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Stage #1: amino-5-bromo-2-toluene; ammonium thiocyanate With bromine In acetic acid at 10 - 20℃; for 1.5h;
Stage #2: 3,5-dimethylisoxazole-4-boronic acid With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In water; toluene at 100℃; for 3h; Inert atmosphere; Sealed tube;
Stage #3: bromocyane; (S)-1-N-boc-β-proline Further stages; |
138.a-138.d
Step a. To a solution of 4-bromo-3-methyl-aniline (26.88 mmol) in glacial acetic acid (77 ml) was added ammonium thiocyanate (53.68 mmol) at rt. The reaction mixture was allowed to stir until it was almost clear. The reaction mixture was cooled to 10°C and a solution of bromine (26.88 mmol) in glacial acetic acid (2.5 ml) was added dropwise to the reaction mixture at 10°C. The resulting reaction mixture was stirred at rt for 1.5 h. The resulting precipitates were collected by filtration and washed with cold acetic acid. The obtained off- white cake was taken up in water and adjusted to pH 9 with 1M NaOH solution. The resulting solids were collected by filtration, washed with water (100 ml) and dried under reduced pressure yielding 14.46 mmol of a mixture of 70% 6-bromo-7-methyl-benzothiazol-2- ylamine. MS: ES+ 243.1 (M) 245.1 (M+2); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.61 (br s, 2H), 7.40, (d, J=8.8 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 2.41 (s, 3H) and 30% 6-bromo-5- methyl-benzothiazol-2-ylamine. MS: ES+ 243.10; JH NMR (400 MHz, DMSO-d6) δ ppm 7.88 (s, 1H), 7.57, (br s, 2H), 7.31 (s, 1H), 2.34 (s, 3H). Step a. A solution of Intermediate 15 (1.23 mmol) and 3,5-dimethylisoxazole-4-boronic acid (2.46 mmol) in ethanol : toluene : water (1 :2: 1, 10 ml) was stirred at rt in a glass tube for 5 min. Na2CC>3 (2.46 mmol) was added to the reaction mixture and purged using nitrogen for 20 min. Pd(PPl)4 (0.12 mmol) was added to the reaction mixture and the glass tube was sealed. The resulting reaction mixture was heated at 100°C (external temperature) for 3 h. The resulting reaction mixture was poured into water (100 ml) and extracted with EtOAc (2 x 80 ml). The combined organic phase was dried over Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (40% EtOAc in hexane) yielding a 75 :25 mixture of 6-(3,5-dimethyl-l,2-oxazol-4-yl)-7-methyl-l,3- benzothiazol-2-amine & 6-(3,5-dimethyl-l,2-oxazol-4-yl)-5-methyl-l,3-benzothiazol-2- amine (0.54 mmol). MS: ES+ 260.33. Step b. To a solution of (3 S)-BOC-l-pyrrolidine-3-carboxylic acid (0.97 mmol) and DIPEA (1.62 mmol) in DCM (5 ml) was added HBTU (1.2 mmol) at rt and the reaction mixture was stirred for 30 mins. A solution of 75:25 mixture of 6-(3,5-dimethyl-l,2-oxazol-4-yl)-7- methyl- 1 , 3 -benzothiazol-2-amine & 6-(3 , 5 -dimethyl- 1 ,2-oxazol-4-yl)-5 -methyl- 1,3- benzothiazol-2-amine (0.81 mmol) in DCM (5 ml) was added dropwise to the reaction mixture and stirred at rt for 2 h. The resulting reaction mixture was poured into water (100 ml) and basified using solid NaHCC>3. The resulting mixture was extracted with EtOAc (2 x 80 ml). The combined organic phase was collected, dried over Na2SC>4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (38% EtOAc in hexane) yielding a 80:20 mixture of tert-butyl (S)-3-((6- (3,5-dimethylisoxazol-4-yl)-7-methylbenzo[d]thiazol-2-yl)carbamoyl)pyrrolidine-l- carboxylate & tert-butyl (S)-3-((6-(3,5-dimethylisoxazol-4-yl)-5-methylbenzo[d]thiazol-2- yl)carbamoyl)pyrrolidine-l-carboxylate (1.24 mmol). MS: ES+ 456.91. Step c. To a solution of a 80:20 mixture of tert-butyl (S)-3-((6-(3,5-dimethylisoxazol-4-yl)-7- methylbenzo[d]thiazol-2-yl)carbamoyl)pyrrolidine-l-carboxylate & tert-butyl (S)-3-((6-(3,5- dimethylisoxazol-4-yl)-5-methylbenzo[d]thiazol-2-yl)carbamoyl)pyrrolidine- 1 -carboxylate (0.43 mmol) in DCM (5 ml) was added TFA (1 ml) at 0°C. The reaction mixture was stirred at rt for 1 h. The resulting reaction mixture was concentrated under reduced pressure. The obtained residue was azetropically distilled using DCM to yielding a 80:20 mixture of (S)-N- (6-(3,5-dimethylisoxazol-4-yl)-7-methylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide & (S)-N-(6-(3,5-dimethylisoxazol-4-yl)-5-methylbenzo[d]thiazol-2-yl)pyrrolidine-3- carboxamide TFA salt (quantitative). This material was used directly for the next step without further purification. MS: ES+ 357.48. Step d. To a solution of a 80:20 mixture of (S)-N-(6-(3,5-dimethylisoxazol-4-yl)-7- methylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide & (S)-N-(6-(3,5-dimethylisoxazol-4- yl)-5-methylbenzo[d]thiazol-2-yl)pyrrolidine-3-carboxamide TFA salt (0.71 mmol) in TFIF (5 ml) was added K2CO3 (7.1 mmol) at rt. Cyanogen bromide (0.56 mmol) was added to the reaction mixture at 0°C and stirred for 10 min. The resulting reaction mixture was poured into water (150 ml) and extracted with EtOAc (2 x 80 ml). The combined organic phase was collected, dried over Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (72% EtOAc in hexane) yielding 70:30 mixture of (3 S)- 1 -cyano-N-[6-(3,5-dimethyl- 1 ,2-oxazol-4-yl)-7-methyl- 1 ,3 -benzothiazol-2- yl] pyrrolidine-3-carboxamide & (3 S)-l-cyano-N-[6-(3,5-dimethyl-l,2-oxazol-4-yl)-5- methyl-l,3-benzothiazol-2-yl]pyrrolidine-3-carboxamide (0.17mmol). The regio-isomers were separated by preparative chiral FIPLC; mobile phase: (A) 75-70% lOmM aq NH4OAc (B) 25-30% MeCN, column: Sunfire C18, 250x19mm, 5μιη, flow rate: 19 ml/min, yielding the title compound (0.057 mmol). MS: ES+ 382.43; XH NMR (400 MHz, DMSO-d6) δ ppm 12.64 (br s, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 3.57 - 3.66 (m, 2H), 3.42 - 3.47 (m, 2H), 3.32 - 3.36 (m, 1H), 2.28 (s, 3H), 2.23 (s, 3H), 2.18 - 2.22 (m, 1H), 2.10 - 2.13 (m, 1H), 2.05 (s, 3H). |
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