CN108191772A - The synthetic method of rosuvastain calcium intermediate impurities - Google Patents
The synthetic method of rosuvastain calcium intermediate impurities Download PDFInfo
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- CN108191772A CN108191772A CN201711471265.XA CN201711471265A CN108191772A CN 108191772 A CN108191772 A CN 108191772A CN 201711471265 A CN201711471265 A CN 201711471265A CN 108191772 A CN108191772 A CN 108191772A
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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 kind of synthetic methods of rosuvastain calcium intermediate impurities.4 (4 fluorophenyl) 6 isopropyl 2 [(N methyl Ns methylsulfonyl) amino] pyrimidine, 5 carboxylate methyl ester (2) generates 4 (4 fluorophenyl) 6 isopropyl 2 [(N methyl Ns methylsulfonyl) amino] pyrimidine, 5 methanol (3) through reduction；Compound (3) generates 5 (bromomethyl) 4 (4 fluorophenyl) 6 isopropyl 2 [methyl (methylsulfonyl) amino] pyrimidine (4) through bromo；Compound (4) and 4 (4 fluorophenyl) 6 isopropyl 2 [(N methyl Ns methylsulfonyl) amino] pyrimidine, 5 methanol (3) coupling generation N, N'(5, 5'(oxygen two (methylene)) bis- (4 (4 fluorophenyl) 6 isopropylpyrimidins 5, 2 diyls)) bis- (N methylmethanesulfonamides) (1), the rosuvastain calcium intermediate impurities for synthesizing high-purity can be as the contamination levels product in the detection and analysis of rosuvastain calcium raw material, so as to promote the detection and analysis of rosuvastain calcium raw material to the accurate positionin of impurity and qualitative, method raw material provided by the invention is cheap and easily-available, it is easy to operate, products obtained therefrom yield 65% ± 5%, HPLC purity >=99%.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, and in particular to a kind of rosuvastain calcium intermediate impurities N, N'- (5,
5'- (oxygen two (methylene)) bis- (4- (4- fluorophenyls) -6- isopropylpyrimidin -5,2- diyls)) bis- (N- methylmethanesulfonamides)
Synthetic method.
Background technology
Rosuvastain calcium is a kind of antihyperlipidemic drug, belongs to HMG-CoA reductase inhibitor, suitable for the high courage of primary
Sterol mass formed by blood stasis (II a types, including heterozygote familial hypercholesterolemia) or Combination dyslipidaemia (II b types) patient are dieting
Or exercise regimen it is undesirable when auxiliary treatment；This product can reduce raised LDL- cholesterol, T-CHOL, triglyceride and
ApoB increases HDL- cholesterol；Homozygote Familial HypercholesterolemicPatients Patients are also applied for, can be used alone or coordinate diet
Or other lipid-lowering armamentariums (such as LDL removal method) use.Rosuvastain calcium is that effect for reducing fat is most in current listing blood lipid-lowering medicine
By force, the most comprehensive statins of fat effect are adjusted, having than the best Atorvastatin of current universally acknowledged curative effect preferably reduces
Low density lipoprotein cholesterol and the effect for improving high-density lipoprotein, and with better tolerance, side effect it is lower and
Unique medicine need to only be taken primary daily for dynamic characteristic, half-life period about 20h.Rosuvastain calcium is opened by Astrazeneca AB
Hair is developed, in multiple countries and regions listings such as the U.S., Japan, Europe, China.
The chemical name of rosuvastain calcium is：(3R, 5S, 6E) -7- [4- (4- fluorophenyls) -6- isopropyls -2- (N- first
Base-N- methylsulfonyls amido) -5- pyrimidines] -3,5- dihydroxy -6- heptenoic acid calcium.The main function position of rosuvastain calcium is
The target organs of liver-reduction cholesterol.Rosuvastain calcium increases liver LDL cell surface receptor numbers, promotes the absorption of LDL
And catabolism, it is suppressed that the thus liver synthesis of VLDL reduces the sum of VLDL and LDL particles.
Impurity N, N'- (5,5'- (oxygen two (methylene)) bis- (4- (4- fluorophenyls) -6- isopropylpyrimidin -5,2- diyls))
Bis- (N- methylmethanesulfonamides) are rosuvastain calcium intermediate 5- (bromomethyl) -4- (4- fluorophenyls) -6- isopropyl -2- [first
Base (methylsulfonyl) amino] pyrimidine (4) and its unreacted complete raw material 4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N-
Methylsulfonyl) amino] impurity that generates of pyrimidine -5- methanol (3) coupling, may residual to rosuvastain calcium next step intermediate or
In finished product, product quality is influenced, structural formula is such as shown in (1).Through retrieval, there has been no the document reports synthesized about the impurity
Road, therefore it provides a kind of synthetic method of rosuvastain calcium intermediate impurities is used for the preparation of contamination levels product with important
Realistic meaning.
Invention content
The shortcomings that it is an object of the invention to overcome the prior art, provide a kind of Rosuvastatin calcium impurities N, N'- (5,
5'- (oxygen two (methylene)) bis- (4- (4- fluorophenyls) -6- isopropylpyrimidin -5,2- diyls)) bis- (N- methylmethanesulfonamides)
Synthetic method, the synthetic method have the advantages that easy to operate, raw material is cheap and easily-available, purity is high.
The purpose of the present invention is achieved through the following technical solutions：A kind of synthesis side of rosuvastain calcium intermediate impurities
Method, the impurity (1) are：N, N'- (bis- (4- (4- the fluorophenyls) -6- isopropylpyrimidins -5,2- two of 5,5'- (oxygen two (methylene))
Base)) bis- (N- methylmethanesulfonamides) synthetic routes are as follows：
4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine -5-carboxylic acid's methyl esters (2)
Ratio with go back original reagent is 1：1.5-5.0, reducing agent are sodium borohydride or potassium borohydride；Solvent is methanol, ethyl alcohol, tetrahydrochysene furan
It mutters one or more mixing；
4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine -5- methanol (3) and bromine
Ratio for reagent is 1:1.0-4.0, brominated reagent are phosphorus tribromide, hydrobromic acid or NBS, and solvent is dichloromethane, toluene, four
Hydrogen furans or dioxane；
(5- (bromomethyl) -4- (4- fluorophenyls) -6- isopropyls -2- [methyl (methylsulfonyl) amino] pyrimidines (4) and the 4-
The ratio of (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine -5- methanol (3) is 1:1.0-1.5
Acid binding agent is potassium carbonate, sodium hydroxide or sodium carbonate, and solvent is toluene, dichloromethane, tetrahydrofuran or dioxane.
The present invention has the following advantages:With 4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino]
Pyrimidine -5-carboxylic acid's methyl esters (2) reduction generation 4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] is phonetic
Pyridine -5- methanol (3)；Compound (3) generates (5- (bromomethyl) -4- (4- fluorophenyls) -6- isopropyls -2- [methyl (first through bromo
Sulphonyl) amino] pyrimidine (4)；Compound (4) and 4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino]
Pyrimidine -5- methanol (3) coupling generation N, N'- (5,5'- (oxygen two (methylene)) it is bis- (4- (4- fluorophenyls) -6- isopropylpyrimidins -
5,2- diyls)) bis- (N- methylmethanesulfonamides) (1) synthesis high-purity rosuvastain calcium intermediate impurities can be used as it is auspicious relax cut down
Contamination levels product in the detection and analysis of statin calcium intermediate, so as to promote standard of the rosuvastain calcium intermediate detection analysis to impurity
True polarization and qualitative, is conducive to strengthen the control to the impurity, method raw material provided by the invention is cheap and easily-available, operation letter
Single, products obtained therefrom yield 65% ± 5%, HPLC purity >=99%.
Specific embodiment
It is further illustrated the present invention below with embodiment, but the present invention is not intended to be limited thereto
Embodiment one：
The preparation of 4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine -5- methanol (3)
It is phonetic that 4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] is added in into 1000ml there-necked flasks
Pyridine -5- carboxylate methyl esters (2) (95.4g, 0.25mol), methanol 477ml start stirring, sodium borohydride are added portionwise at room temperature
(23.7g, 0.625mol) is to slowly warm up to be refluxed reaction after adding, and point TLC detections find that reaction 4h raw materials disappear, instead
It should terminate, be cooled to 0~10 DEG C, 20% dilute hydrochloric acid regulation system pH=4~5 are added dropwise, filter, filtrate pressure is concentrated into substantially without evaporating
It distributes, 500ml dichloromethane and the stirring liquid separation of 300ml purified waters is added in into residue, organic phase uses 300ml purified waters again
It washed once, collect organic phase, be concentrated under reduced pressure into and dry obtain white solid 77.8g.Yield 88.1%, HPLC detections 97.8%.
1HNMR (600MHz, DMSO-d6, δ ppm)：7.80 (m, 2H), 7.23 (m, 2H), 4.54 (s, 2H), 3.56 (s,
3H), 3.50 (s, 3H), 2.60 (s, 1H), 1.36 (d, 6H)；
Embodiment two：
(the preparation of 5- (bromomethyl) -4- (4- fluorophenyls) -6- isopropyls -2- [methyl (methylsulfonyl) amino] pyrimidine (4)
It is phonetic that 4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] is added in into 1000ml there-necked flasks
Pyridine -5- methanol (3) (70g, 0.2mol) and 420ml dichloromethane stir lower ice bath and are cooled to 0~10 DEG C, into reaction system
Phosphorus tribromide (59.0g, 0.22mol) is added dropwise, is stirred to react 1h, TLC detection reactions terminate.The stirring liquid separation of 250ml water is added in, is had
Machine layer respectively washed once again with 8% sodium bicarbonate solutions of 200ml and 200ml purified waters respectively, collects organic phase and is concentrated under reduced pressure
To doing, 200ml petroleum ethers room temperature mashing 2h, filtering are added in residue, filter cake dries to obtain the compound (4) common 75.4g,
Yield 90.6%.HPLC detections 98.9%.
1HNMR (600MHz, DMSO-d6, δ ppm)：7.82 (m, 2H), 7.25 (m, 2H), 4.51 (s, 2H), 3.54 (s,
3H), 3.48 (s, 3H), 1.38 (d, 6H)；
Embodiment three：
N, N'- (5,5'- (oxygen two (methylene)) bis- (4- (4- fluorophenyls) -6- isopropylpyrimidin -5,2- diyls)) bis- (N-
Methylmethanesulfonamide) (1) preparation
(5- (bromomethyl) -4- (4- fluorophenyls) -6- isopropyls -2- [methyl (methylsulfonyl) is added in into 1000ml there-necked flasks
Amino] pyrimidine (4) (70g, 0.17mol), 4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] be phonetic
Pyridine -5- methanol (3) (63.6g, 0.18mol), potassium carbonate (47.0g, 0.34mol) and toluene 560ml stirrings, stirring are warming up to back
Stream reaction 12h, TLC detection reaction terminates, and with 20% dilute hydrochloric acid regulation system pH=6~7, filters, filter cake adds in 420ml methanol
Recrystallization, filtering drying obtain target product (1) 95.4g, yield 82.4%, HPLC detections 99.2%.
1HNMR (600MHz, DMSO-d6, δ ppm)：7.80 (m, 4H), 7.24 (m, 4H), 4.50 (s, 4H), 3.56 (s,
6H), 3.46 (s, 6H), 1.42 (d, 12H).
Claims (4)
1. the synthetic method of rosuvastain calcium intermediate impurities, it is characterised in that：The impurity be N, N'- (5,5'- (oxygen two
(methylene)) bis- (4- (4- fluorophenyls) -6- isopropylpyrimidins -5,2- diyls)) bis- (N- methylmethanesulfonamides) (1), including such as
Lower step：
(1), 4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine -5-carboxylic acid's methyl esters (2) is
Beginning raw material generates 4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine -5- methanol (3)；
(2), 5- (bromomethyl) -4- (4- fluorophenyls) -6- isopropyls -2- [methyl (methylsulfonyl) ammonia is generated after compound (3) bromo
Base] pyrimidine (4)；
(3), compound (4) again with 4- (4- fluorophenyls) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine -5- first
Alcohol (3) generates N, and N'- (5,5'- (oxygen two (methylene)) bis- (4- (4- fluorophenyls) -6- isopropylpyrimidin -5,2- diyls)) is double
(N- methylmethanesulfonamides) (1)；
Synthetic route is as follows：
2. the synthetic method of rosuvastain calcium intermediate impurities according to claim 1, it is characterised in that：4- (the 4-
Fluorophenyl) -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine -5-carboxylic acid's methyl esters (2) and go back original reagent ratio
It is 1：1.5-5.0, reducing agent are sodium borohydride or potassium borohydride；Solvent, which is methanol, ethyl alcohol, tetrahydrofuran is one or more mixes
It closes.
3. the synthetic method of rosuvastain calcium intermediate impurities according to claim 1, it is characterised in that：4- (the 4-
Fluorophenyl) ratio of -6- isopropyls -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine -5- methanol (3) and brominated reagent is 1:
1.0-4.0, brominated reagent are phosphorus tribromide, hydrobromic acid or NBS, and solvent is dichloromethane, toluene, tetrahydrofuran or dioxy six
Ring.
4. the synthetic method of rosuvastain calcium intermediate impurities according to claim 1, it is characterised in that：(5- (the bromines
Methyl) -4- (4- fluorophenyls) -6- isopropyls -2- [methyl (methylsulfonyl) amino] pyrimidines (4) and 4- (4- fluorophenyls) -6- isopropyls
The ratio of base -2- [(N- methyl-N- methylsulfonyls) amino] pyrimidine -5- methanol (3) is 1:1.0-1.5, acid binding agent is potassium carbonate, hydrogen
Sodium oxide molybdena or sodium carbonate, solvent are toluene, dichloromethane, tetrahydrofuran or dioxane.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN115974789A (en) * | 2023-01-17 | 2023-04-18 | 上虞京新药业有限公司 | Rosuvastatin calcium intermediate anhydride impurity, and preparation method and application thereof |
| CN116178280A (en) * | 2022-12-30 | 2023-05-30 | 浙江乐普药业股份有限公司 | Preparation method of rosuvastatin calcium genotoxic impurity |
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| CN1958593A (en) * | 2005-11-03 | 2007-05-09 | 上海医药工业研究院 | Method for preparing intermediate of synthesizing rosuvastatin calcium |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN116178280A (en) * | 2022-12-30 | 2023-05-30 | 浙江乐普药业股份有限公司 | Preparation method of rosuvastatin calcium genotoxic impurity |
| CN115974789A (en) * | 2023-01-17 | 2023-04-18 | 上虞京新药业有限公司 | Rosuvastatin calcium intermediate anhydride impurity, and preparation method and application thereof |
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