CN102219780A - 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 PDF

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CN102219780A
CN102219780A CN2010101463322A CN201010146332A CN102219780A CN 102219780 A CN102219780 A CN 102219780A CN 2010101463322 A CN2010101463322 A CN 2010101463322A CN 201010146332 A CN201010146332 A CN 201010146332A CN 102219780 A CN102219780 A CN 102219780A
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CN102219780B (en
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徐锋
黄悦
王光强
张凯毅
洪赟飞
龚汉芳
金彩芬
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SHANGHAI JINGXIN BIOLOGICAL MEDICAL CO Ltd
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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. R1 is shown in details in the formula, and R2 is alkyl, naphthenic base or benzyl, and methyl, ethyl or tertiary butyl are optimized.

Description

Preparation (3R, 5S, E)-and 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
Technical field
The present invention relates to medication preparation, be specifically related to a kind of one kettle way prepare auspicious rosuvastatin 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
Auspicious rosuvastatin is as a kind of novel fat regulation medicine, at first go on the market in Holland's approval in November, 2002, obtain drugs approved by FDA in August, 2003, got the Green Light and went on the market in China in 2006, country's listing surplus 60 at present is by the most widely used statins.Its structural formula is 5 (compounds 5):
Figure GSA00000085266800011
The preparation technology of auspicious rosuvastatin has numerous documents and patent to report, compound 4 (structural formula 4) is the important intermediate of the auspicious rosuvastatin calcium of preparation, patent WO2002/098854 discloses by 4-(4-fluorophenyl)-6-sec.-propyl-2-[(N-methyl-N-methylsulfonyl) 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, the substep yield is better, but N-methyl Toluidrin and pyrimidine ring be butt joint earlier, 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 disclose another kind of preparation method, but the yield of this method is extremely unstable, is easy to generate a large amount of by products in the reaction, is difficult to suitability for industrialized production.
In sum, above-mentioned preparation method exists operation complicated, consuming time, the defective that yield instability and cost are 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 auspicious rosuvastatin calcium important intermediate (3R, 5S, E)-and 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:
Figure GSA00000085266800031
Wherein, R 1Be one of following groups:
Figure GSA00000085266800032
R 2Be alkyl, cycloalkyl or benzyl, preferable methyl, ethyl or the tertiary butyl.
With 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, is dissolved among 5 times-50 times amount anhydrous solvent V/V; at-78 ℃--under 20 ℃; drip or add highly basic with compound 1 equimolar amount or twice molar weight in batches, then, be warming up to 10-25 ℃ in 2 hours; monitor to raw material by thin-layer chromatography and to disappear; add the highly basic with compound 1 equimolar amount or twice molar weight, add the N-methyl Toluidrin with compound 1 equimolar amount or twice molar weight again, then at 10-25 ℃ of reacting generating compound 4 (3R; 5S; E)-and 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.
Used highly basic is selected from one or more the mixture in hexamethyl two silica-based amido lithiums, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium hydride, potassium hydride KH, butyllithium or the lithium diisopropylamine in the reaction, and its used molar weight is 2.0～4.0 times of compound 1.
In the reaction process, treat that compound 3 generates fully after, reactant need not aftertreatment, directly in reaction system, add N-methyl Toluidrin and the normal highly basic of 1.0-2.0, then, under 10-25 ℃, react to compound 3 completely dissolves (thin-layer chromatography or HPLC monitoring).
Stable yield of the present invention can reach 60%-80%, and easy handling, and intermediate need not aftertreatment for the preparation technology of auspicious rosuvastatin provides a kind of cost lower, simple to operate, is easy to industrialized method.
Embodiment
Embodiment 1:
In the 1000mL there-necked flask, add 15.0 and digest compound 1,22.1 (1.05eq) and digest compound 2; argon shield adds the 300mL anhydrous tetrahydro furan, and dry ice acetone bath is chilled to-60 ℃; the tetrahydrofuran solution of the hexamethyl two silica-based amido lithiums of Dropwise 5 6mL1M under this temperature; finish, be warming up to 25 ℃ of room temperatures in 2 hours, under the argon shield; the sodium hydrogen that adds 4.1 grams 60%; add 7.62 gram N-methyl Toluidrins, reaction is spent the night, and cooling down; add the 100mL ethyl acetate; the saturated ammonia chloride aqueous solution of 20mL, 20mL water, separatory; water 200mL ethyl acetate extraction; merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying; filter; 30 ℃ of water-baths are revolved to steam to remove and are desolvated, and obtain product (3R, 5S; E)-7-(2-(N-methyl methylsulfonyl amido)-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-5-yl)-2; 2-dimethyl-3, the 5-dioxane-6-heptenoic acid tert-butyl ester (16.8 grams, 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 the 1000mL there-necked flask, add 15.0 and digest compound 1,22.1 and digest compound 2; argon shield; add the 300mL anhydrous tetrahydro furan, dry ice acetone bath is chilled to-60 ℃, drips the hexamethyl two silica-based amido lithiums of 70mL1M under this temperature; finish; rise to 25 ℃ of room temperatures in 2 hours, under the argon shield, add the sodium hydrogen and the 10.16 gram N-methyl Toluidrins of 3.73 grams 60%; 20～30 ℃ of reactions are spent the night; cooling adds the 100mL ethyl acetate, the saturated ammonia chloride aqueous solution of 20mL down; 20mL water; separatory, water 200mL ethyl acetate extraction merges organic phase; the saturated common salt water washing; anhydrous sodium sulfate drying filters, and 30 ℃ of water-baths are revolved to steam to remove and desolvated; obtain product (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 the tert-butyl ester (18.95 grams, yield 70.5%).
Embodiment 3:
In the 1000mL there-necked flask, add 15.0 gram formulas, 1 compound, 22.1 digest compound 2; argon shield adds the 300mL anhydrous tetrahydro furan, and dry ice acetone bath is chilled to-60 ℃; under this temperature, add the sodium hydrogen of 6.52 grams 60% in batches, finish, rise to 20～30 ℃ in 2 hours; add 10.16 gram N-methyl Toluidrins, 20～30 ℃ of reactions are spent the night, and cooling down; add the 100mL ethyl acetate; the saturated ammonia chloride aqueous solution of 20mL, 20mL water, separatory; water 200mL ethyl acetate extraction; merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying; filter; 30 ℃ of water-baths are revolved to steam to remove and are desolvated, and obtain product (3R, 5S; E)-7-(2-(N-methyl methylsulfonyl amido)-4-(4-fluorophenyl)-6-sec.-propyl-pyrimidine-5-yl)-2; 2-dimethyl-3, the 5-dioxane-6-heptenoic acid tert-butyl ester (18.31 grams, yield: 68.1%).
Embodiment 4:
In the 1000mL there-necked flask, add 15.0 and digest compound 1,22.1 and digest compound 2, argon shield; add the 200mL anhydrous tetrahydro furan, dry ice acetone bath is chilled to-60 ℃, drips 70mL1M hexamethyl two silica-based amido lithiums under this temperature; finish, be warming up to 20～30 ℃ in 2 hours, standby.
In the 1000mL there-necked flask, under 25 ℃ of the room temperatures, add 10.16 gram N-methyl Toluidrins; under the argon shield, add the 100mL anhydrous tetrahydro furan, add the sodium hydrogen of 3.73 grams 60%; 20～30 ℃ were reacted 0.5-1.0 hour down, dripped above-mentioned standby reaction solution then, finished; reaction is spent the night; cooling adds the 100mL ethyl acetate, the saturated ammonia chloride aqueous solution of 20mL down; 20mL water; separatory, water 200mL ethyl acetate extraction merges organic phase; the saturated common salt water washing; anhydrous sodium sulfate drying filters, and 30 ℃ of water-baths are revolved to steam to remove and desolvated; obtain product (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 the tert-butyl ester (20.24 grams, yield: 75.3%.)
The foregoing description is a preferred implementation 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 the principle, substitutes, combination, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.

Claims (8)

  1. One kind prepare (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 is characterized in that this method comprises the following steps:
    Figure FSA00000085266700011
    Wherein, R 1Be one of following groups:
    Figure FSA00000085266700012
    R 2Be alkyl, cycloalkyl or benzyl, preferable methyl, ethyl or the tertiary butyl;
    With compound 14-(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 is under the protection of dry inert gas; be dissolved in 5 times-50 times amount V/V anhydrous solvents; at-78 ℃--under 20 ℃, drip or add highly basic with compound 1 equimolar amount or twice molar weight in batches, be warming up to 10-25 ℃ in 2 hours then; monitor to raw material by thin-layer chromatography and to disappear; add the highly basic with compound 1 equimolar amount or twice molar weight, add the N-methyl Toluidrin with compound 1 equimolar amount or twice molar weight again, then; 10-25 ℃ of reaction down; generation 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. 2. the method for claim 1 is characterized in that, described reaction solvent is tetrahydrofuran (THF), dioxane, toluene, ether, N, N, and-dimethyl formamide, methyl-sulphoxide or acetonitrile are preferably anhydrous tetrahydro furan.
  3. 3. the method for claim 1, it is characterized in that, described highly basic is one or more the mixture in hexamethyl two silica-based amido lithiums, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium hydride, potassium hydride KH, butyllithium or the lithium diisopropylamine, and its used molar equivalent is 2.0～4.0 equivalents of compound 1.
  4. 4. the method for claim 1 is characterized in that, in compound 1 and compound 2 reaction process, drips or adds the alkaline temperature in batches and be-78 ℃--20 ℃, highly basic finishes, and is warmed up to 10-25 ℃.
  5. 5. the method for claim 1 is characterized in that, compound 1 and compound 2 reaction gained compounds 3 need not separation and purification, direct and N-methyl Toluidrin reaction.
  6. 6. the method for claim 1 is characterized in that, the temperature of compound 3 and the reaction of N-methyl Toluidrin is 10-25 ℃.
  7. 7. the method for claim 1, it is characterized in that, the feed way of described reactant and alkali can be directly to add N-methyl Toluidrin and highly basic in the reaction system of compound 3, or the reaction system of compound 3 is added drop-wise in the strong base solution of N-methyl Toluidrin.
  8. 8. the method for claim 1, it is characterized in that the alkaline feed way is for dripping or add 2.0-4.0 normal alkali in batches, or drip earlier or add the normal alkali of 1.0-2.0 in batches, then after compound 3 generates fully, drip again or add the normal alkali of 1.0-2.0 in batches.
CN201010146332.2A 2010-04-14 2010-04-14 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 Active CN102219780B (en)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
WO2013111946A1 (en) * 2012-01-27 2013-08-01 코오롱생명과학 주식회사 Method for preparing rosuvastatin, and intermediate compound used in preparing rosuvastatin
CN107298675A (en) * 2017-06-19 2017-10-27 浙江美诺华药物化学有限公司 A kind of preparation method of rosuvastain calcium intermediate
CN111518034A (en) * 2019-10-21 2020-08-11 山东理工职业学院 Preparation method of statin compound and intermediate thereof

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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

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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.》, vol. 51, no. 9, 15 April 2008 (2008-04-15), pages 2722 - 2733, XP055003825, DOI: doi:10.1021/jm800001n *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013111946A1 (en) * 2012-01-27 2013-08-01 코오롱생명과학 주식회사 Method for preparing rosuvastatin, and intermediate compound used in preparing rosuvastatin
CN107298675A (en) * 2017-06-19 2017-10-27 浙江美诺华药物化学有限公司 A kind of preparation method of rosuvastain calcium intermediate
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
CN111518034A (en) * 2019-10-21 2020-08-11 山东理工职业学院 Preparation method of statin compound and intermediate thereof

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