Synthesis method of rosuvastatin calcium key intermediate

Abstract

The invention belongs to the field of organic chemistry, and particularly relates to a synthesis method of a rosuvastatin calcium key intermediate, which comprises the following steps: (1) taking (S)-4-chloro-3-hydroxybutyric acid as a raw material, and performing condensation ester with methanol under the condition of an esterification reaction condensing agent to obtain a compound with a structural formula B, and (2) taking the compound with the structural formula B as a raw material, and under the alkaline condition, performing condensation ester reaction to obtain the rosuvastatin calcium key intermediate. The preparation method comprises the following steps: (1) carrying out a reaction with tert-butyl malonate to obtain a compound with a structural formula C, (3) adding glucose and alkali into the compound with the structural formula C as a raw material under an enzyme catalysis condition to obtain a chiral reduction product D, and (4) heating the compound with the structural formula D as a raw material in the presence of only 2, 2-dimethoxypropane to obtain the rosuvastatin calcium key intermediate with a structural formula V. According to the method, tert-butyl bromoacetate and metal organic reagents which are high in cost and difficult to treat are not used, and solvents acetone and acid catalysts are not used in the ketal reaction, so that the production cost is reduced, and the method is more environment-friendly and efficient.

Description

Technical Field

[0001] The invention belongs to the field of organic chemistry, and particularly relates to a method for synthesizing a key intermediate of rosuvastatin calcium. Background Art

[0002] Rosuvastatin calcium (CAS No. 147098-20-2), chemical name is bis(3R,5S,6E)-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-(methylsulfonylamino)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid calcium salt, trade name Crestor.

[0003] Rosuvastatin calcium molecular structure

[0004]

[0005] Rosuvastatin calcium belongs to the statin class of drugs and is an HMG-CoA reductase inhibitor. It is primarily used to lower cholesterol, treat hypertriglyceridemia and primary bile proteinemia, and slow the progression of atherosclerosis.

[0006]

[0007] For the synthesis of rosuvastatin calcium, its key intermediate V is currently a hot topic in process research. The above key intermediate is prepared by the following route:

[0008] Patent CN104016961A reports that (S)-4-chloro-3-hydroxybutyric acid ethyl ester is used as a raw material, the hydroxyl group is protected with tert-butyldimethylsilyl chloride, and then condensed with tert-butyl bromoacetate under strong base conditions. After chiral asymmetric reduction, the dihydroxy group is protected with 2,2-dimethoxypropane to obtain the key intermediate V.

[0009]

[0010] Patent CN105968086A also uses a similar synthetic route, the difference being that hexamethyldisilazane is used instead of trimethylsilyl chloride as the hydroxyl protecting reagent for (S)-4-chloro-3-trihydroxybutyronitrile, and carbonyl reductase is used for chiral reduction in the reduction reaction of δ-hydroxy-β-ketoester.

[0011] In patent CN101613341A, (S)-4-chloro-3-hydroxybutyronitrile and tert-butyl bromoacetate are subjected to a Blaise condensation reaction to synthesize a δ-hydroxy-β-ketoester, which is then reduced and subjected to a ketal reaction to obtain the intermediate V.

[0012]

[0013] The above patents all use expensive tert-butyl bromoacetate as raw material, and the reaction needs a large amount of zinc powder to prepare an organic zinc reagent for Blaise condensation reaction, or uses butyllithium to participate in the reaction, and the reaction condition is severe. Meanwhile, such a reaction system is not friendly to the environment, and a large amount of metal-containing waste residues and waste liquid are generated. In addition, a large amount of acetone solvent and benzenesulfonic acid are used in the ketal reaction, and the reaction process is relatively complex.

[0014] In summary, it is urgent to develop a new method for preparing the key intermediate V of rosuvastatin calcium, which has low cost, mild reaction condition and is more environmentally friendly. SUMMARY

[0015] In order to overcome the shortcomings of the prior art, the present application provides a method for preparing a key intermediate of rosuvastatin calcium, which has mild reaction conditions, low cost and high yield, avoids the use of expensive tert-butyl bromoacetate and metal organic reagents which are not easy to handle, and no longer uses solvent acetone and acidic catalyst in the ketal reaction, thereby reducing the production cost and being more environmentally friendly and efficient.

[0016] In order to achieve the above purpose, the technical scheme of the present application is:

[0017] A synthesis method of a key intermediate of rosuvastatin calcium, comprising the following steps:

[0018] Step 1: using (S)-4-chloro-3-hydroxybutyric acid as a raw material, condensing with methanol under esterification condensing agent conditions to obtain a compound of formula B;

[0019] Step 2: using the compound of formula B as a raw material, reacting with di-tert-butyl malonate under alkaline conditions to obtain a compound of formula C;

[0020] Step 3: using the compound of formula C as a raw material, adding glucose and a base under enzyme catalysis conditions to obtain a chiral reduction product D;

[0021] Step 4: using the compound of formula D as a raw material, heating in the presence of only 2,2-dimethoxypropane to obtain a key intermediate V of rosuvastatin calcium; the reaction scheme is as follows:

[0022]

[0023] Preferably, the reaction solvent of step 1 is tetrahydrofuran.

[0024] Preferably, the molar ratio of methanol to (S)-4-chloro-3-hydroxybutyric acid in step 1 is 1:1 to 20:1; more preferably 5:1 to 8:1.

[0025] Preferably, the esterification reaction condensation agent used in step 1 is selected from N,N'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and N-hydroxybenzotriazole; more preferably N,N'-dicyclohexylcarbodiimide.

[0026] The molar ratio of the condensing agent used in step 1 to the compound of formula A is 1:1 to 2:1, more preferably 1:1.

[0027] Preferably, the reaction temperature of step 1 is 0-80°C, more preferably 25-40°C.

[0028] Preferably, the reaction solvent in step 2 is selected from N,N-dimethylformamide, tetrahydrofuran, acetonitrile, dichloromethane, DMSO and toluene, more preferably N,N-dimethylformamide.

[0029] Preferably, the base required for the reaction in step 2 is selected from sodium tert-butoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, more preferably sodium methoxide.

[0030] Preferably, the molar ratio of di-tert-butyl malonate, the base, and the compound of structural formula B used in the reaction of step 2 is 1:0.8:1 to 1:1.5:1, more preferably 1:1:1.

[0031] Preferably, the reaction temperature of step 2 is 40-120°C, more preferably 80°C.

[0032] Preferably, the enzymes required for step 3 are carbonyl reductase, glucose dehydrogenase, and the coenzyme NADP. The mass ratio of the three enzymes is 1:1:0.2 to 2:1:0.2, and the total amount of the required enzymes is 5%-50%, more preferably 10%, of the mass of the substrate compound of formula C. The molar ratio of glucose and base to the compound of formula C is 1:1:1.

[0033] Preferably, the base in step 3 is sodium carbonate, potassium carbonate or sodium bicarbonate, more preferably sodium carbonate.

[0034] Preferably, the molar ratio of dimethoxypropane used in step 4 to the compound of structural formula D is 1.5:1 to 5:1, more preferably 2.5:1.

[0035] Preferably, the reaction temperature in step 4 is 50-100°C, more preferably 60-75°C.

[0036] Compared with existing processes, this invention solves many process and production problems and has the following advantages: Step 2 uses the low-cost raw material di-tert-butyl malonate instead of the expensive and pungent tert-butyl bromoacetate used in existing processes, while also avoiding the use of equivalent-level metals or hazardous metal reagents. Compared with the present invention, the reaction conditions are milder, the raw material cost and production cost are significantly reduced, and the waste after the reaction is free of metal ions and halogens, making it more environmentally friendly. Step 4 can obtain the key intermediate V without the use of an acidic catalyst, making it simpler than the traditional process. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 This is the GC purity spectrum of the key intermediate V of rosuvastatin calcium in Example 1. DETAILED DESCRIPTION

[0038] The present invention is described below with reference to examples, but is not limited thereto. Simple replacements or improvements made by those skilled in the art to the present invention fall within the technical solutions protected by the present invention.

[0039] The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials, reagents, etc. used in the following examples are commercially available products unless otherwise specified.

[0040] Example 1

[0041] To a 250 ml reaction flask, 1.38 g (10 mmol) (S)-4-chloro-3-hydroxybutyric acid, 2.06 g (10 mmol) N,N'-dicyclohexylcarbodiimide, 3 ml methanol, and 30 ml tetrahydrofuran were added. The reaction was allowed to proceed at 40°C for 4 hours. After completion of the reaction by TLC, the excess solvent was removed using a rotary evaporator at no more than 35°C. The resulting organic compound B (1.50 g) was directly used in the next reaction. A second 250 ml reaction flask was added with organic compound B from the previous step, 2.59 g (12 mmol) di-tert-butyl malonate, and 0.648 g sodium methoxide. 30 ml N,N-dimethylformamide was added, and the reaction was allowed to proceed at 80°C for 10 hours. After completion of the reaction by TLC, 40 ml dichloromethane was added, and the mixture was thoroughly extracted with 30 ml of water. The organic phases were combined and the solvent was removed by distillation to obtain compound C (2.28 g). In a reaction flask, compound C obtained in the previous step, 1.8 g of glucose, 0.2 g of carbonyl reductase, 0.1 g of glucose dehydrogenase, and 0.02 g of coenzyme (Jiangsu Meike Biotechnology Co., Ltd.) were added, 0.37 g of disodium hydrogen phosphate and 0.75 g of sodium dihydrogen phosphate were added, and 50 ml of purified water was added. The reaction was carried out at 30°C for 4 h. 20% potassium carbonate solution was added dropwise during the reaction to control the pH of the reaction system to 7. After the reaction was completed by TLC detection, 20 ml × 3 of ethyl acetate was added for thorough extraction. After combining the organic phases, the solvent was distilled off to obtain compound D (2.12 g), which was used in the next reaction. The compound of the above structural formula D was added to the reaction flask, and 2.60 g (25 mmol) of 2,2-dimethoxypropane was added. The reaction was carried out at 70° C. for 8 hours. After TLC detection, 30 ml of n-hexane and 20 ml of purified water were added for washing and extraction. The organic phase was concentrated by layer to obtain the key intermediate rosuvastatin calcium with structural formula V (2.17 g, yield 78%, purity 98.8%).

[0042] Example 2

[0043] To a 500ml reaction flask, 2.76g (20mmol) of (S)-4-chloro-3-hydroxybutyric acid, 3.24g (20mmol) of N,N'-carbonyldiimidazole, 3ml of methanol, and 30ml of tetrahydrofuran were added and reacted at 50°C for 5 hours. After the reaction was complete as determined by TLC, the excess solvent was removed using a rotary evaporator at no more than 35°C. The resulting organic compound B (3.01g) was directly used in the next reaction. A 500ml reaction flask was added with the organic compound B obtained in the previous step, 5.18g (24mol) of di-tert-butyl malonate, and 1.296g of sodium methoxide. 20ml of tetrahydrofuran was added and the reaction was continued at 70°C for 8 hours. After the reaction was complete as determined by TLC, 40ml of dichloromethane was added and thoroughly extracted with 30ml of water. The organic phases were combined and the solvent was removed by distillation to obtain compound C (4.57g). In a reaction flask, compound C obtained in the previous step, 3.6 g of glucose, 0.3 g of carbonyl reductase, 0.15 g of glucose dehydrogenase, and 0.03 g of coenzyme (Jiangsu Meike Biotechnology Co., Ltd.) were added, 0.74 g of disodium hydrogen phosphate and 1.5 g of sodium dihydrogen phosphate were added, and 80 ml of purified water were added. The reaction was carried out at 30°C for 4 h. 20% potassium carbonate solution was added dropwise during the reaction to control the pH of the reaction system to 7. After the reaction was completed by TLC detection, 30 ml × 3 of ethyl acetate was added for thorough extraction. After combining the organic phases, the solvent was distilled off to obtain compound D (4.28 g), which was used in the next reaction. The compound of the above structural formula D was added to the reaction flask, and 5.2 g (50 mmol) of 2,2-dimethoxypropane was added. The reaction was carried out at 70° C. for 8 hours. After TLC detection, 120 ml of n-hexane and 100 ml of purified water were added for washing and extraction. The organic phase was concentrated by layer to obtain the key intermediate rosuvastatin calcium with structural formula V (4.50 g, yield 81%, purity 98%).

[0044] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in the present invention should be included in the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. A method for synthesizing a key intermediate of rosuvastatin calcium, characterized in that: The steps include: Step 1: Using (S)-4-chloro-3-hydroxybutyric acid, a compound of formula A, as a raw material, condensing it with methanol in the presence of an esterification agent to form an ester to obtain a compound of formula B; Step 2: Using the compound of formula B as a raw material, reacting with di-tert-butyl malonate under alkaline conditions to obtain a compound of formula C; Step 3: Using the compound of formula C as the raw material, glucose and base are added under enzyme catalysis to obtain the chiral reduction product D; Step 4: Using the compound of formula D as a raw material, heating in the presence of only 2,2-dimethoxypropane to obtain the key intermediate rosuvastatin calcium of formula V; the reaction formula is as follows:

2. The synthesis method according to claim 1, wherein The reaction solvent of step 1 is tetrahydrofuran; the molar ratio of the methanol and (S)-4-chloro-3-hydroxybutyric acid in the reaction of step 1 is 1:1 to 20:

1.

3. The synthesis method according to claim 1, wherein The esterification reaction condensing agent used in step 1 is selected from one or more of N,N'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and N-hydroxybenzotriazole; the molar ratio of the condensing agent used in step 1 to the compound of formula A is 1:1 to 2:1; and the reaction temperature of step 1 is 0-80°C.

4. The synthesis method according to claim 1, wherein The reaction solvent of step 2 is selected from N,N-dimethylformamide, tetrahydrofuran, acetonitrile, dichloromethane, DMSO or toluene; the base required for the reaction of step 2 is selected from one or more of sodium tert-butoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide and potassium hydroxide.

5. The synthesis method according to claim 1, characterized in that The molar ratio of di-tert-butyl malonate, base and compound of formula B used in the reaction of step 2 is 1:0.8:1 to 1:1.5:1; the reaction temperature of step 2 is 40-120°C.

6. The synthesis method according to claim 1, characterized in that The enzymes required in step 3 are carbonyl reductase, glucose dehydrogenase and coenzyme NADP, the mass ratio of the three enzymes is 1:1:0.2 to 2:1:0.2, and the total amount of the required enzymes is 5%-50% of the mass of the compound of formula C.

7. The synthesis method according to claim 1, characterized in that The molar ratio of glucose, base and compound of formula C in step 3 is 1:1:1; the base in step 3 is one or more of sodium carbonate, potassium carbonate or sodium bicarbonate.

8. The synthesis method according to claim 1, characterized in that The molar ratio of 2,2-dimethoxypropane used in step 4 to the compound of formula D is 1.5:1 to 5:

1.

9. The synthesis method according to claim 1, characterized in that The reaction temperature in step 4 is 50-100°C.

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