Preparation and application of trans-3-((tert-butoxycarbonyl)amino)-4-hydroxypyridine-1-carboxylic acid benzyl ester_Industrial additives

Preparation and application background and overview of trans-3-((tert-butoxycarbonyl)amino)-4-hydroxypyridine-1-carboxylic acid benzyl ester

Trans-3-((tert-butoxycarbonyl)amino)-4-hydroxypyridine-1-carboxylic acid benzyl ester is a pharmaceutical intermediate that can be synthesized from 1,2,3,6-tetrahydropyridine Prepared in three steps.

Preparation and application of trans-3-((tert-butoxycarbonyl)amino)-4-hydroxypyridine-1-carboxylic acid benzyl ester

Preparation and application of trans-3-((tert-butoxycarbonyl)amino)-4-hydroxypyridine-1-carboxylic acid benzyl ester step 1: 3,6-dihydroxypyridine-1 (2H)-Benzylcarboxylate

Combine 1,2,3,6-tetrahydropyridine (4.90g, 58.9mmol), DCM (40mL), N-(benzyloxycarbonyloxy)succinimide (15.2g, 61.0mmol) and Triethylamine (10.0 mL, 71.7 mmol) was mixed together and stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and water. The organic layer was dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with EtOAc in hexanes (0 to 40%) to afford the subtitle compound as a clear oil. Calculated value of LCMSC13H16NO2(M+H)⁺: m/z=218.1. Actual value: 218.0.

Preparation and application of trans-3-((tert-butoxycarbonyl)amino)-4-hydroxypyridine-1-carboxylic acid benzyl ester Step 2: 7-oxa-3-aza Bicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester

mCPBA (14.6g, 63.3mmol) was slowly added to a stirred solution of 3,6-dihydroxypyridine-1(2H)-carboxylic acid benzyl ester (12.50g, 57.5mmol) in DCM (80mL). Cool it in an ice bath. The reaction mixture was warmed to room temperature and stirred for 16 h. Then the reaction mixture was quenched with Na₂CO₃ aqueous solution and the organic layer was dried over Na₂SO₄, Filtration and concentration under reduced pressure gave the subtitle compound. Calculated value of LCMSC13H16NO3(M+H)⁺: m/z=234.1. Actual value: 234.0.

Preparation and application of trans-3-((tert-butoxycarbonyl)amino)-4-hydroxypyridine-1-carboxylic acid benzyl ester Step 3: trans-3-((tert-butyl) Oxycarbonyl)amino)-4-hydroxypyridine-1-carboxylic acid benzyl ester and (3R,4R)-3-[(tert-butoxycarbonyl)amino]-4-hydroxypiperidine-1-carboxylic acid benzyl ester Ester

Place 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester (13.4g, 57.4mmol) and 14.8M NH₄OH aqueous solution (200 mL, 2.9 mol) and EtOH (200 mL) were mixed together in a sealed flask and heated at 70°C for 5 h. The solvent was removed under reduced pressure. The residue was diluted with DCM (80 mL), then di-tert-butyl dicarbonate (12.5 g, 57.4 mmol) and triethylamine (8.0 mL, 57 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. The solvent was then removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with EtOAc in hexane (0-80%) to give the subtitle compound which was subjected to chiral LC-MS separation (Phenomenex Cellulose-1 Column, 21.2x250mm, 5 micron particles, flow rate 18mL/min, isocratic elution with 45% EtOH in hexanes) to afford both enantiomers. 3,4-trans-3-[(tert-Butoxycarbonyl)amino]-4-hydroxypiperidine-1-carboxylic acid benzyl ester Enantiomer 1. The retention time of the first peak is 7.163min, and the calculated value of LCMS C18H26N2O5Na(M+Na)⁺ is: m/z=373.2. Actual measured value: 373.1. (Temporarily called the 3S, 4S enantiomer, trans-3-((tert-butoxycarbonyl)amino)-4-hydroxypyridine-1-carboxylic acid benzyl ester). 3,4-trans-3-[(tert-Butoxycarbonyl)amino]-4-hydroxypiperidine-1-carboxylic acid benzyl ester Enantiomer 2. The retention time of the second di-tert-butyl dicarbonate peak is 9.247 min, and the calculated value of LCMS C18H26N2O5Na(M+Na)+: m/z=373.2. Actual measured value: 373.1. (tentatively called 3R, 4R enantiomers).

Preparation and applications of trans-3-((tert-butoxycarbonyl)amino)-4-hydroxypyridine-1-carboxylic acid benzyl ester

Sodium carbonate

CN201480012783.3 reported that trans-3-((tert-butoxycarbonyl)amino)-4-hydroxypyridine-1-carboxylic acid benzyl ester can be used to prepare compound 5-amino-N-{4 -[3,4-trans-3-amino-4-hydroxypiperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-2-(2 ,6-Difluorophenyl)-1,3-thiazole-4-carboxamide. The compounds inhibit the activity of Pim kinase and are therefore useful in the treatment of diseases associated with Pim kinase activity, including, for example, cancer and other diseases.