Optical active compound of 1-(3-benzoyloxy-propyl)-5-(2-(1-phenyl ethyl amine) propyl-7-cyano indoline as well as preparation method and application thereof

A technology of optical activity and compounds, applied in the direction of organic chemistry, can solve the problems that are not suitable for industrial production, and achieve the effect of easy industrial production, low cost, and controllable optical purity

Active Publication Date: 2009-11-25
ZHEJIANG HUAHAI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, several steps in this method are purified by column chromatography, which is not suitable for industrial production.

Method used

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  • Optical active compound of 1-(3-benzoyloxy-propyl)-5-(2-(1-phenyl ethyl amine) propyl-7-cyano indoline as well as preparation method and application thereof
  • Optical active compound of 1-(3-benzoyloxy-propyl)-5-(2-(1-phenyl ethyl amine) propyl-7-cyano indoline as well as preparation method and application thereof
  • Optical active compound of 1-(3-benzoyloxy-propyl)-5-(2-(1-phenyl ethyl amine) propyl-7-cyano indoline as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: 5-((R)-2-((R)-1-phenylethylamine)propyl)-1-(3-benzoyloxypropyl)-7-cyanindole Preparation of morphine

[0064] 39.11g of the compound represented by formula (II) was dissolved in dry 300mlTHF, 17g (0.140mol) of R-(+)-α-phenethylamine was added, and 8.4g (0.140mol) of AcOH, 0.5g of PtO 2 , H 2 , stirred at 60°C for 18h at 2.5 atmospheric pressure, filtered off PtO 2 , concentrated under reduced pressure. The diastereomer ratio was determined to be a 5:1 mixture by HPLC (see figure 1 ).

[0065] Treatment: alkali adjustment to pH 9-10, extraction with ethyl acetate, Na 2 SO 4 Dry, filter and concentrate. Salt formation: 500ml ethyl acetate, 30ml EtOH / HCl, add dropwise at 25°C, crystallize, take an ice-water bath, stir overnight, filter, dry, recrystallize from ethanol to obtain a single isomer, diastereomer excess 98 % (98% de value) (see figure 2 ).

[0066] Optical rotation value: [α] 20 D =+45.6, c=0.5, MeOH

[0067] Mass spectrum: m / e 468.18 (8...

Embodiment 2

[0074] Embodiment 2: the preparation of single isomer compound (IV) hydrochloride

[0075] The solid that embodiment 1 obtains is placed in 50ml methanol, adds Pd / C (4.84g, 47.91mmol), feeds into H then 2 , reacted for 28 hours. Pd / C was filtered off and the filtrate was concentrated. Acetone was heated to reflux to dissolve, and cooled naturally to obtain a white solid. The reaction solution was determined by HPLC to have a purity of 94%, and very few impurity compounds such as formula (VI). Such as formula (IV) compound and formula (VI) compound ratio is 93.73: 2.38 (see image 3 )

[0076] Optical rotation value: [α] 20 D =-5.4c=1, MeOH

[0077] Mass spectrum: m / e 364.17 (87%), 365.18 (13%)

[0078] Elemental Analysis: Calculated: C 66.07, H6.56, N10.51

[0079] Measured values: C 65.87, H 6.66, N 10.54

Embodiment 3

[0081] Dissolve 1 g of the compound represented by formula (II) in 30 ml of THF, add 0.5 g of R-(+)-α-phenethylamine, 0.05 g of Raney Ni, under hydrogen, 60-70 ° C, 10 atm, stir for 25 h, filter off the insoluble matter, The solvent was removed under reduced pressure, alkalized, extracted with ethyl acetate, Na 2 SO 4 Dry, filter and concentrate. See embodiment 1 for physical and chemical properties.

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Abstract

The invention provides an optical active compound of 1-(3-benzoyloxy-propyl)-5-(2-(1-phenyl ethyl amine) propyl-7-cyano indoline as well as a preparation method and the application thereof. The optical active compound is shown in a formula (1), comprises a (R,R) configuration and a (S,S) configuration and can be used as an intermediate for synthetizing silodosin. The optical active compound of the single formula (1) can be used for preparing an optical high-purity product and has good yield on the premise of ensuring good optical purity. The preparation method of the optical active compound uses low-cost chiral assistant agent of alpha-phenethylamine and derivatives thereof, has mild reaction conditions, low cost and controllable optical purity and is easy for industrialized production.

Description

technical field [0001] The invention relates to an intermediate compound and a salt thereof for synthesizing silodosin, a drug for treating benign prostatic hyperplasia, as well as a preparation method and application of the intermediate compound and the salt thereof. Background technique [0002] The optically active R-compound of the following formula is a key intermediate for preparing silodosin, a drug for treating benign prostatic hyperplasia. [0003] [0004] JP2002265444 has reported the R-compound (R) shown in formula (IV) 1 = Benzyl, R 2 = cyano group), the method obtains the target product by splitting the intermediate carboxylic acid in the synthesis process. This method has a long synthetic route, low resolution yield, and the resolution reagents used are not easy to obtain. [0005] JP200199956 has reported the R-compound (R) shown in formula (IV) 1 = benzoyl, R 2 =cyano group), the method obtains the target product by the asymmetric reductive amination...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/12
Inventor 王小梅王小妹王哲烽隋强时惠麟
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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