CN106397335A - Preparation method of rosuvastatin intermediate - Google Patents
Preparation method of rosuvastatin intermediate Download PDFInfo
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- CN106397335A CN106397335A CN201610774296.1A CN201610774296A CN106397335A CN 106397335 A CN106397335 A CN 106397335A CN 201610774296 A CN201610774296 A CN 201610774296A CN 106397335 A CN106397335 A CN 106397335A
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- organic solvent
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- rosuvastatin intermediate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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Abstract
The invention discloses a preparation method of a rosuvastatin intermediate, and belongs to the technical field of intermediates. The method comprises the following steps: carrying out a reduction reaction on Z6, KBH4 and a Lewis acid in an organic solvent at 60-100 DEG C to obtain Z7, wherein a mass ratio of the Z6 to KBH4 to the Lewis acid is (105-130):(50-60):(50-70); carrying out a reaction on the Z7 and phosphorous tribromide in an organic solvent at 10-50 DEG C to obtain Z8.1, wherein a mass ratio of the Z7 to phosphorous tribromide is 1:(1-1.3), and the organic solvent is C1-C3 halogenated hydrocarbon; and carrying out a reaction on the Z8.1 and ethyl diphenylphosphinite in an organic solvent at 40-100 DEG C to obtain Z9, wherein a mass ratio of the Z8.1 to ethyl diphenylphosphinite is (1.5-1.8):1. The method has the advantages of easily available raw materials, mild reaction conditions, easy realization of industrial production, high yield, and easiness in separation of the solvents.
Description
Technical field
The invention belongs to intermediate synthesis technical field, particularly to the preparation method of Rosuvastatin intermediate, especially
It is related to a kind of method with Rosuvastatin intermediate Z6 for Material synthesis Rosuvastatin intermediate Z9.
Background technology
Angiocardiopathy is the healthy disease of a class serious harm, in recent years, either east or western countries,
The M ＆ M of such disease is all in rising trend.According to World Health Organization's statistics, the whole world every year about 1500
Ten thousand people die from angiocardiopathy.And in China, the cardiovascular and cerebrovascular incidence of disease is up to 8%, the death rate is close to the 50% of general mortality rate.Heart and brain
Vascular diseases are mostly derived from atherosclerotic, and more than 80% atherosclerotic is to be caused by hyperlipemia.So, reduce
High fat of blood and regulation blood lipid level are of great significance for the treatment tool of atherosclerotic and cardiovascular and cerebrovascular disease.
In the later stage 1980s, scientist have studied a kind of new drug being statin, achieves in treatment blood fat
Important breakthrough.The a large amount of clinical research in the whole world shows, statins adjusts fat intervention can reduce the occurrence risk of coronary heart disease.From 1987
Year first statins Lovastatin listing of United States Merck company, statin series is commercially fluffy due to its remarkable performance
The exhibition of breaking out, the statins come out one after another have Lovastatin, Simvastatin, Pravastatin, Fluvastatin, simvastatin, Ah
Atorvastatin, Pitavastatin, Rosuvastatin.The chain chemistry basic simlarity of these medicines, but because its parent nucleus is joined
Body structure is different, and its lipophilic performance is each variant each other, and drug effect is also each has something to recommend him, even so, they still have common spy
Property：Reduce total plasma cholesterol, cholesterol, the effect of Level of Apolipoprotein B.In addition, they are for reduction plasma triglyceride level
HDL cholesterol is also all effective with raising, and also prevents the effect of senile osteoporosis.Because statins has height
Effect property, the fine quality of low toxicity side effect, this series of products has become as the medicine of most future in contemporary cardiovascular medicament
One of.
The chemical name of Rosuvastatin is（+）-（3R,5S）- bis- { 7-【4-（4- fluorophenyl）- 6- isopropyl -2-（N- first
Base-N- methylsulfonyl amido）Pyrimidine -5- base】- 3,5- dihydroxy -6-（E）- heptenoic acid } half calcium salt.In November, 2002 is first in Holland
First list, in August, 2003 lists in the U.S., at present in the country's listing of more than 60, the whole world, also there is sale in China.Preclinical
Experiment and the multinomial clinical testing carrying out in the whole world show, Rosuvastatin has the regulating lipid more higher than other statinses
With similar security.Identical with other statinses, Rosuvastatin is produced by Reverse transcriptase HMG-COA reductase
The raw effect reducing LDL-C.Except for the difference that, there are the methylsulfonyl amido of a polarity, its hydrophily in the structure of Rosuvastatin
Stronger than other Statins.
Fine chemistry industry 2006 2 months, the 2nd phase of volume 23,《The improvement in synthesis of Rosuvastatin intermediate》And its ginseng
Examine document and provide a kind of circuit of Rosuvastatin intermediate, its process is：Z6 reduction preparation Z7, method one is to use DIBAL-
H is as reducing agent, -28 DEG C of reactions；Two is to use LiAlH4And NaBH4Collective effect, -74 DEG C of reactions.Both reaction conditions are severe
Carve, be all under cryogenic and to be required for nitrogen protection；Z7 and phosphorus tribromide are synthesized Z8.1, and the method for document report is all
It is the solvent pairs using toluene and dichloromethane, there is temperature low（Less than 0 DEG C）, to separate more complicated and yield low（Yield is
91.2%）The problems such as；Then the parent nucleus Z9 in Z8.1 and hexichol base oxethyl phosphorus reaction synthesizing rosuvastatin spit of fland.
Content of the invention
In order to solve the above problems, embodiments provide a kind of preparation method of Rosuvastatin intermediate.Institute
State technical scheme as follows：
Embodiments provide a kind of preparation method of Rosuvastatin intermediate, the method comprises the following steps：
(1) Z6 and KBH4Carry out reduction reaction in organic solvent with lewis acid and obtain Z7, Z6, KBH4, lewis acidic matter
Amount ratio is 105-130:50-60:50-70（It is preferably 115-125:55-58:55-60）, reaction temperature be 60-100 DEG C.This step
Suddenly pass through using other raw materials, make reaction be not required to carry out under nitrogen protection, and reaction temperature is higher, is easy to industrialized production.
(2) Z7 is reacted with phosphorus tribromide in organic solvent and obtains Z8.1, and Z7 is 1 with the mass ratio of phosphorus tribromide:1-1.3
（It is preferably 1:1.1-1.15）, reaction temperature be 10-50 DEG C, reaction time 4-8 hour.Wherein, organic solvent is using single molten
Agent, is the halogenated hydrocarbons of 1-3 carbon atom, is specifically as follows CH3F、CH3CH2F、CH3Cl、CH3Br、CHCl3Deng preferably
CHCl3.Applicant is through groping to find not only to improve reaction temperature using single specific organic solvent moreover it is possible to improve yield
（Yield is 93.4% about）, and facilitate the recycling of solvent, save production cost, production is more conducive to control.
(3) Z8.1 obtains Z9, Z8.1 and hexichol base oxethyl phosphorus in organic solvent with hexichol base oxethyl phosphorus reaction
Mass ratio is 1.5-1.8:1（It is preferably 1.6-1.7:1）, reaction temperature be 40-100 DEG C, the reaction time be 6-15 hour.
Wherein, in said process, the chemical name of Z6 is：4- (4- fluorophenyl) -6- isopropyl -2- [(N- methyl-N- first
Sulfoamido)] -5- pyrimidinecarboxylic acid methyl esters, No. CAS is 289042-11-1.
The chemical name of Z7 is：4- (4- fluorophenyl) -6- isopropyl -2- [(N- methyl-N-methanesulfonamide base)] -5- pyrimidine
Alcohol, No. CAS is 147118-36-3.
The chemical name of Z8.1 is：4- (4- fluorophenyl) -5- bromomethyl -6- isopropyl -2- [(N- methyl-N-methanesulfonamide
Base)]-pyrimidine, No. CAS is 799842-07-2.
The chemical name of Z9 is：4- (4- fluorophenyl) -5-（Diphenyl epoxide）Methyl -6- isopropyl -2- [(N- methyl-N-
Methylsulfonyl amido)]-pyrimidine, No. CAS is 289042-10-0.
Wherein, in step (1), organic solvent is selected from dichloromethane, oxolane and acetonitrile etc., is specifically as follows tetrahydrochysene
Furans.
Wherein, in step (1), lewis acid is metal chloride, selected from calcium chloride, zinc chloride, magnesium chloride and chlorination
Cobalt etc..
Wherein, in step (2), the volume of organic solvent（ml）Quality with Z7（g）Ratio is 4-7ml/g, preferably
5-6ml/g.
Wherein, in step (3), organic solvent is the aromatic hydrocarbon containing 6-12 carbon atom, such as benzene, toluene etc..
The beneficial effect that technical scheme provided in an embodiment of the present invention is brought is：Embodiments provide a kind of auspicious easypro
Cut down the preparation method of statin intermediate, the method has the advantage that：Raw material is easy to get, reaction condition is gentle, industrialized production is easy
It is easily isolated in realization, high income, solvent.
Specific embodiment
For making the object, technical solutions and advantages of the present invention clearer, below the present invention is made further to retouch in detail
State.
Present embodiments provide the preparation method of Rosuvastatin intermediate z9, comprise the following steps：
One：The synthesis of Z7
Averagely single crowd of 94.3g, HPLC content 99.6%, yield 85.7%.
Two：The synthesis of Z8.1
6 hours reaction time, reaction temperature 10-50 DEG C, solvent is CHCl3.
Three：The synthesis of Z9
10 hours reaction time, reaction temperature 40-100 DEG C, solvent is toluene.
The foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all in the spirit and principles in the present invention
Within, any modification, equivalent substitution and improvement made etc., should be included within the scope of the present invention.
Claims (5)
1. the preparation method of Rosuvastatin intermediate is it is characterised in that comprise the following steps：
(1) Z6 and KBH4Carry out reduction reaction in organic solvent with lewis acid and obtain Z7, Z6, KBH4, lewis acidic quality
Than for 105-130:50-60:50-70, reaction temperature is 60-100 DEG C；
(2) Z7 is reacted with phosphorus tribromide in organic solvent and obtains Z8.1, and Z7 is 1 with the mass ratio of phosphorus tribromide:1-1.3, instead
Temperature is answered to be 10-50 DEG C, organic solvent is the halogenated hydrocarbons of 1-3 carbon atom；
(3) Z8.1 obtains Z9, the quality of Z8.1 and hexichol base oxethyl phosphorus in organic solvent with hexichol base oxethyl phosphorus reaction
Than for 1.5-1.8:1, reaction temperature is 40-100 DEG C.
2. the preparation method of Rosuvastatin intermediate according to claim 1 is it is characterised in that in step (1), institute
State organic solvent and be selected from dichloromethane, oxolane and acetonitrile.
3. the preparation method of Rosuvastatin intermediate according to claim 1 is it is characterised in that in step (1), institute
State lewis acid and be selected from calcium chloride, zinc chloride, magnesium chloride and cobalt chloride.
4. the preparation method of Rosuvastatin intermediate according to claim 1 is it is characterised in that in step (2), institute
The mass values of the volume and Z7 of stating organic solvent are 4-7ml/g.
5. the preparation method of Rosuvastatin intermediate according to claim 1 is it is characterised in that in step (3), institute
State the aromatic hydrocarbon that organic solvent is containing 6-12 carbon atom.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107445992A (en) * | 2017-06-19 | 2017-12-08 | 浙江美诺华药物化学有限公司 | A kind of synthetic method of Rosuvastatin Calcium intermediate |
| CN108191772A (en) * | 2017-12-28 | 2018-06-22 | 江苏悦兴医药技术有限公司 | The synthetic method of rosuvastain calcium intermediate impurities |
| CN109030652A (en) * | 2018-08-13 | 2018-12-18 | 江苏悦兴医药技术有限公司 | A kind of high-efficiency liquid chromatography method for detecting of hexichol base oxethyl phosphine |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1418198A (en) * | 2000-02-15 | 2003-05-14 | 阿斯特拉曾尼卡有限公司 | Crystalline salts of 7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl)amino] pyrimidin-5-yl]-(3R5S)-3,5-dihydroxyhept-6-enojc acid |
| WO2004103977A2 (en) * | 2003-05-21 | 2004-12-02 | Ciba Specialty Chemicals Holding Inc. | Process for the preparation of pyrimidine derivatives |
| CN103044339A (en) * | 2012-10-15 | 2013-04-17 | 武汉市江润精细化工有限责任公司 | Preparation method of rosuvastatin calcium intermediate |
| CN103613582A (en) * | 2013-11-25 | 2014-03-05 | 成都摩尔生物医药有限公司 | Rosuvastatin lactone |
| CN105175346A (en) * | 2015-05-19 | 2015-12-23 | 南京博优康远生物医药科技有限公司 | Method for synthesis of rosuvastatin calcium intermediate |
-
2016
- 2016-08-31 CN CN201610774296.1A patent/CN106397335A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1418198A (en) * | 2000-02-15 | 2003-05-14 | 阿斯特拉曾尼卡有限公司 | Crystalline salts of 7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl)amino] pyrimidin-5-yl]-(3R5S)-3,5-dihydroxyhept-6-enojc acid |
| WO2004103977A2 (en) * | 2003-05-21 | 2004-12-02 | Ciba Specialty Chemicals Holding Inc. | Process for the preparation of pyrimidine derivatives |
| CN103044339A (en) * | 2012-10-15 | 2013-04-17 | 武汉市江润精细化工有限责任公司 | Preparation method of rosuvastatin calcium intermediate |
| CN103613582A (en) * | 2013-11-25 | 2014-03-05 | 成都摩尔生物医药有限公司 | Rosuvastatin lactone |
| CN105175346A (en) * | 2015-05-19 | 2015-12-23 | 南京博优康远生物医药科技有限公司 | Method for synthesis of rosuvastatin calcium intermediate |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107445992A (en) * | 2017-06-19 | 2017-12-08 | 浙江美诺华药物化学有限公司 | A kind of synthetic method of Rosuvastatin Calcium intermediate |
| CN108191772A (en) * | 2017-12-28 | 2018-06-22 | 江苏悦兴医药技术有限公司 | The synthetic method of rosuvastain calcium intermediate impurities |
| CN109030652A (en) * | 2018-08-13 | 2018-12-18 | 江苏悦兴医药技术有限公司 | A kind of high-efficiency liquid chromatography method for detecting of hexichol base oxethyl phosphine |
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