Preparation method of tert-butyl hydrogen phthalate_Kain Industrial Additive

Background and overview^[1]

tert-butyl hydrogen phthalate can be used as a pharmaceutical synthesis intermediate. If tert-butyl hydrogen phthalate is inhaled, move the patient to fresh air; if there is skin contact, take off contaminated clothing, rinse the skin thoroughly with soap and water, and seek medical attention if you feel uncomfortable; if the eyes are clear, In case of contact, separate eyelids, rinse with running water or saline, and seek medical attention immediately; if ingested, rinse mouth immediately, do not induce vomiting, and seek medical attention immediately.

Preparation^[1]

tert-butyl hydrogen phthalate can be used as an intermediate in pharmaceutical synthesis, if the following reaction occurs:

To a stirred solution of 4b-d (1.0eq) in DMF was added HOBt (2.0eq), HBTU (2.0eq) and DIPEA (3.0eq), followed by tert-butyl hydrogen phthalate (1.0 eq) and stirred at room temperature for 12 h. The reaction mixture was then diluted with water. The product was filtered, washed with water and dried in vacuo to obtain in 62-71% yield. The product was then treated with 1 M HCl in EtOAc to remove the Boc group to give the CO2tBu-Bz-Orn-benzimidazole intermediate. The solvent was then evaporated to dryness and the crude material was dried under vacuum. To a stirred solution of the corresponding CO2tBu-Bz-Orn-benzimidazole intermediate in anhydrous MeOH, TEA (4.0 eq) was added, followed by haloethymidine ethyl ester HCl (2.0 eq). The reaction was stirred under nitrogen at room temperature for 3 hours. The solvent was then evaporated under reduced pressure, and the crude product was purified by reverse-phase HPLC using MeCN:H2O (0.5% TFA) as eluent to afford compounds 9a-f in 51–67% yield. The compound serves as a novel inhibitor or inactivator of PAD and can be used to treat immune system diseases and inflammatory diseases and conditions (e.g., rheumatoid arthritis, lupus).

Main reference materials

[1] (WO2018102262) INHIBITORS OF PROTEIN ARGININE DEIMINASES (PADS) AND METHODS OF PREPARATION AND USE THEREOF