CA1049514A - Preparation for 1,4-benzodiazepines - Google Patents
Preparation for 1,4-benzodiazepinesInfo
- Publication number
- CA1049514A CA1049514A CA192,533A CA192533A CA1049514A CA 1049514 A CA1049514 A CA 1049514A CA 192533 A CA192533 A CA 192533A CA 1049514 A CA1049514 A CA 1049514A
- Authority
- CA
- Canada
- Prior art keywords
- methyl
- formula
- chlorine
- alkali metal
- reactants
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
- C07D243/28—Preparation including building-up the benzodiazepine skeleton from compounds containing no hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A novel process for producing 1,4-benzodiazepine derivatives of the formula (I), (I) wherein X is halogen, R1 is C1-C5 alkyl, and R2 is C1-C5 alkyl, and their pharmaceutically acceptable salts, which are useful as medicaments. These compounds (I) may be obtained by reacting a compound of the formula (II),
A novel process for producing 1,4-benzodiazepine derivatives of the formula (I), (I) wherein X is halogen, R1 is C1-C5 alkyl, and R2 is C1-C5 alkyl, and their pharmaceutically acceptable salts, which are useful as medicaments. These compounds (I) may be obtained by reacting a compound of the formula (II),
Description
The present invention relates to a process ~or producing 1,4-benzodiazepine dexivatives and their salts. More particularly, the present in~ention relates to a process for producing 1,4-benzodiazepine derivati~es of the formula (I), D~, C = W~ ' ~ ~ 2 X Rl wherein X is a halogen atom, Rl is a Cl-C5 alkyl group and R~ is a Cl-C5 alkyl group and their pharmaceutically acceptable salts.
Examples of the "halogen atom" include chlorine, bro-mine, fluorine and iodine. Examples of Cl-C5 alkyl include methyl, ethyl, propyl and butyl.
The above mentioned compound (I) have been already known as useful medicaments such as sedatives, antispasmodics, muscle-relaxants and sleep inducing agents.
As the result of a study for seeking an advantageous process for producing 1,4-benzodiazepine derivatives (I), the inventors of the present invention have found a novel advantageous process thereof.
Accordingly, the present invention provides an advan-tageous process for producing 1,4-benzodiazepine derivatives (I).
The present invention also provides novel compounds (II) as defined below.
According to the present invention there is provided a process for producing 1,4-benzodiazepine derivatives of the formula (I), ~ N - C (I) X I \\ ~, - . '' , . : . .
5~L~
wherein X, Rl and R2 are a~ defined above, and their salts which comprises reacting a c~mpound of the for~ula (II)I
Il ~
(II) N COfHCONH2 Rl R2 wherein X, Rl and R2 are as defined above, with a halogen or a hypohalogenous acid salt in the presence of a base, and further provides a novel compound of the formula (II) as defined above, which are useful as the intermediate for the preparation of the compound (I~.
According to the invention, the reaction may be carried out preferably in a suitable solvent, for example, an alcohol such as methanol, ethanol, isopropanol, etc. water, chloroform, dioxane, tetrahydrofuran or a mixture thereof. The reaction is preferably carried out under cooling, however it also may be carried out at a boiling point o~ the solvent used.
Preferable examples of the halogen are bromine and chlorine. The said hypohalogenous acid salt may preferably be hypochlorite (for example, potassium hypochlorite, sodium hypo-chlorite) and hypobromite (for example, potassium hypobromite, sodium hypobromite).
The said base includes an alkali metal hydroxide (such ;
as sodium hydroxide; potassium hydroxide, etc) an a~kali metal carbonate (such as sodium carbonate, potassium carbonate, etc) or an alkali metal alcoholate (such as sodium alcoholate, potassium alcoholate).
Thus obtained 1,4-benzodiazepine derivatives may be converted into the acid addition salts thereof by treating with a mineral acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric . ~' ~ :
,., . . . . ., . . : .
- .:
:. :
~09~5~L~
acid, phosphoric acid) or an organic acid (e.g. maleic acid, fumaric acid, succinic acid, formic acid, acetic acid).
The compo~ld (II) may be prepared easily by convention-al methods in the art, for example, the compound ~II) can be obtained by reacting the corresponding 2 amino-benzophenone derivative with the corresponding malonyl halide and then treating the thus obtained malonamyl halide derivative with ammonia.
This reaction may be carried out in the presence or absence of a suitable solventO This reaction may preferably be carried out below room temperature but it is not limitative.
According to the process of the invention, the following 1,4-benzodiazepine derivatives may be obtained.
3-Methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-
Examples of the "halogen atom" include chlorine, bro-mine, fluorine and iodine. Examples of Cl-C5 alkyl include methyl, ethyl, propyl and butyl.
The above mentioned compound (I) have been already known as useful medicaments such as sedatives, antispasmodics, muscle-relaxants and sleep inducing agents.
As the result of a study for seeking an advantageous process for producing 1,4-benzodiazepine derivatives (I), the inventors of the present invention have found a novel advantageous process thereof.
Accordingly, the present invention provides an advan-tageous process for producing 1,4-benzodiazepine derivatives (I).
The present invention also provides novel compounds (II) as defined below.
According to the present invention there is provided a process for producing 1,4-benzodiazepine derivatives of the formula (I), ~ N - C (I) X I \\ ~, - . '' , . : . .
5~L~
wherein X, Rl and R2 are a~ defined above, and their salts which comprises reacting a c~mpound of the for~ula (II)I
Il ~
(II) N COfHCONH2 Rl R2 wherein X, Rl and R2 are as defined above, with a halogen or a hypohalogenous acid salt in the presence of a base, and further provides a novel compound of the formula (II) as defined above, which are useful as the intermediate for the preparation of the compound (I~.
According to the invention, the reaction may be carried out preferably in a suitable solvent, for example, an alcohol such as methanol, ethanol, isopropanol, etc. water, chloroform, dioxane, tetrahydrofuran or a mixture thereof. The reaction is preferably carried out under cooling, however it also may be carried out at a boiling point o~ the solvent used.
Preferable examples of the halogen are bromine and chlorine. The said hypohalogenous acid salt may preferably be hypochlorite (for example, potassium hypochlorite, sodium hypo-chlorite) and hypobromite (for example, potassium hypobromite, sodium hypobromite).
The said base includes an alkali metal hydroxide (such ;
as sodium hydroxide; potassium hydroxide, etc) an a~kali metal carbonate (such as sodium carbonate, potassium carbonate, etc) or an alkali metal alcoholate (such as sodium alcoholate, potassium alcoholate).
Thus obtained 1,4-benzodiazepine derivatives may be converted into the acid addition salts thereof by treating with a mineral acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric . ~' ~ :
,., . . . . ., . . : .
- .:
:. :
~09~5~L~
acid, phosphoric acid) or an organic acid (e.g. maleic acid, fumaric acid, succinic acid, formic acid, acetic acid).
The compo~ld (II) may be prepared easily by convention-al methods in the art, for example, the compound ~II) can be obtained by reacting the corresponding 2 amino-benzophenone derivative with the corresponding malonyl halide and then treating the thus obtained malonamyl halide derivative with ammonia.
This reaction may be carried out in the presence or absence of a suitable solventO This reaction may preferably be carried out below room temperature but it is not limitative.
According to the process of the invention, the following 1,4-benzodiazepine derivatives may be obtained.
3-Methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-
2-one
3-Methyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one 3-Methyl-5-phenyl-7-bromo-1,3-dihydro-2H-1,4-benzodiazepin-2-one 3-Ethyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one 3~Propyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one 3-Butyl-5-phenyl~7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2 one, and 1,3-Dimethyl-5-pheny1-7-chloro-1,3-dihydro-2H-1,4-benzodiaæepin-2-one.
The present invention is illustrated more particularly by the following example, but it is not intended to limit the scope of the present invention.
Example (~) Preparation o~ N-(2-benzoyl-4-chlorophenyl)-2,N-dimethy~malonamide.
.
.. ' , . ' , '~ ' ' , ~ ' . . ' ' ' ' 3LC)4~5 ~
One ~ram of methylmalonyl chloride was added to the solution of 1~ g of 2-methylamino-5-chloro-benzophenone in 20 ml of ether and the mixture was stirred ~or 30 minutes at a room temperature. Then, the yellow color of the reaction mixture turned pale. Ammonia was introduced into the ether solution of the malonamyl chloride derivati~e thus obtained, under cooling.
The precipitated crystals were filtrated off and washed with tetrahydrofuran. The filtrate and the tetrahydrofuran layer were collected and distilled off under reduced pressure.
The resi~ue was treated with ether to give crystals of N-(2-benzoyl-4-chlorophenyl)-2,N-dimethylmalonylamide, m.p. 148 -149C. These crude crystals were recrystallized from a mixture of tetrahydrofuran and ether to give the pure crystals, m.p.
152 - 153~C.
(B) Preparation of 1,3-dimethyl-5-phenyl-7 chloro-1,3-dihydro-2H~1,4-benzodiazepin-2-one.
To a solution of 0,48 g of sodium hydroxide in 4 ml of water was added dropwise 0.38 g of bromine below OC and the ~ -mixture was cooled to -7C. The cooled solution of 0.2 g of N-(2-benzoyl-4-chlorophenyl)2,N-dimethylmalonamide in 4 ml of tetrahydrofuran was added dropwise thereto, while stirring was continued. After addition stirring for one hour at -5 to -3~C, the tetrahydrofuran Iayer was separated and the aqueous layer was extracted with ether.
These collected organic layers were dried over anhydrous sodium sulfate, and distilled off under reduced pressure to give 1,3-dimethyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one. The hydrochloride was obtained by treating it with hydrogen chloride-isopropanol.
IR (Nujal) 1695, 1620, 1595 cm `-1`'~ i , , ~
. ' ' ' . . ' '' '; .
The present invention is illustrated more particularly by the following example, but it is not intended to limit the scope of the present invention.
Example (~) Preparation o~ N-(2-benzoyl-4-chlorophenyl)-2,N-dimethy~malonamide.
.
.. ' , . ' , '~ ' ' , ~ ' . . ' ' ' ' 3LC)4~5 ~
One ~ram of methylmalonyl chloride was added to the solution of 1~ g of 2-methylamino-5-chloro-benzophenone in 20 ml of ether and the mixture was stirred ~or 30 minutes at a room temperature. Then, the yellow color of the reaction mixture turned pale. Ammonia was introduced into the ether solution of the malonamyl chloride derivati~e thus obtained, under cooling.
The precipitated crystals were filtrated off and washed with tetrahydrofuran. The filtrate and the tetrahydrofuran layer were collected and distilled off under reduced pressure.
The resi~ue was treated with ether to give crystals of N-(2-benzoyl-4-chlorophenyl)-2,N-dimethylmalonylamide, m.p. 148 -149C. These crude crystals were recrystallized from a mixture of tetrahydrofuran and ether to give the pure crystals, m.p.
152 - 153~C.
(B) Preparation of 1,3-dimethyl-5-phenyl-7 chloro-1,3-dihydro-2H~1,4-benzodiazepin-2-one.
To a solution of 0,48 g of sodium hydroxide in 4 ml of water was added dropwise 0.38 g of bromine below OC and the ~ -mixture was cooled to -7C. The cooled solution of 0.2 g of N-(2-benzoyl-4-chlorophenyl)2,N-dimethylmalonamide in 4 ml of tetrahydrofuran was added dropwise thereto, while stirring was continued. After addition stirring for one hour at -5 to -3~C, the tetrahydrofuran Iayer was separated and the aqueous layer was extracted with ether.
These collected organic layers were dried over anhydrous sodium sulfate, and distilled off under reduced pressure to give 1,3-dimethyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one. The hydrochloride was obtained by treating it with hydrogen chloride-isopropanol.
IR (Nujal) 1695, 1620, 1595 cm `-1`'~ i , , ~
. ' ' ' . . ' '' '; .
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing 1,4-benzodiazepine derivatives of the formula (I) (I) wherein X is a halogen atom, R1 is a C1-C5 alkyl group, and R2 is a C1-C5 alkyl group, and their pharmaceutically acceptable salts, which comprises reacting a compound of the formula (II), (II) wherein X, Y, R1 and R2 are as defined above, with a halogen or a hypohalic acid salt in the presence of a base in a suitable solvent.
2. A process according to claim 1, wherein the said base is an alkali metal hydroxide, an alkali metal carbonate or an alkali metal alcoholate.
3. A process according to claim 1, wherein the reaction is carried out under cooling.
4. A process according to claim 1, 2 or 3, wherein said solvent is an alcohol, water, chloroform, dioxane, tetra-hydrofuran or a mixture thereof.
5. A process as claimed in claim 1, 2 or 3, in which in the reactants X is chlorine in the 7-position, R2 is methyl, ethyl n-propyl or n-butyl and R1 is methyl.
6. A process as claimed in claim 1, 2 or 3, in which in the reactants R1 is methyl, R2 is methyl and X is chlorine.
7. A process as claimed in claim 1, 2 or 3, in which in the reactants R1 is methyl, R2 is methyl and X is chlorine in the 7-position.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1864673A JPS49102688A (en) | 1973-02-14 | 1973-02-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1049514A true CA1049514A (en) | 1979-02-27 |
Family
ID=11977364
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA192,533A Expired CA1049514A (en) | 1973-02-14 | 1974-02-14 | Preparation for 1,4-benzodiazepines |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS49102688A (en) |
| CA (1) | CA1049514A (en) |
| CH (1) | CH590853A5 (en) |
| DE (1) | DE2407071A1 (en) |
| FR (1) | FR2217334B1 (en) |
| GB (1) | GB1409404A (en) |
| NL (1) | NL7402020A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4820834A (en) * | 1984-06-26 | 1989-04-11 | Merck & Co., Inc. | Benzodiazepine analogs |
-
1973
- 1973-02-14 JP JP1864673A patent/JPS49102688A/ja active Pending
-
1974
- 1974-02-13 FR FR7404881A patent/FR2217334B1/fr not_active Expired
- 1974-02-13 CH CH195574A patent/CH590853A5/xx not_active IP Right Cessation
- 1974-02-14 NL NL7402020A patent/NL7402020A/xx not_active Application Discontinuation
- 1974-02-14 CA CA192,533A patent/CA1049514A/en not_active Expired
- 1974-02-14 GB GB670974A patent/GB1409404A/en not_active Expired
- 1974-02-14 DE DE19742407071 patent/DE2407071A1/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| DE2407071A1 (en) | 1974-08-29 |
| GB1409404A (en) | 1975-10-08 |
| NL7402020A (en) | 1974-08-16 |
| FR2217334B1 (en) | 1977-09-16 |
| FR2217334A1 (en) | 1974-09-06 |
| JPS49102688A (en) | 1974-09-27 |
| CH590853A5 (en) | 1977-08-31 |
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