Preparation of 3-methyl-5-benzyloxy -2-(4-benzyloxy phenyl) -1h-indole

2022-05-08 0 By

Bardoxifene acetate is manufactured by Wyeth, Inc
A novel third-generation selective estrogen receptor was developed in 1997
Modulators, SERMs) competitively inhibit 17β -estradiol with estrogen receptors ERα and ERβ
Which activates estrogen receptors in bone tissue and increases bone density in the spine and hips.This drug is mainly used for the prevention and treatment of osteoporosis in postmenopausal women. It almost does not stimulate the breast and uterus, and will not lead to hyperplasia of mammary gland and endometrium. It has definite curative effect, high tolerance, and little toxic and side effects.Therefore, the research and development of the synthetic technology of bardoxifene has important clinical value as well as economic value.There are many ways to synthesize bardoxifene acetate, among which the most common way is to synthesize the parent nucleus first

5-benzoxy -2-(4-benzoxy phenyl) -3-methyl-1H-indus, then ethoxy benzyl short chain was prepared on the mother nucleus and finally reacted with azacyclic heptane to get the final product.3- methyl -5- benzyloxy -2-(4- benzyloxy phenyl)- 1h-indole is a key intermediate in the synthesis of bardoxifene.3-methyl-5-phenylmethoxy-2-(4-phenylmethoxyphenyl)-1H-indole, CAS Number: 198479-63-9, Molecular formula:C29H25NO2, molecular weight: 419.514, density: 1.188g/cm3, boiling point: 620.5ºC
At 760 mmHg.Preparation of 4 ‘-benzoxy-2-bromophenone and 4-benzoxy-aniline hydrochloride as starting materials, under alkaline conditions to form indole ring, preparation of 3-methyl-5-benzoxy-2 -(4-benzoxy-phenyl) -1h-indole [1].Its synthesis equation is shown as follows:Figure 1 synthesis of 3-methyl-5-benzyloxy-2 -(4-benzyloxy-phenyl) -1h-indole reaction formula 5-benzyloxy-2 -(4-benzyloxy-phenyl) -3-methyl-1h-indole synthesis was weighed 120 g(0. 376 mol) 4 ‘-benzoxy-2-bromophenone and 97. 5 g(0mol)
4-methoxy-aniline hydrochloride was placed in a 2 L three-neck flask, 720 mL DMF and 120 mL triethylamine were added, heated to 100 ℃, stirred for 3 h, TLC
All monitoring compound 2 has been converted to intermediate IM.The reaction liquid was cooled to 60 ℃, adding 97.5 g(0. 41 mol) compound 3, and heating to 120 ℃
After stirring for 6 h, the reaction was completely monitored by TLC.The reaction liquid was cooled to room temperature, and 3.5 L ethyl acetate and 1 L hydrochloric acid (1 mol·L-1) were added
), the organic layer was extracted and separated by saturated sodium bicarbonate solution (500 mL ×2) and saturated salt water (500 mL)
×2) Washing, anhydrous sodium sulfate drying, filtering concentrated brown solid, adding ethyl acetate and ethanol recrystallization, filtering, filter cake washed with anhydrous ethanol (300 mL ×2), drying 128.53
Class G white solid (4), the yield of 81.50%, HPLC determination of purity 99.62%, MP 152 ~ 154 ℃.[1] CHRISTOPHER D, SILVIO I, KADUM A.Crys- Talline polymorph of Bazedoxifene acetate: US, 7683051 [P].2010-03-23