CN106632280A - Method for preparing alfuzosin hydrochloride - Google Patents
Method for preparing alfuzosin hydrochloride Download PDFInfo
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- CN106632280A CN106632280A CN201611093013.3A CN201611093013A CN106632280A CN 106632280 A CN106632280 A CN 106632280A CN 201611093013 A CN201611093013 A CN 201611093013A CN 106632280 A CN106632280 A CN 106632280A
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- alfuzosin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to a method for preparing alfuzosin hydrochloride. The method comprises the following steps of (1) dripping acrylonitrile into a methylamine alcohol solution below 15 DEG C; performing stirring; obtaining (I) through distillation treatment; (2) dripping (I) into an organic solvent dissolved with a reducing agent; performing heating reflux; then, sequentially and slowly dipping 25-percent sodium hydroxide solution and distilled water; obtaining (II) through distillation treatment; (3) under the drying condition, slowly dripping thionyl chloride into 2-tetrahydrofuroic acid to obtain tetrahydro-2-furancarbonylchloride; (4) controlling the temperature to be under the condition of 5 to 15 DEG C; dripping the tetrahydro-2-furancarbonylchloride into a mixed solution containing an acid-binding agent, the organic solvent and the (II); after the dripping completion, performing stirring for 3 hours; performing neutralization by a 25-percent sodium hydroxide solution; performing extraction by an organic solvent to obtain (III); (5) performing reflux stirring on the (III) and 2-chloro-4-amino-6,7-dimethoxy quinazoline for 4 to 10 hours under the existence of the organic solvent; performing cooling and filtering; performing rotary evaporation to remove organic solvents; performing dispersion by acetone to separate out solids; using mixed solvents for recrystallization; obtaining alfuzosin hydrochloride (IV).
Description
Technical field
The invention belongs to pharmaceutical synthesis field, and in particular to a kind of method for preparing alfuzosin.
Background technology
Alfuzosin (Alfuzosin Hydrochloride), its chemical entitled N- [3- [(4- amino -6,7- bis-
Methoxyl group -2- quinazolyls) methylamino] propyl group] -2- tetrahydrofuran carboxamide hydrochlorides are a kind of alpha-2-adrenoceptors
Antagonist, optionally blocking is distributed in the postsynaptic adrenoceptor of bladder, urethra and prostate trigonum, and antagonism should
Receptor-mediated lower urinary tract smooth muscle contraction, so as to improve benign prostatic hyperplasis, improves patients ' life quality, concrete structure
Formula is as follows：
Chemical medicine worker conducts extensive research to the method for synthetic hydrochloric acid Alfuzosin, its have in common that with
2- chlorin-4-amido-6,7-dimethoxy quinazolines carry out synthesising target compound as key intermediate, for example：It is special according to the U.S.
Sharp NO.4,315,007, Alfuzosin hydrochloride is prepared as follows：2- chlorin-4-amido-6,7-dimethoxy quinazolines and 3- methylamines
Base propionitrile reacts preparation N- (4- amido-6,7-dimethoxy quinazoline -2- bases)-N- methyl -2- cyano ethyls in isoamyl alcohol
Amine, is then hydrogenated in the presence of Raney's nickel, then with HCl treatment obtain N- (4- amido-6,7-dimethoxy quinazolines-
2- yls)-N- methyl-prop diamine hydrochloride intermediates, then the intermediate and tetrahydrofuran formic acid reaction are obtained into Alfuzosin hydrochloric acid
Salt.
By United States Patent (USP) NO.4, the alfuzosin purity of technique acquisition described in 315,007 is simultaneously unsatisfactory, and
And the technique first imports the unstable pyrimidine ring of property, reduces the reliability of technique.
Therefore, this area simple, safety of needing a kind of route badly, without accurate operation, stable yield prepares hydrochloric acid Ah furan's azoles
The method of piperazine.
The content of the invention
It is an object of the invention to overcome complex steps in the existing method for preparing alfuzosin, it is dangerous high,
The unstable defect of product yield, there is provided a kind of the simple and reliable, stable yield of suitable industrialized production prepares hydrochloric acid Ah furan
The method of azoles piperazine.
The present inventor has been surprisingly found that under study for action, when 3- methylamino propionitrile Jing reduction reactions generate aminated compounds, choosing
Lithium aluminium hydride reduction is selected as reducing agent, can not only make whole process route become simple and direct reliability, while it also avoid using Raney/Ni
Deng the dangerous and difficulty operation of catalyst hydrogenation.
To achieve these goals, the invention provides a kind of method for preparing alfuzosin, the method include with
Lower step：
1. acrylonitrile is instilled in methylamine alcohol solution and stirred by temperature control below 15 DEG C, and ethanol is removed in then air-distillation,
Vacuum distillation again obtains 3- methylamino propionitrile；
2. 3- methylaminos propionitrile is instilled in the organic solvent dissolved with reducing agent, is heated to reflux, then be slowly dropped into successively
25% sodium hydroxide solution and distilled water, air-distillation is reclaimed after organic solvent, and vacuum distillation obtains N- methyl isophthalic acids, 3- propane diamine；
3. under drying condition, thionyl chloride is slowly dropped into 2- tetrahydrofuran formic acids, obtains 2- tetrahydrofuran formyl chlorides；
4. 2- tetrahydrofurans formyl chloride is instilled and contains acid binding agent, organic solvent and N- first by temperature under the conditions of 5～15 DEG C
Base -1, the mixed solution of 3- propane diamine, drop finishes stirring 3 hours, is neutralized with 25% sodium hydroxide solution, the extraction of Jing organic solvents,
Obtain N- (3- methylamino propyl group) -2- tetrahydrofuran formamides；
5. by N- (3- methylamino propyl group) -2- tetrahydrofurans formamides and 2- chlorin-4-amido-6,7-dimethoxy quinazolines
In the presence of an organic, it is refluxed 4～10 hours, cold filtration, revolving removes organic solvent, is dispersed to precipitate with acetone solid
Body, then recrystallized with mixed solvent, obtain final product alfuzosin.
Step 2. described in reducing agent be lithium aluminium hydride reduction；
Step 2. described in organic solvent be absolute ether or tetrahydrofuran；
Step 4. described in acid binding agent be triethylamine or pyridine；
Step 4. described in organic solvent be organic solvent be dichloromethane, dichloroethanes, chloroform in one kind；
Step 5. described in organic solvent be methyl alcohol, ethanol, isoamyl alcohol in one kind；
Step 5. described in mixed solvent be methyl alcohol, ethanol, ethyl acetate, acetone, ether in one or two；
Preparation method of the present invention is simple and direct, and reaction is reliable, and accessory substance is few, safe, and post processing is easy, economic and society's effect
It is beneficial notable.
Description of the drawings
Fig. 1 is the reaction equation flow chart of the present invention
Specific embodiment
Embodiment 1
The present embodiment prepares the method for alfuzosin and comprises the following steps：
1. less than 15 DEG C, by 160.8g (3.0mol, 99%) acrylonitrile be added dropwise to 345.1g (3.0mol, 27%) methylamine alcohol
Stir in solution, then air-distillation goes ethanol, then vacuum distillation to obtain cut 210.6g, this cut is 3- methylamino propionitrile,
Yield 83.5%；
2. 210.3g (2.50mol) 3- methylaminos propionitrile is instilled into the 4L ether dissolved with 94.9g (2.50mol) lithium aluminium hydride reduction
Solution, is heated to reflux, then is slowly dropped into 25% sodium hydroxide solution and distilled water successively, filters off insoluble matter, and air-distillation is reclaimed
After ether, vacuum distillation obtains 174.3g N- methyl isophthalic acids, and 3- propane diamine, yield is 79.1%；
3. under drying condition, 232.1g (1.95mol) thionyl chloride is slowly dropped into 226.4g (1.95mol) 2- tetrahydrochysene furans
Mutter in formic acid, obtain 2- tetrahydrofuran formyl chlorides；
4. under the conditions of 5～10 DEG C, the 2- tetrahydrofurans formyl chloride that upper step is obtained is instilled and contains 197.8g temperature
(1.95mol) triethylamine, 1483ml dichloroethanes and 174.3g (1.98mol) N- methyl isophthalic acids, the mixed solution of 3- propane diamine, drop
Finish stirring 3 hours, neutralized with 25% sodium hydroxide solution, Jing dichloroethanes extraction, vacuum distillation obtains 261.4gN- (3- methylaminos
Propyl group) -2- tetrahydrofuran formamides, yield 70.9%；
5. by 261.4g (1.40mol) N- (3- methylamino propyl group) -2- tetrahydrofurans formamides and 336.9g (1.40mol)
2- chlorin-4-amido-6,7-dimethoxy quinazolines are refluxed 6 hours, cold filtration in the presence of isoamyl alcohol, and revolving is removed
Isoamyl alcohol, with acetone solid is dispersed to precipitate, then is recrystallized with alcohol-ether, obtains final product alfuzosin 390.3g, the step yield
65.5%.
Embodiment 2
To step 2. used in reaction dissolvent investigate, specifically include following steps：
210.3g 3- methylaminos propionitrile is instilled into the 4L tetrahydrofuran solutions dissolved with 94.9g lithium aluminium hydride reductions, is heated to reflux,
It is slowly dropped into 25% sodium hydroxide solution and distilled water successively again, filters off insoluble matter, air-distillation is reclaimed after ether, vacuum distillation
170.6gN- methyl isophthalic acids are obtained, 3- propane diamine, yield is 77.4%.
Embodiment 3
To step 4. in reaction temperature investigate, specifically include following steps：
Under the conditions of 10～15 DEG C, by step, 3. the instillation of gained 2- tetrahydrofurans formyl chloride contains 197.8g to temperature
(1.95mol) triethylamine, 1483ml dichloroethanes and 174.3g (1.98mol) N- methyl isophthalic acids, the mixed solution of 3- propane diamine, drop
Finish stirring 3 hours, neutralized with 25% sodium hydroxide solution, Jing dichloroethanes extraction, vacuum distillation obtains 221.5g N- (3- methylamines
Base propyl group) -2- tetrahydrofuran formamides, yield 60.1%.
Embodiment 4
To step 4. in reaction acid binding agent investigate, specifically include following steps：
Under the conditions of 5～10 DEG C, by step, 3. the instillation of gained 2- tetrahydrofurans formyl chloride contains 154.6g to temperature
(1.95mol) pyridine, 1483ml dichloroethanes and 174.3g (1.98mol) N- methyl isophthalic acids, the mixed solution of 3- propane diamine, drop finishes
Stirring 3 hours, is neutralized with 25% sodium hydroxide solution, and Jing dichloroethanes extraction, vacuum distillation obtains 204.9g N- (3- methylaminos
Propyl group) -2- tetrahydrofuran formamides, yield 55.6%.
Embodiment 5
To step 4. in reaction temperature investigate, specifically include following steps：
Under the conditions of 5～10 DEG C, by step, 3. the instillation of gained 2- tetrahydrofurans formyl chloride contains 197.8g to temperature
(1.95mol) triethylamine, 1483ml chloroforms and 174.3g (1.98mol) N- methyl isophthalic acids, the mixed solution of 3- propane diamine, drop
Finish stirring 3 hours, neutralized with 25% sodium hydroxide solution, Jing chloroform extractions, vacuum distillation obtains 235.8g N- (3- methylamines
Base propyl group) -2- tetrahydrofuran formamides, yield 63.9%.
Embodiment 6
To step 5. used in organic solvent investigate, specifically include following steps：
By 261.4g (1.40mol) N- (3- methylamino propyl group) -2- tetrahydrofurans formamides and 336.9g (1.40mol) 2-
Chlorin-4-amido-6,7-dimethoxy quinazoline is refluxed 6 hours, cold filtration in the presence of absolute ethyl alcohol, and revolving is removed
Absolute ethyl alcohol, with acetone solid is dispersed to precipitate, then is recrystallized with alcohol-ether, obtains final product alfuzosin 373.7g, and the step is produced
Rate 62.7%.
Embodiment 7
To step 5. in be refluxed the time and investigate, specifically include following steps：
By 261.4g (1.40mol) N- (3- methylamino propyl group) -2- tetrahydrofurans formamides and 336.9g (1.40mol) 2-
Chlorin-4-amido-6,7-dimethoxy quinazoline is refluxed 8 hours, cold filtration in the presence of isoamyl alcohol, and revolving removing has
Machine solvent, with acetone solid is dispersed to precipitate, then is recrystallized with alcohol-ether, obtains final product alfuzosin 389.4g, the step yield
65.3%.
Embodiment 8
To step 5. middle recrystallization with mixed solvent investigate, specifically include following steps：
By 261.4g (1.40mol) N- (3- methylamino propyl group) -2- tetrahydrofurans formamides and 336.9g (1.40mol) 2-
Chlorin-4-amido-6,7-dimethoxy quinazoline is refluxed 6 hours, cold filtration in the presence of isoamyl alcohol, and revolving removes different
Amylalcohol, with acetone solid is dispersed to precipitate, then is recrystallized with EtOH-EtOAc, obtains final product alfuzosin 376.5g, and the step is produced
Rate 63.1%.
Above-described embodiment is used for illustrative purposes only, and not limitation of the present invention, about the common of technical field
Technical staff, in the case of without departing from the principle and scope of the present invention, can also make a variety of changes and deform, therefore, institute
The technical scheme for having equivalent falls within scope of the invention, and the scope of patent protection of the present invention should be defined by the claims.
Claims (9)
1. a kind of method for preparing alfuzosin, it is characterised in that the method is comprised the following steps：
1. acrylonitrile is instilled in methylamine alcohol solution and stirred by temperature control below 15 DEG C, and ethanol is removed in then air-distillation, then is subtracted
Pressure distillation obtains 3- methylamino propionitrile；
2. 3- methylaminos propionitrile is instilled into the diethyl ether solution dissolved with reducing agent, is heated to reflux, then be slowly dropped into 25% hydrogen-oxygen successively
Change sodium solution and distilled water, air-distillation is reclaimed after ether, and vacuum distillation obtains N- methyl isophthalic acids, 3- propane diamine；
3. under drying condition, thionyl chloride is slowly dropped into 2- tetrahydrofuran formic acids, obtains 2- tetrahydrofuran formyl chlorides；
4. temperature is under the conditions of 5～15 DEG C, by 2- tetrahydrofurans formyl chloride instill containing acid binding agent, organic solvent and N- methyl-
The mixed solution of 1,3- propane diamine, drop finishes stirring 3 hours, is neutralized with 25% sodium hydroxide solution, the extraction of Jing organic solvents, obtains N-
(3- methylamino propyl group) -2- tetrahydrofuran formamides；
5. N- (3- methylamino propyl group) -2- tetrahydrofurans formamide is being had with 2- chlorin-4-amido-6,7-dimethoxy quinazolines
In the presence of machine solvent, it is refluxed 4～10 hours, cold filtration, revolving removes organic solvent, and with acetone solid is dispersed to precipitate,
Recrystallized with mixed solvent again, obtain final product alfuzosin.
2. a kind of method for preparing alfuzosin according to claim 1, it is characterised in that step 2. described in also
Former agent is lithium aluminium hydride reduction.
3. a kind of method for preparing alfuzosin according to claim 1, it is characterised in that 2. middle reaction is molten for step
Agent is absolute ether or tetrahydrofuran, preferred absolute ether.
4. a kind of method for preparing alfuzosin according to claim 1, it is characterised in that step 4. middle reaction temperature
Degree is controlled at 5～15 DEG C, preferably 5～10 DEG C.
5. a kind of method for preparing alfuzosin according to claim 1, it is characterised in that step 4. described in tie up
Sour agent is triethylamine or pyridine, preferred triethylamine.
6. a kind of method for preparing alfuzosin according to claim 1, it is characterised in that step 4. described in it is anti-
Organic solvent is answered for dichloroethanes, dichloromethane, chloroform, preferred dichloroethanes.
7. a kind of method for preparing alfuzosin according to claim 1, it is characterised in that 5. middle reaction has step
Machine solvent be absolute ethyl alcohol, isoamyl alcohol, isopropanol, preferred isoamyl alcohol.
8. a kind of method for preparing alfuzosin according to claim 1, it is characterised in that step 5. described in return
The stream time is 4～10 hours, preferably 6 hours.
9. a kind of method for preparing alfuzosin according to claim 1, it is characterised in that step 5. described in mix
Bonding solvent is one or two in methyl alcohol, ethanol, ethyl acetate, acetone, ether；Preferred alcohol-ether mixed solvent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611093013.3A CN106632280A (en) | 2016-11-24 | 2016-11-24 | Method for preparing alfuzosin hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611093013.3A CN106632280A (en) | 2016-11-24 | 2016-11-24 | Method for preparing alfuzosin hydrochloride |
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| CN201611093013.3A Pending CN106632280A (en) | 2016-11-24 | 2016-11-24 | Method for preparing alfuzosin hydrochloride |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111454159A (en) * | 2020-04-04 | 2020-07-28 | 大连理工大学 | Preparation process method of N-methyl-1, 3-propane diamine |
| CN113801069A (en) * | 2020-06-15 | 2021-12-17 | 鲁南制药集团股份有限公司 | Alfuzosin hydrochloride intermediate compound |
| CN114591273A (en) * | 2022-03-31 | 2022-06-07 | 邦恩泰(山东)生物医药科技集团股份有限公司 | Synthesis method and application of N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate |
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| 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 |
| CN101687859A (en) * | 2007-05-04 | 2010-03-31 | 阿克塔维什集团Ptc公司 | Process for the preparation of alfuzosin and salts thereof |
| CN101747323A (en) * | 2009-11-06 | 2010-06-23 | 北京理工大学 | Method for preparing alfuzosin hydrochloride |
| JP2015143194A (en) * | 2014-01-31 | 2015-08-06 | 広栄化学工業株式会社 | Method for producing amine compound |
-
2016
- 2016-11-24 CN CN201611093013.3A patent/CN106632280A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101687859A (en) * | 2007-05-04 | 2010-03-31 | 阿克塔维什集团Ptc公司 | Process for the preparation of alfuzosin and salts thereof |
| CN101747323A (en) * | 2009-11-06 | 2010-06-23 | 北京理工大学 | Method for preparing alfuzosin hydrochloride |
| JP2015143194A (en) * | 2014-01-31 | 2015-08-06 | 広栄化学工業株式会社 | Method for producing amine compound |
Non-Patent Citations (1)
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| 朱星研: "《沈阳药科大学硕士学位论文》", 31 December 2009 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111454159A (en) * | 2020-04-04 | 2020-07-28 | 大连理工大学 | Preparation process method of N-methyl-1, 3-propane diamine |
| 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 |
| CN114591273A (en) * | 2022-03-31 | 2022-06-07 | 邦恩泰(山东)生物医药科技集团股份有限公司 | Synthesis method and application of N-methyl-N' -tetrahydrofuran formyl propane diamine oxalate |
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Application publication date: 20170510 |