FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The patent Rules, 2003
COMPLETE SPECIFICATION
A Process for the preparation of Midazolam
SeQuent Scientific Limited
A Company Incorporated Under The Companies Act, 1956
Having Registered Office at
116 Vardhman Industrial Complex, L.B.S Marg,
Thane (W), Mumbai - 400601, India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:

Field of Invention
The present invention relates to a novel process for the preparation of Midazolam, an anaesthetic drug.
Background of the Invention
Midazolam hydrochloride is a short-acting benzodiazepine central nervous system depressant and a benzodiazepine anxiolytic. It is prescribed for preoperative sedation and impairment of memory of preoperative events and for conscious sedation before short diagnostic endoscopic or dental procedures. Midazolam has anxiolytic, hypnotic, anticonvulsant, muscle relaxant, and anterograde amnestic effects, which are characteristic of benzodiazepines.
Midazolam is a benzodiazepine available as midazolam HC1 syrup for oral administration. Midazolam HC1 syrup has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. Midazolam HC1 syrup has been associated with reports of respiratory depression, airway obstruction, desaturation, hypoxia, and apnea, most often when used concomitantly with other central nervous system depressants.
Midazolam is sold under the trade names "Dormicum", "Hypnovel" and "Versed". The chemical name of midazolam is 8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo[l,5a] [1,4] benzodiazepine represented by formula I,


There are few process reported for the preparation of this compound. Belgian Patent 839364 describes the pharmaceutical utilities of imidazobenzodiazepines as sedatives, anxiolytics, muscle relaxants and anti-convulsant.
German Patent 2540522 describes a process for the preparation of midazolam which comprises the treatment of the corresponding benzodiazepinone derivative with methylamine and titanium tetrachloride, followed by nitrosation and reaction with nitromethane to get the corresponding nitromethylene derivative. This compound is reduced with Raney Nickel and reacted with triethyl orthoacetate to get dihydro midazolam, which on dehydrogenation with manganese dioxide gives midazolam.
US patent 4194049 describes a process for the preparation of midazolam. The process comprises the preparation of midazolam by the deprotection of the corresponding imidazobenzodiazepine phthalimide derivative. This intermediate is produced by a multistep process starting from 4-chloro-2-[(2-flurorophenyl)methyl]benzenamine.
US patent 4226771 describes a process for the preparation of midazolam. The process comprises the cyclization of the corresponding 2-carboxaldoxime derivative with acetaldehyde to give midazolam. The carboxaldoxime intermediate is produced in a five-step process starting from 2-amino-5-chloro-2'-fluorobenzophenone.
The said conventional processes for the preparation of midazolam involve tedious and complex chemistry, result in low yields, require time consuming cumbersome chromatographic separations and are consequently uneconomical for the preparation of midazolam on a commercial scale.
US patent 5792874 describes a process for the preparation of midazolam. The
process comprises treating 4-chloro-l-[2{2-(2-fluorophenyl)-l,3-dithiolan-2-yl}phenyl]-
2-methyl-lH-imidazole-5-carboxaldehyde (hereinafter aldehyde compound) with
hydroxylamine hydrochloride to form l-[4-chloro-2{2-(2-fluorophenyl)l,3-dithiolan-2-
yl}phenyl]-2-methyl-l]-lH-imidazole-5-carboxaldoxime (hereinafter aldoxime
compound). Reacting the carboxaldoxime with ammonium acetate, sodium cyanoborohydride and titanium trichloride in methanol to form l-(l-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyl}-2-methyl-lH-imidazol-5-yl)methanamine

(hereinafter amine compound). Treating the obtained imidazole compound with eeriC
ammonium nitrate in acetonitrile forms midazolam. The main drawback of this process is
that l-(l-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyl}-2-methyl-lH-
imidazol-5-yl)methanamine is prepared in two steps from 4-chloro-l-[2{2-(2-fluorophenyl)-l,3-dithiolan-2-yl}phenyl]-2-methyl-1H-imidazole-5-carboxaldehyde. The aldehyde compound is converted to aldoxime, which is reduced further to get amine compound. Moreover, sodium cynoborohydride and titanium trichloride is used to reduce aldoxime compound to amine compound, which are very toxic and expensive. Apart from that due to highly acidic nature of titanium trichloride, a lot of effluent is generated, which is not environment friendly. Further, eeric ammonium nitrate is used for the treatment of imidazole intermediate to obtain midazolam which is costly.
Thus it is highly desirable to develop a process which overcomes most of the drawbacks of the prior art. The present inventors have developed a very cost effective process which forms amine compound in single step from aldehyde compound and avoids the use of costlier reagents sodium cyanoborohydride and eerie ammonium nitrate.
Summary of the invention
The principal aspect of the present invention is to provide a process for the preparation of l-(l-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyl}-2-methyl-lH-imidazol-5-yl)methanamine of formula II which comprises reductive amination of 1-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyI}-5-methyl-lH-imidazole-5-carboxaldehyde of formula III using a reducing agent and ammonia in an alcoholic solvent to obtain l-(l-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyl}-2-methyl-lH-imidazol-5-yl)methanamine of formula II.
The present invention can be illustrated by the below reaction scheme:


In another aspect of the present invention is to provide a process for the preparation of 8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo[l,5a] [1,4] benzodiazepine of formula I which comprises deprotecting and cyclizing the obtained 1-(}-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithio]an-2-yl]phenyI}-2-methyI-liy-imidazoL-5-yl)methanamine of formula II using a reagent and in presence of a solvent to form 8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo[l,5a] [1,4] benzodiazepine of formula I.
The present invention can be illustrated by the below reaction scheme:

Detail Description of the Invention
Accordingly in an embodiment of the invention, the reductive amination of l-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyl}-5-methyl-lH-imidazole-5-carboxaldehyde of formula III is carried out using a reducing agent selected from lithium aluminium hydride, sodium borohydride, sodium triacetoxy borohydride etc. preferably sodium borohydride and ammonia in an alcoholic solvent selected from methanol,

ethanol, propanol, butanol, isopropanol and the like, preferably methanol to obtain 1-(1-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyl}-2-methyl-lH-imidazol-5-yl)methanamine of formula II. The reaction is carried out at reflux temperature in the range of about 30-70°C, preferably at 40-60 °C.
In another embodiment of the invention, the deprotection and cyclization of 1-(1-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyl}-2-methyl-lH-imidazoI-5-yl)methanamine of formula II is carried out using a reagent selected from ferric chloride, aluminium chloride, manganese dioxide and mixtures thereof, preferably ferric chloride, aluminium chloride and manganese dioxide in presence of a solvent selected from dichloromethane, acetone, acetonitrile, dimethyl formamide, dimethyl sulphoxide, dimethyl acetamide, preferably acetonitrile to form 8-chloro-6-(2-fiuorophenyi)-l-methyl-4H-imidazo[l,5a] [1,4] benzodiazepine of formula I.
In another embodiment, some of the key advantages of the present invention are as below:
1. The process of the present invention provides l-(l-{4-chLoro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyl}-2-methyl-lH-imidazol-5-yl)methanamine in single step by reductive amination of l-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyI}-5-methyl-lH-imidazole-5-carboxaldehyde whereas the state-of-the-art process involves two steps to obtain the above compound.
2. The process of the present invention doesn't use the toxic and costlier reagent sodiumcyanoborohydride instead uses cheap sodium borohydride.
3. The process of the present invention involves the deprotection and cyclization of l-(l-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyl}-2-methyl-l//-imidazol-5-yl)methanamine, which is carried out in presence of reagent ferric chloride, manganese dioxide and aluminium chloride instead of costlier eerie ammonium nitrate.
4. The process of the present invention doesn't use acidic titanium trichloride. This reduces the quantity of effluent significantly, to make the process easy and environment friendly.

The present invention can be illustrated by the following examples, which are not to limit the scope of invention.
Example 1: Preparation of 8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo[l,5a] [1,4] benzodiazepine:
(a) Procedure for the preparation of l-(l-{4-chloro-2-[2-(2-fluorophenyl)-l,3-
dithiolan-2-yl]phenyl}-2-methyl-lH-imidazol-5-yl)methanamine
l-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyl}-2-methyl-lH-imidazole-5-carboxaIdehyde and methanol were charged in the ratio of 1:5 in an autoclave. The reaction mass was saturated with ammonia, heated to 50°C and maintained for 2-3hrs. The reaction mass was transferred to RBF, cooled to 10-15°C, 0.5eq of sodium borohydride in 4 volume of methanol was added in 30 minutes. The reaction mass was then stirred for 30 minutes, after completion of reaction, the reaction mass was concentrated to residue and water was added. Solid was filtered and dried at 50°C under vacuum to yield l-(l-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyl}-2-methyl-lH-imidazol-5-yl)methanamine. Yield: 88% Purity: >96%
(b) Procedure for the preparation of 8-chIoro-6-(2-fluorophenyI)-l-methyI-4H-
imidazo[l,5a] [1,4] benzodiazepine (midazolam)
l-(l-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyl}-2-methyl-lH-imidazol-5-yl)methanamine(5.4g) and of acetonitrile(54 mL) were charged into a RBF. Ferric chloride (3.9g), Mn02 (6.197g) and of aluminum chloride (3.2g) were added to the above reaction mass, stirred for 20-24 hrs until the reaction completion. After the completion of reaction, reaction mass was quenched to water, pH was adjusted to 8 using aqueous ammonia. The product was extracted into ethyl acetate. The ethyl acetate layer was washed with \0% brine solution and dried over anhydrous sodium sulphate. The residue was recrystallized using ethyl acetate to give pure Midazolam. Yield: 56% Purity: 99.9 %

We claim:
1. A process for the preparation of l-(l-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyl}-2-methyl-lH-imidazol-5-yl)methanamine of formula II

which comprises reductive amination of l-{4-chloro-2-[2-(2-fiuorophenyl)-l,3-dithiolan-2-yl]phenyl}-5-methyl-lH-imidazole-5-carboxaldehyde of formula III

using a reducing agent and ammonia in an alcoholic solvent to obtain l-(l-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyl}-2-methyl-lH-imidazol-5-y1)methanamine of formula II.
2. A process according to claim 1, wherein the reducing agent is selected from the group consisting of lithium aluminium hydride, triacetoxy sodium borohydride or sodium borohydride.
3. A process according to claim 1, wherein the reducing agent is sodium borohydride


4. A process for preparation of 8-chloro-(2-fiuorophenyI)-l-methyl-4H-imidazo[I,5a] [1,4] benzodiazepine of formula 1 which comprises;
I
a) Reductive amination of l-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-
yI]phenyI}-5-methyl-lH-imidazole-5-carboxaldehyde of formula III using a reducing agent and ammonia in an alcoholic solvent to obtain l-(l-{4-chIoro-2-[2-(2-fluorophenyl)-1,3-dithioIan-2-yl]phenyl}-2 -methyl- 1H-imidazol-5-yl)methanamine of formula II; and
b) Deprotection and cyclisation of l-(l-{4-chloro-2-[2-(2-fluorophenyl)-l,3-
dithiolan-2-yl]phenyl}-2-methyl-lH-imidazol-5-yl)methanamine of formula
II using a reagent and in presence of a solvent to obtain 8-chloro-6-(2-
fluorophenyl)-l-methyl-4H-imidazo[l,5a] [1,4] benzodiazepine of formula I
5. A process according to claim 4, wherein alcoholic solvent is selected from methanol, ethanol, propanol, butanol or isopropanol.
6. A process according to claim 4, wherein the reducing agent is selected from the group consisting of lithium aluminium hydride, triacetoxy sodium borohydride or sodium borohydride.
7. A process according to claim 4, wherein the reducing agent is sodium borohydride
8. A process according to claim 4, wherein the reagent for cyclization in step b) is ferric chloride, alluminium chloride and manganese dioxide.

9. A process according to claim 4, wherein the solvent for cyclisation in step b) is selected from dichloromethane, acetone, acetonitrile, dimethyl formamide, dimethyl sulphoxide or dimethyl acetamide.
10. A process according to claim 4, wherein the solvent for cyclisation in step b) is acetonitrile.