl and phenethyl groups. The aromatic rings in these aryl and aralkyl groups may contain substituents if they do not interfere with the reaction.
Trin 1Step 1
En forbindelse med formel I omsættes med isocyansyre-ester eller isotiocyansyreester med den almene formel II. Almindeligvis er det fordelagtigt at udføre omsætningen i et passende opløsningsmiddel som f.eks. kan være aromatiske karbonhydrider, pyridin, tetrahydrofuran, kloroform, dimetylformamid og alkoholer, såsom metanol og ætanol, ved eller under stuetemperatur. Undertiden kan det også være fordelagtigt at udføre omsætningen under opvarmning.A compound of formula I is reacted with isocyanic acid ester or isothiocyanic acid ester of general formula II. Generally, it is advantageous to carry out the reaction in a suitable solvent, e.g. may be aromatic hydrocarbons, pyridine, tetrahydrofuran, chloroform, dimethylformamide and alcohols such as methanol and ethanol, at or below room temperature. Sometimes it can also be advantageous to carry out the turnover during heating.
Den anvendte mængde af forbindelsen II ligger sædvanligvis mellem 1 og 1,5 molækvivalenter pr 1 mol af forbindelsen I. Det fremstillede 2-(4-substituerede semikarbazido)-eller 2-(4-substituerede tiosemikarbazido)-1,4-benzodiaze-pinderivat med formel III kan udvindes med ønsket renhedsgrad på konventionel måde, f.eks. ved destillation af et opløsningsmiddel og omkrystallisation.The amount of compound II used is usually between 1 and 1.5 mole equivalents per 1 mole of compound I. The 2- (4-substituted semicarbazido) or 2- (4-substituted thiosemicarbazido) -1,4-benzodiazepine derivative of formula III can be recovered with the desired degree of purity in conventional manner, e.g. by distillation of a solvent and recrystallization.
Trin 2Step 2
Derefter ringsluttes forbindelsen III, der er fremstillet i trin 1. Sædvanligvis skrider denne omsætning glat frem indenfor et temperaturområde fra 120°C til 250°C, idet en alkyl-, aralkyl- eller arylamin fraspaltes. Omsætningen kan udføres ved opvarmning af forbindelsen III til dens smeltepunkt uden nærværelse af et opløsningsmiddel eller ved opvarmning i et passende opløsningsmiddel, såsom pyridin, collidin, dimetylformamid, xylen, tetralin og difenylæter.Then the compound III prepared in step 1. is then cyclized, usually this reaction proceeds smoothly within a temperature range of 120 ° C to 250 ° C, leaving an alkyl, aralkyl or arylamine. The reaction may be carried out by heating compound III to its melting point without the presence of a solvent or by heating in a suitable solvent such as pyridine, collidine, dimethylformamide, xylene, tetralin and diphenyl ether.
Ved fremgangsmåden ifølge opfindelsen kan trin 1 og trin 2 udføres successivt uden isolering af forbindelsen 141846 5 III. Når f.eks. omsætningen mellem en forbindelse med formel I og en forbindelse med formel II udføres ved opvarmning i nærværelse af et opløsningsmiddel, såsom pyridin og collidin, vindes forbindelsen IV i en enkelt operation.In the process of the invention, steps 1 and 2 can be carried out successively without isolation of compound 141846. For example, when the reaction between a compound of formula I and a compound of formula II is carried out by heating in the presence of a solvent such as pyridine and collidine, compound IV is won in a single operation.
Hvis nitrogenet i 5-stillingen er forbundet med oxygen, kan oxygenet om ønsket fjernes ved reduktion med et passende desoxygeneringsmiddel, såsom fosfortrihalogenid, f.eks. fosfortriklorid, eller ved katalytisk hydrogenering, Forbindelsen IV fremstillet på ovennævnte måde kan udvindes i ønsket renhedsgrad på konventionel måde, såsom ved omkrystallisation.If the nitrogen at the 5-position is associated with oxygen, the oxygen may be removed, if desired, by reduction with a suitable deoxygenating agent such as phosphorus trihalide, e.g. phosphorus trichloride, or by catalytic hydrogenation, Compound IV prepared in the above manner can be recovered in the desired degree of purity by conventional means, such as by recrystallization.
Forbindelsen IV har basiske nitrogenatomer i dens molekyle og kan derfor udvindes i form af et farmaceutisk acceptabelt syresalt, såsom hydrokloridet, sulfatet, fosfatet, oxalatet, malonatet, succinatet, tartratet og citratet.Compound IV has basic nitrogen atoms in its molecule and can therefore be recovered in the form of a pharmaceutically acceptable acid salt such as the hydrochloride, sulfate, phosphate, oxalate, malonate, succinate, tartrate and citrate.
1-Oxo- eller l-tioxo-s-triazolo^4,3-a7/l,47benzodiaze-pinderivatet med formel IV kan danne en tautomer med den almene formel HZ-r..........— V»The 1-Oxo or 1-thioxo-5-triazolo 4,3-a7 / 1, 47-benzodiaze-pin derivative of formula IV may form a tautomer of the general formula HZ-r .......... - V »
A ,.R IVA, .R IV
s Is I
hvor R og X er defineret ovenfor, ringene A og B er usub-stitueret eller substitueret som angivet ovenfor, og nitrogenatomet i 5-stillingen er eventuelt forbundet med oxygen.wherein R and X are defined above, rings A and B are unsubstituted or substituted as indicated above, and the nitrogen atom at the 5-position is optionally linked to oxygen.
Forbindelserne III og IV er hidtil ukendte.Compounds III and IV are novel.
Forbindelserne med den almene formel IV har vist sig at have en betydelig farmakologisk virkning på det centrale nervesystem, idet de er jnuskelafslappende, antikonvul-sive, sedative og har søvndyssende virkning. Forbindelser- 6 um6 ne er således nyttige som lægemidler, f.eks. som muskelaf slappende middel, som antikonvulsivisk middel, som beroligende middel og som sovemiddel.The compounds of general formula IV have been found to have a significant pharmacological effect on the central nervous system, being muscle relaxant, anticonvulsant, sedative and have a sleep-inducing effect. Thus, the compounds 6 are useful as drugs, e.g. as a muscle relaxant, as an anticonvulsant, as a sedative and as a sleeping agent.
Som det fremgår af den nedenfor viste biologiske forsøgsrapport er de omhandlede forbindelsers biologiske virkning overraskende bedre end virkningen af tilsvarende, kendte forbindelser.As can be seen from the biological test report shown below, the biological effect of the compounds of the present invention is surprisingly superior to that of similar known compounds.
De omhandlede forbindelser kan indgives oralt eller parenteralt som sådanne, eller hvis det ønskes, kan de blandes med et farmaceutisk acceptabelt bærestof i passende form, f.eks. som pulvere, piller, tabletter og injektionsopløsninger. Den administrerede mængde afhænger f.eks. af den anvendte forbindelse og af sygdommens alvor, og ligger sædvanligvis på en mængde på 1-30 mg pr dag for en voksen ved oral indgift.The subject compounds may be administered orally or parenterally as such or, if desired, may be admixed with a pharmaceutically acceptable carrier in appropriate form, e.g. such as powders, pills, tablets and injection solutions. The amount administered depends, e.g. of the compound used and the severity of the disease, and usually is in the amount of 1-30 mg per day for an adult by oral administration.
Biologisk forsøgsrapportBiological Experimental Report
Undersøgte forbindelser:Compounds examined:
Forbindelse A: „Compound A:
VV
°- Repræsentant for de her . ^ omhandlede forbindelser.° - Representative of these. ^ compounds.
nono
Forbindelse B: ΛΤ Typisk repræsentant for de |- — nn forbindelser, der er be- ^ skrevet i de danske patent- ^\ / ' \ ansøgninger nr. 5836/69, ^ I \ 1303/70 og 5203/70.Compound B: ΛΤ Typical representative of the compounds described in Danish Patent Nos. 5836/69, Nos. 1303/70 and 5203/70.
π 141846 7π 141846 7
Forbindelse C:Compound C:
Repræsentant for de forbin-r —NL delser,der er beskrevet i | dansk patentansøgning nr.Representative of the connections described in | Danish patent application no.
/ 1011/70./ 1011/70.
I /—°HI / - ° H
ΓΓ
Biologiske sanmenllgningsresultaterBiological assessment results
Forbindelse Tranquiliserende Muskelrelakse- Akut toxicitet virkning rende virkning LD^q (mg/kg) E33gQ (mg/kg) ^50 ) hos mus (p.o.)Compound Tranquilizing Muscle Relaxation- Acute Toxicity Effective Effect LD ^ q (mg / kg) E33gQ (mg / kg) ^ 50) in mice (p.o.)
Antimorfin- Skråtstillet virkning hos plade mus (p.o.) mus (p.o.) A 35 150 2200 B 12,4 6,1 678 C - 1500Antimorphine-Oblique effect in flat mouse (p.o.) mice (p.o.) A 35 150 2200 B 12.4 6.1 678 C - 1500
Det fremgår af tabellen ovenfor at forbindelse A har svagere tranquiliserende virkning end forbindelse B, men at index for ED^Q (skråtstillet plade)/ED^0 (antimorfin) er højere for forbindelse A end for forbindelse B (henholdsvis ca. 4,3 og 0,5). Det fremgår således at forbindelse A har lavere forekomst af neurologiske bivirkninger ved klinisk brug. Desuden er forbindelse A væsentligt mindre toxisk sammenlignet med forbindelse B.It can be seen from the table above that Compound A has weaker tranquilizing effect than Compound B, but that the index for ED ^Q (inclined plate) / ED ^0 (antimorphine) is higher for Compound A than for Compound B (about 4.3, respectively). and 0.5). Thus, it appears that compound A has a lower incidence of neurological side effects in clinical use. In addition, Compound A is significantly less toxic compared to Compound B.
Det ses endvidere at forbindelse A er mindre toxisk end forbindelse C.Furthermore, it is seen that Compound A is less toxic than Compound C.
141846 8141846 8
Fremgangsmåden ifølge opfindelsen skal forklares nærmere ved hjælp af et antal udførelseseksempler, hvor eksempel 1, 5, 7, 9, 11 og 14 belyser fremstillingen af udgangsmaterialer med den almene formel III/ og de øvrige eksempler belyser fremgangsmåden ifølge opfindelsen. I eksemplerne svarer forholdet mellem vægtdele og rumfangsdele til forholdet mellem gram og millimeter.The process according to the invention will be explained in more detail by means of a number of exemplary embodiments in which Examples 1, 5, 7, 9, 11 and 14 illustrate the preparation of starting materials of general formula III and the other examples illustrate the process according to the invention. In the examples, the ratio of parts by weight to volume equals the ratio of grams to millimeters.
Udgangsmaterialerne 2-hydrazino-l,4-benzodiazepin- derivaterne eller deres 4N-oxyder kan let fremstilles.The starting materials 2-hydrazino-1,4-benzodiazepine derivatives or their 4N oxides can be readily prepared.
F.eks. fremstilles 7-klor-2-hydrazino-5-fenyl-3H-l,4-benzodiazepin som anvendes som udgangsmateriale i eksemplerne 1, 4 og 5, på den måde der er beskrevet i referenceeksemplerne 1, 2 og 3. De andre udgangsmaterialer kan fremstilles på tilsvarende måde.Eg. 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine is used as starting material in Examples 1, 4 and 5, in the manner described in Reference Examples 1, 2 and 3. The other starting materials may be are prepared in a similar manner.
Referenceeksempel· 1Reference Example · 1
Til en suspension af 3,4 vægtdele 2-amino-7-klor-5-fenyl-3H-l/4-benzodiazepin,dihydroklorid, i 60 rumfangsdele metanol sættes 1,25 vægtdele 80% hydrazinhydrat, og blandingen omrøres i 40 minutter. Efter tilsætning af vand ekstraheres blandingen med metylenklorid. Metylenkloridlaget vaskes med vand og tørres over natriumsulfat, hvorpå opløsningsmidlet afdestilleres. Ved omkrystallisation af remanensen ud fra metylenklorid/benzen vindes 7-klor-2-hydrazino-5-fenyl-3H-l,4-benzodiazepin som farveløse prismer. Smeltepunkt: ca 170°C brunfårvning, ca 202-204°C sønderdeling.To a suspension of 3.4 parts by weight of 2-amino-7-chloro-5-phenyl-3H-1/4-benzodiazepine, dihydrochloride, in 60 parts by volume of methanol, 1.25 parts by weight of 80% hydrazine hydrate are added and the mixture is stirred for 40 minutes. After addition of water, the mixture is extracted with methylene chloride. The methylene chloride layer is washed with water and dried over sodium sulfate, then the solvent is distilled off. Recrystallization of the residue from methylene chloride / benzene gives 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine as colorless prisms. Melting point: about 170 ° C brown staining, about 202-204 ° C decomposition.
Beregnet for C^5H^3C1N4: C 63,43, H 4,48, N 19,27 fundet : C 63,27, H 4,60, N 19,68%Calculated for C C ^HH 3ClNN: C 63.43, H 4.48, N 19.27 found: C 63.27, H 4.60, N 19.68%
Referenceeksempel 2Reference Example 2
Til en opløsning af 2 vægtdele 7-klor-2-metyl-merkap-to-5-fenyl-3H-l,4-benzodiazepin i 70 rumfangsdele metanol sættes 5 rumfangsdele hydrazinhydrat, og blandingen henstår i 3 dage ved stuetemperatur, hvorpå opløsningsmidlet afdestilleres. Remanensen fortyndes med vand, hvorved der vindes 7-klor-2-hydrazino-5-fenyl-3H-l,4“benzodiazepin som krystaller. Ved omkrystallisation ud fra metylenklorid/ benzen vindes farveløse prismer der smelter ved 175°C (blødgøring) og 205-207°C (sønderdeling).To a solution of 2 parts by weight of 7-chloro-2-methyl-mercap-to-5-phenyl-3H-1,4-benzodiazepine in 70 volumes of methanol is added 5 volumes of hydrazine hydrate and the mixture is allowed to stand for 3 days at room temperature, after which the solvent is distilled off. . The residue is diluted with water to give 7-chloro-2-hydrazino-5-phenyl-3H-1,4 'benzodiazepine as crystals. By recrystallization from methylene chloride / benzene, colorless prisms melt at 175 ° C (softening) and 205-207 ° C (decomposing).
Dette produkt er identisk med forbindelsen opnået ved 141846 9 referenceeksempel 1.This product is identical to the compound obtained by Reference Example 1.
Referenceeksempel 3Reference Example 3
En blanding af 2,9 vægtdele 7-klor-l,3-dihydro-5-fenyl-2H-l,4-benzodiazepin-2-tion, 2,5 rumfangsdele di-metylsulfoxyd, 100 rumfangsdele ætanol, 5 rumfangsdele 80% hydrazinhydrat henstilles en dag. Efter fjernelse af ætanolet ved destillering under reduceret tryk, fortyndes koncentratet med vand og ekstraheres med metylenklorid. Metylenkloridlaget opsamles og tørres over vandfrit natriumsulfat, hvorpå opløsningsmidlet fjernes. Ved behandling af remanensen med benzen vindes 7-klor-2-hydra-zino-5-fenyl-3H-l,4-benzodiazepin som krystaller. Ved omkrystallisation ud fra metylenklorid/benzen vindes farveløse prismer, der smelter ved 205-207°C (sønderdeling).A mixture of 2.9 parts by weight of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione, 2.5 parts by volume of dimethylsulfoxide, 100 parts by volume ethanol, 5 parts by volume 80% hydrazine hydrate recommended one day. After removing the ethanol by distillation under reduced pressure, the concentrate is diluted with water and extracted with methylene chloride. The methylene chloride layer is collected and dried over anhydrous sodium sulfate and the solvent is removed. When treating the residue with benzene, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine is obtained as crystals. By recrystallization from methylene chloride / benzene, colorless prisms melting at 205-207 ° C (decomposition) are obtained.
Dette produkt er identisk med produktet opnået i referenceeksemplerne 1 og 2.This product is identical to the product obtained in Reference Examples 1 and 2.
Eksempel 1Example 1
Til en opløsning af 14,2 vægtdele 7-klor-2-hydrazi-no-5-fenyl-3H-l,4-benzodiazepin i 250 rumfangsdele tetra-hydrofuran sættes 3,5 rumfangsdele metylisocyanat dråbevis under isafkøling og omrøring. Efter en times omrøring hældes blandingen i 2000 rumfangsdele vand. Bundfaldet opsamles ved filtrering, vaskes med vand og acetone og tørres derefter, hvorved der vindes 7-klor-2-(4-metylsemi-karbazido)-5-fenyl-3H-l,4-benzodiazepin scan krystaller.To a solution of 14.2 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 250 volumes of tetrahydrofuran, 3.5 volumes of methyl isocyanate are added dropwise under ice-cooling and stirring. After stirring for an hour, the mixture is poured into 2000 parts by volume of water. The precipitate is collected by filtration, washed with water and acetone and then dried to give 7-chloro-2- (4-methylsemi-carbazido) -5-phenyl-3H-1,4-benzodiazepine scan crystals.
Ved omkrystallisation ud fra dimetylformamid/vand vindes farveløse nåle der smelter ved 247°C (sønderdeling).By recrystallization from dimethylformamide / water, colorless needles are melted at 247 ° C (decomposition).
Beregnet for ci7Hi6ClN50: C 59,73, H 4,72, N 20,49 fundet : C 59,53, H 4,62, N 20,80%.Calc'd for C 17 H 16 ClN 5 O: C 59.73, H 4.72, N 20.49 found: C 59.53, H 4.62, N 20.80%.
Eksempel 2 6,8 vægtdele 7-klor-2-(4-metylsemikarbazido)-5-fenyl-3H-l,4-benzodiazepin fremstillet i eksempel 1 opvarmes ved 250°C under omrøring, hvorved udgangsmaterialet smelter under opskumning. Efter opvarmning i ca 15 minutter indtil skummet synker sammen behandles den smeltede sub- ίο 141846 stans med ætylacetat, hvorved der opnås 8-klor-6-fenyl- 2,4-dihydro-lH-s-triazolo^4,3-a/^l,47benzodiazepin-l-on som krystaller. Ved omkrystallisation ud fra metanol vindes farveløse nåle der smelter ved 252-253°C.Example 2 6.8 parts by weight of 7-chloro-2- (4-methylsemicarbazido) -5-phenyl-3H-1,4-benzodiazepine prepared in Example 1 are heated at 250 ° C with stirring, whereby the starting material melts under foaming. After heating for about 15 minutes until the foam sinks, the molten sub-solid is treated with ethyl acetate to give 8-chloro-6-phenyl-2,4-dihydro-1H-s-triazolo ^ 4,3-a / µl, 47benzodiazepine-1-one as crystals. By recrystallization from methanol, colorless needles are obtained which melt at 252-253 ° C.
Beregnet for C^H^ClN^Oi C 61,84, H 3,57, N 18,03 fundet : C 61,83, H 3,47, N 18,18%.Calculated for C C ^H ClClN ^O O C 61.84, H 3.57, N 18.03 found: C 61.83, H 3.47, N 18.18%.
Eksempel 3Example 3
En blanding af 5,1 vægtdele 7-klor-2-(4-metylsemi-karbazido)-5-fenyl-3H-l,4-benzodiazepin fremstillet i eksempel 1 og 180 rumfangsdele pyridin opvarmes under tilbagesvaling i ca 35 timer, indtil der næsten ikke mere observeres frembringelse af metylamin. Opløsningsmidlet afdestil-leres under reduceret tryk, og remanensen behandles med ætylacetat, hvorved der vindes 8-klor-6-fenyl-2,4-dihydro-lH-s-triazolo/4,3-a7</benzodiazepin-l-on som krystaller. Ved omkrystallisation ud fra metanol vindes farveløse nåle, der smelter ved 252-253°C.A mixture of 5.1 parts by weight of 7-chloro-2- (4-methylsemi-carbazido) -5-phenyl-3H-1,4-benzodiazepine prepared in Examples 1 and 180 parts of pyridine is heated at reflux for about 35 hours. hardly any production of methylamine is observed. The solvent is distilled off under reduced pressure and the residue is treated with ethyl acetate to give 8-chloro-6-phenyl-2,4-dihydro-1H-s-triazolo / 4,3-a7 </ benzodiazepin-1-one as crystals. By recrystallization from methanol colorless needles are obtained, melting at 252-253 ° C.
Dette produkt er identisk med forbindelsen opnået i eksempel 2.This product is identical to the compound obtained in Example 2.
Eksempel 4Example 4
Til en opløsning af 2,85 vægtdele 7-klor-2-hydrazino- 5-fenyl-3H-l,4-benzodiazepin i 120 rumfangsdele pyridin sættes 0,7 rumfangsdele metylisocyanat under isafkøling og omrøring, og blandingen holdes ved stuetemperatur i 30 minutter. Efter opvarmning under tilbagesvaling i 35 timer afdestilleres opløsningsmidlet under reduceret tryk hvorved der som remanens vindes rå 7-klor-2-(4-metylsemikarbazido)-5-fenyl-3H-l,4-benzodiazepin.To a solution of 2.85 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 120 volumes of pyridine, 0.7 volumes of methyl isocyanate are added under ice-cooling and stirring and the mixture is kept at room temperature for 30 minutes. . After refluxing for 35 hours, the solvent is distilled off under reduced pressure to afford crude 7-chloro-2- (4-methylsemicarbazido) -5-phenyl-3H-1,4-benzodiazepine.
Remanensen behandles med ætylacetat hvorved der vindes 8-klor-6-fenyl-2,4-dihydro-lH-s-triazolo/4,3-§7^1,47benzo-diazepin-l-on som krystaller. Ved omkrystallisation ud fra metanol vindes farveløse nåle, der smelter ved 252-253°C.The residue is treated with ethyl acetate to give 8-chloro-6-phenyl-2,4-dihydro-1H-s-triazolo / 4,3-§7 ^ 1,47 benzodiazepin-1-one as crystals. By recrystallization from methanol colorless needles are obtained, melting at 252-253 ° C.
Dette produkt er identisk med forbindelsen opnået i eksemplerne 2 og 3.This product is identical to the compound obtained in Examples 2 and 3.
Eksempel 5Example 5
Til en opløsning er 1,4 vægtdele 7-klor-2-hydrazino- 141846 11 5-fenyl-3H-l,4-benzodiazepin i 25 rumfangsdele tetrahydro-furan sættes 0,65 rumfangsdele fenylisocyanat under isafkøling og omrøring. Efter 1 times omrøring sættes den dobbelte mængde vand til blandingen. De fremkomne krystaller opsamles ved filtrering, vaskes med vand og acetone og tørres, hvorved der vindes 7-klor-5-fenyl-2-(4-fenylsemi-karbazido)-3H-1,4-benzodiazepin som krystaller. Ved amkrystallisation ud fra dimetylformamid/vand vindes farveløse fine nåle der smelter ved 220-221°C (sønderdeling).To a solution, 1.4 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 25 parts of tetrahydrofuran are added 0.65 volumes of phenyl isocyanate under ice-cooling and stirring. After stirring for 1 hour, the double amount of water is added to the mixture. The resulting crystals are collected by filtration, washed with water and acetone and dried to give 7-chloro-5-phenyl-2- (4-phenylsemi-carbazido) -3H-1,4-benzodiazepine as crystals. By crystallization from dimethylformamide / water, colorless fine needles are obtained which melt at 220-221 ° C (decomposition).
Beregnet for C22H18C1N50: C 65,42, H 4,49, N 17,34 fundet : C 65,61, H 4,30, N 17,28%.Calcd for C 22 H 18 Cl 1 N 5: C 65.42, H 4.49, N 17.34 found: C 65.61, H 4.30, N 17.28%.
Eksempel 6Example 6
En opløsning af 4 vægtdele 7-klor-5-fenyl-2-(4-fen-ylsemikarbazido)-3H-1,4-benzodiazepin fremstillet ifølge eksempel 5 1 120 rumfangsdele pyridin koges under tilbagesvaling i 5 timer. Opløsningsmidlet sidestilleres under reduceret tryk, hvorved der vindes 8-klor-6-fenyl-2,4-dihydro-lH-s-triazolo/?,3-a7/l,47benzodxazepin-l-on som krystaller. Ved omkrystallisation ud fra metanol vindes farveløse nåle som smelter ved 252-253°C.A solution of 4 parts by weight of 7-chloro-5-phenyl-2- (4-phenylsemicarbazido) -3H-1,4-benzodiazepine prepared according to Example 5 in 120 parts by volume of pyridine is refluxed for 5 hours. The solvent is juxtaposed under reduced pressure to give 8-chloro-6-phenyl-2,4-dihydro-1H-s-triazolo [3,3-a7 / 1,4benzodxazepin-1-one as crystals. By recrystallization from methanol, colorless needles are obtained which melt at 252-253 ° C.
Dette produkt er identisk med forbindelsen opnået i eksemplerne 2, 3 og 4.This product is identical to the compound obtained in Examples 2, 3 and 4.
Eksempel 7Example 7
Til en opløsning af 3,1 vægtdele 7-klor-2-hydrazino- 5-(p-metoxyfenyl)-3H-1,4-benzodiazepin i 40 rumfangsdele pyridin sættes 0,7 rumfangsdele metylisocyanat dråbevis under isafkøling og omrøring. Efter ca 30 minutters omrøring sættes der 100 rumfangsdele vand til blandingen.To a solution of 3.1 parts by weight of 7-chloro-2-hydrazino-5- (p-methoxyphenyl) -3H-1,4-benzodiazepine in 40 volumes of pyridine, 0.7 volumes of methyl isocyanate is added dropwise under ice-cooling and stirring. After about 30 minutes of stirring, 100 volumes of water are added to the mixture.
De fremkomne krystaller opsamles ved filtrering, vaskes med metanol og tørres, hvorved der opnås 7-klor-5-(p-metoxyfenyl) -2-(4-metylsemikarbazido)-3H-1,4-benzodiazepin som krystaller. Ved omkrystallisation ud fra dimetylformamid/vand vindes farveløse nåle som smelter ved 234-235°C (sønderdeling).The resulting crystals are collected by filtration, washed with methanol and dried to give 7-chloro-5- (p-methoxyphenyl) -2- (4-methylsemicarbazido) -3H-1,4-benzodiazepine as crystals. By recrystallization from dimethylformamide / water, colorless needles are obtained which melt at 234-235 ° C (decomposition).
Beregnet for C18H18C1N302: C 58,14, H 4,88, N 18,84 fundet : C 57,83, H 4,74, N 19,17%.Calcd for C 18 H 18 ClN 3 O 2: C 58.14, H 4.88, N 18.84 found: C 57.83, H 4.74, N 19.17%.
12 14-18 4612 14-18 46
Eksempel 8Example 8
En opløsning af 2,0 vægtdele 7-klor-5-(p-metoxyfen-yl)-2-(4-metylsemikarbazido)-3H-l,4-benzodiazepin fremstillet ifølge eksempel 7 i 70 rumfangsdele pyridin koges under tilbagesvaling i 36 timer. Opløsningsmidlet afdestilleres under reduceret tryk. Remanensen behandles med ætylacetat, hvorved der vindes 8-klor-6-(p-metoxyfen-yl) -2,4-dihydro-lH-s-triazolo^4,3-a//l, 4/benzodiazepin-l-on som krystaller. Ved omkrystallisation ud fra metanol vindes farveløse nåle som smelter ved 257-258°C.A solution of 2.0 parts by weight of 7-chloro-5- (p-methoxyphenyl) -2- (4-methylsemicarbazido) -3H-1,4-benzodiazepine prepared according to Example 7 in 70 volumes of pyridine is refluxed for 36 hours . The solvent is distilled off under reduced pressure. The residue is treated with ethyl acetate to give 8-chloro-6- (p-methoxyphenyl) -2,4-dihydro-1H-s-triazolo 4,3-a // 1,4-benzodiazepin-1-one like crystals. By recrystallization from methanol, colorless needles are obtained which melt at 257-258 ° C.
Beregnet for C17H13C1N402: C 59,92, H 3,82, N 16,44 fundet : C 60,16, H 3,77, N 16,22%.Calculated for C 17 H 13 ClN 4 O 2: C 59.92, H 3.82, N 16.44 found: C 60.16, H 3.77, N 16.22%.
Eksempel 9Example 9
En blanding af 2,8 rumfangsdele 2-amino-7-nitro-5-fenyl-3H-l,4-benzodiazepin og 2 rumfangsdele hydrazinhydrat omrøres ved stuetemperatur i en time og hældes i isvand. Kloroformlaget vaskes med vand og tørres over vandfrit natriumsulfat. Opløsningsmidler afdestilleres, hvorved der vindes 2-hydrazino-7-nitro-5-fenyl-3H-l,4-benzo-diazepin som en viskos olieagtig substans.A mixture of 2.8 volumes of 2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepine and 2 volumes of hydrazine hydrate is stirred at room temperature for one hour and poured into ice water. The chloroform layer is washed with water and dried over anhydrous sodium sulfate. Solvents are distilled off to give 2-hydrazino-7-nitro-5-phenyl-3H-1,4-benzodiazepine as a viscous oily substance.
Det således fremstillede 2-hydrazinoderivat opløses i 20 rumfangsdele pyridin, hvorpå der tilsættes 1,1 rumfangsdele metylisocyanat under isafkøling og omrøring.The 2-hydrazino derivative thus obtained is dissolved in 20 parts by volume of pyridine, to which is added 1.1 parts by volume of methyl isocyanate under ice-cooling and stirring.
Efter en times omrøring tilsættes 80 rumfangsdele vand.After stirring for one hour, 80 volumes of water are added.
Det således fremstillede bundfald opsamles ved filtrering, vaskes med acetone og tørres, hvorved der vindes 2—(4— metylsemikarbazido)-7-nitro-5-fenyl-3H-l,4-benzodiazepin som krystaller. Ved omkrystallisation ud fra dimetylform-amid/vand vindes gule fine plader som smelter ved 239-240°C (sønderdeling).The precipitate thus obtained is collected by filtration, washed with acetone and dried to give 2- (4-methylsemicarbazido) -7-nitro-5-phenyl-3H-1,4-benzodiazepine as crystals. Upon recrystallization from dimethylformamide / water, yellow fine plates are obtained which melt at 239-240 ° C (decomposition).
Beregnet for C17H16N603: C 57,95, H 4,58, N 23,85 fundet : C 57,98, H 4,47, N 24,14%.Calculated for C 17 H 16 N 6 O 3: C 57.95, H 4.58, N 23.85 found: C 57.98, H 4.47, N 24.14%.
Eksempel 10Example 10
En opløsning af 4,2 vægtdele 2-(4-metylsemikarbazido)-7-nitro-5-fenyl-3H-l,4-benzodiazepin fremstillet ifølge eksempel 9 i 150 rumfangsdele pyridin koges under tilba- 141866 13 svaling i 25 timer, hvorpå opløsningsmidlet afdestille-res. Remanensen blandes med vand. Det resulterende bundfald opsamles ved filtrering og tørres, hvorved der vindes 8-nitro-6-fenyl-2,4-dihydro-lH-s-triazolo/4,3-a/-</1,4/benzodiazepin-l-on som krystaller. Ved amkrystallisation ud fra vandigt acetone vindes gule nåle der smelter ved 199-200°C.A solution of 4.2 parts by weight of 2- (4-methylsemicarbazido) -7-nitro-5-phenyl-3H-1,4-benzodiazepine prepared according to Example 9 in 150 volumes of pyridine is boiled under reflux for 25 hours, then the solvent is distilled off. The residue is mixed with water. The resulting precipitate is collected by filtration and dried to give 8-nitro-6-phenyl-2,4-dihydro-1H-s-triazolo [4,3-a] - [1,4] benzodiazepin-1-one like crystals. By crystallization from aqueous acetone, yellow needles are obtained which melt at 199-200 ° C.
Beregnet for C16H11N503: c 59,81, H 3,45, N 21,80 fundet : C 60,00, H 3,44, N 21,77%.Calc'd for C 16 H 11 N 5 O 3: c 59.81, H 3.45, N 21.80 found: C 60.00, H 3.44, N 21.77%.
Eksempel 11Example 11
Til en opløsning af 3 vægtdele 7-klor-2-hydrazino- 5-fenyl-3H-l,4-benzodiazepin-4N-oxyd i 6o rumgangsdele pyridin sættes 0,7 rumfangsdele metylisocyanat under isafkøling og omrøring. Efter ca 30 minutters forløb opsamles de resulterende krystaller ved filtrering, vaskes med metanol og tørres, hvorved der vindes 7-klor-2-(4-metylsemikarbazido)-6-fenyl-3H-l,4-benzodiazepin-4N-oxyd som krystaller. Ved amkrystallisation ud fra dimetyl-formamid/vand vindes farveløse fine nåle, der smelter ved 251-252°C (sønderdeling).To a solution of 3 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine-4N-oxide in 60 volumes of pyridine is added 0.7 volumes of methyl isocyanate under ice-cooling and stirring. After about 30 minutes, the resulting crystals are collected by filtration, washed with methanol and dried to give 7-chloro-2- (4-methylsemicarbazido) -6-phenyl-3H-1,4-benzodiazepine-4N-oxide as crystals . By crystallization from dimethylformamide / water, colorless fine needles are obtained, melting at 251-252 ° C (decomposition).
Beregnet for C17H16C1N502: C 57,06, H 4,51, N 19,58 fundet : C 56,86, H 4,35, N 19,81%.Calculated for C 17 H 16 ClN 5 O 2: C 57.06, H 4.51, N 19.58 found: C 56.86, H 4.35, N 19.81%.
Eksempel 12Example 12
En blanding af 3 vægtdele 7-klor-2-(4-metylsemikarb-azido)-6-fenyl-3H-l,4-benzodiazepin-4N-oxyd fremstillet ifølge eksempel 11, 60 rumfangsdele pyridin og 140 rumfangsdele dimetylformamid opvarmes under tilbagesvaling i 8½ time, hvorefter opløsningsmidlet afdestilleres under reduceret tryk. Remanensen behandles med vandigt ætanol, hvorved der vindes 8-klor-6-fenyl-2,4-dihydro-lH-s-triazolo^4,3-a7^1,47benzodiazepin-l-on-5N-oxyd som krystaller. Ved omkrystallisation ud fra vandigt metanol vindes gule prismer af moncmetanolatet, der smelter ved 164-166°C (skumning).A mixture of 3 parts by weight of 7-chloro-2- (4-methylsemicarbazido) -6-phenyl-3H-1,4-benzodiazepine-4N-oxide prepared according to Example 11, 60 parts by volume of pyridine and 140 parts by volume of dimethylformamide is heated at reflux in 8 hours, after which the solvent is distilled off under reduced pressure. The residue is treated with aqueous ethanol to give 8-chloro-6-phenyl-2,4-dihydro-1H-s-triazolo ^ 4,3-a7 ^ 1,47benzodiazepine-1-one-5N-oxide as crystals. By recrystallization from aqueous methanol, yellow prisms of the monc methanolate are obtained, melting at 164-166 ° C (foaming).
Beregnet for ci6HiiclN4°2'CH3OH: C 56,91, H 4,21, N 15,62 fundet : C 56,77, H 4,02, N 15,88%.Calcd for C 18 H 18 N 4 O 2 2 CH 3 OH: C 56.91, H 4.21, N 15.62 Found: C 56.77, H 4.02, N 15.88%.
14 16186614 161866
Ved omkrystallisation ud fra vandigt ætanol vindes gule prismer af monohydrat, der smelter ved 173-174°C (blødgøring).By recrystallization from aqueous ethanol, yellow prisms of monohydrate melting at 173-174 ° C (softening) are obtained.
Beregnet for C^gH^ClN^c^*E^O: C 55,74, Η 3,8ο, N 16,25 fundet : C 55,89, H 3,85, H 16,25%.Calcd for C C gH ^ClN cC ^ * E ^O: C 55.74, Η 3.8ο, N 16.25 found: C 55.89, H 3.85, H 16.25%.
Eksempel 13Example 13
Til en opløsning af 2,85 vægtdele 7-klor-2-hydrazino- 5-fenyl-3H-l,4-benzodiazepin i 25 rumfangsdele pyridin sættes 1,5 vægtdele fenylisotiocyanat, og blandingen opvarmes under tilbagesvaling. Efter 3½ timers forløb af-destilleres pyridin under reduceret tryk, hvorved der som remanens vindes rå 7-klor-5-feny1-2-(4-fenyl-tiosemikarbazido)-3H-1,4-benzodiazepin. Remanensen behandles med æter, hvorved der vindes 8-klor-6-fenyl-2,4-dihydro-lH-s-triazolo^4,3-a//l,4/benzodiazepin -1-tion som krystaller. Ved omkrystallisation ud fra metanol vindes farveløse prismer, der smelter ved 237-238°C.To a solution of 2.85 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 25 parts by volume of pyridine is added 1.5 parts by weight of phenylisothiocyanate and the mixture is heated at reflux. After 3½ hours, pyridine is distilled off under reduced pressure to yield crude 7-chloro-5-phenyl-2- (4-phenylthiosemicarbazido) -3H-1,4-benzodiazepine as the residue. The residue is treated with ether to give 8-chloro-6-phenyl-2,4-dihydro-1H-s-triazolo 4,3-a // 1,4-benzodiazepine -1-thione as crystals. By recrystallization from methanol, colorless prisms melting at 237-238 ° C are obtained.
Beregnet for c16hiic1N4S: C 58,79, H 3,39, N 17,14 fundet : C 58,94, H 3,29, N 17,24%.Calculated for C 16 H 18 N 4 S: C 58.79, H 3.39, N 17.14 found: C 58.94, H 3.29, N 17.24%.
Eksempel 14Example 14
Til en opløsning af 2,85 vægtdele 7-klor-2-hydrazino- 5-fenyl-3H-l,4-benzodiazepin i 250 rumfangsdele ætanol sættes 1,5 vægtdele fenylisotiocyanat, og blandingen henstilles ved stuetemperatur i ca 3 timer. De bundfældede krystaller opsamles ved filtrering, hvorved der vindes 7-klor-5-fenyl-2-(4-fenyltiosemikarbazido)-3H-1,4-benzodiazepin som krystaller. Ved omkrystallisation ud fra acetone vindes bleggule nåle, der smelter ved 199-205°C (sønderdeling).To a solution of 2.85 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 250 parts by volume of ethanol is added 1.5 parts by weight of phenylisothiocyanate and the mixture is allowed to stand at room temperature for about 3 hours. The precipitated crystals are collected by filtration to give 7-chloro-5-phenyl-2- (4-phenylthiosemicarbazido) -3H-1,4-benzodiazepine as crystals. By recrystallization from acetone pale yellow needles are obtained, melting at 199-205 ° C (decomposition).
Beregnet for C22H1gClN^S: C 62,96, H 4,31, N 16,67 fundet : C 62,51, H 4,31, N 16,65%.Calcd for C 22 H 1 ClCl 3 S: C 62.96, H 4.31, N 16.67 found: C 62.51, H 4.31, N 16.65%.
Eksempel 15Example 15
En opløsning af 3 vægtdele 7-klor-5-fenyl-2-(4-fenyltiosemikarbazido) -3H-1,4-benzodiazepin fremstillet ifølge eksempie 14 i 25 rumfangsdele pyridin opvarmes under tilbagesvaling i 2 timer, hvorpå opløsningsmidlet af-destilleres under reduceret tryk. Remanensen behandles med æter. De resulterende krystaller opsamles ved filtre- 141866 15 ring og tørres, hvorved der vindes 8-klor-6-fenyl-2,4-dihydro-lH-s-triazolo^4,3-a//I,47benzodiazepin-l-tion som krystaller. Ved omkrystallisation ud fra metanol vindes farveløse prismer der smelter ved 237-238°C.A solution of 3 parts by weight of 7-chloro-5-phenyl-2- (4-phenylthiosemicarbazido) -3H-1,4-benzodiazepine prepared according to Example 14 in 25 parts of pyridine is heated at reflux for 2 hours, then the solvent is distilled off under reduced pressure. pressure. The residue is treated with ether. The resulting crystals are collected by filtration and dried to give 8-chloro-6-phenyl-2,4-dihydro-1H-s-triazolo [4,3-a] l, 47benzodiazepine-1-thione like crystals. By recrystallization from methanol, colorless prisms melt at 237-238 ° C.
Dette produkt er identisk med produktet opnået i eksempel 13.This product is identical to the product obtained in Example 13.
Eksempel 16Example 16
Udgangsforbindelsen 7-klor-5-fenyl-2-(4-fenyltiosemi-karbazido)-3H-benzodiazepin-4N-oxyd (formel III) fremstilles in situ ved at sætte 1,5 vægtdele fenylisotiocyanat til en opløsning af 3 vægtdele 7-klor-2-hydrazino-5-fenyl-3H-l,4-benzodiazepin-4N-oxyd i 20 rumfangsdele pyridin, og blandingen opvarmes under tilbagesvaling i 2 i timer hvorved den in situ dannede udgangsforbindelse ringsluttes. Efter afkøling af blandingen fjernes det uopløselige materiale ved filtrering. Filtratet koncentreres til tørhed under reduceret tryk. Ved oønkrystallisation af remanensen ud fra en blanding af ætanol og acetone vindes 8-klor-6-f enyl-2,4-d ihydro-lH-s-tr iazolo</4,3 -a//l, 47benzodiazepin-l-tion-5N-oxyd som gule prismer, der smelter ved 243-244°C (sønderdeling).The starting compound 7-chloro-5-phenyl-2- (4-phenylthiosemi-carbazido) -3H-benzodiazepine-4N-oxide (Formula III) is prepared in situ by adding 1.5 parts by weight of phenylisothiocyanate to a solution of 3 parts by weight of 7-chloro 2-Hydrazino-5-phenyl-3H-1,4-benzodiazepine-4N-oxide in 20 parts of pyridine and the mixture is heated under reflux for 2 hours, whereby the in situ formed compound is cyclized. After cooling the mixture, the insoluble material is removed by filtration. The filtrate is concentrated to dryness under reduced pressure. On crystallization of the residue from a mixture of ethanol and acetone, 8-chloro-6-phenyl-2,4-dihydro-1H-s-tr iazolo <4,3-a // 1,47benzodiazepine-1 thion-5N oxide as yellow prisms melting at 243-244 ° C (dec.).
Beregnet for ci6HllClN4OS'C2H50H: C 55,93, H 3,56, N 15,81 fundet : C 56,09, H 3,74, N 15,79%.Calcd for C 16 H 11 ClN 4 OS · C 2 H 5 O: C 55.93, H 3.56, N 15.81 found: C 56.09, H 3.74, N 15.79%.
Eksempel 17Example 17
Til en opløsning af 1,8 vægtdele 8-klor-6-fenyl-2,4-dihydro-lH-s-triazolo74,3-a771f47benzodiazepin-l-on-5N-oxyd.(metanolat) fremstillet ifølge eksempel 12 i 200 rumfangsdele kloroform sættes 2,1 rumfangsdele fosfortriklo-rid, og blandingen opvarmes under tilbagesvaling i 5 timer. Efter afkøling af blandingen opsamles de bundfældede krystaller ved filtrering. Ved behandling af krystallerne med fortyndet vandig ammoniak vindes 8-klor-6-fen-yl-2,4-dihydro-lH-s-triazolo74,3-a77l> ^benzodiazepin-l-on i fri form. Ved omkrystallisation ud fra metanol vindes farveløse nåle, der smelter ved 252-253°C.To a solution of 1.8 parts by weight of 8-chloro-6-phenyl-2,4-dihydro-1H-s-triazolo74,3-a771f47 benzodiazepine-1-one-5N-oxide (methanolate) prepared according to Example 12 in 200 parts by volume chloroform is added 2.1 parts by volume of phosphorus trichloride and the mixture is heated under reflux for 5 hours. After cooling the mixture, the precipitated crystals are collected by filtration. By treating the crystals with dilute aqueous ammonia, 8-chloro-6-phen-yl-2,4-dihydro-1H-s-triazolo74,3-a77l> benzodiazepin-1-one is obtained in free form. By recrystallization from methanol colorless needles are obtained, melting at 252-253 ° C.
Dette produkt er identisk med forbindelsen opnået i eksemplerne 2, 3, 4 og 6.This product is identical to the compound obtained in Examples 2, 3, 4 and 6.
141846 16141846 16
Eksempel 18Example 18
En blanding af 1,77 vægtdele 7-klor-6-fenyl-2,4-di-hydro-lH-s-triazolo^?,3-a//l,47benzodiazepin-l-tion-5N-oxyd (1/4 ætanolat) fremstillet ifølge eksempel 16, 2,1 rumfangsdele fosfortriklorid og 200 rumfangsdele kloroform opvarmes under tilbagesvaling i 4 timer, hvorefter blandingen koncentreres. Remanensen neutraliseres med fortyndet vandig ammoniak og ekstraheres med kloroform. Klo-r of omlaget vaskes med vand, tørres over vandfrit natriumsulfat og koncentreres. Remanensen behandles med ætylæter, hvorved der vindes 8-klor-6-fenyl-2,4-dihydro-lH-s-triazo-lo/4,3-a//l,4/benzodiazepin-l-tion som krystaller. Ved omkrystallisation ud fra metanol vindes farveløse nåle, der smelter ved 234-236°C.A mixture of 1.77 parts by weight of 7-chloro-6-phenyl-2,4-di-hydro-1H-s-triazolo, 3-a // 1,47-benzodiazepine-1-thione-5N-oxide (1 4 ethanolate) prepared according to Example 16, 2.1 volumes of phosphorus trichloride and 200 volumes of chloroform are heated at reflux for 4 hours, after which the mixture is concentrated. The residue is neutralized with dilute aqueous ammonia and extracted with chloroform. The chlorine of the coating is washed with water, dried over anhydrous sodium sulfate and concentrated. The residue is treated with ethyl ether to give 8-chloro-6-phenyl-2,4-dihydro-1H-s-triazolo-4,3-a // 1,4-benzodiazepine-1-thione as crystals. By recrystallization from methanol, colorless needles are obtained, melting at 234-236 ° C.
Dette produkt er identisk med forbindelsen opnået i eksemplerne 13 og 15.This product is identical to the compound obtained in Examples 13 and 15.
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP44092366A JPS4910958B1 (en) | 1969-11-18 | 1969-11-18 | |
| JP9236669 | 1969-11-18 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK141846B true DK141846B (en) | 1980-06-30 |
| DK141846C DK141846C (en) | 1980-11-24 |
Family
ID=14052400
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK582970AA DK141846B (en) | 1969-11-18 | 1970-11-17 | Analogous process for preparing 1-oxo- or 1-thioxo-s-triazolo (4,3-a) (1,4) benzodiazepine derivatives. |
Country Status (15)
| Country | Link |
|---|---|
| JP (2) | JPS5010659B1 (en) |
| AT (2) | AT300816B (en) |
| BE (1) | BE759099A (en) |
| CH (2) | CH549588A (en) |
| DE (2) | DE2064926A1 (en) |
| DK (1) | DK141846B (en) |
| ES (1) | ES385641A1 (en) |
| FI (1) | FI51701C (en) |
| FR (1) | FR2073379B1 (en) |
| GB (2) | GB1337736A (en) |
| NL (1) | NL167697C (en) |
| NO (1) | NO126085B (en) |
| SE (1) | SE363111B (en) |
| YU (1) | YU34898B (en) |
| ZA (1) | ZA707644B (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA713364B (en) * | 1970-06-18 | 1972-01-26 | Upjohn Co | Prganic compounds and process |
| JPS494470B1 (en) * | 1970-08-26 | 1974-02-01 | ||
| CH545302A (en) * | 1971-04-08 | 1974-01-13 | Ciba Geigy Ag | Triazolobenzodiazepine derivs - with anticonvulsant, cns depressant and muscle-relaxant activity |
| US3751426A (en) * | 1971-04-28 | 1973-08-07 | Upjohn Co | 1-substituted-6-phenyl-4h-s-triazolo(4,3-a)(1,6)benzodiazepine compounds |
| GB1377230A (en) * | 1971-09-13 | 1974-12-11 | Upjohn Co | 4h-s-triazolo -4,3-a- 1,4-benzodiazepines |
| BE790356A (en) * | 1971-10-21 | 1973-04-20 | Takeda Chemical Industries Ltd | BENZODIAZEPINE DERIVATIVES |
| JPS5418280B2 (en) * | 1971-10-30 | 1979-07-06 | ||
| BE793629A (en) * | 1972-01-03 | 1973-07-03 | Upjohn Co | NEW BENZODIAZEPINE DERIVATIVES AND THEIR PREPARATION |
| DE3021107A1 (en) * | 1980-06-04 | 1981-12-17 | Hoechst Ag, 6000 Frankfurt | CARBAMOYLOXYAMINO-1,4-BENZODIAZEPINE, METHOD FOR IRER PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THE SAME |
| CA1211437A (en) * | 1981-08-12 | 1986-09-16 | Rene Borer | Benzazepines |
| CN111533745A (en) * | 2020-05-20 | 2020-08-14 | 成都药明康德新药开发有限公司 | Process for preparing tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -carboxylic acid ester |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI50981C (en) * | 1968-11-05 | 1976-09-10 | Takeda Chemical Industries Ltd | Process for the preparation of s-triat solo- (4,3-a) (1,4) -benzodiazepines acting as hypnotics and sedatives. |
| US3987052A (en) * | 1969-03-17 | 1976-10-19 | The Upjohn Company | 6-Phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines |
-
0
- BE BE759099D patent/BE759099A/en not_active IP Right Cessation
-
1969
- 1969-11-17 JP JP44092336A patent/JPS5010659B1/ja active Pending
- 1969-11-18 JP JP44092366A patent/JPS4910958B1/ja active Pending
-
1970
- 1970-11-11 ZA ZA707644A patent/ZA707644B/en unknown
- 1970-11-13 NO NO4341/70A patent/NO126085B/no unknown
- 1970-11-14 DE DE19702064926 patent/DE2064926A1/en active Pending
- 1970-11-14 DE DE19702056174 patent/DE2056174A1/en active Pending
- 1970-11-17 ES ES385641A patent/ES385641A1/en not_active Expired
- 1970-11-17 NL NL7016848A patent/NL167697C/en not_active IP Right Cessation
- 1970-11-17 FR FR7041215A patent/FR2073379B1/fr not_active Expired
- 1970-11-17 DK DK582970AA patent/DK141846B/en unknown
- 1970-11-18 GB GB5479770A patent/GB1337736A/en not_active Expired
- 1970-11-18 YU YU2827/70A patent/YU34898B/en unknown
- 1970-11-18 CH CH1060273A patent/CH549588A/en not_active IP Right Cessation
- 1970-11-18 SE SE15638/70A patent/SE363111B/xx unknown
- 1970-11-18 AT AT1038070A patent/AT300816B/en not_active IP Right Cessation
- 1970-11-18 FI FI703096A patent/FI51701C/en active
- 1970-11-18 GB GB2860172A patent/GB1337737A/en not_active Expired
- 1970-11-18 AT AT995571A patent/AT311993B/en not_active IP Right Cessation
- 1970-11-18 CH CH1708170A patent/CH551432A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ES385641A1 (en) | 1973-10-01 |
| DE2064926A1 (en) | 1971-07-22 |
| DE2056174A1 (en) | 1971-06-24 |
| JPS5010659B1 (en) | 1975-04-23 |
| AT311993B (en) | 1973-12-10 |
| DK141846C (en) | 1980-11-24 |
| GB1337737A (en) | 1973-11-21 |
| NL167697C (en) | 1982-01-18 |
| BE759099A (en) | 1971-04-30 |
| JPS4910958B1 (en) | 1974-03-13 |
| NO126085B (en) | 1972-12-18 |
| SE363111B (en) | 1974-01-07 |
| ZA707644B (en) | 1971-08-25 |
| AT300816B (en) | 1972-08-10 |
| CH551432A (en) | 1974-07-15 |
| NL7016848A (en) | 1971-05-21 |
| GB1337736A (en) | 1973-11-21 |
| FI51701C (en) | 1977-03-10 |
| FI51701B (en) | 1976-11-30 |
| CH549588A (en) | 1974-05-31 |
| NL167697B (en) | 1981-08-17 |
| FR2073379A1 (en) | 1971-10-01 |
| FR2073379B1 (en) | 1974-08-23 |
| YU34898B (en) | 1980-04-30 |
| YU282770A (en) | 1979-10-31 |
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