CN108003106A - The method that one kettle way prepares 3- hydroxyl -5- oxo technique of heptenoic acid ester derivative - Google Patents
The method that one kettle way prepares 3- hydroxyl -5- oxo technique of heptenoic acid ester derivative Download PDFInfo
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- CN108003106A CN108003106A CN201610954659.XA CN201610954659A CN108003106A CN 108003106 A CN108003106 A CN 108003106A CN 201610954659 A CN201610954659 A CN 201610954659A CN 108003106 A CN108003106 A CN 108003106A
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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
A kind of one kettle way prepares 3 hydroxyl, 5 oxo, 6 technique of heptenoic acid ester derivative（Auspicious easypro statin calcium intermediate）Method; using compound shown in compound shown in formula 1 and formula 2 as raw material; compound shown in the formula 3 obtained by Witting condensation reactions, without isolation, directly carries out dehydroxylation protection reaction and is prepared; this method shortens the step of unit operation; eliminate column chromatography operation so that synthesis technique is more suitable for industrialized production, and products obtained therefrom cost is low; quality is good, can be used for the preparation of rosuvastain calcium.
Description
Technical field
The present invention relates to the preparation method of rosuvastain calcium intermediate, by document（Such as：EP0521471）Synthesis
The improvement of method, prepares intermediate 3- hydroxyl -5- oxo -6- technique of heptenoic acid ester derivative using one kettle way, shortens unit operation
The step of, eliminating column chromatography operation so that synthesis technique is more suitable for industrialized production, and products obtained therefrom cost is low, and quality is good,
It can be used for the preparation of rosuvastain calcium.
Background technology
Rosuvastain calcium is the ammonia that Japanese Shionogi company obtains in late 1980s synthesis, screening
Yl pyrimidines derivative, its original exploitation code name is S-4522.World wide exploitation, listing in addition to some Asian countries such as Japan
AstraZeneca companies are assigned in June, 1998 with sale rights and interests, in August, 2003 is approved to list in United States Non-Provisional.
Trade name CrestorTM.
Though the pharmacophoric group dihydroxy heptyl acid moieties that rosuvastain calcium is shared with statins, its molecule its
Remaining structure but falls far short with other similar drugs, and the presence of wherein polarity methanesulfonamido makes it that relatively low lipophilic be presented
Property.The log D values that rosuvastain calcium is measured in pH 7.4 are -0.33, suitable and remote with Pravastatin (provastatin)
Each statins has been listed less than other (about between 1.1~1.7).The hydrophily of rosuvastain calcium means its passive expansion
The ability of dissipating is relatively low, therefore is difficult to enter non-liver cell.But it can be by selective organic anion transport process and for liver cell
A large amount of intakes, have the characteristics that selective distribution and act on HMG-CoA reductase in liver.
The synthetic method that Rui Shu is cut down sees EP0521471, shown in following schema：
Compound is Rosuvastatin parent nucleus wherein shown in formula 1, with compound shown in formula 2（Ylide reagent）Flow back in acetonitrile
Under the conditions of carry out witting condensation reactions, then slough hydroxyl protection base through hydrofluoric acid, obtain compound shown in intermediate formula 4, then
Again by 5- carbonyl reductions into alcoholic extract hydroxyl group.Again target product is obtained through hydrolysis, into calcium salt.
It is grease in compound shown in compound shown in route Chinese style 3 and formula 5, the bad control of product quality, and the institute of formula 4
Show that compound can obtain solid product, therefore compound shown in formula 4（3- hydroxyl -5- oxo -6- technique of heptenoic acid ester derivative）Can
Using the key intermediate as centre control.
In EP0521471, during compound shown in compound and formula 2 obtains compound shown in formula 4 as shown in formula 1
By two step unit operations, and each step has been directed to column chromatography operation, is unfavorable for industrialized production.
The content of the invention
Synthetic method of the invention based on rosuvastain calcium in EP0521471, to chemical combination shown in its key intermediate formula 4
Thing（3- hydroxyl -5- oxo -6- technique of heptenoic acid ester derivative）Preparation method be improved, two-step reaction in document is combined into a step
Carry out, one kettle way obtains compound shown in intermediate formula 4, compared to literature method, enormously simplify operation, reduce solvent for use
Species and dosage, provide for the industry manufacture of rosuvastain calcium and a kind of be commercialized available key intermediate.
It is more than rosuvastain calcium key intermediate 3- hydroxyls -5- oxo -6- technique of heptenoic acid ester derivative provided by the invention
It is raw material to state compound shown in compound shown in route Chinese style 1 and formula 2 in route, the formula 3 obtained by Witting condensation reactions
Shown compound, without isolation, directly carries out dehydroxylation protection reaction and is prepared.
In above-mentioned preparation method, the process of the Witting condensation reactions is：By compound shown in compound shown in formula 1 and formula 2
By a certain percentage, it is added in a kind of aprotic solvent, is heated to flowing back, or insulation, in certain temperature range, stirring is anti-
It should terminate to reaction；
The certain proportion is 1 compound of formula：The molar ratio of 2 compound of formula is 1:1~1:2, preferably 1:1.1~1:1.2；It is described non-
Proton solvent is acetonitrile, tetrahydrofuran, toluene, preferably dioxane one of which, acetonitrile；The certain temperature range refers to
40 ~ 110 DEG C, preferably 75 ~ 85 DEG C.
In above-mentioned preparation method, the process of the dehydroxylation protection reaction is：Witting after reaction, after cooling, drips
Adding a certain amount of deprotecting regent, then heat up, stirring reaction is extracted to the reaction was complete by extractant, saturated sodium bicarbonate washing,
Washing, concentration, crystallization obtain compound described in formula 4；
The deprotecting regent is hydrofluoric acid, hydrochloric acid, tetra-n-butyl ammonium fluoride one of which；
The deprotecting regent and 1 compound mole ratio of formula：1:1~1:20, preferably 1:5~1:10
The dropping temperature is -10 DEG C ~ 20 DEG C, preferably 0 ~ 5 DEG C
The reaction temperature is 10 ~ 70 DEG C, preferably 20 ~ 40 DEG C
The extractant is ethyl acetate, isopropyl acetate, dichloromethane, chloroform one of which；
The recrystallisation solvent is methanol, ethanol, isopropanol, petroleum ether, ethyl acetate, n-hexane one of which or two kinds and two kinds
Mixed solvent above.
Embodiment：
Embodiment 1：
1 compound of 5.0g formulas and 2 compound of 10.6g formulas are dissolved in 80ml tetrahydrofurans, reflux is warming up to, is stirred at reflux 24h,
0 DEG C or so is cooled to, the mixed solution of 14.2g aqueous hydrogen fluoride solutions and 200ml tetrahydrofurans is added dropwise, process control temp is added dropwise
At 0-5 DEG C, room temperature, stirring reaction 4h are then warming up to, reaction terminates.Saturated sodium bicarbonate tune pH value is layered, water layer to 7-8
Extracted with ethyl acetate, merge organic phase, anhydrous sodium sulfate drying, is spin-dried for, residue isopropanol, is beaten, filters to obtain 4.8g
Faint yellow target product.
Implement Lie 2：
1 compound of 10.0g formulas and 2 compound of 24.2g formulas are dissolved in 260ml acetonitriles, reflux is warming up to, is stirred at reflux 24h, it is cold
But to 0 DEG C or so, the mixed solution of 32.3g aqueous hydrogen fluoride solutions and 500ml acetonitriles is added dropwise, process control temp is added dropwise in 0-5
DEG C, 35 DEG C are then warming up to, stirring reaction 5h, reaction terminates.Saturated sodium bicarbonate tune pH value is layered, water layer acetic acid to 7-8
Ethyl ester extracts, and merges organic phase, anhydrous sodium sulfate drying, is spin-dried for, residue is with 3:1 petroleum ether：Ethyl acetate is beaten, and is filtered
10.1g faint yellow target product.
Claims (5)
- A kind of 1. compound shown in formula 4（3- hydroxyl -5- oxo -6- technique of heptenoic acid ester derivative, in rosuvastain calcium key Mesosome）Method, it includes：Using compound shown in compound shown in formula 1 and formula 2 as raw material, chemical combination shown in the formula 3 that is obtained by Witting condensation reactions Thing, without isolation, directly carries out dehydroxylation protection reaction and is prepared.
- 2. method as claimed in claim 1, witting condensation reaction features are as follows：Compound shown in compound shown in formula 1 and formula 2 by a certain percentage, is added in a kind of aprotic solvent, is heated to back Stream, or insulation, in certain temperature range, stirring reaction to reaction terminates.
- 3. method as claimed in claim 2, its feature is as follows：The certain proportion is 1 compound of formula：The molar ratio of 2 compound of formula is 1:1~1:2, preferably 1:1.1~1:1.2；It is described non- Proton solvent is acetonitrile, tetrahydrofuran, toluene, preferably dioxane one of which, acetonitrile；The certain temperature range refers to 40 ~ 110 DEG C, preferably 75 ~ 85 DEG C.
- 4. method as claimed in claim 1, dehydroxylation protection response feature is as follows：Witting after reaction, after cooling, drips Adding a certain amount of deprotecting regent, then heat up, stirring reaction is extracted to the reaction was complete by extractant, saturated sodium bicarbonate washing, Washing, concentration, crystallization obtain compound described in formula 4.
- 5. method as claimed in claim 4, its feature is as follows：The deprotecting regent is hydrofluoric acid, hydrochloric acid, tetra-n-butyl ammonium fluoride one of which；The deprotecting regent and 1 compound mole ratio of formula：1:1~1:20, preferably 1:5~1:10The dropping temperature is -10 DEG C ~ 20 DEG C, preferably 0 ~ 5 DEG CThe reaction temperature is 10 ~ 70 DEG C, preferably 20 ~ 40 DEG CThe extractant is ethyl acetate, isopropyl acetate, dichloromethane, chloroform one of which；The recrystallisation solvent is methanol, ethanol, isopropanol, petroleum ether, ethyl acetate, n-hexane one of which or two kinds and two kinds Mixed solvent above.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111518035A (en) * | 2020-06-18 | 2020-08-11 | 安徽鼎旺医药有限公司 | Rosuvastatin tert-butylamine salt and preparation method thereof |
-
2016
- 2016-10-27 CN CN201610954659.XA patent/CN108003106A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111518035A (en) * | 2020-06-18 | 2020-08-11 | 安徽鼎旺医药有限公司 | Rosuvastatin tert-butylamine salt and preparation method thereof |
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Application publication date: 20180508 |
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| WD01 | Invention patent application deemed withdrawn after publication |