WO1998038180A1 - Process for the preparation of benzothiazolone compounds - Google Patents

Process for the preparation of benzothiazolone compounds Download PDF

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Publication number
WO1998038180A1
WO1998038180A1 PCT/SE1998/000274 SE9800274W WO9838180A1 WO 1998038180 A1 WO1998038180 A1 WO 1998038180A1 SE 9800274 W SE9800274 W SE 9800274W WO 9838180 A1 WO9838180 A1 WO 9838180A1
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Prior art keywords
formula
compound
prepared
preparation
solution
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Application number
PCT/SE1998/000274
Other languages
French (fr)
Inventor
Christopher Goodwin
Original Assignee
Astra Pharmaceuticals Ltd.
Astra Aktiebolag
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Filing date
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Priority to PL98334901A priority Critical patent/PL334901A1/en
Application filed by Astra Pharmaceuticals Ltd., Astra Aktiebolag filed Critical Astra Pharmaceuticals Ltd.
Priority to JP53756798A priority patent/JP2001513770A/en
Priority to SK1114-99A priority patent/SK111499A3/en
Priority to NZ336877A priority patent/NZ336877A/en
Priority to IL13112198A priority patent/IL131121A0/en
Priority to CA002280010A priority patent/CA2280010A1/en
Priority to HU0000766A priority patent/HUP0000766A3/en
Priority to EP98908361A priority patent/EP0970064A1/en
Priority to AU66407/98A priority patent/AU724616B2/en
Priority to EEP199900373A priority patent/EE9900373A/en
Priority to BR9807785-6A priority patent/BR9807785A/en
Priority to US09/029,831 priority patent/US6087508A/en
Publication of WO1998038180A1 publication Critical patent/WO1998038180A1/en
Priority to IS5162A priority patent/IS5162A/en
Priority to NO994131A priority patent/NO994131L/en
Priority to US09/410,066 priority patent/US6194614B1/en
Priority to US09/410,042 priority patent/US6124468A/en
Priority to US09/410,069 priority patent/US6114578A/en
Priority to US09/411,162 priority patent/US6147219A/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D277/00Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62Benzothiazoles
    • C07D277/68Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00Carboxylic acid amides
    • C07C233/01Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00Carboxylic acid amides
    • C07C233/01Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/35Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/36Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04Derivatives of thiourea
    • C07C335/16Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C335/20Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04Derivatives of thiourea
    • C07C335/24Derivatives of thiourea containing any of the groups, X being a hetero atom, Y being any atom
    • C07C335/26Y being a hydrogen or a carbon atom, e.g. benzoylthioureas
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D277/00Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62Benzothiazoles
    • C07D277/68Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82Nitrogen atoms

Definitions

  • the present invention relates to a process for the preparation of benzothiazolone compounds and to novel intermediates in the process of the invention.
  • Benzothiazolone compounds are known.
  • WO 93/24473 describes 7-(2- aminoethyl)-benzothiazolone compounds of general formula
  • X and Y independently represent -S(O) n - or -O-, n represents 0, 1 or 2, p, q and r independently represent 2 or 3,
  • Z represents phenyl optionally substituted by halogen, -OR , NO2 or NR R ; or a 5- or
  • R , R and R independently represent hydrogen or 1 and pharmaceutically acceptable derivatives thereof.
  • the compounds of WO 93/24473 may be prepared by any of several methods, for example by alkylation of the benzothiazolone compound of formula I
  • the present invention relates in particular to a novel process for the synthesis of compound I.
  • the compound of formula II is novel and may be prepared by halogenating the 2- aminobenzothiazole compound of formula III, for example using copper (II) chloride and copper (I) chloride and optionally ethanol, in HC1, e.g., 20% HC1 to which is added sodium nitrite:
  • the compound of formula III is novel and may be prepared from a thiourea of formula IV,
  • a halogenating/oxidising agent for example N-bromosuccinimide, bromine or N- chlorosuccinimide in an acidic solvent, e.g., a mixed acid solvent e.g. MeSO 3 H/AcOH.
  • the compound of formula IV is novel and may be prepared by hydrolysis of a compound of formula V
  • NHCOPh for example in water using a base such as K 2 CO 3 or an alkali metal hydroxide, e.g. NaOH or KOH.
  • a base such as K 2 CO 3 or an alkali metal hydroxide, e.g. NaOH or KOH.
  • the compound of formula V is novel and may be prepared by reacting an aniline hydrochloride of formula VI
  • benzoylisothiocyanate for example in acetone or methylisobutylketone (MIBK).
  • the compound of formula VI is novel and may be prepared by hydrogenating a nitroacetamide of formula VII and treating with HC1
  • the compound of formula VII is novel and may be prepared by nitrating an acetamide of formula VIII
  • the compound of formula VIII may be prepared from a compound of formula IX:
  • the present invention provides a process for the preparation of compounds of formula I, comprising (i) converting a compound of formula IX into a compound of formula VIII, for example using acetic anhydride or acetyl chloride, either as solvent and reagent, or in the presence of dichloromethane and triethylamine, and (ii) converting the compound of formula VIII into the compound of formula I, for example by the stepwise preparation of compounds VII, VI, V, IV, III and II as described above.
  • the process of the present invention provides an easy process for the preparation of compound II, without the need to use undesirable starting materials, and giving the product compound in good yield.
  • the present invention also provides the novel compounds of formulae II, III, IV, V, VI and VII.
  • the reaction mixture was poured into iced water (2.7L) forming a precipitate/ suspension.
  • the product oiled out on stirring at room temperature.
  • the mixture was extracted with dichloromethane (2xlL).
  • a sample of the extract was washed with NaHCO3 dried and concentrated for analysis.
  • the extract was washed with saturated Na2CO3 solution (2xlL), causing the extract to become saturated with water.
  • the extract was diluted slightly with dichloromethane ( ⁇ 100 ml), then dried over anhydrous MgSO_ ⁇ , filtered and concentrated, in vacuo.
  • Ammonium thiocyanate (12.35 g) was dissolved in acetone (AR grade, 120 ml) and benzoylchloride (17.3 ml) was added drop wise with stirring over 2 mins. The temperature rose from 22° C to 38° C over the addition and a white precipitate formed. The reaction was stirred at room temperature for a further 75 mins and then filtered, and washed with acetone (20 ml) to give a solution of benzoylisothiocyanate. This was added dropwise with stirring to the amine solution, over 40 mins. The temperature rose from 23° C to 36° C during the addition. A thick cream precipitate formed. The reaction was allowed to stir at room temperature for 16 hours and then the product was collected by filtration, washed with water (30 ml), sucked dry and then dried in vacuo at 60° C.
  • the mixture was cooled to room temperature with the aid of a cold water bath and then acidified to pH 7-8 using hydrochloric acid ( ⁇ 4N, 80 ml).
  • the mixture was cooled further in an ice bath - internal temp to 5° C, stirred cold for 15 mins and the product collected by filtration, washed with water (50 ml) and sucked dry. Dried in vacuo at 50° C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

There are described processes for the preparation of a compound of formula (I), and novel intermediates in the preparative process.

Description

PROCESS FOR THE PREPARATION OF BENZOTHIAZOLONE COMPOUNDS
The present invention relates to a process for the preparation of benzothiazolone compounds and to novel intermediates in the process of the invention.
Benzothiazolone compounds are known. For example, WO 93/24473 describes 7-(2- aminoethyl)-benzothiazolone compounds of general formula
CH2CH2-NH-(CH2)p-X-(CH2)q-Y-(CH2)r-Z S
N OH H
wherein
X and Y independently represent -S(O)n- or -O-, n represents 0, 1 or 2, p, q and r independently represent 2 or 3,
1 2 3
Z represents phenyl optionally substituted by halogen, -OR , NO2 or NR R ; or a 5- or
6-membered N, O, or S containing heterocycle, and
1 2 3
R , R and R independently represent hydrogen or 1 and pharmaceutically acceptable derivatives thereof.
The compounds of WO 93/24473 may be prepared by any of several methods, for example by alkylation of the benzothiazolone compound of formula I
Figure imgf000003_0001
with an alkylating agent of formula
L-(CH2)p-X-(CH2)q-Y-(CH2)r-Z
in which p, q, r, X, Y and Z are as defined above and L represents a leaving group, or alkylation of a compound of formula I, as defined above, with a compound of formula,
0=CH-(CH2)p.1-X-(CH2)q-Y-(CH2)r-Z
in which p, q, r, X, Y and Z are as defined above, in the presence of a reducing agent.
The present invention relates in particular to a novel process for the synthesis of compound I.
Routes for the synthesis of the compound are known, for example from Weinstock et al, J. Med. Chem., 1987, 30, 1166-1176.
According to the present invention, a process for the preparation of the compound of formula I
Figure imgf000004_0001
comprises converting the chlorobenzothiazole compound of formula II
Figure imgf000005_0001
into the compound or formula I, for example using concentrated hydrobromic acid.
The compound of formula II is novel and may be prepared by halogenating the 2- aminobenzothiazole compound of formula III, for example using copper (II) chloride and copper (I) chloride and optionally ethanol, in HC1, e.g., 20% HC1 to which is added sodium nitrite:
Figure imgf000005_0002
The compound of formula III is novel and may be prepared from a thiourea of formula IV,
Figure imgf000005_0003
NH2 using a halogenating/oxidising agent, for example N-bromosuccinimide, bromine or N- chlorosuccinimide in an acidic solvent, e.g., a mixed acid solvent e.g. MeSO3H/AcOH.
The compound of formula IV is novel and may be prepared by hydrolysis of a compound of formula V
Figure imgf000006_0001
NHCOPh for example in water using a base such as K2CO3 or an alkali metal hydroxide, e.g. NaOH or KOH.
The compound of formula V is novel and may be prepared by reacting an aniline hydrochloride of formula VI
Figure imgf000006_0002
with benzoylisothiocyanate, for example in acetone or methylisobutylketone (MIBK).
The compound of formula VI is novel and may be prepared by hydrogenating a nitroacetamide of formula VII and treating with HC1
Figure imgf000006_0003
in any suitable solvent, for example in ethanol or 2-propanol, in the presence of palladium on charcoal.
The compound of formula VII is novel and may be prepared by nitrating an acetamide of formula VIII
Figure imgf000006_0004
for example using HNO3 in acetic acid.
The compound of formula VIII may be prepared from a compound of formula IX:
Figure imgf000007_0001
for example using acetic anhydride or acetyl chloride, either as solvent and reagent, or in the presence of dichloromethane and triethylamine.
In another aspect, the present invention provides a process for the preparation of compounds of formula I, comprising (i) converting a compound of formula IX into a compound of formula VIII, for example using acetic anhydride or acetyl chloride, either as solvent and reagent, or in the presence of dichloromethane and triethylamine, and (ii) converting the compound of formula VIII into the compound of formula I, for example by the stepwise preparation of compounds VII, VI, V, IV, III and II as described above.
The process of the present invention provides an easy process for the preparation of compound II, without the need to use undesirable starting materials, and giving the product compound in good yield.
The present invention also provides the novel compounds of formulae II, III, IV, V, VI and VII.
The following Example illustrates, but is not intended to limit, the invention.
a) Under an atmosphere of nitrogen, 2-(4-methoxyphenyl)ethylamine (100 g) was dissolved in dichloromethane. To this triethylamine (92.18 ml) was added and the resulting solution was cooled to 0° C. Acetic anhydride (62.40 ml) was added dropwise, over 35 mins, to the cold solution. A maximum exotherm of 6° C was observed. The reaction mixture was stirred at room temperature for 40 mins. Tic showed no trace of starting material on complete addition.
The reaction mixture was washed with dilute hydrochloric acid (2xlL) and saturated
NaHCO3 solution (2xlL) then dried over anhydrous MgSO4, filtered and concentrated, in vacuo. to yield an off-white solid. This was dried, in vacuo. (T = 40° C).
b) A solution of 2-(4-methoxyphenyl)ethylacetamide (70 g) in glacial acetic acid (350 ml) was added, over 25 mins, to cone, nitric acid (339.6 ml) at 20° C. Cooling was applied so that the temperature was maintained between 18 and 20° C. The resulting solution was stirred at room temperature (24° C) for 45 mins. Reaction progress was monitored by HPLC.
The reaction mixture was poured into iced water (2.7L) forming a precipitate/ suspension. The product oiled out on stirring at room temperature. The mixture was extracted with dichloromethane (2xlL). A sample of the extract was washed with NaHCO3 dried and concentrated for analysis. The extract was washed with saturated Na2CO3 solution (2xlL), causing the extract to become saturated with water. The extract was diluted slightly with dichloromethane (~ 100 ml), then dried over anhydrous MgSO_ι, filtered and concentrated, in vacuo.
c) 2-(4-Methoxy-3-nitrophenyl)ethylacetamide (4.82 g) was dissolved in hot ethyl acetate (9.5 ml), then left to cool to room temperature. Cooling to 0° C resulted in the formation of yellow crystals. These were filtered off, washed with cold ethyl acetate, and dried in vacuo (T = 40° C).
d) 2-(4-Methoxy-3-nitrophenyl)ethylacetamide (5.98 g) was dissolved in ethanol (150 ml), 10% palladium on charcoal (0.18 g) was added and the resulting mixture was hydrogenated at 3 bar, overnight. The catalyst was filtered off and the filtrate concentrated to approximately one third of its volume. The solution was then gassed with hydrogen chloride until with cooling, a pale brown solid precipitated out. The mixture was allowed to stir overnight. The off- white solid was filtered off, washed with diethyl ether then dried, in vacuo. (T = 50° C).
e) The aniline hydrochloride (40.0 g) was dissolved in water (200 ml) and basified with aqueous sodium hydroxide solution (25% w/v) to pH « 1 1, extracted with dichloromethane (100 ml x 3), dried (Na2SO_ι) and evaporated to dryness in vacuo to leave a pale pink solid. The solid was dissolved in acetone (140 ml).
Ammonium thiocyanate (12.35 g) was dissolved in acetone (AR grade, 120 ml) and benzoylchloride (17.3 ml) was added drop wise with stirring over 2 mins. The temperature rose from 22° C to 38° C over the addition and a white precipitate formed. The reaction was stirred at room temperature for a further 75 mins and then filtered, and washed with acetone (20 ml) to give a solution of benzoylisothiocyanate. This was added dropwise with stirring to the amine solution, over 40 mins. The temperature rose from 23° C to 36° C during the addition. A thick cream precipitate formed. The reaction was allowed to stir at room temperature for 16 hours and then the product was collected by filtration, washed with water (30 ml), sucked dry and then dried in vacuo at 60° C.
f) The N-benzoylthiourea (45.0 g) was suspended in water (330 ml). Sodium hydroxide solution (25 % w/v, 58 ml) was added and the stirred mixture heated to 75-80°C for 20 minutes.
The mixture was cooled to room temperature with the aid of a cold water bath and then acidified to pH 7-8 using hydrochloric acid (~ 4N, 80 ml). The mixture was cooled further in an ice bath - internal temp to 5° C, stirred cold for 15 mins and the product collected by filtration, washed with water (50 ml) and sucked dry. Dried in vacuo at 50° C.
g) Under an atmosphere of nitrogen, glacial acetic acid (112 ml) was added to methanesulfonic acid (823 ml). Cooling was required to keep the temperature below 30° C. The thiourea (93.5 g) was added to the resulting solution at 28° C. The resulting solution was cooled to 2° C for the addition over 30 mins, of a solution of N- bromosuccinimide (59.14 g) in methanesulfonic acid (187 ml). The temperature was maintained between 2 and 5° C. The resulting solution was stirred at ~2° C for 1 hour then allowed to stir at room temperature (max temp of 30° C observed) for 22 hours. Reaction progress was monitored by HPLC. The reaction mixture was transferred to a dropping funnel then added, over 3.5 hours to a 25% solution of sodium hydroxide (4.675L) at 4° C. The temperature was maintained below 1 1°C for the whole addition. An off-white solid precipitated from the reaction quench. The mixture was stirred between 7-10° C for 1.25 hours then filtered. The solid was washed with water (2x200 ml), sucked dry, then dried in vacuo. (T = 50° C) to yield an off-white solid.
h) Under an atmosphere of nitrogen, 2-amino-benzothiazole (5 g) was dissolved in concentrated hydrochloride acid at 22° C. To this was added copper (II) chloride
(1.26 g), copper(I) chloride (0.93 g) and ethanol (0.32 g). Complete dissolution of the aminobenzothiazole was observed. The solution was cooled to 15° C for the gradual addition, over 1.75 hours, of an aqueous solution of sodium nitrite (3.9 g) - added below the surface of the reaction mixture via a syringe pump. The temperature was maintained between 13 and 18° C. N2 evolution was observed. The reaction progress was monitored by HPLC. After 1.75 hours stirring at room temperature, the reaction mixture was quenched, over 5 mins, into stirred water at room temperature. A milky yellow solution was formed in which the product oiled out towards the end of the addition. The mixture was stirred for -60 hours. The solid was filtered off, washed with water (250 ml), air dried then dried, in vacuo (T = 55 C), yielding on orange solid. i) The chlorobenzothiazole (15.0 g) was suspended in concentrated hydrobromic acid (165 ml) under a nitrogen atmosphere and the mixture heated under reflux for 7.5 hours. The mixture was allowed to cool overnight and the precipitated product was collected by filtration, washed with isopropanol (20 ml) and sucked dry to give a yellow-brown powder which was dried in vacuo at 45° C.
j) The hydrobromide salt (13.3g) was suspended in water (130 ml) and warmed to 80 - 90° C under a nitrogen atmosphere. Further water (20 ml) was added. Charcoal (1.1 g) was added and the solution/suspension stirred at ~70° C for 15 minutes and then filtered hot to give a clear solution.
Concentrated hydrochloric acid (18 ml) was added to the filtrate and the mixture left to stir under nitrogen overnight. The solid was collected by filtration, washed with iso- propanol (20 ml) and sucked dry to give a yellow powder, which was dried in vacuo at
45° C.
The product (5.0 g) was suspended in water (50 ml) under a nitrogen atmosphere and warmed to ~70° C. Charcoal (0.3 g) was added and the mixture stirred for 10 minutes and then filtered slowly to give a pale yellow solution. Concentrated hydrochloric acid
(7 ml) was added and the mixture stirred and allowed to cool under nitrogen. The precipitated product was collected by filtration, washed with isopropanol (10 ml), sucked dry to give a pale yellow powder, and dried in vacuo at 45° C.

Claims

Claims
1. A process for the preparation of the compound of formula I
Figure imgf000012_0001
comprising converting the chlorobenzothiazole compound of formula II
Figure imgf000012_0002
into the compound of formula I.
2. A process as claimed in claim 1 wherein the compound of formula II is prepared by halogenating the 2-aminobenzothiazole compound of formula III:
Figure imgf000012_0003
3. A process as claimed in claim 2 wherein the compound of formula III is prepared from a thiourea of formula IV,
Figure imgf000013_0001
NH2 using a halogenating/oxidising agent.
4. A process as claimed in claim 3, wherein the compound of formula IV is prepared by 5 hydrolysis of a compound of formula V:
Figure imgf000013_0002
NHCOPh
5. A process as claimed in claim 4, wherein the compound of formula V is prepared by 10 reacting an aniline hydrochloride of formula VI
Figure imgf000013_0003
with benzoylisothiocyanate.
i5
6. A process as claimed in claim 5, wherein the compound of formula VI is prepared by hydrogenating a nitroacetamide of formula VII and treating with HC1
Figure imgf000013_0004
in any suitable solvent.
7. A process as claimed in claim 6, wherein the compound of formula VII is prepared by nitrating an acetamide of formula VIII:
Figure imgf000014_0001
8. A process as claimed in claim 7, wherein the compound of formula VIII is prepared from a compound of formula IX:
Figure imgf000014_0002
for example using acetic anhydride or acetyl chloride, either as solvent and reagent, or in the presence of dichloromethane and triethylamine.
9. A process for the preparation of compounds of formula I, comprising (i) converting a compound of formula IX into a compound of formula VIII, and (ii) converting the compound of formula VIII into the compound of formula I.
10. Compounds of formula X
Figure imgf000014_0003
wherein Y is H and X is selected from the group NO2, NH2-HC1, NH-CS-NHCOPh and NH-CS-NH2, or X and Y together form a five membered ring, as in formula II or III.
11. A compound of formula II:
H-
Figure imgf000015_0001
12. A compound of formula III:
Figure imgf000015_0002
13. A compound of formula IV:
Figure imgf000015_0003
N
14. A compound of formula V:
Figure imgf000015_0004
NHCOPh
15. A compound of formula VI:
Figure imgf000016_0001
16. A compound of formula VII:
Figure imgf000016_0002
PCT/SE1998/000274 1997-02-27 1998-02-17 Process for the preparation of benzothiazolone compounds WO1998038180A1 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
EP98908361A EP0970064A1 (en) 1997-02-27 1998-02-17 Process for the preparation of benzothiazolone compounds
JP53756798A JP2001513770A (en) 1997-02-27 1998-02-17 Method for producing benzothiazolone compound
SK1114-99A SK111499A3 (en) 1997-02-27 1998-02-17 Process for the preparation of benzothiazolone compounds
NZ336877A NZ336877A (en) 1997-02-27 1998-02-17 Process for the preparation of benzothiazolone compounds
IL13112198A IL131121A0 (en) 1997-02-27 1998-02-17 Process for the preparation of benzothiazolone compounds
CA002280010A CA2280010A1 (en) 1997-02-27 1998-02-17 Process for the preparation of benzothiazolone compounds
EEP199900373A EE9900373A (en) 1997-02-27 1998-02-17 Process for the preparation of benzothiazolone compounds
AU66407/98A AU724616B2 (en) 1997-02-27 1998-02-17 Process for the preparation of benzothiazolone compounds
HU0000766A HUP0000766A3 (en) 1997-02-27 1998-02-17 Process for the preparation of benzothiazolone derivatives
PL98334901A PL334901A1 (en) 1997-02-27 1998-02-17 Method of obtaining benzothiazolones
BR9807785-6A BR9807785A (en) 1997-02-27 1998-02-17 Process for the preparation of the compound, e, compound
US09/029,831 US6087508A (en) 1997-02-27 1998-02-17 Process for the preparation of benzothiazolone compounds
IS5162A IS5162A (en) 1997-02-27 1999-08-23 Process for producing compounds from benzothiazolone
NO994131A NO994131L (en) 1997-02-27 1999-08-26 Procedure for the preparation of benzothiazolone compounds
US09/410,066 US6194614B1 (en) 1997-02-27 1999-10-01 Process for the preparation of benzothiazolone compounds
US09/410,042 US6124468A (en) 1997-02-27 1999-10-01 Process for the preparation of benzothiazolone compounds
US09/411,162 US6147219A (en) 1997-02-27 1999-10-01 Process for the preparation of benzothiazolone compounds
US09/410,069 US6114578A (en) 1997-02-27 1999-10-01 Process for the preparation of benzothiazolone compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9700706A SE9700706D0 (en) 1997-02-27 1997-02-27 Process for the preparation of benzothiazoline compounds
SE9700706-6 1997-02-27

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US09/029,831 Continuation US6087508A (en) 1997-02-27 1998-02-17 Process for the preparation of benzothiazolone compounds
US09/410,068 Division US6232498B1 (en) 1998-01-30 1999-10-01 Process for the preparation of benzothiazolone compounds

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US7700782B2 (en) 2006-12-20 2010-04-20 Astrazeneca Ab Compounds 569
US7709511B2 (en) 2005-08-09 2010-05-04 Astrazeneca Ab Benzothiazolone derivatives
US7951954B2 (en) 2006-03-14 2011-05-31 Astrazeneca Ab Bezothiazol derivatives as Beta2 adrenoreceptor agonists
US8017602B2 (en) 2008-06-18 2011-09-13 Astrazeneca Ab N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethylamino)ethyl)-3-(phenethoxy)propanamide derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy
US8058294B2 (en) 2007-02-08 2011-11-15 Astrazeneca Ab Pharmaceutical salts of N-[2-(diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-3-[2-(1-napthyl)ethoxy]propanamide

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US7158870B2 (en) * 2002-01-24 2007-01-02 Ford Global Technologies, Llc Post collision restraints control module
US7270805B1 (en) * 2006-03-30 2007-09-18 Conopco, Inc. Skin lightening agents, compositions and methods

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7709511B2 (en) 2005-08-09 2010-05-04 Astrazeneca Ab Benzothiazolone derivatives
US7951954B2 (en) 2006-03-14 2011-05-31 Astrazeneca Ab Bezothiazol derivatives as Beta2 adrenoreceptor agonists
US7700782B2 (en) 2006-12-20 2010-04-20 Astrazeneca Ab Compounds 569
US8058294B2 (en) 2007-02-08 2011-11-15 Astrazeneca Ab Pharmaceutical salts of N-[2-(diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-3-[2-(1-napthyl)ethoxy]propanamide
US8017602B2 (en) 2008-06-18 2011-09-13 Astrazeneca Ab N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethylamino)ethyl)-3-(phenethoxy)propanamide derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy

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IS5162A (en) 1999-08-23
IL131121A0 (en) 2001-01-28
EP0970064A1 (en) 2000-01-12
NO994131D0 (en) 1999-08-26
AU6640798A (en) 1998-09-18
KR20000075720A (en) 2000-12-26
HUP0000766A2 (en) 2000-10-28
CN1083447C (en) 2002-04-24
US6114578A (en) 2000-09-05
SE9700706D0 (en) 1997-02-27
BR9807785A (en) 2000-02-22
ID22430A (en) 1999-10-14
CN1248252A (en) 2000-03-22
HUP0000766A3 (en) 2001-12-28
NO994131L (en) 1999-08-26
US6118024A (en) 2000-09-12
US6124468A (en) 2000-09-26
EE9900373A (en) 2000-04-17
US6194614B1 (en) 2001-02-27
US6147219A (en) 2000-11-14
CA2280010A1 (en) 1998-09-03
JP2001513770A (en) 2001-09-04
NZ336877A (en) 2001-07-27
AU724616B2 (en) 2000-09-28
SK111499A3 (en) 2000-05-16
PL334901A1 (en) 2000-03-27
TR199902057T2 (en) 2000-02-21
US6087508A (en) 2000-07-11

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