CN103724278A - Preparation method for tatin intermediate and derivatives thereof - Google Patents
Preparation method for tatin intermediate and derivatives thereof Download PDFInfo
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- CN103724278A CN103724278A CN201310681045.5A CN201310681045A CN103724278A CN 103724278 A CN103724278 A CN 103724278A CN 201310681045 A CN201310681045 A CN 201310681045A CN 103724278 A CN103724278 A CN 103724278A
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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
Abstract
The invention discloses a preparation method for a tatin intermediate and derivatives thereof. The compound adopts a structure shown in a formula I (refer to the specification); the preparation method is that a compound shown in a formula II (refer to the specification) and a nucleophile reagent are subjected to the ring-opening reaction, wherein R is a C1-10 alkoxy group. The preparation method has the advantages that the mild conditions are realized, the reaction operation is simple, the reaction time is short, the product transformation ratio is high and the method is suitable for large-scale production.
Description
Technical field
The preparation method who the present invention relates to a kind of Statins intermediate and derivative thereof (formula I compound), belongs to field of medicine and chemical technology.
Background technology
Rosuvastain calcium; English name: Rosuvastatin Calcium; chemistry is by name: two-[E-7-[4-(the fluorine-based phenyl of 4-)-6-sec.-propyl-2-[methyl (methylsulfonyl) amino]-pyrimidine-5-yl] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid] calcium salt.This medicine is by the Statins blood lipid regulation medicine of new generation of Japanese Shionogi company research and development, belongs to aminopyridine derivative, can powerfully suppress HMG-CoA reductase enzyme, and have liver cell effect selectivity.Reduce acting in the statins having gone on the market of low density lipoprotein cholesterol (LDC-C), high density lipoprotein increasing cholesterol (HDL-C) optimum, for the research of this medicine, also more and more receive numerous concerns.
Patent EP521471 discloses respectively a kind of synthetic method of rosuvastain calcium, wherein, just relates to the preparation method of described formula [I] compound, and key step is as follows:
The subject matter of this technique is raw material complicated process of preparation, expensive, causes target product Rosuvastatin methyl esters cost very high, and this route also uses methoxyl group diethyl borine, and operational danger is high, is not suitable for suitability for industrialized production.
Patent wo2011/160974 has announced a kind of preparation method of Rosuvastatin methyl esters: the rosuvastain calcium of take is made solvent as raw material with DMF and prepare Rosuvastatin methyl esters reacting with methyl alcohol in the presence of trimethylchlorosilane.
The problem that this technique mainly exists is that feedstock conversion is incomplete, low conversion rate, and product is difficult for purifying.
Summary of the invention
The object of the invention is the deficiency for existing technique, the experiment effort through a large amount of, provides a kind of new rosuvastain calcium intermediate and the preparation method of derivative thereof, brief, simple to operate, the applicable industrialized production of the method step.
Object of the present invention can reach by following measures:
A preparation method for formula I compound, formula II compound and nucleophilic reagent carry out ring-opening reaction, obtain formula I compound,
Wherein, R is C
1~10alkoxyl group.
In the present invention, preferred R is C
1~6straight or branched alkoxyl group.Further, R is C
1~4straight or branched alkoxyl group.
In present method, nucleophilic reagent attack formula II compound makes its open loop and reacts, and specifically can adopt alcohol compound as nucleophilic reagent, the carbonyl of actual attack formula II compound, and open loop obtains formula I compound.Therefore generally refer to alcohol compound or the little alcohol compound of steric hindrance of short chain in the application as the alcohol compound of nucleophilic reagent, can adopt C1~10 alcohol compound, preferred C1~6 alcohol compound, further preferred C1~4 alcohol compound; Such as methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol or n-hexyl alcohol etc.The mol ratio of formula II compound and nucleophilic reagent is 1.0:0.5~100, preferably 1.0:0.5~30.
Solvent in present method ring-opening reaction is selected from one or more in ethyl acetate, isopropyl acetate, n-butyl acetate, toluene, dimethylbenzene, methylene dichloride, ethylene dichloride or described nucleophilic reagent; Be can add the single or mixed solvents such as toluene, dimethylbenzene, ethyl acetate in present method, also can be directly solubilizing agent not, adopt excessive alcohol compound as solvent.
In the present invention, the temperature of ring-opening reaction can be-10 ℃~150 ℃, and as-10 ℃ of boiling points to solvent for use, wherein preferably temperature is 20 ℃~100 ℃, particularly 20 ℃ of boiling points to solvent for use.
Ring-opening reaction can not adopt catalyzer, also can adopt alkali as catalyzer, but adds alkali can make reaction more rapidly with complete as catalyzer.In the present invention, described alkali can be mineral alkali, such as hydrogen-carbonate sodium carbonate, saleratus, salt of wormwood, can be also organic weak base, such as triethylamine, pyridine.Preferably organic weak base is catalyzer.
After ring-opening reaction, solvent distillation is to dry, and residuum is added to the water, with being concentrated into the dry product type I compound that obtains after organic solvent extraction.
In the present invention, also relate to the purification of formula I compound: the formula I compound preparing can adopt single or mixed solvent to refine to reach the object of purification, and refining solvent can be one-component or the mixture of ethyl acetate, methyl alcohol, ethanol, acetonitrile, ether, isopropyl ether, normal hexane, sherwood oil etc.
In the present invention, adopt formula II compound preparationⅠcompound, mild condition, operation is simple, and the reaction times is short, and conversion rate of products is high, is suitable for large production.
Embodiment
With reference to following non-limiting examples, will describe in detail the present invention, this should not be interpreted as limiting scope of invention embodiment 1: the preparation of Rosuvastatin methyl esters
Formula II compound 10g and 200ml methyl alcohol are dropped in bottle, add salt of wormwood 1g, stirring at room 8-10 hour, stopped reaction, concentrating under reduced pressure methyl alcohol is to dry, residuum adds water 50ml, by ethyl acetate 100ml*2 extracting twice, merges organic layer, saturated aqueous common salt 50ml washing, organic layer adds suction filtration after 10g anhydrous sodium sulfate drying, and filtrate decompression is concentrated into dry product Rosuvastatin methyl esters 9.8g, the MS:495.18 of obtaining.
Embodiment 2: the preparation of Rosuvastatin ethyl ester
Formula II compound 10g and 200ml ethanol are dropped in bottle, add N-methyl piperidine 2g, stirring at room 8-10 hour, stopped reaction, concentrating under reduced pressure ethanol is to dry, residuum adds water 50ml, by ethyl acetate 100ml*2 extracting twice, merges organic layer, saturated aqueous common salt 50ml washing, organic layer adds suction filtration after 10g anhydrous sodium sulfate drying, and filtrate decompression is concentrated into dry product Rosuvastatin ethyl ester 10.3g, the MS:509.20 of obtaining.
Embodiment 3: the preparation of Rosuvastatin propyl ester
Formula II compound 10g and 60ml n-propyl alcohol are dropped in bottle, add pyridine 1.5g, stirring at room 12 hours, stopped reaction, concentrating under reduced pressure n-propyl alcohol is to dry, residuum adds water 50ml, by ethyl acetate 100ml*2 extracting twice, merges organic layer, saturated aqueous common salt 50ml washing, organic layer adds suction filtration after 10g anhydrous sodium sulfate drying, and filtrate decompression is concentrated into dry product Rosuvastatin propyl ester 9.9g, the MS:523.22 of obtaining.
Claims (10)
2. preparation method according to claim 1, is characterized in that R is C
1~6straight or branched alkoxyl group.
3. preparation method according to claim 1, is characterized in that described nucleophilic reagent is alcohol compound.
4. according to the preparation method described in claim 1 or 3, it is characterized in that described nucleophilic reagent is C
1~6alcohol compound.
5. according to the preparation method described in claim 1 or 3, it is characterized in that described nucleophilic reagent is methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol or n-hexyl alcohol.
6. according to the preparation method described in claim 1 or 3, the mol ratio that it is characterized in that formula II compound and nucleophilic reagent is 1.0:0.5~100, preferably 1.0:0.5~30.
7. preparation method according to claim 1, is characterized in that the solvent of ring-opening reaction is selected from one or more in ethyl acetate, isopropyl acetate, n-butyl acetate, toluene, dimethylbenzene, methylene dichloride, ethylene dichloride or described nucleophilic reagent.
8. preparation method according to claim 1, the temperature that it is characterized in that ring-opening reaction is-10 ℃~150 ℃, preferably 20 ℃~100 ℃.
9. preparation method according to claim 1, is characterized in that not adopting in ring-opening reaction process catalyzer, or with alkali as catalyzer.
10. preparation method according to claim 9, it is characterized in that described alkali is mineral alkali or organic bases, described mineral alkali is selected from one or more in sodium bicarbonate, saleratus, salt of wormwood, and described organic bases is selected from one or more in triethylamine, pyridine.
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105646369A (en) * | 2015-12-30 | 2016-06-08 | 安徽美诺华药物化学有限公司 | Method for preparing rosuvastatin |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0521471A1 (en) * | 1991-07-01 | 1993-01-07 | Shionogi Seiyaku Kabushiki Kaisha | Pyrimidine derivatives as HMG-CoA reductase inhibitors |
CN1543468A (en) * | 2001-08-16 | 2004-11-03 | ������ҩ��ҵ����˾ | Processes for preparing calcium salt forms of statins |
WO2005068435A1 (en) * | 2004-01-16 | 2005-07-28 | Zentiva, A. S. | A method of preparation of the hemi-calcium salt of (e)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonvl)aminolpyrimidin-5-yl](3r,5s)-3,5-, dihvdroxy-6-heptenoic acid |
CN1763015A (en) * | 2004-10-22 | 2006-04-26 | 四川抗菌素工业研究所有限公司 | Preparation method and intermediate of rosuvastatin and its pharmaceutical salts |
CN1898233A (en) * | 2003-10-24 | 2007-01-17 | 阿斯利康(英国)有限公司 | Process for the manufacture of the calcium salt of rosuvatatin (e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-enoic acid and crystallin |
WO2011160974A2 (en) * | 2010-06-21 | 2011-12-29 | Nicox S.A. | Statin derivatives |
CN102387800A (en) * | 2009-03-10 | 2012-03-21 | 莱德克斯制药有限公司 | Rosuvastatin and atorvastatin derivatives |
-
2013
- 2013-12-12 CN CN201310681045.5A patent/CN103724278B/en active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0521471A1 (en) * | 1991-07-01 | 1993-01-07 | Shionogi Seiyaku Kabushiki Kaisha | Pyrimidine derivatives as HMG-CoA reductase inhibitors |
CN1543468A (en) * | 2001-08-16 | 2004-11-03 | ������ҩ��ҵ����˾ | Processes for preparing calcium salt forms of statins |
CN1898233A (en) * | 2003-10-24 | 2007-01-17 | 阿斯利康(英国)有限公司 | Process for the manufacture of the calcium salt of rosuvatatin (e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-enoic acid and crystallin |
WO2005068435A1 (en) * | 2004-01-16 | 2005-07-28 | Zentiva, A. S. | A method of preparation of the hemi-calcium salt of (e)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonvl)aminolpyrimidin-5-yl](3r,5s)-3,5-, dihvdroxy-6-heptenoic acid |
CN1763015A (en) * | 2004-10-22 | 2006-04-26 | 四川抗菌素工业研究所有限公司 | Preparation method and intermediate of rosuvastatin and its pharmaceutical salts |
CN102387800A (en) * | 2009-03-10 | 2012-03-21 | 莱德克斯制药有限公司 | Rosuvastatin and atorvastatin derivatives |
WO2011160974A2 (en) * | 2010-06-21 | 2011-12-29 | Nicox S.A. | Statin derivatives |
Non-Patent Citations (4)
Title |
---|
JUNJIE LIU等: "Sequential aldol condensation catalyzed by DERA mutant Ser238Asp and a formal total synthesis of atorvastatin", 《TETRAHEDRON LETTERS》 * |
M. VENKAT RAM REDDY等: "Asymmetric allylboration for the synthesis of b-hydroxy-d-lactone unit of statin drug analogs", 《JOURNAL OF ORGANOMETALLIC CHEMISTRY》 * |
张付利主编: "《有机化学》", 31 January 2010, 开封:河南大学出版社 * |
王玉炉主编: "《有机合成化学 第一版》", 28 February 2005, 北京:科学出版社 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105646369A (en) * | 2015-12-30 | 2016-06-08 | 安徽美诺华药物化学有限公司 | Method for preparing rosuvastatin |
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Address after: 223800 No.5 Yanshan Road, eco Chemical Technology Industrial Park, Suqian City, Jiangsu Province Patentee after: Jiangsu alpha Pharmaceutical Co.,Ltd. Address before: 223800 No.9 Yanshan Road, eco Chemical Technology Industrial Park, Suqian City, Jiangsu Province Patentee before: ALPHA PHARMACEUTICAL Co.,Ltd. JIANGSU PROVINCE |