Abstract: The group of 18 new amide derivatives of mycophenolic acid (MPA) and selected heterocyclic amines was synthesised as potential immunosuppressive agents functioning as inosine-5′-monophosphate dehydrogenase (IMPDH) uncompetitive inhibitors. The synthesis of 14 of them employed uronium-type activating system (TBTU/HOBt/DIPEA) while 4 of them concerned phosphonic acid anhydride method (T3P/Py) facilitating amides to be obtained in moderate to excellent yields without the need of phenolic group protection. Most of optimised protocols did not require complicated reaction work-ups, including chromatographic, solvent-consuming methods. The biological activity assay was performed on the T-Jurkat cell line and peripheral mononuclear blood cells (PBMCs) which are both dedicated for antiproliferative activity determination. Each of designed derivatives was characterised by reduced cytotoxicity and benzoxazole analogue (A2) revealed the most promising activity. Subsequently, an observed structure-activity relationship was discussed.
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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 %). 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).
With stannous chloride;
5-Aminobenzothiazole To a solution of SnCl2 (7.0 g, 8.8 mmol) and 14 mL of con.HCl was added 5-nitrobenzothiazole (0.65 g, 3.6 mmol) in a portion and resulting reaction mixture was stirred for 1 h at 25 C. The reaction mixture was basified with aqueous NaOH and extracted with EtOAc. Combined organic layers were dried over Na2 SO4 and concentrated in vacuo, yielding an oil (0.47 g, 3.2 mmol, 89%) which was identified as the amine (>95% pure) and subjected to the following reaction without further purification.
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; methanol;
Step 9.2: 5-Amino-benzothiazole Purified 5-nitro-benzothiazole (7.2 g, 0.04 mol, see WO 98/23612, example 7A), dissolved in 160 mL of methanol and 160 mL of THF, is hydrogenated in the presence of 1.6 g Pd/C (10%; Engelhard 4505). The catalyst is filtered off, the filtrate concentrated and the residual oil purified by flash chromatography on silica gel using dichloromethanol/methanol 97:3 as eluent. The title compound is obtained as a colorless solid: m.p. 76-78 C., HPLC tR=0.76 min; MS-ES+: (M+H)+=151; Rf (dichloromethane/methanol 97:3)=0.76.
With hydrogen;10% palladium on activated carbon; In tetrahydrofuran; methanol;
Purified 5-nitro-benzothiazole (7.2 g, 0.04 mol, see WO 98/23612, example 7A), dissolved in 160 mL of methanol and 160 mL of THF, is hydrogenated in the presence of 1.6 g Pd/C (10 %; Engelhard 4505). The catalyst is filtered off, the filtrate concentrated and the residual oil purified by flash chromatography on silica gel using dichloromethanol/methanol 97:3 as eluent. The title compound is obtained as a colorless solid: m.p. 76-78 0C, HPLC tR = 0.76 min; MS-ES+: (M+H)+ = 151 ; Rf (dichloromethane/methanol 97:3) = 0.76.
5-Nitrobenzo[d]thiazole (150 mg) was dissolved in THF (20 mL) at 0 0C and AcOH (1 mL) was added followed by Zinc dust (1.65 g). Mixture was stirred at RT for 1 h and was filtered on silica pad (rinsed with EtOAc). Solvent was evaporated, residue was diluted with NaHCO3 and extracted with EtOAc. Organic phases was dried, filtered and evaporated to give benzo[d]thiazol-5-amine.
2.1 g
With tin(II) chloride dihdyrate; In ethyl acetate;Reflux;
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): oe 8.92 (s, 1H), 7.69 (d, 1H), 7.41 (d, 1H), 6.86 (dd, 1H), 3.82 (brs, 2H); LCMS: 151 (M+H).
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.
B. 5-Aminobenzothiazole A mixture of 3.46 g of 5-nitrobenzothiazole and 15.7 g of stannous chloride dihydrate in 55 mL of 2-propanol is heated to reflux for 3 hours. The cooled reaction mixture is poured into 150 mL of ice/water and neutralized to pH 7 using solid sodium hydroxide. The mixture is extracted with ethyl acetate (3*50 mL). The combined organic layers are dried over sodium sulfate, filtered through a short pad of silica gel, and rotary evaporated to provide 2.45 g of 5-aminobenzothiazole as a yellow-brown 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).
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