* 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.
Reference：
[1] Journal of the Chemical Society, 1927, p. 1190
[2] Collection of Czechoslovak Chemical Communications, 1962, vol. 27, p. 1533 - 1548
[3] Patent: US5968942, 1999, A,
[4] Patent: US6046190, 2000, A,
2
[ 333-20-0 ]
[ 94-09-7 ]
[ 50850-93-6 ]
Yield
Reaction Conditions
Operation 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
3
[ 94-09-7 ]
[ 50850-93-6 ]
Yield
Reaction Conditions
Operation in experiment
31%
With bromine In acetic acid
(195-1) A solution of ethyl p-aminobenzoate (23.2 g) and potassium thiocyanate (40.9 g) in acetic acid (280 mL) was cooled to 0° C., and thereto was added dropwise bromine (22.4 g), and the mixture was stirred at 0° C. for 20 minuts, and stirred at room temperature for 135 minutes, and stirred for 5 hours. The precipitated solid was collected by filtration to give ethyl 2-amino-1,3-benzothiazole-6-carboxylate (9.62 g, 31percent) 1H NMR (DMSO-d6, 400 MHz) δ 8.65 (brs, 2H), 8.38 (d, 1H, J=1.7 Hz), 7.89 (dd, 1H, J=8.5, 1.7 Hz), 7.44 (d, 1H, J=8.5 Hz), 4.30 (q, 2H, J=7.1 Hz), 1.32 (t, 3H, J=7.1 Hz).
31%
With bromine In acetic acid
(195-1) A solution of ethyl p-aminobenzoate (23.2 g) and potassium thiocyanate (40.9 g) in acetic acid (280 mL) was cooled to 0°C, and thereto was added dropwise bromine (22.4 g), and the mixture was stirred at 0°C for 20 minuts, and stirred at room temperature for 135 minutes, and stirred for 5 hours. The precipitated solid was collected by filtration to give ethyl 2-amino-1,3-benzothiazole-6-carboxylate (9.62 g, 31 percent). 1H NMR (DMSO-d6, 400MHz) δ 8.65 (brs, 2H), 8.38 (d, 1H, J=1.7Hz), 7.89 (dd, 1H, J=8.5, 1.7Hz), 7.44 (d, 1H, J=8.5Hz), 4.30 (q, 2H, J=7.1Hz), 1.32 (t, 3H, J=7.1Hz).
Reference：
[1] Patent: US2003/181496, 2003, A1,
[2] Patent: EP1479384, 2004, A1,
[3] Patent: US5496816, 1996, A,
[4] Archiv der Pharmazie (Weinheim, Germany), 1928, p. 215[5] Archiv der Pharmazie (Weinheim, Germany), 1929, p. 205
[6] Patent: US5498777, 1996, A,
[7] Patent: US5538964, 1996, A,
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1962, vol. 27, p. 1533 - 1548
[2] Journal of Medicinal Chemistry, 1997, vol. 40, # 1, p. 105 - 111
[3] Tetrahedron, 2005, vol. 61, # 38, p. 9075 - 9081
6
[ 1147550-11-5 ]
[ 94-09-7 ]
[ 50850-93-6 ]
Reference：
[1] Farmaco, 1994, vol. 49, # 3, p. 153 - 166
[2] Yakugaku Zasshi, 1950, vol. 70, p. 271,276[3] Chem.Abstr., 1951, p. 10212
7
[ 114224-05-4 ]
[ 50850-93-6 ]
Reference：
[1] Archiv der Pharmazie (Weinheim, Germany), 1928, p. 215[2] Archiv der Pharmazie (Weinheim, Germany), 1929, p. 205
[3] Archiv der Pharmazie (Weinheim, Germany), 1928, p. 215[4] Archiv der Pharmazie (Weinheim, Germany), 1929, p. 205
[5] Archiv der Pharmazie (Weinheim, Germany), 1928, p. 215[6] Archiv der Pharmazie (Weinheim, Germany), 1929, p. 205
[7] Archiv der Pharmazie (Weinheim, Germany), 1928, p. 215[8] Archiv der Pharmazie (Weinheim, Germany), 1929, p. 205
8
[ 23933-10-0 ]
[ 50850-93-6 ]
Reference：
[1] Archiv der Pharmazie und Berichte der Deutschen Pharmazeutischen Gesellschaft, 1969, vol. 302, # 7, p. 511 - 517
9
[ 150-13-0 ]
[ 50850-93-6 ]
Reference：
[1] Yakugaku Zasshi, 1946, vol. 66, p. Ausg. B, S. 75[2] Chem.Abstr., 1952, p. 112
[3] European Journal of Medicinal Chemistry, 2013, vol. 61, p. 26 - 40
10
[ 93-85-6 ]
[ 50850-93-6 ]
Reference：
[1] Yakugaku Zasshi, 1946, vol. 66, p. Ausg. B, S. 75[2] Chem.Abstr., 1952, p. 112
11
[ 23051-16-3 ]
[ 50850-93-6 ]
Reference：
[1] Journal of the Chemical Society, 1927, p. 1190
12
[ 15192-76-4 ]
[ 94-09-7 ]
[ 50850-93-6 ]
Reference：
[1] Chemische Berichte, 1934, vol. 67, p. 944,947
[2] Yakugaku Zasshi, 1946, vol. 66, p. Ausg. B, S. 75[3] Chem.Abstr., 1952, p. 112
13
[ 2536-91-6 ]
[ 50850-93-6 ]
Reference：
[1] Yakugaku Zasshi, 1946, vol. 66, p. Ausg. B, S. 75[2] Chem.Abstr., 1952, p. 112
14
[ 20600-51-5 ]
[ 50850-93-6 ]
Reference：
[1] Yakugaku Zasshi, 1946, vol. 66, p. Ausg. B, S. 75[2] Chem.Abstr., 1952, p. 112
15
[ 50850-93-6 ]
[ 99073-88-8 ]
Yield
Reaction Conditions
Operation in experiment
96%
With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 20℃; for 1 h;
Step 1: To a solution of tert-butyl nitrite (4.5 mL, 37.5 mmol) and copper(II) bromide (6.0 g, 27 mmol) in CH3CN(100 mL) at rt was added a mixture of ethyl 2-aminobenzo[d]thiazole-6-carboxylate (5.0 g, 22.5 mmol) in CH3CN (50mL). The reaction suspension was stirred at rt for 1 h. The resulting reaction mixture was quenched with 300 mL of 1 NHCl aqueous solution and extracted with CH2Cl2 (3x200 mL). The combined organic layers were dried over MgSO4,and concentrated under reduced pressure. The crude product was purified on a silica gel column using a mixture ofCH2Cl2-hexanes (4:1, v/v) as eluent to give ethyl 2-bromobenzo[d]thiazole-6-carboxylate as a white solid (6.2 g, 96percent).1H NMR (300 MHz, CDCl3) δ 8.54 (d, J= 1.1 Hz, 1H), 8.16 (dd, J= 1.5, 8.7 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.43 (t, J= 7.2 Hz, 3H). LCMS (ESI) m/z 288, 286 (M+H)+.
89%
With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 20℃; for 0.75 h;
Add a solution of commercially available ethyl 2- aminobenzothiazole-6-carboxylate (10 g, 45 mmol) in acetonitrile (40 ML) to a solution of copper (II) bromide (12 G, 54 mmol) and tert-butyl nitrite (9 mL, 75 mmol) in acetonitrile (100 mL) at room temperature under nitrogen and stir for 45 min. Dilute the mixture with 1 N HCL (300 mL) and extract with methylene chloride (3 x 300 mL). Wash the combined organic extracts with water (300 mL), dry over MGS04, filter though a plug of silica gel and remove the solvents under reduced pressure to afford ethyl 2- bromobenzothiazole-6-carboxylate (Step 1) as an off-white solid (11.5 g, 89percent): 1H NMR (CDC13) 5 1.40 (t, 3H), 4.40 (q, 2H), 8.00 (d, 1H), 8.20 (d, 1H), 8.60 (s, 1H).
Reference：
[1] Patent: US5496816, 1996, A,
[2] Patent: US5498777, 1996, A,
[3] Patent: US5538964, 1996, A,
17
[ 50850-93-6 ]
[ 114224-05-4 ]
[ 2268-79-3 ]
Reference：
[1] Patent: US5538964, 1996, A,
18
[ 50850-93-6 ]
[ 78485-37-7 ]
Yield
Reaction Conditions
Operation in experiment
86%
With tert.-butylnitrite; copper dichloride In acetonitrile at 0 - 20℃;
Cupric chloride (6.0 g, 44.6 mmol), tert-butyl nitrite (7.1 mL, 59.4 mmol) and acetonitrile (200 mL) are added to a 500 ml single neck bottle and the mixture is cooled to 0 °C, followed by adding ethyl 2-aminobenzo[d]thiazole-6-carboxylate (6.6 g, 29.7 mmol) in batches in 30 min, then the temperature is increased to room temperate, the mixture reacts overnight, then it is filtered with siliceousearth, and 1HCL (60 mL) is dripped into the filtrate, and the mixture is stirred for 10min, and forms layering, wherein the aqueous layer is extracted with ethyl acetate (100 mL), and the organic layer is combined, washed with saturated salt solution, dried with anhydrous Na2SO4, then filtered again, rotated to dryness and purified by column chromatography (PE:EA= 25:1), so as to obtain a light yellow of 6.2 g, that is ethyl 2-chlorobenzo[d]thiazole-6-carboxylate, with a yield of 86percent. Spectrum is: 1H NMR (400 MHz, CDCl3) δ: 8.54(d, J = 0.8 Hz, 1H), 8.20(dd, J = 1.6 Hz, 8.4 Hz, 1H), 8.01(d, J = 8.0Hz, 1H), 4.45(q, J = 7.2 Hz, 2H), 1.45(t, J = 7.2 Hz, 3H).
Part B: Preparation of 2-Amino-6-Carboxy-Benzothiazole. A 50 mL round bottom flask equipped with magnetic stir bar was charged with 250 mg 2-Amino-6-Carboxy-Benzothiazole Ethyl Ester, 190 mg (4 eq.) LiOH in 3 mL dioxane and 3 mL water. The slurry was heated to 60° C. for 2 hours. After 2 hours the solution was acidified with 1N HCl and concentrated in vacuo to a light grey solid which was identified as 2-amino-6-carboxy-benzothiazole, m/e=195(M+H). It was used without further purification.
With LiOH; In 1,4-dioxane; water;
Part B Preparation of 2-Amino-6-Carboxy-Benzothiazole A 50 mL round bottom flask equipped with magnetic stir bar was charged with 250 mg 2-Amino-6-Carboxy-Benzothiazole Ethyl Ester, 190 mg (4 eq.) LiOH in 3 mL dioxane and 3 mL water. The slurry was heated to 60° C. for 2 hours. After 2 hours the solution was acidified with 1N HCl and concentrated in vacuo to a light grey solid which was identified as 2-amino-6-carboxy-benzothiazole, m/e=195(M+H). It was used without further purification.
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20℃; for 1h;
Step 1: To a solution of tert-butyl nitrite (4.5 mL, 37.5 mmol) and copper(II) bromide (6.0 g, 27 mmol) in CH3CN(100 mL) at rt was added a mixture of ethyl 2-aminobenzo[d]thiazole-6-carboxylate (5.0 g, 22.5 mmol) in CH3CN (50mL). The reaction suspension was stirred at rt for 1 h. The resulting reaction mixture was quenched with 300 mL of 1 NHCl aqueous solution and extracted with CH2Cl2 (3x200 mL). The combined organic layers were dried over MgSO4,and concentrated under reduced pressure. The crude product was purified on a silica gel column using a mixture ofCH2Cl2-hexanes (4:1, v/v) as eluent to give ethyl 2-bromobenzo[d]thiazole-6-carboxylate as a white solid (6.2 g, 96%).1H NMR (300 MHz, CDCl3) delta 8.54 (d, J= 1.1 Hz, 1H), 8.16 (dd, J= 1.5, 8.7 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.43 (t, J= 7.2 Hz, 3H). LCMS (ESI) m/z 288, 286 (M+H)+.
89%
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20℃; for 0.75h;
Add a solution of commercially available ethyl 2- aminobenzothiazole-6-carboxylate (10 g, 45 mmol) in acetonitrile (40 ML) to a solution of copper (II) bromide (12 G, 54 mmol) and tert-butyl nitrite (9 mL, 75 mmol) in acetonitrile (100 mL) at room temperature under nitrogen and stir for 45 min. Dilute the mixture with 1 N HCL (300 mL) and extract with methylene chloride (3 x 300 mL). Wash the combined organic extracts with water (300 mL), dry over MGS04, filter though a plug of silica gel and remove the solvents under reduced pressure to afford ethyl 2- bromobenzothiazole-6-carboxylate (Step 1) as an off-white solid (11.5 g, 89%): 1H NMR (CDC13) 5 1.40 (t, 3H), 4.40 (q, 2H), 8.00 (d, 1H), 8.20 (d, 1H), 8.60 (s, 1H).
(195-4) Ethyl 2-bromo-1,3-benzothiazole-6-carboxylate was obtained from the compound of Example 195-3 in a similar manner to Example 125-2. 1H NMR (CDCl3, 400 MHz) delta 9.71 (brs, 1H), 9.16 (s, 1H), 8.56 (d, 1H, J=1.2 Hz), 8.24 (d, 1H, J=8.5 Hz), 8.09 (dd, 1H, J=8.5, 1.2 Hz), 7.19 (m, 1H), 6.95 (m, 1H), 6.39 (m, 1H).
(195-4) Ethyl 2-bromo-1,3-benzothiazole-6-carboxylate was obtained from the compound of Example 195-3 in a similar manner to Example 125-2. 1H NMR (CDCl3, 400MHz) delta 9.71 (brs, 1H), 9.16 (s, 1H), 8.56 (d, 1H, J=1.2Hz), 8.24 (d, 1H, J=8.5Hz), 8.09 (dd, 1H, J=8.5, 1.2Hz), 7.19 (m, 1H), 6.95 (m, 1H), 6.39 (m, 1H).
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 0 - 20℃; for 2.16667h;Inert atmosphere;
EXAMPLE 1; 2-[l-(3,4,5-Tribromobenzyl)-lH-L2,3-triazol-4-yl]-L3-benzothiazole-6-carboxylic acid Step 1: Ethyl 2-bromo-L3-benzothiazole-6-carboxylateA suspension Of CuBr2 (1.20 g, 5.40 mmol) in anhydrous acetonitrile (15 niL) was purged with nitrogen. The mixture was cooled in an ice-bath and treated with t- BuONO (696 mg, 6.75 mmol). After further stirring for 10 min at about 0 to 5 0C, the mixture was reacted with 2-amino-l,3-benzothiazole-6-carboxylate (1.0 g, 4.5 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature for 2 h. The mixture was then diluted with water (30 mL) and extracted with ether (100 mL x 2). The combined organic phase was filtered to removed copper salts, then washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated to afford the title compound.1H NMR (CDCl3, 400 MHz): delta 8.54 (d, IH), 8.16 (dd, IH), 8.02 (d, IH), 4.42 (q, 2H), 1.42 (t, 3H).
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 65℃; for 2h;
STEP A: Ethyl 2-aminobenzothiazole-6-carboxylate (8.91 g) and CuBr2 (13.43 g) were combined in acetonitrile (300 mL). To the resulting deep green solution was added tert-butylnitrite (7.14 mL). The resulting mixture was heated to ~65 C for two hours, then concentrated to ~50 mL. The resulting concentrate was diluted with water (250 mL) and extracted with EtOAc (2*250 mL). The resulting yellow solution was concentrated to yield ethyl 2-bromobenzo[d]thiazole-6-carboxylate as a yellow solid. 1H NMR delta 8.55 (s, 1H), 8.16 (dd, 1H, J=8.6, 1.7 Hz), 8.03 (d, 1H, J=8.3 Hz), 4.43 (q, 2H, J=7.1 Hz), 1.43 (t, 3H, J=7.1 Hz). MS: 286.0 (M+H).
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20℃; for 14h;Cooling with ice;
To the solution of ethyl 2-aminobenzo[d]thiazole-6-carboxylate (8.0 g, 36.0 mmol) and CuBr2 (16.07 g, 72.0 mmol) in acetonitrile (200 mL), tert-butyl nitrite (7.42 mL, 72.0 mmol) was added on ice bath. The reaction mixture was stirred at room temperature for 14 h. The solvent was removed under reduced pressure and to the residue ethyl acetate (200 mL) and NH4Cl solution (200 mL) were added. The organic phase was washed with brine (100 mL) and NH4Cl solution (100 mL), dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. Yield: 8.0 g (78%); pale brown solid. (0862) 1H NMR (400 MHz, DMSO-d6): d 1.36 (t, J = 7.1 Hz, 3H), 4.37 (q, J = 7.1 Hz, 2H), 8.10 (s, 2H), 8.82 (s, 1H) ppm.
With tris(2,2'-bipyridyl)ruthenium dichloride In acetonitrile at 20℃; for 18h; Irradiation;
General procedure for the synthesis of 2-aminobenzothiazoles 2
General procedure: A mixture ofaniline 1 (1 mmol), NH4SCN 2 (1.0 mmol), ruthinium (2 mol%), and CH3CN (3mL) was taken in a flask open to air and stirred at rt for 10-18 h (Table 2). Aftercompletion of the reaction (monitored by TLC), water (5 mL) was added andthe mixture was extracted with ethyl acetate (3 5 mL). The combinedorganic phase was dried over anhydrous Na2SO4, filtered, and evaporatedunder reduced pressure. The resulting crude product was purified by silica gelchromatography using a mixture of hexane/ethyl acetate (4:1) as eluent toafford an analytically pure sample of product 2. All the compounds 2 areknown and were characterized by comparison of their spectral data with thosereported in the literature.
44%
With bromine In acetic acid for 12h; Ambient temperature;
With tert.-butylnitrite; copper dichloride; In acetonitrile; at 0 - 20℃;
Cupric chloride (6.0 g, 44.6 mmol), tert-butyl nitrite (7.1 mL, 59.4 mmol) and acetonitrile (200 mL) are added to a 500 ml single neck bottle and the mixture is cooled to 0 C, followed by adding ethyl 2-aminobenzo[d]thiazole-6-carboxylate (6.6 g, 29.7 mmol) in batches in 30 min, then the temperature is increased to room temperate, the mixture reacts overnight, then it is filtered with siliceousearth, and 1HCL (60 mL) is dripped into the filtrate, and the mixture is stirred for 10min, and forms layering, wherein the aqueous layer is extracted with ethyl acetate (100 mL), and the organic layer is combined, washed with saturated salt solution, dried with anhydrous Na2SO4, then filtered again, rotated to dryness and purified by column chromatography (PE:EA= 25:1), so as to obtain a light yellow of 6.2 g, that is ethyl 2-chlorobenzo[d]thiazole-6-carboxylate, with a yield of 86%. Spectrum is: 1H NMR (400 MHz, CDCl3) delta: 8.54(d, J = 0.8 Hz, 1H), 8.20(dd, J = 1.6 Hz, 8.4 Hz, 1H), 8.01(d, J = 8.0Hz, 1H), 4.45(q, J = 7.2 Hz, 2H), 1.45(t, J = 7.2 Hz, 3H).
2.1 (1) Preparation of ethyl 2-aminobenzo[d]thiazole-6-carboxylate.
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 100%. 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).
98%
With sodium iodide dichloride at 70℃; for 6h;
97%
With copper(ll) sulfate pentahydrate In methanol for 6h; Reflux;
5.1.1. Ethyl 2-aminobenzo[d]thiazole-6-carboxylate (5)
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, 79%) as white powder, mp: 242-243 °C([45], mp, 241-242 °C).
69%
Stage #1: potassium thioacyanate; p-aminoethylbenzoate With acetic acid at 20℃; for 0.333333h;
Stage #2: With bromine at 10 - 20℃;
2-aminobenzo[d]thiazole-6-carboxylate
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 69% 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: potassium thioacyanate; p-aminoethylbenzoate With bromine; acetic acid at 20℃;
Stage #2: With ammonium hydroxide In water
5.19 Ethyl 2-aminobenzo[d]thiazole-6-carboxylate (29)
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, 67%) as light yellow solid. The compound was used, without structure determination, directly for the next step.
59%
With bromine In acetic acid for 2h;
50%
With copper(II) sulfate In methanol at 70℃; for 3h;
50%
With copper(II) sulfate In methanol at 70℃; for 5h;
1.1
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, 50% yield) as a pale yellow solid. NMR 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%
With bromine; acetic acid at 10 - 20℃;
165.1 [1067] Step 1: ethyl 2-aminobenzo[d]thiazol-6-carboxylate
[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: 46%).
46%
With bromine; acetic acid at 10 - 20℃;
165.1 Step 1: ethyl 4-aminobenzo[d]thiazol-6-carboxylate
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: 46%).
With bromine; acetic acid for 21h; Ambient temperature;
With bromine In acetic acid Cooling with ice;
General synthetic procedurefor 2-amino-6-Substituted benzothiazoles (2a-q)
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.
With malic acid at 20℃; for 6h; Irradiation; Green chemistry;
General procedure for the synthesis of 2-aminobenzothiazole 2.
General procedure: To a solution of aromatic amine 1 (0.3 mmol) and KSCN (0.6 mmol) in bis(methoxypropy) ether (1.5 mL) was added malic acid (0.3 mmol). The reaction mixture was opened to the air and stirred at room temperature under the irradiation of a 6 W blue LED lamp. The progress of the reaction was monitored by TLC. The reaction typically took within 6 hours. After completion of the reaction, the solvent was then removed under vacuum. The residue was purified by aluminum oxide column chromatography using a mixture of petroleum ether and ethyl acetate as eluent to give the desired products 2.
The acetic acid filtrate and ether washings were combined and evaporated under vacuum to an amber gum. The water washings from the yellow solid were added and the mixture was neutralized with solid sodium bicarbonate. The resulting precipitate was collected, washed with water and dried under vacuum to a pale tan solid (8.74 g). Proton NMR analysis of this material revealed a 65:35 mixture of ethyl 4-amino-3-thiocyanatobenzoate to 2-amino-6-ethoxycarbonylbenzothiazole. The mixture was dissolved in acetic acid (100 mL) and stirred at room temperature for 42 hours. A fine precipitate formed. The mixture was filtered and the cake washed with diethyl ether and dried under vacuum to give additional 2-amino-6-ethoxycarbonylbenzothiazole (2.28 g) as a cream colored powder. 1 H NMR (DMSO-d6, 500 MHz) delta1.30 (t, CH3), 4.28 (q, CH2), 7.38 (d, H-4), 7.82 (dd, H-5), 8.07 (br s, NH2), and 8.29 (d, H-7). 13 C NMR (DMSO-d6, 125.7 MHz) delta14.2, 60.4, 116.8, 122.3, 122.7, 127.2, 130.5,155.5, 165.5, and 169.8.
Step 2 2-Bromo-6-ethoxycarbonylbenzothiazole A mixture of copper(II) bromide (2.70 g, 12.09 mmol) and anhydrous acetonitrile (50 mL) was purged with nitrogen, cooled in an ice bath, treated with tert-butyl nitrite (1.8 mL, 15.13 mmol), stirred 10 minutes at 0-5 C., and then treated with solid 2-amino-6ethoxycarbonylbenzothiazole (2.24 g, 10.08 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (300 mL) and extracted with ether (2*100 mL). The extracts were filtered to remove copper salts, then washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and evaporated under vacuum to provide crude 2-bromo-6-ethoxycarbonylbenzothiazole (1.90 g) as an orange-tan solid. 1 H NMR (CDCl3, 500 MHz) delta1.42 (t, CH3), 4.42 (q, CH2), 8.02 (d, H-4), 8.15 (dd, H-5), and 8.53 (d, H-7). 13 C NMR (CDCl3, 125.7 MHz) delta14.3, 61.5, 122.5, 122.9, 127.8, 137.2, 142.3, 155.0, and 156.7.
With tert.-butylnitrite; In acetonitrile;
Step 2 2-Bromo-6-ethoxycarbonylbenzothiazole A mixture of copper(II) bromide (2.70 g, 12.09 mmol) and anhydrous acetonitrile (50 mL) was purged with nitrogen, cooled in an ice bath, treated with tert-butyl nitrite (1.8 mL, 15.13 mmol), stirred 10 minutes at 0-5 C., and then treated with solid 2-amino-6 -ethoxycarbonylbenzothiazole (2.24 g, 10.08 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (300 mL) and extracted with diethyl ether (2*100 mL). The extracts were filtered to remove copper salts, then washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and evaporated under vacuum to provide crude 2-bromo-6-ethoxycarbonylbenzothiazole (1.90 g) as an orange-tan solid. 1 H NMR (CDCl3, 500 MHz) delta1.42 (t, CH3), 4.42 (q, CH2), 8.02(d, H-4), 8.15 (dd, H-5), and 8.53 (d, H-7). 13 C NMR (CDCl3, 125.7 MHz) delta14.3, 61.5, 122.5, 122.9, 127.8, 137.2, 142.3, 155.0, and 165.7.
With tert.-butylnitrite; In acetonitrile;
Step 2 2-Bromo-6-ethoxycarbonylbenzothiazole A mixture of copper(II) bromide (2.70 g, 12.09 mmol) and anhydrous acetonitrile (50 mL) was purged with nitrogen, cooled in an ice bath, treated with tert-butyl nitrite (1.8 mL, 15.13 mmol), stirred 10 minutes at 0-5 C., and then treated with solid 2-amino-6 ethoxycarbonylbenzothiazole (2.24 g, 10.08 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (300 mL) and extracted with diethyl ether (2*100 mL). The extracts were filtered to remove copper salts, then washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and evaporated under vacuum to provide crude 2-bromo-6-ethoxycarbonylbenzothiazole (1.90 g) as an orange-tan solid. 1 H NMR (CDCl3, 500 MHz) delta1.42 (t, CH3), 4.42 (q, CH2), 8.02(d, H-4), 8.15 (dd, H-5), and 8.53 (d, H-7). 13 C NMR (CDCl3, 125.7 MHz) delta14.3, 61.5, 122.5, 122.9, 127.8, 137.2, 142.3, 155.0, and 165.7.
[1069] Step 2: (2-aminobenzo[d]thiazol-6-yl)methanol[1070] To a solution of ethyl 2-aminobenzo[d]thiazol-6-carboxylate (10.10 g, 45.44 mmol) prepared in Step 1 in THF (320 mL) was added portionwise LAH (7.59 g, 199.94 mmol) at 0 ?. The reaction mixture was stirred at room temperature for 7 hours. Water (8.0 mL), 20% sodium hydroxide (8.0 mL), and water (24 mL) were sequentially added to the reaction mixture, which was then stirred for 2 hours. The resulting solid was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The resulting solid was suspended with diethyl ether, filtered, and then dried under reduced pressure to give 5.52 g of the titled compound as a white solid (Yield: 67%).
67%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 7h;
Step 2: (2-aminobenzo[d]thiazol-6-yl)methanol To a solution of ethyl 2-aminobenzo[d]thiazol-6-carboxylate (10.10 g, 45.44 mmol) prepared in Step 1 in THF (320 mL) was added portionwise LAH (7.59 g, 199.94 mmol) at 0 C. The reaction mixture was stirred at room temperature for 7 hours. Water (8.0 mL), 20% sodium hydroxide (8.0 mL), and water (24 mL) were sequentially added to the reaction mixture, which was then stirred for 2 hours. The resulting solid was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The resulting solid was suspended with diethyl ether, filtered, and then dried under reduced pressure to give 5.52 g of the titled compound as a white solid (Yield: 67%).
52%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 24h;
The ester (1.0 g, 4.5 mmol) was dissolved in anhydrous THF and the RB flask was cooled to 0 C. Then LiAlH4 was added slowly and the flask was stirred at 0 C. for additional 10 min. The flask was then stirred at room temperature for 24 h. The reaction was then cooled, quenched with methanol, NH4Cl Rochelle's salt and diluted with ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was extracted with additional ethyl acetate (3×10 mL). The organic layers were combined, dried over Na2SO4 and concentrated under vacuo on a rotary evaporator to obtain a yellow solid. The crude product was purified via gradient silica gel column chromatography using a mixture of CH2Cl2 and methanol (100:1 to 5:1) to obtain the desired alcohol as yellow solid (420 mg, 52%). The alcohol (420 mg, 2.33 mmol) was dissolved in a mixture of CH2Cl2 and methanol (5:1) and MnO2 (81 mg, 9.32 mmol). The mixture was then stirred at room temperature for 48 h following which additional amount of MnO2 (40 mg) was added after TLC showed incompletion of the reaction. The mixture was stirred for additional 24 h and then filtered through a whatman filter paper (grade 8) and the filtrate was concentrated under vacuo on a rotary evaporator to obtain the desired aldehyde as a yellow solid (400 mg, 95%). 1H NMR (500 MHz, CDCl3): delta 7.57 (d, J=0.9 Hz, 1H), 7.35-7.46 (m, 1H), 7.25 (dd, J=8.2, 1.8 Hz, 1H), 6.45 (br s, 1H), 4.53 (s, 2H), 4.0 (br s, 1H). 13C NMR (125 MHz, CDCl3): delta 167.6, 150.5, 134.9, 130.6, 125.1, 119.4, 117.7, 64.2. 2-aminobenzo[d]thiazole-6-carbaldehyde: 1H NMR (500 MHz, CDCl3): delta 9.81 (s, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.70 (dd, J=8.2, 1.5 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 3.70 (br s, 1H). 13C NMR (125 MHz, CDCl3): delta 191.3, 164.5, 157.1, 130.3, 128.7, 122.6, 118.0
52%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 4h;
Commercially available ester 1 (1.0g, 4.5mmol) was dissolved in anhydrous THF and the RB flask was cooled to 0C. Then LiAlH4 was added slowly and the flask was stirred at 0C for additional 10min. The flask was then stirred at room temperature for 24h. The reaction was then cooled, quenched with methanol, NH4Cl Rochelle's salt and diluted with ethyl acetate (10ml). The organic layer was separated and the aqueous layer was extracted with additional ethyl acetate (3×10ml). The organic layers were combined, dried over Na2SO4 and concentrated under vacuo on a rotary evaporator to obtain a yellow solid. The crude product was purified via gradient silica gel column chromatography using a mixture of CH2Cl2 and methanol (100:1 to 5:1) to obtain the desired alcohol as yellow solid 2 (420mg, 52%). (0009) 1H NMR (500MHz, CDCl3): delta 7.57 (d, J=0.9Hz, 1H), 7.35-7.46 (m, 1H), 7.25 (dd, J=8.2, 1.8Hz, 1H), 6.45 (br s, 1H), 4.53 (s, 2H), 4.0 (br s, 1H). (0010) 13C NMR (125MHz, CDCl3): delta 167.6, 150.5, 134.9, 130.6, 125.1, 119.4, 117.7, 64.2,.
46%
EXAMPLE l; 6-(4-(4-fluorophenyI)oxazol-5-yl)-N-(2-morpholinoethyl)benzo[d]thiazoI-2-amine; 1. (2-aminobenzo[d]thiazol-6-yl)methanoI[00149]; To a solution of ethyl 2-aminobenzo[d]thiazole-6-carboxylate (5.05 g, 22.7 mmol, 1.0 eq.) in THF (60 mL) under nitrogen at 00C was added LAH (IM, THF; 100 mL, 100 mmol, 4.4 eq.) over 20 min. After 6.5 h, ice was added, and the solution was stirred overnight. The precipitate was filtered and rinsed with EtOAc. The filtrate was concentrated in vacuo to give a solid which was triturated with Et2O to give (2- aminobenzo[d]thiazol-6-yl)methanol as a yellow solid (1.90 g, 46% yield).
25.5 g (63%)
With sodium chloride; diisobutylaluminium hydride; In tetrahydrofuran; ethanol; water; toluene;
(a) 2-Amino-6-hydroxymethylbenzothiazole (1a) 50 g (0.225 mol) of ethyl 2-aminobenzothiazole-6-carboxylate are suspended in 1,000 ml of THF, cooled to -70 C., and 562.5 ml (0.675 mol) of diisobutylaluminum hydride (DIBAL, 20% strength in toluene, 1.2 molar) are slowly added dropwise under nitrogen. The reaction solution is stirred at -70 C. to -40 C. overnight and then without cooling for a further 3 hours. Then it is cooled to -70 C., 61.5 ml of water are added dropwise (vigorous exothermic reaction), and the mixture is allowed to reach room temperature. 305 ml of saturated sodium chloride solution are added, and the mixture is stirred at 20 C. for 1 hour. Precipitated aluminum hydroxide is filtered off with suction and washed with THF, and the filtrate is evaporated to dryness (36 g). The residue is dissolved in boiling ethanol, some insolubles are filtered off, and the filtrate is evaporated to dryness. Yield: 25.5 g (63%).
Synthesis of 2-[2-(4-Chloro-2-fluoro-phenyl)-acetylamino]-benzothiazole-6- carboxylic acid (37)Starting material 18 (100 mg, 0.5 mmol) was dissolved in 2 ml DMF. Now EDCI (125 mg, 0.7 mmol) and HOBt (99 mg, 0.7 mmol) were added. After stirring 3 h at room temperature, starting material 33 (103 mg, 0.5 mmol) was added and the reaction was stirred 48 h at room temperature. The solution was poured into 1 N HCI and the resulting precipitate was filtered and dried yielding the desired product 37 (60 mg, 0.2 mmol, 70 % content, 31 % yield).
With silver(I) nitrite; In 1,2-dichloro-ethane; at 100℃; for 36.0h;Sealed tube;
It was added in a closed reaction vessel 0.3mmol2-amino-benzothiazole-6-ester, 0.6mmol silver nitrite, 4 ml of 1,2-dichloroethane,the reaction mixture was stirred at 100 for 36 hours. After the reactionwas stopped, cooled to room temperature, the reaction mixture was added 10mLdiluted with dichloromethane, filtration and stripped of solvent under reducedpressure, the residue was purified by column chromatography, eluent V(petroleum ether) / V (ethyl ester) = 6/1, to give 6-ester-benzothiazole, yield62%
ethyl 3-(diethylcarbamoyl)-2-methylbenzo[d]imidazo[2,1-b]thiazole-7-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With Bromotrichloromethane; potassium <i>tert</i>-butylate In acetonitrile for 16h; Reflux; regioselective reaction;
Representative procedure for the synthesis of benzo[d]imidazo[2,1-b]thiazole
General procedure: A 25 mL two-neck round-bottomed flask was charged with 2-aminobenzothiazole (1a, 180 mg,1.2 mmol), methyl acetoacetate (2a, 108 μL, 1.0 mmol), in 3 mL of CBrCl3/MeCN 1:9 (v/v) solvent mixture. KOt-Bu(224 mg, 2.0 mmol) was added slowly at room temperature and the reaction mixture was stirred under reflux for 16 h. Upon completion, the reaction mixture was diluted with 30 mL of ethyl acetate, filtered through a short pad of silica gel and washed down with an additional 60 mL ethyl acetate. The filtrate was washed with distilled water (3 × 30 mL) and the organic phase was dried with anhydrous Na2SO4. After filtration,the solvent was removed by rotary evaporation and the residue was purified by column chromatography using hexane and ethyl acetate (v/v = 8:1) as eluent to afford 3a with 84%yield.
Stage #1: ethyl 2-aminobenzothiazole-6-carboxylate With nitrosylsulfuric acid In acetic acid; propionic acid at 0 - 20℃; for 0.25h;
Stage #2: julolidine With aminosulfonic acid In methanol; water; acetic acid; propionic acid at 0 - 4℃; for 1.08333h;
1 Ethyl 2-[(E)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-9-yldiazenyl]-1,3-benzothiazole-6-carboxylate (42)
A solution of ethyl 2-amino-l,3-benzothiazole-6-carboxylate (2.22 g, 10 mmol) in a 1:1 mixture of acetic and propionic acids (50 mL) was cooled to 0-4°C and then treated with 3.1 mL of 40% nitrosylsulfuric acid over the course of 5 min. The resulting suspension was stirred at 0-4°C for 5 min and then at room tem perature for another 5 min to give a clear solution and then cooled back to 0-4°C before being used in the next step. A solution of julolidine (2.1 g, 12 mmol) in MeOH (15 mL) was combined with a solution of sulfamic acid (0.3 g) in water (100 mL) and then cooled to 0-4°C. To this mixture was added the previously prepared diazonium salt over the course of 5 min. The reaction was stirred for 1 h and then diluted with water (400 mL) and neutralized with 90 mL of thiethylamine. The precipitated solid was extracted with ethyl acetate, washed with saturated NaHC03, dried over Na2SC>4 and concentrated under reduced pressure. The obtained residue was triturated with warm 1:1 hexane-ethyl acetate (30 mL) and the resultant solid collected by filtration. Drying under reduced pressure afforded 0.8 g (48%) of sufficiently pure dye 42 as a dark purple solid. *H N MR (CDCI3) δ 8.51 (d, J=1.5 Hz, 1H), 8.11 (skewed dd, Ji=8.7 Hz, J2=1.5 Hz, 1H), 8.01 (skewed d, J=8.7 Hz, 1H), 7.61 (s, 2H), 4.42 (q, J=7.2 Hz, 2H), 3.39 (t, J=6 Hz, 4H), 2.80 (t, J=6 Hz, 4H), 2.00 (m, 4H), 1.43 (t, J=7.2 Hz, 3H).
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