WO2005021005A2 - Process for the preparation of 1,4-benzodiazepine derivatives - Google Patents

Process for the preparation of 1,4-benzodiazepine derivatives Download PDF

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WO2005021005A2
WO2005021005A2 PCT/IB2004/002775 IB2004002775W WO2005021005A2 WO 2005021005 A2 WO2005021005 A2 WO 2005021005A2 IB 2004002775 W IB2004002775 W IB 2004002775W WO 2005021005 A2 WO2005021005 A2 WO 2005021005A2
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acid
formula
lower alkyl
mixtures
trifluoromethyl
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PCT/IB2004/002775
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WO2005021005A3 (en
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Yatendra Kumar
Chandra Has Khanduri
Mukesh Kumar Sharma
Atulya Kumar Panda
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Ranbaxy Laboratories Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • 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

Definitions

  • the field of the invention relates to a process for the preparation of 1,4- benzodiazepine derivatives. It also relates to pharmaceutical compositions that include the 1,4-benzodiazepine derivatives. Background of the Invention 1,4 benzodiazepine derivatives such as clorazepate are useful for the treatment of anxiety disorders. Several processes have been reported for the preparation of 1,4 benzodiazepine derivatives, including 7-chloro-2,3-dihydro-2-oxo-5-phenyl-lH-l,4- benzodiazepine-3-carboxylic acid i.e.
  • U.S. Patent Nos. 3,516,988; 3,657,223; 4,051,127; GB 1117200, EP 22710; and ES 428622 discloses aprocess for the preparation of 1,4 benzodiazepine derivatives including ethyl clorazepate, comprising reacting an ortho-aminoarylketimine with anhydrous lower aliphatic acid or mineral acid. J. Org. Chem.
  • R represents hydrogen, alkyl of C1-C 5 , aryl or arylalkyl
  • R 1 represents hydrogen, halogen, trifluoromethyl, lower alkyl (C ⁇ -C 4 ), lower alkoxy(C 1 -C 4 ), nitro or amino groups
  • R 2 represents furyl, thienyl, cyclohexyl, lower alkyl ( -C ) or phenyl, which may be substituted by halogen atom, trifluoromethyl, nitro, lower alkyl (C ⁇ -C 4 ) or lower alkoxy (C ⁇ -C 4 ) groups.
  • the process includes reacting an oxime of formula II,
  • R, R 1 andR 2 are as defined above, with sodium nitrite in the presence of a strong inorganic acid.
  • a pharmaceutical composition that includes a therapeutically effective amount of a 1,4-benzodiazepine derivative; and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • R represents hydrogen, alkyl of C1-C 5 , aryl or arylalkyl
  • R 1 represents hydrogen, halogen, trifluoromethyl, lower alkyl(Ci-C 4 ), lower alkoxy(CrC 4 ), nitro or amino groups
  • R 2 represents furyl, thienyl, cyclohexyl, lower alkyl (CrC 4 ) or phenyl, which may be substituted by halogen atom, trifluoromethyl, nitro, lower alkyl (C1-C 4 ) or lower alkoxy (C ⁇ -C 4 ) groups.
  • the process involves reacting an oxime of formula II, with a reducing agent, in the presence of an acid catalyst, wherein R, R and R are as defined above.
  • halogen includes fluorine, chlorine, bromine, and iodine.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, and tert-butyl groups.
  • R represents methyl or ethyl
  • R 1 represents chlorine
  • R 2 represents phenyl in the compounds of formula I and II.
  • the reducing agents which can be used for the preparation of compounds of formula I include metal/acids and hydrogenation catalysts.
  • transition metals such as Zn, Fe, and Sn used with acid such as hydrochloric acid, acetic acid and formic acid may be employed as the metal/acid reducing agents.
  • hydrogenation catalysts include transition metals or compounds thereof such as Raney nickel and rhodium complexes used in the presence of hydrogen. The reduction may be carried out at normal pressure, or at elevated pressure depending on the choice of catalyst. In particular, it may be carried out at a hydrogen pressure of from about 1-7 Kg/cm 2 .
  • acid catalysts include organic and inorganic acids, for example, carboxylic acids such as formic acid, acetic acid and propionic acid and inorganic acids such as hydrochloric acid, hydrobromic acid and mixtures thereof.
  • the acid used in the metal/acid combination as the reducing agent may also be used as acid catalysts.
  • the reaction of compound of formula II to obtain the compound of formula I may be carried out in the presence of a suitable solvent. Suitable solvents for the reaction are inert organic solvents that do not change under the reaction conditions.
  • solvents examples include ethers such as diethylether, diisopropylether and dimethoxyethane; alcohols such as methanol, ethanol, isopropanol and butanol; ketones such as acetone and methyl isobutyl ketone; nitriles such as acetonitrile; chlorinated hydrocarbons such as methylene chloride, ethylene dichloride and carbon tetrachloride; esters such as ethylacetate and isopropylacetate; dipolar aprotic solvents such as dimethylsulfoxide and dimethylformamide; cyclic ethers such as dioxane and tetrahydrofuran; and mixtures thereof.
  • ethers such as diethylether, diisopropylether and dimethoxyethane
  • alcohols such as methanol, ethanol, isopropanol and butanol
  • ketones such as acetone and methyl isobutyl
  • the acid catalysts used in the process may also be used as a solvent.
  • the reaction may be carried out at a temperature range from about 35°C to about 75°C. In particular, it may be carried out at a temperature range from about 45°C to about 65°C.
  • the reaction mixture may be stirred from about 3 to 5 hours depending on the temperature.
  • the compounds of formula I may be converted to compounds of formula IV, wherein M represents an alkali metal; R 1 represents hydrogen, halogen, trifluoromethyl, lower alkyl (C 1 -C 4 ), lower alkoxy(C-
  • alkali metal examples include lithium, sodium and potassium.
  • alkali metal examples include lithium, sodium and potassium.
  • examples of alcohol include methanol, ethanol, isoprapanol, butanol, and mixtures thereof.
  • the inventors have also developed a process for the preparation of compound of formula II, wherein R represents hydrogen, alkyl of C1 .
  • R 1 represents hydrogen, halogen, trifluoromethyl, lower alkyl(C ⁇ -C 4 ), lower alkoxy(C-
  • R 2 represents furyl, thienyl, cyclohexyl, lower alkyl (C 1 -C 4 ) or phenyl, which may be substituted by halogen atom, trifluoromethyl, nitro, lower alkyl (C 1 -C 4 ) or lower alkoxy(C ⁇ -C 4 ) group.
  • the process involves nitrosating an amide of formula III, with sodium nitrite in the presence of a strong inorganic acid.
  • Examples of inorganic acids which can be used in nitrosation of the compound of formula III to obtain the compound of formula II include hydrochloric acid, hydrobromic acid, hy ⁇ rogenthiocyanide, and mixtures thereof.
  • the nitrosation reaction to obtain the oxime of formula II is faster in the presence of a strong acid and side reactions or decomposition of the product are minimized.
  • the reaction was found to equilibrate and not go to completion in the presence of a weak acid such as acetic acid.
  • the nitrosation reaction may be carried out in the presence of a suitable solvent. Suitable solvents for the reaction are inert solvents that do not change under the reaction conditions.
  • solvents examples include ethers such as dimethoxyethane, dioxane and tetrahydrofuran; alcohols such as methanol, ethanol, isopropanol and butanol; chlorinated hydrocarbons such as methylene dichloride and ethylenedichloride; esters such as ethylacetate and isopropylacetate; dipolar aprotic solvents such as dimethylsulfoxide and dimethylformamide; water, and mixtures thereof.
  • the compounds of formula III can be prepared by conventional procedures such as those reported in J Org. Chem. 1973, 38, 449-456.
  • the present invention is further illustrated by the following examples which are provided to be exemplary of the inventions and is not intended to limit the scope of the invention.
  • Example 2 Preparation of ethyl 2 ' -benzoyl-4-chloromesoxanilate
  • a solution of sodium nitrite (228.6g) in water (420 ml) was added slowly to a vigorously stirred suspension of ethyl 2' benzoyl-4-chloromalonanilate (140g) in denatured spirit (1400ml) and concentrated hydrochloric acid (700ml). After stirring for 2 hours, the product was isolated by cooling and filtration, and washed with water to remove salts. The wet material was washed with toluene (980 ml) and dried to yield 123g of the title compound.

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Abstract

The field of the invention relates to a process for the preparation of 1,4-benzodiazepine derivatives. It also relates to pharmaceutical compositions that include the 1,4- benzodiazepine derivatives.

Description

PROCESS FOR THE PREPARATION OF 1, 4- BENZODIAZEPINE DERIVATIVES Field of the Invention The field of the invention relates to a process for the preparation of 1,4- benzodiazepine derivatives. It also relates to pharmaceutical compositions that include the 1,4-benzodiazepine derivatives. Background of the Invention 1,4 benzodiazepine derivatives such as clorazepate are useful for the treatment of anxiety disorders. Several processes have been reported for the preparation of 1,4 benzodiazepine derivatives, including 7-chloro-2,3-dihydro-2-oxo-5-phenyl-lH-l,4- benzodiazepine-3-carboxylic acid i.e. clorazepate, for example, in U.S. Patent Nos. 3,516,988; 3,657,223; 4,051,127; GB 1117200, EP 22710; and ES 428622. U.S. Patent No. 3,516,988 discloses aprocess for the preparation of 1,4 benzodiazepine derivatives including ethyl clorazepate, comprising reacting an ortho-aminoarylketimine with anhydrous lower aliphatic acid or mineral acid. J. Org. Chem. 1973, 38, 449-456 describes the synthesis of ethyl clorazepate by reducing ethyl 2'-benzoyl-4- chloromesoxalanilate-2-oxime with zinc dust and acetic acid and further refluxing the residue, obtained after workup, in benzene in the presence of acetic acid to obtain ethyl clorazepate. It further discloses the synthesis of ethyl 2'-benzoyl-4-chloromesoxalanilate- 2-oxime by nitrosating ethyl 2'-benzoyl
4-chloromalonilate with sodium nitrite in acetic acid. Summary of the Invention In one general aspect there is provided a process for preparing 1,4 benzodiazepine derivatives of formula I in a single step,
Figure imgf000002_0001
Formula I wherein R represents hydrogen, alkyl of C1-C5, aryl or arylalkyl; R1 represents hydrogen, halogen, trifluoromethyl, lower alkyl (Cι-C4), lower alkoxy(C1-C4), nitro or amino groups; and R2 represents furyl, thienyl, cyclohexyl, lower alkyl ( -C ) or phenyl, which may be substituted by halogen atom, trifluoromethyl, nitro, lower alkyl (Cι-C4) or lower alkoxy (Cι-C4) groups. The process includes reacting an oxime of formula II,
Figure imgf000003_0001
wherein R, R1 and R2 are as defined above, with a reducing agent, in the presence of an acid catalyst at a temperature. Thus the reduction of the oxime of formula II, and cyclization to get the compound of formula I are achieved simultaneously in a single step. In another general aspect there is provided a process for preparing the compound of formula II. The process includes nitrosation of an amide of formula III,
Figure imgf000003_0002
wherein R, R1 andR2 are as defined above, with sodium nitrite in the presence of a strong inorganic acid. In another general aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of a 1,4-benzodiazepine derivative; and one or more pharmaceutically acceptable carriers, excipients or diluents. The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims. Detailed Description of the Invention The inventors have developed an efficient process for the preparation of 1,4- benzodiazepine derivatives of formula I in a single step, wherein R represents hydrogen, alkyl of C1-C5, aryl or arylalkyl; R1 represents hydrogen, halogen, trifluoromethyl, lower alkyl(Ci-C4), lower alkoxy(CrC4), nitro or amino groups; and R2 represents furyl, thienyl, cyclohexyl, lower alkyl (CrC4) or phenyl, which may be substituted by halogen atom, trifluoromethyl, nitro, lower alkyl (C1-C4) or lower alkoxy (Cι-C4) groups. The process involves reacting an oxime of formula II, with a reducing agent, in the presence of an acid catalyst, wherein R, R and R are as defined above. The term "halogen" includes fluorine, chlorine, bromine, and iodine. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, and tert-butyl groups. In some particular examples, R represents methyl or ethyl, R1 represents chlorine and R2 represents phenyl in the compounds of formula I and II. The reducing agents which can be used for the preparation of compounds of formula I include metal/acids and hydrogenation catalysts. For example, transition metals such as Zn, Fe, and Sn used with acid such as hydrochloric acid, acetic acid and formic acid may be employed as the metal/acid reducing agents. Examples of hydrogenation catalysts include transition metals or compounds thereof such as Raney nickel and rhodium complexes used in the presence of hydrogen. The reduction may be carried out at normal pressure, or at elevated pressure depending on the choice of catalyst. In particular, it may be carried out at a hydrogen pressure of from about 1-7 Kg/cm2. Examples of acid catalysts include organic and inorganic acids, for example, carboxylic acids such as formic acid, acetic acid and propionic acid and inorganic acids such as hydrochloric acid, hydrobromic acid and mixtures thereof. The acid used in the metal/acid combination as the reducing agent may also be used as acid catalysts. The reaction of compound of formula II to obtain the compound of formula I may be carried out in the presence of a suitable solvent. Suitable solvents for the reaction are inert organic solvents that do not change under the reaction conditions. Examples of such solvents include ethers such as diethylether, diisopropylether and dimethoxyethane; alcohols such as methanol, ethanol, isopropanol and butanol; ketones such as acetone and methyl isobutyl ketone; nitriles such as acetonitrile; chlorinated hydrocarbons such as methylene chloride, ethylene dichloride and carbon tetrachloride; esters such as ethylacetate and isopropylacetate; dipolar aprotic solvents such as dimethylsulfoxide and dimethylformamide; cyclic ethers such as dioxane and tetrahydrofuran; and mixtures thereof. The acid catalysts used in the process may also be used as a solvent. The reaction may be carried out at a temperature range from about 35°C to about 75°C. In particular, it may be carried out at a temperature range from about 45°C to about 65°C. The reaction mixture may be stirred from about 3 to 5 hours depending on the temperature. The compounds of formula I may be converted to compounds of formula IV, wherein M represents an alkali metal; R1 represents hydrogen, halogen, trifluoromethyl, lower alkyl (C1-C4), lower alkoxy(C-|-C4), nitro or amino groups; and R2 represents furyl, thienyl, cyclohexyl, lower alkyl (C1-C4) or phenyl, which may be substituted by halogen atom, trifluoromethyl, nitro, lower alkyl (C1-C4) or lower alkoxy (C1-C4) groups, by method known in the art such as reacting compounds of formula I with alkali metal hydroxides in the presence of an alcohol. Examples of alkali metal include lithium, sodium and potassium. Examples of alcohol include methanol, ethanol, isoprapanol, butanol, and mixtures thereof. The inventors have also developed a process for the preparation of compound of formula II, wherein R represents hydrogen, alkyl of C1.-C5, aryl or arylalkyl; R1 represents hydrogen, halogen, trifluoromethyl, lower alkyl(Cι-C4), lower alkoxy(C-|-C4), nitro or amino group; and R2 represents furyl, thienyl, cyclohexyl, lower alkyl (C1-C4) or phenyl, which may be substituted by halogen atom, trifluoromethyl, nitro, lower alkyl (C1-C4) or lower alkoxy(Cι-C4) group. The process involves nitrosating an amide of formula III, with sodium nitrite in the presence of a strong inorganic acid. Examples of inorganic acids which can be used in nitrosation of the compound of formula III to obtain the compound of formula II include hydrochloric acid, hydrobromic acid, hyάrogenthiocyanide, and mixtures thereof. The nitrosation reaction to obtain the oxime of formula II is faster in the presence of a strong acid and side reactions or decomposition of the product are minimized. The reaction was found to equilibrate and not go to completion in the presence of a weak acid such as acetic acid. The nitrosation reaction may be carried out in the presence of a suitable solvent. Suitable solvents for the reaction are inert solvents that do not change under the reaction conditions. Examples of such solvents include ethers such as dimethoxyethane, dioxane and tetrahydrofuran; alcohols such as methanol, ethanol, isopropanol and butanol; chlorinated hydrocarbons such as methylene dichloride and ethylenedichloride; esters such as ethylacetate and isopropylacetate; dipolar aprotic solvents such as dimethylsulfoxide and dimethylformamide; water, and mixtures thereof. The compounds of formula III can be prepared by conventional procedures such as those reported in J Org. Chem. 1973, 38, 449-456. The present invention is further illustrated by the following examples which are provided to be exemplary of the inventions and is not intended to limit the scope of the invention. Example 1
Preparation of methyl 2'-benzoyl-4-chloromesoxanilate
A solution of sodium nitrite (238g) in water (420 ml) was added slowly to a vigorously stirred suspension of methyl 2' benzoyl-4-chloromalonanilate (140g) in denatured spirit (1400ml) and concentrated hydrochloric acid (700ml). After stirring for 2 hours, the product was isolated by cooling and filtration, and washed with water to remove salts. The wet material was washed with toluene (980 ml) and dried to obtain 126g of the title compound.
(HPLC Purity = 99.31%)
Example 2 Preparation of ethyl 2 ' -benzoyl-4-chloromesoxanilate A solution of sodium nitrite (228.6g) in water (420 ml) was added slowly to a vigorously stirred suspension of ethyl 2' benzoyl-4-chloromalonanilate (140g) in denatured spirit (1400ml) and concentrated hydrochloric acid (700ml). After stirring for 2 hours, the product was isolated by cooling and filtration, and washed with water to remove salts. The wet material was washed with toluene (980 ml) and dried to yield 123g of the title compound.
(HPLC Purity = 99.69%) Example 3 Preparation of methyl ester of clorazepate To acetic acid (1300 ml) were added methyl 2'-benzoyl-4'-chloromesoxalanilate (175g) and activated Raney Nickel (93g) and stirred. Hydrogen pressure (5.0 kg/cm2) was then applied to the reaction mixture and heated to 53 °C. The reaction was continued for 3 to 5 hours at 2 to 5 Kg/cm2. After the reaction was over, the reaction mixture was filtered and acetic acid was recovered (about 70%) to give a concentrate. The title product was isolated by cooling the concentrate and filtration of the precipitate obtained. The precipitate so obtained was then washed with water and dried to get 125 g of the product. (HPLC Purity = 99.26%) Example 4 Preparation of ethyl clorazepate To acetic acid (1300 ml) was added ethyl 2'-benzoyl-4'-chloromesoxalanilate (175g) and activated Raney Nickel (93g) and stirred. Hydrogen pressure (5.0 kg/cm2) was then applied to it and heated to 62 °C. The reaction was continued for 3 to 5 hours at 2 to 5 Kg/cm2. After the reaction was over, the reaction mixture was filtered and the solvent was recovered (about 70%) to give a concentrate. The product was isolated by cooling the concentrate and filtration of the precipitate obtained. The precipitate so obtained was then washed with water and dried to get 118.5g of the product. (HPLC Purity = 99.22%). While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

WE CLAIM.
1. A process for the preparation of 1 ,4 benzodiazepine derivative of formula I in a single step,
Figure imgf000008_0001
Formula I herein R represents hydrogen, alkyl of C1-C5, aryl or arylallcyl; R1 represents hydrogen, halogen, trifluoromethyl, lower alkyl (C1-C4), lower allcoxy(C1-C4), nitro or amino group; and R2 represents furyl, thienyl, cyclohexyl, lower alkyl(Cι -C ) or phenyl, which may be substituted by halogen atom, trifluoromethyl, nitro, lower alkyl(Ci-C4) or lower alkoxy(Cι-C ) group, the process comprising reacting an oxime of formula II,
Figure imgf000008_0002
Formula II wherein R, Rl andR2 are as defined above, with a reducing agent, in the presence of an acid catalyst.
2. The process of claim 1, wherein R represents methyl or ethyl, R1 represents chlorine and R2 represents phenyl.
3. The process of claim 1, wherein the reducing agent comprises one or more of metal/acids and hydrogenation catalysts.
4. The process of claim 3, wherein the metal is a transition metal.
5. The process of claim 4, wherein the transition metal comprises one or more of Zn, Fe, and Sn.
6. The process of claim 3, wherein the acid comprises one or more of hydrochloric acid, acetic acid and formic acid.
7. The process of claim 3, wherein the hydrogenation catalyst comprises one or more of Raney nickel and rhodium complexes.
8. The process of claim 1 , wherein the reaction is carried out in the presence of a hydrogen gas.
9. The process of claim 8, wherein the pressure of hydrogen gas ranges from about 1.0 to about 7.0 kg/cm .
10. The process of claim 1 , wherein the reaction is carried out in the presence of a suitable solvent.
11. The process of claim 10, wherein the solvent comprises one or more of alcohols, ethers, chlorinated hydrocarbons, esters, cyclic ethers, ketones, nitriles, dipolar aprotic solvents and mixtures thereof.
12. The process of claim 11, wherein the alcohol comprises one or more of methanol, ethanol, isoprapanol, butanol, and mixtures thereof.
13. The process of claim 11, wherein the ether comprises one or more of diethylether, diisopropylether, and dimethoxyethane.
14. The process of claim 11, wherein the chlorinated hydrocarbon comprises one or more of methylene chloride, ethylene dichloride, and carbon tetrachloride.
15. The process of claim 11 , wherein the esters comprises one or more of ethylacetate and isopropylacetate.
16. The process of claim 11, wherein the cyclic ethers comprises one or more of dioxane and tetrahydrofuran.
17. The process of claim 11 , wherein the ketone comprises one or more of acetone and methylisobutyl ketone.
18. The process of claim 11 , wherein the nitrile is acetonitrile.
19. The process of claim 11, wherein the dipolar aprotic solvents comprises one or more of dimethylformamide and dimethylsulfoxide.
20. The process of claim 1, wherein the acid catalyst comprises one or more of organic acids and inorganic acids.
21. The process of claim 20, wherein the organic acid comprises one or more of acetic acid, formic acid, propionic acid, and mixtures thereof.
22. The process of claim 20, wherein the inorganic acid comprises one or more of hydrochloric acid, hydrobromic acid, and mixtures thereof.
23. The process of claim 1, wherein the reaction is carried out at a temperature from about 35°C to about 75°C.
24. The process of claim 23, wherein the reaction is carried out a temperature from about 45°C to about 65°C.
25. The process of claim 1 further comprising converting the compound of Formula I to a salt of Formula IV,
Figure imgf000010_0001
Formula IV wherein M represents an alkali metal acid; R1 represents hydrogen, halogen, trifluoromethyl, lower alkyl(C1-C4), lower alkoxy(CrC ), nitro or amino group; and R2 represents furyl, thienyl, cyclohexyl, lower alkyl(Cι -C4) or phenyl, which may be substituted by halogen atom, trifluoromethyl, nitro, lower alkyl(Cι-C4) or lower alkoxy (Cι-C ) group.
26. The process for preparation of compound of formula II,
Figure imgf000011_0001
wherein R represents hydrogen, alkyl of Cι-C5, aryl or arylalkyl; R1 represents hydrogen, halogen, trifluoromethyl, lower alkyl (C1-C4), lower alkoxy(C-|-C4), nitro or amino group; and R2 represents furyl, thienyl, cyclohexyl, lower alkyl(C-|-C4) or phenyl, which may be substituted by halogen atom, trifluoromethyl, nitro, lower alkyl (C1-C4) or lower alkoxy(Cι-C4) group, the process comprising nitrosating an amide of formula III,
Figure imgf000011_0002
Formula III wherein R, R1 andR2 are as defined above, with sodium nitrite in the presence of a strong inorganic acid.
27. The process of claim 25, wherein the inorganic acid comprises one or more of hydrochloric acid, hydrobromic acid, hydro genthiocyanide, and mixtures thereof.
28. The process of claim 25, wherein the reaction is carried out in the presence of a solvent.
29. The process of claim 27, wherein the solvent comprises one or more of alcohols, ethers, chlorinated hydrocarbons, esters, dipolar aprotic solvents, water, and mixtures thereof.
30. The process of claim 28, wherein the alcohol comprises one or more of methanol, ethanol, isoprapanol, butanol, and mixtures thereof.
31. The process of claim 28, wherein the ether comprises one or more of dimethoxyethane, dioxane, and tetrahydrofuran.
32. The process of claim 28, wherein the chlorinated hydrocarbon comprises one or more of methylene dichloride and ethylene dichloride.
33. The process of claim 28, wherein the ester comprises one or more of ethylacetate and isopropylacetate.
34. The process of claim 28, wherein the dipolar aprotic solvent comprises one or more of dimethylsulfoxide and dimethylformamide.
35. A pharmaceutical composition comprising a therapeutically effective amount of 1,4-benzodiazepine derivative obtained by the process of claim 1; and one or more pharmaceutically acceptable carriers, excipients or diluents.
PCT/IB2004/002775 2003-08-28 2004-08-27 Process for the preparation of 1,4-benzodiazepine derivatives WO2005021005A2 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3405123A (en) * 1965-02-08 1968-10-08 Hoffmann La Roche Process for preparing 1, 4-benzodiazepin-2-ones

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3405123A (en) * 1965-02-08 1968-10-08 Hoffmann La Roche Process for preparing 1, 4-benzodiazepin-2-ones

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* Cited by examiner, † Cited by third party
Title
WALSER A ET AL: "CYCLIZATION PRODUCTS DERIVED FROM O-BENZOYL MALONANILATES" JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 38, no. 3, 1973, pages 449-456, XP001026819 ISSN: 0022-3263 *

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