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Indoline compound with optical activity and preparation method thereof

A compound, the technology of cyanoindoline, which is applied in the preparation of the intermediate compound, the intermediate compound field of synthesizing the drug silodosin for the treatment of benign prostatic hyperplasia, can solve the problem that the multi-step reaction yield is low and is not suitable for industrial production , L-Phenylglycinol is expensive and other problems, to achieve the effect of high asymmetric induction rate

Active Publication Date: 2014-01-15
ZHEJIANG HUAHAI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the low multi-step reaction yield in this route, the synthesis yield of the chiral intermediate is only 4%; and there is a column chromatography step, which is not suitable for industrial production, and the price of L-phenylglycinol is relatively expensive

Method used

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  • Indoline compound with optical activity and preparation method thereof
  • Indoline compound with optical activity and preparation method thereof
  • Indoline compound with optical activity and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: the preparation of compound (2)

[0042] Referring to the compound (2) synthetic route diagram provided in the summary of the invention

[0043] A: Preparation of compound (9)

[0044] 264 grams of 4-fluorobenzoic acid was dissolved in 550ml of DMF. Put 375ml of bromochloropropane, 265ml of triethylamine, and 300ml of DMF in a reaction flask, add 4-fluorobenzoic acid dropwise at room temperature, and react at room temperature for 12h. Add water, extract with ethyl acetate, wash the organic layer with saturated aqueous sodium bicarbonate solution and brine, dry the organic layer with anhydrous sodium sulfate, remove the solvent under reduced pressure to obtain oil compound (8)

[0045] The mass spectrometry of the oil showed that the molecular ion peak [M+1] was 217.

[0046] Compound (8) 391 grams, diisopropylethylamine 473ml, indoline 182ml) and DMF1600ml, stirred at 105°C for 16 hours. Added water, extracted with ethyl acetate, washed with saturated a...

Embodiment 2

[0066] Embodiment 2: the preparation of compound (3)

[0067] 100 g (0.243 mol) of compound (2) was dissolved in 450 ml of DMF, and at 0-5°C, 58 ml (0.389 mol) of DBU was added, then 125 ml (0.738 mol) of triethylchlorosilane was added dropwise at low temperature, and the reaction 3 hours, then dropwise added 30% H 2 o 2 41 grams (0.362mol), after the dropwise addition, react for 1 hour. The reaction solution was added dropwise to water, and extracted with ethyl acetate to obtain 97.27 g of compound (3) oil

[0068] The mass spectrum of the oil showed that the molecular ion peak [M+1] was 381; the HPLC purity was 93%.

Embodiment 3

[0069] Embodiment 3: the preparation of compound (4)

[0070] Compound (3) 97.27 grams, dissolved in 500mlTHF, added R-(+)-α-phenylethylamine 29.5 grams (0.243mol), 0.4 grams of PtO 2 , AcOH14.5ml (0.243mol), transferred to hydrogenation kettle, 40-70 ℃, hydrogen pressure 2-5atm. Platinum oxide was filtered out, concentrated under reduced pressure to obtain an oily product, heated and dissolved in ethyl acetate, extracted with water, dried over anhydrous sodium sulfate, filtered, and concentrated to remove the solvent to obtain 119 g of an oily product (greater than the theoretical amount). This gave a mixture with a diastereomeric ratio of 6:1.

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Abstract

The invention provides an indoline compound with optical activity, namely R-5-(2-amidopropyl)-1-(3-(4-fluorine benzoyl oxygen group) propyl)-7-cyan indoline. The compound can be used as a key intermediate and used for preparing a chiral drug, namely, Silodosin. The invention also provides a preparation method of R-5-(2-amidopropyl)-1-(3-(4-fluorine benzoyl oxygen group) propyl)-7-cyan indoline, which is characterized by comprising the following steps: taking 1-(3-(4-fluorine benzoyl oxygen group) propyl)-5-(2-nitrylpropyl)-7-cyan indoline as a raw material to obtain the 1-(3-(4-fluorine benzoyl oxygen group) propyl)-5-(2-oxopropyl)-7-cyan indoline, carrying out asymmetric reaction on the 1-(3-(4-fluorine benzoyl oxygen group) propyl)-5-(2-oxopropyl)-7-cyan indoline and a cheap chiral auxiliary agent, namely alpha-phenylethylamine, wherein asymmetric inductivity is 6:1, and finally removing protective group.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an intermediate compound used for synthesizing silodosin, a drug for treating benign prostatic hyperplasia, and a preparation method of the intermediate compound. Background technique [0002] Silodosin has a selective inhibitory effect on the contraction of urethral smooth muscle, and reduces urethral pressure, but has no great effect on blood pressure, and has little side effects. It is used for the treatment of benign prostatic hyperplasia. At present, there are many reports on the synthesis methods of silodosin, but there is a lack of methods with high yield and suitable for industrial production. [0003] JP200199956 reported the use of benzoic acid as a raw material to prepare R-5-(2-aminopropyl)-1-(3-benzoyloxypropyl)-7-cyanoindoline L through a multi-step reaction - Tartrate, a key chiral intermediate for the synthesis of silodosin. Due to the low multi-step reaction ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/08
CPCY02P20/55
Inventor 王小梅王哲烽隋强刘启皓时惠麟
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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