Background and overview of application examples of N-CBZ-2,4-dichloro-5,6,7,8-tetrahydropyridine[3,4-D]pyrimidine
N-CBZ-2,4-dichloro-5,6,7,8-tetrahydropyridine[3,4-D]pyrimidine is a pharmaceutical intermediate that can be used to prepare compound 1-(2-( Methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6,7, 8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one, this compound is a KRAS G12C inhibitor. KRas acts as a molecular switch that cycles between inactive (GDP-bound) and active (GTP-bound) states to transduce upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a variety of processes , including cell proliferation.
Application examples of N-CBZ-2,4-dichloro-5,6,7,8-tetrahydropyridine[3,4-D]pyrimidine
N-CBZ-2,4-dichloro-5,6,7,8-tetrahydropyridine[3,4-D]pyrimidine for the preparation of 1-(2-(methoxymethyl)-4 -(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphth-1-yl)-5,6,7,8-tetrahydropyrido[3 The method of ,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one is as follows:
Step A: 4-(4-(tert-butoxycarbonyl)-3-(methoxymethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3, 4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester: 2-(methoxymethyl)piperazine-1-carboxylic acid tert-butyl ester (0.715g, 3.10mmol) was dissolved in N,N-dimethyl The solution in acetamide (3 ml) was cooled on an ice bath with stirring and N-CBZ-2,4-dichloro-5,6,7,8-tetrahydropyridine [3,4-D ]pyrimidine (1.00 g, 2.96 mmol) was added, followed by DIPEA (0.57 mL, 3.25 mmol, 1.1 eq.). The resulting solution was allowed to warm to room temperature over 1 hour and then partitioned between water (15 mL) and MTBE (50 mL). The organic layer was washed with water (2×10 mL), brine (10 mL), dried over Na2SO4 and evaporated in vacuo to yield a yellow solid (1.54 g, 98%). ES+APCI MS m/z 532.3, [M+H]+.
Step B: 4-(4-(tert-butoxycarbonyl)-3-(methoxymethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidine- 2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester: Crude 4-(4-(tert-butoxycarbonyl)- 3-(Methoxymethyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid benzyl ester (500 mg, 0.940mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (216mg, 1.88mmol), Cs2CO3 (612mg, 1.88 mmol) and dioxane (0.5 mL) was flushed with nitrogen. The vial was capped and stirred at 120°C overnight. The reaction mixture was cooled, partitioned between EtOAc (20 mL) and water (10 mL), the organic layer was washed with water and brine (5 mL each), dried over Na2SO4 and evaporated in vacuo. The compound was purified by silica gel chromatography, Redisep 40g, eluting with 4 to 10% MeOH/DCM + 0.2% NH4OH, to yield a yellow solid (197 mg, 34%). ES+APCI MS m/z 611.4[M+H]+.
Step C: 2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8 – Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester: 4-(4-(tert-butoxycarbonyl)-3-(methoxymethyl) )piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidine- A mixture of 7(6H)-carboxylic acid benzyl ester (197 mg, 0.323 mmol), methanol (10 mL) and palladium on carbon (10 mg, 5%, Degussa type E101 NO/W) was degassed and stirred under a hydrogen atmosphere (balloon) 1 Hour. The reaction mixture was filtered through celite (2 mL), washed with MeOH (3×3 mL), evaporated in vacuo, and dried by evaporation with toluene under vacuum and high vacuum to yield a colorless solid (150 mg, 98%). ES+APCI MS m/z 477.2[M+H]+.
Step D: 2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalene-1- base)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-basic magnesium carbonate 1-carboxylic acid tert-butyl ester: 2-(methoxy Methyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido-[3,4-d ]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (150mg, 0.315mmol), Cs2CO3 (308mg, 0.944mmol), di Oxane (1mL), 1-iodonaphthalene (0.0689ml, 0.472mmol) and aluminum magnesium carbonate methanesulfonic acid (2-dicyclohexylphosphine-2′,6′-diisopropoxy-1,1′- A mixture of phenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II) (26.3 mg, 0.0315 mmol) (RuPhos-Pd-G3) was purged with nitrogen, the flask was capped and Stir at 70°C overnight. The reaction mixture was cooled, partitioned between EtOAc (15 mL) and water (5 mL), the organic layer was washed with water and brine (5 mL each), dried over Na2SO4 and Evaporate under vacuum. The compound was purified by silica gel chromatography, Redisep 40g, using 4 to 10% MeOH + 0.5% NH4OH as eluent, yielding a colorless solid, 131 mg. ES+APCI MS m/z 603.3[M+H]+.
Step E: 1-(2-(methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalene) -1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one: convert 2 -(Methoxymethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(naphthalen-1-yl)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (130 mg, 0.2157 mmol) was dissolved in 1 M trifluoroacetic acid in DCM and allowed to The resulting solution was kept at room temperature for one hour. The reaction mixture was partitioned between 2M Na2CO3 (5 mL) and DCM (15 mL), and the organic layer was evaporated in vacuo. The solid residue was dissolved in DCM (5 mL), cooled to -30°C with stirring on an ice-EtOH-CO2 bath, triethylamine (0.09 ml, 0.64 mmol) was added, then Acryloyl chloride (0.035ml, 0.43mmol). After 1 min at -30°C, use NH4OH (0.05mL)The reaction mixture was quenched, evaporated in vacuo and dried under high vacuum. The residue was dissolved in DCM (5 mL), filtered through a cotton plug, and purified by silica gel chromatography, Redisep 40 g, eluting with 5 to 10% MeOH/DCM + 0.25% NH4OH, A colorless solid (19.6 mg, 16%) was produced. ES+APCI MS m/z557.3，[M+H]+.
References
[1] [Invented in China] CN201780044670.5 KRAS G12C inhibitor
