CN102219780B - Method for preparing (3R, 5S, E)-7-{2-(N-methylsulphonylamino) -4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-yl}-2,2-dimethyl-3,5-dioxane-6-heptenoic acid - Google Patents
Method for preparing (3R, 5S, E)-7-{2-(N-methylsulphonylamino) -4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-yl}-2,2-dimethyl-3,5-dioxane-6-heptenoic acid Download PDFInfo
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Abstract
The invention relates to a method for preparing (3R, 5S, E)-7-{2-(N-methylsulphonylamino) -4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-yl}-2,2-dimethyl-3,5-dioxane-6-heptenoic acid (compound shown by a formula 4) which is an important intermediate of Rosuvastatin Calcium in a one-pot way. The method comprises the steps of adding a compound in the formula 1 and a compound in the formula 2 into a solvent under protection of dried inert gas, adding a certain amount of strong base at minus 60 DEG C, then slowly increasing temperature to room temperature, supplementing the strong base after a compound in the formula 3 is completely produced, adding N-methylsulphonylamino, and reacting to produce a compound in the formula 4 at the room temperature. The method is stable in yield and easy to operate, and provides a method for preparing Rosuvastatin, and the method has lower cost, is simplified for operation and easy for industrialization. The formula 1, 2, 3, and 4 are shown in the description, wherein R1 is shown in description, and R2 is alkyl, naphthenic base or benzyl, and preferably methyl, ethyl or tertiary butyl.
Description
Technical field
The present invention relates to medicine preparation, be specifically related to a kind of one kettle way and prepare Rosuvastatine calcium important intermediate (3R, 5S, E)-7-(2-(N-methyl methylsulfonyl amido)-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-5-yl)-2,2-dimethyl-3, the method for 5-dioxane-6-heptenoic acid esters.
Background technology
Rosuvastatine is as the novel fat regulation medicine of one, first in Holland's approval listing, obtain U.S. FDA approval in November, 2002 in August, 2003, got the Green Light and went on the market in China in 2006, at present more than 60 country's listings, by the most widely used statins.Its structural formula is 5 (compounds 5):
The preparation technology of Rosuvastatine has numerous documents and patent to report, compound 4 (structural formula 4) is the important intermediate of preparing Rosuvastatine calcium, patent WO2002/098854 discloses the methylsulfonyl by 4-(4-fluorophenyl)-6-sec.-propyl-2-[(N-methyl-N-) amino] pyrimidine-5-formaldehyde and 2-[(4R, 6S)-2, 2-dimethyl-6-[(1-phenyl-1H-1, 2, 3, 4,-tetrazole-5-yl) methyl]-1, 3-dioxane-4-carboxylicesters reacts the method that obtains compound 4, substep yield is better, but N-methyl Toluidrin and pyrimidine ring first dock, after to connect the process aftertreatment of side chain complicated, total recovery is unsatisfactory.Patent WO 2005/030758 and document J.M.C., 2008.Vol51.No.9, pp2722-2733 discloses another kind of preparation method, but the yield of the method is extremely unstable, easily produces a large amount of by products in reaction, is difficult to suitability for industrialized production.
In sum, above-mentioned preparation method exists operation complicated, consuming time, the defect that yield is unstable and cost is higher.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned preparation method's deficiency, provides a kind of easy and simple to handle, stable yield, cost low, is suitable for the preparation method of suitability for industrialized production.
The invention provides a kind of one kettle way and prepare Rosuvastatine calcium important intermediate (3R, 5S, E)-7-(2-(N-methyl methylsulfonyl amido)-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-5-yl)-2,2-dimethyl-3, the method for 5-dioxane-6-heptenoic acid esters (compound 4).
The inventive method specifically comprises the following steps:
Wherein, R
1for one of following groups:
R
2for alkyl, cycloalkyl or benzyl, preferable methyl, ethyl or the tertiary butyl.
By compound 1 (4-(4-fluorophenyl)-6-sec.-propyl-2-methyl sulfuryl-pyrimidine-5-formaldehyde) and equimolar compound 22-[(4R, 6S)-2, 2-dimethyl-6-[(1-phenyl-1H-1, 2, 3, 4,-tetrazole-5-yl) methyl]-1, 3-dioxane-4-carboxylicesters, under the protection of dry inert gas, be dissolved in 5 times-50 times amount anhydrous solvent V/V, at-78 DEG C--at 20 DEG C, drip or add and the highly basic of compound 1 equimolar amount or twice molar weight in batches, then, in 2 hours, be warming up to 10-25 DEG C, monitor to raw material and disappear by thin-layer chromatography, add the highly basic with compound 1 equimolar amount or twice molar weight, add again the N-methyl Toluidrin with compound 1 equimolar amount or twice molar weight, then at 10-25 DEG C of reacting generating compound 4 (3R, 5S, E)-7-(2-(N-methyl methylsulfonyl amido)-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-5-yl)-2, 2-dimethyl-3, 5 dioxy alkane-6-heptenoic acid esters.
The solvent of reaction is selected from tetrahydrofuran (THF), dioxane, toluene, ether, N, N ,-dimethyl formamide, methyl-sulphoxide or acetonitrile.
In reaction, highly basic used is selected from one or more the mixture in LHMDS, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium hydride, potassium hydride KH, butyllithium or lithium diisopropylamine, and its molar weight used is 2.0～4.0 times of compound 1.
In reaction process, after compound 3 generates completely, reactant is without aftertreatment, directly toward the highly basic that adds N-methyl Toluidrin and 1.0-2.0 equivalent in reaction system, then,, at 10-25 DEG C, react to compound 3 completely dissolves (thin-layer chromatography or HPLC monitoring).
Stable yield of the present invention, can reach 60%-80%, easy handling, and intermediate is without aftertreatment, for the preparation technology of Rosuvastatine provides a kind of cost lower, simple to operate, is easy to industrialized method.
Embodiment
Embodiment 1:
In 1000mL there-necked flask, add 15.0 and digest compound 1, 22.1 (1.05eq) digest compound 2, argon shield, add 300mL anhydrous tetrahydro furan, dry ice acetone bath is chilled to-60 DEG C, at this temperature, drip the tetrahydrofuran solution of the LHMDS of 56mL1M, finish, in 2 hours, be warming up to 25 DEG C of room temperatures, under argon shield, add the sodium hydrogen of 4.1 gram 60%, add 7.62 grams of N-methyl Toluidrins, reaction is spent the night, under cooling, add 100mL ethyl acetate, the saturated ammonia chloride aqueous solution of 20mL, 20mL water, separatory, 200mL ethyl acetate extraction for water, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filter, 30 DEG C of water-baths are revolved and are steamed except desolventizing, obtain product (3R, 5S, E)-7-(2-(N-methyl methylsulfonyl amido)-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-5-yl)-2, 2-dimethyl-3, (16.8 grams of 5-dioxane-6-heptenoic acid tert-butyl esters, yield 62.5%).
1HNMR(300MHz，CDCl
3)：δ1.16-1.56(23H，m)，2.27(1H，dd，J＝15.29，6.28Hz)，2.43(1H，dd，J＝15.36，6.88Hz)，3.36(1H，m)，3.50(3H，s)，3.55(3H，s)，4.40(1H，m)，4.42(1H，m)，5.45(1H，dd，J＝16.27，5.41Hz)，6.50(1H，dd，J＝14.96Hz)，7.06(2H，m)，7.63(2H，m)。
MS(ESI)：578.6(M+1).
Embodiment 2:
In 1000mL there-necked flask, add 15.0 and digest compound 1, 22.1 digest compound 2, argon shield, add 300mL anhydrous tetrahydro furan, dry ice acetone bath is chilled to-60 DEG C, at this temperature, drip the LHMDS of 70mL1M, finish, in 2 hours, rise to 25 DEG C of room temperatures, under argon shield, add sodium hydrogen and 10.16 grams of N-methyl Toluidrins of 3.73 gram 60%, 20～30 DEG C of reactions are spent the night, under cooling, add 100mL ethyl acetate, the saturated ammonia chloride aqueous solution of 20mL, 20mL water, separatory, 200mL ethyl acetate extraction for water, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filter, 30 DEG C of water-baths are revolved and are steamed except desolventizing, obtain product (3R, 5S, E)-7-(2-(N-methyl methylsulfonyl amido)-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-5-yl)-2, 2-dimethyl-3, (18.95 grams of 5-dioxane-6-heptenoic acid tert-butyl esters, yield 70.5%).
Embodiment 3:
In 1000mL there-necked flask, add 15.0 grams of formula 1 compounds, 22.1 digest compound 2, argon shield, add 300mL anhydrous tetrahydro furan, dry ice acetone bath is chilled to-60 DEG C, at this temperature, add the sodium hydrogen of 6.52 gram 60% in batches, finish, in 2 hours, rise to 20～30 DEG C, add 10.16 grams of N-methyl Toluidrins, 20～30 DEG C of reactions are spent the night, under cooling, add 100mL ethyl acetate, the saturated ammonia chloride aqueous solution of 20mL, 20mL water, separatory, the extraction of water 200mL ethyl acetate, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filter, 30 DEG C of water-baths are revolved and are steamed except desolventizing, obtain product (3R, 5S, E)-7-(2-(N-methyl methylsulfonyl amido)-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-5-yl)-2, 2-dimethyl-3, (18.31 grams of 5-dioxane-6-heptenoic acid tert-butyl esters, yield: 68.1%).
Embodiment 4:
In 1000mL there-necked flask, add 15.0 and digest compound 1,22.1 and digest compound 2, argon shield; add 200mL anhydrous tetrahydro furan, dry ice acetone bath is chilled to-60 DEG C, drips 70mL1M LHMDS at this temperature; finish, in 2 hours, be warming up to 20～30 DEG C, for subsequent use.
In 1000mL there-necked flask, at 25 DEG C of room temperatures, add 10.16 grams of N-methyl Toluidrins, under argon shield, add 100mL anhydrous tetrahydro furan, add the sodium hydrogen of 3.73 gram 60%, at 20～30 DEG C, react 0.5-1.0 hour, then drip above-mentioned reaction solution for subsequent use, finish, reaction is spent the night, under cooling, add 100mL ethyl acetate, the saturated ammonia chloride aqueous solution of 20mL, 20mL water, separatory, the extraction of water 200mL ethyl acetate, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filter, 30 DEG C of water-baths are revolved and are steamed except desolventizing, obtain product (3R, 5S, E)-7-(2-(N-methyl methylsulfonyl amido)-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-5-yl)-2, 2-dimethyl-3, (20.24 grams of 5-dioxane-6-heptenoic acid tert-butyl esters, yield: 75.3%.)
Above-described embodiment is preferably embodiment of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification made under spirit of the present invention and principle, substitutes, combination, simplify; all should be equivalent substitute mode, within being included in protection scope of the present invention.
Claims (7)
1. prepare (3R for one kind, 5S, E)-7-(2-(N-methyl methylsulfonyl amido)-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-5-yl)-2,2-dimethyl-3, the method of 5-dioxane-6-heptenoic acid esters, is characterized in that the method comprises the following steps:
Wherein, R
1for group:
R
2for methyl, ethyl or the tertiary butyl;
By compound 1 4-(4-fluorophenyl)-6-sec.-propyl-2-methyl sulfuryl-pyrimidine-5-formaldehyde and equimolar compound 2 2-((4R, 6S)-2, 2-dimethyl-6-((1-phenyl-1H-tetrazole-5-base sulfuryl) methyl)-1, 3-dioxane-4-carboxylicesters, under the protection of dry inert gas, be dissolved in 5 times-50 times amount V/V anhydrous solvents, at-78 DEG C to-20 DEG C, drip or add and the highly basic of compound 1 equimolar amount or twice molar weight in batches, then in 2 hours, be warming up to 10-25 DEG C, monitor to raw material and disappear by thin-layer chromatography, add the highly basic with compound 1 equimolar amount or twice molar weight, add again the N-methyl Toluidrin with compound 1 equimolar amount or twice molar weight, then, reaction at 10-25 DEG C, generate compound 4 (3R, 5S, E)-7-(2-(N-methyl methylsulfonyl amido)-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-5-yl)-2, 2-dimethyl-3, 5-dioxane-6-heptenoic acid esters.
2. the method for claim 1, is characterized in that, described anhydrous solvent is tetrahydrofuran (THF), dioxane, toluene, ether, DMF, methyl-sulphoxide or acetonitrile.
3. method as claimed in claim 2, is characterized in that, described anhydrous solvent is anhydrous tetrahydro furan.
4. the method for claim 1, it is characterized in that, described highly basic is one or more the mixture in LHMDS, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium hydride, potassium hydride KH, butyllithium or lithium diisopropylamine, and its molar equivalent used is 2.0～4.0 equivalents of compound 1.
5. the method for claim 1, is characterized in that, in compound 1 and compound 2 reaction process, drips or the temperature that in batches adds highly basic is-78 DEG C to-20 DEG C, and highly basic finishes, and is warmed up to 10-25 DEG C.
6. the method for claim 1, is characterized in that, compound 1 and compound 2 react gained compound 3 without separation and purification, direct and N-methyl Toluidrin reaction.
7. the method for claim 1, is characterized in that, the temperature of compound 3 and the reaction of N-methyl Toluidrin is 10-25 DEG C.
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| KR20130087153A (en) * | 2012-01-27 | 2013-08-06 | 코오롱생명과학 주식회사 | Method for preparing rosuvastatin and intermediate compound used therefor |
| CN107298675B (en) * | 2017-06-19 | 2020-08-11 | 浙江美诺华药物化学有限公司 | Preparation method of rosuvastatin calcium intermediate |
| CN111454216B (en) * | 2019-10-21 | 2021-06-29 | 山东理工职业学院 | Process for the preparation of HMG-CoA reductase inhibitors and intermediates thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005030758A1 (en) * | 2003-09-25 | 2005-04-07 | Bristol-Myers Squibb Company | Pyrimidine and pyridine derivatives useful as hmg-coa reductase inhibitors and method of preparation thereof |
| CN1656077A (en) * | 2001-06-06 | 2005-08-17 | 布里斯托尔-迈尔斯斯奎布公司 | Process for preparing chiral diol sulfones and dihydroxy acid HMG CoA reductase inhibitors |
| CN1821242A (en) * | 2006-02-16 | 2006-08-23 | 亚邦化工集团有限公司 | Novel method for preparing dihydroxy acid HMG CoA reductase inhibitor |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1656077A (en) * | 2001-06-06 | 2005-08-17 | 布里斯托尔-迈尔斯斯奎布公司 | Process for preparing chiral diol sulfones and dihydroxy acid HMG CoA reductase inhibitors |
| WO2005030758A1 (en) * | 2003-09-25 | 2005-04-07 | Bristol-Myers Squibb Company | Pyrimidine and pyridine derivatives useful as hmg-coa reductase inhibitors and method of preparation thereof |
| CN1821242A (en) * | 2006-02-16 | 2006-08-23 | 亚邦化工集团有限公司 | Novel method for preparing dihydroxy acid HMG CoA reductase inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| Saleem Ahmad，等.(3R,5S,E)-7-(4-(4-Fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1H-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic Acid (BMS-644950): A Rationally Designed Orally Efficacious 3-Hydroxy-3-methylglutaryl Coenzyme-A Reductase Inhibitor with.《J. Med. Chem.》.2008,第51卷(第9期),第2722-2733页. * |
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