ChemInform Abstract: Practical Synthesis of Ethyl cis‐4‐Amino‐3‐methoxy‐1‐piperidine Carboxylate, a Key Intermediate of Cisapride.

Abstract

Practical Synthesis of Ethyl cis-4-Amino-3-methoxy-1-piperidine Carboxylate, a Key Intermediate of Cisapride. -The title compound (X) is prepared from the tetrahydropyridine (I) via an efficient stereoselective formation of cis-fused oxazolidinopiperidine (VIII) from the trans-bromohydrin (V) and a regioselective oxazolidinone ring opening of (VIII) as key steps. -(KIM, BONG J.; PYUN, DO K.; JUNG, HEE J.; KWAK, HYUN J.; KIM, JAE H.; KIM, EUN J.; JEONG, WON J.; LEE, CHEOL H.; Synth. Commun.

Optimization of Pyrrolamide Topoisomerase II Inhibitors Toward Identification of an Antibacterial Clinical Candidate (AZD5099)

“…Prepared as described for the preceding compound from 94 mg (0.49 mmol) of 3,4-dichloro-5-methyl-1 H -pyrrole-2-carboxylic acid, ethyl (3 R ,4 S )-4-amino-3-methoxypiperidine-1-carboxylate 4a (100 mg, 0.49 mmol), 108 mg (0.49 mmol) of HATU, 67 mg (0.49) of HOAt, and 0.86 mL (4.9 mmol) of DIEA to afford 76 mg (41%) of product. MS (ESI) m / z (M + H) + : 378, 380 for C 15 H 21 Cl 2 N 3 O 4 .…”

“…42,43 Ethyl 4-oxopiperidine-1carboxylate was converted to methoxypiperidine ketal 8 upon reaction with iodosobenzene diacetate and potassium hydroxide according to established procedures 44 followed by methylation with sodium hydride and methyl iodide. 42,43 Ethyl 4-oxopiperidine-1carboxylate was converted to methoxypiperidine ketal 8 upon reaction with iodosobenzene diacetate and potassium hydroxide according to established procedures 44 followed by methylation with sodium hydride and methyl iodide.…”

“…The 3-methoxy group on the piperidine ring imparted the best overall profile for final products (Results and Discussion), and the synthesis of the corresponding 4-amino-3-methoxypiperidine linker 4 is shown in Scheme , considerably shortening previous synthetic routes. , Ethyl 4-oxopiperidine-1-carboxylate was converted to methoxypiperidine ketal 8 upon reaction with iodosobenzene diacetate and potassium hydroxide according to established procedures, followed by methylation with sodium hydride and methyl iodide. The intermediates for the other R3 ethers shown in Table (compounds 28 – 31 ) were prepared analogously as detailed in the Supporting Information.…”

“…MS (ESI) m/z (M + H) + Ethyl (3S,4R)-4-[(3,4-Dichloro-5-methyl-1H-pyrrole-2carbonyl)amino]-3-methoxy-piperidine-1-carboxylate (Scheme 1: 5, R1 = OMe, chiral). NMM (43.7 mL, 354 mmol) was slowly added to a mixture of 3,4-dichloro-5-methyl-1H-pyrrole-2carboxylic acid 42 (19.6 g, 101 mmol), ethyl (3S,4R)-4-amino-3methoxypiperidine-1-carboxylate 4b (1.2 g, 5.9 mmol), and HOBt (13.6 g, 101 mmol) in 400 mL of anhydrous CH 2 Cl 2 . After 1 h stirring, 39.9 g (182 mmol) of EDC was added, and stirring was continued overnight.…”

“…MS (ESI) m/z (M + H) + Ethyl (3R,4S)-4-[(3,4-Dichloro-5-methyl-1H-pyrrole-2carbonyl)amino]-3-methoxy-piperidine-1-carboxylate (Scheme 1: 5, R1 = OMe, chiral). Prepared as described for the preceding compound from 94 mg (0.49 mmol) of 3,4-dichloro-5methyl-1H-pyrrole-2-carboxylic acid, 42 3,4-Dichloro-N-(3S,4R)-[3-Methoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide Hydrochloride Salt (Scheme 1: Chiral 6a, R1 = OMe). N 2 was bubbled through a solution of 94.3 g (249 mmol) of ethyl (3S,4R)-4-[(3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)amino]-3-methoxy-piperidine-1-carboxylate in 1.8 L of CH 3 CN for 10 min.…”