A synthesis method of a key intermediate of atorvastatin side chain

Abstract

The application discloses a synthesis method of a key intermediate of atorvastatin side chain. Under the protection of nitrogen or argon, compound II is reacted with zinc powder in an organic solvent at room temperature for 1-2 hours to generate an organic zinc reagent, then a cuprous lithium salt is added, and the reaction is carried out at 0°C for 0.5-1 hour to generate an active copper-zinc metal organic compound III; then compound IV is slowly added, and the reaction is carried out at room temperature for 1-2 hours; after the reaction is completed, hydrochloric acid is added to quench the reaction, and compound I is obtained through separation and purification; compound IV is acyl chloride, and the substituent group R is cyano or dibenzylaminomethyl; and the cuprous lithium salt is a combination of cuprous cyanide and lithium chloride. The raw material is cheap and easy to obtain, the reaction condition is mild, an ultralow-temperature environment is not needed, the device requirement and energy consumption are low, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for synthesizing a key intermediate of the atorvastatin side chain. Background Technology

[0002] Atorvastatin calcium (CAS: 134523-03-8), chemically named (3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(benzylcarbamoyl)-1H-pyrrolo-1-yl]-3,5-dihydroxyheptanoate calcium trihydrate, is a selective hydroxymethylglutaryl-CoA (HMG-CoA) inhibitor. It works by inhibiting the rate-limiting enzyme in cholesterol synthesis, reducing cholesterol production in the liver, and upregulating the expression of low-density lipoprotein (LDL) receptors on the surface of hepatocytes, thus accelerating the clearance of LDL cholesterol from the blood. Developed by Warner-Lambert, it was approved by the FDA in 1996 and became the first drug in the world to surpass $10 billion in annual sales after being acquired by Pfizer in 2000. Its core patent expired in 2011, and several generic versions are now available.

[0003] Currently, the synthesis of atorvastatin calcium typically employs a strategy of docking the parent nucleus with a chiral side chain, as shown in route 1 of the retrosynthetic analysis. The preparation of the key chiral side chain diol compound 1 generally involves first synthesizing a monool compound 2, followed by sequential reduction of the carbonyl group using a sodium borohydride / borane system and then hydrogenation reduction of the cyano group using Raney nickel catalysis (see US5155251). However, this route requires the use of expensive chiral alcohols as starting materials, resulting in high costs for side chain preparation.

[0004] Route 1:

[0005] Currently, there are few reports on the synthesis of compound I. Chinese patent CN109503542A discloses a synthetic route for compound Ia, using tert-butyl bromoacetoacetate as a raw material. After protecting the carbonyl group of the ketone with ethylene glycol, a magnesium or zinc organometallic reagent is prepared, which then reacts with malononitrile, cyanoacetate, or cyanoacetyl chloride to obtain Ia. The reaction route is shown in Route 2. However, this route has obvious drawbacks, such as the tendency of ethylene glycol protection to cause the tert-butyl ester group to be removed; poor selectivity and numerous side reactions in the reaction of the magnesium Grignard reagent with cyano, ester, and acyl chloride groups; and low activity and insufficient conversion efficiency of the common zinc reagent. Therefore, this route has poor practicality and is difficult to apply on a large scale.

[0006] Route 2:

[0007] Furthermore, Chinese patent CN101326154A reports a synthetic route for compound Ib, which involves treating tert-butyl acetoacetate with sodium hydride and n-butyllithium, followed by condensation with ethyl 3-(dibenzylamino)propionate to obtain Ib, as shown in Route 3. However, this route has a yield of only 30%, and the sodium hydride and n-butyllithium used are extremely reactive and prone to spontaneous combustion. The reaction must be carried out under ultra-low temperature conditions, which places high demands on equipment, consumes a lot of energy, and poses significant safety risks, making it difficult to apply to large-scale industrial production.

[0008] Route 3: . Summary of the Invention

[0009] The purpose of this invention is to provide a method for synthesizing a key intermediate of the atorvastatin side chain, which uses inexpensive and readily available raw materials, has mild reaction conditions, does not require an ultra-low temperature environment, has low equipment requirements and low energy consumption, and is suitable for industrial production.

[0010] The technical solution adopted by this invention to solve its technical problem is: A method for synthesizing a key intermediate of the atorvastatin side chain.

[0011] Under nitrogen or argon protection, in an organic solvent, compound II is reacted with zinc powder at room temperature for 1-2 hours to generate an organozinc reagent. Then, copper lithium salt is added and reacted at 0°C for 0.5-1 hours to obtain active copper-zinc organometallic compound III. Subsequently, compound IV is slowly added and the temperature is raised to room temperature for 1-2 hours. After the reaction is completed, hydrochloric acid is added to quench the reaction. After separation and purification, compound I is obtained. Compound IV is an acyl chloride, and the substituent R is a cyano or dibenzylaminomethyl (CH2NBn2). The copper-lithium salt is a combination of cuprous cyanide and lithium chloride.

[0012] To reduce the requirements for reaction conditions, improve production safety, and lower production costs, this invention develops a novel synthetic route for compound I. Through this innovative synthetic route, chiral alcohol raw materials are not used; instead, inexpensive and readily available raw materials are employed, avoiding the use of sodium hydrogen and n-butyllithium, and eliminating the need for stringent reaction conditions.

[0013] The molar ratio of the raw materials is: Compound II: Zinc powder: Cuprous cyanide: Lithium chloride: Acyl chloride = 1.0: 1.2~1.5: 1.2~2.0: 2.4~4.0: 1.0.

[0014] The organic solvent is dichloromethane or tetrahydrofuran.

[0015] When R is dibenzylaminomethyl, the acyl chloride is 3-(dibenzylamino)propionyl chloride, and the preparation method of 3-(dibenzylamino)propionyl chloride is as follows: Under nitrogen or argon protection, dibenzylamine reacts with methyl acrylate via Michael addition reaction, followed by hydrolysis and acyl chloride reaction to yield 3-(dibenzylamino)propionyl chloride (i.e., compound IVb). The solvent used in the Michael addition reaction is acetonitrile, and the base used is DBU; .

[0016] The molar ratio of the reactants in the Michael addition reaction is dibenzylamine: methyl acrylate: base = 1.0: 1.1~1.2: 0.2~0.5.

[0017] The hydrolysis reaction is carried out by compound VII in an aqueous solution of tetrahydrofuran in the presence of sodium hydroxide at a temperature of 60–65 °C for 15–16 hours.

[0018] The volume percentage of tetrahydrofuran in the aqueous solution of tetrahydrofuran is 60-70%.

[0019] In the hydrolysis reaction, the molar ratio of compound VII to sodium hydroxide is 1:2 to 2.5.

[0020] The acyl chloride reagent for the acyl chloride reaction is oxalyl chloride, the catalyst is DMF, and the solvent is dichloromethane or tetrahydrofuran.

[0021] The molar ratio of the starting materials for the acyl chloride reaction is compound VIII: oxalyl chloride: DMF = 1.0: 1.0~1.2: 0.005.

[0022] The beneficial effects of this invention are: 1. It avoids the use of flammable and dangerous reagents such as sodium hydroxide and n-butyllithium, ensuring high safety; 2. The raw materials are cheap and readily available, the reaction conditions are mild, no ultra-low temperature environment is required, the equipment requirements and energy consumption are low, and it is suitable for industrial production. 3. The process steps are simple and the operation is convenient, making it an economical, safe and efficient new synthesis process. Detailed Implementation

[0023] The technical solution of the present invention will be further described in detail below through specific embodiments.

[0024] Unless otherwise specified, all raw materials and equipment used in this invention are commercially available or commonly used in the field. Unless otherwise specified, the methods described in the following embodiments are conventional methods in the field. Cyanoacetic acid (CAS 372-09-8), dibenzylamine (CAS 103-49-1), and other raw materials were purchased from Anaiji Chemical.

[0025] Cyanoacetyl chloride (compound IVa) is obtained by reacting cyanoacetic acid with an acyl chloride reagent at room temperature in the presence of a catalyst: In addition, cyanoacetyl chloride is also available on the market.

[0026] The preparation of compound II is described in the method for synthesizing compound IV in the applicant's earlier application (application number 2026108397642).

[0027] Example 1: Preparation of compound Ia (1) Preparation of compound IVa: Under nitrogen protection, cyanoacetic acid (100.0 g, 1.0 eq), dichloromethane (500 mL), and a catalytic amount of DMF (0.43 g, 0.005 eq) were added to reaction flask A. After stirring until homogeneous, oxalyl chloride (149.1 g, 1.0 eq) was slowly added dropwise at room temperature. After the addition was complete, the reaction was stirred at room temperature for 3 hours. After TLC monitoring showed that the reaction was complete, the resulting reaction solution was used directly for the next reaction without any post-treatment.

[0028] (2) Preparation of compound Ia: Under nitrogen protection, compound II (278.6 g, 1.0 eq) and tetrahydrofuran (1.0 L) were added to reaction flask B. Zinc powder (92.1 g, 1.2 eq) was added in batches with stirring. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour. The reaction solution was then cooled to 0°C, and cuprous cyanide (157.8 g, 1.5 eq) and lithium chloride (149.1 g, 3.0 eq) were added sequentially. The reaction was stirred at 0°C for 0.5 hours. The reaction solution obtained in step (1) was slowly transferred to flask B (theoretical amount of acyl chloride 1.0 eq). After the addition was complete, the temperature was naturally raised to room temperature, and the reaction was stirred for another 1 hour. After TLC monitoring showed that the reaction was complete, the reaction solution was cooled to 0-5°C, and the pH was adjusted to 2-3 with 2 N hydrochloric acid. The solution was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was slurried with n-heptane-ethyl acetate (20:1, volume ratio) at 0–5 °C, the light yellow solid was collected by filtration, and dried under vacuum at 40 °C to constant weight to give compound Ia (245.5 g), with a yield of 92.8%. 1 H NMR (400 MHz, CDCl 3, (Predominantly enol structure) δ 5.58 (s, 1H), 4.00 (s, 2H), 3.71 (s, 2H), 1.44 (s, 9H).

[0029] Example 2: Preparation of compound Ia (1) Preparation of compound IVa: Under nitrogen protection, cyanoacetic acid (100.0 g, 1.0 eq), tetrahydrofuran (500 mL) and catalytic amount of DMF (0.43 g, 0.005 eq) were added to reaction flask A. After stirring evenly, oxalyl chloride (178.9 g, 1.2 eq) was slowly added dropwise at room temperature. After the addition was complete, the reaction was stirred at room temperature for 5 hours. After TLC monitoring showed that the reaction was complete, the resulting reaction solution was used directly for the next reaction without post-treatment.

[0030] (2) Preparation of compound Ia: Under nitrogen protection, compound II (278.6 g, 1.0 eq) and tetrahydrofuran (1.0 L) were added to reaction flask B. Zinc powder (115.1 g, 1.5 eq) was added in batches with stirring. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours. The reaction solution was then cooled to 0°C, and cuprous cyanide (210.3 g, 2 eq) and lithium chloride (198.8 g, 4 eq) were added sequentially. The reaction was stirred at 0°C for 1 hour. The reaction solution obtained in flask A from the first step was slowly transferred to flask B (theoretical amount of acyl chloride 1.0 eq). After the addition was complete, the temperature was naturally raised to room temperature, and the reaction was stirred for another 2 hours. After TLC monitoring showed that the reaction was complete, the reaction solution was cooled to 0–5°C, and the pH was adjusted to 2–3 with 2N hydrochloric acid. The solution was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was slurried with n-heptane-ethyl acetate (20:1, volume ratio) at 0–5 °C, the light yellow solid was collected by filtration, and dried under vacuum at 40 °C to constant weight to give compound Ia (239.3 g), with a yield of 90.4%. 1 H NMR (400 MHz, CDCl) 3, (Predominantly enol structure) δ 5.58 (s, 1H), 4.00 (s, 2H), 3.71 (s, 2H), 1.44 (s, 9H).

[0031] Example 3: Preparation of compound Ia (1) Preparation of compound IVa: Under nitrogen protection, cyanoacetic acid (100.0 g, 1.0 eq), dichloromethane (500 mL), and a catalytic amount of DMF (0.43 g, 0.005 eq) were added to reaction flask A. After stirring until homogeneous, thionyl chloride (167.8 g, 1.2 eq) was slowly added dropwise at room temperature. After the addition was complete, the reaction was stirred at room temperature for 3 hours. After TLC monitoring showed that the reaction was complete, the resulting reaction solution was used directly for the next reaction without any post-treatment.

[0032] (2) Preparation of compound Ia: Under nitrogen protection, compound II (278.6 g, 1.0 eq) and tetrahydrofuran (1.0 L) were added to reaction flask B. Zinc powder (92.1 g, 1.2 eq) was added in batches with stirring. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour. The reaction solution was then cooled to 0°C, and cuprous cyanide (126.2 g, 1.2 eq) and lithium chloride (119.3 g, 2.4 eq) were added sequentially. The reaction was stirred at 0°C for 0.5 hours. The reaction solution obtained in flask A from the first step was slowly transferred to flask B. After the addition was complete, the temperature was naturally raised to room temperature, and the reaction was stirred for another 1 hour. After TLC monitoring showed that the reaction was complete, the reaction solution was cooled to 0–5°C, and the pH was adjusted to 2–3 with 2 N hydrochloric acid. The solution was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was slurried with n-heptane-ethyl acetate (20:1, volume ratio) at 0–5 °C, the light yellow solid was collected by filtration, and dried under vacuum at 40 °C to constant weight to give compound Ia (242.0 g), with a yield of 91.4%. 1 H NMR (400 MHz, CDCl) 3, (Predominantly enol structure) δ 5.58 (s, 1H), 4.00 (s, 2H), 3.71 (s, 2H), 1.44 (s, 9H).

[0033] Example 4: Preparation of Compound VII Dibenzylamine (1.0 kg, 1.0 eq), methyl acrylate (480.0 g, 1.1 eq), and acetonitrile (5.0 L) were added to a reaction flask and stirred until homogeneous. DBU (385.9 g, 0.5 eq) was then added, and the mixture was stirred at room temperature for 16 hours. After TLC monitoring showed complete reaction, the acetonitrile was removed by concentration under reduced pressure. The mixture was then redissolved in ethyl acetate, washed three times with saturated ammonium chloride solution, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a pale yellow oily liquid, which was compound VII (1345.8 g), with a yield of 93.7%. 1 H NMR (300 MHz, CDCl3) δ 7.46-7.18 (m, 10H), 3.66 (s, 3H), 3.62 (s,4H), 2.85 (t, J = 7.2 Hz, 2H), 2.55 (t, J = 7.2 Hz, 2H).

[0034] Example 5: Preparation of Compound VII Dibenzylamine (100.0 g, 1.0 eq), methyl acrylate (52.4 g, 1.2 eq), and acetonitrile (500 mL) were added to a reaction flask and stirred until homogeneous. DBU (15.4 g, 0.2 eq) was then added, and the mixture was stirred at room temperature for 16 hours. After TLC monitoring showed complete reaction, the acetonitrile was removed by concentration under reduced pressure. The mixture was redissolved in ethyl acetate, washed three times with saturated ammonium chloride solution, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a pale yellow oily liquid, which was compound VII (131.5 g), with a yield of 91.5%.

[0035] Example 6: Preparation of compound VIII Compound VII (1.2 kg, 1.0 eq), tetrahydrofuran (6.0 L), and water (3.6 L) prepared in Example 4 were added to a reaction flask. Sodium hydroxide (338.8 g, 2.0 eq) was added in portions with stirring. After the addition was complete, the temperature was raised to 60°C, and the reaction was stirred for 16 hours. After TLC monitoring showed that the reaction was complete, the reaction solution was cooled to 0–5°C, and the pH was adjusted to 5–6 with 2 N hydrochloric acid. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid, which was compound VIII (1101.5 g), with a yield of 96.6%.

[0036] Example 7: Preparation of compound Ib Step 1: Preparation of Compound IVb: Under nitrogen protection, compound VIII (100 g, 1.0 eq) prepared in Example 6, dichloromethane (500 mL), and a catalytic amount of DMF (0.14 g, 0.005 eq) were added to reaction flask A. After stirring until homogeneous, oxalyl chloride (47.1 g, 1.0 eq) was slowly added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 3 hours. After TLC monitoring showed that the reaction was complete, the resulting reaction solution was used directly for the next reaction without any post-treatment.

[0037] Step 2: Preparation of Compound Ib: Under nitrogen protection, compound II (88.0 g, 1.0 eq) and tetrahydrofuran (500 mL) were added to reaction flask B. Zinc powder (29.1 g, 1.2 eq) was added in portions with stirring, and the reaction was allowed to proceed at room temperature for 1 hour after the addition was complete. The reaction solution was then cooled to 0 °C, and cuprous cyanide (49.8 g, 1.5 eq) and lithium chloride (47.1 g, 3.0 eq) were added sequentially. The reaction was stirred at 0 °C for 1 hour. The reaction solution obtained in step A was slowly transferred to flask B (theoretical amount of acyl chloride 1.0 eq). After the addition was complete, the temperature was naturally raised to room temperature, and the reaction was continued with stirring for 2 hours. After TLC monitoring showed that the reaction was complete, the reaction solution was cooled to 0–5 °C, and the pH was adjusted to 2–3 with 2 N hydrochloric acid. The solution was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was slurried with n-heptane-ethyl acetate (20:1, volume ratio) at 0–5 °C, the light yellow solid was collected by filtration, and dried under vacuum at 40 °C to constant weight to give compound Ib (139.4 g), with a yield of 91.7%. 1 H NMR (300 MHz, CDCl 3, (Predominantly enol structure) δ 7.45-7.16 (m, 10H), 5.46 (s, 1H), 3.58 (s, 4H), 3.19 (s, 2H), 2.78 (t, J = 7.2 Hz, 2H), 2.47 (t, J = 7.2 Hz, 2H), 1.44 (s, 9H).

[0038] Example 8: Preparation of compound Ib Step 1: Preparation of Compound IVb. Under nitrogen protection, compound VIII (100.0 g, 1.0 eq), tetrahydrofuran (500 mL), and a catalytic amount of DMF (0.14 g, 0.005 eq) were added to reaction flask A. After stirring until homogeneous, oxaloyl chloride (56.5 g, 1.2 eq) was slowly added dropwise at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. Once TLC monitoring showed that the reaction was complete, the resulting reaction solution was used directly for the next reaction without further processing.

[0039] Step 2: Preparation of Compound Ib. Under nitrogen protection, compound II (88.0 g, 1.0 eq) and tetrahydrofuran (500 mL) were added to reaction flask B. Zinc powder (36.4 g, 1.5 eq) was added in portions with stirring, and the reaction was allowed to proceed at room temperature for 1 hour after the addition was complete. The reaction solution was then cooled to 0°C, and cuprous cyanide (39.9 g, 1.2 eq) and lithium chloride (37.7 g, 2.4 eq) were added sequentially. The reaction was stirred at 0°C for 0.5 hours. The reaction solution obtained in step 1 (flask A) was slowly transferred to flask B. After the addition was complete, the temperature was naturally raised to room temperature, and the reaction was stirred for another hour. After TLC monitoring showed that the reaction was complete, the reaction solution was cooled to 0–5°C, and the pH was adjusted to 2–3 with 2 N hydrochloric acid. The solution was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was slurried with n-heptane-ethyl acetate (20:1, volume ratio) at 0–5 °C, the light yellow solid was collected by filtration, and dried under vacuum at 40 °C to constant weight to give compound Ib (135.5 g), with a yield of 89.1%. 1 H NMR (300 MHz, CDCl) 3, (Predominantly enol structure) δ 7.45-7.16 (m, 10H), 5.46 (s, 1H), 3.58 (s, 4H), 3.19 (s, 2H), 2.78 (t, J = 7.2 Hz, 2H), 2.47 (t, J = 7.2 Hz, 2H), 1.44 (s, 9H).

[0040] Example 9: Preparation of compound Ia in hundreds of kilograms Step 1: Preparation of Compound IVa. Under nitrogen protection, cyanoacetic acid (100.0 kg, 1.0 eq), dichloromethane (500 L), and a catalytic amount of DMF (0.43 kg, 0.005 eq) were added to reactor A. After stirring until homogeneous, oxalyl chloride (149.1 kg, 1.0 eq) was slowly added dropwise at room temperature. After the addition was complete, the reaction was stirred at room temperature for 5 hours. After TLC monitoring showed that the reaction was complete, the resulting reaction solution was used directly for the next reaction without post-treatment.

[0041] Step 2: Preparation of Compound Ia. Under nitrogen protection, Compound II (278.6 kg, 1.0 eq) and tetrahydrofuran (1000 L) were added to reactor B. Zinc powder (92.1 kg, 1.2 eq) was added in batches with stirring, and the reaction was allowed to proceed at room temperature for 2 hours after the addition was complete. The reaction solution was then cooled to 0 °C, and cuprous cyanide (157.8 kg, 1.5 eq) and lithium chloride (149.1 kg, 3.0 eq) were added sequentially. The reaction was stirred at 0 °C for 1 hour. The reaction solution obtained in reactor A from step 1 was slowly transferred to reactor B (theoretical amount of acyl chloride 1.0 eq). After the addition was complete, the temperature was naturally raised to room temperature, and the reaction was stirred for another 2 hours. After TLC monitoring showed that the reaction was complete, the reaction solution was cooled to 0–5 °C, and the pH was adjusted to 2–3 with 2 N hydrochloric acid. The solution was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was slurried with n-heptane-ethyl acetate (20:1, volume ratio) at 0–5 °C, the light yellow solid was collected by filtration, and dried under vacuum at 40 °C to constant weight to give compound Ia (about 240.8 kg), with a yield of 91.0%.

[0042] Comparative Example 1: Preparation of Compound Ib Compound Ib was prepared using route 3. Under nitrogen protection, sodium hydride (2.53 g, 60% mineral oil, 1.0 eq) and tetrahydrofuran (50 mL) were added to a reaction flask, followed by stirring of compound 7 (10.0 g, 1.0 eq). The reaction mixture was cooled to 0 °C, and n-butyllithium (27.8 mL, 2.5 M, 1.1 eq) was slowly added dropwise, with stirring at 0 °C for 10 minutes. The reaction mixture was then cooled to -78 °C, and compound 6 (18.8 g, 1.0 eq) was added, with stirring continuing for 45 minutes. The reaction mixture was then heated to -30 °C over 30 minutes, held at this temperature for 15 minutes, and then cooled to -78 °C and held for 15 minutes. After the reaction was complete, the reaction mixture was quenched in a pre-cooled mixture of ethyl acetate and pH 10 buffer. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using petroleum ether-ethyl acetate (10:1, v / v) as the eluent. The target component was collected and concentrated under reduced pressure to give a light yellow solid, which was compound Ib (7.77 g), with a yield of 30.0%.

[0043] Comparative Example 2: Preparation of Compound Ia Compound Ia was prepared using method 2: .

[0044] 40.0 g (1.0 eq) of bromoacetoacetate and 23.1 g (2.2 eq) of ethylene glycol were added sequentially to the reaction flask. After stirring for 10 minutes, methanesulfonic acid (1.6 g, 0.1 eq) was added dropwise. The reaction was carried out at room temperature for 3 hours. TLC showed that a large amount of starting material remained, so the temperature was increased to 55 °C and the reaction was continued, extending the total reaction time to 17 hours. After the reaction solution was cooled to room temperature, a sample was taken for LCMS analysis, and the molecular ion peak of target compound 4 was not detected. The reaction solution was quenched with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was distilled under reduced pressure at an external temperature of 50 °C, and the fraction collected at 35 °C yielded 15.5 g of a colorless oily liquid. 1H NMR spectroscopy identified the structure of this fraction as 2-(bromomethyl)-2-methyl-1,3-dioxolane (compound 8), not target compound 4, indicating that the reaction did not proceed according to the expected pathway under these conditions, and the main product was a five-membered cyclic ketal compound after the removal of the tert-butyl group. After the failure to prepare compound 4 using route 2, the synthesis of compound 1a was not continued.

[0045] To better illustrate the features and advantages of the process of this invention, a comparison is made between the process of this invention and the prior art (Comparative Example 1). The comparison of the key evaluation elements of the two is shown in Table 1 below: Table 1 .

[0046] As shown in Table 1, compared with the prior art, the process of the present invention has mild reaction conditions, significantly improved yield, high operational safety, low reagent cost, and is friendly to industrial scale-up, making it suitable for large-scale industrial production.

[0047] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the present invention in any way. Other variations and modifications are possible without departing from the technical solutions described in the claims.

Claims

1. A method for synthesizing a key intermediate of the atorvastatin side chain, characterized in that, Under nitrogen or argon protection, in an organic solvent, compound II is reacted with zinc powder at room temperature for 1-2 hours to generate an organozinc reagent. Then, copper lithium salt is added and reacted at 0°C for 0.5-1 hours to obtain active copper-zinc organometallic compound III. Subsequently, compound IV is slowly added, and the temperature is raised to room temperature for 1-2 hours. After the reaction is completed, hydrochloric acid is added to quench the reaction. After separation and purification, compound I is obtained. Compound IV is an acyl chloride, and the substituent R is a cyano or dibenzylaminomethyl. The copper-lithium salt is a combination of cuprous cyanide and lithium chloride.

2. The synthesis method according to claim 1, characterized in that, The molar ratio of the raw materials is: Compound II: Zinc powder: Cuprous cyanide: Lithium chloride: Acyl chloride = 1.0: 1.2~1.5: 1.2~2.0: 2.4~4.0: 1.

0.

3. The synthesis method according to claim 1, characterized in that, The organic solvent is dichloromethane or tetrahydrofuran.

4. The synthesis method according to claim 1, characterized in that, When R is dibenzylaminomethyl, the acyl chloride is 3-(dibenzylamino)propionyl chloride, and the preparation method of 3-(dibenzylamino)propionyl chloride is as follows: Under nitrogen or argon protection, dibenzylamine reacts with methyl acrylate via Michael addition reaction, followed by hydrolysis and acyl chloride reaction to yield 3-(dibenzylamino)propionyl chloride. The solvent used in the Michael addition reaction is acetonitrile, and the base used is DBU; 。 5. The synthesis method according to claim 4, characterized in that, The molar ratio of the reactants in the Michael addition reaction is dibenzylamine: methyl acrylate: base = 1.0: 1.1~1.2: 0.2~0.

5.

6. The synthesis method according to claim 4, characterized in that, The hydrolysis reaction is carried out by compound VII in an aqueous solution of tetrahydrofuran in the presence of sodium hydroxide at a temperature of 60–65 °C for 15–16 hours.

7. The synthesis method according to claim 6, characterized in that, The volume percentage of tetrahydrofuran in the aqueous solution of tetrahydrofuran is 60-70%.

8. The synthesis method according to claim 6, characterized in that, In the hydrolysis reaction, the molar ratio of compound VII to sodium hydroxide is 1:2 to 2.

5.

9. The synthesis method according to claim 4, characterized in that, The acyl chloride reagent for the acyl chloride reaction is oxalyl chloride, the catalyst is DMF, and the solvent is dichloromethane or tetrahydrofuran.

10. The synthesis method according to claim 9, characterized in that, The molar ratio of the starting materials for the acyl chloride reaction is compound VIII: oxalyl chloride: DMF = 1.0: 1.0~1.2: 0.005.

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