CN1083451C - Process for synthesizing doxazosin mesylate - Google Patents
Process for synthesizing doxazosin mesylate Download PDFInfo
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- CN1083451C CN1083451C CN99117037A CN99117037A CN1083451C CN 1083451 C CN1083451 C CN 1083451C CN 99117037 A CN99117037 A CN 99117037A CN 99117037 A CN99117037 A CN 99117037A CN 1083451 C CN1083451 C CN 1083451C
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- piperazine
- pyrocatechol
- dibromo
- benzodioxan
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Abstract
The present invention discloses a new technique for synthesizing doxazosin mesylate. Original six reaction steps are shortened to four reaction steps. The present invention is characterized in that pyrocatechol reacts with 2, 3-dibromophenyl propionic ether under an alkaline condition to obtain 1, 4-phenylpropyl dioxane-2-formic ether, and then the pyrocatechol reacts with piperazine to obtain 1-(1 4-phenylpropyl dioxane-2-formic ether) piperazine, and finally, the pyrocatechol condenses with 6 7-dimethoxy-2-chlorine-4-aminoquinoline to obtain a final product through salification. The present invention has the characteristics of simple operatin, low consumption of raw materials, high yield and low cost, and greatly reduces environmental pollution caused by waste water, waste gas and waste residues.
Description
The present invention relates to the new synthetic process of a kind of medicine synthesising process, particularly doxazosin mesylate.
Along with the trend development of society to astogeny, hypertension and cardiovascular and cerebrovascular disease have become common complaint among the elderly, in the medicine of hypertension disease, doxazosin mesylate has become a new generation's one line medicine of external widespread usage, and China researchs and develops at present.According to reported in literature (1.J.Med.chem, 1987.30.40-45; 2.J.Med.chem.1987.30,49～57), the manufacture method of this medicine is to adopt pyrocatechol and propylene oxide effect, gets the hydrochloric acid Doxazosin, gets the finished product through salify again with 6.7-dimethoxy-2-chloro-4-amido quinazoline condensation again through cyclization, oxidation, chlorination, amination.Cyclization of this operational path and oxidizing reaction recovery rate are low, the recovery rate of oxidizing reaction very low (generally at 25-30%) particularly, and can produce heavy metal-polluted environmental pollution by water, equipment corrosion is serious during chlorination reaction.
The purpose of this invention is to provide a new synthetic route, got rid of oxidation, chlorination reaction, thereby reach purpose easy and simple to handle, that raw material consumption is few, recovery rate is high, cost is low.
The present invention realizes in such a way: add 2.3-dibromo-propionic acid ester (pyrocatechol and 2 with pyrocatechol under alkali metal hydroxide or amine solution, the mole ratio of the add-on of 3-dibromo-propionic acid ester is 0.5: 1-1: 0.5,2,3-dibromo-propionic acid ester is the ester of the alcohol of 1-5 carbon atom.) stirring reaction gets 1.4-benzodioxan-2-manthanoate; react with piperazine again; get 1-(1.4-benzodioxan-2-formyl piperazine; (1; the mole ratio of 4-benzodioxan-2-manthanoate and piperazine is 1: 10-10: 1; it is reflected in the strongly-acid liquid and carries out, and used acid can be strong acid such as hydrochloric acid, sulfuric acid, phosphoric acid.) last and 6.7-dimethoxy-2-chloro-4-amido quinazoline condensation, behind salify, get the finished product doxazosin mesylate.Its reaction equation and flow process are:
The hydrochloric acid Doxazosin
Doxazosin mesylate
Below enforcement of the present invention is described in further detail:
One, cyclization
Charging capacity: pyrocatechol 55g
2,3-dibromo-propionic acid methyl esters 123g
10% caustic lye of soda 440g
In reaction flask, add earlier under pyrocatechol and sodium hydroxide solution, the stirring, drip 2,3-dibromo-propionic acid methyl esters, stirring reaction 4 hours, the product chloroform extraction, chloroform layer merges concentrated, get 1,4-benzodioxan-2-methyl-formiate, output 75.7g (yield 78%).
Two, amination
Charging capacity: 1,4-benzodioxan-2-methyl-formiate 91g
(abbreviation methyl esters)
Piperazine 86g
Propyl carbinol 615ml
Hydrochloric acid 50ml
In reaction flask, drop into piperazine, propyl carbinol, hydrochloric acid and methyl esters, stir back flow reaction 4 hours; cooling adds water 300ml, adds dilute alkali to PH10; leave standstill branch vibration layer, oil reservoir washing; add water 300ml and be acidified to PH1 with dilute hydrochloric acid; divide water-yielding stratum, water layer transfers to alkalescence with ammoniacal liquor, suction filtration, drying; get 1-(1,4-benzodioxan-2-formyl radical) piperazine.Fusing point 105-110 ℃, output 85.0g (yield 68.5%).
Three, hydrochloric acid Doxazosin: in reaction flask, drop into 6; 7-dimethoxy-2-chloro-4-amido quinazoline 140g (0.58Mol), 1-(1; 4-benzodioxan-2-formyl radical) piperazine 150g (0.60Mol) butanols 2L; stir temperature rising reflux reaction 3.5 hours; be cooled to 80 ℃, filter, washing; drying gets hydrochloric acid Doxazosin 251g (yield 88%).Fusing point 289-290 ℃.
Four, doxazosin mesylate: 72.5g is dissolved in chloroform with the hydrochloric acid Doxazosin, and the ammonification scaleization is to PH10, and branch vibration layer, chloroform layer wash with water once, slowly add methanesulfonic 14g, separate out white solid, freezing and filtering, oven dry gets doxazosin mesylate, output 74.5g (yield 93%).
Novel process of the present invention shortens to four reactions steps to six reactions steps of prior art, thereby shortened technical process greatly, reduced reaction (production) time, and saved raw-material consumption, improved the recovery rate of product, reduced cost, and easy and simple to handle, significantly reduced the pollution of " three wastes " in the production process to environment.
Embodiment 1:
One, ring-closure reaction: in reaction flask, drop into pyrocatechol 55g (0.5Mol), 10% caustic lye of soda 440g.Stirring drips 2 down, and 3-dibromo-propionic acid methyl esters 123g (0.5Mol) added temperature rising reflux 4 hours, was chilled to room temperature, the product chloroform extraction, and chloroform layer merges concentrated, gets 1,4-benzodioxan-2-methyl-formiate, output 75.7g (yield 78%).
Two, amination reaction: in reaction flask, drop into piperazine 86g (1Mol), propyl carbinol 615ml, hydrochloric acid 50ml and 1,4-benzodioxan-2-methyl-formiate 97g (0.5Mol), stirring and refluxing reaction 4 hours; cooling adds water 300ml, is neutralized to PH10 with alkali, leaves standstill; branch vibration layer; after the oil reservoir washing, add water 300ml with hcl acidifying to PH1, divide water-yielding stratum; water layer transfers to PH9 with ammoniacal liquor; suction filtration, drying get 1-(1,4-benzodioxan-2-formyl radical) piperazine.Fusing point 105-110 ℃, output 85.0g (yield 68.5%).
Three, hydrochloric acid Doxazosin: in reaction flask, drop into 6; 7-diformazan oxidation-2-chloro-4-amido quinazoline 140g (0.58Mol), 1-(1; 4-benzo dioxane-2-formyl radical) piperazine 150g (0.60Mol) butanols 2L; stir temperature rising reflux reaction 3.5 hours; be cooled to 80 ℃, filter, washing; drying gets hydrochloric acid Doxazosin 251g (yield 88%).Fusing point 289-290 ℃.
Four, doxazosin mesylate: 72.5g is dissolved in chloroform with the hydrochloric acid Doxazosin, and the ammonification scaleization is to PH10, and branch vibration layer, chloroform layer wash with water once, slowly add methanesulfonic 14g, separate out white solid, freezing and filtering, oven dry gets doxazosin mesylate, output 74.5g (yield 93%).
Embodiment 2:
One, ring-closure reaction: in reaction flask, drop into pyrocatechol 82.5g (0.75Mol), 10% potassium hydroxide 440g.Stir dropping 2 down, 3-dibromo ethyl propionate 130g (0.5Mol), dropping back temperature rising reflux reaction 8 hours is chilled to room temperature, the product chloroform extraction, chloroform layer merges concentrated, gets 1,4-benzodioxan-2-ethyl formate, output 78g (yield 75%).
Two, amination reaction: in reaction flask, drop into piperazine 120.4g (1Mol), propyl carbinol 500ml, 1; 4-benzodioxan-2-methyl-formiate 104g (0.5Mol); stir and drip sulfuric acid 68.6g (0.70Mol) down; stirring and refluxing reaction 4 hours; cooling adds water 300ml; adding alkali alkalizes to PH10; leave standstill, branch vibration layer is after the oil reservoir washing; add water 300ml with hcl acidifying to PH1; divide water-yielding stratum, water layer transfers to PH9 with ammoniacal liquor, suction filtration, drying; get 1-(1,4-benzodioxan-2-formyl radical) piperazine.Fusing point 105-110 ℃, output 80.7g (yield 65.1%).
The hydrochloric acid Doxazosin is identical with embodiment 1 with the technology of doxazosin mesylate.
Claims (6)
1; a kind of process for synthesizing doxazosin mesylate; comprise by pyrocatechol and 2; 3-dibromo-propionic acid ester; piperazine; 6; 7-dimethoxy-2-chloro-4-amido quinazoline is through cyclization; amination; become salt refining to form; wherein; " cyclization " is meant by pyrocatechol and 2; the reaction of 3-dibromo-propionic acid methyl esters generates 1.4-benzdioxan-2-methyl-formiate; because in this reaction, generated " benzdioxan " six-ring; " amination " is meant that 1.4-benzdioxan-2-manthanoate and piperazine reaction generate 1-(1.4-benzdioxan-2-formyl) piperazine; the amido of piperazine be is characterized in that pyrocatechol and 2 by acidylate in this reaction, and the reaction of 3-dibromo-propionic acid ester generates 1; 4-benzodioxan-2-manthanoate; its reaction is to carry out ring-closure reaction in basic solution, gained intermediate 1, and 4-benzodioxan-2-manthanoate and piperazine reaction generate 1-(1; 4-benzodioxan-2-formyl radical) piperazine, its amination is to react in strongly acidic solution.
2, synthesis technique according to claim 1 is characterized in that pyrocatechol and 2, and the mole ratio of 3-dibromo-propionic acid ester is 0.5: 1-1: 0.5.
3, synthesis technique according to claim 1 is characterized in that 2, and 3-dibromo-propionic acid ester is the ester that contains the alcohol of 1-5 carbon atom.
4, synthesis technique according to claim 1 is characterized in that alkaline solution used in the ring-closure reaction is metal hydroxides or amine.
5, synthesis technique according to claim 1 is characterized in that 1, and the mole ratio of 4-benzodioxan-2-manthanoate and piperazine is 1: 10-10: 1.
6, synthesis technique according to claim 1 is characterized in that the used acid of amination reaction can use strong acid such as hydrochloric acid, sulfuric acid, phosphoric acid.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN99117037A CN1083451C (en) | 1999-08-20 | 1999-08-20 | Process for synthesizing doxazosin mesylate |
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| Application Number | Priority Date | Filing Date | Title |
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| CN99117037A CN1083451C (en) | 1999-08-20 | 1999-08-20 | Process for synthesizing doxazosin mesylate |
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| CN1285353A CN1285353A (en) | 2001-02-28 |
| CN1083451C true CN1083451C (en) | 2002-04-24 |
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| CN99117037A Expired - Lifetime CN1083451C (en) | 1999-08-20 | 1999-08-20 | Process for synthesizing doxazosin mesylate |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100391459C (en) * | 2003-05-26 | 2008-06-04 | 沈阳药科大学 | Doxazosin mesilate slow releasing preparation |
| CN100396282C (en) * | 2006-07-25 | 2008-06-25 | 山东省医药工业研究所 | Slow released doxazosin mesilate capsule and its prepn process |
| CN105985328B (en) * | 2015-02-03 | 2019-03-19 | 中国科学院广州生物医药与健康研究院 | The synthetic method of Doxazosin |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4188390A (en) * | 1977-11-05 | 1980-02-12 | Pfizer Inc. | Antihypertensive 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl) piperazin-1-yl or homopiperazin-1-yl]quinazolines |
-
1999
- 1999-08-20 CN CN99117037A patent/CN1083451C/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4188390A (en) * | 1977-11-05 | 1980-02-12 | Pfizer Inc. | Antihypertensive 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl) piperazin-1-yl or homopiperazin-1-yl]quinazolines |
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Effective date of registration: 20090605 Address after: Nanhu Lake Industrial Zone, Mount Xia, Puning, Guangdong Patentee after: Kangmei Pharmaceutical Co., Ltd. Address before: Nanhu Lake Industrial Zone, Mount Xia, Puning, Guangdong Patentee before: Guangdong Kangmei Pharmaceutical Industry Co., Ltd. |
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