Methyl N-Boc-piperidine-3-carboxylate

White solid

To a room temperature solution of piperidine-1, 3-dicarboxylic acid-1-tert-butyl ester (5.00 g, 21.81 mmol) in 20percent MeOH/toluene (100 ml) was added 14.18 ml of (trimethylsilyl)diazomethane (2.0 M, 28.35 mmol) dropwise and the reaction was monitored by TLC until completion and then concentrated under reduced pressure to yield 4.44 g (83.7percent) of piperidine-1, 3-dicarboxylic acid 1-tert-butyl ester-3-methyl ester (Intermediate 53). K2CO3 (33.15 g, 0.24 mol) was added to a stirred solution of l-(tert- butoxycarbonyl)piperidine-3-carboxylic acid [84358-12-3] (50.0 g, 0.22 mol) in DMF (600 mL) at RT. Methyl iodide (34.05 g, 0.24 mol) was added after 30 minutes and the reaction mixture was stirred for another 2.5 h at rt. The volatiles were evaporated in vacuo and the resulting residue placed in water and extracted with DIPE. The combined OL was dried over MgS030 g of N-Boc-3-piperidinecarboxylic acid was added to 220 ml of methanol, 25 g of trimethyl orthoformate was added, Stirred at room temperature for 24 hours, concentrate, The residue was chromatographed on silica gel to give 32 g of ethyl N-tert-butoxycarbonylpiperidine-3-carboxylate.145 2-(lH-Indazol-4-v?-6-(3-methoxymethyl-piperidin-l-ylmethyl)-4-mophiholin- 4- yl-thieno [3 , 2-dip yrimidine.Via 2-Chloro-6-(3-methoxymethyl-piperidin-l-ylmethyl)-4-mophiholin-4-yl- thieno[3, 2-d]pyrimidine, prepared from 3-methoxymethyl-piperidine.Amine preparation: To a solution of l-BOC-3-piperidine carboxylic acid (3.0 g) in DMF (25mL) was added potassium carbonate (3.62 g) followed by iodomethane (4.07mL). After 2.5 h the reaction was diluted with water and extracted into diethyl ether. The organic layer was washed with brine, separated and dried (MgSO4). The solvent was evaporated to give piperidine-l, 3-dicarboxylic acid l-tert- butyl ester 3-methyl ester (2.98 g).To a suspension of lithium aluminium hydride (1.41 g) in THF (15mL) at 0C was added piperidine-l, 3-dicarboxylic acid l-tert-butyl ester 3-methyl ester as a solution in THF (1OmL) and the mixture stirred at room temperature for 3 h. The reaction was cooled to 0 0C and quenched by addition of aqueous ammonium chloride and the mixture filtered through celite. The filtrate was diluted with ethyl acetate, washed with water, separated and dried (MgSO4). The solvent was evaporated to give 3-hydroxymethyl-piperidine-l -carboxylic acid tert-butyl ester (1.25 g). To a solution of this alcohol (422 mg) in THF (8mL) was added sodium hydride (94 mg; 60% dispersion in mineral oil). After 15 min iodomethane (0.49mL) was added and the reaction stirred for 18 h. The mixture was then diluted with ethyl acetate and washed sequentially with water, brine, separated and dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography to give 3- EPO K2CO3 (33.15 g, 0.24 mol) was added to a stirred solution of l-(tert- butoxycarbonyl)piperidine-3-carboxylic acid [84358-12-3] (50.0 g, 0.22 mol) in DMF (600 mL) at RT. Methyl iodide (34.05 g, 0.24 mol) was added after 30 minutes and the reaction mixture was stirred for another 2.5 h at rt. The volatiles were evaporated in vacuo and the resulting residue placed in water and extracted with DIPE. The combined OL was dried over MgS04, filtered and evaporated to provide 54.75 g of intermediate 31, which was used as such in the next stepA solution of 1 -(1 , 1 -dimethylethyl) 3-methyl 1 , 3-piperidinedicarboxylate (D4; 10.61 g, 43.6 mmol) in tetrahydrofuran (100 mL) was cooled to -78 C under an argon atmosphere. To the reaction was added LiHMDS (56.7 mL, 56.7 mmol, 1 M in hexane) over a period of 15 minutes. The reaction was stirred at -78 C for one hour before the addition of allyl bromide (4.53 mL, 52.3 mmol). The cooling bath was removed and the reaction stirred for a further 5 hours. To the reaction was added saturated aqueous ammonium chloride (200 mL) and water (100 mL). The mixture was then extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were washed with 10% aqueous citric acid (2 x 200 mL), saturated aqueousNaHCC>3 (200 mL), brine (200 mL), passed through a hydrophobic frit and reduced in vacuo to yield 1 -(1 , 1 -dimethylethyl) 3-methyl 3-(2-propen-1 -yl)-1 , 3-piperidine- dicarboxylate (1 1.6 g, 40.9 mmol, 94% yield) as an orange oil. 1 H NMR (400 MHz, CHLOROFORM-d) delta ppm 1 .5 (m, 9 H) 1 .6 (m, 3 H) 2.0 (m, 1 H) 2.2 (dd, J=13.8, 7.9 Hz, 1 H) 2.4 (dd, J=13.8, 7.0 Hz, 1 H) 3.2 (m, 2 H) 3.5 (m, 1 H) 3.7 (m, 3 H) 3.9 (m, 1 H) 5.0 (d, J=6.1 Hz, 1 H) 5.1 (m, 1 H) 5.7 (m, 1 H).To a high pressure rated reaction vessel was added 670 mg Na metal (30 mmol, 5 equiv.) and 25 mL EtOH (0.25 M). Upon complete consumption of the Na metal (no further gas evolution), 1.2 g enamine 2 (6 mmol, 1.0 equiv.) and 1.45 g of methyl N-Boc-piperidine-3- carboxylate (6 mmol, 1.0 equiv.) were added to the solution which was then heated to 100 C for 5 hours. The tube was sealed and heated at 100 C for 5 hr. The reaction was then concentrated and redissolved in water. The aqueous layer was acidified to pH ~4 and extracted with a mixture of EtOAc-THF (1:1) The combined organic layer was dried over Na2S04, filtered and (0777) concentrated. The crude material was then purified using silica gel column chromatography (1:2 Ethyl Acetate: Hexanes to 4:1 Ethyl Acetate: Hexanes) to give 650 mg of the desired product as a white solid in 62% yield.

Molecular Weight:243.30
XLogP3:1.5
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:4
Exact Mass:243.14705815
Monoisotopic Mass:243.14705815
Topological Polar Surface Area:55.8
Heavy Atom Count:17
Complexity:295
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes