MXPA99007649A - Process for the preparation of benzothiazolone compounds - Google Patents
Process for the preparation of benzothiazolone compoundsInfo
- Publication number
- MXPA99007649A MXPA99007649A MXPA/A/1999/007649A MX9907649A MXPA99007649A MX PA99007649 A MXPA99007649 A MX PA99007649A MX 9907649 A MX9907649 A MX 9907649A MX PA99007649 A MXPA99007649 A MX PA99007649A
- Authority
- MX
- Mexico
- Prior art keywords
- formula
- compound
- prepared
- dried
- preparation
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- BXQNSPXDWSNUKE-UHFFFAOYSA-N 1,3-benzothiazole 1-oxide Chemical class C1=CC=C2S(=O)C=NC2=C1 BXQNSPXDWSNUKE-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 5
- WETWJCDKMRHUPV-UHFFFAOYSA-N Acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- MMCPOSDMTGQNKG-UHFFFAOYSA-N Anilinium chloride Chemical compound Cl.NC1=CC=CC=C1 MMCPOSDMTGQNKG-UHFFFAOYSA-N 0.000 claims description 3
- UMGDCJDMYOKAJW-UHFFFAOYSA-N Thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- CPEKAXYCDKETEN-UHFFFAOYSA-N benzoyl isothiocyanate Chemical compound S=C=NC(=O)C1=CC=CC=C1 CPEKAXYCDKETEN-UHFFFAOYSA-N 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 2
- -1 chlorobenzothiazole compound Chemical class 0.000 claims description 2
- 238000005658 halogenation reaction Methods 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000005984 hydrogenation reaction Methods 0.000 claims 1
- 230000001590 oxidative Effects 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000000203 mixture Substances 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 238000007792 addition Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- ORTQZVOHEJQUHG-UHFFFAOYSA-L Copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-Bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- VWDWKYIASSYTQR-UHFFFAOYSA-N Sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 229960000583 Acetic Acid Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- UHGULLIUJBCTEF-UHFFFAOYSA-N 1,3-benzothiazol-2-amine Chemical compound C1=CC=C2SC(N)=NC2=C1 UHGULLIUJBCTEF-UHFFFAOYSA-N 0.000 description 2
- BSQLQMLFTHJVKS-UHFFFAOYSA-N 2-chloro-1,3-benzothiazole Chemical compound C1=CC=C2SC(Cl)=NC2=C1 BSQLQMLFTHJVKS-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 239000003245 coal Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- 239000004317 sodium nitrate Substances 0.000 description 2
- 235000010344 sodium nitrate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing Effects 0.000 description 2
- WSMPABBFCFUXFV-UHFFFAOYSA-N 6-amino-2-[[2-amino-3-(1H-imidazol-5-yl)propanoyl]amino]hexanoic acid;hydrobromide Chemical compound Br.NCCCCC(C(O)=O)NC(=O)C(N)CC1=CN=CN1 WSMPABBFCFUXFV-UHFFFAOYSA-N 0.000 description 1
- SOIFLUNRINLCBN-UHFFFAOYSA-N Ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M Copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- PWBJWDKDPAPGED-UHFFFAOYSA-N N'-chlorobutanediamide Chemical compound NC(=O)CCC(=O)NCl PWBJWDKDPAPGED-UHFFFAOYSA-N 0.000 description 1
- GWFRSQBGIGLMFD-BBKOCAQVSA-N N-[9-[(2R,3R,4S,5R)-5-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-3,4-dihydroxyoxolan-2-yl]purin-6-yl]-2-phenoxyacetamide Chemical compound C1=CC(OC)=CC=C1C(C=1C=CC(OC)=CC=1)(C=1C=CC=CC=1)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C3=NC=NC(NC(=O)COC=4C=CC=CC=4)=C3N=C2)O1 GWFRSQBGIGLMFD-BBKOCAQVSA-N 0.000 description 1
- DQMWMUMCNOJLSI-UHFFFAOYSA-N N-carbamothioylbenzamide Chemical compound NC(=S)NC(=O)C1=CC=CC=C1 DQMWMUMCNOJLSI-UHFFFAOYSA-N 0.000 description 1
- IOUNQDKNJZEDEP-UHFFFAOYSA-N Phosalone Chemical class C1=C(Cl)C=C2OC(=O)N(CSP(=S)(OCC)OCC)C2=C1 IOUNQDKNJZEDEP-UHFFFAOYSA-N 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000001272 nitrous oxide Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 239000003638 reducing agent Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
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 BENZOTIAZOLONE COMPOUNDS.
Field of Invention
The present invention relates to processes for the preparation of benzothiazolones and to novel intermediates in the process of the invention.
Background of the Invention
The benzo ia zolone compounds are known. For example, WO 93/24473 discloses compounds of .7 - (2-amino-thi-1) -benzothiazolone of the general formula
where X and Y independently represent -S (0) n- u
-o-, n represents 0, 1 or 2,
Ref: 030910
p, qyr independently represent 2 or 3, Z represents phenyl optionally substituted by halogen, -ORJ N02 NR2R3, a 5- or 6-membered heterocycle containing N, O, or S, and R1, R2 and R3 independently represent hydrogen or C-alkyl? _6, and pharmaceutically acceptable derivatives thereof.
The compounds of WO 93/24473 can be prepared by any of several methods, for example by alkylation of the benzothiazone compound of formula I
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 starting group,
or the alkylation of a compound of formula I, as defined above, with a compound of formula,
0 = CH- (CH2) P -? - X- (CH2) q-Y- (CH2) r-Z
wherein p, q, r, X, Y, and Z are as defined above, in the presence of a reducing agent.
Description of the invention
The present invention relates in particular to a novel process for the synthesis of a compound I.
The routes for the synthesis of the compounds are known, for example from Weinstock et al, J. Med. Ch em. , 1987, 30, 1166-1176.
In accordance with the present invention, a process for the preparation of the compound of formula I
it comprises converting the compound of chlorobenzothiazole of formula II
in the compound or formula I, for example using concentrated hydrobromic acid.
The compounds of formula II is novel and can be prepared by halogenation of the 2-aminobenzothiazole compound of formula III, for example using copper (II) chloride and copper (I) chloride and optionally, in HCl, for example 20% of HCl to add sodium nitrate:
The compound of formula III is novel and can be prepared from a thiourea of formula IV,
NH "
using a halogenant and / or oxidant agent, for example N-bromosuccinimide, bromide or N-chlorosuccinamide in an acidic solvent, for example a mixed acid solvent for example MeS03H / AcOH.
The compound of formula IV is novel and can be prepared by hydrolysis of a compound of formula V
NHCOPh
for example in water using a base such as K2C03 or an alkali metal hydroxide, for example NaOH or KOH.
The compound of formula V is novel and can be prepared by reacting an aniline hydrochloride of formula VI
with benzoylisothiocyanate, for example in acetone or methylisobutylcetone (MIBK).
The compound of formula VI is novel and can be prepared by hydrogenating a nitrous oxide of formula VII and treating with HCl
in any suitable solvent, for example in ethanol or 2-propanol, in the presence of palladium or mineral coal.
The compound of formula VII is novel and can be prepared by treatment with nitrate of an acetamide of formula VIII
for example using HN03 in acetic acid
The compound of formula VII can be prepared from a compound of formula IX:
for example using acetic anhydride or acetyl chloride, either as solvent or 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, which comprises (i) converting a compound of formula IX into a
compound of formula VIII, for example using acetic anhydride or acetyl chloride, either as a solvent or reagent, or in the presence of dichloromethane and triethylamine, and (ii) converting the compound of formula VIII to the compound of formula I, for example the gradual 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 for the use of undesirable starting materials, and giving the compounds of the product in good yield.
The present invention also provides the novel compounds of the formulas II, III, IV, V, VI and VII.
The following Examples illustrate, but do not intend to limit, the invention.
a) Under a nitrogen atmosphere, 2- (-methyxyphenyl) e t i lamina (100 g) was dissolved in dichloromethane. To this was added triethylamine (92.18 ml) and the
The resulting solution was cooled to 0 ° C. Acetic anhydride (62.40 ml) was added dropwise, during 35 minutes, to the cold solution. An exothermic maximum of 6 ° C was observed. The reaction mixture was stirred at room temperature for 40 minutes. The Tic showed no trace of starting material in the completed addition.
The reaction mixture was washed with dilute hydrochloric acid (2 x 1L) and saturated NaHCO 3 solution (2xlL) and then dried over anhydrous MgSO 4, filtered and concentrated, in vacuo, to yield an off white solid. This was dried in vacuo, (T \ = 40 ° CJ ._
b) A solution of 2- (4-methyl t-oxy phenyl) t-tilate (70 g) in glacial acetic acid (350 ml) was added, over 25 minutes, to concentrated nitric acid (339.6 ml) at 20 ° C. Cooling was applied so that the temperature stayed between 18 and 20 ° C. The resulting solution was stirred at room temperature (24 ° C) for 45 minutes. The progress of the reaction was monitored by CLAP.
The reaction mixture was poured into ice water (2.7L) to form a precipitate / suspension. The product was oiled off under stirring at room temperature. The mixture was extracted with dichloromethane (2xlL). A sample of the extract was washed with NaHCO 3, dried and concentrated for analysis. The extract was washed with a saturated Na2C03 solution (2xlL), causing the extract to be re-saturated with water. The extract was slightly diluted with dichloromethane (~100 mL), and then dried over anhydrous gSO4, filtered and concentrated, in vacuo.
c) 2 - (- Methoxy-3-nitrophenyl) ethylacece tamide (4.82 g) was dissolved in hot ethyl acetate (9.5 ml), then cooled laterally to room temperature. Cooling to 0 ° C resulted in the formation of yellow crystals. These were completely filtered, washed with cold ethyl acetate, and dried in vacuo (T = 40 ° C).
d) 2- (-methoxy-3-nitrophenyl) ethylacecetamide (5.98 g) was dissolved in ethanol (150 ml), 10% palladium in mineral coal was added
(0.18 g) and the resulting mixture was hydrogenated at 3 bar, overnight.
The catalyst was completely filtered and the filtrate was concentrated to about one third of this volume. The solution was then gassed with hydrogen chloride until cooled, a pale brown solid precipitate emerged. The mixture was allowed to stir overnight. The off white solid was filtered off completely, washed with diethyl ether and then dried, in vacuo, (T = 50 ° C).
e) Aniline hydrochloride (40.0 g) was dissolved in water (200 ml) and basified with an aqueous sodium hydroxide solution (25% weight / volume) to a pH of 11, extracted with dichloromethane (100 ml). x 3), dried (Na 2 SO 4) and evaporated to dry in vacuo to give 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 benzochloride (17.3 ml) was added dropwise with stirring for 2 minutes. The temperature rose from
22 ° C to 38 ° C during the addition and a white precipitate formed. the reaction was stirred at room temperature for an additional 75 minutes and then filtered, and washed with acetone (20 ml) to give a benzoylisothiocyanate solution. This was added dropwise with stirring to the amine solution, for 40 minutes. The temperature rose from 23 ° C to 36 ° C during the addition. A thick creamy 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), dried by suction and then dried in vacuo at 60 ° C.
f) The N-benzoyl thiourea (45.0 g) was suspended in water (330 ml). A solution of sodium hydroxide (25% w / v, 58 ml) was added and the stirred mixture was 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 a pH of 7-8 using hydrochloric acid (~ 4N, 80 ml).
The mixture was further cooled in an ice bath with an internal temperature of 5 ° C, stirred cold for 15 minutes and the product was collected by filtration, washed with water (50 ml) and dried by suction. It was dried in vacuo at 50 ° C.
g) Under a nitrogen atmosphere, glacial acetic acid (112 ml) was added to methanesulfonic acid (823 ml). Cooling was required to take care of the temperature between 30 ° C. 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 minutes 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, and then allowed to stir at room temperature (maximum observed temperature of 30 ° C) for 22 hours. The progress of the reaction was monitored by CLAP. The reaction mixture was transferred to a dropping funnel and then added, for 3.5 hours, to a 25% solution of sodium hydroxide (4.675L) at 4 ° C. The temperature was kept under 11 ° C for the complete addition. A white solid precipitate
Shut off the reaction off. The mixture was stirred between 7-10 ° C for 1.25 hours and then filtered. The solid was washed with water (2x200 ml), dried by suction, and then dried in vacuo, (T = 50 ° C) to yield an off white solid.
h) Under a nitrogen atmosphere, 2-amino-benzothiazole (5 g) was dissolved in concentrated hydrochloric acid at 22 ° C. To this was added copper chloride (II) (1.26 g), copper chloride (I) (0.93 g) and ethanol (0.32 g). The complete dissolution of the aminobenzothiazole was observed. The solution was cooled to 15 ° C by the gradual addition, during 1.75 hours, of an aqueous solution of sodium nitrate (3.9 g) added under the surface of the reaction mixture by means of a pumping syringe. The temperature was maintained between 13 and 18 ° C. The evolution of N2 was observed. The progress of the reaction was monitored by CLAP. After 1.75 hours of stirring at room temperature, the reaction mixture was quenched, during 5 minutes, in water stirred at room temperature. A milky yellow solution was formed in which the oiled product was near the end of the addition. The mixture was stirred for ~ 60 hours. The solid leaked
Completely, it was washed with water (250 ml), dried with air and then dried, in vacuo (T = 55 ° C), producing an orange solid.
i) Chlorobenzothiazole (15.0 g) was suspended in concentrated hydrobromic acid (165 ml) under a nitrogen atmosphere and the mixture was 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 dried by suction to give a brown yellow powder which was dried in vacuo at 45 ° C.
j) The hydrobromide salt (13.3 g) was suspended in water (130 ml) and warmed to 80-90 ° C under a nitrogen atmosphere. Additional water was added (20 ml). Mineral carbon (1.1 g) was added and the solution / suspension was 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 was stirred laterally under nitrogen overnight. The solid is
collected by filtration, washed with isopropanol (20 ml) and dried by suction 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. Mineral carbon (0.3 g) was added and the mixture was stirred for 10 minutes and then slowly filtered to give a pale yellow solution. Concentrated hydrochloric acid (7 ml) was added and the mixture was stirred and allowed to cool under nitrogen. The precipitated product was collected by filtration, washed with isopropanol (10 ml), dried by suction to give a pale yellow powder, and dried in vacuo at 45 ° C.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Having described the invention as above, the content of the following is claimed as property.
Claims (16)
1. A process for the preparation of the compound of formula I characterized in that it comprises converting the chlorobenzothiazole compound of formula II in the compound of formula I.
2. The process as claimed in claim 1, characterized in that the compound of formula II is prepared by the halogenation of the compound 2-aminobenzo t ia zol of formula III:
3. The process as claimed in claim 2, characterized in that the compound of formula III is prepared from a thiourea of formula IV, using a halogenated agent / oxidant
4. The process as claimed in claim 3, characterized in that the compound of formula IV is prepared by the hydrolysis of a compound of formula V: NHCOPh
5. The process as claimed in claim 4, characterized in that the compound of formula V is prepared by reacting an aniline hydrochloride of formula VI with benzoylisothiocyanate
6. The process as claimed in claim 5, characterized in that the compound of formula VI is prepared by hydrogenation of a tropoacetamide of formula VII and treating with HCl in any suitable solvent.
7. The process as claimed in claim 6, characterized in that the compound of formula VII is prepared by treating with nitrogen an acetamide of formula VIII:
8. The process as claimed in claim 7, characterized in that the compound of formula VIII is prepared from a compound of formula IX: IX for example using acetic anhydride or acetyl chloride, either as solvent or reagent, or in the presence of dichloromethane and triethylamine.
9. A process for the preparation of compounds of formula I, characterized in that it comprises (i) converting a compound of formula IX to a compound of formula VIII, and (ii) converting the compound of formula VIII to the compound of formula I.
10. Compounds of formula X characterized in that Y is H and X is selected from the group N02, NH2-HC1, NH-CS-NHCOPh and NH-CS-NH2, or X and Y together form a five-membered ring, as in formulas II or III.
11. The compound of formula II H,
12. The compound of formula III
13. The compound of formula IV NH,
14. The compound of formula V NHCOPh
15. The compound of formula VI
16. The compound of formula VII 15 20 25
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9700706-6 | 1997-02-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA99007649A true MXPA99007649A (en) | 2000-01-01 |
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