A kind of synthetic method of rosuvastatin tert-butyl ester

Abstract

The invention discloses a method for synthesizing rosuvastatin calcium tert-butyl ester. A Grignard reagent is synthesized by reacting a compound I with magnesium powder, the Grignard reagent is reacted with trimethylsilane under the action of a catalyst to prepare a compound III (4R-CIS)-6-trimethylsilyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester, the compound III reacts with a compound IV under the action of a catalyst to prepare a compound V, and the compound V is hydrolyzed under alkaline or acidic conditions to prepare rosuvastatin tert-butyl ester. The method has the following beneficial effects: compound III is prepared by reacting the Grignard reagent with trimethylsilane, the yield of the synthesis of the side chain of rosuvastatin calcium is improved, a cesium fluoride catalyst is selected for catalysis through a Peterson olefination reaction, the selectivity of the olefination reaction is effectively increased, and the generation of by-products and three wastes is reduced.

Description

Technical Field

[0001] The invention relates to the technical field related to pharmaceutical synthesis, and in particular to a method for synthesizing rosuvastatin tert-butyl ester. Background Art

[0002] Rosuvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) and can be used to treat hypercholesterolemia and mixed dyslipidemia. It can reduce elevated low-density lipoprotein cholesterol, total cholesterol, triglycerides and apoprotein B concentrations, while increasing high-density lipoprotein concentrations. It can be used for the comprehensive treatment of primary hypercholesterolemia, mixed lipodystrophy and homozygous familial hypercholesterolemia and is known as a super statin.

[0003] Rosuvastatin is administered as a single enantiomer calcium salt and has been marketed in the United States, Japan, Europe, China and other countries and regions. Its chemical name is bis-[E-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt (2:1), and its chemical structure is as follows:

[0004]

[0005] The key step of the main synthesis method of rosuvastatin is to synthesize by constructing the carbon-carbon double bond connecting the pyrimidine mother core of rosuvastatin calcium and the key chiral side chain. At present, the synthesis route of rosuvastatin calcium mainly relies on the following two schemes:

[0006] Solution 1

[0007] A synthetic method for constructing a carbon-carbon double bond connecting the pyrimidine core of rosuvastatin calcium and the key chiral side chain through Witting olefination reaction, preparing the intermediate rosuvastatin tert-butyl ester through Witting reaction of the key intermediate pyrimidine core and the key chiral side chain, and then preparing the rosuvastatin calcium raw material through deprotection, hydrolysis and salt formation. It is mainly divided into the following two categories: (1) introducing an aldehyde group on the pyrimidine core, making the side chain into a Wittig reagent, and obtaining a trans-olefin intermediate through Wittig reaction, and further transforming to obtain the product (as shown in the following route 1); (2) introducing a ylide reagent or other reagent on the pyrimidine core, making the side chain into an aldehyde compound, and obtaining a trans-olefin intermediate through Wittig reaction, and further transforming to obtain the product.

[0008] Route 1

[0009]

[0010] Route 2

[0011]

[0012] Solution 2

[0013] The synthesis method of the carbon-carbon double bond connecting the pyrimidine core of rosuvastatin calcium and the key chiral side chain is constructed by Julia olefination reaction, which is suitable for industrial production. The two key intermediate pyrimidine cores and the key chiral side chains are prepared by Julia reaction to obtain the intermediate rosuvastatin tert-butyl ester, and the tert-butyl ester of rosuvastatin is then deprotected, hydrolyzed and salified to obtain the rosuvastatin calcium raw material. The synthesis route is similar to the witting reaction. The main synthesis routes are shown in the following routes 3 and 4:

[0014] Route 3

[0015]

[0016] Route 4

[0017] The side chain starting materials of route 1 are relatively expensive, and the stereoselectivity of docking is not ideal. There are a large number of isomers, resulting in a low yield, which brings difficulties to industrial production. The cost of this route is also high. The reaction of route 2 is carried out at an extremely low temperature of -75°C, the reaction conditions are relatively harsh, and the stereoselectivity of docking is also not ideal, the yield is low, and it is not conducive to large-scale industrial production. Although the stereoselectivity of docking in route 3 has been well solved, the side chain is difficult to obtain through oxidation, the yield of the preparation side chain is low-cost, the atom economy of the reaction is poor, and the olefination reaction temperature is -60°C, which has high requirements for equipment, making the industrial production of this route difficult. Route 4 overcomes the shortcomings of route 3 that the side chain is difficult to oxidize completely and the raw materials are not easy to obtain, but the docking reaction is an ultra-low temperature reaction (-60°C), and the yield of the olefination reaction is only about 50%, so the energy consumption is high and the cost is high, which is difficult to achieve industrial production.

[0018] Chemical invention disclosure document CN104829600B discloses a synthesis process of (4R, 6S, E)-2-{6-[2-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl(methylsulfonyl)amino)pyrimidin-5-yl]vinyl]-2,2-dimethyl-1,3-epoxyhexane-4-yl} alkyl acetate, and the synthesis route is as follows:

[0019]

[0020] 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-methylpyrimidine was prepared by reacting 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-methylpyrimidine with trimethylchlorosilane in the presence of a catalyst, and then the rosuvastatin calcium intermediate 6-[(1E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidine]vinyl]-2,2-dimethyl-1,3 -dioxane-4-acetic acid alkyl ester, the reaction conditions are mild, the stereoselectivity is higher than that of the Witting reaction, the yield is higher than that of the Julia reaction, and the overall yield is high. However, the yield of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)-5-methylpyrimidine prepared by reacting 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)-5-methylpyrimidine with trimethylchlorosilane in the presence of a catalyst is low, only 60%, the atom economy is poor, and the final yield of the product is still low.

[0021] In summary, the preparation of rosuvastatin tert-butyl ester through the current synthetic route of rosuvastatin calcium has the problems of harsh reaction conditions, poor stereoselectivity, more by-products, and low overall yield.

[0022] In view of the shortcomings of the existing synthesis route, the present invention improves the Peterson olefination reaction process provided in the public document CN104829600B to provide a synthesis method of rosuvastatin tert-butyl ester. The synthesis route is as follows:

[0023] Summary of the invention

[0024] Aiming at the problems that the above-mentioned existing rosuvastatin calcium preparation method has poor stereoselectivity, harsh reaction conditions and low yield when preparing rosuvastatin tert-butyl ester, the present invention improves the Peterson olefination reaction process to provide a synthesis method of rosuvastatin tert-butyl ester with mild reaction conditions, good stereoselectivity and high yield.

[0025] A method for synthesizing rosuvastatin tert-butyl ester comprises the following steps:

[0026] In the first step, (4R-CIS)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (compound Ⅰ) reacts with magnesium powder to obtain Grignard reagent compound Ⅱ;

[0027] In the second step, compound II reacts with trimethylsilane to prepare (4R-CIS)-6-trimethylsilyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester;

[0028] In the third step, compound III is further reacted with 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine-5-carboxaldehyde (compound IV) in the presence of a catalyst. After the reaction is completed, 6-[(1E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidine]vinyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (compound V) is obtained after extraction, separation and purification.

[0029] In the fourth step, compound V is hydrolyzed under acidic or alkaline conditions to obtain rosuvastatin tert-butyl ester.

[0030] Furthermore, the solvent for the first step is anhydrous THF.

[0031] Furthermore, the molar ratio of the magnesium powder to the solvent in the first step reaction is 1:5-7, preferably 1:6.2.

[0032] Furthermore, the reaction temperature of the first step reaction is 30° C. and the reaction time is 2 h.

[0033] Furthermore, the solvent selected in the second step is a non-protonic solvent THF.

[0034] Furthermore, in the second step reaction, the molar ratio of the Grignard reagent to trimethylsilane is 1:0.6 to 1:1, preferably 1:0.8.

[0035] Furthermore, the reaction temperature of the second step reaction is 62-65°C, preferably 65°C.

[0036] Furthermore, the catalyst selected for the third step reaction is cesium fluoride, and the amount of the catalyst used is 5-10% of the mass of compound III.

[0037] Furthermore, the solvent for the third step reaction is DM, and the reaction temperature for the third step reaction is 80-150°C.

[0038] The beneficial effects of the present invention are as follows: the preparation method of rosuvastatin tert-butyl ester provided by the present invention has the advantages of easy-to-obtain raw materials, high yield of the side chain synthesized by the Grignard reagent method, good selectivity of the Peterson olefination reaction, good atom economy, mild reaction conditions and convenient operation, easy separation and convenient treatment of by-products such as magnesium chloride and silicide produced during the reaction, solid intermediates III and IV of the reaction products, which are easy to purify, so that the purity of the intermediate R1 in the next step becomes higher, and the impurities become smaller, which is beneficial to the purification of the product, so the total yield and purity of the final product are high, the post-processing of the product is simple, the production cost is greatly reduced, and large-scale production is easy. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 It is a schematic diagram of the reaction flow of the present invention;

[0040] Figure 2 is the structural formula of rosuvastatin calcium;

[0041] Figure 3 It is a schematic diagram of the reaction flow of Witting olefination reaction route 1 and 2;

[0042] Figure 4 It is a schematic diagram of the reaction flow of Julia olefination reaction routes 3 and 4;

[0043] Figure 5 This is a schematic diagram of the reaction process of the comparative document CN104829600B. DETAILED DESCRIPTION

[0044] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0045] Under nitrogen protection, 8.75 g (0.36 mol) of magnesium powder was added to a 1000 ml four-necked flask, 150 ml of THF reagent was added, and 100 g of compound I was slowly added to the solution. The mixture was stirred for 30 min, and initiator ethyl bromide was added at 27 °C. After initiation, 65 ml of THF was added, and stirring was continued. The temperature was controlled at 30 °C and kept warm for 2 h. After the reaction was completed, the excess magnesium powder was filtered out to obtain compound II with a yield of 89.6%.

[0046] Under nitrogen protection, 8.75 g (0.36 mol) of magnesium powder was added to a 1000 ml four-necked flask, 150 ml of THF reagent was added, and 100.3 g of compound I was added to the solution. The mixture was stirred for 30 min, and initiator ethyl bromide was added at 27 °C. After initiation, 120 ml of THF was added, and stirring was continued. The temperature was controlled at 30 °C and the reaction was carried out for 2 h. After the reaction was completed, the excess magnesium powder was filtered out to obtain compound II with a yield of 93.6%.

[0047] Under nitrogen protection, 8.75 g (0.36 mol) of magnesium powder was added to a 1000 ml four-necked flask, 150 ml of THF reagent was added, and 100.3 g of compound I was added to the solution. The mixture was stirred for 30 min, and initiator ethyl bromide was added at 27 °C. After initiation, 150 ml of THF was added, and stirring was continued. The temperature was controlled at 30 °C and kept warm for 2 h. After the reaction was completed, the excess magnesium powder was filtered out to obtain compound II with a yield of 93.8%.

[0048] To the Grignard reagent obtained in the first step, 31.3 g (0.288 mol) of trimethylsilyl chloride was added dropwise, and the reaction temperature was controlled between 62 and 67 °C. After the addition was completed, it was heated to reflux at 65 °C for 2 h, cooled to below 10 °C, hydrolyzed with 5% HCl, separated, and the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain Compound III with a yield of 96.3% and a purity of 99.5%.

[0049] To the Grignard reagent obtained in the first step, 39.1 g (0.36 mol) of trimethylsilyl chloride was added dropwise, and the reaction temperature was controlled between 62 and 67°C. After the addition was completed, the mixture was heated to reflux at 65°C for 2 h, cooled to below 10°C, hydrolyzed with 5% HCl, separated, and the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain Compound III with a yield of 90.2% and a purity of 99.5%.

[0050] To the Grignard reagent obtained in the first step, 23.4 g (0.216 mol) of trimethylsilyl chloride was added dropwise, and the reaction temperature was controlled between 62 and 67 °C. After the addition was completed, it was heated to reflux at 65 °C for 2 h, cooled to below 10 °C, hydrolyzed with 5% HCl, separated, and the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain compound III with a yield of 89.3% and a purity of 99.5%.

[0051] In a 250 ml three-necked flask, a thermometer, a pH meter, a constant pressure dropping funnel and a magnetic stirrer were installed. At room temperature, 10 g of compound II, 100 ml of DMF, 11 g of 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine-5-carboxaldehyde and 0.5 g of cesium fluoride were added to the reaction flask and stirred for 1 hour. Then the temperature was raised to 120°C, kept warm for 2 hours, cooled, poured into 200 ml of ice water, extracted with 150 ml*2 of toluene in layers, concentrated under reduced pressure, dissolved with 100 ml of methanol, cooled to room temperature, kept warm for 6 hours for crystallization, filtered, and dried under reduced pressure to obtain the product (4R, 6S, E)-2-{6-[2-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl(methylsulfonyl)amino)pyrimidin-5-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl}acetate 15.41 g, yield 85%, HPLC purity 99.5%.

[0052] In a 250ml three-necked flask, a thermometer, a pH meter, a constant pressure dropping funnel and a magnetic stirrer were installed. At room temperature, 10g of compound III, 100ml of DMSO, 11g of 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine-5-carboxaldehyde and 0.5g of cesium fluoride were added to the reaction flask and stirred for 1 hour. Then the temperature was raised to 90-92°C, kept warm for 4 hours, cooled, poured into 200 ml of ice water, extracted with 150 ml*2 of toluene in layers, concentrated under reduced pressure, dissolved with 100 ml of methanol, cooled to room temperature, kept warm for 6 hours for crystallization, filtered, and dried under reduced pressure to obtain the product (4R, 6S, E)-2-{6-[2-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl(methylsulfonyl)amino)pyrimidin-5-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl}acetic acid methyl ester 14.86 g yield 82%, HPLC purity 99.3%.

[0053] In a 250 ml three-necked flask, a thermometer, a pH meter, a constant pressure dropping funnel and a magnetic stirrer were installed. At room temperature, 10 g of compound II, 100 ml of NMP, 11 g of 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine-5-carboxaldehyde and 0.5 g of cesium fluoride were added to the reaction flask and stirred for 1 hour. Then the temperature was raised to 130°C, kept warm for 1.5 hours, cooled, poured into 200 ml of ice water, extracted with 150 ml*2 of toluene in layers, concentrated under reduced pressure, dissolved with 100 ml of methanol, cooled to room temperature, kept warm for 6 hours for crystallization, filtered, and dried under reduced pressure to obtain the product (4R, 6S, E)-2-{6-[2-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl(methylsulfonyl)amino)pyrimidin-5-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl}acetate 13.23 g, yield 73%, HPLC purity 99.4%.

[0054] In a 250 ml three-necked flask, a thermometer, a pH meter, a constant pressure dropping funnel and a magnetic stirrer were installed. At room temperature, 10 g of compound II, 100 ml of DMF, 11 g of 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine-5-carboxaldehyde and 1.0 g of cesium fluoride were added to the reaction flask and stirred for 1 hour. Then the temperature was raised to 120°C, kept warm for 2 hours, cooled, poured into 200 ml of ice water, extracted with 150 ml*2 of toluene in layers, concentrated under reduced pressure, dissolved with 100 ml of methanol, cooled to room temperature, kept warm for 6 hours to crystallize, filtered, and dried under reduced pressure to obtain the product compound V (4R, 6S, E)-2-{6-[2-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl(methylsulfonyl)amino)pyrimidin-5-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl}acetate 15.05 g, yield 83%, HPLC purity 99.5%.

[0055] In a 2000mL four-necked round-bottom flask, add 100g (0.173mol) of compound V and 700mL of acetonitrile, slowly heat to about 40°C and stir to dissolve, slowly drop 80mL of 0.05mol / L hydrochloric acid, keep warm for 2h after the addition is complete, detect by HPLC that the raw material is completely converted, cool to 0°C, drop saturated sodium carbonate aqueous solution to adjust the pH of the reaction system to about 7, continue stirring for 3h, filter, wash, and dry to obtain 87g of white rosuvastatin tert-butyl ester with HPLC purity of 99.5%.

[0056] Comparative Document (CN104829600B) Example 1

[0057] In a 500ml four-necked bottle, install a thermometer, a constant pressure dropping funnel and a magnetic stirrer under N2 protection. At room temperature, add 14 grams of compound I to the reaction bottle, then add about 150ml of THF, protect with nitrogen, stir to dissolve, then slowly cool to -5 to -10°C, slowly start to drop 30ml of n-butyl lithium (2.5N) in n-hexane solution, maintain the temperature at -10°C to 0°C, drop for about 45min, heat to 0°C to 10°C, keep warm for 30min, cool to about -15°C, drop 2,2,6,6-tetramethylpiperidine 11g / THF 20ml of the mixed solution, the addition time is about 30min, the temperature is controlled at -15±2℃, and it is kept warm for 2 hours. Trimethylsilyl chloride / THF (8g / 20ml) is slowly added dropwise and kept warm for 3 hours (TLC detection shows cyclohexane: ethyl acetate = 20:1). After the reaction is complete, pour it into 300ml of ice water, extract it twice with 200ml of toluene, wash it once with 100ml of saturated baking soda water, concentrate it to dryness under reduced pressure, add 20ml of n-heptane and 1ml of ethyl acetate, heat to dissolve, slowly cool it to -5℃, crystallize it for more than 6 hours, filter it, and dry it under reduced pressure to obtain product II with a yield of 63.2%.

[0058] Comparative Document (CN104829600B) Example 2

[0059] In a 250 ml three-necked flask, a thermometer, a pH meter, a constant pressure dropping funnel and a magnetic stirrer were installed. At room temperature, 10 g of compound II, 100 ml of DMF, 6.5 g of (4R-cis)-6-formyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester and 0.4 g of cesium fluoride were added to the reaction flask and stirred for 1 hour. Then the temperature was raised to 120°C, kept warm for 2 hours, cooled, poured into 200 ml of ice water, extracted with 150 ml*2 of toluene in layers, concentrated under reduced pressure, dissolved with 100 ml of methanol, cooled to room temperature, kept warm for 6 hours for crystallization, filtered, and dried under reduced pressure to obtain the product (4R, 6S, E)-2-{6-[2-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl(methylsulfonyl)amino)pyrimidin-5-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl} tert-butyl acetate 11.0 g, yield 77.8%.

[0060] According to the above examples, it can be concluded that compared with the 60% preparation yield of rosuvastatin side chain in the public document CN104829600B, the preparation yield of rosuvastatin tert-butyl ester is 49.0%. The preparation yield of rosuvastatin side chain in the present invention exceeds 90%, and the yield of Peterson olefination reaction reaches 80%, which is higher than the technical solution published in the public document.

[0061] It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above and that the invention can be implemented in other specific forms without departing from the spirit or essential features of the invention. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations falling within the meaning and scope of the equivalent elements of the claims be included in the invention. Any reference numeral in a claim should not be considered as limiting the claim to which it relates.

[0062] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A method for synthesizing rosuvastatin tert-butyl ester, characterized in that The following steps are involved: In the first step, (4R-CIS)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester compound I reacts with magnesium powder to obtain Grignard reagent compound II; In the second step, the Grignard reagent compound II reacts with trimethylsilyl chloride to prepare (4R-CIS)-6-trimethylsilyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester; In the third step, compound III is further reacted with 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine-5-carboxaldehyde compound IV under the action of a catalyst, and after the reaction is completed, extraction, separation and purification are performed to obtain 6-[(1E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidine]vinyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester compound V; The fourth step is to hydrolyze compound V under acidic or alkaline conditions to obtain rosuvastatin tert-butyl ester compound VI; The reaction formula is as follows: ； The first step reaction solvent is anhydrous THF; The molar ratio of magnesium powder to solvent in the first step reaction is 1:5-7; The reaction temperature of the first step reaction is 30° C. and the reaction time is 2 h; the solvent selected for the second step is the aprotic solvent THF; In the second step reaction, the molar ratio of the Grignard reagent compound II to trimethylsilane is 1:0.6 to 1:1; The reaction temperature of the second step reaction is 62-65°C; The catalyst selected for the third step reaction is cesium fluoride, and the amount of the catalyst used is 5-10% of the mass of compound III; The solvent for the third step reaction is DMF, and the reaction temperature for the third step reaction is 80-150°C.

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