IL44068A - Process for the preparation of 6-phenyl-4h-s-triazolo(4,3a)(1,4)benzodiazepines and intermediate 2(2-(methanesulfonyl)methyl)-4h-1,2,4-triazol-4yl)benzophenones - Google Patents

Process for the preparation of 6-phenyl-4h-s-triazolo(4,3a)(1,4)benzodiazepines and intermediate 2(2-(methanesulfonyl)methyl)-4h-1,2,4-triazol-4yl)benzophenones

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IL44068A
IL44068A IL44068A IL4406874A IL44068A IL 44068 A IL44068 A IL 44068A IL 44068 A IL44068 A IL 44068A IL 4406874 A IL4406874 A IL 4406874A IL 44068 A IL44068 A IL 44068A
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alkyl
loro
methy
triazol
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • 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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  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

1454682 Benzophenones; triazolobenzodiazepines UPJOHN CO 7 Feb 1974 [14 Feb 1973] 05764/74 Heading C2C Benzophenones and triazolobenzodiazepines are prepared by the following route (R 1 =H, C 1-3 alkyl, Ph, PhCH 2 , C 2-4 alkoxycarbonyl; R 2-5 =H, halogen, CF 3 , NO 2 , CN, di(C 1-3 alkyl)amino, C 1-3 alkyl, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl or alkanoylamino). The first step is effected by reacting the alcohol with phthalimide, triphenylphosphine and a dialkyl azodicarboxylate, and the product is converted to (III) by treatment with hydrazine hydrate. [GB1454682A]

Description

PROCESS FOR THE PREPARATION OF 6-PHENYL-4H-srTRIAZ0L0 [4.3-d3D ^BENZODIAZEPINES AND INTERMEDIATE 2[2- (METHANESULF0NYL)METHYL]-4H-1.2.4-TRIAZ0L-4-YL] BENZOPHENONES 44068/2 ABSTRACT OF THE DISCLOSURE A process to make 6-phenyl-4H-s-triazolo[4,3-a][l ^-benzodiazepines by converting 2-[3-(hydroxymethyl)-4H-l,2,4-tr1azol-4-yl] benzpphenones to 2-[2-[methanesulfonyl)methyl]-4H-l ,2,4-tr1azol-4-yl] benzophenones and converting these compounds to the highly active 6-phenyl-4H-s-tr1azolo[4,3-a][l ,4]benzod1azepines useful as tranquilizers and sedatives. 44068/2 f BACKGROUND OF THE INVENTION Fl ELD OF THE I NVENTI ON This invention is directed tc organic compounds and is particularly concerned with a novel process for the preparation of 6-pheny 1 -4H-s-tr iazolof^^-a] [1,4 jbenzod i -azepines and the intermediates thereof.
The novel process or production can be i llustra i ely represented as fol lows: wherein is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive, phenyl, benzyl, and C00R' wherein R' is alkyl defined as above; and wherein R2, 3, R^, and Rg are selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive, halogen, nitro, cyano, trlfluoromethyl, and alkoxy, alkylthlo, alkylsul inyl, alkylsulfonyl, and alkanoylamlno, 1n which the carbon chain moieties are of 1 to 3 carbon atoms, Inclusive, and d1alkylam1no In which alkyl 1s defined as above.
The Intermediates corresponding to formula II are specifically claimed.
The process of this Invention comprises: treating a 2-[3-(hydroxymethyl )-4H-l ,2,4-tr1azol-4-yl]benzophenone (I) with methanesul fonyl chloride 1n the presence of a base (e.g. tri ethyl amine, or other volatile compound II wherei The compound of formula II gaseous ammonia, preferably in the presence or? an alkali iodide, between 10 to 50° C. to give the compound III.
DESCRIPTION OF THE PREFERRED EMBODIMENT Alkyl groups of 1 to 3 carbon gfoms, inclusive, are exemplified by methyl, ethyl, propyl, and isopropyl.
The carbon chain moiety of alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, dial kyl ami no which is of 1 to 3 carbon atoms, inclusive, is defined as lower-alkyl of 1 to 3 carbon atoms, inclusive, as above.
The alkanoylamlno group of 1 to 3 carbon atoms consists of formamido (-NH-H-H), acetamido and propionamido.
The term halogen includes fluorine, chlorine, and bromine.
The compounds of the formula II are intermediates in the new synthesis of compounds of formula III, 6-phenyl-4H-s-tr1azolo[4,3-a] [l,4]benzodiazepines. Compounds III are a new class of very potent sedatives 44068/ 3 and tranquilizers which have been recently invented and are described in detail by Hester et al . J. Medicinal Chemistry 14, 1078 (1971) and in Canadian Patent 905,954.
The starting compounds of formula I of this invention are synthesized as shown in the Preparations.
In carrying out the process of this invention a selected compound I, preferably dissolved in an organic solvent is treated with methanesul fonyl chloride in the presence of a volatile, tertiary amine. Solvents useful in this reaction are chloroform, methylene chloride, ethylene dichloride, tetrahydrofuran, dioxane, mixtures thereof and the like. As tertiar amine, triethylamine is preferred but any tertiary amine with a boiling point below about 150°C. and pK in the range of about 3 to about 5 can be used. The reaction is carried out at between -40 to 10°C, preferably between -20 and 0°C. The product II is recovered from the reaction mixture by conventional means e.g. extraction with an organic solvent such as chloroform, ether, methylene chloride or the like. Vacuum distillation is used to remove the solvent and to obtain the methanesul fonate II.
Compound II is dissolved in an organic sol ent e.g. tetrahydrofuran, dioxane, ether or the like, and treated with ammonia (gas) or hexamethylenetetramine preferably after an alkali iodide, e.g. sodium or potassium iodide, has been added. After saturating the reaction mixture with ammonia, or after adding hexamethylenetetramine, the mixture is preferably stirred for from 4 to 48 hours at room temperature. The product III is obtained by conventional means, e.g. quenching the mixture, extraction, chromatography, crystallization, and the like.
According to Patent No. 38505, which corresponds to German Patent Application No.2, 203, 782 the final steps of the synthesis are from compound VI — VII — >VIII . The corresponding steps according to the present patent appl ication are I » II »III , as defined on page 2 of the present application.
Compound VII of patent No. 38505 is Identi cal with compound I of the present appl ication. According to Patent 38505 the yield of VI — VII »VIII 1s 40.6%. In addition , the bromide VII must be Isol ated 1n order to avoid products which Interfere with the VII — ^VIII step of said patent. When VII Is a chloride, I t takes more than two days to complete the step VI — ^ VII and the yields are very low.
This course of reaction, going from VII to VIII , wherein X is chlorine, was never carried out on a commercial scale.
Contrasted with the above, the sequence I — ^ II ^III according to the present invention proceeds 1n 58% yield without necessity to Isolate the Intermediate II .
The fol lowing examples and preparations are I llustrati ve of the processes and products of the present Invention, but are not to be construed as limiting.
Preparation 1 2,-Benzoyl-4' -chloroacetan1 l1de Acetyl chloride (81 .3 g. , 1.037 mole) was added to a sti rred solution of 2-amino-5-chlorobenzopheno#e (200.0 g. , 0.864 mole) and pyridine (68.4 g. , 0.864 mole) In dry ether (4 1. ) ; the mixture was kept at ambient temperature for 2 hours and treated with 500 ml . of water. The l ayers were separated and the ether l ayer was dried over anhydrous sodium sulfate and concentrated. Crystal lization of the residue from ethyl acetate-Skellysolve B hexanes gave : 124.0 g. of 2' -benzoyl*4,-chloroacetan1 H de of melting point 114-115°C. Two more crops of 2,-benzoyl-4, -chloroacetan111de also were obtained: 67.8 g of mel ting point 113.5-114.5°C. and 33.0 g.
Of mel ting point 113-114°C. - 44068/2 Preparat i on 2 6- Ch 1 oro-4- pheny 1 -2 (1H ) - qu i no 1 i ne v The procedure (reaction of 2 ' -benzoy 1 - ' -ch 1 oroacetan-i l ide with sodium hydroxide) of A. E. Drukker and C. I .
Judd, J. , Heterocycl ic Chem. 3, 359 (1 66) was used for this preparation. The yield was 77$. Two other preparat ions have been described : S. C. Bel l , T. S. Sulkowski , C. Gochman and S. J. Chi ldress, J. Org. Chem. 27, 562 (1962) ; G. A. Reynolds and C. R. Hauser, J. Amer. Chem.
Soc. 72, I85 (I950) .
Preparation 3 2 ,6- D i ch 1 oro-4-pheny 1 qu i no l i ne The procedure of A. E. Drukker and C. I . Judd, J.
Heterocycl ic Chem. 3, 359 (I966) was used for this preparation. The yield was 62$.
Preparat ion 4 6-Chloro-2-hydrazino-4-phenylquinol ine A st i rred mixture of 2 ,6-d i ch loro-4- pheny 1 qu i no 1 i ne (2.7 g. , 0.01 mole) and hydrazine hydrate (6.8 g. ) was ref luxed under nitrogen for 1 hour and concentrated j_n vacuo. The residue was suspended in warm water, and the sol id was col lected by fi ltration, dried and recrysta l l-ized from ethyl acetate-Ske 11 y B hexanes to give 1.81 g. (67 ) yield) of 6-ch 1 oro- -hyd raz i no- 4- pheny 1 qu i no 1 i ne of me lt ing point 156.5-157° C.
Ana 1. ca lcd. for Ci5Hi2ClN3 : C, 66,79; H, 4.49; CI , 13.15 ; N, 15.58.
Found : C, 67-15; H, 4.65 ; CI , 13.19; N, 15.32.
Preparation 5 7- Ch 1 oro- 1 -me th 1 -5- phen l-s-triazolo[4,3-a]-qu i no 1 i ne A sti rred mixture of 6-ch loro-2-hydraz i no-4-pheny 1 -quinol ine (1.4 g. , 0.0052 mole), triethyl orthoacetate (Ο.925 g. , Ο.ΟΟ57 mole) and xylene (100 ml . ) was refluxed, under nitrogen, for 2 hours 40 minutes. During this per- ^ iod the ethanol formed in the reaction was removed by disti llation through a short, glass helix-packed column. The mixture was concentrated to dryness i n vacuo and the resi-due was crystallized from methanol -ethy 1 acetate to give: 1.28 g. of 7-ch loro-l-methy 1 -5-pheny 1 -s-t r i azo1o[ , 3-a] -quinoline of melting point 255.5-255° C. (83.9% yield).
The analytical sample was crystall ized from methylene chloride: methanol and had a melting point 252.5-253.5° C.
Ana 1. calcd. for Ci7Hi2ClN3: C, 69. 0; H, 4.12; CI, 12.07; N, 1 .31.
Found: C, 69-38; H, 4.02; CI, 12.10; N, 14.49.
Preparation 6 5"Chloro-2- (3-methy 1 -4H-1,2 , - t r i azol -4- y 1 )-benzophenone (Oxidation of 7-ch loro-l-methy 1 -5-pheny 1 -s-triazolo[4,3-a]quinol ine) A stirred suspension of 7-ch 1 oro-l-methy 1 -5- phen 1 -s-triazolo[4,3-a]quinol ine (2.94 g., 0.01 mole) in acetone (110 ml.) was cooled in an ice-bath and treated slowly with a solution prepared by adding sodium periodate (2 g.) to a stirred suspension of ruthenium dioxide (200 mg.) in water (35 ml.). The mixture became dark. Additional sodium periodate (8 g.) was added during the next 15 minutes. The ice bath was removed and the mixture was stirred for 5 minutes . Additional sodium periodate (4 g.) was added and the mixture was stirred at ambient temperature for l8 hours and fi ltered. The solid was washed with acetone and the combined fi ltrate was concentrated in vacuo. The residue was suspended in water and extracted with methylene chloride. The extract was dried over anhydrous potassium carbonate and 44068/2 concentrated. The residue was chromatographed on s i 1 i ca gel (100 g.) with 10$ of methanol -90$ ethyl acetate; 50 ml . fractions were col lected. The product was eluted in fractions 10-20 and was crystal l ized from ethyl acetate to give : 0.405 g. of melting point 168-169.5° C. and 0.291 g. of melting point 167.5-169° (23.4$ yield) of f,-ch loro-2- (3-meth 1 -4H-1 ,2 , 4- t r i azol -4- y 1 )benzophenone . The analytical sample had a melting point of 168° C.
Ana 1. calcd. for CiaHi2Cl 30: C, 64.54; H, 4.Ο6; CI, 11.91; N, 14.11.
Found: C, 64.56; H, 4.35; CI, 11.97; 11-93; N, 14.29.
Preparation 7 - Ch loro-2- [3- (hydroxymethy 1 ) -5-methy 1 -4H-l,2,4-triazol-4-yl Jbenzophenone A sti rred mixture of 5-ch loro-2- (3-methy 1 -4H-1 ,2,4-triazolo-4-y 1 )benzophenone, (2.98 g., 0.01 mole) paraformaldehyde (3 g. ) and xylene (100 ml . ) was warmed under nitrogen, in a bath maintained at J ° C. for 7 hours .
The mixture was then concentrated in vacuo. The res idue was chromatographed on si l ica gel (150 g. ) with 3 methanol "9 $ chloroform. Fi fty-ml . fractions were col lected.
The product was eluted in fractions 20-44. The fractions were concentrated and the residue was crystal l ized from ethanol -ethy 1 acetate to give: 1.(54 g. of 5-ch 1 oro-2- [3_ (h yd ro ymethyl ) -5-methy 1 -4H-l,2,4-triazol-4-yl Jbenzophen-one, of melting point 138-142° C. ; 0.316 g. of melting point 138.5-141° C ; and 0.431 g. of melting point I39-141° C., ' (72.8# yield) . The analyti ca 1 sample had a melting point of 138-139° C.
Ana 1. calcd. for Ci7Hi4C 1 302 : C, 62.30; H, 4.30; CI, 10.8l; N, 12.82. 44068/2 Found : C, 62.23; H, 4.22; Cl, 10.82; , 11.73-Preparat ion 8 ' - (o- Ch 1 orobenzoy 1 ) - 1 -ch loroacetan i 1 i de I n the manner given in Preparation 1, 2-am i no-2 ' ,5~ d i ch lorobenzophenone, acety l chloride and pyridine were reacted in ether to give ' - (o-ch lo robenzoy I ) - ' -ch 1 oroacet an i 1 ide .
Preparation 9 6-ch loro-4- (o-ch loropheny I ) -2 (1H )-qu i no lone I n the manner given in Preparation 2, 1 - (o-ch ) orobenzoy 1 )-4 ' -ch loroacetan i 1 ide was reacted with sodium hydroxide to give 6-ch loro-4- (o-ch loropheny 1 )-2 (1H ) -qu i no-lone .
Preparat ion 10 2,6-d i ch 1 oro-4- (o-ch lorophen 1 )qu i no 1 i ne I n the manner given by A. E. Drukker and C. I . Judd, J. Heterocycl ic Chem. 3, 359 (1966), 6-ch loro-4- (o-ch 1 oropheny 1 ) -2- (1H )- qu i no lone was ch lorinated to give 2.6-d i ch loro-4- (o-ch 1 oropheny 1 )qu i no 1 i ne .
Preparation 11 6-chloro-2-hydrazino-4- (o-ch lorophen 1 ) -qu i no 1 i ne I n the manner given in Preparation , 2 ,6-d i ch loro-4- (o-ch lorophen 1 )qu i nol ine was heated with hydrazine hydrate to give 6-ch 1 oro-2-hydraz i no-4- (o-ch 1 oropheny 1 )qu i n-o 1 i ne .
Preparation 12 7-Ch loro-l-methyl-5~ (o-ch 1 oropheny 1 ) -s -triazolo[4,3-a]quinol ine I n the manner given in Preparation 5 > 6-chloro-2-hydraz i no-4- (o- ch loropheny 1 )qu i nol i ne and triethyl ortho-acetate in xylene were refluxed to give "ch loro-l-me thy 1 -5" (o-chlorophenyl )-s-triazolo[4i3~a]quinol ine.
Preparation 13 2 ' ,5"d i ch 1 oro-2- (j-methy 1 - H-1,2 ,4-t r i azol -4-y 1 )benzophenone In the manner given in Preparation 6, 7-chloro-l-methyl-5"(o-ch 1 oropheny l )-s-triazolo[4 3-a]qu incl ine in acetone was oxidized with sodium periodate and ruthenium dioxide to give 21 , 5-d i ch lo ro-2- (3-methy - 4H- 1 ,2 , 4- 1 r i azol o-4- y 1 )benzophenone of meltipg point 147.5-148.5° C.
Anal . calcd. for CiaH_ _C12N30: C, 57.85; H, -54; CI , 21.35; N, 12.65.
Found: C, 57-70; H, 3.21; Cl, 21.58; N, 12.47.
Preparation 14 2 ',5-dichloro-2-[3- (hyd ro yme thy 1 ) ~5 _ methyl-4H-l,2,4-triazol-4-yl jbenzophenone In the manner given in Preparation J, 21 ,5~ i ch loro- 2- (3-methy 1 -4H-1 ,2 , 4- t r iazol -4- y 1 )benzophenone was treated at 125° C. in xylene with paraformaldehyde to give 2 ', 5-di ch lor 0-2- [3- (hyd roxyme thy 1 ) -5-methy 1 - 4H- 1 ,2 , 4- 1 r ί azo 1 - 4- o y 1 Jbenzophenone of melting point 193- -195 C.
In the same manner given in the prior Preparations other starting compounds of formula I can be made. Representative compounds thus obtained include: 2 ' -ch loro-5-ni tro-2- [3- (hyd roxyme thy 1 ) -5-methy 1 -4H-1,2 ,4-t r i azol - 4- y 1 ] benzophenone ; 5-ch loro-2- [3- (hydroxymethy 1 )-5-e h l-4H-l,2i4-triazol-4-y 1 ] benzophenone ; 5-ch1oro-2- [3- (hydroxymethy 1 ) -5- pheny 1 - 4H- 1 , , 4- 1 r i azo 1 - 4-y 1 Jbenzophenone ; 5-ch loro-2- [3- (hydroxymethy 1 ) -5 -benz 1 - 4H-1 ,2 , 4- t r i azo 1 -4-y 1 jbenzophenone ; 21 , 6 ' -d i f 1 uoro-5" (me thy lthio)-2-[3- (hyd roxyme th y 1 ) -5 -propyl- 4H -1,2, 4-triazol -4-yl Jbenzophenone ; 5-bromo- 1 -ch loro-2- [3- (hydroxymethy l )-4H-l,2,4-triazol-4-y 1 ] benzophenone ; 44068/2 2 » -ch loro-5- f luoro-2- [3- (hyd roxymethy 1 )- H-l,2, -triazol - -·^ y 1 Jbenzophenone ; 2 ' -ch loro-6-cyano-2- [3- (hyd roxymethy 1 )-5-carbomethoxy-4H-l,2,4-triazol-4-yl Jbenzophenone ; 2 ' -ch lor o-4-di ethyl ami no-2- [3- (hyd roxymethy 1 )-5-methyl-4H-l,2,4-triazol-4-yl Jbenzophenone ; 2 ' -ch loro-5- (methy 1 thio)-2-[3" (hydroxymethy 1 ) - -me thy 1 -4H-l,2,4-triazol-4-yl Jbenzophenone ; 21 -ch loro-3- formamido-2- - (hydroxymeth ! )-5-ethyl-4H-l,2,,4-triazol-4-yl Jbenzophenone ; 2 ' -ch loro-4- (ethylsulfinyl)-2-[3- (h droxymethy 1 )~5" phenyl -4H-l,2,4-triazol-4-yl Jbenzophenone ; 2 ' -ch loro-5- (propyl sul fon l )-2- [3~ (hyd roxymethy 1 ) -5-ca rbopro-poxy-4H-l ,2 , - 1 r i azo 1 -4- y 1 Jbenzophenone ; 6-methyl-3 (p ropy lth i o) -2- [ - (hyd roxymethy 1 ) -4H-1 ,2 , 4- t r i -azo 1 -4- y 1 J benzophenone ; 2 ' - (d i methy lam i no) -4- is op ropy 1 -2- [3" (hyd roxymeth 1 ) -4H- 1,2, -triazol-4-yl Jbenzophenone ; 2 '-chloro-4;,5-dicyano-2-[3- (hyd roxymethy 1 )-5-methyl-4H-lj,2:,4-triazol-4-yl Jbenzophenone ; 3'-(ethylsulfinyl ) -3,,5-d i propy I -2- [3- (hydroxymethy 1 ) -5-methyl-4H-l,2,4-triazol-4-yl Jbenzophenone ; 5-ch 1 or 0-21 -acetam i do-2 - [3- (hyd roxymethy l)-5-methy 1 -4H~ l,2,4-triazol-4-yl Jbenzophenone ; 5-ch loro-2- [3- (hyd roxymethy 1 ) - 4H-1 ,2 , 4- t r i azol -4- y 1 Jbenzophenone ; 2 ' -ch loro-2- [3- (hyd roxymethy 1 ) -4H-1 ,2 , 4- 1 r i azol -4- y 1 Jbenzophenone ; 2 ' ,5-d ich loro-2- 3- (hyd roxymethy I ) -4H- 1 , 2 , - 1 r i azo 1 -4- y 1 J -benzophenone; 2- [3- (hydroxymethy 1 )-4H-l,2,4-triazol-4-yl ]benzophenone ; 2-[ (hydroxymethy 1 ) -5 -me thy 1 -4H- 1 ,2 , 4- 1 r i azo 1 -4-y 1 Jbenzo-phenone ; and the 1 i ke .
Example 1 8-Chloro-l-methyl-6-phenyl-4H-s-triazolo[4, 3_a ] -[1,J ] benzodiazepine A solution of Ο.328 g. (1.00 mmol . ) of 5~ch loro-2- [3-(hyd rox ymethy l )-5-methyl-4H-l,2,4-triazol-4-yl] benzophe none dissolved in 5.0 ml . hydrocarbon-stabi l ized-chloroform was cooled to -20° C. in a Dry Ice acetone bath, treated with 0.206 ml . (O.15O g. , 1.5 mmol , ) of t r i e t hy 1 am i ne , and stirred for minutes. The solution was treated dropwise wi h 0.106 ml . (1.3 mmol . ) of methanesu 1 f ony 1 chloride and sti rred for 10 minutes. Ammonia gas was introduced to the atmosphere above the cold solution. Immediately a white precipitate appeared. Sti rring was maintained at -20° C„ for 10 minutes after which the temperature was gradual ly raided to 25° C. After 20 minutes, 3 ml . of freshly disti l led tet rahydrof u ran and 0. 3 g. (2.00 mmol . ) of potassi urn iodide was added and the resulting mixture was sti rred overnight (24 hrs. ). The reaction mixture was quenched n a 5$ aqueous sodium hydroxide solution, extracted with chloroform, dried over anhydrous sodium sulfate and concentrated in vacuo to yield an oi l. On trituration with ethyl acetate, fine, white needles of 8-ch loro-l-methy 1 -6-pheny 1 -4H- s - t r i azol o[ 4, 3_a ] [ 1 , 4 Jbenzod i azep i ne were depos ited.
This was recrysta 11 i zed from ethyl acetate to yield 0 mg. of white needles of melting point 228-230° C. and 1 mg. , of melting point 215-223°.
I nstead of ammonia hexam thy lentet ram i ne can be used.
Example 2 8- Ch loro-l-methy 1 -6- (o-ch lorophen 1 )-4H-s-tri-azolo ,3-a][l,4]benzodiazepine A suspension of Ο.363 g. (l.OO mmo ) . ) of 2 ' , -d i ch 1 oro-2- 5- (1 ydroxymethy 1 ) -5-methy 1 - H-1 ,2 , - 1 r iazo 1 -4- y 1 jbenzo-phenon< in 5<0 ml. of methylene chloride was cooled to -20° C. in r Dry Ice/acetone bath and treated with 0.206 ml.
(O.I50 g., I.50 mmol.) of t r i ethy lami ne, fol lowed by drop-wise addition of 0.106 ml. (1.3 mmol.) of methanesu 1 fony 1 chloride. (Most of the starting material dissolved during the ad< ition of the methanesu 1 fony 1 chloride.) During 15 minutes the temperature was gradually raised to 0°. The reaction mixture was quenched on ice and extracted with methylene chloride. The organic extracts were treated with a saturated aqueous sodium bicarbonate solution, dried e er anhydrous sodium sulfate and concentrated i n vacuo to yield an oi l. The oil was dissolved in 5 ml . of freshly disti lled tet rahydrofuran in a dry flask and treated first with 0.332 g. (2.00 mmol .) of potassium iodide, then ammonia (gas). After saturating the reaction mixture with ammonia, the mixture was warmed to room temperature (22-24° C.) and stir ed for 24 hours. The mixture was quenched in a saturated aqueous sodium hydroxide solution, extracted with chloroform, dried over anhydrous sodium sulfate and concentrated i n vacuo to afford an oi l . Crystal lization from ethyl acetate and methano l/ethyl acetate yielded 25 mg. of a tan sol id of melting point 210-221° C. Recrysta U izat i on from ethyl acetate gave pure 8-chloro-1-meth 1 -6- (o-ch loropheny l)-4H-s-triazolo[4,3-a][l,4]benzo-diazepine of melting point 223-2;?50 C.
- - Example 3 8-Ch loro-l-methy 1 -6- (2,6-di fluorophenyl )-4H-s-tria olo[4,3-a][l, 4]benzod iazepi ne I n the manner given in Example 1, 2 ' ,6 ' -d i f 1 uoro-5- chlc-o-2- [3- (hydroxymethy 1 ) -5-methy 1 - 4H-1 ,2 ,4- 1 r i azo 1 - 4- y 1 ] ben? phenone was treated with methanesu 1 f ony 1 chloride and t r i eth lami ne in chloroform. The resulting solution was then treated with ammonia (gas) to give 8-ch 1 oro- l-methy 1 -6- (2,6-di f luoropheny 1 )-4H-s-tr i azo lo[ 4, "a ] [l,4]b anzo-pher one .
Exam le 4 8- Ch 1 oro-6- pheny 1 - LH-s - 1 r i azol o[ h, 3" a ] [1,4]-benzod i azep i ne In the manner given in Example 1, 5-ch 1 oro- [3- (hydro; ymethy 1 ) -4H- 1 , 2 , - 1 r i a zo] - 4- y 1 ] benzophenone was treated witl methanesu 1 f ony 1 chloride and t r i ethy 1 am i ne in chlorc-forr . The result ing solution was then treated with ammonia (qa' ) to give 8-ch loro-6-phenvl-4H-s-triazolo[4,"-a] ("1,4 I -ben, ophenone .
Exai pie 5 6- (o- c h 1 or opheny 1 )- 4H~ s - t r i azo 1 o [ , -a ] [ 1 , 4 ] benzodiaze ine I n the mann r given in E Examp le 7 1-ethy 1 -8-bi omo-6- (2, 4-d ieth 1 hen 1 )-4H-s-t r i -azolo[4,,3~a] [l,4]benzodiazepine In the manner given in Example 1, 5_b romo-2 ' , 41 -diethyl -2- [3- (hydroxymet hy 1 )-5-ethyl-4H-l,2J4-triazol-4-y 1 ] benzophenone was treated with methanesu 1 fony 1 chloride and t r i ethy 1 am i ne in chloroform. The resulting solution was then treated with ammonia (gas) to give l-ethyl-8-bromo-6- (234-diethylphenyl)-4H-s-triazolo[4J3-a][li4J-benzophenone .
Example 8 l-Benzyl-8-trif 1 uor omethy 1 -6- (o- ch 1 oropheny 1 ) -4H-s-triazolo[4J3_a][l,4]benzodiazepine in the manner given in Example 1, 5" t r i f 1 uoromethy 1 -2'-chloro-2-[3-( yd roxymethy 1 ) - 5~ enz y 1 - 4H- 1 , , 4- t r i azol -4- y 1 Jbenzophenone was treated with methanesu 1 fon 1 chloride and 1 i ethy 1 am i ne in chloroform. The resulting solution was then treated with ammonia (gas) to give 1 - benzy 1 -8- t r i -f 1 uoromethy 1-6- (o-ch 1 oropheny 1 ] [1,4]-benzophenone .
Example 9 l-Propyl-9~(ethylsul fony 1 ) -6- [ p- (d i ethy 1 am i no) -phenyl ]~4H-s-triazolo[4,3_a; [1, Jbenzod i azep i ne In the manner given in Example 1, 4- (ethy 1 su 1 fony 1 ) - ' - (d ieth lam i no) -2- [J- (hydroxy nethy 1 ) -5 - P ropy 1 - H - 1 , 2 , 4-t r i azol -4- y I ] benzophenone was treated with me thanes u 1 fony 1 chloride and t r i ethy lami ne in chloroform. The resulting solution was then treated with ammonia (gas) to give 1-pro-py 1 -9- (ethylsul fony 1 ) -6- [ p- (diethyl am ino)phenyl ]-4H-s-tri- azol o[4,3~a ] [ 1 , 4 ] benzophenone .
Example 0 1- Pheny 1 -7- p ropy 1 -6- (o-b romopheny 1 )-4H-s-tri-azolo[4,3-a] [l,4]benzod iazepi ne In the manner given in Example 1, 6-prop 1 -2 ' -b romo-2- [3- (hydroxymethy 1 ) -5 - pheny 1 -4H-1 , 2 , 4- 1 r i azo 1 - 4- y 1 ] benzophenone was treated with methanesu 1 f ony 1 chloride and tri-ethylamine in chloroform. The resulting solution was then treated with ammonia (gas) to give 1-phenyl -7-propy 1 -6- (o-bromo phenyl ) -4H-s - 1 r i azo 1 o[ , 3 -a ] [ 1 , 4] I enzophenone .
Examp e ] _ 8- Ch 1 oro-l-methy 1 - 6- pheny l-4H-s-triazolo- [ ,3- a] [1,4] benzod iazepi ne )- Ch 1 or 0-2- [3- [ (methyl su 1 f on 1 ox )methy 1 ]-5-methyl-4H-l, ,4-tr iazol-4-yl Jbenzophenone (5 g.) (see Example l), dissolved in water-free tetrahydrofuran, was treated with 4 g. of hexamethy 1 enetet rami ne 1 g. of potassium iodide and 20 ml . of ethanol . The mixture was refluxed for 15 hours, then cooled, fi ltered, and the fi ltrate evaporated to dryness to give a yel low gum. The gum was dissolved in ch oroform, the chloroform solution extracted with water then ch romatog raphed over 300 g. of Si l ica Gel and 3# met hanol -97$ chloroform. Fractions 52-132 gave a colorless oi l which upon recrysta 11 i zat i on from ethylacetate gave 800 mg. of 8-ch 1 oro-l-methy 1 -6-pheny 1 -4(H-s - 1 ri azol o-[4,3 ] [1, 4]benzod i azep i ne .

Claims (1)

1. 4 068/2 WHAT IS CLAIMED IS: _χ. A process for the production of a 6-phen 1 -4H-s-tr i -azolo[4,3~a] [l,4]benzodiazepine of formula I I I wherein Ri is selected from the group consisting of hydro-gen, alkyl of 1 to 3 carbon atoms, inclusive, phenyl , benzyl and C00R' in which R' is alkyl defined as above; and wherein R2, R3, R4, and R:3 are selected from the group consisting of hydrogen, alkyl as defined above, halogen, nitro, cyano, tr i f luoromethyl , and alkoxy, alkylthto, a 1 ky 1 su 1 f i ny 1 , a 1 ky 1 su 1 f ny 1 , and a 1 kanoy 1 ami no in which the carbon moiety is between 1 to 3 carbon atoms, inclusive, and dialkylamino in which alkyl is defined as above, which comprises: treating a compound of formula I : 4Ό68/2 wherein Rx, R2, R3 , R4, and R5 are defined as above, with methanesu 1 fony 1 chloride and a tertiary volati le amine selected from t r i ethy lami ne, d i ethy Imeth lami no, dimethyl-ethylamine and d i propy le thy 1 am i ne at between -40° to 10° C. to obtain the corresponding compound of formula I I wherein Ri, RS} R3, R4, and R5 are defined as above and A is 0 and heating I I with a compound selected from the group consisting of ammonia and hexame thy 1 entet rami ne in the presence of an alkali metal iodide to obtain the corresponding compound of formu la I I I . V 4 Ί068/Ρ The process of claim 1 wherein the reacti on is carried out in chloroform at between -20 and 0° C. -3- The process of claim 1 wherein the alkal i metal iodide is po tassium iodide. -4- The process of claim 1 wherein the starting material is r) - ch loro-2- [3- (hyd roxymel hy 1 ) -5 -methy 1 - 4H- 1 2,4-triazol-4- y 1 ] benzophenone . The process of claim 1 wherein the starting material i s .' 1 i ch loro-2-[3- (hydroxy me ' hy 1 ) -5-methy 1 - H-1 ,2 , 4-t r i c-.zo 1 -4- y 1 Jbenzophenone . -6- Λ 2-f3r l -4-yl ]-benzop enone of the formula: wherein R. is hydrogen, alkyl of 1 to 3 carbon atoms, inclusive, R9, R„, R- and R are each hydrogen, alkyl o inclusive, and halogen. Attorneys for Applicant
IL44068A 1973-02-14 1974-01-24 Process for the preparation of 6-phenyl-4h-s-triazolo(4,3a)(1,4)benzodiazepines and intermediate 2(2-(methanesulfonyl)methyl)-4h-1,2,4-triazol-4yl)benzophenones IL44068A (en)

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IL49503A IL49503A (en) 1973-02-14 1974-01-24 Process for the preparation of 6-phenyl-4h-s-triazolo(4,3-a)(1,4)-benzodiazepines and intermediate 2-(3-(phthalimidomethyl)-4h-1,2,4-triazol-4-yl)benzophenones
IL49503A IL49503A0 (en) 1973-02-14 1976-04-30 Novel benzophenone derivatives and their preparation

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IL49503A IL49503A0 (en) 1973-02-14 1976-04-30 Novel benzophenone derivatives and their preparation

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