3,5-Dimethyl-piperazine-1-carboxylic acid tert-butyl ester

2, 6-Dimethylpiperazine (200.0 mg, 1.75 mmol) and TEA (0.6 mL, 4.37 mmol) were dissolved in DCM (6.0 mL), and (Boc)[Referential Example 87] ;3, 5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester ; cis-2, 6-Dimethylpiperazine (5.08 g) was added to 2-(tert-butoxycarbonylimino)-2-phenylacetonitrile (11.35 g) in tetrahydrofuran (150 mL) at 0°C, followed by stirring for 2 hours. The reaction solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform - 7N ammonia/methanol mixture), to thereby give the title compound (15.36 g, 72percent) .1H-NMR(400MHz, CDCl3)δ: 1.16(6H, d, J=6.5Hz), 1.47(9H, s), 2.50(2H, br), 2.90(2H, br), 4.02(2H, br). MS(ESI)m/z: 214(M+H)+.General procedure: To a stirred solution of compound 13a-b, 17a-b (1.0 mmol) inCH3CN (20 mL) were added N-Boc-piperazine (180.9 mg, 0.9 mmol), K2CO3 (205.9 mg, 1.5 mmol), KI (166.0 mg, 1.0 mmol)and 18-crown-6 (26.4 mg, 0.1 mmol) at room temperature. Themixture was stirred overnight at 80 C and filtered. The filtrate wasdiluted by DCM and washed by brine. The organic layer was concentrated for next step. To a stirred solution of the abovecompounds in DCM (20 mL) was added TFA (3 mL) at room temperature.The mixture was stirred for 3e4 h and concentrated toafford the crude products 15a-o and 19a-f in a yield of 35%e42%. Toa stirred solution of above crudes in anhydrous MeOH (10 mL) wasadded BTZ core compound 11 (403.2 mg, 1.0 mmol) and Et3N(0.2 mL, 1.5 mmolj) at room temperature. The mixture was stirredfor 1e3 h at 40 C and concentrated. The residue was purified bysilica gel column (DCM: MeOH 20: 1) to give 1a-f and 2a-e (25%e41% for two steps).General procedure: To a stirred solution of compound 13a-b, 17a-b (1.0 mmol) inCH3CN (20 mL) were added N-Boc-piperazine (180.9 mg, 0.9 mmol), K2CO3 (205.9 mg, 1.5 mmol), KI (166.0 mg, 1.0 mmol)and 18-crown-6 (26.4 mg, 0.1 mmol) at room temperature. Themixture was stirred overnight at 80 C and filtered. The filtrate wasdiluted by DCM and washed by brine. The organic layer was concentrated for next step. To a stirred solution of the abovecompounds in DCM (20 mL) was added TFA (3 mL) at room temperature.The mixture was stirred for 3e4 h and concentrated toafford the crude products 15a-o and 19a-f in a yield of 35%e42%. Toa stirred solution of above crudes in anhydrous MeOH (10 mL) wasadded BTZ core compound 11 (403.2 mg, 1.0 mmol) and Et3N(0.2 mL, 1.5 mmolj) at room temperature. The mixture was stirredfor 1e3 h at 40 C and concentrated. The residue was purified bysilica gel column (DCM: MeOH 20: 1) to give 1a-f and 2a-e (25%e41% for two steps).General procedure: To a stirred solution of compound 13a-b, 17a-b (1.0 mmol) inCH3CN (20 mL) were added N-Boc-piperazine (180.9 mg, 0.9 mmol), K2CO3 (205.9 mg, 1.5 mmol), KI (166.0 mg, 1.0 mmol)and 18-crown-6 (26.4 mg, 0.1 mmol) at room temperature. Themixture was stirred overnight at 80 C and filtered. The filtrate wasdiluted by DCM and washed by brine. The organic layer was concentrated for next step. To a stirred solution of the abovecompounds in DCM (20 mL) was added TFA (3 mL) at room temperature.The mixture was stirred for 3e4 h and concentrated toafford the crude products 15a-o and 19a-f in a yield of 35%e42%. Toa stirred solution of above crudes in anhydrous MeOH (10 mL) wasadded BTZ core compound 11 (403.2 mg, 1.0 mmol) and Et3N(0.2 mL, 1.5 mmolj) at room temperature. The mixture was stirredfor 1e3 h at 40 C and concentrated. The residue was purified bysilica gel column (DCM: MeOH 20: 1) to give 1a-f and 2a-e (25%e41% for two steps).General procedure: To a stirred solution of compound 13a-b, 17a-b (1.0 mmol) inCH3CN (20 mL) were added N-Boc-piperazine (180.9 mg, 0.9 mmol), K2CO3 (205.9 mg, 1.5 mmol), KI (166.0 mg, 1.0 mmol)and 18-crown-6 (26.4 mg, 0.1 mmol) at room temperature. Themixture was stirred overnight at 80 C and filtered. The filtrate wasdiluted by DCM and washed by brine. The organic layer was concentrated for next step. To a stirred solution of the abovecompounds in DCM (20 mL) was added TFA (3 mL) at room temperature.The mixture was stirred for 3e4 h and concentrated toafford the crude products 15a-o and 19a-f in a yield of 35%e42%. Toa stirred solution of above crudes in anhydrous MeOH (10 mL) wasadded BTZ core compound 11 (403.2 mg, 1.0 mmol) and Et3N(0.2 mL, 1.5 mmolj) at room temperature. The mixture was stirredfor 1e3 h at 40 C and concentrated. The residue was purified bysilica gel column (DCM: MeOH 20: 1) to give 1a-f and 2a-e (25%e41% for two steps).A solution of compounds of general structure 1 (1 equiv), Boc protected amine (1-3 equiv) and DIPEA (3 equiv) in DMSO were reacted at 100-110 °C. The reaction mixture was cooled to room temperature and quenched by addition of water and crude residue extracted with EtOAc. Combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure to provide crude compound of general strucutre 2, which was used in the following step without further purification. To a solution of compounds of general structure 2 in CH2C12 was added HCl/dioxane (4 N) or TFA. The reaction was stirred at room temperature for 2 hrs and mixture was concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to afford final compounds of general structure 3.A solution of compounds of general structure 1 (1 equiv), Boc protected amine (1-3 equiv) and DIPEA (3 equiv) in DMSO were reacted at 100-110 °C. The reaction mixture was cooled to room temperature and quenched by addition of water and crude residue extracted with EtOAc. Combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure to provide crude compound of general strucutre 2, which was used in the following step without further purification. To a solution of compounds of general structure 2 in CH2C12 was added HCl/dioxane (4 N) or TFA. The reaction was stirred at room temperature for 2 hrs and mixture was concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to afford final compounds of general structure 3.Add to 100mL three-necked bottle under argon protectiontert-Butyl 3, 5-dimethylpiperazine-1-carboxylate (520 mg, 2.43 mmol) and THF (10 mL), cooled to about 0 ° C, Add NaH (70 mg, 2.91 mmol), After stirring for half an hour, a solution of CH3I (690 mg, 4.86 mmol) in THF (1 mL) was added dropwise.After the dropwise addition, the mixture was stirred for 1 hour, and the reaction was further stirred up to room temperature. The reaction was monitored by TLC. After the reaction was completed, 50 mL of purified water and 30 mL of ethyl acetate were added, and the mixture was stirred. The aqueous phase was extracted twice with ethyl acetate (30 mL×2), and the organic phase was combined and washed with saturated brine (50 mL×2) After 2 times, anhydrous sodium sulfate was dried, filtered, and the mother liquid was concentrated under reduced pressure to give 510 mg of product.General procedure: Add to 100mL three-necked bottle under argon protectiontert-Butyl 3, 5-dimethylpiperazine-1-carboxylate (520 mg, 2.43 mmol) and THF (10 mL), cooled to about 0 ° C, Add NaH (70 mg, 2.91 mmol), After stirring for half an hour, a solution of CH3I (690 mg, 4.86 mmol) in THF (1 mL) was added dropwise.After the dropwise addition, the mixture was stirred for 1 hour, and the reaction was further stirred up to room temperature. The reaction was monitored by TLC. After the reaction was completed, 50 mL of purified water and 30 mL of ethyl acetate were added, and the mixture was stirred. The aqueous phase was extracted twice with ethyl acetate (30 mL×2), and the organic phase was combined and washed with saturated brine (50 mL×2) After 2 times, anhydrous sodium sulfate was dried, filtered, and the mother liquid was concentrated under reduced pressure to give 510 mg of product.Example 3 7-(2, 6-dimethylpiperazin-1-yl)-2-ethyl-5H-[1, 3, 4]thiadiazolo[3, 2-a]pyrimidin-5-one This example is prepared by following the same procedures as described in above except substituting

Molecular Weight:214.30
XLogP3:1.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:214.168127949
Monoisotopic Mass:214.168127949
Topological Polar Surface Area:41.6
Heavy Atom Count:15
Complexity:225
Undefined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes