The preparation method of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1h-indole

A technology of benzyloxyphenyl and benzyloxy is applied in the field of preparation of 5-benzyloxy-2--3-methyl-1H-indole, and can solve the problems of complicated operation, low yield and complicated preparation process and other problems, to achieve the effect of high reaction yield, easy operation and high purity

Active Publication Date: 2016-05-04
SHANGHAI INST OF PHARMA IND CO LTD +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] The technical problem solved by the present invention is in order to overcome the complex preparation process of the existing 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole, complicated operation and low yield Low defects, a preparation method of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole is provided

Method used

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  • The preparation method of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1h-indole
  • The preparation method of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1h-indole
  • The preparation method of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1h-indole

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Embodiment 1

[0036] Synthesis of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (I)

[0037] Add 2-bromo-(4-benzyloxyphenyl) acetone (12.7g, 0.04mol), p-benzyloxyaniline hydrochloride (11.1g, 0.047mol) to n-butanol (120ml), add triethyl Amine (12.2ml) was heated to 118°C and refluxed. After 3 hours, the reaction of 2-bromo-(4-benzyloxyphenyl)acetone was complete; concentrated hydrochloric acid (1.0ml) was added, and the temperature was raised to 118°C to continue the reaction for 7 hours. The reaction liquid was cooled, filtered with suction, and dried to obtain 15.2 g of white solid, HPLC purity: 98%, yield 90.5%.

[0038] 1 H-NMR (400MHz, d 6-DMSO)δ(ppm):7.798(brs,1H,-NH-),7.102-7.557(m,14H,Ar-H),7.255(d,1H,J=2.4Hz,Ar-H),7.174( d,1H,J=4.0Hz,Ar-H),6.978(dd,1H,J=4.0Hz,2.4Hz,Ar-H),5.192(s,2H,-OCH 2 -),5.153(s,2H,-OCH 2 -),2.436(s,3H,-CH 3 )MS (m / z): 420 (M+1)

Embodiment 2

[0040] Synthesis of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (I)

[0041] Add 2-bromo-(4-benzyloxyphenyl) acetone (12.7g, 0.04mol), p-benzyloxyaniline hydrochloride (11.1g, 0.047mol) to isobutanol (120ml), add triethyl Amine (12.2ml), heated to 107°C and refluxed, 2-bromo-(4-benzyloxyphenyl)acetone reacted completely after 3 hours; added p-toluenesulfonic acid monohydrate (1.7g), heated to 107°C The reaction was continued for 14 hours. The reaction solution was cooled, filtered with suction, and dried to obtain 14.4 g of a tan solid, with an HPLC purity of 97% and a yield of 86%.

Embodiment 3

[0043] Synthesis of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (I)

[0044] Add 2-bromo-(4-benzyloxyphenyl) acetone (12.7g, 0.04mol), p-benzyloxyaniline hydrochloride (11.1g, 0.047mol) to isopropanol (120ml), add pyridine ( 7.1ml), the temperature was raised to 84°C, and after 4 hours, the reaction of 2-bromo-(4-benzyloxyphenyl)acetone was complete; acetic acid (0.7ml) was added to continue the reaction for 15 hours. The reaction solution was cooled, filtered with suction, and dried to obtain 14.6 g of white solid, HPLC purity: 96%, yield 87%.

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Abstract

The invention discloses a preparation method for 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole as shown in the specification. The preparation method comprises the following steps: (1) subjecting a compound II and a compound III to a condensation reaction in an alcohol solvent under the action of alkali; and (2) mixing a reaction solution obtained in the step (1) with protonic acid and carrying out Bischler-Mohlau indole cyclization. Compared with the prior art, the invention has the following advantages: the condensation reaction in the first step and Bischler-Mohlau indole cyclization at the second step are integrated into a one-pot reaction, so operation is simple and convenient; a reaction product I is directly precipitated from the reaction solvent, so reaction post-treatment is substantially simplified, and high purity and high reaction yield are realized; and the method is applicable to enlarged production.

Description

technical field [0001] The invention relates to a preparation method of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole. Background technique [0002] Bazedoxifene, developed by Wyeth, is a new generation of SERM (selective estrogen receptor modulator), which can competitively inhibit the binding of 17β-estradiol to ERα and ERβ, and is used alone for human breast cancer The cell line has no agonist activity. Preclinical tests show that it is superior to raloxifene (second generation SERM) and lasofoxifene (third generation SERM) in improving uterine properties among similar products, and the vasomotor instability model Tests have shown that it has little side effects on the central nervous system, and it is a relatively effective agonist in activating the hepatic lipase promoter, while raloxifene is ineffective. When combined with raloxifene, it can Inhibiting the stimulating effect of raloxifene on the uterus of rodents, it can be seen that the effects of the two on ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/12
CPCC07D209/12
Inventor 陈姗袁哲东刘相奎孔锐顾红梅王祥建
Owner SHANGHAI INST OF PHARMA IND CO LTD
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