FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
As amended by the Patents (Amendment Act 2005
&
The Patents Rules, 2003
As amended by the Patents (Amendment) Rules 2006
COMPLETE SPECIFICATION
(See section 10 and rule 13) TITLE OF INVENTION
A process for the preparation of tizanidine hydrochloride
INVENTORS
Names : Babasaheb Pandurang Bandgar, Sanjay, Suresh Sawant, Vinod Tribhuvannath Kamble, Sawant Ajay suresh & More Parmeshwar Eknath
Nationality : all Indian Nationals
Address : School of Chemical Sciences, SolapurUnivercity Solapur -Pune Highway, Kegaon Solapur-413255 Maharashtra, India
APPLICANTS
Names : Babasaheb Pandurang Bandgar, Sanjay Suresh Sawant Vinod
Tribhuvannath Kamble, Sawant Ajay Suresh & More
Parmeshwar Eknath
Nationality : all Indian Nationals
Address : School of Chemical Sciences, Solapur Univercity Solapur-Pune Highway, Kegaon Solapur-413255 Maharashtra, India
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the nat ure of this invention and the manner in which it is to be performed:

l2 AUG 2008

Field of the Invention
The present invention relates to a process for the preparation of preparing a tizanidine hydrochloride, (5- chloro - N -(4,5 - dihydro - 1H - imidazole - 2-y\) -2, 1,3 - benzothiadiazole - 4 - amine hydrochloride of the formula (I);

Formula I and intermediates thereof.
Background of the invention
(5- chloro - N -(4,5 - dihydro -1H - imidazole - 2 - yl) -2, 1,3 - benzothiadiazole - 4 - amine hydrochloride of the formula (I) is commonly known as Tizanidine hydrochloride. Tizanidine is a centrally acting skeletal muscle relaxant. It preferentially inhibits polysynaptic mechanism responsible for exclusive muscle tone. Tizanidine is a well tolerated and effective against both acute painful muscle spasms and chronic plasticity of spinal and cerebral origin. It reduces resistance to passive movements, alleviates spasms and clonus, and improves voluntary strength. Tizanidine acts on the central nervous system (CNS) to produce its muscle relaxant effects. Tizanidine, clonidine derivatives, is a centrally acting skeletal muscle relaxant with alpha-2-adrenergic activity. This drug is indicated for the acute and intermittent management of increased muscle tone associated with spasticity. Tizanidine undergoes extensive first pass metabolism, resulting in an oral bioavailability of only 40 % plasma protein binding is low 30 %. Tizanidine is contraindicated in patients taking other alpha-2 adrenergic agonists (e.g., clonidine).
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German patent DE 2322880 (Equivalent US 3843668) describes a process for preparation of Tizanidine. 4-amino-5-chloro -2, 1,3-benzothiadiazole is reacted with methyl iodide to obtain s-methyl isothiourea, which is further reacted with ethylenediamine in the presence of potassium hydroxide and lead acetate in methanol at reflux condition to give Tizanidine. The drawback of this process is low yield and longer reaction time. Further lead acetate is hazardous and it is difficult to use in industrial scale. Moreover, s-methyl isothiourea and ethylene-diamine get self-condensed to produce dimmer impurities at the reaction temperature.
Swiss patent 579565 describes the process for preparation of Tizanidine. 4-
amino-7-chloro -2,1,3-benzothiadiazole is reacted with CSCl2 to obtained 7-
chloro-4-isothiocyano-2,1,3-benzothiadiazole, which is reacted with
ethylenediamine to obtain 4-(3-(2-aminoethyl)-2-thioureido) 7-chloro-2, 1,3-
benzothiadiazole. 4-(3-(2-aminoethyl)-2-thioureido)7-chloro-2,1,3-
benzothiadiazole is cyclized in the presence of potassium hydroxide and lead
acetate in methanol at reflux condition to yield Tizanidine. However, the
limitations of this process is low yield (60 % in methanol and 37 % in ethanol).
Australian patent 505664 discloses a process for the preparation of Tizanidine in which 4-amino-5-chloro-2,1,3-benzothiadiazole is reacted with ammonium thiocyanate in the presence of benzoyl chloride and acetone at reflux temperature to give thiourea derivative. Thiourea derivative is treated with methyl iodide in presence of sodium hydride to obtain s-methyl-isothiourea derivative, which is further cyclized with ethylenediamine in isoamyl alcohol at 132° C to obtain Tizanidine. However, such high temperature of 132° C is difficult to achieve on industrial scale.
DE patent 246764 describes one pot synthesis for the preparation of Tizanidine base in which 5-chloro-4-cyanoamino-2, 1,3-benzothiadiazole is reacted with
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ethylenediamine tosylate in xylene at 142° C to give Tizanidine base. However, we observed that 15-20 % of 5-chloro-4-cyanoamin2( 1,3-benzothiadiazole remains un-reacted in the reaction mixture. This reduces overall yield of Tizanidine hydrochloride.
JP patent 07258251 describes one pot synthesis for the preparation of tizanidine base. In this process, 5-chloro-4-cyanoamino-2,1f3-ben Zothiadiazole is reacted with 1 -acetyl-2-imidazolidone in the presence of POCI3 at 60° C for 48 hours. The reaction mixture is concentrated and hydrolyzed with sodium hydroxide in methanol at reflux temperature to give Tizanidine base (80 o/0 yield). This process uses POCI3, which is environmentally hazardous.
JP patent 08176150 describes one pot synthesis for the Preparation of Tizanidine base in which 5-chloro-4-cyanoamino-2,1,3-benzothiadiazole is reacted with 1-chloro-2- imidazolidone in the presence of sulfuric acid(H2so4) in methanol at 60° C for 30 hours. After completion of the reaction, the reaction mixture is concentrated and hydrolyzed with sodium hydroxide in methanol at reflux temperature for 6 hour to give Tizanidine base (yield 75 %). This process uses H2S04, which is environmentally hazardous. The use of H2so4 at industrial scale is not practically feasible. The process also required longr reaction time.
Objects of the invention:
An object of the invention is to provide a process for the Preparation of Tizanidine hydrochloride by using less hazardous and environme ntally benign reagents, thus making the process eco-friendly.
Another object of the invention is to provide a process for the preparation of Tizanidine hydrochloride with the yield of at least 96 % and| having purity 99.99 %, thus making the process cost-effective.
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Another object of the invention is to provide a process for the preparation of Tizanidine hydrochloride by using less hazardous and environmentally benign reagents, thus making the process simple and easy to handle.
Another object of the invention is to provide a process for the preparation of Tizanidine hydrochloride which' reduces the reaction time, thus making the process Cost-effective.
Another object of the invention is to provide intermediates, which are used in the process for the preparation of Tizanidine hydrochloride.
Another object of the invention is to provide processes for the preparation of intermediates, which are used in the process for the preparation of Tizanidine hydrochloride.
Detailed description of the invention
According to the invention there is provided a process for preparation of 5 - N -(4,5 - dihydro - 1H - imidazole - 2 - yl) -2, 1,3 - benzothiadiazole -4 hydrochloride commonly known as Tizanidine hydrochloride of fomula (I);

Formula I the process comprising:
a. Preparation of 4-chloro-o-phenylenediamine of the formula (III) by
reducing 4-chlro-o-nitro aniline of the formula (II) in presence of Raney
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Nickel and alcohol as a solvent, under hydrogen pressure of 2 - 6 kg /cm'2 at 30-35° C;
b. Preparation of 5-chloro- 2, 1,3-benzothiadiazole of the formula (IV) by
cyclizing the compound of formula (III) with thionyl chloride in presence
of toluene as a solvent;
c. Preparation of 4-nitro-5-chloro-2, 1,3-benzothiadiazole of the formula
(V) by treating the compound of formula (IV) with nitrating mixture at 0
- 5° C;
d. Preparation of 5-chloro-4-amino-2, 1,3-benzothiadiazole of the formula
,(VI) by reducing the compound of formula (V) with Fe /aqueous FeCI3
solution in presence of toluene as a solvent at 85 - 90° C;
e. Preparation of N -(5-chloro-2, 1,3-benzothiadiazole-4-yl) thiourea of the
formula (VII) by adding benzoyl chloride in a solution of ammonium
thiocyanate in methanol and / or monoisobutyl ketone with continuous
stirring; further adding the compound of the formula (VI) in methanol
and / or monoisobutyl ketone with stirring; stirring the reaction mixture
at 30 - 35° C to obtain benzoyl derivative, hydrolyzing the benzoyl
derivative by treating it with dilute 5% sodium hydroxide solution,
further neutralizing the reaction mixture with dilute 5%hydrochlohc acid
and filtering the reaction mixture to obtain the compound of the formula
(VII);
f. Preparation of s - methyl -N - (5 - chloro -2, 1,3-benzothiadiazole - 4 -
yl) isothiourea of the formula (VIII) by treating the solution of the
compound of the formula (VII) in methanol with sodium bicarbonate
and dimethylsulphate at refluxed temperature, concentrating the
reaction mixture; quenching the reaction mixture with water and
filtering precipitated product comprising the compound of the formula
(VIII);
g. Preparation of (5 - chloro - N - (4,5 - dihydro - 1H - imidazole - 2 -yl) -2,
1,3-benzothiadiazole - 4 - amine of the formula ((X) by treating the
solution of the compound of the formula (VIII) in isopropyl alcohol
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xylene or bromobenzene with ethylenediamihe-p-toluene sulfonic acid at reflux temperature; concentrating the reaction mixture; quenching the reaction mixture with water and filtering precipitated product comprising the compound of the formula (IX); and( h. Preparation of 5- chloro - N -(4,5 - dihydro -1H - imidazole - 2 - yl) -2, 1,3 - benzothiadiazole - 4 - amine hydrochloride of the formula (I) by treating an aqueous solution of the compound of the formula (IX) with concentrated hydrochloric acid to obtain the compound of formula (I).
The alcohol used in step (a) is methanol or ethanol. The step (a) of the process further comprises filtration of the reaction mixture to remove the catalyst and concentrating the reaction mixture to obtain the compound of the formula (III). The step (b) of the process particularly, further comprises concentrating the reaction mixture under reduced pressure and distilling out the solvent under vacuum to obtain the compound of the formula (!V). The step (c) of the process further comprises quenching the reaction mixture with Water followed by filtration to obtain the compound of formula (V). The step c; of the process further comprises purifying the compound of formula (V) by Crystallization with water. The step (d) of the process further comprises filtering the reaction mixture on completion of the reaction mixture; separation of organjc layer from the reaction mixture and concentrating the same under pressure of 100 - 150 mm / hg to obtain the compound of the formula (VI). The step (§) 0f the process further comprises purifying the compound of formula (IX) by crystallization with methanol and / or water.
According to the invention there is provided a process for the preparation of 4-chloro-o-phenylenediamtne of the formula (III), an intermediate of Tizanidine hydrochloride; the process comprises reducing 4-chlor-o-nitro aniline of the ormula (II) in presence of Raney Nickel and alcohol as a selovent under hydrogen pressure of 2 - 6 kg /cm2 at 30 - 35° C.
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The alcohol used in step (a) is methanol or ethanol. The process further comprises filtration of the reaction mixture to remove the catalyst and concentrating the reaction mixture to obtain the compound of the formula (III).
According to the invention there is provided a process for the preparation of 5-chloro- 2, 1,3-benzothiadiazole of the formula (IV), an intermediate of Tizanidine hydrochloride; the process comprises cyclizing the compound of formula (III) with thionyl chloride in presence of toluene as a solvent.
The process further comprises concentrating the reaction mixture under reduced pressure and distilling out the solvent under vacuum to obtain the compound of the formula (IV).
According to the invention there is provided a process for the preparation of 4-nitro-5-chloro-2, 1,3-benzothiadiazole of the formula (V)l, an intermediate of Tizanidine hydrochloride; the process comprises treating the compound of formula (IV) with nitrating mixture at 0 - 5° C.
The process further comprises quenching the reaction mixture with water followed by filtration to obtain the compound of formula (V). The process further comprises purifying the compound of formula (V) by crystallization with water.
According the invention there is provided a process for the preparation of 5-chloro-4-amino-2, 1,3-benzothiadiazole of the formula (VI), an intermediate of Tizanidine hydrochloride; the process comprises reducing the compound of formula (V) with Fe /aqueous FeCl3 solution in presence of toluene as a solvent at 85-90° C.
The process further comprises filtering the reaction mixture on completion of the reaction mixture; separation of organic layer from the reaction mixture and concentrating the same under pressure of 100 - 150 mm / Hg to obtain the compound of the formula (VI).
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According to the invention there is provided a process for the preparation of (N -(5-chloro-2, 1,3-benzothiadiazole-4-yl) thiourea of the formula (VII), an intermediate of Tizanidine hydrochloride; the process comprises adding benzoyl chloride in a solution of ammonium thiocyanate in methanol and / or monoisobutyl ketone with continuous stirring; further adding the compound of the formula (VI) in methanol and / or monoisobutyl ketone with stirring; refluxing the reaction mixture to obtain benzoyl derivative, hydrolyzing the benzoyl derivative by treating it with dilute 5% sodium hydroxide solution, further neutralizing the reaction mixture with dilute 5% hydrochloric acid and filtering the reaction mixture to obtain the compound of the formula (VII).
According to the invention there is provided a process for the preparation of s -methyl -N - (5 - chloro -2, 1,3-benzothiadiazole - 4 -yl) isothiourea of the formula (VIII), an intermediate of Tizanidine hydrochloride; the process comprises treating the solution of the compound of the formula (VII) in methanol with sodium bicarbonate and dimethylsulphate at refluxed temperature, concentrating the reaction mixture; quenching the reaction mixture with water and filtering precipitated product comprising the compound of the formula (Vlll).
According to the invention there is provided a process for the preparation of (5 -chloro - N - (4,5 - dihydro - 1H - imidazole - 2 -yl) -2, 1,3-benzothiadiazole - 4 -amine of the formula (IX), an intermediate of Tizanidine hydrochloride, the process further comprises treating the solution of the compound of the formula (Vlll) in isopropyl alcohol, xylene or bromobenzene with ethylenediamine-p-toluene sulfonic acid at reflux temperature; concentrating the reaction mixture; quenching the reaction mixture with water and filtering precipitated product comrpising the compound of the formula (IX).
The process further comprises purifying the compound of formula (IX) by crystallization with methanol and / or.
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The compound of formula (IX) is further treated with concentrated hydrochloric acid to convert it into hydrochloride salt.
The process of the present invention eliminates the use °f hazardous reagents such as lead acetate, POCI3 and H2S04 thereby making the process eco-friendly and simple and easy to handle. According to the present invention, Tizanidine hydrochloride obtained with at least 96 % yield and ^9.99 % Purity in 10 - 12 hours thereby making the process is cost-effective.
The schematic representation of the process is given be'ow:

The present invention is further exemplified by the following non-limiting examples.
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Example 1 4-chloro-o-phenylenediamine (III)
To a solution of 4-chloro-o-nitroanoline (10 g) in methanol (30 ml) was added raney nickel (0.5 g) in methanol (5 ml) and maintained the reaction mixture under hydrogen pressure at 30 - 35° C for 1 hour. After completion of the reaction, the reaction mixture was cooled and the reaction mixture was filtered to remove the raney nickel at suction. The organic layer was concentrated to give 4-chloro-o-phenylenediamine (III). Yield = 7.9g, 96 %, HPLC Purity - 99.50 % IR cm'3 (KBr): 620,759,1510,2920,2938,3320.
1H NMR (300 MHz, CDCl3): 67.4 (d, 1H, J = 8Hz), 7.32 (dd, 1H, J= 8 Hz, J= 2 Hz), 7.23 (d, 1H, J = 2 Hz), 5.28 - 5.30 (m 4H). Anal. Calcd for C6H7N2CI: C 50.52 (50.53), H 4.91 (4.92), N 19.65 (19.60).
Example 2
5-chloro- 2,1,3-benzothiadiazole (IV)
To a suspension of 4-chloro-o-phenylenediamine (10 g) in toluene (100 ml) was
added thionyl chloride (12.5 g) with continuous stirring. The resulting solution
was heated under reflux for 1 hour. After completion of the reaction, the reaction
mixture was concentrated under reduced pressure and distilled out solvent under
high vacuum to obtain 5-chloro- 2,1,3-benzothiadiazole (IV).
Yield = 11.3 g, 95 %, HPLC Purity - 99.59 %
IR cm"3 (KBr): 731,1635,2528,2940.
1H NMR (300 MHz, CDCI3): 5 7.6 (d, 1H, J = 8Hz), 7.5 (d, 1H, J =2Hz), 7.23 (dd,
1H, J=8Hz, J =2 Hz)
Anal. Calcd for C6H3N2CI S: C 42.22 (42.23), H 1.75 (1.75), N 16.42 (16.43).
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Example 3
4-nitro-5-chloro-2,1,3-benzothiadiazole (V)
To a solution of 5-chloro- 2, 1,3-benzothiadiazole (10 g) in concentrated sulfuric
acid (50 ml) at 0 to 5° C, mixture of concentrated sulfuric acid (26 g),
concentrated nitric acid (6.5 g) was added dropwise and further stirred for 1 hour
at same temperature. After completion of the reaction, the reaction was
quenched with water and crude product was filtered at suction. The crude
compound was crystallized from water to furnish pure product 4-nitro-5-chloro-2,
1,3-benzothiadiazole (V).
Yield = 11.6 g, 92 %, HPLC Purity-99.65 %
IR cm-3 (KBr): 1410,1603,1620,2535,2918.
1H NMR (300 MHz, CDCI3): 6 7.8 (d, 1H, J = 8 Hz), 7.4 (d, 1H, J = 8 Hz)
Anal. Calcd for C6H2N3CI S: C 33.41 (33.40), H 0.93 (0.95), N 19.48 (19.45).
Example .4
5-chloro-4-amino-2,1,3-benzothiadiazole (VI)
To a solution of 4-nitro-5-chloro-2, 1,3-benzothiadiazole (10 g) in toluene (100 ml) iron powder (20 g) was added at 60-65° C with continuous stirring. A black suspension was formed to which a solution of FeCl3 (20 g) in water (50 ml) was added at 70-75° C and reaction mixture was stirred for 2 hours at 85-90° C. After completion of the reaction, the reaction mixture was filtered in hot condition and washed with hot toluene (10 ml). The organic layer was separated and concentrated under reduced pressure to produce 5-chloro-4-amino-2, 1,3-benzothiadiazole.
Yield = 8.1g, 94 %, HPLC Purity - 99.80 % IRcm"3 (KBr): 658,686,726.26,754.0,794.,837.3,891.7,926.4,065.2, 1110.3,1225.9,1343.5,1361.3,1418.4,1488.7,1540.2,1620.7,3323.6,3448.4. 1H NMR (300 MHz, CDCI3); 5 4.8 (BrS, 2H, J = 8 Hz), 7.25 (d, 1H), 7.45 (d, 1H). Anal. Calcd for C6H4N3CI S: C 38.81 (38.80), H 2.15 (2.14), N 22.64 (22.61).
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Example 5
N -(5-chloro-2,1,3-benzothiadiazole - 4 -yl) thiourea (VII)
To a solution of ammonium thiocyanate (4.1 g), in methanol (100 ml) was added
benzoyl chloride (7.6 g) with continuous stirring. To this, a solution of the 5-
chloro-4-amino -2,1,3-benzothiadiazole (10 g) in methanol (100 ml) was added
and the stirring was continued at reflux temperature for 30 minutes. The reaction
mixture was filtered and benzoyl derivative was hydrolyzed with dilute 5% sodium
hydroxide solution (100 ml) and stirring was continued for further 30 min at room
temperature. After completion of the reaction, the reaction mixture was
neutralized with dilute 5% hydrochloric acid (100 ml). The reaction mixture was
filtered at suction to obtain N -(5-chloro-2, 1,3-benzothiadiazole - 4 -yl) thiourea.
Yield = 12.8 g, 97 %, HPLC Purity - 99.75 %
IRcm-3(KBr): 628.05,710.88,820,856,878.6,916.7,945.8,1069.2,1128.2,
1198.6,1264.8,1283.9,1323.9,1409.8,1471.1,1528.8,1591.1,1616.5,1636,2948.1,
3151.3,3266.3,3387.2.
1H NMR (300 MHz, CDCl3); 5 7.4 (BrS, 3H), 7.7 (d, 1H),7.9(d, 1H).
Anal. Calcd for C7H5N4CI S2: C 34.35 (34.35), H 2.05 (2.05), N 22.90 (22.90).
Example 6
s-methyl -N -(5 -chloro -2,1,3-benzothiadiazole - 4 -yl) isothiourea (VIII)
To a solution of thiourea 7 (10 g) in methanol (100 ml) was added sodium
bicarbonate (1.4 g), dimethylsulphate (5.16 g) with continuous stirring. The
resulting solution was refluxed for 1 hour. After completion of the reaction, the
reaction mixture was concentrated and quenched with water (150 ml) with
continuous stirring. The precipitated product was filtered at suction to yield s-
methyi-N - (5-chloro-2, 1,3-benzothiadiazole - 4 -yl) isothiourea.
Yield =10 g 95 %, HPLC Purity- 99.72 %
IRcm-3(KBr): 628.8,710.2,809.9,834,865.6,940,906.2,980.9,1021.8,
1122.2,1207.7,1270.9,1290.1,1323.8,1356.5,1397.4,1434.6,1475.4,
1521.9,1588.9,1641,2909.5,2979.9,3230,3321.2,3428.1,3712.
1H NMR (300 MHz, CDCI3); 5 2.5 (s, 6H,), 3.2 (s, 3H), 6.1 (s, 2H), 7.6 (s, 2H)
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Anal. Calcd for C8H7N4CI S2: C 37.13 (37.12), H 2.70 (2.69), N 21.66 (21.60).
Example 7
(5 - chloro - N - (4,5 - dihydro - 1H - imidazole - 2 -yl) -2,1,3-benzothiadiazole
-4 -amine (IX)
To a solution of isothiourea (10 g) in isopropyl alcohol (100 ml),
ethylenediamine-p-toluene sulfonic acid (15 g) was added with continuous
stirring. The resulted reaction mixture was heated under reflux for 1 hour. After
completion of the reaction, the reaction mixture was concentrated and quenched
with water (175 ml). The crude product was filtered at suction and recrystallized
with methanol to give (5- chloro - N - (4,5 - dihydro - 1H - imidazole - 2 - yl) -2,
1,3-benzothiadiazole - 4 - amine.
Yield = 9.5 g, 97 %, HPLC Purity - 99.90 %
IRcm'3(KBr): 673.1,745.6,791,813.7,834.6,860.8,902.8,942.5,974.3,
1062.8,1121.8,1198.1,1271.9,1295.8,1332.1,1350.3,1427.4,1446.3,
1475.1,1501.2,1519.4,1668.1,2856.7,3351.1.
1H NMR (300 MHz, CDCI3): δ 3.11 (t, 2H), 3.22 (t 2H), 5.1 (s, 1H), 7.03 (d, 1H, J=
8Hz),7.3(d, 1H=8 Hz).
13CNMR(75MHz,CDCI3):5 21.395,22.0,42.314,115.420,131.616,151.67,154.36,
158.94,173.49.
Anal. Calcd for C9H8N5CI S: C 42.56 (42.50), H 3.15 (3.10), N 27.59 (27.60).
Example 8 5-chloro-N-(4,5-dihydro-1H-imidazole-2-yl)-2,1,3-benzothiadiazole-4-amine
hydrochloride (I)
To a solution of (5- chloro- N - (4,5 - dihydro -1H -imidazole -2 - yl) -2, 1,3-benzothiadiazole - 4-amine (10 g) in water ( 90 ml ) was added concentrated hydrochloric acid ( 1.5 g) with continuous stirring. After completion of the reaction, the reaction mixture was filtered at suction to obtain (5- chloro - N - (4,5
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- dihydro - 1H - imidazole -2 -yl) -2, 1,3-benzothiadiazole -4 - amine
hydrochloride.
Yield = 11 g, 96 %, HPLC Purity - 99.99 %
IRcm'3(KBr): 675.7,713.1749.9,786.9, 822.1,838.7,865.2,960.3,1070.7,
1106.2,1120.4,1191.8,1270.5,1290.9,1340.7,1352.2,1407.7,1454.1,
1488.3,1537.6,1610.3,1653.1,2823.2,2968,3078.8,3230,3561.2.
1H NMR (300 MHz, CDCI3): 5 3.02 (t, 2H), 3.13 (t 2H), 5.1 (s, 1H), 7.02 (d, 1H, J
= 8Hz), 7.31 (d, 1H, J =8 Hz).
13CNMR(75MHz,CDCI3):6 44.52,123.05,124.93,132.95,135.24,152.27,
155.052,159.74
Anal. Calcd for C9H9N5Cl2: C 37.24 (37.25), H 3.10 (3.11), N 24.13 (24.14). Although the invention has been explained in relation to its preferred embodiment, it is to be understood that many other possible modifications and variations can be made without departing from the spirit and scope of the invention as hereinafter claimed.
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We Claim
1. A process for preparation of 5- chloro - N -(4,5 - dihydro - 1H - imidazole -2 - yl) -2, 1,3 - benzothiadiazole - 4 - amine hydrochloride commonly known as Tizanidine hydrochloride of fomula (I);

Formula I the process comprising:
a. Preparation of 4-chloro-o-phenylenediamine of the formula (III) by
reducing 4-chlro-o-nitro aniline of the formula (II) in presence of Raney
Nickel and alcohol as a solvent under hydrogen pressure of 2 - 6 kg
/cm2 at 30- 35°C;

b. Preparation of 5-chloro- 2, 1,3-benzothiadiazole of the formula (IV) by cyclizing the compound of formula (III) with thionyl chloride in presence of toluene as a solvent;

Cl^k^N
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c. Preparation of 4-nitro-5-chloro-2, 1,3-benzothiadiazole of the formula (V) by treating the compound of formula (IV) with nitrating mixture at 0 -5°C;

d. Preparation of 5-chloro-4-amino-2, 1,3-benzothiadiazole of the formula (VI) by reducing the compound of formula (V) with Fe /aqueous FeCI3 solution in presence of solvent such as toluene at 85 - 90° C;


NH f C=S
I NH2
7
17
e. Preparation of N -(5-chloro-2, 1,3-benzothiadiazole-4-yl) thiourea of the formula (VII) by adding benzoyl chloride in a solution of ammonium thiocyanate in methanol and / or monoisobutyl ketone with continuous stirring; further adding a solution of the compound of the formula (VI) in methanol and / or monoisobutyl ketone with stirring; refluxing the reaction mixture to obtain benzoyl derivative, hydrolyzing the benzoyl derivative by treating it with dilute 5% sodium hydroxide solution, further neutralizing the reaction mixture with dilute 5% hydrochloric acid and filtering the reaction mixture to obtain the compound of the formula (VII);

f. Preparation of s - methyl -N - (5 - chloro -2, 1,3-benzothiadiazole - 4 -
yl) isothiourea of the formula (VIII) by treating the solution of the
compound of the formula (VII) in methanol with sodium bicarbonate
and dimethylsulphate at refluxed temperature, concentrating the
reaction mixture; quenching the reaction mixture with water and
filtering precipitated product comprising the compound of the formula
(VIII);

g. Preparation of (5 - chloro - N - (4,5 - dihydro -1H - imidazole - 2 -yl) -2,
1,3-benzothiadiazole - 4 - amine of the formula (IX) by treating the
solution of the compound of the formula (VIII) in isopropyl alcohol,
xylene or bromobenzene with ethylenediamine-p-toluene sulfonic acid
at reflux temperature; concentrating the reaction mixture; quenching
the reaction mixture with water and filtering precipitated product
comprising the compound of the formula (IX); and

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h. Preparation of 5- chloro - N -(4,5 - dihydro - 1H - imidazole - 2 - yl) -2, 1,3 - benzothiadiazole - 4 - amine hydrochloride of the formula (I) by
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treating an aqueous solution of the compound of the formula (IX) with concentrated hydrochloric acid to obtain the compound of formula (I).
2. The process as claimed in claim 1, wherein the solvent used in step (a) is methanol or ethanol.
3. The process as claimed in claim 1, step (a) further comprises filtration of the reaction mixture to remove the catalyst and concentrating the reaction mixture to obtain the compound of the formula (III).
4. The process as claimed in claim 1, step (b) further comprises concentrating the reaction mixture under reduced pressure and distilling out the solvent under vacuum to obtain the compound of the formula (IV).
5. The process as claimed in claim 1, step (c) further comprises quenching the reaction mixture with water followed by filtration to obtain the compound of formula (V).
6. The process as claimed in claim 1, step c further comprises purifying the compound of formula (V) by crystallization with water.
7. The process as claimed in claim 1, step (d) further comprises filtering the reaction mixture on completion of the reaction mixture; separation of organic layer from the reaction mixture and concentrating the same under pressure of 100 - 150 mm / Hg to obtain the compound of the formula (VI).
8. The process as claimed in claim 1, step (g) further comprises purifying the compound of formula (IX) by crystallization with methanol and /or water.
9. A process for the preparation of 4-chloro-o-phenylenediamine of the formula (III), an intermediate of Tizanidine hydrochloride; the process comprises reducing 4-chlro-o-nitro aniline of the formula (II) in presence of Raney Nickel and alcohol as a solvent under hydrogen pressure of 2 - 6 kg /crrr2 at 30- 35° C.
10. The process as claimed in claim 9, wherein the solvent used in step (a) is methanol or ethanol.
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11. The process as claimed in claim 9, further comprises filtration of the reaction mixture to remove the catalyst and concentrating the reaction mixture to obtain the compound of the formula (III).
12. A process for the preparation of 5-chloro- 2, 1,3-benzothiadiazole of the formula (IV), an intermediate of Tizanidine hydrochloride; the process comprises cyclizing the compound of formula (III) with thionyl chloride in presence of toluene as a solvent.
13. The process as claimed in claim 12, further comprises concentrating the reaction mixture under reduced pressure and distilling out the solvent under vacuum to obtain the compound of the formula (IV).
14. A process for the preparation of 4-nitro-5-chloro-2, 1,3-benzothiadiazole of the formula (V) I, an intermediate of Tizanidine hydrochloride; the process comprises treating the compound of formula (IV) with nitrating mixture at 0 -5°C.
15. The process as claimed in claim 14, further comprises quenching the reaction mixture with water followed by filtration to obtain the compound of formula (V).
16. The process as claimed in claim 14, further comprises purifying the compound of formula (V) by crystallization with water.
17. A process for the preparation of 5-chloro-4-amino-2, 1,3-benzothiadiazole of the formula (VI), an intermediate of Tizanidine hydrochloride; the process comprises reducing the compound of formula (V) with Fe /aqueous FeCl3 solution in presence of solvent such as toluene at 85 - 90° C.
18.The process as claimed in claim 17, further comprises filtering the reaction mixture on completion of the reaction mixture; separation of organic layer from the reaction mixture and concentrating the same under pressure of 2 - 6 kg /cm"2 to obtain the compound of the formula (VI).
19. A process for the preparation of (N -(5-chloro-2, 1,3-benzothiadiazole-4-yl) thiourea of the formula (VII), an intermediate of Tizanidine hydrochloride; the process comprises adding benzoyl chloride in a solution of ammonium
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thiocyanate in methanol and / or monoisobutyl ketone with continuous stirring; further adding a solution of the compound of the formula (VI) in methanol and / or monoisobutyl ketone with stirring; refluxing the reaction mixture to obtain benzoyl derivative, hydrolyzing the benzoyl derivative by treating it with dilute 5% sodium hydroxide solution, further neutralizing the reaction mixture with dilute 5% hydrochloric acid and filtering the reaction mixture to obtain the compound of the formula (VII).
20. A process for the preparation of s - methyl -N - (5 - chloro -2, 1,3-benzothiadiazole - 4 -yl) isothiourea of the formula (VIII), an intermediate of Tizanidine hydrochloride; the process comprises treating the solution of the compound of the formula (VII) in methanol with sodium bicarbonate and dimethylsulphate at refluxed temperature, concentrating the reaction mixture; quenching the reaction mixture with water and filtering precipitated product comprising the compound of the formula (VIII).
21.A process for the preparation of (5 - chloro - N - (4,5 - dihydro - 1H -imidazole - 2 -yl) -2, 1,3-benzothiadiazole - 4 - amine of the formula (IX), an intermediate of Tizanidine hydrochloride, the process further comprises treating the solution of the compound of the formula (VIII) in isopropyl alcohol, xylene or bromobenzene with ethylenediamine-p-toluene sulfonic acid at reflux temperature; concentrating the reaction mixture; quenching the reaction mixture with water and filtering precipitated product comprising the compound of the formula (IX).
22. The process as claimed in claim 21, further comprises purifying the compound of formula (IX) by crystallization with methanol and /or water.
Dated this 11th day of August 2008
Babasaheb Pandurang Bandgar, Sanjay Suresh Sawant Vinod Tribhuvannath Kamble, Sawant Ajay Suresh & More Parmeshwar Eknath By their Agent
(Dr Shilpa Gharve)
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