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 301, 'Dosti Pinnacle', 3rd Floor,
Plot No.E7, Road No.22, Wagle Industrial Area,
Thane (W)-400 604
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:

CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a patent of addition of Indian Patent Application No. 3460/MUM/2012. filed December 7, 2012, which is incorporated herein in its entirety.
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)methyI]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-1 -[2 {2-(2-fluorophenyl)-l ,3-dithiolan-2-
yl}phenyl]-2-methyl-lH-imidazole-5-carboxaldehyde (hereinafter aldehyde compound)
with hydroxylamine hydrochloride to form 1-[4-chloro-2{2-(2-fluorophenyl) 1,3-
dithiolan-2-yl}phenyl]-2-methyl-l]-lH-imida2ole-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 eerie 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)-1,3-dithiolan-2-yl }phenyl]-2-methyl-1H-imidazoIe-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, cerie 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 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5a] [1,4] benzodiazepine of formula I which comprises:

a) 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 using a reducing agent and ammonia in an alcoholic solvent to obtain 1-(l-{4-chIoro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyl}-2-methyl-lH-imidazol-5-yl)methanamine of formula II; and
b) deprotection and cyclization 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 in monochlorobenzene (MCB) using a reagent and in presence of manganese dioxide (Mn02) to form 8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo[l,5a] [1,4] benzodiazepine of formula I.
This process may be represented by following reaction scheme:

Description of the figures /Diagram
Figure 1: HPLC chromatogram of Midazolam in-process monitoring when the solvent is
Acetonitrile Figure 2: HPLC chromatogram of Midazolam in-process monitoring when the solvent is
MCB and reagent is Ferric chloride. MnO2 and aluminium chloride Figure 3: HPLC chromatogram of Midazolam in-process monitoring when the solvent is
MCB and reagent is borontrifloride diethyletherate and Mn02 Tablel: Formation of uncyclized impurity and purity of midazolam in different solvent/reagent
Table 2: Comparative requirement of Mn02 & FeCl3 in different reagent and the colour of the obtained product

Detail Description of the Invention
Accordingly in an embodiment of the invention, the reductive amination of 1-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyl}-5-methyl-lH-imidazoIe-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 l-(l-{4-chloro-2-[2-(2-fluorophenyl)-1,3-dithiolan-2-yl]phenyl}-2-methyl-lH-imidazoI-5-yI)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-
(l-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyl}-2-methyl-lH-imidazol-
5-yl)methanamine of formula II is carried out in monochlorobenzene (MCB), which
facilitates the reaction at very high temperature i.e. at 110 to 130 °C. The use of this
solvent and reaction at this temperature leads to formation of <0.5% uncyclized
impurity [2-(5-aminomethyl-2-methyl-imidazol-l-yl)-5-chloro-phenyl]-(2-fluoro-
phenyl)-methanone of formula IV during the reaction, which otherwise is formed upto 5-10% in prior art processes. We observed that the uncyclized impurity of formula IV is formed 7.08% when acetonitrile is used as solvent for the said deprotection and cyclization which leads to yield loss. At the same time when MCB is used instead of acetonitrile the formation of uncyclized impurity of formula IV is 0.44%. This increases the yield of the product from 57% to 71% and purity is achieved >99.8% without any purification which otherwise needs purification using ethyl acetate when acetonitrile is used as a solvent as given in table 1.

Method During the reaction After Isolation

Uncyclized impurity (RRT 0.88) Uncyclized impurity (RRT 0.88) Purity of Midazolam
Acetonitrile 7.08% 0.106% 96.65%
MCB 0.44% NIL 99.84% with impurity < 0.07%
BF3 diethyl etherate 0.217% NIL 99.78% with impurity
< 0.07%
Table 1: Formation of uncyclized impurity and purity of midazolam in different solvent/reagent
In another embodiment of the invention, the deprotection and cyclization in step b) is carried using a reagent ferric chloride and aluminium chloride or borontrifloride diethyletherate to form 8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo[l,5a] [1,4] benzodiazepine of formula I. Deprotection and cyclization using borontrifloride diethyletherate improves the colour of the product from light brown to off white at the same time reduces the consumption of MnO2 by 50% as evident in below table 2.

Method Reagents Colour

MnO2 FeCl3

A1C13 6.0 eq 2.0eq Light brown
BF3 diethyletherate 3.0eq NIL Off White
Table 2: Comparative requirement of MnO2 & FeCl3 in different reagent and the colour of the obtained product

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-yI]phenyl}-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 doesn't use acidic titanium trichloride. This reduces the quantity of effluent significantly, to make the process easy and environment friendly.
4. The deprotection and cyclization of l-(l-{4-chloro-2-[2-(2-fluorophenyl)-l,3-dithiolan-2-yl]phenyl}-2-methyl-lH-imidazol-5-yl)methanamine in the present invention is carried out in MCB at 118-120 °C in presence of manganese dioxide and reagent either ferric chloride and aluminium chloride or borontrifloride diethyletherate. This almost eliminates the formation uncyclized product of formula IV leading to a significant improvement in yield and quality. It also obviates the use of costlier cerie ammonium nitrate. The MCB can be recovered. It further gives good purity of the product without purification.
5. Borontrifloride diethyletherate as a reagent in deprotection and cyclization improves the colour of the product from light brown to off white at the same time reduces the consumption of MnO2 by 50% as compared to AlCl3.
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-f1uorophenyl)-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)-1,3-dithiolan-2-yl]phenyl}-2-methyl-lH-imidazole-5-carboxaldehyde 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-fluorophenyl)-l-methyl-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-imidazoI-5-yl)methanamine(5.4g) and MCB (54 mL) were charged into a RBF. Ferric chloride (3.9g), MnO2 (6.197g) and aluminium chloride (3.2g) were added to the above reaction mass. The reaction mass was heated to 110-115 °C and stirred for 10-12 hrs. After completion of the reaction, the reaction mass was quenched to water, pH was adjusted to 8 using aqueous ammonia. The product was extracted into toluene. The toluene layer was washed with 10% brine solution. The product was extracted to aq. layer by using HC1. The impurities were removed by washing the aq. Layer with toluene. The aq. Layer was basified by aq. ammonia and the solid was precipitated, filtered and dried.
Yield: 71% Purity: more than 99.8 %
(c) Procedure for the preparation of 8-chloro-6-(2-fluorophenyl)-l-methyl-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 MCB (54 mL) were charged into a RBF. MnO2 (3.098g) and borontrifluoride diethyletherate (4.7ml) were added to the above reaction mass. The reaction mass was heated to 110-115 °C and stirred for 10-12 hrs. After

completion of the reaction, the reaction mass was quenched to water, pH was adjusted to 8 using aqueous ammonia. The product was extracted into toluene. The toluene layer was washed with 10% brine solution. The product was extracted to aq. layer by using HC1. The impurities were removed by washing the aq. Layer with toluene. The aq. Layer was basified by aq. ammonia and the solid was precipitated, filtered and dried. Yield: 71% Purity: more than 99.8 %

We claim:
1. A process for preparation of 8-chloro-6-(2-fluorophenyl)-1 -methyl-4H-imidazo[l,5a] [1,4] benzodiazepine of formula I which comprises;

a) 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 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; and

b) deprotection and cyclization of l-(l-{4-chloro-2-[2-(2-fluorophenyl)-l,3-
dithiolan-2-yl]phenyl} -2-methyl-1 H-imidazol-5-yl)methanamine of
formula II in MCB using a reagent and in presence of manganese dioxide (Mn02) to form 8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo[l,5a] [1,4] benzodiazepine of formula I.
2. A process according to claim 1, wherein alcoholic solvent is selected from methanol, ethanol, propanol, butanol or isopropanol.

3. 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.
4. A process according to claim 1, wherein the reducing agent is sodium borohydride
5. A process according to claim 1, wherein the reagent for cyclization in step b) is ferric chloride and aluminium chloride.
6. A process according to claim 1, wherein the reagent for cyclization in step b) is borontrifloride diethyletherate.