* 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.
Stage #1: With tin(ll) chloride In isopropyl alcohol for 24 h; Heating / reflux Stage #2: With sodium hydroxide In water; isopropyl alcohol
A mixture OF 5-NITRO-1, 3-benzothiazole (Description 5,1. 9 g, 11 mmol) and tin (II) chloride dihydrate (8.6 g, 38 mmol) in 2-propanol (30 ml) was heated to reflux for 24 h. The cooled reaction mixture was poured onto an ice/water mixture (85 ml) and adjusted to pH7 with sodium hydroxide (s). The mixture was extracted with ethyl acetate (3 X 50 ml) and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica (eluant 1 : 1 hexane: ethyl acetate) to give 1, 3-benzothiazol-5-amine (820 mg, 52 percent). LHNMR (CDCL3) 6 6.85 (1H, dd, J2. 3,8. 6), 7.40 (1H, d, J2. 1), 7.66 (1H, d, J 8.4), 8.90 (1H, s).
2.1 g
With tin(II) chloride dihdyrate In ethyl acetateReflux
A mixture of 5-nitrobenzo[d]thiazole (3.0 g, 16.7 mmol) and SnCl2*2H2O (19 g, 84.2 mmol) in EtOAc (150 mL) was stirred at reflux overnight. The reaction mixture was basified with Et3N until pH 8 and the precipitate was filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (EtOAc/DCM = 2:1) to afford the title compound as a yellow solids (2.1 g). 1H NMR (400 MHz, CDCl3): ö 8.92 (s, 1H), 7.69 (d, 1H), 7.41 (d, 1H), 6.86 (dd, 1H), 3.82 (brs, 2H); LCMS: 151 (M+H).
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 957 - 971
[2] Catalysis Letters, 2014, vol. 144, # 7, p. 1258 - 1267
[3] Patent: WO2005/28445, 2005, A2, . Location in patent: Page/Page column 28
[4] Yakugaku Zasshi, 1942, vol. 62, p. 47,51; dtsch. Ref. S. 19, 22[5] Chem.Abstr., 1951, p. 609
[6] Helvetica Chimica Acta, 1950, vol. 33, p. 1429,1431
[7] Zhurnal Obshchei Khimii, 1956, vol. 26, p. 3388,3390; engl. Ausg. S. 3773
[8] Zhurnal Obshchei Khimii, 1956, vol. 26, p. 797,800; engl. Ausg. S. 911, 913
[9] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1972, vol. 8, p. 36 - 38[10] Khimiya Geterotsiklicheskikh Soedinenii, 1972, vol. 8, # 1, p. 38 - 40
[11] Patent: US5677321, 1997, A,
[12] Patent: US2006/35897, 2006, A1, . Location in patent: Page/Page column 23
[13] Patent: WO2008/8821, 2008, A2, . Location in patent: Page/Page column 42; 43
[14] Patent: WO2007/48070, 2007, A2, . Location in patent: Page/Page column 112
[15] Phytochemistry, 2012, vol. 74, p. 159 - 165
[16] Patent: WO2013/142266, 2013, A1, . Location in patent: Page/Page column 00506
2
[ 2942-07-6 ]
[ 1123-93-9 ]
Reference：
[1] Patent: US2001/345, 2001, A1,
3
[ 98556-09-3 ]
[ 1123-93-9 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1972, vol. 8, p. 36 - 38[2] Khimiya Geterotsiklicheskikh Soedinenii, 1972, vol. 8, # 1, p. 38 - 40
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 957 - 971
4
[ 6283-25-6 ]
[ 1123-93-9 ]
Reference：
[1] Phytochemistry, 2012, vol. 74, p. 159 - 165
5
[ 53666-48-1 ]
[ 1123-93-9 ]
Reference：
[1] Phytochemistry, 2012, vol. 74, p. 159 - 165
6
[ 10403-47-1 ]
[ 1123-93-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 957 - 971
7
[ 58759-63-0 ]
[ 1123-93-9 ]
Reference：
[1] Helvetica Chimica Acta, 1950, vol. 33, p. 1429,1431
8
[ 97-00-7 ]
[ 1123-93-9 ]
Reference：
[1] Helvetica Chimica Acta, 1950, vol. 33, p. 1429,1431
9
[ 1123-93-9 ]
[ 769-19-7 ]
Yield
Reaction Conditions
Operation in experiment
2.3 g
With bromine In chloroform at 10 - 20℃; for 1 h;
A solution of Br2 (2.3 g, 14.4 mmol) in CHC13 (10 mL) was added dropwise to a solution of benzo[d]thiazol-5-amine (2.1 g, 14.0 mmol) in CHC13 (100 mL) at 10 °C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was basified with saturated aqueous Na2CO3 (100 mL) and extracted with DCM (3x30 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/petroleum ether = 1 :81 :4) to afford the title compound as yellow solids (2.3 g). 1H NMR (300 MHz, CDCl3): ö 9.01 (s, 1H), 7.66 (d, 1H), 6.95 (d, 1H), 4.33 (s, 2H).
Reference：
[1] Journal of the Chemical Society, 1965, p. 2248 - 2250
[2] Patent: US2009/118295, 2009, A1, . Location in patent: Page/Page column 23-24
[3] Patent: WO2013/142266, 2013, A1, . Location in patent: Paragraph 00507
10
[ 1336-21-6 ]
[ 1123-93-9 ]
[ 769-19-7 ]
Reference：
[1] Patent: US2001/345, 2001, A1,
11
[ 1123-93-9 ]
[ 58249-57-3 ]
Reference：
[1] Journal of Organic Chemistry, 1976, vol. 41, # 8, p. 1328 - 1331
12
[ 1123-93-9 ]
[ 768-11-6 ]
Reference：
[1] Journal of Organic Chemistry, 1976, vol. 41, # 8, p. 1328 - 1331
[2] Patent: US2006/35897, 2006, A1, . Location in patent: Page/Page column 23
[3] Patent: WO2008/8821, 2008, A2, . Location in patent: Page/Page column 42
With bromine; In dichloromethane; chloroform; ethyl acetate;
C. 5-Amino-4-bromobenzothiazole To a cooled (5° C.) solution of 2.04 g of <strong>[1123-93-9]5-aminobenzothiazole</strong> in 60 mL of chloroform are added dropwise 2.15 g of bromine while maintaining the temperature below 10° C. After completion of the addition, the reaction mixture is stirred for 30 minutes at room temperature, then diluted with 14 mL of concentrated ammonium hydroxide and 16 mL of methylene chloride. The aqueous layer is washed with methylene chloride (2*16 mL) and the combined organic layers are rotary evaporated. The residue is purified by an aspirator vacuum-filtration through silica gel, eluding with 15percent to 30 ethyl acetate in hexanes to provide 2.44 g of 5-amino-4-bromobenzothiazole as a reddish solid.
In tetrahydrofuran; dichloromethane; acetic acid; ethyl acetate;
A. 1-Benzothiazol-6-yl-pyrrole-2,5-dione (481A) A mixture of <strong>[1123-93-9]5-aminobenzothiazole</strong> (2.00 g, 13.3 mmol) and maleic anhydride (1.96 g, 20.0 mmol) in AcOH (27 mL) was heated at 115° C. for 20 h. The mixture was cooled and concentrated under reduced pressure. The residue was taken up in THF and washed with saturated Na2CO3. The aqueous layer was extracted several times with THF and the combined organic layers were dried over MgSO4. Purification by flash chromatography on silica gel eluding with 0 to 50percent EtOAc in CH2Cl2 gave 1.37 g (45percent) of compound 481A as a pale yellow solid. HPLC: 100percent at 2.62 min (retention time) (YMC S5 ODS column, 4.6*50 mm, eluding with 10-90percent aqueous methanol over 4 min containing 0.2percent phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 231.0 [M+H]+.
Example 8; Preparation of Compound 51; Step A - Synthesis of Compound 51A; To a suspension of l,3-benzothiazol-5-amine (16 g, 107 mmol) in concentrated HCl (180 mL) at -10 0C was added very slowly a solution of sodium nitrite (7.66 g,l 11 mmol) in water (35 mL). After addition, the mixture was vigorously allowed to stirat -5 0C to 0 °C for 0.5 hours. To the reaction mixture was then added dropwise a solution of tin(II) chloride (81.0 g, 359 mmol) in concentrated HCl (60 mL). The internal temperature was maintained at or below -5 0C during the addition and the resulting suspension was allowed to stir at -10 0C to 20 0C for about 1.5 hours. The precipitate was filtered off and the flask was rinsed with a small amount of water. The collected solids were dissolved into water (100 mL), and to the resulting solution was added Na2S.9H2O (39 g). The aqueous layer was adjusted to pH 11 using 50percent aqueous sodium hydroxide solution (4 mL). The solids were removed by filtration and washed with water. The aqueous layer was extracted with THF/ethyl acetate (1:2) (2 X 200 mL). The combined organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo to provide compound 51A (14.8 g, 84percent), which was used without further purification.
84%
A solution of <strong>[1123-93-9]1,3-benzothiazol-5-amine</strong>, (11A, Maybridge, 16 g, 107 mmol) in concentrated HCl (180 mL) was cooled to -10° C. and to the cooled solution was added very slowly a solution of sodium nitrite (7.66 g,111 mmol) in water (35 mL). After the addition was complete, the reaction mixture was vigorously stirred at -5° C. to 0° C. for 30 minutes. To the reaction mixture was then added, dropwise, a solution of tin(II) chloride (81.0 g, 359 mmol) in concentrated HCl (60 mL). The internal reaction temperature was maintained at or below -5° C. during the addition. The resulting suspension was stirred at -10° C. for about 90 minutes, during which time the reaction mixture was allowed to warm to room temperature. The resulting precipitates were filtered off and the flask was rinsed with small amount of water. The collected solids were dissolved into water (100 mL), and Na2S.9H2O (39 g) was added. The aqueous layer was adjusted to pH 11 using aqueous sodium hydroxide solution (50percent, 4 mL). The solids were removed by filtration and washed with water. The aqueous layer was extracted with a mixture of THF/ethyl acetate (1:2) (2.x.200 mL). The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo to provide compound 11B (14.8 g, 84percent), which was used without further purification.
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 90℃; for 3h;
Example 19 N4-(benzo[D]thiazol-5-yl)-N2-(1H-indazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine To a solution of 2,4-dichloro-7-tosyl-pyrrolo[2,3-d]pyrimidine (0.1 g, 0.28 mmol) in n-butyl alcohol (0.8 mL) was added <strong>[1123-93-9]5-aminobenzothiazole</strong> (0.046 g, 0.31 mmol) and DIPEA (0.1 mL, 0.56 mmol) at room temperature. After heating at 90° C. for 3 h, the mixture was diluted with H2O, and the precipitates were collected by filtration to give N-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzolthiazol-5-amine (0.19 g).
With sodium t-butanolate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 85℃; for 16h;Product distribution / selectivity;
A mixture of 2,6-dichloropyrazine (0.150 g, 1.006 mmol), 5-amino-benzothiazole (0.151 g , 1.006 mmol), BINAP (0.0137 g, 0.02215 mmol), sodium tertiary butoxide (0.136 g, 1.409 mmol) and palladium acetate (0.005 g, 0.02215 mmol) in toluene (8 mL) was heated at 85 0C for 16 h under nitrogen. CH2CI2 was added, the reaction mixture was filtered through Celite, and the solvent was evaporated. The residue was purified by column chromatography (5percent methanol in CH2CI2 as eluent) to give 0.140 g (53percent) of intermediate benzothiazol-5-yl-(6-chloro-pyrazin-2-yl)-amine. 1H NMR (CDCl3) delta 10.12 (s, IH), 9.38 (s, IH), 8.59 (s, IH), 8.22 (s, IH), 8.11-8.08 (d, J= 8.67 Hz, 1 H), 8.02 (s, IH), 7.6-7.57 (d, J= 8.67 Hz, 1 H); MS (API-E S/Positive); m/z: 263 (M+H)+.
With 2,4,6-trimethyl-pyridine; HATU; In dichloromethane; at 140℃; for 0.5h;Microwave irradiation;
General procedure for the preparation of compounds 161-164; 3-([2-(Trifluoromethyl)phenyl]carbonyl}amino)benzoic acid (31 mg, 0.10 ramol), HATU (N-[[(dime1tyl-arm^o)-lH-l,2,3-triazolo[455-b]-pyridin-l-yl]methylene]-N-methyl- methanaminium hexafluorophosphate N-oxide, 46 mg, 0.12 mM), TMP (2,4,6- trimethylpyridine, 48.4 mg, 0.40 mmol) and the appropriate amine (0.40 mmol) were mixed in dichloromethane. The reaction mixture was stirred in a microwave oven for 0.5h at 14O0C. The reaction mixture was filtered on a pad of silica (eluent: n-hexane/ethyl acetate 1:1) and finally purified on a preparative LC-MS (reverse-phase column, gradient elution using the following eluents: A= water/etaCOOeta 99.95:0.05 and B= acetonitrile/etaCOOeta 99.95:0.05. Elution started at the proportions A/B 9:1, and ended at A/B 1:7).; N-(3-(benzo[d]thiazol-5-ylcarbamoyl)phenyI)-2-(trifluoromethyl)benzamide (161); This Example was prepared and purified according to titte general procedure above, using <strong>[1123-93-9]benzo[d]thiazol-5-amine</strong> (60 mg, 0.40 mmol), to give 26percent of the title compound. MS m/z: 442.1 (M+l).
With triethylamine; In dichloromethane; acetonitrile; at 0 - 20℃;
General procedure: Procedure A: The isothiocyanate compound (1 equiv) was added to the solution of amine (1 equiv) in 5 ml of a mixture of dichloromethane and acetonitrile (1:1, v/v). The mixture was cooled to 0°C. Then, triethylamine (2 equiv) was added gradually. The mixture was stirred at 0°C for 15 min, after which stirring was continued at room temperature for 2?10 h. The reaction mixture was concentrated, extracted with dichloromethane, and washed with brine.The organic layer was dried over MgSO4 and purified by column chromatography (MeOH/CH2Cl2) or by preparative TLC (MeOH/CH2Cl2) to afford the desired product.
4,7-dichloro-6-[(1,1-dimethylethyl)sulfonyl]quinazoline[ No CAS ]
N-(6-(tert-butylsulfonyl)-7-chloroquinazolin-4-yl)benzo[d]thiazol-5-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
With 1-methyl-pyrrolidin-2-one; at 90℃; for 0.333333h;
To a solution of 4,7-dichloro-6-[(1,1-dimethylethyl)sulfonyl]quinazoline (60 mg,0.15 mmol) inN-methyl-2-pyrrolidone (1 mL) was added <strong>[1123-93-9]1,3-benzothiazol-5-amine</strong> (27mg, 0.18 mmol). The reaction mixture was heated at 90°C for 20 min. The solution wasallowed to cool to rt. The reaction mixture was filtered and the filtrate was purified by25 HPLC and free based with a carbonate SPE cartridge to provide 21 mg of the titlecompound (32percent). MS: m/z: 433.1 [M+H( 1H NMR (400 MHz, DMSO-d6) 8 1.24 (d, 9H), 7.87-8.07 (m, 2 H), 8.14-8.31 (m, 2 H), 8.66 (d, J= 1.77 Hz, 1 H), 8.77 (s, 1 H), 9.27(d, J = 1.52 Hz, 1 H), 9.44 (s, 1 H), 10.63 (s, 1 H).
32%
at 90℃; for 0.333333h;
Example 40 N-(6-(tert-butylsulfonyl)-7-chloroquinazolin-4-yl)<strong>[1123-93-9]benzo[d]thiazol-5-amine</strong> To a solution of 4,7-dichloro-6-[(1,1-dimethylethyl)sulfonyl]quinazoline (60 mg, 0.15 mmol) in N-methyl-2-pyrrolidone (1 mL) was added <strong>[1123-93-9]1,3-benzothiazol-5-amine</strong> (27 mg, 0.18 mmol). The reaction mixture was heated at 90°C for 20 min. The solution was allowed to cool to rt. The reaction mixture was filtered and the filtrate was purified by HPLC and free based with a carbonate SPE cartridge to provide 21 mg of the title compound (32percent). MS: m/z: 433.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) delta 1.24 (d, 9 H), 7.87 - 8.07 (m, 2 H), 8.14 - 8.31 (m, 2 H), 8.66 (d, J = 1.77 Hz, 1 H), 8.77 (s, 1 H), 9.27 (d, J = 1.52 Hz, 1 H), 9.44 (s, 1 H), 10.63 (s, 1 H).
N-(1,3-benzothiazol-5-yl)-6-iodo-7-(methyloxy)-4-quinazolinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
In isopropyl alcohol; at 90℃; for 0.5h;
To asolution of 4-chloro-6-iodo-7-(methyloxy)quinazoline (2.0 g, 5.4 mmol) in isopropanol (3030 mL) was added <strong>[1123-93-9]1,3-benzothiazol-5-amine</strong> (1.2 g, 8.1 mmol). The suspension was heated inoil bath at 90C (preheated). The reaction mixture stirred at this temperature for 30 min.A yellow solid precipitated out as the reaction mixture was allowed to cool to rt. The solid-was filtered to provide 2.1 g of the title compound (77%, 93% pure). MS: m/z: 471[M+H+]
55.2%
In propan-1-ol; at 90℃; for 0.5h;
Step 5. N-l,3-benzothiazol-5-yl-6-iodo-7-(methyloxy)-4-quinazolinamine: To a solution of 4-chloro-6-iodo-7-(methyloxy)quinazoline (2.0 g, 5.4 mmol) in 1-propanol (30 mL) was added l,3-benzothiazol-5-amine (1.2 g, 8.1 mmol). The suspension was heated in oil bath at 90C (preheated). The reaction mixture was stirred at this temperature for 30 min. A yellow solid precipitated out as the reaction mixture was allowed to cool to rt. The solid was filtered, washed with toluene and dried to provide 1.3g of the title compound (55.2%, 99% pure). MS: m/z: 435 [M+H]+.
In isopropyl alcohol; at 90℃; for 0.5h;
To a solution of 4-chloro-6-iodo-7-(methyloxy)quinazoline (2.0 g, 5.4 mmol) in isopropanol (30 mL) was added <strong>[1123-93-9]1,3-benzothiazol-5-amine</strong> (1.2 g, 8.1 mmol). The suspension was heated in oil bath at 90C (preheated). The reaction mixture stirred at this temperature for 30 min. A yellow solid precipitated out as the reaction mixture was allowed to cool to rt. The solid was filtered to provide 2.1 g of the title compound (77%, 93% pure). MS: m/z: 471 [M+H]+.
N-1,3-benzothiazol-5-yl-6-iodo-4-quinazolinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
In isopropyl alcohol; at 20℃; for 0.5h;
To a solution of 4-chloro-6-iodoquinazoline (2.60 g, 8.95 mmol) in isopropanol (60 mL) was added <strong>[1123-93-9]1,3-benzothiazol-5-amine</strong> (1.479 g, 9.85 mmol). The mixture was then placed in oil bath10 preheated to 90°C. The reaction was complete in 30 min., and the solution was allowed tocool to room temperature. A yellow solid precipitated and was filtered and dried toprovide 3.6 g (91 percent) of the title compound.
91%
In isopropyl alcohol; at 90℃; for 0.5h;
N-1,3-benzothiazol-5-yl-6-iodo-4-quinazolinamine To a solution of 4-chloro-6-iodoquinazoline (2.60 g, 8.95 mmol) in isopropanol (60 mL) was added <strong>[1123-93-9]1,3-benzothiazol-5-amine</strong> (1.479 g, 9.85 mmol). The mixture was then placed in oil bath preheated to 90°C. The reaction was complete in 30 min., and the solution was allowed to cool to room temperature. A yellow solid precipitated and was filtered and dried to provide 3.6 g (91 percent) of the title compound. The following intermediate, N-(5-fluoro-1H-indazol-3-yl)-6-iodo-4-quinazolinamine, was made in the same manner:
With phosphomolybdic acid; In dichloromethane; at 20℃; for 0.333333h;Inert atmosphere;
General procedure: A mixture of the 2-cyclopropylpyrimidine 4-carbaldehyde (4) (0.148g, 1.0 mmol), aniline (5a) (0.093 g, 1.0 mmol) and diphenyl phosphite (6a) (0.280 g, 1.2 mmol) were taken into a 25 ml round bottomflask in dry dichloromethane (10 ml) in the presence of 0.5 molpercent of phosphomolybidic acid (0.0370 g, 0.02 mmol) was stirred at room temperature for20 min. The progress of the reaction was monitored by TLC analysis. Aftercompletion of the reaction solvent was filtered to recover the catalyst. The filtrate was evaporated under reduced pressure and the residue was purified bycolumn chromatography on silica gel (100-200 mesh) using 20-30percent petroleum etherand ethyl acetate as eluents to obtain the pure alpha-aminophosphonate as a solid (7a) in 95percent (0.434 g) yield. This procedure was applied successfully for the preparation of other compounds 7b-n (Table 2).
90%
With hydrogen trititanate; In neat (no solvent); at 20℃; for 0.25h;Green chemistry;
General procedure: Dialkyl/diaryl phosphite (1.0 mmol) was added portion wise over a period of 5 min to the stirred mixture of heterocyclic aldehyde (1.0 mmol) and benzothiazole amine (1.0 mmol) at room temperature. Further 5 mol percent of TNT was added to the reaction mixture and the stirring was continued for 15 min. After the completion of the reaction as monitored through TLC, the reaction mixture was dissolved in EtOAc (2 mL) and the catalyst was separated by centrifugation followed by subsequent washings with EtOAc. The recovered catalyst was reused for the next cycle. The filtrate was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated on a rotary evaporator and the resulting residue was purified by silica gel column chromatography (70:30, hexane/EtOAc) to afford the corresponding pure alpha-aminophosphonate. The novel alpha-aminophosphonates were structurally assigned by their IR, NMR (1H, 13C & 31P), and mass spectral (HRMS) analyses.
With phosphomolybdic acid; In dichloromethane; at 20℃; for 0.333333h;Inert atmosphere;
General procedure: A mixture of the 2-cyclopropylpyrimidine 4-carbaldehyde (4) (0.148g, 1.0 mmol), aniline (5a) (0.093 g, 1.0 mmol) and diphenyl phosphite (6a) (0.280 g, 1.2 mmol) were taken into a 25 ml round bottomflask in dry dichloromethane (10 ml) in the presence of 0.5 molpercent of phosphomolybidic acid (0.0370 g, 0.02 mmol) was stirred at room temperature for20 min. The progress of the reaction was monitored by TLC analysis. Aftercompletion of the reaction solvent was filtered to recover the catalyst. The filtrate was evaporated under reduced pressure and the residue was purified bycolumn chromatography on silica gel (100-200 mesh) using 20-30percent petroleum etherand ethyl acetate as eluents to obtain the pure alpha-aminophosphonate as a solid (7a) in 95percent (0.434 g) yield. This procedure was applied successfully for the preparation of other compounds 7b-n (Table 2).
With phosphomolybdic acid; In dichloromethane; at 20℃; for 0.333333h;Inert atmosphere;
General procedure: A mixture of the 2-cyclopropylpyrimidine 4-carbaldehyde (4) (0.148g, 1.0 mmol), aniline (5a) (0.093 g, 1.0 mmol) and diphenyl phosphite (6a) (0.280 g, 1.2 mmol) were taken into a 25 ml round bottomflask in dry dichloromethane (10 ml) in the presence of 0.5 molpercent of phosphomolybidic acid (0.0370 g, 0.02 mmol) was stirred at room temperature for20 min. The progress of the reaction was monitored by TLC analysis. Aftercompletion of the reaction solvent was filtered to recover the catalyst. The filtrate was evaporated under reduced pressure and the residue was purified bycolumn chromatography on silica gel (100-200 mesh) using 20-30percent petroleum etherand ethyl acetate as eluents to obtain the pure alpha-aminophosphonate as a solid (7a) in 95percent (0.434 g) yield. This procedure was applied successfully for the preparation of other compounds 7b-n (Table 2).
With phosphomolybdic acid; In dichloromethane; at 20℃; for 0.333333h;Inert atmosphere;
General procedure: A mixture of the 2-cyclopropylpyrimidine 4-carbaldehyde (4) (0.148g, 1.0 mmol), aniline (5a) (0.093 g, 1.0 mmol) and diphenyl phosphite (6a) (0.280 g, 1.2 mmol) were taken into a 25 ml round bottomflask in dry dichloromethane (10 ml) in the presence of 0.5 molpercent of phosphomolybidic acid (0.0370 g, 0.02 mmol) was stirred at room temperature for20 min. The progress of the reaction was monitored by TLC analysis. Aftercompletion of the reaction solvent was filtered to recover the catalyst. The filtrate was evaporated under reduced pressure and the residue was purified bycolumn chromatography on silica gel (100-200 mesh) using 20-30percent petroleum etherand ethyl acetate as eluents to obtain the pure alpha-aminophosphonate as a solid (7a) in 95percent (0.434 g) yield. This procedure was applied successfully for the preparation of other compounds 7b-n (Table 2).
To a solution of <strong>[1123-93-9]benzo[d]thiazol-5-amine</strong> (0.500 g, 3.329 mmol) in pyridine (5 mL) was added phenyl chloroformate (0.639 g, 3.995 mmol) at 0°C and further stirred for 12 h at room temperature. The reaction mixture was diluted with water (50 mL) and extractedwith ethyl acetate (2 x 50 mL). The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the titled compound (0.550 g, crude). The crude product was taken to the next step without further purification.
(E)-2-((benzo[d]thiazol-5-ylimino)methyl)-3,4-dibromo-6-methoxyphenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87.5%
With acetic acid; In i-Amyl alcohol;Reflux; Inert atmosphere;
2,3-Dibromo-6-hydroxy-5-methoxybenzaldehyde (0.1 g, 0.32 mmol), 5-benzothiazolamine (0.03 g, 0.21 mmol), and isoamyl alcohol (2 mL) were stirred at room temperature under N2. Acetic acid (0.07 mL) was added drop-wise, and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH2Cl2, MeOH, and dried to yield 27 (0.08 g, 0.18 mmol, 87.5percent) as an orange powder. 1H NMR (DMSO, 300 MHz) delta 15.12 (s, 1H), 9.49 (s, 1H), 9.25 (s, 1H), 8.29 (d, 1H, J=8.4 Hz), 8.22 (d, 1H, J=1.8 Hz), 7.65 (dd, 1H, J=8.4 Hz, 1.8 Hz), 7.42(s, 1H), 3.86 (s, 3H); 13C NMR (DMSO, 700 MHz) delta 164.89, 158.70, 154.49, 154.33, 149.34, 145.16, 133.37, 124.00, 121.49, 120.28, 119.30, 117.71, 115.64, 113.35, 57.07. Rf=0.59 (Hexane/EtOAc 2:1)
87.5%
With acetic acid; In i-Amyl alcohol;Inert atmosphere; Reflux;
2,3-dibromo-6-hydroxy-5-methoxybenzaldehyde (0.1g, 0.32 mmol), 5- benzothiazolyl asleep Min (0.03g, 0.21 mmol) and isoamyl alcohol (2 mL) and N2It was stirred at room temperature.It was added dropwise acetic acid (0.07 mL) and the mixture was refluxed overnight.Filtering the reaction mixture, CH2Cl2and dried and then washed with MeOH, the orange powder obtained in27to give a (0.08g, 0.18mmol, 87.5percent).
(E)-2-((benzo[d]thiazol-5-ylimino)methyl)-3,4-dibromo-6-ethoxyphenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91.3%
With acetic acid; In i-Amyl alcohol;Reflux; Inert atmosphere;
2,3-Dibromo-5-ethoxy-6-hydroxybenzaldehyde (0.1 g, 0.31 mmol), 5-benzothiazolamine (0.03 g, 0.20 mmol), and isoamyl alcohol (2 mL) were stirred at room temperature under N2. Acetic acid (0.07 mL) was added drop-wise, and the mixture was refluxed overnight. The reaction was quenched with H2O, and the aqueous layer was extracted with EtOAc. The organic layer was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (Hexane/EtOAc) to yield 30 (0.08 g, 0.18 mmol, 91.3percent) as a yellow powder.1H NMR (CDCl3, 300 MHz,) delta 15.41 (s, 1H), 9.31 (d, 1H, J=1.5 Hz), 9.08 (s, 1H), 8.10 (d, 1H, J=2.1 Hz), 8.02 (d, 1H, J=8.4 Hz), 7.47 (dd, 1H, J=8.4 Hz, 2.1 Hz), 7.16(s, 1H), 4.12 (q, 2H, J=6.9 Hz), 1.52 (t, 3H, J=6.9 Hz); 13C NMR (CDCl3, 700 MHz,) delta 164.05, 155.84, 154.84, 154.32, 148.42, 145.18, 132.95, 122.79, 120.06, 119.57, 117.74, 117.54, 115.19, 113.32, 64.99, 14.64. Rf=0.50 (Hexane/EtOAc 2:1)
91.3%
With acetic acid; In i-Amyl alcohol;Inert atmosphere; Reflux;
2,3-dibromo-5-ethoxy-6- hydroxybenzaldehyde (0.1g, 0.31 mmol), 5-benzothiazolyl asleep Min (0.03g, 0.20 mmol) and isoamyl alcohol (2 mL) and N2It was stirred at room temperature.It was added dropwise acetic acid (0.07 mL) and the mixture was refluxed overnight.? Referred to the reaction with H2O and the aqueous layer was extracted with EtOAc.The organic layer was washed with H2O and brine, MgSO4dried over and concentrated under vacuum.That the residue was purified by column chromatography (hexane / EtOAc), compound30was obtained as a yellow powder (0.08g, 0.18mmol, 91.3percent).
Paraformaldehyde (80 mg, 2.7 mmol) was added to a stirred solution of <strong>[1123-93-9]benzo[d]thiazol-5-amine</strong> (200 mg, 1.332 mmol) in MeOH (5 mL) The resulting suspension was then treated with 25percentw/w NaOMe in MeOH (1.5 mL, 6.7 mmol) and the clear reaction mixture was stirred at 60 °C for 16 h. The reaction was allowed to cool to RT and then treated with NaBH4 (126 mg, 3.33 mmol) and stirredat RT for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with CHC13 (3 x 20 mL). The combined organic component was concentrated and purified using a Biotage Horizon (12g Si02, 0-50percent EtOAc/hexanes) to yield Nmethyl<strong>[1123-93-9]benzo[d]thiazol-5-amine</strong> (217 mg) as yellow gum. .LC-MS retention time = 0.67 mm; mlz = 165.05 [M+H]. (Column: Waters Aquity BEH C18, 2.0 x 50 mm,1.7-.im particles. Solvent A = 100percent Water: 0.05percent TFA. Solvent B = 100percentAcetonitrile : 0.05percent TFA. Flow Rate = 0.8 mL/min. Start percent B = 2. Final percent B = 98.Gradient Time = 1.5 mm. Wavelength = 220). ?H NMR (400MHz,CHLOROFORIVI-d) oe 8.92 (s, 1H), 7.69 (d,J=8.5 Hz, 1H), 7.31 (d,J=2.3 Hz, 1H),6.82 (dd, J=8.8, 2.3 Hz, 1H), 3.93 (br. s., 1H), 2.94 (s, 3H).
217 mg
Paraformaldehyde (80 mg, 2.7 mmol) was added to a stirred solution of benzo[d]thiazol- 5-amine (200 mg, 1.332 mmol) in MeOH (5 mL). The resulting suspension was then treated with 25percent w/w NaOMe in MeOH (1.5 mL, 6.7 mmol) and the clear reaction mixture was stirred at 60 °C for 16 h. The reaction was allowed to cool to rt and then treated with NaB (126 mg, 3.33 mmol) and stirred at rt for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with CHCh (3 x 20 mL). The combined organic component was concentrated and purified using a Biotage Horizon (12g SiC , 0- 50percent) EtOAc/hexanes) to yield Intermediate 16 (217 mg) as yellow gum. LC-MS retention time = 0.67 min; m/z = 165.1 [M+H]+. (Column: Waters Aquity BEH C18, 2.0 x 50 mm, 1.7-muiotaeta particles. Solvent A = 100percent Water : 0.05percent TFA. Solvent B = 100percent Acetonitrile : 0.05percent TFA. Flow Rate = 0.8 mL/min. Start percent B = 2. Final percent B = 98. Gradient Time = 1.5 min. Wavelength = 220 nm). NMR (400 MHZ, CDCh) delta ppm 8.92 (s, IH), 7.69 (d, J=8.5 Hz, IH), 7.31 (d, J=2.3 Hz, IH), 6.82 (dd, J=8.8, 2.3 Hz, IH), 3.93 (br. s., IH), 2.94 (s, 3H).
217 mg
Paraformaldehyde (80 mg, 2.7 mmol) was added to a stirred solution of benzo[d]thiazol- 5-amine (200 mg, 1.332 mmol) in MeOH (5 mL). The resulting suspension was then treated with 25percentw/w NaOMe in MeOH (1.5 mL, 6.7 mmol) and the clear reaction mixture was stirred at 60 °C for 16 h. The reaction was allowed to cool to rt and then treated with NaB (126 mg, 3.33 mmol) and stirred at rt for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with CHCh (3 x 20 mL). The combined organic component was concentrated and purified using a Biotage Horizon (12 g S1O2, 0- 50percent EtOAc/hexanes) to yield Intermediate ZY-1 (217 mg) as yellow gum. LC-MS retention time = 0.67 min; m/z = 165.05 [M+H]+. (Column: Waters Aquity BEH C18, 2.0 x 50 mm, 1.7-muiotaeta particles. Solvent A = 100percent Water : 0.05percent TFA. Solvent B = 100percent Acetonitrile : 0.05percent TFA. Flow Rate = 0.8 mL/min. Start percent B = 2. Final percent B = 98. Gradient Time = 1.5 min. Wavelength = 220). NMR (400 MHz, CDCh) delta 8.92 (s, IH), 7.69 (d, J=8.5 Hz, IH), 7.31 (d, J=2.3 Hz, IH), 6.82 (dd, J=8.8, 2.3 Hz, IH), 3.93 (br. s., IH), 2.94 (s, 3H).
4-chloro-6-(4-morpholinylsulfonyl)quinoline[ No CAS ]
N-1,3-benzothiazol-5-yl-6-(4-morpholinylsulfonyl)-4-quinolinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.2 g
With hydrogenchloride; In 1,4-dioxane; ethanol; at 80℃; for 2h;
To a solution of 4-chloro-6-(4-morpholinylsulfonyl)quinoline (1.3 g, 4.16 mmol) in ethanol (30 mL) was added <strong>[1123-93-9]1,3-benzothiazol-5-amine</strong> (0.75 g, 5.0 mmol) and 4 M HCl in dioxane (0.50 ml, 2.0 mmol). The reaction mixture was heated at 80 °C. The bright yellow solid was precipitated out from ethanol. After 2 hours the reaction was allowed to cool to room temperature. The solution was filtered and the solid was suspended in DCM (200 ml). 1 N NaOH (20 ml) was added and the solution was stirred for 10 minutes during which time the solid dissolved. The two layers were then separated and the organic layer was washed with NaOH again, dried over Na2SO4, and concentrated in vacuo. The residue was triturated with hot ethanol to provide the title compound as an off white solid (1.2 g). 1H NMR(DMSO-d6) delta 9.71 (s, 1H), 9.45 (s, 1H), 8.94 (d, J = 1.8 Hz, 1H), 8.61 (d, J = 5.3 Hz, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.04 - 8.12 (m, 2H), 7.94 (dd, J = 8.8, 1.8 Hz, 1 H), 7.57 (dd, J = 8.6, 2.0 Hz, 1H), 7.07 (d, J = 5.3 Hz, 1 H), 3.59 - 3.72 (m, 4H), 2.93 - 3.04 (m, 4H). MS (m/z) 427.1 (M+H+).
N-1,3-benzothiazol-5-yl-6-(methylsulfonyl)-4-quinolinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With sulfuric acid; In ethanol; at 80℃; for 18h;
A mixture of 4-chloro-6-(methylsulfonyl)quinoline (9.0 g, 37 mmol), <strong>[1123-93-9]1,3-benzothiazol-5-amine</strong> (5.6 g, 37 mmol), sulfuric acid (0.16 ml, 1.9 mmol) and ethanol (370 ml) was heated at 80 °C for 18 h. The reaction was cooled to room temperature, diluted with diethyl ether and filtered. The material was dissolved in 10 percent methanol/ethyl acetate and washed with saturated sodium bicarbonate solution. The aqueous layer was extracted with 10percent methanol/ethyl acetate (2x) and the combined organics were washed with brine (1x) and concentrated to yield the desired product along with minor amounts of methanol. The material was suspended in 2:1 acetonitrile/water (50 mL), filtered, and the resulting solid was dried overnight. The reaction was repeated on a 7g scale and the 2 batches were combine to yield N-1,3-benzothiazol-5-yl-6-(methylsulfonyl)-4-quinolinamine (16 g, 44.6 mmol, 67 percent yield). 1H NMR (400 MHz, CHLOROFORM-d) delta 9.11 (s, 1H), 8.88 (s, 1H), 8.67 (d, J = 5.6 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.09 - 8.18 (m, 2H), 8.05 (d, J = 8.6 Hz,1H), 7.48 (dd, J = 8.6, 2.0 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 3.20 (s, 3H); MS (m/z) 356 (M+H+). Alternatively, this reactioncan be done with a drop of con. HCl (or catalytic 4M HCl in dioxane) or in a microwave reactor in the absence of acidat 80 °C - 150 °C for 5 to 15 minutes. NMP may also be used as the solvent in select cases. Select compounds werepurified by reverse phase HPLC.
4-chloro-6-(4-morpholinylsulfonyl)quinoline[ No CAS ]
N-1,3-benzothiazol-5-yl-6-(4-morpholinylsulfonyl)-4-quinolinamine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In 1,4-dioxane; ethanol; at 80℃;
General procedure: To a solution of a 4-chloro-6-quinolinesulfonamide (1eq.) in ethanol (0.02 M) was added amine/aniline (1.2 eq.)and 4M HCl in dioxane (0.2 eq.). The reaction was heated to 80 °C. The resulting product was basified with carbonatebases and purified by silica gel chromatography.
4-chloro-N-(3-methyl-3-oxetanyl)-6-quinolinesulfonamide[ No CAS ]
4-(1,3-benzothiazol-5-ylamino)-N-(3-methyl-3-oxetanyl)-6-quinolinesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15 mg
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 1h;Inert atmosphere; Sealed tube;
To a solution of 4-chloro-N-(3-methyl-3-oxetanyl)-6-quinolinesulfonamide (30 mg, 0.096 mmol), <strong>[1123-93-9]1,3-benzothiazol-5-amine</strong> (14.41 mg, 0.096 mmol), Cs2CO3 (75 mg, 0.230 mmol) and Xantphos (11.10 mg, 0.019 mmol) in 1,4-Dioxane (1 mL) in a sealed tube bubbled with N2 was added Pd2(dba)3 (17.57 mg, 0.019 mmol). The reaction mixture was heated to 120°C for 1h. The mixture was then loaded directly onto a Biotage column and purified (0 - 5 percent MeOH/DCM) to provide 15.0 mg of 4-(1,3-benzothiazol-5-ylamino)-N-(3-methyl-3-oxetanyl)-6-quinolinesulfonamide. MS (m/z) 427.1 (M+H+) 1H NMR (DMSO-d6) d: 9.69 (s, 1H), 9.44 (s, 1H), 8.98 (d, J = 1.3 Hz, 1H), 8.58 (d, J = 5.6 Hz, 1H), 8.50 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 7.98 - 8.12 (m, 3H), 7.57 (dd, J = 8.6, 2.0 Hz, 1H), 7.08 (d, J = 5.6 Hz, 1H), 4.61 (d, J = 6.1 Hz, 2H), 4.15 (d, J = 6.3 Hz, 2H), 1.44 (s, 3H).
4-(1,3-benzothiazol-5-ylamino)-N-(1-methylethyl)-6-quinolinesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; at 160℃;Sealed tube;
General procedure: A reaction vessel containing a 4-chloro-6-quinolinesulfonamide (1 eq.), ethanol (0.05 M), and amine/aniline (1eq.) was sealed and heated to 160 °C. After completion, as determined by LCMS, the reaction was cooled to roomtemperature, then diluted with Et2O to generate a precipitate. The solid was isolated by filtration.
N-1,3-benzothiazol-5-yl-6-(1-piperidinylsulfonyl)-4-quinolinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In 1,4-dioxane; 1-methyl-pyrrolidin-2-one; at 80℃; for 1h;Microwave irradiation;
General procedure: A 10 mL microwave vial was charged with a 4-chloro-6-quinolinesulfonamide (1 eq.), amine/aniline (2 eq.), Nmethyl-2-pyrrolidone (NMP) (0.06 M), and 4M HCl in dioxane (0.3 eq.). The vessel was sealed and heated to 80 °C.After 1 hr the reaction was cooled to room temperature, filtered and purified directly via reverse phase HPLC.
4-(1,3-benzothiazol-5-ylamino)-N-methyl-N-[2-(methyloxy)ethyl]-6-quinolinesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In 1,4-dioxane; at 80℃;
General procedure: To a solution of a 4-chloro-6-quinolinesulfonamide (1eq.) in ethanol (0.02 M) was added amine/aniline (1.2 eq.)and 4M HCl in dioxane (0.2 eq.). The reaction was heated to 80 °C. The resulting product was basified with carbonatebases and purified by silica gel chromatography.
4-(1,3-benzothiazol-5-ylamino)-N-3-oxetanyl-6-quinolinesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 1h;Sealed tube; Inert atmosphere;
General procedure: To a solution of a 4-chloro-6-quinolinesulfonamide (1 eq.), amine/aniline (1 eq.), Cs2CO3 (2.4 eq.) and Xantphos(0.2 eq.) in 1,4-Dioxane (0.1 M) in a sealed tube bubbled with N2 was added Pd2(dba)3 (0.2 eq.). The reaction mixturewas heated to 120 °C for 1 hr. The mixture was then purified by silica gel chromatography.
diphenyl (benzo[d]thiazol-5-ylamino)(5-methoxybenzofuran-2-yl)methylphosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With hydrogen trititanate; In neat (no solvent); at 20℃; for 0.25h;Green chemistry;Catalytic behavior;
General procedure: Dialkyl/diaryl phosphite (1.0 mmol) was added portion wise over a period of 5 min to the stirred mixture of heterocyclic aldehyde (1.0 mmol) and benzothiazole amine (1.0 mmol) at room temperature. Further 5 mol percent of TNT was added to the reaction mixture and the stirring was continued for 15 min. After the completion of the reaction as monitored through TLC, the reaction mixture was dissolved in EtOAc (2 mL) and the catalyst was separated by centrifugation followed by subsequent washings with EtOAc. The recovered catalyst was reused for the next cycle. The filtrate was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated on a rotary evaporator and the resulting residue was purified by silica gel column chromatography (70:30, hexane/EtOAc) to afford the corresponding pure alpha-aminophosphonate. The novel alpha-aminophosphonates were structurally assigned by their IR, NMR (1H, 13C & 31P), and mass spectral (HRMS) analyses.
diphenyl (benzo[d]thiazol-5-ylamino)(thiophen-2-yl)methylphosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With hydrogen trititanate; In neat (no solvent); at 20℃; for 0.25h;Green chemistry;
General procedure: Dialkyl/diaryl phosphite (1.0 mmol) was added portion wise over a period of 5 min to the stirred mixture of heterocyclic aldehyde (1.0 mmol) and benzothiazole amine (1.0 mmol) at room temperature. Further 5 mol percent of TNT was added to the reaction mixture and the stirring was continued for 15 min. After the completion of the reaction as monitored through TLC, the reaction mixture was dissolved in EtOAc (2 mL) and the catalyst was separated by centrifugation followed by subsequent washings with EtOAc. The recovered catalyst was reused for the next cycle. The filtrate was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated on a rotary evaporator and the resulting residue was purified by silica gel column chromatography (70:30, hexane/EtOAc) to afford the corresponding pure alpha-aminophosphonate. The novel alpha-aminophosphonates were structurally assigned by their IR, NMR (1H, 13C & 31P), and mass spectral (HRMS) analyses.
diphenyl (benzo[d]thiazol-5-ylamino)(furan-2-yl)methylphosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With hydrogen trititanate; In neat (no solvent); at 20℃; for 0.25h;Green chemistry;
General procedure: Dialkyl/diaryl phosphite (1.0 mmol) was added portion wise over a period of 5 min to the stirred mixture of heterocyclic aldehyde (1.0 mmol) and benzothiazole amine (1.0 mmol) at room temperature. Further 5 mol percent of TNT was added to the reaction mixture and the stirring was continued for 15 min. After the completion of the reaction as monitored through TLC, the reaction mixture was dissolved in EtOAc (2 mL) and the catalyst was separated by centrifugation followed by subsequent washings with EtOAc. The recovered catalyst was reused for the next cycle. The filtrate was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated on a rotary evaporator and the resulting residue was purified by silica gel column chromatography (70:30, hexane/EtOAc) to afford the corresponding pure alpha-aminophosphonate. The novel alpha-aminophosphonates were structurally assigned by their IR, NMR (1H, 13C & 31P), and mass spectral (HRMS) analyses.
diphenyl (benzo[d]thiazol-5-ylamino)(pyridin-2-yl)methylphosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With hydrogen trititanate; In neat (no solvent); at 20℃; for 0.25h;Green chemistry;
General procedure: Dialkyl/diaryl phosphite (1.0 mmol) was added portion wise over a period of 5 min to the stirred mixture of heterocyclic aldehyde (1.0 mmol) and benzothiazole amine (1.0 mmol) at room temperature. Further 5 mol percent of TNT was added to the reaction mixture and the stirring was continued for 15 min. After the completion of the reaction as monitored through TLC, the reaction mixture was dissolved in EtOAc (2 mL) and the catalyst was separated by centrifugation followed by subsequent washings with EtOAc. The recovered catalyst was reused for the next cycle. The filtrate was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated on a rotary evaporator and the resulting residue was purified by silica gel column chromatography (70:30, hexane/EtOAc) to afford the corresponding pure alpha-aminophosphonate. The novel alpha-aminophosphonates were structurally assigned by their IR, NMR (1H, 13C & 31P), and mass spectral (HRMS) analyses.
5-chloro-2-fluoropyridine-3-carbaldehyde[ No CAS ]
[ 1123-93-9 ]
[ 4712-55-4 ]
diphenyl (benzo[d]thiazol-5-ylamino)(5-chloro-2-fluoropyridin-3-yl)methylphosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With hydrogen trititanate; In neat (no solvent); at 20℃; for 0.25h;Green chemistry;
General procedure: Dialkyl/diaryl phosphite (1.0 mmol) was added portion wise over a period of 5 min to the stirred mixture of heterocyclic aldehyde (1.0 mmol) and benzothiazole amine (1.0 mmol) at room temperature. Further 5 mol percent of TNT was added to the reaction mixture and the stirring was continued for 15 min. After the completion of the reaction as monitored through TLC, the reaction mixture was dissolved in EtOAc (2 mL) and the catalyst was separated by centrifugation followed by subsequent washings with EtOAc. The recovered catalyst was reused for the next cycle. The filtrate was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated on a rotary evaporator and the resulting residue was purified by silica gel column chromatography (70:30, hexane/EtOAc) to afford the corresponding pure alpha-aminophosphonate. The novel alpha-aminophosphonates were structurally assigned by their IR, NMR (1H, 13C & 31P), and mass spectral (HRMS) analyses.
diphenyl (benzo[d]thiazol-5-ylamino)(2,6-dimethoxypyridin-3-yl)methylphosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With hydrogen trititanate; In neat (no solvent); at 20℃; for 0.25h;Green chemistry;
General procedure: Dialkyl/diaryl phosphite (1.0 mmol) was added portion wise over a period of 5 min to the stirred mixture of heterocyclic aldehyde (1.0 mmol) and benzothiazole amine (1.0 mmol) at room temperature. Further 5 mol percent of TNT was added to the reaction mixture and the stirring was continued for 15 min. After the completion of the reaction as monitored through TLC, the reaction mixture was dissolved in EtOAc (2 mL) and the catalyst was separated by centrifugation followed by subsequent washings with EtOAc. The recovered catalyst was reused for the next cycle. The filtrate was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated on a rotary evaporator and the resulting residue was purified by silica gel column chromatography (70:30, hexane/EtOAc) to afford the corresponding pure alpha-aminophosphonate. The novel alpha-aminophosphonates were structurally assigned by their IR, NMR (1H, 13C & 31P), and mass spectral (HRMS) analyses.
diphenyl (benzo[d]thiazol-5-ylamino)(1H-indol-3-yl)methylphosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With hydrogen trititanate; In neat (no solvent); at 20℃; for 0.25h;Green chemistry;
General procedure: Dialkyl/diaryl phosphite (1.0 mmol) was added portion wise over a period of 5 min to the stirred mixture of heterocyclic aldehyde (1.0 mmol) and benzothiazole amine (1.0 mmol) at room temperature. Further 5 mol percent of TNT was added to the reaction mixture and the stirring was continued for 15 min. After the completion of the reaction as monitored through TLC, the reaction mixture was dissolved in EtOAc (2 mL) and the catalyst was separated by centrifugation followed by subsequent washings with EtOAc. The recovered catalyst was reused for the next cycle. The filtrate was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated on a rotary evaporator and the resulting residue was purified by silica gel column chromatography (70:30, hexane/EtOAc) to afford the corresponding pure alpha-aminophosphonate. The novel alpha-aminophosphonates were structurally assigned by their IR, NMR (1H, 13C & 31P), and mass spectral (HRMS) analyses.
diphenyl (benzo[d]thiazol-5-ylamino)(3-(pyrimidin-5-yl)phenyl)methylphosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With hydrogen trititanate; In neat (no solvent); at 20℃; for 0.25h;Green chemistry;
General procedure: Dialkyl/diaryl phosphite (1.0 mmol) was added portion wise over a period of 5 min to the stirred mixture of heterocyclic aldehyde (1.0 mmol) and benzothiazole amine (1.0 mmol) at room temperature. Further 5 mol percent of TNT was added to the reaction mixture and the stirring was continued for 15 min. After the completion of the reaction as monitored through TLC, the reaction mixture was dissolved in EtOAc (2 mL) and the catalyst was separated by centrifugation followed by subsequent washings with EtOAc. The recovered catalyst was reused for the next cycle. The filtrate was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated on a rotary evaporator and the resulting residue was purified by silica gel column chromatography (70:30, hexane/EtOAc) to afford the corresponding pure alpha-aminophosphonate. The novel alpha-aminophosphonates were structurally assigned by their IR, NMR (1H, 13C & 31P), and mass spectral (HRMS) analyses.
(+)-diphenyl(benzo[d]thiazol-5-ylamino)(2-cyclopropylpyrimidin-4-yl)methyl phosphonate[ No CAS ]
(-)-diphenyl(benzo[d]thiazol-5-ylamino)(2-cyclopropylpyrimidin-4-yl)methyl phosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1,1'-((1R,3S)-1,2,2-trimethylcyclopentane-1,3-diyl)bis(3-(3,5-bis(trifluoromethyl)phenyl)thiourea); In toluene; at -40℃; for 6h;Inert atmosphere;
General procedure: A mixture of the 2-cyclopropyl pyrimidine 4-carbaldehyde (4) (0.148g, 1.0mmol), aniline (5a) (0.093g, 1.0mmol), and diphenylphosphite (6) (0.280g, 1.2mmol) were taken into a 25mL round bottom flask in dry toluene (10mL) in the presence of 20molpercent of bis-thiourea 3c (0.0370g, 0.02mmol) and the reaction mixture was stirred at ?40°C for 6h. The progress of the reaction was monitored by TLC analysis. The reaction mass was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (100?200mesh) using 30percent ethyl acetate and petroleum ether as eluents to obtain the pure enantioselective alpha-aminophosphonate 7a as a colorless solid in 74percent (0.338g) yield. This procedure was applied successfully for the preparation of other compounds 7b?e.
N-(benzo[d]thiazol-5-yl)-5-chloro-2-hydroxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In o-xylene; at 135℃; for 2h;
[0136] 5-Chlorosalicyclic acid (215.7 mg, 1.250 mmol) was dissolved in TIIF (8.0 mL), followed by the addition of catalytic amount of DMF (10 .iL) and oxalyl chloride (0.13 mL, 1.500 mmol) respectively. The reaction was allowed to stir at rt for 30 mm and then concentrated in vacuo. The residue was re-dissolved in o-xylene followed by addition of benzo[d]thiazol-5- amine (150.2 mg, 1.000 mmol). The mixture was then heated to 135 °C and stirred at this temperature for 2 hours before it was cooled to rt and filtered. The filter cake was washed with cold diethyl ether to give N-(benzo[d]thiazol-5-yl)-5-chloro-2-hydroxybenzamide 15 as an off- white solid (40.6 mg, 13percent yield). ?H NMR (300 MHz, DMSO-d6) 6 11.10 (brs, 1H), 69.41 (d, J = 0.8 Hz, 1H), 8.59 (d, J= 2.0 Hz, 1H), 8.14 (dd, J= 8.7, 0.9 Hz, 1H), 7.95 (dd, J= 2.7, 0.9 Hz, 1H), 7.73 (dd, J= 8.7, 2.1 Hz, 1H), 7.44 (ddd, J= 8.9, 2.7, 0.9 Hz, 1H), 7.00 (dd, J 8.7, 0.9 Hz, 1H). MS (ESI) exact mass calculated for [M+H] (C14H1OC1N2O2S) requires m/z 305.0, found m/z 305.1.
In ethanol; at 150℃; for 0.166667h;Microwave irradiation;
7-bromo-4-chloro-6-(methylsulfonyl) Indolyl) quinoline (500 mg, 1.6 mmol), <strong>[1123-93-9]1,3-benzothiazol-5-amine</strong> (234 mg, 1.56 mmol) and EtOH (3.1 mL) were combined and heated in a microwave at 150 °C for 10 min. The reaction was concentrated to drynessN-1,3-benzothiazol-5-yl-7-bromo-6-(methylsulfonyl)-4-aminoquinoline was obtained as a HCl salt in quantitative yield.
N-1,3-benzothiazol-5-yl-6-[(1,1-dimethylethyl)thio]-7-(methyloxy)quinolin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
In isopropyl alcohol; at 150℃; for 0.25h;Irradiation;
4-chloro-6-[(1,1-dimethylethyl)thio]-7-(methyloxy)quinoline (0.20 g, (0.66 mmol) and <strong>[1123-93-9]1,3-benzothiazol-5-amine</strong> (0.10 g, 0.66 mmol) were irradiated in microwave at 150° C. for 15 mins in isopropanol (2 mL). The reaction mixture was concentrated and purified via flash chromatography (0-50percent EtOAc/hexanes, 0-5percent MeOH/DCM). . N-1,3-benzothiazol-5-yl-6-[(1,1-dimethylethyl)thio]-7-(methyloxy)quinolin-4-amine (0.26 g, 0.67 mmol, 94percent yield) was obtained.
94%
In isopropyl alcohol; at 150℃; for 0.25h;Microwave irradiation;
Step 1. N-1,3-benzothiazol-5-yl-6-[(1,1-dimethylethyl)thio]-7-(methyloxy)-4-quinolinamine: 4-chloro-6-[(1,1-dimethylethyl)thio]-7-(methyloxy)quinoline (0.20 g, 0.66 mmol) and <strong>[1123-93-9]1,3-benzothiazol-5-amine</strong> (0.10 g, 0.66 mmol) in isopropanol (2 mL) were irradiated by microwave at 150 °C for 15 mins. The reaction mixture was concentrated, purified via flash chromatography (0-50percent EtOAc/Hexane, 0-5percent MeOH/DCM) to yield N-1,3-benzothiazol-5-yl-6-[(1,1-dimethylethyl)thio]-7-(methyloxy)-4-quinolinamine (0.26 g, 0.67 mmol, 94 percent yield). 1H NMR (400 MHz, DMSO-d) delta ppm 1.28 (s, 9H), 3.93 (s, 3H), 6.90 (d, J= 5.3 Hz, 1H), 7.32 (s, 1H), 7.54 (dd, J= 8.6 Hz, 2 Hz, 1H), 8.02 (d, J= 2 Hz, 1H), 8.18 (d, J= 8.6 Hz, 1H), 8.42 (d, J= 5.3 Hz, 1H), 8.60 (s, 1H), 9.27 (s, 1H), 9.42 (s, 1H). MS (m/z) 396 (M+H+).
94%
In isopropyl alcohol; at 150℃; for 0.25h;Microwave irradiation;
4-Chloro-6-[(1,1-dimethylethyl)thio]-7-(methyloxy)quinoline (0.20 g, 0.66 mmol) and 1,3-benzothiazole-5 -amine (0.10 g, 0.66 mmol) in isopropanol (2 mL) was irradiated with microwave at 15OC for 15 mins. The reaction mixture is concentrated,Purification via flash chromatography (0-50percent EtOAc/hexane,0-5percent MeOH/DCM),N-1,3-benzothiazol-5-yl-6-[(1,1-dimethylethyl)thio]-7-(methyloxy)-4-aminoquinoline is obtained(0.26 g, 0.67 mmol, 94percent yield).
2-((6-bromo-4-chloroquinolin-7-yl)oxy)ethanol[ No CAS ]
2-((4-(benzo[d]thiazol-5-ylamino)-6-bromoquinolin-7-yl)oxy)ethanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With hydrogenchloride; In 1,4-dioxane; water; at 150℃; for 0.5h;Irradiation;
2-((6-bromo-4-chloroquinolin-7-yl)oxy)ethanol (0.97 g, 3.21 mmol), <strong>[1123-93-9]benzo[d]thiazol-5-amine</strong> (0.58 g, 3.85 mmol), 1 ,4-dioxane (5 mL) and 2 drops of concentrated HCl were mixed and heated via microwave to 150 °C for 30 min. It was concentrated onto tannin and purified by flash chromatography. The title compound was obtained as a yellow solid (560 mg, 40percent).
40%
With hydrogenchloride; In 1,4-dioxane; water; at 150℃; for 0.5h;Microwave irradiation;
Step 2. 2-((4-(benzo[d]thiazol-5-ylamino)-6-bromoquinolin-7-yl)oxy)ethanol: 2-((6-bromo-4-chloroquinolin-7-yl)oxy)ethanol (0.97 g, 3.21 mmol), <strong>[1123-93-9]benzo[d]thiazol-5-amine</strong> (0.58 g, 3.85 mmol), 1,4-dioxane (5 mL), and 2 drops of conc. HCl were combined and heated to 150 °C for 30 min via microwave. It was concentrated onto silica gel and purified by flash chromatography. The title compound was obtained as a yellow solid (560 mg, 40 percent). MS (m/z): 416, 418 (M+H+).
40%
With hydrogenchloride; In 1,4-dioxane; water; at 150℃; for 0.5h;Microwave irradiation;
2-((6-bromo-4-chloroquinoline)- 7-yl)oxy)ethanol (0.97 g, 3.21 mmol),Benzo[d]thiazol-5-amine (0.58 g, 3.85 mmol),1,4-Dioxane (5 mL) and 2 drops of concentrated HCl were mixed and heated via microwaves to 150 °C for 30 min.It was concentrated onto tannin and purified by flash chromatography.The title compound was obtained as a yellow solid (560 mg, 40percent).
In ethanol; at 150℃; for 0.25h;Microwave irradiation;
A mixture of 6-(tert-butylsulfonyl)-4-chloro-7-methoxyquinoline (2 g, 6.37 mmol) and <strong>[1123-93-9]benzo[d]thiazol-5-amine</strong> (0.957 g, 6.37 mmol) in ethanol (10 mL) was irradiated bymicrowave at 1502C for 15 mins. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous layer was extracted with EtOAc twice and the combined EtOAc layers were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified via flash chromatography (100 g prepacked silica cartridge, 0-75percent ethyl acetate/cyclohexane) to yield the title compound (2.11g, 4.94 mmol, 77 percent yield). LCMS RT= 0.58 mi ES-i-ye 428
77%
In ethanol; at 150℃; for 0.25h;Microwave irradiation;
A mixture of 6-(tert-butylsulfonyl)-4-chloro-7-methoxyquinoline (2 g, 6.37 mmol) and <strong>[1123-93-9]benzo[d]thiazol-5-amine</strong> (0.957 g, 6.37 mmol) in ethanol (10 mL) was irradiated by microwave at 150°C for 15 mins. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous layer was extracted with EtOAc twice and the combined EtOAc layers were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified via flash chromatography (100 g prepacked silica cartridge, 0-75percent ethyl acetate/cyclohexane) to yield the title compound (2.11 g, 4.94 mmol, 77 percent yield). LCMS RT= 0.58 min, ES+ve 428
77%
In ethanol; at 150℃; for 0.25h;Microwave irradiation;
(0138) A mixture of 6-(tert-butylsulfonyl)-4-chloro-7-methoxyquinoline (2 g, 6.4 mmol) and <strong>[1123-93-9]benzo[d]thiazol-5-amine</strong> (0.957 g, 6.4 mmol) in ethanol (10 mL) was irradiated by microwave at 150° C. for 15 mins. The cooled reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous layer was extracted with EtOAc twice and the combined EtOAc layers were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified via flash chromatography (100 g pre-packed silica cartridge) using a gradient elution from 0-75percent ethyl acetate/cyclohexane to yield the title compound (2.11 g, 4.9 mmol, 77percent yield). LCMS RT=0.58 min, ES+ve 428
Intermediate 74 B0C2O (0.51 mL, 2.2 mmol) and then DMAP (49 mg, 0.4 mmol) were added to a solution of <strong>[1123-93-9]benzo[d]thiazol-5-amine</strong> (300 mg, 2.0 mmol) in THF (5 mL) and the reaction mixture was stirred at 68 °C for 16 h. The reaction mixture was filtered, concentrated and purified by flash silica chromatography (0 - 30percent EtOAc/hexanes) to yield Intermediate 74 (447 mg) as white solid. LC-MS retention time = 1.08 min; m/z = 251.0 [M+H]+. (Column: Waters Aquity BEH C18, 2.1 x 50 mm, 1.7-muiotaeta particles. Solvent A = 100percent Water : 0.05percent TFA. Solvent B = 100percent Acetonitrile : 0.05percent TFA. Flow Rate = 0.8 mL/min. Start percent B = 2. Final percent B = 98. Gradient Time = 1.5 min. Wavelength = 220). NMR (400 MHZ, CDCh) delta ppm 9.00 (s, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.67 - 7.52 (m, 1H), 6.69 (br. s., 1H), 1.56 (s, 9H).
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