IL49503A - 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 - Google Patents

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

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IL49503A
IL49503A IL49503A IL4950374A IL49503A IL 49503 A IL49503 A IL 49503A IL 49503 A IL49503 A IL 49503A IL 4950374 A IL4950374 A IL 4950374A IL 49503 A IL49503 A IL 49503A
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triazol
chloro
jbenzophenone
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    • 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
    • C07D215/20—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
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • 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

, ■ * 4 503./2 PROCESS FOR THE PREPARATION OF 6-PHENYL-4H-S-TRIAZOLO ^iliAi^immkt^n^ AND ΪΝ^ΕΡΪΑ¾ 2>A-CPHTHALI IDdfeTHYL)-4H-l.-2.4-TRIAZOL-4-yl7¾ENZOPHENONES ABSTRACT OF THE DISCLOSURE A process to make 6-phenyl-4H-s-triazolo[4,3-a][l ,4]-benzo-diazepines by converting 2-[3-(hydroxymethyl )-4H-l ,2,4-triazol -4-yl ] benzophenones to 2-[3-[phthal imido)methyl ]-4H-l ,2 ,4-tri azol -4-yl ] benzophenones and converting these compounds to the highly active 6-phenyl-4H-s-triazolo[4,3-a][l ,4]benzodiazepines useful as tranquilizers and sedatives.
BACKGROUND OF THE I NVENT I ON Fl ELD OF THE I NVENTI ON Th is invent ion is d i rected to organ ic compounds and is part icu lar ly concerned with a nove l process for the. pn.;pa rat i on of 6- pheny 1 - ^H- s - t r i azo 1 o [ , j5-a j [ 1 , 'I jbenzod i -azepines and the intermediates thereof, The novel process or product ion can be i l lust rat i e ly represented as fol lows : wherein R-j is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive, phenyl, benzyl, and COOR1 wherein R-j is alkyl defined as above; and wherein R^, R^, R^s and R5 are selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive, halogen, nitro, cyano, trifluoromethyl , and alkoxy, alkylthio, al kylsul finyl , alkylsulfonyl , and alkanoylamino, in which the carbon chain moieties are of 1 to 3 carbon atoms, inclusive, and dialkylamino in which alkyl is defined as above.
The intermediates corresponding to formula II are specifically cl aimed.
The process of this invention comprises: treating a 2-[3-(hydroxymethyl )-4H-l ,2,4-triazol-4-yl]benzophenone (I ) with phthalimide and triphenylphosphine in the presence of a hydrogen acceptor e.g. diethyl azodicarboxylate to give the compound II wherein A is The compound of formula II wherein A is is treated with hydrazine hydrate in a lower alkanol (1 to 3 carbon atoms) for one to five hours at 25-100° to give the corresponding compound of formula III above.
DESCRIPTION OF THE PREFERRED EMBODIMENT Alkyl groups of 1 to 3 carbon atoms, inclusive, art^ exempl i fied by methyl, ethyl, propyl, and isopropyl .
The carbon chain moiety of alkoxy, alkylthio, al kyl- sul inyl, a 1 ky 1 su 1 f ony 1 , dialkylamino which is of 1 to 3 carbon atoms, inclusive, is defined as lower-alkyl of 1 to 3 carbon atoms, inclus ive, as above.
The a 1 kanoy 1 am i no group of 1 to 3 carbon atoms con- 0 s ists of formamido (-NH-C-H), acetamido and rop i onam i do , The term halogen includes f luorine, chlorine, and b rom i ne .
The compounds of the formu la I I are intermediates in the new synthes is of compounds of formula I I I , 6-phenyl-4H-s- t r iazol o[4,3~a ] [1, ]benzod i azepi nes . Compounds I I I are a new class of very potent sedatives and tranqui l izers which have been recently invented and are described in detai l by Hester et al . J. Medicina l Chemistry 14, 1078 (I971) and in Canadian Patent 905,954.
The starting compounds of formu la I of this invention are synthesized as shown in the Preparations .
When the intermediate I I is a phthal imido derivative, the process consists of treating the starti ng materia I n a so I vent wi th phtha 1 imi de i n about equ i mo 1 ecu lar quant 1 ty or preferably with a s I ight excess of 5"20# of the calculated amounts and an equimoiecular amount of t r i pheny I phosph i ne , and a hylrogen acceptor , for example, a dialkyl azod i ca rboxy I a te , preferably diethy I azod i ca rboxy I ate . The reaction is carried out at temperatures between 0-100° C. I n the pre erred embodi -ment of th i s react i on, temperatures between 20-40° L . and s i rring between 2-36 hou rs a r.e used to comp 1 ete the react i on .
Solvents used are preferably water-free tet rahyd rofu rar?' . dioxane, 1,2-d imethoxyethane, ether, chloroform, methylene chloride and the like. At the termination of the reaction, the product I I is recovered and purified in conventional manner, e.g. concentrating the react i on m ixture, extraction, chromatography and recrysta 11 i zat i on .
This product I I is then treated with hydrazine hydrate in a lower alkanol e.g. methanol, ethanol, 1-propanol, or 2-propanol at a temperature of 25-100° C. for 1 to 5 hours. Preferably, the temperature is kept between 65-IOO0 C. The product (i l l ) is recovered and purified in conventional manner, e.g. extraction, chromatography crystall ization and the 1 i ke .
The fol lowing examples and preparations are i llus-trative of the processes and products of the present invention, but are not to be construed as l imiting.
Preparation 1 2 '-Benzoyl-4'-chloroacetani 1 ide Acetyl chloride (81.3 g., 1.037 mole) was added to a stirred solution of 2-ami no-5~ch lorobenzophenone (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 layers were separated and the ether layer was dried over anhydrous sodium sulfate and concentrated. Crysta 11 i zat i on of the residue from ethyl acetate-Ske 11 ysol ve B hexanes gave: 124.0 g. of 21 -benzoy 1 -4 ' -ch loroacetan i 1 ide of melting point 114 115° C. Two more crops of 2 ' -benzoy 1 -41 -ch loro-acetani lide also were obtained: 67.8 g. of melting point 11 .5-114.5° C. and' 33.0 g. of melting point II5- ' 114° C.
Preparation 2 6- Ch loro- - pheny 1 -2 (lH)-qu inol i ne The procedure (reaction of 21 -benzo 1 -51 -ch loroacetan-i lide with sodium hydroxide) of A. E. Drukker and C. I .
Judd, J . , Heterocyclic Chem. 3* 559 (1966) was used for this preparation. The yield was 77$. Two other preparations have been described: S. C. Bell, 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, 1852 (19 0).
Preparation 3 2 ,6- D i ch 1 oro- 4- pheny 1 qu i nol i ne The procedure of A.. E. Drukker and C. I . Judd, J.
Heterocyclic Chem. 3 , 359 (1966) was used for this preparation. The yield was 62#.
Preparation *f 6- Ch 1 oro-2-hyd raz i no-4^pheny 1 qu i no 1 i ne A stirred 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 refluxed under nitrogen for 1 hour and concen rated i n vacuo . The residue was suspended in warm water, and the solid was collected by fi ltration, dried and recrystal l-ized from ethyl acetate-Ske 11 y B hexanes to give 1.81 g. (6 $) yield) of 6-ch loro-2-hyd raz i no-4-pheny lqu i nol i ne of melting point 156.5-157° C Ana 1. calcd. for C15Hi2ClN3: C, 66,79; H, A9; CI, 13.15; N, 15.58.
Found: C, 67-15; H, 4.6 ; CI, 13.19; N, 15-32.
Preparation 5 7- Ch 1 oro- 1-meth 1 -5 -pheny l-s-triazolo[4,3-a]-qu i no 1 i ne s A stirred mixture of 6-ch 1 oro-2-hyd raz i no- 4- pheny 1 -quinoline (1Λ g., 0.0052 mole), triethyl orthoacetate (Ο.925 g., Ο.ΟΟ57 mole) and xylene (100 ml. ) was refluxed, under nitrogen, for 2 hours 40 minutes. During this iod the ethanol formed in the reaction was removed b ti l lation through a short, glass helix-packed column. The mixture was concentrated to dryness in vacuo and the resi-due was crystallized from methanol -ethy 1 acetate to give.-1.28 g. of 7-chloro-l-methyl-5-phenyl-s-triazolo[4,3-a]-quinoline of melting point 253.5-255° C. (83.9$ 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 Ci7Hi2C 1N3 : C, 69.50; H, 4.12; CI, 12.07; N, 14.31.
Found: C, 69-38; H, 4.02; Cl, 12.10; N, 14.49.
Preparation 6 5"Ch loro-2- (3-methy 1 - 4h*-l,2 , - 1 r i azo 1 - 4- y 1 )-benzophenone (Oxidation of 7- ch 1 oro- 1-methy 1 -5-pheny 1 - s-t r i azo lo[4,3-a ] qu i no 1 i ne ) A stirred suspension of 7~ch i oro- 1-methy 1 -5- pheny 1 -s - t r i azol o[4,3_a ] qu i nol i ne (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 45 minutes. Additional sodium periodate (4 g.) was added and the mixture was stirred at ambient temperature for 18 hours and fi ltered. The sol id, 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 concentrated. The residue was ch romatographed on si l ica gel (100 g. ) with 10$ of methano1-90# ethyl acetate; . fractions were col lected. The product was eluted in fractions 10-20 and was crystal l ized from ethyl acetate to gi e : 0.405 g. of melting point 168-169.5° C. and 0.291 g. of melting point 167.5-169° (23. H yield) of 5-ch loro-2- (3-me thy 1 -4H-1 ,2 , 4- 1 r i azo 1 -4-y 1 )benzo.phenone . 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; 11.95; N, 14.29. Preparation 7 5" Ch loro-2- [3- (h yd roxymethy 1 ) - -methyl -4H-l,2 4-triazol-4-yl ] benzophenone A sti rred mixture of 5-ch loro-2- (3-methyl -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 ni trogen, in a bath maintained at 125° 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 m thano 1 -97 chloroform. Fi fty-ml . fractions were col lected.
The product was eluted in fractions 20-44. The fractions we re concentrated and the residue was crystal l ized from et hano 1 -ethy 1 acetate to give: 1.64 g. of -ch 1 oro-2 - [3_ ( d roxymethy 1 ) -5 -methyl -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 139" 141° C.,- (72.8$ yield). The analytical sample had a melting point of 138-139° C Ana 1. calcd. for C17H14CI N30a : C, 62.30; H , 4.30; CI, 10.8l; N, 12.82.
Found: C, 62.23; H, 4.22; CI, 10.82; N, 11.75- ψ Preparation 8 2 ' - (o- Ch lorobenzoy 1 ) -41 -ch loroacetan i 1 ide In the manner given in Preparation 1, 2-am i no-2 ' ,5~ d i ch lorobenzophenone, acetyl chloride and pyridine were reacted in ether to give 2 ' - (o-ch 1o robenzoy 1 )- 1 -ch loroacet an i 1 i de .
Preparation 9 6-ch loro-4- (o-ch 1 oropheny 1 )-2 (lH)-qu i no lone In the manner given in Preparation 2, 21 - (o-ch lorobenzoy 1 ) -4 '- ch loroacetan i li de was reacted with sodium hydroxide to give 6-ch 1 oro- - (o-ch 1 oropheny 1 ) - (1H )- qu i no-lone.
Preparation 10 2 ,6-d i ch 1 oro- 4- (o-ch 1 orophen 1 )qu i no 1 i ne In the manner given by A. E. Drukker and C. I . Judd, J. Heterocycl ic Chem. 5, 559 (1966), 6-ch loro-4- (o-ch 1 oro-phenyl )-2- (lH)-qu inolone was chlorinated to give 2.6-d i ch 1 oro- 4- (o-ch 1 oropheny 1 ) qu i no 1 i ne .
Preparation 11 6-chloro-2-hydrazino-4- (o-chlorophenyl )-qu i no 1 i ne In the manner given in Preparation 4, 2 ,6-d ί ch 1 oro-4- (o-ch loropheny 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-methy 1 ~5- (o-chlorophenyl )-s-triazolo[4,5-a]quinol ine In the manner given in Preparation * 6-chloro-2-hyd raz i no-4- (o- ch loropheny 1 )qu i npl ί ne and triethyl ortho-acetate in xylene were refluxed to give 7~c loro-l-me thy 1 -5" (o-ch loropheny 1 )-s-triazolo[4,5-a]quinol ine.
Preparation 15 21 ,5"d i ch 1 oro-2 - (3-.methy 1 -4H-1 ,2 , 4- 1 r i azol -4- y 1 )benzophenone acetone was oxidized with sodium periodate and ruthenium dioxide to give 21 ,5-d i ch 1oro-2- (3-methy 1 - 4H-1 ,2 , 4- 1 r i azol o- 4- y 1 )benzophenone of melting point 147.5-148.5° C.
Ana 1. calcd. for C_eHi i ClaN30: C, 57.85; H, 3.3^; 1 , 21.35; N, 12.65.
Found; C, 57-70; H, 3.21; CI, 21.58; N, 12.47.
Preparation 14 2 ',5"dichloro-2-[3- (hyd roxymethy 1 ) -5" methy 1 -4H-1 ,2 , 4-t r iazol -4- y 1 )benzophenone I n the manner given in Preparation J, 21 ,5"d i ch 1 oro- 2- (3-methy 1 -4H-1,2 , 4- t r i azol -4-y 1 )benzophenone was treated at 125° C. in xylene with para ormaldehyde to give 2 ',5- . dichloro-2- [3" (h yd roxymethy 1 ) -5-methy 1 - 4H- 1 ,2 , 4- 1 r i azo 1 - 4- y 1 jbenzophenone of melting point 193.5_195° C.
In the same manner given in the prior Preparations other starting compounds of formu la I can be made. Representative compounds thus obtained include: 2 ■ - ch loro-5-ni tro-2- [5- (h yd roxymethy 1 ) -5-methy 1 - 4H-1 ,2 , 4- tr iazol -4-y 1 ]benzophenone ; 5-chloro-2- [3- (hydroxymethy 1 ) -5-ethy 1 - 4H-1 ,2 , 4- 1 r i azo 1 -4- y 1 ] enzophenone ; 5-chloro-2- [3- (h yd roxymethy 1 ) -5" pheny 1 - 4H-1 ,2,, 4- 1 r i azo 1 - 4- y 1 ] benzophenone ; 5-chloro-2- [3" (h yd roxymethy 1 ) - -benzy 1 - 4H-1 , , 4- 1 r i azol - 4- y 1 ] benzophenone ; 2 ',6'-difluoro-5- (me thy lthio)-2-[3- (hyd roxymeth y 1 ) -5~pro- pyl-4H-l,2,4-triazol-4-y1 ] benzophenone ; 5-bromo-2 ' -ch loro-2- [3~ (hyd roxyme thy 1 )-4H-l,2, 4-t ri azol -4- y 1 ] benzophenone ; 2 ' -chloro-5-f luoro-2-[3- (hyd roxymethy 1 )-4H-l,2,4-triazo^4-y 1 ]benzophenone ; 21 -ch loro-6-cyano-2- [3- (hyd roxymethy 1 )-5-carbomethoxy-4H-l,2,4-triazol-4-yl jbenzophenone ; 2 '-chloro-4-diethy1amino-2- [3" (hyd roxymethy 1 ) -5 -me thy 1 -4H-l,2,4-triazol-4-yl Jbenzophenone ; 2 '-chloro-5- (meth lthio)-2-[3- (hyd roxymethy 1 ) -5 -me thy 1 - 4H-1 , 4- 1 r i azol - 4- y 1 Jbenzophenone ; 2 '-ch lor 0-3- formamido-2- [3- (hyd roxymethy l")-5-ethy 1 -4H-l,2,4-triazol-4-yl Jbenzophenone ; 21 -ch loro-4- (ethy lsu 1 f i ny 1 )-2- [3- (hyd roxymethy 1 )-5~phenyl-4H-l,2,4-triazol-4-yl Jbenzophenone ; 21 -ch loro-5- (propy 1 su 1 fony 1 )-2- [3- (hyd roxymethy 1 ) - 5-ca rbopr o-poxy-4H-l,2,4-t r i azol -4-y 1 Jbenzophenone ; S-methyl^1- (propy 1th io) -2- [5 - (hyd roxymethy 1 ) -4H-1 ,2 , 4- 1 r i -azol -4-y 1 Jbenzophenone ; 2 ' - (d imethy lami no) -4- i sop ropy 1 -2- [3- (hyd roxymethy 1 )-4H-l,2 ,4-triazol-4-yl Jbenzophenone ; 2 '-chloro-4,5-dicyano-2-[3- (hydroxymethyl )-5_methyl-4H-1,2 , 4- t r i azo 1 -4- y 1 Jbenzophenone ; 3' - (ethylsulfinyl ) -3,5 -d i propy 1-2- [3- (hyd roxymeth y 1 )~5-methy 1-4H- 1,2,4- triazol -4- 1 jbenzophenone ; 5-ch loro-21 -acetami do-2- [3- (hyd roxymethy l)-5-methy 1 -4H-l,2,4-triazol-4-yl Jbenzophenone ; 5-ch loro-2- [3- (hydroxymethyl ) - 4H-1 ,2 , 4- t r i azo 1 -4- y 1 ] benzo-phenone; 2 ' -ch loror2- [3- (hydroxymethyl ) - 4H- 1 ,2 , 4- 1 r i azol - 4- y 1 Jbenzophenone ; 2 ' ,5-dich loro-2 - [3- (hydroxymethyl ) -4H-1 ,2 , 4- 1 r i azo 1 -4- y 1 "J -benzophenone ; - - - - - Example 1 5-Chloro-2-[3-(phtal i mi dome th 1 )-5-methyl -4H-1,2, 4-tr iazol -4-y 1 )benzophenone A- A stirred mixture of 5~ch loro-2- [5_ (hydroxymethy 1 )~~ methy l-4H-l,2,4-tr iazol-4-y 1 jbenzophenone (Ο.656 g., a.002 mole), phthal imide (0.524 g., 0.0022 mole), tr i pheny 1 phos -phine (Ο.576 g., 0.0022 mole) and dry tet rahydrofu ran (20 ml.), under nitrogen, was treated with diethyl azodi-carboxylate (0.585 g., 0.0022 mole) and stirred at ambient temperature for 25 hours. It was concentrated in vacuo and the residue was chromatographed on si lica gel (75 g. ) with 1.5% methanol 98.5% chloroform; 10 ml . fractions were col lected. The product was eluted in fractions 51~57 and crystall ized from methanol -ethy 1 acetate to give 0.148 g. of 5-chloro-2- [5- (phtha 1 imi domethy 1 )-5-methyl -4H-1,2,4-tr iazol -4-y 1 Jbenzophenone of melting point 217.5-2190 C ; 0.257 g. of product of melting point 219-220°; O.I89 g. of melting point 218.5-220° C. and 0.082 g. of melting . point 219-220.5° of 5-chloro-2- [5- (phthal imidomethy 1 )-5-met 1 -4H-l,2,4-triazol-4-yl )benzopherione .
The analytical sample had a melting point of 219-221° Ana 1. calcd. for C25Hi 7C 1 403 : C, 65.72; H, 5.75; CI, 7-76; N, 12.26.
Found: C, 65.86; H, 5-85; Cl, 7.-72; N, 12. 5.
Alternatively 2- [5- (phthal imi domethy 1 )-4H-l,2, 4-t r i -azo 1 -4-y 1 ] benzophenones of formula I I A= can be prepared f ron 5-am i no~5j 4-d i hyd ro-4- hyd roxy-4 phenylquinazpl ines of formula I by al lowi formula IV to react with an activated derivative of phthalo g 1 yci ne , e. g . the acid chloride, mixed anhydride or imidazo- lide, and then warming the resulting product in acetic ac M to give a compound of formula I I , A is The 3-am i no-3, 4-d i hydro-4-hyd roxy-4-pheny 1 qu i nazo 1 i nes (IV) may be prepared as described in the literature for 5ramino-6-ch 1 oro-3,4-d i hyd ro-4-hyd roxy-4- phenyl qu i nazol i ne by M. E. Deri.eg.et al.,. J. Org. Chem. 36,782 (1971): wherein Ri , Ra, R3, R4, and R5 have the same significance as in formula I I ; wherein X is CI , Br , --00-- C- 0 OCC2H5 , or and wherein A is 0 Example 2 5-Ch loro-2- [3_ (phtha 1 i.midomethyl ) -5 -methyl -4H-l,2 ,4-triazol-4-yl )benzophenone A st i rred solut ion of phtha loy 1 g 1 yc i ne (2.26 g. , 0.01 mole) in dry tet rahydrofu ran (20 ml . ), under . n i t rogen, was cooled in an ice-bath and treated with ca rbony Id i i m i da-zole. This mixture was kept at ambient temperature (22-24°) for 1.5 hours, cooled in an ice bath and treated wi th a mixture of 3-am i no-6-ch 1 or 0-3, 4-d i hyd ro-4-hyd roxy-4-phr>ny 1 qu i nazol i ne (2.88 g. , 0.01 mole) in tet rahyd rofu ran (2[> ml . ) . This mixture was kept at ambient temperature for 42 hours and concentrated in vacuo. The residue was mixed with a di lute sodium bicarbonate solution and extracted with methylene ch loride. The extract was washed wi th a saturated sodium ch loride solution, dried over anhydrous sodium su l fate and concentrated to give a crude oi l . Th is oi l .was mixed wi th acetic acid (50 ml . ) and warmed in an oi l bath at 120° for 1 hour. The acetic acid was then concentrated in vacuo and the res idue was mixed with water, neutral ized with sodium bicarbonate and extracted with methylene chloride. The extract was washed with dried over anhydrous sodium sulfate and concentra residue was ch romatographed over si lica gel (400 g.) with 2.5$ methanol -97.5^ chloroform. The product obtained from the column was crystal l ized from methylene chloride-ethyl acetate to give 0.24 g. of 5- ch 1 or o-2 - [3_ (phtha 1 im i domet hy 1 ) -5-methy 1 -4H-1 ,2 , 4- t r iazo 1 -4- y 1 jbenzophenone of melting point 215-218° C. An additional 0.135 g. of this product of melting point 216-218.5° C. was obtained by working up the mother l iquors.
Example 3 8- Ch 1 or o- 1-met hy 1 -6-pheny 1 - 4H- s - 1 r i azo 1 o[ 4,3_a ] -[1, 4]benzod i azep i ne A stirred mixture of 5~ h 1 oro-2 - [3~ (pht ha 1 i m i dome t hy 1 ) -5-methyl-4H-l,2,4-triazol-4-yl Jbenzophenone (0.257 g., Ο.562 mmole) and absolute ethanol (3 ml.) was treated with hydrazine hydrate (0.05 ml ., 1.04 mmole) and warmed in an oi l bath at 73° C. for 80 minutes. (The solution precipitated a white sol id after 30 minutes.) The cooled mixture was mixed with water and extracted with chloroform. The extract was washed with brine, dried, over anhydrous sodium sulfate and concentrated. The residue was ch romatog raphed on si l ica gel (42 g.) with 2$ methanol-98^ chloroform; 10 ml . fractions were col lected. The product was eluted in fractions 33~57 and crystal l ized from ethyl acetate to give 77 mg., of melting point 229-230° C. and 26 mg., of melting point 223-229.5° C. of 8-ch 1 oro- 1 -me thy 1 -6- pheny 1 - 4H~s-triazolo[4,3-a][l,4]benzodiazepine.
Ana 1. calcd. for Ci7Hi3ClN4: C, 66.15;· Hi .24; CI, 11.48; N, 18.15.
Found: C, 66.05; H, 4.13; CI, 11.34; N, 18.00.
Example ,4 8-n i tro-l-methy 1-6- (o-ch 1 oropheny 1 )-4H-s-tr i -azolo[4,3-a] [1,4] benzodiazepine In the manner given in Example I.'., a mixture of 5-nitr 2 · -ch loro-2- [3- (hyd roxymethy 1 ) -5-metl- y 1 - 4H-1,2 , 4- 1 r i azo 1 -4- y 1 Jbenzophenone, phthal imide and t r i pheny 1 phos ph i ne in tet rahyd rofu an was treated with diethyl azod i carboxy 1 ate to give 5-n i t ro-2 ' -ch loro-2- [3- (phthe 1 imt-domethy 1 )-5-methyl-4H-l,2,4-triazol-4-yl jbenzophenone .
In the manner given in Example 2:, 5- n i t ro-2 ' -ch 1 oro-2-[3- (phthal imidomethyl ) -5-methy 1 -4H-1 ,2 , 4- t r i azol -4- y 1 Jbenzophenone was heated in ethanol with hydrazine hydrate to give 8-nitr o-l- methyl -6- (o- ch 1 oropheny 1 )-4H-s-triazolo-[4,3~a] [1,4] benzodiazepine.
Example 5 8-Fluoro-l-ethyl-6-[p-(propylsulfinyl )phenyl]-4H-s-triazo1o[4,3-a][l,4]benzodiazepine In the manner given in Example 1. a mixture of 5" f luoro-41 - (propy 1 su 1 i ny 1 )-2- [3- (hyd roxymethy 1 -5-ethy 1 -4H-1, , 4-triazol-4-yl Jbenzophenone, phthal imide and triphenyl-phosphine in dioxane was treated with diethyl azodicar-boxylate to give 5" f luoro-41 - (propy lsu 1 fi ny 1 )-2- [ >- (phtha 1 -imidomethyl )-5-ethyl-4H-l,2,4:triazol-4-y1 Jbenzophenone.
In the manner given in Example 3, 5" fl uoro-41 - (p^-py lsu If iny 1 )-2- [3- (phthal imidomethyl )-5-ethy 1 -4H-l,2,4-tri -azol -4- y 1 ] benzophenone was heated in ethanol with hydrazine hydrate to give 8- f 1 uoro-l-ethy 1 -6- [ p- (propy 1 su 1 f i ny 1 ) phen-y 1 J-4H-s-triazolo[4,3-aJ [l,4]benzod iazepi ne .
Example 6 8- Me thy 1 th i o-l-methy 1 -6- (o-ch loropheny 1 )-4H-s-triazolo[4,3-a][l, 4] benzod iazepi ne In the manner given in Example 1 , a mixture of 5" me thy 1 th i o-2, -ch loro-2- [3_ (hyd roxymethy 1 ) -5 -me thy 1 -4H-1 ,2, 4- t r i azol -4- y 1 ] benzophenone , phthalimide and triphenyl-phosphine in tet rahydrofuran was treated with diethyl azo-d i ca rboxy late to give 5-methy 1 th i o- ' -ch 1 oro-2- [3- (phtha 1 i -mi dome thy 1 )-5-methyl-4H-l,2,4-triazol-4-yl ] benzophenone .
In the manner given in Example 5, 5-meth 1 th io-2 ' -chloro-2- [3- (phtha 1 im idomethy 1 ) -5-me thy 1 -4H-1 ,2 , 4- 1 r i azo 1 -4- y 1 Jbenzophenone was heated in ethanol with hydrazine hydrate to gi e 8-meth lth i o-l-methy 1 -6- (o-ch loropheny 1 )-4H-s-triazolo[4,3-a] [1 , 4 Jbenzod i azepi ne .
Example .7 1-Pheny 1 -9-ethoxy-8- isopropyl-6-[m- (me thy 1 th i o)-phenyl]-4H-s-triazolo[4,3-a][li4]benzodiazepine In the manner given in Example a mixture of 4-ethoxy-5-i sop ropy l-3'-methylthio-2-[3- (hyd roxymethy 1 )-5- phenyl-4H-1,2, 4-tri azol -4- 1 Jbenzophenone , phtha 1 imi de and t r i pheny 1 phosph i ne in tet rahyd rofu ran was treated with diethyl azod i ca rboxy 1 ate to give 4-ethoxy-5" i sopropy 1 - ' _ methylthio-2-[3- (phthal imidomethyl ) -5 -phen 1 -4H-1 ,2 , 4-t riazol -4-y 1 Jbenzophenone .
" In the manner given in Example3:i 4-ethoxy-5~ i so-p ropy 1 -31 -methy 1 th i o-2- [3- (phtha 1 imi dome thy 1 ) -5- pheny 1 -4H-l,2,4-triazol-4-y 1 jbenzophenone was heated in ethanol with hydrazine hydrate to give 1-pheny 1 - 9-ethoxy-8- isopropy^ 6- [m- (me thy lth io) phenyl ] -4H-s- 1 r i azol o[4, 3-a] [ 1 , 4]benzod i aze-p i ne .
Example .8 1-propy 1 -8- i sop ropy lsu 1 fony 1 -6- (o- f 1 uoropheny 1 ) -4H-s-tr iazolo[4,3-a] [l,4]benzodiazepi ne In the manner given in Example 1, a mixture of 5~iso-propy lsul fony 1-21 -f luoro-2- [3~ (hyd roxyme h 1 ) -5- p ropy 1 -4H-1, 2,4-triazol -4-yl Jbenzophenone, phthalimide and triphenyl-phosphine in tet rahyd rofu ran was treated with diethyl azo-dicarboxylate to give 5 - i sopropy lsu 1 fony 1 - '- f luoro-2- [3- ( phtha 1 imidomethy 1 ) -5 - propy 1 -4H- 1 ,2 , 4- t r i azol - 4-y 1 jbenzo-phenone .
In the manner given in Example3 a solution of 5 ~ i sopropy 1 su 1 fony 1 -2 ' -f luoro-2- [3- (phtha 1 imidomethy 1 ) -5-propyl - 4H-1,2, 4-tr iazol-4-yl ] benzophenone in methanol was heated with hydrazine hydrate to give 1-propy 1 -8- i sopropy 1 su 1 fony 1 - 6 - ( o- f 1 uoropheny 1 )-4H-s-triazolo[4,3-a] [1,4]-benzod i azep i ne .
Example 9 1-Benzy 1 - 7 - formamido- 6 - (o-ch 1 oropheny 1 ) - H-s-t r i azo1o[4,3"a ] [ 1 > 4]benzod i azep i ne In the manner given in Example 1 , a mixture of 6 - formami do-2 ' -ch 1 o ro-2- [3- (hyd roxymethy 1 ) -5-benzy 1 - 4H -l, 2,4-t.riazo1- 4-yl jbenzophenone, phthal imide and triphenyl-phosphine in tet rahyd rofu ran was treated with diethyl azo-dicarboxylate to give 6 - formami do-21 -ch 1 oro-2- [>- (phtha 1 i -mi dome th 1 ) -5-benzy l-4H-l,2,4-triazol-4-yl ] benzophenone .
In the manner given in Example 3 / 6 - ormam ido- 1 -ch loro-2- [3- (phtha 1 imidomethy 1 ) - 5-benzy 1 - H-1 ,2,4- tr iazo-1 -4- y 1 Jbenzophenone was heated in ethanol with hydrazine hy-drate to give 1-benzy 1 -7 - formamido-6 - (o-c loropheny 1 )-4H- s - 1 r iazo1o[4,3-a] [1, 4]benzod iazepi ne . .
Example 10 8-ch 1 oro-l-methy 1 -6- (o-ch 1 oropheny 1 )-4H-s- t< i -azolo[4,3_a] [ 1, 4 Jbenzod iazepi ne In the manner given in Example 1 , a mixture of 2 ' , 5 ~ di chloro-2- [3- ( yd roxymethy 1 ) -5-methy 1 -4H-1 ,2 , 4- 1 r iazol - 4-y 1 Jbenzophenone, phthalimide and t r i pheny 1 phosph i ne in tetrahydr ofuran was treated with diethyl azod i ca rboxy late to give 2 ' i ch loro-2- [3- (phtha 1 imidomethy 1 )-5-meth 1 -4H-l^^-triazol^-yljbenzophenone of melting point 262-265° C Ana 1. calcd. for C25HieC 12N403 : C, 61.11; j 5.28; CI, 14.43; N, 11.40.
Found: C, 60.77; H, 3.26; CI, 14.49; N, 11.45.
In the manner given in Example 2 , 21 , 5"d i ch 1 oro- - [3-( phtha 1 imdomethy 1 ) -5-methy l-4H-l,2,4-triazo1-4-yl ] benzophen one was heated in ethanol with hydrazine hydrate to give 8-ch 1 oro-l-meth 1 -6- (o-ch 1 oropheny 1 )-4H-s-triazolo[4,3-a]-[l,4]benzod iazepine of melting point 223-225° C.

Claims (1)

  1. 2. CLAIMS ι -'- A process for the production of a 6-pheny 1 -4H- azolo[4, 3. -a] [l,4]benzodiazepi ne of the formula I I I wherein Ri is selected from the group consisting of hydro- en, alkyl of 1 to 3 carbon atoms, inclusive, phenyl, benzyl and -C00R' in which R ' is alkyl defined as above; and wherein Rs, R3, R4, and R5 are selected from the group consisting of hydrogen, alkyl as defined above, halogen, nitro, cyano, t r i f 1 uoromethy 1 , and alkoxy, alkylthio, alkylsul finyl , a 1 ky Isu I fony 1 , and a 1 kanoy lanii no in which the carbon moiety is between 1 to carbon atoms, inclu- sive, and d i a 1 ky 1 am i no in which alkyl is defined as above. which comprises: treating a compound of formula I : wherein Ri , R2, R3 R4, and R5 are defined as above, in a mixture with phthal imide and t r i pheny 1 phosph i ne in an i nert water-free organic solvent with diethyl azodicar-boxylate between a temperature of 0 to 100° C , for a period of 2 to hours ; extracting the mixture and recovering the thus obtained phthal imido compound of formula I I wherein i , R2, R3, R4, and R5 are defined as above and wherein A is 0 treating compound I I , in an alkanol of 1 to 5 carbon atoms, inclusive, with hydrazine hydrate at a temperature between- 25-100° C. to obtain the compound of formula I I I above. •A The process of claim ^ in which the inert, water-free organic solvent is tet rahyd rof u ran and the reaction temperature is between 20-40° C. The process of claim 1 wherein- the alkanol of 1 to ''> carbon atoms, inclusive, is ethanol . 4. -4- The process of claim 1, wherein the starting materia is 5-ch loro-2-[3- (hydroxymethy 1 ). -5 -met hy 1 - 4H-1 ,2 , 4- 1 r i azo 4- y 1 Jbenzophenone . -5- The process of claim 1 wherein the starting material is :? 1 ,5-d i ch loro-2- f 3- (hyd roxymethy 1 ) -5 -me thy 1 - 4H- 1 ,2 , 4 -t r i azo 1 -4- y 1 Jbenzophenone . -6- ■ A compound of the formula: wherein A is wherein R, is selected from tbe group consisting of hydrogen, alkyl of , 1 to 3 carbon atoms, inclusive, and wherein R£. Rg> ^, and ^ are hydrogen or halogen. -7- A compound according to claim 6 wherein R^ is methyl, R^ is 5-chloro, R3» and R5 are hydrogen, and thje compound is therefore 5-chloro-2-[3-(phthal imidomethyl )-5-methyl-4H-l ,2,4-triazol-4-yl] benzophenone. -8- A compound according to claim 6 wherein R^ is methyl, R2 is o-chloro, R^ is 5. -chloro, R3 and R5 are hydrogen and the compound is therefore V ,5-dichloro-2-[3-(phthal imidomethyl ) -5 -methyl -4H-1 ,2,4-triazol-4-yl]benzophenone. ttorneys or pp can
IL49503A 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 (en)

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IL44068A IL44068A (en) 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
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