Synthesis of a key intermediate of sodium fluvastatin

Abstract

The application provides a method for synthesizing a sodium fluvastatin intermediate, which adopts an organic zinc reagent and (E)-3-[3'-(4''-fluorophenyl)-1'-isopropyl-1H-indol-2''-yl]-2-propenal to react under mild conditions to prepare a target product. The method for synthesizing the key sodium fluvastatin intermediate provided by the application has the advantages of being green and efficient, low in cost, and easy to be applied in industrialization.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to the synthesis method of key intermediates of fluvastatin sodium. Background Technology

[0002] Fluvastatin sodium, developed by Sandoz (now Novartis) of Switzerland, is the first fully synthetic HMG-CoA reductase inhibitor, a lipid-lowering drug. It was approved by the US FDA in December 1993 and launched in the UK and US the following year. The FDA approved its capsule form in 1994 and its extended-release tablet form in 2001. Fluvastatin is an excellent lipid-lowering drug due to its relatively simple structure, selective action, and low incidence of adverse reactions. Fluvastatin directly inhibits HMG-CoA reductase in the liver, and its hydroxyl metabolites also have enzyme-inhibiting effects. It is used to treat primary hypercholesterolemia and primary mixed dyslipidemia that are unresponsive to diet. Fluvastatin sodium was introduced to China in 1997 under the brand name Lesco, and is now included in China's National Reimbursement Drug List, considered one of the most promising domestically produced statins. The chemical structure of fluvastatin sodium is as follows:

[0003]

[0004] Compounds of formulas I, II, and III can all serve as key intermediates in the synthesis of fluvastatin sodium, and their structures are as follows:

[0005]

[0006] US Patent 5354772A discloses a method for synthesizing a key intermediate of fluvastatin sodium, compound of formula I, via the following synthetic route:

[0007]

[0008] This method uses [3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal as a raw material, and prepares intermediate I with methyl acetoacetate under strong alkaline conditions. This method employs sodium hydride and n-butyllithium, making the process highly hazardous and unsuitable for large-scale industrial application.

[0009] Chinese patent CN1217930C discloses a method for synthesizing a key intermediate of fluvastatin sodium, a compound of formula I. The synthetic route is as follows:

[0010]

[0011] This process employs a segmented side-chain construction strategy. First, the indole compound undergoes a Vilsmeier-Haack reaction at the 2-position to obtain an aldehyde intermediate. Then, under the action of a strong base such as n-butyllithium, nucleophilic substitution and other reactions occur to construct the side chain segmentally. This process has a long reaction time, low overall yield, and uses sodium hydride and n-butyllithium, making it highly hazardous. The condensation reaction takes place at -78°C, with harsh reaction conditions, making it unsuitable for industrial production.

[0012] Chinese patent CN1217930C discloses a method for synthesizing a key intermediate of fluvastatin sodium, a compound of formula I. The synthetic route is as follows:

[0013]

[0014] This process uses 4-haloacetoacetate as the starting material, first preparing a phosphorus ylide reagent, which then undergoes a Wittig reaction with an indolealdehyde compound to construct a dicarbonyl side chain. Subsequently, an asymmetric hydrogenation reaction occurs under a Noyori catalyst to construct a chiral alcohol, followed by a nucleophilic substitution reaction under strong base conditions.

[0015] The process involves a long reaction time, low overall yield, requires the introduction of large amounts of phosphorus reagents, causes significant environmental pollution, and has harsh reaction conditions, requiring the reaction to be carried out at -78°C. Furthermore, it requires the use of the precious metal ruthenium, resulting in high production costs. Summary of the Invention

[0016] To address the shortcomings of existing technologies, this invention provides a green, efficient, low-cost, and easily industrially applicable method for synthesizing compound I.

[0017] According to the present invention, a method for synthesizing a fluvastatin sodium intermediate is provided, which involves using an organozinc reagent and (E)-3-[3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal in the presence of a dinitrogen ligand to synthesize the key intermediate of fluvastatin sodium as shown in Formula I. The chemical reaction equation is as follows:

[0018]

[0019] The organozinc reagent is obtained by reacting α-bromoacetate with active zinc, wherein the molar ratio of the halogenated product to active zinc is 1:1.5 to 1:2.5, preferably 1:1.8 to 1:2; wherein the active zinc is obtained by the activation reaction of zinc powder with tetramethylchlorosilane (TMSCl), and the activation process can be carried out simultaneously during the preparation of the zinc reagent, and the chemical reaction equation is as follows:

[0020]

[0021] In the synthesis method, the molar ratio of organozinc reagent to α-bromoacetic acid ester is 1:3 to 1:5, preferably 1:4.5 to 1:5.

[0022] In the synthesis method, the dinitrogen ligand is N-methylimidazolium, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 2,2'-bipyridine, o-phenanthroline, N,N-dimethylethanolamine, tetramethylethylenediamine, N,N'-dimethylethylenediamine, preferably tetramethylethylenediamine. The molar ratio of the dinitrogen ligand to (E)-3-[3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal is 1.5:1 to 2.5:1, preferably 2:1.

[0023] In the synthesis method, the iodide catalyst is sodium iodide, potassium iodide, magnesium iodide, cesium iodide, cuprous iodide, or zinc iodide, with cuprous iodide being preferred. The molar ratio of the iodide catalyst to (E)-3-[3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal is 0.05:1 to 0.5:1, preferably 0.2:1.

[0024] The synthesis method is performed at a reaction temperature of 0–80°C, preferably 50–60°C.

[0025] The reaction solvents used in the synthesis method are N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone, and tetrahydrofuran, preferably N,N-dimethylformamide and dimethyl sulfoxide.

[0026] After the reaction was complete, the mixture was cooled to 10-25°C and diluted with ethyl acetate. The reaction solution was then washed sequentially with 20% citric acid aqueous solution, 10% sodium chloride aqueous solution, 5% sodium bicarbonate aqueous solution, and tap water. After standing and separating the layers, the organic phase was separated and concentrated under reduced pressure at 40-50°C. The product was then recrystallized from a mixture of 10 times the volume of n-heptane and 5 times the volume of ethyl acetate, with a yield of 65-90% and a purity greater than 98.5%.

[0027] In the existing technology, the synthetic method of compound I reported in literature and patents uses extremely low reaction temperatures of -20℃ and -78℃ and strong bases, which not only increases the risk of industrialization, but also increases the difficulty of post-processing, and generates a large amount of wastewater, which is not conducive to environmental protection. In addition, the yield is low, which increases the cost of industrialization and does not meet the environmental protection requirements of current green chemical industry.

[0028] The synthesis of compound I in this invention has significant advantages: compound I is synthesized using an organozinc reagent and (E)-3-[3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal under the action of a dinitrogen ligand. The organozinc reagent can be prepared by simply heating zinc powder with tetramethylchlorosilane (TMSCl) and α-bromoacetic acid ester. It can be directly activated during the preparation process without separation and can be used directly. The reaction process is mild and does not require extremely low reaction temperatures. The post-processing is convenient and simple. Conventional extraction, washing, and layering operations avoid the generation of large amounts of wastewater, making it more environmentally friendly. The raw materials are readily available, the product yield is high, reaching up to 90% or more, and the cost is low. Therefore, it is more suitable for industrialization. Detailed Implementation

[0029] The embodiments of the present invention will be described in detail below with reference to specific examples. However, those skilled in the art should understand that the examples are only for illustrating the present invention and should not be regarded as limiting the scope of the present invention.

[0030] Unless otherwise specified in the examples, the procedures should be performed under standard conditions or as recommended by the manufacturer or supplier. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0031] Example 1: Synthesis of the organozinc reagent BrZnCH2CO2Me

[0032] Under nitrogen protection, 57.5 g (0.88 mol) of zinc powder, 220 mL of tetrahydrofuran, and 4.8 g (44 mmol) of tetramethylchlorosilane were added to a 1.0 L reaction flask. The temperature was raised to 40-50 °C, and then 67.3 g (0.44 mol) of methyl α-bromoacetate in 500 mL of tetrahydrofuran solution was slowly added dropwise. The reaction was stirred for 1-3 hours. After the reaction was completed, the mixture was allowed to stand (or centrifuged) and separated. The clear liquid was collected, and the yield of the organozinc reagent was calculated as 100% and used for subsequent reactions.

[0033] Example 2: Synthesis of the organozinc reagent BrZnCH2CO2Et

[0034] Under nitrogen protection, 57.5 g (0.88 mol) of zinc powder, 220 mL of tetrahydrofuran, and 4.8 g (44 mmol) of tetramethylchlorosilane were added to a 1.0 L reaction flask. The temperature was raised to 40-50 °C, and then 73.5 g (0.44 mol) of α-bromoethyl acetate in 500 mL of tetrahydrofuran solution was slowly added dropwise. The reaction was stirred for 1-3 hours. After the reaction was completed, the mixture was allowed to stand (or centrifuged) and separated. The clear liquid was collected, and the yield of the organozinc reagent was calculated as 100% and used for subsequent reactions.

[0035] Example 3 Synthesis of the organozinc reagent BrZnCH2CO2-i-Pr

[0036] Under nitrogen protection, 57.5 g (0.88 mol) of zinc powder, 220 mL of tetrahydrofuran, and 4.8 g (44 mmol) of tetramethylchlorosilane were added to a 1.0 L reaction flask. The temperature was raised to 40-50 °C, and then 79.6 g (0.44 mol) of α-bromoacetic acid isopropyl ester in 500 mL of tetrahydrofuran solution was slowly added dropwise. The reaction was stirred for 1-3 hours. After the reaction was completed, the mixture was allowed to stand (or centrifuged) and separated. The clear liquid was collected, and the yield of the organozinc reagent was calculated as 100% and used for subsequent reactions.

[0037] Example 4: Synthesis of methyl ester (R=Me), a key intermediate of fluvastatin sodium

[0038]

[0039] Under nitrogen protection, 100 mL (50 mmol) of a 0.5 mol / L BrZnCH2CO2Me tetrahydrofuran solution, 3.0 mL of tetramethylethylenediamine (TMEDA, 20 mmol), and 3.1 g (10 mmol) of (E)-3-[3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal were added to a 250 mL reaction flask. After stirring and mixing, the mixture was heated to 50-60 °C and reacted for 3 hours. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, and 100 mL of water was slowly added dropwise to quench the reaction. The mixture was extracted twice with ethyl acetate (100 mL x 2). The organic phases were combined and washed successively with 100 mL of 20% citric acid aqueous solution, 100 mL of 5% sodium bicarbonate aqueous solution, and 100 mL of water. The organic phase was concentrated under reduced pressure and recrystallized with a mixture of 30 mL of n-heptane and 15 mL of ethyl acetate to give 2.59 g of light brown crystalline product, with a yield of 61.6%.

[0040] Example 5: Synthesis of key intermediate (R=Me) of fluvastatin sodium

[0041] Under nitrogen protection, 100 mL (50 mmol) of a 0.5 mol / L BrZnCH2CO2Me tetrahydrofuran solution, 0.30 g of sodium iodide (2 mmol), 3.0 mL of tetramethylethylenediamine (TMEDA, 20 mmol), and 3.1 g (10 mmol) of (E)-3-[3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal were added to a 250 mL reaction flask. After stirring and mixing, the mixture was heated to 50-60 °C. The reaction was carried out at 0℃ for 3 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the temperature was lowered to room temperature, and 100 mL of water was slowly added dropwise to quench the reaction. The mixture was extracted twice with ethyl acetate (100 mL x 2), and the organic phases were combined. The mixture was washed successively with 100 mL of 20% citric acid aqueous solution, 100 mL of 5% sodium bicarbonate aqueous solution, and 100 mL of water. The organic phase was concentrated under reduced pressure and recrystallized with a mixture of 30 mL of n-heptane and 15 mL of ethyl acetate to obtain 3.46 g of light brown crystalline product, with a yield of 82.4%.

[0042] Example 6: Synthesis of key intermediate (R=Me) of fluvastatin sodium

[0043] Under nitrogen protection, 100 mL (50 mmol) of a 0.5 mol / L tetrahydrofuran solution of BrZnCH2CO2Me, 0.64 g of zinc iodide (2 mmol), 3.0 mL of tetramethylethylenediamine (TMEDA, 20 mmol), and 3.1 g (10 mmol) of (E)-3-[3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal were added to a 250 mL reaction flask. After stirring and mixing, the mixture was heated to 50-60 °C. The reaction was carried out at 0℃ for 3 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the temperature was lowered to room temperature, and 100 mL of water was slowly added dropwise to quench the reaction. The mixture was extracted twice with ethyl acetate (100 mL x 2), and the organic phases were combined. The mixture was washed successively with 100 mL of 20% citric acid aqueous solution, 100 mL of 5% sodium bicarbonate aqueous solution, and 100 mL of water. The organic phase was concentrated under reduced pressure and recrystallized with a mixture of 30 mL of n-heptane and 15 mL of ethyl acetate to obtain 3.86 g of light brown crystalline product, with a yield of 91.8%.

[0044] Example 7 Synthesis of key intermediate (R=Me) of fluvastatin sodium

[0045] Under nitrogen protection, 100 mL (50 mmol) of a 0.5 mol / L tetrahydrofuran solution of BrZnCH2CO2Me, 0.38 g of cuprous iodide (2 mmol), 3.0 mL of tetramethylethylenediamine (TMEDA, 20 mmol), and 3.1 g (10 mmol) of (E)-3-[3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal were added to a 250 mL reaction flask. After stirring and mixing, the mixture was heated to 50 °C. The reaction was carried out at 60℃ for 3 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the temperature was lowered to room temperature, and 100 mL of water was slowly added dropwise to quench the reaction. The mixture was extracted twice with ethyl acetate (100 mL x 2), and the organic phases were combined. The mixture was washed successively with 100 mL of 20% citric acid aqueous solution, 100 mL of 5% sodium bicarbonate aqueous solution, and 100 mL of water. The organic phase was concentrated under reduced pressure and recrystallized with a mixture of 30 mL of n-heptane and 15 mL of ethyl acetate to obtain 4.01 g of light brown crystalline product, with a yield of 95.5%.

[0046] Example 8 Synthesis of key intermediate (R=Me) of fluvastatin sodium

[0047] Under nitrogen protection, 100 mL (50 mmol) of a 0.5 mol / L tetrahydrofuran solution of BrZnCH2CO2Me, 0.38 g of cuprous iodide (2 mmol), and 3.12 g of... were added to a 250 mL reaction flask. 2,2'-Bipyridyl (2,2'-Dipyridyl, 20 mmol), (E)-3-[3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal 3.1 g (10 mmol), were stirred and mixed, and then heated to 50-60 °C for 3 hours. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, and 100 mL of water was slowly added dropwise to quench the reaction. The mixture was extracted twice with ethyl acetate (100 mL x 2). The organic phases were combined and washed successively with 100 mL of 20% citric acid aqueous solution, 100 mL of 5% sodium bicarbonate aqueous solution, and 100 mL of water. The organic phase was concentrated under reduced pressure and recrystallized with a mixture of 30 mL of n-heptane and 15 mL of ethyl acetate to give 3.52 g of light brown crystalline product, with a yield of 83.7%.

[0048] Example 9: Synthesis of key intermediate (R=Me) of fluvastatin sodium

[0049] Under nitrogen protection, 100 mL (50 mmol) of a 0.5 mol / L tetrahydrofuran solution of BrZnCH2CO2Me, 0.38 g of cuprous iodide (2 mmol), and 1.96 mL of [other chemicals] were added to a 250 mL reaction flask. N,N'-Dimethylethylenediamine (DMEDA, 20 mmol), (E)-3-[3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal 3.1 g (10 mmol), were stirred and mixed, and then heated to 50-60 °C for 3 hours. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, and 100 mL of water was slowly added dropwise to quench the reaction. The mixture was extracted twice with ethyl acetate (100 mL x 2). The organic phases were combined and washed successively with 100 mL of 20% citric acid aqueous solution, 100 mL of 5% sodium bicarbonate aqueous solution, and 100 mL of water. The organic phase was concentrated under reduced pressure and recrystallized with a mixture of 30 mL of n-heptane and 15 mL of ethyl acetate to give 3.75 g of light brown crystalline product, with a yield of 89.2%.

[0050] Example 10 Synthesis of key intermediate (R = Et) of fluvastatin sodium

[0051] Under nitrogen protection, 100 mL (50 mmol) of a 0.5 mol / L tetrahydrofuran solution of BrZnCH2CO2Et, 0.38 g of cuprous iodide (2 mmol), 3.0 mL of tetramethylethylenediamine (TMEDA, 20 mmol), and 3.1 g (10 mmol) of (E)-3-[3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal were added to a 250 mL reaction flask. After stirring and mixing, the mixture was heated to 50-60 °C. The reaction was carried out at 0℃ for 3 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the temperature was lowered to room temperature, and 100 mL of water was slowly added dropwise to quench the reaction. The mixture was extracted twice with ethyl acetate (100 mL x 2), and the organic phases were combined. The mixture was washed successively with 100 mL of 20% citric acid aqueous solution, 100 mL of 5% sodium bicarbonate aqueous solution, and 100 mL of water. The organic phase was concentrated under reduced pressure and recrystallized with a mixture of 30 mL of n-heptane and 15 mL of ethyl acetate to obtain 4.04 g of light brown crystalline product, with a yield of 92.3%.

[0052] Example 11 Synthesis of key intermediate (R = i-Pr) of fluvastatin sodium

[0053] Under nitrogen protection, 100 mL (50 mmol) of a 0.5 mol / L tetrahydrofuran solution of BrZnCH2CO2-i-Pr, 3.0 mL of tetramethylethylenediamine (TMEDA, 20 mmol), 0.38 g of cuprous iodide (2 mmol), and 3.1 g (10 mmol) of (E)-3-[3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal were added to a 250 mL reaction flask. After stirring and mixing, the mixture was heated to 50 °C. The reaction was carried out at -60℃ for 3 hours, and the reaction progress was monitored by TLC. After the reaction was completed, the temperature was lowered to room temperature, and 100 mL of water was slowly added dropwise to quench the reaction. The mixture was extracted twice with ethyl acetate (100 mL x 2), and the organic phases were combined. The mixture was washed successively with 100 mL of 20% citric acid aqueous solution, 100 mL of 5% sodium bicarbonate aqueous solution, and 100 mL of water. The organic phase was concentrated under reduced pressure and recrystallized with a mixture of 30 mL of n-heptane and 15 mL of ethyl acetate to give 4.10 g of light brown crystalline product, with a yield of 91.0%.

Claims

1. A method for synthesizing a key intermediate of fluvastatin sodium, characterized in that, The key intermediate of fluvastatin sodium as shown in Formula I was synthesized by using an organozinc reagent with (E)-3-[3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal in the presence of an iodide catalyst and a dinitrogen ligand. The reaction temperature in the synthesis method was 50-60℃. ； The organozinc reagent is obtained by reacting α-bromoacetate with active zinc, wherein the active zinc is obtained by activating zinc powder with tetramethylchlorosilane (TMSCl); The iodized salt catalyst is sodium iodide, potassium iodide, cuprous iodide, or zinc iodide.

2. The synthesis method according to claim 1, characterized in that, The molar ratio of α-bromoacetate to active zinc is 1:1.5 to 1:2.5; the activation process in the active zinc can be carried out simultaneously during the preparation of the zinc reagent.

3. The synthesis method according to claim 1, characterized in that, The molar ratio of α-bromoacetic acid ester to active zinc is 1:

2.

4. The synthesis method according to claim 1, characterized in that, The molar ratio of the organozinc reagent to (E)-3-[3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal is 4:1 to 6:

1.

5. The synthesis method according to claim 1, characterized in that, The molar ratio of the organozinc reagent to (E)-3-[3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal is 5:

1.

6. The synthesis method according to claim 1, characterized in that, The dinitrogen ligand is N-methylimidazolium, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 2,2'-bipyridine, o-phenanthroline, N,N-dimethylethanolamine, tetramethylethylenediamine, N,N'-dimethylethylenediamine; wherein the molar ratio of the dinitrogen ligand to (E)-3-[3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal is 1.5:1 to 2.5:

1.

7. The synthesis method according to claim 1, characterized in that, The dinitrogen ligand is tetramethylethylenediamine, and the molar ratio of the dinitrogen ligand to (E)-3-[3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal is 2:

1.

8. The synthesis method according to claim 1, characterized in that, The iodine salt catalyst is cuprous iodide.

9. The synthesis method according to claim 1, characterized in that, The molar ratio of iodized salt catalyst to (E)-3-[3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal is 0.05:1 to 0.5:

1.

10. The synthesis method according to claim 1, characterized in that, The molar ratio of iodized salt catalyst to (E)-3-[3'-(4"-fluorophenyl)-1'-isopropyl-1H-indol-2"-yl]-2-propenal is 0.2:

1.

11. The synthesis method according to claim 1, characterized in that, The reaction solvents used in the method for synthesizing the key intermediate of fluvastatin sodium shown in Formula I are N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone, tetrahydrofuran, and dimethyltetrahydrofuran.

12. The synthesis method according to claim 1, characterized in that, The reaction solvents used in the method for synthesizing the key intermediate of fluvastatin sodium shown in Formula I are tetrahydrofuran and dimethyltetrahydrofuran.

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