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Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.5 h; Stage #2: at 20℃; for 2 h;
To a stirring solution of 2,2,6,6-tetramethylpiperidine (1.484 mL, 8.79 mmol) inanhydrous THF (15 mL) at 0 °C under nitrogen was added 2.5 M BuLi in hexanes (3.52mL, 8.79 mmol) dropwise. The reaction mixture was stirred at 0 °C for 30 minutes, thenthe mixture was added to a solution of 4-chlorothieno[3,2-d]pyrimidine (Compound 12;1.00 g, 5.86 mmol) in anhydrous THF (15 mL) at -78°C dropwise over a period of 30minutes. The reaction was stirred at -78 °C for 1 hour, and then dry ice (2.58 g, 58.6mmol) was added to the reaction. The reaction was allowed to warm up to roomtemperature over a period of 2 hours. The reaction was diluted with EtOAc (100 mL) and washed with 0.1 M HC1. The organic layer was dried over MgSO4 and evaporated to dryness to obtain 4-chlorothieno[3,2-d]pyrimidine-6-carboxylic acid (Compound 13; 1.1 g, 83percent). MS (ESI) calcd for C7H3C1N2025: 213.96; found: 215.0 [M+H].
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 9, p. 3666 - 3679
[2] Patent: WO2014/138562, 2014, A1, . Location in patent: Page/Page column 63
To a stirring solution of 2,2,6,6-tetramethylpiperidine (1.484 mL, 8.79 mmol) inanhydrous THF (15 mL) at 0 C under nitrogen was added 2.5 M BuLi in hexanes (3.52mL, 8.79 mmol) dropwise. The reaction mixture was stirred at 0 C for 30 minutes, thenthe mixture was added to a solution of <strong>[16269-66-2]4-chlorothieno[3,2-d]pyrimidine</strong> (Compound 12;1.00 g, 5.86 mmol) in anhydrous THF (15 mL) at -78C dropwise over a period of 30minutes. The reaction was stirred at -78 C for 1 hour, and then dry ice (2.58 g, 58.6mmol) was added to the reaction. The reaction was allowed to warm up to roomtemperature over a period of 2 hours. The reaction was diluted with EtOAc (100 mL) and washed with 0.1 M HC1. The organic layer was dried over MgSO4 and evaporated to dryness to obtain <strong>[16269-66-2]4-chlorothieno[3,2-d]pyrimidine</strong>-6-carboxylic acid (Compound 13; 1.1 g, 83%). MS (ESI) calcd for C7H3C1N2025: 213.96; found: 215.0 [M+H].
Stage #1: 4-chlorothieno[3,2-d]pyrimidine-6-carboxylic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 60℃; for 3.66667h;
Stage #2: With ammonia In 1,4-dioxane at 0℃; for 0.666667h;
7.2 Step 2. Synthesis of 4-chiorothieno [3,2-dj pyrimidine-6-carboxamide (Compound 14):
To a solution of oxalyl chloride (4.17 mL, 47 mmol) in anhydrous dichloromethane (50 mL) at 0 °C under nitrogen was added DMF (0.8 mL). The solution was stirred at 0 °C for30 minutes, and then a suspension of 4-chlorothieno[3,2-d]pyrimidine-6-carboxylic acid (13; 5.04 g, 23.5 mmol) in dichloromethane (50 mL) was added dropwise over 10 minutes at 0 °C. The reaction mixture was heated to 60 °C for 3.5 hours and concentrated to dryness. The crude acid chloride was dissolved in dioxane (80 mL) and 182 mL (91 mmol) of a solution of 0.5 M ammonia in dioxane was added dropwise over 10 mm at 0°C. The reaction mixture was stirred at 0 °C for 30 mi warmed to room temperature, diluted with water (150 mL) and extracted with CH2C12 (3x). The combined organic layers were washed with water (2x), dilute aq. NaHCO3, brine and concentrated to dryness. The product was recrystallized from CH3CN to obtain 4-chlorothieno[3,2-d]pyrimidine-6- carboxamide (Compound 14; 0.842 g). The mother liquor was concentrated to obtain asecond crop (Compound 14; 1.499 g) and a third crop (Compound 14; 0.259 g) of 4- chlorothieno[3,2-d]pyrimidine-6-carboxamidefor a total of 2.6 g (52%) of Compound 14. MS (ESI) calcd for C7H4C1N3OS: 212.98; found: 214.0 [M+H].
Multi-step reaction with 2 steps
1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 3.5 h / 0 °C / Inert atmosphere; Reflux
2: ammonia / 1,4-dioxane / 0.67 h / 0 °C
With N-ethyl-N,N-diisopropylamine In <i>tert</i>-butyl alcohol at 100℃; for 16h; Sealed tube;
31.1 Step 1.
To a mixture of 4-chlorothieno[3,2-ri]pyrimidine-6-carboxylic acid (200 mg, 0.93 mmol) in /-BuOH (4 mL) was added 3-|( 1 R)- 1 -ami noethyl |-5-(tririuoromethyl (aniline (228 mg, 1.12 mmol) and DIPEA (1.62 mL, 9.32 mmol). The mixture was heated to 100 °C and stirred for 16 h in a crimped vial. The solvent was concentrated under reduced pressure and the residue was purified by prep-HPLC to give 4-[[(li?)-l-[3-amino-5- (trifluoromethyl (phenyl |ethyl |amino |thieno|3.2-6/|pyrimidine-6-carboylic acid (40 mg, 11% yield). LCMS (ESI): m/z: [M+H] calculated for C16H14F3N4O2S: 383.1; found 383.1.
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