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Chemical Structure| 333-20-0
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Product Details of [ 333-20-0 ]

CAS No. :333-20-0 MDL No. :MFCD00011413
Formula : CKNS Boiling Point : -
Linear Structure Formula :- InChI Key :ZNNZYHKDIALBAK-UHFFFAOYSA-M
M.W : 97.18 Pubchem ID :516872
Synonyms :

Safety of [ 333-20-0 ]

Signal Word:Danger Class:8
Precautionary Statements:P261-P264-P270-P271-P273-P280-P301+P312+P330-P302+P352+P310-P304+P340+P312-P305+P351+P338+P310-P501 UN#:3261
Hazard Statements:H302-H312-H332-H318-H401-H412 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 333-20-0 ]

* 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.

  • Upstream synthesis route of [ 333-20-0 ]
  • Downstream synthetic route of [ 333-20-0 ]

[ 333-20-0 ] Synthesis Path-Upstream   1~73

  • 1
  • [ 3473-63-0 ]
  • [ 333-20-0 ]
  • [ 7552-07-0 ]
Reference: [1] Patent: US2009/124655, 2009, A1, . Location in patent: Page/Page column 14
[2] Patent: US2009/131440, 2009, A1, . Location in patent: Page/Page column 19
  • 2
  • [ 333-20-0 ]
  • [ 6313-33-3 ]
  • [ 7552-07-0 ]
Reference: [1] Chemische Berichte, 1954, vol. 87, p. 68,74[2] Chemische Berichte, 1956, vol. 89, p. 1534,1540
[3] Gazzetta Chimica Italiana, 1977, vol. 107, p. 1 - 5
  • 3
  • [ 115948-81-7 ]
  • [ 333-20-0 ]
  • [ 7552-07-0 ]
Reference: [1] Chemische Berichte, 1954, vol. 87, p. 68,74[2] Chemische Berichte, 1956, vol. 89, p. 1534,1540
  • 4
  • [ 67-56-1 ]
  • [ 7726-95-6 ]
  • [ 333-20-0 ]
  • [ 463-52-5 ]
  • [ 7552-07-0 ]
Reference: [1] Chemische Berichte, 1954, vol. 87, p. 68,74[2] Chemische Berichte, 1956, vol. 89, p. 1534,1540
  • 5
  • [ 333-20-0 ]
  • [ 4091-39-8 ]
  • [ 2289-75-0 ]
Reference: [1] Tetrahedron Letters, 2002, vol. 43, # 9, p. 1717 - 1720
[2] Tetrahedron, 2006, vol. 62, # 14, p. 3201 - 3213
  • 6
  • [ 333-20-0 ]
  • [ 20846-52-0 ]
  • [ 17467-35-5 ]
YieldReaction ConditionsOperation in experiment
32% at 0 - 20℃; for 12 h; Compound LXII (5.1 g, 55 mmol) was dissolved in methanol (250 mL) and the resulting solution was cooled to 0° C. Potassium thiocyanate (5.3 g, 55 mmol) was then added. The resulting solution was stirred for 12 hours at room temperature, concentrated under reduced pressure, diluted with ethyl acetate (200 mL), and filtered under reduced pressure to remove a solid. The filtrate was concentrated under reduced pressure, creating a solid which was filtered under reduced pressure to yield Compound LXIII (2 g (32percent)). The filtrate was further concentrated and applied to column chromatography (SiO2, n-hex:EA=4:1) to yield Compound LXIII (2 g (32percent)).1H NMR (600 MHz, CD3OD) δ 3.27 (s, 3H)
32% at 0 - 20℃; for 12 h; Compound LXII (5,1 g, 55 mmol) was dissolved in methanol (250 mL) and the resulting solution was cooled to 0 . Potassium thiocyanate (5.3 g, 55 mmol) was then added. The resulting solution was stirred for 12 hours at room temperature, concentrated under reduced pressure, diluted with ethyl acetate (200 mL), and filtered under reduced pressure to remove a solid. The filtrate was concentrated under reduced pressure, creating a solid which was filtered under reduced pressure to yield Compound LXIII (2 g (32percent)). The filtrate was further concentrated and applied to column chromatography (SiO2, n-hex : EA = 4 : 1) to yield Compound LXIII (2 g (32percent)). 1H NMR (600MHz, CD3OD) δ 3.27(s, 3H)
Reference: [1] Patent: US2012/264727, 2012, A1, . Location in patent: Page/Page column 53
[2] Patent: EP2706062, 2014, A2, . Location in patent: Paragraph 0199
  • 7
  • [ 124-42-5 ]
  • [ 333-20-0 ]
  • [ 17467-35-5 ]
Reference: [1] Gazzetta Chimica Italiana, 1977, vol. 107, p. 1 - 5
[2] Bioorganic and medicinal chemistry, 2001, vol. 9, # 12, p. 3231 - 3241
  • 8
  • [ 333-20-0 ]
  • [ 78-95-5 ]
  • [ 7305-71-7 ]
Reference: [1] Tetrahedron, 2006, vol. 62, # 14, p. 3201 - 3213
  • 9
  • [ 188290-36-0 ]
  • [ 333-20-0 ]
  • [ 20300-02-1 ]
Reference: [1] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 17, p. 2317 - 2320
[2] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 5, p. 527 - 532
  • 10
  • [ 62147-49-3 ]
  • [ 593-51-1 ]
  • [ 333-20-0 ]
  • [ 38993-84-9 ]
Reference: [1] Organic and Biomolecular Chemistry, 2007, vol. 5, # 20, p. 3299 - 3309
  • 11
  • [ 333-20-0 ]
  • [ 108-44-1 ]
  • [ 14779-17-0 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: With nano-BF3/SiO2 In acetonitrile for 0.5 h; Cooling with ice
Stage #2: With bromine In acetonitrile at 0 - 20℃; for 5 h;
General procedure: A solution of substituted aniline (2 mmol) in acetonitrile (15 ml) was added to a solution of KSCN (8 mmol) in acetonitrile (15 ml). Then, 0.06 g (30 mol percent BF3) of nano-BF3/SiO2 was added to the mixture, then was placed in a freezing mixture of ice and salt and mechanically stirred for 30 min. Then, bromine (4 mmol, 0.2 ml) in acetonitrile (3 ml) as solvent was added from a dropping funnel at such a rate that the temperature never rose beyond 0°C. After all the bromine was added at 60 min, the solution was stirred for 4 h at room temperature. The progress of the reaction was monitored by TLC. Then, the mixture was poured into water with stirring and the mixture was heated to 70°C on a steam bath and filtered hot to remove the catalyst and the recovered catalyst was washed with acetone and reused in the reaction. The filtrate was neutralized with 10 percent NaOH solution and the precipitate was collected on a filter, dried and recrystallized from ethanol (10 ml) to afford the corresponding products. All of the 2-aminobenzothiazole products were identified by physical and spectroscopic data as reported below, compared and contrasted with authentic samples.#10;Spectral data for selected products#10;6-Bromo-1,3-benzothiazol-2-amine (2e) Yellow solid; Yield = 93 percent; m.p. =202–204°C; (m.p. = 203°C), FT-IR (KBr)/t(cm-1): 3315, 3012, 2835,1580, 1476, 1261, 920, 742, 512. 1H NMR (400 MHz, CDCl3)/d ppm: 5.44 (s, 2H, NH2) 7.4–7.5 (d, 2H, Ar–H), 7.71 (s, 1H, Ar–H); 13C NMR/(100 MHz, DMSO-d6)/d ppm: 119, 120.9, 125.15, 126.07, 133.1, 152.15, 167.75.#10;
Reference: [1] Research on Chemical Intermediates, 2016, vol. 42, # 12, p. 7855 - 7868
[2] Journal of Pharmaceutical Sciences, 1994, vol. 83, # 10, p. 1425 - 1432
  • 12
  • [ 5049-61-6 ]
  • [ 333-20-0 ]
  • [ 31437-05-5 ]
Reference: [1] Journal of the American Chemical Society, 1952, vol. 74, p. 3617,3618,3620
  • 13
  • [ 333-20-0 ]
  • [ 589-16-2 ]
  • [ 21224-16-8 ]
Reference: [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 15, p. 2828 - 2843
  • 14
  • [ 333-20-0 ]
  • [ 81852-50-8 ]
  • [ 5398-36-7 ]
YieldReaction ConditionsOperation in experiment
80% With ferrous(II) sulfate heptahydrate In ethanol at 80℃; for 12 h; A mixture of ethyl 2-azidoacrylate7. 05 g (0.5 mol),Potassium thiocyanate9. 72 g (0.1 mol),150 ml of ethanol,Heptahydrate ferrous sulfate6. 95 g (0.025 mol) was added to a 250 ml reaction flask,Stir,Heating to 80 ° C for 12 hours,TLC to detect the reaction solution(Petroleum ether: ethyl acetate = 1: 1 by volume)2'-azidoethyl acrylate disappears;The resulting reaction solution was cooled to about 40 ° C,Rotary evaporator concentrated to remove ethanol,The residue was added to 150 ml of water, extracted with 50 mL of ethyl acetate, and the organic layer (on the upper layer) was combined, washed with 50 ml of water, 50 ml of saturated brine, dried over anhydrous sodium sulfate (5.0 g) for 30 minutes, The rotary evaporator was concentrated to remove ethyl acetate and the residue was recrystallized from 40 ml of ethanol to give 6. 94 g of a white solid in 80percent yield.
Reference: [1] Advanced Synthesis and Catalysis, 2015, vol. 357, # 5, p. 1065 - 1069
[2] Patent: CN104163802, 2016, B, . Location in patent: Paragraph 0029-0030
  • 15
  • [ 333-20-0 ]
  • [ 123-30-8 ]
  • [ 26278-79-5 ]
Reference: [1] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 1 - 13
  • 16
  • [ 333-20-0 ]
  • [ 371-40-4 ]
  • [ 348-40-3 ]
YieldReaction ConditionsOperation in experiment
84% at 5 - 6℃; for 2 h; General procedure: Arylamine (0.1 mol) and potassiumthiocyanate (0.4 mol) were dissolved in glacial aceticacid (40 mL) and cooled. Bromine (0.04 mol) mixed withglacial acetic acid (24 mL) was added from droppingfunnel at such a rate that temperature does not rise beyond5–6°C. After all bromine had been added, the solutionwas stirred with glass rod for an additional 2 h at lowtemperature. The mixture was allowed to stand overnight,during which period orange-yellow precipitates get settledat the bottom. Water was added and slurry formed washeated at 850°C on steam bath for 20 min and fi ltered hot.The fi ltrate was cooled and neutralised with ammoniasolution to pH 6. Yellow precipitates obtained werecollected, washed with water and recrystallized frombenzene to get crystals of 1,3-benzothiazol-2-amine andits derivatives 1-3 [21, 22].
80%
Stage #1: at 20℃; Cooling with ice
Stage #2: With ammonium hydroxide In water
General procedure: A mixture of 0.1 mol of 4-substituted aniline and 0.1 mol of Potassium thiocyanate (KCNS) in 100 ml glacial acetic acid (AcOH) was cooled in an ice bath and stirred for 10-20 min, and then 0.1 mol bromine in glacial acetic acid was added dropwise at such a rate to keep the temperature below 10 °C throughout the addition. The reaction mixture was stirred at room temperature for 2-4 h, the hydrobromide (HBr) salt thus separated out was filtered, washed with acetic acid, dried, dissolved in hot water and basified to pH 11.0 with ammonia solution (NH4OH) and the resulting precipitate was filtered, washed with water and dried to get the desired product 3a-k. The progress of the reaction was monitored by Thin Layer Chromatography using toluene: acetone (8:2) solvent system.
77.3%
Stage #1: at -10 - 20℃; for 12.5 h;
Stage #2: With ammonium hydroxide In waterHeating
General procedure: An appropriately p-substituted aniline (0.1 mol) and potassiumthiocyanate (KCNS, 9.718 g, 0.1 mol) were dissolvedin 100 mL of glacial acetic acid (AcOH), cooled inice–salt mixture and stirred mechanically, while a solutionof bromine (15.980 g, 0.1 mol) in AcOH (20 mL)was slowly added drop by drop (Palkar et al. 2010).External cooling was applied throughout the process to keepthe temperature below 10 °C and the stirring was continuedfor 30 min. After all of the bromine had been added, thesolution was stirred for 2 h below room temperature and atroom temperature for 10 h. It was then allowed to standovernight during which the precipitate of imino-benzo[d]thiazole hydrobromide salt thus separated out was filtered,washed with acetic acid, dried, dissolved in hot water andbasified to pH 11.0 with ammonia solution (NH4OH) andthe resulting precipitate was filtered, washed with water anddried to get the desired products 2-amino-6-substitutedbenzo[d]thiazole (1a–d). The progress of the reaction wasmonitored by TLC using acetone (20percent) in toluene solvent.
Reference: [1] Organic Letters, 2017, vol. 19, # 21, p. 5836 - 5839
[2] Molecular Crystals and Liquid Crystals, 2013, vol. 575, # 1, p. 64 - 76
[3] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 24, p. 8599 - 8607
[4] Russian Journal of Applied Chemistry, 2015, vol. 88, # 12, p. 2065 - 2073[5] Zh. Prikl. Khim. (S.-Peterburg, Russ. Fed.),
[6] European Journal of Medicinal Chemistry, 2008, vol. 43, # 5, p. 1114 - 1122
[7] Archiv der Pharmazie, 2015, vol. 348, # 4, p. 254 - 265
[8] European Journal of Medicinal Chemistry, 2012, vol. 53, p. 41 - 51
[9] Medicinal Chemistry Research, 2017, vol. 26, # 9, p. 1969 - 1987
[10] Journal of Organic Chemistry, 2017, vol. 82, # 18, p. 9312 - 9320
[11] Journal of Pharmaceutical Sciences, 1994, vol. 83, # 10, p. 1425 - 1432
[12] Journal of Medicinal Chemistry, 1999, vol. 42, # 15, p. 2828 - 2843
[13] Journal of the Indian Chemical Society, 2008, vol. 85, # 3, p. 333 - 335
[14] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3443 - 3446
[15] Archiv der Pharmazie, 2010, vol. 343, # 6, p. 353 - 359
[16] Patent: WO2011/151361, 2011, A1, . Location in patent: Page/Page column 53-54
[17] Asian Journal of Chemistry, 2011, vol. 23, # 9, p. 3969 - 3974
[18] Asian Journal of Chemistry, 2010, vol. 22, # 7, p. 5487 - 5492
[19] Heteroatom Chemistry, 2012, vol. 23, # 4, p. 399 - 410
[20] Organic Letters, 2012, vol. 14, # 20, p. 5334 - 5337,4
[21] Journal of Enzyme Inhibition and Medicinal Chemistry, 2013, vol. 28, # 1, p. 1 - 10
[22] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 1 - 13
[23] European Journal of Medicinal Chemistry, 2014, vol. 71, p. 24 - 30
[24] Archiv der Pharmazie, 2013, vol. 346, # 11, p. 819 - 831
[25] Journal of Heterocyclic Chemistry, 2014, vol. 51, # 2, p. 459 - 465
[26] Chemical Biology and Drug Design, 2014, vol. 84, # 1, p. 123 - 129
[27] Medicinal Chemistry, 2013, vol. 9, # 4, p. 596 - 607
[28] Journal of Heterocyclic Chemistry, 2014, vol. 51, # 6, p. 1641 - 1658
[29] Research on Chemical Intermediates, 2015, vol. 41, # 8, p. 5599 - 5609
[30] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5561 - 5565
[31] Research on Chemical Intermediates, 2016, vol. 42, # 12, p. 8329 - 8344
[32] Archiv der Pharmazie, 2018, vol. 351, # 12,
  • 17
  • [ 333-20-0 ]
  • [ 106-47-8 ]
  • [ 95-24-9 ]
YieldReaction ConditionsOperation in experiment
93%
Stage #1: With nano-BF3/SiO2 In acetonitrile for 0.5 h; Cooling with ice
Stage #2: With bromine In acetonitrile at 0 - 20℃; for 5 h;
General procedure: A solution of substituted aniline (2 mmol) in acetonitrile (15 ml) was added to a solution of KSCN (8 mmol) in acetonitrile (15 ml). Then, 0.06 g (30 mol percent BF3) of nano-BF3/SiO2 was added to the mixture, then was placed in a freezing mixture of ice and salt and mechanically stirred for 30 min. Then, bromine (4 mmol, 0.2 ml) in acetonitrile (3 ml) as solvent was added from a dropping funnel at such a rate that the temperature never rose beyond 0°C. After all the bromine was added at 60 min, the solution was stirred for 4 h at room temperature. The progress of the reaction was monitored by TLC. Then, the mixture was poured into water with stirring and the mixture was heated to 70°C on a steam bath and filtered hot to remove the catalyst and the recovered catalyst was washed with acetone and reused in the reaction. The filtrate was neutralized with 10 percent NaOH solution and the precipitate was collected on a filter, dried and recrystallized from ethanol (10 ml) to afford the corresponding products. All of the 2-aminobenzothiazole products were identified by physical and spectroscopic data as reported below, compared and contrasted with authentic samples.#10;Spectral data for selected products#10;6-Bromo-1,3-benzothiazol-2-amine (2e) Yellow solid; Yield = 93 percent; m.p. =202–204°C; (m.p. = 203°C), FT-IR (KBr)/t(cm-1): 3315, 3012, 2835,1580, 1476, 1261, 920, 742, 512. 1H NMR (400 MHz, CDCl3)/d ppm: 5.44 (s, 2H, NH2) 7.4–7.5 (d, 2H, Ar–H), 7.71 (s, 1H, Ar–H); 13C NMR/(100 MHz, DMSO-d6)/d ppm: 119, 120.9, 125.15, 126.07, 133.1, 152.15, 167.75.#10;
85%
Stage #1: at 15 - 20℃; for 2 h;
Stage #2: at 15 - 20℃;
6.38 g (0.05 mol) of p-chloroaniline was placed in a 100 ml round bottom flask, dissolved in 50 ml of glacial acetic acid, and then 5.40 g (0.055 mol) of potassium thiocyanate was added.Stir at 15-20 ° C for 2 h until the solid disappears completelyThen, 1 ml of bromine acetic acid solution was added dropwise at 15-20 ° C.When the temperature is controlled, the temperature is not more than 20 ° C, and the addition is completed in about 1 h.Normal temperature reaction for 2-4 hours, TLC tracking reaction,After the raw material amine is completely reacted, dissolved in hot water, filtered after a little cold.A white filter droplet is added to add 5 ml of concentrated ammonia water to adjust the pH to neutral or weakly alkaline. During this period, a large amount of white solid precipitates, and after standing, it is filtered, the filter cake is washed with water, and dried under vacuum.7.86 g of a white to slightly yellow powdery solid product are obtained.Melting point: 199-200 ° C, yield 85percent.
72%
Stage #1: at 20℃; Cooling with ice
Stage #2: With ammonium hydroxide In water
General procedure: A mixture of 0.1 mol of 4-substituted aniline and 0.1 mol of Potassium thiocyanate (KCNS) in 100 ml glacial acetic acid (AcOH) was cooled in an ice bath and stirred for 10-20 min, and then 0.1 mol bromine in glacial acetic acid was added dropwise at such a rate to keep the temperature below 10 °C throughout the addition. The reaction mixture was stirred at room temperature for 2-4 h, the hydrobromide (HBr) salt thus separated out was filtered, washed with acetic acid, dried, dissolved in hot water and basified to pH 11.0 with ammonia solution (NH4OH) and the resulting precipitate was filtered, washed with water and dried to get the desired product 3a-k. The progress of the reaction was monitored by Thin Layer Chromatography using toluene: acetone (8:2) solvent system.
68.5%
Stage #1: at -10 - 20℃; for 12.5 h;
Stage #2: With ammonium hydroxide In waterHeating
General procedure: An appropriately p-substituted aniline (0.1 mol) and potassiumthiocyanate (KCNS, 9.718 g, 0.1 mol) were dissolvedin 100 mL of glacial acetic acid (AcOH), cooled inice–salt mixture and stirred mechanically, while a solutionof bromine (15.980 g, 0.1 mol) in AcOH (20 mL)was slowly added drop by drop (Palkar et al. 2010).External cooling was applied throughout the process to keepthe temperature below 10 °C and the stirring was continuedfor 30 min. After all of the bromine had been added, thesolution was stirred for 2 h below room temperature and atroom temperature for 10 h. It was then allowed to standovernight during which the precipitate of imino-benzo[d]thiazole hydrobromide salt thus separated out was filtered,washed with acetic acid, dried, dissolved in hot water andbasified to pH 11.0 with ammonia solution (NH4OH) andthe resulting precipitate was filtered, washed with water anddried to get the desired products 2-amino-6-substitutedbenzo[d]thiazole (1a–d). The progress of the reaction wasmonitored by TLC using acetone (20percent) in toluene solvent.
57.58% at 10 - 20℃; for 3 h; To a solution of 4-chloroaniline (3.0g, 23.52mmol, l .Oeq) in acetic acid (90mL) were added Potassium thiocyanate (2.28g, 23.52mmol, l .Oeq). The reaction mixture was cooled at 10°C and bromine solution (3.76g, 23.52mmol, l .Oeq) was added dropwise. Reaction mixture was further stirred at room temperature for 3h. After completion of reaction, reaction mixture was filtered and washed with acetic acid. Filtered solid was heated in water and then neutralized with aqueous ammonia to obtain solid which was filtered and dried well to obtain pure 118.1. (2.5g, 57.58percent). MS(ES): m/z 185.64 [M+H]+
42% at 25 - 35℃; for 20 h; General procedure: A solution of bromine (0.26mL, 10.0mmol) in acetic acid (5.0mL)was added over about 30 min to a mixture of aromatic amine(10.0 mmol) and potassium thiocyanate (1.07 g, 11.0 mmol) in aceticacid (20 mL), the temperature being kept between 25 and 35 °C. The slurry was then stirred for 20 h at room temperature. The precipitate was filtered, washed with a little acetic acid, slurried in water, made neutral with aqueous ammonia, and filtered again. The residue was boiled for 20 min with excess of hydrochloric acid (15percent v:v) and the hot mixture was filtered from impurities. The filtrate, cooled to 10 °C,was made alkaline with aqueous ammonia and the precipitate was filtered,washed, and dried. The crude product was recrystallized from ethanol–water to afford I–IV, respectively.

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[2] Research on Chemical Intermediates, 2016, vol. 42, # 12, p. 7855 - 7868
[3] Journal of Organic Chemistry, 2017, vol. 82, # 18, p. 9312 - 9320
[4] Patent: CN108623537, 2018, A, . Location in patent: Paragraph 0104; 0105
[5] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2010, vol. 49, # 6, p. 818 - 825
[6] Phosphorus, Sulfur and Silicon and the Related Elements, 2008, vol. 183, # 5, p. 1124 - 1133
[7] Journal of the Indian Chemical Society, 2008, vol. 85, # 3, p. 333 - 335
[8] European Journal of Medicinal Chemistry, 2008, vol. 43, # 5, p. 1114 - 1122
[9] Archiv der Pharmazie, 2015, vol. 348, # 4, p. 254 - 265
[10] European Journal of Medicinal Chemistry, 2012, vol. 53, p. 41 - 51
[11] Medicinal Chemistry Research, 2017, vol. 26, # 9, p. 1969 - 1987
[12] Patent: WO2018/71794, 2018, A1, . Location in patent: Paragraph 00630; 00631
[13] Journal of Molecular Liquids, 2013, vol. 188, p. 173 - 177
[14] Polish Journal of Chemistry, 1996, vol. 70, # 10, p. 1250 - 1256
[15] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3443 - 3446
[16] Archiv der Pharmazie, 2010, vol. 343, # 6, p. 353 - 359
[17] Journal of Enzyme Inhibition and Medicinal Chemistry, 2011, vol. 26, # 3, p. 332 - 340
[18] Patent: WO2011/151361, 2011, A1, . Location in patent: Page/Page column 43-44
[19] Asian Journal of Chemistry, 2011, vol. 23, # 9, p. 3969 - 3974
[20] Journal of the Korean Chemical Society, 2012, vol. 56, # 2, p. 251 - 256
[21] Asian Journal of Chemistry, 2011, vol. 23, # 11, p. 5133 - 5136
[22] Asian Journal of Chemistry, 2010, vol. 22, # 7, p. 5487 - 5492
[23] Heteroatom Chemistry, 2012, vol. 23, # 4, p. 399 - 410
[24] Medicinal Chemistry Research, 2012, vol. 21, # 9, p. 2661 - 2670
[25] Organic Letters, 2012, vol. 14, # 20, p. 5334 - 5337,4
[26] Journal of Enzyme Inhibition and Medicinal Chemistry, 2013, vol. 28, # 1, p. 1 - 10
[27] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 1 - 13
[28] European Journal of Medicinal Chemistry, 2014, vol. 71, p. 24 - 30
[29] Archiv der Pharmazie, 2013, vol. 346, # 11, p. 819 - 831
[30] Journal of Heterocyclic Chemistry, 2014, vol. 51, # 2, p. 459 - 465
[31] Combinatorial Chemistry and High Throughput Screening, 2013, vol. 16, # 3, p. 244 - 247
[32] Medicinal Chemistry, 2013, vol. 9, # 4, p. 596 - 607
[33] Journal of Heterocyclic Chemistry, 2014, vol. 51, # 6, p. 1641 - 1658
[34] Research on Chemical Intermediates, 2015, vol. 41, # 8, p. 5599 - 5609
[35] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5561 - 5565
[36] Synthetic Communications, 2016, vol. 46, # 2, p. 169 - 178
[37] Bioorganic Chemistry, 2016, vol. 67, p. 130 - 138
[38] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 2, p. 1327 - 1341
[39] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 6, p. 3282 - 3293
[40] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 16, p. 2568
[41] Archiv der Pharmazie, 2018, vol. 351, # 12,
  • 18
  • [ 333-20-0 ]
  • [ 62-53-3 ]
  • [ 95-24-9 ]
Reference: [1] Medicinal Chemistry Research, 2013, vol. 22, # 7, p. 3316 - 3328
  • 19
  • [ 333-20-0 ]
  • [ 106-40-1 ]
  • [ 15864-32-1 ]
YieldReaction ConditionsOperation in experiment
93%
Stage #1: With nano-BF3/SiO2 In acetonitrile for 0.5 h; Cooling with ice
Stage #2: With bromine In acetonitrile at 0 - 20℃; for 5 h;
A solution of substituted aniline (2 mmol) in acetonitrile (15 ml) was added to a solution of KSCN (8 mmol) in acetonitrile (15 ml). Then, 0.06 g (30 mol percent BF3) of nano-BF3/SiO2 was added to the mixture, then was placed in a freezing mixture of ice and salt and mechanically stirred for 30 min. Then, bromine (4 mmol, 0.2 ml) in acetonitrile (3 ml) as solvent was added from a dropping funnel at such a rate that the temperature never rose beyond 0°C. After all the bromine was added at 60 min, the solution was stirred for 4 h at room temperature. The progress of the reaction was monitored by TLC. Then, the mixture was poured into water with stirring and the mixture was heated to 70°C on a steam bath and filtered hot to remove the catalyst and the recovered catalyst was washed with acetone and reused in the reaction. The filtrate was neutralized with 10 percent NaOH solution and the precipitate was collected on a filter, dried and recrystallized from ethanol (10 ml) to afford the corresponding products. All of the 2-aminobenzothiazole products were identified by physical and spectroscopic data as reported below, compared and contrasted with authentic samples. Spectral data for selected products 6-Bromo-1,3-benzothiazol-2-amine (2e) Yellow solid; Yield = 93 percent; m.p. =202–204°C; (m.p. = 203°C), FT-IR (KBr)/t(cm-1): 3315, 3012, 2835,1580, 1476, 1261, 920, 742, 512. 1H NMR (400 MHz, CDCl3)/d ppm: 5.44 (s, 2H, NH2) 7.4–7.5 (d, 2H, Ar–H), 7.71 (s, 1H, Ar–H); 13C NMR/(100 MHz, DMSO-d6)/d ppm: 119, 120.9, 125.15, 126.07, 133.1, 152.15, 167.75.
79%
Stage #1: at 20℃; for 1.33333 h; Inert atmosphere
A solution of 4-bromoaniline (0.500 g, 2.91 mmol) and potassium thiocyanate (1.13 g, 11.6 mmol) in AcOH (10 ml) was stirred at 20 °C for 10 min. Bromine (150 μl, 2.91 mmol) was added over 20 min to the above solution. The reaction mixture was stirred further at room temperature for 60 min. On completion of reaction following a TLC examination, the reaction mixture was poured into a solution of NH3 5M and extracted with AcOEt. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product obtained was purified by flash chromatography (Hex:AcOEt 1:1) to afford 1e as white solid (2.67 g, yield 79percent). 1H NMR (DMSO-d6, 400 MHz): δ 7.91 (1H, d, J = 2.5 Hz), 7.63 (2H, s), 7.35 (1H, dd, J = 11.6, 2.5 Hz), 7.26 (1H, d, J = 11.6 Hz). MS-EI m/z [M]+ 228.
76%
Stage #1: at 20℃; Cooling with ice
Stage #2: With ammonium hydroxide In water
General procedure: A mixture of 0.1 mol of 4-substituted aniline and 0.1 mol of Potassium thiocyanate (KCNS) in 100 ml glacial acetic acid (AcOH) was cooled in an ice bath and stirred for 10-20 min, and then 0.1 mol bromine in glacial acetic acid was added dropwise at such a rate to keep the temperature below 10 °C throughout the addition. The reaction mixture was stirred at room temperature for 2-4 h, the hydrobromide (HBr) salt thus separated out was filtered, washed with acetic acid, dried, dissolved in hot water and basified to pH 11.0 with ammonia solution (NH4OH) and the resulting precipitate was filtered, washed with water and dried to get the desired product 3a-k. The progress of the reaction was monitored by Thin Layer Chromatography using toluene: acetone (8:2) solvent system.
76% With bromine In acetic acidCooling with ice General procedure: A mixture of 0.1 mol of 4–substituted aniline and 0.1 mol ofPotassium thiocyanate (KCNS) in 100 ml glacial acetic acid (AcOH) was cooled inan ice bath and stirred for 10 to 20 min, and then 0.1 mol bromine in glacialacetic acid was added dropwise at such a rate to keep the temperature below 10C throughout the addition. Theprogress of the reaction was monitored by Thin Layer Chromatography usingtoluene: acetone (8:2) solvent system. The reaction mixture was stirredat room temperature for 2 to 4 hrs, the hydrobromide (HBr) salt thus separatedout was filtered, washed with acetic acid, dried, dissolved in hot water and basified to pH 11.0 with ammonia solution (NH4OH)and the resulting precipitate was filtered, washed with water and dried to getthe desired product 2a-q.
72.3%
Stage #1: at -10 - 20℃; for 12.5 h;
Stage #2: With ammonium hydroxide In waterHeating
General procedure: An appropriately p-substituted aniline (0.1 mol) and potassiumthiocyanate (KCNS, 9.718 g, 0.1 mol) were dissolvedin 100 mL of glacial acetic acid (AcOH), cooled inice–salt mixture and stirred mechanically, while a solutionof bromine (15.980 g, 0.1 mol) in AcOH (20 mL)was slowly added drop by drop (Palkar et al. 2010).External cooling was applied throughout the process to keepthe temperature below 10 °C and the stirring was continuedfor 30 min. After all of the bromine had been added, thesolution was stirred for 2 h below room temperature and atroom temperature for 10 h. It was then allowed to standovernight during which the precipitate of imino-benzo[d]thiazole hydrobromide salt thus separated out was filtered,washed with acetic acid, dried, dissolved in hot water andbasified to pH 11.0 with ammonia solution (NH4OH) andthe resulting precipitate was filtered, washed with water anddried to get the desired products 2-amino-6-substitutedbenzo[d]thiazole (1a–d). The progress of the reaction wasmonitored by TLC using acetone (20percent) in toluene solvent.
65.5% at 25 - 35℃; for 20 h; General procedure: A solution of bromine (0.26mL, 10.0mmol) in acetic acid (5.0mL)was added over about 30 min to a mixture of aromatic amine(10.0 mmol) and potassium thiocyanate (1.07 g, 11.0 mmol) in aceticacid (20 mL), the temperature being kept between 25 and 35 °C. The slurry was then stirred for 20 h at room temperature. The precipitate was filtered, washed with a little acetic acid, slurried in water, made neutral with aqueous ammonia, and filtered again. The residue was boiled for 20 min with excess of hydrochloric acid (15percent v:v) and the hot mixture was filtered from impurities. The filtrate, cooled to 10 °C,was made alkaline with aqueous ammonia and the precipitate was filtered,washed, and dried. The crude product was recrystallized from ethanol–water to afford I–IV, respectively.
49% With N-Bromosuccinimide; acetic acid In tetrahydrofuran at -30 - 20℃; 4-Bromoaniline (I−1) (120 g, 0.697 mol) and KSCN (69 g, 0.697 mol) were dissolved in a mixture of THF (500 mL) and AcOH (450 mL). The mixture was stirred at RT for 30 min. and then was cooled to −30° C., solid NBS (124 g, 0.697 mol) was added slowly. The resulting mixture was stirred at −30° C. for 30 min., and then was allowed to warm to RT and stirred overnight. The solution was poured into stirred ice-water (3000 mL), ammonia solution was added to adjust the pH value to 9 and then filtered. The filtrate was extracted with ethyl acetate (2000 mL), washed with water (500 mL), dried over Na2SO4 and filtered. The filtrate was heated to reflux for 20 min., and then cooled to 0° C. The mixture was filtered through silica gel (10 g), and the filtrate was concentrated in vacuo. The crude product was taken in chloroform (1500 mL), heated to reflux for 30 min., and then cooled to 0° C. The precipitate was collected by filtration and further dried in vacuo to afford the desired product, 6-bromobenzo[d]thiazol-2-amine I-2 (78 g, 49percent yield) as a white solid. ESI-MS (M+H)+m/z: 230.90

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[3] European Journal of Medicinal Chemistry, 2008, vol. 43, # 5, p. 1114 - 1122
[4] European Journal of Medicinal Chemistry, 2012, vol. 47, # 1, p. 239 - 254
[5] European Journal of Medicinal Chemistry, 2012, vol. 53, p. 41 - 51
[6] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5561 - 5565
[7] Medicinal Chemistry Research, 2017, vol. 26, # 9, p. 1969 - 1987
[8] Journal of Molecular Liquids, 2013, vol. 188, p. 173 - 177
[9] Patent: US2015/225407, 2015, A1, . Location in patent: Paragraph 0408
[10] Science China Chemistry, 2013, vol. 56, # 4, p. 505 - 513
[11] Polish Journal of Chemistry, 1996, vol. 70, # 10, p. 1250 - 1256
[12] Journal of Medicinal Chemistry, 1999, vol. 42, # 15, p. 2828 - 2843
[13] Journal of the Indian Chemical Society, 2008, vol. 85, # 3, p. 333 - 335
[14] Archiv der Pharmazie, 2010, vol. 343, # 6, p. 353 - 359
[15] Asian Journal of Chemistry, 2010, vol. 22, # 7, p. 5487 - 5492
[16] Heteroatom Chemistry, 2012, vol. 23, # 4, p. 399 - 410
[17] Organic Letters, 2012, vol. 14, # 20, p. 5334 - 5337,4
[18] Molecules, 2013, vol. 18, # 8, p. 8845 - 8857
[19] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 1 - 13
[20] European Journal of Medicinal Chemistry, 2014, vol. 71, p. 24 - 30
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[22] Chemical Biology and Drug Design, 2014, vol. 84, # 1, p. 123 - 129
[23] Turkish Journal of Chemistry, 2013, vol. 37, # 6, p. 909 - 916
[24] Medicinal Chemistry, 2013, vol. 9, # 4, p. 596 - 607
[25] Patent: WO2014/151147, 2014, A1, . Location in patent: Paragraph 00154
[26] Journal of Heterocyclic Chemistry, 2014, vol. 51, # 6, p. 1641 - 1658
[27] Patent: US2014/357651, 2014, A1, . Location in patent: Paragraph 0499
[28] Research on Chemical Intermediates, 2015, vol. 41, # 8, p. 5599 - 5609
[29] Patent: US9174994, 2015, B2, . Location in patent: Page/Page column 126
[30] Synthetic Communications, 2016, vol. 46, # 2, p. 169 - 178
[31] Journal of Organic Chemistry, 2017, vol. 82, # 18, p. 9312 - 9320
[32] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 6, p. 3282 - 3293
[33] Archiv der Pharmazie, 2018, vol. 351, # 12,
  • 20
  • [ 333-20-0 ]
  • [ 540-37-4 ]
  • [ 16582-58-4 ]
YieldReaction ConditionsOperation in experiment
70%
Stage #1: at 20℃; Cooling with ice
Stage #2: With ammonium hydroxide In water
General procedure: A mixture of 0.1 mol of 4-substituted aniline and 0.1 mol of Potassium thiocyanate (KCNS) in 100 ml glacial acetic acid (AcOH) was cooled in an ice bath and stirred for 10-20 min, and then 0.1 mol bromine in glacial acetic acid was added dropwise at such a rate to keep the temperature below 10 °C throughout the addition. The reaction mixture was stirred at room temperature for 2-4 h, the hydrobromide (HBr) salt thus separated out was filtered, washed with acetic acid, dried, dissolved in hot water and basified to pH 11.0 with ammonia solution (NH4OH) and the resulting precipitate was filtered, washed with water and dried to get the desired product 3a-k. The progress of the reaction was monitored by Thin Layer Chromatography using toluene: acetone (8:2) solvent system.
Reference: [1] European Journal of Medicinal Chemistry, 2012, vol. 53, p. 41 - 51
[2] Heteroatom Chemistry, 2012, vol. 23, # 4, p. 399 - 410
[3] European Journal of Medicinal Chemistry, 2014, vol. 71, p. 24 - 30
[4] Medicinal Chemistry, 2013, vol. 9, # 4, p. 596 - 607
[5] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5561 - 5565
  • 21
  • [ 333-20-0 ]
  • [ 108-42-9 ]
  • [ 20358-00-3 ]
YieldReaction ConditionsOperation in experiment
89%
Stage #1: With nano-BF3/SiO2 In acetonitrile for 0.5 h; Cooling with ice
Stage #2: With bromine In acetonitrile at 0 - 20℃; for 5 h;
General procedure: A solution of substituted aniline (2 mmol) in acetonitrile (15 ml) was added to a solution of KSCN (8 mmol) in acetonitrile (15 ml). Then, 0.06 g (30 mol percent BF3) of nano-BF3/SiO2 was added to the mixture, then was placed in a freezing mixture of ice and salt and mechanically stirred for 30 min. Then, bromine (4 mmol, 0.2 ml) in acetonitrile (3 ml) as solvent was added from a dropping funnel at such a rate that the temperature never rose beyond 0°C. After all the bromine was added at 60 min, the solution was stirred for 4 h at room temperature. The progress of the reaction was monitored by TLC. Then, the mixture was poured into water with stirring and the mixture was heated to 70°C on a steam bath and filtered hot to remove the catalyst and the recovered catalyst was washed with acetone and reused in the reaction. The filtrate was neutralized with 10 percent NaOH solution and the precipitate was collected on a filter, dried and recrystallized from ethanol (10 ml) to afford the corresponding products. All of the 2-aminobenzothiazole products were identified by physical and spectroscopic data as reported below, compared and contrasted with authentic samples. Spectral data for selected products 6-Bromo-1,3-benzothiazol-2-amine (2e) Yellow solid; Yield = 93 percent; m.p. =202–204°C; (m.p. = 203°C), FT-IR (KBr)/t(cm-1): 3315, 3012, 2835,1580, 1476, 1261, 920, 742, 512. 1H NMR (400 MHz, CDCl3)/d ppm: 5.44 (s, 2H, NH2) 7.4–7.5 (d, 2H, Ar–H), 7.71 (s, 1H, Ar–H); 13C NMR/(100 MHz, DMSO-d6)/d ppm: 119, 120.9, 125.15, 126.07, 133.1, 152.15, 167.75.
Reference: [1] Research on Chemical Intermediates, 2016, vol. 42, # 12, p. 7855 - 7868
[2] Asian Journal of Chemistry, 2011, vol. 23, # 9, p. 3969 - 3974
[3] Patent: WO2012/6068, 2012, A2, . Location in patent: Page/Page column 118
[4] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 1 - 13
  • 22
  • [ 333-20-0 ]
  • [ 104-94-9 ]
  • [ 1747-60-0 ]
YieldReaction ConditionsOperation in experiment
71%
Stage #1: at 20℃; Cooling with ice
Stage #2: With ammonium hydroxide In water
General procedure: A mixture of 0.1 mol of 4-substituted aniline and 0.1 mol of Potassium thiocyanate (KCNS) in 100 ml glacial acetic acid (AcOH) was cooled in an ice bath and stirred for 10-20 min, and then 0.1 mol bromine in glacial acetic acid was added dropwise at such a rate to keep the temperature below 10 °C throughout the addition. The reaction mixture was stirred at room temperature for 2-4 h, the hydrobromide (HBr) salt thus separated out was filtered, washed with acetic acid, dried, dissolved in hot water and basified to pH 11.0 with ammonia solution (NH4OH) and the resulting precipitate was filtered, washed with water and dried to get the desired product 3a-k. The progress of the reaction was monitored by Thin Layer Chromatography using toluene: acetone (8:2) solvent system.
56% With bromine In acetic acid at 7 - 20℃; for 5 h; Cooling with ice A vigorously stirred solution of 12.3 g of p-anisidine (0.1 mol) and 9.7 g of potassium thiocyanate (0.1 mol) in 100 mL acetic acid was cooled to 7-10°C in an ice bath. To this solution was added 5.2 mL of bromine (0.1 mol) dropwise keeping temperature below 10°C throughout the addition. Reaction mixture was stirred at room temperature for 5 h, filtrated and washed with acetic acid. Filtrate was dissolved in 400 mL of water, basified with concentrated NH4OH to pH 10 and kept crystallizing overnight. Filtration gave 10.1 g (56percent) of desired product as light purple crystals.
Reference: [1] Synlett, 2012, vol. 23, # 15, p. 2219 - 2222
[2] Synlett, 2009, # 16, p. 2682 - 2684
[3] Heterocyclic Communications, 2018, vol. 24, # 5, p. 255 - 258
[4] Phosphorus, Sulfur and Silicon and the Related Elements, 2008, vol. 183, # 5, p. 1124 - 1133
[5] European Journal of Medicinal Chemistry, 2008, vol. 43, # 5, p. 1114 - 1122
[6] Archiv der Pharmazie, 2015, vol. 348, # 4, p. 254 - 265
[7] Arkivoc, 2012, vol. 2012, # 6, p. 281 - 294
[8] Polish Journal of Chemistry, 2008, vol. 82, # 12, p. 2341 - 2347
[9] European Journal of Medicinal Chemistry, 2012, vol. 53, p. 41 - 51
[10] Tetrahedron Letters, 2017, vol. 58, # 24, p. 2330 - 2333
[11] Journal of Organic Chemistry, 2017, vol. 82, # 18, p. 9312 - 9320
[12] Zhurnal Obshchei Khimii, 1944, vol. 14, p. 113[13] Chem.Abstr., 1945, p. 934
[14] Journal of the American Chemical Society, 1949, vol. 71, p. 3417
[15] Bulletin de la Societe Chimique de France, 1968, p. 2832 - 2842
[16] Polish Journal of Chemistry, 1996, vol. 70, # 10, p. 1250 - 1256
[17] Farmaco, 2005, vol. 60, # 1, p. 1 - 5
[18] Journal of the Indian Chemical Society, 2008, vol. 85, # 3, p. 333 - 335
[19] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3443 - 3446
[20] Asian Journal of Chemistry, 2011, vol. 23, # 9, p. 3969 - 3974
[21] Asian Journal of Chemistry, 2011, vol. 23, # 11, p. 5133 - 5136
[22] Asian Journal of Chemistry, 2010, vol. 22, # 7, p. 5487 - 5492
[23] Heteroatom Chemistry, 2012, vol. 23, # 4, p. 399 - 410
[24] Medicinal Chemistry Research, 2012, vol. 21, # 9, p. 2644 - 2651
[25] Turkish Journal of Chemistry, 2013, vol. 37, # 6, p. 909 - 916
[26] Organic Letters, 2012, vol. 14, # 20, p. 5334 - 5337,4
[27] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 1 - 13
[28] European Journal of Medicinal Chemistry, 2014, vol. 71, p. 24 - 30
[29] Journal of Heterocyclic Chemistry, 2014, vol. 51, # 2, p. 459 - 465
[30] Chemical Biology and Drug Design, 2014, vol. 84, # 1, p. 123 - 129
[31] Combinatorial Chemistry and High Throughput Screening, 2013, vol. 16, # 3, p. 244 - 247
[32] Medicinal Chemistry, 2013, vol. 9, # 4, p. 596 - 607
[33] Journal of Heterocyclic Chemistry, 2014, vol. 51, # 6, p. 1641 - 1658
[34] Research on Chemical Intermediates, 2015, vol. 41, # 8, p. 5599 - 5609
[35] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5561 - 5565
[36] Synthetic Communications, 2016, vol. 46, # 2, p. 169 - 178
[37] Bioorganic Chemistry, 2016, vol. 67, p. 130 - 138
[38] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 22, p. 5387 - 5394
[39] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 2, p. 1327 - 1341
[40] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 6, p. 3282 - 3293
[41] Archiv der Pharmazie, 2018, vol. 351, # 12,
  • 23
  • [ 333-20-0 ]
  • [ 90-04-0 ]
  • [ 1747-60-0 ]
YieldReaction ConditionsOperation in experiment
2.3 g at 20℃; for 16 h; p-Anisidine (2 g, 16.2 mmol) and potassium thiocyanate (6.29 g, 64.8 mmol) was solved in acetic acid (30 ml). Bromine (0.83 ml, 16.2 mmol) in acetic acid (5 ml) was added dropwise. The resulting mixture was stirred at RT for 16 hours. After completion of the reaction, the reaction mixture was poured into ice water and neutralized with aqueous ammonia. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulphate and concentrated under reduced pressure. Yield of 6-methoxy-1 ,3-benzothiazol-2-amine after flash chromatography (100-200 mesh size silica gel, 25-30percent ethyl acetate in hex- ane) was 2.3 g.
Reference: [1] Patent: WO2014/191632, 2014, A1, . Location in patent: Page/Page column 54
  • 24
  • [ 333-20-0 ]
  • [ 104-94-9 ]
  • [ 1747-60-0 ]
  • [ 14372-55-5 ]
Reference: [1] New Journal of Chemistry, 2016, vol. 40, # 3, p. 2547 - 2553
  • 25
  • [ 333-20-0 ]
  • [ 61296-22-8 ]
  • [ 23056-10-2 ]
YieldReaction ConditionsOperation in experiment
70% at 20℃; for 48 h; A mixture of 2-arnrno3-bromothiazole hydrobromide (7.8 g, 30 rnmol) and potassium thiocyanate (20.46 g, 210.93 mmoi) in methanol (230 mL) was stirred at room temperature for 48 h. Methanol was evaporated and water (30 ml) was added. The pH of the aqueous solution was adjusted to pFI=12 with 10percent NaOH aq and precipitate formed. The solid was collected by filtration to yield compound YLIU4i1-OO44 (3.3 g, 70 percent) as a brownish solid. LCMS (rnlz): 158 [M ± H]±.
47%
Stage #1: at 20℃; for 18 h;
Stage #2: With sodium hydroxide In methanol; water
To a solution of 2-amino-5-bromothiazole hydrobromide (10.0 g, 38.4 mmol)in MeOH (50 mL) was added KSCN (15.0 g, 160 mmol). The reaction mixture was stirred at RT for 18 h, then was concentrated in vacuo, and H2O (40 mL) was added to the residue. The mixture was brought to pH 12 with 1N aqueous NaOH. The precipitate was collected by suction filtration, and was washed with H2O (3.x.) and Et2O (3.x.). The solid was dried under vacuum for 18 h to give Part B compound as a brown solid (2.8 g, 47percent).
47% at 20℃; for 18 h; To a solution of 2-amino-5-bromothiazole hydrobromide (10.0 g, 38.4 mmol) in MeOH (50 mL) was added KSCN (15.0 g, 160 mmol). The reaction mixture was stirred at RT for 18 h, then was concentrated in vacuo, and H2O (40 mL) was added to the residue. The mixture was adjusted to pH 12 with 1N aqueous NaOH. A precipitate was formed, which was collected by suction filtration, and washed with H2O (3 .x.) and Et2O (3 .x.). The solid was dried in vacuo for 18 h to give Part A compound as a brown solid (2.8 g, 47percent).
44% at 20℃; for 20 h; 5-Thiocyanatothiazol-2-amine (Compound 0107) A mixture of 2-amino-5-bromothiazole hydrobromide (0106, 53.0 g, 0.204 mol) and potassium thiocyanate (78.5 g, 0.808 mol) in methanol (1.4 L) was stirred at room temperature for 20 h. Methanol was evaporated and water (180 ml) was added. The pH of the aqueous solution was adjusted to pH=12 with 10percent NaOH and precipitate formed. The solid was collected by filtration to yield compound 0107 (14.0 g, 44percent) as a brownish solid: LCMS: 157 [M+l]+.
44% at 20℃; for 20 h; Step Ie: 5-Thiocyanatothiazol-2-amine (Compound 0107)A mixture of 2-amino-5-bromothiazole hydrobromide 0106 (53.0 g, 0.204 mol) and potassium thiocyanate (78.5 g, 0.808 mol) in methanol (1.4 L) was stirred at room temperature for 20 h. Methanol was evaporated. The residue was added water (180 ml) and adjusted the pH of the solution to pH=12 with 10percent NaOH. The resulting solid was filtered to give the title product 0107 as a brown solid (14.0 g, 44percent): LCMS: 157 [M+l]+.

Reference: [1] Patent: WO2017/44858, 2017, A2, . Location in patent: Paragraph 00325; 00505; 00468
[2] Patent: US2008/21052, 2008, A1, . Location in patent: Page/Page column 25
[3] Patent: US2008/9465, 2008, A1, . Location in patent: Page/Page column 48-49
[4] Patent: WO2010/75542, 2010, A1, . Location in patent: Page/Page column 52
[5] Patent: WO2009/36016, 2009, A1, . Location in patent: Page/Page column 54
  • 26
  • [ 96-50-4 ]
  • [ 333-20-0 ]
  • [ 23056-10-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 7, p. 1719 - 1728
  • 27
  • [ 13534-97-9 ]
  • [ 333-20-0 ]
  • [ 934266-82-7 ]
YieldReaction ConditionsOperation in experiment
77% at -15 - 20℃; Inert atmosphere Example 1; Preparation of intermediates N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(2-hydroxypropan-2-yl)benzamide (1D) and N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-(trifluoromethyl)benzamide (1E); Step A: Commercially available 6-bromopyridin-3-amine (1A, 20 g, 1.0 equivalent) was added in portions to a solution of potassium thiocyanate (5.0 equivalents) in acetic acid (0.4 M) at -5° C. After addition, the mixture was cooled to -15° C., and a solution of Br2 (1.3 equivalent) in acetic acic (9.4 M) was added drop wise via an additional funnel. The mixture was then warmed to room temperature and stirred for 12 h. The resulting precipitate was filtered; 100 mL EtOAc and 200 mL H2O were added to the filtrate and then 200 mL of solvent was removed in vacuo. The residue was stirred in ice bath for 10 minutes, and then the resulting precipitate was collected by filtration and washed twice with cold 10percent MeOH in Et2O. The filtrate was concentrated and the product was crystallized in ice bath to obtain a second crop of product after washing twice with cold 10percent MeOH in Et2O. The product 1B (77percent) was obtained as a brown solid after drying under vacuum, and then used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.94 (br. s., 1H) 7.44 (d, J=8.34 Hz, 1H) 7.57 (d, J=8.34 Hz, 1H) 8.04 (br. s., 1H); ESI-MS: m/z 230.0 (M+H)+.
68.93% With bromine In acetic acid at 20℃; for 3.5 h; Step 1:
5-bromothiazolo[5,4-b]pyridin-2-amine
To a suspension of KSCN (2.2 g, 22.83 mmol) in acetic acid (10 ml) was added 6-bromopyridin-3-amine (1 g, 5.78 mmol) and the mixture was stirred at room temperature for 15 min.
A solution of bromine (0.38 ml 7.51 mmol) in acetic acid (10 ml) was added dropwise to the obtained solution at room temperature for 15 min.
After the completion of dropwise addition the mixture was stirred at room temperature for 3 h.
Reaction was monitored by TLC.
On completion to the reaction mixture was added water (25 ml); the solid so precipitated was filtered out.
The filtrate was concentrated under reduced pressure; the residue was neutralised to pH=7 with aq. sol.
of NaHCO3 and extracted with mixture of THF:ethyl acetate (1:1).
The organic layer was dried over sodium sulphate, concentrated under reduced pressure to afford 5-bromothiazolo[5,4-b]pyridin-2-amine (0.910 g, 68.93percent) as reddish brown solid. MS: 231.86[M++1]
61% With bromine In acetic acid at -15 - 20℃; Inert atmosphere Example 1; Preparation of 7V-(5-Bromothiazolo[5,4-Z>]pyridin-2-yl)acetamide (1); 1A 1B Example 1[0376] To a 500 ml 3-neck under N2 was added KSCN (42.1 g, 433 mmol), followed by 225 mL of HOAc. It was cooled to -5 0C and 6-bromo-3-aminopyridine (15 g, 86.7 mmol) was added in portions. The mixture was further cooled to -15 0C, and a solution of Br2 (5.7 mL) in 12 mL of HOAc was added dropwise while keeping the bath temperature below 10 0C. It was then allowed to slowly warm up to room temperature and stirred overnight. The small amount of precipitate was filtered off. The mother liquor was cooled to 0 0C, and water was added (200 mL). It was stirred for 5 min, and the precipitate formed was collected and washed with cold MeOH/Et2O (1 :3, 50 mL, 2 times). The solid was dried under vacuum overnight to give 5-bromothiazolo[5,4-b]pyridin-2- amine the titled compound as a yellow solid (10.2 g, 51percent). The solvent was stripped from the filtrate to half the volume, and the precipitation was collected, washed with cold MeOH-Et2O, and dried to give another 2 g of product with a combined yield of 12.2 g (61percent yield).
Reference: [1] Patent: US2009/318425, 2009, A1, . Location in patent: Page/Page column 39-40
[2] Patent: US2017/291910, 2017, A1, . Location in patent: Paragraph 0253; 0254
[3] Patent: WO2010/8847, 2010, A2, . Location in patent: Page/Page column 123
[4] Yakugaku Zasshi, 1951, vol. 71, p. 662,665[5] Chem.Abstr., 1952, p. 8109
[6] Patent: EP2426135, 2012, A1, . Location in patent: Page/Page column 114
  • 28
  • [ 333-20-0 ]
  • [ 95-55-6 ]
  • [ 7471-03-6 ]
Reference: [1] Synlett, 2012, vol. 23, # 15, p. 2219 - 2222
  • 29
  • [ 333-20-0 ]
  • [ 95-51-2 ]
  • [ 19952-47-7 ]
YieldReaction ConditionsOperation in experiment
87%
Stage #1: With nano-BF3/SiO2 In acetonitrile for 0.5 h; Cooling with ice
Stage #2: With bromine In acetonitrile at 0 - 20℃; for 5 h;
General procedure: A solution of substituted aniline (2 mmol) in acetonitrile (15 ml) was added to a solution of KSCN (8 mmol) in acetonitrile (15 ml). Then, 0.06 g (30 mol percent BF3) of nano-BF3/SiO2 was added to the mixture, then was placed in a freezing mixture of ice and salt and mechanically stirred for 30 min. Then, bromine (4 mmol, 0.2 ml) in acetonitrile (3 ml) as solvent was added from a dropping funnel at such a rate that the temperature never rose beyond 0°C. After all the bromine was added at 60 min, the solution was stirred for 4 h at room temperature. The progress of the reaction was monitored by TLC. Then, the mixture was poured into water with stirring and the mixture was heated to 70°C on a steam bath and filtered hot to remove the catalyst and the recovered catalyst was washed with acetone and reused in the reaction. The filtrate was neutralized with 10 percent NaOH solution and the precipitate was collected on a filter, dried and recrystallized from ethanol (10 ml) to afford the corresponding products. All of the 2-aminobenzothiazole products were identified by physical and spectroscopic data as reported below, compared and contrasted with authentic samples.#10;Spectral data for selected products#10;6-Bromo-1,3-benzothiazol-2-amine (2e) Yellow solid; Yield = 93 percent; m.p. =202–204°C; (m.p. = 203°C), FT-IR (KBr)/t(cm-1): 3315, 3012, 2835,1580, 1476, 1261, 920, 742, 512. 1H NMR (400 MHz, CDCl3)/d ppm: 5.44 (s, 2H, NH2) 7.4–7.5 (d, 2H, Ar–H), 7.71 (s, 1H, Ar–H); 13C NMR/(100 MHz, DMSO-d6)/d ppm: 119, 120.9, 125.15, 126.07, 133.1, 152.15, 167.75.#10;
69% With tetra-N-butylammonium tribromide In ethanol for 0.0833333 h; Microwave irradiation General procedure: 1. Substituted aromatic aniline (where R represents CI or OCH3 or N02 substituent on aromatic ring) (1.0 mmol), potassium thiocyanate (4.0 mmol), and Tetra-butyl ammonium tribromide (1.0 mmol) were taken in ethanol. 2. Subjected to microwave irradiation at power of 195 W (watt) for 5 min. 3. The resulting solid was poured in water, neutralized with 25percent of ammonia solution which results precipitation. 4. The precipitate was collected by filtration and recrystallized from ethanol and water.
Reference: [1] Synlett, 2012, vol. 23, # 15, p. 2219 - 2222
[2] Research on Chemical Intermediates, 2016, vol. 42, # 12, p. 7855 - 7868
[3] Patent: WO2017/25980, 2017, A2, . Location in patent: Page/Page column 9; 12
[4] Asian Journal of Chemistry, 2011, vol. 23, # 9, p. 3969 - 3974
[5] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 1 - 13
  • 30
  • [ 333-20-0 ]
  • [ 615-36-1 ]
  • [ 20358-02-5 ]
Reference: [1] Synlett, 2012, vol. 23, # 15, p. 2219 - 2222
[2] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 1 - 13
  • 31
  • [ 333-20-0 ]
  • [ 873-74-5 ]
  • [ 19759-66-1 ]
YieldReaction ConditionsOperation in experiment
0.70 g
Stage #1: at 10 - 20℃; for 0.5 h;
Stage #2: at 20℃; for 16 h;
To a solution of 4-aminobenzonitrile (1.00 g, 8.47 mmol) in acetic acid (12 ml) was added potassium thiocyanate (1.00 g, 16.9 mmol) at 10°C. The reaction mixture was stirred at rt for 30 mm. A solution of bromine (0.5 ml, 10.16 mmol) in acetic acid (3 ml) was added dropwise to the reaction at rt. The reaction mixture was stirred at rt for 16 h. The resulting solid precipitates were collected byfiltration under reduced pressure, washed with acetic acid (10 ml) and dried under vacuum. The obtained precipitates were suspended in ice cold aqueous solution of NH4OH (10 ml) and stirred at rt for 30 mm. The resulting solid precipitates were collected by filtration under reduced pressure, dried under vacuum yielding 2-aminobenzo[djthiazole-6-carbonitrile (0.70 g, 4.00 mmol). This material was directly used in the next step without further purification. LCMS: Method C, 1.62 mi MS: ES+176.13.
Reference: [1] Heterocycles, 2006, vol. 68, # 11, p. 2285 - 2299
[2] Journal of Medicinal Chemistry, 2009, vol. 52, # 6, p. 1744 - 1756
[3] Journal of Organic Chemistry, 2017, vol. 82, # 18, p. 9312 - 9320
[4] Journal of Medicinal Chemistry, 1999, vol. 42, # 15, p. 2828 - 2843
[5] Organic Letters, 2010, vol. 12, # 15, p. 3567 - 3569
[6] European Journal of Medicinal Chemistry, 2014, vol. 71, p. 24 - 30
[7] Chemical Biology and Drug Design, 2014, vol. 84, # 1, p. 123 - 129
[8] Medicinal Chemistry, 2013, vol. 9, # 4, p. 596 - 607
[9] Research on Chemical Intermediates, 2015, vol. 41, # 8, p. 5599 - 5609
[10] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5561 - 5565
[11] Patent: WO2017/103614, 2017, A1, . Location in patent: Page/Page column 81
  • 32
  • [ 333-20-0 ]
  • [ 90-04-0 ]
  • [ 5464-79-9 ]
Reference: [1] Synlett, 2012, vol. 23, # 15, p. 2219 - 2222
  • 33
  • [ 31872-63-6 ]
  • [ 333-20-0 ]
  • [ 64-19-7 ]
  • [ 89284-05-9 ]
Reference: [1] Pharmaceutical Bulletin, 1956, vol. 4, p. 20,23
  • 34
  • [ 333-20-0 ]
  • [ 536-38-9 ]
  • [ 2103-99-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 3, p. 613 - 623
  • 35
  • [ 333-20-0 ]
  • [ 150-13-0 ]
  • [ 93-85-6 ]
Reference: [1] Synlett, 2012, vol. 23, # 15, p. 2219 - 2222
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1991, vol. 30, # 5, p. 494 - 498
[3] Patent: WO2010/62171, 2010, A2, . Location in patent: Page/Page column 156
[4] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5561 - 5565
[5] Patent: KR2018/81285, 2018, A, . Location in patent: Paragraph 0132; 0144-0147
  • 36
  • [ 333-20-0 ]
  • [ 100-01-6 ]
  • [ 6285-57-0 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With nano-BF3/SiO2 In acetonitrile for 0.5 h; Cooling with ice
Stage #2: With bromine In acetonitrile at 0 - 20℃; for 5 h;
General procedure: A solution of substituted aniline (2 mmol) in acetonitrile (15 ml) was added to a solution of KSCN (8 mmol) in acetonitrile (15 ml). Then, 0.06 g (30 mol percent BF3) of nano-BF3/SiO2 was added to the mixture, then was placed in a freezing mixture of ice and salt and mechanically stirred for 30 min. Then, bromine (4 mmol, 0.2 ml) in acetonitrile (3 ml) as solvent was added from a dropping funnel at such a rate that the temperature never rose beyond 0°C. After all the bromine was added at 60 min, the solution was stirred for 4 h at room temperature. The progress of the reaction was monitored by TLC. Then, the mixture was poured into water with stirring and the mixture was heated to 70°C on a steam bath and filtered hot to remove the catalyst and the recovered catalyst was washed with acetone and reused in the reaction. The filtrate was neutralized with 10 percent NaOH solution and the precipitate was collected on a filter, dried and recrystallized from ethanol (10 ml) to afford the corresponding products. All of the 2-aminobenzothiazole products were identified by physical and spectroscopic data as reported below, compared and contrasted with authentic samples.#10;Spectral data for selected products#10;6-Bromo-1,3-benzothiazol-2-amine (2e) Yellow solid; Yield = 93 percent; m.p. =202–204°C; (m.p. = 203°C), FT-IR (KBr)/t(cm-1): 3315, 3012, 2835,1580, 1476, 1261, 920, 742, 512. 1H NMR (400 MHz, CDCl3)/d ppm: 5.44 (s, 2H, NH2) 7.4–7.5 (d, 2H, Ar–H), 7.71 (s, 1H, Ar–H); 13C NMR/(100 MHz, DMSO-d6)/d ppm: 119, 120.9, 125.15, 126.07, 133.1, 152.15, 167.75.#10;
74%
Stage #1: at 20℃; Cooling with ice
Stage #2: With ammonium hydroxide In water
General procedure: A mixture of 0.1 mol of 4-substituted aniline and 0.1 mol of Potassium thiocyanate (KCNS) in 100 ml glacial acetic acid (AcOH) was cooled in an ice bath and stirred for 10-20 min, and then 0.1 mol bromine in glacial acetic acid was added dropwise at such a rate to keep the temperature below 10 °C throughout the addition. The reaction mixture was stirred at room temperature for 2-4 h, the hydrobromide (HBr) salt thus separated out was filtered, washed with acetic acid, dried, dissolved in hot water and basified to pH 11.0 with ammonia solution (NH4OH) and the resulting precipitate was filtered, washed with water and dried to get the desired product 3a-k. The progress of the reaction was monitored by Thin Layer Chromatography using toluene: acetone (8:2) solvent system.
74% at 5 - 6℃; for 2 h; General procedure: Arylamine (0.1 mol) and potassiumthiocyanate (0.4 mol) were dissolved in glacial aceticacid (40 mL) and cooled. Bromine (0.04 mol) mixed withglacial acetic acid (24 mL) was added from droppingfunnel at such a rate that temperature does not rise beyond5–6°C. After all bromine had been added, the solutionwas stirred with glass rod for an additional 2 h at lowtemperature. The mixture was allowed to stand overnight,during which period orange-yellow precipitates get settledat the bottom. Water was added and slurry formed washeated at 850°C on steam bath for 20 min and fi ltered hot.The fi ltrate was cooled and neutralised with ammoniasolution to pH 6. Yellow precipitates obtained werecollected, washed with water and recrystallized frombenzene to get crystals of 1,3-benzothiazol-2-amine andits derivatives 1-3 [21, 22].
70.7%
Stage #1: at -10 - 20℃; for 12.5 h;
Stage #2: With ammonium hydroxide In waterHeating
General procedure: An appropriately p-substituted aniline (0.1 mol) and potassiumthiocyanate (KCNS, 9.718 g, 0.1 mol) were dissolvedin 100 mL of glacial acetic acid (AcOH), cooled inice–salt mixture and stirred mechanically, while a solutionof bromine (15.980 g, 0.1 mol) in AcOH (20 mL)was slowly added drop by drop (Palkar et al. 2010).External cooling was applied throughout the process to keepthe temperature below 10 °C and the stirring was continuedfor 30 min. After all of the bromine had been added, thesolution was stirred for 2 h below room temperature and atroom temperature for 10 h. It was then allowed to standovernight during which the precipitate of imino-benzo[d]thiazole hydrobromide salt thus separated out was filtered,washed with acetic acid, dried, dissolved in hot water andbasified to pH 11.0 with ammonia solution (NH4OH) andthe resulting precipitate was filtered, washed with water anddried to get the desired products 2-amino-6-substitutedbenzo[d]thiazole (1a–d). The progress of the reaction wasmonitored by TLC using acetone (20percent) in toluene solvent.

Reference: [1] Synlett, 2012, vol. 23, # 15, p. 2219 - 2222
[2] Research on Chemical Intermediates, 2016, vol. 42, # 12, p. 7855 - 7868
[3] European Journal of Medicinal Chemistry, 2008, vol. 43, # 5, p. 1114 - 1122
[4] European Journal of Medicinal Chemistry, 2012, vol. 53, p. 41 - 51
[5] Russian Journal of Applied Chemistry, 2015, vol. 88, # 12, p. 2065 - 2073[6] Zh. Prikl. Khim. (S.-Peterburg, Russ. Fed.),
[7] Archiv der Pharmazie, 2015, vol. 348, # 4, p. 254 - 265
[8] Medicinal Chemistry Research, 2017, vol. 26, # 9, p. 1969 - 1987
[9] Farmaco, 2005, vol. 60, # 1, p. 1 - 5
[10] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3443 - 3446
[11] Archiv der Pharmazie, 2010, vol. 343, # 6, p. 353 - 359
[12] Asian Journal of Chemistry, 2011, vol. 23, # 9, p. 3969 - 3974
[13] Asian Journal of Chemistry, 2010, vol. 22, # 7, p. 5487 - 5492
[14] Heteroatom Chemistry, 2012, vol. 23, # 4, p. 399 - 410
[15] Journal of Enzyme Inhibition and Medicinal Chemistry, 2013, vol. 28, # 1, p. 1 - 10
[16] European Journal of Medicinal Chemistry, 2014, vol. 71, p. 24 - 30
[17] Chemical Biology and Drug Design, 2014, vol. 84, # 1, p. 123 - 129
[18] Medicinal Chemistry, 2013, vol. 9, # 4, p. 596 - 607
[19] Journal of Heterocyclic Chemistry, 2014, vol. 51, # 6, p. 1641 - 1658
[20] Research on Chemical Intermediates, 2015, vol. 41, # 8, p. 5599 - 5609
[21] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5561 - 5565
[22] Bioorganic Chemistry, 2016, vol. 67, p. 130 - 138
  • 37
  • [ 333-20-0 ]
  • [ 88-74-4 ]
  • [ 6973-51-9 ]
YieldReaction ConditionsOperation in experiment
86%
Stage #1: With nano-BF3/SiO2 In acetonitrile for 0.5 h; Cooling with ice
Stage #2: With bromine In acetonitrile at 0 - 20℃; for 5 h;
General procedure: A solution of substituted aniline (2 mmol) in acetonitrile (15 ml) was added to a solution of KSCN (8 mmol) in acetonitrile (15 ml). Then, 0.06 g (30 mol percent BF3) of nano-BF3/SiO2 was added to the mixture, then was placed in a freezing mixture of ice and salt and mechanically stirred for 30 min. Then, bromine (4 mmol, 0.2 ml) in acetonitrile (3 ml) as solvent was added from a dropping funnel at such a rate that the temperature never rose beyond 0°C. After all the bromine was added at 60 min, the solution was stirred for 4 h at room temperature. The progress of the reaction was monitored by TLC. Then, the mixture was poured into water with stirring and the mixture was heated to 70°C on a steam bath and filtered hot to remove the catalyst and the recovered catalyst was washed with acetone and reused in the reaction. The filtrate was neutralized with 10 percent NaOH solution and the precipitate was collected on a filter, dried and recrystallized from ethanol (10 ml) to afford the corresponding products. All of the 2-aminobenzothiazole products were identified by physical and spectroscopic data as reported below, compared and contrasted with authentic samples.#10;Spectral data for selected products#10;6-Bromo-1,3-benzothiazol-2-amine (2e) Yellow solid; Yield = 93 percent; m.p. =202–204°C; (m.p. = 203°C), FT-IR (KBr)/t(cm-1): 3315, 3012, 2835,1580, 1476, 1261, 920, 742, 512. 1H NMR (400 MHz, CDCl3)/d ppm: 5.44 (s, 2H, NH2) 7.4–7.5 (d, 2H, Ar–H), 7.71 (s, 1H, Ar–H); 13C NMR/(100 MHz, DMSO-d6)/d ppm: 119, 120.9, 125.15, 126.07, 133.1, 152.15, 167.75.#10;
Reference: [1] Synlett, 2012, vol. 23, # 15, p. 2219 - 2222
[2] Research on Chemical Intermediates, 2016, vol. 42, # 12, p. 7855 - 7868
  • 38
  • [ 333-20-0 ]
  • [ 94-09-7 ]
  • [ 50850-93-6 ]
YieldReaction ConditionsOperation in experiment
100% at 19 - 20℃; Ethyl 4-aminobenzoate (4.9 g, 30.0 mmol) and potassium thiocyanate (11.6 g,120.0 mmol) are dissolved in acetic acid(180 mL), followed by dripping acetic acid solution(20 mL) with bromine (1.5 mL,30.0 mmol) at 19 °C in 20 min, then the temperature is increased to room temperature and the mixture continues to react overnight.
Then, the reaction solution is poured into water (100 mL), and stirred for 10 min, then ammonium hydroxide is dripped into the mixture to regulate pH to approximately 8, then the mixture is filtered, wherein filter cake is successively washed with water and petroleum ether, and finally the product is vacuumed to dryness, so as to obtain a yellow solid of 6.7 g, that is ethyl 2-aminobenzo[d]thiazole-6-carboxylate, with a yield of 100percent.
Spectrum is: 1H NMR (400 MHz, DMSO) δ: 8.28(d, J = 1.6 Hz, 1H), 7.88(s ,2H), 7.82(dd, J = 1.6 Hz, 8.4 Hz, 1H), 7.37(d, J = 8.4Hz, 1H), 4.29(q, J = 7.2 Hz ,2H), 1.32(t, J = 7.2 Hz, 3H).
97% With copper(ll) sulfate pentahydrate In methanol for 6 h; Reflux To methanol (800 mL) were added ethyl 4-aminobenzoate 4 (49.5 g, 0.3 mol), KSCN (291 g, 3 mol) and CuSO4*5H2O (275 g,1.5 mol). The mixture was heated to reflux by mechanical stir for 6 h. After cooling to room temperature, the precipitate was filtered, about 2/3 of the filtrate was evaporated under reduced pressure. Water (600 mL) was added, the precipitate obtained was filtered and added to 2 N NaOH solution (500 mL), stirred for 10 min at room temperature. The precipitate was filtered, washed with waterand dried to get 5 (52.6 g, 79percent) as white powder, mp: 242-243 °C([45], mp, 241-242 °C).
69%
Stage #1: at 20℃; for 0.333333 h;
Stage #2: at 10 - 20℃;
Ethyl 4-aminobenzoate (1 eq.) and KSCN (4 eq.) were dissolved in acetic acid (4 mL/mmol) and stirred at rt for 20mins. Then the reaction mixture was cooled to 10 °C and bromine (2 eq.) dissolved in small amount of acetic acid was added dropwise. Afterwards the reaction mixture was left to warm up to rt and stirred overnight. After the reaction was completed (monitored by TLC), reaction mixture was added dropwise into the sat. aq. NH3 solution (15 mL/mmol) while cooling in an ice bath. The product was extracted to EtOAc and the organic layer was washed with Na2S2O3, sat. aq. NaHCO3 and brine, dried using anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was recrystallized from diethyl ether to obtain ethyl 2-aminobenzo[d]thiazole-6-carboxylate in 69percent yield. 1H NMR (500 MHz, DMSO-d6): (ppm) 8.27 (d, J = 1.8Hz, 1H), 7.88 (s, 2H), 7.81 (dd, J = 8.4, 1.8 Hz, 1H), 7.36 (d,J = 8.4 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz,3H).
67%
Stage #1: at 20℃;
Stage #2: With ammonium hydroxide In water
Compound 28 (2.0 g, 12 mmol) was dissolved in 16 mL of acetic acid, and to the resulting solution was suspended potassium thiocyanate (4.67 g, 48 mmol). A solution of 0.61 mL of bromine in 8 ml of acetic acid was slowly added, and the reaction mixture was stirred at room temperature overnight. Water was added and the mixture was made neutral by addition of aqueous ammonium hydroxide. The precipitation was collected by filtration and then washed with water and subsequently dried to afford compound 29 (1.80 g, 67percent) as light yellow solid. The compound was used, without structure determination, directly for the next step.
50% With copper(II) sulfate In methanol at 70℃; for 5 h; Step: 1 Preparation of ethyl 2-amino-l,3-benzothiazole-6-carboxylate.A mixture of ethyl-4-amino benzoate (1.65g, lOmmol), KCNS (9.72g, 100 mmol) and CuSO4 (8g, 50mmol) in methanol (3OmL) was stirred for 5 hours at 7O0C. Subsequently, the suspension was cooled and filtered; the filtrate was diluted with water (4OmL) and heated to boiling. Ethanol was added to the boiling filtrate until a clear, although slightly yellowish solution was formed. Cooling of this solution resulted in crystallization of the product (l.lg, 50percent yield) as a pale yellow solid. NMR <n="17"/>o(DMSO-de) 1H δ (ppm): 8.34 (IH, d, Ar-H), 7.87 (IH, dd, Ar-H), 7.42 (IH, d, Ar-H), 4.30 (2H, q, CH2), and 1.32 (3H, t, CH3). MS m/z: 223 (M+l)
46% at 10 - 20℃; [1067] Step 1: ethyl 2-aminobenzo[d]thiazol-6-carboxylate[1068] To a solution of ethyl 4-aminobenzoate (16.5 g, 100.0 mmol) and potassium thiocyanate (10.7 g, 110.0 mmol) in acetic acid (150 mL) was added dropwise a solution of bromine (5.1 mL, 100.0 mmol) in acetic acid (50 mL) at below 10 ℃. The reaction mixture was stirred at room temperature overnight. The resulting solid was filtered and then dissolved in warm water (50 ℃). The aqueous layer was washed with chloroform and then basified to pH 11 with solid sodium carbonate. The resulting solid was filtered, washed with water, and then dried under reduced pressure to give 10.2 g of the titled compound as a white solid (Yield: 46percent).
46% at 10 - 20℃; Step 1:
ethyl 4-aminobenzo[d]thiazol-6-carboxylate
To a solution of ethyl 4-aminobenzoate (16.5 g, 100.0 mmol) and potassium thiocyanate (10.7 g, 110.0 mmol) in acetic acid (150 mL) was added dropwise a solution of bromine (5.1 mL, 100.0 mmol) in acetic acid (50 mL) at below 10° C.
The reaction mixture was stirred at room temperature overnight.
The resulting solid was filtered and then dissolved in warm water (50° C.).
The aqueous layer was washed with chloroform and then basified to pH 11 with solid sodium carbonate.
The resulting solid was filtered, washed with water, and then dried under reduced pressure to give 10.2 g of the titled compound as a white solid (Yield: 46percent).

Reference: [1] Patent: EP3401315, 2018, A1, . Location in patent: Paragraph 0062; 0063
[2] Synlett, 2012, vol. 23, # 15, p. 2219 - 2222
[3] European Journal of Medicinal Chemistry, 2013, vol. 63, p. 702 - 712
[4] Medicinal Chemistry, 2017, vol. 13, # 4, p. 345 - 358
[5] European Journal of Medicinal Chemistry, 2013, vol. 61, p. 26 - 40
[6] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1991, vol. 30, # 5, p. 494 - 498
[7] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 7, p. 2509 - 2522
[8] Patent: WO2007/113644, 2007, A2, . Location in patent: Page/Page column 15-16
[9] Patent: WO2013/43001, 2013, A1, . Location in patent: Paragraph 1067; 1068
[10] Patent: US2015/11528, 2015, A1, . Location in patent: Paragraph 0600
[11] Journal of Medicinal Chemistry, 1999, vol. 42, # 15, p. 2828 - 2843
[12] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5561 - 5565
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  • 43
  • [ 333-20-0 ]
  • [ 20677-73-0 ]
  • [ 60-56-0 ]
YieldReaction ConditionsOperation in experiment
150 kg With hydrogenchloride In water at 20 - 30℃; Large scale in 5 of adding the reactor 410 kg methylamino acetaldehyde diethyl acetal, 270 kg of potassium thiocyanate and 500 kg of purified water, stirring the mixture at room temperature after completely dissolved, to the 5 of the pre-prepared reaction in the cauldron adds by drops 1mol/L dilute hydrochloric acid 1000 kg, control of the temperature of the reaction solution in the 30 °C left and right.After the reaction, the reaction liquid water is removed by reduced pressure distillation, the resulting solid with ethyl acetate is dissolved again, after the undissolved substances, ethyl acetate is removed by reduced pressure distillation. The resulting solid is dissolved in purified water, adjust the pH to 1, the cooling crystallization to obtain the purity is greater than 99percent of the product, vacuum drying to obtain 2-mercapto-1-methyl imidazole final product 150 kg, yield of 47.2percent.
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YieldReaction ConditionsOperation in experiment
19% at 0 - 15℃; for 16 h; j00320j To a mixture of 3,4-dichloroaniline (10 g, 62 mmol) and potassium thiocyanate (48 g, 0.49 mol) in acetic acid (160 mL) at 0 °C was added slowly with constant stirring a solution of liquidbromine (31 g, 0.19 mol) in acetic acid (160 mL). The temperature was maintained at 0 °C throughout the addition. The solution was stirred for 2 hours at 0°C and 14 hours at 15 °C, then diluted with water (100 mL), adjusted to pH 78 with ammonium hydroxide and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 x 300 mL) and concentrated in vacuo. The residue was purified by prep-HPLC [Instmment: GX-B; Column: GEMNI 250 x 50 mm, particle size: 10 .im; Mobile phase: 25-50percent acetonitrile in H20 (add 0.1percent TFA, v/v)j to give compound B- 24 (2.6 g, 19percent yield) as a white solid. LCMS (J): tR=0.694 mi (ES) m/z (M+H)219.0. ‘H-NMR (CD3OD, 400 MHz): 7.89 (s, 1H), 7.55 (s, 1H).
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