CN106928118B

CN106928118B - Method for preparing silodosin intermediate

Info

Publication number: CN106928118B
Application number: CN201710231920.8A
Authority: CN
Inventors: 史卫明
Original assignee: Changzhou Ruiming Pharmaceutical Co ltd
Current assignee: Changzhou Ruiming Pharmaceutical Co ltd
Priority date: 2017-04-11
Filing date: 2017-04-11
Publication date: 2022-08-23
Anticipated expiration: 2037-04-11
Also published as: CN106928118A

Abstract

The invention provides a method for preparing silodosin intermediate, which has a structural formula shown as a formula (I):

the preparation method comprises the following steps: taking benzoic acid 3- (7-cyano-5- (2-nitropropyl) indoline-1-yl) propyl ester (II) as a raw material, and reducing in a zinc powder/hydrochloric acid system to obtain a silodosin intermediate (I), wherein the reduction reaction formula is as follows:

Description

Method for preparing silodosin intermediate

Technical Field

The invention belongs to the field of medicine research, and particularly relates to a method for preparing a silodosin intermediate.

Background

The invention relates to a method for preparing silodosin intermediate benzoic acid-3- (5- (2-aminopropyl) -7-cyanoindolin-1-yl) propyl ester (I). Silodosin is a drug for treating benign prostatic hyperplasia, has a remarkable curative effect and small side effects, and is popular with patients in various countries. The structural formula is as follows:

the invention relates to an important intermediate compound (I) for preparing silodosin

The reaction equation involved in the invention is as follows:

the reaction for preparing the compound (I) from the compound (II) has been reported in various documents, and mainly includes the following two main groups: the first type is a catalytic hydrogenation or hydrogen transfer process: journal of Medicinal Chemistry, 2016, 59(8), 3826-3839 reports that methanol and tetrahydrofuran are used as solvents, Pd/C is used as a catalyst, catalytic hydrogenation is carried out, and the product is obtained after reaction for 48 hours at 40 ℃; india patent 2013DE01072 reports that methanol and ethyl acetate are used as a mixed solvent, palladium hydroxide is used as a catalyst, and the target product is obtained by catalytic hydrogenation at 50-55 ℃; PCT patent WO2014167507 discloses that methanol and ethyl acetate are used as a mixed solvent, Pd (OH)2 is used as a catalyst, and hydrogenation reaction is carried out at 50-55 ℃ and 10atm H2 to obtain a target product. PCT patent WO2013056842 discloses a target product obtained by catalytic hydrogenation for 8-10h at 25-30 ℃ under the condition of 8-10bar by using Pt as a catalyst and ethyl acetate as a catalyst. Chinese patent CN102746210 reports that a target product is obtained by carrying out catalytic hydrogenation reaction for 10 hours at 50 ℃ and under 0.5MPa by taking Pd as a catalyst and methanol and tetrahydrofuran as a mixed solvent; PCT patent WO2012147107 discloses a method of using Ni as a catalyst, CaCO3 as a carrier, and methanol as a solvent, and performing catalytic hydrogenation to obtain a target product; PCT patent WO2011124704 reports that a target product is obtained by using water, ethanol and DMF as solvents, Pd/C as a catalyst and ammonium formate as a hydrogen transfer reagent.

The second type is a metal reduction method: indian patent 2015CH06154 discloses an iron powder/acetic acid system reduced with ethyl acetate and water as solvents to obtain the target product (I).

Disclosure of Invention

The invention aims at solving the problems that a plurality of methods for preparing a compound (I) reported in the above documents generally need high-pressure equipment, increase potential safety hazard and generally have long reaction time, a cyano group which is easy to hydrogenate is also contained in the compound (I), and impurities which are difficult to separate are easily generated due to over hydrogenation, and a reported metal reduction method takes iron powder as a reducing agent, ferrous salts generated after the reduction of the iron powder can be oxidized into ferric salts in the presence of trace oxygen, and the latter can easily oxidize the product (I) to generate a small amount of nitrogen oxidation products which are difficult to separate.

The technical scheme of the invention is as follows: a process for the preparation of silodosin intermediates having the formula (I):

in the above scheme, the reduction reaction is carried out in an organic solvent.

In the scheme, the temperature range of the reduction reaction is 20-120 ℃, and the reaction time is up to the consumption of the raw material (II).

In the scheme, the zinc powder and the hydrochloric acid are in excess compared with the compound (II).

Compared with the prior art, the invention has the beneficial effects that: compared with a hydrogenation method, the zinc powder reduction method of the reaction does not need special equipment, can be smoothly finished by a common reaction kettle, and can not reduce cyano groups to cause the product purity to be poor; compared with the iron powder method, the method has the advantages that the metal mud is easier to remove, and the nitrogen oxide products which are difficult to separate are not generated, so that the method is more beneficial to industrial production.

Detailed Description

EXAMPLE 1 preparation of the Compound benzoic acid-3- (5- (2-aminopropyl) -7-cyanoindolin-1-yl) propyl ester (I)

Adding a raw material (II) and hydrochloric acid into an organic solvent, heating to a certain temperature, slowly adding zinc powder in batches, detecting by thin-layer chromatography (TLC) or High Performance Liquid Chromatography (HPLC) until the raw material (II) completely reacts, filtering, washing a filter cake by using the solvent until the product (I) is not contained, separating and purifying by conventional means such as concentration, washing, drying, salifying and the like to obtain a salt of the compound (I), and alkalifying to obtain the free base of the compound (I). ¹ H NMR(400MHz，MeOD)δ8.06-8.00(m，2H)，7.63-7.56(m，1H)，7.49-7.42(m，2H)，7.02(d，J＝1.5Hz，1H)，6.95(s，1H)，4.45(t，J＝6.2Hz，2H)，3.76(t，J＝7.1Hz，2H)，3.61(t，J＝8.7Hz，2H)，3.06-2.90(m，3H)，2.54-2.38(m，2H)，2.21-2.08(m，2H)，1.06(d，J＝6.4Hz，3H)； ¹³ C NMR(126MHz，MeOD)δ168.02，153.13，134.60，134.20，132.32，131.32，130.95，130.63，129.50，120.56，88.48，63.97，54.14，49.27，46.36，45.34，28.16，27.86，22.45，ESI-MS:364(M+H ⁺ )，386(M+Na ⁺ )。

Example 2 examination of the Effect of different temperatures on the reaction

The method of example 1 was used, 95% ethanol was used as solvent, zinc powder and hydrochloric acid were both doubled in excess, and the effect of different temperatures on the reaction was examined, as shown in table 1:

TABLE 1 Effect of different temperatures on the reduction reaction

As can be seen from Table 1, when the temperature exceeds 60 ℃, the selectivity of the reaction is significantly decreased, resulting in a lower yield; when the temperature is low (such as 30 ℃ to 40 ℃), the yield is satisfactory, but the reaction rate is slow, the reaction time is too long, and the practical value is reduced, so that the temperature is preferably 50 ℃ to 60 ℃.

Example 3 examination of the Effect of different molar ratios on the reaction

The method of example 1 is adopted, 95% ethanol is used as a solvent, the reaction is carried out at 50 ℃, the influence of the molar ratio of different zinc powders to the raw material (II) on the reaction is examined, and the specific results are shown in Table 2:

TABLE 2 Effect of different molar ratios on the reduction reaction

As is clear from Table 2, when the molar ratio is 1.5 or more, the selectivity of the reaction approaches 100%. But continues to increase without significant effect on yield.

Claims

1. A process for the preparation of silodosin intermediate, wherein the intermediate has the formula (I):

the temperature range of the reduction reaction is 20-120 ℃, and the reaction time is up to the consumption of the raw material (II).

2. The method for preparing silodosin intermediate according to claim 1, wherein the reduction reaction is performed in an organic solvent.

3. The process for preparing silodosin intermediate as claimed in claim 1, wherein the zinc powder and hydrochloric acid are in excess of compound (II).