CN102617481A - Preparation method of rosuvastatin calcium - Google Patents
Preparation method of rosuvastatin calcium Download PDFInfo
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- CN102617481A CN102617481A CN201210069448XA CN201210069448A CN102617481A CN 102617481 A CN102617481 A CN 102617481A CN 201210069448X A CN201210069448X A CN 201210069448XA CN 201210069448 A CN201210069448 A CN 201210069448A CN 102617481 A CN102617481 A CN 102617481A
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Abstract
The invention discloses a preparation method of rosuvastatin calcium. The method comprises the following steps of: synthesizing an important intermediate, i.e., [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-mesyl amino)pyrimidine-5-radical]methanol (compound IV); and preparing the rosuvastatin calcium (compound I). The method has the advantages of readily available raw materials, high stereoselectivity, high yield and suitability for industrial production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry technical field, be specifically related to a kind of preparation method of rosuvastain calcium.
Background technology
Rosuvastain calcium (Rosuvastatin calcium); Chemistry (+)-(3R by name; 5S)-and 7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl is amino) pyrimidine-5-yl]-3,5-dihydroxyl-6 (E)-heptenoic acid calcium is that the wild justice of Japanese salt (Osaka Shionogi company) is developed; Transfer Britain AstraZeneca company in April, 1998, gone on the market by drugs approved by FDA in August, 2003.Rosuvastain calcium can reduce LDL-SUV, total cholesterol, tri-glyceride and the ApoB of rising, increases the HDL-SUV.From comparison two aspects of existing Clinical results and like product, rosuvastain calcium has efficiently, low, advantage such as spinoff is little, is called as " super he spit of fland ", is the blood lipid-lowering medicine of effect the most by force up to now, and market outlook are very good.
Ⅰ
Present a lot of about the Study of synthesis method of rosuvastain calcium; All be to adopt a parent nucleus pyrimidine derivatives and a chain portion the two to be combined through Wittig Reaction or Wittig-Horner Reaction; And then it is basic to remove protection; Last hydrolysis salify obtains rosuvastain calcium.Summarize and get up to have following two types:
First kind method:
Ⅱ 2
Second class methods:
4 5
5 Ⅰ
Midbody compound II that above-mentioned two class methods are used and compound 4 all need be used midbody IV of common; I.e. [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol, and the synthetic of this compound all is to adopt following method:
Ⅴ Ⅳ
The reductive agent that adopts is and two (2-methoxyethoxy) sodium aluminates of isobutyl-aluminum hydride (DIBAl-H) or dihydro
(Red-Al), therefore these two kinds of reductive agent prices make that all than higher the cost of compound IV is high.
Summary of the invention
The objective of the invention is to overcome deficiency of the prior art, a kind of preparation method of rosuvastain calcium is provided.
A kind of preparation method of rosuvastain calcium may further comprise the steps:
(1) adds compound V and butylacetate in the reaction flask, stir down, be cooled to 10 ℃, add Peng Qinghuana; Continuation was stirred 20--40 minute under this temperature, reduced to 0-5 ℃ then, slowly dripped boron trifluoride ether solution, after dropwising; Recovered room temperature reaction 5--7 hour, reaction is reduced to 5 ℃ after finishing, and slowly drips the 2mol/l aqueous sodium hydroxide solution; To PH=6-7, continue to stir 20--40 minute, leave standstill the reaction solution layering; Water layer is used n-butyl acetate extraction again, merges organic layer, uses the saturated common salt water washing, uses anhydrous sodium sulfate drying at last; Filter, filtrating is concentrated into dried, obtains bullion, with toluene and sherwood oil recrystallization, obtains the compound IV;
(2) add compound IV, ETHYLE ACETATE and catalyzer 4-methoxyl group-2,2,6,6-tetramethyl piperidine oxyradical in the reaction flask; Stir down, drip aqueous sodium hypochlorite solution, dropwise stirring at room 1--2 hour; After reaction finishes, filter, the filtrating layering, water layer is used ethyl acetate extraction again; Merge organic layer, use the saturated common salt water washing again, use anhydrous sodium sulfate drying at last; Filter, filtrating is concentrated into dried, and resistates obtains compound ii with toluene and re-crystallizing in ethyl acetate;
(3) add compound VI, trimethyl phosphite and toluene in the reaction flask, back flow reaction is spent the night, and after reaction finishes, concentrates and removes toluene and unreacted trimethyl phosphite completely, obtains the bullion of compound III, can directly drop into down to go on foot and react; Under the nitrogen protection, add compound III and anhydrous tetrahydro furan in the reaction flask, stir down, add sodium hydride in batches, reinforced finishing; Stirring at room 20--40 minute, be cooled to 5 ℃ then, drip the tetrahydrofuran solution that is dissolved with compound ii, dropwise back flow reaction 4--6 hour; Reaction is poured into reaction solution in the frozen water after finishing, and stirs layering 10--20 minute; Water layer is used ethyl acetate extraction again, merges organic layer, uses the saturated common salt water washing, uses anhydrous sodium sulfate drying at last; Filter, filtrating is concentrated into dried, and resistates adds the Virahol recrystallization, obtains the compound VII;
(4) add compound VII and THF in the reaction flask, stir down, drip 4N hydrochloric acid; Dropwise, stirring at room reaction 2--4 hour is after reaction finishes; Reaction solution is cooled to 0 ℃, slowly drips the 2mol/l aqueous sodium hydroxide solution to PH=6, adds dichloromethane extraction then; Dichloromethane layer with washing, is used anhydrous sodium sulfate drying more at last; Filter, filtrating is concentrated into dried, and resistates adding isopropyl ether stirs to be washed, and obtains solid, and the solid that obtains is used second alcohol and water recrystallization again, obtains white solid, i.e. the compound VIII;
(5) add compound VIII and absolute ethyl alcohol in the reaction flask, be cooled to 5 ℃, add aqueous sodium hydroxide solution; Kept this temperature stirring reaction 1--3 hour, and dripped the aqueous solution of calcium chloride then, dropwise; Continue stirring reaction and spend the night, suction filtration, filter cake is used water washing; Drying promptly obtains chemical compounds I, i.e. rosuvastain calcium.
In the present invention, described compound V and Peng Qinghuana mol ratio are 1.00:1.50-1.00:2.50; The mol ratio of compound V and boron trifluoride ether solution is 1.00:2.00-1.00:3.00.
In the present invention, the mol ratio of described compound IV and catalyzer is 1.00:0.01-1.00:0.05, and the mol ratio of compound IV and aqueous sodium hypochlorite solution is 1.00:3.00-1.00:5.00; The mol ratio of compound VI and trimethyl phosphite is 1.00:2.00-1.00:5.00; The mol ratio of compound ii and compound III is 1.00:1.00-1.00:0.80, and the mol ratio of compound III and sodium hydride is 1.00:1.10-1.00:1.50; The mol ratio of compound VII and hydrochloric acid is 1.00:3.00-1.00:10.00; The mol ratio of compound VIII and sodium hydroxide is 1.00:1.00-1.00:1.10; The mol ratio of compound VIII and calcium chloride is 1.00:0.50-1.00:0.60.
A kind of preparation method of rosuvastain calcium, its preparation method is expressed as with chemical equation:
V VI
Ⅳ Ⅱ
Ⅵ Ⅲ
Ⅱ Ⅲ
Ⅰ
The present invention has also announced the synthetic of midbody:
Chiral catalyst (s)-α, what α-di-isopropyl dimethyl-tertiary butyl siloxy dried meat ammonia was pure synthesizes:
1
2 3
Beneficial effect:
The present invention has following beneficial features:
(1) the compound IV is synthetic, adopts Peng Qinghuana/boron trifluoride ether solution reduction system, and, mild condition more simple to operate than existing method of reducing, cost of material are cheap;
(2) under the synthetic employing catalyst of compound ii, make oxygenant with aqueous sodium hypochlorite solution, PCC oxygenant (chromium trioxide/pyridine) or pyridine/sulphur trioxide of comparing the prior art employing pollute little, simple to operate;
(3) simple, the suitable suitability for industrialized production of whole process lock out operation.
Embodiment
Be easy to understand and understand in order to make technique means of the present invention, creation characteristic, workflow, method of use reach purpose and effect,, further set forth the present invention below in conjunction with specific embodiment.
V VI
Ⅳ Ⅱ
Ⅵ Ⅲ
Ⅱ Ⅲ
Ⅰ
Compound V and compound VI can directly be bought or be synthetic with reference to existing bibliographical information.
Synthesizing of compound IV:
Add 762 in the reaction flask and digest compound V (2.00mol) and 2500 milliliters of butylacetates, stir down, be cooled to 10 ℃, add 152 in batches and restrain Peng Qinghuanas (4.00mol); Continuation was stirred 30 minutes under this temperature, reduced to 0-5 ℃ then, slowly dripped the boron trifluoride ether solution (5.00mol) of 1434.8 grams 46%, after dropwising; Recovered room temperature reaction 6 hours, reaction is reduced to 5 ℃ after finishing, and slowly drips the 2mol/l aqueous sodium hydroxide solution; To PH=6-7, continue to stir 30 minutes, leave standstill the reaction solution layering; Water layer is used 1200 milliliters of n-butyl acetate extractions again, merges organic layer, with 2000 milliliters of saturated common salt water washings, uses anhydrous sodium sulfate drying at last; Filter, filtrating is concentrated into dried, obtains bullion, with toluene and sherwood oil recrystallization, obtains 587.2 and restrains white solids, be i.e. compound IV, yield: 83.17% (with the calculating of compound V).
Fusing point: 145.1-146.0 ℃.
Synthesizing of compound ii:
Add 353 in the reaction flask and digest compound IV (1.00mol), 2000 milliliters of ETHYLE ACETATE and 5.58 gram catalyzer 4-methoxyl groups-2,2,6,6-tetramethyl piperidine oxyradical (0.03mol); Stir down, drip the aqueous sodium hypochlorite solution (4.00mol) of 2980 grams 10%, dropwise stirring at room 1 hour; After reaction finishes, filter, the filtrating layering, water layer is used 1000 milliliters of ethyl acetate extractions again; Merge organic layer, use the saturated common salt water washing again, use anhydrous sodium sulfate drying at last; Filter, filtrating is concentrated into dried, and resistates obtains 310.2 gram white solids with toluene and re-crystallizing in ethyl acetate, i.e. compound ii, yield: 88.38% (with the calculating of compound IV).
Fusing point: 186.3-187.1 ℃.
Synthesizing of compound III:
Add 322 in the reaction flask and digest compound VI (1.00mol), 372 gram trimethyl phosphite (3.00mol) and 2000 milliliters of toluene; Back flow reaction is spent the night; After reaction finishes; Concentrate and to remove toluene and unreacted trimethyl phosphite completely, obtain 355.1 digest the compound III bullion, can directly drop into down to go on foot and react;
Synthesizing of compound VII:
Under the nitrogen protection, add to go up 355.1 gram bullion compound III and 1500 milliliters of step preparation in the reaction flask
Anhydrous tetrahydro furan stirs down, adds the sodium hydride (1.20mol) of 48 grams 60% in batches, reinforced finishing, and stirring at room 30 minutes is cooled to 5 ℃ then, and dropping is dissolved with 358.0 and digests compound II (1.02mol)
1000 milliliters of tetrahydrofuran solutions, dropwise, back flow reaction 5 hours after reaction finishes, is poured into reaction solution in 3000 milliliters of frozen water; Stirred 15 minutes, layering, water layer is used 1200 milliliters of ethyl acetate extractions again, merges organic layer; Use the saturated common salt water washing, use anhydrous sodium sulfate drying at last, filter, filtrating is concentrated into dried; Resistates adds the Virahol recrystallization, obtains 509.2 gram off-white color solids, i.e. compound VII, yield: 88.25% (calculating with the compound VI).
Fusing point: 152.1-153.0 ℃.
Synthesizing of compound VIII:
Add 288.5 in the reaction flask and digest compound VII (0.50mol) and 500 milliliters of THFs, stir down, drip 625 milliliters of 4N hydrochloric acid; Dropwise, stirring at room reaction 3 hours is after reaction finishes; Reaction solution is cooled to 0 ℃, slowly drips the 2mol/l aqueous sodium hydroxide solution to PH=6, adds 2000 milliliters of dichloromethane extractions then; Dichloromethane layer is used 800 milliliters of washings again, uses anhydrous sodium sulfate drying at last; Filter, filtrating is concentrated into dried, and resistates adds isopropyl ether and stirs and washes, and obtains solid, and the solid that obtains is used second alcohol and water recrystallization again, obtains 255.4 gram white solids, i.e. compound VIII, yield: 95.12% (calculating with the compound VII).
Chemical compounds I is the preparation of rosuvastain calcium:
Add 429.6 in the reaction flask and digest compound VIII (0.80mol) and 300 milliliters of ethanol, be cooled to 5 ℃, add the aqueous sodium hydroxide solution of 420 milliliters of 2.0mol/l, kept this temperature stirring reaction 2 hours; Drip 250 milliliters of the aqueous solution being dissolved with 45.3 gram calcium chloride then, dropwise, continue stirring reaction and spend the night suction filtration; Filter cake is used water washing, and drying obtains 382.1 gram white solids; Be chemical compounds I, i.e. rosuvastain calcium, yield: 95.43% (calculating) with the compound VIII.
e.e:99.4%
HPLC:99.1% (external standard method).
More than show and described ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; The present invention is not restricted to the described embodiments; That describes in the foregoing description and the specification sheets just explains principle of the present invention; Under the prerequisite that does not break away from spirit and scope of the invention, the present invention also has various changes and modifications, and these variations and improvement all fall in the scope of the invention that requires protection.The scope of the present invention is required by the appended claims and their equivalents define
.
Claims (3)
1. the preparation method of a rosuvastain calcium is characterized in that, may further comprise the steps:
(1) adds compound V and butylacetate in the reaction flask, stir down, be cooled to 10 ℃, add Peng Qinghuana; Continuation was stirred 20--40 minute under this temperature, reduced to 0-5 ℃ then, slowly dripped boron trifluoride ether solution, after dropwising; Recovered room temperature reaction 5--7 hour, reaction is reduced to 5 ℃ after finishing, and slowly drips the 2mol/l aqueous sodium hydroxide solution; To PH=6-7, continue to stir 20--40 minute, leave standstill the reaction solution layering; Water layer is used n-butyl acetate extraction again, merges organic layer, uses the saturated common salt water washing, uses anhydrous sodium sulfate drying at last; Filter, filtrating is concentrated into dried, obtains bullion, with toluene and sherwood oil recrystallization, obtains the compound IV;
(2) add compound IV, ETHYLE ACETATE and catalyzer 4-methoxyl group-2,2,6,6-tetramethyl piperidine oxyradical in the reaction flask; Stir down, drip aqueous sodium hypochlorite solution, dropwise stirring at room 1--2 hour; After reaction finishes, filter, the filtrating layering, water layer is used ethyl acetate extraction again; Merge organic layer, use the saturated common salt water washing again, use anhydrous sodium sulfate drying at last; Filter, filtrating is concentrated into dried, and resistates obtains compound ii with toluene and re-crystallizing in ethyl acetate;
(3) add compound VI, trimethyl phosphite and toluene in the reaction flask, back flow reaction is spent the night, and after reaction finishes, concentrates and removes toluene and unreacted trimethyl phosphite completely, obtains the bullion of compound III, can directly drop into down to go on foot and react; Under the nitrogen protection, add compound III and anhydrous tetrahydro furan in the reaction flask, stir down, add sodium hydride in batches, reinforced finishing; Stirring at room 20--40 minute, be cooled to 5 ℃ then, drip the tetrahydrofuran solution that is dissolved with compound ii, dropwise back flow reaction 4--6 hour; Reaction is poured into reaction solution in the frozen water after finishing, and stirs layering 10--20 minute; Water layer is used ethyl acetate extraction again, merges organic layer, uses the saturated common salt water washing, uses anhydrous sodium sulfate drying at last; Filter, filtrating is concentrated into dried, and resistates adds the Virahol recrystallization, obtains the compound VII;
(4) add compound VII and THF in the reaction flask, stir down, drip 4N hydrochloric acid; Dropwise, stirring at room reaction 2--4 hour is after reaction finishes; Reaction solution is cooled to 0 ℃, slowly drips the 2mol/l aqueous sodium hydroxide solution to PH=6, adds dichloromethane extraction then; Dichloromethane layer with washing, is used anhydrous sodium sulfate drying more at last; Filter, filtrating is concentrated into dried, and resistates adding isopropyl ether stirs to be washed, and obtains solid, and the solid that obtains is used second alcohol and water recrystallization again, obtains white solid, i.e. the compound VIII;
(5) add compound VIII and absolute ethyl alcohol in the reaction flask, be cooled to 5 ℃, add aqueous sodium hydroxide solution; Kept this temperature stirring reaction 1--3 hour, and dripped the aqueous solution of calcium chloride then, dropwise; Continue stirring reaction and spend the night, suction filtration, filter cake is used water washing; Drying promptly obtains chemical compounds I, i.e. rosuvastain calcium.
2. the preparation method of a rosuvastain calcium is characterized in that, may further comprise the steps: described compound V and Peng Qinghuana mol ratio are 1.00:1.50-1.00:2.50; The mol ratio of compound V and boron trifluoride ether solution is 1.00:2.00-1.00:3.00.
3. the preparation method of a rosuvastain calcium; It is characterized in that; May further comprise the steps: the mol ratio of described compound IV and catalyzer is 1.00:0.01-1.00:0.05, and the mol ratio of compound IV and aqueous sodium hypochlorite solution is 1.00:3.00-1.00:5.00; The mol ratio of compound VI and trimethyl phosphite is 1.00:2.00-1.00:5.00; The mol ratio of compound ii and compound III is 1.00:1.00-1.00:0.80, and the mol ratio of compound III and sodium hydride is 1.00:1.10-1.00:1.50; The mol ratio of compound VII and hydrochloric acid is 1.00:3.00-1.00:10.00; The mol ratio of compound VIII and sodium hydroxide is 1.00:1.00-1.00:1.10; The mol ratio of compound VIII and calcium chloride is 1.00:0.50-1.00:0.60.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103420919A (en) * | 2013-08-22 | 2013-12-04 | 南京欧信医药技术有限公司 | Synthetic method for pyrimidine derivatives |
| CN103755643A (en) * | 2013-12-31 | 2014-04-30 | 连云港金康医药科技有限公司 | Rosuvastatin calcium I crystal form |
| CN103848790A (en) * | 2012-12-05 | 2014-06-11 | 安徽省庆云医药化工有限公司 | Novel crystal form of rosuvastatin |
| CN105153040A (en) * | 2015-10-15 | 2015-12-16 | 江苏师范大学 | New rosuvastatin calcium crystal form and preparation method thereof |
| CN105837516A (en) * | 2016-05-16 | 2016-08-10 | 山东新时代药业有限公司 | Rosuvastatin calcium crystal form and preparation method thereof |
| CN107235918A (en) * | 2017-06-30 | 2017-10-10 | 苏州卫生职业技术学院 | The preparation method of rosuvastain calcium intermediate |
| CN109734672A (en) * | 2019-03-07 | 2019-05-10 | 烟台舜康生物科技有限公司 | A kind of synthetic method and rosuvastain calcium parent nucleus of rosuvastain calcium parent nucleus |
| CN110963971A (en) * | 2019-12-13 | 2020-04-07 | 浙江工业大学 | Preparation method for synthesizing rosuvastatin calcium intermediate |
| CN113831295A (en) * | 2021-09-26 | 2021-12-24 | 江苏福瑞康泰药业有限公司 | Method for synthesizing rosuvastatin ester by using continuous flow tubular reactor |
| CN115521260A (en) * | 2022-09-27 | 2022-12-27 | 江苏阿尔法药业股份有限公司 | Synthetic method of rosuvastatin calcium tert-butyl ester |
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Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103848790B (en) * | 2012-12-05 | 2016-08-03 | 安徽省庆云医药化工有限公司 | Crystal formation of Rosuvastatin ester and preparation method thereof |
| CN103848790A (en) * | 2012-12-05 | 2014-06-11 | 安徽省庆云医药化工有限公司 | Novel crystal form of rosuvastatin |
| WO2014086072A1 (en) * | 2012-12-05 | 2014-06-12 | 安徽省庆云医药化工有限公司 | Crystal form of rosuvastatin ester and method of preparing same |
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| CN103755643A (en) * | 2013-12-31 | 2014-04-30 | 连云港金康医药科技有限公司 | Rosuvastatin calcium I crystal form |
| CN105153040B (en) * | 2015-10-15 | 2018-04-13 | 江苏师范大学 | Rosuvastain calcium novel crystal forms and preparation method thereof |
| CN105153040A (en) * | 2015-10-15 | 2015-12-16 | 江苏师范大学 | New rosuvastatin calcium crystal form and preparation method thereof |
| CN105837516A (en) * | 2016-05-16 | 2016-08-10 | 山东新时代药业有限公司 | Rosuvastatin calcium crystal form and preparation method thereof |
| CN105837516B (en) * | 2016-05-16 | 2018-07-10 | 山东新时代药业有限公司 | A kind of rosuvastain calcium crystal form and preparation method thereof |
| CN107235918A (en) * | 2017-06-30 | 2017-10-10 | 苏州卫生职业技术学院 | The preparation method of rosuvastain calcium intermediate |
| CN109734672A (en) * | 2019-03-07 | 2019-05-10 | 烟台舜康生物科技有限公司 | A kind of synthetic method and rosuvastain calcium parent nucleus of rosuvastain calcium parent nucleus |
| CN109734672B (en) * | 2019-03-07 | 2021-12-07 | 烟台舜康生物科技有限公司 | Synthetic method of rosuvastatin calcium mother nucleus and rosuvastatin calcium mother nucleus |
| CN110963971A (en) * | 2019-12-13 | 2020-04-07 | 浙江工业大学 | Preparation method for synthesizing rosuvastatin calcium intermediate |
| CN110963971B (en) * | 2019-12-13 | 2021-10-15 | 浙江工业大学 | Preparation method for synthesizing rosuvastatin calcium intermediate |
| CN113831295A (en) * | 2021-09-26 | 2021-12-24 | 江苏福瑞康泰药业有限公司 | Method for synthesizing rosuvastatin ester by using continuous flow tubular reactor |
| CN113831295B (en) * | 2021-09-26 | 2024-03-19 | 江苏福瑞康泰药业有限公司 | Method for synthesizing rosuvastatin ester by using continuous flow tubular reactor |
| CN115521260A (en) * | 2022-09-27 | 2022-12-27 | 江苏阿尔法药业股份有限公司 | Synthetic method of rosuvastatin calcium tert-butyl ester |
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Application publication date: 20120801 |