CA1122980A - Benzodiazoncine method - Google Patents
Benzodiazoncine methodInfo
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- CA1122980A CA1122980A CA323,078A CA323078A CA1122980A CA 1122980 A CA1122980 A CA 1122980A CA 323078 A CA323078 A CA 323078A CA 1122980 A CA1122980 A CA 1122980A
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- chloro
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- hydroxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
- C07D209/66—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles with oxygen atoms in positions 1 and 3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
- C07D245/04—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D245/06—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
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Abstract
ABSTRACT OF THE DISCLOSURE
A method for producing 3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocines corresponding to the formula:
and pharmaceutically acceptable acid-addition salts thereof, wherein R represents a hydrogen atom or a methyl group, R1 represents a phenyl group, a 2-halo-phenyl group or a 2-trifluoromethyl-phenyl group, and R2 represents a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group.
In such method 2-aminobenzophenones corresponding to the formula:
A method for producing 3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocines corresponding to the formula:
and pharmaceutically acceptable acid-addition salts thereof, wherein R represents a hydrogen atom or a methyl group, R1 represents a phenyl group, a 2-halo-phenyl group or a 2-trifluoromethyl-phenyl group, and R2 represents a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group.
In such method 2-aminobenzophenones corresponding to the formula:
Description
8~
The object of the present invention is to provide a method for producing 3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1, 5-benzodiazocines corresponding to the formllla I:
,,DH
Rl and acid-addition salts thereof,wherein R represents a hydrogen atom or a methyl group, Rl represents a phenyl group, a 2-halo-phenyl group or a 2-trifluoromethyl~phenyl group, and R2 represents a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group, characterized in that 2-aminobenzophenones corresponding to the formula II:
~ - C~12 - Cl'll - C1l2Nll2 /~J\
R2 C = O
Rl wherein R, Rl and R2 are as already defined, or the addi.tion salts thereof, are cyclized at an elevated temperature in the presence of an inert organic solvent.
In this cyclization reaction, there may be used as inert organic solvents: low molecular weight monovalent or bivalent alcoAols such as methanol, ethanol, propanol, isopropanol, butanols and ethylene glycol, acetic acid or aprotic solvents such as benzene, toluene, xylene, dioxan, tetrahy~rofuran, Sulfolane (thiocyclopentane l-dioxide), or dimethyl sulfoxide. The cyclization reaction is preferably carried`out at temperatures of between about 40C and about 200C. Generally speaking, most satisfactory yields are obtained at temperatures of between about 80C and about 160C, at normal or elevated pressure. If acetic acid ~s used as the solvent, however, the temperature should then be between about 4~C and about 100C.
In many cases the cyclization may be improved by the addition of gaseous ammonia or an ammonium salt, such as ammonium chloride or ammonium sulfate.
The optimum cyclization conditions depend, inter alia, upon the nature of the substituents in the 2~aminobenzophenone.
The ring is genèrally closed more readily and more completely if the nltrogen atom in the l-position is methylated. In the case of 2-aminobenzophenones substituted in th~ 5-position, it may be ~articularly advantag_ous to use an acid addition salt thereof, the salts with hydrochloric acid, sulphuric acid or phosphoric acid being particularly suitable.
At the conclusion of the reaction, th~ reaction products may be processed in a conventional manner, and the products may isolated as bases, or itl the form of salts with organic or inorganic acids, e.g. as hydrochlorides, sulphates, maleinates, etc.
In the above formulae, the optional halogen atom in the 2-phenyl group Rl, represents fluorine, chlorine or bromine~ in the R2 group it represents chlorine, bromine or iodine and preferably chlorine or bromine.
The 3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1, ~.12i~30 5-benzodiazocines of the above formula 1 are known as intermediate products useful in the manufacture of pharmacologic-ally valuable 1,4-benzodiazepine derivatives. Furthermore, such 3-hydroxy-1,5-benzodiazocines have useful effects on the central nervous system. These compounds and their pharmaceutically applicable acid-addition salts, are useful anti-convulsives, muscle relaxants and sedatives, as may be determined by reference to published German Specification 23 53 165.
Published German Specification # 22 21 558 discloses a method for producing benzodiazocines of the preceding formula.
In that method, acyldiamines corresponding to the formula:
R2 ~ N - CH2 - CH - CH2 - NH - C - R
R O - Acyl O
wherein R, Rl and R2 arc as hereinbefore defined and the acyl group is preferably an acetyl or benzoyl group, are cyclized using phosphorus oxychloride at ~emperatures of between 50C
and 105C, and preferably betwe~en 110C and 130~C, and the resulting 3-acyloxy-1,5-bellzodiazocines are hydrolyzed, in a known manner, to the corresponding 3-hydroxy-1,5-~enzodiazocines.
The disadvantage of this known procedure is that the cyclization reaction ahd the subsequent hydrolysis proceed differently, depending upon the substituents on the phenyl rings of the acyldiamines. In many cases, the yields are also unsatisfactory.
It has already been proposed to produce 6-phenyl-1 5-benzodiazocine derivatives by cyclizing 2-(3-aminopropylamino)-benzophenone derivatives, but this method succeeds to only a limited extent. For example, in J. Org. Chem. 34 (1969), p, 179-183! M.E. DERIEG, RM. SCHWEININGER and R.I. ERYER describe how, starting with 2-(~ -benzyloxycarbonylalanyl-N-methyl-amido)-5-chlorobenzophenone, it is possible to obtain 8-chloro-3, 4-dihydro-1-methyl-6-phenyl-1,5-benzodiazocine-2(1H)-one.
However, any attempt to cyclize the non-methylated compound at the Nl-nitrogen atom leads, by dimerization, to a tetraaza-cycloheXadecane derivative.
The object of the present invention is to provide a method for producing 3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1, 5-benzodiazocines corresponding to the formllla I:
,,DH
Rl and acid-addition salts thereof,wherein R represents a hydrogen atom or a methyl group, Rl represents a phenyl group, a 2-halo-phenyl group or a 2-trifluoromethyl~phenyl group, and R2 represents a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group, characterized in that 2-aminobenzophenones corresponding to the formula II:
~ - C~12 - Cl'll - C1l2Nll2 /~J\
R2 C = O
Rl wherein R, Rl and R2 are as already defined, or the addi.tion salts thereof, are cyclized at an elevated temperature in the presence of an inert organic solvent.
In this cyclization reaction, there may be used as inert organic solvents: low molecular weight monovalent or bivalent alcoAols such as methanol, ethanol, propanol, isopropanol, butanols and ethylene glycol, acetic acid or aprotic solvents such as benzene, toluene, xylene, dioxan, tetrahy~rofuran, Sulfolane (thiocyclopentane l-dioxide), or dimethyl sulfoxide. The cyclization reaction is preferably carried`out at temperatures of between about 40C and about 200C. Generally speaking, most satisfactory yields are obtained at temperatures of between about 80C and about 160C, at normal or elevated pressure. If acetic acid ~s used as the solvent, however, the temperature should then be between about 4~C and about 100C.
In many cases the cyclization may be improved by the addition of gaseous ammonia or an ammonium salt, such as ammonium chloride or ammonium sulfate.
The optimum cyclization conditions depend, inter alia, upon the nature of the substituents in the 2~aminobenzophenone.
The ring is genèrally closed more readily and more completely if the nltrogen atom in the l-position is methylated. In the case of 2-aminobenzophenones substituted in th~ 5-position, it may be ~articularly advantag_ous to use an acid addition salt thereof, the salts with hydrochloric acid, sulphuric acid or phosphoric acid being particularly suitable.
At the conclusion of the reaction, th~ reaction products may be processed in a conventional manner, and the products may isolated as bases, or itl the form of salts with organic or inorganic acids, e.g. as hydrochlorides, sulphates, maleinates, etc.
In the above formulae, the optional halogen atom in the 2-phenyl group Rl, represents fluorine, chlorine or bromine~ in the R2 group it represents chlorine, bromine or iodine and preferably chlorine or bromine.
The 3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1, ~.12i~30 5-benzodiazocines of the above formula 1 are known as intermediate products useful in the manufacture of pharmacologic-ally valuable 1,4-benzodiazepine derivatives. Furthermore, such 3-hydroxy-1,5-benzodiazocines have useful effects on the central nervous system. These compounds and their pharmaceutically applicable acid-addition salts, are useful anti-convulsives, muscle relaxants and sedatives, as may be determined by reference to published German Specification 23 53 165.
Published German Specification # 22 21 558 discloses a method for producing benzodiazocines of the preceding formula.
In that method, acyldiamines corresponding to the formula:
R2 ~ N - CH2 - CH - CH2 - NH - C - R
R O - Acyl O
wherein R, Rl and R2 arc as hereinbefore defined and the acyl group is preferably an acetyl or benzoyl group, are cyclized using phosphorus oxychloride at ~emperatures of between 50C
and 105C, and preferably betwe~en 110C and 130~C, and the resulting 3-acyloxy-1,5-bellzodiazocines are hydrolyzed, in a known manner, to the corresponding 3-hydroxy-1,5-~enzodiazocines.
The disadvantage of this known procedure is that the cyclization reaction ahd the subsequent hydrolysis proceed differently, depending upon the substituents on the phenyl rings of the acyldiamines. In many cases, the yields are also unsatisfactory.
It has already been proposed to produce 6-phenyl-1 5-benzodiazocine derivatives by cyclizing 2-(3-aminopropylamino)-benzophenone derivatives, but this method succeeds to only a limited extent. For example, in J. Org. Chem. 34 (1969), p, 179-183! M.E. DERIEG, RM. SCHWEININGER and R.I. ERYER describe how, starting with 2-(~ -benzyloxycarbonylalanyl-N-methyl-amido)-5-chlorobenzophenone, it is possible to obtain 8-chloro-3, 4-dihydro-1-methyl-6-phenyl-1,5-benzodiazocine-2(1H)-one.
However, any attempt to cyclize the non-methylated compound at the Nl-nitrogen atom leads, by dimerization, to a tetraaza-cycloheXadecane derivative.
2-(3-aminopropylamino)-5-chloro-benzophenone may, however; be cyclized somewhat more successfully to the desired 1,5-benzodiazocine. However, the initial compounds for this method a~e not easily available. They are obtained by hydrolyzing 9-chlor~o-l,2,3,5-tetrahydro-7-phenylpyrimido-[1,2-a],[1,4]-benzodiazepine. Another method produces the corresponding 2-(3-halopropylamino)-5-chlorobenzophenone. However, these products are not obtainable by directly alkylating 2-amlnobenzo-phenones, but or;ly by either hydrolyis of 7-chloro-1-(3-chloro-propyl)-1,3-dihydro-5-phenyl-21~-1,4-benzodiazepine-2-one or from the reactive 2-tosylamido-5-chlorobenzopherlone intermediate 8 tage. ;
Statements mad0 by M. STEINMANN and J.G. TOPLISS, in 29 J.Pharm! Sci. (1969), p. 830-832, confirm the above-mentioned possibility of obtaining 1-metllyl-1,5-benzodiazocine-2-one from 2-(~ -benzyloxycarbonylalanyl-N-methylamido)-5-chlorobenzo-phenone. At the same time, however, the authors point out that, if use is made of a phthalimido group in order to introduce nitrogen into the 5-position, the desired 1,5~benzodiazocine derivative is not obtained, only ring-constricted quinolones being formed.
In contrast to this, the cyclization according to the present invention of the 2-(3-amino-2-hydroxypropylamino)-benzophenones of the above formula proceeds smoothly, with liZ~
good yields despite the presence of the ~-located hydroxy group. This is surprising for several reasons. For instance, according to the relevant literature what was to be expected was a conversion to aminals, with the formation of a bicyclic 4, l-oxepin-1,5-diazocine system. On the other hand, it would not have been impossible, during the reaction of the 2-(3-amino-2-hydroxy-propylamino)-benzophenone and, because the tendency to form a 7-ring system, for the 2-(2-hydroxypropylamino) group to react, without the participation of the terminal 3-amino ~roup, to the 4,1-oxepin-semi-ketal stage, thus interfering conside~ably with formation of the desired 3-hydroxy-1,5-benzo-diazocine compounds.
As another advantage of this invention, it has been found that the aforementioned 2-(3-amino-2-hydroxypropylamino)-benzophenones can be produced, for example, both from the corresponding 2-(3-halo-2-hydroxypropylAmino)-benzophenones of the general Formula III (see below) dircctly with ammonia and from well purified phthalimide compounds of the Formula IV
(see below). In this case, it is not absolutely necess~ry to isol~te the2-(3-unino-2-hydroxypropylamino)-benzophenones at an intermediate stage. Instead, cyclization to a 3-hydroxy-1,5-benzodiazocine may be carried out in the reaction mixture itself. Another unpredictable advantage is that compounds of the general Formulae III and IV (see below) may be produced directly by reaction 2-amino-benzophenones of the general Formula V (see below) with epichlorohydrin or N-(2-3-epoxy-propyl)-phthalimide.
The 2-aminobenzophenones as used in the method of this invention may be produced by various known methods.
; For example, compounds of the following formula III:
Statements mad0 by M. STEINMANN and J.G. TOPLISS, in 29 J.Pharm! Sci. (1969), p. 830-832, confirm the above-mentioned possibility of obtaining 1-metllyl-1,5-benzodiazocine-2-one from 2-(~ -benzyloxycarbonylalanyl-N-methylamido)-5-chlorobenzo-phenone. At the same time, however, the authors point out that, if use is made of a phthalimido group in order to introduce nitrogen into the 5-position, the desired 1,5~benzodiazocine derivative is not obtained, only ring-constricted quinolones being formed.
In contrast to this, the cyclization according to the present invention of the 2-(3-amino-2-hydroxypropylamino)-benzophenones of the above formula proceeds smoothly, with liZ~
good yields despite the presence of the ~-located hydroxy group. This is surprising for several reasons. For instance, according to the relevant literature what was to be expected was a conversion to aminals, with the formation of a bicyclic 4, l-oxepin-1,5-diazocine system. On the other hand, it would not have been impossible, during the reaction of the 2-(3-amino-2-hydroxy-propylamino)-benzophenone and, because the tendency to form a 7-ring system, for the 2-(2-hydroxypropylamino) group to react, without the participation of the terminal 3-amino ~roup, to the 4,1-oxepin-semi-ketal stage, thus interfering conside~ably with formation of the desired 3-hydroxy-1,5-benzo-diazocine compounds.
As another advantage of this invention, it has been found that the aforementioned 2-(3-amino-2-hydroxypropylamino)-benzophenones can be produced, for example, both from the corresponding 2-(3-halo-2-hydroxypropylAmino)-benzophenones of the general Formula III (see below) dircctly with ammonia and from well purified phthalimide compounds of the Formula IV
(see below). In this case, it is not absolutely necess~ry to isol~te the2-(3-unino-2-hydroxypropylamino)-benzophenones at an intermediate stage. Instead, cyclization to a 3-hydroxy-1,5-benzodiazocine may be carried out in the reaction mixture itself. Another unpredictable advantage is that compounds of the general Formulae III and IV (see below) may be produced directly by reaction 2-amino-benzophenones of the general Formula V (see below) with epichlorohydrin or N-(2-3-epoxy-propyl)-phthalimide.
The 2-aminobenzophenones as used in the method of this invention may be produced by various known methods.
; For example, compounds of the following formula III:
3~1Z;~80 ~ / N - CH2 = Z
R2 C =
Rl wherein R, Rl and R2 have the meanings hereinbefore given and Zr~presents aCH-~H2 group or a -CH(OH)-CH2-halogen group, the halogen atom preferably being chlorine or bromine, may be reac~ed with ammonia gas in the presence of an inert;solvent.
Suitable inert solvents are, for example, low molecular weight alkanols such as methanol, ethanol, propanol, isopropanol and butanols, and dioxan and tetrahydrofuran. Reaction temperatures of between 10C and 60C generally produce the desired compounds.
The 2-aminobenzophenones so obtained may then be cyclized, as described above, at elevated temperature and, if necessary, at elevated pressure.
Such starting compounds need not be lsolated from the reaction medium in which they are formed; instead, they may be converted directly into corresponding l,5-benzodiazocines by heating in the reaction mixture.
According to another ernbodiment, the 2-aminobenzophenones of the general formula I may be obtained by acid or alkaline splitting of compounds of the following formula IV:
R C
~ R2 C = O
112;~g80 wherein R, Rl and R~ have the meanings already given above, by splitting off the phthaloyl group. In order to carry out acid fission, such compounds are preferably heated with concentrated aqueous hydrochloric acid. The 2-aminobenzophenones may be isloated from the reaction mixture as bases or as hydrochlorides, and may then be purified. It is advantageous to obtain the 2-aminobenzophenones in which R represents a methyl ~group as the hydrochlorides. The crude oils may also be used in the cyclization reaction.
In the case of alkaline fission of the phthaloyl ~roup, compounds of the Formula IV are obtained by reacting with hydrazine, hydrazine hydrate,water-soluble low molecular weight primary amines such as methyl-, ethyl-, propyl- or butyl-amine, preferably methylamine or aminoethanol. The reaction is prefera41y carried out in the presence of low molecular weight alkanols such as methanol, ethanol, isopropanol, or mixtures thereof, possibly with the addition of water, and at the boiling point of the solvent. The compounds of the Formula II thus obtainedlmay be converted in the pure form, or in the form of crude oils as described above, by heating, preferably to 160C, in the presence of a solvent, into the desired 1,5-benzodiazocines of the Formula I.
Compounds of the Formula II, obtained by hydrazinolysis or aminolysis, need not be isolated from their reaction medium, but may be converted directly into corresponding compounds of the Formula I by heating the reaction mixture. In many cases, the subsequent cyclization of compounds of the Formula II into the desired compounds of the Formula I proceeds at a reaction velocity such that, at the temperature at which the phthaloyl radical is split off, a partial to complete cycliza~ion of the 2 aminobenzophenone takes place simultaneously.
Compounds of the Formula III.
~ N - CH2 - Z
,~, R2 C = O
Rl ~
wherein R, Rl and R2 and Z have the meanings already given, may also be obtained by known methods. Initial compounds of the Formula III, wh~rein Z signifies -CH(OH)-CH2-halogen may be produced by reacting 2-aminobenzophenones of the Formula V:
R
NH
,~
R2 C = O
R
wherein R, Rl and R2 have the mcaninc3s alreacly c3iven abovQ, with epichlorohydrin or epibromohydrin, at temperatures below 100C in the presence of acetic acid, for example.
Initial compounds of the Formula III, wherein z rep--resents`a epoxyethyl group, may be ob~ained, according to the "HOU~EN-WEYL" methods described in Organische Chemie 6/3, p. 374 et seq. (1965), by reacting a 1,2-hydrin halide of the Formul~ III, in the presence of the strong base such as sodium or potassium hydroxide, and in an inert solvent such as ether, dioxan, tetrahydrofuran, benzene or toluene, with concentrated llZ~?80 aqueous alkali hydroxide solutions,at room temperature.
Phthalimide compounds of the Formula IV can be prepared from compounds of the Formula III, wherein Z may have two different meanings. Thus compounds of the Formula III, wherein Z is an epoxyethyl group may be reacted with phthalimide at an elevated temperature, in an inel~ solvent such as dimethyl-formamide. Using 1,2-hydrin halides of the Formula III makes it possible to produce corresponding phthalimides of Formula IV by reacting the former compounds with potassium phthalimide in the presence of an inert solvent such as dimethylformamide by a base-catalyzed reaction, in the presence of pyridine, for example, and at an elevated temperature. It is also possible to react 2-aminobenzophenones of the Formula V with N-(2,3-epoxypropyl)-phthalimide, at an elevated temperature, in the presence of acetic acid, to form phthalimide compounds of the Formula IV.
In producing compounds of the Fo~mula I, whcrein R
represents a methyl group, it is possible to st~rt with the corresponding 2-methylaminoben~ophenones of the Formula V, wherein Rl and R2 have the meanirlgs givell a~ove. It is also possible to introduce the methyl group into compounds of the Formula III, when 2 represents a -CH2-C~I(OI-I)-Cll2-halogen group or into compounds of the Formula IV, by methods known from the relevant literat~lre, for example by reductive carbonyl-aminating with a formalin solution, in the presence of formic acid and at an elevated temperature (see the Leuckart-Wallach or Eschweiler-Clark reaction in H. KRAUCH, W. KUNZ, Reactions in Organic Chemistry (1976), p. 126 and 131), if R in these compounds represents a hydrogen atom.
The following Examples serve to illustra-te tlle invention.
_XAMP ~E 1 8-chloro-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine.
232 g of 2-~mino-5-chloro-benzophenone were heated to 60C with 102 g of epichlorohydrin and 60 g of acetic acid.
The product, which crystalli~ed upon cooling, was placed in water, drawn off, and then extracted llom 800 ml of acetone.
With the crystalline product obtained from the concentrated mother liquid, the yield of 2-(3-chloro-2-hydroxypropylamino)-5-chloro-benzophenone was 279 g (86~). The melting point was between 105C and 107C.
16.2 g of the above 2-(3-chloro-2-hydroxypropylamino)-5-chloro-benzophenone were reacted in 50 ml of isopropanol and 50 ml of dioxan with 2.2 g of sodium hydroxide and 4.1 ml of wat~r, for 10 hours, at room teperature. After the organic solvent had been drawn off in vacuo, the resulting crude oil was dissolved in chloroform. The chloroform phase was then washed until neutral with water, dried over sodium sulphate, and filtered. After the chloroform had been removed, an oil was obtained, recrystallizi~ this out oE isoprop~nol/petroleum ether produced 8.0 g (55.6~) of 2-(2,3-epoxypropylamino)-5-chloro-benzophenone having a melting point o~ betwecll 61C
and 62C.
R2 C =
Rl wherein R, Rl and R2 have the meanings hereinbefore given and Zr~presents aCH-~H2 group or a -CH(OH)-CH2-halogen group, the halogen atom preferably being chlorine or bromine, may be reac~ed with ammonia gas in the presence of an inert;solvent.
Suitable inert solvents are, for example, low molecular weight alkanols such as methanol, ethanol, propanol, isopropanol and butanols, and dioxan and tetrahydrofuran. Reaction temperatures of between 10C and 60C generally produce the desired compounds.
The 2-aminobenzophenones so obtained may then be cyclized, as described above, at elevated temperature and, if necessary, at elevated pressure.
Such starting compounds need not be lsolated from the reaction medium in which they are formed; instead, they may be converted directly into corresponding l,5-benzodiazocines by heating in the reaction mixture.
According to another ernbodiment, the 2-aminobenzophenones of the general formula I may be obtained by acid or alkaline splitting of compounds of the following formula IV:
R C
~ R2 C = O
112;~g80 wherein R, Rl and R~ have the meanings already given above, by splitting off the phthaloyl group. In order to carry out acid fission, such compounds are preferably heated with concentrated aqueous hydrochloric acid. The 2-aminobenzophenones may be isloated from the reaction mixture as bases or as hydrochlorides, and may then be purified. It is advantageous to obtain the 2-aminobenzophenones in which R represents a methyl ~group as the hydrochlorides. The crude oils may also be used in the cyclization reaction.
In the case of alkaline fission of the phthaloyl ~roup, compounds of the Formula IV are obtained by reacting with hydrazine, hydrazine hydrate,water-soluble low molecular weight primary amines such as methyl-, ethyl-, propyl- or butyl-amine, preferably methylamine or aminoethanol. The reaction is prefera41y carried out in the presence of low molecular weight alkanols such as methanol, ethanol, isopropanol, or mixtures thereof, possibly with the addition of water, and at the boiling point of the solvent. The compounds of the Formula II thus obtainedlmay be converted in the pure form, or in the form of crude oils as described above, by heating, preferably to 160C, in the presence of a solvent, into the desired 1,5-benzodiazocines of the Formula I.
Compounds of the Formula II, obtained by hydrazinolysis or aminolysis, need not be isolated from their reaction medium, but may be converted directly into corresponding compounds of the Formula I by heating the reaction mixture. In many cases, the subsequent cyclization of compounds of the Formula II into the desired compounds of the Formula I proceeds at a reaction velocity such that, at the temperature at which the phthaloyl radical is split off, a partial to complete cycliza~ion of the 2 aminobenzophenone takes place simultaneously.
Compounds of the Formula III.
~ N - CH2 - Z
,~, R2 C = O
Rl ~
wherein R, Rl and R2 and Z have the meanings already given, may also be obtained by known methods. Initial compounds of the Formula III, wh~rein Z signifies -CH(OH)-CH2-halogen may be produced by reacting 2-aminobenzophenones of the Formula V:
R
NH
,~
R2 C = O
R
wherein R, Rl and R2 have the mcaninc3s alreacly c3iven abovQ, with epichlorohydrin or epibromohydrin, at temperatures below 100C in the presence of acetic acid, for example.
Initial compounds of the Formula III, wherein z rep--resents`a epoxyethyl group, may be ob~ained, according to the "HOU~EN-WEYL" methods described in Organische Chemie 6/3, p. 374 et seq. (1965), by reacting a 1,2-hydrin halide of the Formul~ III, in the presence of the strong base such as sodium or potassium hydroxide, and in an inert solvent such as ether, dioxan, tetrahydrofuran, benzene or toluene, with concentrated llZ~?80 aqueous alkali hydroxide solutions,at room temperature.
Phthalimide compounds of the Formula IV can be prepared from compounds of the Formula III, wherein Z may have two different meanings. Thus compounds of the Formula III, wherein Z is an epoxyethyl group may be reacted with phthalimide at an elevated temperature, in an inel~ solvent such as dimethyl-formamide. Using 1,2-hydrin halides of the Formula III makes it possible to produce corresponding phthalimides of Formula IV by reacting the former compounds with potassium phthalimide in the presence of an inert solvent such as dimethylformamide by a base-catalyzed reaction, in the presence of pyridine, for example, and at an elevated temperature. It is also possible to react 2-aminobenzophenones of the Formula V with N-(2,3-epoxypropyl)-phthalimide, at an elevated temperature, in the presence of acetic acid, to form phthalimide compounds of the Formula IV.
In producing compounds of the Fo~mula I, whcrein R
represents a methyl group, it is possible to st~rt with the corresponding 2-methylaminoben~ophenones of the Formula V, wherein Rl and R2 have the meanirlgs givell a~ove. It is also possible to introduce the methyl group into compounds of the Formula III, when 2 represents a -CH2-C~I(OI-I)-Cll2-halogen group or into compounds of the Formula IV, by methods known from the relevant literat~lre, for example by reductive carbonyl-aminating with a formalin solution, in the presence of formic acid and at an elevated temperature (see the Leuckart-Wallach or Eschweiler-Clark reaction in H. KRAUCH, W. KUNZ, Reactions in Organic Chemistry (1976), p. 126 and 131), if R in these compounds represents a hydrogen atom.
The following Examples serve to illustra-te tlle invention.
_XAMP ~E 1 8-chloro-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine.
232 g of 2-~mino-5-chloro-benzophenone were heated to 60C with 102 g of epichlorohydrin and 60 g of acetic acid.
The product, which crystalli~ed upon cooling, was placed in water, drawn off, and then extracted llom 800 ml of acetone.
With the crystalline product obtained from the concentrated mother liquid, the yield of 2-(3-chloro-2-hydroxypropylamino)-5-chloro-benzophenone was 279 g (86~). The melting point was between 105C and 107C.
16.2 g of the above 2-(3-chloro-2-hydroxypropylamino)-5-chloro-benzophenone were reacted in 50 ml of isopropanol and 50 ml of dioxan with 2.2 g of sodium hydroxide and 4.1 ml of wat~r, for 10 hours, at room teperature. After the organic solvent had been drawn off in vacuo, the resulting crude oil was dissolved in chloroform. The chloroform phase was then washed until neutral with water, dried over sodium sulphate, and filtered. After the chloroform had been removed, an oil was obtained, recrystallizi~ this out oE isoprop~nol/petroleum ether produced 8.0 g (55.6~) of 2-(2,3-epoxypropylamino)-5-chloro-benzophenone having a melting point o~ betwecll 61C
and 62C.
4 g of the above 2-(2,3-epoxypropylamino)-5-chloro-benzophenone were reacted in 400 ml of methanol with 12.0 g of ammonia gas, for 20 hours, at room temperat-lre. After the solvent had been removed in vacuo, 3.6 g (85~) of 2-(3-amino-2-hydroxypropylamino)-5-chloro-benzophenone crystallised out of isopropanol/petroleum ether; the substance melted at between 125C and 129C.
3g of the above 2-(3-amino-2-hydroxypropylamino)-5-112~80 chloro-benzophenone were heated in 100 ml of methanol with 0.6 g of ammonium chloride, for 20 hours, in a steel autoclave, at 140C.
The solvent was drawn off in vacuo, the substance was isolated out of chloroform, and aluminum oxide of activity stage II was removed by chromatography with chloroform/methanol. 2.0 g (70.9~) of 8-chloro-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,
3g of the above 2-(3-amino-2-hydroxypropylamino)-5-112~80 chloro-benzophenone were heated in 100 ml of methanol with 0.6 g of ammonium chloride, for 20 hours, in a steel autoclave, at 140C.
The solvent was drawn off in vacuo, the substance was isolated out of chloroform, and aluminum oxide of activity stage II was removed by chromatography with chloroform/methanol. 2.0 g (70.9~) of 8-chloro-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,
5-benzodiazocine were obtained in the form of an oil. The hydrochloride, crystallized out of isopropanol/ether, melted at between 206C and 208C.
8-chloro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1, 5-benzodiazocine.
16.2 g of 2-(3-chloro-2-hydroxypropylamino)-5-chloro-benzophenone were heated in 19 ml of formic acid and 9.5 ml of a 37% formalin solution, for 2.5 hours in a water-bath. The solution was then poured onto ice and ncutralized with a dilute aqueous solution of sodium hydroxide. The reaction pro~uct was reduced in chloroform, the solution washcd witll a sodium carbonate solution, dried, and the chloro~orm drawrl off. This produced 19.2 g of crude oil containing 78% of 2-(3-chloro-2-hydroxypropyl-methylamino)-5-chloro-benzophenone, corresponding to a yield of 88.6%. The substance, crystallized out of isopropanol/petroleum ether, melted at between 71C and 72C.
The crude oil could be used without purification.
18.6 g of this crude oil were reacted in 30 ml of isopropanol, with 2.4 g of sodium hydroxide, in 4.5 ml of water for 12 hours, at room temperature. The filtered solution was drawn off in vacuo, the crude oil taken up in chloroform and processed. 15 g of 2-(2,3 epoxypropyl-methylamino)-5-chloro-benzophenone were obtained in the form of an oil.
11~'~0 9 g of this 2-(2,3-epoxypropyl-methylamino)-5-chloro-benzophenone were reacted in a steel autoclave, for 10 hours at ]50C, with 5.1 g of ammonia gas, in 100 ml of ethanol.
After drawing off the solvent in vacuo, 85.1'~ of a raw product containing 8-chloro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetra-hydro-1,5-benzodiazocine were isolate~, according to HPLC analysis.
The compound, crystallized out of ether, had a melting point of between 169C and 170C.
_XAMPLE 3 8-chloro-3-hydroxy-6-phenyl-ll2~3~4-tetrahydro-l~5-benzodiazocine.
64.8 g of the 2-(3-chloro-2-hydroxypropylamino)-5-chloro-benzophenone, produced from 2-amino-5-chloro-benzophenone, dissolved in 200 ml of dimethylformamide, were dripped at 130C, into a suspension consisting of 40.5 g of potassium phthalimide, 1.2 ml of pyridine, and 60 ml of dimethylformamide, in such a manner that the temperature was maintained at between 130C and 140C during the exothermal reaction. The solution was allowed to stand for a further 1.5 hours at the reaction telllperature.
After removal of the solvent in vacuo, the product was isolated from ether and the crude oil was crystallized out o~ isopropanol.
This produced 64 g (73.6~) of 2-(3-phthalimido-2-hydroxy-propylamino)-5-chloro-benzopllenone; the substallce m~lted at between 131C and 133C.
22 g of the above 2 (3-phthalimido-2-hydroxypropylamino)-5-chloro-benzophenone were heated, for 1.5 hours under reflux, in 4no ml of methanol, with 5.5 g of hydrazine hydrate. The cooled solution was acidified with aqùeous hydrochloric acid and filtered, and the filtrate was concentrated in vacuo. After being alkalinized, the base was isolated, using an aqueous sodium hydroxide solution, from chloroform. 11.0 g (71.4%) of 2-(3-amino-1~;2298() 2-hydroxy-propylamino)-5-chloro-benzophenone crystallized out of isopropanol.
For the cyclization, 3.0 g of 2-(3-amino-2-hydroxy-propylamino)-5-chloro-benzophenone were heated, in 80 ml of dioxan, with 1.7 g of ammonia gas in 50 ml of methanol, for 20 hours in an autoclave, at 140C. ~, Ler the reaction mixLure has been processed, 1.9 g (67.396) of 8-chloro-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine were obtained.
The melting point of the hydrochloride was between 206C and 208C.
8-chloro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1, 5-benzodiazocine.
16.2 g of 2-(3-chloro-2-hydroxypropylamino)-5-chloro~
benzophenone were heated in 19 ml of formic acid and 9.5 ml of a 37% formalin solution, for 2.5 hours, in a water bath. The solution was then poured onto ice and neutralized with a dilute aqueous sodium hydroxide solution. The reaction product was transferred into chloroform, the solution w~sh~cl witll a sodium carbonate solution, and the chlorofonn drawn off. This produced 19.2 g of crude oil containing 789~ of 2-(3-cllloro-2-hydroxypropyl-methylamino)-5-chloro-benzophenone, corresponding to a yield of 88.6%. The substance crystallized out of isopropanol/petroleum ether, melted at between 71C and 72C. l'he crude oil could be used without purification.
18.6 g of this crude oil were reacted, in 30 ml of isopropanol, with 2.4 g of sodium hydroxide in 4.5 ml of water, for 12 hours, at room temperature. The filtered solution was drawn off in vacuo, the crude oil taken up in chloroform and processed. This produced 15 g of 2-(2,3-epoxypropyl-methylamino)-S-chloro-benzophenone in the form of an oil.
15 g of the 2-(2,3-epoxypropyl-methylamino)-5-chloro-benzophenone, in the form of the crude oil, were reacted with 8.1 g of phthalimide and 0.5 ml of pyridine, dissolved in 100 ml of dimethylformamide, for 2 hours at between 130C and 140C.
The substance isolated from chloroform, after removal of the solvent, was dissolved i~ isopropanol ~nd the insolubles filtered out. This produced 15.0 g of 2-(3-phthalimideo-2-hydroxypropyl-methylamino)-5-chloro-benzophenone which melted at between 132C
and 134C. A crystalline material, melting at between 128C and 130C,was obtained from toluene/petroleum ether. The two crystal systems were transferred into each other.
12.1 g of the 2-(3-phthalimido-2-hydroxypropyl-methylamino)-5-chloro-benzophenone were heated, in 75 ml of ethanol, with 1.5 g of hydrazine hydrate, for 1.5 hours under reflux. The solution was filtered hot and the filtrate concentrated in vacuo. The base was isolated in chloroform after treatment with an aqueous sodium hydroxide solution. 6.8 g (84.0%) of 8-chloro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydxo-1,5-benzodiazocine were obtained from ether. 'l`he base had a melting point of between 169C and 170C.
8-chloro-1-methyl-3-hydroxy-6-)2'-chlorophcnyl)-1,2,3,4-tetrahydro-1,5-benzodiaxocine.
31 g of 2-(3-chloro-2-hydroxypropylamino)-2,5-dichlorobenzophenone were heated with 38 ml of formic acid and 19 ml of a 37~ formalin solution, for 3 hours under reflux. The solution was poured onto ice, neutralized with an aqueous sodium hydroxide solution, and extracted with chloroform. After the chloroform had been distilled off, 35.5 g of crude oil were obtained which contained, according to HPLC analysis, 55.5~ of i~Z~ O
2-(3-chloro-2-hydroxypropyl-methylamino)-2',j-dichlorobenzophenone.
18.6 g of this crude oil, dissolved in 100 ml of dimethylformamide were dripped, at 125C, into a suspension of 10.2 g of potassium phthalimide in 1.5 ml of pyridine and 100 ml of dimethylformamide. This was allowed to stand for 2.5 hours at this temperature. Af-er removal ol ~he solvent, the crude product, isolated from chloroform, was recrystallized out of isopropanol. This produced 6.2 g of 2-(3-phthalimido-2-hydroxypropyl-methylamino)-2',5-dichlorobenzophenone having a melting point of between 186C and 188C.
8-chloro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1, 5-benzodiazocine.
16.2 g of 2-(3-chloro-2-hydroxypropylamino)-5-chloro-benzophenone were heated in 19 ml of formic acid and 9.5 ml of a 37% formalin solution, for 2.5 hours in a water-bath. The solution was then poured onto ice and ncutralized with a dilute aqueous solution of sodium hydroxide. The reaction pro~uct was reduced in chloroform, the solution washcd witll a sodium carbonate solution, dried, and the chloro~orm drawrl off. This produced 19.2 g of crude oil containing 78% of 2-(3-chloro-2-hydroxypropyl-methylamino)-5-chloro-benzophenone, corresponding to a yield of 88.6%. The substance, crystallized out of isopropanol/petroleum ether, melted at between 71C and 72C.
The crude oil could be used without purification.
18.6 g of this crude oil were reacted in 30 ml of isopropanol, with 2.4 g of sodium hydroxide, in 4.5 ml of water for 12 hours, at room temperature. The filtered solution was drawn off in vacuo, the crude oil taken up in chloroform and processed. 15 g of 2-(2,3 epoxypropyl-methylamino)-5-chloro-benzophenone were obtained in the form of an oil.
11~'~0 9 g of this 2-(2,3-epoxypropyl-methylamino)-5-chloro-benzophenone were reacted in a steel autoclave, for 10 hours at ]50C, with 5.1 g of ammonia gas, in 100 ml of ethanol.
After drawing off the solvent in vacuo, 85.1'~ of a raw product containing 8-chloro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetra-hydro-1,5-benzodiazocine were isolate~, according to HPLC analysis.
The compound, crystallized out of ether, had a melting point of between 169C and 170C.
_XAMPLE 3 8-chloro-3-hydroxy-6-phenyl-ll2~3~4-tetrahydro-l~5-benzodiazocine.
64.8 g of the 2-(3-chloro-2-hydroxypropylamino)-5-chloro-benzophenone, produced from 2-amino-5-chloro-benzophenone, dissolved in 200 ml of dimethylformamide, were dripped at 130C, into a suspension consisting of 40.5 g of potassium phthalimide, 1.2 ml of pyridine, and 60 ml of dimethylformamide, in such a manner that the temperature was maintained at between 130C and 140C during the exothermal reaction. The solution was allowed to stand for a further 1.5 hours at the reaction telllperature.
After removal of the solvent in vacuo, the product was isolated from ether and the crude oil was crystallized out o~ isopropanol.
This produced 64 g (73.6~) of 2-(3-phthalimido-2-hydroxy-propylamino)-5-chloro-benzopllenone; the substallce m~lted at between 131C and 133C.
22 g of the above 2 (3-phthalimido-2-hydroxypropylamino)-5-chloro-benzophenone were heated, for 1.5 hours under reflux, in 4no ml of methanol, with 5.5 g of hydrazine hydrate. The cooled solution was acidified with aqùeous hydrochloric acid and filtered, and the filtrate was concentrated in vacuo. After being alkalinized, the base was isolated, using an aqueous sodium hydroxide solution, from chloroform. 11.0 g (71.4%) of 2-(3-amino-1~;2298() 2-hydroxy-propylamino)-5-chloro-benzophenone crystallized out of isopropanol.
For the cyclization, 3.0 g of 2-(3-amino-2-hydroxy-propylamino)-5-chloro-benzophenone were heated, in 80 ml of dioxan, with 1.7 g of ammonia gas in 50 ml of methanol, for 20 hours in an autoclave, at 140C. ~, Ler the reaction mixLure has been processed, 1.9 g (67.396) of 8-chloro-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine were obtained.
The melting point of the hydrochloride was between 206C and 208C.
8-chloro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1, 5-benzodiazocine.
16.2 g of 2-(3-chloro-2-hydroxypropylamino)-5-chloro~
benzophenone were heated in 19 ml of formic acid and 9.5 ml of a 37% formalin solution, for 2.5 hours, in a water bath. The solution was then poured onto ice and neutralized with a dilute aqueous sodium hydroxide solution. The reaction product was transferred into chloroform, the solution w~sh~cl witll a sodium carbonate solution, and the chlorofonn drawn off. This produced 19.2 g of crude oil containing 789~ of 2-(3-cllloro-2-hydroxypropyl-methylamino)-5-chloro-benzophenone, corresponding to a yield of 88.6%. The substance crystallized out of isopropanol/petroleum ether, melted at between 71C and 72C. l'he crude oil could be used without purification.
18.6 g of this crude oil were reacted, in 30 ml of isopropanol, with 2.4 g of sodium hydroxide in 4.5 ml of water, for 12 hours, at room temperature. The filtered solution was drawn off in vacuo, the crude oil taken up in chloroform and processed. This produced 15 g of 2-(2,3-epoxypropyl-methylamino)-S-chloro-benzophenone in the form of an oil.
15 g of the 2-(2,3-epoxypropyl-methylamino)-5-chloro-benzophenone, in the form of the crude oil, were reacted with 8.1 g of phthalimide and 0.5 ml of pyridine, dissolved in 100 ml of dimethylformamide, for 2 hours at between 130C and 140C.
The substance isolated from chloroform, after removal of the solvent, was dissolved i~ isopropanol ~nd the insolubles filtered out. This produced 15.0 g of 2-(3-phthalimideo-2-hydroxypropyl-methylamino)-5-chloro-benzophenone which melted at between 132C
and 134C. A crystalline material, melting at between 128C and 130C,was obtained from toluene/petroleum ether. The two crystal systems were transferred into each other.
12.1 g of the 2-(3-phthalimido-2-hydroxypropyl-methylamino)-5-chloro-benzophenone were heated, in 75 ml of ethanol, with 1.5 g of hydrazine hydrate, for 1.5 hours under reflux. The solution was filtered hot and the filtrate concentrated in vacuo. The base was isolated in chloroform after treatment with an aqueous sodium hydroxide solution. 6.8 g (84.0%) of 8-chloro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydxo-1,5-benzodiazocine were obtained from ether. 'l`he base had a melting point of between 169C and 170C.
8-chloro-1-methyl-3-hydroxy-6-)2'-chlorophcnyl)-1,2,3,4-tetrahydro-1,5-benzodiaxocine.
31 g of 2-(3-chloro-2-hydroxypropylamino)-2,5-dichlorobenzophenone were heated with 38 ml of formic acid and 19 ml of a 37~ formalin solution, for 3 hours under reflux. The solution was poured onto ice, neutralized with an aqueous sodium hydroxide solution, and extracted with chloroform. After the chloroform had been distilled off, 35.5 g of crude oil were obtained which contained, according to HPLC analysis, 55.5~ of i~Z~ O
2-(3-chloro-2-hydroxypropyl-methylamino)-2',j-dichlorobenzophenone.
18.6 g of this crude oil, dissolved in 100 ml of dimethylformamide were dripped, at 125C, into a suspension of 10.2 g of potassium phthalimide in 1.5 ml of pyridine and 100 ml of dimethylformamide. This was allowed to stand for 2.5 hours at this temperature. Af-er removal ol ~he solvent, the crude product, isolated from chloroform, was recrystallized out of isopropanol. This produced 6.2 g of 2-(3-phthalimido-2-hydroxypropyl-methylamino)-2',5-dichlorobenzophenone having a melting point of between 186C and 188C.
6.0 g of this product were heated in 150 ml of ethanol with 0.7 g of hydrazine hydrate, for three hours, under reflux.
The solvent was drawn off in vaeuo from the hot-filtered solution.
After the residue had been proeessed, 5 g of erude oil were obtained, whieh, aceording to HPLC analysis, produee 30% of cyclized produet in addition to the 2-(3-amino-2-hydroxypropyl-methylamino)2',5-diehlorobenzophenone.
The erude oilwas heated for a further 2 hours, to 150C
in an autoelave, in 100 ml of methane. This increasccl the proportion of cyelized product to 75~. This produeccl, after removal of the solvent, and removing aluminum oxide of aetivity stage II from the base by column ehromatography, 2.8 g (67.2%) of8-ehloro-1-methyl-3-hydroxy-6-(2'-ehlorophenyl~1,2,3,4-tetrahydro-1,5-benzodiazoeine. The base, reerystallized out of ether, had a meltin~ point of between 176C ancl 178C.
The hydroehloride, reerystallized from aeetone, melted at 195C.
llZZ9130 8-~hloro-1-methyl-3-hydroxy-6-(2'chlorophenyl)-1,2,3,4-tetrahydro-1,5-benzodiazocine.
29.0 g of 2-(3-chloro-2-hydroxypropylamino)-2',5-dichlorobenzophenone, dissolved in 75 ml of dimethylformamide, were dripped into a susp2nsion of 16.4 g of potassium phthalimide in 1.3 ml of pyridine and 75 ml of dimethylformamide at 120 to 130C and were left at this temperature for 2.5 hours. The crude oil, subsequently isolated out of chloroform, contained, according to HPLC analysis, 67.8~, in relation to the preliminary product, of 2-(3-phthalimido-2-hydroxypropylamino)-2',5-dichlorobenzophenone. The pure base had a melting point of between 143C and 145C.
39.9 g of the crude oil were heated under reflux, for 3 hours, with 32 ml of formic acid and 16 ml of a 37%
aqueous formalin solution. After processing and recrystallizing out of isopropanol, 13.9 g of 2-(3-phthalimido2-hydroxypropyl-methylamino)-2',5-dichlorobenzophenone were obtained, with a melting point of between 186C and 188C.
The solvent was drawn off in vaeuo from the hot-filtered solution.
After the residue had been proeessed, 5 g of erude oil were obtained, whieh, aceording to HPLC analysis, produee 30% of cyclized produet in addition to the 2-(3-amino-2-hydroxypropyl-methylamino)2',5-diehlorobenzophenone.
The erude oilwas heated for a further 2 hours, to 150C
in an autoelave, in 100 ml of methane. This increasccl the proportion of cyelized product to 75~. This produeccl, after removal of the solvent, and removing aluminum oxide of aetivity stage II from the base by column ehromatography, 2.8 g (67.2%) of8-ehloro-1-methyl-3-hydroxy-6-(2'-ehlorophenyl~1,2,3,4-tetrahydro-1,5-benzodiazoeine. The base, reerystallized out of ether, had a meltin~ point of between 176C ancl 178C.
The hydroehloride, reerystallized from aeetone, melted at 195C.
llZZ9130 8-~hloro-1-methyl-3-hydroxy-6-(2'chlorophenyl)-1,2,3,4-tetrahydro-1,5-benzodiazocine.
29.0 g of 2-(3-chloro-2-hydroxypropylamino)-2',5-dichlorobenzophenone, dissolved in 75 ml of dimethylformamide, were dripped into a susp2nsion of 16.4 g of potassium phthalimide in 1.3 ml of pyridine and 75 ml of dimethylformamide at 120 to 130C and were left at this temperature for 2.5 hours. The crude oil, subsequently isolated out of chloroform, contained, according to HPLC analysis, 67.8~, in relation to the preliminary product, of 2-(3-phthalimido-2-hydroxypropylamino)-2',5-dichlorobenzophenone. The pure base had a melting point of between 143C and 145C.
39.9 g of the crude oil were heated under reflux, for 3 hours, with 32 ml of formic acid and 16 ml of a 37%
aqueous formalin solution. After processing and recrystallizing out of isopropanol, 13.9 g of 2-(3-phthalimido2-hydroxypropyl-methylamino)-2',5-dichlorobenzophenone were obtained, with a melting point of between 186C and 188C.
7.5 g of the 2-(3-phthalimido-2-hydroxypropyl-methylamino)-2',5-dichlorobenzophenone were heated at 150C, in an autoclave, with 150 ml of methanol and 0.9 g of hydrazine, for 2 hours. ~his produced, after processing, 3.3 ~ (63.5~) of 8-chloro-1-methyl-3-hydroxy-6-(2'-chloro-phenyl)-1,2,3,4-tetrahydro-1,5-benzodiazocine with a meltin~ point of between 176C and 178C.
:llZ2980
:llZ2980
8-chloro-3-1--ydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine.
19.6 g of 5-chloro-2-aminoben~ophenone were heated with 20.0 g of N-(2,3-epoxypropyl)-phthalimide in 50 ml of acetic acid, for 14 hours, at about 90C. The solution, diluted with chloroform, was poured onto ice a-~d alkalinized with an aqueous sodium hydroxide solution. The product, isolated out of ether, was recrystallized with isopropanol. This produced 28.5 g (77.5~) of 2-(3-phthalimido-2-hydroxypropylamino)-5-chloro-benzophenone.
4.3 g of this 2-(3-phthalimido-2-hydroxypropylamino)-5-chloro-benzophenone were heated in an autoclave, with 0.5 g of methylamine in 150 ml of methanol, initially for 2 hours at 60C and subsequently for 15 hours at 150C. The crude oil obtained, after removal of the solvent in vacuo, had the aluminum oxide of activity stage II removed by cleaning. This produced 0.9 g (31.7%) of 8-chloro-3-hydroxy-6-~henyl-1,2,3,4-tetrahydro-1,5-benzodiazocine. The meltillg ~oint o~ the hydrochloride was between 206C and 208C.
_XAMPLE 8 8-chloro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1, 5-benzodiazocine.
24.5 g of 2-methylamino-5-chloro-benzophenone were heated with 10.2 g of epichlorohydrin and 6.0 g of acetic acid, for 72 hours at 70C. After processing, 33.6 g of a crude oil containing 2-(3-chloro-2-hydroxypropyl-methylamino)-5-chloro-benzophenone were isolated. The product was used without further purification.
33.6 g of the crude oil, dissolved in 80 ml of dimethylformamide, were dripped at 130C into a suspension ~lZ;~80 consisting of 20 g of potassium phthalimide, 1.5 ml of pyridine and 80 ml of dimethylformamide. After about 2 hours, the solvent was drawn off. The 2-(3-phthalimido-2-hydroxypropyl-methylamino)-5-chloro-benzophenone, isolated out of toluene, crystallized after addition of petroleum ether. The yield amounted to 22.3 g (49.7%) in relation tc the 2-methylamino-5-chloro-benzophenone.
2.0 g of 2-(3-phthalimido-2-hydroxypropyl--methylamino)-5-chloro-benzophenone were heated in 50 ml of methanol with 6 ml of a 33~ aqueous methylamine solution for 45 minutes under reflux. Processing consisted of drawing off the solvent in vacuo, dissolving the residue in chloroform, and washing with water. After drying and drawing off the solvent, the oleaginous residue was digested with ether. 1.2 g of 8-chloro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine (89.6%) were obtained in the form of a crude oil The product obtained by recrystallization had a melting point oE between 169C and 170C.
_.
8-chloro-1-methyl-3-hydroxy-6-(2'-chlorophellyl)-1,2,3,4-tetrahydro-l,S-benzodiazocine.
g.3 g of 2-amino-~',5-dichloro-benzophenonc were heated with 7.8 g of N-(2,3-epoxypropyl)-phthalimide in 17.5 ml of acetic acid, for 17 hours at 90C. The solution was poured onto ice and extracted with chloroform. After the chloroform had been distilled off, 15.5 g of 2-(3-phthalimido-2-hydroxypropyl-amino)-2',5-dichloro-benzophenone were obtained in the form of crude oil. This was heated with 14 ml of formic acid and 7 ml of a 37~ aqueous formalin solution, for 3 hours under reflux.
After the reaction product had been processed, the substance, isolated out of chloroform, was recrystallized out of isopropanol.
This produced 5.5 g of 2-(3-phthalimido-2-hydroxypropyl-~2'~80 methylamino)-2',5-dichloro-benzophenone having a melting point of between 186C and 188C.
2.0 g of 2-(3-phthalimido-2-hydroxypropylamino)-2', 5-dichloro-benzophenone were heated in 20 ml of aminoethanol, for 2.5 hours to 150C. After the excess of aminoethanol had been drawn off in vacuo, the base was i~olated out of chloroform.
After pur~fication by preparatory layer chromatography, 1 g (72.1~)of ~-cl~ ro-]-methyl-3-hydroxy-6-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1,5-benzodiazocine was obtained which, after recrystallizing out of ether, had a melting point of between 176C and 178C.
_ AMPLE 10 8-chloro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4,-tetrahydro-1, 5-benzodiazocine.
21.7 g of 2-(3-phthalimido-2-hydroxypropylamino)-5-chloro-benzophenone were reacted in 19 ml of formic acid and
19.6 g of 5-chloro-2-aminoben~ophenone were heated with 20.0 g of N-(2,3-epoxypropyl)-phthalimide in 50 ml of acetic acid, for 14 hours, at about 90C. The solution, diluted with chloroform, was poured onto ice a-~d alkalinized with an aqueous sodium hydroxide solution. The product, isolated out of ether, was recrystallized with isopropanol. This produced 28.5 g (77.5~) of 2-(3-phthalimido-2-hydroxypropylamino)-5-chloro-benzophenone.
4.3 g of this 2-(3-phthalimido-2-hydroxypropylamino)-5-chloro-benzophenone were heated in an autoclave, with 0.5 g of methylamine in 150 ml of methanol, initially for 2 hours at 60C and subsequently for 15 hours at 150C. The crude oil obtained, after removal of the solvent in vacuo, had the aluminum oxide of activity stage II removed by cleaning. This produced 0.9 g (31.7%) of 8-chloro-3-hydroxy-6-~henyl-1,2,3,4-tetrahydro-1,5-benzodiazocine. The meltillg ~oint o~ the hydrochloride was between 206C and 208C.
_XAMPLE 8 8-chloro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1, 5-benzodiazocine.
24.5 g of 2-methylamino-5-chloro-benzophenone were heated with 10.2 g of epichlorohydrin and 6.0 g of acetic acid, for 72 hours at 70C. After processing, 33.6 g of a crude oil containing 2-(3-chloro-2-hydroxypropyl-methylamino)-5-chloro-benzophenone were isolated. The product was used without further purification.
33.6 g of the crude oil, dissolved in 80 ml of dimethylformamide, were dripped at 130C into a suspension ~lZ;~80 consisting of 20 g of potassium phthalimide, 1.5 ml of pyridine and 80 ml of dimethylformamide. After about 2 hours, the solvent was drawn off. The 2-(3-phthalimido-2-hydroxypropyl-methylamino)-5-chloro-benzophenone, isolated out of toluene, crystallized after addition of petroleum ether. The yield amounted to 22.3 g (49.7%) in relation tc the 2-methylamino-5-chloro-benzophenone.
2.0 g of 2-(3-phthalimido-2-hydroxypropyl--methylamino)-5-chloro-benzophenone were heated in 50 ml of methanol with 6 ml of a 33~ aqueous methylamine solution for 45 minutes under reflux. Processing consisted of drawing off the solvent in vacuo, dissolving the residue in chloroform, and washing with water. After drying and drawing off the solvent, the oleaginous residue was digested with ether. 1.2 g of 8-chloro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine (89.6%) were obtained in the form of a crude oil The product obtained by recrystallization had a melting point oE between 169C and 170C.
_.
8-chloro-1-methyl-3-hydroxy-6-(2'-chlorophellyl)-1,2,3,4-tetrahydro-l,S-benzodiazocine.
g.3 g of 2-amino-~',5-dichloro-benzophenonc were heated with 7.8 g of N-(2,3-epoxypropyl)-phthalimide in 17.5 ml of acetic acid, for 17 hours at 90C. The solution was poured onto ice and extracted with chloroform. After the chloroform had been distilled off, 15.5 g of 2-(3-phthalimido-2-hydroxypropyl-amino)-2',5-dichloro-benzophenone were obtained in the form of crude oil. This was heated with 14 ml of formic acid and 7 ml of a 37~ aqueous formalin solution, for 3 hours under reflux.
After the reaction product had been processed, the substance, isolated out of chloroform, was recrystallized out of isopropanol.
This produced 5.5 g of 2-(3-phthalimido-2-hydroxypropyl-~2'~80 methylamino)-2',5-dichloro-benzophenone having a melting point of between 186C and 188C.
2.0 g of 2-(3-phthalimido-2-hydroxypropylamino)-2', 5-dichloro-benzophenone were heated in 20 ml of aminoethanol, for 2.5 hours to 150C. After the excess of aminoethanol had been drawn off in vacuo, the base was i~olated out of chloroform.
After pur~fication by preparatory layer chromatography, 1 g (72.1~)of ~-cl~ ro-]-methyl-3-hydroxy-6-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1,5-benzodiazocine was obtained which, after recrystallizing out of ether, had a melting point of between 176C and 178C.
_ AMPLE 10 8-chloro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4,-tetrahydro-1, 5-benzodiazocine.
21.7 g of 2-(3-phthalimido-2-hydroxypropylamino)-5-chloro-benzophenone were reacted in 19 ml of formic acid and
9.5 ml of a 37'~ a~ueous formalin solution, or 2.5 hours under reflux. After processing, 17.5 g (78.1%) o~ 2-(3-phthalimido-2-hydroxypropyl-methylamino)-5-chloro-benzo~llenonc werc obtained in crystallin~ form out of isopropanol/petroleum e~her.
22.5 g of 2-(3-phthalimido-2-hydroxypropyl-methylamino)-5-chloro-benzophenone were heated with 100 ml of concentrated hydrochloric acid, for 7 hours under reflux. The cooled solution was filtered, the filtrate alkalinized with sodium hydroxide and extra~ted with chloroform. The 2-(3-amino-2-hydroxypropyl-methylamino)-5-chloro-benzophenone, contained in the crude oil after drying and drawing off the solvent, was dissolved in 100 ml of glacial acetic acid and heated for 1 hour at 90C. The solvent was then drawn off and the substance was isolated out of chloroform. This produced 7.7 g (51.1~) of 8-chloro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1, 5-benzodiazocine having a melting point of between 169C and 170C.
The base was cyclized in a similar manner by heating 11~2~80 for 8 hours, wlder reflux, in isopropanol. According to HPLC
an~lysis, the 1,5-benzodiazocine content amounted to 90%.
In the same way, the hydrochloride cyclized, under the conditions given above, in both acetic acid and isopropanol.
The 1,5-benzodiazocine content, accor~ling to HPLC analysis, amounted to 80% and 70~ respectively.
8-nitro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine.
8 g of 2-(3-bromo-2-hydroxypropyl-methylamino)-5-nitrobenzophenone were heated with a suspension consisting of 5.6 g of potassium phthalimide, 2.2 g of pyridine and 200 ml of dimeWIylformamide, for 3 hours at 130C. The solution was then dispersed in water and the reaction product tilUS obtained was taken up in chloroform and isolated. Recrystallizing out of toluene produced 5.8 g (62.0'~) of 2-(3-ph~halimido-2-hydroxypropyl-methylamino)-5-nitrobenzoph~llonc havin~ a mclting point of between 183C and 188C.
5.8 g of this phthaloyl compound were hcated in 60 ml of concentrated llydrochloric acid, for 4 hours unclcl rc~lux.
The cooled colution was extracted with chloroform arl(l the aqueous phase drawn off in vacuo until dry. ~Eter azeotropic distillation with toluene, in vacuo, the 2-(3-amin~-~-hydroxy-propyl-metllylamino)-5-nitrobenzophenone hydrochloride thus obtained was heated in 100 ml of acetic acid for 1 hour at 90C.
After distilling the solvent off in vacuo and alkalinizing with a dilute aqueous sodium hydroxide solution, 2.9 I (73.8~) of 8-nitro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine were isolated after extraction with chloroform.
The substance, recrystallized out of me-th~nol, had a melting ~zz~o point of b~tween 206C and 209C.
8-chloro-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine.
6.4 g of 2-(3-chloro-2-hydroxypropylamino)-5-chloro-benzophenone in 150 ml of methanol were heated in an autocalve with 10.2 g of ammonia g~s, for 18 houLs at 60C. After the solvent had been drawn off in vacuo, the substance was dissolved in chlo~oform. After treatment with a dilute aqueous sodium hydroxide solution, the chloroform was drawn off in vacuo.
After recrystallizing the residue out of isopropanol, 4.4 g (73.1~) of 2-(3-amino-2-hydroxypropylamino)-5-chloro-benzophenone were obtained.
For the cyclization, 3 g of the 2-(3-amino-2-hydroxy-proplyamino)-5-chl~ro-benzophenone were heated in 90 ml of methanol, in an autoclave, for 18 hours at 90C. After the reaction product had been processed, a 40'~ yield of 8-chloro-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine was obtained. The melting point of the hydrochloride was between 206 and 208C.
.
8-chloro-3-hydroxy-6-phenyl-1,2,3,4-tetrallydro-~,5-benzodiazocine.
16.1 g of 2-(3-chloro-2-hydroxypropylamino)-5-chloro-benzophenone, dissolved in 170 ml of methanol, were heated in a steel autoclave, with 8.5 g of ammonia gas, for 20 hours at 140C. The solvent was then drawn off, the residue dissolved in chloroform, the solution washed with an aqueous sodium hydroxide solution and water,dried, and the solvent drawn off in vacuo. The 8-chloro-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine, purified chromatographically over aluminum oxide, was converted into the hydrochloride. 9.8 g (61.1%) of 8() of that compound were obtained, it had a meltin~ point of between 206C and 208C.
8-chloro-1-methyl-3-hydroxy-6-pnenyl-1,2,3,4-tetrahydro-1, 5-benzodiazocine.
33.8 g of 2-(3-chloro-2-hydroxypropyl-methylamino)-5-chloro-benzophenone were heated, with 17.0 g of ammonia gas, in 300 ml of methanol, in a steel autoclave, for 12 hours at 150C. After drawing off the solvent and alkalinizing with a dilute aqueous sodium hydroxide solution, the 8-chloro-1-methyl-3-hydroxy-6 -phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine was isolated out of chloroform. The yield of product, crystallized out of ether, was 21.5 g (71.5%). The melting point was 169-170C.
8-chloro-3-hydroxy-6-(2'-chlorophenyl)-1,2,3,4-tetrallydro-1, 5-benzodiazocine.
79.8 g of 2-amino-2', 5-dichloro-~nz.o~lcrlone were heated wi-th 30.5 g of epichlorollydrin and 18.2 g of acetic acid, for 18 hours at 70C. After dilution with chloroform, the solution was washed until neutral with water and thc solvent then distilled off. 108 g of the crude product were obtained.
According to H~l,C analysis, this contained 75% of 2-(3-chloro-2-hydroxypropylamino)-2',--dichloro-benzophenone. The benzo-phenone, crystallized out of isopropanol/petroleum ether, had a melting point of between 74C and 76C.
6.2 g of the crude oil containing the 2-(3-chloro-2-hydroxypropylamino)-2',5-dichloro-benzophenone were reacted, in 100 ml of methanol, with 3.4 g of ammonia gas, for 18 hours at 150C in the autoclave. The reaction mixture was processed and purified by column chromatography. The 8-chloro-3-hydroxy-6-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1,5-benzodiazocine, occurring in the form of .In oil, was converted into the hydrochloride in an ether solution with hydrogen chloride. The product, crystallized out of acetone, had a melting point of between 174C and 178C.
. .
8-chloro-1-methyl-3-hydroxy-6-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1, S-benzodiazocine.
6.3 g of 2-(3-chloro-2-hydroxypropyl-methylamino)-2~, 5-dichloro-benzophenone were dissolved in 50 ml of ethanol and heatea with 4.4 g of ammonia gas, in 80 ml of ethanol, for 20 hours in an autoclave at 150C. The crude base obtained after proccssing the reaction mixture was purified chromatographically.
Recrystallizing out of ether produced 1.2 g (56.5%) of 8-chloro-l-methyl-3-hydroxy-6-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1,5-benzodiazocine having a melting point of between 176C and 178C.
-8-bromo-1-methyl-3-hydroxy-6-(2'-fluorophenyl)-1,2,3,4-tetrahydro-1,5-benzodiazocine.
34.7 g of 2-~nino-5-~romo-2'-f]uorobcllzophellone were heated with 12.0 g of epichlorohydrin and 7.1 g of acetic acid, for 5 hours at 60C. The 2-(3-chloro-2-hydroxypropylamino)~5-bromo-2'-fluorobenzophenone crystallized out of isopropanol/
petroleum ether with a melting point of between 119C and 121C.
The yield was 27.2 g (59.6%).
18.2 g of 2-(3-chloro-2-hydroxypropylamino)-5-bromo-2'-fluorobenzophenone were reacted with 18 ml of formic acid and 9 ml of a 37~ aqueous formalin solution, for 3 hours at reflux temperature, and were then processed. This produced a crude oil colltaining, according to HPLC analysis, 75~ of 2-(3-chloro-2-hydroxypropyl-methylamino)-5-bromo-2'-fluoro-benzophenone.
9.6 g of this crude oil were then reacted in 130 ml of ethan~ with 3.4 g of ammonia, for 20 hours at 30C and then processed. After the aluminum oxide of activity stage 11 had been removed by column chromatograplly with chloroform/ethanol, and after recrystallizing with ether, 3.2 g (49~) of 8-bromo-1-methyl-3-hydroxy-6-(2'-fluoro-phenyl)-1,2,3,4-tetrallydro-1,5-benzodiazocine were obtained, with a melting point of 223C.
.. . . .
3-hydroxy-6-phenyl-1,2,3,4~tetrahydro-1,5-benzodiazocine.
17.8 g of 2-aminobenzophenone were reacted with 9.2 g of epichlorohydrin and 5.4 ml of glacial acetic acid, Eor 18 hours at 60C. 27.3 g of the crude product, isolatcd after processing, cont~ined, according to HPLC analysis, 75~ of 2-t3-chloro-2-11ydroxypropylamino)-benzopllenone. The product, which crystallized out of ether, melted at betwcen 73C and 75C.
11.7 g of the crude product were reacted in 100 ml of methanol with 8.0 g of a~nonia gas, for 16 hours at 150C, in an autoclave. After the solvent had been drawn off, the reaction product was distributed between toluene and dilute aqueous hydrochloric acid. After alkalinizin~J with an aqueous sodiwn hydroxide solution, 3.1 g (40.2~) of 3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine were extracted with methylene chloride. The substance, crystallized out of ether, melted at between 149C and 151C.
l-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine.
22.5 g of 2-(3-phthalimido-2-hydroxypropyl-methylamino)-5-chloro-benzophenone were heated with 100 ml of concentrated hydrochloric acid, for 7 hours under reflux. The cooled solution was filtered, the filtrate alkalinized with sodium hydroxide and extra~ted with chloroform. The 2-(3-amino-2-hydroxypropyl-methylamino)-5-chloro-benzophenone, contained in the crude oil after drying and drawing off the solvent, was dissolved in 100 ml of glacial acetic acid and heated for 1 hour at 90C. The solvent was then drawn off and the substance was isolated out of chloroform. This produced 7.7 g (51.1~) of 8-chloro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1, 5-benzodiazocine having a melting point of between 169C and 170C.
The base was cyclized in a similar manner by heating 11~2~80 for 8 hours, wlder reflux, in isopropanol. According to HPLC
an~lysis, the 1,5-benzodiazocine content amounted to 90%.
In the same way, the hydrochloride cyclized, under the conditions given above, in both acetic acid and isopropanol.
The 1,5-benzodiazocine content, accor~ling to HPLC analysis, amounted to 80% and 70~ respectively.
8-nitro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine.
8 g of 2-(3-bromo-2-hydroxypropyl-methylamino)-5-nitrobenzophenone were heated with a suspension consisting of 5.6 g of potassium phthalimide, 2.2 g of pyridine and 200 ml of dimeWIylformamide, for 3 hours at 130C. The solution was then dispersed in water and the reaction product tilUS obtained was taken up in chloroform and isolated. Recrystallizing out of toluene produced 5.8 g (62.0'~) of 2-(3-ph~halimido-2-hydroxypropyl-methylamino)-5-nitrobenzoph~llonc havin~ a mclting point of between 183C and 188C.
5.8 g of this phthaloyl compound were hcated in 60 ml of concentrated llydrochloric acid, for 4 hours unclcl rc~lux.
The cooled colution was extracted with chloroform arl(l the aqueous phase drawn off in vacuo until dry. ~Eter azeotropic distillation with toluene, in vacuo, the 2-(3-amin~-~-hydroxy-propyl-metllylamino)-5-nitrobenzophenone hydrochloride thus obtained was heated in 100 ml of acetic acid for 1 hour at 90C.
After distilling the solvent off in vacuo and alkalinizing with a dilute aqueous sodium hydroxide solution, 2.9 I (73.8~) of 8-nitro-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine were isolated after extraction with chloroform.
The substance, recrystallized out of me-th~nol, had a melting ~zz~o point of b~tween 206C and 209C.
8-chloro-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine.
6.4 g of 2-(3-chloro-2-hydroxypropylamino)-5-chloro-benzophenone in 150 ml of methanol were heated in an autocalve with 10.2 g of ammonia g~s, for 18 houLs at 60C. After the solvent had been drawn off in vacuo, the substance was dissolved in chlo~oform. After treatment with a dilute aqueous sodium hydroxide solution, the chloroform was drawn off in vacuo.
After recrystallizing the residue out of isopropanol, 4.4 g (73.1~) of 2-(3-amino-2-hydroxypropylamino)-5-chloro-benzophenone were obtained.
For the cyclization, 3 g of the 2-(3-amino-2-hydroxy-proplyamino)-5-chl~ro-benzophenone were heated in 90 ml of methanol, in an autoclave, for 18 hours at 90C. After the reaction product had been processed, a 40'~ yield of 8-chloro-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine was obtained. The melting point of the hydrochloride was between 206 and 208C.
.
8-chloro-3-hydroxy-6-phenyl-1,2,3,4-tetrallydro-~,5-benzodiazocine.
16.1 g of 2-(3-chloro-2-hydroxypropylamino)-5-chloro-benzophenone, dissolved in 170 ml of methanol, were heated in a steel autoclave, with 8.5 g of ammonia gas, for 20 hours at 140C. The solvent was then drawn off, the residue dissolved in chloroform, the solution washed with an aqueous sodium hydroxide solution and water,dried, and the solvent drawn off in vacuo. The 8-chloro-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine, purified chromatographically over aluminum oxide, was converted into the hydrochloride. 9.8 g (61.1%) of 8() of that compound were obtained, it had a meltin~ point of between 206C and 208C.
8-chloro-1-methyl-3-hydroxy-6-pnenyl-1,2,3,4-tetrahydro-1, 5-benzodiazocine.
33.8 g of 2-(3-chloro-2-hydroxypropyl-methylamino)-5-chloro-benzophenone were heated, with 17.0 g of ammonia gas, in 300 ml of methanol, in a steel autoclave, for 12 hours at 150C. After drawing off the solvent and alkalinizing with a dilute aqueous sodium hydroxide solution, the 8-chloro-1-methyl-3-hydroxy-6 -phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine was isolated out of chloroform. The yield of product, crystallized out of ether, was 21.5 g (71.5%). The melting point was 169-170C.
8-chloro-3-hydroxy-6-(2'-chlorophenyl)-1,2,3,4-tetrallydro-1, 5-benzodiazocine.
79.8 g of 2-amino-2', 5-dichloro-~nz.o~lcrlone were heated wi-th 30.5 g of epichlorollydrin and 18.2 g of acetic acid, for 18 hours at 70C. After dilution with chloroform, the solution was washed until neutral with water and thc solvent then distilled off. 108 g of the crude product were obtained.
According to H~l,C analysis, this contained 75% of 2-(3-chloro-2-hydroxypropylamino)-2',--dichloro-benzophenone. The benzo-phenone, crystallized out of isopropanol/petroleum ether, had a melting point of between 74C and 76C.
6.2 g of the crude oil containing the 2-(3-chloro-2-hydroxypropylamino)-2',5-dichloro-benzophenone were reacted, in 100 ml of methanol, with 3.4 g of ammonia gas, for 18 hours at 150C in the autoclave. The reaction mixture was processed and purified by column chromatography. The 8-chloro-3-hydroxy-6-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1,5-benzodiazocine, occurring in the form of .In oil, was converted into the hydrochloride in an ether solution with hydrogen chloride. The product, crystallized out of acetone, had a melting point of between 174C and 178C.
. .
8-chloro-1-methyl-3-hydroxy-6-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1, S-benzodiazocine.
6.3 g of 2-(3-chloro-2-hydroxypropyl-methylamino)-2~, 5-dichloro-benzophenone were dissolved in 50 ml of ethanol and heatea with 4.4 g of ammonia gas, in 80 ml of ethanol, for 20 hours in an autoclave at 150C. The crude base obtained after proccssing the reaction mixture was purified chromatographically.
Recrystallizing out of ether produced 1.2 g (56.5%) of 8-chloro-l-methyl-3-hydroxy-6-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1,5-benzodiazocine having a melting point of between 176C and 178C.
-8-bromo-1-methyl-3-hydroxy-6-(2'-fluorophenyl)-1,2,3,4-tetrahydro-1,5-benzodiazocine.
34.7 g of 2-~nino-5-~romo-2'-f]uorobcllzophellone were heated with 12.0 g of epichlorohydrin and 7.1 g of acetic acid, for 5 hours at 60C. The 2-(3-chloro-2-hydroxypropylamino)~5-bromo-2'-fluorobenzophenone crystallized out of isopropanol/
petroleum ether with a melting point of between 119C and 121C.
The yield was 27.2 g (59.6%).
18.2 g of 2-(3-chloro-2-hydroxypropylamino)-5-bromo-2'-fluorobenzophenone were reacted with 18 ml of formic acid and 9 ml of a 37~ aqueous formalin solution, for 3 hours at reflux temperature, and were then processed. This produced a crude oil colltaining, according to HPLC analysis, 75~ of 2-(3-chloro-2-hydroxypropyl-methylamino)-5-bromo-2'-fluoro-benzophenone.
9.6 g of this crude oil were then reacted in 130 ml of ethan~ with 3.4 g of ammonia, for 20 hours at 30C and then processed. After the aluminum oxide of activity stage 11 had been removed by column chromatograplly with chloroform/ethanol, and after recrystallizing with ether, 3.2 g (49~) of 8-bromo-1-methyl-3-hydroxy-6-(2'-fluoro-phenyl)-1,2,3,4-tetrallydro-1,5-benzodiazocine were obtained, with a melting point of 223C.
.. . . .
3-hydroxy-6-phenyl-1,2,3,4~tetrahydro-1,5-benzodiazocine.
17.8 g of 2-aminobenzophenone were reacted with 9.2 g of epichlorohydrin and 5.4 ml of glacial acetic acid, Eor 18 hours at 60C. 27.3 g of the crude product, isolatcd after processing, cont~ined, according to HPLC analysis, 75~ of 2-t3-chloro-2-11ydroxypropylamino)-benzopllenone. The product, which crystallized out of ether, melted at betwcen 73C and 75C.
11.7 g of the crude product were reacted in 100 ml of methanol with 8.0 g of a~nonia gas, for 16 hours at 150C, in an autoclave. After the solvent had been drawn off, the reaction product was distributed between toluene and dilute aqueous hydrochloric acid. After alkalinizin~J with an aqueous sodiwn hydroxide solution, 3.1 g (40.2~) of 3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine were extracted with methylene chloride. The substance, crystallized out of ether, melted at between 149C and 151C.
l-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine.
10.6 g of 2-methylaminobenzophenone were reacted with - 2~ -5.2 g of epichlorohydrin and 3.0 g of glacial acetic acid, for 24 hours at 60C. 14.4 g of isolated 94~ (according to HPLC
analysis) 2-~3-chloro-2-hydroxypropyl-methylamino)-benzophenone were reacted, without further purification, with lQ.0 g of amnlonia gas in 300 ml of methanol, for 12 hours at 150C in an autoclave. After processing, 7.2 g of 1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-l,S-benzodiazocine were isolated. The salt of maleic acid crystallized out of isopropanol and had a melting point of between 135C and 137C.
, 8-trifluoromethyl-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1, 5-benzodiazocine.
6.0 g of 2-(3-phthalimido-2-hydroxypropyl-methylamino)-5-trifluoro-methyl-benzophenone were heated in 60 ml of concentrated hydrochloric acid, for 4 hours under reflux. The cooled solution was extracted with chloroform, and the aqueous phase drawn off in vacuo until dry. After azeotro~ic distillation with toluene in vacuo, the 2-(3-amino-2-hydroxypro~yl-methylamino)-5-trifluoromethyl-benzophenone hydrochloride thus o~tained was heated in 100 ml of acetic acid, for 1 hour, at 90C. After the solvent had been distilled of in vacuo, and after alkalinizing with a dilute aqueous sodium hydroxide solution,an oily material containing 8-trifluoromethyl-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine was isolated.
Having described what is believed to be the bes~
mode by which the invention may be performed, it will be seen that the invention may be particularly defined as foLlows:
A method for producing 3-hydroxy-6-phenyl-1,2,3,4-te~:rahydro-1,5-benzodiazocines corresponding to the formu~a:
~llZZ~80 Z R
j N Oll ~,~
. .
and pharmaceutically acceptable acicl-addition salts thereof, I wherein R represents a hydrogen atom or a methyl group, R
j represents a phenyl group, a 2-halo-phenyl group or a ¦ 10 2-trifluoromethyl-phenyl group, and R2 represents a hydro<Jen atom, a halogen atom, a nitro grou~ or a trifluoromethyl cJroup, characterized in that 2-aminobenzo~henones corresponding to the formula:
R
~1 - C~12 ~ - C112N~12 R2 C = O
wherein R, Rl and R2 have the meal-lings giv~n above, or addition salts t}-ereof, are cycli~d at an elevated temper-ature in the presence of an inert organi-~ solvent.
The foregoing is a description of a preferred embodiment of the invention which is given here by way of example only. The invention is not to be taken as limited to any of the specific features as described, but compre-hends all such variations thereof as come within the scope of the appended claims.
~ j - 26 -
analysis) 2-~3-chloro-2-hydroxypropyl-methylamino)-benzophenone were reacted, without further purification, with lQ.0 g of amnlonia gas in 300 ml of methanol, for 12 hours at 150C in an autoclave. After processing, 7.2 g of 1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-l,S-benzodiazocine were isolated. The salt of maleic acid crystallized out of isopropanol and had a melting point of between 135C and 137C.
, 8-trifluoromethyl-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1, 5-benzodiazocine.
6.0 g of 2-(3-phthalimido-2-hydroxypropyl-methylamino)-5-trifluoro-methyl-benzophenone were heated in 60 ml of concentrated hydrochloric acid, for 4 hours under reflux. The cooled solution was extracted with chloroform, and the aqueous phase drawn off in vacuo until dry. After azeotro~ic distillation with toluene in vacuo, the 2-(3-amino-2-hydroxypro~yl-methylamino)-5-trifluoromethyl-benzophenone hydrochloride thus o~tained was heated in 100 ml of acetic acid, for 1 hour, at 90C. After the solvent had been distilled of in vacuo, and after alkalinizing with a dilute aqueous sodium hydroxide solution,an oily material containing 8-trifluoromethyl-1-methyl-3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocine was isolated.
Having described what is believed to be the bes~
mode by which the invention may be performed, it will be seen that the invention may be particularly defined as foLlows:
A method for producing 3-hydroxy-6-phenyl-1,2,3,4-te~:rahydro-1,5-benzodiazocines corresponding to the formu~a:
~llZZ~80 Z R
j N Oll ~,~
. .
and pharmaceutically acceptable acicl-addition salts thereof, I wherein R represents a hydrogen atom or a methyl group, R
j represents a phenyl group, a 2-halo-phenyl group or a ¦ 10 2-trifluoromethyl-phenyl group, and R2 represents a hydro<Jen atom, a halogen atom, a nitro grou~ or a trifluoromethyl cJroup, characterized in that 2-aminobenzo~henones corresponding to the formula:
R
~1 - C~12 ~ - C112N~12 R2 C = O
wherein R, Rl and R2 have the meal-lings giv~n above, or addition salts t}-ereof, are cycli~d at an elevated temper-ature in the presence of an inert organi-~ solvent.
The foregoing is a description of a preferred embodiment of the invention which is given here by way of example only. The invention is not to be taken as limited to any of the specific features as described, but compre-hends all such variations thereof as come within the scope of the appended claims.
~ j - 26 -
Claims (12)
1. A method for producing 3-hydroxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzodiazocines corresponding to the formula:
and pharmaceutically acceptable acid-addition salts thereof, wherein R represents a hydrogen atom or a methyl group, R1 represents a phenyl group, a 2-halo-phenyl group or a 2-trifluoromethyl-phenyl group, and R2 represents a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group, characterized in that 2-aminobenzophenones corresponding to the formula:
wherein R, R1 and R2 have the meanings given above, or addition salts thereof, are cyclized at an elevated temperature in the presence of an inert organic solvent.
and pharmaceutically acceptable acid-addition salts thereof, wherein R represents a hydrogen atom or a methyl group, R1 represents a phenyl group, a 2-halo-phenyl group or a 2-trifluoromethyl-phenyl group, and R2 represents a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group, characterized in that 2-aminobenzophenones corresponding to the formula:
wherein R, R1 and R2 have the meanings given above, or addition salts thereof, are cyclized at an elevated temperature in the presence of an inert organic solvent.
2. A method as claimed in Claim 1 and in which the cyclization is effected at a temperature of from about 40°C
to about 200°C.
to about 200°C.
3. A method as claimed in Claim 2 and in which the cyclization is effected at normal or elevated pressure.
4. A method as claimed in Claim 3 and in which the cyclization is effected at a temperature of from about 80°C
to about 160°C.
to about 160°C.
5. A method as claimed in Claim 2, in which the cyclization is effected at a temperature of from about 40°C to about 100°C
and in which the inert organic solvent is acetic acid.
and in which the inert organic solvent is acetic acid.
6. A method as claimed in Claim 4 and in which said inert organic solvent is a low molecular weight monovalent or bivalent alkanol.
7. A method as claimed in Claim 6 and in which said inert organic solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanols and ethylene glycol.
8. A method as claimed in Claim 4 and in which said inert organic solvent is an aprotic solvent.
9. A method as claimed in Claim 8 and in which said aprotic solvent is selected from the group consisting of benzene, toluene, xylene, dioxan , tetrahydrofuran, thiocyclopentane 1-dioxide and dimethyl sulfoxide.
10. A method as claimed in Claim 1 and in which the cyclization of the 2-aminobenzophenone is effected in the reaction mixture in which such 2-aminobenzophenone is produced.
11. A method as claimed in Claim 1 and in which the cyclization is carried out in the presence of gaseous ammonia or an ammonium salt.
12. A method as claimed in Claim 11 and in which said ammonium salt is ammonium chloride or ammonium sulfate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19782810349 DE2810349A1 (en) | 1978-03-10 | 1978-03-10 | PROCESS FOR THE PREPARATION OF 3-HYDROXY-6-PHENYL-1,2,3,4-TETRAHYDRO-1,5-BENZODIAZOCINES |
| DEP2810349 | 1978-03-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1122980A true CA1122980A (en) | 1982-05-04 |
Family
ID=6034032
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA323,078A Expired CA1122980A (en) | 1978-03-10 | 1979-03-09 | Benzodiazoncine method |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0004024B1 (en) |
| JP (1) | JPS54122287A (en) |
| AT (1) | AT368138B (en) |
| CA (1) | CA1122980A (en) |
| DE (2) | DE2810349A1 (en) |
| HU (1) | HU178593B (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6818607B1 (en) | 1999-08-27 | 2004-11-16 | Procter & Gamble Company | Bleach boosting components, compositions and laundry methods |
| US6821935B1 (en) | 1999-08-27 | 2004-11-23 | Procter & Gamble Company | Color safe laundry methods employing zwitterionic formulation components |
| US6825160B1 (en) | 1999-08-27 | 2004-11-30 | Procter & Gamble Company | Color safe laundry methods employing cationic formulation components |
| US6903060B1 (en) | 1999-08-27 | 2005-06-07 | Procter & Gamble Company | Stable formulation components, compositions and laundry methods employing same |
| US6919304B2 (en) | 1999-08-27 | 2005-07-19 | Procter & Gamble Company | Stability enhancing formulation components, compositions and laundry methods employing same |
| US7109156B1 (en) | 1999-08-27 | 2006-09-19 | Procter & Gamble Company | Controlled availability of formulation components, compositions and laundry methods employing same |
| US7169744B2 (en) | 2002-06-06 | 2007-01-30 | Procter & Gamble Company | Organic catalyst with enhanced solubility |
| US7504371B2 (en) | 2005-06-17 | 2009-03-17 | The Procter & Gamble Company | Organic catalyst with enhanced enzyme compatibility |
| US7557076B2 (en) | 2002-06-06 | 2009-07-07 | The Procter & Gamble Company | Organic catalyst with enhanced enzyme compatibility |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001016110A1 (en) * | 1999-08-27 | 2001-03-08 | The Procter & Gamble Company | Bleach boosting components, compositions and laundry methods |
| US20010018446A1 (en) | 1999-09-23 | 2001-08-30 | G.D. Searle & Co. | Substituted N-Aliphatic-N-Aromatictertiary-Heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity |
| AU2003278592A1 (en) | 2003-10-16 | 2005-04-27 | Symed Labs Limited | A novel crystalline form of linezolid |
| PL1737850T3 (en) | 2004-04-19 | 2008-02-29 | Symed Labs Ltd | A novel process for the preparation of linezolid and related compounds |
| ATE429423T1 (en) * | 2004-07-20 | 2009-05-15 | Symed Labs Ltd | NEW INTERMEDIATE PRODUCTS FOR LINEZOLID AND RELATED COMPOUNDS |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL31987A0 (en) * | 1968-04-24 | 1969-06-25 | Hoffmann La Roche | Benzodiazocines,their preparation and pharmaceutical composition containing them |
| DE2265371C3 (en) * | 1972-05-03 | 1980-12-11 | Kali-Chemie Ag, 3000 Hannover | N- (3-Benzoylaminopropyl) anilines |
-
1978
- 1978-03-10 DE DE19782810349 patent/DE2810349A1/en not_active Withdrawn
-
1979
- 1979-02-28 DE DE7979100587T patent/DE2962167D1/en not_active Expired
- 1979-02-28 EP EP79100587A patent/EP0004024B1/en not_active Expired
- 1979-03-02 HU HU79KA1520A patent/HU178593B/en unknown
- 1979-03-07 JP JP2570179A patent/JPS54122287A/en active Granted
- 1979-03-09 CA CA323,078A patent/CA1122980A/en not_active Expired
- 1979-03-09 AT AT0179079A patent/AT368138B/en not_active IP Right Cessation
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7109156B1 (en) | 1999-08-27 | 2006-09-19 | Procter & Gamble Company | Controlled availability of formulation components, compositions and laundry methods employing same |
| US6818607B1 (en) | 1999-08-27 | 2004-11-16 | Procter & Gamble Company | Bleach boosting components, compositions and laundry methods |
| US6825160B1 (en) | 1999-08-27 | 2004-11-30 | Procter & Gamble Company | Color safe laundry methods employing cationic formulation components |
| US6887838B2 (en) | 1999-08-27 | 2005-05-03 | Procter & Gamble Company | Bleach boosting components, compositions and laundry methods |
| US6903060B1 (en) | 1999-08-27 | 2005-06-07 | Procter & Gamble Company | Stable formulation components, compositions and laundry methods employing same |
| US6919304B2 (en) | 1999-08-27 | 2005-07-19 | Procter & Gamble Company | Stability enhancing formulation components, compositions and laundry methods employing same |
| US6821935B1 (en) | 1999-08-27 | 2004-11-23 | Procter & Gamble Company | Color safe laundry methods employing zwitterionic formulation components |
| US7557076B2 (en) | 2002-06-06 | 2009-07-07 | The Procter & Gamble Company | Organic catalyst with enhanced enzyme compatibility |
| US7507700B2 (en) | 2002-06-06 | 2009-03-24 | The Procter & Gamble Company | Organic catalyst with enhanced solubility |
| US7169744B2 (en) | 2002-06-06 | 2007-01-30 | Procter & Gamble Company | Organic catalyst with enhanced solubility |
| US7994109B2 (en) | 2002-06-06 | 2011-08-09 | The Procter & Gamble Company | Organic catalyst with enhanced solubility |
| US8021437B2 (en) | 2002-06-06 | 2011-09-20 | The Procter & Gamble Company | Organic catalyst with enhanced enzyme compatiblity |
| US8147563B2 (en) | 2002-06-06 | 2012-04-03 | The Procter & Gamble Company | Organic catalyst with enhanced enzyme compatibility |
| US8246854B2 (en) | 2002-06-06 | 2012-08-21 | The Procter & Gamble Company | Organic catalyst with enhanced solubility |
| US7504371B2 (en) | 2005-06-17 | 2009-03-17 | The Procter & Gamble Company | Organic catalyst with enhanced enzyme compatibility |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS54122287A (en) | 1979-09-21 |
| HU178593B (en) | 1982-05-28 |
| EP0004024A2 (en) | 1979-09-19 |
| EP0004024B1 (en) | 1982-02-24 |
| JPS6344750B2 (en) | 1988-09-06 |
| AT368138B (en) | 1982-09-10 |
| DE2962167D1 (en) | 1982-03-25 |
| ATA179079A (en) | 1982-01-15 |
| EP0004024A3 (en) | 1979-10-17 |
| DE2810349A1 (en) | 1979-09-20 |
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