JPS6249273B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides pharmaceutically active imidazo[1,5-
a] [1.4] Regarding diazepine compound series.
The chemical structure of these compounds is the formula [In the formula, A represents -C(R ₆ )=N-; R ₁ is hydrogen, lower alkyl, hydroxy lower alkyl, acyloxy lower alkyl, phenyl, alkoxy lower alkyl, halo lower alkyl, amino lower alkyl, substituted amino lower alkyl, substituted phenyl,
pyridyl, aralkyl or the group -COR ₁₀ (wherein R ₁₀ represents hydrogen or lower alkyl) or -COOR (where R represents lower alkyl); R ₂ represents chloro, bromo, iodo,
Hydroxy lower alkyl, acyloxy lower alkyl, alkoxy lower alkyl, halo lower alkyl, amino lower alkyl, cyano, cyano lower alkyl, acylamino, lower alkoxycarbonylamino, aralkyloxycarbonylamino,
Substituted amino lower alkyl, group -COOR ₁₀ (where
R ₁₀ represents hydrogen or lower alkyl), group -
COR ₁₀ (here R ₁₀ represents hydrogen or lower alkyl) or its derivative group, i.e. (a) group -C(R ₁₀ )=
N-R ₁₁ (wherein R ₁₁ represents hydrogen, lower alkyl, hydroxy, alkoxy, amino, mono- or di-alkylamino or arylamino, and R ₁₀ represents hydrogen or lower alkyl), (b) Group -CONR ₁₂ R ₁₃ {where R ₁₂ and R ₁₃ are individually hydrogen, lower alkyl, hydroxy lower alkyl, lower alkenyl, aryl or group -
(CH ₂ )nNR ₁₄ R ₁₅ , where R ₁₄ and R ₁₅ individually represent hydrogen, lower alkyl, hydroxy-lower alkyl or lower alkenyl, or R ₁₄ and R ₁₅
together form part of a heterocycle, and n
is a number from 1 to 4), or R ₁₂ and
R ₁₃ together form part of a heterocycle}, or (c) the group -CON(R ₁₅ )NR ₁₇ R ₁₈ {where R ₁₆ ,
One of R ₁₇ and R ₁₈ is hydrogen, lower alkyl, or a group -(CH ₂ )nNR ₁₄ R ₁₅ (where n is 1 to 4
and R ₁₄ and R ₁₅ individually represent hydrogen, lower alkyl, hydroxy lower alkyl or lower alkenyl, or R ₁₄ and R ₁₅ together form part of a heterocycle; and the remaining R ₁₆ , R ₁₇ and R ₁₈ represent hydrogen or lower alkyl; and R ₂ further represents R ₁
is hydroxy lower alkyl, acyloxy lower alkyl, halo lower alkyl, amino lower alkyl,
Substituted amino lower alkyl, group -COR ₁₀ (where
R ₁₀ represents hydrogen or lower alkyl) or -COOR (wherein R represents lower alkyl), it also represents hydrogen or lower alkyl; R ₃ represents hydrogen or lower alkyl;
R ₆ represents phenyl, monosubstituted phenyl, disubstituted phenyl, pyridyl or monosubstituted pyridyl; and

[Formula] is a group

【formula】

【formula】 【formula】

[Formula _] (where, (represents amino, hydroxy lower alkyl or lower alkanoyl), and R ₅ represents hydrogen and

When [Formula] represents the above group (a), (b) or (c), it also represents alkanoyloxy or hydroxy] and a pharmaceutically acceptable salt thereof. Various analogous compounds derived from the above compounds as well as various novel intermediates leading to the above compounds are also considered to be within the scope of the present invention and exhibit pharmaceutical activity in themselves or in combination with pharmaceutically active compounds. It is a useful intermediate. Analogues of the above compounds which form part of the invention include the formula [In the formula, A is a group

【formula】 【formula】

Express [formula] eagle, I,

[Formula] represents the above formulas (a), (b) and (c), R ₅ represents hydrogen, R ₁ , R ₂ , R ₃ and R ₆ are the same as in the above formula, and hydrogen or lower alkyl] and pharmaceutically acceptable salts thereof. As used herein, the term "lower alkyl" or "alkyl" refers to straight and branched chain C _1
-C7 hydrocarbon groups, preferably _C1 - _C4 carbon-hydrogen groups such as methyl, ethyl, propyl, isopropyl, butyl, and the like. The term "lower alkyl" also includes cyclic hydrocarbon groups such as cyclopropyl. The term "lower alkanoyl" or "acyl" as used herein refers to the acyl moiety of a _C1 - _C7 preferably _C1 - _C4 alkanoic acid, such as acetyl, propionyl, butyryl, etc., i.e., having the formula _-COR20 (where R ₂₀ is C ₁ -C ₆ or hydrogen). Additionally, the term "lower alkanoyl" used herein is
For example, protected ketones such as acetals or ketals having 2 to 7 carbon atoms, such as ethylenedioxy groups, are included. Ketal or aldehyde protecting groups are used to prevent conversion of the contained ketone or aldehyde in oxidation, reduction and condensation reactions. The term "halogen" is used to include all four forms thereof: chlorine, bromine, fluorine and iodine. The term "aromatic and aliphatic sulfonyl groups" includes compounds of the formula SO ₂ X, where X is C ₁
~ _C7 is preferably a _C1 - _C4 aliphatic group (eg methyl) or a substituted or unsubstituted aromatic group (eg phenyl or substituted phenyl derivative group, eg tolyl). The _R6 phenyl moiety can be mono- or di-substituted, provided that such di-substitution occurs in the 2, 3 or 2, 5-position or particularly preferably in the 2, 6-position of the phenyl moiety. shall be.
Suitable mono-substituents include halogen and nitro, preferably substituted at the 2-position of the phenyl moiety. Suitable di-substituents are 2,6 or 2,5 di-halogen and 2,6 or 2,5
Halogen-nitro. For mono-substituted pyridyl, suitable substituents include halogen and nitro. In the case of differently substituted R ₃ and R ₅ substituents, optical isomerism occurs and such optical antipodes and racemates are within the scope of this invention. The word "aryl" includes, for example, phenyl,
Refers to substituted or unsubstituted monocyclic aromatic moieties such as chlorphenyl, tolyl, and the like. Although various moieties are shown herein to form part of a heterocycle, these moieties preferably together with the nitrogen atom to which it is attached contain at most one It is intended to form a 5- or 6-membered ring containing additional heteroatoms, preferably nitrogen or oxygen atoms. Thus, by heterocycle, moieties such as morpholino, piperazino, piperidino and pyrrolidino are intended. The term "alkoxy" means 1 to 7 carbon atoms
, preferably from 1 to 4, such as methoxy, ethoxy, propoxy, etc. The term "substituted amino" herein refers to an _-NH2 group which may be mono- or di-substituted by a lower alkyl group, such as a methylamino or dimethylamino group, and a nitrogen atom by a lower alkyl group (e.g. methyl). It means an acylamino group which may be substituted above, such as an acetamino group. The term "aralkyl" refers to a hydrocarbon group having both aromatic and aliphatic structure, i.e., a hydrocarbon group in which the H atom of the lower alkyl is replaced by a monocyclic aryl group (e.g., phenyl, tolyl, etc.). means. Preferred compounds included in the invention have the general formula [wherein R ₁ ′ is hydrogen and lower alkyl, preferably methyl, and R ₄ ′ is hydrogen, nitro or halogen, particularly preferably chlorine, located on the fused benzo moiety of the imidazobenzodiazebin. In a particularly preferred embodiment, R ₆ ' is phenyl or phenyl substituted with halo, nitro or lower alkyl, preferably halo, and in particular fluorine is the preferred halogen. and preferably the substituted fluorine is located at the 2-position of the phenyl moiety, and R ₂ ' is hydroxy lower alkyl (e.g. hydroxymethyl), carboxylic acid hydrazide (e.g. -
CONHNH ₂ ) or carboxamide (i.e. formula -
CONH ₂ group)] Another type of compound that falls within the scope of the formula is the general formula [wherein R ₁ ', R ₂ ', R ₄ ' and R ₆ ' are the same as in formula B above, and R ₃ ' is lower alkyl, preferably methyl]. Compounds of formula C and their pharmaceutically acceptable salts exhibit optical isomerism. Compounds (C) in which R ₃ ′=CH ₃ are described in the literature (Advanced Organic
Chemistry, L.Fieser and M.Fieser, Fieser,
1961, pp. 85-88, Reinnolt Publishing Co.). Both optical isomers and racemic forms of Compound C exhibit pharmaceutical activity. For example, in the case of the tartrate salt of a compound of formula C, the (+) isomer is more transiently active than the (-) isomer. The less active (-) isomer is optionally converted to the active racemate by treatment, for example with a non-aqueous base (e.g. sodium-tert.-butoxide) in the presence of an organic solvent in which the isomer is soluble. be able to. A further preferred group of compounds is in the formula

[Formula] is 8-chlorophenyl or 8-chlorothieno[3.2-f] group, R ₁ is hydrogen or methyl, R ₂ is acetyl, carboxamide or dimethylcarboxamide, and R ₆ is 2'-fluoro - or 2'-chlorophenyl, and
R ₃ and R ₅ are hydrogen. The expression "pharmaceutically acceptable salts" includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid, etc. Including salts with inorganic and organic pharmaceutically acceptable acids such as. Such salt is
Considering the prior art and the nature of the compound to be in salt form, it can be produced quite easily by one skilled in the art. Also, the formula compound (however

Also within the scope of the invention are compounds obtained by ring opening of R ₄ -phenyl. Such compounds have the formula where X ^- is an anion of an organic or inorganic acid and R ₁ , R ₂ , R ₃ , R ₄ and R ₆ are the same as in the formula. Certain formula compounds in solution have the corresponding formula D
It was found that the ring opened to the compound of Such ring-opened compounds are in a pH-dependent equilibrium with the compound of formula, ie, the corresponding ring-closed compound, in solution. Compounds of formula D can be isolated as acid addition salts by treating the corresponding ring-closed compound with an aqueous mineral acid and evaporating the solvent. When isolated, these salts exhibit comparable pharmaceutical activity to their corresponding parent ring closures. The present invention also provides imidazo[1.5-a]
[1.4] It also relates to a method for producing a diazepine compound. More specifically, the present invention provides the formula [In the formula, A,

[Formula] R ₁ , R ₃ and R ₅ have the meanings indicated in the formula; R ₂ ″ is hydrogen, lower alkyl, chlor, bromo, iodo, hydroxy lower alkyl, acyloxy lower alkyl, alkoxy lower alkyl, halo lower Alkyl, amino lower alkyl, cyano, cyano lower alkyl, acylamino, lower alkoxycarbonylamino, aralkyloxycarbonylamino, substituted amino lower alkyl, group -COOR ₁₀ (here R ₁₀ represents hydrogen or lower alkyl), group - COR ₁₀ (here
R ₁₀ represents hydrogen or lower alkyl) or its derivative group (a) group -C(R ₁₀ )=N-R ₁₁ (where R ₁₁ is hydrogen, lower alkyl, hydroxy, alkoxy, amino, mono- or represents di-alkylamino or arylamino, and
R ₁₀ represents hydrogen or lower alkyl), (b) group -
CONR ₁₂ R ₁₃ {Here, R ₁₂ and R ₁₃ are each hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkenyl, aryl, or a group -(CH ₂ )
nNR ₁₄ R ₁₅ , (where R ₁₄ and R ₁₅ are each hydrogen,
represents lower alkyl, hydroxy lower alkyl or lower alkenyl, or R ₁₄ and R ₁₅ together form part of a heterocycle, and n is 1 to
4) or R ₁₂ and R ₁₃ together form part of a heterocycle}, and (c) the group -CON(R ₁₆ )NR ₁₇ R ₁₈ {where _R16 , _R17 and
One of R ₁₈ is hydrogen or lower alkyl or a group -(CH ₂ )nNR ₁₄ R ₁₅ (where n is 1 to 4,
and R ₁₄ and R ₁₅ individually represent hydrogen, lower alkyl, hydroxy lower alkyl or lower alkenyl, or R ₁₄ and R ₁₅ together form part of a heterocycle), and the remaining
R ₁₆ , R ₁₇ and R ₁₈ represent hydrogen or lower alkyl}, analogs thereof having the above formula A, and pharmaceutically acceptable salts thereof are prepared by formula (a) or its N-oxide with the formula R ₁ C
(OR) ₃ (where R is lower alkyl and R ₁ is hydrogen, lower alkyl, alkoxy lower alkyl or halo lower alkyl)
with an alkanoic acid orthoester, or its technical equivalent, to directly give the corresponding compound of formula ', during which reaction the amino or alkylamino group is present in protected form, or (b) formula or its N-oxide to give the corresponding compound of formula ', or (c) [In the formula, R ₁ is hydrogen, lower alkyl, phenyl,
alkoxy lower alkyl, substituted phenyl, pyridyl or aralkyl] or its N-oxide is dehydrated with simultaneous cyclization to give the corresponding compound of formula ', or (d) (e) reducing the compound of formula XII to give the corresponding free acid; or (e) reducing the compound of formula or by alsifying the compound of formula (f) with the corresponding compound of formula and the substituent which undergoes undesired acylation during this reaction is present in protected form, or (g) the hydroxyl group in the 3-substituent of the compound of formula is replaced by a halogen; h) formula In _the formula, and the hydroxyalkyl substituent is present in protected form during the reaction with the alkoxide, or (i) reacting the aldehyde group at the 3-position of the compound with a lower alkyl, Grignard or lithium reagent, during which reaction the R ₁ /R ₄ hydroxyalkyl substituents are present in a protected form;
or (j) by reductively dehalogenating the substituent at the 3-position of the compound of formula ( _{k )} Compounds _{of formula} hydrogen, lower alkyl, hydroxy lower alkyl,
Lower alkenyl, aryl, or group -
(CH ₂ )nHR ₁₄ R ₁₅ , R ₁₄ and R ₁₅ are hydrogen, lower alkyl, hydroxy lower alkyl or lower alkenyl or together form part of a heterocycle, and n is 1 to 4], in this case haloalkyl or ROOC-
The substituents are formed subsequent to the above ammonolysis, or (l) is reacted with an amino compound of the formula HNR ₁₂ R ₁₃ , where R ₁₂ and R ₁₃ have the meanings given in formula ' above, in which the haloalkyl or ROOC-substituent is aminated as above. or (m) For the production of nitrile, the corresponding −
_{CONH 2} compound is dehydrated or ( _n ) compound of _formula
[wherein R ₁₆ , R ₁₇ and R ₁₈ have the meanings given in formula '] directly with hydrazinolysis, in which case the haloalkyl or ROOC-substituent is formed subsequent to the above hydrazinolysis. or (o) the acid chloride of a compound of formula HN
(R ₁₆ )NR ₁₇ R ₁₈ (wherein R ₁₆ , R ₁₇ and R ₁₈ have the meanings given in formula ′ above) with hydrazine, in which case haloalkyl or ROOC
- substituents are generated following the hydrazine treatment described above, or decarboxylate a compound of formula (p), or (q) a compound of formula compound is heated with an alkanol or aralkanol, in which case the haloalkyl substituent undergoes a Curtius type reaction.
reaction) followed by the formation, or (r) expression where R ₁₉ is benzyl is hydrogenated to the corresponding free amine and the compound thus obtained is alkanoylated, in which case the haloalkyl, nitro or cyano substituent is formed following the above hydrogenation. seshime or (s) expression alkylating the 4-position of the compound, in which case no substituent with active hydrogen is present and no haloalkyl substituent is present if alkylation of such substituent is not desired;
or (t) expression [wherein R ₁₀ is hydrogen or lower alkyl] is oxidized to form the corresponding formula in which R ₁₀ has the same meaning as in formula XII, and during said oxidation the hydroxyalkyl substituent is present in a protected form;
or (u) by hydrazine of formula H ₂ NNR ₂₀ , where R ₂₀ is amino, mono- or di-alkylamino or arylamino, or by ammonia, hydroxylamine, lower alkyl during the above reaction by treatment with amino or lower alkoxyamino
R ₁ /R ₄ acyl groups are present in protected form,
and the haloalkyl substituent is formed subsequent to the above reaction, or (v) [wherein R ₂₁ is hydrogen, hydroxy, lower alkyl or lower alkoxy, and R ₁₀ is hydrogen or lower alkyl] or a compound of the formula wherein R ₂₀ is amino, mono- or di-alkylamino or arylamino, and R ₁₀ is hydrogen or lower alkyl, is reduced to the corresponding amino compound, in which case haloalkyl , the nitro or cyano substituent is generated following the above reduction, or (w) of the formula A halogenated compound in which a chloro, bromo or iodo substituent is introduced in the 3-position of the compound, the hydroxyalkyl or aminoalkyl substituent is present in a protected form during the halogenation, and R ₁ is hydrogen, produced following the above halogenation step, or (x) formula [In the formula, A is -C(R ₆ )=N- or -C
(R ₆ )=N(→O)−,

[Formula] is a group (a), (b) or (c) in formula ′, and R ₁
is lower alkyl and R ₆ is phenyl or mono- or di-substituted phenyl. [In the formula, R ₁₀ is hydrogen or lower alkyl,
And A,

[Formula] and R ₆ are the same as for formula ′], during the above transformation the R ₄ -hydroxyalkyl substituent is present in protected form, or (y) a compound of formula LI ,formula [In the formula, A,

[Formula] R ₁₀ and R ₆ are the same as in the case of formula L] or (aa) oxidize the compound of formula XL to obtain the compound of formula [In the formula, A,

[Formula] R ₁₀ and R ₆ are the same as for formula L] and during the above oxidation the hydroxyalkyl substituent is present in a protected form, or (bb) A compound with the formula wherein R ₂₃ is phenyl, substituted phenyl or pyridyl, and R ₂₄ is lower alkoxy or di-lower alkylamino. [wherein R ₂₃ and R ₂₄ are the same as for formula XL], or (cc) in the compound of formula ', aminomethyl, substituted aminomethyl, cyanomethyl, halomethyl, methyl, The R ₂ ″ substituent in the sense of acyloxymethyl or alkoxymethyl is homologated to a higher homologous group, or (dd) the above formula in which the R ₂ substituent is isomeric to α-hydroxy lower alkyl. ′ or (ee) of formula [In the formula, R ₂ is chlor, bromo, iodo, hydroxy lower alkyl, acyloxy lower alkyl,
alkoxy lower alkyl, halo lower alkyl,
Amino lower alkyl, cyano, cyano lower alkyl, acylamino, lower alkoxycarbonylamino, aralkyloxycarbonylamino, substituted amino lower alkyl, group -COOR ₁₀
(here R ₁₀ represents hydrogen or lower alkyl), the group -COR ₁₀ (here R ₁₀ represents hydrogen or lower alkyl) or its derivative group, i.e. (a) the group -C(R ₁₀ )=N −R ₁₁ (here R ₁₁ is hydrogen, lower alkyl, hydroxy, alkoxy, amino,
mono- or di-alkylamino or arylamino and R ₁₀ represents hydrogen or lower alkyl), (b) the group -CONR ₁₂ R ₁₃
{Here, R ₁₂ and R ₁₃ are each hydrogen, lower alkyl, hydroxy lower alkyl, lower alkenyl, aryl, or a group -(CH ₂ )nNR ₁₄ R ₁₅ ,
(wherein R ₁₄ and R ₁₅ individually represent hydrogen, lower alkyl, hydroxy lower alkyl or lower alkenyl, or R ₁₄ and R ₁₅ together form part of a heterocycle, and n is 1-4
or R ₁₂ and R ₁₃ together form part of a heterocycle}, or
(c) Group -CON (R ₁₆ ) NR ₁₇ R ₁₈ {Here, R ₁₆ and R ₁₇
and one of R ₁₈ is hydrogen or lower alkyl or a group -(CH ₂ )nNR ₁₄ R ₁₅ (where n is 1 to
4, and R ₁₄ and R ₁₅ are individually hydrogen,
(or R ₁₄ and R ₅ together form part of a heterocycle) and the remaining R ₁₆ , R ₁₇ and R ₁₈ are hydrogen or represents lower alkyl; and
R ₂ is further characterized in that R ₁ is hydroxy lower alkyl, acyloxy lower alkyl, halo lower alkyl, amino lower alkyl, substituted amino lower alkyl,
When the group -COR ₁₀ (wherein R ₁₀ represents hydrogen or lower alkyl) or -COOR (wherein R represents lower alkyl) is represented, it also represents hydrogen or lower alkyl]. (ff) a compound of the above formula or corresponding to the formula or A represents a group (e), (f) or (g) as above;

[Formula] represents the above group (a), (b) or (c), R ₅ represents hydrogen and V represents hydrogen or lower alkyl [provided that in the formula A
is structure (f), R ₄ is not nitro, and R 6 is not nitro-substituted], the amino substituent present in R 4 is not nitro, and R ₆ is not nitro-substituted] is converted to the corresponding nitro-, cyano-, chloro- or bromo-substituted substituent by a Sandmeyer reaction. or (gg) expression cyclize the compound to form the corresponding cyclized compound, or (hh) a compound of the above formula (however,

[Formula] is a group (a), (b) or (c) as defined above and R ₅ is hydrogen) into its corresponding N-oxide, or (ii) a compound of the above formula (with the proviso that

[Formula] is a group (a), (b) or (c) as defined above and R ₅ is hydrogen) by changing the N-oxide to the corresponding compound of formula where R ₅ is alkanoyloxy, or (jj) a compound of the above formula (however,

[Formula] is the above group (a), (b) or (c), and R ₅
is alkanoyloxy) by the corresponding compound of the above formula (wherein R ₅ is hydroxy), or (kk) is a compound of the above formula (where A is -CH
(R ₆ )-N(R ₇ )-, where R ₇ is hydroxy, acyl or an aromatic or aliphatic sulfonyl group) is replaced by the corresponding compound of formula ₁ above, or (ll) (mm) where A is the group (f) above into the corresponding compound of the above formula, or (mm) reacting the compound of the above formula with ethylene oxide or propylene oxide in the presence of a Lewis acid catalyst. or (nn) expression with ethanolamine or 1- or 2-alkyl-substituted ethanolamine, or (oo) a racemate of the above formula or an analogue thereof as defined above is resolved into optical enantiomers, or (pp) a compound of the above formula or an analogue thereof as defined above into a pharmaceutically acceptable salt, with the proviso that in the formulas shown in (a) to (pp) R ₁ ,
_R2 ″, _R3 , _R5 and

[Formula] unless otherwise specified has the same meaning as given in Formula ' and R is lower alkyl. The general reaction schemes shown in five sheets A-E below illustrate some of the reactions useful in preparing compounds of formula formula. In these reaction formulas, unless otherwise specified, R is lower alkyl, and A,
R ₁ , R ₃ , R ₄ and R ₆ are the same as in the formula. It will be appreciated by those skilled in the art that certain substituents may be attacked during the reactions described below, and that such sensitive groups can be transformed before or after performing such reactions. That's obvious. The reaction shown on Sheet A also shows that the corresponding N-oxide [A=-C(R ₆ )=N(→O)
-] can also be carried out, but the N-oxide moiety present in the formula compound will be removed during the conversion →. Step → A compound of formula is prepared by nitrosation of a compound of formula. Such nitrosation can be carried out with "in situ" nitrous acid. Reagents that may be used include (1) alkali metal nitrites such as sodium nitrite in the presence of organic or inorganic acids such as glacial acetic acid and aqueous or non-aqueous solvents; (2) alcohols, chlorinated hydrocarbons, or such as dimethyl alkyl nitrites such as methyl nitrite in the presence of an inert solvent such as formamide; and
(3) Includes gaseous solutions of nitrosyl chloride in an inert solvent and in the presence of an acid acceptor such as pyridine. Such nitrosation reactions should be carried out at about room temperature or below, ie, within the range of -20 to 25°C. Amino or alkylamino groups present in the molecule can be protected during the nitrosation reaction, for example by acylation. Such protecting groups can be removed at a later convenient reaction step. Step → A compound of formula can be made by reaction of a compound of formula with dimorpholinophosphinic chloride. The reaction of a compound of formula and a phosphorylating agent to form a compound of formula is accomplished by treating the compound of formula with a strong base sufficient to ionize the compound of formula to form the corresponding anion. Suitable bases include alkali metal alkoxides (e.g. potassium tert-
butoxide or sodium methoxide) and alkali metal hydrides (eg, sodium hydride) and alkyllithium compounds (eg, n-butyllithium). The reaction temperature ranges from 0 DEG to 100 DEG C., and the reaction is preferably carried out in an aprotic polar inert solvent, ie a solvent which completely or at least partially dissolves the salt present of the formula compound. Suitable solvents are ethers (eg tetrahydrofuran or dioxane) or tertiary amides (eg dimethylformamide). The amino or substituted amino groups to be present are in protected form in this reaction step, and this protected moiety can be removed at any convenient later step, eg following the formation of the formula XII compound. Step or → Formula or compound of formula [where R is lower alkyl] can be condensed with an anion generated from a malonic acid ester to form a compound of the formula. The anion is generated by deprotonating the malonate ester using a suitable strong base such as an alkali metal or alkaline earth metal alkoxide, hydride or amide. The reaction of a formula or compound with a malonate anion is preferably carried out with a hydrocarbon (e.g. benzene, toluene, hexane), an ether (e.g. dioxane, THF, diethyl ether),
The reaction is carried out in a solvent such as DMF, DMSO, etc. at a temperature ranging from below room temperature to 150°C, preferably from 0 to 100°C, particularly preferably at room temperature. Process → A compound of formula is prepared by combining a compound of formula with an alkali metal hydroxide (e.g. NaOH or KOH) and a suitable solvent (e.g. alcohol, ether or
DMSO) at room temperature to reflux temperature, preferably 60 to
It is made by decarboxylation of compounds of the formula by reacting in the temperature range of 100°C. Process → Compounds of formula can be prepared by nitrosation of compounds of formula by reacting the compound with nitrous acid generated, for example, by the reaction of alkali metal nitrites, alkyl nitrites or nitrosyl chlorides with organic or inorganic acids. made by.
Suitable solvents for the nitrosation reaction include ether,
Alcohol, water, acids (e.g. acetic acid), DMF,
Includes DMSO, and chlorinated hydrocarbons. Although the reaction can be carried out at about room temperature, such temperatures are not critical. Process → Compounds of formula are made by reduction of compounds of formula, for example with Raney nickel and hydrogen or with zinc and acetic acid. This reaction produces primarily a compound of formula, along with small amounts of several possible isomers, i.e.

【formula】

【formula】

【formula】 [wherein R is lower alkyl and R ₁ is hydrogen, lower alkyl, alkoxy lower alkyl or halo lower alkyl]

is formed by reacting with an alkanoic acid orthoester, in which case oxidation to compound XII occurs spontaneously.
Technical equivalents of the above orthoesters include orthoamides (e.g. dimethyl acetal of N.N.-dimethylformamide);
Included are N''.N''-hexamethylmethanetriamine; nitriles (eg, acetonitrile); and esterimidates (eg, _CH3 -C(=NH) _{-OC2H5 )} . It is clear that any amino or alkylamino groups present must be protected during this reaction. _{Step → XI} Compounds _of formula
substituted phenyl, pyridyl or aralkyl. Solvents for the above process steps include methylene chloride, ethers, chlorinated hydrocarbons, etc., preferably in combination with an acid acceptor such as an organic or inorganic base (e.g. triethylamine, pyridine or alkali metal carbonate). . The reaction may be carried out above or below room temperature, but is preferably carried out at room temperature. Compounds of formula XI are isomeric in nature, ie they can exhibit any of the following three-dimensional structures.

【formula】 [wherein R ₁ is the same as in the formula, but the amino or substituted amino group and preferably the RCO- group should be present in protected form]

It is produced by the reaction of aldehyde. The protected moiety can be removed later, eg, following formation of the Formula XII compound. Suitable solvents for this reaction step include hydrocarbons (e.g. benzene), alcohols, ethers, chlorinated hydrocarbons, DMF,
DMSO, etc., and the reaction is carried out in the presence or absence of a water binder such as a molecular sieve at a temperature above or below room temperature, preferably from room temperature to the reflux temperature of the solvent. Step → XII The compound of formula is, for example, manganese dioxide,
It can be converted to Formula XII compounds by in situ oxidation with oxidizing agents such as air, oxygen, etc. As mentioned above, the final compound of formula XII in which R ₄ is amino can be converted to the corresponding compound in which R ₄ is nitro or cyano via a Sandmeyer reaction as shown herein. . Another method of preparing compounds of formula XII in which R ₄ is nitro or cyano consists in preparing the corresponding compounds of formula. The latter compound has the corresponding compound of formula [wherein R is lower alkyl and Z is benzyloxycarbonyl] and the thus obtained R ₁ is benzyloxy and R ₄ is nitro or cyano. The compound of formula is converted into the corresponding compound of formula _XI as described above in Step → It can be made by producing a compound of a certain formula.
Intermediates of formula and XI do not need to be isolated. The compound of the formula thus obtained can be prepared by the above reaction step →
and →XII to further convert to the final compound of formula XII. Step XII→ Compound of formula XII is preferably treated with an alkali metal hydroxide such as NaOH or
It is produced by hydrolysis with KOH to the corresponding acid. This hydrolysis is conveniently carried out in an inert solvent. Suitable solvents are combinations of alcohols (eg methanol, ethanol), ethers (eg dioxane, tetrahydrofuran), dimethylformamide, and water.
This reaction step is preferably carried out at a temperature between room temperature and the boiling point of the reaction mixture. It is clear that during this reaction step the acyloxyalkyl groups present are hydrolyzed to the corresponding hydroxyalkyl groups, and the latter can be converted back to acyloxyalkyl in a further convenient later step. - The R ₁ group in the sense of COOR ₁₀ will also be hydrolyzed and decarboxylated to the corresponding compounds in which R ₁ is hydrogen - The COOR ₁₀ moiety can be removed from the formyl or hydroxymethyl group by known methods. Can be reintroduced. The haloalkyl groups present are affected in this reaction step to form the corresponding hydroxyalkyl compounds, which can be converted back to haloalkyl compounds in a later stage according to conventional methods. Any compound of formula XII in which R ₄ is hydroxyalkyl should be protected during this halogenation reaction step, for example in the form of its tetrahydropyranyl ether derivative. Step XII→ A compound of formula XII is preferably produced by reduction of a compound of formula XII with lithium aluminum hydride or an equivalent reducing agent. This reduction is conveniently carried out in an inert solvent. Suitable solvents are hydrocarbons (eg hexane, toluene), ethers (eg diethyl ether, tetrahydrofuran, 2-dimethoxyethane), or mixtures thereof. This reaction is preferably carried out at a temperature between about -50°C and the boiling point of the reaction mixture, particularly preferably at about -20° to 0°C. The nitro and cyano groups present may be affected during this reaction step. Such groups can be generated in later synthetic steps. Step → A compound of formula can be converted to a compound of formula by acylation with an acid anhydride or an acid chloride in the presence or absence of an acid acceptor. This acylation is conveniently carried out in an inert solvent. Suitable solvents are hydrocarbons (eg hexane, toluene), chlorinated hydrocarbons (eg methylene chloride), ethers (eg tetrahydrofuran), dimethylformamide. Preferably, this acylation is carried out at a temperature of about -50° to 150°C, particularly preferably at room temperature. Acid acceptors that can be used in this reaction step are, for example, pyridine, toluethylamine, potassium carbonate. Substituents present as R ₁ and/or R ₄ and susceptible to acylation during this reaction step are
In order to avoid undesired acylation of such groups, they should be protected according to conventional methods. Steps→ Compounds of formula can be prepared by oxidation of compounds of formula with known oxidizing agents such as chromium trioxide or manganese dioxide. This oxidation is conveniently carried out in an inert solvent. Suitable solvents include hydrocarbons [e.g. hexane,
toluene), chlorinated hydrocarbons (eg methylene chloride), ketones (eg acetone), organic acids (eg acetic acid), pyridine, dimethylformamide, dimethyl sulfoxide. The oxidation is preferably carried out at a temperature of about -50°C to the boiling point of the reaction mixture, particularly preferably at about 0°C to room temperature. It is clear that the substituents present as R ₁ and/or R ₄ in the hydroxyalkyl sense must be protected in the customary manner during this reaction step. Step → A compound of formula is made by substituting the hydroxy group of the 3-position substituent of a compound of formula with a halogen. This reaction is preferably carried out with reagents such as phosphorous halides (eg phosphorous trichloride, phosphorous tribromide) or thionyl chloride.
This reaction step is conveniently carried out in an inert solvent or in the absence of a solvent. Suitable solvents are hydrocarbons (eg hexane, toluene), chlorinated hydrocarbons (eg methylene chloride), ethers (eg tetrahydrofuran). The temperature at which this reaction step is carried out is preferably about -50° to 100°C.
°C, particularly preferably between about 0 °C and room temperature. It is clear that R ₁ /R ₂ hydroxyalkyl groups should be protected if conversion to the corresponding haloalkyl derivative is undesirable. Step →,
lower alkyl, or acyl), alkoxide (XI) and cyanide () can be reacted to be nucleophilically replaced. In reaction step →, the compound of formula is treated with ammonia or a mono- or di-alkylamine. The resulting compounds in which R′ and/or R″ are hydrogen can be acylated, if desired, with a suitable acylating agent. This reaction step may be carried out in the presence or absence of an inert solvent. Suitable solvents are hydrocarbons (e.g. hexane, toluene), chlorinated hydrocarbons (e.g. methylene chloride, chlorobenzene), ethers (e.g. diethyl ether, tetrahydrofuran), dimethylformamide, dimethyl sulfoxide. This reaction is preferably is carried out at a temperature between about 0° C. and the boiling point of the reaction mixture, with or without superatmospheric pressure. Compounds of formula where R ₁ is haloalkyl are
It is clear that they must be prepared in a further step, for example according to known methods, using the corresponding hydroalkyl derivatives as starting materials. Reaction step →XI is conveniently carried out by treating the compound of formula with an alkali metal alkoxide, preferably in the presence of an inert solvent. Suitable solvents are hydrocarbons (eg hexane, toluene), ethers (eg tetrahydrofuran), dimethylformamide, dimethyl sulfoxide, alcohols corresponding to the alkoxide used. Alternatively, a compound of formula is treated with an alkanol in the presence of an organic base such as pyridine or triethylamine. The temperature used in this reaction step is preferably between about -50°C and the boiling point of the reaction mixture, particularly preferably between room temperature and about 100°C, and the reaction is carried out with or without superatmospheric pressure. It is clear that compounds of formula XI in which R ₁ is haloalkyl must be made in a separate step as described above. It is also clear that any hydroxyalkyl substituents present must be protected during this reaction step and unprotected at a later stage. The reaction step → is conveniently carried out by treating the compound of formula with an alkali cyanide, preferably in an inert solvent. Suitable solvents are hydrocarbons (eg hexane, toluene), ethers (eg tetrahydrofuran), dimethylformamide, dimethylsulfoxide. The temperature for this reaction step is preferably between room temperature and the boiling point of the reaction mixture, particularly preferably between about 25° and 160°C. It is clear that even in this step, compounds of the formula in which R ₁ is haloalkyl must be prepared in a separate step as described above. Steps→ Compounds of formula are produced by reduction of compounds of formula with hydrogen using a suitable catalyst such as palladium or Raney nickel. This reaction step is conveniently carried out in the presence of an inert solvent. Suitable solvents are hydrocarbons (eg hexane, toluene), ethers (eg tetrahydrofuran, dioxane). The reaction is preferably carried out at a temperature between about room temperature and the boiling point of the reaction mixture, particularly preferably at room temperature. Pressures above atmospheric pressure can be applied if desired. It is clear that nitro, cyano or additional haloalkyl substituents in compounds of formula must be generated in a later synthetic step. Step XII' Compounds of formula XII' are formed by reaction of an aldehyde in the 3-position of the formula with an organometallic reagent such as a Grignard reagent or an alkyllithium reagent. This reaction is conveniently carried out in an inert solvent. Suitable solvents are hydrocarbons (eg hexane, toluene), chlorinated hydrocarbons (eg methylene chloride), ethers (eg diethyl ether, tetrahydrofuran, dimethoxyethane). The reaction is preferably carried out at about -100°~
It is carried out at a temperature of 50°C, particularly preferably between about -20°C and room temperature. It is clear that the carbonyl groups in the substituents R ₁ and R ₄ must be protected during this reaction step. Since the R ₁₀ OOC group will be affected in step →XII′, such a group
After the preparation of the XII′ compound, e.g. the protected α
They must be produced by using as starting materials the corresponding aldehydes with -hydroxyalkyl substituents in the 3-position. The cyano substituent must be generated in a later synthetic step. Step XII or → _The compound is prepared by direct ammonolysis of the _formula expression
It can be prepared by reaction of HNR ₁₂ R ₁₃ (wherein R ₁₂ and R ₁₃ have the meanings shown in the formula) with an amino compound. Step XII→ is conveniently carried out in an inert solvent or in the absence of a solvent. Suitable solvents are hydrocarbons (eg hexane, toluene), ethers (eg tetrahydrofuran), alcohols (eg methanol, ethanol), dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide. This reaction step takes place at a temperature of approximately 50°C.
Preferably, the reaction is carried out at a temperature of -200°C, particularly preferably about 100-150°C, at atmospheric pressure or higher. It is clear that the haloalkyl- or ROOC-substituents must be generated after the preparation of the compounds of formula. Step → is conveniently carried out in an inert solvent. Suitable solvents are hydrocarbons (eg hexane, toluene), ethers (eg tetrahydrofuran), chlorinated hydrocarbons (eg methylene chloride, chlorobenzene). This reaction is about −
Preference is given to carrying out the reaction at a temperature between 20°C and the boiling point of the reaction mixture, particularly preferably at about 0° to 50°C. It is clear that the hydroxyalkyl substituent must be protected during this reaction step. Step→ A compound of formula is produced by dehydration of a compound of formula in which R ₁₂ and R ₁₃ are hydrogen. Dehydration is accomplished by reactants such as phosphorus pentoxide, phosphorus oxychloride, in compatible solvents. Suitable solvents are pyridine, hydrocarbons (eg hexane, toluene), chlorinated hydrocarbons (eg methylene chloride). The reaction is preferably carried out at a temperature between room temperature and the boiling point of the reaction mixture, particularly preferably at a temperature of about 50 DEG to 120 DEG C. Step XII or → Formula compounds are produced by direct hydrazinolysis or conversion to acid chlorides, for example by treatment with phosphorus pentachloride followed by treatment with hydrazine. Symbols R ₁₆ , R ₁₇ in the formula
and R ₁₈ have the same meaning as shown in the formula. The same reaction conditions as indicated for step → can be used for step →, and the same restrictions should be considered regarding sensitive substituents during the reaction. Reaction XII
→ is conveniently carried out in an inert solvent or in the absence of a solvent. Suitable solvents are hydrocarbons (eg hexane, toluene), ethers (eg tetrahydrofuran), alcohols (eg methanol, ethanol). This reaction is preferably carried out at a temperature of about 50-150°, particularly preferably about
It is carried out at 80-100°C. For sensitive substituents during this reaction step, reaction step XII→
The same limitations as shown in should be considered. Steps→ Compounds of formula are produced by decarboxylation, with or without catalysts and with or without solvents. This decarboxylation is conveniently carried out, for example, by heating to a temperature of about 100-850°C, preferably about 150-230°C. Solvents that can be used in this reaction step are hydrocarbons (eg mineral oil), chlorinated hydrocarbons, ethers, alcohols (eg ethylene glycol), dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide. Useful catalysts include metals such as copper powder, or
Metal salts such as Cu ⁺ or Ag ⁺ salts. Step → The formula compound is produced by a modified calcium reaction, i.e., the formula compound and the phosphoryl azide [e.g.
N ₃ PO(OC ₆ H ₅ ) ₂ ] to form the acid, a compound of the formula formula, and then by heating the azide together with the alcohol involved in the reaction. This azide-forming reaction is conveniently carried out in an inert solvent. Suitable solvents are hydrocarbons (eg hexane, toluene), ethers (eg tetrahydrofuran). This reaction step is preferably carried out at a temperature of 0 DEG to 100 DEG C., preferably at room temperature, preferably using pressures above atmospheric pressure. It is clear that the amino and substituted amino groups present must be protected during this reaction step.
It is also recommended to use compounds of the formula with protected hydroxyalkyl groups. Removal of the protecting group can be carried out after formation of the formula compound. The reaction of converting an azide of formula into a carbamate ester of formula where R ₁₀ is lower alkyl or aralkyl is conveniently carried out in an alcohol reactant serving as a solvent. Additionally, hydrocarbons (e.g. hexane, toluene), chlorinated hydrocarbons (e.g. methylene chloride), ethers (e.g. tetrahydrofuran),
Inert solvents such as pyridine, triethylamine can also be present. Preferably, the reaction is carried out at a temperature of about 50-200°C, particularly preferably about 80-160°C.
It is carried out at ℃. Since the haloalkyl substituents present will be affected during this reaction step, it is clear that this must be generated according to known methods after the preparation of the formula compound. Process → formula compound is a formula compound (but
R ₁₉ is benzyl) with palladium and hydrogen to yield the free amine, which is then acylated with an acid halide or anhydride. Generation of free amines is conveniently carried out in an inert solvent. Suitable solvents are hydrocarbons (e.g. hexane, toluene), ethers (e.g. tetrahydrofuran), alcohols (e.g. methanol, ethanol), organic acids (e.g. acetic acid, acid anhydrides e.g. acetic anhydride); Acylation occurs in situ. The preferred temperature range for this reaction step is room temperature to about 100 ℃
℃ and use pressures above atmospheric pressure if desired. For the acylation, the same reaction conditions as indicated in step → can be used. Haloalkyl, nitro and cyano substituents are
It is clear that the preparation of compounds of formula must then be produced according to known methods. It is also clear that the amino group must be protected, for example in the form of a corresponding phthalyl-derived group. Step XII'→ A compound of formula XII' is formed by alkylation of a compound of formula XII' with methyl iodide in the presence of an alkyl halide, such as potassium tert-butoxide, in the presence of a strong base.
This reaction step is conveniently carried out in an inert solvent. Suitable solvents include hydrocarbons (e.g. hexane,
toluene), ethers (eg, tetrahydrofuran), dimethylformamide, and dimethylsulfoxide. Preferably, the reaction is carried out at a temperature between about -50°C and room temperature, particularly preferably between about -30°C and -10°C.
It is carried out at a temperature of It is clear that the substituents present should not be haloalkyl substituents or substituents with active hydrogen, especially if alkylation of the latter substituents is undesirable. Step XII→ A compound of formula (comprising) is produced by oxidation of a compound of formula XII as carried out in Step→ (wherein R ₁₀ is hydrogen or lower alkyl). Step → XI Formula XI where R ₁₀ is hydrogen or lower alkyl
The compound is a hydrazine of the formula NH ₂ R ₂₀ , where R ₂₀ is amino, mono- or di-alkylamino or arylamino;
It is produced by processing a compound (including). This reaction is conveniently carried out in an inert solvent. Suitable solvents include hydrocarbons (e.g. hexane,
toluene), chlorinated hydrocarbons (e.g. methylene chloride), ethers (e.g. tetrahydrofuran), alcohols (e.g. methanol, ethanol), organic acids (e.g. acetic acid), pyridine. Preferably, the reaction is carried out at a temperature between room temperature and the boiling point of the reaction mixture. It is clear that the R ₁ and/or R ₄ acyl group must be protected during this reaction step and that the haloalkyl group must be generated subsequent to the preparation of the formula XI compound. Step → Compounds of the formula where R ₂₁ is hydrogen, hydroxy, lower alkyl or lower alkoxy and R ₁₀ is hydrogen or lower alkyl are combined with a compound of formula (comprising) and ammonia, hydroxylamine, lower alkyl amine or lower alkoxy amine It is produced by the reaction with
This reaction step is conveniently carried out in an inert solvent. Suitable solvents include hydrocarbons (e.g. hexane,
toluene), chlorinated hydrocarbons (e.g. methylene chloride), ethers (e.g. tetrahydrofuran), alcohols (e.g. methanol, ethanol), organic acids (e.g. acetic acid), pyridine. Preferably, the reaction is carried out at a temperature between room temperature and about 150° C., if desired at pressures above atmospheric. It is clear that the R ₁ and/or R ₄ acyl group must be protected during this reaction step and that the haloalkyl group must be generated subsequent to the preparation of the formula compound. Formula compounds in which step XI or → R ₁₀ is hydrogen or lower alkyl are obtained by reduction of compounds of formula XI or with, for example, Raney nickel and hydrogen. This reaction step is conveniently carried out in an inert solvent. Suitable solvents are hydrocarbons (e.g. hexane, toluene), ethers (e.g. tetrahydrofuran), alcohols (e.g. methanol, ethanol), dimethylformamide, organic acids (e.g. acetic acid), organic acid anhydrides (e.g. acetic anhydride); In the case of acid anhydrides, acylation of the formed amino group occurs in situ, leading to the acylated compound of formula. This reaction step is preferably carried out at a temperature of about 0 DEG to 100 DEG C., particularly preferably at room temperature, and superatmospheric pressure can be applied if desired. It is clear that the haloalkyl, nitro and cyano groups must be generated subsequent to the preparation of the formula compounds. Step → L Formula XL where X is chloro, brome or iodo
The compounds are obtained by reacting a compound of formula where _R22 is hydrogen with a suitable halogenating agent such as bromine, N-bromosuccinimide, N-chlorosuccinimide and the like. This reaction step is conveniently carried out in an inert solvent. Suitable solvents are hydrocarbons (eg hexane, toluene), chlorinated hydrocarbons (eg methylene chloride), organic acids (eg acetic acid), inorganic acids (eg sulfuric acid). Preferably, the reaction is carried out at a temperature between about 0° C. and the boiling point of the reaction mixture, depending on the reagents used. It is clear that the hydroxyalkyl and aminoalkyl substituents present must be protected during this reaction step. Furthermore, the meaning of R ₁ must be different from hydrogen. Compounds of formula L in which R ₁ is hydrogen are those in which R ₁ is -
It can be prepared from the corresponding compound which is COOR by oxidation and then decarboxylation. Step →→L Compounds of the formula in which R ₂₂ is hydrogen, lower alkyl, lower alkoxyalkyl, or acyloxylower alkyl can be obtained by reacting the corresponding compound of the formula with a peracid, such as methachloroperbenzoic acid or peracetic acid. It will be done. When R ₁ is lower alkyl and R ₂ is hydrogen, compounds of formula L are formed by subsequent reaction with an acid anhydride. Formula and L
The symbol A in is the group -C(R ₆ )=N- and -
C(R ₆ )=N(→O)−. The reaction step → is conveniently carried out in an inert solvent. Suitable solvents include hydrocarbons (e.g. hexane,
toluene), chlorinated hydrocarbons (e.g. methylene chloride), and organic acids (e.g. acetic acid). Preferably, the reaction is carried out at a temperature of about 0-50°C. It is clear that the acyl groups and preferably also the hydroxyalkyl groups present should be protected during this reaction step. Furthermore, a tertiary amino group,
Z in the sense of ROOC group and pyrazole,
and the presence of R ₆ in the sense of pyridyl is excluded for this reaction step. Acyloxyalkyl groups present can be converted to hydroxyalkyl, haloalkyl, aminoalkyl, substituted aminoalkyl or cyanoalkyl groups following formation of compounds of formula. Treatment with an acid anhydride (eg acetic anhydride) for the →L conversion is conveniently carried out in an inert solvent. Suitable solvents are hydrocarbons (eg hexane, toluene), chlorinated hydrocarbons (eg methylene chloride), ethers (eg tetrahydrofuran), dimethylformamide, dimethylsulfoxide. The acid anhydrides involved in the reaction can also be used as solvents. This reaction step is advantageously carried out at a temperature between room temperature and about 150°C, preferably at a temperature of about 80-100°C. It is clear that during this reaction step the amino groups present are acylated and the hydroxyalkyl groups present are esterified. Step L→L A compound of formula L (wherein A is the same in the formula) is obtained by reacting a corresponding compound of formula L with an alkoxide or hydroxide of an alkali metal. This reaction step is conveniently carried out in an inert solvent. Suitable solvents include hydrocarbons (e.g. hexane, toluene), chlorinated hydrocarbons (e.g. methylene chloride), ethers (e.g. tetrahydrofuran), alcohols (e.g. methanol, ethanol), dimethylformamide,
Dimethyl sulfoxide, hexamethylphosphoric triamide, pyridine, amines (eg triethylamine). The reaction is preferably carried out at a temperature between about 0° C. and the boiling point of the reaction mixture, depending on the reagents used. Step L→ A compound of the formula (where A is the same as in the formula) is produced by an oxidation similar to Step →. Step '→L A compound of formula L is prepared by strongly combining a compound of formula ' with a compound of formula L where R ₂₃ is phenyl, substituted phenyl or pyridyl and R ₂₄ is lower alkoxy or di-lower alkylamino. It is made by reacting with the nitrone anion resulting from reaction with a base (eg, butyllithium, potassium tert-butoxy, etc.). reaction('
→L) is carried out in situ without isolating intermediate compounds such as XL and XL. Suitable solvents for this reaction include hydrocarbons (eg, hexane, toluene, etc.), ethers (eg, THF), DMF, and DMSO. The reaction temperature should be in the range -100°C to room temperature, preferably -80 to 25°C, such as about -70°C, followed by warming to room temperature to allow in situ oxidation. Homologues of compounds of formulas, , , XI and formulas XII in which the functional group in the substituent R ₂ is present in another position than the α-position
The compounds can be made by homologation and/or modification of the appropriate compounds mentioned above. For example, a compound of formula can be converted to the corresponding ester, which is then subjected to reactions similar to those described above for the conversion of formula XII compounds. Compounds of formula A, where A is -C( _R6 )=N(→O)-, are produced by converting the corresponding compound of formula to its N-oxide. This transformation is carried out by oxidizing the formula compound with an organic peracid. To carry out this reaction, conventional organic peracids such as peracetic acid, perpropionic acid, m-chloroperbenzoic acid, etc. can be used. Oxidation can be carried out at room temperature or above or below room temperature. Reactions similar to those described above for the transformation of the R ₂ substituent in formula ′ can also be carried out for the R ₁ substituent in formula ′, e.g., the conversion of halo via the corresponding azide compound, if desired. Such is the amination of lower alkyl groups or the conversion of halo-lower alkyl groups to the corresponding acyloxy lower alkyl groups. Next, using a compound of formula A in which A is -C( _R6 )=N(→O)-, a compound of formula A in which _R5 is alkanoyloxy or hydroxy can be prepared by a known method. For example, Polonovski rearrangement (Polonovski rearrangement)
rearrangement), which is a reaction in which an acid anhydride is used to form an alkanoyloxy group, which can be converted to a hydroxyl by treatment with an alkali metal hydroxide, such as sodium hydroxide. An example of such a Polonowski rearrangement can be found in US Pat. No. 3,296,249. Compounds of A, where A is -CH( _R6 )NH-, can be substituted with the corresponding formula compound by the formula [In the formula, R ₁ , R ₂ , R ₃ , R ₆ and

[Formula] is the same as in the formula], which is then produced by reduction to the compound of the formula [wherein R ₁ , R ₂ , R ₃ and R ₆ are the same as in formula A′ and R ₇ is hydroxy, acyl or an aromatic or aliphatic sulfonyl group] Can be done. Reduction of the formula compound to the A' compound is accomplished with any suitable cyclizing agent, but particularly preferably with hydrogen in the presence of a platinum oxide catalyst or zinc in the presence of acetic acid. If R ₄ is nitro or R ₄ is nitro-substituted, it is recommended to use an alkali metal polyhydride such as sodium borohydride. These compounds (A') can be prepared by reacting with an alkyl or arylsulfonyl halide (e.g. tosyl chloride, mesyl chloride) or a reagent giving a lower alkanoyl group (e.g. acetyl chloride) to form a non-hydroxy
A″ compound with R ₇ group. This step is carried out in the presence of an inert organic solvent such as alkanols (e.g. ethanol or methanol), ethers (e.g. diethyl ether and tetrahydrofuran), dimethylformamide, etc. Suitably, an acid acceptor is provided in the reaction zone to capture the hydrogen halide formed, which hydrogen halide is a halogen such as an arylsulfonyl (e.g. tosyl) halide or an alkylsulfonyl (e.g. mesyl) halide. is formed when used with the above formula A' compound. Suitable acid acceptors are tertiary amines such as triethylamine, pyridine, etc. Temperature and pressure can convert the above formula compound into the corresponding formula A compound. However, the reaction is not critical for the first step of the method, which involves
Particularly preferably for the preparation of compound A′ at about room temperature and atmospheric pressure, or at R ₇ other than hydroxy.
_The conversion of compound A' into compound A'' having a group is carried out at room temperature or above. Reduction with hydrogen in the presence of hydroxyl leads to the A″ compound where R ₇ is hydroxy. A compound of formula A″ in which R ₇ is hydroxy can be converted to an unsaturated imine of the corresponding formula by treating it with an acetic anhydride/pyridine mixture. No other solvent is required for this reaction. The reaction is best carried out at room temperature, although temperature is not critical.Formula A above, where R ₇ is an acyl (e.g. acetyl), a fatty acid sulfonyl group (e.g. mesyl) or an aromatic sulfonyl group (e.g. tosyl) ” compound, this can be treated with an inert solvent (e.g. THF,
It can be converted to the unsaturated imine of the corresponding formula by treatment with non-aqueous chlorine (e.g. potassium-tert-butoxide) in the presence of DMF, etc.). Such reactions and conditions for conducting them are well known in the art (e.g., U.S. Pat.
(See No. 3625957). Compounds of formula A' above can be converted to analogous formula unsaturated compounds by oxidation of the secondary amine in the 5-position. Such selective oxidation can be accomplished with known oxidizing agents and reaction schemes (eg, US Pat. No. 3,322,758). The reaction of converting a compound of the formula in which R ₄ is amino into a compound in which R 4 _is nitro can be suitably carried out, for example, by a Sandmeyer reaction in which an amino group is replaced with a nitro group.

When a compound of the formula is aminophenyl is treated with excess sodium nitrite using dilute sulfuric acid as the solvent in the presence of a sulfuric acid/sodium nitrite mixture,
formula An intermediate is formed in which R ₁ , R ₂ , R ₃ and R ₆ are the same as in the formula, which can then be converted into analogous formula compounds. The process is carried out in two steps without isolation of the intermediate, i.e. the intermediate is prepared by preparing a compound of formula D' above with phosphorus tribromide in an inert solvent (e.g. dichloromethane) from about -10 to
It is produced by treatment at 25° C. (temperature is not critical), which is then treated in situ with ammonia, preferably liquid ammonia warmed to room temperature. It has been found that the Sandmeyer reaction can also be used to prepare compounds containing cyano, chloro or bromo groups instead of nitro groups. formula
The corresponding compound of D' can be converted into a ring-closed analog in the same manner as described above for the nitro compound. Certain substituents may be present during the above reaction, e.g.
When R ₁ or R ₂ is a primary amine, alcohol, carboxylic acid, or ester thereof, such sensitive groups can be blocked with appropriate protecting groups to prevent the above reaction. It will be clear to those skilled in the art that the changes can be made before proceeding. Such methods of altering or protecting vulnerable groups are well known in the art. A is Compounds of formula A that are prepared by direct reaction of a compound of formula with ethylene oxide or propylene oxide in the presence of a Lewis acid catalyst (to yield compounds in which V is hydrogen or methyl) or [In the formula, R ₁ , R ₂ , R ₃ ,

and R ₆ are the same as in the formula] (with the proviso that R ₄ is not amino or substituted amino) and phosphorus tribromide followed by intermediate (D), ethanolamine, 1- It can be produced by treatment with alkyl-substituted ethanolamine or 2-alkyl-substituted ethanolamine (as shown in the reaction formula below). The reaction between a compound of formula D and sodium nitrite is
For example, it is carried out in the presence of a compatible solvent such as water or a dilute mineral acid. The temperature of the reaction can be from -10°C to room temperature. The reaction of a compound of formula D'' with phosphorus tribromide is preferably carried out in an inert organic solvent such as dichloromethane, as described above, at about room temperature, although temperature is not critical.Formula D compound and ethanolamine or 1
-The reaction with alkyl- or 2-alkyl-substituted ethanolamine is carried out in situ, i.e. at -10°C using a suitable inert solvent such as dichloromethane.
The reaction is carried out in a temperature range of from reflux temperature to reflux temperature, preferably about room temperature. The direct reaction of the formula compound with ethylene oxide or propylene oxide is preferably catalyzed by a Lewis acid such as titanium tetrachloride, boron trifluoride, and the like. In compounds of the formula and analogs thereof in which a ketal group such as an ethylenedioxy group is present in the imidazobenzodiazepine, such a ketal group can be converted to the corresponding ketone by subjecting it to mild acid hydrolysis. This ketone can then be converted into a secondary or tertiary alcohol, which is racemic in nature. Reaction conditions for the above two steps can be found in US Pat. No. 3,646,410. As mentioned above, a compound of formula A can be prepared by directly reacting with ethylene oxide or propylene oxide to form a compound of formula A
Compounds of the oxazolo type can be made. Reaction parameters and conditions for carrying out such reactions are known (see, eg, US Pat. No. 3,868,362). Some of the functional groups in compounds of formula and D'' are susceptible to attack during the formation of compounds of formula A. These may be suitably protected in a manner similar to that described herein. or later introduced from other functional groups. Compounds of formulas, A, and D, and their pharmaceutically acceptable acid addition salts, are useful as muscle relaxants, sedatives, and anticonvulsants, and are used in many are particularly useful in intravenous and intramuscular formulations because their acid addition salts are soluble in aqueous solutions. Decided.
The compounds used in these experiments were: 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide
(Compound A) 8-chloro-6-(2-fluorophenyl)-1-
Methyl-4H-imidazo [1.5-a] [1.4]
Benzodiazepine-3-carboxylic acid/2,2-dimethylhydrazide (Compound B) 8-chloro-N-N-diethyl-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a ] [1.4] Benzodiazepine-3-
Carboxamide (Compound C) 8-chloro-3-hydroxymethyl-1-methyl-6-phenyl-4H-imidazo[1.5-a]
[1.4] Benzodiazepine (Compound D) 8-chloro-6-(2-fluorophenyl)-3-
Hydroxymethyl-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine
(Compound E) 8-chloro-1-methyl-6-phenyl-4H-
imidazo[1,5-a][1,4]benzodiazepine-3-N-methylcarboxamide
(Compound F) 8-chloro-6-(2-fluorophenyl)-1-
Methyl-4H-imidazo [1.5-a] [1.4]
Benzodiazepine-3-carboxylic acid hydrazide
(Compound G) 8-chloro-6-(2-fluorophenyl)-1-
Methyl-4H-imidazo [1.5-a] [1.4]
Benzodiazepine-3-carboxylic acid 2,2-dimethylhydrazide (Compound H) 8-chloro-N·N-diethyl-6-(2-fluorophenyl)-1-methyl-4H-imidazo [1,5-a] [1.4] Benzodiazepine-3-
Carboxamide (Compound I) 8-chloro-6-(2-fluorophenyl)-1.
N・N-trimethyl-4H-imidazo[1,5-
a] [1,4] Benzodiazepine-3-carboxamide (Compound J) 8-chloro-1-methyl-6-phenyl-4H-
Imidazo[1,5-a][1,4]Benzodiazepine-3-carboxamide (Compound K) 6-(2-chlorophenyl)-1-methyl-8-nitro-4H-imidazo[1,5a][1,4 [Benzodiazepine-3-carboxamide (Compound L) 8-chloro-N-cyclopropyl-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1.5-a][1.4]benzodiazepine- 3-
Carboxamide (Compound M) 8-chloro-6-(2-fluorophenyl)-1-
Methyl-4H-imidazo [1.5-a] [1.4]
Benzodiazepine-3-carboxamide
(Compound N) 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide
(Compound O) 8-chloro-6-(2-fluorophenyl)-4H
-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide (compound P) 8-chloro-6-(2-chlorophenyl)-1.
N・N-trimethyl-4H-imidazo[1,5-
a] [1.4] Benzodiazepine-3-carboxamide (Compound Q) 8-chloro-6-(2-chlorophenyl)-N・N
-dimethyl-4H-imidazo [1.5-a] [1.
4] Benzodiazepine-3-carboxamide
(Compound R) 8-chloro-6-(2-chlorophenyl)-4H-
Imidazo[1.5-a][1.4]benzodiazepine-3-carboxamide (Compound S) 8-chloro-6-(2-chlorophenyl)-1.N
-dimethyl-4H-imidazo [1.5-a] [1.
4] Benzodiazepine-3-carboxamide
(Compound T) 8-chloro-6-(2-chlorophenyl)-N-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide
(Compound U) 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide
Compound V The results obtained in the inclined screen test, leg shock test and unanesthetized cat test using the above compounds of the invention are summarized in the table below. The details of these test methods are as follows. A. Tilted Screen Test This test is useful for measuring muscle relaxation and/or sedation. Groups of 6 male mice are given the test drug (maximum dose 500 mg/Kg) and then placed on an inclined screen for at least 4 hours to observe the paralyzing effect to the extent that the mice slide off the screen. PD ₅₀ using 6 mice per dose and at least 2 points between 100 and 0%.
is calculated as follows: doses of mice that fall off the screen due to toxicity or excitement are not included in the PD ₅₀ calculation. PD ₅₀ is determined from a graph where dose is plotted against percentage of mice paralyzed. This PD ₅₀ value is the dose (mg/Kg) that is expected to cause 50 percent of the mice to slide off the screen. B. Leg Shock Test This test is a test method for screening compounds that have muscle relaxing and/or anxiolytic (tranquilizer) effects. A pair of mice is trapped under a 1 liter beaker placed on a net that provides a shock to the legs. At least 5 fighting episodes occur within 2 minutes.
Pairs of mice are marked and treated by oral administration of drug 1 hour before the second shot. Administer at logarithmic dose intervals up to 100 mg/Kg. The dose that blocked all three pairs of mice from fighting was the 100 percent blocking dose. C. Unanesthetized cat test This Tetus test is a suitable test method for measuring muscle relaxation effects. Cats are administered the test drug orally and observed for minimal signs - usually ataxia. One cat is used at a dose of 50 mg/Kg. If an effect occurs, use 3 cats per dose. Results are expressed as minimum effective dose (MED).

【table】

[Table] As contemplated by the present invention, new features of Eq.
Compounds and their acid addition salts can be administered at
Approximately 0.1 to approximately 40 depending on the type and individual requirements
mg, particularly preferably from 1 to 40 mg.
It can be embodied as an agent. expression, Ao
and D novel compounds and their pharmaceutical acceptability
Salts that can be used internally as a common pharmaceutical dosage form
For example, it can be administered parenterally or enterally.
can. For example, they contain water, gelatin,
Powder, magnesium stearate, talc, vegetable oil
in ordinary liquid or solid vehicles such as
Mixed with tablets, elixirs, capsules, solutions,
made emulsions, etc., acceptable medical practice.
I am able to give. Example 1 In 250 ml of tetrahydrofuran and benzene
7-chloro-1,3-dihydro-5-(2-ph)
fluorophenyl)-2H-1,4-benzodiazepi
A solution of 200 g (0.695 mol) of ion-2-one in an ice bath
The mixture was saturated with methylamine while cooling at . ben
Dissolution of 190 g (1 mol) of titanium tetrachloride in 250 ml of Zen
The liquid was added via dropper within 15 minutes. After addition
The mixture was stirred and refluxed for 3 hours. Water (600
ml) was slowly added to the cooled reaction mixture.
Inorganic substances are separated by filtration and tetrahydro
Thoroughly washed with furan. Separate the aqueous layer and the organic
Dry the phase over sodium sulfate and evaporate
Ta. 7-chloro-5-(2-fluorophenyl)-
2-Methylamino-3H-1,4-benzodiaze
The crystalline residue of the pin was collected. Melting point is 204-206℃
It was hot. Sample for analysis is methylene chloride/ethanol
It was recrystallized from The melting point was 204-206°C. (A) 8.63g (0.125mol) of sodium nitrite in ice
7-chloro-5-(2-fluoro) in 150 ml of acetic acid
phenyl)-2-methylamino-3H-1・4-
In a solution of 30.15 g (0.1 mol) of benzodiazepine
Addition was made in three portions over 15 minutes. 1 at room temperature
After stirring for an hour, dilute the reaction mixture with water and
and extracted with methylene chloride. Bicarbonate extract
Wash with sodium saturated solution and sodium sulfate
dry on top and finally azeotropically with toluene
Crude 7-chloro-5-
(2-fluorophenyl)-2-(N-nitroso
methylamino)-3H-1,4-benzodiazepi
29 g of yellow oil were obtained. (B) Sodium nitrite (27.6 g, 0.4 mol),
7-chloro-5-(2-fluoro) in 400 ml of glacial acetic acid.
(ruphenyl)-2-methylamino-3H-1.4
- A solution of 90.45 g (0.3 mol) of benzodiazepine
was added in small portions over 30 minutes. addition
Once complete, the mixture was then stirred at room temperature for 1 hour.
Stir and dilute with 1 part water and add methane chloride.
Extracted with Len. The extract was dissolved twice in water and then carbonated.
Washed with 10% aqueous sodium solution. Dry the solution
Dry and evaporate to give crude 7-chloro-5-
(2-fluorophenyl)-2-(N-nitroso
methylamino)-3H-1,4-benzodiazepi
This was obtained as a yellow oil. This substance was dissolved in 300 ml of dimethylformamide.
Melt and stir at room temperature for about 10 minutes.
150 ml of dimethyl phosphate, potassium t-butoxide
Mixture of 40.4g and 500ml of dimethylformamide
Added to things. The reaction mixture was incubated overnight at room temperature under nitrogen.
Stir and acidify by adding 50 ml of glacial acetic acid and water.
diluted with sodium carbonate, washed with aqueous sodium carbonate solution, and washed with sulfuric acid.
dried over sodium chloride and evaporated. Residue
By crystallizing the residue from ethanol,
7-chloro-1,3-dihydro-2-(dimeth)
ximalonylidene)-5-(2-fluorophene)
-2H-1,4-benzodiazepine has a melting point
Obtained as colorless crystals at 170-172°C. analysis
This product was converted into methylene chloride/ethanol for
The melting point did not change even though it was recrystallized from a
Ta. 7-chloro-1,3-dihydro-2-(dime
Toximalonylidene)-5-(2-fluorophene)
)-2H-1,4-benzodiazepine 20g
(0.05 mol), methanol 400ml and potassium hydroxide
A mixture of 3.3 g (0.059 mol) of
The mixture was heated to reflux for an hour. Most of the solvent is evaporated
After cooling, the residue was gradually diluted with water and precipitated.
The crystals are collected, washed with water and dried to reduce the melting point.
7-chloro-1,3-dihydro- at 158-160℃
5-(2-fluorophenyl)-2-(dimethoxy
(cycarbonylmethylene)-2H-1,4-benzo
Obtained diazepine. Treat it with methylene chloride/hexane for analysis.
It was recrystallized from Melting point is 161-162℃
Ta. Sodium nitrite (8.8g, 0.125mol),
7-chloro-1,3-dihyde in 250 ml of glacial acetic acid
Rho-5-(2-fluorophenyl)-2-(meth)
(oxycarbonylmethylene)-2H-1,4-ben
Added to a solution of 28 g (0.08 mol) of zodiazepine
Ta. The mixture was stirred at room temperature for 10 minutes and then poured with water at 250 °C.
diluted in ml. Filter the crystalline product, add water and
Wash with tanol and ether and dry
7-chloro-5-(2-fluorophenyl)-
α-Hydroxyimino-3H-1,4-benzo
The melting point of diazepine-2-acetic acid methyl ester
Obtained as yellow crystals at 238-241℃ (decomposition)
Ta. 7-chloro-5-(2-fluorophenyl)-
α-Hydroxyimino-3H-1,4-benzo
Diazepine-2-acetic acid methyl ester (11.25
g, 0.03 mol) in 750 ml of tetrahydrofuran
and methanol in a mixture of 500 ml
Hydrogenation was carried out using Kel at atmospheric pressure. Ranenits
Filter and evaporate the liquid. residue
Dissolve triethyl alcohol in 100 ml of methanol.
11ml toacetate and ethanolic hydrogen chloride
(5%) 5ml was added. Heat the mixture to reflux for 10 minutes.
Flow, evaporate and remove the residue in methylene chloride.
and aqueous sodium bicarbonate solution.
Dry and evaporate the methylene chloride solution,
Then, the residue was mixed with methylene chloride/ethyl acetate 1:3.
(v/v) on 300 g of silica gel.
romatographed. Clear fraction
Combine, evaporate, and ether
By crystallizing from
Methyl-8-chloro-6-(2-fluorophe
Nyl)-1-methyl-4H-imidazo[1,5-
a] [1,4]-benzodiazepine-3-carbo
Obtained xylate. The sample for analysis is ethyl acetate/
Recrystallized from hexane. Example 2 7-chloro-5-(2-fluorophenyl)-α
-Hydroxyimino-3H-1,4-benzodia
Zepine-2-acetic acid methyl ester (11.25g,
0.03 mol) in 750 ml of tetrahydrofuran and meth
Dissolved by heating in a mixture of 500 ml of alcohol.
I understand. Add raneh nitskel (20g), and
The mixture was hydrogenated at atmospheric pressure for 4 hours. passing through the catalyst
and the liquid was finally mixed with toluene.
Evaporated boilingly. Residue in 100ml of methanol
Dissolved. Triethyl orthoformate
(triethyl orthofrmate) 10ml and ethanolic salt
After adding 5 ml of hydrogen oxide (5%), the mixture was stirred for 10 minutes.
The mixture was heated to reflux for a while. then evaporate it and
The residue was dissolved in methylene chloride and saturated sodium bicarbonate water.
distributed between the solutions. Separate the methylene chloride layer;
Dry and evaporate and remove the residue with ether.
By crystallizing from
6-(2-fluorophenyl)-4H-imidazo
[1.5-a] [1.4] Benzodiazepine 3-ka
Ruboxylate is obtained, which is diluted with methylene chloride.
Recrystallized from ether/hexane. melting point
The temperature was 179-181℃. Example 3 Methyl 8-chloro-6-(2-fluorophene
)-1-methyl-4H-imidazo[1,5-a]
[1.4] Benzodiazepine 3-carboxylene
7.7g (0.02mol), potassium hydroxide 2.24g
(0.04 mol), a mixture of 200 ml of methanol and 6 ml of water
The mixture was heated to reflux for 3 1/2 hours. Solvent partially
and acidify the residue with glacial acetic acid.
diluted with water while hot. Place the precipitated crystals on ice/water.
collected after cooling in a
Ru-6-(2-fluorophenyl)-1-methyl-
4H-Imidazo [1.5-a] [1.4] Benzodi
Azepine 3-carboxylic acid was obtained. For analysis,
from methylene chloride/methanol/ethyl acetate.
Recrystallized. Melting point is 271-274℃ (decomposition)
Ta. Example 4 8-chloro-6- in 25 ml of 2-propanol
(2-fluorophenyl)-1-methyl-4H-y
Midazo [1.5-a] [1.4] Benzodiazepi
Suspension of 1.85 g (5 mmol) of carbon-3-carboxylic acid
on a steam bath, and 5N potassium hydroxide
Treated with 2.2 ml of solution. After the dissolution is complete, the potash
crystallizes by cooling the salt in ice/water.
I set it. Collect it, add 2-propanol and ether.
and dried in a high vacuum at 90°C.
um8-chloro-6-(2-fluorophenyl)-
1-Methyl-4H-imidazo [1.5-a] [1.
4] Benzodiazepine 3-carboxylate high
Dreit is obtained as colorless crystals with a melting point of 245-255℃.
It was done. Example 5 Methyl 8-chloro-6-(2-fluorophene
)-4H-imidazo [1.5-a] [1.4]
Nzodiazepine 3-carboxylate 1.48g
(0.004 mol), potassium hydroxide 0.5 g (0.009 mol)
), 50 ml of methanol and 2 ml of water in a nitrogen atmosphere.
The mixture was heated under reflux for 3 hours. Part methanol
Evaporate portionwise and acidify the residue with glacial acetic acid.
and diluted with water while the solution was still hot.
Collect crystals after cooling in ice/water and dry in vacuo.
8-chloro-6 with a dry melting point of 245-247°C (decomposition)
-(2-fluorophenyl)-4H-imidazo
[1,5-a] [1,4]-Benzodiazepine 3-
Carboxylic acid was obtained. Example 6 Methyl 8-chloro in 100 ml of tetrahydrofuran
Ru-6-(2-fluorophenyl)-1-methyl-
4H-Imidazo [1.5-a] [1.4] Benzodi
Azepine 3-carboxylate 7.7g (0.02mol)
A solution of lithium hydride in 100 ml of ether
In a suspension of 2 g (0.05 mol) of aluminum,
Added at 5°C. Do not cool the mixture after addition 15
Stir for a minute, then add 15 ml of water to hydrolyze.
Ta. Inorganic substances are separated by filtration and chloride
Washed with tyrene. Dry the liquid and evaporate
I set it. The residue was dissolved in methylene chloride/ether/hexane.
8-chloro-6-
(2-fluorophenyl)-3-hydroxymethyl
-1-methyl-4H-imidazo [1,5-a]
[1.4] Benzodiazepine is obtained, this one
was reconstituted from ethyl acetate/methanol for analysis.
crystallized. The melting point was 233-235°C. Example 7 8-chloro-6-(2-fluorophenyl)-3
-Hydroxymethyl-1-methyl-4H-imida
Zo[1,5-a][1,4]Benzodiazepine 4
g, 200 ml of methylene chloride and activated dioxide
A mixture of 20 g of manganese was stirred at room temperature for 1 hour.
Manganese dioxide is removed by filtration and chloride
Thoroughly washed with methylene. Evaporate the liquid and then
and remove the residue from methylene chloride/ether/hexane.
Crystallized to give 8-chloro-6-(2-fluorophore)
enyl)-1-methyl-4H-imidazo[1,5-
a] [1,4] Benzodiazepine-3-carboxy
The sialdehyde is obtained and its methylene chloride/vinegar
Melt after recrystallization from ethyl acid/hexane
The temperature was 190-192°C. Example 8 8-chloro-6-(2-fluor) in 20 ml of pyridine
(orphenyl)-3-hydroxymethyl-1-methane
Chill-4H-imidazo [1.5-1] [1.4] Be
A solution of 0.71 g (2 mmol) of nzodiazepine was
It was treated with 2 ml of hydroacetic acid. After leaving it at room temperature overnight,
The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride.
and sodium bicarbonate solution.
The organic phase was dried and evaporated. The residue is crystallized
Since it was not, methylene chloride/ethyl acetate 1:
Chromatograph on 30 g of silica gel using
Purified by phytochemistry. One homogeneous fraction
Combine and evaporate to give 3-acetoxymethylene
Ru-8-chloro-6-(2-fluorophenyl)-
1-Methyl-4H-imidazo [1.5-a] [1.
4] Benzodiazepine was obtained. This one is
Since it did not crystallize, it was determined qualitatively by spectral analysis.
did. Example 9 Potassium t-butoxide (26g, 0.232mol)
, 300 ml of dimethylformamide and dimalonic acid
50 ml (0.44 mol) of methyl was added to the mixture. nitrogen
After stirring for 10 min under dimethylformamide
7-chloro-2-(N-nitrosomethyl in 100ml)
Amino)-5-phenyl-3H-1,4-benzodi
A solution of 66 g (0.209 mol) of azepine 4-oxide
was added over 10 minutes. Then steam bath the mixture
Heat gently on top and hold at 65℃ for 10 minutes
did. After cooling to room temperature, add 40 ml of glacial acetic acid and continue
water for 30 minutes, stirring occasionally.
(scratching) added. Collect the precipitated crystals,
Washed with water and dissolved in methylene chloride.
Dry the solution over sodium sulfate and reduce the volume to
It was concentrated until Add the product to hexane
7-chlor with a melting point of 188-190℃
-1,3-dihydro-2-(dimethoxymalonyl)
den)-5-phenyl-2H-1,4-benzodia
Zepine 4-oxide was obtained. Samples for analysis are chlorinated
Recrystallized from tyrene/hexane. Melting point is 194
It was ~195℃. (A) 7-chloro-1,3-dihydro-2-(dimethyl
Toximalonylidene)-5-phenyl-2H-
1,4-benzodiazepine 4-oxide 40.8g
(0.1 mol), methanol 250ml, tetrahydrofu
250 ml of orchid and 1 teaspoon of ranee nickel
The mixture was hydrogenated at atmospheric pressure for 5 hours. catalyst
It was removed by filtration and the liquid was evaporated. Residue
Crystallize the residue from methylene chloride/2-propanol
7-chloro-1,3-di
Hydro-2-(dimethoxymalonylidene)-5-
Phenyl-2H-1,4-benzodiazepine
Obtained as colorless crystals with a melting point of 160-163°C.
For analysis, it was reconstituted from 2-propanol.
crystallized. The melting point was 165-166°C. The second modification of the crystal with a melting point of 138-140 °C
were obtained in some cases. (B) Phosphorus trichloride (4 ml), methylene chloride 100 ml
7-chloro-1,3-dihydro-2-(2
-dimethoxymalonylidene)-5-phenyl-
2H-1,4-benzodiazepine 4-oxide
4 g (0.01 mol) of the solution was added. overnight at room temperature
After standing, the solution is diluted with 10% sodium carbonate aqueous solution.
Washed with. Dry and evaporate the methylene chloride layer.
I let it emanate. Crystallize the residue from 2-propanol
and methylene chloride/2-propanol
By recrystallizing from
7-chloro-1,3-dihydro-2-(dimeth)
ximalonylidene)-5-phenyl-2H-1.
4-benzodiazepine was obtained. 7-chloro-1,3-dihydro-2-(dime
Toximalonylidene)-5-phenyl-2H-
1,4-benzodiazepine 115g (0.3mol),
Methanol 1.5 and sodium hydroxide 14.4g
(0.36 mol) under nitrogen atmosphere for 5 hours.
The mixture was heated to reflux for a while. Place the cooled reaction mixture on ice.
Gradually diluted with 2.5 ml of cooled water. precipitation
The crystals were collected, washed with water, and placed in vacuo.
Dry at 60℃ to obtain 7-chloro-1,3-dihydro
-2-(methoxycarbonylmethylene)-5-ph
Enyl-2H-1,4-benzodiazepine is fused.
Obtained as a yellowish product with a temperature of 167-170°C.
It was. Analytical samples were recrystallized from ether.
Ta. The melting point was 171-173°C. Sodium nitrite (2.8g, 0.04mol),
7-chloro-1,3-dihyde in 100 ml of glacial acetic acid
rho-2-(methoxycarbonylmethylene)-5-
Phenyl-2H-1,4-benzodiazepine 8
g (0.025 mol) of the solution. Nitrogenize the mixture
The mixture was stirred subtly for 10 minutes. The product crystallizes after a few minutes
I started doing it. After diluting with 100ml of water, the precipitated raw material
The product was collected, washed with water, dried and tetra
Recrystallized from hydrofuran/methanol,
7-chloro-α-hydroxyimino-5-phene
Nyl-3H-1,4-benzodiazepine-2-
Acetate methyl ester has a melting point of 235-237℃ (decomposition)
Obtained as yellow crystals. 7-chloro-α-hydroxyimino-5-ph
enyl-3H-1,4-benzodiazepine-2
-acetic acid methyl ester (3.6 g, 0.01 mol)
, 200ml of tetrahydrofuran and methanol
Dissolve in 100 ml of the mixture by heating.
I understand. Add raney nitskel (1 teaspoon)
, and then stir the mixture until hydrogen uptake stops.
(1 hour 10 minutes) at atmospheric pressure. catalyst
filtration, and the liquid is finally torrefied.
evaporated azeotropically with ene. Methanol the residue
Dissolved in 20ml. Triethylortho-acetate
3 ml of salt and ethanolic hydrogen chloride (5%)
Following the addition of 0.3ml, the solution was heated to reflux for 5 minutes.
I let it happen. The residue remaining after evaporation is diluted with methylene chloride.
and a saturated aqueous solution of sodium bicarbonate
did. Separate the organic phase, dry and evaporate
Ta. by crystallizing the residue from ether.
, methyl-8-chloro-1-methyl-6-phthalate
enyl-4H-imidazo [1.5-a] [1.
4] Benzodiazepine 3-carboxylate is
methylene chloride/ether/
Melting point after recrystallization from hexane is 254 ~
It was 256℃. Example 10 Methyl 8-chloro-1-methyl-6-phenyl
-4H-imidazo[1.5-a][1.4]benzo
Diazepine 3-carboxylate 7.3g (0.02mol)
), potassium hydroxide 2.24g (0.04mol), methane
A mixture of 200 ml of alcohol and 6 ml of water was heated under reflux for 4 hours.
did. Partially remove the methanol under reduced pressure and
The residue was acidified with glacial acetic acid and water was added.
crystallized. Collect the crystals, wash with water, and
Dry to give 8-chloro-1-methyl-6-phenylene
Ru-4H-imidazo [1.5-a] [1.4] Ben
Yellowish formation of zodiazepine 3-carboxylic acid
Obtained as a thing. Ethyl acetate it for analysis
It was recrystallized from Le. Melting point is 270-273℃ (decomposition)
It was hot. Example 11 Methyl 8-chlor in 50 ml of tetrahydrofuran
-1-methyl-6-phenyl-4H-imidazo
[1.5-a] [1.4] Benzodiazepine 3-ka
A solution of 0.73 g (2 mmol) of ruboxylate,
Water in 20 ml of tetrahydrofuran cooled to -10°C
Lithium aluminum chloride 0.3g (7.5 mmil)
was added to the suspension. Stir the mixture for 30 minutes without cooling following the addition.
Then, 2 ml of water was added for hydrolysis. inorganic matter
and dry and evaporate the liquid.
Ta. Dilute the residue with methylene chloride/ether/hexane.
By crystallizing from
Droxymethyl-1-methyl-6-phenyl-
4H-Imidazo [1.5-a] [1.4] Benzodi
Azepine is obtained as colorless crystals with a melting point of 252-255℃.
It was done. Example 12 8-chloro-6-(2-fluoro) in 10 ml of mineral oil
phenyl)-4H-imidazo[1.5-a][1.
4] Suspension of 1.5 g of benzodiazepine 3-carboxylic acid
The suspension was heated to 230°C for 5 minutes. reaction mixture
Partitioned between 1N hydrochloric acid and ether. Aqueous phase
Alkaline with ammonia and methylene chloride
Extracted with. Dry and evaporate the extract,
and the residue was chlorinated with 25% (v/v) in ethyl acetate.
Chroma on 60g silica gel using methylene
I put it on a tograph. Less polar 8-chlor
-6-(2-fluorophenyl)-6H-imidazo
[1.5-a] [1.4] Benzodiazepine with acetic acid
Crystallized from ethyl, colorless, melting point 195-196°C
crystals were obtained. The larger polar components are crystallized from ether.
8-chloro-6-(2-
fluorophenyl)-4H-imidazo[1,5-
a] [1,4]-benzodiazepine was obtained. Example 13 8-chloro-3-hydroxymethyl-1-methy
-6-phenyl-4H-imidazo[1,5-
a] [1.4] 3 g of benzodiazepine, methic chloride
300ml of Ren and 15g of activated manganese dioxide
The mixture was stirred at room temperature for 1 hour. manga dioxide
The solution was filtered and washed with methylene chloride.
Evaporate the liquid and dissolve the residue in methylene chloride/ether.
Crystallized from tel/hexane, melting point 218-220
8-chloro-1-methyl-6-phenyl- at °C
4H-Imidazo [1.5-a] [1.4] Benzodi
Azepine 3-carboxaldehyde was obtained. Example 14 Methyl 8-chloro-1-methyl-6-phenyl
-4H-imidazo[1.5-a][1.4]benzo
Diazepine 3-carboxylate (0.74g, 2mg)
limol) in 30 ml of methanolic ammonia.
Heated in a sealed container at 120°C for 18 hours. solvent
Evaporate and dissolve the residue in methylene chloride/ethanol.
8-chloro-1-methyl-
6-phenyl-4H-imidazo [1,5-a]
[1.4] Benzodiazepine 3-carboxamide
was obtained as colorless crystals with a melting point of 335-340°C. Example 15 Methyl-8-chloro-1-methyl-6-phenylene
Ru-4H-imidazo [1.5-a] [1.4] Ben
Zodiazepine 3-carboxylate 0.74g (2mg)
Ethanol 20 containing 25% methylamine (Limol) and 25% methylamine
Heat the mixture with ml in a sealed container at 120 °C for 18 h.
did. Evaporate the solvent and dissolve the residue in methylene chloride.
crystallized from ethanol/ethanol, melting point 260-263
8-chloro-1-methyl-6-phenyl- at °C
4H-Imidazo [1.5-a] [1.4] Benzodi
Azepine 3-N-methyl-carboxamide was obtained.
Ta. The analysis sample is tetrahydrofuran/ethanol
It was recrystallized from Example 16 Zinc powder (2 g) was added to 50 ml of methylene chloride and ice.
Methyl 8-chloro-1-methyl-6 in 10 ml of acetic acid
-Phenyl-4H-imidazo [1.5-a] [1.
4] Benzodiazepine 3-carboxylate 1.83
g (5 mmol). Bring the mixture to room temperature
The mixture was stirred for 2 hours. Pass inorganic matter and liquid
was washed with dilute aqueous ammonia. methylene chloride
The solution was dried and evaporated. Treat the residue with chloride
Crystallize from tyrene/ethyl acetate/ether
By this, methyl 8-chloro-5,6-dihyde
rho-1-methyl-6-phenyl-4H-imidazo
[1.5-a] [1.4] Benzodiazepine 3-ka
Ruboxylate is a colorless crystal with a melting point of 233-235℃.
Obtained by doing. Samples for analysis were ethyl acetate/method chloride.
Recrystallized from tyrene/methanol. The melting point is
The temperature was 234-236°C. Example 17 Methyl 8-chloro-6-(2-fluorophene
)-1-methyl-4H-imidazo [1,5-a]
[1.4] Benzodiazepine 3-carboxylene
7.7 g, isobutanol 100 ml and hydrazine 20
ml of the mixture was heated to reflux for 1 hour. obtained after evaporation
The crude product was dissolved in 5% ethanol in methylene chloride.
Chromatograph on 250 g of silica gel using a
I applied it to the graph. Bringing together clear fractions
and evaporated. The residue is diluted with methylene chloride/ether.
8-chloro-6 by crystallization from
-(2-fluorophenyl)-1-methyl-4H-
imidazo[1.5-a][1.4]benzodiaze
Pin 3-carboxylic acid hydrazide has a melting point of 235-237℃
Obtained as colorless crystals. Example 18 Methyl 8-chloro-5,6-dihydro-1-methyl
Chil-6-phenyl-4H-imidazo[1,5-
a] [1,4] Benzodiazepine 3-carboxy
Rayto 7.4g, hydrazine 20ml and isobutanol
200 ml of the mixture was heated to reflux for 3 hours. Decompression
After evaporation, the residue is dissolved in ethanol/ether.
8-Chlorine with a melting point of 225-230℃
-5,6-dihydro-1-methyl-6-phenyl
-4H-imidazo[1.5-a][1.4]benzo
Diazepine 3-carboxylic acid hydrazide was obtained.
Samples for analysis were recrystallized from ethyl acetate/methanol.
I let it happen. The melting point was 228-230°C. Example 19 Methyl 8- in 20 ml of dry dimethylformamide
Chlor-1-methyl-6-phenyl-4H-imi
Dazo [1.5-a] [1.4] Benzodiazepine
Dissolution of 0.73 g (2 mmol) of 3-carboxylate
The liquid was cooled to −30° C. with stirring under nitrogen.
Potassium t-butoxide (0.25 g, 2.2 mmol
methyl iodide) and stirred for 5 minutes.
0.3 g (2.1 mmol) was added. mixture at 1 o'clock
Allow to reach room temperature within a few minutes, then saturate with bicarbonate.
Partitioned between aqueous solution and methylene chloride. Methyl chloride
Wash the tyrene layer with water, dry and evaporate
Ta. by crystallizing the residue from ether.
methyl 8-chloro-1,4-dimethyl-6-
Phenyl-4H-imidazo [1.5-a] [1.
4] Benzodiazepine 3-carboxylate melts
Obtained as colorless crystals with a temperature of 217-221°C. analysis
Samples were recrystallized from ethyl acetate/hexane.
Ta. The melting point was 220-222°C. Example 20 Potassium t-butoxide (0.25 g, 2.2 mmol)
) in dimethylformamide cooled to -30°C.
Methyl 8-chloro-6-(2-fluoro) in 20 ml of
(ruphenyl)-4H-imidazo[1,5-a]
[1.4] Benzodiazepine 3-carboxylene
To a solution of 0.74 g (2 mmol) of under nitrogen
After stirring for 5 minutes at
mmol) and the reaction mixture within 30 min.
The mixture was warmed to room temperature. Then it is aqueous bicarbonate
Partitioned between salt and methylene chloride. water the organic phase
Washed with water, dried and evaporated. Remove the residue
methyl 8-chloro-6-
(2-fluorophenyl)-4-methyl-4H-y
Midazo [1.5-a] [1.4] Benzodiazepi
3-carboxylate is obtained, which is diluted with vinegar.
Melting point after recrystallization from ethyl acid/hexane
The temperature was 190-191℃. Example 21 8-chloro-1-methyl-6-phenyl-4H
-imidazo[1.5-a][1.4]benzodia
Zepine-3-carboxaldehyde (3.4g,
0.01 mol) in 200 ml of ethanol.
It was partially dissolved. hydroxyamine salt
Acid salt (1.05g, 0.015mol) and triethylamide
Add 4 ml of water and stir the mixture until dissolution is complete.
was heated on a steam bath. partially evaporate the solvent
and crystallize by diluting the product with water.
turned into Collect crystals and add ethanol and ether
Clean and dry to a melting point of 280-282℃ (min.
solution) of 8-chloro-1-methyl-6-phenyl-
4H-Imidazo [1.5-a] [1.4] Benzodi
Azepine-3-carboxaldoxime was obtained.
Is the sample for analysis ethanol/tetrahydrofuran?
It was recrystallized from Example 22 8-chloro-1-methyl-6-phenyl-4H
-imidazo[1.5-a][1.4]benzodia
Zepine-3-carboxaldoxime (2.1g)
, 100ml of ethanol and 100ml of tetrahydrofuran
ml by heating. Rune the solution
At atmospheric pressure in the presence of nickel (1 teaspoon)
Hydrogenation was carried out for 3 hours. Pass the catalyst and vaporize the liquid.
I let it emanate. Pour the residue into 2-propanol/ether
crystallized from 3-aminomethyl-8-chloro
-1-methyl-6-phenyl-4H-imidazo
[1.5-a] [1.4] Obtain benzodiazepine
Ta. For analysis, convert it to ethanol/ether.
It was recrystallized from The melting point was 217-219°C. Example 23 8-chloro-3-hydro in 5 ml thionyl chloride
xymethyl-1-methyl-6-phenyl-4H-
imidazo[1.5-a][1.4]benzodiaze
Stir a solution of 1.7 g (0.005 mol) of pin at room temperature for 30 minutes.
Stirred. 8-chloro-3-chloromethyl-1-meth
Chil-6-phenyl-4H-imidazo[1,5-
a] [1.4] Add benzodiazepine hydrochloride to vinegar.
Crystallized by addition of ethyl acid and ether
Ta. Collect the crystals and add methylene chloride and sodium bicarbonate.
and a saturated aqueous solution of aluminum. dry the organic phase
and evaporated. The residue is diluted with methylene chloride/ether.
8-chloro-3 by crystallization from
-chloromethyl-1-methyl-6-phenyl-
4H-Imidazo [1.5-a] [1.4] Benzodi
Azepine is obtained and this is added to sodium methoxychloride.
Heat for 10 minutes in 50 ml of methanol containing 0.5 g of cid.
Refluxed. Evaporate the methanol and the residue
of methylene chloride and a saturated solution of sodium bicarbonate
distributed between. Dry and evaporate the organic phase
Ta. This crude raw material was mixed with methylene chloride/ethyl acetate 1:
3 (v/v) on 30 g of silica gel.
By romatographing, 8-chloro-
3-methoxymethyl-1-methyl-6-phenyl
-4H-imidazo[1.5-a][1.4]benzo
Diazepine crystallized from ethyl acetate/hexane
A colorless substance with a melting point of 163-165℃ after
Obtained as crystals. Example 24 Triethylamine (2 ml) and methoxyamine
0.5 g of hydrochloride in 8-chlor in 40 ml of ethanol
-1-methyl-6-phenyl-4H-imidazo
[1.5-a] [1.4] Benzodiazepine-3-
0.67g (0.002mol) of carboxaldehyde
Added to the oyster solution. The mixture was left for 30 minutes. melt
Partially evaporate the medium and dilute the product with water.
It was crystallized by collect crystals and
Dry, 8-chloro-3-(N-methoxyimino
methyl)-1-methyl-6-phenyl-4H-imi
Dazo [1.5-a] [1.4] Benzodiazepine
I got it. Recrystallize the analytical sample from ether
Ta. The melting point was 193-195°C. Example 25 Pyrrolidine (4 ml) was added to 8-chloro-6-(2
-fluorophenyl)-1-methyl-4H-imida
Zo[1,5-a][1,4]benzodiazepine-
In 1.85 g of 3-carboxylic acid and 250 ml of methylene chloride
A solution of acid chloride prepared from 1.25 g of phosphorus pentachloride of
added to. followed by 10% sodium carbonate aqueous solution 100
ml and the resulting biphasic mixture was diluted with 1 ml at room temperature.
Stir for hours. Separate the organic phase, dry and evaporate.
I let it emanate. Pour the residue into 2-propanol/ether
1-[8-chloro-
6-(2-fluorophenyl)-1-methyl-4H
-imidazo[1.5-a][1.4]benzodia
Zepin-3-oil] Pyrrolidine is a colorless product
was obtained from ethyl acetate/hexane.
The melting point after recrystallization is 220-221℃.
Ta. Example 26 2,2-dimethylhydrazine (10ml) was added to 8-
Chlor-6-(2-fluorophenyl)-1-methy
Ru-4H-imidazo [1.5-a] [1.4] Ben
1.85 g of zodiazepine-3-carboxylic acid and medicinal chloride
Example 25 from 1.25 g of phosphorus pentachloride in 250 ml of tyrene
A solution of acid chloride prepared as described in
added to. Add 100ml of 10% sodium carbonate aqueous solution.
After addition, the mixture was stirred at room temperature for 30 minutes. organic phase
Separated, dried and evaporated. Ete the residue
6 by crystallization from Le/ethanol.
-chloro-6-(2-fluorophenyl)-1-methane
Chill-4H-imidazo [1.5-a] [1.4] Be
Nzodiazepine-3-carboxylic acid 2,2-dimethylate
Ruhydrazide was obtained as a colorless product.
Analytical samples were prepared using 10% (v/v) ethyl chloride in methylene chloride.
Cloth on 30x volume of silica gel using tanol.
Purification was achieved by chromatography. this
Crystallized from methylene chloride/ethyl acetate/hexane
I let it happen. The melting point was 238-240°C. Example 27 8-chloro-6-(2-fluorophenyl)-1
-Methyl-4H-imidazo [1.5-a] [1.
4] Benzodiazepine-3-carboxylic acid 1.85g
(5 mmol), diphenylphosphoric azide
1.5g, dimethylformamide 30ml and triethyl
A mixture of 2 ml of Lamine was stirred at room temperature for 15 minutes.
The solvent is removed under reduced pressure and finally azeotropically with xylene.
I left. Crystallizing the residue from ethyl acetate
8-chloro-6-(2-fluorophenyl)
)-3-(methoxycarbonylamino)-1-meth
Chill-4H-imidazo [1.5-α] [1.4] Be
Nzodiazepine is obtained, which is treated with methylene chloride.
Recrystallized from methanol/ethyl acetate.
The melting point was 270-275°C. The sample for analysis is tetra
Recrystallized from hydrofuran/ethanol. So
The melting point was 272-275°C (decomposition). Example 28 8-chloro-6-(2-fluorophenyl)-1
-Methyl-4H-imidazo-[1.5-a][1.
4] Benzodiazepine-3-carboxylic acid 1.85g
(5 mmol), diphenylphosphoric azide
1.5g, dimethylformamide 10ml, toluene 25
ml and 2 ml of triethylamine at room temperature.
Stir for a minute. Add benzyl alcohol (10ml)
and the mixture was heated to reflux for 30 minutes. Decompression
After evaporating the solvent under
3-(benzyl oxychloride) with a melting point of 250 to 253℃ is crystallized.
(cyclocarbonylamino)-8-chloro-6-(2-ph)
fluorophenyl)-1-methyl-4H-imidazo
[1.5-a] [1.4] Obtain benzodiazepine
Ta. Samples for analysis are methylene chloride/methanol/vinegar
Recrystallized from ethyl acid. Melting point is 253-255℃
It was hot. Example 29 Sodium nitrite (1.8 g, 2.5 mmol) was
8-chloro-5,6-dihydro- in 35 ml of glacial acetic acid
1-Methyl-6-phenyl-4H-imidazo
[1.5-a] [1.4]-Benzodiazepine-3
- 3.7 g (10 mmol) of carboxylic acid hydrazide
Added to solution in portions over 5 minutes. 30 at room temperature
After stirring for a minute, the azide was dissolved by the addition of ice and water.
precipitated. Collect the solid and dissolve in methylene chloride
Dissolved. The solution is mixed with water, sodium bicarbonate solution and
Washed with ice, dried and evaporated. Remove the residue
100ml of methylformamide and 25ml of methanol
Dissolve in the mixture, and for 20 minutes (temperature approx. 103
°C) and heated to reflux. the solvent was removed under reduced pressure;
The residue was then crystallized from methanol/ethyl acetate.
8-chloro-3-methoxycarbonylamine
Nor-1-methyl-5-nitroso-6-phenyl-
5,6-dihydro-4H-imidazo[1,5-
a] [1.4] Benzodiazepine has a melting point of 255-258
Obtained as colorless crystals at °C (decomposition). for analysis
The sample was reconsolidated from tetrahydrofuran/ethanol.
crystallized and their melting points were the same. Example 30 8-chloro-3-methoxycarbonylamino-
1-Methyl-5-nitroso-6-phenyl-5.
6-dihydro-4H-imidazo [1,5-a]
[1.4] Benzodiazepine (2.06 g, 5 mmol)
), 200 ml of tetrahydrofuran and methanol
Dissolved by heating in 100ml of the mixture.
did. Added Raney nitskel (2 teaspoons)
Afterwards, the mixture was hydrogenated at atmospheric pressure for 1 hour. catalyst
It was separated by filtration and the filtrate was evaporated. Residue
By crystallizing the residue from methanol, 8
-chloro-5,6-dihydro-3-(methoxyca
(rubonylamino)-1-methyl-6-phenyl-
4H-Imidazo [1.5-a] [1.4] Benzodi
Azepine is a colorless crystal with a melting point of 280-290℃ (decomposition).
Obtained by doing. The sample for analysis was ethyl acetate/methano
It was recrystallized from a glass. Example 31 Sodium methoxide (0.3g) was added to methanol.
1-acetoxymethyl-8-chloro- in 20ml of
6-(2-fluorophenyl)-4H-imidazo
[1.5-a] [1.4] 1 g of benzodiazepine
added to the solution. After 10 minutes at room temperature, separate
Collect the crystals, add aqueous methanol, methanol and
Washing with ether gives the colorless 8-chloro-6-(2
-fluorophenyl)-1-hydroxymethyl-
4H-Imidazo [1.5-a] [1.4] Benzodi
I got azepine. The sample for analysis was methylene chloride/ethyl chloride.
Recrystallized from tanol. Its melting point is 258-260
It was warm at ℃. Example 32 8-chloro-6-(2-fluorophenyl)-1
-Hydroxymethyl-4H-imidazo[1,5-
a] [1.4] Benzodiazepine 0.2g, Methyl chloride
20 ml of Ren and 1 g of activated manganese dioxide
The mixture was stirred at room temperature for 2 hours. manganese dioxide
was removed by passing it through Celite, and then
The filtrate was evaporated. The residue was dissolved in methylene chloride/acetic acid.
By crystallizing from ethyl/hexane,
8-chloro-6-(2-fluorophenyl)-4H
-imidazo[1.5-a][1.4]benzodia
Zepine-1-carboxaldehyde is a colorless crystal
The melting point was 182-183°C. Example 33 N-bromsuccinimide (13.7g, 0.077mol)
) in 450 ml of chloroform and 30 ml of glacial acetic acid.
8-chloro-6-(2-fluorophenyl)-1-
Methyl-4H-imidazo [1.5-a] [1.4]
Stirring of benzodiazepine (10 g, 0.030 mol)
and added to the solution. Stir the mixture under reflux for 1.5 h.
Stir and then cool. The mixture was then diluted with sodium bicarbonate.
Wash with thorium saturated solution and chloroform
The layers were dried and evaporated. Boe oily residue
Using 150g of Woelm neutral aluminum oxide.
It was chromatographed using Salt the impurities first
Removed with methylene chloride and then purified with ethyl acetate.
I took out things. Combine the fractions containing the product.
Combined and evaporated. Crystallize the residue with ether
3-build with a melting point of 201-205℃
rom-8-chloro-6-(2-fluorophene
)-1-methyl-4H-imidazo[1,5-a]
[1.4] Benzodiazepine was obtained. Sample for analysis
was recrystallized from ether/hexane. The fusion
The temperature was 203-205°C. Example 34 Phosphorus pentachloride (1.25 g, 0.006 mol) was added to
8-chloro-6-(2-fluoro) in 250 ml of tyrene
phenyl)-1-methyl-4H-imidazo[1.5
-a] [1,4] Benzodiazepine-3-carbo
was added to a suspension of 1.85 g (0.005 mol) of phosphoric acid. ice
After stirring in the bath for 30 minutes, add 15 ml of diethylamine.
followed by 100ml of 10% sodium carbonate aqueous solution.
added. The resulting biphasic system was stirred at room temperature for 30 minutes.
Separate the organic phase and dry over sodium sulfate.
and evaporated. Dilute the residue with methylene chloride/ether
8 with a melting point of 182-188℃.
-chloro-N・N-diethyl-6-(2-fluoro
(ruphenyl)-1-methyl-4H-imidazo[1.
5-a] [1.4] Benzodiazepine-3-cal
Boxamide was obtained. The sample for analysis is ethyl acetate/
Recrystallized from hexane. Its melting point is 183-185
It was warm at ℃. Example 35 2-(dimethylamino)ethylamine (5ml)
, 8-chloro-6-(2-fluorophenyl)-
1-Methyl-4H-imidazo [1.5-a] [1.
4] Benzodiazepine-3-carboxylic acid 1.85g
(5 mmol) and lithium pentachloride in 250 ml of methylene chloride.
Prepared as described in Example 34 from 1.25 g of
was added to the acid chloride solution. 10% sodium carbonate
Add 100 ml of aqueous solution and then leave the mixture at room temperature for 30 min.
Stir for a while. Separate the methylene chloride layer and dry it.
and evaporated. The residue was dissolved in 2-propanol/A
It is crystallized from 8-chloride with a melting point of 209-211℃.
Lor-N-(2-dimethylaminoethyl)-6-
(2-fluorophenyl)-1-methyl-4H-y
Midazo [1.5-a] [1.4] Benzodiazepi
3-carboxamide was obtained. The sample for analysis is vinegar.
Recrystallized from ethyl acid/hexane. its melting point
The temperature was 210-213℃. Example 36 Methanolic ammonia (20 ml, 25%) was added to 8
-chloro-6-(2-fluorophenyl)-1-methane
Chill-4H-imidazo [1.5-a] [1.4] Be
1.85 g of nzodiazepine-3-carboxylic acid and medicinal chloride
Example from 1.25g of phosphorus pentachloride in 250ml of tyrene
34 to a solution of acid chloride prepared as described in 34.
I got it. After stirring for 10 minutes, add 10% aqueous sodium carbonate solution.
50ml was added and stirring continued for 1 hour at room temperature.
Separate the methylene chloride layer, dry and evaporate
Ta. The residue was dissolved in a mixture of methylene chloride and ethanol.
dissolved in it. Pass the solution over a bed of silica gel.
The liquid was evaporated. The residue is separated from ethanol.
By crystallization, 8-chloro-6-(2-
fluorophenyl)-1-methyl-4H-imidazo
[1.5-a] [1.4] Benzodiazepine-3-
The carboxamide was obtained as colorless crystals. minutes
The sample for analysis is made from ethanol/tetrahydrofuran.
Recrystallized. Its melting point is 300-305℃
Ta. Example 37 Dimethylamine (4 ml) was added to 8-chloro-6-
(2-fluorophenyl)-1-methyl-4H-y
midazo[1,5-a][1,4]-benzodiazepi
1.85 g (0.005 mol) of carbon-3-carboxylic acid and chloride
1.25 g (0.006 mole) of phosphorus pentachloride in 250 ml of methylene
was made as described in Example 34 from
Added to acid chloride solution. Stirred at room temperature for 1 hour
After that, the reaction mixture was washed with 10% aqueous sodium carbonate solution.
Cleaned, dried and evaporated. The residue is treated with chloride
Using 5% (v/v) ethanol in tyrene
By chromatography on 40 g of silica gel.
and purified. Combine clear fractions
By crystallizing from ether/hexane,
8-chloro-6-(2-fluorophenyl)-1-
N・N-trimethyl-4H-imidazo[1,5-
a] [1,4] Benzodiazepine-3-carboxy
The samide is obtained as colorless crystals, the melting point of which is
The temperature was 177-179℃. Low with melting point 158-160℃
Melting point modifications were also obtained. Example 38 In 150 ml of dry tetrahydrofuran under argon
7-cyano-2,3-dihydro-5-(2-ph)
fluorophenyl)-1H-1,4-benzodiazepi
A solution of 10 g (0.0358 mol) of ion-2-one was added to 54% water.
treated with 2.4 g (0.0537 mol) of sodium chloride,
and the reaction mixture was stirred and refluxed for 1 hour.
Ta. This was cooled to 0°C and the phosphorodimol
Added 13.7g (0.0537mol) of holizic chloride.
Ta. After 18 hours strain the reaction mixture and reduce to a small volume.
Concentrate until dry and add ether. the precipitate
and a mixture of dichloromethane and ether.
By recrystallizing from the compound, 7-cyano-
5-(2-fluorophenyl)-2-bis-(mol
phorino)phosphinyloxy-3H-1,4-be
Nzodiazepine is obtained as white rod-like crystals;
The melting point was 194-197°C. Example 39 Dry N.N-dimethylformamide under nitrogen
1.6g of 54% sodium hydride per 100ml
(0.036 mol) and acetamidodiethyl
While stirring 8.3 g (0.038 mol) of lumalonate
added. After 30 minutes, 7-cyano-5-(2-fluoro
(ruphenyl)-2-bis(morpholino)phosphine
Nyloxy-3H-1,4-benzodiazepine 10
g (0.02 mol) and after 64 hours the reaction mixture was
The mixture was poured into ice water containing 4 ml of acetic acid. this
filtrate and dissolve the solid in 100 ml of methylene chloride.
Dissolve, wash the solution with 50 ml of water, and dilute with anhydrous sodium sulfate.
The mixture was dried on a platter and concentrated to a small volume.
This solution was chromatographed on a Florisil column.
and then elute with dichloromethane 2.
I threw away that. Next, dichloromethane and ether
mixture (10/1) of 1 part and then 2 parts of ether.
It eluted. Ether fraction to dichlormeth
recrystallized twice from a mixture of ion and ether.
(acetylamino)[7-cyano-5-
(2-fluorophenyl)-3H-1,4-benzo
Diazepin-2-yl malonate diethyl ester
is obtained as a white prism, and its melting point is
The temperature was 138-140℃. Fill the column with a mixture of ethyl acetate and methanol
(10/1) eluted at 1.5. Concentrate the eluent and
The residue was crystallized from ether. Dichlorme
Recrystallization from a mixture of tane and ether
ethyl 8-cyano-6-(2-fluoro)
phenyl)-1-methyl-4H-imidazo[1.5
-a] [1,4] Benzodiazepine-3-carbo
Xylate is obtained as yellowish prisms.
Its melting point was 272-274°C. Example 40 Ethyl 8-silane in 100 ml ethanol and 10 ml water
Ano-6-(2-fluorophenyl)-1-methyl
-4H-imidazo[1.5-a][1.4]benzo
Diazepine-3-carboxylate 0.5g
(0.00129 mol) solution of potassium hydroxide 0.14g
(0.0026 mol). After refluxing for 30 minutes,
Evaporate the reaction mixture and add 10 ml of water.
Ta. This is acidified with acetic acid, filtered and dichloromethane.
Extract with 20 ml of methane, separate the extract and dry.
and evaporated. Approximately 0.2g of hydrolyzed product
was obtained by filtration and the same amount was obtained by extraction.
It was done. Dissolve this material in dry hexamethylphosphorus.
Add to 3 ml of foramide and under argon for 30 min.
The temperature was maintained between 200 and 205°C. let it cool, and
50 ml of ice water and 1 ml of ammonium hydroxide were added.
Strain the solution and add 25 ml of dichloromethane.
and evaporated to dryness. The water
add and strain the solution and combine the precipitate with
dissolved in dichloromethane, and 15% meth
Two sheets of silica in a solution of ethyl acetate containing
It was spread on a gel thick plate. Silicage containing products
scrape off (R _f 0.4-0.5), with methanol
Stir and filter. Add this to isopropanol
by crystallization from a mixture of
8-cyano-6-(2-fluorophenyl)-
1-Methyl-4H-imidazo [1.5-a] [1.
4] Benzodiazepine is a yellowish prism
The melting point was 198-203°C. Example 41 300ml of tetrahydrofuran and 200ml of methanol
7-chloro-5-(2-fluorophenyl)-
α-Hydroxyimino-3H-1,4-benzodi
Methyl ethyl azepine-2-acetate 3.75g (0.01
mol) of Raney nickel solution with 1 teaspoon of Raney nickel.
Hydrogenated in the presence of hydrogen at atmospheric pressure for 1 1/2 hours. catalyst
Separate by filtration on Celite and reduce the liquid.
under pressure and finally evaporated azeotropically with toluene.
Ta. Dissolve the residue in 20 ml of pyridine and chloride
Treated with 4 ml of benzoyl. Leave at room temperature for 15 minutes
After that, the reaction mixture was diluted with methylene chloride and 1N sodium hydroxide.
Partitioned between thorium solution. dry the organic layer
and finally evaporated azeotropically with toluene.
Ta. by crystallizing the residue from ether.
2-(benzoylamino) with a melting point of 210-213℃
Methoxycarbonylmethylene]-7-chloro-5
-(2-fluorophenyl)-1,3-dihydro-
2H-1.4-benzodiazepine was obtained. for analysis
The sample was recrystallized from ethyl acetate/hexane.
This material softens at 150-160℃ and has a melting point of 217-219
It was warm at ℃. in 10 ml of hexamethylphosphoric triamide.
2 [(benzoylamino)-methoxycarbonyl
tylene]-7-chloro-5-(2-fluorophene
)-1,3-dihydro-2H-1,4-benzodi
A solution of 1.15 g (2.5 mmol) of azepine for 10 minutes.
Heat to reflux. Add the dark mixture to the water.
and ether/methylene chloride. Yes
The organic layer was washed with water, dried and evaporated. Residue
The residue was dissolved in methylene chloride and activated
The mixture was filtered over aluminum oxide with ethyl acetate.
Evaporate the liquid and 10% in methylene chloride
(V/V) 20g of silica gel using ethyl acetate
Chromatographed on a tube. clear flax
Crystallize from ether/hexane together
Methyl 8- with a melting point of 208-209℃
Chlor-6-(2-fluorophenyl)-1-phene
Nil-4H-imidazo[1.5-a][1.4]be
Nzodiazepine-3-carboxylate was obtained. Example 42 Methyl 8-chloro-6 in 50 ml of refluxing methanol
-(2-fluorophenyl)-1-phenyl-4H
-imidazo[1.5-a][1.4]benzodia
Zepin-3-carboxylate 2.66g 5.77 mm
755 ml of potassium hydroxide in 10 ml of water
(11.5 mmol), and obtain
The mixture was heated for 2.5 hours. Remove solvent in vacuo
The residue was dissolved in 50 ml of hot acetic acid and the solution
Pour into 100ml of cold water. Collect the product and wash with water.
By washing and air drying, the 8-chlor
-6-(2-fluorophenyl)-1-phenyl-
4H-Imidazo [1.5-a] [1.4] Benzodi
Azepine 3-carboxylic acid forms a yellowish solid.
obtained. Samples for analysis were recrystallized from benzene.
Its melting point was 267-269°C. Example 43 8-chloro-6-(2-fluoro) in 20 ml of mineral oil
phenyl)-1-phenyl-4H-imidazo[1.
5-a] [1.4] Benzodiazepine-3-cal
A suspension of 1.5 g (3.48 mmol) of bonic acid was prepared at 190°C.
Stir vigorously for 1/2 hour. Next, a dark suspension
Slurry the liquid with hexane and add 1N hydrochloric acid.
Extracted twice. The acidic aqueous layer was then diluted with hexane.
washed twice and neutralized with 5% aqueous sodium carbonate.
did. Collect the precipitated product and air dry.
additional yield can be obtained by concentrating the liquid;
8-chloro-6-(2-fluorophenyl)-1-
Phenyl-4H-imidazo [1.5-α] [1.
4] Benzodiazepine as a yellowish solid
Obtained. Samples for analysis are column coated on silica gel.
Romatograph and drain with ethyl acetate.
Obtained by. The melting point was 241-243°C. Example 44 8-chloro-6-(2-
Fluoro-phenyl)-1-phenyl-4H-imy
Dazo [1.5-a] [1.4] Benzodiazepine
-3-Carboxylic acid 1.0g (2.31 mmol) solution
reflux for 1/2 hour, then add cold 40% aqueous dimethyl
Carefully poured into 70ml of amine. Collect the brown solid
washed with water, dried and acetic acid as eluent.
Chromatograph on silica gel using ethyl
By applying N.N-dimethyl-[8-
Chlor-6-(2-fluorophenyl)-1-phene
Nil-4H-imidazo[1.5-a][1.4]be
Nzodiazepine]-3-carboxamide has a brown color
Obtained as a foam. Reconstitute three times from acetone/water
By crystallization, the melting point is 221-223℃ for analysis.
A sample was obtained. Example 45 8-chloro-6-(2-
Fluorophenyl)-1-phenyl-4H-imida
Zo[1,5-a][1,4]benzodiazepine-
A solution of 1.0 g (2.31 mmol) of 3-carboxylic acid
Reflux for 1/2 hour, then cool ammonium hydroxide 70
ml carefully dropwise. Collect the pink solid and add water
Wash, air dry and use ethyl acetate as eluent.
Chromatographed on silica gel using
8-chloro-6-(2-fluoro
(ruphenyl)-1-phenyl-4H-imidazo
[1.5-a] [1.4] Benzodiazepine-3-
The carboxamide was obtained as a brown foam.
For analysis by tritylation with acetone
The sample was obtained as a white powder with a melting point of 260-262℃.
Ta. Example 46 7-chloro-5-(2-fluorophenyl)-2
−[Bis(morpholino)phosphinyloxy]3H
-1,4-benzodiazepine (5.3g, 0.01mol)
The malts were pre-stirred for 5 min at room temperature under nitrogen.
10ml of dimethyl phosphate, 20ml of dimethylformamide and
and potassium t-butoxide 2.2g (0.02mol)
Added to the mixture. The reaction mixture is then stirred,
and heated on a steam bath for 15 minutes. 1.5ml glacial acetic acid
After adding , gradually dilute the product with water.
crystallized. Collect the precipitated crystals and wash with water.
and dried in vacuo to give 7-chloro-5-
(2-chloro-phenyl)-2-dimethoxy-malo
Nylidene-1,3-dihydro-2H-1,4-be
Nzodiazepine was obtained and this was used for analysis.
The melting point of the product recrystallized from ethyl acetate is 205
It was -207℃. 7-chloro-5-(2-chlorophenyl)-2-
Dimethoxymalonylidene-1,3-dihydro-2H
-1,4-benzodiazepine 12.6g (0.03mol)
), methanol 300ml and potassium hydroxide 2.1g
(0.0375 mol) was heated under nitrogen for 4 1/2 hours.
Heat to reflux, distill off 200 ml of methanol, and
The residue was diluted with water. Collect the separated crystals and add water
Washed and dried to give a 7-
Chlor-5-(2-chlorophenyl)-2,3-di
Hydro-2-[(methoxycarbonyl)methylene]
-1H-1,4-benzodiazepine was obtained. analysis
Reconstitute it from methylene chloride/methanol for
The melting point of the crystallized product was 158-159°C. Sodium nitrite (2.2 g, 0.031 mol) on ice
7-chloro-5-(2-chlorophene) in 75 ml of acetic acid.
)-2,3-dihydro-2[(methoxycarbo
Nyl)-methylene]-1H-1,4-benzodiaze
Add 7.2 g (0.02 mol) of pin to a stirred solution for 5 minutes.
Add it little by little over time. another 15 minutes
After stirring, the mixture is diluted with 100 ml of water and
Collect the precipitated crystals and add water, methanol and ether.
Crude 7-chloro-5-
(2-Chlorphenyl)-α-hydroxyimino-
3H-1,4-benzodiazepine-2-methyacetate
This gives a tetrahydrofuric acid ester.
By recrystallizing from oran/methanol,
Pale yellow crystals with a melting point of 223-225°C (decomposed) were obtained. 100ml of tetrahydrofuran and 50ml of methanol
7-chloro-5-(2-chlorophenyl)-α in
-Hydroxyimino-3H-1,4-benzodia
Zepin-2-acetic acid methyl ester 3.9g (0.01mol)
2 teaspoons of Raney nickel solution.
Hydrogenation was carried out for 1 1/2 hours at atmospheric pressure. catalyst
filtration, and the liquid is finally purified by toluene.
The mixture was evaporated azeotropically. Ethanol the residue
Dissolved in 20ml. Triere orthoacetate
(3 ml) and 0.2 ml of ethanolic hydrogen chloride (10%)
was added and the mixture was heated to reflux for 15 minutes, then
evaporated until dry. The residue was dissolved in methylene chloride.
Partitioned between saturated aqueous bicarbonate solution. organic phase
Separate, dry over sodium sulfate, and evaporate
I let it happen. Crystallize the residue from methylene chloride/ether
methyl 8 with a melting point of 225-227℃
-chloro-6-(2-chlorophenyl)-1-methy
Ru-4H-imidazo [1.5-a] [1.4] Ben
Zodiazepine-3-carboxylate was obtained. minutes
The sample for analysis was made from 2-propanol and ethyl acetate.
Recrystallized. Its melting point was 228-230°C. Example 47 Methyl 8-chlor in 10 ml of tetrahydrofuran
-6-(2-chlorophenyl)-1-methyl-4H
-imidazo[1.5-a][1.4]benzodia
Zepine 3-carboxylate 1.2g (3 mmol)
) in 30 ml of ether cooled to 10°C.
Lithium aluminum hydride 0.4g (10mm
1) was added to the suspension. Following the addition, the mixture
Stir at room temperature for 10 minutes, then add 2 ml of water to rehydrate.
Disassembled. Filter the inorganic matter and evaporate the liquid
Ta. The residue was crystallized from methylene chloride/ether.
8-chloro- with a melting point of 215-217℃
6-(2-chlorophenyl)-3-hydroxymethy
Ru-1-methyl-4H-imidazo [1,5-a]
[1.4] Benzodiazepine was obtained. Sample for analysis
was recrystallized from tetrahydrofuran/hexane.
Ta. The melting point was 217-218°C. Example 48 7-chloro-5-(2-chlorophenyl)-α-
Hydroxyimino-3H-1,4-benzodiase
Pin-2-acetic acid methyl ester (7.8 g, 0.02 mole
), 200 ml of tetrahydrofuran and ethanol
Dissolve by heating in 100ml of the mixture.
Ta. Presence of solution with Raney nickel (2 teaspoons)
The mixture was hydrogenated at atmospheric pressure for 2 hours. celite catalyst
Separate by filtration on top and evaporate the liquid under reduced pressure.
I let it emanate. Crystallizing the residue from ethanol
2-[(amino)-methoxycarbonyl
Methylene]-7-chloro-5-(2-chlorophenylene)
)-1,3-dihydro-2H-1,4-benzodi
Azepine has an orange color with a melting point of 115-117℃ (decomposition)
Obtained as crystals. This solvated product is
By recrystallizing from ether/hexane,
Yellow needle-shaped crystals with melting point 145-150°C (decomposition)
was gotten. Acetaldehyde (0.25ml), methylene chloride
2-[(amino)methoxycarbonylmethylene in 25ml
Ren]-7-chloro-5-(2-chlorophenyl)
-1,3-dihydro-2H-1,4-benzodia
Added to a solution of 0.5 g of zepine. molecular sieve
sieves) Following the addition of 5A, the mixture was incubated at room temperature for 15
Stir for a minute. Then activated man dioxide
Add gun (1g) and continue stirring for 30 minutes
Ta. The solid material is separated by filtration over Celite;
The liquid was then evaporated. The residue was dissolved in ethyl acetate/hexane.
By crystallizing from xane, the melting point is 228−
Methyl 8-chloro-6-(2-chlorophene) at 230℃
Nyl)-1-methyl-4H-imidazo[1,5-
a] [1,4] Benzodiazepine-3-carboxy
I got Silate. Example 49 Hydrogen in 315 ml of dimethylformamide under nitrogen
4 g (0.09 mol) of a 54% dispersion of sodium chloride in mineral oil
Add the stirred suspension of diethylacetamide
Treatment with 21g (0.096mol) of Ronate in several doses.
I understood. Continue stirring at room temperature for 30 minutes, then
Lor-5-(2-chlorophenyl)-2-[bis
(morpholino)phosphinyloxy]-3H-1.
31.4 g (0.06 mol) of 4-benzodiazepine once
I added it. After further stirring at room temperature for 7 hours,
Pour the mixture onto ice and acetic acid with stirring,
and diluted with water (approximately 2) to form a cream-colored solid.
I got it. Filter the solids, wash with water and place on a funnel.
Air-dried with acetylamino[7-chloro-
5-(2-chlorophenyl)-3H-1,4-ben
Zodiazepin-2-yl] diethyl ester malonate
Got a tell. Warm the dried product on a steam bath
until dissolved with a small amount of 2-propanol.
Stirred. Cool to room temperature to obtain a yellowish solid.
Ta. Recrystallize the sample from 8 times the volume of ethanol.
As a result, acicular microcrystals with a temperature of 153-155°C were obtained.
0.8g of metallic sodium in 50ml of absolute ethanol
natri by dissolving (0.04 g atom)
Make a solution of methoxide and put it in a drying tube.
I moved over and protected it. Acetylamino [7-chloro-
5-(2-chlorophenyl)-3H-1,4-ben
Zodiazepin-2-yl] diethyl ester malonate
(10.1 g, 0.02 mol) was added to the stirred solution.
solution in one go and at room temperature in a dry atmosphere for 5 minutes.
Stirring was continued for an hour. Acidify the resulting mixture with acetic acid
and concentrated in vacuo. Dilute the residue with water
Partition between ammonium oxide and methylene chloride
Ta. After separating the layers, the organic layer was poured over sodium sulfate.
and evaporated under reduced pressure to a yellow-brown color.
A shaped solid was obtained. Dissolve the solid in 75 ml of absolute ether.
and 4 g of maleic acid in 200 ml of ether.
into a warm solution of A small amount of brown rubbery substance
After decanting, place the solution on a steam bath for approx.
It was concentrated to 100ml. At room temperature, stirring occasionally
Upon cooling, crystallization occurred after about 30 minutes. Conclusion
When crystallization is complete, orange crystals are formed and ether
and air dry on the funnel for 2-
[(acetylamino)ethoxycarbonyl methyl
]-7-chloro-5-(2-chlorophenyl)-
1,3-dihydro-2H-1,4-benzodiaze
Obtained pin maleate. Add a small amount of sample to ethyl acetate
(5ml/g), melting point 139-142℃
Yellow needle-like microcrystals of (decomposition) were obtained. 2-[(A) in 15 ml of hexamethylphosphoramide
Cetylamino)ethoxycarbonylmethylene〕-
7-chloro-5-(2-chlorophenyl)-1.3
-dihydro-2H-1,4-benzodiazepine 3.2
A solution of g (0.0073 mol) was stirred under nitrogen and
and heated at 200-210°C for 10 minutes. cooled to room temperature
After that, pour the solution into ice water and let the precipitation complete.
diluted with plenty of water until Pass through the tan solid.
washed with water and air dried on the funnel. vinegar
Stir with ethyl acid (2 ml/g) to dissolve the solid.
and immediately recrystallized. yellowish brown solid
1:1 ethyl acetate/petroleum ether
and air dry with ethyl 8-chlor.
-6-(2-chlorophenyl)-1-methyl-4H
-imidazo[1.5-a][1.4]benzodia
Zepin 3-carboxylei was obtained. sample with chloride
Methyl chloride is obtained by boiling from a tyrene/ethyl acetate solution.
The melting point is recrystallized by removing the
Yellowish needle-shaped crystals were obtained at 214-215°C. Example 50 Potassium hydroxide 1.2g (0.02mol) and water 3ml
Ethyl 3-chlor in 100 ml of methanol containing
-6-(2-chlorophenyl)-1-methyl-4H
-imidazo[1,5-a][1,4]-benzodia
Zepin-3-carboxylate 4.1g (0.01mol)
Heat the stirred solution of
Allow to flow and concentrate under reduced pressure to remove methanol.
I left. Dissolve the residue in cold water and acidify with acetic acid.
A yellowish solid was obtained. overnight on the funnel
After air drying, 8-chloro-6-(2-chlor
phenyl)-1-methyl-4H-imidazo[1.5
-a] [1,4] Benzodiazepine-3-carbo
obtained phosphoric acid. Samples in methylene chloride/ethanol
By recrystallizing from
White platelets of solution) were obtained. Example 51 Ethyl 8-chloro-6- in 25 ml of methylene chloride
(2-chlorophenyl)-1-methyl-4H-imy
Dazo[1,5-a][1,4]-benzodiazepine
-3-carboxylate 1.2 g (0.0031 mol)
Cool the stirred suspension in an ice bath and divide
treated with 0.7 g (0.004 mol) of phosphorus pentachloride.
Ta. The mixture is protected by a drying tube and kept in a cold state.
Continue stirring for at least 30 minutes, during which time most of the solids are
Dissolved. While continuing to cool and stir, stir the mixture.
Treated with gaseous ammonia for 5 min, and further 30 min.
Stir at low temperature for a minute. Evaporate the mixture in vacuo
A light solid is obtained, which is added to dilute aqueous ammonia.
Stir with a sieve and through a coarse sintered glass funnel.
passed. After washing with water, the solids are air-fed onto the funnel.
Dry to give 8-chloro-6-(2-chlorphenylene)
)-1-methyl-4H-imidazo[1,5-a]
[1.4] Benzodiazepine-3-carboxamide
I got a de. The sample was diluted with 2:1 methylene chloride/ethano.
melting point 318 by recrystallizing from a solution of
White plate crystals at -320°C (decomposed) were obtained. Example 52 8-chloro-6-(2-chlorophenyl)-3-
Hydroxymethyl-1-methyl-4H-imidazo
[1.5-a] [1.4] Benzodiazepines (3.7
g, 0.01 mol) with stirring and 20 ml of thionyl chloride.
added to. After stirring for 30 minutes at room temperature, the product salt
Dilute the acid salt with 30 ml of ethyl acetate and 100 ml of ether.
It was crystallized by dilution. Collect crystals and
and diluted with methylene chloride and sodium bicarbonate.
Partitioned between saturated aqueous thorium solutions. methylene chloride
Dry and evaporate the dye layer and evaporate the residue.
8-chlor by crystallization from
-3-chloromethyl-6-(2-chlorophenylene)
)-1-methyl-4H-imidazo[1,5-a]
[1.4] Benzodiazepines as colorless crystals
This product does not melt even when slowly heated.
Katsuta is melted at 200-210℃ by capillary immersion.
Ta. Analytical samples were reconsolidated from ethyl acetate/hexane.
crystallized. Example 53 8-chloro-3-chloromethyl-6-(2-chloromethyl)
(rolfenyl)-1-methyl-4H-imidazo
[1.5-a] [1.4] 2 g of benzodiazepine,
10ml diethylamine and 10ml tetrahydrofuran
The mixture was heated at 100° C. for 2 hours in a sealed tube.
The solvent was evaporated and the residue was dissolved in methylene chloride and
Partitioned between 10% aqueous sodium carbonate solution. organic
Dry and evaporate the phase and evaporate the residue.
8-chloro, melting point 136-138°C, crystallized from
-6-(2-chlorophenyl)-3-dimethyla
Minomethyl-1-methyl-4H-imidazo [1.
5-a][1.4]benzodiazepine was obtained. child
of substance was dissolved in 10 ml of ethanol and 2 equivalents of
of ethanolic hydrogen chloride. in the ether
By diluting and crystallizing, 8-chloro-
6-(2-chlorophenyl)-3-dimethylamino
Methyl-1-methyl-4H-imidazo[1,5-
a] [1.4] Benzodiazepine dihydrochloride
-ethanol is obtained as colorless crystals;
reconsolidate from ethanol/ether for analysis.
The melting point of the crystallized product was 275-277°C. Example 54 8-chloro-3-chloromethyl-6-(2-chloromethyl-6-(2-chloromethyl)
(rolfenyl)-1-methyl-4H-imidazo
[1.5-a] [1.4] 1 g of benzodiazepine,
Potassium cyanide 250mg and dimethylformamide
20 ml of the mixture was placed on a steam bath for 3 hours with stirring.
Heated. After diluting with water, the mixture is diluted with methylene chloride.
Extracted with Wash the extract with water and dry it.
and evaporated. The residue was dissolved in methylene chloride/ethyl acetate.
Chroma on 30g silica gel using 1:2
to a graph, and the clear fraction is extracted.
By crystallizing from ether, the melting point is 212−
8-chloro-6-(2-chlorophenyl) at 214℃
-3-cyanomethyl-1-methyl-4H-imida
Zo[1,5-a][1,4]benzodiazepine
Obtained. Analytical samples were reconstituted from ethyl acetate/hexane.
It crystallized and its melting point was 215-217°C. Example 55 1,3-di in 500 ml of dry tetrahydrofuran
Hydro-5-(2-fluorophenyl)-7-nito
rho-2H-1,4-benzodiazepine-2-one
29.9 g (0.1 mol) of the stirred solution was added to the hydrogenated solution.
5.5 g (0.125 mol) of a 54% mineral oil dispersion of thorium
Treat in portions under argon and for 1 hour.
Stirring was continued for a long time. Dimorpholinophosphincro
Dark solution obtained from lido (38 g, 0.15 mol)
in one batch and stirred under argon for 8 hours.
continued. The resulting blackish mixture is poured over a superaid.
by filtration and concentration in vacuo at 50 °C.
A dark, rubbery substance was obtained. blackish rubbery substance
Stir in 75 ml of ethyl acetate at room temperature to crystallize.
That's how I got the base. Cool in ice bath for 30 minutes
After washing, the mixture was filtered and a light tan solid was obtained.
3 times with 1 ethyl/ethyl acetate 35 ml each and final
was washed with ether. Air dry on funnel
almost pure 5-(2-fluorophore)
)-2-[bis(morpholino)phosphinyl
[oxy]-7-nitro-3H-1,4-benzodiaze
Got the pin. Recrystallize from 15 times the volume of ethyl acetate.
Yellowish needle-like substance with a melting point of 169-172℃
Obtained crystals. Sodium hydride in 55 ml of dry dimethylformamide
0.85 g (0.018 mol) of a 54% mineral oil dispersion of
Add the stirred suspension to diethylacetamidomarone
Process under argon with 3.5 g of light in small portions.
did. After stirring for 30 minutes, the 5-(2-fluorophore
enyl)-2-[bis(morpholino)-phosphini
[ruoxy]-7-nitro-3H-1,4-benzodi
Add 5.2 g (0.01 mol) of azepine at once, and
Stirring was continued for more than 7 hours under argon. black
Add the mixture to a stirred mixture of ice and acetic acid.
and diluted with water to form a brownish yellow solid.
I got a body. Wash the solid with water and air over the funnel.
A residue was obtained after drying. thin layer chromatography
(ethyl acetate) _f with 0.8, 0.5 and 0.25
Three yellow spots were shown. as eluent
Chromatograph on silica gel using ethyl acetate
By applying it roughly, R _f Ethi with 0.25
6-(2-fluorophenyl)-1-methyl-8
-Nitro-4H-imidazo [1.5-a] [1.
4] Benzodiazepine 3-carboxylate is brown
Obtained as a pale yellow solid. hot acetic acid
by dissolving in a chill and cooling in a water bath.
Then, the sample was recrystallized from ethyl acetate (5 ml/g).
By doing this, a yellow prism with a melting point of 231-233℃ is produced.
Obtained. Example 56 54% Sodium Hydride (11 g,
0.25 mol) in tetrahydrofuran 1
ROM-1,3-dihydro-5-(2-pyridyl)-
2H-1,4-benzodiazepine-2-one 63.2
g (0.2 mol) in a stirred solution under argon.
Divide and add. After refluxing for 1 hour on a steam bath,
The solution was cooled to room temperature and dimorpholinophosphide was added.
Divided and treated with 76.2g (0.3mol) of nickel chloride.
I understood. Stirring was continued for 5 hours at room temperature. hot mix
The mixture was passed through Celite. liquid in vacuum
Concentrate and boil the dark residue in ether.
Possibly 7-bromo-2-[bis(morpholy
) Phosphinyloxy]-5-(2-pyridyl)
Yellow-brown crystals of -3H-1,4-benzodiazepine
I got it. Dissolve the sample in 2 ml of methylene chloride,
filtered, diluted with 10 ml of ethyl acetate and cooled in an ice bath.
It is recrystallized by cooling to a melting point of 180-182℃.
(Decomposition) Obtained pale yellowish brown plate crystals. Diethylacetamide malonate (43g, 0.2
mol) in 500 ml of dry dimethylformamide.
10 g of a 50% dispersion of sodium hydride in mineral oil
(0.2 mol) was added to the suspended suspension. The mixture was heated under argon for 1 hour at room temperature and evaporated.
The mixture was stirred for 20 minutes while heating on a gas bath. then 7
-bromo-2[bis(morpholino)phosphinyl
Oxy]-5-(2-pyridyl)-3H-1,4-be
Bring nzodiazepine (53.4 g, 0.1 mol) to room temperature.
was added to the prepared reaction mixture. Stir at room temperature for 1 hour.
After that, it was heated again on a steam bath for 2 hours. cooled
Partition the solution between water and methylene chloride/ether
did. Separate the organic phase, wash with water and dry.
and evaporated. The residue was dissolved in ethyl acetate with the addition of crystal seeds.
By crystallizing from alcohol/ether,
-8-Bromo-1-methyl-6-(2-pyridi
)-4H-imidazo [1.5-a] [1.4]-be
Nzodiazepine 3-carboxylate has a melting point of 240
Obtained as yellow crystals at -243°C. Conclusion
Seed is 5% (V/V) methanol in ethyl acetate
Chromatograph on 30x volume of silica gel using
Obtained by purification with roughy. analysis sample
The material was recrystallized from ethyl acetate. Its melting point is
The temperature was 243-244℃. Example 57 Ethyl 8-bromo-1-methyl-6-(2-pi
lysyl)-4H-imidazo [1.5-a] [1.
4] Benzodiazepine-3-carboxylate
2.15g (5 mmol), methanol 50ml, hydroxide
A mixture of 0.84 g (15 mmol) potassium and 2.5 ml water.
The mixture was heated to reflux for 5 hours. Most of the methanol
and the residue is partitioned between water and ether.
Arranged. The aqueous phase is acidified with acetic acid and methyl chloride is added.
Extracted with Len. Dry and evaporate the extract
Ta. Crystallize the residue from methylene chloride/ethyl acetate
8-bromo-1-methyl-5
-(2-pyridyl)-4H-imidazo[1,5-
a] [1.4] Benzodiazepine-3-carvone
The acid was obtained as colorless crystals, which were analyzed.
It was recrystallized from methanol for this purpose. Its melting point is
245−250 with previous sintering
℃ (decomposition). Example 58 8-bromo-1- in 20 ml of ethylene glycol
Methyl-6-(2-pyridyl)-4H-imidazo
[1.5-a] [1.4] Benzodiazepine-3-
A solution of 1.3 g of carboxylic acid was heated under reflux for 1 hour.
The reaction mixture was mixed with water and methylene chloride/toluene.
distributed between. The organic phase is saturated with sodium bicarbonate.
Washed with liquid, dried and evaporated. Remove the residue
Crystallization from ether/2-propanol
8-bromo-1-methyl-6-(2-pyri
Jill) -4H-imidazo [1.5-a] [1.4]
The benzodiazepine is obtained as yellow-brown crystals.
Ta. Analytical samples were reconsolidated from ethyl acetate/hexane.
crystallized. Its melting point was 189-190°C. Example 59 Sodium hydride in 480 ml of dimethylformamide
Stirring 7.8 g (0.174 mol) of a 54% mineral oil dispersion of
Diethylacetamide malonate suspension
39 g (0.18 mol) was treated in portions under argon.
Ta. When the reaction has weakened (about 30 minutes) 7-chlor-5-
(2-fluorophenyl)-2-[bis(morpholy
)-phosphinyloxy]-3H-1,4-ben
Zodiazepine was added in bulk. Argon at room temperature
Stirring was continued for 5 hours. Add the dark mixture to ice.
Add to the mixture of glacial acetic acid and glacial acetic acid with stirring.
A pale tan solid was obtained, which was filtered,
Wash with water and partially air dry on a funnel.
Ta. Dissolving the moist solid in methylene chloride
Ta. After separating the aqueous layer, the solution was poured over sodium sulfate.
dried, filtered and evaporated under reduced pressure to a yellow-brown color.
A colored foam was obtained. Add isopropylene while stirring the foam.
Dissolved in panol (4 ml/g) and occasionally scraped
Keep it at room temperature for 1 hour while rubbing until it turns yellow.
Obtained crystals. Equal volume of petroleum ether (30−60°)
and bring the mixture to room temperature for a further 30 hrs.
Hold for minutes. Wash and funnel with petroleum ether
with a melting point of 150-180℃ by air drying on
Acetylamino [7-chloro-5-(2-fluoro
(ruphenyl)-3H-1,4-benzodiazepine-
2-yl]malonic acid diethyl ester was obtained. trial
The material can be recrystallized from ethanol (10ml/g).
As a result, the melting point increases to 185-195℃ with pre-softening.
did. (0.2 metallic sodium in 25 ml of absolute ethanol)
g, made from 0.01g atoms) sodium etho
A stirred solution of the oxide was added to the acetylamino[7-
Chlor-5-(2-fluorophenyl)-3H-
1,4-Benzodiazepin-2-yl]-malon
Treated with acid diethyl ester 2.4g (0.005mol)
protected in a drying tube and kept at room temperature for no longer than 5 hours.
Stirred. The precipitated yellow solid was collected by filtration,
successively washed with ethanol and ether and
The product was obtained after air drying. Solids in water and chloride
Partitioned between tylene, acidified with acetic acid and again
Extracted with methylene chloride. dilute ammonium hydroxide
The methylene chloride extract was washed with sulfuric acid solution.
Dry over sodium and evaporate in vacuo.
A tan foam was obtained. This salt in 25 ml of ether
A solution of 1 g (0.0024 mol) of the group in 25 ml of ether
Mix with a solution of 0.56 g (0.0048 mol) of maleic acid.
and kept at room temperature. Scratch the numbers from time to time.
Orange crystals were obtained after minutes. overflowing with crystals
collected, washed with ether and air dried.
2-[(acetylamino)ethoxy with a melting point of about 150℃
carbonylmethylene]-7-chloro-1,3-di
Hydro-5-(2-fluorophenyl)-2H-
1,4-Benzodiazepine maleate was obtained. 1/
Concentrate to 2 volumes and seed with ethyl acetate.
Melting point 149-
An orange prism with a temperature of 151°C was obtained. Make the above maleate basic with ammonia and salt
Extract with methylene chloride and evaporate in vacuo.
The crude 2-[(acetylamino)ethyl
Toxycarbonylmethylene]-7-chloro-1.
3-dihydro-5-(2-fluorophenyl)-
2H-1,4-benzodiazepine (6.3g, 0.015mol)
hexamethylphosphoramide (HMPA)
Dissolve in 35ml and stir at 200-210℃ for 5 minutes.
Heat the dark solution while cooling and ice
Pressure into water gave a tan solid. passing through solids
then rinse with water and funnel partially
Air dried on top. Methyl chloride
Dissolve in solution and dry over sodium sulfate.
ethyl 8-chloro by evaporation under reduced pressure.
Ru-6-(2-fluorophenyl)-1-methyl-
4H-Imidazo [1.5-a] [1.4] Benzodi
Azepine-3-carboxylate is a yellowish brown foam.
Obtained as a body. 1g of foam to 5ml of ethyl acetate
and recrystallized from 5 ml of petroleum ether (30−60
°C), the product becomes light yellowish brown prisms.
This material melts at 176-179℃ and is
It re-solidifies and melts again at 195-198°C.
Ta. Example 60 Diethylacetamide malonate (43g, 0.2
mol) of water in 500 ml of dry dimethylformamide
Sodium chloride (50% in mineral oil) 10g (0.2 mol)
was added to the suspension. Mixture under argon for 30 min
Heated to 50°C. 5-(2-chlorophenyl)-2
−[Bis(morpholino)-phosphinyloxy]−
7-nitro-3H-1,4-benzodiazepine 53
After adding g (0.1 mol), the reaction mixture was steamed.
Heated on bath for 1 hour. Pour the cooled brown mixture into water.
and methylene chloride/ether. Yes
The organic phase was washed with water, dried and evaporated. Residue
The residue was purified on 1 kg of silica gel using ethyl acetate.
romatographed. One clear fraction
Combined and evaporated. The residue is diluted with methylene chloride/
Ethyl 6- by crystallization from ether
(2-chlorophenyl)-1-methyl-8-nitro
-4H-imidazo[1.5-a][1.4]benzo
Diazepine-3-carboxylate has a melting point of 233-
Obtained as pale yellow crystals at 234°C. Sample for analysis
was recrystallized from ethyl acetate. Melting point 234-235℃
It was hot. Example 61 Ethyl 6-(2-chlorophenyl)-1-methyl
-8-Nitro-4H-imidazo [1,5-a]
[1.4] Benzodiazepine-3-carboxylene
4.25 g (0.01 mole), methanol 100 ml, hydroxide
Mixture of 1.12g (0.02mol) of potassium chloride and 4ml of water
The material was heated to reflux for 3 hours under nitrogen. of methanol
Most of it is evaporated and the residue is dissolved in water and ether.
distributed between. Wash the aqueous phase with ether and acetic acid.
Acidified and extracted with methylene chloride. extract
was dried and evaporated. Dilute the residue with methylene chloride
by crystallization from ethyl acetate/ethyl acetate.
(decomposition) of 6-(2-chlorphenylene) at point 272-274℃
)-1-methyl-8-nitro-4H-imidazo
[1.5-a] [1.4] Benzodiazepine 3-ka
The sample for analysis was methanol/acetic acid.
Recrystallized from ethyl. The melting point is 274-276℃ (min.
Solution). Example 62 6-(2-chlorophenyl)-1-methyl-8-
Nitro-4H-imidazo [1.5-a] [1.4]
1.5 g of benzodiazepine-3-carboxylic acid and
Heat a mixture of 10 ml of ethylene glycol under reflux for 1 hour.
I let it happen. The reaction mixture was then diluted with methylene chloride/torr.
Partition between ene and saturated aqueous sodium bicarbonate solution
did. The organic phase was washed with water, dried and evaporated.
I set it. Dissolve the residue in 10 ml of 2-propanol.
and treated with 0.6 g of maleic acid. in warm solution
The salt crystallized by adding ether. So
Collect and wash with 2-propanol and ether.
and 6-(2-chlorophenyl)-1-methyl-8
-Nitro-4H-imidazo [1.5-a] [1.
4] Benzodiazepine maleate is a yellowish brown crystal
This is obtained as 2-pro for analysis.
Recrystallized from panol. Its melting point is 150−152
It was warm at ℃. Add the free base liberated from this salt to vinegar.
Crystallized from ethyl acid/hexane. its melting point
The temperature was 170-173℃. Example 63 6 g of sodium hydride dispersion (50% in mineral oil)
(0.125 mol) in 800 ml of dry tetrahydrofuran
1,3-dihydro-7-nitro-5-phenyl
-2H-1,4-benzodiazepine-2-one
28.1 g (0.1 mol) was added to the solution. 1 hour at room temperature
After stirring for a while, add dimorpholinophosphinic chloride.
Add 30.2 g (0.12 mol) of chloride and stir for 4 hours.
continued. Adding the product to water and ether
More crystallized. Collect the precipitate and add methane chloride
dissolved in water. Dry and evaporate the solution
The residue was then crystallized from ethyl acetate, melting point:
Crude 7-nitro-2-[bis(morpho)
lino)phosphinyloxy]-5-phenyl-3H
-1,4-benzodiazepine was obtained. A portion of this material was pre-heated at 40°C for 30 minutes.
8.6g of diethylacetaminomalonate
(0.04 mol), sodium hydride suspension (50 mol) in mineral oil
%) 2g (0.04 mol) and dimethylformamide
Added to 75ml of mixture. Steam the reaction mixture after addition
Heat on a bath for 30 minutes and then between water and ether
distributed. Wash the organic phase with water, dry and evaporate.
I let it emanate. The residue was dissolved in 250 g using ethyl acetate.
Chromatographed on silica gel. clear
Combine the fractions, evaporate and remove the residue.
Crystallized from methylene chloride/ether
Ethyl 1-methyl-8-nitro-6-phenylene
Ru-4H-imidazo [1.5-a] [1.4] Ben
Zodiazepine-3-carboxylate has a melting point of 240
Obtained as yellow crystals with a temperature of −241°C.
Ta. Analytical samples were recrystallized from ethyl acetate. Example 64 Ethyl 1-methyl-8-nitro-6-phenyl
-4H-imidazo[1.5-a][1.4]benzo
Diazepine-3-carboxylate 1.95g (5mg)
rimole), methanol 50ml, potassium hydroxide 0.56
g (0.01 mol) and 2 ml of water under nitrogen.
The mixture was heated to reflux for an hour. Partially evaporated solvent
Afterwards, the residue was acidified with 2 ml of glacial acetic acid and diluted with ethanol.
Between methylene chloride and water containing 10% (V/V)
distributed to. The organic phase was dried and evaporated.
Crystallize the residue from ethyl acetate/methanol
Possibly 1-methyl-8-nitro-6-phenylene
Ru-4H-imidazo [1.5-a] [1.4] Ben
Zodiazepine-3-carboxylic acid forms pale yellow crystals.
and then use the same solvent for analysis.
It was recrystallized from Melting point is 240-243℃ (decomposition)
Ivy. Example 65 Hexamethylphosphoric acid triamide
1-Methyl-8-nitro-6-phenyl in 15ml
-4H-imidazo[1.5-a][1.4]benzo
A suspension of 1.2 g of diazepine-3-carboxylic acid was
The mixture was heated to reflux for a minute. Pour the cooled solution into methylene chloride.
between ion/ether and aqueous sodium bicarbonate solution.
distributed. Wash the organic phase with bicarbonate solution and dry
and evaporated. The residue was dissolved in methylene chloride.
30g of silicon using % (V/V) ethanol
Chromatographed on Kagel. clear hula
ether/methylene chloride/ethyl acetate
By crystallizing from
1-methyl-8-nitro-6-phenyl-
4H-Imidazo [1.5-a] [1.4] Benzodi
I got azepine. Convert this to maleate salt,
This salt was crystallized from 0.5 mol of ethyl acetate.
Ta. The melting point was 125-128°C (decomposed). Example 66 8-chloro-1-methyl-6-phenyl-4H
-imidazo[1.5-a][1.4]benzodia
Zepine-3-carboxamide 2.45g (0.07mol)
), 50 ml of pyridine and 7 g of phosphorus pentoxide.
was heated to reflux for 15 minutes. Evaporate pyridine under reduced pressure
and soak the residue in ice, 10% sodium carbonate solution.
and methylene chloride. Separate the organic layer
, dried and evaporated. The residue was dissolved in ethyl acetate.
50g of silica using 1:1 dichloromethane/methylene chloride
Chromatographed on gel. Ethyl acetate/
Melting point 228− by crystallization from hexane
8-chloro-3-cyano-1-methyl- at 229℃
6-phenyl-4H-imidazo [1,5-a]
[1.4] Benzodiazepine was obtained. Example 67 Activated manganese dioxide (5 g) was added to
8-chloro-6-(2-chlorf) in 50 ml of tyrene
enyl)-3-hydroxymethyl-1-methyl-
4H-Imidazo [1.5-a] [1.4] Benzodi
Added to a solution of 1 g of azepine. Mixture at room temperature
Stir for hours. Manganese dioxide and
The liquid was evaporated. Crystallize the residue from ethanol
8-chloro-6-(2-chloroph)
enyl)-1-methyl-4H-imidazo[1,5-
a] [1,4] Benzodiazepine-3-carboxy
Sialdehyde forms colorless crystals with a melting point of 237-239℃.
obtained. The sample for analysis is tetrahydrofuran/
Recrystallized from ethanol. Example 68 8-chloro-6-(2-fluorophenyl)-1
-Methyl-4H-imidazo [1.5-a] [1.
4] Benzodiazepine-3-carboxaldehyde
1.4 g (4 mmol) of triethylamine, 2 ml of triethylamine,
30ml ethanol and hydroxylamine hydrochloride
0.56 g (8 mmol) of the mixture at room temperature for 1 1/2 hours
I left it for a while. Collect the precipitated crystals after diluting with water
and dried to give 8-chloro-
6-(2-fluorophenyl)-1-methyl-4H
-imidazo[1,5-a][1,4]-benzodia
Zepine-3-carboxaldoxime was obtained. minutes
Prepare the sample for analysis from tetrahydrofuran/ethanol.
Recrystallized. The melting point was 272-275°C. Example 69 A solution of 3-(benzene) in 10 ml of glacial acetic acid and 2 ml of acetic anhydride
(oxycarbonylamino)-8-chloro-6-
(2-fluorophenyl)-1-methyl-4H-y
Midazo [1.5-a] [1.4] Benzodiazepi
A solution of 0.2 g of chlorine was heated on charcoal for 1 hour at atmospheric pressure.
hydrogenated over 10% fluoride. Remove the catalyst
The liquid is finally evaporated azeotropically with xylene.
I let it happen. Dissolve the residue in 10% ethanol in methylene chloride.
Chromatograph on 6 g of silica gel using
I put it on. Combine the pure fractions with ethyl acetate/
3-acetate by crystallization from ether
toamino-8-chloro-6-(2-fluorophe
Nyl)-1-methyl-4H-imidazo[1,5-
a] [1.4] Benzodiazepine has a melting point of 175-178
Obtained as colorless crystals at °C. Example 70 Hydroxylamine hydrochloride (0.14 g, 2 mmol)
10ml of ethanol and 0.5ml of triethylamine
8-chloro-6-(2-chlorophenyl)- in ml
1-Methyl-4H-imidazo [1.5-a] [1.
4] Benzodiazepine-3-carboxaldehyde
was added to a suspension of 0.37 g (1 mmol). mixture
Heat the material on a steam bath until melting is complete, and then
The liquid was allowed to stand for 2 hours. Collect the separated crystals, add water,
Wash with ethanol and ether to remove 8-chloro
-6-(2-chlorophenyl)-1-methyl-4H
-imidazo[1.5-a][1.4]benzodia
Zepine-3-carboxaldoxime was obtained. minutes
The sample for analysis is made from tetrahydrofuran/ethanol.
Recrystallized. Melting point is 290-292℃ (decomposition)
Ta. Example 71 Methylmagnesium iodide (5
ml, approximately 1 mol) solution in 10 ml of tetrahydrofuran.
8-chloro-6-(2-chlorophenyl)-1 in
-Methyl-4H-imidazo [1.5-a] [1.
4] Benzodiazepine-3-carboxaldehyde
It was added to a solution of 0.37 g (1 mmol). at room temperature
After stirring for 15 minutes the mixture was decomposed with water. inorganic matter
was filtered and washed with methylene chloride. liquid
Dry and evaporate. Crystallize the residue from ether
and recrystallize from ethyl acetate/hexane.
Possibly 8-chloro-6-(2-chlorphenylene)
)-8-(1-hydroxyethyl)-1-methyl
-4H-imidazo[1.5-a][1.4]benzo
Diazepine as colorless crystals with a melting point of 197-199℃
Obtained. Example 72 8-chloro-6-(2-
Chlorphenyl)-8-(1-hydroxyethyl)
-1-methyl-4H-imidazo [1,5-a]
[1.4] Activate a solution of 0.1 g of benzodiazepine
3 at room temperature in the presence of 0.5 g of manganese dioxide
Stir for hours. Manganese dioxide and
The liquid was evaporated. The crystalline residue was dissolved in ethyl acetate/hexane.
3-acetyl-
8-chloro-6-(2-chlorophenyl)-1-meth
Chill-4H-imidazo [1.5-a] [1.4] Be
Nzodiazepine is a colorless crystal with a melting point of 234-236℃.
Obtained by doing. Example 73 Ethyl 8-chloro-6 in 200 ml of methylene chloride
-(2-chlorophenyl)-1-methyl-4H-y
Midazo [1.5-a] [1.4] Benzodiazepi
Stirring of 12.4 g (0.08 mol) of 3-carboxylate
Add 12 g (0.07 g) of m-chloroperbenzoic acid to the stirred solution.
mol) and treated at room temperature. 2.5
Stirring was continued for an hour. Solution 1N sodium hydroxide
Wash with solution and separate cloudy methylene chloride layer
diluted with methanol and dried over sodium sulfate.
It was dried. filtered and evaporated under reduced pressure.
A rubbery substance is obtained, which is converted into ether.
Tritylation with ethyl 8-chloro-6-(2
-chlorophenyl)-1-methyl-4H-imidazo
[1.5-a] [1.4]-Benzodiazepine-3
-Carboxylate-4-oxide is yellowish and
It was obtained as a crystal. Samples for analysis are 1:1 ratio
Recrystallize twice from nol/methylene chloride solution
It was obtained by Melting point is 247-249℃
Ta. Example 74 Phenylacetaldehyde (2.4 g, 0.02 mole)
2-[(amino)methoxy] in methylene chloride
carbonylmethylene]-7-chloro-5-(2-k
rolfenyl)-1,3-dihydro-2H-1,4
- in a solution of 3.8 g (0.01 mol) of benzocyazepine
added. Addition of 10 g molecular sieve 5A followed by mixing
Stir the mixture for 15 minutes at room temperature and
It was treated with 10 g of manganese oxide for a further 15 minutes at room temperature.
Inorganics were separated by filtration over Celite. past
and the residue from ether/hexane.
Methyl 1-benzyl-8 by crystallization
-chloro-6-(2-chlorophenyl)-4H-i
Midazo [1.5-a] [1.4] Benzodiazepi
N-3-carboxylate has a melting point of 155-158°C.
Obtained as colorless crystals. The sample for analysis is vinegar.
Recrystallized from ethyl acid/hexane. The melting point is
The temperature was 160-162℃. Example 75 Methyl-1-benzyl-8-chloro-6-(2
-chlorophenyl)-4H-imidazo[1,5-
a] [1,4] Benzodiazepine-3-carboxy
2 g (4.2 mmol) of silate, 1 potassium hydroxide
g, a mixture of 50 ml of methanol and 5 ml of water was heated with nitrogen.
The mixture was heated to reflux under atmosphere for 4 hours. evaporate the solvent
Dissolve the residue in water and acidify the solution with acetic acid.
I made it. Collect the precipitated crystals, wash with water and
Dissolved in methylene chloride. dry the solution and
Evaporated. Crystallized from methylene chloride/ethyl acetate
With a melting point of 305-310℃ (decomposition),
1-benzyl-8-chloro-6-(2-chlorof
enyl)-4H-imidazo[1.5-a][1.
4] Benzodiazepine-3-carboxylic acid was obtained. Example 76 The material obtained in Example 75 was dissolved in 30 ml of methylene chloride.
suspended in. Add phosphorus pentachloride (0.8g) and
The mixture was stirred on ice/water for 30 minutes. Next, a
ammonia gas until the reaction mixture becomes alkaline.
Introduced. aqueous ammonia after stirring for 15 min at room temperature.
Add A and stir the two-phase system for an additional 15 minutes.
Ta. Separate the methylene chloride phase, dry and evaporate
I let it happen. Convert the crystalline residue into ethyl acetate/methanol
By recrystallizing from
Chlor-6-(2-chlorophenyl)-4H-imy
Dazo [1.5-a] [1.4] Benzodiazepine
-3-Carboxamide is a colorless compound with a melting point of 282-284℃.
Obtained as a product. Analytical samples were prepared using methylene chloride/acetic acid for elution.
Silica gel using ethyl 1:1 (V/V)
(40x volume). The melting point is
The temperature was 286-288℃. Example 77 8-chloro-6-(2-chlorophenyl)-1-
Methyl-4H-imidazo [1.5-a] [1.4]
Benzodiazepine-3-carboxaldehyde
370 mg, 10 ml of ethanol and 1,1-dimethylhydrogen
A mixture of 0.5 ml of dorazine was heated to reflux for 15 minutes.
Evaporate the solvent and extract the residue from ethanol/water.
crystallize to give a light 3-chloro-6-(2-chloro
(ruphenyl)-1-methyl-4H-imidazo[1.
5-a] [1.4] Benzodiazepine-3-cal
Boxaldehyde dimethylhydrazone ethanol
(2/1) yellow crystals were obtained. Remove the sample for analysis.
Recrystallized from nol. Melting point is 238-242℃
Ivy. According to nuclear magnetic resonance spectra and analysis, this
The crystals contained 0.5 equivalents of ethanol. Example 78 Phosphorus pentachloride (1.1 g, 5.2 mmol) in ice-water
6-(2-chloride) in 100 ml of methylene chloride cooled at
(ruphenyl)-1-methyl-8-nitro-4H-y
midazo[1.5-α][1.4]benzodiazepi
Suspension of 1.6 g (4 mmol) of 8-carboxylic acid
liquid was added. After stirring in ice-water for 30 minutes,
Introduce a stream of Monia until the mixture becomes alkaline.
and continued stirring at room temperature for 1 hour. Add water
The organic layer was separated, dried and evaporated.
Crystallize the residue from methanol/ethyl acetate
By this, 6-(2-chlorophenyl)-1-methane
Chil-8-nitro-4H-imidazo[1,5-
α〕[1,4]-benzodiazepine-3-carboxy
The samide is obtained as yellowish crystals with a melting point of 300℃.
It was done. Analytical samples were recrystallized from the same solvent.
Ta. Example 79 In 50 ml of benzene and 300 ml of tetrahydrofuran
1,3-dihydro-5-phenyl-2H-thie
No-[3.2-e][1.4]Diazepine-2-o
Stir a mixture of 10 g (0.036 mole) on an ice bath.
It was then saturated with methylamine gas. This mixture
Titanium tetrachloride (9.48 g,
A solution of 0.05 mol) was added dropwise. Addition completed
Afterwards, the mixture was stirred on an ice bath for 15 minutes. Then ice
Replace the bath with a heating mantel and mix
was refluxed for 1/2 hour. Cool the mixture and ice
100g was carefully added. strain the mixture and
The residue was washed with tetrahydrofuran. One liquid
Combined, dried and evaporated. Chloride the product
2- crystallized from methylene and has a melting point of 228-227°C.
Methylamino-5-phenyl-3H-thieno-
[3.2-e] [1.4] Obtain benzodiazepine
Ta. Further production from concentrated mother liquor with melting point of 222-225℃
I got something. Analytical samples were recrystallized from methylene chloride.
I let it happen. The melting point was 222-229°C. Nitrosyl chloride was added to methoxychloride cooled in ice water.
2-methylamine in 100 ml of ethylene and 40 ml of pyridine
Nor-5-phenyl-3H-thieno [3.2-e]
[1.4] 7.8 g (0.08 mol) of benzodiazepine
introduced into the solution. The reaction is performed using thin layer chromatography.
and when the starting material is exhausted, the salt
Terminate the addition of the nitrosyl compound and add the reaction mixture.
was partitioned between methylene chloride and water. Methyl chloride
The solution was dried and evaporated. Dilute the residue with methylene chloride
2- by crystallization from ion/hexane
(N-nitrosomethylamino)-5-phenyl-
8H-thieno [3.2-e] [1.4] diazepine
was obtained as yellow crystals with a melting point of 156-159°C. minutes
The analytical sample was recrystallized from ether/hexane.
The melting point was 158-160°C. Example 80 7-chloro-1,3-dihydro-5-phenyl
-2H-thieno [2.3-e] [1.4] diazepi
7.7 g (0.278 mol) of 1-2-one, 50 ml of benzene
and 250 ml of tetrahydrofuran on an ice bath.
and saturated with methylamine gas.
Titanium tetrachloride in 50 ml of benzene to this mixture.
Add a solution of (7.38 g, 0.0389 mol) from the dropping funnel.
I got it. After the addition is complete, place the mixture on an ice bath for 15 minutes.
Stir for a while. Then replace the ice bath with a heated mantel.
The reaction mixture was then refluxed for 20 minutes. Cool the mixture
Cool and carefully add 100 g of ice. Then mix
The mixture was filtered and the residue was dissolved in tetrahydrofuran.
Washed with. Combine the liquids, dry and evaporate
I let it happen. Crystallize the residue from methylene chloride/ether
7-chloro-5-fluorine having a melting point of 246-249°C.
enyl-2-methylamino-3H-thieno-[2.
3-e][1.4]diazepine was obtained. analysis sample
The material was recrystallized from methylene chloride. Melting point is 247
It was -250℃. Add nitrosyl chloride to 100 ml of methylene chloride and pyri
7-chloro-5-phenyl-2-methane in 50 ml of gin
Thylamino-8H-thieno-[2.3-e][1.
4] Add reaction to a solution of 5.8 g (0.02 mol) of diazepine.
Addition is continued until the reaction is completed as determined by thin layer chromatography.
I got it. The mixture was partitioned between water and toluene.
The organic phase was dried and evaporated. Ete the residue
7-
Chlor-2-(N-nitrosomethylamino)-5-
Phenyl-3H-thieno [2,3-e] [1,4]
Benzodiazepines form yellow crystals with a melting point of 108-110℃.
Obtained by doing. Transfer it to ether/for analysis.
Recrystallized from xane. Melting point is 111-113℃
Ta. Example 81 900ml dry tetrahydrofuran and dry benzene
7-chloro-5-(2-chlorphenylene) in 300 ml of
)-1,3-dihydro-2H-thieno[2,3-
e] [1.4] Diazepine-2-one 50g (0.161
Cool the solution of (mol) in an ice bath until the solution is saturated.
Blow methylamine until 100ml of benzene.
Stir a solution of 40 g (0.209 mol) of titanium tetrachloride in
Add dropwise with stirring. After 4 hours at room temperature, several grams of ice
was added and the reaction solution was filtered. Heat the precipitate to tetra
Wash several times with hydrofuran and combine the liquids.
and evaporated. Dilute the residue with 250ml of dichloromethane and water.
Dispense between 200 ml and strain. Dichloro
The methane solution was separated, dried and evaporated.
This residue and precipitate were mixed with tetrahydrofuran and ethanol.
7-chloro-5-
(2-chlorophenyl)-2-methylamino-3H
-thieno [2.3-e] [1.4] diazepine
Obtained. The sample was mixed with tetrahydrofuran and hexane.
Recrystallized from the mixture for analysis, melting point 259−262.
℃ pale yellow prisms were obtained. 7-chloro-5-(2-chlorophenyl)-2-
Methylamino-3H-thieno[2.3-e][1.
4]-Diazepine 40g (0.123 mol), dichloromethane
A mixture of 700 ml of pyridine and 350 ml of pyridine in an ice bath.
Cool and stir the nitrosyl chloride for 20 minutes.
There was a pause. After an hour, spray it on for another 5 minutes.
and then slowly added 600 ml of water. Jiku
Separate the lolomethane layer, wash with 200 ml of water, and dry
Dry over sodium sulfate and evaporate to dryness.
I let it happen. Dissolve the oil in dichloromethane and
The mixture was filtered through 400 g of Florisil. Jiku this
Elute with lolomethane then ether
Ta. Dichloromethane fraction with ether and stone
7-chloro, crystallized from a mixture with oil ether.
-5-(2-chlorophenyl)-2-(N-nito
rosomethylamino)-3H-thieno[2,3-e]
[1.4] Obtain diazepine and obtain ether flora
Further product was obtained from the cushion. sample for analysis
recrystallized from a mixture of ether and petroleum ether
A yellow prism with a melting point of 104-107°C was obtained. Potassium t-butoxide 3.4g (0.03mol), di
7ml of methylmalonate and dimethylformamide
Stir 20 ml of the mixture for 5 minutes under nitrogen atmosphere.
Ta. 7-chloro-5-(2-chlorophenyl)-2
-(N-nitrosomethylamino)-3H-thieno
[2.3-e] [1.4] Diazepine 3.55g (0.01
Following the addition of mol), the mixture was stirred and evaporated.
Heat on an air bath for 5 minutes and add 3 ml of acetic acid to make it acidic.
Then water was slowly added to crystallize it. precipitation
Collect, wash with water and methanol and chlorinate
Dissolved in methylene. Dry and evaporate the solution
and the residue was crystallized from ethanol.
-Chlor-5-(2-chlorophenyl)-1,3-
Dihydro-2-dimethoxymalonylidene-2H-
Chieno [2.3-e] [1.4] Diazepine is peach
Obtained as colored crystals and used for analysis
It was recrystallized from ethanol. Melting point is 158-160℃
It was hot. 7-chloro-5-(2-chlorophenyl)-1.
3-dihydro-2-methoxymalonylidene-2H
-thieno [2.3-e] [1.4] diazepine 215
g (5 mmol), methanol 50 ml and potassium hydroxide.
A mixture of 0.7 g (1.25 mmol) of lithium was added under nitrogen.
The mixture was refluxed for 8 hours. Partially evaporate the solvent and
The residue was dissolved in methylene chloride and saturated sodium bicarbonate.
It was distributed between the liquid and the liquid. Dry and evaporate the organic phase
I let it happen. The resulting phase 7-chloro-5-(2-chloro
(ruphenyl)-2,3-dihydro-2-(methoxy
carbonylmethylene)-2H-thieno[2,3-
e] [1.4] Dissolve diazepine in 20 ml of glacial acetic acid.
did. Add sodium nitrite (0.5g) and
The mixture was stirred at room temperature for 15 minutes, diluted with water and
Extracted with methylene chloride. Extract with water and bicarbonate
Washed with sodium solution, dried and evaporated. Residue
The residue was crystallized from methylene chloride/ether.
and recrystallized from tetrahydrofuran/methanol.
7-chloro-5-(2-chloroph)
enyl)-α-hydroxyimino-3H-thieno-
[2.3-e] [1.4] Diazepine-2-acetic acid
The thyl ester forms a yellow solid with a melting point of 242-245℃ (decomposition).
Obtained as crystal. 7-chloro-5-(2-chlorophenyl)-α-
Hydroxyimino-3H-thieno [3.2-f]
[1.4] Diazepine-2-acetic acid methyl ester
(0.4 g, 1 mmol) in tetrahydrofuran 30
ml and by warming in 20 ml of ethanol.
Dissolved. Sprinkle with raney nitskel (1/2 teaspoon)
Following addition, the mixture was hydrogenated at atmospheric pressure for 45 min.
Ta. The catalyst was filtered and the liquid was evaporated. Residue
Dissolve the residue in 10 ml of methanol and
0.4ml of fluoroacetate and ethanolic chloride
Treated with 8 drops of hydrogen. After heating to reflux for 10 min, remove the solvent.
and the residue was dissolved in methylene chloride and bicarbonate.
Partitioned between sodium solutions. dry the organic phase
and evaporated. The residue was dissolved in methylene chloride/acetic acid.
10g silica using ethyl 3:5 (V/V)
Chromatograph on gel and eluent
Crystallize the residue obtained after removal from ethanol
methyl 8 with a melting point of 211-212℃
-chloro-6-(2-chlorophenyl)-1-methy
Ru-4H-imidazo [1.5-α] Chieno [3.
2-f] [1,4] diazepine-3-carboxy
I got a rate. Example 82 Lithium aluminum hydride in 20 ml of ether under nitrogen
38 mg (0.001 mole) of Nium was added. reaction mixture
was cooled in an ice bath and methyl 8-chloro-6
-(2-chlorophenyl)-1-methyl-4H-y
Midazo [1.5-α] Chieno [3.2-f]
[1,4]-Diazepine-3-carboxylate
0.2g (0.000493mol) of dried tetrahydrofura
and stir into the reaction mixture.
I added it dropwise. After 1 hour, add 5 ml of ethyl acetate.
followed by 8 ml of a saturated solution of sodium bicarbonate.
added. Pass the reaction mixture through Celite;
Then wash with dichloromethane and drain the liquid.
evaporate together and dichloromethane and acetic acid.
8-chloro-
6-(2-chlorophenyl)-3-hydroxymethy
Ru-1-methyl-4H-imidazo [1,5-α]
Thieno [3.2-f] [1.4] Obtain diazepine
Ta. Recrystallization from the same solvent produces a yellow color.
A solid prism was obtained. Melting point is 100-110℃
The melting point of the re-solidified product is 190-194℃.
Ta. Example 83 Methyl 8-chloride was added to 10 ml of methanol and 1 ml of water.
Ru-6-(2-chlorophenyl)-1-methyl-
4H-imidazo[1,5-α]thieno[3,2-
f] [1,4] diazepine-3-carboxylei
0.1g (0.000247mol) and potassium hydroxide
0.028 g (0.000493 mol) was added. reaction mixture
was refluxed for 2 hours and evaporated. Water the residue 10
ml, washed with 10 ml of ether, then vinegar
Acidified with acid. Extract this with 80ml of dichloromethane.
and dry the extract over anhydrous sodium sulfate.
Concentrate, cool and filter. dichloromethane the precipitate
recrystallization from a mixture of methane and ether.
8-chloro-6-(2-chlorphenylene)
)-1-methyl-4H-imidazo [1,5-α]
Thieno [3.2-f] [1.4] Benzodiazepi
N-3-carboxylic acid is a white precipitate with a melting point of 242-247℃.
obtained as a rhythm. Example 84 8-chloro in 100 ml of dry methylene chloride in an ice bath
Ru-6-(2-chlorophenyl)-1-methyl-
4H-imidazo[1,5-α]thieno[3,2-
f] [1,4] diazepine-3-carboxylic acid 0.8 g
(0.00204 mol), 0.46 g (0.0022 mol) of phosphorus pentachloride
) was added. After 30 minutes, add the ammonia without stirring.
for 5 minutes. After 2 hours, add 75ml of water.
and strained the product. Separate dichloromethane
, dried and evaporated. ethanol residue
The product obtained by crystallizing from
together with the first precipitate and chloroform
Recrystallized from a mixture of
Lor-6-(2-chlorophenyl)-1-methyl-
4H-imidazo[1,5-α]thieno[3,2-
f] [1,4] diazepine-3-carboxamide
was obtained as white rod-like crystals with a melting point of 300-305°C. Example 85 125ml dry tetrahydrofuran and dry benzene
6,8-dihydro-3-ethyl-1- in 50 ml of
Methyl-4H-phenylpyrazolo [3,4-e]
[1.4] Diazepine-7(1H)-one 6.8g
A solution of (0.0255 mol) was cooled in an ice bath and
Methylamine was bubbled into the solution until it was saturated. Next
So, 6.3g of titanium tetrachloride in 20ml of benzene.
(0.0331 mol) was added dropwise with stirring;
After 18 hours at room temperature, the mixture was refluxed for 30 minutes.
The solution was cooled and treated with 4 g of ice. reaction mixture
The mixture is filtered and the precipitate is diluted with tetrahydrofurane.
The mixture was washed with water and dichloromethane. One liquid
Evaporate to dryness and dissolve the residue in methanol.
crystallized from a mixture of and ether, and
Recrystallize from a mixture of lormethane and ether
By this, 3-ethyl-1,6-dihydro-1
-Methyl-7-methylamino-4-phenylpyra
Zoro [3.4-e] [1.4] Benzodiazepine
as a yellowish prism with a melting point of 218-221℃
Obtained. 3 in 100ml dichloromethane and 50ml pyridine
-ethyl-1,6-dihydro-1-methyl-7-
Methylamino-4-phenylpyrazolo[3,4-
e] [1.4] 5.6 g (0.0199 mol) of diazepine
The solution was stirred in an ice bath and the nitrosyl chloride
I blew it for 10 minutes. After 2 hours at room temperature, nitrochloride
Sill was blown for another 5 minutes. Leave the mixture for 30 minutes.
Then, it was poured into 200 ml of ice water. organic phase
Separate, wash with 100 ml of water and anhydrous sodium sulfate
Dry on top and pass through 100g of Florisil.
passed. Wash Florisil thoroughly with ether,
The liquids were then combined and evaporated to dryness.
This intermediate N-nitroso derivative was not purified further.
and used in the next step as described below. 14 ml of dimethyl malonate and N・N-dimethyl
Add a mixture of 35 ml of formamide to potassium t-butylene.
treated with 6.5 g (0.0580 mol) cid and 5 minutes
After stirring for 10 minutes, N.N-dimethylformamide 10
N-nitroso compound prepared as above in ml
A solution of was added. Steam bath the resulting mixture for 5 minutes.
Heat above, cool, and add 6 ml of glacial acetic acid.
Ta. Then pour the reaction mixture into 300ml of cold water and
After 15 minutes, the solution was decanted. Residue
Dissolve the oil in 75 ml dichloromethane and
Wash with 50 ml of dilute ammonium hydroxide and anhydrous sulfur.
dried over sodium hydroxide and washed with florisil.
chromatographed. Column first dichloromethane
with methane, then with ether and finally with acetic acid.
Eluted with ethyl. Ether and ethylfuranoacetate
The cushions were combined and evaporated. Tie off the residue
crystallized and recrystallized from methanol,
(3-ethyl-6,8-dihydro-1-methyl-
4-phenylpyrazolo [3.4-e] [1.4]
diazepine-7(1H)-ylidene)-malonate di
The methyl ester has a yellow color with a melting point of 145-148℃.
Obtained as rod-shaped crystals. (3-ethyl-6,8-di) in 40 ml of methanol
Hydro-1-methyl-4-phenylpyrazolo
[3.4-e] [1.4] Diazepine-7(1H)-
Ylidene)-malonic acid dimethyl ester 1.7g
(0.00445 mol) solution of potassium hydroxide (0.56 g)
(0.01 mol) and refluxed the solution for 2.5 h.
did. Evaporate the solvent and dissolve the residue in dichloromethane.
Divide between 50ml of tongue and 30ml of water. Salt the water layer first
Acidified with acid, then base with ammonium hydroxide
The mixture was dried and extracted with 75 ml of dichloromethane. Yes
Combine the layers and dry over anhydrous sodium sulfate.
and treated with Florisil. Florigi
The solution was eluted with ether and then with ethyl acetate. melt
The raw materials are combined and evaporated to form a crude monoester.
was obtained as an oil. This product is further
Dissolve in 10 ml of glacial acetic acid without purification and stir
Sodium nitrite 0.35g (0.005mol)
Processed with. After 45 minutes, the reaction mixture was poured into 100 ml of water.
and extracted with 75 ml of dichloromethane.
Wash the organic layer with 50 ml of dilute solution of sodium bicarbonate.
dried over anhydrous sodium sulfate, and dried
evaporated until The residue was dissolved in ethyl acetate and ether.
It was crystallized from a mixture of Dichloromethane and
3 by recrystallization from a mixture of
-ethyl-1,6-dihydro-α-hydroxyi
Mino-1-methyl-4-phenylpyrazolo [3.
4-e][1,4]-diazepine-7-methyl acetate
The ester is a yellowish rod-like crystal with a melting point of 225-227°C.
obtained as. 20ml dry tetrahydrofuran and 25ml methanol
3-ethyl-1,6-dihydro-α-hydro in ml
Roxiimino-1-methyl-4-phenylpyrazo
B [3.4-e] [1.4] Diazepine-7-vinegar
Solution of acid methyl ester 0.35g (0.000986 mol)
2ml of triethyl orthoacetate (0.0109mol)
) and 1 scoop of Raney Nickel. reaction
The mixture was hydrogenated at room temperature and atmospheric pressure for 2.5 hours.
The catalyst is removed by filtration and the spent nitrogen is
The tube was washed with methanol. mix the liquids together
evaporate and dissolve the residue in 50 ml of dichloromethane.
dissolved in. dilute ammonium hydroxide solution
ml and dried over anhydrous sodium sulfate;
and evaporated until dry. Residue, triethyl
2 ml (0.109 mol) of orthoacetate and 5.7N
Contains 0.2 ml (0.00114 mol) of tanolic hydrogen chloride
It was refluxed for 20 minutes in a 50 ml methanol solution. solvent
removed by evaporation under reduced pressure and the residue
Dissolve the residue in dichloromethane and then dilute the solution.
Wash with dilute ammonium hydroxide and anhydrous sodium sulfate.
dried over aluminum and evaporated. as an oily substance
The crude product obtained by
Developed in a mixture of 5% methanol in chill.
R _f Scrape off the product with 0.5 and add methanol
Stir and filter together. Evaporate the solution and
The residue was crystallized from ether to give 3-ethyl
Ru-1,6-dihydro-1,9-dimethyl-4-
Phenyl-imidazo[1,5-α]-pyrazolo
[4.3-f] [1.4] Diazepine-7-carbo
Acid methyl ester is a white puriform with a melting point of 181-184℃.
obtained as a rhythm. Example 86 7-chloro-1,3-dihydro-2-(dimeth)
ximalonidene)-5-phenyl-2H-1・4-
Benzodiazepine 4-oxide 31g (0.075mol)
), sodium hydroxide 4g (0.095 mol), meth
A mixture of 300 ml of alcohol and 5 ml of water was heated to reflux for 3 hours.
It flowed. After cooling, the mixture was diluted with water. precipitated
Collect the crystals and recrystallize them from methanol.
7-chloro-1,3-dihyde with a melting point of 215-216℃
Dro-2-(methoxycarbonylmethylene)-5-
Phenyl-2H-1,4-benzodiazepine 4O
I got Kisido. Sodium nitrite (1.4 g, 0.02 mol) on ice
7-chloro-1,3-dihydro- in 100 ml of acetic acid
2-(methoxycarbonylmethylene)-5-phenylene
Ru-2H-1,4-benzodiazepine-4-oxy
Added to a solution of 6.8 g (0.02 mol) of cid. at room temperature
After stirring for 15 minutes, dilute the reaction mixture with 100 ml of water.
did. Collect the crystals, wash with water, and dry
7-chloro-α-hydroxyimino-5-pheni
Ru-3H-1,4-benzodiazepine-2-acetic acid
Methyl ester-4-oxide has a melting point of 237-239℃
Obtained as a yellow product (decomposition). analysis sample
Reconsolidate the sample from dimethylformamide/methanol.
crystallized, and it had the same melting point. Example 87 5-(2-F) in 140 ml of dry tetrahydrofuran
fluorophenyl)-1,3-dihydro-7-io
Do-2H-1,4-benzodiazepin-2-one
54% sodium hydride in a solution of 10 g (0.0264 mol)
1.8 g (0.039 mol) of lithium was stirred under argon.
I added while doing so. The reaction mixture was refluxed for 1 hour at 0°C.
Cool to a temperature, and remove the phosphorescent material.
10.8 g (0.0422 mol) of lido was added. 18 hours later,
The solution was filtered, concentrated to a small volume, and diluted with ether.
added. Filter the solid and dichloromethane
and ether to give 5-(2
-fluorophenyl)-7-iodo-2-bis
(morpholino)-phosphinyloxy-3H-1.
4-benzodiazepine is a white plate with a melting point of 104-112℃
Obtained as solid crystals. Example 88 54% in mineral oil in 267 ml of dimethylformamide
Sodium hydride dispersant (3.35g, 0.075mol)
Add the stirred suspension of diethylacetamide
Several times under argon with 17.5 g (0.08 mol) of ronate
It was processed separately. Keep the mixture at room temperature for longer than 30 minutes
Stir and then add 7-bromo-2-[bis(morpho)
lino)phosphinyloxy]-5-(2-pyridi
-3H-1,4-benzodiazepine 26.7 (0.05
mol) once. Stir at room temperature under argon
continued for 7 hours. Ice the resulting dark mixture.
Pour over acetic acid and dilute with water to obtain a green-yellow solid
I got it. Filter the solids, wash with water, and funnel
Air dried on top. Approximately 7 g of solid was placed on silica gel.
Chromatograph and elute with ethyl acetate
An amorphous solid is obtained, which has R _f 0.5 thin
One by layer chromatography (ethyl acetate)
The spots were shown. with a small amount of isopropanol
Stirring caused the solid to crystallize. Isopropyl
Acetyl alcohol is obtained by recrystallization from alcohol.
Mino[7-bromo-5-(2-pyridyl)-3H-
1,4-Benzodiazepin-2-yl]malonic acid
Diethyl ester is a light yellowish brown plate with a melting point of 178-180.
Obtained as crystal. Example 89 0.46 g (2.2 mmol) of phosphorus pentachloride was added to
8-chloro-6-(2-chlorf) in 50 ml of tyrene
enyl)-1-methyl-4H-imidazo[1,5-
α] Thieno [3.2-f] [1.4] Diazepine
-Suspension of 0.785 g (2 mmol) of 3-carboxylic acid
added to the liquid. Stir for 30 min in an ice bath under nitrogen.
After adding dimethylamine, the reaction mixture becomes alkaline.
It was introduced until the end. Stir it for 30 minutes at room temperature, then
washed with saturated sodium bicarbonate solution and dried.
and evaporated. Dilute the residue with ethyl acetate/ether
8-chloro-6-
(2-chlorophenyl)-1・N・N-trimethyl
-4H-imidazo[1,5-α]thieno[3,2
-f] [1,4] diazepine-3-carboxya
Mido is obtained as yellowish crystals, and this
was recrystallized from ethyl acetate for analysis. Melt
The point was 197-200℃. Example 90 Ethyl-2- in 200 ml of tetrahydrofuran
[(phenylmethylene)amino]acetate *N-
A solution of 4.15 g (20.1 mmol) of oxide was heated to −73°C.
and n-butyllithium in hexane.
Slowly add 13.2 ml (21.1 mmol) of the solution dropwise.
A pale orange solution was obtained. After 15 minutes, tetrahydrof
7-Chlor-2-di(morphol) in 225 ml of run
2) Phosphinyloxy-5-(2-fluorophosphinyloxy-5-(2-fluorophosphinyloxy)
enyl)-3H-1,4-benzodiazepine 10.15
g (20 mmol) of the solution was slowly added dropwise, and then
Warm the resulting dark brown suspension to room temperature.
and stirred overnight. Quench the mixture with 3 ml of water.
(quenched) and the solvent was removed in vacuo.
Dilute the residue with 300 ml of water and repeat with ether
and extracted. Combine the organic phases and rinse twice with water.
Wash once with water and dry with anhydrous magnesium sulfate.
and concentrated in vacuo to give the crude product as a pale yellow solid.
Obtained as a body. Recrystallized from aqueous acetone
ethyl 8-chloro-6-(2-ph)
fluorophenyl)-1-phenyl-4H-imidazo
[1.5-α] [1.4] Benzodiazepine-3-
Carboxylate as a white crystallized solid
Obtained. Concentrate the mother liquor to further obtain the final product.
Ta. * E.B.E.B. and G.B.B.
Round Journal of Organism
Chemistry, 32, 265 (1967) [E.Buehler
and G.B.Brown, J.Org.Chem., 32, 265
(1967). ] Example 91 2-[(amino)methoxycarbonyl methylene
]-7-chloro-5-(2-chlorophenyl)-
1,3-dihydro-2H-1,4-benzodiaze
Pin 375mg, toluene 20ml, and benzalde
Heat the mixture of 0.5 ml of hydrogen to reflux on molecular sieve 5A for 10 minutes.
It flowed. Added 1g of activated manganese dioxide
Afterwards, refluxing was continued for an additional 10 minutes. celite mixture
and the liquid was evaporated. crystalline residue
The residue was collected with ether and ethyl acetate/hexane.
Recrystallize methyl 8 with a melting color of 272-275°C.
-chloro-6-(2-chlorophenyl)-1-phene
Nyl-4H-imidazo[1,5-α][1,4]be
The yellow color of nzodiazepine-3-carboxylate
Obtained crystals. Example 92 In 2 tetrahydrofuran and 300 ml of benzene
5-(2-chlorophenyl)-1,3-dihydro
-7-nitro-2H-1,4-benzodiazepine
-2-one 94.6g (0.3mol) solution in ice water
Cooled and saturated with methylamine. ben
Titanium tetrachloride 40.2ml (0.36 mol) in 300ml Zen
solution was added through the addition funnel. After addition, mix
The mixture was stirred and refluxed for 3 hours. Water (300ml)
was added slowly to the cooled reaction mixture. inorganic
The solid was separated by filtration and tetrahydrofuran
Thoroughly washed with a lantern. Separate the water from the liquid and
The organic phase was dried over sodium sulfate and evaporated.
I let it emanate. The residue was dissolved in 10% (v/v) methylene chloride.
v) On 500g silica gel using ethanol
It was chromatographed. clear fraction
can be crystallized from methylene chloride/ethanol.
5-(2-chlorophenyl)-7-nito
rho-2-methylamino-3H-1,4-benzodi
Azepine is a yellow product with a melting point of 219-221 °C
obtained as. Sodium nitrite (8.63g, 0.125mol),
5-(2-chlorophenyl)-7 in 200 ml of glacial acetic acid
-nitro-2-methylamino-3H-1,4-be
15 minutes in a solution of 83.9 g (0.1 mol) of nzodiazepine
It was added in three parts over time. After addition, at room temperature
Continue stirring for 1 1/2 hours and add the product to water.
It was precipitated by Collect yellow solid and wash with water
, vacuum dried and recrystallized from ethanol.
5-(2-chlorophenyl)-7-nitro-
2-(N-nitrosomethylamino)-3H-1.4
- Benzodiazepine is a yellow crystal with a melting point of 164-166℃
obtained as. The sample for analysis was methylene chloride/ethyl chloride.
Recrystallized from tanol. Melting point is 167-169℃
It was hot. Example 93 Tetrahydrofuran (approximately 20 moles of monomethylamine)
1,3-dihydro-5 in 1
-Phenyl-2H-1,4-benzodiazepine-
A solution of 23.6 g (0.10 mol) of 2-one was cooled in an ice bath.
It chilled. For this mixture, benzene
14 ml of titanium tetrachloride in 200 ml (d=1.73, 0.12 mo
) was added. This mixture was stirred at room temperature for 2 days. generated
The titanium complex was decomposed with 20 ml of water. precipitated inorganic salts
was removed by filtration. Evaporate the solvent in vacuo
and the residue was partitioned between methylene chloride and water. Melt
A colorless amorphous solid at a temperature of 227 to 229℃ is removed by filtration.
I left. Methylene chloride mother liquor anhydrous sodium sulfate
Dry on top, evaporate to dryness and ethyl acetate.
Melting point 226-228℃ by crystallizing from
An additional sample of a colorless solid was obtained. Analytical samples were recrystallized from dimethylformamide.
It has a melting point of 227-229℃.
Colorless prisms were obtained. 2-methylamino-5-ph in 100 ml of pyridine
Enyl-3H-1,4-benzodiazepine 10.0g
(0.04 mol) for a cooled and stirred solution of
A saturated solution of nitrosyl chloride in acetic anhydride 100
Added ml. Stir the solution for 3.5 h, during which time it
was warmed to ambient temperature. Solution in 300ml of ice water
and add 150 ml of the aqueous solution each time.
Extracted with methylene 5 times. Combine organic extracts
washed with water and prine, dried (CaSO _Four )
The solvent was then removed under reduced pressure to obtain a dark semi-solid.
Ta. Chromatography on 500g silica gel
(chloroform elution), melting point 192-199℃
(Decomposition) of 2-(N-nitrosomethylamino)-5
-phenyl-3H-1,4-benzodiazepine
Obtained. Example 94 7- in 100 ml of dry tetrahydrofuran
Chlor-1,3-dihydro-5-(2-fluoro
phenyl)-3-methyl-2H-1,4-benzodi
6 g (0.02 mol) of azepin-2-one stirred
Dispersion of 57% sodium hydride in mineral oil into a solution
1.05 g (0.25 mol) of liquid was added. Argo the mixture
The mixture was placed under vacuum and refluxed for 1 hour. cooled to room temperature
After that, mix the mixture with dimorpholinophosphinic
treated with 7.4 g (0.03 mol) of loride and at room temperature.
Stirring was continued under argon for 2 hours. mixture
filtered and evaporated under reduced pressure to leave a gummy residue.
Obtained. Add this rubbery substance to 100ml of anhydrous ether.
When stirred, white crystals are obtained, which are filtered.
Collected by washing with a small amount of ether and air
Dry. The thus obtained 7-chloro-2-di
-(morpholino)-phosphinyloxy-5-(2
-fluorophenyl)-3-methyl-3H-1.4
- The melting point of the benzodiazepine was 90-95°C. Example 95 1 in 300 ml of dry tetrahydrofuran
3-dihydro-7-(2-methyl-1,3-dio
xolan-2-yl)-5-phenyl-2H-1.
4-benzodiazepine-2-one 19.3g (0.06mol)
A solution of 57% sodium hydride in mineral oil
Argon atmosphere with 3.1 g (0.075 mol) suspension
Processed below. The mixture was heated under reflux for 1 hour,
Cool to room temperature, then dimorpholinophosphini
22.2 g (0.087 mol) of cuchloride was added. mixture
The mixture was stirred at room temperature for 2 hours and then left overnight.
Sodium chloride was removed by filtration and the solvent
removal of and crystallization of the residue from ether.
The crude 7-(2-methyl-1,3-dioxo
Ran-2-yl)-2-[bis(morpholino)phosph
[ynyloxy]-5-phenyl-3H-1,4-be
Nzodiazepine was obtained. Example 96 Tetrahydrof containing 4 moles of monomethylamine
1,8-dihydro-7-ethyl- in run 2.0
5-(2-fluorophenyl)-2H-1,4-be
56.4 g (0.20 mol) of nzodiazepine-2-one
The solution was cooled in an ice bath. To this, benzene 350
Add 33.0 ml (0.30 mol) of titanium tetrachloride in ml
Ta. The mixture was stirred at room temperature for 3 days. The obtained titanium tetrachloride was decomposed with 100 ml of water.
Ta. Inorganic salts were removed by filtration. liquid in vacuum
evaporated to dryness. Dilute the residue with methylene chloride
and water. Methylene chloride layer with anhydrous sulfur
dry over sodium chloride and in vacuo until dry.
Evaporated. Crystallize the residue from acetonitrile
7-ethyl-5-(2-fluoro
(ruphenyl)-2-methylamino-3H-1,4-
Benzodiazepine is a pale yellow puri with a melting point of 172-174℃.
obtained as a rhythm. Samples for analysis were recrystallized from acetonitrile.
A light yellow powder with a melting point of 172-174°C
obtained as a rhythm. Sodium nitrite (8.6 g, 0.125 mol) on ice
7-ethyl-5-(2-fluorophore) in 100 ml of acetic acid
enyl)-2-methylamino-3H-1,4-ben
3 times in a solution of 29.5 g (0.1 mol) of zodiazepine
Added in portions over 1/2 hour. Another 1/2 hour at room temperature
After stirring for a while, the mixture is diluted with ice water and salted.
Extracted with methylene chloride. Extract with water and bicarbonate
Wash with aqueous solution and dry over sodium sulfate.
Crude 7-ethyl-5-
(2-fluorophenyl)-2-(N-nitrosome
thylamino)-3H-1,4-benzodiazepine
Obtained as a yellow oil. Example 97 Method A: 7-ethyl-1,9-dimethyl-6-ph
enyl-4H・9H-imidazo[1.5-α]pi
Lazoro [4.3-f] [1.4] Diazepine-
3-Carboxylic acid methyl ester 3-ethyl- in 20 ml of dry tetrahydrofuran
1,6-dihydro-α-hydroxyimino-1-
Methyl-4-phenylpyrazolo[3,4-e]
[1.4] Diazepine-7-acetic acid/methyl ester
0.35 g (0.000986 mol) solution and methanol
25ml of triethyl orthoacetate
(0.0109 mol) and 1 scoop of Raneynickel
Processed. The reaction mixture was heated at room temperature and atmospheric pressure.
Hydrogenation was carried out for 2.5 hours. Remove catalyst by filtration
and wash the used Raney nickel with methanol.
did. Combine the liquids, evaporate and discard the residue.
Dissolved in 50 ml of chloromethane. Dilute this solution with diluted water
Wash with 40ml of ammonium oxide and anhydrous sodium sulfate.
and evaporated to dryness. residue
, 2 ml of triethyl orthoacetate (0.109 mole)
) and 0.2 ml of 5.7N ethanolic hydrogen chloride
A solution in 50 ml of methanol containing (0.00114 mol)
The mixture was refluxed for 20 minutes. By evaporation under reduced pressure
to remove the solvent and dissolve the residue in dichloromethane.
This was then dissolved in dilute ammonium hydroxide.
and dry over anhydrous sodium sulfate.
and evaporated. Crude product obtained as oil
in a mixture of 5% methanol in ethyl acetate.
and spread it on three thick layers of silica gel.
Ta. R _f Scrape off the product with 0.5 methanol
and filtered. evaporate solution
and crystallize the residue from ether.
and the pure product with a melting point of 186-189℃ is a white prism.
Obtained by doing. Method B: 7-ethyl-1,9-dimethyl-6-ph
enyl-4H・9H-imidazo[1.5-α]pi
Lazoro [4.3-f] [1.4] Diazepine-
3-carboxylic acid methyl ester 3-carboxylic acid methyl ester in 10 ml dichloromethane and 0.35 ml acetic acid
Ethyl-1,6-dihydro-α-hydroxyimi
Nor-1-methyl-4-phenylpyrazolo [3,4
-e] [1,4] Diazepine-7-acetic acid/methyl
A stirred solution of 0.2 g (0.000567 mol) of ester
Treated with 0.4 g (0.0061 mol) of lead powder and stirred
continued for 5 minutes. Strain this mixture and
Lead in dichloromethane and tetrahydrofuran
Washed. Combine the solutions, then add triethylortho
Mixture treated with 0.3 ml (0.00164 mol) of acetate
The material was evaporated under reduced pressure and the residue was dissolved in triethyl
15 ml of ethyl acetate containing 0.3 ml of orthoacetate
The solution was heated under reflux for 1 minute. evaporate solution
and acetic acid ester containing methanol (10%).
Two thick layers of silica gel in chilled solution
expanded on top. R _f Scratch the area with 0.2-0.4
and washed with methanol. methanol solution
filtered and evaporated. Crystallize the residue from ethyl acetate
and a mixture of ethyl acetate and ether
When recrystallized from
The product was obtained as a white rod. Example 98 Methyl 8-chloro-6-(2-chlorophenylene)
)-1-(2-pyridyl)-4H-imidazo1.
5-α] [1.4] Benzodiazepine-3-ka
Ruboxylate 2-[(amino)methoxycarbonyl-methylene
]-7-chloro-5-(2-chlorophenyl)-
1,3-dihydro-2H-1,4-benzodiaze
Pine ethanolate 8.5g (0.02mol), toluene
200ml, pyridine-2-carboxaldehyde 4
ml and 15 g of molecular sieve 4A was heated for 10 minutes.
Refluxed. Added 20g of activated manganese dioxide
Heating and stirring was then continued for an additional 10 minutes. blend
was filtered over Celite and the liquid was evaporated. residue
When crystallized from ethyl acetate/ether, the melting point
Yellowish crystals were obtained at 282-285°C. analysis
Reconsolidate the sample from methylene chloride/ethyl acetate.
crystallized. Melting point 283-285℃. Example 99 Methyl 8-chloro-6-(2-chloropheni
)-1-propyl-4H-imidazo[1,5-
α] [1,4] Benzodiazepine-3-carbo
Xylate 2-[(amino)methoxycarbonyl-methylene
]-7-chloro-5-(2-chlorophenyl)-
1,3-dihydro-2H-1,4-benzodiaze
Pin ethanolate 4.5g (0.0107mol), methane chloride
100 ml of tyrene, 2 ml of butyraldehyde and molecule
A mixture of 5 g of Sieve 5A was stirred at room temperature for 15 minutes. Next
Add 10g of activated manganese dioxide and stir.
Stirring was continued for an additional 15 minutes. Mixture on celite
filtered and the liquid was evaporated. Ether the residue
When crystallized from, the final product has a melting point of 196-198 °C
was gotten. Analytical samples were prepared using ethyl acetate/tetate.
Recrystallized from lahydrofuran/hexane. Melt
Point 197-198℃. Example 100 Methyl 8-chloro-6-(2-chloropheni
)-1-isopropyl-4H-imidazo[1.
5-α] [1.4] Benzodiazepine-3-ka
Ruboxylate Follow the procedure of Example 99, but with butyraldehyde
Using isobutyraldehyde instead of
The final product was obtained which was crystallized from tel. for analysis
This was converted into ethyl acetate/tetrahydrofurane.
Recrystallized from chlorine/hexane. Melting point 234-235
℃. Example 101 Methyl 8-chloro-1-chloromethyl-6-
(2-chlorophenyl)-4H-imidazo[1.
5-α] [1.4] Benzodiazepine-3-ka
Ruboxylate 50ml of 2N hydrochloric acid and chloroacetaldehyde
Heat a mixture of 50 ml of methyl acetal to reflux for 30 minutes.
5ml of the chloroacetaldehyde solution prepared by
of 2-[(amino)meth in 200 ml of methylene chloride.
[xycarbonyl methylene]-7-chloro-5-
(2-chlorophenyl)-1,3-dihydro-2H
-1,4-benzodiazepine ethanolate 4.5g
(0.0107 mol). stirred for 15 minutes
Afterwards, the reaction mixture was diluted with methylene chloride and sodium bicarbonate.
and a saturated aqueous solution. Dry the organic phase
Then, it was treated with 12 g of activated manganese dioxide.
After stirring for 15 minutes at room temperature, the
Yotsute MnO ₂ Separate and evaporate the liquid
Ta. Crystallize the residue from methylene chloride/ether.
The final product was obtained. Sample for analysis
, methylene chloride/ethyl acetate 7:3 (V/V)
Chromatograph on 30x volume of silica gel using
Purified by roughy. Ether the pure product
It was crystallized from. Melting point 237-239°C (decomposition). Example 102 Methyl 8-chloro-6-(2-chloropheni
)-1-(2-dimethylaminoethyl)-4H-
imidazo[1,5-α][1,4]benzodia
Zepine-3-carboxylate dimethylamine 5 ml and acrolein 2 ml
of 2-[(amino)meth in 100 ml of methylene chloride.
[xycarbonylmethylene]-7-chloro-5-(2
-chlorophenyl)-1,3-dihydro-2H-
1,4-benzodiazepine ethanolate 4.5g
(0.0107 mol). Stir for 10 minutes at room temperature.
After stirring, add 12g of activated manganese dioxide and
and stirring continued for 15 minutes. over celite
Yotsute MnO ₂ and evaporate the liquid.
Ta. The residue was crystallized from ethanol/ether.
The final product was obtained and was converted into ethyl acetate/methanol.
It was recrystallized for analysis from L/hexane. Melt
Point 203-204℃. Example 103 8-chloro-6-(2-chlorophenyl)-1-
(2-pyridyl)-4H-imidazo[1,5-
α] [1,4] Benzodiazepine-3-carbo
methyl 8-chloro-6-(2-chlorophenylene)
)-1-(2-pyridyl)-4H-imidazo[1.
5-α] [1.4] Benzodiazepine-3-cal
Boxylate 4.3g (0.009mol), methanol 200
ml, water 10ml and potassium hydroxide 1.7g (0.03mol)
The mixture was heated to reflux for 4 hours. part solvent
After evaporation, the residue was acidified with glacial acetic acid.
and diluted with water. Collect the precipitated product.
filtered, washed with water and dried to obtain a crystalline material, separated.
For analysis, mix this with methylene chloride/methanol/vinegar.
Recrystallized from ethyl acid. Melting point 262-265℃ (min.
solution). Example 104 8-chloro-6-(2-chlorophenyl)-1-
(2-pyridyl)-4H-imidazo[1,5-
α] [1,4] Benzodiazepine-3-carbo
Xamide 250 ml of methylene chloride cooled with ice water
8-chloro-6-(2-chlorophenyl)-1 in
-(2-pyridyl)-4H-imidazo[1,5-
α] [1,4] Benzodiazepine-3-carvone
3 g of phosphorus pentachloride in suspension of 4 g (0.0089 mol) of acid
(0.0145 mol) was added. Stir on ice water for 30 minutes.
then add ammonia until the mixture is alkaline.
introduced gas. 20ml aqueous ammonia and chloride
Then add 200ml of methylene and stir for 15 minutes
continued. Separate the organic layer and dry over sodium sulfate.
dried and 5% ethanol in methylene chloride
(v/v) onto a pad of silica gel.
Ta. Evaporate the solution and dissolve the residue in ethanol/
Crystallized from ethyl acetate to produce yellowish crystals.
This was converted into methylene chloride/ethyl acetate for analysis.
It was recrystallized from Le. Melting point 225-257℃. Reset
and melted again at 275-278°C. Example 105 8-chloro-6-(2-chlorophenyl)-1-
Propyl-4H-imidazo [1.5-α] [1.
4] Benzodiazepine-3-carboxamide methyl 8-chloro-6-(2-chloropheni
)-1-propyl-4H-imidazo[1,5-
α] [1,4] Benzodiazepine-3-carboxy
1.5 g (3.5 mmol) of sylate and methanol
By reaction with 20 ml of ammonia, as described in Example 106
Under the same conditions, the final product was obtained, which was treated with chloride
Crystallized from tyrene/ethanol. Melting point 298
~300℃. Example 106 8-chloro-6-(2-chlorophenyl)-1-
Isopropyl-4H-imidazo [1,5-α]
[1.4] Benzodiazepine-3-carboxa
Midomethyl 8-chloro-6-(2-chloropheni
)-1-isopropyl-4H-imidazo[1.5
-α〕[1,4]-benzodiazepine-3-carbo
1.3 g (3 mmol) of xylate and 20 g of ammonia
Auto mix with 20 ml of methanol containing wt%
Heated in a crepe at 130°C for 20 hours. solvent
Evaporate and dissolve the residue in methylene chloride/ethanol.
When crystallized from mol, the final product has a melting point of 328-330°C.
I got something. Recrystallize analytical samples from the same solvent
I let it happen. Example 107 8-chloro-6-(2-chlorophenyl)-1-
(2-dimethylaminoethyl)-4H-imidazo
[1.5-α] [1.4] Benzodiazepine-3
-carboxamide methyl 8-chloro-6-(2-chlorophenylene
)-1-(2-dimethylaminoethyl)-4H-i
midazo[1.5-α][1.4]benzodiazepi
0.46 g of N-3-carboxylate and 20 g of ammonia
% of the mixture with 10 ml of methanol in a cylinder.
The mixture was heated at 130°C for 20 hours. Evaporate the solvent
and the residue in 20% ethanol in methylene chloride.
Chromatograph on silica gel (7 g).
I got it. Is the clear fraction 2-propanol?
to obtain a pure product with a melting point of 249-251℃.
Ta. Example 108 8-chloro-6-(2-chlorophenyl)-N-
Methyl-1-(methylaminomethyl-4H-imi)
Dazo [1.5-α] [1.4] Benzodiazepi
Tetrahydrocarbon-3-carboxamide containing 20% methylamine
75 ml of a solution of methylamine in furan was added to the
Methyl 8-chloro-1-chloro in 50 ml of Dorofuran
lomethyl-6-(2-chlorophenyl)-4H-y
midazo[1.5-α][1.4]benzodiazepi
3 g (6.9 mmol) of ion-3-carboxylate
solution. Heat the mixture to 100℃ in a sealed container.
Heated for 18 hours. Evaporate the solvent and leave the residue
The final product was obtained by crystallization from ethanol;
5% (v/v) ethanol in methylene chloride
Chromatographed on 50 g of silica gel.
and purified. The combined distinct fraction is the evaporation
crystallization from methylene chloride/ethanol
gave a product with a melting point of 270-273°C. Example 109 Methyl 1-aminomethyl-8-chloro-6-
(2-chlorophenyl)-4H-imidazo[1.
5-α] [1.4] Benzodiazepine-3-ka
Ruboxylate Hydrochloride Tetrahydrofuran 50ml and Ethanol 50ml
Methyl 1-azido-methyl-8-chloro-6 in
-(2-chlorophenyl)-4H-imidazo[1.
5-α] [1.4] Benzodiazepine-3-cal
A solution of 2.4 g (5.4 mmol) of boxylate was
2 at atmospheric pressure using Raney nickel as a medium.
Hydrogenated for an hour. Remove the catalyst by filtration and
The liquid was evaporated. Dilute the residue with 2-propanol
and the solution in ethanolic chloride water.
The sample was treated with 5 mmol of sodium chloride. Collect the precipitated hydrochloride
and reconstituted from 2-propanol/methanol.
Crystallize to produce a product with a melting point of 265-270℃ (decomposition)
Obtained. Recrystallize the analytical sample from the same solvent.
Ta. Melting point 270-275℃ (decomposition). Example 110 Methyl-8-chloro-6-(2-chloropheni
)-1-dimethylaminomethyl-4H-imida
Zo[1,5-α][1,4]benzodiazepine
-3-carboxylate methyl 8-chloro-1-chloromethyl-6-
(2-chlorophenyl)-4H-imidazo[1.5
-α] [1,4] Benzodiazepine-3-carbo
Xylate 0.435g (1 mmol), tetrahydro
A mixture of 15ml furan and 1.5ml dimethylamine
was heated in a sealed tube at 100°C for 3 hours. solvent
Evaporate and dissolve the residue in methylene chloride and sodium bicarbonate.
It was partitioned between thorium and aqueous solution. Dry the organic phase
Dry, evaporate and remove the residue from ether.
The final product was obtained by crystallization. Sample for analysis
was recrystallized from ethyl acetate/hexane. melting point
181-183℃. Example 111 Methyl 1-azidomethyl-8-chloro-6-
(2-chlorophenyl)-4H-imidazo[1.
5-α] [1.4] Benzodiazepine-3-ka
Ruboxylate Methyl 8-chloro-1-chloromethyl-6-
(2-chlorophenyl)-4H-imidazo[1.5
-α] [1,4] Benzodiazepine-3-carbo
2.18 g (5 mmol) xylate, sodium acetate
Dido 0.65g (10mmol) and dimethylform
A mixture of 30 ml of amide was heated to reflux for 5 minutes. water
to precipitate the product by addition of and collect it;
and dissolved in methylene chloride. dry the solution
and evaporated. Ethyl acetate/ether
When crystallized, colorless crystals with a melting point of 187-189℃ are formed.
Obtained. The sample for analysis was ethyl acetate/hexane.
It was recrystallized from Melting point 188-190℃. Example 112 Methyl 1-acetoxymethyl-8-chloro-6
-(2-chlorophenyl)-4H-imidazo
[1.5-α] [1.4] Benzodiazepine-3
-carboxylate methyl 8-chloro-1-chloromethyl-6-
(2-chlorophenyl)-4H-imidazo[1.5
-α] [1,4] Benzodiazepine-3-carbo
Xylate 0.435g (1 mmol), sodium acetate
Mixture of 0.5g of aluminum and 20ml of dimethylformamide
The material was heated to reflux under nitrogen atmosphere for 10 minutes. solvent
was removed under reduced pressure and the residue was dissolved in water and methylene chloride.
It was distributed between Dry the methylene chloride layer
evaporate and dissolve the residue 30% in methylene chloride.
(v/v) of ethyl acetate onto 7 g of silica gel.
was chromatographed. clear frac
Crystallized from ether, melting point 186~
A final product of 188°C was obtained. For analysis, this
recrystallized from methylene chloride/ether/hexane
I let it happen. Example 113 1-aminomethyl-8-chloro-6-(2-k)
rolophenyl)-4H-imidazo[1,5-α]
[1.4] Benzodiazepine-3-carboxa
Mid-hydrochloride/hemi-hydro
Hemiisopropanolate 150ml of tetrahydrofuran and 75ml of ethanol
1-azidomethyl-8-chloro-6-(2
-chlorophenyl)-4H-imidazo[1,5-
α] [1,4] Benzodiazepine-3-carboxy
A solution of 2 g (4.65 mmol) of samide was used as a catalyst.
using a Raney nickel at atmospheric pressure for 1 1/2 hours.
Hydrogenated for a while. The catalyst is separated by filtration and
The liquid was evaporated. From ethanol/ether
Crystallization yields a final product with a melting point of 230-235°C.
This was converted to the hydrochloride as follows. the above
Mix 1.2 g of base with hot ethanol and methanol.
Dissolved in liquid. Ethanolic hydrochloric acid (3 mmol)
) was added. Concentrate the mixture and add isopropyl
Crystallize the hydrochloride by adding panol and cooling
turned into Collect the crystals and add 2-propanol and
When washed with ether, a product with a melting point of 250-260 °C
remained. Samples for analysis were mixed with methanol/2-prop.
Hemihydrate is recrystallized from lopanol.
Melting point analyzed for hemiisopropanolate
Crystals were obtained at 250-260°C (undefined). Example 114 8-chloro-6-(2-chlorophenyl)-1-
Dimethylaminoethyl-4H-imidazo [1.
5-α] [1.4] Benzodiazepine-3-ka
Ruboxamide Methyl 8-chloro-6-(2-chlorophenylene)
)-1-dimethylaminomethyl-4H-imidazo
[1.5-α] [1.4] Benzodiazepine-3-
0.44 g (1 mmol) of carboxylate and
A mixture of 15 ml of methanol containing 20% ammonia,
Heated in an autoclave to 130°C for 16 hours. melt
Evaporate the solvent and dissolve the residue in ethanol/ether.
The final product was obtained by crystallization from the solution. for analysis
The sample was methylene chloride/ethyl acetate 1:1
Passage over silica gel using (v/v) and
It was purified by crystallization from ethyl acetate and ethyl acetate. Melt
Point 242-245℃. Example 115 1-azidomethyl-8-chloro-6-(2-k)
rolophenyl)-4H-imidazo[1,5-α]
[1.4] Benzodiazepine-3-carboxa
Midomethyl 1-azidomethyl-8-chloro-6-
(2-chlorophenyl)-4H-imidazo[1.5
-α] [1,4] Benzodiazepine-3-carbo
Xylate 4.4g (0.01mol), methanol 200
ml, water 10ml and potassium hydroxide 1.7g (0.03mol)
The mixture was heated to reflux for 3 hours. partial evaporation
After cooling, the mixture was acidified with glacial acetic acid and
and diluted with water. Collect the precipitated product, and
Dissolved in methylene chloride. Let the solution dry;
Evaporate and dissolve the residue in methylene chloride/ethyl acetate.
1-azidomethyl
Ru-8-chloro-6-(2-chlorophenyl)-
4H-Imidazo [1,5-α] [1,4] Benzodi
azepine-3-carboxylic acid was obtained, which was
and changed it to amide. in 200ml of methylene chloride.
2.1 g (0.01 mol) of phosphorus pentachloride in a suspension of the above substance
was added and the mixture was stirred in ice water for 20 min.
Ta. The ammonia stream is then passed through the reaction mixture.
It was introduced until it became alkaline. Stir for an additional 15 minutes.
After stirring, add aqueous ammonia and bring to room temperature.
Stirring was continued for 1 hour. Mixture with methylene chloride
Dilute and wash with saturated sodium chloride solution
Ta. The organic phase was dried and evaporated. residue
2.5% (v/v) ethanol in methylene chloride
Chromatograph on 120 g of silica gel using
I put it on. Combine distinct fractions and evaporate
The residue was then crystallized from ethanol and the melting point
The final product was obtained at 258-260°C (decomposition). for analysis
Samples were recrystallized from methylene chloride/ethyl acetate.
I let it happen. Example 116 Methyl 8-chloro-6-phenyl-4H-imy
Dazo [1.5-α] [1.4] Benzodiazipi
-3-carboxylate Raneynickel (2 scoops) in methanol
7 in a mixture of 200 ml and 200 ml of tetrahydrofuran
-Chloro-α-hydroxyimino-5-phenyl
-3H-1,4-benzodiazepine-2-acetic acid-
Added to the methyl ester solution. mixture at atmospheric pressure
The mixture was hydrogenated for 5 hours. catalyst on celite
Separate by filtration and evaporate the liquid to dryness.
Ta. Dissolve the residue in 100 ml of methanol and
Add this solution to 10 ml of triethylorthoformate and
and 5 ml of ethanolic hydrogen chloride. blend
After refluxing for 10 min, the solvent was evaporated under reduced pressure.
and dissolve the residue in methylene chloride and sodium bicarbonate.
and a saturated aqueous solution. Dry the organic phase
and evaporated. Drain the residue from ether.
Crystallize to obtain the final product and use it for analysis.
Recrystallized from methylene chloride/ether. melting point
235-236℃. Example 117 Methyl 8-chloro-6-(2-chloropheni
)-4H-imidazo [1.5-α] [1.4]
Benzodiazepine-3-carboxylate 2-[(amino)methoxycarbonylmethylene]
-7-chloro-5-(2-chlorophenyl)-1.
3-dihydro-2H-1,4-benzodiazepine
9 g of ethanolate, 100 ml of toluene and Torie
Heat a mixture of 20 ml of tylorthoformate for 15 minutes
Refluxed. Evaporate the solvent under reduced pressure and
The crystalline residue was collected in ether and diluted with acetic acid.
Recrystallized from chill/methanol, melting point 206 ~
A final product of 208°C was obtained. Example 118 8-chloro-6-phenyl-4H-imidazo
[1.5-α] [1.4] Benzodiazepine-3
-carboxamide methyl 8-chloro-6-phenyl-4H-imi
Dazo [1.5-α] [1.4] Benzodiazepine
Contains 5g of -3-carboxylate and 20% ammonia.
Autoclave the mixture with 100 ml of methanol.
The mixture was heated to 130°C for 8 hours in a microwave oven. The precipitated crystals
Collect, and tetrahydrofuran/methanol?
The final product with a melting point of 295-296℃ is obtained by recrystallizing it from
Obtained. Samples for analysis are dimethylformamide/
Recrystallized from ether. Melting point 296-297℃. Example 119 8-chloro-6-(2-fluorophenyl)-
4H-imidazo[1.5-α][1.4]benzo
Diazepine-3-carboxamide 8-chloride in 200 ml of methylene chloride cooled with ice water
Rolo-6-(2-fluorophenyl)-4H-imy
Dazo [1.5-α] [1.4] Benzodiazepine
-Suspension of 3.55 g (0.01 mol) of 3-carboxylic acid
To this, 2.6 g (0.0125 mol) of phosphorus pentoxide was added. 30
After stirring for a minute, ammonia gas is added to the reaction mixture.
was introduced until it became alkaline. another 15 minutes
Then add aqueous ammonia and stir for 30 minutes.
continued. The reaction mixture was then diluted with water and ethanol.
Partitioned between 10% (v/v) of methylene chloride
I let it happen. Dry the organic phase and coat with silica gel.
It passed over the patch. evaporate the solution, and
The final product is obtained by recrystallizing the solid residue from ethanol.
I got something. Samples for analysis are diluted with tetrahydrofuran/
Recrystallized from ethanol. Melting point 292-294℃. Example 120 8-chloro-6-(2-chlorophenyl)-4H
-imidazo[1.5-α][1.4]benzodi
Azepine-3-carboxamide Methyl 8-chloro-6-(2-chlorophenylene)
)-4H-imidazo [1.5-α] [1.4]
Nzodiazepine-3-carboxylate 5g
(0.018 mol) and methano containing 20% ammonia
75ml of the mixture in an autoclave at 130°C.
The mixture was heated for 18 hours. Reaction mixture from which the product crystallized
in methanol/methoxychloride until dissolution is complete.
It was heated in a microwave. filtered and concentrated to a melting point >
A final product of 300°C was obtained. The sample for analysis is salt.
Recrystallized from methylene chloride/ethanol. Example 121 8-chloro-N.N-dimethyl-6-phenyl
-4H-imidazo[1,5-α][1,4]ben
Zodiazepine-3-carboxamide methyl 8-chloro-6-phenyl-4H-imi
Dazo [1.5-α] [1.4] Benzodiazepine
-3-carboxylate 5g (0.014 mol), hydroxy acid
2.4 g (0.043 mol) of potassium chloride, 10 ml of water and
Heat a mixture of 140ml of tanol under reflux for 6 hours.
Ta. Evaporate the solvent and dissolve the residue in water.
I set it. Filter the solution and acidify with glacial acetic acid.
Ta. Collect the precipitated crystals and dilute with methylene chloride/
8 crystallized from ethanol with a melting point of 268-270℃
-Chloro-6-phenyl-4H-imidazo[1.
5-α] [1.4] Benzodiazepine-3-cal
Bonic acid was obtained. 1 g of this acid is mixed with 1.3 g of phosphorus pentachloride and methoxychloride.
The mixture was stirred at room temperature for 2 hours with 100 ml of water. Jime
Bubble the thylamine into the mixture while cooling.
A clear solution with a basic pH was obtained.
This solution is then mixed with sodium chloride solution and water.
Washed with. Dry and evaporate the methylene chloride layer.
I let it emanate. Crystallize the residue from ether to obtain the final product.
This was added to methylene chloride/ethyl acetate for analysis.
It was recrystallized as Melting point 231-233℃. Example 122 8-chloro-6-(2-chlorophenyl)-N.
N-dimethyl-4H-imidazo [1,5-α]
[1.4] Benzodiazepine-3-carboxa
Midomethyl 8-chloro-6-(2-chloropheni
)-4H-imidazo [1.5-α] [1.4]
2 g of nzodiazepine-3-carboxylate,
15ml of hexamethylphosphate triamide and lithium chloride
1.5 g of the mixture was heated to 225°C. cooled anti-
The reaction mixture is mixed between water and methylene chloride/ether.
It was distributed. The organic phase was washed with aqueous bicarbonate solution,
Dry and evaporate. crystal from ether
to give the final product, which was diluted with ethyl acetate/meth
It was recrystallized from alcohol for analysis. melting point 240
~242℃. Example 123 8-chloro-6-(2-chlorophenyl)-3-
Hydroxymethyl-4H-imidazo[1,5-
α] [1.4] Benzodiazepine isopropano
Methyl 8-chloro in 250 ml of tetrahydrofuran
rho-6-(2-chlorophenyl)-4H-imidazo
[1.5-α] [1.4] Benzodiazepine-3-
A solution of 25 g (0.065 mol) of carboxylate is -
Lithium hydride solution in 200 ml of ether at 10°C
A suspension of 5 g of aluminum was added. After addition, mix
The mixture was stirred at -5 to 0°C for 15 minutes. Then mix
The compound was hydrolyzed by adding 25 ml of water. Nothing
Separate the organic material by passing it through celite and
The liquid was dried and evaporated. Treat the residue with chloride
Crystallized from tyrene/ether/ethyl acetate
to give a solvated product. 2-
When recrystallized from propanol/ether, the melting point
This gives the solvate at 103-105 °C (decomposition).
According to analytical and spectral data, 1 mole of
Contains isopropanol. Example 124 8-chloro-6-(2-chlorophenyl)-4H
-imidazo[1.5-α][1.4]benzodi
Azepine-3-carboxaldehyde 8-chloro-6-(2-chlorophenyl)-3-
Hydroxymethyl-4H-imidazo[1,5-
α] [1.4] Benzodiazepine isopropanol
0.5 g of salt, 40 ml of methylene chloride and activated diacid
A mixture of 2.5 g of manganese chloride was stirred at room temperature for 2 hours.
Ta. MnO by passing over Celite ₂ remove
and the liquid was evaporated. Is the residue ether?
crystallize the final product with a melting point of 213-215℃.
Obtained. Example 125 8-chloro-3-chloromethyl-6-(2-k)
rolophenyl)-4H-imidazo[1,5-α]
[1.4] Benzodiazepine Crude 8-chloro-6-(2-chlorophenylene)
)-3-hydroxymethyl-4H-imidazo
[1.5-α] [1.4] Benzodiazepine 6g
was slowly added to 30 ml of thionyl chloride. addition
Following, the mixture was stirred at room temperature for 15 min and then
Gradually diluted with 100 ml of ethyl acetate. Precipitated crystals
Collect the crystals after 15 minutes and add methylene chloride and bicarbonate.
Partitioned between sodium saturated aqueous solution. chloride
Methylene/ether gave the final product. analysis
The sample was 10% (v/v) in methylene chloride.
Passed through silica gel using ethyl acetate and then evaporated.
It was purified by crystallization from ether.
Melting point approximately 165℃. Crystals form slowly and dissolve when heated.
It does not melt, but when immersed it melts at about 165℃. Example 126 8-acetyl-8-chloro-6-(2-chloro
phenyl)-4H-imidazo [1,5-α]
[1.4] Benzodiazepine 8-chloro-6 in 150 ml of tetrahydrofuran
-(2-chlorophenyl)-4H-imidazo[1.
5-α] [1.4] Benzodiazepine-3-cal
Solution of 2.8 g (7.8 mmol) boxaldehyde
, methylmagnesium ion die in ether
50 ml of a 1 molar solution of Stir for 15 minutes at room temperature
After that, the reaction mixture is hydrolyzed by the addition of water.
diluted with tetrahydrofuran and diluted with sodium sulfate.
and filtered onto celite.
Evaporate the liquid and dissolve the residue in methylene chloride.
% (v/v) ethanol on 60 g of silica gel
It was chromatographed. 8-chloro-6-
(2-chlorophenyl)-3-(1-hydroxyethyl)
chill)-4H-imidazo [1.5-α] [1.4]
Combine well-defined fractions containing benzodiazepines.
and evaporated. Dilute the residue with methylene chloride 100
Dissolved and activated manganese dioxide in 15 ml
After addition of g, the mixture was stirred at room temperature for 2 hours. MnO ₂ of
Remove by filtration over celite and remove
was evaporated. Residue 10% in methylene chloride
(v/v) on 30 g of silica gel with ethyl acetate
Purified again by chromatography
did. The combined distinct fractions were dissolved in ethyl acetate/
It is crystallized from hexane and has a maximum melting point of 214-216℃.
The final product was obtained. Example 127 8-chloro-6-(2-chlorophenyl)-3-
Methoxymethyl-4H-imidazo[1,5-
α] [1,4] Benzodiazepine 8-chloro-3-chloromethyl-6-(2-k
rolophenyl)-4H-imidazo[1,5-α]
[1.4] Benzodiazepine 2.7g (7.15 mmol)
), methanol 50ml and triethylamine 3
ml mixture was heated to reflux for 20 minutes. evaporate the solvent
and dissolve the residue in methylene chloride and sodium carbonate.
and a 10% aqueous solution. methylene chloride
Dry the layer and evaporate and remove the residue by 2
- soluble in propanol and ethanolic
Treated with hydrogen chloride. Precipitated melting point over 230°
Collect the crystalline dihydrochloride (decomposition) and
between methylene chloride and aqueous sodium carbonate solution.
It was distributed. Dry the organic phase and evaporate
and crystallize the residue from ether/hexane.
The final product was obtained with a melting point of 126-130°C. minutes
The analytical sample was recrystallized from ether. Example 128 8-chloro-6-phenyl-1.N.N-tri
Methyl-4H-imidazo [1.5-α] [1.
4] Benzodiazepine-3-carboxamide 8-chloro-1-methyl-6-phenyl-4H
-imidazo[1.5-α][1.4]benzodia
1.5 g (4.2 mmol) of zepine-3-carboxylic acid,
1.7 g (8 mmol) of phosphorus pentachloride and methylene chloride
Stir 100 ml of the mixture under argon for 3 hours.
Ta. A clear solution of dimethylamine at basic pH
The solution was introduced at room temperature until the temperature was reached. Wash the solution with water
, dried and evaporated. Residue in acetic acid
crystallized from ethyl/ether/hexane and
Recrystallized from ether to give a maximum melting point of 173-177°C.
The final product was obtained. Example 129 8-chloro-6-(2-fluorophenyl)-1
-Methyl-N-phenyl-4H-imidazo
[1.5-α] [1.4] Benzodiazepine-3
-Carboxamide 1.3 g (6.25 mmol) of phosphorus pentachloride is
8-chloro-6-(2-fluorophore) in 100 ml of
enyl)-1-methyl-4H-imidazo[1,5-
α] [1,4] Benzodiazepine-3-carvone
Added to a suspension of 1.9 g (5 mmol) of acid. ice water
After stirring for 30 minutes while cooling on top, add aniline 7
ml and continued stirring at room temperature for 30 minutes. anti
The reaction mixture was mixed with a 10% aqueous solution of sodium carbonate and methane chloride.
It was divided between him and Ren. Dry the organic layer and
and evaporated. The residue was crystallized from ether and
and recrystallized from methylene chloride/ethanol.
The final product was obtained and was dissolved in tetrahydrofuran/ethyl
It was recrystallized from alcohol for analysis. Melting point 228
~288℃. Example 130 8-chloro-N-cyclopropyl-6-(2-
Fluorophenyl)-1-methyl-4H-imida
Zo[1,5-α][1,4]benzodiazepine
-3-Carboxamide 1.3 g (6.25 mmol) of phosphorus pentachloride was added to methoxychloride.
8-chloro-6-(2-fluorophore) in 100 ml of
enyl)-1-methyl-4H-imidazo[1,5-
α] [1,4] Benzodiazepine-3-carvone
1.9 g (5.1 mmol) of acid was added to the suspension. ice water
After stirring for 30 minutes above, add cyclopropylamine 3
ml and continued stirring for 10 minutes. reaction mixture
Wash the items with an aqueous sodium carbonate solution and dry them.
and evaporated. Residue 10% in methylene chloride
(v/v) Pad of silica gel with ethanol
I passed it on top. Product from ethyl acetate/hexane
Crystallize to form a final crystal with a melting point of 196-197℃
The product was obtained. Example 131 8-chloro-6-(2-chlorophenyl)-1.
N・N-trimethyl-4H-imidazo [1.5
-α] [1.4] Benzodiazepine-3-cal
Boxamide 8-chloro-6-(2
-chlorophenyl)-1-methyl-4H-imidazo
[1.5-α] [1.4] Benzodiazepine-3-
A stirred suspension of 3.6 g (0.0093 mol) of carboxylic acid
Cool in an ice bath and add 2.1 g (0.01 mole) of phosphorus pentachloride.
I processed it little by little. Protect the reaction with a drying tube
and continue stirring in cold conditions for at least 30 minutes.
Continued. Add dimethylamine while continuing to cool.
Bubble into the solution for 5 minutes and continue stirring for an additional 30 minutes.
Lasted for a minute. The mixture was evaporated to dryness under reduced pressure.
Stir the gummy residue with water and add hydroxide.
Made basic with ammonium. Extracted with methylene chloride
and then dried and evaporated under reduced pressure to produce a yellowish brown color.
I got foam. Boil this foam with 600ml of ether.
Remove insoluble substances by dissolving in
did. Concentrate the liquid on a steam bath to about 250 ml.
After doing this again. Sometimes Hitsukakinaga
When further concentrated to about 100 ml, crystallization begins.
Ta. Remove the flask from the heat and let it cool at room temperature overnight.
Rejected. Through the yellowish prism, the ether
Melt point 225~
The final product was obtained at 230°C. Benzene the sample
When recrystallized from carbon/ether, the melting point is 228 ~
The temperature rose to 232℃. Example 132 8-chloro-5,6-dihydro-6-(2-ph)
(fluorophenyl)-1-methyl-4H-imidazo
[1.5-α] [1.4] Benzodiazepine-3
-Carboxylic acid 2,2-dimethylhydrazide 8-chloro-6-(2-fluorophenyl)-1
-Methyl-4H-imidazo [1.5-α] [1.
4] Benzodiazepine-3-carboxylic acid 2.2
-dimethyl hydrazide 1.2 g (2.9 mmol), salt
50 ml of methylene chloride, 5 ml of glacial acetic acid and 2.5 g of zinc powder
The mixture was stirred at room temperature for 2 hours. Separate inorganic substances
I let go. Wash the solution with sodium carbonate solution and dry.
Dry and evaporate. The residue was dissolved in ethyl acetate/ethyl acetate.
The final product is obtained by crystallization from
It was recrystallized for analysis from ethyl acetate. melting point
218-219℃. Example 133 8-chloro-6-(2-chlorophenyl)-5.
6-dihydro-1-methyl-4H-imidazo
[1.5-α] [1.4] Benzodiazepine-3
-carboxamide 8-chloro-6-(2-chloro-carboxamide) in 70 ml of glacial acetic acid
phenyl)-1-methyl-4H-imidazo[1.5
-α] [1,4] Benzodiazepine-3-carbo
Add a stirred solution of 7 g (0.018 mol) of xamide to zinc powder.
5.6 g (0.087 gram atom) was treated in portions.
The stirred mixture was heated at 110 °C under argon in an oil bath for 5 hrs.
heated for an hour. After cooling to room temperature, the mixture
filtrate and wash the solid with methylene chloride.
Concentrate the liquid under reduced pressure at 60°C to remove methylene chloride.
and pour the residue into cold water and chill on ice.
The mixture was made basic with ammonia. Obtained white solid
filtered, washed with water, and partially dried on a stove.
Ta. Treat the solid solid with 200ml of hydrochloric acid for 5 minutes.
Stir and then filter to remove approximately 3 g of unreacted material.
Obtained as a white solid. Cold dilute ammonium hydroxide solution
When made basic with monium, a white solid separates.
So, collect this by sieving, wash with water, and
Air drying on a funnel gave the final product. Etano
- white plate when recrystallized from methylene chloride
Crystals were obtained. Melting point 298-305°C (decomposition). Example 134 8-chloro-6-(2-chlorophenyl)-5.
6-dihydro-1-methyl-4H-imidazo
[1.5-α] [1.4] Benzodiazepine-3
-Carboxamide-hydrochloride 1 1/3 hydrate 1.3 g of the base of Example 133 in 75 ml of 95% ethanol
(0.0034 mol) suspension of 5.7N salt in ethanol
treated with 10 ml of hydrogen chloride solution and boiled on a steam bath.
A clean solution was obtained. Pass the solvent
and kept at room temperature overnight. White needle crystals separate
Ta. Filter the product, wash with ethanol, and
The final product was obtained by air drying. This thing is
The melting point is 310~ after changing to prism at about 250℃
The temperature was 315℃ (decomposition). To concentrate the mother liquor
Further, a product with a melting point of 305-310°C (decomposition) was obtained.
Ta. Example 135 8-chloro-6-(2-fluorophenyl)-1
-Methyl-4H-imidazo [1.5-α] [1.
4] Benzodiazepines and 8-chloro-6
-(2-fluorophenyl)-1-methyl-6H
-imidazo[1.5-α][1.4]benzodi
Azepine 8-chloro-6- in 5 ml of ethylene glycol
(2-fluorophenyl)-1-methyl-4H-y
midazo[1.5-α][1.4]benzodiazepi
A solution of 185 ml of carbon-3-carboxylic acid was added under a nitrogen atmosphere.
The mixture was heated to reflux for 1 hour. Cooled reaction mixture
Ether/toluene and saturated sodium bicarbonate solution
It was distributed between. Separate the organic phase and dry
and evaporated. The residue was dissolved in methylene chloride.
% (V/V) on 7 g of silica gel with ethanol
Chromatographed with less polar 8-chlorine
Rolo-6-(2-fluorophenyl)-1-methyl
-6H-imidazo[1,5-α][1,4]benzo
Diazepine (melting point 177-179°C) and 8-chloro
-6-(2-fluorophenyl)-1-methyl-
4H-Imidazo [1,5-α] [1,4] Benzodi
Both azepine (melting point 151-153°C) were obtained. Each of the formulations below contains the following compounds as active ingredients:
Can be used as: 8-chloro-6-(2-chlorophenyl)-1-
Methyl-4H-imidazo [1,5-α] [1,4]
Benzodiazepine-3-carboxamide, 8-chloro-6-(2-fluorophenyl)-1
-Methyl-4H-imidazo [1.5-α] [1.
4] Benzodiazepine-3-carboxylic acid 2.2
-dimethylhydrazide, 8-chloro-N・N-diethyl-6-(2-ph)
(fluorophenyl)-1-methyl-4H-imidazo
[1.5-α] [1.4] Benzodiazepine-3-
Carboxamide, 8-chloro-3-hydroxymethyl-1-methy
-6-phenyl-4H-imidazo[1,5-
α][1,4]benzodiazepine, and 8-chloro-6-(2-fluorophenyl)-3
-Hydroxymethyl-1-methyl-4H-imida
Zo[1,5-α][1,4]benzodiazepine. Example A Tablet formulation containing the following ingredients: per tablet Active Ingredients 100mg Lactose 113.5mg Cornstarch 70.5mg Pre-jellized Cornstarch 8.0mg Calcium Stearate 3.0mg Total Weight 205.0mg Active ingredients combined with lactose, cornstarch and
Add jelly-formed cornstarch to an appropriate size.
mixed in a mixer and passed through a pulverizer.
Ta. Return the mixture to the mixer and moisten with water
Make a thick paste. Shredder for wet lumps
and the resulting wet granules are passed through a paper liner.
Dry at 45°C on paper lined trays.
It was dry. Return the dry granules to the mixer and stir
Calcium phosphate was added and mixed thoroughly.
The granules were compressed into tablets weighing 200 mg. Example B Tablet formulation containing the following ingredients: per tablet Active Ingredients 25.00 mg Lactose 64.50 mg Corn Starch 10.00 mg Magnesium Stearate 0.50 mg Total Weight 100.00 mg were prepared as follows: The active ingredients were combined with lactose, corn starch and starch.
In a suitable mixer with magnesium thearate
mixed with. The mixture is passed through a pulverizer and mixed further.
It matched. The mixed powder is turned into a slug on a tablet compressor.
(slugged), and the slugs as appropriate.
Grind to mesh size and mix well. lock
The drug was compressed into tablets weighing 100 mg. Example C Capsule formulation containing the following ingredients: per capsule Active Ingredients 25 mg Lactose 158 mg Corn Starch 37 mg Talc 5 mg Total Weight 225 mg were prepared as follows: The active ingredients were combined with lactose and corn starch.
in a suitable mixer. Mixture shredder
Further mixing was achieved by passing through the solution. mixed
Return the powder to the mixer, add the talc and mix well
mixed with. The mixture is then passed through a capsule making machine.
and filled into hard-shelled gelatin capsules. Example D Capsule formulation containing the following ingredients: per capsule Active ingredient 50mg Lactose 125mg Cornstarch 30mg Talc 5mg Total weight 210mg was prepared as follows: Active ingredient was combined with lactose and cornstarch.
in a suitable mixer. Mixture shredder
Further mixing was achieved by passing through the solution. mixed
Return the powder to the mixer, add the talc and mix well
mixed with. The mixture is hardened by a capsule making machine.
The shell was filled with gelatin. Example E Capsule formulation containing the following ingredients: per capsule Active Ingredients 50 mg Lactose 125 mg Corn Starch 30 mg Talc 5 mg Total Weight 210 mg were prepared as follows: The active ingredients were combined with lactose and corn starch.
in a suitable mixer. Mixture shredder
Further mixing was achieved by passing through the solution. mixed
Return the powder to the mixer, add the talc and mix well
mixed with. The mixture is hardened by a capsule making machine.
Filled into shell gelatin capsules. Example F Capsule formulation containing the following ingredients: per capsule Active Ingredients 25 mg Lactose 158 mg Corn Starch 37 mg Talc 5 mg Total Weight 225 mg were prepared as follows: The active ingredients were combined with lactose and corn starch.
in a suitable mixer. Mixture shredder
Further mixing was achieved by passing through the solution. mixed
Return the powder to the mixer, add the talc and thoroughly
Mixed. The mixture is then passed through a capsule making machine.
Filled into hard shell gelatin capsules. Example G Tablet formulation containing the following ingredients: per tablet Active Ingredients 25.00 mg Lactose 64.50 mg Corn Starch 10.00 mg Magnesium Stearate 0.50 mg Total Weight 100.00 mg were prepared as follows: The active ingredients were combined with lactose, corn starch and starch.
In a suitable mixer with magnesium thearate
mixed with. Passing the mixture through a pulverizer
The mixture was further mixed. Mixed powder into tablet compression machine
Make the slag more slag and process the slag appropriately.
Finely grind and mix well. Tablets are 100mg
compressed to a tablet weight of . Example H Tablet formulation containing the following ingredients: per tablet Active Ingredients 10.0 mg Lactose 113.5 mg Corn Starch 70.5 mg Pre-Jellified Corn Starch 80 mg Calcium Stearate 3.0 mg Total Weight 205.0 mg was prepared as follows: The active ingredients were combined with lactose, corn starch and
Add jelly-formed cornstarch to an appropriate size.
Mixed in a mixer and passed through a pulverizer
I set it. Return the mixture to the mixer and dampen with water.
Let it cool and make a thick paste. Shredder for wet lumps
and the resulting wet granules at 45°C.
Dry on lined tray. dried granules
Return to mixer and add calcium stearate.
and mixed thoroughly. Granules into tablets weighing 200mg
Compressed.

Claims (1)

[Claims] 1. General formula In the formula, R ₁ is hydrogen, lower alkyl, hydroxy lower alkyl, lower alkanoyloxy lower alkyl,
phenyl, halo-lower alkyl, amino-lower alkyl, mono- or di-lower alkylamino-lower alkyl, pyridyl or the group -CHO; R ₂ is bromo, hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, lower alkoxy-lower alkyl, halo lower alkyl, amino lower alkyl, cyano, cyano lower alkyl, lower alkanoylamino, lower alkoxycarbonylamino, phenyl lower alkyloxycarbonylamino, mono- or di-lower alkylamino lower alkyl, group -COOR ₁₀ (where R ₁₀ is hydrogen or lower alkyl), the group -CHO or its derivative group, i.e. (a) the group -CH=N-R ₁₁ (wherein
R ₁₁ represents hydroxy, lower alkoxy or di-lower alkylamino), (b) group -CONR ₁₂ R ₁₃
[Here, R ₁₂ is hydrogen, lower alkyl, or group -
(CH ₂ ) _o NR ₁₄ R ₁₅ (wherein R ₁₄ and R ₁₅ represent lower alkyl and n is a number from 1 to 4) and R ₁₃ represents hydrogen, lower alkyl or phenyl; , or R ₁₂ and R ₁₃ together form pyrrolidino], or (c) the group -CON
(R ₁₆ )N(R ₁₇ R ₁₈ ) [where R ₁₆ , R ₁₇ and R ₁₈ individually represent hydrogen or lower alkyl]; R ₃ represents hydrogen or lower alkyl; [Formula] is a group [Formula] or [Formula] (where R ₄ represents halogen, nitro or cyano); and A represents a group [Formula] [Formula] or [Formula] (where R ₆ represents phenyl, halofenyl or pyridyl); Imidazo[1,5-a][1,4]diazepine compounds and pharmaceutically acceptable acid addition salts thereof, represented by: 2 R ₁ represents hydrogen, lower alkyl, hydroxy lower alkyl, lower alkanoyloxy lower alkyl, phenyl, halo lower alkyl, amino lower alkyl, mono- or di-lower alkylamino lower alkyl, pyridyl or the group _-CHO ; is bromo, α-hydroxy lower alkyl,
lower alkanoyloxymethyl, lower alkoxymethyl, halomethyl, α-amino lower alkyl,
cyano, cyanomethyl, lower alkanoylamino, lower alkoxycarbonylamino, benzyloxycarbonylamino, mono- or di-lower alkylaminomethyl, group -COOR ₁₀ (wherein
R ₁₀ represents hydrogen or lower alkyl), group -
CHO or its derivative group, i.e. (a) group -CH=N-
R ₁₁ (where R ₁₁ represents hydroxy, lower alkoxy or di-lower alkylamino), (b) group -
CONR ₁₂ R ₁₃ [where R ₁₂ is hydrogen, lower alkyl or group -(CH ₂ ) _o NR ₁₄ R ₁₅ , (where R ₁₄ and R ₁₅
represents lower alkyl and n is a number from 1 to 4), and R ₁₃ represents hydrogen, lower alkyl or phenyl, or R ₁₂ and R ₁₃
together form pyrrolidino], or
(c) Group -CON(R ₁₆ )N(R ₁₇ R ₁₈ ) [where R ₁₆ ,
R ₁₇ and R ₁₈ individually represent hydrogen or lower alkyl; R ₃ represents hydrogen or lower alkyl; [Formula] is a group [Formula] or [Formula] (where R ₄ is halogen, nitro or and A represents the radical [Formula] [Formula] or [Formula] (wherein R ₆ represents phenyl, halophenyl or pyridyl). 3. Claims in which R ₁ is hydrogen or lower alkyl, [Formula] is R ₄ [Formula], R ₄ is nitro or halogen, R ₆ is phenyl or halofenyl, and R ₃ is hydrogen A compound according to item 1 or 2 of the scope. 4. A compound according to any one of claims 1 to 3, wherein _R4 is 8-halo and _R6 is 2-halophenyl. 5. A compound according to claim ₄ , wherein R4 is 8-chloro and _R6 is 2-chloro- or 2-fluorophenyl. 6 Claims 1 to 5 in which R ₁ is methyl
A compound according to any one of paragraphs. 7 Claim 1 in which R ₃ is methyl,
A compound according to item 2, 4, 5 or 6. 8. A compound according to any one of claims 1 to 7, wherein _R2 is hydroxy lower alkyl, carboxylic acid hydrazide or carboxamide. 9. The compound according to claim 8, wherein R ₂ is hydroxymethyl or -CONHNH ₂ or -CONH ₂ group. 10 [Formula] is 8-chlorophenyl or 8-chlorothieno[3.2-f] group, R ₁ is hydrogen or methyl, R ₂ is acetyl, carboxamide or dimethylcarboxamide, and R ₆ is 2'- 6. A compound according to claim 1, 2, 4 or 5 which is fluorophenyl or 2'-chlorophenyl and _R3 is hydrogen. 11 8-chloro-6-(2-fluorophenyl)-3-hydroxymethyl-1-methyl-4H-
The compound according to claim 1, which is an imidazo[1,5-a][1,4]benzodiazepine. 12 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a]
[1.4] The compound according to claim 1, which is benzodiazepine-3-carboxylic acid hydraside. 13 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a]
[1.4] The compound according to claim 1, which is benzodiazepine-3-carboxamide. 14 8-chloro-6-(2-chlorophenyl)-
The compound according to claim 1, which is 1-methyl-4H-imidazo[1,5-a]thieno[3,2-f][1,4]-diazepine-3-carboxamide. 15 8-chloro-6-(2-chlorophenyl)-
1.N.N-trimethyl-4H-imidazo [1.
The compound according to claim 1, which is 5-a]thieno[3.2-f][1.4]diazepine-3-carboxamide. 16 3-acetyl-8-chloro-6-(2-chlorophenyl)-4H-imidazo[1.5-a]
[1.4] The compound according to claim 1, which is a benzodiazepine. 17 8-chloro-6-(2-chlorophenyl)-
N・N-dimethyl-4H-imidazo[1,5-
a] [1,4] The compound according to claim 1, which is benzodiazepine-3-carboxamide. 18 8-chloro-6-(2-chlorophenyl)-
1.N.N-trimethyl-4H-imidazo [1.
The compound according to claim 1, which is 5-a][1,4]-benzodiazepine-3-carboxamide. 19 The compound according to claim 1, which is 8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide. 20 formula In the formula, R ₁ represents hydrogen or lower alkyl; R ₂ represents hydroxy lower alkyl or a group -
CONR ₁₂ R ₁₃ or -CON(R ₁₆ )N(R ₁₇ R ₁₈ )
(where R ₁₂ and R ₁₃ and R ₁₆ , R ₁₇ and R ₁₈
each individually represents hydrogen or lower alkyl); R ₄ represents halogen or nitro; and R ₆ represents phenyl or halophenyl, imidazo[1,5-a][1,4]diazepine compounds of or a pharmaceutically acceptable salt thereof as an active ingredient. 21 formula In the formula, R ₁ represents hydrogen or lower alkyl; R ₂ represents hydroxy lower alkyl or a group -
CONR ₁₂ R ₁₃ or -CON(R ₁₆ )N(R ₁₇ R ₁₈ )
(where R ₁₂ and R ₁₃ and R ₁₆ , R ₁₇ and R ₁₈
each individually represents hydrogen or lower alkyl); R ₄ represents halogen or nitro; and R ₆ represents phenyl or halophenyl, imidazo[1,5-a][1,4]diazepine compounds of or a sedative containing a pharmaceutically acceptable salt thereof as an active ingredient. 22 formula In the formula, R ₁ represents hydrogen or lower alkyl; R ₂ represents hydroxy lower alkyl or a group -
CONR ₁₂ R ₁₃ or -CON(R ₁₆ )N(R ₁₇ R ₁₈ )
(where R ₁₂ and R ₁₃ and R ₁₆ , R ₁₇ and R ₁₈
each individually represents hydrogen or lower alkyl); R ₄ represents halogen or nitro; and R ₆ represents phenyl or halophenyl, imidazo[1,5-a][1,4]diazepine compounds of or a pharmaceutically acceptable salt thereof as an active ingredient. 23 formula In the formula, R represents lower alkyl; R ₃ represents hydrogen or lower alkyl; [Formula] represents a group [Formula] or [Formula] (where R ₄ represents halogen, nitro or cyano); and A' represents a group [Formula] or [Formula] (where R ₆ represents phenyl, halophenyl or pyridyl), and a compound of the formula R'1C(OR) ₃ , where R'1 is hydrogen or lower alkyl or halo-lower alkyl; and R has the meaning given above, and the resulting compound is optionally converted into a pharmaceutically acceptable salt. Expressions characterized by changing In the formula, R, R′1, R ₃ , [Formula] and A′ have the above-mentioned meanings, and imidazo[1,5-a][1,4]diazepine compounds and pharmaceutically acceptable compounds thereof A method for producing a salt of a compound of 24 formula In the formula, R represents lower alkyl; R ₁ is hydrogen, lower alkyl, hydroxy lower alkyl, lower alkanoyloxy lower alkyl,
represents phenyl, halo-lower alkyl, amino-lower alkyl, mono- or di-lower alkylamino-lower alkyl, pyridyl or the group -CHO; R ₃ represents hydrogen or lower alkyl; [Formula] represents the group [Formula] or [Formula] ] (wherein R ₄ represents halogen, nitro or cyano); and A′ represents the group [formula] or [formula] (wherein R ₆ represents phenyl, halophenyl or pyridyl). oxidation and, if necessary, converting the resulting compound into a pharmaceutically acceptable salt. In the formula, R, R ₁ , R ₃ , [Formula] and A' have the above meanings, and imidazo[1,5-a][1,4]diazepine compounds and pharmaceutically acceptable compounds thereof Method for producing salts of compounds. 25 formula In the formula, R represents lower alkyl; R″ ₁ represents hydrogen, lower alkyl, phenyl or pyridyl; R ₃ represents hydrogen or lower alkyl; [Formula] is a group [Formula] or [Formula] (where in the presence of a _{solvent ;} or in the absence, with or without the presence of a catalyst and a water binder;
A formula characterized by heating to a temperature of 100° to 300°C and, if necessary, converting the resulting compound into a pharmaceutically acceptable salt. In the formula, R, R″ ₁ , R ₃ , [Formula] and A′ have the above-mentioned meanings, and imidazo[1,5-a][1,4]diazepine compounds of A method for producing a salt of a compound of formula 26. In the formula, R represents a lower alkyl group; R ₁ represents hydrogen, lower alkyl, hydroxy-lower alkyl, phenyl, halo-lower alkyl, amino-lower alkyl, mono- or di-lower alkylamino-lower alkyl, pyridyl or the group -CHO; R ₃ represents hydrogen or lower alkyl; [Formula] represents the group [Formula] or [Formula] (where R ₄ represents halogen, nitro or cyano); and A″ represents the group [Formula] ( wherein R ₆ represents phenyl, halophenyl or pyridyl) and, if necessary, converting the resulting compound into a pharmaceutically acceptable salt. In the formula, R ₁ , R ₃ , [Formula] and A″ have the above meanings, and imidazo[1,5-a][1,4]diazepine compounds and pharmaceutically acceptable compounds thereof. Method for producing salt. 27 formula In the formula, R ₁ represents hydrogen, lower alkyl, hydroxy lower alkyl, phenyl, halo lower alkyl, amino lower alkyl, mono- or di-lower alkylamino lower alkyl, pyridyl or the group -CHO; R ₃ represents hydrogen or lower represents alkyl; [Formula] represents a group [Formula] or [Formula] (where R ₄ represents halogen, nitro or cyano); and A″ represents a group [Formula] (where R ₆ represents phenyl, halofenyl); or pyridyl), and optionally converting the resulting compound into a pharmaceutically acceptable salt. Imidazo[1,5-a][1,4]diazepine compounds and pharmaceutically acceptable compounds thereof, wherein R″ ₁ , R ₃ , [Formula] and A″ have the above-mentioned meanings Method of manufacturing salt. 28 formula In the formula, R ₁ 〓 represents hydrogen, lower alkyl, phenyl, halo-lower alkyl, di-lower alkylamino lower alkyl, pyridyl or the group -CHO; R ₃ represents hydrogen or lower alkyl; [Formula] represents the group [ and A _{″ represents a group [formula] (wherein R 6 represents} phenyl, halophenyl or pyridyl); and, if necessary, converting the resulting compound into a pharmaceutically acceptable salt. In the formula, R represents lower alkyl; and R ₁ 〓, R ₃ , [Formula] and A″ have the above-mentioned meanings. A method for producing a salt of these compounds that is acceptable for the purpose of formula 29. In the formula, R ₁ 〓 represents hydrogen, lower alkyl, phenyl, halo-lower alkyl, amino-lower alkyl, mono- or di-lower alkylamino-lower alkyl, pyridyl or the group -CHO; R ₃ represents hydrogen or lower alkyl. [Formula] represents the group [Formula] or [Formula] (where R ₄ represents halogen, nitro or cyano); and A″ represents the group [Formula] (where R ₆ represents phenyl, halofenyl or pyridyl); (representing) with a halogenating agent and optionally converting the resulting compound into a pharmaceutically acceptable salt. In the _{formula ,} A method for producing salts of these compounds acceptable to the formula 30. In the formula, R ₁ 〓 is hydrogen, lower alkyl, phenyl, amino lower alkyl, mono- or di-lower alkylamino lower alkyl, pyridyl or a group -
represents CHO; _{R 3} represents hydrogen or lower alkyl; A'' represents a group [formula] (wherein R ₆ represents phenyl, halofenyl or pyridyl), the halogen in the 3-substituent of the compound is nucleophilically substituted by an amine, alkoxide or cyanide, and A formula characterized in that, if necessary, the resulting compound is converted into a pharmaceutically acceptable salt. In the formula, R″ ₂ represents aminomethyl, lower alkoxymethyl or cyanomethyl; and R ₁ 〓, R ₃ , [Formula] and A″ have the above meanings, imidazo[1.5-a][1 -4] Method for producing diazepine compounds and pharmaceutically acceptable salts of these compounds. 31 formula In the formula, R represents hydrogen, lower alkyl, phenyl, halo lower alkyl, amino lower alkyl, mono- or di-lower alkylamino lower alkyl or pyridyl; R ₃ represents hydrogen or lower alkyl; [Formula] is a group A compound of formula or formula where R′ ₄ represents halogen or nitro; and A″ represents a group formula where R ₆ represents phenyl, halophenyl or pyridyl. reacting the aldehyde group in the 3-position with a lower alkyl Grignard or lithium reagent and, if necessary, converting the resulting compound into a pharmaceutically acceptable salt. In the formula, R ₂ 〓 represents α-hydroxy lower alkyl; and R ₁ , R ₃ , [Formula] and A″ have the above meanings, imidazo[1,5-a][1,4]diazepine Methods for producing compounds and pharmaceutically acceptable salts of these compounds. In the formula, R represents lower alkyl; R ₁ represents hydrogen, lower alkyl, hydroxy lower alkyl, phenyl, amino lower alkyl, mono- or di-lower alkylamino lower alkyl or pyridyl; R ₃ represents hydrogen or lower alkyl [Formula] represents the group [Formula] or [Formula] (where R ₄ represents halogen, nitro or cyano); and A″ represents the group [Formula] (where R ₆ represents phenyl, halofenyl or pyridyl), represented by the formula H ₂ NR ₁₂ , where R ₁₂ is hydrogen, lower alkyl or a group -
(CH ₂ ) _o NR ₁₄ R ₁₅ (wherein R ₁₄ and R ₁₅ represent lower alkyl and n is 1 to 4), subjected to ammonolysis using an amino compound of
and, if necessary, converting the resulting compound into a pharmaceutically acceptable salt. In the formula, R ₁ , R ₃ , R ₁₂ , [Formula] and A″ have the above-mentioned meanings, and imidazo[1,5-a][1,4]diazepine compounds of A method for producing a salt of a compound of formula 33. In the formula, R ₁ 〓 represents hydrogen, lower alkyl, phenyl, halo-lower alkyl, amino-lower alkyl, mono- or di-lower alkylamino-lower alkyl, pyridyl or the group -CHO; R ₃ represents hydrogen or lower alkyl. [Formula] represents the group [Formula] or [Formula] (where R ₄ represents halogen, nitro or cyano); and A″ represents the group [Formula] (where R ₆ represents phenyl, halofenyl or pyridyl); represents the acid chloride of a compound of the formula HNR ₁₂ R ₁₃ where R ₁₂ is hydrogen, lower alkyl or a group -
(CH ₂ ) _o NR ₁₄ R ₁₅ (wherein R ₁₄ and R ₁₅ represent lower alkyl and n is a number from 1 to 4) and R ₁₃ represents hydrogen, lower alkyl or phenyl; , or R ₁₂ and R ₁₃ taken together to form pyrrolidino, and optionally converting the resulting compound into a pharmaceutically acceptable salt. In the formula, R ₁ 〓, R ₃ , R ₁₂ , R ₁₃ , [Formula] and A″ have the above-mentioned meanings. Process for producing acceptable salts of these compounds. In the formula, R ₁ represents hydrogen, lower alkyl, hydroxy lower alkyl, phenyl, halo lower alkyl, amino lower alkyl, mono- or di-lower alkylamino lower alkyl, pyridyl or the group -CHO; R ₃ represents hydrogen or lower represents alkyl; [Formula] represents a group [Formula] or [Formula] (where R ₄ represents halogen, nitro or cyano); and A″ represents a group [Formula] (where R ₆ represents phenyl, halofenyl); or pyridyl) with a dehydrating agent such as phosphorus pentachloride or phosphorus oxychloride, and optionally converting the resulting compound into a pharmaceutically acceptable salt. formula to In the formula, R ₁ , R ₃ , [Formula] and A″ have the above meanings, and imidazo[1,5-a][1,4]diazepine compounds and pharmaceutically acceptable compounds thereof. Method for producing salt. 35 formula In the formula, R represents lower alkyl; R ₁ represents hydrogen, lower alkyl, hydroxy lower alkyl, phenyl, amino lower alkyl, mono- or di-lower alkylamino lower alkyl or pyridyl; R ₃ represents hydrogen or lower alkyl [Formula] represents the group [Formula] or [Formula] (where R ₄ represents halogen, nitro or cyano); and A″ represents the group [Formula] (where R ₆ represents phenyl, halofenyl or Representing pyridyl), a compound of formula HN(R ₁₆ )NR ₁₇ R ₁₈ in which R ₁₆ , R ₁₇ and R ₁₈ individually represent hydrogen or lower alkyl is subjected to hydrazinolysis using hydrazine of Attached,
and, if necessary, converting the resulting compound into a pharmaceutically acceptable salt. In the formula, R ₁ , R ₃ , R ₁₆ , R ₁₇ , R ₁₈ , [Formula] and A″ have the above-mentioned meanings. A method for producing legally acceptable salts of these compounds. 36 Formula In the formula, R ₁ 〓 represents hydrogen, lower alkyl, phenyl, halo-lower alkyl, amino-lower alkyl, mono- or di-lower alkylamino-lower alkyl, pyridyl or the group -CHO; R ₃ represents hydrogen or lower alkyl. [Formula] represents the group [Formula] or [Formula] (where R ₄ represents halogen, nitro or cyano); and A″ represents the group [Formula] (where R ₆ represents phenyl, halofenyl or pyridyl); ) is treated with hydrazine of the formula HN(R ₁₆ )NR ₁₇ R ₁₈ where R ₁₆ , R ₁₇ and R ₁₈ individually represent hydrogen or lower alkyl, and optionally according to the formula, which converts the resulting compound into a pharmaceutically acceptable salt. Imidazo[1.5-a][1.4]diazepine compounds and pharmaceuticals in which R ₁ 〓, R ₃ , R ₁₆ , R ₁₇ , R ₁₈ , [Formula] and A″ have the above-mentioned meanings. Method for producing chemically acceptable salts of these compounds. 37 Formula In the formula, R ₁ represents hydrogen, lower alkyl, hydroxy lower alkyl, phenyl, halo lower alkyl, amino lower alkyl, mono- or di-lower alkylamino lower alkyl, pyridyl or the group -CHO; R ₃ represents hydrogen or lower represents alkyl; [Formula] represents a group [Formula] or [Formula] (where R ₄ represents halogen, nitro or cyano); and A″ represents a group [Formula] (where R ₆ represents phenyl, halofenyl); or pyridyl) is heated in the presence or absence of a solvent, with or without a catalyst, to a temperature between 100° and 350°C and, if necessary, the resulting compound is Formulas characterized by conversion into pharmaceutically acceptable salts In the formula, R ₁ , R ₃ , [Formula] and A″ have the above meanings, and imidazo[1,5-a][1,4]diazepine compounds and pharmaceutically acceptable compounds thereof. Method for producing salt. 38 formula In the formula, R ₁ represents hydrogen, lower alkyl, phenyl, pyridyl or a group -CHO; R ₃ represents hydrogen or lower alkyl; [Formula] is a group [Formula] or [Formula] (where R ₄ is a halogen , nitro or cyano); and A″ represents the group [formula], where R ₆ represents phenyl, halophenyl or pyridyl, is heated with a lower alkanol or phenyl lower alkanol, and the compound of a formula characterized by converting the resulting compound into a pharmaceutically acceptable salt according to In the formula, R ₂ 〓 represents lower alkoxycarbonylamino or phenyl lower alkoxycarbonylamino; and R ₁ , R ₃ , [Formula] and A″ have the above-mentioned meanings, and the imidazo [1.5-a] [ 1.4] Method for producing diazepine compounds and pharmaceutically acceptable salts of these compounds. 39 Formula In the formula, R ₁ represents hydrogen, lower alkyl, phenyl, pyridyl or the group -CHO; R ₃ represents hydrogen or lower alkyl; R ₁₉ is benzyl; [Formula] is the group [Formula] or [Formula] (wherein R″ ₄ represents halogen); and A″ represents a group [formula] (wherein R ₆ represents phenyl, halophenyl or pyridyl), to obtain the corresponding free amine by hydrogenation of the compound of and lower alkanoylating the compound thus obtained, and optionally converting the compound obtained into a pharmaceutically acceptable salt. In the formula, R ₂ 〓 represents lower alkanoylamino; and R ₁ , R ₃ , [Formula] and A″ have the above-mentioned meanings. Method for producing chemically acceptable salts of these compounds. 40 Formula In the formula, R represents lower alkyl; R ₁ ^x represents hydrogen, lower alkyl, hydroxy lower alkyl, phenyl, amino lower alkyl, mono-
or di-lower alkylamino lower alkyl,
represents pyridyl or the group -CHO; [formula] represents the group [formula] or [formula] (wherein R ₄ represents halogen, nitro or cyano); and A'' represents the group [formula] (where R ₆ represents phenyl, halophenyl or pyridyl), is alkylated in the 4-position, and if alkylation of the substituent is not desired, no substituent with active hydrogen is present, and optionally to convert the resulting compound into a pharmaceutically acceptable salt. Imidazo[1,5-a][1,4]diazepine compounds and pharmaceuticals, wherein R ₃ ' represents lower alkyl; and R, R ₁ ^x , [Formula] and A'' have the above meanings. Method for producing chemically acceptable salts of these compounds. 41 Formula In the formula, R ₁ represents hydrogen, lower alkyl, phenyl, halo lower alkyl, amino lower alkyl, mono- or di-lower alkylamino lower alkyl, or pyridyl; R ₃ represents hydrogen or lower alkyl; [Formula] represents the group [formula] or [formula], in which R ₄ represents halogen, nitro or cyano; and A'' represents the group [formula], in which R ₆ represents phenyl, halofenyl or pyridyl. , and optionally converting the resulting compound into a pharmaceutically acceptable salt. In the formula, R ₁ , R ₃ , [Formula] and A″ have the above meanings, and imidazo[1,5-a][1,4]diazepine compounds and pharmaceutically acceptable compounds thereof. Method for producing salt. 42 formula In the formula, R ₁ XI represents hydrogen, lower alkyl, phenyl, amino lower alkyl, mono- or di-lower alkylamino lower alkyl or pyridyl; R ₃ represents hydrogen or lower alkyl; ] or [formula] (wherein R ₄ represents halogen, nitro or cyano); and A″ represents the group [formula] (wherein R ₆ represents phenyl, halophenyl or pyridyl). treatment with hydrazine or hydroxylamine or lower alkoxyamine of the formula H ₂ NR ₂₀ in which R ₂₀ represents di-lower alkylamino, and optionally the resulting compound is pharmaceutically acceptable. Formulas characterized by turning into salt In the formula, R ₁₁ is hydroxy, lower alkoxy or di-
represents _lower alkylamino; and R ₁ formula In the formula, R ₁ XI represents hydrogen, lower alkyl, phenyl, amino lower alkyl, mono- or di-lower alkylamino lower alkyl or pyridyl; R ₃ represents hydrogen or lower alkyl; R ₂₁ represents hydroxy or lower alkoxy [Formula] represents the group [Formula] or [Formula] (where R ₄ represents halogen, nitro or cyano); and A″ represents the group [Formula] (where R ₆ represents phenyl, halofenyl or pyridyl) In the formula _, R ₂₀ represents di-lower alkylamino; and R ₁ into a pharmaceutically acceptable salt. An imidazo[ _1,5 -a][1,4]diazepine compound and pharmaceutically acceptable compounds thereof, in which R ₁ Method for producing salt. 44 formula In the formula, R ₁ XII represents lower alkyl, phenyl, halo-lower alkyl, mono- or di-lower alkylamino lower alkyl, pyridyl or the group -CHO; R ₃ represents hydrogen or lower alkyl; [Formula] or [Formula] (wherein R ₄ represents halogen, nitro or cyano); and A″ is a compound of the group [Formula] (wherein R ₆ represents phenylhalophenyl or pyridyl) with a brominating agent and, if necessary, converting the resulting compound into a pharmaceutically acceptable salt. An imidazo[1,5-a][ _1,4 ]diazepine compound and pharmaceutically acceptable compounds thereof, in which R ₁ Method for producing salt. 45 formula In the formula, R ₃ represents hydrogen or lower alkyl; R ₁₀ represents hydrogen or lower alkyl; [Formula] represents a group [Formula] or [Formula] (where R ₄ represents halogen, nitro or cyano); and A″ represents a group [formula], where R ₆ represents phenyl, halophenyl or pyridyl, is reacted with an alkali metal alkoxide or alkali metal hydroxide and, if necessary, the obtained A formula characterized by converting a compound into a pharmaceutically acceptable salt. In the formula, R ₃ , R ₁₀ , [Formula] and A″ have the above meanings, and imidazo[1,5-a][1,4]diazepine compounds and pharmaceutically acceptable compounds thereof. Method for producing salt. 46 formula In the formula, R ₃ represents hydrogen or lower alkyl; [Formula] represents a group [Formula] or [Formula] (wherein R ₄ represents halogen, nitro or cyano); and A″ represents a group [Formula] (wherein R ₆ represents phenyl, halophenyl or pyridyl) and optionally converting the resulting compound into a pharmaceutically acceptable salt. Production of imidazo[1,5-a][1,4]diazepine compounds and pharmaceutically acceptable salts of these compounds, wherein R ₃ , [Formula] and A'' have the above-mentioned meanings Method. 47 formula In the formula, R ₃ represents hydrogen or lower alkyl; R ₄ represents halogen, nitro or cyano; and R ₆ represents phenyl, halofenyl or pyridyl. where R ₂₃ represents phenyl or pyridyl; and R ₂₄ represents lower alkoxy or di-lower alkylamino, and optionally the resulting compound is a pharmaceutically acceptable compound. Formulas characterized by turning into salt In the formula, R ₃ , R ₄ , R ₆ , R ₂₃ and R ₂₄ have the above-mentioned meanings, and imidazo[1,5-a][1,4]diazepine compounds of Method for producing salts of compounds. 48 formula In the formula, R ₁ is hydrogen, lower alkyl, hydroxy lower alkyl, lower alkanoyloxy lower alkyl,
phenyl, halo-lower alkyl, amino-lower alkyl, mono- or di-lower alkylamino-lower alkyl, pyridyl or the group -CHO; R ₂ is bromo, hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, lower alkoxy-lower alkyl, halo lower alkyl, amino lower alkyl, cyano, cyano lower alkyl, lower alkanoylamino, lower alkoxycarbonylamino, phenyl lower alkyloxycarbonylamino, mono- or di-lower alkylamino lower alkyl, group -COOR ₁₀ (where R ₁₀ is hydrogen or lower alkyl), the group -CHO or its derivative group, i.e. (a) the group -CH=N-R ₁₁ (wherein
R ₁₁ represents hydroxy, lower alkoxy or di-lower alkylamino), (b) group -CONR ₁₂ R ₁₃
[Here, R ₁₂ is hydrogen, lower alkyl, or group -
(CH ₂ ) _o NR ₁₄ R ₁₅ (wherein R ₁₄ and R ₁₅ represent lower alkyl and n is a number from 1 to 4) and R ₁₃ represents hydrogen, lower alkyl or phenyl; , or R ₁₂ and R ₁₃ together form pyrrolidino], or (c) the group -CON
(R ₁₆ )N(R ₁₇ R ₁₈ ) [where R ₁₆ , R ₁₇ and R ₁₈ individually represent hydrogen or lower alkyl]; R ₃ represents hydrogen or lower alkyl; [Formula] is a group [Formula] or [Formula] (wherein R ₄ represents halogen, nitro or cyano); and A″ represents the group [formula] (wherein R ₆ represents phenyl, halofenyl or pyridyl); A formula characterized in that the compound is reduced and, if necessary, the resulting compound is converted into a pharmaceutically acceptable salt. In the formula, A represents [Formula] (wherein R ₆ has the above-mentioned meaning); and R ₁ , R ₂ , R ₃ and [Formula] have the above-mentioned meaning; -a] [1.4] Method for producing diazepine compounds and pharmaceutically acceptable salts of these compounds. 49 formula In the formula, R ₁ is hydrogen, lower alkyl, hydroxy lower alkyl, lower alkanoyloxy lower alkyl,
represents phenyl, halo-lower alkyl, amino-lower alkyl, mono- or di-lower alkylamino-lower alkyl, pyridyl or the group -CHO; R″ ₂ is hydrogen, bromo, hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, lower alkoxy-lower Alkyl, halo-lower alkyl, amino-lower alkyl, cyano, cyano-lower alkyl, lower alkanoylamino, lower alkoxycarbonylamino, phenyl-lower alkyloxycarbonylamino, mono- or di-lower alkylamino lower alkyl, group -COOR ₁₀ (wherein
R ₁₀ represents hydrogen or lower alkyl), group -
CHO or its derivative group, i.e. (a) group -CH=N-
R ₁₁ (here R ₁₁ represents hydroxy, lower alkoxydi-lower alkylamino), (b) group -
CONR ₁₂ R ₁₃ [where R ₁₂ is hydrogen, lower alkyl or a group -(CH ₂ ) _o NR ₁₄ R ₁₅ (where R ₁₄ and R ₁₅ represent lower alkyl, and n is a number from 1 to 4) ) and R ₁₃ represents hydrogen, lower alkyl or phenyl, or R ₁₂ and R ₁₃ together form pyrrolidino], or (c)
The group -CON(R ₁₆ )NR ₁₇ R ₁₈ [where R ₁₆ , R ₁₇ and R ₁₈ individually represent hydrogen or lower alkyl]; R ₃ represents hydrogen or lower alkyl; [Formula] represents the group [Formula] or [Formula] (wherein R ₄ represents halogen, nitro or cyano); and A″ represents the group [formula] (wherein R ₆ represents phenyl, halofenyl or pyridyl); A formula characterized in that the compound is subjected to N-oxidation and, if necessary, the resulting compound is converted into a pharmaceutically acceptable salt. In the formula, A〓 represents a group [formula] (wherein R ₆ has the above meaning); R ₁ , R″ ₂ , R ₃ and [formula] have the above meaning, imidazo[1. 5-a] [1.4] Method for producing diazepine compounds and pharmaceutically acceptable salts of these compounds.