CA1299576C - Process for the production of tizanidine - Google Patents
Process for the production of tizanidineInfo
- Publication number
- CA1299576C CA1299576C CA000532965A CA532965A CA1299576C CA 1299576 C CA1299576 C CA 1299576C CA 000532965 A CA000532965 A CA 000532965A CA 532965 A CA532965 A CA 532965A CA 1299576 C CA1299576 C CA 1299576C
- Authority
- CA
- Canada
- Prior art keywords
- chloro
- mixture
- benzothiadiazole
- minutes
- production
- 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 - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
Abstract A process for the production of 5-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3-benzothiadiazole by reacting 5-chloro-4-cyanamino-2,1,3-benzothiadiazole with ethylenediamine mono-p-toluene-sulfonate in xylene. The compound is a centrally acting myotonolytic and has the structural formula I.
Description
~Z~g~76 ` C~se 500-5699 PROCE$~ FO~ THE P~ODUCTIQN OF TIZ~NEDINE
.
The present invention relates to a process for the production of 5-chloro-4-(2-imidazolin~2-ylamino)-2,1,3-benzothiadiazole (tizanidine) of formula I, ~f' \S
Cl ~ N
H
~ NH
The compound is a centrally acting myotonolytic.
It has been found that pure crystalline tizanidine can be produced in a simple manner and very good yield by reacting 5-chloro-4-cyanamino-2,1,3-benzothiadiazole of formula II, N \
N / II
NH
CN
with ethylenediamine mono-p-toluenesulfonate in xylene.
The process is conveniently effected at temperatures of 75 to 140, preferably from 80 to 110? more prefera~ly 90 to 100C.
~ZS~9S~6 - 2 - 500~56q9 The prQcesA~ according t~ the inven~jon has~ ~everal advantages.. T~e process: can ~e ef~ected as- a one~tep reac~i~on and the solvents need not to ~e evaporated. Ti~zani~dine crystallize~ out from t~e reaction mixture ~ithout effecting any furt~er process steps and is of high purity. The process is characterised ~y high yield.
Another advantage is that the process can easily be carried out in industrial scale, ~ecause solvents are employed, which are not detrimental to the environment or are not hard to handle. The process is economi~c, ~eaause the energy demand is low and the solvents are cheap.
5-chloro-4-cyanamino-2,1,3-benzothiadiazole used as starting material can be prepared from 5-chloro~4-amino-Z,1,3-benzothiadiazole.
In the following examples al1 temperatures are given in degrees centigrade and are uncorrected, The temperatures refer if not otherwise stated to internal temperature.
~29~3S~7~
_ 3 ~ 500~5699 Example 1~ 5~C~lQrQ-~4~ d?zoli~nr2-~1aminQ~-2,1,3-~enzot~iadiazo~e To a mi~ture of 130 1 xylene and 4~ 1 w~ter are added under nitrogen and stirri~ng 125 kg p~toluene-sul~ni~ aci~d mone~ydrate. The mixture i~ hea~ed to 50~ and then treated wi~t~tn 1 hsur with 44 1 et~ylene~
diamine. T~e mi~xture i~s heated to ~5-~6, T~ereafter 27.6 ~9 S~chloro~
4~cyanami~no-2,1,3-~enzothiadiazole are added within 2 ~ours and the mixture is ~tirred for 2 ~ours at 100 (surface temperature). There-after ~0 1 water are added ~ithin 10 minutes with ~he mixture cooled to 40 during the addition pertod. Thereafter at 40 78 1 30X
sodtum hydroxide solution are added over a 30 minutes period and the mixture cooled to 20~25~.The suspensi~on is centrifuged, the residue washed with 30 1 water and dried 24 hours tn vacuo at a~out 20 mm Hg and 70 to give 30 kg of the title compound, m.p. 223-225~purity~ 98%).
Example 2. 5~hloro-4~2~imidazolin-2-ylamino~2,1,3~enzothiadiazole hydrochlori~de 51.5 kg 5-Chloro-4 (2-~midazolin-2-yl~mino)-2,1~3-ben~othiadiazole in 280 1 dimethylformamide are heated to 80, treated with 1 kg decolorizing carbon in 5 1 dimethylformamide and stirred 15 minutes at 80. The suspension ;s filtered, ;nto the f;ltrate 8.3 kg gaseous HCl are introduced at ~0 and the mixture is stirred for further 30 minutes. After cooling to 20 the mlxture is stirred ~or 2 hours.
The resulting suspension is centrifuged and the solids washed first with dimethyl~ormamide and then with ethanol. The resulting crude salt is refluxed under st~rring in 62 1 water and 240 1 ~5X ethanol until all is d;ssolved. The mixture is treated with I 1 37% hydro-chloric acid to pH 2 and cooled to 0. After centrifuging the crystalline precipitate is washed with ethanol and dried in vacuo (60 nm Hg) a~ 70 (surface temperature). M.P. of the hydrochloride 2~8-290 .
~g576 - 4 - 500~5699 5~Chlor~4~cy~namino-2,1,3~enzst~;~adi~azsle used ~s starti~ny materi~al is Q~tai~ned a~ follow~.
23 ~g ammpni~um rhodanide and ~0 1 acetone are stirred 30 minute at 20~25~. Thereafter 27 1 benzoyl c~loride are ~dded at 20~30 wit~in 30 minutes and the mixture is stirred at 20~25 ~or 20 minutes.
The resulting suspension is centrifuged and the filtrate kept.
37.5 kg 4~Amino~5-chloro~2,1,3-henzothiadiazole and 90 1 acetone are brought to reflux and treated with the above filtrate. The mixture is refluxed for 2 ll2 hours. The reaction is followed by thin layer chromatography. After cooling to 20~25 the suspension is centrifuged. The solid is taken up in 475 1 water, heated to 80 and treated at that temperature with 85 I 30% sodium hydroxide solution within 15 minutes. The clear solution is treated at 80 with 74 kg lead acetate trihydrate wit~in 40 minutes and the mixture is stirred 30 minutes at 80. Thereafter the mixture is cooled to 50, and simultaneously treated with 2 1 phosphoric acid and ca. 5 1 30% sodium hydroxide solution. The mixture is stirred for a further hour at 50. The resulting suspension is centrifuged and the filtrate treated under stirring with 0.3 kg ethylenediaminete-traa~cetic acid disodiumsalt-dihydrate. The mixture is cooled to 20~25 and adjusted to pH 5.5 with ca. 31 1 30% hydrochloric acid.
The mixture is stirred for 30 minutes at 20~25. The resulting s:uspension is centrifuged, the solid dried for 24 hours at about 60 and 20 mm Hg to give 5-chloro~4~cyanamino~2,1,3~benzothiadiazole, m. p . 215 ~220 .
.
The present invention relates to a process for the production of 5-chloro-4-(2-imidazolin~2-ylamino)-2,1,3-benzothiadiazole (tizanidine) of formula I, ~f' \S
Cl ~ N
H
~ NH
The compound is a centrally acting myotonolytic.
It has been found that pure crystalline tizanidine can be produced in a simple manner and very good yield by reacting 5-chloro-4-cyanamino-2,1,3-benzothiadiazole of formula II, N \
N / II
NH
CN
with ethylenediamine mono-p-toluenesulfonate in xylene.
The process is conveniently effected at temperatures of 75 to 140, preferably from 80 to 110? more prefera~ly 90 to 100C.
~ZS~9S~6 - 2 - 500~56q9 The prQcesA~ according t~ the inven~jon has~ ~everal advantages.. T~e process: can ~e ef~ected as- a one~tep reac~i~on and the solvents need not to ~e evaporated. Ti~zani~dine crystallize~ out from t~e reaction mixture ~ithout effecting any furt~er process steps and is of high purity. The process is characterised ~y high yield.
Another advantage is that the process can easily be carried out in industrial scale, ~ecause solvents are employed, which are not detrimental to the environment or are not hard to handle. The process is economi~c, ~eaause the energy demand is low and the solvents are cheap.
5-chloro-4-cyanamino-2,1,3-benzothiadiazole used as starting material can be prepared from 5-chloro~4-amino-Z,1,3-benzothiadiazole.
In the following examples al1 temperatures are given in degrees centigrade and are uncorrected, The temperatures refer if not otherwise stated to internal temperature.
~29~3S~7~
_ 3 ~ 500~5699 Example 1~ 5~C~lQrQ-~4~ d?zoli~nr2-~1aminQ~-2,1,3-~enzot~iadiazo~e To a mi~ture of 130 1 xylene and 4~ 1 w~ter are added under nitrogen and stirri~ng 125 kg p~toluene-sul~ni~ aci~d mone~ydrate. The mixture i~ hea~ed to 50~ and then treated wi~t~tn 1 hsur with 44 1 et~ylene~
diamine. T~e mi~xture i~s heated to ~5-~6, T~ereafter 27.6 ~9 S~chloro~
4~cyanami~no-2,1,3-~enzothiadiazole are added within 2 ~ours and the mixture is ~tirred for 2 ~ours at 100 (surface temperature). There-after ~0 1 water are added ~ithin 10 minutes with ~he mixture cooled to 40 during the addition pertod. Thereafter at 40 78 1 30X
sodtum hydroxide solution are added over a 30 minutes period and the mixture cooled to 20~25~.The suspensi~on is centrifuged, the residue washed with 30 1 water and dried 24 hours tn vacuo at a~out 20 mm Hg and 70 to give 30 kg of the title compound, m.p. 223-225~purity~ 98%).
Example 2. 5~hloro-4~2~imidazolin-2-ylamino~2,1,3~enzothiadiazole hydrochlori~de 51.5 kg 5-Chloro-4 (2-~midazolin-2-yl~mino)-2,1~3-ben~othiadiazole in 280 1 dimethylformamide are heated to 80, treated with 1 kg decolorizing carbon in 5 1 dimethylformamide and stirred 15 minutes at 80. The suspension ;s filtered, ;nto the f;ltrate 8.3 kg gaseous HCl are introduced at ~0 and the mixture is stirred for further 30 minutes. After cooling to 20 the mlxture is stirred ~or 2 hours.
The resulting suspension is centrifuged and the solids washed first with dimethyl~ormamide and then with ethanol. The resulting crude salt is refluxed under st~rring in 62 1 water and 240 1 ~5X ethanol until all is d;ssolved. The mixture is treated with I 1 37% hydro-chloric acid to pH 2 and cooled to 0. After centrifuging the crystalline precipitate is washed with ethanol and dried in vacuo (60 nm Hg) a~ 70 (surface temperature). M.P. of the hydrochloride 2~8-290 .
~g576 - 4 - 500~5699 5~Chlor~4~cy~namino-2,1,3~enzst~;~adi~azsle used ~s starti~ny materi~al is Q~tai~ned a~ follow~.
23 ~g ammpni~um rhodanide and ~0 1 acetone are stirred 30 minute at 20~25~. Thereafter 27 1 benzoyl c~loride are ~dded at 20~30 wit~in 30 minutes and the mixture is stirred at 20~25 ~or 20 minutes.
The resulting suspension is centrifuged and the filtrate kept.
37.5 kg 4~Amino~5-chloro~2,1,3-henzothiadiazole and 90 1 acetone are brought to reflux and treated with the above filtrate. The mixture is refluxed for 2 ll2 hours. The reaction is followed by thin layer chromatography. After cooling to 20~25 the suspension is centrifuged. The solid is taken up in 475 1 water, heated to 80 and treated at that temperature with 85 I 30% sodium hydroxide solution within 15 minutes. The clear solution is treated at 80 with 74 kg lead acetate trihydrate wit~in 40 minutes and the mixture is stirred 30 minutes at 80. Thereafter the mixture is cooled to 50, and simultaneously treated with 2 1 phosphoric acid and ca. 5 1 30% sodium hydroxide solution. The mixture is stirred for a further hour at 50. The resulting suspension is centrifuged and the filtrate treated under stirring with 0.3 kg ethylenediaminete-traa~cetic acid disodiumsalt-dihydrate. The mixture is cooled to 20~25 and adjusted to pH 5.5 with ca. 31 1 30% hydrochloric acid.
The mixture is stirred for 30 minutes at 20~25. The resulting s:uspension is centrifuged, the solid dried for 24 hours at about 60 and 20 mm Hg to give 5-chloro~4~cyanamino~2,1,3~benzothiadiazole, m. p . 215 ~220 .
Claims (4)
1. A process for the production of 5-chloro-4-(2-imidazolin-
2-ylamino)-2,1,3-benzothiadiazole characterized by reacting 5-chloro-4-cyanamino-2,1,3-benzothiadiazole with ethylenediamine mono-p-toluenesulfonate in xylene.
2. A process according to claim 1, in which the reaction is effected at a temperature of from 75° to 140°C.
2. A process according to claim 1, in which the reaction is effected at a temperature of from 75° to 140°C.
3. A process according to claim 1, in which the reaction is effected at a temperature of from 80° to 110°C.
4. A process according to claim 1, in which the reaction is effected at a temperature of from 90° to 100°C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3610407.8 | 1986-03-27 | ||
| DE19863610407 DE3610407A1 (en) | 1986-03-27 | 1986-03-27 | Process for the preparation of tizanidine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1299576C true CA1299576C (en) | 1992-04-28 |
Family
ID=6297425
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000532965A Expired - Lifetime CA1299576C (en) | 1986-03-27 | 1987-03-25 | Process for the production of tizanidine |
Country Status (7)
| Country | Link |
|---|---|
| KR (1) | KR960001725B1 (en) |
| AT (1) | AT396237B (en) |
| CA (1) | CA1299576C (en) |
| DE (1) | DE3610407A1 (en) |
| HU (1) | HU197005B (en) |
| IT (1) | IT1216800B (en) |
| MX (1) | MX172623B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110263863A1 (en) * | 2008-12-18 | 2011-10-27 | Pavel Hradil | Method for the preparation of tizanidine hydrochloride |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH579565A5 (en) * | 1973-03-15 | 1976-09-15 | Wander Ag Dr A | Imidazolin-2-ylamino-2,1,3-benzothiadiazoles prodn. - by cyclising corresp. beta aminoethyl (thio) ureas, active against muscle tremors and rigor |
| AU505664B2 (en) * | 1977-04-12 | 1979-11-29 | Wander A.G. | 2, 1, 3-benzothiadiazoles |
-
1986
- 1986-03-27 DE DE19863610407 patent/DE3610407A1/en not_active Withdrawn
- 1986-04-21 HU HU861667A patent/HU197005B/en unknown
-
1987
- 1987-03-24 IT IT8747764A patent/IT1216800B/en active
- 1987-03-25 CA CA000532965A patent/CA1299576C/en not_active Expired - Lifetime
- 1987-03-25 MX MX005705A patent/MX172623B/en unknown
- 1987-03-26 AT AT0073487A patent/AT396237B/en not_active IP Right Cessation
- 1987-04-18 KR KR1019870003738A patent/KR960001725B1/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110263863A1 (en) * | 2008-12-18 | 2011-10-27 | Pavel Hradil | Method for the preparation of tizanidine hydrochloride |
| US8487113B2 (en) * | 2008-12-18 | 2013-07-16 | Farmak, A.S. | Method for the preparation of tizanidine hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| KR960001725B1 (en) | 1996-02-03 |
| IT1216800B (en) | 1990-03-14 |
| HU197005B (en) | 1989-02-28 |
| KR880012600A (en) | 1988-11-28 |
| AT396237B (en) | 1993-07-26 |
| HUT43596A (en) | 1987-11-30 |
| MX172623B (en) | 1994-01-04 |
| IT8747764A0 (en) | 1987-03-24 |
| ATA73487A (en) | 1992-11-15 |
| DE3610407A1 (en) | 1987-10-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |