CN1616438A - Process for preparing alfuzosin hydrochloride - Google Patents
Process for preparing alfuzosin hydrochloride Download PDFInfo
- Publication number
- CN1616438A CN1616438A CN 200410080024 CN200410080024A CN1616438A CN 1616438 A CN1616438 A CN 1616438A CN 200410080024 CN200410080024 CN 200410080024 CN 200410080024 A CN200410080024 A CN 200410080024A CN 1616438 A CN1616438 A CN 1616438A
- Authority
- CN
- China
- Prior art keywords
- alfuzosin
- reaction
- alfuzosin hydrochloride
- tetrahydrofuran
- hydrochloride
- 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.)
- Granted
Links
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses the preparation process of alfuzosin hydrochloride. N-methyl propylenediamine as material is condensed with 2-tetrahydrofuran formyl chloride or 2-tetrahydrofuran formic acid to obtain condensate; the condensate without being purified is then condensed with 2-chloro-4-amino-6, 7-dimethoxy quinazoline to obtain alfuzosin; and alfuzosin is finally reacted with hydrochloric acid to form alfuzosin hydrochloride. The said process has simple operation, low cost, high yield and easy-to-realize reaction conditions, and is suitable for industrial production.
Description
Technical field
The present invention relates to alfuzosin hydrochloride (N-[3-(4-amino-6,7-dimethoxy-2-quinazolyl) methylamino-] propyl group) tetrahydrochysene-2-furoyl amine hydrochlorate) the preparation method.
Background technology
Alfuzosin hydrochloride (Alfuzosin hydrochloride) is N-[3-(4-amino-6, a 7-dimethoxy-2-quinazolyl) methylamino-] propyl group) common name of tetrahydrochysene-2-furoyl amine hydrochlorate, its structural formula is:
Alfuzosin hydrochloride is a quinazoline derivant, energy highly selective and prostate gland, prostatic utriculus, the α of nearly side urethra and fundus of bladder
1The combination of-receptor competition, antagonism α
1-receptor-mediated smooth muscle contraction.Alfuzosin hydrochloride can significantly alleviate the dysuria of benign prostatic hyperplasia clinical patients, increases the urine flow rate, effectively improves patient's quality of life.Alfuzosin hydrochloride is developed by German Beiezsdozf company, is widely used in the treatment of benign prostatic hyperplasia clinical symptom at present first in France's listing in 1988.
Patent Ger.Pat.2,904,445 and U.S.Pat.4, the main preparation methods of 315,007 disclosed alfuzosin hydrochlorides is to be raw material with the veratric acid, through nitrated, reduction, cyclization, chlorination, ammonia is separated, intermediate 2-chloro-4-amino-6, the 7-dimethoxyquinazoline.Then with β-cyanoethyl methylamine condensation, again behind the High Temperature High Pressure reduction cyano group with the tetrahydrochysene furoic acid condensation, obtain alfuzosin.Get product with the hydrochloric acid salify then.During cyano reduction, need High Temperature High Pressure in its preparation method, so special autoclave is used in pilot scale.Above-mentioned condition makes alfuzosin hydrochloride be difficult to realize large-scale industrial production.
Summary of the invention
Defective in view of present alfuzosin hydrochloride synthetic method existence, and utilize the active difference of primary amine and secondary amine in the N-methyl-prop diamines, and the active difference of secondary amine and acid amides in the condenses, the invention provides a kind of preparation method of new preparation alfuzosin hydrochloride.
It is raw material that the present invention adopts N-methyl-prop diamines, with 2-tetrahydrofuran (THF) formyl chloride, perhaps 2-tetrahydrofuran formic acid generation condensation reaction, and the not purified direct and 2-chlorine 4-amino-6 of gained condenses, 7-dimethoxyquinazoline generation condensation reaction obtains alfuzosin.With the hydrochloric acid salify, obtain alfuzosin hydrochloride then.
The present invention includes following steps:
A, in the presence of organic bases, in solvent, make N-methyl-prop diamines and 2-tetrahydrofuran (THF) formyl chloride or 2-tetrahydrofuran formic acid generation condensation reaction, temperature of reaction is-10 ℃～60 ℃, the reaction times is 6～28 hours;
B, react completely after, reaction system is not treated, directly adds 2-chloro-4-amino-6, the 7-dimethoxyquinazoline, in 30 ℃～50 ℃ the reaction 4～22 hours, obtain alfuzosin;
C, alfuzosin are through washing, 5%NaHCO
3Wash, the salt washing removes solvent under reduced pressure after the drying, add the hydrogen chloride solution of dehydrated alcohol, promptly obtains alfuzosin hydrochloride, obtains the alfuzosin hydrochloride elaboration through the ethyl alcohol recrystallization purifying again.
Wherein the organic bases that adopted of step a is triethylamine or pyridine; Solvent is a chloroform, methylene dichloride, ethyl acetate, formic acid, ethanol, Virahol, N, one or more in the dinethylformamide.
Preparation technology of the present invention, the reaction condensate intermediate is not purified to be directly used in the synthetic of alfuzosin, has simplified operation, and controllability is strong, having reduced three-waste pollution, is a kind of easy and simple to handle, and cost is low, yield height, reaction conditions are easy to realize, are suitable for large-scale commercial production.
Embodiment
Further elaborate preparation method of the present invention by following examples.
Embodiment 1: the preparation of alfuzosin hydrochloride
In having churned mechanically 3000 milliliters of there-necked flasks, add 1800 milliliters of trichloromethanes and 82 milliliters of triethylamines, stir, ice-water bath cools to 0 ℃, adds 88 gram N-methyl-prop diamines and 134.5 gram 2-tetrahydrofuran (THF) formyl chlorides, room temperature reaction 18 hours, add 245.5 gram 2-chloro-4-amino-6 again, the 7-dimethoxyquinazoline, 35～40 ℃ of temperature controls reacted 12 hours.After reaction finishes, the washing with 1000 milliliters * 2,800 milliliters of 5%NaHCO
3Solution washing, 800 milliliters of saturated common salt water washings, anhydrous Na
2SO
4Dry.After removing solvent under reduced pressure,, add 380 milliliters of dehydrated alcohol-hydrogen chloride solutions, after stirring, place crystallization with 1500 milliliters of anhydrous alcohol solutions.Suction filtration, the dry white crystalline solid that gets is used the dehydrated alcohol recrystallization once again, gets white crystalline solid 219 grams, is the alfuzosin hydrochloride elaboration, and yield is 51%.
Embodiment 2: the preparation of alfuzosin hydrochloride
In having churned mechanically 3000 milliliters of there-necked flasks, add 1600 milliliters of DMF (N, dinethylformamide) and 98 milliliters of pyridines, 5 gram DMAP stir down, be cooled to 0 ℃, add 88 gram N-methyl-prop diamines and 104.5 gram 2-tetrahydrofuran formic acids, room temperature reaction is after 20 hours, add 245.5 gram 2-chloro-4-amino-6, the 7-dimethoxyquinazoline.35～40 ℃ of temperature controls reacted 14 hours.After reaction finished, water (1000 milliliters * 2) was washed 5%NaHCO
3The aqueous solution is washed for 800 milliliters, and saturated aqueous common salt is washed anhydrous Na for 800 milliliters
2SO
4Dry.After removing solvent under reduced pressure,, add 180 milliliters in dehydrated alcohol-hydrogenchloride, stir, place crystallization with 1500 milliliters of anhydrous alcohol solutions, suction filtration, dry that white crystalline solid 226 restrains, be the alfuzosin hydrochloride elaboration, yield is 53%.
Claims (3)
1. the preparation method of an alfuzosin hydrochloride is characterized in that this method may further comprise the steps:
A, in the presence of organic bases, in solvent, make N-methyl-prop diamines and 2-tetrahydrofuran (THF) formyl chloride or 2-tetrahydrofuran formic acid generation condensation reaction, temperature of reaction is-10 ℃～60 ℃, the reaction times is 6～28 hours;
B, react completely after, reaction system is not treated, directly adds 2-chloro-4-amino-6, the 7-dimethoxyquinazoline, in 30 ℃～50 ℃ the reaction 4～22 hours, obtain alfuzosin;
C, alfuzosin are through washing, 5%NaHCO
3Wash, the salt washing removes solvent under reduced pressure after the drying, add the hydrogen chloride solution of dehydrated alcohol, obtains alfuzosin hydrochloride, obtains the alfuzosin hydrochloride elaboration through the ethyl alcohol recrystallization purifying again.
2. method according to claim 1 is characterized in that organic bases used among the step a is triethylamine or pyridine.
3. method according to claim 1 is characterized in that solvent used among the step a is a chloroform, methylene dichloride, ethyl acetate, formic acid, ethanol, Virahol, N, one or more in the dinethylformamide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410080024 CN1288139C (en) | 2004-09-24 | 2004-09-24 | Process for preparing alfuzosin hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410080024 CN1288139C (en) | 2004-09-24 | 2004-09-24 | Process for preparing alfuzosin hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1616438A true CN1616438A (en) | 2005-05-18 |
| CN1288139C CN1288139C (en) | 2006-12-06 |
Family
ID=34765582
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410080024 Expired - Fee Related CN1288139C (en) | 2004-09-24 | 2004-09-24 | Process for preparing alfuzosin hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1288139C (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007063556A2 (en) * | 2006-12-07 | 2007-06-07 | Msn Laboratories Limited | An improved and industrial process for the preparation of alfuzosin hydrochloride and its novel polymorphs |
| WO2008015525A2 (en) * | 2006-07-31 | 2008-02-07 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of alfuzosin hydrochloride |
| CN100564376C (en) * | 2006-09-19 | 2009-12-02 | 浙江华纳药业有限公司 | Process for preparing alfuzosin |
| CN113801069A (en) * | 2020-06-15 | 2021-12-17 | 鲁南制药集团股份有限公司 | Alfuzosin hydrochloride intermediate compound |
-
2004
- 2004-09-24 CN CN 200410080024 patent/CN1288139C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008015525A2 (en) * | 2006-07-31 | 2008-02-07 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of alfuzosin hydrochloride |
| WO2008015525A3 (en) * | 2006-07-31 | 2009-09-11 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of alfuzosin hydrochloride |
| CN100564376C (en) * | 2006-09-19 | 2009-12-02 | 浙江华纳药业有限公司 | Process for preparing alfuzosin |
| WO2007063556A2 (en) * | 2006-12-07 | 2007-06-07 | Msn Laboratories Limited | An improved and industrial process for the preparation of alfuzosin hydrochloride and its novel polymorphs |
| WO2007063556A3 (en) * | 2006-12-07 | 2008-07-31 | Msn Lab Ltd | An improved and industrial process for the preparation of alfuzosin hydrochloride and its novel polymorphs |
| CN113801069A (en) * | 2020-06-15 | 2021-12-17 | 鲁南制药集团股份有限公司 | Alfuzosin hydrochloride intermediate compound |
| CN113801069B (en) * | 2020-06-15 | 2024-03-15 | 鲁南制药集团股份有限公司 | Alfuzosin hydrochloride intermediate compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1288139C (en) | 2006-12-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106966947B (en) | A kind of preparation method of vildagliptin | |
| CN1321121C (en) | Preparation and post-treatment method of levofloxacin | |
| CN109320474A (en) | A kind of preparation method of Febustat | |
| CN103304492B (en) | The synthetic method of a kind of EGFR inhibitor Dacomitinib | |
| CN107298678B (en) | Preparation method of bulk drug suvorexant | |
| CN1288139C (en) | Process for preparing alfuzosin hydrochloride | |
| CN101717363A (en) | Method for preparing roxatidine acetate hydrochloride | |
| CN106467513A (en) | A kind of synthetic method preparing Niraparib | |
| CN110668977B (en) | Preparation process of lauroyl arginine ethyl ester hydrochloride | |
| CN103232356B (en) | Technology for preparing 3-phenyl-4-aminobutyric acid hydrochloride | |
| CN105218390A (en) | A kind of Propacetamol Hydrochloride preparation technology of improvement | |
| CN112521339A (en) | Preparation method of chlorphenazine | |
| CN106632280A (en) | Method for preparing alfuzosin hydrochloride | |
| CN104513292A (en) | Preparation method of ramipril | |
| CN102675267A (en) | Preparation method of dronedarone hydrochloride and intermediate of dronedarone hydrochloride | |
| CN1931857A (en) | Prepn process of 5-losartan carboxylate | |
| CN102382165A (en) | Preparation method of dutasteride | |
| WO2021259051A1 (en) | Method for improving synthesis process of hypidone free base | |
| CN1603324A (en) | Leavo halogenated salt and its preparation process and use | |
| CN114249723A (en) | Preparation method of zolpidem and key intermediate thereof | |
| CN103193699A (en) | Novel method for preparing prucalopride intermediate | |
| CN113307810B (en) | Synthesis method and application of 2, 4-fluoro-pyrrole [1,2] pyrimidine-7-carbonitrile | |
| CN115536599B (en) | Preparation method of fampicin intermediate 3, 6-difluoro-2-pyrazinecarbonitrile | |
| CN112062761B (en) | Synthetic method of berberberrubine ester substances | |
| CN113651800B (en) | Preparation method of oxitinib mesylate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Assignor: LUNAN PHARMACEUTICAL Group Corp. Contract record no.: 2010370000509 Denomination of invention: Process for preparing alfuzosin hydrochloride Granted publication date: 20061206 License type: Exclusive License Open date: 20050518 Record date: 20100908 |
|
| EC01 | Cancellation of recordation of patent licensing contract |
Assignee: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Assignor: LUNAN PHARMACEUTICAL Group Corp. Contract record no.: 2010370000509 Date of cancellation: 20121226 |
|
| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20061206 |