CN103848772A - Preparation method of important intermediate of Silodosin - Google Patents
Preparation method of important intermediate of Silodosin Download PDFInfo
- Publication number
- CN103848772A CN103848772A CN201210503131.2A CN201210503131A CN103848772A CN 103848772 A CN103848772 A CN 103848772A CN 201210503131 A CN201210503131 A CN 201210503131A CN 103848772 A CN103848772 A CN 103848772A
- Authority
- CN
- China
- Prior art keywords
- reaction
- obtains
- ethanoyl
- completion
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
Abstract
The invention discloses a preparation method of an important intermediate of Silodosin. The method comprises the following steps: carrying out a Gabriel primary amine synthesis reaction of raw materials comprising 1-acetyl-5-(2-bromopropyl)indoline and phthalimide potassium to obtain an intermediate 1-acetyl-5-(2-aminopropyl)indoline, brominating, and cyanating to obtain a product 1-acetyl-5-(2-bromopropyl)-7-cyanindoline, that is the important intermediate of Silodosin. The preparation method has the advantages of simple operation, high reaction yield, easy product separation and the like, and is suitable for industrialized production.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to a kind of preparation method of (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide important intermediate.
Background technology
(R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide (Silodosin) is the invention of Japanese Ju Sheng drugmaker
α 1-receptor antagonist, is used for the treatment of the relevant symptoms such as benign prostatic hyperplasia or hypertrophy.Clinical experiment shows, has 25% Patients with Prostatic Hyperplasia need to carry out medicine or operative treatment.Although prostatectomy effect is better, mortality ratio is not high, and patient brings infringement in various degree.So find a kind of not only effective but also safe non-surgical treatment, can not only control further developing of disease, can alleviate again patient's symptom simultaneously.
Benign prostatic hyperplasia sickness rate in Elderly male patient is higher, and alternative medicine is little clinically, therefore develops a kind of medicine for the treatment of benign prostatic hyperplasia, not only has good social effect, also can bring good economic benefits simultaneously.Confirm after deliberation, (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide is a class important drugs for the treatment of at present benign prostatic hyperplasia.
At present, the preparation method of disclosed bibliographical information to (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide compounds research, mainly contains:
As far back as nineteen ninety-five, the people such as Kitazawa M in patent US5387603, the total synthesis method of report (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide, but the method reactions steps is longer, productive rate is not too high, is not suitable for our suitability for industrialized production.
In 2009, the patent CN102115455A that the people such as Zhai rich people deliver, it has reported a kind of preparation method of psilocine key intermediate.The method has been carried out suitably improvement for existing method, though more previous method shortens a step in step, but the synthesis yield of the method is lower, can not meet the demand of our suitability for industrialized production.
To sum up, preparation method is more for (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide compounds, and synthetic method is also being updated, but still has a lot of defects.Therefore, be necessary further the preparation method of (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide compounds to be studied, to obtain, simple process, product yield are high, the segregative new preparation process of product.
Summary of the invention
The object of the invention is to overcome the above problem that prior art exists, a kind of preparation method of (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide important intermediate is provided, simple process of the present invention, product yield is high, product is easily separated, the method that suitability for industrialized is produced.
For realizing above-mentioned technical purpose, reach above-mentioned technique effect, the present invention is achieved through the following technical solutions:
A preparation method for (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide important intermediate, comprises the following steps:
Step 1), in flask, adds 282g raw material 1-ethanoyl-5-(2-bromopropyl) indoline, 222g potassium phthalimide and 700mL DMF heat 2h at 110 DEG C; After completion of the reaction, add wherein appropriate water, wash away excessive solvent DMF and salt, rear EA extraction precipitation, obtains 296g crude product;
Step 2) in flask, add 296g step 1 gained crude product, with after 800mL dissolve with ethanol, add 165mL hydrazine hydrate, 50 DEG C are heated to white solid and separate out; After completion of the reaction, cooling suction filtration, filter cake is washed with ethanol, then mother liquor decompression precipitation; After dissolving with EA, water washes away unnecessary hydrazine, and last organic phase desolvation obtains 165g intermediate, i.e. 1-ethanoyl-5-(2-aminopropyl) indoline;
Step 3), in there-necked flask, adds 165g intermediate 1-ethanoyl-5-(2-aminopropyl) indoline, with after 600mL dissolve with methanol, stirring at room temperature, slowly drips bromine wherein; After adding, stirring at room temperature 5-6h; After completion of the reaction, be slowly poured into saturated NaHSO
3in, wash away excessive bromine; After be extracted with ethyl acetate, respectively water and saturated common salt water washing, with anhydrous sodium sulfate drying; After filtration, vacuum removal solvent obtains crude product, with after toluene recrystallization, obtains 177g sterling;
Step 4), in flask, adds 177g step 3 gained sterling and 65g CuCN, and the rear 700mL DMF that uses heats 3 to 5h at 110 DEG C; After completion of the reaction, add wherein appropriate water, wash away excessive solvent DMF and salt, rear EA extraction precipitation obtains crude product, obtains 121g sterling 1-ethanoyl-5-(2-bromopropyl after recrystallization)-7-cyanoindole quinoline, i.e. (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide important intermediate;
The reaction formula of step (1), (2), (3), (4) synthesis technique is:
Further, described step 1) to step 4) is followed the tracks of detection reaction by TLC point plate.
The invention has the beneficial effects as follows:
The preparation method of (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide important intermediate of the present invention, carry this method have easy and simple to handle, the advantage such as reaction yield is high, and product is easily separated, suitability for industrialized production.
embodiment
A preparation method for (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide important intermediate, comprises the following steps:
Step 1), in flask, adds 282g raw material 1-ethanoyl-5-(2-bromopropyl) indoline, 222g potassium phthalimide and 700mL DMF heat 2h at 110 DEG C; After completion of the reaction, add wherein appropriate water, wash away excessive solvent DMF and salt, rear EA extraction precipitation, obtains 296g crude product;
Step 2) in flask, add 296g step 1 gained crude product, with after 800mL dissolve with ethanol, add 165mL hydrazine hydrate, 50 DEG C are heated to white solid and separate out; After completion of the reaction, cooling suction filtration, filter cake is washed with ethanol, then mother liquor decompression precipitation; After dissolving with EA, water washes away unnecessary hydrazine, and last organic phase desolvation obtains 165g intermediate, i.e. 1-ethanoyl-5-(2-aminopropyl) indoline;
Step 3), in there-necked flask, adds 165g intermediate 1-ethanoyl-5-(2-aminopropyl) indoline, with after 600mL dissolve with methanol, stirring at room temperature, slowly drips bromine wherein; After adding, stirring at room temperature 5-6h; After completion of the reaction, be slowly poured into saturated NaHSO
3in, wash away excessive bromine; After be extracted with ethyl acetate, respectively water and saturated common salt water washing, with anhydrous sodium sulfate drying; After filtration, vacuum removal solvent obtains crude product, with after toluene recrystallization, obtains 177g sterling;
Step 4), in flask, adds 177g step 3 gained sterling and 65g CuCN, and the rear 700mL DMF that uses heats 3 to 5h at 110 DEG C; After completion of the reaction, add wherein appropriate water, wash away excessive solvent DMF and salt, rear EA extraction precipitation obtains crude product, obtains 121g sterling 1-ethanoyl-5-(2-bromopropyl after recrystallization)-7-cyanoindole quinoline, i.e. (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide important intermediate;
The reaction formula of step (1), (2), (3), (4) synthesis technique is:
Further, described step 1) to step 4) is followed the tracks of detection reaction by TLC point plate.
Claims (1)
1. a preparation method for (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide important intermediate, is characterized in that, comprises the following steps:
Step 1), in flask, adds 282g raw material 1-ethanoyl-5-(2-bromopropyl) indoline, 222g potassium phthalimide and 700mL DMF heat 2h at 110 DEG C; After completion of the reaction, add wherein appropriate water, wash away excessive solvent DMF and salt, rear EA extraction precipitation, obtains 296g crude product;
Step 2) in flask, add 296g step 1 gained crude product, with after 800mL dissolve with ethanol, add 165mL hydrazine hydrate, 50 DEG C are heated to white solid and separate out; After completion of the reaction, cooling suction filtration, filter cake is washed with ethanol, then mother liquor decompression precipitation; After dissolving with EA, water washes away unnecessary hydrazine, and last organic phase desolvation obtains 165g intermediate, i.e. 1-ethanoyl-5-(2-aminopropyl) indoline;
Step 3), in there-necked flask, adds 165g intermediate 1-ethanoyl-5-(2-aminopropyl) indoline, with after 600mL dissolve with methanol, stirring at room temperature, slowly drips bromine wherein; After adding, stirring at room temperature 5-6h; After completion of the reaction, be slowly poured into saturated NaHSO
3in, wash away excessive bromine; After be extracted with ethyl acetate, respectively water and saturated common salt water washing, with anhydrous sodium sulfate drying; After filtration, vacuum removal solvent obtains crude product, with after toluene recrystallization, obtains 177g sterling;
Step 4), in flask, adds 177g step 3 gained sterling and 65g CuCN, and the rear 700mL DMF that uses heats 3 to 5h at 110 DEG C; After completion of the reaction, add wherein appropriate water, wash away excessive solvent DMF and salt, rear EA extraction precipitation obtains crude product, obtains 121g sterling 1-ethanoyl-5-(2-bromopropyl after recrystallization)-7-cyanoindole quinoline, i.e. (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide important intermediate;
The reaction formula of step (1), (2), (3), (4) synthesis technique is:
The preparation method of a kind of (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide important intermediate according to claim 1, is characterized in that: described step 1) to step 4) is followed the tracks of detection reaction by TLC point plate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210503131.2A CN103848772A (en) | 2012-11-30 | 2012-11-30 | Preparation method of important intermediate of Silodosin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210503131.2A CN103848772A (en) | 2012-11-30 | 2012-11-30 | Preparation method of important intermediate of Silodosin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103848772A true CN103848772A (en) | 2014-06-11 |
Family
ID=50856935
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210503131.2A Pending CN103848772A (en) | 2012-11-30 | 2012-11-30 | Preparation method of important intermediate of Silodosin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103848772A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104974072A (en) * | 2014-04-10 | 2015-10-14 | 江苏和成新材料有限公司 | Preparation method of silodosin intermediate |
| CN108047116A (en) * | 2017-12-28 | 2018-05-18 | 常州瑞明药业有限公司 | The preparation method of R-5- (2- aminopropyls) -1- (3- hydroxypropyls) -7- itrile group indolines |
| US10421719B2 (en) | 2015-09-30 | 2019-09-24 | Urquima S.A. | Maleic acid salt of a silodosin intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5387603A (en) * | 1992-12-02 | 1995-02-07 | Kissei Pharmaceutical Co., Ltd. | 1,5,7-trisubstituted indoline compounds and salts thereof |
| CN101759627A (en) * | 2009-09-15 | 2010-06-30 | 傅军 | Novel preparation method of silodosin |
| CN102690223A (en) * | 2012-05-24 | 2012-09-26 | 临海天宇药业有限公司 | Preparation method for 1-acetyl-7-cyanopyridine-5-(2-amino propyl) indoline |
-
2012
- 2012-11-30 CN CN201210503131.2A patent/CN103848772A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5387603A (en) * | 1992-12-02 | 1995-02-07 | Kissei Pharmaceutical Co., Ltd. | 1,5,7-trisubstituted indoline compounds and salts thereof |
| CN101759627A (en) * | 2009-09-15 | 2010-06-30 | 傅军 | Novel preparation method of silodosin |
| CN102690223A (en) * | 2012-05-24 | 2012-09-26 | 临海天宇药业有限公司 | Preparation method for 1-acetyl-7-cyanopyridine-5-(2-amino propyl) indoline |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104974072A (en) * | 2014-04-10 | 2015-10-14 | 江苏和成新材料有限公司 | Preparation method of silodosin intermediate |
| CN104974072B (en) * | 2014-04-10 | 2017-11-03 | 江苏和成新材料有限公司 | A kind of method for preparing Silodosin intermediate |
| US10421719B2 (en) | 2015-09-30 | 2019-09-24 | Urquima S.A. | Maleic acid salt of a silodosin intermediate |
| CN108047116A (en) * | 2017-12-28 | 2018-05-18 | 常州瑞明药业有限公司 | The preparation method of R-5- (2- aminopropyls) -1- (3- hydroxypropyls) -7- itrile group indolines |
| CN108047116B (en) * | 2017-12-28 | 2021-08-13 | 常州瑞明药业有限公司 | Preparation method of R-5- (2-aminopropyl) -1- (3-hydroxypropyl) -7-nitrilindoline |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106854176A (en) | A kind of method for preparing Ni Lapani tosilate monohydrates | |
| CN103980263B (en) | The synthesis technique of canagliflozin | |
| CN102002016A (en) | Improvement method for synthesizing febuxostat | |
| CN103554003A (en) | Method for synthesizing silodosin | |
| CN103848772A (en) | Preparation method of important intermediate of Silodosin | |
| CN102395591B (en) | Method for preparing prasugrel | |
| CN111518031B (en) | Hydroxamic acid-containing compound and preparation method and application thereof | |
| CN110872247A (en) | Xofluza sulfur-containing heterocyclic compound, intermediate thereof and preparation method | |
| CN102351790B (en) | Method for synthesizing 7-bromo-6-chloro-4-quinazolinone | |
| CN102367236A (en) | Synthesizing technology of donepezil hydrochloride | |
| CN104003934B (en) | The synthesis of the fluoro-2-pyridine carboxylic acid of the chloro-3-of 6- | |
| CN105837493A (en) | A synthetic method of Nintedanib and an intermediate of Nintedanib | |
| CN104230743B (en) | Method for preparing 4-benzyl-1-phenethyl piperazine-2,6-diketone | |
| CN105622380B (en) | Preparation method of apremilast and intermediate thereof | |
| CN106432053A (en) | Preparation method of niraparib intermediate 4-(3S-piperidine-3-yl)bromobenzene | |
| CN106008316A (en) | New method for synthesizing Ledipasvir chiral intermediate | |
| TWI725710B (en) | SYNTHESIS OF 3-BROMO-5- (2-ETHYLIMIDAZO [1,2a] PYRIDINE-3-CARBONYL) -2-HYDROXYBENZONITRILE | |
| CN103193699B (en) | Novel method for preparing prucalopride intermediate | |
| CN103739540B (en) | A kind of preparation method of bazedoxifene acetate intermediate | |
| CN105585547A (en) | 4-sulfur pentafluoride phenol compound, preparing method and preparing method for sulfur pentafluoride substituted benzopyran compound | |
| CN105777852A (en) | Deflazacort synthetic method | |
| CN101812071A (en) | Method for processing mother liquor obtained by splitting clopidogrel hydrogen sulfate intermediate | |
| CN101613317B (en) | Mozavaptan synthesis technology for treating congestive heart failure (CHF) | |
| CN105481831B (en) | A kind of method for preparing dabigatran etexilate intermediate | |
| CN103880747B (en) | The preparation method of amorphous tolvaptan |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140611 |