CA1051905A - 1,3-dioxo-2-isoindolineacetic acid, [[n-(2-benzoyl-phenyl)-1, 3-dioxo-2-isoindolineacetamido] methylene] hydrazides - Google Patents
1,3-dioxo-2-isoindolineacetic acid, [[n-(2-benzoyl-phenyl)-1, 3-dioxo-2-isoindolineacetamido] methylene] hydrazidesInfo
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- CA1051905A CA1051905A CA310,228A CA310228A CA1051905A CA 1051905 A CA1051905 A CA 1051905A CA 310228 A CA310228 A CA 310228A CA 1051905 A CA1051905 A CA 1051905A
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- chloro
- dioxo
- methyl
- triazol
- benzophenone
- Prior art date
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Abstract
ABSTRACT OF THE DISCLOSURE
A multistep process is disclosed for the production of a compound of the formula V:
V
wherein R' and R" are alkyl of 1 to 3 carbon atoms, inclusive or together is pyrrolidino, piperidino, 4-methylpiper-azino or morpholino; and wherein the rings A and B are unsub-stituted, or substituted by one or more substituents selected from the group consisting of fluoro, chloro, bromo, nitro and trifluoromethyl. Compounds of formula V are used for treatment of anxieties and/or depressions in mammals and birds. This divisional application is directed to the production of inter-mediate compounds of the formula II:
wherein R1 is hydrogen or halogen. The process comprises treating one mole of a compound of the formula
A multistep process is disclosed for the production of a compound of the formula V:
V
wherein R' and R" are alkyl of 1 to 3 carbon atoms, inclusive or together is pyrrolidino, piperidino, 4-methylpiper-azino or morpholino; and wherein the rings A and B are unsub-stituted, or substituted by one or more substituents selected from the group consisting of fluoro, chloro, bromo, nitro and trifluoromethyl. Compounds of formula V are used for treatment of anxieties and/or depressions in mammals and birds. This divisional application is directed to the production of inter-mediate compounds of the formula II:
wherein R1 is hydrogen or halogen. The process comprises treating one mole of a compound of the formula
Description
~0519VS
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
This in~ention is directed to organic compounds and is particularly concerned with a no~el process for the prep-aration of 1-aminomethyl-6-phenyl-4H-s-triazolo~4,3-a][1,4]-benzodiazepines and the intermediates thereof.
The no~el process or products can be illustrati~ely represented as follows:
~ N ~ H
NHz HO
.
~1~
'" ~
0~0 C~=O
~ ~H
¢~ ~11
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
This in~ention is directed to organic compounds and is particularly concerned with a no~el process for the prep-aration of 1-aminomethyl-6-phenyl-4H-s-triazolo~4,3-a][1,4]-benzodiazepines and the intermediates thereof.
The no~el process or products can be illustrati~ely represented as follows:
~ N ~ H
NHz HO
.
~1~
'" ~
0~0 C~=O
~ ~H
¢~ ~11
-2-lOS~905 C--N~
.
R~N H
15 ¢~C~ C
` \b R,~N H~
~25 ¢~;3 ¢~ V
wherein R~ and R" are alkyl of 1 to 3 carbon atoms, Inclusl\~e 30 or together -N~ Ts pyrrol idino, piperidino9 4-methyl-2~61B
105~905 piperazino or morpholino.
The in~ention encompasses besides the process I~
III~IV~V the novel intermediates of formulae II and IV
abo~e.
The more desirable intermediates of the type II ha~e the more specific formula IIA:
~ d , o o=~o fH2 C - O
"N - CH- N - NH
~. - I .
. ~ C H2 R~Z 0~ o IIA
wherein Rl` is hydrogen, fluoro, chloro, bromo, nitro, or trifluoromethyl; wherein R2 is hydrogen, fluoroJ or chloro;
and wherein R3 is hydrogen, or fluoro if R2 is also fluoro.
The most desirable intermediates of type II are of the fonnula IIB:`
29~ t~
lOS~90S
o~o 1 .
I O
~ --CH= N--NH
R~ . 1'2 [~2 ~
- I IB
whe re i n R l l and R '2 a re hyd rogen o r ch l o ro .
The mo~re desirable products of formula IV ha\~e the rnore specific formula IVA:
:
_N--C ~ N
R~o ~
~ I VA
~ ' , ~
wheretn R~o and R"O are alkyl of 1 to 3 carbon atoms, inclu~
30 sl~ve; wheretn Rl ts hydrogen, fluoro, chloro, b;omo, nitro, ~5~ ~
.. , . . .. .,, .,.. , ' ' ':
~ fjl p, ~C)$190S
or trifluoro~ethyl; wherein Rz is hydrogen, fluoro, chloro;
and wherein R3 is hydrogen or fluorc, if Rz is also fluoro.
The most desirable inter~ediates of type IY have the specific formula IVB:
CH9 = ~ C N
IVB
.
wherein R'1 and R'2 are hydrogen or chlorine.
The process of this in~ention comprises: treating an equi~alent of compound I with two equi~alents of a-phthal-imidoacetyl chloride or bromide in an inert organic sol~ent to obtain compound 11; treating compound lt with trifluoro-acetic acid to obtain compound 111; treating compound 111 with a dialkylmethylenea~onium chloride or bromide to obtain compound IV; and treating compound IV with hydrazine in ethanol to obtain c~pound V abo~e.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Lower alkyl groups of 1 to 3 carbon ato~s inclusi~e, are exemplified by methyl, ethyl, propyl and Isopropyl.
The final products of formula V are known conpounds, ~-àctT~e as tranquilizing, antianxiety and antTdepressant agents whlch are useful in the treatment of mam~als and birds. Single unit dosage forms between 0.02 and 1 mg./kg ~6-105~90S
are used as described in detail in C~nadian Patent No.
1,020,940, issued Novenb~r 15, 1977.
The object of this In~ention is the new process for the production oF compounds of for~ula V and the new intermediates II and IV in this process.
Some of the starting compounds of fonmu1a 1 are described in the art by Derieg et al.,J, Org. Che~. 36,783 (1971).
Other substituted co~pounds of formula I are ~ade by the same process using the well-known and a~ailable substituted 2-aminobenzophenones VI:
¢~ a~ld Vl / : Vl / hydrazine ~ in ethanol ;Ha ~ ' .~' ' '.
~ I
;n which the rings A and B are unsubstituted or substituted as described abo~e.
In carry;ng out the process of the present in~ention a selected 3-amino-3,4-d7hydro-4-hydroxy-4-phenylquTnazoline 1 is suspended in an inert organic sol~ent e.g. ethylene 29~1E3 ,-105~gOS
dichloride, chloroform, carbon tetrachloride, tetrahydro-furan, dioxane or the like, in the presence of an organic base. To this suspension is added ~-phthalimidoacetyl chloride or bromide ~C A!nsworth et al , J. Am. Chem. Soc.
76, 5651 (1954)]. In the preferred embodiment of this in~ention, the reaction is carried out in a nitrogen atmos-phere with 2 to 2.5 mol equi~alents pyridine as base, and a similar a~ount of the a-phthaljmidoacetyl halide reagent in an inert organic sol~ent is added dropwise during t to ~ hours. The preferred temperature during the reaction is from -5 to 15 C. After al1 of the reagent has been added, the mixture is allowed to stand from t to 2 hoyrs at -5 to 15 C., and finally from 1 to 24 hours at room temperature (22 to 28). At the termination of the reaction, the product II is reco~ered by con~entional means, i.e. adding water and extracting with an organic water-immiscible sol~ent e.g. chloroform, methylene chloride. The product is purified by con~entional means, generally by crystallization.
Compound II is con~erted to compound III by reacting a solution of compound II in an inert organic sol~ent with a halogenated acetic acld, e.g. chloroacetic, dichloroacetic, monofluoroacetic, dlfluoroacetic or trifluoroacetic acid, with trifluoroacetic acid preferred. Sol~ents such as benzene, toluene, xylene, chlorobenzene are employed.
In the preferred embodiment of this in~ention the solution -of compound II is reacted with the trifluoroacetic acid at temperatures between 80 to 125C. for ~ to 4 hours. There-after the product III ts reco~ered and purlfied by con~en-tTonal procedures: concentrating the reactlon mixture, adding water, neutrallz1ng the acid, extracting with a ~8-~'~Gi~
~ 0 51Y~5 water-l~miscible or~anlc sol~ent, chro~atography and/or crystalllzation.
Co~pound lll is con~erted to co~pound IV by reacttng lll with a substltuted methyleneammonlum hallde prepared as shown by H. Boh~e et al.,Chem. Ber. 93,1305 (1960) or J.Schreiber et al., Angew. Chem., Int. ed. 10, ~30 (1971).
The dlalkylmethylenea~monium halide can be prepared also In sltu rather than being prefonned and added subsequently to the reactlon. In;the preferred embodlment of this reaction a selected N,N,N',N'-tetraalkyldiaminomethane in a sol~ent such as dlmethylfonmamlde, dTethylformamide, dimethyl- or di'ethylacetamide or the like, is treated at -5 to 15C., In a nTtrogen atmosphere,with an acylhallde usually acetyl chloride. The mi~ture is allowed to warm to room temperature (cc. 25C~) and to stand for ~ to 4 hours ~t room temperature.
To this mixture is added the compound lll and the reaction mixture is t~en allowed to react for 10 to 48 hours at temperatures be~ween ?5 to 100C. Thereafter the reaction m;xture is' poured into water, neutralized and the precipi-tated product IV reco~ered. Product IV Is purified by con~entTonal procedures such as recrystallization or -chromatography.
Compound IV Is con~erted to compound V by treatment of IV with hydrazine, usually as the hydrate, in a lower alkanol 2S `f 1 to 4 carbon ato~s between 25-100C. Instead of hydra-~in~ methylamlne, ethylamine, propylamlne or butylamlne -~
and sol~ents such as tetrahydrofuran, methylene'~chloride can be used. In the preferred meth~d hydrazlne hydrate In ethanol at about the reflux temperature Is employed for 1 to 4 hours. The product Is reco~ered and purlfled by .
_g_ .
' ' ' f~ 2961~
lOS~90S
con~entional p rocedures: ~iItration> extraction, chromato-g raphy, crystallization and the like.
The following examples are illustrative of the process and p rod~cts of t~,e p resent in~ention, but a re not to be construed as limiting.
ExamPle 1 1~3-Dioxo-2-isoindolineacetic acid, [[N-(2-benzoyl-4-chlorophenyl)-1,3-dioxo-2-isoindolineacetamido]-methylene]hyd razide A stirred mixture of 3-arnino-6-chloro-3,~-dihydro-4-hydroxy-4-phenylquinazoline (2.74 g, 0.01 mole) in dry tetrahydrofuran (150 ml) is cooled in an ice bath, under nitrogen and treated with dry pyridine (1.77 ml, 1.22 mole).
This mixture is then treated, dropwise, during 1 hour,with a solution of a-phthalirnidoacetyl chloride (4.92 g. 0.22 mole) in tetrahydrofuran (25 ml). The mixture is kept in the ice bath for 1 hour and at ambient temperature (25) for 4 hours. It is then poured into ice water and extracted -;
with chloroform. The extract is washed with brine, dried o~er anhydrous sodium sulfate and concentrated. The solid r~sidue is suspended in ethyl acetate, collected by filtra-tion, washed with ethyl acetate and dried to gi\~e 5.36 9 of 1,3-dioxo-2-isoindolineacetic acid, [[N-(2-benzoyl-4-chlorophenyl)-1,3-dioxo-2-isoindolineacetamido]methylene]-hydrazide of melting point 167-172.5C. (dec.). A small second crop, 0.517 9 of rnelting point 164.5-167C dec, is obtained by concentrating the ethyl acetate filtrate. The analytical sample is crystallized from methylene chloride-ethyl acetate and has a melting point 19~.5-198.5C.
Anal. Calcd. for Cg4Hz2ClN507:
C, 63.02; H, 3.42; Cl, 5.47; N, 10.81.
-10- . , ~9 10 5~V5 Found: CJ 63.10; H~ ~.59; Cl, 5.50; N, 10.97.
Exam~le 2 1,3-Dioxo-2-isoindolineacetic acid [[N-[2-~o-chlorobenzoyl)-4-chlorophenyl~-1,3-dioxo-2-isoindoline-acetamido]methylene]hydrazide In the rnanner given in Example 1, 3-amino-6-chloro-3J4-dihydro-4-hydroxy-4-(o-chlorophenyl)quinazoline with pyridine is reacted with a-phthalimidoacetyl chloride to gi~e 1,3-dioxo-2-isoindolineacetic acid [[N-[2-(o-chloro-benzoyl)-4-chlorophenyl]-1,3-dioxo-2-isoindolineacetamido]-methylene]hydrazide.
Example ~ 1~3-Dioxo-2-isoindolineacetic acid, [[N-[2-(o-chlorobenzoyl)-4-nitrophenyl]-1,3-dioxo-2-isoindoline-acetamido]~ethylene]hydrazide In the manner gi~en in Example 1, 3-amino-6-nitro-1~ 3,4-dihydro-4-hydroxy-4-(o-chlorophenyl)quinazoline with pyridine is reacted with a-phthalimidoacetyl chloride to gi~e 1~3-dioxo-2-i$oindolineacetic acid, [[N-[2-(o-chloro- ~:
benzoyl)-4-nitrophenyl]-1,3-dioxo-2-isoindolineacetamido]-methylene]hydrazide. - :
Example 4 1,3-Dioxo-2-isoindolineacetic acid, [[N-[2-(2,6-difluorobenzoyl)-4-chlorophenyl]-1,3-dioxo-2-isoindoline-acetamido3methylene]hydrazide in the manner gi~en in Example 1, 3-amino-6-chloro-
.
R~N H
15 ¢~C~ C
` \b R,~N H~
~25 ¢~;3 ¢~ V
wherein R~ and R" are alkyl of 1 to 3 carbon atoms, Inclusl\~e 30 or together -N~ Ts pyrrol idino, piperidino9 4-methyl-2~61B
105~905 piperazino or morpholino.
The in~ention encompasses besides the process I~
III~IV~V the novel intermediates of formulae II and IV
abo~e.
The more desirable intermediates of the type II ha~e the more specific formula IIA:
~ d , o o=~o fH2 C - O
"N - CH- N - NH
~. - I .
. ~ C H2 R~Z 0~ o IIA
wherein Rl` is hydrogen, fluoro, chloro, bromo, nitro, or trifluoromethyl; wherein R2 is hydrogen, fluoroJ or chloro;
and wherein R3 is hydrogen, or fluoro if R2 is also fluoro.
The most desirable intermediates of type II are of the fonnula IIB:`
29~ t~
lOS~90S
o~o 1 .
I O
~ --CH= N--NH
R~ . 1'2 [~2 ~
- I IB
whe re i n R l l and R '2 a re hyd rogen o r ch l o ro .
The mo~re desirable products of formula IV ha\~e the rnore specific formula IVA:
:
_N--C ~ N
R~o ~
~ I VA
~ ' , ~
wheretn R~o and R"O are alkyl of 1 to 3 carbon atoms, inclu~
30 sl~ve; wheretn Rl ts hydrogen, fluoro, chloro, b;omo, nitro, ~5~ ~
.. , . . .. .,, .,.. , ' ' ':
~ fjl p, ~C)$190S
or trifluoro~ethyl; wherein Rz is hydrogen, fluoro, chloro;
and wherein R3 is hydrogen or fluorc, if Rz is also fluoro.
The most desirable inter~ediates of type IY have the specific formula IVB:
CH9 = ~ C N
IVB
.
wherein R'1 and R'2 are hydrogen or chlorine.
The process of this in~ention comprises: treating an equi~alent of compound I with two equi~alents of a-phthal-imidoacetyl chloride or bromide in an inert organic sol~ent to obtain compound 11; treating compound lt with trifluoro-acetic acid to obtain compound 111; treating compound 111 with a dialkylmethylenea~onium chloride or bromide to obtain compound IV; and treating compound IV with hydrazine in ethanol to obtain c~pound V abo~e.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Lower alkyl groups of 1 to 3 carbon ato~s inclusi~e, are exemplified by methyl, ethyl, propyl and Isopropyl.
The final products of formula V are known conpounds, ~-àctT~e as tranquilizing, antianxiety and antTdepressant agents whlch are useful in the treatment of mam~als and birds. Single unit dosage forms between 0.02 and 1 mg./kg ~6-105~90S
are used as described in detail in C~nadian Patent No.
1,020,940, issued Novenb~r 15, 1977.
The object of this In~ention is the new process for the production oF compounds of for~ula V and the new intermediates II and IV in this process.
Some of the starting compounds of fonmu1a 1 are described in the art by Derieg et al.,J, Org. Che~. 36,783 (1971).
Other substituted co~pounds of formula I are ~ade by the same process using the well-known and a~ailable substituted 2-aminobenzophenones VI:
¢~ a~ld Vl / : Vl / hydrazine ~ in ethanol ;Ha ~ ' .~' ' '.
~ I
;n which the rings A and B are unsubstituted or substituted as described abo~e.
In carry;ng out the process of the present in~ention a selected 3-amino-3,4-d7hydro-4-hydroxy-4-phenylquTnazoline 1 is suspended in an inert organic sol~ent e.g. ethylene 29~1E3 ,-105~gOS
dichloride, chloroform, carbon tetrachloride, tetrahydro-furan, dioxane or the like, in the presence of an organic base. To this suspension is added ~-phthalimidoacetyl chloride or bromide ~C A!nsworth et al , J. Am. Chem. Soc.
76, 5651 (1954)]. In the preferred embodiment of this in~ention, the reaction is carried out in a nitrogen atmos-phere with 2 to 2.5 mol equi~alents pyridine as base, and a similar a~ount of the a-phthaljmidoacetyl halide reagent in an inert organic sol~ent is added dropwise during t to ~ hours. The preferred temperature during the reaction is from -5 to 15 C. After al1 of the reagent has been added, the mixture is allowed to stand from t to 2 hoyrs at -5 to 15 C., and finally from 1 to 24 hours at room temperature (22 to 28). At the termination of the reaction, the product II is reco~ered by con~entional means, i.e. adding water and extracting with an organic water-immiscible sol~ent e.g. chloroform, methylene chloride. The product is purified by con~entional means, generally by crystallization.
Compound II is con~erted to compound III by reacting a solution of compound II in an inert organic sol~ent with a halogenated acetic acld, e.g. chloroacetic, dichloroacetic, monofluoroacetic, dlfluoroacetic or trifluoroacetic acid, with trifluoroacetic acid preferred. Sol~ents such as benzene, toluene, xylene, chlorobenzene are employed.
In the preferred embodiment of this in~ention the solution -of compound II is reacted with the trifluoroacetic acid at temperatures between 80 to 125C. for ~ to 4 hours. There-after the product III ts reco~ered and purlfied by con~en-tTonal procedures: concentrating the reactlon mixture, adding water, neutrallz1ng the acid, extracting with a ~8-~'~Gi~
~ 0 51Y~5 water-l~miscible or~anlc sol~ent, chro~atography and/or crystalllzation.
Co~pound lll is con~erted to co~pound IV by reacttng lll with a substltuted methyleneammonlum hallde prepared as shown by H. Boh~e et al.,Chem. Ber. 93,1305 (1960) or J.Schreiber et al., Angew. Chem., Int. ed. 10, ~30 (1971).
The dlalkylmethylenea~monium halide can be prepared also In sltu rather than being prefonned and added subsequently to the reactlon. In;the preferred embodlment of this reaction a selected N,N,N',N'-tetraalkyldiaminomethane in a sol~ent such as dlmethylfonmamlde, dTethylformamide, dimethyl- or di'ethylacetamide or the like, is treated at -5 to 15C., In a nTtrogen atmosphere,with an acylhallde usually acetyl chloride. The mi~ture is allowed to warm to room temperature (cc. 25C~) and to stand for ~ to 4 hours ~t room temperature.
To this mixture is added the compound lll and the reaction mixture is t~en allowed to react for 10 to 48 hours at temperatures be~ween ?5 to 100C. Thereafter the reaction m;xture is' poured into water, neutralized and the precipi-tated product IV reco~ered. Product IV Is purified by con~entTonal procedures such as recrystallization or -chromatography.
Compound IV Is con~erted to compound V by treatment of IV with hydrazine, usually as the hydrate, in a lower alkanol 2S `f 1 to 4 carbon ato~s between 25-100C. Instead of hydra-~in~ methylamlne, ethylamine, propylamlne or butylamlne -~
and sol~ents such as tetrahydrofuran, methylene'~chloride can be used. In the preferred meth~d hydrazlne hydrate In ethanol at about the reflux temperature Is employed for 1 to 4 hours. The product Is reco~ered and purlfled by .
_g_ .
' ' ' f~ 2961~
lOS~90S
con~entional p rocedures: ~iItration> extraction, chromato-g raphy, crystallization and the like.
The following examples are illustrative of the process and p rod~cts of t~,e p resent in~ention, but a re not to be construed as limiting.
ExamPle 1 1~3-Dioxo-2-isoindolineacetic acid, [[N-(2-benzoyl-4-chlorophenyl)-1,3-dioxo-2-isoindolineacetamido]-methylene]hyd razide A stirred mixture of 3-arnino-6-chloro-3,~-dihydro-4-hydroxy-4-phenylquinazoline (2.74 g, 0.01 mole) in dry tetrahydrofuran (150 ml) is cooled in an ice bath, under nitrogen and treated with dry pyridine (1.77 ml, 1.22 mole).
This mixture is then treated, dropwise, during 1 hour,with a solution of a-phthalirnidoacetyl chloride (4.92 g. 0.22 mole) in tetrahydrofuran (25 ml). The mixture is kept in the ice bath for 1 hour and at ambient temperature (25) for 4 hours. It is then poured into ice water and extracted -;
with chloroform. The extract is washed with brine, dried o~er anhydrous sodium sulfate and concentrated. The solid r~sidue is suspended in ethyl acetate, collected by filtra-tion, washed with ethyl acetate and dried to gi\~e 5.36 9 of 1,3-dioxo-2-isoindolineacetic acid, [[N-(2-benzoyl-4-chlorophenyl)-1,3-dioxo-2-isoindolineacetamido]methylene]-hydrazide of melting point 167-172.5C. (dec.). A small second crop, 0.517 9 of rnelting point 164.5-167C dec, is obtained by concentrating the ethyl acetate filtrate. The analytical sample is crystallized from methylene chloride-ethyl acetate and has a melting point 19~.5-198.5C.
Anal. Calcd. for Cg4Hz2ClN507:
C, 63.02; H, 3.42; Cl, 5.47; N, 10.81.
-10- . , ~9 10 5~V5 Found: CJ 63.10; H~ ~.59; Cl, 5.50; N, 10.97.
Exam~le 2 1,3-Dioxo-2-isoindolineacetic acid [[N-[2-~o-chlorobenzoyl)-4-chlorophenyl~-1,3-dioxo-2-isoindoline-acetamido]methylene]hydrazide In the rnanner given in Example 1, 3-amino-6-chloro-3J4-dihydro-4-hydroxy-4-(o-chlorophenyl)quinazoline with pyridine is reacted with a-phthalimidoacetyl chloride to gi~e 1,3-dioxo-2-isoindolineacetic acid [[N-[2-(o-chloro-benzoyl)-4-chlorophenyl]-1,3-dioxo-2-isoindolineacetamido]-methylene]hydrazide.
Example ~ 1~3-Dioxo-2-isoindolineacetic acid, [[N-[2-(o-chlorobenzoyl)-4-nitrophenyl]-1,3-dioxo-2-isoindoline-acetamido]~ethylene]hydrazide In the manner gi~en in Example 1, 3-amino-6-nitro-1~ 3,4-dihydro-4-hydroxy-4-(o-chlorophenyl)quinazoline with pyridine is reacted with a-phthalimidoacetyl chloride to gi~e 1~3-dioxo-2-i$oindolineacetic acid, [[N-[2-(o-chloro- ~:
benzoyl)-4-nitrophenyl]-1,3-dioxo-2-isoindolineacetamido]-methylene]hydrazide. - :
Example 4 1,3-Dioxo-2-isoindolineacetic acid, [[N-[2-(2,6-difluorobenzoyl)-4-chlorophenyl]-1,3-dioxo-2-isoindoline-acetamido3methylene]hydrazide in the manner gi~en in Example 1, 3-amino-6-chloro-
3,4-dihydro-4-hydroxy-4-~2,6-difluorophenyl)quinazoline with pyridine is reacted with a-phthalimidoacetyl chloride to gi~e 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(2,6-dlfluorobenzoyl)-4-chlorophenyl]-1,3-dioxo-2-isoindoline-acetamido~methylene]hydrazide.
Examp1e 5 1,3-Dioxo-2-isoindolineacetic acid, [[N-[2-(o-chlorobenzoyl)-4-f1uorophenyl]-1,3-dioxo-2-isoindoline-2~
1051gOS
acetamido]mc~thylene]hydrazide In the manner gi~en in Example 1, 3-amino-6-fluoro-3,4-dihydro-4-hydroxy-4-(o-chlorophenyl)quinazoline with pyridine is reacted with ~-phthalimldoacetyl chloride to gi~e 1,3-dioxo-2-isoindolineacetic acid) [[N-[2-(o-chloro-benzoyl)-4-fluorophenyl]-1,3-dioxo-2-isoindolineacetamido]-methylene]hydrazide.
Example 6 1,3-Dioxo-2-isoindolineacetic acid, [[N-[2-(o-chlorobenzoyl)-4-(trifluoromethyl)phenyl]-1,3-dioxo-2-.isoindolineacetamido]methylene]hydrazide In the manner gi~en in Example 1, 3-amino-6-trifluoro-methyl-3,4-dihydro-4-hydroxy-4-(o-chlorophenyl)quinazoline with pyridine is reacted with a-phthalimidoacetyl chloride to gi~e 1,3-dioxo-2-isoindolineacetic acid, [[N-[~-(o-chloro-benzoyl)-4-(trifluoromethyl)phenyl]-1,3-dioxo-2-isoindoline-acetamido]methylene]hydrazide.
In the manner gi~en in the preceding examples other compounds of formula II structure can be synthesized.
Representati~e compounds thus obtained include:
1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(o-fluor~-benzoyl)-4-chlorophenyl]-1,3-dioxo-2-isoindolineacetamido]-methylene]hydrazide;
1,3-dioxo-2-isoindolineacetic acid, [~N-[2-benzoyl-4-nitro- ~.
phenyl]-1,3-dioxo-2-isoindolineacetamido]methyleneihydrazide;
1,~-dioxo-2-isoindolineacetic acid~ [[N-[2-benzoyl-4-(tri- .
fluoromethyl)phenyl]-1,3-dioxo-2-isoindolineacetamido]- :
methylene]hydraztde; - ~ `
1,3-dloxo-2-isoindolineacetic acid, ~[N-[2-benz~yl-4-~luoro-phenyl]-1,3-dioxo-2-isoindolineacetamido~methylene]hydrazide, 1,3-dioxo-2-lsoindolineacetic acid, [[N-[2-benzoyl-3-nitro-phenyl~ -dloxo-2-Tsoindolineacetarnido]methylene]hy~razide;
1,3-dToxo-2-isoindolineacetic acid, [[N-[2-(m~bronlobenzoyl~-
Examp1e 5 1,3-Dioxo-2-isoindolineacetic acid, [[N-[2-(o-chlorobenzoyl)-4-f1uorophenyl]-1,3-dioxo-2-isoindoline-2~
1051gOS
acetamido]mc~thylene]hydrazide In the manner gi~en in Example 1, 3-amino-6-fluoro-3,4-dihydro-4-hydroxy-4-(o-chlorophenyl)quinazoline with pyridine is reacted with ~-phthalimldoacetyl chloride to gi~e 1,3-dioxo-2-isoindolineacetic acid) [[N-[2-(o-chloro-benzoyl)-4-fluorophenyl]-1,3-dioxo-2-isoindolineacetamido]-methylene]hydrazide.
Example 6 1,3-Dioxo-2-isoindolineacetic acid, [[N-[2-(o-chlorobenzoyl)-4-(trifluoromethyl)phenyl]-1,3-dioxo-2-.isoindolineacetamido]methylene]hydrazide In the manner gi~en in Example 1, 3-amino-6-trifluoro-methyl-3,4-dihydro-4-hydroxy-4-(o-chlorophenyl)quinazoline with pyridine is reacted with a-phthalimidoacetyl chloride to gi~e 1,3-dioxo-2-isoindolineacetic acid, [[N-[~-(o-chloro-benzoyl)-4-(trifluoromethyl)phenyl]-1,3-dioxo-2-isoindoline-acetamido]methylene]hydrazide.
In the manner gi~en in the preceding examples other compounds of formula II structure can be synthesized.
Representati~e compounds thus obtained include:
1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(o-fluor~-benzoyl)-4-chlorophenyl]-1,3-dioxo-2-isoindolineacetamido]-methylene]hydrazide;
1,3-dioxo-2-isoindolineacetic acid, [~N-[2-benzoyl-4-nitro- ~.
phenyl]-1,3-dioxo-2-isoindolineacetamido]methyleneihydrazide;
1,~-dioxo-2-isoindolineacetic acid~ [[N-[2-benzoyl-4-(tri- .
fluoromethyl)phenyl]-1,3-dioxo-2-isoindolineacetamido]- :
methylene]hydraztde; - ~ `
1,3-dloxo-2-isoindolineacetic acid, ~[N-[2-benz~yl-4-~luoro-phenyl]-1,3-dioxo-2-isoindolineacetamido~methylene]hydrazide, 1,3-dioxo-2-lsoindolineacetic acid, [[N-[2-benzoyl-3-nitro-phenyl~ -dloxo-2-Tsoindolineacetarnido]methylene]hy~razide;
1,3-dToxo-2-isoindolineacetic acid, [[N-[2-(m~bronlobenzoyl~-
4-chlorophenyl~-1,3-dioxo-2-isoindolineacetamTdo]methylene]-hydrazide;
1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(o-bromobenzoyl)-
1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(o-bromobenzoyl)-
5-nitrophenyl]-1~3-dioxo-2-isoindolineacetarnido]methylene]-hydrazide;
1,~-dioxo-2-isoindolineacetic acid, [[N-[2-(p-bromobenzoyl)-
1,~-dioxo-2-isoindolineacetic acid, [[N-[2-(p-bromobenzoyl)-
6-fluorophenyl]-1J3-dioxo-2-isoindolineacetamido]methylene]-hydrazide;
1,3-dioxo-2-isoindolineacetic acid, [[N-[2-~2,6-difluoro-. benzoyl)-5-bromophenyl]-1,3-dioxo-2-isoindo1ineacetamido]-methylene]hydrazide;
1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(p-ch10robenzoyl)-3-nitrophenyl]-1,3-dioxo-2-isoindo1ineacetamido]methy1ene]-hydrazide;
1,3-dioxo-2-isoindo1ineacetic acid, [[N-[2-(m-f1uorobenzoyl)-3-fluoropheny1]-1,3-dioxo-2-isoindo1ineacetamido]methy1ene]- ~ -. hydrazide, 1,3-dioxo-2-isoindolineacetic acid, [~N-(2-benzoy1-3-ch10ro-phenyl)-1,3-dioxo-2-isoindolineacetamido]methy1eneJhydrazide;
1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(o-ch10robenzoy~-~-~tri~luoromethy1)pheny1]-1,3-dioxo-2-isoindo1ineacetamido]-methylene]hydrazide;
1,3-dioxo-2-Tsoindoltneacetic acid, ~[N-[2-~o-ch10robenzoy1)-6-chloro~henyl]-1,3-dloxo-2-isoindo1ineacetamido]methylene]-hydrazide;
1,3-dioxo-2-Tsoindolineacettc acid, ~N-(2-benzoy1-4-bromo-phenyl~-1,3-dioxo-2-isoindolineacetamido]methy1ene]hydrazlde;
1,3-dioxo-2-isoindolineacetic acld, [~N-(2-benzoy1phenyl)- `
. -13-~ 9~1 &
. . .
105~5V5 1,3-dioxo-2-isoindolineacetamido~methylene]hydrazide;
and the like.
Exa~ple 7 5-Chloro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone A stirred mixture of 1,3-dioxo-2-isoindolineacetic acid, [[N-(2-benzoyl-4-chlorophenyl)-1,3-dioxo-2-isoindoline-acetamido]methylene]hydrazide (8.o 9, 0.0123 mole) and tolùene (200 ml3 is treated with trifluoroacetic acid (0.9 ml) and heated to 100-110C for 1.5 hours. The mixture ~is concentrated in ~acuo, and the residue is mixed with cold water and chloroform and made alkaline with aqueous sodium hydroxide. This mixture is extracted with chloroform; the extract is washed with brine, dried o~er anhydrous sodium sulfate and concentrated. The residue is chromatographed ~5 on ~ilica gel (400 9) with 1.5~ methanol-98.5~ chloroform.
The product thus obtained is crystallized from methylene chloride-methanol to gi~e: 2.54 9, melting point 228-228.5C. and 0.361 9, melting poin~ 229-230C. (53% yield) of 5-chloro-2-[3-(phthali~idomethyl)-4H-1,2,4-triazol-4-yl]-benzophenone. The analytical sample has a melting point 229;5-230.5.
Anal. Calcd. for C24H~5ClN403:
C, 65.og; H, 3.41; Cl, 8.oo; N, 12.65.
Found: C, 65.01; H, 3.67; Cl, 8.01; N, 12.84.
Example 8 2',5-dlchloro-2-~3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone In the manner gi~en in Example 7, 1,3-dioxo-2-iso-tndolineacetic acld, ~tN-[2-(o-chlorobenzoyl)-4-chlorophenyl]-1,3-dioxo-2-tsoindolineacetamldo]methylene]hydraztde ts heat-ed to 100-110C wlth trtfluoroacetic acld to gl~e 2',5-dtchloro--~C36l e 105~905 ~-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]ben20phenone.
Example 9 2'-Chloro-5-nitro-2-[3-(phthalimidomethyl)~-4H-1,2,4-triazol-4-yl]benzophenone In the manner gi~en in Example 7, 1,3-dioxo-2-iso-indolineacetic acid, [~-[2-(o-chlorobenzoyl)-4~nitrophenyl]
1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide is heated to 100-110C with trifluoroacetic acid to gi~e 2'-chloro-5-nitro-2-[3-~phthalimidomethyl)-4H-1,2,4-triazol 4-yl]benzophenone.
Example 10 2',6'-Di~luoro-5-chloro-2-[3-(phthali~ido-methyl)-4H-1,2,4-triazol-4-yl]benzophenone In the manner gi~en in Example 7, 1,3-dioxo-2-iso-indolineacetic acid, [[N-[2-(2,6-difluorobenzoyl~-4-chloro-phenyl~-1,3-dioxo-2-isoindolineacetamido]methylene]hydra-zide is heated to 100-110 C. with trifluoroacetic acid to gi~e 2',6'-difluoro-5-chloro-2-[3-(phthalimidomethyl)-4H-1,2~4-triazol-4-yl]benzophenone.
ExamPle 11 2'-Chloro-5-fluoro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl~ben~ophenone In the manner gi~en in Example 7, 1,3-dioxo-2-iso--indolineacetic acid, ~[N-[2-(o-chlorobenzoyl)-4-fluoro-phenyl]-1,3-dioxo-2-isoindolineacetamido]methylene]hydra-zide is heated to 100-110C with trifluoroacetic acid to gl~e 2'-chloro-5-fluoro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Example 12 2'-Chloro-5-trifluoromethyl-2-[3-(phthalimido-~ethyl)-4H-1,2,4-triazol-4-yl]benzophenone In the manner gi~en in Example 7, 1,3-dioxo-2-isoin-dollneacetic acid, [[N-[2-(o-chlorobenzoyl)-4-(trifluoro-methyl)phenyl]-1,3-dioxo-2-isoindolineacetamido~methylene]-~9~1 ~
105~905 hydra~ide is heated to 100-110 C. with trifluoroacetic acid to give 2'-chloro-5-trifluoromethyl-2-[3-(phthalimido-methyl)-4H-1,2,4-triazol-4-yl]benzophenone.
In the manner ~i~en in Example 7 other 2-[3 -(phthal-imido~ethyl~4H-1,2,4-triazol-4-yl]benzophenones of formula III can be synthesized. Representati~e compounds thus obtained include:
5-chloro-2'-fluoro-2-[~-(phthali~idomethyl)-4H-1,2,4-tria~ol-4-yl~benzophenone;
.5-nitro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]-benzophenone;
5-trifluoromethyl-2-[3-(phthalimidomethyl3-4H-1,2,4-triazol-4-yl]benzophenone;
5-fluoro-2-[3-(phthalimidomethyl~-4H-1,2,4-triazol-4-yl3benzophenone;
6-nitro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophènone;
3'-bromo-5-chloro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
2'-bromo-4-nitro-2-[3-~phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
4'-bromo-3-fluoro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-~-yl]benzophenone;
2~,6'-difluoro-4-bromo-2-~3-(phthalimidomethyl)-4H-1,2,4-trtazol-4-yl~benzophenone;
4'-chloro-6-nltro-2-[3-(phthalimidomethyl)-4H-1,2,4-trtazol-4-yl]benzophenone;
3'~fluoro-6-fluoro-2-[3-(phthalimidomethyl)-4H-1,2,4-tr1azol-4-yl]benzophenone;
6-chloro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-2961E~
~ 5~9 ~ 5 yl]benzophenone;
2'-chloro-4~tri~luoromethyl-2-~3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
2'-chloro^3-chloro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
5-bromo-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]- -benzophenone;
2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]bPnzo-phenone;
and the like.
Example 13 5- Chloro-2-[3-[(dimethylamino)lnethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone A stirred solution of N,N,N',N'-tetramethyldiamino-methane (1.531 g, 0.015 mole) in dry di~ethylformamide (45 ml3 is cooled in an ice bath, under nitrogen~ and treated dropwise with freshly distilled acetyl chloride (1.06 ml, 0.015 mole). The resuiting suspension is allowed to warm to 25C. and stand for about 2 hours. 5-Chloro-2-[~-(phthalimidomethyl~-4H-1,2,4-triazol-4-yl]benzophenone (4.429 g, 0.01 mole) is added and the resulting mixture is kept at 50-54 C for 25 hours. It is then cooled and poured into cold water. The resulting solution is neutralized with sodium bicarbonate. The product which precipitates is collectèd by filtration, washed with water and dissol~e~
in methylene chloride. The methylene chloride solution is washed with water and brine, dried o~er anhydrous sodium sutfate and concentrated. The residuç is crystallized from ~ethylene chloride-methanol, decolorized with acti~ated carbon (Darco) to gi~e: 4.02 ~, melting point 206-207.5 C and 0.224 g. melti~g point 206-208.5 C of 5-chloro-2-105~05 ~3-[(dimethyla~ino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl~benzophenone. The analytical sample has a melting point 206.5-20~.5C.
Anal. Calcd, for C~7H22ClN503:
C, 64.87; H, 4.44; Cl, 7.09; N, 14.01.
Found: C, 64.51; H, 4.59; Cl, 7.17; N, 13.90.
Example 14 2',5-dichloro-2-[3-[(dimethylamino)methy!]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone In the manner gi~en in Example 13, N,N,N'~N'-tetra-methyldia~ino~ethane and acetyl chloride were reacted together in dimethylformamide to gi~e a suspension of dimethylmethyleneammonium chloride.
This suspension is reacted with 2',5-dichloro-2-t3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone to gi~e 2',5-dichloro-2-[3-[(dimethylamino)methyl]-5-~phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Example 15 2'-Chloro-5-nitro-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H--1,2,4-triazol-4-yl~benzophenone In the manner gi~en in Example 13, N,N,N',N'-tetra-methyldiamino~ethane and acetyl chloride were reacted together in dimethyrformamide to gi~e a suspension of d;methylmethyleneammonium chloride.
This suspension is reacted with 2'-chloro-5-nitro-2-[3-(phthalimidome~hy~)-4H-1,2,4-triazol-4-yl]benzophenone to gi~e 2'-chloro-5-nitro-2-[3-[(dimethylamino)methyl]-5-(phthali~idomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
`Example 16 2',6'-Difluoro-S-chloro-2-[3-[(dimethylamino~-methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzo-phenone tn the manner gi~en in Example 13, N,N,N',N'-tetra-29~1B
"
lOSl~OS
methyldia~inomethane and acetyl chloride were reacted together in di~ethylfor~amide to gi~e a suspension of dimethyl~ethyleneammoniurn chloride.
This suspension is reacted with 2',6'-difluoro-5-chloro-2-[~-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]-benzophenone to gi~e 2',6'-difluoro-5-chloro-2-[3-~(di-methylamino)~ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Exa~ple 17 2'-Chloro-5-fluoro 2-[3-[(dimethylamino)-methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]-benzophenone In the manner gi~en in Example 13, N,N,N',N'-tetra-methyldiaminomethane and acetyl chloride were reacted together in dimethylformamide to gi~e a suspension df dimethylmethyleneammonium chloride.
This suspension is reacted with 2~-chloro-5-fluoro-2-[3-(phth~limidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone to gi~e 2'-chloro-5-fluoro-2-~3-[(dimethylamino)methyl]-5-(phthalimidomethyl~)-4H-1,2,4-triazol-4-yl]benzophenone.
Example 18 2'-Chloro-5-trlfluoromethyl-2-[3-[(dimethyl-amino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone In the manner gi~en in Example 13, N,N,N',N'-tetra-methyldiaminomethane and acetyl chloride were reacted together in dimethylformamide to gi~e a suspension of dimethylmethyleneammonium chloride. '~
This suspension is reacted with 2'-chloro-5-trifluoro-methyl~2-[3-(phthalimidomethyl)-4H-i,2,4-triazol-4-yl]benzo-phenone to g;~e 2'-chloro-5-trifluoromethyl-2-[3-~dimethyl-amino3methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]-.
- 2~61~
, lOS1905 benzophenone.
In the manner gi~en in Example 13, other 2-~3-[(di-methylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenones of formula IV can be synthesized.
Representati~e compounds, thus obtained, include:
5-chloro-2'-~luoro-2-[3-[(dimethylamino)methyl]-5-(phthal-imidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
5-nitro-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
5-trifluoromethyl-2-[3-[(dimethylamino)methyl]-5-(phthal-imidomethyl)-4H-1,2~4-triazol-4-yl]benzophenone;
5-fluoro-2-~3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
6-nitro-2-[3-[(dimethylaminojmethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-y~]benzophenone;
3'-bromo-5-chloro-2-[3-[(dimethylamino)methyl]-5-(phthal-imidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
2'-bromo-4-nitro-2-[3-[(dimethylamino)methyl]-5-(phthal-i~idomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
4'-bromo-3-fluoro-2-[3-[(dimethylamino)methyl]-5-(phthal-tmidomethyl)-4H-1,2,4-triazol-4-yl3benzophenone;
21,6~-dtfluoro-4-bromo-2-[3-[(dimethylamino)methyl]-5-(phtha1imtdomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
4'-chloro-6-nitro-2-[3-~(dimethylamino)methyl]-5-(phtha!-imldomethyl)-4H-1,2,4-tr1azol-4-yl]benzophenone; -;
3'-fluoro-6-fluoro-2-~3-~(dimethylamino)methyl]-5-(phthal- i`
imldomethyl)-4H-1,2,4-trlazol-4-yl]benzophenone; .
.6-chloro-2-[3-~(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophe.none;
30 2~-chloro-4-trifluoromethyl-2-~3-~(dimethylamino)methyl3-5-. 20 ~0 ~9 ~ 5 (phth~limidomethyl)-4H-1,2,4-triazdl-4-yl]benzophenone;
2l-chloro-~-chloro-2-[3-[(dimethyl~mino)methyl]-5-(phthal-I~idomethyl)-4H-1,2,4-triazol-4-yl~benzophenone;
5-bromo-2-[3-[(dimethylamino)methyl]-5-~phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
and the like.
ExamDle 19 5-Chloro-2-[3-[(diethylamino)methyl]-5-(phthal-;midomethyl)-4H-1,2,4-triazol-4-yl]benzophenone N,N,N',N'-tetraethyldiaminomethane and acetyl chloride in dimethylformamide were reacted together to gi~e a suspen-sion of N,N-diethylmethyleneammonium chloride.
In the manner gi~en in Example 1~, 5-chloro-2-[3-(phthalimidomethyl)-4H-1,2,4-friazol-4-yl]benzophenone is reacted with the abo~e suspension, then neutralized with sodium bicarbonate to ~i~e 5-chloro-2-[3-[(diethylamino)-~ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzo-phenone.
ExamPle 20 2',5-Dichloro-2-[3-[(ethylmethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone N,N'-dimethyl-N,N'-diethyldiaminomethane and acetyl chloride In dimethylformamide were reacted together to gi~e ` a suspension of N-methyl-N-ethyl-methyleneammonium chloride.
In the manner gi~en in Example 13, 21,5-dichloro-2-~3-(phthalimidomethyl)-4H-1,2,4-trlazol-4-yl]benzophenone is reacted wTth the abo~e suspension, then neutraliz-ed wTth-sodium blcarbonate to g he 2',5-dichloro-2-[3-~(ethyl-methylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-trlazol-4-yl]benzophenone.
2961~
.
Example 21 5-Chloro-2-[3-[(dipropylamino~methyl]-5-(phthal-imidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone N,N,N',N'-tetrapropyldiaminomethane and acetyl chloride in dimethylfonnamide were reacted together to gi~e a suspen-sion o~ N,N-dipropylmethyleneammonium chloride.
- In the manner gi~en in Example 13,. 5-chloro-2-[3-(phtha1imidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is reacted with the above suspension then neutralized with sodium bicarbonate to gi~e 5-chloro-2-[3-[(dipropylamino)-.methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]-benzophenone.
ExamD!e 22 2',5-Dichloro-2-~3-[(diisopropylamino)methy~]-5-(phthalimidomethylJ-4H-1,2,4-triazol-4-yl]benzophenone N,N,N',N'-Tetraisopropyldiaminomethane and acetyl chloride in dimethylfo ~amide were reacted together to .
gi~e a suspension of di-isopropylmethyleneammonium chloride.
In the manner gi~en in Example 13, 2',5-dichloro-2-:
~-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is reacted with the abo~e suspension then neutralized with sodium bicarbonate to gi~e 2',5-dichloro-2-[3-[(diisopropyl-amino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]-benzophenone.
i~amPle 23 2'-Chloro-5-nitro-2-[3-(pyrrolidinomethyl)-5-(phthalimidomethyl)-4H-1,2,4-triazol-~-yl]benzophenone Dipyrrolidinomethane and acetyl chloride in dimethyl-fonnamide were reacted together to gi~e-a-suspension of 1-methylenepyrrolidinium chloride.
In the manner gi~en in Example 13, 2'-chloro-5-nitro-2-~3-~phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone Is reacted with the abo~e suspension theh neutralized with 105~9~5 sodlum bicarbonate to gi~e 2l-chloro-5-nitro-2-~-(pyrrolidin methyl)-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzo-phenone.
Example 24 2'-Chloro-5-trifluoromethyl-2-[3-(piperidlno-methyl)-5-(phthalimido~ethyl)-4H-1,2,4-triazol 4-yl]benzo-phenone Dipiperidino~ethane and acetyl chloride in dimethyl-forma~ide are reacted together to gi~e a suspension of 1-methy!enepiperidinium chloride.
In the manner gi~en in Example 13~ 2'-chloro-5-tri-fluoromethyl-2-[3-(phthalimidomethyl)-4H-1,2,4~triazol-4-yl]benzophenone is reacted with the abo~e suspension then neutralized with sodium bicarbonate to gi~e 2'-chloro-5-trifluoromethyl-2-~3-(piperidinonethyl)-5-(phthalimidomethyl~-4H-1,2,4-triazol-4-yl]benzophenone.
Example 2~ 21,5-dichloro-2-~3- [~4-mèthylpiperazino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone Bis(4-methylpiperazino)methane and acetyl chloride in dimethylformamide are reacted together to gi~e a suspension of ~-methyl-l-methylenepiperazinlum chloride.
In the manner gi~en in Example 13, 2',5-dichloro-2-~3-(phthalimidomethyl)-4H-1j2,4-triazol-4-yl]benzophenone Is reacted with the abo~e suspension then neutralized with sodtum blcarbonate to give 2',`5-dichloro-2-[3-[(4-methyl-ptperaztno)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl~benzophenone.
ExamDle 26 2',5-Dichloro-2-~3-(morpholinomethyl)-5-(phthalimTdomethyl)-4H-1,2,4-triazol-4-yl]benzophenone D1morpholinomethane and-acetyl chloride 1n dlmethyl-formamlde were reacted together to gt~e ~ suspenslon of 1 0 51 ~ ~ 5 4-methylenemorphollniu~ chloride.
In the manner gi~en in Example 13, 2',5-dichloro-2-[3-(phthalimidomethyl)-4H-1,2,4-tria~ol-4-yl~benzophenone Is reacted wlth the abo~e suspension then neutralized with sodium bicarbonate to gi~e 2',5-dichloro-2-[~-(morpholino-methyl)-5-tphthalimidomethylJ-4H-1,2,4-triazol-4 yl]-benzophenone.
Example 27 8-Chloro-1-[(dlmethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine `10 A stirred suspension of 5-chloro-2-[3-[(dimethylamino)- "
methyl]-5 (phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzo-phenone (1.0 9, 0.002 mole) in absolute ethanol (10 ml) is treated with hydrazine hydrate (0.145 ml, 0.003 mole) and warmed in a bath at 70-77C for 2 hours. As the reaction progressed the starting material dissol~es and a second solid precipitates. The mixture is cooled and filtered. The solid is washed with ethanol and methylene chloride and the com-bined filtrate is concentrated'. The residue is mixed with water and extracted with methylene chlorlde. The extract ~20 is washed with brine, dried o~er anhydrous sodium sulfate and concentrated. The residue is dissol~ed in ethyl acetate, flltered through a small pad of sillca gel and crystallized from ethyl acetate-Skellysol~e B hexanes to gi~e in two crops 0.365 9, melting point 171.5-174 and o.o78 9, mel`t-Ing point 170.5-174 of 8-chloro-1-~(dimethylamino)methy:l]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Exa~le 28 8-Chloro-1-~(dimethylamino)methyl]-6-(o-chloro-phenyl)-4H-s-triazolo[4~3-a]~l~4]benzodiazeplne In the manner gi~en in Example 27, 2',5-dichloro-2-~30 ~3-[(dimethylamino)methyl]-5-(phthallmidomethyl)-4H-1,2,4-.
- 29~1 triazol-~-ylJbenzophcnone is heated in ethanol with hydra-zine hydrate to gi~e 8-chloro-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]~1,4]benzo~iazepine.
Example 29 8-Nitro-1-[(dimethylamino)methyl]-6-(o-chloro-phenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner ~i~en in Exa~ple 27, 2'-chloro-5-nitro-2-[3-[(dimethylamino~methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydra-zine hydrate to gi~e 8-nitro-1-[(dimethylamino)methyl]-6-(o-chlorophenylr4H-s-triazolo[4~3-a][1~4]benzodiazepine~
Exa~ple 30 8-Trifluoromethyl-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner gi~en in Examp.le 27, 2'-chloro-5-(tri-fluoromethyl?-2-[3-[(dimethylamino)methyl]-5-(phthalimido-methyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to gi~e 8-trifluoromethyl-1-r(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo-t4,3-a][1,4]benzodiazepine.
Example 31 8-Fluoro-1-[(di~ethylamino)methyl]-6-(o-chloro-phenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner gi~en in Example 27, 2'-chloro-5-fluoro-2-[3-~(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydra-zine hydrate to g;~e 8-fluoro-1-[(dimethylamino)methyl]-6 (o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Example ~? 8-Chloro-1-[(dimethylamino)methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner gi~en in Example 27, 2',6'-difluoro-5-chloro-2-[3-[(di~ethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol . -25-2 ~
lOSl~OS
with hydrazin~ hydrate to gi~e 8-chloro-1-[(dimethylamino)-methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Exa~ple ~'~ 8-Chloro-1-[(diethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner gi~en in Exa~ple 27, 5-chloro-2-[3-[(diethylamino)methyl]-5-(phthalimidomethyl3-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydra-zine hydrate to gi~e 8-chloro-1-[(diethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Example ~4 8-Chloro-1-[(ethylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo~4,3-a][1,4]benzodiazepine ' In the' manner gi~en in Example 27, 2',5-dichloro-2-[~-[(ethylmethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazolo-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to gi~e 8-chloro-1-[(ethylmethylamino)-methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4~benzo-diazepine.
Examp!e 35 8-Chloro-1-[(dipropylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner gi~en in Example 27, 5-chloro-2-[3-[(dipropylamino)methyl]-5-(phthalimidomethyl')-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydra-zine hydrate to gi~e 8-chloro-1-[(dipropylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Example ~6 8-Chloro-1-[(diisopropylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner gi~en in Example 27, 2',5-dichloro-2-~-[(di;sopropylamino)methyl]-5-(phthalimidomethyl)-4H-1~2,4-triazol-4-yl]benzophenone is heated in ethanol with ..
~OSl90S
hydrazine hydrate to gi~e 8 chloro-1-[~diisopropylamino)-~ethylJ-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzo-dia7epine.
Example ~7 8-Nitro-l-(pyrrolidinomethyl)-~-(o-chlorophen~l)-4H-s-triazoio~4,3-a][1,4]benzodiazepine In the manner gi~en in Example 27~ 2'-chloro-5-nitro-2-~3 (pyrrolidinomethyl)-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydra-z;ne hydrate to gi~e 8-nitro-1-(pyrrolidinomethy?)-6-(o-chlorophenyl3-4H-s-triazolo[4,3-a][1~4]benzodiazepine.
ExamDle 38 8-Trifluoromethyl-1-(piperidinomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner gi~en in Example 27, 2'-chloro-5-tri-fluoromethyl-2-~3-(piperidinomethyl)-5-(phthalimidomethyl)-4H-1,2,4-tr;azol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to gi~e 8-trifluoromethyl-1-(piper-idinomet~yl)-6-(o-chlorophenyl)-4H-s-triazolo[4~3-a][1,4J-benzodiazepine.
Example ~9 8-Chloro-1-[(4-methylpiperazino3methyl]-6-(o- -chlorophenyl)-4H-s-triazolo[4,~-a][1,4]benzodiazepine In the manner gi~en in Example 27, 2',5-diçhloro-2-~3-~(4-methylpiperazino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hy~razine hydrate to gi~e 8-chloro-1-[(4-methylpiper-azino~methyl~-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a~[1s4]-benzodiazepine.
Example 40 8-~hloro-1-(morpholinomethyl)-6-(o-chlorophenyl)-4H-s-triazolo~4,3-a~1,4]benzodiazepine In the ~.anner gi~en in Example 27, 21,5-dichloro-2-t3-(morpholinomethyl)-5-(phtha!imidomethyl)-4H-1,2,4-tria~ol-~27-4-yl3benzophenone is heated in ethanol with hydrazine hydrate to gi~e 8-chloro-1-(morpholinomethyl)-6-(o-chloro-phenyl)-4H-s-tria~olo[4J3-a][1,4]benzodiazepine.
In the ~anner gi~en in Example 27, other 1-aminomethyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines (V) can be synthesized from the corresponding 2-~3-(aminomethyl)-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenones.
Representati~e compounds, thus obtained, include:
8-chloro-1-[(dimethylamino)methyl]-6-(o-~luorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine;
8-nitro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine;
8-trifluoromethyl-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine;
8-fluoro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo-~4,3-a]~1,4]benzodiazepine;
1,3-dioxo-2-isoindolineacetic acid, [[N-[2-~2,6-difluoro-. benzoyl)-5-bromophenyl]-1,3-dioxo-2-isoindo1ineacetamido]-methylene]hydrazide;
1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(p-ch10robenzoyl)-3-nitrophenyl]-1,3-dioxo-2-isoindo1ineacetamido]methy1ene]-hydrazide;
1,3-dioxo-2-isoindo1ineacetic acid, [[N-[2-(m-f1uorobenzoyl)-3-fluoropheny1]-1,3-dioxo-2-isoindo1ineacetamido]methy1ene]- ~ -. hydrazide, 1,3-dioxo-2-isoindolineacetic acid, [~N-(2-benzoy1-3-ch10ro-phenyl)-1,3-dioxo-2-isoindolineacetamido]methy1eneJhydrazide;
1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(o-ch10robenzoy~-~-~tri~luoromethy1)pheny1]-1,3-dioxo-2-isoindo1ineacetamido]-methylene]hydrazide;
1,3-dioxo-2-Tsoindoltneacetic acid, ~[N-[2-~o-ch10robenzoy1)-6-chloro~henyl]-1,3-dloxo-2-isoindo1ineacetamido]methylene]-hydrazide;
1,3-dioxo-2-Tsoindolineacettc acid, ~N-(2-benzoy1-4-bromo-phenyl~-1,3-dioxo-2-isoindolineacetamido]methy1ene]hydrazlde;
1,3-dioxo-2-isoindolineacetic acld, [~N-(2-benzoy1phenyl)- `
. -13-~ 9~1 &
. . .
105~5V5 1,3-dioxo-2-isoindolineacetamido~methylene]hydrazide;
and the like.
Exa~ple 7 5-Chloro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone A stirred mixture of 1,3-dioxo-2-isoindolineacetic acid, [[N-(2-benzoyl-4-chlorophenyl)-1,3-dioxo-2-isoindoline-acetamido]methylene]hydrazide (8.o 9, 0.0123 mole) and tolùene (200 ml3 is treated with trifluoroacetic acid (0.9 ml) and heated to 100-110C for 1.5 hours. The mixture ~is concentrated in ~acuo, and the residue is mixed with cold water and chloroform and made alkaline with aqueous sodium hydroxide. This mixture is extracted with chloroform; the extract is washed with brine, dried o~er anhydrous sodium sulfate and concentrated. The residue is chromatographed ~5 on ~ilica gel (400 9) with 1.5~ methanol-98.5~ chloroform.
The product thus obtained is crystallized from methylene chloride-methanol to gi~e: 2.54 9, melting point 228-228.5C. and 0.361 9, melting poin~ 229-230C. (53% yield) of 5-chloro-2-[3-(phthali~idomethyl)-4H-1,2,4-triazol-4-yl]-benzophenone. The analytical sample has a melting point 229;5-230.5.
Anal. Calcd. for C24H~5ClN403:
C, 65.og; H, 3.41; Cl, 8.oo; N, 12.65.
Found: C, 65.01; H, 3.67; Cl, 8.01; N, 12.84.
Example 8 2',5-dlchloro-2-~3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone In the manner gi~en in Example 7, 1,3-dioxo-2-iso-tndolineacetic acld, ~tN-[2-(o-chlorobenzoyl)-4-chlorophenyl]-1,3-dioxo-2-tsoindolineacetamldo]methylene]hydraztde ts heat-ed to 100-110C wlth trtfluoroacetic acld to gl~e 2',5-dtchloro--~C36l e 105~905 ~-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]ben20phenone.
Example 9 2'-Chloro-5-nitro-2-[3-(phthalimidomethyl)~-4H-1,2,4-triazol-4-yl]benzophenone In the manner gi~en in Example 7, 1,3-dioxo-2-iso-indolineacetic acid, [~-[2-(o-chlorobenzoyl)-4~nitrophenyl]
1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide is heated to 100-110C with trifluoroacetic acid to gi~e 2'-chloro-5-nitro-2-[3-~phthalimidomethyl)-4H-1,2,4-triazol 4-yl]benzophenone.
Example 10 2',6'-Di~luoro-5-chloro-2-[3-(phthali~ido-methyl)-4H-1,2,4-triazol-4-yl]benzophenone In the manner gi~en in Example 7, 1,3-dioxo-2-iso-indolineacetic acid, [[N-[2-(2,6-difluorobenzoyl~-4-chloro-phenyl~-1,3-dioxo-2-isoindolineacetamido]methylene]hydra-zide is heated to 100-110 C. with trifluoroacetic acid to gi~e 2',6'-difluoro-5-chloro-2-[3-(phthalimidomethyl)-4H-1,2~4-triazol-4-yl]benzophenone.
ExamPle 11 2'-Chloro-5-fluoro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl~ben~ophenone In the manner gi~en in Example 7, 1,3-dioxo-2-iso--indolineacetic acid, ~[N-[2-(o-chlorobenzoyl)-4-fluoro-phenyl]-1,3-dioxo-2-isoindolineacetamido]methylene]hydra-zide is heated to 100-110C with trifluoroacetic acid to gl~e 2'-chloro-5-fluoro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Example 12 2'-Chloro-5-trifluoromethyl-2-[3-(phthalimido-~ethyl)-4H-1,2,4-triazol-4-yl]benzophenone In the manner gi~en in Example 7, 1,3-dioxo-2-isoin-dollneacetic acid, [[N-[2-(o-chlorobenzoyl)-4-(trifluoro-methyl)phenyl]-1,3-dioxo-2-isoindolineacetamido~methylene]-~9~1 ~
105~905 hydra~ide is heated to 100-110 C. with trifluoroacetic acid to give 2'-chloro-5-trifluoromethyl-2-[3-(phthalimido-methyl)-4H-1,2,4-triazol-4-yl]benzophenone.
In the manner ~i~en in Example 7 other 2-[3 -(phthal-imido~ethyl~4H-1,2,4-triazol-4-yl]benzophenones of formula III can be synthesized. Representati~e compounds thus obtained include:
5-chloro-2'-fluoro-2-[~-(phthali~idomethyl)-4H-1,2,4-tria~ol-4-yl~benzophenone;
.5-nitro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]-benzophenone;
5-trifluoromethyl-2-[3-(phthalimidomethyl3-4H-1,2,4-triazol-4-yl]benzophenone;
5-fluoro-2-[3-(phthalimidomethyl~-4H-1,2,4-triazol-4-yl3benzophenone;
6-nitro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophènone;
3'-bromo-5-chloro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
2'-bromo-4-nitro-2-[3-~phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
4'-bromo-3-fluoro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-~-yl]benzophenone;
2~,6'-difluoro-4-bromo-2-~3-(phthalimidomethyl)-4H-1,2,4-trtazol-4-yl~benzophenone;
4'-chloro-6-nltro-2-[3-(phthalimidomethyl)-4H-1,2,4-trtazol-4-yl]benzophenone;
3'~fluoro-6-fluoro-2-[3-(phthalimidomethyl)-4H-1,2,4-tr1azol-4-yl]benzophenone;
6-chloro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-2961E~
~ 5~9 ~ 5 yl]benzophenone;
2'-chloro-4~tri~luoromethyl-2-~3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
2'-chloro^3-chloro-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
5-bromo-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]- -benzophenone;
2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]bPnzo-phenone;
and the like.
Example 13 5- Chloro-2-[3-[(dimethylamino)lnethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone A stirred solution of N,N,N',N'-tetramethyldiamino-methane (1.531 g, 0.015 mole) in dry di~ethylformamide (45 ml3 is cooled in an ice bath, under nitrogen~ and treated dropwise with freshly distilled acetyl chloride (1.06 ml, 0.015 mole). The resuiting suspension is allowed to warm to 25C. and stand for about 2 hours. 5-Chloro-2-[~-(phthalimidomethyl~-4H-1,2,4-triazol-4-yl]benzophenone (4.429 g, 0.01 mole) is added and the resulting mixture is kept at 50-54 C for 25 hours. It is then cooled and poured into cold water. The resulting solution is neutralized with sodium bicarbonate. The product which precipitates is collectèd by filtration, washed with water and dissol~e~
in methylene chloride. The methylene chloride solution is washed with water and brine, dried o~er anhydrous sodium sutfate and concentrated. The residuç is crystallized from ~ethylene chloride-methanol, decolorized with acti~ated carbon (Darco) to gi~e: 4.02 ~, melting point 206-207.5 C and 0.224 g. melti~g point 206-208.5 C of 5-chloro-2-105~05 ~3-[(dimethyla~ino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl~benzophenone. The analytical sample has a melting point 206.5-20~.5C.
Anal. Calcd, for C~7H22ClN503:
C, 64.87; H, 4.44; Cl, 7.09; N, 14.01.
Found: C, 64.51; H, 4.59; Cl, 7.17; N, 13.90.
Example 14 2',5-dichloro-2-[3-[(dimethylamino)methy!]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone In the manner gi~en in Example 13, N,N,N'~N'-tetra-methyldia~ino~ethane and acetyl chloride were reacted together in dimethylformamide to gi~e a suspension of dimethylmethyleneammonium chloride.
This suspension is reacted with 2',5-dichloro-2-t3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone to gi~e 2',5-dichloro-2-[3-[(dimethylamino)methyl]-5-~phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Example 15 2'-Chloro-5-nitro-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H--1,2,4-triazol-4-yl~benzophenone In the manner gi~en in Example 13, N,N,N',N'-tetra-methyldiamino~ethane and acetyl chloride were reacted together in dimethyrformamide to gi~e a suspension of d;methylmethyleneammonium chloride.
This suspension is reacted with 2'-chloro-5-nitro-2-[3-(phthalimidome~hy~)-4H-1,2,4-triazol-4-yl]benzophenone to gi~e 2'-chloro-5-nitro-2-[3-[(dimethylamino)methyl]-5-(phthali~idomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
`Example 16 2',6'-Difluoro-S-chloro-2-[3-[(dimethylamino~-methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzo-phenone tn the manner gi~en in Example 13, N,N,N',N'-tetra-29~1B
"
lOSl~OS
methyldia~inomethane and acetyl chloride were reacted together in di~ethylfor~amide to gi~e a suspension of dimethyl~ethyleneammoniurn chloride.
This suspension is reacted with 2',6'-difluoro-5-chloro-2-[~-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]-benzophenone to gi~e 2',6'-difluoro-5-chloro-2-[3-~(di-methylamino)~ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Exa~ple 17 2'-Chloro-5-fluoro 2-[3-[(dimethylamino)-methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]-benzophenone In the manner gi~en in Example 13, N,N,N',N'-tetra-methyldiaminomethane and acetyl chloride were reacted together in dimethylformamide to gi~e a suspension df dimethylmethyleneammonium chloride.
This suspension is reacted with 2~-chloro-5-fluoro-2-[3-(phth~limidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone to gi~e 2'-chloro-5-fluoro-2-~3-[(dimethylamino)methyl]-5-(phthalimidomethyl~)-4H-1,2,4-triazol-4-yl]benzophenone.
Example 18 2'-Chloro-5-trlfluoromethyl-2-[3-[(dimethyl-amino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone In the manner gi~en in Example 13, N,N,N',N'-tetra-methyldiaminomethane and acetyl chloride were reacted together in dimethylformamide to gi~e a suspension of dimethylmethyleneammonium chloride. '~
This suspension is reacted with 2'-chloro-5-trifluoro-methyl~2-[3-(phthalimidomethyl)-4H-i,2,4-triazol-4-yl]benzo-phenone to g;~e 2'-chloro-5-trifluoromethyl-2-[3-~dimethyl-amino3methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]-.
- 2~61~
, lOS1905 benzophenone.
In the manner gi~en in Example 13, other 2-~3-[(di-methylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenones of formula IV can be synthesized.
Representati~e compounds, thus obtained, include:
5-chloro-2'-~luoro-2-[3-[(dimethylamino)methyl]-5-(phthal-imidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
5-nitro-2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
5-trifluoromethyl-2-[3-[(dimethylamino)methyl]-5-(phthal-imidomethyl)-4H-1,2~4-triazol-4-yl]benzophenone;
5-fluoro-2-~3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
6-nitro-2-[3-[(dimethylaminojmethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-y~]benzophenone;
3'-bromo-5-chloro-2-[3-[(dimethylamino)methyl]-5-(phthal-imidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
2'-bromo-4-nitro-2-[3-[(dimethylamino)methyl]-5-(phthal-i~idomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
4'-bromo-3-fluoro-2-[3-[(dimethylamino)methyl]-5-(phthal-tmidomethyl)-4H-1,2,4-triazol-4-yl3benzophenone;
21,6~-dtfluoro-4-bromo-2-[3-[(dimethylamino)methyl]-5-(phtha1imtdomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
4'-chloro-6-nitro-2-[3-~(dimethylamino)methyl]-5-(phtha!-imldomethyl)-4H-1,2,4-tr1azol-4-yl]benzophenone; -;
3'-fluoro-6-fluoro-2-~3-~(dimethylamino)methyl]-5-(phthal- i`
imldomethyl)-4H-1,2,4-trlazol-4-yl]benzophenone; .
.6-chloro-2-[3-~(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophe.none;
30 2~-chloro-4-trifluoromethyl-2-~3-~(dimethylamino)methyl3-5-. 20 ~0 ~9 ~ 5 (phth~limidomethyl)-4H-1,2,4-triazdl-4-yl]benzophenone;
2l-chloro-~-chloro-2-[3-[(dimethyl~mino)methyl]-5-(phthal-I~idomethyl)-4H-1,2,4-triazol-4-yl~benzophenone;
5-bromo-2-[3-[(dimethylamino)methyl]-5-~phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone;
and the like.
ExamDle 19 5-Chloro-2-[3-[(diethylamino)methyl]-5-(phthal-;midomethyl)-4H-1,2,4-triazol-4-yl]benzophenone N,N,N',N'-tetraethyldiaminomethane and acetyl chloride in dimethylformamide were reacted together to gi~e a suspen-sion of N,N-diethylmethyleneammonium chloride.
In the manner gi~en in Example 1~, 5-chloro-2-[3-(phthalimidomethyl)-4H-1,2,4-friazol-4-yl]benzophenone is reacted with the abo~e suspension, then neutralized with sodium bicarbonate to ~i~e 5-chloro-2-[3-[(diethylamino)-~ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzo-phenone.
ExamPle 20 2',5-Dichloro-2-[3-[(ethylmethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone N,N'-dimethyl-N,N'-diethyldiaminomethane and acetyl chloride In dimethylformamide were reacted together to gi~e ` a suspension of N-methyl-N-ethyl-methyleneammonium chloride.
In the manner gi~en in Example 13, 21,5-dichloro-2-~3-(phthalimidomethyl)-4H-1,2,4-trlazol-4-yl]benzophenone is reacted wTth the abo~e suspension, then neutraliz-ed wTth-sodium blcarbonate to g he 2',5-dichloro-2-[3-~(ethyl-methylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-trlazol-4-yl]benzophenone.
2961~
.
Example 21 5-Chloro-2-[3-[(dipropylamino~methyl]-5-(phthal-imidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone N,N,N',N'-tetrapropyldiaminomethane and acetyl chloride in dimethylfonnamide were reacted together to gi~e a suspen-sion o~ N,N-dipropylmethyleneammonium chloride.
- In the manner gi~en in Example 13,. 5-chloro-2-[3-(phtha1imidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is reacted with the above suspension then neutralized with sodium bicarbonate to gi~e 5-chloro-2-[3-[(dipropylamino)-.methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]-benzophenone.
ExamD!e 22 2',5-Dichloro-2-~3-[(diisopropylamino)methy~]-5-(phthalimidomethylJ-4H-1,2,4-triazol-4-yl]benzophenone N,N,N',N'-Tetraisopropyldiaminomethane and acetyl chloride in dimethylfo ~amide were reacted together to .
gi~e a suspension of di-isopropylmethyleneammonium chloride.
In the manner gi~en in Example 13, 2',5-dichloro-2-:
~-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is reacted with the abo~e suspension then neutralized with sodium bicarbonate to gi~e 2',5-dichloro-2-[3-[(diisopropyl-amino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]-benzophenone.
i~amPle 23 2'-Chloro-5-nitro-2-[3-(pyrrolidinomethyl)-5-(phthalimidomethyl)-4H-1,2,4-triazol-~-yl]benzophenone Dipyrrolidinomethane and acetyl chloride in dimethyl-fonnamide were reacted together to gi~e-a-suspension of 1-methylenepyrrolidinium chloride.
In the manner gi~en in Example 13, 2'-chloro-5-nitro-2-~3-~phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone Is reacted with the abo~e suspension theh neutralized with 105~9~5 sodlum bicarbonate to gi~e 2l-chloro-5-nitro-2-~-(pyrrolidin methyl)-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzo-phenone.
Example 24 2'-Chloro-5-trifluoromethyl-2-[3-(piperidlno-methyl)-5-(phthalimido~ethyl)-4H-1,2,4-triazol 4-yl]benzo-phenone Dipiperidino~ethane and acetyl chloride in dimethyl-forma~ide are reacted together to gi~e a suspension of 1-methy!enepiperidinium chloride.
In the manner gi~en in Example 13~ 2'-chloro-5-tri-fluoromethyl-2-[3-(phthalimidomethyl)-4H-1,2,4~triazol-4-yl]benzophenone is reacted with the abo~e suspension then neutralized with sodium bicarbonate to gi~e 2'-chloro-5-trifluoromethyl-2-~3-(piperidinonethyl)-5-(phthalimidomethyl~-4H-1,2,4-triazol-4-yl]benzophenone.
Example 2~ 21,5-dichloro-2-~3- [~4-mèthylpiperazino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone Bis(4-methylpiperazino)methane and acetyl chloride in dimethylformamide are reacted together to gi~e a suspension of ~-methyl-l-methylenepiperazinlum chloride.
In the manner gi~en in Example 13, 2',5-dichloro-2-~3-(phthalimidomethyl)-4H-1j2,4-triazol-4-yl]benzophenone Is reacted with the abo~e suspension then neutralized with sodtum blcarbonate to give 2',`5-dichloro-2-[3-[(4-methyl-ptperaztno)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl~benzophenone.
ExamDle 26 2',5-Dichloro-2-~3-(morpholinomethyl)-5-(phthalimTdomethyl)-4H-1,2,4-triazol-4-yl]benzophenone D1morpholinomethane and-acetyl chloride 1n dlmethyl-formamlde were reacted together to gt~e ~ suspenslon of 1 0 51 ~ ~ 5 4-methylenemorphollniu~ chloride.
In the manner gi~en in Example 13, 2',5-dichloro-2-[3-(phthalimidomethyl)-4H-1,2,4-tria~ol-4-yl~benzophenone Is reacted wlth the abo~e suspension then neutralized with sodium bicarbonate to gi~e 2',5-dichloro-2-[~-(morpholino-methyl)-5-tphthalimidomethylJ-4H-1,2,4-triazol-4 yl]-benzophenone.
Example 27 8-Chloro-1-[(dlmethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine `10 A stirred suspension of 5-chloro-2-[3-[(dimethylamino)- "
methyl]-5 (phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzo-phenone (1.0 9, 0.002 mole) in absolute ethanol (10 ml) is treated with hydrazine hydrate (0.145 ml, 0.003 mole) and warmed in a bath at 70-77C for 2 hours. As the reaction progressed the starting material dissol~es and a second solid precipitates. The mixture is cooled and filtered. The solid is washed with ethanol and methylene chloride and the com-bined filtrate is concentrated'. The residue is mixed with water and extracted with methylene chlorlde. The extract ~20 is washed with brine, dried o~er anhydrous sodium sulfate and concentrated. The residue is dissol~ed in ethyl acetate, flltered through a small pad of sillca gel and crystallized from ethyl acetate-Skellysol~e B hexanes to gi~e in two crops 0.365 9, melting point 171.5-174 and o.o78 9, mel`t-Ing point 170.5-174 of 8-chloro-1-~(dimethylamino)methy:l]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Exa~le 28 8-Chloro-1-~(dimethylamino)methyl]-6-(o-chloro-phenyl)-4H-s-triazolo[4~3-a]~l~4]benzodiazeplne In the manner gi~en in Example 27, 2',5-dichloro-2-~30 ~3-[(dimethylamino)methyl]-5-(phthallmidomethyl)-4H-1,2,4-.
- 29~1 triazol-~-ylJbenzophcnone is heated in ethanol with hydra-zine hydrate to gi~e 8-chloro-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]~1,4]benzo~iazepine.
Example 29 8-Nitro-1-[(dimethylamino)methyl]-6-(o-chloro-phenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner ~i~en in Exa~ple 27, 2'-chloro-5-nitro-2-[3-[(dimethylamino~methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydra-zine hydrate to gi~e 8-nitro-1-[(dimethylamino)methyl]-6-(o-chlorophenylr4H-s-triazolo[4~3-a][1~4]benzodiazepine~
Exa~ple 30 8-Trifluoromethyl-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner gi~en in Examp.le 27, 2'-chloro-5-(tri-fluoromethyl?-2-[3-[(dimethylamino)methyl]-5-(phthalimido-methyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to gi~e 8-trifluoromethyl-1-r(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo-t4,3-a][1,4]benzodiazepine.
Example 31 8-Fluoro-1-[(di~ethylamino)methyl]-6-(o-chloro-phenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner gi~en in Example 27, 2'-chloro-5-fluoro-2-[3-~(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydra-zine hydrate to g;~e 8-fluoro-1-[(dimethylamino)methyl]-6 (o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Example ~? 8-Chloro-1-[(dimethylamino)methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner gi~en in Example 27, 2',6'-difluoro-5-chloro-2-[3-[(di~ethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol . -25-2 ~
lOSl~OS
with hydrazin~ hydrate to gi~e 8-chloro-1-[(dimethylamino)-methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Exa~ple ~'~ 8-Chloro-1-[(diethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner gi~en in Exa~ple 27, 5-chloro-2-[3-[(diethylamino)methyl]-5-(phthalimidomethyl3-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydra-zine hydrate to gi~e 8-chloro-1-[(diethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Example ~4 8-Chloro-1-[(ethylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo~4,3-a][1,4]benzodiazepine ' In the' manner gi~en in Example 27, 2',5-dichloro-2-[~-[(ethylmethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazolo-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to gi~e 8-chloro-1-[(ethylmethylamino)-methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4~benzo-diazepine.
Examp!e 35 8-Chloro-1-[(dipropylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner gi~en in Example 27, 5-chloro-2-[3-[(dipropylamino)methyl]-5-(phthalimidomethyl')-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydra-zine hydrate to gi~e 8-chloro-1-[(dipropylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Example ~6 8-Chloro-1-[(diisopropylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner gi~en in Example 27, 2',5-dichloro-2-~-[(di;sopropylamino)methyl]-5-(phthalimidomethyl)-4H-1~2,4-triazol-4-yl]benzophenone is heated in ethanol with ..
~OSl90S
hydrazine hydrate to gi~e 8 chloro-1-[~diisopropylamino)-~ethylJ-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzo-dia7epine.
Example ~7 8-Nitro-l-(pyrrolidinomethyl)-~-(o-chlorophen~l)-4H-s-triazoio~4,3-a][1,4]benzodiazepine In the manner gi~en in Example 27~ 2'-chloro-5-nitro-2-~3 (pyrrolidinomethyl)-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydra-z;ne hydrate to gi~e 8-nitro-1-(pyrrolidinomethy?)-6-(o-chlorophenyl3-4H-s-triazolo[4,3-a][1~4]benzodiazepine.
ExamDle 38 8-Trifluoromethyl-1-(piperidinomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine In the manner gi~en in Example 27, 2'-chloro-5-tri-fluoromethyl-2-~3-(piperidinomethyl)-5-(phthalimidomethyl)-4H-1,2,4-tr;azol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to gi~e 8-trifluoromethyl-1-(piper-idinomet~yl)-6-(o-chlorophenyl)-4H-s-triazolo[4~3-a][1,4J-benzodiazepine.
Example ~9 8-Chloro-1-[(4-methylpiperazino3methyl]-6-(o- -chlorophenyl)-4H-s-triazolo[4,~-a][1,4]benzodiazepine In the manner gi~en in Example 27, 2',5-diçhloro-2-~3-~(4-methylpiperazino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hy~razine hydrate to gi~e 8-chloro-1-[(4-methylpiper-azino~methyl~-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a~[1s4]-benzodiazepine.
Example 40 8-~hloro-1-(morpholinomethyl)-6-(o-chlorophenyl)-4H-s-triazolo~4,3-a~1,4]benzodiazepine In the ~.anner gi~en in Example 27, 21,5-dichloro-2-t3-(morpholinomethyl)-5-(phtha!imidomethyl)-4H-1,2,4-tria~ol-~27-4-yl3benzophenone is heated in ethanol with hydrazine hydrate to gi~e 8-chloro-1-(morpholinomethyl)-6-(o-chloro-phenyl)-4H-s-tria~olo[4J3-a][1,4]benzodiazepine.
In the ~anner gi~en in Example 27, other 1-aminomethyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines (V) can be synthesized from the corresponding 2-~3-(aminomethyl)-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenones.
Representati~e compounds, thus obtained, include:
8-chloro-1-[(dimethylamino)methyl]-6-(o-~luorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine;
8-nitro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine;
8-trifluoromethyl-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine;
8-fluoro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo-~4,3-a]~1,4]benzodiazepine;
7-nitro-1-~(dimethylamino)methyl]-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine;
8-chloro-1-[(dimethylamino~methyl]-6-(m-bromophenyl~-4H-s-triazolo[4,3-a][1,4]benzodiazepine;
9-nitro-1-[(dimethylamino)methyl]-6-(o-bromophenyl)-4H-s-triazolo[4,3-a~[1,4]benzodiazepine;
l~-fluoro-1-~dimethylamino)methyl]-6-(p-bromophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine;
2~ 9-bromo-1-[(dimethylamino)methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine;
7-nitro-1-[(dimethylamino)methyl]-6-(p-chlorophenyl)-4H-s-trtazolo[4,3-a][1,4]benzodiazepine;
7-fluoro-1-t(dimethylamino)methyl]-6-(m-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine;
lOSl90S
7-chloro-1-[(~irnethylamino)mcthyl]-6-phcnyl-4H-s-triazolo-~4,3-a~1J4]b~nzodiazepine;
9-trifluorom~thyl-1-~(dimethylamino)methyl]-6-(o-chloro-phenyl)-4H s-triazolo[4,3-a][1,4]benzodiazepine;
l~-fluoro-1-~dimethylamino)methyl]-6-(p-bromophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine;
2~ 9-bromo-1-[(dimethylamino)methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine;
7-nitro-1-[(dimethylamino)methyl]-6-(p-chlorophenyl)-4H-s-trtazolo[4,3-a][1,4]benzodiazepine;
7-fluoro-1-t(dimethylamino)methyl]-6-(m-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine;
lOSl90S
7-chloro-1-[(~irnethylamino)mcthyl]-6-phcnyl-4H-s-triazolo-~4,3-a~1J4]b~nzodiazepine;
9-trifluorom~thyl-1-~(dimethylamino)methyl]-6-(o-chloro-phenyl)-4H s-triazolo[4,3-a][1,4]benzodiazepine;
10-chl~ro-1-[(~imethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine;
8-bromo-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazo1O-[4,3-a][1,4]benzodiazepine;
1-~(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a]-~ [1,4]benzodiazepine;
8-nitro-1-[(ethylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine;
8-fluoro-1-(pyrrolidinomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1J4]benzodiazepine;
8-trifluoro~ethyl-1-(morpholinomethyl)-6-(o-chlorophenyl)-4H-s-triazolo~4,3-a~t1,4]benzodiazepine;
9-bromo-1-[(4-methylpiperazino)methyl~-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine;
9-nitro-1-~(diisopropylamino)methyl]-6-phenyl-4H-s-triazolo-~4,3-a]t1,4]benzodiazepine;
10-fluoro-1-[(dipropylamino)methyl]-6-phenyl-4H-s-triazolo-[4,3~a]~1,4]benzodiazepine;
7-chloro-l-[(diethylamino)methyl]-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4~benzodiazepine;
and the like.
This application is a division of copending Canadian application Serial No. 227,597, filed.May 22, 1975.
.
,
8-bromo-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazo1O-[4,3-a][1,4]benzodiazepine;
1-~(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a]-~ [1,4]benzodiazepine;
8-nitro-1-[(ethylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine;
8-fluoro-1-(pyrrolidinomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1J4]benzodiazepine;
8-trifluoro~ethyl-1-(morpholinomethyl)-6-(o-chlorophenyl)-4H-s-triazolo~4,3-a~t1,4]benzodiazepine;
9-bromo-1-[(4-methylpiperazino)methyl~-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine;
9-nitro-1-~(diisopropylamino)methyl]-6-phenyl-4H-s-triazolo-~4,3-a]t1,4]benzodiazepine;
10-fluoro-1-[(dipropylamino)methyl]-6-phenyl-4H-s-triazolo-[4,3~a]~1,4]benzodiazepine;
7-chloro-l-[(diethylamino)methyl]-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4~benzodiazepine;
and the like.
This application is a division of copending Canadian application Serial No. 227,597, filed.May 22, 1975.
.
,
Claims (6)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of a compound of the formula II:
II
wherein R1 is hydrogen or halogen which comprises treating in an inert organic solvent a mole equivalent of a compound of formula I:
(I) wherein R1 is defined as above, with two mole equivalents of .delta.-phthalimidoacetyl chloride or bromide in the presence of a base at -5° to 15° C to give the desired compound II.
II
wherein R1 is hydrogen or halogen which comprises treating in an inert organic solvent a mole equivalent of a compound of formula I:
(I) wherein R1 is defined as above, with two mole equivalents of .delta.-phthalimidoacetyl chloride or bromide in the presence of a base at -5° to 15° C to give the desired compound II.
2. The process according to claim 1. wherein the starting compound is 3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-phenyl-quinazoline.
3. The process according to claim 1 wherein the starting compound is 3-amino-3,4-dihydro-4-hydroxy-4-phenylquinazoline.
4. A compound of formula II:
wherein R1 is hydrogen or halogen; whenever prepared or produced by the process defined in claim 1 or by the obvious chemical equivalent.
wherein R1 is hydrogen or halogen; whenever prepared or produced by the process defined in claim 1 or by the obvious chemical equivalent.
5. 1,3-Dioxo-2-isoindolineacetic acid, [[N-(2-benzoyl-4-chlorophenyl)-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide, whenever prepared or produced by the process defined in claim 2 or by the obvious chemical equivalent.
6. 1,3-Dioxo-2-isoindolineacetic acid, [[N-(2-benzoyl-phenyl)-I,3-dioxo-2-isoindolineacetamido]methylene]hydrazide, whenever prepared or produced by the process defined in claim 3 or by the obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/480,979 US3957761A (en) | 1973-02-14 | 1974-06-19 | Process for the production of 1-aminomethyl-6-phenyl-4h-s-triazolo-[4,3-a][1]benzodiazepines and intermediates |
| CA227,597A CA1055490A (en) | 1974-06-19 | 1975-05-22 | Process for preparing triazolobenzodiazepines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1051905A true CA1051905A (en) | 1979-04-03 |
Family
ID=25667957
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA310,228A Expired CA1051905A (en) | 1974-06-19 | 1978-08-29 | 1,3-dioxo-2-isoindolineacetic acid, [[n-(2-benzoyl-phenyl)-1, 3-dioxo-2-isoindolineacetamido] methylene] hydrazides |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1051905A (en) |
-
1978
- 1978-08-29 CA CA310,228A patent/CA1051905A/en not_active Expired
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