* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With bromine In chloroform at 5℃; Inert atmosphere; Reflux
In a 100 ml two-necked flask equipped with stir bar, appropriately substituted aryl thiourea (2) (5g, 29.7mmol) was dissolved in chloroform (30 mL). Then bromine (5 g, 29.7 mmol) in chloroform (15 mL) was placed in a dropping funnel and was added drop wise with stirring to the reaction mixture by maintaining the temperature below 5°C. After the complete addition of bromine, the stirring was continued for a period of 4-6 h, and the content of the flask was refluxed on water bath till the evolution of hydrogen bromide vapors ceased. The resulting solid material was treated with ice water and filtered off. The filtrate was neutralized with an aqueous ammonia solution, the white precipitate obtained was filtered off, washed with water; compound 3 was crystallized from ethanol (4g, 80percent yield, solid white powder). 1H NMR (DMSO-d6, 400 MHz): δ ppm: 9.10 (s, 1H, -OH), 7.13 (d, J = 8.4 Hz, 1H, ArH, C5-H), 7.06 (s, 2H, -NH2), 7.01 (d, J = 2.4 Hz, 1H, ArH, C4-H), 6.65 (dd, J = 2.6, 8.6 Hz, 1H, ArH, C7-H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 15, p. 3460 - 3463
[2] Medicinal Chemistry Research, 2012, vol. 21, # 7, p. 1136 - 1148
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 21, p. 9814 - 9824
2
[ 1753-90-8 ]
[ 26278-79-5 ]
Yield
Reaction Conditions
Operation in experiment
91%
With aluminum (III) chloride In toluene at 115℃; for 2 h;
To a solution of Example 18d (444 mg, 2.67 mmol) in Tol (10 mL) was added A1C13 (1 .1 g, 8.02 mmol) at r.t. After addition, the reaction mixture was heated to 115°C for 2h. Water (50 mL) and EA (50 mL) were added, the organic layer was washed with water (20 mL*2), brine (20 mL), dried overNa2S04, filtered and concentrated, purified by flash column chromatography to give the desired product (Example 18e, 370 mg, yield 91percent) as yellow solid. LCMS [M+1]+= 153
1. A 22 L 3 -neck round bottom flask was equipped with a mechanical agitator, thermocouple probe, reflux condenser, and a heating mantle.2. The flask was charged with 48percent hydrobromic acid (14 L, 123.16 mol, 13.10 eq). The heating was initiated and 2-amino-6- methoxybenzothiazole was added (1.7 Kg, 9.4 mol, 1.00 eq) with stirring over 10 minutes.3. The heating of the reaction mixture was continued to reflux, and maintained (> 107 0C) for approximately 5 hours. The reaction mixture turned into a clear solution between 75 0C and 85 0C.4. The reaction progress was monitored by TLC until no starting material was observed [5percent Methanol/Dichloromethane; Rf (product) = 0.35; Rf (starting material) = 0.40]. For preparation of samples for TLC analysis, a ~0.5 mL reaction mixture aliquot was diluted with ~0.5 mL of water as a clear solution, neutralized with sodium acetate to pH -5 and extracted with 1 mL of dichloromethane; the organic layer was spotted5. The reaction mixture was cooled to - 20 0C (overnight). White solids precipitated. The solids were filtered onto a polypropylene filter and pressed to remove as much of the hydrobromic acid from the solids as possible.6. The slightly wet crude product was dissolved in hot (50 0C) water (5 L). The clear solution was filtered to remove the any insoluble material present. The solids were washed with 50 0C water, then the filtrated was cooled to 10 0C.7. The cooled filtrate was neutralized with sodium acetate (- 1.0 Kg) to pH 4.5 to 5.5 with vigorous stirring. A thick white solid precipitated. The solids were collected by filtration, and washed with cool (-10 0C) water (2 x 1.0 L) and air dried.8. The wet crude product was briefly slurried in hot (50 0C) isopropanol (3 L) and allowed to stand in a cool room (-5 0C) overnight. The solids were collected by filtration and washed with methyl tert-butylether (2 x 500 mL).9. The solids were dried in a vacuum oven overnight (<30mmHg) at 30 0C, (first lot).10. Secondary crop: The organic filtrate was collected to a total volume of 1.0 L, cooled to 10 0C, and the off- white solids were collected by filtration.11. The solids were dried in a vacuum oven overnight (<30mmHg) at 30 0C, (second lot). First lot:Yield: 1068 g (68percent), white solid.HPLC: 99.4percent (area)1R NMR: conforms (300 MHz, DMSO)Second lot:Yield: 497 g (32percent), off-white solid. HPLC: 99.8percent (area) Overall Yield: 1565 g, (99percent)
89%
Stage #1: at 105 - 110℃; for 4 h; Industry scale Stage #2: With sodium hydrogencarbonate In water at 20℃; for 0.5 h; Industry scale
A. Preparation of 2-amino-6-hydroxybenzothiazole 1.; Example A-l; To a 1-L 3-necked round bottom flask fitted with a condenser, heating mantle, and mechanical stirrer was charged aqueous hydrobromic acid (48percent, 632 mL, 5.6 mol, 10 equiv). 2-Amino-6-methoxybenzothiazole (100 g, 0.55 mol, 1 equiv) was added to the above flask over 15 minutes. The reaction temperature was raised slowly to reflux (105-110 °C). A clear dark brown colored solution was observed at about 80 °C. The reflux was continued at 105-110 °C for about 4 hr. The progress of the reaction was monitored by HPLC. When 2-amino-6-methoxybenzothiazole was less than 2percent, the reaction was substantially complete.[00253] The reaction mass was cooled to 0-5 °C and at this point precipitation of a solid was observed. The mixture was maintained at 0-5 °C for 0.5 hr and filtered, and the cake was pressed to remove HBr. The wet cake was transferred to a 2-L round bottom flask fitted with a mechanical stirrer. Saturated aqueous sodium bicarbonate solution (-1500 mL) was added slowly at ambient temperature, whereupon considerable frothing was observed. The pH of the solution was found to be about 6.5 to 7. The mixture was stirred for 0.5 hr at ambient temperature and filtered. The filter cake was washed with water (500 mL), dried on the filter and then under vacuum at 30-35 °C for 10-12 hr to give the product 2-amino-6-hydroxybenzothiazole (82 g, 89percent yield, HPLC purity = 99percent). JH NMR (DMSO-if6, 500 MHz): δ 7.12 (d, 1H), 7.06 (S, 2H, NH2), 7.01 (d, 1H), 6.64 (dd, 1H); MS (m/z) = 167.1 [M+ + 1].[00254] Table: Summary of Plant Batches[00255] HPLC chromatographic conditions were as follows: The column used was XTerra RP8, 250 X 4.6 mm, 5μ or equivalent. Mobile Phase A was buffer, prepared by mixing 3.48 g of dipotassium hydrogen phosphate in 1.0 L of water, and adjusting the pH to 9.0 with phosphoric acid. Mobile Phase B was methanol. The flow rate was 1.0 mL/minute. Detection was set at UV 270 nm. The injection volume was 20 μ^, and the sample was diluted with a diluent (Mobile Phase A : Mobile Phase B = 70:30). Test solution was prepared by weighing accurately about 25 mg of sample and transferring it into a 100 mL volumetric flask, dissolving with 20-30 mL of diluent, making up the volume to the mark with diluent, and mixing. The HPLC was performed by separately injecting equal volumes of blank and test solution, and recording the chromatogram for all injections. The purity was calculated by area normalization method.
5.81 g
With bromic acid In water for 5 h; Reflux
[1082] Step 1: 2-aminobenzo[d]thiazol-6-ol[1083] A mixture of 6-methoxy-2-aminobenzothiazole (5.0 g, 27.74 mmol) in a bromic acid solution (48 percent, 41 mL) was refluxed for 5 hours and then cooled to room temperature. The reaction mixture was diluted with water and then neutralized with sodium carbonate. The resulting solid was filtered, washed with water, and then dried under reduced pressure to give 5.81 g of the titled compound as a gray solid.
5.81 g
for 5 h; Reflux
Step 1: 2-aminobenzo[d]thiazol-6-ol A mixture of 6-methoxy-2-aminobenzothiazole (5.0 g, 27.74 mmol) in a bromic acid solution (48percent, 41 mL) was refluxed for 5 hours and then cooled to room temperature. The reaction mixture was diluted with water and then neutralized with sodium carbonate. The resulting solid was filtered, washed with water, and then dried under reduced pressure to give 5.81 g of the titled compound as a gray solid.
Reference：
[1] Patent: WO2010/54058, 2010, A1, . Location in patent: Page/Page column 73-75
[2] Patent: WO2011/56939, 2011, A1, . Location in patent: Page/Page column 69-71
[3] European Journal of Medicinal Chemistry, 2016, vol. 115, p. 201 - 216
[4] Chemistry - A European Journal, 2015, vol. 21, # 7, p. 2893 - 2904
[5] ACS Medicinal Chemistry Letters, 2012, vol. 3, # 1, p. 58 - 62
[6] Journal of Pharmaceutical Sciences, 1994, vol. 83, # 10, p. 1425 - 1432
[7] Ukrainskii Khimicheskii Zhurnal (Russian Edition), 1955, vol. 21, p. 344[8] Chem.Abstr., 1955, p. 14738
[9] Journal of Heterocyclic Chemistry, 1973, vol. 10, # 5, p. 769 - 772
[10] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1987, p. 1781 - 1784
[11] Patent: WO2009/38757, 2009, A2, . Location in patent: Page/Page column 87
[12] Patent: EP2181987, 2010, A1, . Location in patent: Page/Page column 66
[13] Patent: WO2013/43001, 2013, A1, . Location in patent: Paragraph 1082; 1083
[14] Archiv der Pharmazie, 2014, vol. 347, # 4, p. 268 - 275
[15] Patent: US2015/11528, 2015, A1, . Location in patent: Paragraph 0608
[16] Molecules, 2016, vol. 21, # 3,
[17] Molecules, 2016, vol. 21, # 2,
[18] Patent: US2017/12072, 2017, A1, . Location in patent: Paragraph 0477; 0478; 0479
[19] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3614 - 3622
Hydrobromic acid (208.60 g, 1.3 mol) was added to a 250 ml round bottom flask equipped with a mechanicalstirrer over 15 minutes, and then 2-amino-5-methoxybenzothiazole (17 g, 94.32 mmol) was added thereto. The mixturewas heated and refluxed for 4 hours, then cooled to 0-5 °C until a solid precipited, then stirred for half an hour at 0-5 °Cand then the suction filtration under reduced pressure was performed. The solid was transferred to a 1 L round bottomflask and slowly added with saturated sodium carbonate solution under mechanical stirring to adjust till the pH was 6.5to 7, and then stirred at room temperature for 0.5 hour, filtered and the filter cake was washed with 300 ml of water, andthen dried under vacuum at 50 °C to give a gray compound 161A as solid (11.7 g, the yield was 74.64percent).1H NMR (400MHz, DMSO-d6) = 9.11 (s, 1H), 7.15 (s, 1H), 7.12 (s, 2H), 7.03 (d, J=2.3 Hz, 1H), 6.65 (dd, J=2.3, 8.5 Hz, 1H)
A. The intermediate 2-amino-1,3-benzothiazol-6-ol was prepared according to a slightly modified literature procedure by Lau and Gompf: J. Org. Chem. 1970, 35, 4103-4108. To a stirred solution of thiourea (7.6 g, 0.10 mol) in a mixture of 200 mL ethanol and 9 mL concentrated hydrochloric acid was added a solution of 1,4-benzoquinone (21.6 g, 0.20 mol) in 400 mL of hot ethanol. The reaction was stirred for 24 hours at room temperature and then concentrated to dryness. The residue was triturated with hot acetonitrile and the resulting solid was filtered and dried. The free base was obtained by dissolving the hydrochloride salt in water, neutralizing with sodium acetate, and collecting the solid by filtration. The product (2-amino-1,3-benzothiazol-6-ol) was obtained as a dark solid that was pure by LCMS (M+H=167) and NMR. Yield: 13.0 g (78percent). NMR (DMSO-d6) ?7.6 (m, 2H), 6.6 (d, 1H).
1. A 22 L 3 -neck round bottom flask was equipped with a mechanical agitator, thermocouple probe, reflux condenser, and a heating mantle.2. The flask was charged with 48% hydrobromic acid (14 L, 123.16 mol, 13.10 eq). The heating was initiated and 2-amino-6- methoxybenzothiazole was added (1.7 Kg, 9.4 mol, 1.00 eq) with stirring over 10 minutes.3. The heating of the reaction mixture was continued to reflux, and maintained (> 107 0C) for approximately 5 hours. The reaction mixture turned into a clear solution between 75 0C and 85 0C.4. The reaction progress was monitored by TLC until no starting material was observed [5% Methanol/Dichloromethane; Rf (product) = 0.35; Rf (starting material) = 0.40]. For preparation of samples for TLC analysis, a ~0.5 mL reaction mixture aliquot was diluted with ~0.5 mL of water as a clear solution, neutralized with sodium acetate to pH -5 and extracted with 1 mL of dichloromethane; the organic layer was spotted5. The reaction mixture was cooled to - 20 0C (overnight). White solids precipitated. The solids were filtered onto a polypropylene filter and pressed to remove as much of the hydrobromic acid from the solids as possible.6. The slightly wet crude product was dissolved in hot (50 0C) water (5 L). The clear solution was filtered to remove the any insoluble material present. The solids were washed with 50 0C water, then the filtrated was cooled to 10 0C.7. The cooled filtrate was neutralized with sodium acetate (- 1.0 Kg) to pH 4.5 to 5.5 with vigorous stirring. A thick white solid precipitated. The solids were collected by filtration, and washed with cool (-10 0C) water (2 x 1.0 L) and air dried.8. The wet crude product was briefly slurried in hot (50 0C) isopropanol (3 L) and allowed to stand in a cool room (-5 0C) overnight. The solids were collected by filtration and washed with methyl tert-butylether (2 x 500 mL).9. The solids were dried in a vacuum oven overnight (<30mmHg) at 30 0C, (first lot).10. Secondary crop: The organic filtrate was collected to a total volume of 1.0 L, cooled to 10 0C, and the off- white solids were collected by filtration.11. The solids were dried in a vacuum oven overnight (<30mmHg) at 30 0C, (second lot). First lot:Yield: 1068 g (68%), white solid.HPLC: 99.4% (area)1R NMR: conforms (300 MHz, DMSO)Second lot:Yield: 497 g (32%), off-white solid. HPLC: 99.8% (area) Overall Yield: 1565 g, (99%)
89%
A. Preparation of 2-amino-6-hydroxybenzothiazole 1.; Example A-l; To a 1-L 3-necked round bottom flask fitted with a condenser, heating mantle, and mechanical stirrer was charged aqueous hydrobromic acid (48%, 632 mL, 5.6 mol, 10 equiv). 2-Amino-6-methoxybenzothiazole (100 g, 0.55 mol, 1 equiv) was added to the above flask over 15 minutes. The reaction temperature was raised slowly to reflux (105-110 C). A clear dark brown colored solution was observed at about 80 C. The reflux was continued at 105-110 C for about 4 hr. The progress of the reaction was monitored by HPLC. When 2-amino-6-methoxybenzothiazole was less than 2%, the reaction was substantially complete.[00253] The reaction mass was cooled to 0-5 C and at this point precipitation of a solid was observed. The mixture was maintained at 0-5 C for 0.5 hr and filtered, and the cake was pressed to remove HBr. The wet cake was transferred to a 2-L round bottom flask fitted with a mechanical stirrer. Saturated aqueous sodium bicarbonate solution (-1500 mL) was added slowly at ambient temperature, whereupon considerable frothing was observed. The pH of the solution was found to be about 6.5 to 7. The mixture was stirred for 0.5 hr at ambient temperature and filtered. The filter cake was washed with water (500 mL), dried on the filter and then under vacuum at 30-35 C for 10-12 hr to give the product 2-amino-6-hydroxybenzothiazole (82 g, 89% yield, HPLC purity = 99%). JH NMR (DMSO-if6, 500 MHz): delta 7.12 (d, 1H), 7.06 (S, 2H, NH2), 7.01 (d, 1H), 6.64 (dd, 1H); MS (m/z) = 167.1 [M+ + 1].[00254] Table: Summary of Plant Batches[00255] HPLC chromatographic conditions were as follows: The column used was XTerra RP8, 250 X 4.6 mm, 5mu or equivalent. Mobile Phase A was buffer, prepared by mixing 3.48 g of dipotassium hydrogen phosphate in 1.0 L of water, and adjusting the pH to 9.0 with phosphoric acid. Mobile Phase B was methanol. The flow rate was 1.0 mL/minute. Detection was set at UV 270 nm. The injection volume was 20 mu^, and the sample was diluted with a diluent (Mobile Phase A : Mobile Phase B = 70:30). Test solution was prepared by weighing accurately about 25 mg of sample and transferring it into a 100 mL volumetric flask, dissolving with 20-30 mL of diluent, making up the volume to the mark with diluent, and mixing. The HPLC was performed by separately injecting equal volumes of blank and test solution, and recording the chromatogram for all injections. The purity was calculated by area normalization method.
With hydrogen bromide; In water; at 70℃; for 3h;Product distribution / selectivity;
Preparation of 2- Amino-6-hydroxybenzothiazole (Intermediate 1). 2-Amino-6-methoxybenzothiazole is reacted with hot aqueous HBr for about 3 hrs and then the clear solution is cooled to ambient temperature overnight. The precipitated solids are collected, dissolved in hot water and the pH is adjusted to between 4.5-5.5. The resultant solids are collected, dried and recrystallized from Isopropanol. Second crop material is collected. The solids are vacuum dried to give Intermediate 1.
(iv) Production of 2-amino-1,3-benzothiazol-6-ol; 6-Methoxy-1,3-benzothiazole-2-amine (10.4 g, 57.8 mmol) was dissolved in 25% hydrogen bromide acetic acid solution (80 mL), water (40 mL) was added and the mixture was heated under reflux for 16 hr. To the reaction mixture was added sodium iodide (10.4 g, 69.4 mmol) and the mixture was heated under reflux for 12 hr. Sodium iodide (15.2 g, 101 mmol) was added and the mixture was heated under reflux for 16 hr. The reaction mixture was cooled to room temperature, and added to 8N aqueous sodium hydroxide solution (350 mL) stirred vigorously. The reaction mixture was neutralized with 6N hydrochloric acid and stood at 0C. The resulting dark-gray crystals were collected by filtration and the mother liquid was preserved. The obtained crystals were dissolved in methanol (35 mL) and ethyl acetate (350 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off and the filtrate was concentrated to give the title compound (6.90 g, 72%) as a gray solid. The mother liquid preserved earlier was extracted with ethyl acetate (250 mL×2), the collected organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated to give the title compound (3.4 g, 35%) as a secondary harvest. 1H-NMR (DMSO-d6, 300 MHz) delta 6.65 (1H, dd, J = 2.7, 8.7 Hz), 7.02 (1H, d, J = 2.7 Hz), 7.07 (2H, br s), 7.13 (1H, d, J = 8.7 Hz), 9.08 (1H, br s).
5.81 g
With bromic acid; In water; for 5h;Reflux;
[1082] Step 1: 2-aminobenzo[d]thiazol-6-ol[1083] A mixture of 6-methoxy-2-aminobenzothiazole (5.0 g, 27.74 mmol) in a bromic acid solution (48 %, 41 mL) was refluxed for 5 hours and then cooled to room temperature. The reaction mixture was diluted with water and then neutralized with sodium carbonate. The resulting solid was filtered, washed with water, and then dried under reduced pressure to give 5.81 g of the titled compound as a gray solid.
With hydrogen bromide; In water;Reflux;
A mixture of 6-methoxy-2,3-dihydrobenzo[d]thiazol-2-amine (1) (10 g, 55.56 mmol) and 40 mL ofhydrobromic acid (48% water solution) was refluxed for 20 h. The mixture was allowed to cool to roomtemperature and neutralized with NaOH solution to pH 7-8. The precipitate was filtered and washedwith water. The filtrate was stirred with 100 mL hot water for 0.5 h and the remaining precipitate wasfiltered to yield a brown solid, compound 2.
5.81 g
With bromic acid; for 5h;Reflux;
Step 1: 2-aminobenzo[d]thiazol-6-ol A mixture of 6-methoxy-2-aminobenzothiazole (5.0 g, 27.74 mmol) in a bromic acid solution (48%, 41 mL) was refluxed for 5 hours and then cooled to room temperature. The reaction mixture was diluted with water and then neutralized with sodium carbonate. The resulting solid was filtered, washed with water, and then dried under reduced pressure to give 5.81 g of the titled compound as a gray solid.
6-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)benzo[d]thiazol-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; In bromobenzene; at 150℃; for 12h;
Step A: Preparation of 6-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)benzo[d]thiazol-2-amine: A 20 mL sealable tube was charged with 1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (0.500 g, 1.74 mmol; prepared according to the procedure of Example 43, Step E), 2-aminobenzo[d]thiazol-6-ol (0.433 g, 2.61 mmol), N,N-dimethylpyridin-4-amine (0.0425 g, 0.348 mmol), and bromobenzene (4 mL). The reaction mixture was heated under nitrogen to 150 C. for 12 hours, then cooled to room temperature and concentrated under reduced pressure. The crude material was used directly in next step. LRMS (APCI pos) m/e 418.2 (M+1).
6-(6,7-dimethoxyquinolin-4-yloxy)benzo[d]thiazol-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; copper; In dichloromethane; at 100℃; for 0.166667h;Microwave irradiation;
Example 1; (2-Chlorobenzyl)- [6- (6, 7- dimethoxy-quinolin-4-yloxy)- benzothiazol-2-yl-amine; (a) 6- (6, 7-Dimethoxy-quinolin-4-yloxy)-benzothiazol-2-ylamine.; To a microwave vial was added 4-chloro-6,7-dimethoxy-quinoline prepared by the method of Miwa, et al. , (WO 03/33472) (0.300 g, 1.3 mmol), 2-amino-benzothiazol-6-ol (0. 334 g, 2.0 mmol) and KOH pellets (0.140 g, 2.6 mmol), followed by 4% by weight of Cu powder in 3 mL of dry CH2C12. The sealed vial was microwaved for 10 min at 100 C and 60 W. (Powermax, CEM). The mixture was diluted with CH2C12 and transferred to a separation funnel. NaOH (40 mL) was added and the organic layer was extracted 3X with CH2C12. The organics were combined, dried over Na2S04, filtered, and concentrated in-vacuo. The crude compound was purified by crystallization from 10% CH2C12/Hexanes to give the titled compound as a light purple powder. MS (ESI pos. ion) m/z: 354 (M+H). Calc'd Exact Mass for C18Hl5N303S : 353.08.
With dmap; triethylamine; In dichloromethane; at 20℃;
A solution of 2-aminobenzothiazol-6-ol (intermediate 1) (1.91 g, 11.49 mmol), di-tert-butyl dicarbonate (7.52 g, 34.47 mmol), triethylamine (4.9 ml, 34.47 mmol) and 4-dimethylaminopyridine (168 mg, 1.38 mmol) in 50 ml of dichloromethane, in a 100 ml round-bottomed flask equipped with a magnetic bar, is stirred overnight at room temperature. The reaction medium is evaporated to dryness and the residue obtained is washed with dichloromethane and ethyl ether to give 4.2 g of carbonic acid 2-tert-butoxy-carbonylaminobenzothiazol-6-yl ester tert-butyl ester in quantitative yield. LC/MS: [M+H]+:311.16, retention time: 5.27 min.
4-(6-hydroxybenzothiazol-2-ylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (276 mg, 1.203 mmol), of HATU (549 mg, 1.444 mmol) and of diisopropylethylamine (187 mg, 1.44 mmol) in 3 ml of DMF is stirred at room temperature for 15 minutes. The 2-aminobenzothiazol-6-ol (intermediate 1) (200 mg, 1.203 mmol) dissolved in 3 ml of DMF is added in a single portion. The reaction medium is stirred at room temperature for 2 hours, poured into a 10% solution of Na2CO3 in water (20 ml) and extracted with ethyl acetate. The crude reaction product is purified by column chromatography (eluent: EtOAc/heptane (1/1)) to give 401 mg of 4-(6-hydroxybenzothiazol-2-ylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (white solid). LC/MS (method A2): [M+H]+=378.0, retention time: 3.9 minutes.
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
Preparation of cyclopropanecarboxylic acid (6-hydroxybenzo-thiazol-2-yl)amide A solution of 2-aminobenzothiazol-6-ol (intermediate 1) (850 mg, 4.6 mmol), cyclopropanecarboxylic acid (1.564 g, 18.1 mmol), N,N-diisopropylethylamine (3.6 ml, 24.4 mmol) and HBTU (4.1 g, 5.53 mmol) in 40 ml of dimethyl-formamide, in a 100 ml round-bottomed flask equipped with a magnetic bar, is stirred at room temperature for 16 hours. 150 ml of water are added to the reaction medium, the mixture is extracted with ethyl acetate and the extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness. The residue obtained is washed with ethyl acetate to give 893 mg of cyclopropanecarboxylic acid 2-(cyclo-propanecarbonylamino)benzothiazol-6-yl ester. LC/MS: [M+H]+=303.18, retention time=3.53 min.
A solution of 2-amino-6-ethoxybenzothiazole (5 g, 25.74 mmol) and of 48% hydrobromic acid in water (130 ml, 1.141 mol) in 65 ml of acetic acid is distributed in ten 20 ml microwave tubes, and then heated at 150 C. by microwave for 200 seconds. The reaction medium is concentrated. The residue is taken up in 200 ml of water, basified to pH 8 by addition of 75 ml of saturated NaHCO3 solution and extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness to give 3.4 g of 2-aminobenzothiazol-6-ol (gray powder). LC/MS (method A1): [M+H]+=167.00, retention time: 1.07 min.
d) 2-Amino-1,3-benzothiazol-6-ol2-Amino-1,3-benzothiazol-6-ol may be prepared in the following manner:To a solution of 7 g of 6-ethoxy-1,3-benzothiazol-2-amine (commercial) in 65 cm3 of glacial acetic acid are added 130 cm3 of a 48% solution of hydrobromic acid in water. The solution is refluxed for about 20 hours. After concentrating to dryness under reduced pressure (13 kPa), the residue is taken up in 50 cm3 of water and the pH of the solution is brought to about 8 by addition of solid sodium hydrogen carbonate. The mixture is extracted with four times 250 cm3 of ethyl acetate and the combined organic phases are washed with three times 20 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). The solid obtained is taken up in 20 cm3 of dichloromethane, filtered off by suction, washed with three times 10 cm3 of dichloromethane and then three times 20 cm3 of diethyl ether, and dried under reduced pressure (13 kPa) over phosphorus pentoxide. 5.3 g of 2-amino-1,3-benzothiazol-6-ol are thus obtained in the form of a pink powder, the characteristics of which are as follows:Melting point: melting at 235-240 C. (Koefler block)1H NMR spectrum at 300 MHz: 6.64 (dd, J=2.5 and 9.0 Hz, 1H); 7.01 (d, J=2.5 Hz, 1H); 7.05 (broad s, 2H); 7.12 (d, J=8.5 Hz, 1H); 9.07 (broad s, 1H)Mass spectrum: IE: m/z 166: [M+.](base peak)
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;
Under nitrogen, 2-amino-benzo [d] thiazol-6-ol (3.0g, 18.0mmol) was dissolved in DMF (25mL), was added successively imidazole (2.5g, 36.0mmol) and TBSCl (3.3g, 21.7 mmol), the mixed solution was stirred at room temperature overnight, concentrated under reduced pressure, water was added (100 mL) The reaction was quenched with ethyl acetate (a 500 mL) was extracted, the organic phase washed with water (150 mL) washed with saturated sodium chloride solution (100 mL) wash, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, column chromatography (the V (ethyl acetate) / V (petroleum ether) = 1/2) to give a white solid 4.5g, 89% yield.
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 16h;
A solution of <strong>[26278-79-5]2-amino-6-hydroxybenzothiazole</strong> (5.00 g, 30.1 mmol), TBDMSCl (5.40 g, 1.2 equiv) and imidazole (2.46 g, 1.2 equiv) in DMF (160 ml) was stirred at ambient temperature for 16 h. The reaction mixture was then partitioned between water and ethyl acetate. The aquous phase was extracted twice with ethyl acetate and the combined organics dried (MgSO4) and concentrated in vacuo. The crude product thus obtained was purified by silica gel chromatography by gradient elution («-heptane:ethyl acetate) to yield 3.0 g of the title compound as a yellowish solid. 1H NMR delta 7.23 (br s, 2H) 7.18 (d, IH) 7.16 (d, IH) 6.70 (dd, IH) 0.95 (s, 9H) 0.16 (s, 6H); MS m/z (M+H) 281.
6-(2-morpholinoethoxy)benzo[d]thiazol-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With sodium hydrogencarbonate; triphenylphosphine; In tetrahydrofuran; ethyl acetate;
Step 2: 6-(2-Morpholin-4-yl-ethoxy)-benzothiazol-2-ylamine (226) To a solution of benzothiazole 225 (3.62 g, 21.8 mmol) in THF at room temperature under nitrogen, were successively added 4-(2-hydroxyethyl)morpholine (3.17 mL, 26.1 mmol), triphenylphosphine (7.43 g, 28.3 mmol) followed by a dropwise addition of diethyl azodicarboxylate (4.46 mL, 28.3 mmol). The solution was stirred for 3.5 h and THF was partially removed in vacuo. The mixture was partitioned between ethyl acetate and H2O. The combined organic layers were extracted with 1N HCl. The combined acidic extracts were neutralized using a saturated aqueous solution of NaHCO3 and the precipitate was dissolved with ethyl acetate. These combined organic layers were washed with brine, dried over MgSO4, and concentrated. The filtrate was concentrated to afford the title compound 226 (5.83 g, 96% yield) as a light yellow oil. 1H NMR: (Acetone-d6) delta (ppm): 7.37 (d, J=8.8 Hz, 1H), 7.34 (d, J=2.6 Hz, 1H), 6.94 (dd, J=8.8, 2.6 Hz, 1H), 6.60 (bs, 2H), 4.19 (t, J=6.2 Hz, 2H), 3.70-3.67 (m, 4H), 2.90 (s, 2H), 2.81 (t, J=6.2 Hz, 2H), 2.62-2.58 (m, 4H).
96%
With sodium hydrogencarbonate; triphenylphosphine; In tetrahydrofuran; ethyl acetate;
Step 2: 6-(2-Morpholin-4-yl-ethoxy)-benzothiazol-2-ylamine (226) To a solution of benzothiazole 225 (3.62 g, 21.8 mmol) in THF at room temperature under nitrogen, were successively added 4-(2-hydroxyethyl)morpholine (3.17 mL, 26.1 mmol), triphenylphosphine (7.43 g, 28.3 mmol) followed by a dropwise addition of diethyl azodicarboxylate (4.46 mL, 28.3 mmol). The solution was stirred for 3.5 h and THF was partially removed in vacuo. The mixture was partitioned between ethyl acetate and H2O. The combined organic layers were extracted with 1N HCl. The combined acidic extracts were neutralized using a saturated aqueous solution of NaHCO3 and the precipitate was dissolved with ethyl acetate. These combined organic layers were washed with brine, dried over MgSO4, and concentrated. The filtrate was concentrated to afford the title compound 226 (5.83 g, 96% yield) as a light yellow oil. 1H NMR: (Acetone-d6) delta (ppm): 7.37 (d, J=8.8 Hz, 1H), 7.34 (d, J=2.6 Hz, 1H), 6.94 (dd, J=8.8, 2.6 Hz, 1H), 6.69 (bs, 2H), 4.19 (t, J=6.2 Hz, 2H), 3.70-3.67 (m, 4H), 2.90 (s, 2H), 2.81 (t, J=6.2 Hz, 1H), 2.62-2.58 (m, 4H).
96%
With sodium hydrogencarbonate; triphenylphosphine; In tetrahydrofuran; ethyl acetate;
Step 2: 6-(2-Morpholin-4-yl-ethoxy)-benzothiazol-2-ylamine (226) To a solution of benzothiazole 225 (3.62 g, 21.8 mmol) in THF at room temperature under nitrogen, were successively added 4-(2-hydroxyethyl)morpholine (3.17 mL, 26.1 mmol), triphenylphosphine (7.43 g, 28.3 mmol) followed by a dropwise addition of diethyl azodicarboxylate (4.46 mL, 28.3 mmol). The solution was stirred for 3.5 h and THF was partially removed in vacuo. The mixture was partitioned between ethyl acetate and H2O. The combined organic layers were extracted with 1N HCl. The combined acidic extracts were neutralized using a saturated aqueous solution of NaHCO3 and the precipitate was dissolved with ethyl acetate. These combined organic layers were washed with brine, dried over MgSO4, and concentrated. The filtrate was concentrated to afford the title compound 226 (5.83 g, 96% yield) as a light yellow oil. 1H NMR: (Acetone-d6) delta (ppm): 7.37 (d, J=8.8 Hz, 1H), 7.34 (d, J=2.6 Hz, 1H), 6.94 (dd, J=8.8, 2.6 Hz, 1H), 6.60 (bs, 2H), 4.19 (t, J=6.2 Hz, 2H), 3.70-3.67 (m, 4H), 2.90 (s, 2H), 2.81 (t, J=6.2 Hz, 2H), 2.62-2.58 (m, 4H).
With sodium hydrogencarbonate; In butan-1-ol; at 110 - 115℃;Industry scale;Product distribution / selectivity;
B. Preparation of 2-(4-nitrophenyl)imidazo[2,l-b]benzothiazol-7-ol; 1. Example B-l; A 3-L 3-neck round bottom flask fitted with a condenser, a heating mantle, and a mechanical stirrer was charged with H-butanol (1.5 L), followed by 2-amino-6- hydroxybenzothiazole (75 g, 0.45 mol, 1.0 equiv), 2-bromo-4'-nitroacetophenone (121 g, 0.50 mol, 1.1 equiv), and sodium bicarbonate (41.6 g, 0.50 mol, 1.0 equiv). The reaction temperature was gradually raised to reflux and maintained at reflux (110-115 C) for 2-3 hr. During the temperature increase, the reaction mass turned into a clear solution and then immediately changed into an orange colored suspension at 65-75 C. The progress of the reaction was monitored by HPLC analysis every 1 hr (reaction mass sample was submitted to QC). When the level of <strong>[26278-79-5]2-amino-6-hydroxybenzothiazole</strong> was less than 2%, the reaction was substantially complete.[00265] The reaction mass was slowly cooled to 50-60 C and then further cooled to 0-5 C and stirred for 15 min. The precipitated solids were collected by filtration, and dried on the filter. The wet cake was transferred in to a 1-L round bottom flask, and water (600 mL) was added. The suspension was stirred for 0.5 hr and filtered, and the solid was dried on the filter. The wet cake was again taken in to a 1-L round bottom flask and stirred with acetone (200 mL). The slurry was filtered and washed with acetone (2 X 100 mL), and the solid was dried on the filter, unloaded and further dried in a vacuum oven at ambient temperature to give the product 2-(4-nitrophenyl)imidazo[2,l- b]benzothiazol-7-ol (V) (120 g, 85.7% yield, HPLC purity = 98.7%). JH NMR (DMSO- d6, 500 MHz): delta 9.96 (s, 1H, OH), 8.93 (s, 1H), 8.27 (d, 2H), 8.06 (d, 2H), 7.78 (d, 1H), 7.38 (d, 1H), 6.97 (dd, 1H); MS (m/z) = 312 [M+ + 1].[00266] Table: Summary of Plant Batches* Input of <strong>[26278-79-5]2-amino-6-hydroxybenzothiazole</strong> (III)[00267] HPLC chromatographic conditions were as follows: The column used was XTerra RP8, 250 X 4.6 mm, 5mu or equivalent. Mobile Phase A was buffer, prepared by mixing 3.48 g of dipotassium hydrogen phosphate in 1.0 L of water, and adjusting the H to 9.0 with phosphoric acid. Mobile Phase B was methanol. The flow rate was 1.0 mL/minute. Detection was set at UV 235 nm. The injection volume was 10 mu^. The blank was prepared by transferring 200 mu. of DMSO and 200 mu. of 2M NaOH into a 10 mL volumetric flask, making up the volume to the mark with methanol, and mixing. The test solution was prepared by weighing accurately about 10 mg of sample and transferring it into a 50 mL volumetric flask, dissolving with 1 mL of DMSO and 1 mL of 2M NaOH, sonicating to dissolve, making up the volume to the mark with methanol, and mixing. The HPLC was performed by separately injecting equal volumes of blank and test solution, and recording the chromatogram for all injections. The purity was calculated by area normalization method.
65%
In isopropyl alcohol; for 24h;Reflux;
This product was prepared according to J. Med. Chem. 2009, 52, 7808-7816 with some modifications. A mixture of 2-amino-1 ,3-benzothiazol-6-ol (2.0 g, 12.18 mmol) and 2-bromo-4'-nitroacetophenone (2.97 g, 12.18 mmol) in IPA (40 ml) was heated to reflux for 24 h. The reaction mixture was then cooled to 0QC and the resulting precipitate was filtrated and washed with IPA to afford 2-(4- nitrophenyl)imidazo[2,1 - 3][1 ,3]benzothiazol-7-ol (65% c.y.). To a DMF (52ml) solution of 2-(4-nitrophenyl)imidazo[2,1 -ifc>][1 ,3]benzothiazol-7-ol was added potassium carbonate (2.94 g) and 4-(2-chloroethyl)morpholine hydrochloride (1 .97 g). The reaction mixture was heated to 85QC and stirred at the same temperature for 48 h. Then it was poured into water (100 ml), filtered and washed with water and ethyl ether to give 7-(2-morpholin-4-yl-ethoxy)-2-(4-nitrophenyl)imidazo[2,1 - £>][1 ,3]benzothiazole (86% c.y.). A mixture of 7-(2-morpholin-4-yl-ethoxy)-2-(4- nitrophenyl)imidazo[2,1 -ifc>][1 ,3]benzothiazole and ammonium chloride (0.77 g) in ethanol (50 ml) was heated to reflux, and then iron powder (3.0 g) was added. The mixture was refluxed for 5 h and then immediately filtered though Celite and washed with hot ethanol. The filtrate was concentrated, neutralized with saturated NaHC03 solution and extracted with DCM. The organic solution was dried with Na2C03 and the solvent was removed under reduced pressure to afford the desired product [4-(7-(2-morpholin-4-yl-ethoxy)imidazo[2,1 -£>]benzothiazol-2- yl]aniline (32% c.y.).
46%
In ethanol;Heating / reflux;
B. To prepare the intermediate 2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-ol, 2-amino-1,3-benzothiazol-6-ol, (20.0 g, 0.12 mol) and 2-bromo-4'-nitroacetophenone (29.3 g, 0.12 mol) were dissolved in 600 mL ethanol and heated to reflux overnight. The solution was then cooled to 0 C. in an ice-water bath and the product was collected by vacuum filtration. After drying under vacuum with P2O5, the intermediate (2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-ol) was isolated as a yellow solid. Yield: 17.0 g (46%) NMR (DMSO-d6) ? 10 (s, 1H), 8.9 (s, 1H), 8.3 (d, 2H), 8.1 (d, 2H), 7.8 (d, 1H), 7.4 (s, 1H), 6.9 (d, 1H).
46%
In ethanol;Heating / reflux;Product distribution / selectivity;
To prepare the 2-(4-nitrophenyl)imidazo[2,l-b][l,3]benzothiazol-7-ol intermediate, 2-amino-l,3-benzothiazol-6-ol (20.0 g, 0.12 mol) and 2-bromo-4'- nitroacetophenone (29.3 g, 0.12 mol) were dissolved in 600 mL ethanol and heated to reflux overnight. The solution was then cooled to O0C in an ice-water bath and the product was collected by vacuum filtration. After drying under vacuum with P2O5, the intermediate (2- (4-nitrophenyl)imidazo[2,1-b][l,3]benzothiazol-7-ol) was isolated as a yellow solid. Yield: 17.0 g (46 %) NMR (DMSO-d6) delta 10 (s, IH), 8.9 (s, IH), 8.3 (d, 2H), 8.1 (d, 2H), 7.8 (d, IH), 7.4 (s, IH), 6.9 (d, IH).
46%
With tetra-(n-butyl)ammonium iodide; In ethanol; for 37h;Reflux;
1. 50 L 3 -neck round bottom flask was equipped with a mechanical agitator, thermocouple probe, reflux condenser, and a heating mantle.2. The flask was charged with <strong>[26278-79-5]2-amino-6-hydroxybenzothiazole</strong> (1068 g, 6.43 mol, 1.0 eq) and ethanol (200 pf, 32.0 L) and the suspension was stirred for 10 minutes. 3. 2-Bromo-4-nitroacetophenone (1667 g, 6.49 mol, 1.01 eq) was added in one portion.4. The reaction mixture was heated to reflux (78 0C). Reflux was maintained for approximately 25 hours, resulting in a yellow suspension.5. The reaction progress was monitored by TLC: [20% methanol/ethyl acetate; Rf (product) = 0.85; Rf (starting material) = 0.30]. TLC indicated -50% starting material after 24 hours of reflux.Tetrabutylammonium iodide (10 g) was added and reflux was maintained for an additional 12 hours, TLC indicated still -50% starting material present. Coupling was seen to occur at both the thiazole and the amine.6. The reaction mixture was cooled to 0-5 0C. The solids were collected by filtration, washing the yellow solid with ethanol, 200 pf. (2 x 1.0 L) and diethyl ether (2 x 1.5 L).7. The solids were dried in a vacuum oven (<10mmHg) at 40 0C. Yield: 930 g (46%), yellow solid.HPLC: 99.5% (area)1R NMR: conforms (300 MHz, DMSO).
Preparation of 2-(4-Nitrophenyl) imidazo [2J-b]benzothiazol-7-ol(Intermediate 2). 2-Amino-6-hydroxybenzothiazole, 2-Bromo-4-nitroacetophenone and absolute Ethanol are added together and heated to reflux for approximately 24 hours. Tetrabutylammonium iodide is added and the reaction is refluxed an additional 12 hours. The resulting yellow suspension is cooled and the solids collected and washed with Ethanol and Diethyl ether. The solids are dried under vacuum to give Intermediate 2.
With sodium hydrogencarbonate; In methanol; dichloromethane; water;
Step 1: 2-Amino-benzothiazol-6-ol (225): A suspension of 2-amino-6-methoxybenzothiazole (5.00 g, 27.8 mmol) in dichloromethane (70 mL) was cooled to 0 C. under nitrogen and boron tribromide (3.93 mL, 41.6 mmol) was added dropwise. The light yellow mixture was stirred for 3 h, allowing to warm-up slowly from 0 C. to 10 C. The reaction was slowly quenched by dropwise addition of methanol and tafter stirring overnight at room temperature, the white solid was collected by filtration (6.04 g, 88% yield). This hydrobromic salt was dissolved in water, washed with ethyl acetate, and neutralized with a saturated aqueous solution of NaHCO3. The resulting crystals were collected by filtration and dried in the oven at 135 C. for 1 h to afford the title compound 225 as colorless crystals (3.63 g, 79% yield). 1H NMR: (CD3OD) delta (ppm): 7.27 (d, J=8.8 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.80 (dd, J=8.4, 2.2 Hz, 1H).
2-amino-1,3-benzothiazol-6-yl 2,6-difluorobenzenesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In water; at 20℃; for 120h;
b) 2-Amino-1,3-benzothiazol-6-yl 2,6-difluorobenzenesulfonate may be prepared in the following manner:To a solution of 1 g of 2-amino-1,3-benzothiazol-6-ol in 66 cm3 of aqueous 0.1N sodium hydroxide solution are added 1.279 g of <strong>[60230-36-6]2,6-difluorobenzenesulfonyl chloride</strong>. The solution is stirred for 5 days at a temperature in the region of 20° C. After addition of 10 cm3 of water, the precipitate is filtered off by suction and then washed with twice 3 cm3 of ice-cold water and dried under reduced pressure over phosphorus pentoxide. 2.1 g of 2-amino-1,3-benzothiazol-6-yl 2,6-difluorobenzenesulfonate are obtained in the form of a pink powder, the characteristics of which are as follows:Melting point: melting at 179° C. (Koefler block)Mass spectrum: EI: m/z=342 [M+]
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2h;
To a solution of 30 (9.03g, 54.3mmol), triethylamine (8.27mL, 59.7mmol) in THF (100mL) was added a solution of cyclopropanecarbonyl chloride (5.19mL, 57.0mmol) in THF (25mL) at 0C, and the mixture was stirred at room temperature for 2h. The mixture was diluted with water and extracted with AcOEt. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residual solid was collected and washed with AcOEt-hexane to give 31 (12.3g, 97%) as a white solid: 1H NMR (DMSO-d6) delta 0.95-1.05 (4H, m), 1.84-1.99 (1H, m), 6.93 (1H, dd, J=8.8, 2.6Hz), 7.29 (1H, d, J=8.8Hz), 7.45-7.50 (3H, m).
97%
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2h;
Reference Example 59; N- (6-hydroxy-l, 3-benzothiazol-2-yl) cyclopropanecarboxamide; To a solution of 2-amino-l, 3-benzothiazol-6-ol (9.03 g, 54.3 mmol) and triethylamine (8.27 mL, 59.7 mmol) in tetrahydrofuran (100 mL) was added with stirring under ice- cooling a solution of cyclopropanecarbonyl chloride (5.19 mL, 57.0 mmol) in tetrahydrofuran (25 mL) , and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with hexane-ethyl acetate to give the title compound (12.3 g, 97%) as a white solid. <n="202"/>1H-NMR (DMSO-d6, 300 MHz) delta 0.95 - 1.05 (4H, m) , 1.84 - 1.99 (IH, m), 6.93 (IH, dd, J = 8.8, 2.6 Hz), 7.29 (IH, d, J = 8.8 Hz), 7.45 - 7.50 (3H, m) .
76%
(v) Production of N-(6-hydroxy-1,3-benzothiazol-2-yl)cyclopropanecarboxamide; To a solution of 2-amino-1,3-benzothiazol-6-ol (3.43 g, 20.6 mmol) in pyridine (50 mL) were added cyclopropanecarbonyl chloride (4 mL, 44.1 mmol) and N,N-dimethylpyridine-4-amine (220 mg, 1.80 mmol), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added lithium hydroxide monohydrate (2.06 g, 49.1 mmol) in water (50 mL) and the mixture was stirred at the same temperature for 1 hr. 5N Aqueous sodium hydroxide solution (50 mL) was added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dilute hydrochloric acid (300 mL, pH 2.0), and extracted with ethyl acetate (250 mL). The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution (150 mL). The earlier aqueous layer was extracted with ethyl acetate (150 mL), and the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution (100 mL). The collected organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (3.67 g, 76%) as a pale-gray solid. 1H-NMR (DMSO-d6, 300 MHz) delta 0.91-0.94 (4H, m), 1.91-1.99 (1H, m), 6.87 (1H, dd, J = 2.4, 8.7 Hz), 7.25 (1H, d, J = 2.4 Hz), 7.52 (1H, d, J = 8.7 Hz), 9.49 (1H, br s), 12.39 (1H, br s).
In N,N-dimethyl acetamide; at 0 - 20℃;
30.0 mmol) in N, N-dimethylacetamide (20 mL) was added cyclopropanecarbonyl chloride (4.08 mL, 45.0 mmol) at O0C, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with water, . dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate/diisopropyl ether and collected by filtration to give the title compound (3.22 g, 13.7 mmol) as a white solid.1H-NMR (DMSO-ddelta, 300MHz) delta 0.87 - 0.97 (4H, m) , 1.92 - 2.01 (IH, m) , 6.87 (IH, dd, J = 8.7, 2.3 Hz), 7.25 (IH, d, J = 2.3 Hz), 7.52 (IH, d, J = 8.7 Hz), 9.53 (IH, br s), 12.41 (IH, br s)
Stage #1: 2-amino-6-hydroxybenzothiazole With potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 1h;
Stage #2: 2-chloro-6 fluorobenzyl chloride In N,N-dimethyl-formamide at 20℃; for 20h;
8
add 337 mg of anhydrous potassium hydroxide to a solution of 1g of 2-amino-1,3-benzothiazol-6-ol in 5 cm3 of N,N-dimethylformamide. After stirring for one hour at a temperature close to 20° C., a solution of 1.08 g of 1-chloro-2-(chloromethyl)-3-fluorobenzene in 2 cm3 of N,N-dimethylformamide is added dropwise. Stir the resultant mixture for about twenty hours at about 20° C. The reaction mixture is poured into 30 cm3 of water, and extracted three times with 50 cm3 of dichloromethane. The organic phases are combined and washed three times with 50 cm3 of a 0.1N aqueous solution of sodium hydroxide, then dried over magnesium sulphate, filtered and concentrated under reduced pressure (0.2 kPa). The residue is taken up in 10 cm3 of a dichloromethane/methanol mixture (98/2 by volume), drained and then washed twice with 5 cm3 of the same mixture, stove-dried under reduced pressure (0.2 kPa) and at a temperature close to 35° C. We obtain 339 mg of 6-[(2-chloro-6-fluorobenzyl)oxy]-1,3-benzothiazol-2-amine in the form of a white solid, which has the following characteristics:Melting point: 175° C. (Köfler)1H NMR spectrum (400 MHz, DMSO-d6) δ ppm: 5.12 (d, J=2.0 Hz, 2H) 6.90 (dd, J=8.5, 2.7 Hz, 1H) 7.24 (m, 3H) 7.31 (t, J=8.8 Hz, 1H) 7.41 (m, 2H) 7.51 (td, J=8.8, 6.4 Hz, 1H)Mass spectrum: LC-MS-DAD-ELSD: 309(+)=(M+H)(+)
With triethylamine; In 1,4-dioxane; at 110℃; for 0.5h;Microwave irradiation;
6-Hydroxy-benzothiazol-2-amine 20 (100 mg, 0.60 mmol) was suspended in 2 ml dry dioxane. N1,N2-di-boc-N3-(trifluoromethylsulfonyl)guanidine 17 (236 mg, 0.60 mmol) and triethylamine (0.1 ml, 0.66 mmol) were added and the vessel was sealed. The mixture was heated in the microwave oven for 15 min at 110C. The vessel was opened and another portion N1,N2-di-boc-N3-(trifluoromethylsulfonyl)guanidine (236 mg, 0.60 mmol) was added, the vessel sealed and the mixture was heated again for 15 min at 110C. The solution was concentrated in vacuo and the residue was applied on silica gel. Purification by flash column chromatography with pentane-ethyl acetate (4:1) as eluent afforded 21 (101 mg, 41%) as a white solid: 1H NMR (500 MHz, CDCl3) Tautomer 1 1.55 (s, 18H), 5.65 (bs, 1H), 6.92-7.00 (m, 1H), 7.25-7.28 (m, 1H), 7.66 (d, J=8.7 Hz, 1H), 11.32 (s, 1H), 11.56 (bs, 1H); Tautomer 2 1.58 (s, 18H), 5.65 (bs, 1H), 6.92-7.00 (m, 1H), 7.18-7.23 (m, 1H), 7.61 (d, J=8.6 Hz, 1H), 10.35 (bs, 1H), 12.72 (bs, 1H); T1:T2=1:0.75; 13C NMR (125 MHz, CDCl3) 28.21, 28.37, 80.92, 85.05, 106.92, 107.24, 115.33, 115.58, 121.81, 122.03, 145.45, 151.80, 153.02, 153.20, 169.50; MS (ESI): m/z 409 [M+H]+.
With bromine; In chloroform; at 5℃;Inert atmosphere; Reflux;
In a 100 ml two-necked flask equipped with stir bar, appropriately substituted aryl thiourea (2) (5g, 29.7mmol) was dissolved in chloroform (30 mL). Then bromine (5 g, 29.7 mmol) in chloroform (15 mL) was placed in a dropping funnel and was added drop wise with stirring to the reaction mixture by maintaining the temperature below 5C. After the complete addition of bromine, the stirring was continued for a period of 4-6 h, and the content of the flask was refluxed on water bath till the evolution of hydrogen bromide vapors ceased. The resulting solid material was treated with ice water and filtered off. The filtrate was neutralized with an aqueous ammonia solution, the white precipitate obtained was filtered off, washed with water; compound 3 was crystallized from ethanol (4g, 80% yield, solid white powder). 1H NMR (DMSO-d6, 400 MHz): delta ppm: 9.10 (s, 1H, -OH), 7.13 (d, J = 8.4 Hz, 1H, ArH, C5-H), 7.06 (s, 2H, -NH2), 7.01 (d, J = 2.4 Hz, 1H, ArH, C4-H), 6.65 (dd, J = 2.6, 8.6 Hz, 1H, ArH, C7-H).
With dmap; triethylamine; In tetrahydrofuran; at 20℃;
[1084] Step 2: 2-((4-methylbenzoyl)imino)-2,3-dihydrobenzo[d]thiazol-6-yl 4-methylbenzoate[1085] To a solution of 2-aminobenzo[d]thiazol-6-ol (4.61 g, 27.74 mmol) prepared in Step 1 in tetrahydrofuran (250 mL), were sequentially added triethylamine (5.77 mL, 41.61 mmol), dimethylaminopyridine (339 mg, 2.77 mmol), and p-toluoyl chloride (5.13 mL, 38.84 mmol. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and then washed with an aqueous 1N HCl solution, a saturated sodium hydrogen carbonate solution, and brine. The organic layer was dried over magnesium sulfate and then filtered. The filtrate was evaporated, suspended with isopropyl ether and then filtered. The resulting solid was dried under reduced pressure to give 5.81 g of the titled compound as a gray solid.[1086] 1H NMR (DMSO-d6, 400 MHz); 8.04 (t, 4H), 7.54 (s, 1H), 7.47 (d, 1H), 7.42 (d, 2H), 7.20 (d, 2H), 7.06 (d, 1H), 2.42 (s, 3H), 2.34 (s, 3H)
5.81 g
With dmap; triethylamine; In tetrahydrofuran; at 20℃;
Step 2: 2-((4-methylbenzoyl)imino)-2,3-dihydrobenzo[d]thiazol-6-yl 4-methylbenzoate To a solution of 2-aminobenzo[d]thiazol-6-ol (4.61 g, 27.74 mmol) prepared in Step 1 in tetrahydrofuran (250 mL), were sequentially added triethylamine (5.77 mL, 41.61 mmol), dimethylaminopyridine (339 mg, 2.77 mmol), and p-toluoyl chloride (5.13 mL, 38.84 mmol. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and then washed with an aqueous 1N HCl solution, a saturated sodium hydrogen carbonate solution, and brine. The organic layer was dried over magnesium sulfate and then filtered. The filtrate was evaporated, suspended with isopropyl ether and then filtered. The resulting solid was dried under reduced pressure to give 5.81 g of the titled compound as a gray solid. 1H NMR (DMSO-d6, 400 MHz); 8.04 (t, 4H), 7.54 (s, 1H), 7.47 (d, 1H), 7.42 (d, 2H), 7.20 (d, 2H), 7.06 (d, 1H), 2.42 (s, 3H), 2.34 (s, 3H)
Sodium hydride (60%) (106 mg, 2.65 mmol) was added while stirring under ice cooling to an N,N'-dimethylformamide (7 ml) solution containing <strong>[26278-79-5]2-amino-6-hydroxybenzothiazole</strong> (400 mg, 2.41 mmol) under an argon atmosphere and stirred for 30 minutes, and then 4-bromoethyl butyrate (521 mul, 3.62 mmol) was added thereto and stirred overnight at room temperature. After completion of the reaction, the reaction solution was diluted with ethyl acetate and washed with a saturated ammonium chloride aqueous solution and a saturated sodium chloride aqueous solution. The solution was dried over sodium sulfate and the solvent was evaporated, thereby obtaining 372 mg of ethyl 4-((2-aminobenzothiazol-6-yl) (oxy)butanoate in a yield of 55%.
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In acetone;Reflux;
General procedure: A mixture of compound 2 (2 g, 12 mmol), potassium carbonate (2 g, 14.4 mmol), appropriate alkylbromide or benzyl chloride derivatives (1.32 mmol), and a catalytic amount of benzyltriethylaminechloride (TEBA) in 50 mL acetone was heated under reflux for 18-24 h. After removing the solventunder reduced pressure, 80 mL of hot water was poured into the flask and the mixture was stirred for0.5 h to eliminate the excess of potassium carbonate. The remaining precipitate was filtered to yield arusset solid (3a-m), which was used without further purification.
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In acetone;Reflux;
General procedure: A mixture of compound 2 (2 g, 12 mmol), potassium carbonate (2 g, 14.4 mmol), appropriate alkylbromide or benzyl chloride derivatives (1.32 mmol), and a catalytic amount of benzyltriethylaminechloride (TEBA) in 50 mL acetone was heated under reflux for 18-24 h. After removing the solventunder reduced pressure, 80 mL of hot water was poured into the flask and the mixture was stirred for0.5 h to eliminate the excess of potassium carbonate. The remaining precipitate was filtered to yield arusset solid (3a-m), which was used without further purification.
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In acetone;Reflux;
General procedure: A mixture of compound 2 (2 g, 12 mmol), potassium carbonate (2 g, 14.4 mmol), appropriate alkylbromide or benzyl chloride derivatives (1.32 mmol), and a catalytic amount of benzyltriethylaminechloride (TEBA) in 50 mL acetone was heated under reflux for 18-24 h. After removing the solventunder reduced pressure, 80 mL of hot water was poured into the flask and the mixture was stirred for0.5 h to eliminate the excess of potassium carbonate. The remaining precipitate was filtered to yield arusset solid (3a-m), which was used without further purification.
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In acetone;Reflux;
General procedure: A mixture of compound 2 (2 g, 12 mmol), potassium carbonate (2 g, 14.4 mmol), appropriate alkylbromide or benzyl chloride derivatives (1.32 mmol), and a catalytic amount of benzyltriethylaminechloride (TEBA) in 50 mL acetone was heated under reflux for 18-24 h. After removing the solventunder reduced pressure, 80 mL of hot water was poured into the flask and the mixture was stirred for0.5 h to eliminate the excess of potassium carbonate. The remaining precipitate was filtered to yield arusset solid (3a-m), which was used without further purification.
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In acetone;Reflux;
General procedure: A mixture of compound 2 (2 g, 12 mmol), potassium carbonate (2 g, 14.4 mmol), appropriate alkylbromide or benzyl chloride derivatives (1.32 mmol), and a catalytic amount of benzyltriethylaminechloride (TEBA) in 50 mL acetone was heated under reflux for 18-24 h. After removing the solventunder reduced pressure, 80 mL of hot water was poured into the flask and the mixture was stirred for0.5 h to eliminate the excess of potassium carbonate. The remaining precipitate was filtered to yield arusset solid (3a-m), which was used without further purification.
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In acetone;Reflux;
General procedure: A mixture of compound 2 (2 g, 12 mmol), potassium carbonate (2 g, 14.4 mmol), appropriate alkylbromide or benzyl chloride derivatives (1.32 mmol), and a catalytic amount of benzyltriethylaminechloride (TEBA) in 50 mL acetone was heated under reflux for 18-24 h. After removing the solventunder reduced pressure, 80 mL of hot water was poured into the flask and the mixture was stirred for0.5 h to eliminate the excess of potassium carbonate. The remaining precipitate was filtered to yield arusset solid (3a-m), which was used without further purification.
methyl 4-((6-hydroxybenzo[d]thiazol-2-yl)carbamoyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 16h;
Example 60 : N 1 -(6-hydroxybenzo [d]thiazol-2-yl)-N4-(prop-2-yn- 1 -yl)terephthalamide. To a vial equipped with a magnetic stir bar was added 2-aminobenzo[d]thiazol-6-ol (500 mg, 3.0 mmol), mono-methyl terephthalate (597 mg, 3.3 mmol), HATU (1.38 g, 3.6 mmol), and DMF (6 ml). The resulting solution was treated with N,N-diisopropylethyl amine (1.0 ml, 6.0 mmol), and the mixture was allowed to stir for 16 h at ambient temperature. Water was added to the mixture, and the resulting precipitate was washed with water and dried by aspiration to give methyl 4-((6- hydroxybenzo[d]thiazol-2-yl)carbamoyl)benzoate (907 mg, 92%): LCMS (ESI) m/z 329.2 [M+l]+.
6-(prop-2-yn-1-yl-1,1-deutero-oxy)benzo[d]thiazol-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;
Example 47 : 6-(prop-2-yn- 1 -yl- 1 , 1 -deutero-oxy)benzo [d]thiazol-2-amine. 2-aminobenzo[d]thiazol-6-ol (25 mg, 0.15 mmol) was dissolved in DMF (0.3 ml) and the resulting solution was treated with cesium carbonate (98 mg, 0.3 mmol) and prop-2-yn-l-yl-l,l-deutero- 4- methylbenzenesulfonate (35 mg, 0.17 mmol) and the mixture was allowed to stir 16 h at room temperature. The mixture was diluted with water and extracted with ethyl acetate several times, and the combined organic layer was dried (sodium sulfate), filtered, and concentrated under vacuum. The resulting solid was triturated with ether /methanol to give the title compound (25 mgs, 81 >) as a solid: 1H NMR (400 MHz, Methanol-d4) delta 7.32 - 7.22 (m, 2H), 6.92 (dd, J= 8.8, 2.6 Hz, 1H), 2.91 (s, 1H); LCMS (ESI) m/z 206.9 [M+l]+.
4-((2-chloroquinazolin-4-yl)oxy)-2H-chromen-2-one[ No CAS ]
4-((2-((6-hydroxybenzo[d]thiazol-2-yl)amino)quinazolin-4-yl)oxy)-2H-chromen-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With potassium carbonate; In acetone; for 8h;Inert atmosphere; Reflux;
General procedure: A mixture of intermediate 4 (10 mmol), potassium carbonate (12 mmol) and various 2-aminobenzothiazoles (10 mmol) in acetone solvent (30 mL) was refluxed for 8 h. The progress of the reaction was monitored by TLC. After cooling to room temperature, the reaction mixture was treated with 200 mL cold water, and the resulting precipitate was filtered off. The crude products 5a-j were recrystallized from DMF.
4-((2-aminobenzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22.7%
With caesium carbonate; In dimethyl sulfoxide; at 20 - 135℃; for 5.25h;
4.2 4-((2-Aminobenzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide (3) [33] To a stirred solution of compound 2 (10.0 g, 60.25 mmol) in anhydrous dimethyl sulfoxide (DMSO, 100 mL), cesium carbonate (49.0 g, 150.63 mmol) and 4-chloro-N-methylpicolinamide (1) (10.25 g, 60.25 mmol) were added at room temperature (rt). The mixture was stirred at rt for 15 min then heated at 135 C for 5 h. The reaction mixture was cooled and quenched with water (500 mL), and the resultant suspension was extracted with ethyl acetate (3 * 350 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, and filtered. The solvent was evaporated under reduced pressure yielding an oily residue that was purified by flash column chromatography on silica gel using (50-75% ethyl acetate in hexane) to afford the title compound as pure white solid; yield 22.7%; mp 230-232 C; IR (KBr) nu/cm-1: 3306, 3062, 1645; 1H NMR (400 MHz, DMSO-d6) delta 8.78 (q, J = 4.4 Hz, 1H, exchangeable with D2O, CONHCH3), 8.51 (d, J = 5.6 Hz, 1H, Py-H6), 7.63 (d, J = 2.4 Hz, 1H, Py-H3), 7.57 (s, 2H, exchangeable with D2O, NH2), 7.42 (d, J = 8.4 Hz, 1H, BT-H4), 7.38 (d, J = 2.8 Hz, 1H, BT-H7), 7.15 (dd, J = 5.6, 2.4 Hz, 1H, Py-H5), 7.07 (dd, J = 8.8, 2.8 Hz, 1H, BT-H5), 2.80 (d, J = 4.8 Hz, 3H, CH3); 13C NMR (100 MHz, DMSO-d6) delta 167.46, 166.79, 164.28, 152.88, 151.33, 150.80, 147.48, 132.82, 119.22, 119.01, 114.38, 114.36, 109.14, 26.45; HRMS (ESI-TOF) m/z calcd for C14H12N4O2SNa [M+Na]+: 323.0579, found: 323.0567.
ethyl 10-hydroxy-7-thia-2,5-diazatricyclo[6.4.0.02,6]dodeca-1(8),3,5,9,11-pentaene-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With N,N-dimethyl acetamide; at 100℃; for 3h;Inert atmosphere;
Example 113 Ethyl 10-hydroxy-7-thia-2,5-diazatricyclo[6.4.0.02'6]dodeca-l(8),3,5,9,ll-pentaene-4- carboxylate To a solution of 2-amino-l ,3-benzothiazol-6-ol (1.10 g, 6.62 mmol) in DMA (25 mL) was added ethyl 3-bromo-2-oxopropanoate (1.25 mL, 9.93 mmol). The resulting solution was stirred at 100C for 3 h under an inert atmosphere. The cooled mixture was poured into ice water (-150 mL) and the resulting mixture filtered and the solid washed with more water. This was triturated in hot MeOH and filtered again. The collected solid was dried under vacuum to afford the title compound as a brown solid (600 mg, 35% yield); m/z = 263.0 (MH)+.
In N,N-dimethyl acetamide; at 100℃; for 3h;
Ethyl 3-bromo-2-oxopropanoate (4.2 mL, 33.1 mmol) was added dropwise to a stirred solution of 2-amino- 1,3-benzothiazol-6-ol (5 g, 30.1 mmol) in N,N-dimethylacetamide (100 mL) at room temperature. The reaction mix- tare was heated to 1000 C. for 3 hours. The reaction was cooled to room temperature and water (200 mL) added. A precipitate formed and the mixture was filtered. The collected solid was dried under vacuum to give the title compound. ?H NMR (500 MHz, DMSO) 10.03 (s, 1H), 8.89 (s, 1H), 7.95 (d, J=8.7 Hz, 1H), 7.38 (d, J=2.3 Hz, 1H), 6.94 (dd, J=8.8, 2.3 Hz, 1H), 4.28 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H). Tr(METCR141O)=0.91 mi mlz (ES) (M+H)263
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In acetone;Reflux;
General procedure: A mixture of compound 2 (2 g, 12 mmol), potassium carbonate (2 g, 14.4 mmol), appropriate alkylbromide or benzyl chloride derivatives (1.32 mmol), and a catalytic amount of benzyltriethylaminechloride (TEBA) in 50 mL acetone was heated under reflux for 18-24 h. After removing the solventunder reduced pressure, 80 mL of hot water was poured into the flask and the mixture was stirred for0.5 h to eliminate the excess of potassium carbonate. The remaining precipitate was filtered to yield arusset solid (3a-m), which was used without further purification.
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In acetone;Reflux;
General procedure: A mixture of compound 2 (2 g, 12 mmol), potassium carbonate (2 g, 14.4 mmol), appropriate alkylbromide or benzyl chloride derivatives (1.32 mmol), and a catalytic amount of benzyltriethylaminechloride (TEBA) in 50 mL acetone was heated under reflux for 18-24 h. After removing the solventunder reduced pressure, 80 mL of hot water was poured into the flask and the mixture was stirred for0.5 h to eliminate the excess of potassium carbonate. The remaining precipitate was filtered to yield arusset solid (3a-m), which was used without further purification.
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In acetone;Reflux;
General procedure: A mixture of compound 2 (2 g, 12 mmol), potassium carbonate (2 g, 14.4 mmol), appropriate alkylbromide or benzyl chloride derivatives (1.32 mmol), and a catalytic amount of benzyltriethylaminechloride (TEBA) in 50 mL acetone was heated under reflux for 18-24 h. After removing the solventunder reduced pressure, 80 mL of hot water was poured into the flask and the mixture was stirred for0.5 h to eliminate the excess of potassium carbonate. The remaining precipitate was filtered to yield arusset solid (3a-m), which was used without further purification.
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In acetone;Reflux;
General procedure: A mixture of compound 2 (2 g, 12 mmol), potassium carbonate (2 g, 14.4 mmol), appropriate alkylbromide or benzyl chloride derivatives (1.32 mmol), and a catalytic amount of benzyltriethylaminechloride (TEBA) in 50 mL acetone was heated under reflux for 18-24 h. After removing the solventunder reduced pressure, 80 mL of hot water was poured into the flask and the mixture was stirred for0.5 h to eliminate the excess of potassium carbonate. The remaining precipitate was filtered to yield arusset solid (3a-m), which was used without further purification.
6-[(2-chlorobenzyl)oxy]-1,3-benzothiazol-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In acetone;Reflux;
General procedure: A mixture of compound 2 (2 g, 12 mmol), potassium carbonate (2 g, 14.4 mmol), appropriate alkylbromide or benzyl chloride derivatives (1.32 mmol), and a catalytic amount of benzyltriethylaminechloride (TEBA) in 50 mL acetone was heated under reflux for 18-24 h. After removing the solventunder reduced pressure, 80 mL of hot water was poured into the flask and the mixture was stirred for0.5 h to eliminate the excess of potassium carbonate. The remaining precipitate was filtered to yield arusset solid (3a-m), which was used without further purification.
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In acetone;Reflux;
General procedure: A mixture of compound 2 (2 g, 12 mmol), potassium carbonate (2 g, 14.4 mmol), appropriate alkylbromide or benzyl chloride derivatives (1.32 mmol), and a catalytic amount of benzyltriethylaminechloride (TEBA) in 50 mL acetone was heated under reflux for 18-24 h. After removing the solventunder reduced pressure, 80 mL of hot water was poured into the flask and the mixture was stirred for0.5 h to eliminate the excess of potassium carbonate. The remaining precipitate was filtered to yield arusset solid (3a-m), which was used without further purification.
6-(2-methoxyethoxy)benzo[d]thiazol-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;
Method G. To a solution of 2-aminobenzo[i/]fhiazol-6-ol (500mg, 3.0mmol, 1 eq) in DMF (30ml) was added cesium carbonate (4.9g, 15.0 mmol, 5 eq), and 1 -bromo-2-methox ethane (310 ul, 3.3 mmol, 1.1 eq). The reaction was stirred overnight at room temperature and subsequently taken up in EtOAc. The EtOAc layer was washed 2 x water, 1 x brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography and recrystallized from EtOAc to give 6-(2-methoxyethoxy)benzo[ /]thiazol-2-amine (251 mg, 37 yield) as a white solid.
2-((4-methylphenyl)methylamino)benzo[d]thiazol-6-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With phenylsilane; dibutyltin chloride; In tetrahydrofuran; at 20℃; for 12h;
Compound 13 (50 mg, 0.3 mmol), 4-methylbenzaldehyde(39.6 mg, 0.33mmol), dibutyltin dichloride (9.11 mg, 0.03 mmol) and THF (1ml) in It was dissolved by the addition of phenylsilane (49 mg, 0.45mmol) slowly and stirred at room temperature for 12 hours. After checking the completion of the reaction, the cells using the light,filtered under reduced pressure, ethyl acetate (2 ml) to the residue and concentrated under reduced pressure, filtered to give theresidue, and water (0.5 ml), washed with a 1N HCl aqueous solution (0.5 ml) It was. Then, the organic layer was again washedagain using the aqueous solution of NaHCO3. The organic layer was filtered, and then dried over anhydrous magnesium sulfate,filtered, evaporated under reduced pressure and the solution was purified by column chromatography. As a result, the 15 compound(55.1 mg, yield: 68%) was obtained.
6-(2-morpholinoethoxy)benzo[d]thiazol-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 24h;
2-Aminobenzo[d]thiazol-6-ol (1.0 equiv.) To the dissolved DMF, 4- (2-chloroethyl) morpholine HCl (1.2 equiv.)And Cs2CO3 (1.2 equiv.) Were added thereto, followed by stirring at 80 DEG C for one day to give the title compound.
With aluminum (III) chloride; In toluene; at 115℃; for 2h;
To a solution of Example 18d (444 mg, 2.67 mmol) in Tol (10 mL) was added A1C13 (1 .1 g, 8.02 mmol) at r.t. After addition, the reaction mixture was heated to 115C for 2h. Water (50 mL) and EA (50 mL) were added, the organic layer was washed with water (20 mL*2), brine (20 mL), dried overNa2S04, filtered and concentrated, purified by flash column chromatography to give the desired product (Example 18e, 370 mg, yield 91%) as yellow solid. LCMS [M+1]+= 153
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 0.5h;
Compound 161A (105.34 mg, 0.634 mmol), the compound of Example IE (100 mg, 0.422 mmol), cesiumcarbonate (275.36 mg, 0.845 mmol) and 2.5 ml of DMF were mixed and then placed in a microwave reactor at 100 °Cfor 30 minutes, cooled to room temperature, 20 ml of water was poured thereinto, and filtered. The filter cake and thenwashed with water and finally dried to give a yellow solid crude of compound 161B (70 mg) which was used directly inthe next step.1H NMR (400MHz, DMSO-d6) = 8.92 (d, J=6.3 Hz, 1H), 8.78 - 8.72 (m, 1H), 8.50 - 8.13 (m, 2H), 7.98 (br. s., 1H), 7.96(s, 1H), 7.91 (br. s., 1H), 7.82 (d, J=2.3 Hz, 1H), 7.65 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.27 (dd, J=2.1, 8.7 Hz, 1H), 6.84(d, J=6.3 Hz, 1H), 4.09 (s, 3H)
diazonium tetrafluoroborate salt of 2-amino-6-hydroxybenzothiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With tetrafluoroboric acid; sodium nitrite; In water; at 0℃; for 1h;
An aqueous solution of HBF4 (48%, 2.5 mL) was added to the cold slurry of the <strong>[26278-79-5]2-amino-6-hydroxybenzothiazole</strong>(1.0 equiv.) in water (3 mL). Then, to this mixture, a solution of sodium nitrite (1.1 equiv.) in water (1.5 mL) was added dropwise. Afterwards, the reaction mixture was stirred for 1 h at 0 C and then permitted to warm at 25 C. The excess of oxidant was eliminated by the addition of urea. The resulting diazonium tetrafluoroboratesalt was separated and dissolved in a minimum quantity of acetone.Consequently, by adding diethyl ether, the dissolved salts precipitated, brown in color. The productwas washed with ice-cooled HBF4 (10 mL), H2 O (20 mL), and EtOH (10 mL). The obtained diazoniumtetrafluoroborate salt (1.8 g) was dried under vacuum and stored at 0 C until required.
General procedure: solution of various derivative of 2-amino benzothiazole derivatives(1 eq.) in CHCl3 (5 mL) were cooled at 0 C. Triethylamine(3.0 eq., d 0.726 g/mL, 1.4 mL) and chloro acetyl chloride 4 (1.1eq.) were sequentially added to the reaction mixture at 0 C. The reaction mixturewas stirred at 0 C for 30 min and allowed to reach to room temperature. The reaction mixture was further refluxed for18 h. The progress of the reaction was monitored by TLC (5% MeOH:DCM). The reaction mixture was diluted with CHCl3 (10 mL) and washed with saturated bicarbonate solution (2 15 mL). The organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford N-(benzo[d]thiazol-2-yl)-2-chloroacetamide derivatives (11a-11e) with good yield which is used in the next step without further purification.
6-([1,1′-biphenyl]-3-yl-methoxy)benzo[d]thiazole-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29.6 g
With potassium carbonate; In acetone; for 1h;Reflux;
In a reaction flask, add 17 g of 2-amino-6-hydroxybenzothiazole and 20 g of potassium carbonate to 200 mL of acetone, and slowly add 150 mL of an acetone solution in which 25 g of bromomethylbiphenyl is dissolved at room temperature. After completion, gradually raise the temperature to reflux, continue the reaction for 1 hour, concentrate the reaction solution, and then pour it into 200 mL of water. Adjust the pH of the reaction solution to neutral with dilute hydrochloric acid, evaporate the solvent under vacuum, and extract with 50 mL of methylene chloride The reaction solution was mixed several times, and the organic phases were combined and concentrated to obtain 29.6 g of 6-([1,1?-bidiphenyl]-3-yl-methoxy)benzo[d]thiazole-2-amine;
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