CN113979951A

CN113979951A - Synthetic process method of rosuvastatin

Info

Publication number: CN113979951A
Application number: CN202111399838.9A
Authority: CN
Inventors: 秦华利; 冯康; 范晓庆
Original assignee: Institute Of Advanced Research Wuhan University Of Technology Shangyu District Shaoxing City
Current assignee: Institute Of Advanced Research Wuhan University Of Technology Shangyu District Shaoxing City
Priority date: 2021-11-24
Filing date: 2021-11-24
Publication date: 2022-01-28

Abstract

The invention introduces a synthetic process of rosuvastatin and a preparation method of an intermediate thereof. Taking [4- [ 4-fluorophenyl-6- (1-methylethyl) -2- [ N-methyl- (N-methylsulfonyl) amino ] ] -5-pyrimidyl ] methyl triphenyl phosphine bromide as an initial raw material, performing wittig condensation, deprotection, hydrolysis and calcium salt formation to obtain a final product. Structures of key intermediate and target compound¹H‑NMR、¹³The C-NMR and MS spectra confirmed that the overall yield was 32.2% and the HPLC purity was 99.9%. The process route is simple, the operation is simple and convenient, each intermediate is easy to separate and purify, and the yield is relatively high.

Description

Synthetic process method of rosuvastatin

Technical Field

The invention relates to organic chemistry and pharmaceutical chemistry, in particular to a synthetic process method of rosuvastatin.

Background

ROSUVASTATIN (ROSUVASTATIN) has the chemical name (+) - (3R,5S) -bis {7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonamido) pyrimidin-5-yl ] -3, 5-dihydroxy-6- (E) -heptenoic acid } hemicalcium salt and the trade name CRESTOR. Is a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor developed by AstraZeneca and is mainly used for treating adult hyperlipidemia and mixed dyslipidemia clinically. The drug is approved to be marketed in European Union for the first time in 3 months in 2003, has powerful HMG-CoA reductase inhibition activity, has the effects of reducing LDL-C and increasing HDL-C, is superior to other statins on the market, has good tolerance and safety, and is known as super statin. The product has the advantages of high efficiency, low toxicity, less adverse reaction, etc., and is widely applied clinically. Currently, rosuvastatin calcium is marketed in more than 30 countries and regions of the world.

At present, a plurality of documents report the synthesis of rosuvastatin calcium. In the route reported in the first document, a mother nucleus is a substituted pyrimidine formaldehyde derivative, a chiral side chain is prepared into a phosphorus ylide form, then a Wittig condensation reaction is carried out to obtain a rosuvastatin calcium skeleton, and finally a target compound is prepared by acid hydrolysis deprotection, carbonyl reduction, alkali hydrolysis and salt formation. The synthesis route is a synthesis route for compound discovery, reaction conditions are harsh, the selectivity of Wittig reaction E/Z is poor, the yield is low, and the synthesis route is not suitable for industrial production. The second document has a synthetic strategy completely different from the first one, and reports that a mother nucleus is prepared into a diphenyl phosphine oxide derivative, a chiral side chain is prepared into an aldehyde form, a framework of rosuvastatin calcium is prepared by Wittig reaction condensation, and a compound is prepared by reactions such as deprotection, basic hydrolysis, salt formation and the like. In the process route, although the E/Z selectivity of the Wittig reaction reaches more than 90 percent, the di (trimethylsilyl) amino potassium with over-strong alkalinity is used in the reaction process, so that chiral side chain aldehyde is unstable, the yield is greatly reduced, and the advantage of cost is not achieved. The synthetic process of rosuvastatin calcium reported in the literature basically adopts Wittig reaction on the linkage of a parent nucleus and a side chain, is not ideal in the aspects of E/Z selectivity and yield, is not friendly in process conditions, and is not suitable for scale-up production. In view of the above disadvantages of the synthesis process, the authors of the present invention propose a new process for synthesizing rosuvastatin calcium, which has high yield, friendly process conditions and mild reaction conditions.

Disclosure of Invention

The invention aims to overcome the technical defects and provides a synthetic method, a simple technological method for synthesizing rosuvastatin calcium with industrial yield.

In order to achieve the technical purpose, the invention adopts the following technical scheme based on the wittig condensation method, and specifically comprises the following steps:

Detailed Description

The following examples further illustrate the technical solutions of the present invention, but should not be construed as limiting the scope of the present invention.

The embodiment of the invention provides a process method for synthesizing rosuvastatin calcium, which comprises the following steps:

example 1: synthesis of intermediate 2

Adding 92 g of zinc powder into 800mL of tetrahydrofuran under the protection of nitrogen, stirring for 20min, adding 69 g a, slowly adding 112.4 g b at room temperature, heating to reflux reaction for 3 h, slowly dropwise adding 2 mol/L hydrochloric acid, adjusting pH to 5-6, adding 400mL of ethyl acetate and 400mL of water, separating an organic phase, extracting a water layer with 200 mL of ethyl acetate for three times, combining the organic phases, washing the organic phase with 200 mL of saturated saline solution, drying the organic phase with anhydrous sodium sulfate, and removing the solvent through reduced pressure distillation to obtain an oily substance c 101.2 g.

Dissolving 93.8 g of a compound c in 1.3L of dried tetrahydrofuran and 400mL of ethanol, cooling to-65 ℃ under the protection of nitrogen, adding 595mL of a sodium borohydride tetrahydrofuran solution (1 mol/L), stirring for reaction for 20min, adding 22.6 g of sodium borohydride, reacting for 3 h at the temperature, stopping stirring when TLC detection raw materials disappear, evaporating the solvent tetrahydrofuran, extracting with 400mL of dichloromethane for three times, combining organic phases, washing with 300mL of a saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, evaporating the solvent to obtain a solid d, recrystallizing n-hexane to obtain 80.6 g of a light yellow solid, and obtaining the yield of 86.7%.

80.6 g of compound d was dissolved in 400mL of acetone, 1.2 g of benzenesulfonic acid was added, the mixture was reacted at 50 ℃ for 4 hours, poured into water (800 mL), extracted with ethyl acetate (300 mL. times.3), the organic phases were combined, washed with water (200 mL. times. 3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 78.6g of oil e.

Dissolving 78.6g of the compound e in 200 mL of DMF, adding 31.25 g of potassium acetate, reacting at 100 ℃ for 10 hours, pouring the mixture into 400mL of ice water, extracting with ethyl acetate (150 mL multiplied by 3), drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure to obtain 72.4 g of light yellow solid, recrystallizing the obtained solid with n-hexane to obtain 68.2 g of white solid 2, wherein the yield is 86.7%, and the chemical purity is 99.6% and the optical purity is 99.3% ee as determined by GC, and the m.p.64-65 ℃.

Example 2: synthesis of intermediate 3

6.78 g 1 (0.01 mol), 3.02 g 2 (0.01 mol), 30 mL dimethyl sulfoxide were added to a reaction flask, and the mixture was dissolved and stirred, and heated to 70-80 ︒ C, 3.52 g sodium carbonate was added, and the reaction was stirred overnight, and monitored by TLC. After the reaction, the reaction solution is stopped heating and cooled to room temperature, 80 mL of water and 100mL of toluene are slowly added, the mixture is stirred and phase-separated, toluene is added into the water phase for extraction (50 mL multiplied by 2), the organic phases are combined, 60 mL of saturated saline solution is added for washing, the solvent is removed under reduced pressure at 45 ︒ C, 5.2 g of light yellow crude product is obtained, and the crude product is recrystallized by using anhydrous methanol to obtain 5 g of white solid product 3. The yield thereof was found to be 85%. Melting point 145 ℃. m.p.145 ℃. ESI-MS m/z: 590.3 [ M + H ]⁺。¹HNMR（300MHz，DMSO-d ₆），δ：1.23~1.21（d，J=6.66Hz，6H），1.58~1.79（m，8H），1.81~2.29（m，2H），2.42~2.51（d，J =13.44，4.74 Hz，2H），3.28~3.39（m，1H），2.95（s，3H），3.05（s，3H），4.26（m，1H），4.52~5.09（m，2H），5.56（dd，J ₁=3.35，J ₂=3.33 Hz，1H），6.56（d，J =9.49 Hz，1H），7.28（t，J =5.33 Hz，2H），7.68（dd，J ₁=3.38，J ₂=3.35 Hz，2H）。

Example 3: synthesis of intermediate 4

2.886 g (5 mmol) of intermediate 3 and 25 mL of acetonitrile are added into a reaction flask, dissolved and stirred, 1 mol/L of 8 mL of hydrochloric acid solution is added dropwise at 30-35 ℃, the reaction is kept warm, and the reaction is monitored by TLC. After the reaction is finished, cooling to room temperature, dropwise adding 8 mL of 1 mol/L hydrochloric acid solution, and after dropwise adding, carrying out heat preservation reaction at 30-35 ℃; TLC monitored the reaction. After the reaction is finished, cooling to room temperature, dropwise adding 3 mL of 1 mol/L sodium hydroxide, maintaining the pH value at 9-10, then evaporating at 45 ℃ under reduced pressure to remove acetonitrile, adding 30 mL of water, extracting with ethyl acetate (10 mL multiplied by 2), combining organic phases, washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, carrying out suction filtration, and concentrating under reduced pressure to dryness to obtain 2.68 g of a crude white solid. The crude product was purified with 20 mL of isopropanol to give 2.55 white solid 4. m.p153 ℃. The yield thereof was found to be 95%.

Example 4: synthesis of intermediate 5

Dissolving 2.5 g of compound 4 in 30 ml of ethanol, adding 70 ml (0.1 mol/L) of NaOH ethanol solution dropwise in an ice water bath under the protection of nitrogen, stirring at room temperature for 2 h after adding dropwise, adjusting the pH value to 7 by using glacial acetic acid, removing the solvent under reduced pressure until the residual volume is about 25 ml, adding 30 ml of isopropyl ether, stirring, and filtering to obtain 2.25 g of white powdery solid with the yield of 90.0%.

Example 5: synthesis of rosuvastatin calcium 6

2.25 g of sodium salt is dissolved in 30 ml of purified water, and 1 mol/L CaCl is added dropwise₂After the solution was added dropwise, the mixture was stirred at room temperature for 4 hours, filtered, washed with purified water and dried to obtain 2.0 g of a white solid, and the crude product was recrystallized from water-ethyl acetate (1: 1) to obtain 1.58 g of a white crystal with a purity of 99.2% (HPLC, area normalization). The yield thereof was found to be 95.2%. m.p. 152 ℃. ESI-MS m/z: 1001.3 [ M + H ]⁺、1023.3 ［M+Na］⁺。¹HNMR（500 MHz，DMSO -d ₆），δ：1.21~1.22（d，J =6.0 Hz，6H），1.35 ~1.54 （m，2H），2.07~2.24 （d，J =13.2，8.2 Hz，2H）， 3.40~ 3.45 （m，1H），3.45 （s，3H），3.55（s，3H），3.85~4.24（m，2H），5.54（dd，J ₁ =16.1，J ₂ =5.3 Hz，1H），6.53（d，J=15.9 Hz，1H），7.26（t，J =8.7 Hz，2H），7.72 （dd，J ₁ =8.5，J ₂ =5.8 Hz，2H）。

The rosuvastatin calcium of the research has the advantages of reasonable and simple synthetic route, simple process operation, convenient purification of an intermediate, high total yield up to 32.2 percent, low cost and suitability for pilot scale-up and industrial production. In the process, the Wittig reaction is carried out by using super-strong base with high danger and avoiding ultralow temperature condition, and the preparation is carried out by using mild experimental conditions with good safety, so that the synthesis route is short, the raw and auxiliary materials of the used reagent are economical and easy to obtain, the reaction yield is high, the quality of the intermediate is easy to control, and the cost is low. Meanwhile, most of the solvent in the process route can be recycled, the production amount of solid wastes is small, and the influence on the environment is reduced.

Claims

1. A synthetic process method of rosuvastatin is characterized by comprising the following steps:

(1) adding 2- (6- (4-fluorophenyl) -2- (N-methylmethanesulfonamido) -5- ((triphenyl-lambda 4-phosphono) methyl) pyrimidine-4-yl) propane-1-ammonium bromite, 2- ((4R, 6S) -6- (acetoxymethyl) -2, 2-dimethyl-1, 3-dioxane-4-yl) tert-butyl ester, sodium bicarbonate and dimethyl sulfoxide into a reaction kettle, and recrystallizing the crude product by using anhydrous methanol to obtain white solid tert-butyl 2- ((4R, 6S) -6- ((E) -2- (4-fluorophenyl) -6-isopropyl-2- (N-methylsulfonamido) pyrimidine-5-yl) vinyl) 2, 2-dimethyl-1, 3-dioxan-4-yl) acetate;

(2) adding tert-butyl 2- ((4R, 6S) -6- ((E) -2- (4- (4-fluorophenyl) -6-isopropyl-2- (N-methylsulfonamido) pyrimidin-5-yl) vinyl) -2, 2-dimethyl-1, 3-dioxane-4-yl) acetate, acetonitrile and hydrochloric acid into a reaction kettle, adjusting the pH to 9-10 by using sodium hydroxide after the reaction is finished, refining the crude product by using isopropanol to obtain a white solid, namely tert-butyl (3R,5S, E) -7- (4- (4-fluorophenyl) -6-isopropyl-2- (N-methylsulfonamido) pyrimidin-5-yl) -3, 5-dihydroxyhept-6-enoate;

(3) adding tert-butyl (3R,5S, E) -7- (4- (4-fluorophenyl) -6-isopropyl-2- (N-methylsulfonylamino) pyrimidin-5-yl) -3, 5-dihydroxyhept-6-enoate and sodium hydroxide into a reaction kettle, and adjusting the pH value to 7 by glacial acetic acid to obtain white solid sodium (3R,5S, E) -7- (4- (4-fluorophenyl) -6-isopropyl-2- (N-methylsulfonylamino) pyrimidin-5-yl) -3, 5-dihydroxyhept-6-enoate;

(4) adding the sodium (3R,5S, E) -7- (4- (4-fluorophenyl) -6-isopropyl-2- (N-methylsulfonylamino) pyrimidin-5-yl) -3, 5-dihydroxyhept-6-enoate and the calcium chloride solution into a reaction kettle, stirring at room temperature for 4 hours, filtering, washing with purified water, drying to obtain 2.0 g of off-white solid, recrystallizing the crude product with water-ethyl acetate (1: 1), and processing to obtain rosuvastatin.

2. A process for synthesizing rosuvastatin according to claim 1, wherein the base used in the wittig condensation reaction is sodium carbonate.

3. A synthetic process of rosuvastatin according to claim 1, wherein the key intermediate for wittig condensation reaction is tert-butyl 2- ((4R, 6S) -6- (acetoxymethyl) -2, 2-dimethyl-1, 3-dioxane-4-yl); is prepared from (S) -4-chloro-3-hydroxybutyronitrile.

4. A process for synthesizing rosuvastatin according to claim 1, wherein the acid used in the deprotection reaction is hydrochloric acid with a concentration of 1 mol/L.

5. A process for synthesizing rosuvastatin according to any one of claims 2 to 4, wherein the wittig condensation reaction is completed, heating and cooling to room temperature are stopped, saturated brine and toluene are slowly added, phase separation by stirring is performed, toluene is added into the water phase for extraction, organic phases are combined, water washing is performed, 45 ︒ C is performed under reduced pressure to remove the solvent, a light yellow crude product is obtained, the crude product is dissolved by anhydrous methanol, the temperature is raised to reflux, the temperature is reduced to room temperature, crystallization by stirring is performed, suction filtration is performed, a filter cake is washed by methanol, and a white solid product is obtained by drying; the yield thereof was found to be 85%.

6. A process for rosuvastatin synthesis according to any of claims 2 to 4, characterized by: cooling to room temperature after the deprotection reaction is finished, dropwise adding 1 mol/L hydrochloric acid solution, and carrying out heat preservation reaction at 30-35 ℃ after dropwise adding; after the reaction is finished, cooling to room temperature, dropwise adding 1 mol/L sodium hydroxide, maintaining the pH value at 9-10, then evaporating at 45 ℃ under reduced pressure to remove acetonitrile, adding water, extracting with ethyl acetate, combining organic phases, washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, performing suction filtration, and concentrating under reduced pressure to dryness to obtain a white solid crude product; the crude product was refined with isopropanol to give a white solid with a yield of 95%.

7. A process for synthesizing rosuvastatin according to any of claims 2 to 4, wherein the hydrolysis reaction is carried out under nitrogen protection, 0.1 mol/L NaOH ethanol solution is added dropwise in an ice water bath, after the addition, the mixture is stirred at room temperature for 2 hours, glacial acetic acid is used to adjust the pH value to 7, the solvent is removed under reduced pressure, isopropyl ether is added, the mixture is stirred, and the white powdery solid is obtained by filtration with a yield of 90.0%.

8. A process for synthesizing rosuvastatin according to any of claims 2 to 4, wherein the calcium salt forming reaction is carried out by dissolving sodium salt in purified water, adding 1 mol/L CaCl dropwise₂After the solution is dripped, the solution is stirred for 4 hours at room temperature, filtered, washed by purified water and dried to obtain white solid, and the crude product is recrystallized by water-ethyl acetate (1: 1) with the yield of 70 percent.