Preparation method of atorvastatin calcium intermediate

Abstract

The invention belongs to the technical field of medical chemistry, and particularly relates to a preparation method of an atorvastatin calcium intermediate, which realizes continuous preparation through a fixed bed reactor.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of an atorvastatin calcium intermediate. BACKGROUND

[0002] Atorvastatin calcium is a powerful lipid-lowering drug launched by Pfizer in 1997, which can reduce total cholesterol and triglycerides at the same time, and belongs to HMG-CoA reductase inhibitors. The molecular level research of cardiovascular diseases shows that HMG-CoA reductase is a rate-limiting enzyme of cholesterol biosynthesis, and factors affecting the synthesis or functional expression of the enzyme can effectively inhibit the synthesis of cholesterol. Statins inhibit the synthesis of cholesterol by inhibiting the binding of HMG-CoA reductase and substrate. Atorvastatin has attracted widespread attention of domestic and foreign pharmaceutical companies due to its wider indications, better tolerance and safety.

[0003] US4681893A and US5273995A disclose atorvastatin calcium compounds and preparation methods thereof, and the chemical formula structure is as follows:

[0004]

[0005] In addition, US5298627A and WO8907598A2 disclose a method for synthesizing atorvastatin calcium by Paal-Knorr pyrrole method, and introduce a key intermediate (4R, 6R)-2, 2-dimethyl-6-(2-aminoethyl)-1, 3-dioxane-4-acetic acid tert-butyl ester (AJ).

[0006]

[0007]

[0008] Further, WO2003053950A1 and US20090216029A1 disclose a synthesis method of atorvastatin calcium intermediate, which uses compound (4R, 6R)-6-cyanomethyl-2, 2-dimethyl-1, 3-dioxane-4-acetic acid tert-butyl ester (SM1) as raw material, uses traditional kettle process, and uses powdered Raney nickel as catalyst to synthesize intermediate compound AJ (see the following reaction formula), and the reaction time is as long as 20 hours, the product is a light red oily liquid, and needs to be purified and separated by column chromatography, so the preparation efficiency is low.

[0009]

[0010] Therefore, there is a need to develop a new method for the production of atorvastatin calcium intermediate (4R,6R)-2,2-dimethyl-6-(2-aminoethyl)-1,3-dioxane-4-acetic acid tert-butyl ester (AJ), which is simple, low-cost, and easy to industrialize, and can avoid time-consuming and labor-intensive purification steps while achieving high yield. Summary of the Invention

[0011] This invention provides a method for preparing atorvastatin calcium intermediates, which achieves continuous cyano reduction via a fixed-bed reactor.

[0012] The preparation method of the present invention includes continuously pumping a solution containing compound (4R,6R)-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (SM1) and hydrogen into a fixed-bed reactor packed with a catalyst to continuously prepare the atorvastatin calcium intermediate compound (4R,6R)-2,2-dimethyl-6-(2-aminoethyl)-1,3-dioxane-4-acetic acid tert-butyl ester (AJ).

[0013]

[0014] The method for preparing the atorvastatin calcium intermediate of the present invention has the following advantages: the fixed-bed reactor enables efficient mixing of the solution of compound SM1 with the hydrogen gas flow, the reaction liquid residence time is short, the generation of impurities can be effectively controlled, the product purity reaches more than 99%, no purification is required, and the quality is better; the amount of catalyst used is reduced, the particulate catalyst used is stable and does not spontaneously combust in air, the safety risk is controllable, and intrinsic safety is achieved; the equipment has high integration, small footprint, high degree of automation, and good batch stability. Attached Figure Description

[0015] Figure 1 This is a flow chart of the atorvastatin calcium intermediate fixed-bed reactor reduction continuous reaction equipment of the present invention.

[0016] Figure 2 This is the GC spectrum of the product obtained in Example 1.

[0017] Figure 3 This is the GC spectrum of the product obtained in Example 2.

[0018] Figure 4 This is the GC spectrum of the product obtained in Example 3.

[0019] Figure 5 This is the GC spectrum of the product obtained in Example 4. Detailed Implementation

[0020] This invention provides a continuous fixed-bed reactor reduction method for preparing atorvastatin calcium intermediates. The method includes the following steps: continuously pumping a solution containing compound (4R,6R)-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate tert-butyl ester (SM1) and hydrogen gas into a fixed-bed reactor packed with a catalyst to continuously prepare compound (4R,6R)-2,2-dimethyl-6-(2-aminoethyl)-1,3-dioxane-4-acetate tert-butyl ester (AJ).

[0021]

[0022] In an embodiment of the fixed-bed reactor reduction continuous preparation method for atorvastatin calcium intermediate of the present invention, the volume hourly space velocity (VHSV) of the solution in the fixed-bed reactor is 0.05-1.0 min. -1 The preferred time is 0.06-0.80 min. -1 The molar equivalent of the hydrogen feed stream is 2-20, preferably 3-15, more preferably 4-10, based on the molar amount of compound SM1.

[0023] In embodiments of the present invention, the reaction temperature of the fixed-bed reactor is 25-150°C, preferably 28-100°C, more preferably 30-60°C; the pressure is 0.1-3.0 MPa, preferably 0.5-2.5 MPa, more preferably 1.0-2.0 MPa; and the residence time of the reactants is 0.2-20 min.

[0024] In embodiments of the present invention, the catalyst packed in the fixed-bed reactor is selected from granular Raney nickel catalyst, Pd catalyst and Ru catalyst or mixtures thereof; preferably selected from granular Raney nickel catalyst, palladium on carbon catalyst, Pd / Al2O3 catalyst or mixtures thereof.

[0025] In embodiments of the invention, the bulk density of the catalyst packed in the fixed-bed reactor is from about 0.3 g / ml to about 2.5 g / ml, preferably from about 0.4 g / ml to about 2.2 g / ml. In a preferred embodiment, the bulk density of the catalyst packed in the fixed-bed reactor varies depending on the type of catalyst. In a specific embodiment, the bulk density of the palladium catalyst packed in the fixed-bed reactor is from about 0.3 g / ml to about 1.0 g / ml, preferably from about 0.4 g / ml to about 0.8 g / ml. In a more specific embodiment, the bulk density of the palladium-on-carbon catalyst packed in the fixed-bed reactor is from about 0.3 g / ml to about 0.8 g / ml, preferably from about 0.4 g / ml to about 0.7 g / ml. In another specific embodiment, the bulk density of the Pd / Al₂O₃ catalyst packed in the fixed-bed reactor is from about 0.5 g / ml to about 1.0 g / ml, preferably from about 0.6 g / ml to about 0.8 g / ml. In yet another specific embodiment, the Raney nickel catalyst packed in the fixed-bed reactor has a bulk density of about 0.8 g / ml to about 3.0 g / ml, preferably about 1.0 g / ml to about 2.5 g / ml, and more preferably about 1.2 g / ml to about 2.2 g / ml.

[0026] In a preferred embodiment of the present invention, the average particle size of the particulate solid catalyst in step 1) is 0.2-5 mm, preferably 0.5-3 mm.

[0027] In embodiments of the invention, the solvent for dissolving compound SM1 is selected from ethyl acetate, methanol, ethanol, isopropanol, and ammonia, or mixtures thereof; methanol is preferred, and a mixture of methanol and ammonia is more preferred. As used herein, the ammonia in the solvent has an ammonia mass fraction of 25-28%.

[0028] In embodiments of the present invention, the mass ratio of compound SM1 to the solvent used is 1:(2-11), preferably 1:(3-9), and more preferably 1:(4-8).

[0029] In an embodiment of the present invention where the solvent is a mixture of methanol and ammonia, the mass ratio of compound SM1 to methanol is 1:(2-10), preferably 1:(3-8), more preferably 1:(4-7), even more preferably 1:(5-6), and most preferably 1:5.5. Furthermore, the mass ratio of compound SM1 to ammonia is 1:(0.1-3), preferably 1:(0.3-2), more preferably 1:(0.4-1), even more preferably 1:(0.5-0.8), and most preferably 1:0.76.

[0030] In an embodiment of the present invention, hydrogen gas and the reaction solution are premixed using a gas-liquid mixer.

[0031] In an embodiment of the present invention, the product discharge collection device is used to discharge gas and collect liquid.

[0032] In one embodiment, the method for continuous reduction preparation of atorvastatin calcium intermediates using a fixed-bed reactor according to the present invention includes the following steps:

[0033] Step 1) Turn on the hydrogen generator and fill the catalyst column with the catalyst;

[0034] Step 2) Rinse the tubing with blank solvent, set the catalyst reaction column temperature and reaction pressure, and start heating and instrument back pressure;

[0035] Step 3) Prepare a solution containing compound SM1;

[0036] Step 4) Set the material flow rate, turn on the hydrogen gas, and transport the solution and hydrogen gas obtained in step 3) to the fixed bed reactor.

[0037] Step 5) The material and hydrogen flow through the catalyst bed of the catalyst column in the reactor, so that they come into contact with the catalyst and undergo a chemical reaction;

[0038] Step 6) Discharge, gas-liquid separation, gas discharge, and liquid collection.

[0039] In a preferred embodiment of the present invention, the catalyst in step 1) is selected from Raney nickel catalyst, Pd catalyst, and Ru catalyst, or a mixture thereof, preferably Raney nickel catalyst, palladium on carbon catalyst, Pd / Al2O3 catalyst, or a mixture thereof. In a preferred embodiment of the present invention, the catalyst in step 1) is a particulate solid catalyst. In a preferred embodiment of the present invention, the average particle size of the particulate solid catalyst in step 1) is 0.2-5 mm, preferably 0.5-3 mm.

[0040] In a preferred embodiment of the present invention, the bulk density of the catalyst in step 1) is from about 0.3 g / ml to about 2.5 g / ml, preferably from about 0.4 g / ml to about 2.2 g / ml. In a preferred embodiment, the bulk density of the catalyst varies depending on the type of catalyst. In a specific embodiment, a palladium catalyst is used in step 1) with a bulk density of from about 0.3 g / ml to about 1.0 g / ml, preferably from about 0.4 g / ml to about 0.8 g / ml. In a more specific embodiment, a palladium-on-carbon catalyst is used in step 1) with a bulk density of from about 0.3 g / ml to about 0.8 g / ml, preferably from about 0.4 g / ml to about 0.7 g / ml. In another specific embodiment, a Pd / Al₂O₃ catalyst is used in step 1) with a bulk density of from about 0.5 g / ml to about 1.0 g / ml, preferably from about 0.6 g / ml to about 0.8 g / ml. In yet another specific embodiment, step 1) uses a Raney nickel catalyst with a bulk density of about 0.8 g / ml to about 3.0 g / ml, preferably about 1.0 g / ml to about 2.5 g / ml, and more preferably about 1.2 g / ml to about 2.2 g / ml.

[0041] In a preferred embodiment of the present invention, the blank solvent in step 2) is selected from ethyl acetate, methanol, ethanol, and isopropanol, with methanol being preferred.

[0042] In a preferred embodiment of the present invention, the column temperature in step 2) is 25-150°C, preferably 28-100°C, and more preferably 30-60°C.

[0043] In a preferred embodiment of the present invention, the reaction pressure in step 2) is 0.1-3.0 MPa, preferably 0.5-2.5 MPa, and more preferably 1.0-2.0 MPa.

[0044] In a preferred embodiment of the present invention, the solvent for dissolving compound SM1 in step 3) is selected from ethyl acetate, methanol, ethanol, isopropanol, and ammonia, or mixtures thereof; methanol is preferred; a mixture of methanol and ammonia is more preferred. The ammonia in the ammonia solution has an ammonia mass fraction of 25-28%.

[0045] In a preferred embodiment of the present invention, the mass ratio of compound SM1 to solvent in step 3) is SM1:solvent = 1:(2-11), preferably 1:(3-9), and more preferably 1:(4-8).

[0046] In a more preferred embodiment of the present invention, the solvent for dissolving compound SM1 in step 3) is a mixture of methanol and ammonia. In this embodiment where the solvent is a mixture of methanol and ammonia, the mass ratio of compound SM1 to methanol is 1:(2-10), preferably 1:(3-8), more preferably 1:(4-7), even more preferably 1:(5-6), and most preferably 1:5.5, and the mass ratio of compound SM1 to ammonia is 1:(0.1-3), preferably 1:(0.3-2), more preferably 1:(0.4-1), further more preferably 1:(0.5-0.8), and most preferably 1:0.76.

[0047] In a preferred embodiment of the present invention, the volume hourly space velocity (VHSV) of the solution material in step 4) is 0.05-1.0 min. -1 The preferred time is 0.06-0.80 min. -1 .

[0048] In a preferred embodiment of the present invention, the molar equivalent of the hydrogen feed stream in step 4) is 2-20, preferably 3-15, more preferably 4-10, based on the molar amount of compound SM1.

[0049] In a preferred embodiment of the present invention, the residence time of the solution material and hydrogen gas in the reactor during step 5) is 0.2-20 min.

[0050] Example

[0051] The following specific embodiments further illustrate the above-described content of the present invention, but should not be construed as limiting the scope of protection of the present invention in any way. All technical solutions implemented based on the above-described content of the present invention fall within the scope of the present invention. The present invention provides a general and / or specific description of the materials and experimental methods used in the experiments. Without departing from the spirit of the present invention, changes can be made to the specific parameters in the following embodiments, or equivalent substitutions can be made to the process steps, thereby forming more specific embodiments. These are all common variations within the scope of the present invention and fall within its scope.

[0052] Those skilled in the art will understand that, unless otherwise specified, the operations performed in this invention are carried out under conventional room temperature conditions in the art, where room temperature has a well-known technical meaning in the art, generally referring to 20 to 35°C, preferably 20 to 30°C, and more preferably 20 to 25°C.

[0053] In this invention, the endpoints of the disclosed ranges and any values ​​are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be considered as specifically disclosed herein.

[0054] As used herein, the term “about” refers to a quantity, value, or amount that differs from a reference quantity, value, or amount by as much as 25%, 20%, 15%, or 10%.

[0055] In the following embodiments 1-4 of the present invention, the fixed-bed reactor is equipped with a feed pump, a hydrogen source and controller, a fixed-bed packed column, a gas-liquid separator, etc., and the outlet pipeline adopts a back pressure valve for back pressure, hydrogen tail gas is discharged, and liquid material is collected.

[0056] Test methods

[0057] The gas chromatography method for determining product purity is shown in Table 1.

[0058] Table 1. Relevant parameters for gas chromatography.

[0059]

[0060] Solution preparation:

[0061] Blank solution: dichloromethane

[0062] System suitability solution: Weigh 60 mg of compound SM1 into a 10 ml volumetric flask as the SM1 control stock solution; weigh 200 mg of compound AJ into a 10 ml volumetric flask, transfer 1 ml of the SM1 control stock solution into this volumetric flask, dilute to the mark with dichloromethane, and shake well to obtain the solution.

[0063] Test solution: Weigh approximately 1.8 g of the final product AJ from each example to be tested, accurately weigh it, place it in a 10 ml volumetric flask, dissolve and dilute it to the mark with dichloromethane, and shake well to obtain the solution.

[0064] Reference solution: Accurately transfer 0.5 ml of the test solution into a 100 ml volumetric flask, dilute to the mark with dichloromethane, and shake well.

[0065] Calculation method: Calculated using the area normalization method.

[0066] Example 1

[0067] Referring to the reaction route below, this embodiment provides a method for preparing atorvastatin calcium intermediates, which is carried out continuously in a fixed-bed reactor and includes the following steps:

[0068]

[0069] (1) Turn on the hydrogen generator and pack 8.8g of Raney nickel catalyst into a 6.6mL catalyst column;

[0070] (2) Set the flow rate to 5.0 mL / min, use methanol as a blank solvent to rinse the tubing, set the reaction column temperature to 50.0℃, the reaction end back pressure to 2.0 MPa, and balance the instrument;

[0071] (3) Weigh 10.0g of compound SM1 and dissolve it in 55.3g of methanol. Slowly add 7.6g of ammonia water and stir until dissolved and ready for use.

[0072] (4) Set the hydrogen flow rate to 30.0 sccm and the material flow rate to 0.50 mL / min, and pump the solution obtained in step (3) into the fixed bed reactor;

[0073] (5) Collect the reaction solution continuously for 160 min;

[0074] (6) The colorless oily liquid obtained by vacuum concentration is compound AJ, with a weight of 9.8g, purity of 99.71%, and yield of 98.6%.

[0075] Example 2

[0076] Referring to the reaction route described in Example 1, this example provides a method for preparing atorvastatin calcium intermediates, which is carried out continuously in a fixed-bed reactor and includes the following steps:

[0077] (1) Turn on the hydrogen generator and pack 4.5g of palladium on carbon catalyst into a 6.6mL catalyst column;

[0078] (2) Set the material flow rate to 5.0 mL / min, use methanol as a blank solvent to flush the pipeline, set the reaction column temperature to 35.0℃, the reaction end back pressure to 1.0 MPa, and balance the instrument;

[0079] (3) Weigh 10.0g of compound SM1 and dissolve it in 55.3g of methanol. Slowly add 7.6g of ammonia water and stir until dissolved and ready for use.

[0080] (4) Set the hydrogen flow rate to 300.0 sccm and the material flow rate to 5.0 mL / min, and pump the material obtained in step (3) into the fixed bed reactor;

[0081] (5) Collect the reaction solution for 17 minutes;

[0082] (6) The colorless oily liquid obtained by vacuum concentration is compound AJ, weighing 9.9g, with a purity of 99.80% and a yield of 97.5%.

[0083] Example 3

[0084] Referring to the reaction route described in Example 1, this example provides a method for preparing atorvastatin calcium intermediates, which is carried out continuously in a fixed-bed reactor and includes the following steps:

[0085] (1) Turn on the hydrogen generator and pack 4.3g of Pd / Al2O3 catalyst into a 6.6mL catalyst column;

[0086] (2) Set the material flow rate to 5.0 mL / min, use methanol as a blank solvent to flush the pipeline, set the reaction column temperature to 35.0℃, the reaction end back pressure to 1.0 MPa, and balance the instrument;

[0087] (3) Weigh 10.0g of compound SM1 and dissolve it in 55.3g of methanol. Slowly add 7.6g of ammonia water, add 10% activated carbon for adsorption, and filter to obtain a clear solution for later use.

[0088] (4) Set the hydrogen flow rate to 300.0 sccm and the material flow rate to 5.0 mL / min, and pump the solution into the fixed-bed reactor;

[0089] (5) Collect the reaction solution for 16 minutes;

[0090] (6) The colorless oily liquid obtained by vacuum concentration is compound AJ, with a weight of 10.1g, purity of 99.64%, and yield of 99.5%.

[0091] Example 4

[0092] Referring to the reaction route described in Example 1, this example provides a method for preparing atorvastatin calcium intermediates, which is carried out continuously in a fixed-bed reactor and includes the following steps:

[0093] (1) Turn on the hydrogen generator and pack 80.0g of Raney nickel catalyst into a 60.0mL catalyst column;

[0094] (2) Set the material flow rate to 45.5 mL / min, use methanol as a blank solvent to flush the pipeline, set the reaction column temperature to 50.0℃, the reaction end back pressure to 2.0 MPa, and balance the instrument;

[0095] (3) Weigh 90.0g of compound SM1 and dissolve it in 498.0g of methanol. Slowly add 68.4g of ammonia water and stir until dissolved and ready for use.

[0096] (4) Set the hydrogen flow rate to 270.0 sccm and the material flow rate to 4.5 mL / min, and pump the solution into the fixed bed reactor;

[0097] (5) Collect the reaction solution for 175 minutes;

[0098] (6) The colorless oily liquid obtained by vacuum concentration is compound AJ, with a weight of 89.4g, a purity of 99.56%, and a yield of 97.9%.

[0099] The purities of each product, tested and calculated by gas chromatography according to the method described above, are shown in Table 2 below.

[0100] Table 2 Purity of each product determined by gas chromatography

[0101]

[0102] Appendix Figure 1 Illustration

[0103] 1 is the feed pump

[0104] 1-1 shows the connecting pipe between the feed pump and the gas-liquid mixer.

[0105] 2 is a hydrogen mass flow controller

[0106] 2-1 is the hydrogen gas source

[0107] 2-2 is the connecting pipe between the hydrogen mass flow controller and the gas-liquid mixer; 3 is the gas-liquid mixer.

[0108] 4 is a fixed bed filling column

[0109] 4-1 is the catalyst bed

[0110] 4-2 is a temperature control jacket for a fixed bed filling column.

[0111] 4-3 is the outlet of the fixed bed filling column.

[0112] 4-4 shows the connecting pipes between the fixed bed and the gas-liquid separator.

[0113] 5 is a gas-liquid separator

[0114] 5-1 is the feed liquid inlet of the gas-liquid separator.

[0115] 5-2 is the liquid outlet of the gas-liquid separator.

[0116] 5-3 is the gas outlet of the gas-liquid separator.

[0117] 5-4 shows the connecting pipe between the gas-liquid separator and the back pressure valve.

[0118] 6 is the back pressure valve

[0119] 6-1 is the connecting pipe between the gas-liquid separator and the liquid collection tank; 7 is the liquid collection tank.

Claims

1. A process for the preparation of an intermediate of atorvastatin calcium characterized in that, The method comprises continuously pumping a solution containing compound (4R,6R)-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (SM1) and hydrogen into a fixed bed reactor packed with catalyst to continuously produce intermediate compound (4R,6R)-2,2-dimethyl-6-(2-aminoethyl)-1,3-dioxane-4-acetic acid tert-butyl ester (AJ), 2. The process of claim 1, wherein the volumetric space velocity of the solution in the fixed bed reactor is 0.05-1.0 min -1 .

3. The method according to claim 1 or 2, wherein the molar equivalent of the hydrogen stream in the fixed bed reactor is 2-20, based on the molar amount of compound SM1.

4. The method according to claim 1 or 2, wherein the reaction temperature of the fixed bed reactor is 25-150°C, preferably 28-100°C, more preferably 30-60°C; the reaction pressure is 0.1-3.0 MPa, preferably 0.5-2.5 MPa, more preferably 1.0-2.0 MPa; and the residence time of the reaction material is 0.2-20 min.

5. The method according to claim 1 or 2, wherein the catalyst packed in the fixed bed reactor is selected from the group consisting of granular Raney nickel catalyst, Pd catalyst and Ru catalyst or mixtures thereof; preferably selected from the group consisting of granular Raney nickel catalyst, palladium on carbon catalyst, Pd / Al2O3 catalyst or mixtures thereof.

6. The method according to claim 1 or 2, wherein the solvent for dissolving compound SM1 is selected from the group consisting of ethyl acetate, methanol, ethanol, isopropanol and ammonia water or mixtures thereof, preferably methanol, more preferably a mixture of methanol and ammonia water.

7. The method according to claim 6, wherein the mass ratio of compound SM1 to solvent is 1:(2-11), preferably 1:(3-9), more preferably 1:(4-8).

8. The method according to claim 6, wherein the solvent for dissolving compound SM1 is a mixture of methanol and ammonia water, and wherein the mass ratio of compound SM1 to methanol is 1:(2-10), preferably 1:(3-8), more preferably 1:(4-7), and the mass ratio of compound SM1 to ammonia water is 1:(0.1-3), preferably 1:(0.3-2), more preferably 1:(0.4-1).

9. The method according to claim 1 or 2, wherein the hydrogen and the reaction solution are pre-mixed by a gas-liquid mixer.

10. The method according to claim 1 or 2, wherein the discharge collection product uses a gas-liquid separation device to discharge gas and collect liquid.

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