CN105461636A - Synthetic method for rosuvastatin methyl ester - Google Patents
Synthetic method for rosuvastatin methyl ester Download PDFInfo
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- CN105461636A CN105461636A CN201511022872.9A CN201511022872A CN105461636A CN 105461636 A CN105461636 A CN 105461636A CN 201511022872 A CN201511022872 A CN 201511022872A CN 105461636 A CN105461636 A CN 105461636A
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- 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
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- C07D239/42—One nitrogen atom
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Abstract
The invention provides a synthetic method for rosuvastatin methyl ester. According to the method, protected butyl ester is used as a raw material and esterified again in presence of a catalyst to prepare rosuvastatin methyl ester. The method is low in cost and high in yield, and a new valuable path is provided for synthesis of rosuvastatin methyl ester.
Description
Technical field
The invention belongs to medicinal chemistry arts, relate in particular to a kind of synthetic method of Rosuvastatin methyl esters.
Background technology
HMG-CoA reductase inhibitor (Statins) is used to the level reducing blood low density lipoprotein cholesterol.Cholesterol is produced by mevalonate pathway.The formation reducing mevalonic acid is the prerequisite reducing cholesterol generation, thus forces the corresponding minimizing of the biosynthesizing of cholesterol in liver, and then reduces the cholesterol level in cell.
Two [(E)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-[methyl (first sulfo group) is amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxyl-6-heptenoic acid calcium (rosuvastain calcium) is a kind of reductase inhibitor, and it is used for the treatment of hyperlipidaemia.Its chemical structure is as shown in Equation 1:
Structural formula 1 rosuvastain calcium
Japanese Shionogi makes public for the first time Rosuvastatin and pharmacy acceptable salt in the patent EP521471 of 1993.
Main at present two the suitability for industrialized production routes of Rosuvastatin are shown in route 1 and route 2.Both differences are Witting reaction is carried out on which position of molecule.Based on the practicality of starting material, methyl esters prepared by the tert-butyl ester prepared by route 1 respectively and route 2 is as key intermediate.Also have certain methods to be by the lactone of amino side chain or silyl protection, Witting reaction linearly occurs on pyrimidine scaffold, but these routes are worth little.
Route 1
Route 2
Compare synthetic route 2, the preparation cost of route 1 is relatively cheap.But the product obtained required by some clients is methyl esters prepares key intermediate Rosuvastatin methyl esters (structural formula 2), not treated direct reaction obtains Rosuvastatin.But the methyl esters be similar to described in route 1 is difficult to acquire and expensive.It is feasible that commitment carries out resterification reaction, but the product yield that synthesis similar afterwards obtains is low.
Structural formula 2 Rosuvastatin methyl esters
From former grind patent disclosure after, also have some patents in succession to announce, these patents are all the adjustment carried out on former basis of grinding technique in some details.
Such as, based on the synthetic method of route 1, the difference of patent US2004049036 and US2004049036 is mainly the solvent that adopts in Witting reaction and alkali.Japanese chemists reports the technique using Witting reagent sulfur ylide, also can with reference to the embodiment in patent WO2007125547.
Based on the method for route 2, also report to some extent in many patents and periodical.What first mention the method is formerly grind patent EP521471 (1993), and the patents such as US5260440 (1993), US2006004200 and US2005222415 have afterwards carried out associated description to the method equally.
But do not have pertinent literature to report the technique transformed between the Rosuvastatin tert-butyl ester and Rosuvastatin methyl esters at present.
Summary of the invention
The object of the present invention is to provide the method for a kind of lower-cost synthesizing rosuvastatin spit of fland methyl esters.
Specifically, present invention employs following technical scheme:
A kind of synthetic method of Rosuvastatin methyl esters, it is characterized in that, in the presence of a catalyst, with (E)-({ 2-[4-(fluorophenyl)-6-sec.-propyl-2-[methyl (first sulfo group) is amino] pyrimidine-5-base] vinyl } (4R, 6S)-2, 2-dimethyl [1, 3] dioxane-4-base) butylacetate is raw material, by resterification synthesis (E)-({ 2-[4-(fluorophenyl)-6-sec.-propyl-2-[methyl (first sulfo group) is amino] pyrimidine-5-base] vinyl } (4R under excessive methanol exists, 6S)-2, 2-dimethyl [1, 3] dioxane-4-base) methyl acetate, then deprotection generates (E)-7-[4-(4-(fluorophenyl)-6-sec.-propyl-2-[methyl (first sulfo group) amino] pyrimidine-5-base] (3R, 5S)-3, 5-dihydroxyl-6-heptenoic acid methyl esters.In the above-mentioned methods, described catalyzer is an acidic catalyst or neutral titanium isopropylate catalyzer.Wherein, described an acidic catalyst is selected from the group be made up of organic sulfonic acid, trifluoroacetic acid or hydrochloric acid.Further, described organic sulfonic acid is selected from the group be made up of toluenesulphonic acids, methylsulfonic acid or sulfonic acid polymer.Most preferably, what described catalyzer was selected is methylsulfonic acid.
Beneficial effect: the invention provides at lower cost a kind of and obtain the method for Rosuvastatin methyl esters with higher yields.
Embodiment
The invention provides the method being prepared Rosuvastatin methyl esters by isopropylidene butyl ester resterification.Be methylsulfonic acid or titanium isopropylate for the preferred catalyzer of resterification.
We disclose a kind of Rosuvastatin methyl esters and prepare rosuvastain calcium method, it is characterized in that, under methyl alcohol condition, other Rosuvastatin ester class resterification are prepared Rosuvastatin methyl esters.
According to the preparation method of above rosuvastain calcium, adopt key intermediate (E)-({ 2-[4-(fluorophenyl)-6-sec.-propyl-2-[methyl (first sulfo group) is amino] pyrimidine-5-base] vinyl } (4R, 6S)-2,2-dimethyl [1,3] dioxane-4-base) butylacetate carries out resterification reaction.
In above method; compound (E)-({ 2-[4-(fluorophenyl)-6-sec.-propyl-2-[methyl (first sulfo group) is amino] pyrimidine-5-base] vinyl } (4R; 6S)-2; 2-dimethyl [1; 3] dioxane-4-base) methyl acetate is converted into (E)-7-[4-(4-(fluorophenyl)-6-sec.-propyl-2-[methyl (first sulfo group) amino] pyrimidine-5-base] (3R by currently known methods deprotection; 5S)-3,5-dihydroxyl-6-heptenoic acid methyl esters (Rosuvastatin methyl esters).
The preparation method of rosuvastain calcium can also adopt key intermediate (E)-7-[4-(4-(fluorophenyl)-6-sec.-propyl-2-[methyl (first sulfo group) is amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxyl-6-heptenoic acid butyl ester (Rosuvastatin butyl ester) carries out resterification reaction.
In addition, the preparation method of rosuvastain calcium can also adopt key intermediate N-[4-(4-fluorophenyl)-6-(1-methylethyl)-5-[(1E)-2-[(2S, 4R)-tetrahydrochysene-4-hydroxyl-6-oxygen-2H-pyrans-2-base] vinyl]-2-pyrimidyl]-N-methylmethanesulfonamide (Rosuvastain statin lactone) to carry out resterification reaction.
Directly rosuvastain calcium can be converted into through aftertreatment according to the Rosuvastatin methyl esters that above method prepares; or carry out purifying process; by being converted into (E)-({ 2-[4-(fluorophenyl)-6-sec.-propyl-2-[methyl (first sulfo group) is amino] pyrimidine-5-base] vinyl } (4R; 6S)-2; 2-dimethyl [1; 3] dioxane-4-base) methyl acetate, after purifying, deprotection obtains Rosuvastatin methyl esters.
In the preparation method of above rosuvastain calcium, resterification reaction selected by catalyzer be selected from the organic sulfonic acids such as toluenesulphonic acids, methylsulfonic acid, sulfonic acid polymer (proton type ion exchange resin), or trifluoroacetic acid, trifluoro formic acid etc., or hydrochloric acid.Preferred acid is methylsulfonic acid.
In another embodiment, the resterification of the preparation method of rosuvastain calcium reacts the titanium isopropylate that the catalyzer that uses is neutrality.
(E)-7-of being obtained by the preparation method of above rosuvastain calcium [4-(4-(fluorophenyl)-6-sec.-propyl-2-[methyl (first sulfo group) is amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxyl-6-heptenoic acid methyl esters can prepare rosuvastain calcium by ordinary method.
We find that the direct resterification of the tert-butyl ester is very difficult under excessive methyl alcohol.Conventional catalytic is not only all lower in acetonide deprotection efficiency, and catalytic efficiency in condensation step is all lower, and the product using acid catalysis to carry out being obtained by reacting contains a large amount of impurity, and it cannot be applied in subsequent production.
In reaction process, especially when reaction closes to an end, have by product-methyl ether class impurity (two hydroxyl isomer) to produce, the formation of methyl ether is well-known in acid condition, react for a long time with HCl and can obtain pure methyl ether compound, particular content can refer to periodical J.Org.Chem.2010, and 6681.
Relative to the methylsulfonic acid mentioned in this invention, use other acid that by-products content not only can be impelled to raise, and speed of reaction is slack-off.In addition, acid to be carried out partially or completely when using pyridine and time, the ion pair thereupon produced or buffer system equally also can have side effects to reaction.
Acid catalyst levels is the 0.1-2% (mass ratio) of substrate, preferred 0.2-0.6%, and methanol usage is 5-20 times of volume of butyl ester, is preferably 10 times of volumes.Temperature of reaction is 15-40 degree, is preferably 20-30 degree.
The present invention embodies on the other hand; add 2 after reacting or in reaction; 2-Propanal dimethyl acetal, makes the methyl esters of generation be converted into the more stable and isopropylidene derivative of easily crystallization of chemistry, and deprotection becomes to dissociate before methyl esters and realizes intermediate isolation and purification in acid solution.The formation that temperature of reaction promotes acetonide can be slightly improved after resterification reaction.For Propanal dimethyl acetal consumption, be generally the mol ratio of 2-20, preferable amount is 3-6 mol ratio.
In addition, we have employed another kind of resterification catalyzer in the invention.Under above-mentioned reaction conditions, acid catalyzedly to affect by bronsted, a certain amount of ether impurity can be produced in reaction process, and can not directly use traditional lewis acid catalyst under proton alcohol system.But we find that neutral titanium isopropylate can as the good catalyzer of one at this; because it effectively inhibits the formation of ether impurity; use another benefit of this catalyzer to be that the tert-butyl ester can be converted into methyl esters after deprotection, but use bronsted acid to be this technique irrealizable.Moreover titanate catalyst is as a kind of neutral catalyst, and on acetonide, protection is acceptable, and the tert-butyl ester of protection is directly prepared into methyl esters, and this methyl esters can be separated out with crystalline form, and is easy to purifying.Here, we can choice for use lactone, the tert-butyl ester of upper protection or upper protection.
The titanate catalyst catalysis tert-butyl ester (or lactone) obtains the mixture of a certain proportion of methyl esters and lactone in the reaction.The formation of lactone in fact belongs to a kind of competitive resterification reaction, and the amount of generation remains on about 5% substantially.If but using protected isopropylidene intermediate to react, its above-mentioned situation is no longer applicable.
The shortcoming of this catalyzer can lose activity gradually in the reaction, is converted into do not have activated tetramethoxy titanic acid ester through self resterification.But can address this problem by adding new catalyzer in reaction process.Due to relative instability, the advantage of this deactivation to remove from system (in normal pressure situation, its boiling point is 200 DEG C, and isopropoxy boiling point under 10mbar condition reaches 218 DEG C), can repeatedly distill with excessive methyl alcohol and be removed, aftertreatment can be made so more easy, and a large amount of titanium oxide being difficult to filter is removed.
Catalyst levels can be the 5-100% (quality) of starting material consumption.Catalyst levels increase can accelerate speed of reaction, but also can cause aftertreatment difficulty, product loss simultaneously.Preferable amount is 5% of 2-3 times of starting material quality.
Usual Rosuvastatin methyl esters crude product exists with the form of oily matter, but when purity is more than 90%, can be easy to from MTBE, crystallizes out in the ether solvent such as diisopropyl ether or diethyl ether, the preferred diethyl ether of recrystallisation solvent.
The product that crystallization goes out can comprise some free acids, but does not belong to impurity category due to this free acid, and is easy to remove in last handling process, so can't impact technique.
Rosuvastatin methyl esters is converted into rosuvastain calcium by conventional methods afterwards.
Embodiment
Prepare Rosuvastatin methyl esters
The first step
(E)-({ 2-[4-(fluorophenyl)-6-sec.-propyl-2-[methyl (first sulfo group) is amino] pyrimidine-5-base] vinyl } (4R, 6S)-2,2-dimethyl [1,3] dioxane-4-base) synthesis of butylacetate
The dimethyl sulfoxide (DMSO) of 600 milliliters, 104 grams of (0.75 mole) salt of wormwood, 170 grams (0.25 mole) [4-(4-fluorophenyl)-6-sec.-propyl-2-[methyl (first sulfo group) is amino] pyrimidine-5-base-methyl] triphenyl phosphorus bromine and 65 grams of (0.26mol) (4R-cis)-6-aldehyde radicals-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate is uniformly mixed, and is heated to 70-75 degree two hours.Add 1L toluene, then cold filtration removes most inorganic impurity and phosphorus oxide.By 1L water washing organic phase, be then atmospherically distilled to dry, 750 ml methanol joined in residuum, then heated and boiled.Crystallization product under 25-30 degree.Be cooled to 11 degree further again, be separated and obtain 108 grams of products (yield is 75%).
Second step, resterification synthesis (E)-({ 2-[4-(fluorophenyl)-6-sec.-propyl-2-[methyl (first sulfo group) is amino] pyrimidine-5-base] vinyl } (4R, 6S)-2,2-dimethyl [1,3] dioxane-4-base) methyl esters
108 grams obtained in the previous step (0.1867 mole) products add 1L methyl alcohol and 5 grams of titanium isopropylates, are heated to backflow 16 hours, vacuum distilling removing methyl alcohol.Then add 1L fresh methanol and 5g titanium isopropylate, reflux is distillation for removing methanol after 8 hours, adds 1L fresh methanol and 5g titanium isopropylate, reflux 8 hours, so just can obtain transformation efficiency more than 98%.Steam methyl alcohol, add 300ml Virahol and continue distillation, residue can direct crystallization from fresh Virahol, and finally obtain 87g (theoretical yield 87%) product, HPLC purity is 98.9%.
3rd step, deprotection synthesizing rosuvastatin spit of fland methyl esters
86 grams obtained in the previous step (0.16 mole) products, 1.8L acetonitrile and 160 grams of 1N-HCl stir 8 hours at 20-25 degree, use solid NaHCO
3in and pH to 7-7.5.With saturated aqueous common salt, water is separated with organic phase.Aqueous phase, by 2 × 500 milliliters of extraction into ethyl acetate, merges oil phase 20% strong brine and strips.By dried over sodium sulfate, evaporating solvent obtains 75.3 grams, and purity is the oil phase of 94.5%.Add 500 milliliters of ether and Rosuvastatin methyl esters crystal seed.Stir at ambient temperature and obtain crystallization suspension in 48 hours, be cooled to 0 degree afterwards, add 1 gram of product under agitation, then use cold diethyl ether washing filtering, obtaining productive rate is 62.7 grams of (theoretical yield 79%) crystallized products, and purity is 96%.
Rosuvastain calcium is prepared by Rosuvastatin methyl esters
A) free acid not purifying
62 grams obtained in the previous step (0.125 mole) crystallized products add 860 milliliters of ethanol, 140 milliliters of 1N-NaOH 25 degree of stirrings 1 hour.Under 35-40 degree, vacuum distilling removes ethanol, extracts 2 times by 1 liter of methyl tertiary butyl ether.Water layer appropriate diatomite and activated carbon filtration, dissolve lime acetate with a small amount of water, is added in filtrate, and 25 degree of stirrings 2 hours, washing filtering, drying obtained 52.9 grams of (theoretical yield is 84.5%) rosuvastain calciums.
If use oil phase methyl esters direct hydrolysis, then theoretical yield is from 6, and 5% is increased to 91%.
Free acid purifying
75 grams of oily methyl esters are in 900 milliliters of acetonitriles, and 140 milliliters of 1N-NaOH stir 1 hour at 25 degrees c.Add 60 grams of NaCl and then stir 1 hour again at-5 degree.Add 35 grams of NaCl again, be acidified to pH3.6 with 1N-HCl, under-5 degree, stir then layering in 10 minutes.Bottom discharge, upper strata diatomite and activated carbon filtration, the acetonitrile solution obtained adds the aqueous methylamine solution of 18 milliliter 40% under-5 degree.Then be heated to 35 degree slowly, be incubated 1.5 hours.Be cooled to-5 degree again and be incubated half an hour, crystallization is filtered, with the acetonitrile wash of 2x100 milliliter, then vacuum-drying.Obtain crystallization methylamine salt, HPLC purity 99.1%.
Salt is dissolved in 3L water, under 20 degree, adds the NaOH of 510 milliliter 8%.Stir 1 hour under 30 degree, in vacuum, under 40 degree, the water of 4/5 is distilled out of, and continues to distill until methylamine removes completely.Add fresh distilled water (volume is identical with the volume steaming water), continue distillation until remove methylamine completely.In the residuum after distillation, adding the distilled water identical with steaming volume of water dilute, at 20 DEG C, then adding the calcium chloride solution (being prepared from by 110gCaCl2.2H2O and 500ml water) prepared, and stir 1 hour.With 2L water filtration washing, then drying obtains the rosuvastain calcium of 58.4 grams (theoretical yield is 81%) under vacuo, HPLC purity 99.3%.
In conjunction with specific examples, embodiments of the present invention are described in detail above, but the invention is not restricted to above-mentioned embodiment, in the ken that art those of ordinary skill possesses, can also make a variety of changes under the prerequisite not departing from present inventive concept.
Claims (5)
1. the synthetic method of a Rosuvastatin methyl esters, it is characterized in that, in the presence of a catalyst, with (E)-({ 2-[4-(fluorophenyl)-6-sec.-propyl-2-[methyl (first sulfo group) is amino] pyrimidine-5-base] vinyl } (4R, 6S)-2, 2-dimethyl [1, 3] dioxane-4-base) butylacetate is raw material, by resterification synthesis (E)-({ 2-[4-(fluorophenyl)-6-sec.-propyl-2-[methyl (first sulfo group) is amino] pyrimidine-5-base] vinyl } (4R under excessive methanol exists, 6S)-2, 2-dimethyl [1, 3] dioxane-4-base) methyl acetate, then deprotection generates (E)-7-[4-(4-(fluorophenyl)-6-sec.-propyl-2-[methyl (first sulfo group) amino] pyrimidine-5-base] (3R, 5S)-3, 5-dihydroxyl-6-heptenoic acid methyl esters.
2. the synthetic method of Rosuvastatin methyl esters as claimed in claim 1, it is characterized in that, described catalyzer is an acidic catalyst or neutral titanium isopropylate catalyzer.
3. the synthetic method of Rosuvastatin methyl esters as claimed in claim 2, it is characterized in that, described an acidic catalyst is selected from the group be made up of organic sulfonic acid, trifluoroacetic acid or hydrochloric acid.
4. the synthetic method of Rosuvastatin methyl esters as claimed in claim 3, it is characterized in that, described organic sulfonic acid is selected from the group be made up of toluenesulphonic acids, methylsulfonic acid or sulfonic acid polymer.
5. the synthetic method of Rosuvastatin methyl esters as claimed in claim 4, it is characterized in that, what described catalyzer was selected is methylsulfonic acid.
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