CN101948438A - Novel method for preparing rosuvastatin calcium - Google Patents
Novel method for preparing rosuvastatin calcium Download PDFInfo
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- CN101948438A CN101948438A CN201010245642XA CN201010245642A CN101948438A CN 101948438 A CN101948438 A CN 101948438A CN 201010245642X A CN201010245642X A CN 201010245642XA CN 201010245642 A CN201010245642 A CN 201010245642A CN 101948438 A CN101948438 A CN 101948438A
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Abstract
The invention discloses a novel method for preparing rosuvastatin calcium, which is characterized by comprising the following steps of: performing a series of reactions such as condensation, oxidation, reduction and substitution on fluorobenzaldehydes, methyl isobutyrylacetate, urea and cuprous chloride serving as raw materials to finally obtain the final product rosuvastatin calcium. The method is an economic, safe, high-purity and high-yield route, and is suitable for industrial production.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of novel method for preparing rosuvastain calcium.
Background technology
Background technology of the present invention is as follows:
Rosuvastain calcium is the third generation statins of complete synthesis single enantiomer, belong to the HMG-CoA reductase inhibitor, can reduce low density cholesterol, total cholesterol, triglyceride level and the apoB concentration of rising, simultaneously the concentration of increasing high density cholesterol.Can be used for the complex therapy of primary hypercholesterolemia and mixed type lipodystrophy disease and the familial hypercholesterolemia that isozygotys.
Though this product has the total pharmacophoric group dihydroxy heptyl acid moieties of statins, the similar medicine with other of all the other structures in the molecule is totally different, so lipid lowering properties is also inequality.Confirm other statins (comprise and be acknowledged as the strongest Zarator of effectiveness now) that the effect of this product reduction LDL-C, rising HDL-C is better than having gone on the market through a large amount of clinical trials.And it acts on onset time also faster than Zarator, can make the obvious blood fat disorder patient of more different sick types reach U.S.'s " NCEP (National Cholesterol Education Program; NCEP) " fixed index, so clinical meaning is great.
This route is a starting raw material with p-Fluorobenzenecarboxaldehyde and isobutyryl methyl acetate; through condensation and cyclization, oxidation, replacement sulfonylation, reduction, bromination, phosphineization, condensation, go protection, (branch line passes through hydrolysis, oxidation obtains) obtains rosuvastain calcium to be hydrolyzed into reaction such as calcium salt; route is shorter relatively; easy to operate; process stabilizing; cost is low, and the yield height is fit to suitability for industrialized production.
The operational path three wastes of the present invention are handled simple, do not use heavy metal, have more environment-friendly property.Its objective is the rosuvastain calcium synthetic route that an economy, safety, high purity, high yield are provided, be suitable for large-scale industrialization production.
Summary of the invention
The rosuvastain calcium synthetic route is: with fluorobenzaldehyde, isobutyryl methyl acetate, urea, cuprous chloride is raw material, gets 4-(4-fluorophenyl)-6-sec.-propyl-5-methoxycarbonyl-3 through condensation reaction, 4-2 (1H)-dihydropyrimidinonesand (I); Secondly in reactor, add 65～68% nitric acid, Sodium Nitrite, add intermediate compound I under 10～25 ℃ in batches, get [4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-methoxycarbonyl pyrimidine (II) through oxidizing reaction; Be raw material then with n-butyl acetate, intermediate II, Anhydrous potassium carbonate, nitrogen protection, and successively add Tosyl chloride, methylsulfonyl methylamine, salt of wormwood be substituted react [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl-formiate (III); Be raw material with toluene and intermediate III again, heated and stirred makes molten entirely, the nitrogen protection cooling, the toluene solution of the diisobutyl aluminium hydride (DIBAL-H) of dropping 1.5mol/L gets [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (IV) through reduction reaction; In reactor, add methylene dichloride and intermediate compound IV, drip phosphorus tribromide, get N-[5-brooethyl-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-2-base through bromo-reaction]-N-methyl Toluidrin (V); It is molten entirely to add the toluene heating again in the intermediate V, adds phenylbenzene methoxy base phosphine, is substituted reaction, N-[5-(phenylbenzene phosphinylidyne methyl)-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-2-base]-N-methyl Toluidrin (VI); VI by add tetrahydrofuran (THF) and drip NaHMDS through phosphineization react (6-" 2-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl]-vinyl "-(4R, 6S)-2,2-dimethyl-[1,3] dioxan-4-yl)-tert.-butyl acetate (VII); Add intermediate VII, acetonitrile at last in reactor, reaction adds solid sodium chloride, stir, and dissolving, the separatory aftertreatment gets the finished product rosuvastain calcium.
What we invented is the route of a complete synthesis rosuvastain calcium, and synthesizing of its main ring is simple, workable, be fit to very much the workshop and amplify production, and the processing of the operational path three wastes is simple, does not use heavy metal, has more environment-friendly property.
Embodiment
Further describe the complete synthesis of rosuvastain calcium below by embodiment
1,4-(4-fluorophenyl)-6-sec.-propyl-5-methoxycarbonyl-3,4-2 (1H)-dihydropyrimidinonesand (L) synthetic
In reactor, add p-Fluorobenzenecarboxaldehyde (500g), isobutyryl methyl acetate (860g), urea 200g, cuprous chloride, methyl alcohol, sulfuric acid, be heated to backflow.Ice-water bath cools off, and continues to stir the back suction filtration, and the methyl alcohol drip washing of gained solid gets white crystal 1460.17g, yield 98.7% after the loft drier oven dry.
2, [synthesizing of 4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-methoxycarbonyl pyrimidine (II)
Add 65～68% nitric acid, Sodium Nitrite in reactor, add intermediate compound I under 10～25 ℃ in batches, add common need, continue reaction between 10～20 ℃, the TLC detection reaction is complete.Add entry in reaction solution, dropping sodium solution is transferred pH again, notes temperature control.Cool off, continue to stir the back suction filtration, the gained solid washes with water, gets light yellow solid 1396.49g, yield 95.9% after the loft drier oven dry.
3, [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl-formiate (III) is synthetic
Add n-butyl acetate, intermediate II, Anhydrous potassium carbonate in reactor, nitrogen protection adds Tosyl chloride, reacting by heating, and the TLC detection reaction is complete.Add methylsulfonyl methylamine, salt of wormwood, reflux, TLC detects and still has minute quantity raw material unreacted intact.Cooling is poured in the water, stirs, leave standstill, aftertreatment, loft drier dry white solid 2193.91g, yield 93.8%.
4, [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (IV) is synthetic
Add toluene and intermediate III in reactor, heated and stirred makes molten entirely, the nitrogen protection cooling, and the toluene solution of the diisobutyl aluminium hydride (DIBAL-H) of dropping 1.5mol/L, temperature control drips off and continues reaction, and the TLC detection reaction is complete.Aftertreatment, dry white solid 1743.77g, yield 96.1%.
5, N-[5-brooethyl-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-2-base]-N-methyl Toluidrin (V) synthetic
Add methylene dichloride and intermediate compound IV in reactor, drip phosphorus tribromide, the TLC detection reaction is complete.Get white solid 1877.48g, yield 95.6% after the aftertreatment.
6, N-[5-(phenylbenzene phosphinylidyne methyl)-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-2-base]-N-methyl Toluidrin (VI) synthetic
Go on foot up that to add the toluene heating among the intermediate VI of gained molten entirely, add phenylbenzene methoxy base phosphine, be heated to reaction, TLC detects and has responded.Aftertreatment, vacuum drying oven dry white solid 2026.0g, yield 89.3%.
7, (6-" 2-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl]-vinyl "-(4R, 6S)-2,2-dimethyl-[1,3] dioxan-4-yl)-tert.-butyl acetate (VII) synthetic
Add main chain, tetrahydrofuran (THF) in reactor, stir, thermosol is clear a little, and liquid nitrogen is cold under nitrogen protection, drips NaHMDS, and temperature control drips complete insulation reaction, drips the toluene solution of side chain, and temperature control drips Bi Fanying to finishing.Aftertreatment gets product 1577.6g, yield 90.3%.
8, rosuvastain calcium is synthetic
Add intermediate VII, acetonitrile in reactor, 1 drips 1M hydrochloric acid, and reaction is to complete.Cooling drips 1M sodium hydroxide down, and reaction extremely fully.Cooling slowly drips 1MHCl down, transfers pH, adds solid sodium chloride, stir, and dissolving, separatory, aftertreatment gets white solid 1673.34g, yield 96.5%.Total yield is 63.5%, optical purity ee＞99.5%.
Claims (9)
1. novel method for preparing rosuvastain calcium, it is characterized in that with fluorobenzaldehyde, isobutyryl methyl acetate, urea, cuprous chloride be raw material, get 4-(4-fluorophenyl)-6-sec.-propyl-5-methoxycarbonyl-3 through condensation reaction, 4-2 (1H)-dihydropyrimidinonesand (I); Secondly in reactor, add 65～68% nitric acid, Sodium Nitrite, add intermediate compound I under 10～25 ℃ in batches, get [4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-methoxycarbonyl pyrimidine (II) through oxidizing reaction; Be raw material then with n-butyl acetate, intermediate II, Anhydrous potassium carbonate, nitrogen protection, and successively add Tosyl chloride, methylsulfonyl methylamine, salt of wormwood be substituted react [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl-formiate (III); Be raw material with toluene and intermediate III again, heated and stirred makes molten entirely, the nitrogen protection cooling, the toluene solution of the diisobutyl aluminium hydride (DIBAL-H) of dropping 1.5mol/L gets [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (IV) through reduction reaction; In reactor, add methylene dichloride and intermediate compound IV, drip phosphorus tribromide, get N-[5-brooethyl-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-2-base through bromo-reaction]-N-methyl Toluidrin (V); It is molten entirely to add the toluene heating again in the intermediate V, adds phenylbenzene methoxy base phosphine, is substituted reaction, N-[5-(phenylbenzene phosphinylidyne methyl)-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-2-base]-N-methyl Toluidrin (VI); VI by add tetrahydrofuran (THF) and drip NaHMDS through phosphineization react (6-" 2-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl]-vinyl "-(4R, 6S)-2,2-dimethyl-[1,3] dioxan-4-yl)-tert.-butyl acetate (VII); Add intermediate VII, acetonitrile at last in reactor, reaction adds solid sodium chloride, stir, and dissolving, the separatory aftertreatment gets the finished product rosuvastain calcium.
2. the method for preparing rosuvastain calcium according to claim 1, it is characterized in that with fluorobenzaldehyde, isobutyryl methyl acetate, urea, cuprous chloride be raw material, through condensation reaction, prepare 4-(4-fluorophenyl)-6-sec.-propyl-5-methoxycarbonyl-3,4-2 (1H)-dihydropyrimidinonesand (I).
3. the method for preparing rosuvastain calcium according to claim 1, it is characterized in that in reactor, adding 65～68% nitric acid, Sodium Nitrite, add intermediate compound I under 10～25 ℃ in batches, get [4-(4-fluorophenyl)-2-hydroxyl-6-sec.-propyl-5-methoxycarbonyl pyrimidine (II) through oxidizing reaction.
4. the method for preparing rosuvastain calcium according to claim 1; it is characterized in that with n-butyl acetate, intermediate II, Anhydrous potassium carbonate be raw material; nitrogen protection, and successively add Tosyl chloride, methylsulfonyl methylamine, salt of wormwood be substituted react [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl-formiate (III).
5. the method for preparing rosuvastain calcium according to claim 1; it is characterized in that with toluene and intermediate III be raw material; heated and stirred makes molten entirely; the nitrogen protection cooling; the toluene solution of the diisobutyl aluminium hydride (DIBAL-H) of dropping 1.5mol/L gets [4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl] methyl alcohol (IV) through reduction reaction.
6. the method for preparing rosuvastain calcium according to claim 1, it is characterized in that in reactor, adding methylene dichloride and intermediate compound IV, drip phosphorus tribromide through bromo-reaction, get N-[5-brooethyl-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-2-base]-N-methyl Toluidrin (V).
7. the method for preparing rosuvastain calcium according to claim 1, it is characterized in that by in intermediate V, adding the toluene heating molten entirely, add phenylbenzene methoxy base phosphine, be substituted reaction, get N-[5-(phenylbenzene phosphinylidyne methyl)-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-2-base]-N-methyl Toluidrin (VI).
8. the method for preparing rosuvastain calcium according to claim 1; it is characterized in that by in intermediate VI, add tetrahydrofuran (THF) and drip NaHMDS through phosphineization react (6-" 2-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-yl]-vinyl "-(4R; 6S)-2; 2-dimethyl-[1,3] dioxan-4-yl)-tert.-butyl acetate (VII).
9. the method for preparing rosuvastain calcium according to claim 1 is characterized in that adding intermediate VII, acetonitrile in reactor, and reaction adds solid sodium chloride again, stir, and dissolving, the separatory aftertreatment gets the finished product rosuvastain calcium.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103755643A (en) * | 2013-12-31 | 2014-04-30 | 连云港金康医药科技有限公司 | Rosuvastatin calcium I crystal form |
| CN105837516A (en) * | 2016-05-16 | 2016-08-10 | 山东新时代药业有限公司 | Rosuvastatin calcium crystal form and preparation method thereof |
| CN107235918A (en) * | 2017-06-30 | 2017-10-10 | 苏州卫生职业技术学院 | The preparation method of rosuvastain calcium intermediate |
| CN107428703A (en) * | 2015-01-23 | 2017-12-01 | 中化帝斯曼制药有限公司荷兰公司 | For preparing the improved method of statin precursor |
| CN116217494A (en) * | 2022-12-30 | 2023-06-06 | 浙江乐普药业股份有限公司 | Rosuvastatin intermediate and preparation method thereof |
-
2010
- 2010-08-02 CN CN201010245642XA patent/CN101948438A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103755643A (en) * | 2013-12-31 | 2014-04-30 | 连云港金康医药科技有限公司 | Rosuvastatin calcium I crystal form |
| CN107428703A (en) * | 2015-01-23 | 2017-12-01 | 中化帝斯曼制药有限公司荷兰公司 | For preparing the improved method of statin precursor |
| CN107428703B (en) * | 2015-01-23 | 2021-01-12 | 灿盛制药有限公司荷兰公司 | Improved process for the preparation of statin precursors |
| CN105837516A (en) * | 2016-05-16 | 2016-08-10 | 山东新时代药业有限公司 | Rosuvastatin calcium crystal form and preparation method thereof |
| CN105837516B (en) * | 2016-05-16 | 2018-07-10 | 山东新时代药业有限公司 | A kind of rosuvastain calcium crystal form and preparation method thereof |
| CN107235918A (en) * | 2017-06-30 | 2017-10-10 | 苏州卫生职业技术学院 | The preparation method of rosuvastain calcium intermediate |
| CN116217494A (en) * | 2022-12-30 | 2023-06-06 | 浙江乐普药业股份有限公司 | Rosuvastatin intermediate and preparation method thereof |
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Open date: 20110119 |