A preparation method of fluvastatin sodium impurity F

Abstract

The application discloses a preparation method of fluvastatin sodium impurity F, and specifically comprises the following steps: firstly, fluvastatin alcohol ketone is dissolved in an acid solvent to perform a dehydration reaction, then a reduction reaction is performed under the condition of a reducing catalyst, and finally, a hydrolysis reaction is performed with sodium hydroxide to obtain fluvastatin sodium impurity F. The application provides a preparation method of fluvastatin sodium impurity F, which is low in cost, simple in operation, high in yield and easy in process purification. The method uses fluvastatin sodium intermediate (fluvastatin alcohol ketone) as a raw material, the raw material is easy to obtain, and the impurity F can be prepared through only three chemical reactions, and each step does not need a complicated refining process. The fluvastatin sodium impurity F prepared by the application is high in yield and high in purity, and can be used as a standard or control product for quality control and production monitoring of fluvastatin sodium.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of organic synthesis, and particularly relates to a preparation method of fluvastatin sodium impurity F. BACKGROUND

[0002] Fluvastatin sodium, chemically named as (3RS, 5SR, 6E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3, 5-dihydroxy-6-heptenoic acid sodium, is marketed in the form of a pair of enantiomers with two hydroxyl groups in the same direction (syn), and is the first full-synthetic HMG-CoA reductase inhibitor type lipid-lowering drug developed by Novartis Pharmaceutical Company in Switzerland. It inhibits the synthesis of cholesterol by reversibly competing to inhibit the reduction of HMG-CoA to mevalonic acid, and the compound is commonly used for treating primary hypercholesterolemia and primary mixed dyslipidemia which is ineffective for diet regulation.

[0003] Fluvastatin sodium impurity F is an impurity recorded in the European Pharmacopoeia, and is a fluvastatin sodium dehydration degradation impurity, and its chemical structural formula is as follows: At present, there are few literatures reported on the preparation method of the impurity, and CN106905218A uses fluvastatin diol as a raw material to prepare the impurity through 6 steps of selective oxidation, silyl ether protection, reduction, esterification, palladium catalysis dehydration, deprotection and hydrolysis. The method uses selective reduction and heavy metal catalysis, and the operation is very complicated, the cost is high, and the method cannot provide high-quality, inexpensive and easily-obtained impurity reference substance for the quality research of fluvastatin sodium.

[0004] With the increasingly strict requirements for the impurity research in the development of drugs in China, especially the degradation products which need to be particularly concerned in the research process, therefore, the preparation of fluvastatin sodium impurity F has important significance. SUMMARY

[0005] The purpose of the present application is to overcome at least one deficiency of the prior art, and to provide a preparation method of fluvastatin sodium impurity F.

[0006] The technical scheme adopted by the present application is as follows:

[0007] The present application provides a preparation method of fluvastatin sodium impurity F, comprising the following steps:

[0008] 1) Dissolving fluvastatin alcohol ketone in an acidic solvent to perform a dehydration reaction, concentrating and recrystallizing to obtain compound 1

[0009] ;

[0010] 2) Dissolving compound 1 in an organic solvent to perform a reduction reaction under the condition of a reducing catalyst to obtain compound 2

[0011] ;

[0012] 3) hydrolysis reaction of compound 2 with sodium hydroxide to obtain fluvastatin sodium impurity F

[0013] .

[0014] In some examples, the acidic solvent is a mixed solution of an organic solvent and an inorganic acid, wherein the organic solvent is selected from any one of acetonitrile, methanol, toluene, and the inorganic acid is selected from any one of hydrochloric acid and sulfuric acid.

[0015] In some examples, the volume ratio of the organic solvent to the inorganic acid is (1-40):1.

[0016] In some examples, the volume ratio of the acidic solvent to fluvastatin ketone is (2-10):1.

[0017] In some examples, the dehydration reaction temperature is 20-80℃.

[0018] In some examples, the dehydration reaction time is 1-10 hours.

[0019] In some examples, the reducing catalyst is selected from any one of sodium borohydride, potassium borohydride, and lithium borohydride.

[0020] In some examples, the reduction reaction temperature is 0-30℃.

[0021] In some examples, the molar amount of sodium hydroxide used in the hydrolysis reaction is 0.9-1.2 times that of compound 2.

[0022] In some examples, the hydrolysis reaction temperature is 40-60℃.

[0023] The present application has the following advantages:

[0024] The present application provides a preparation method of fluvastatin sodium impurity F, which is low in cost, simple in operation, high in yield, and easy in process purification. The method uses fluvastatin sodium intermediate (fluvastatin ketone) as a raw material, which is easy to obtain, and impurity F can be prepared in three steps of chemical reaction without complex refining process.

[0025] Flovastatin ketone has many side reactions in the degradation process, such as dehydration, lactonization, decarboxylation, etc. The dehydration step of fluvastatin ketone is explored, and suitable dehydration solvent and inorganic acid catalyst are selected, and solvents such as ethyl acetate and isopropyl acetate are used, and high-purity product can be obtained by simple recrystallization.

[0026] The preparation process is simple in operation, high in yield, and easy to purify the product. The prepared fluvastatin sodium impurity F can be used as a standard or control product for quality control and production monitoring of fluvastatin sodium. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 The nuclear magnetic resonance hydrogen spectrum of fluvastatin sodium impurity F prepared in Example 1 of the present application.

[0028] Figure 2 The mass spectrum of fluvastatin sodium impurity F prepared in Example 1 of the present application.

[0029] Figure 3 The high performance liquid chromatogram of fluvastatin sodium impurity F prepared in Example 1 of the present application. DETAILED DESCRIPTION

[0030] A preparation method of fluvastatin sodium impurity F, comprising the following steps:

[0031] 1) Dissolve fluvastatin ketone in an acidic solvent to perform a dehydration reaction, concentrate and recrystallize to obtain compound 1

[0032]

[0033] 2) Dissolve compound 1 in an organic solvent, and perform a reduction reaction under the condition of a reducing catalyst to obtain compound 2

[0034]

[0035] 3) Perform a hydrolysis reaction of compound 2 with sodium hydroxide to obtain fluvastatin sodium impurity F

[0036]

[0037] In some examples, the acidic solvent is a mixed solution of an organic solvent and an inorganic acid, wherein the organic solvent is selected from any one of acetonitrile, methanol, toluene, and the inorganic acid is selected from any one of hydrochloric acid and sulfuric acid.

[0038] In some examples, the volume ratio of the organic solvent to the inorganic acid is (1-40):1, preferably (2-30):1, (4-20):1.

[0039] In some examples, the volume ratio of the acidic solvent to fluvastatin ketone is (2-10):1.

[0040] In some examples, the dehydration reaction temperature is 20-80°C. The specific reaction temperature can be adjusted accordingly according to the reaction condition to obtain a satisfactory reaction speed while producing as few impurities as possible. ​​​

[0041] In some examples, the dehydration reaction time is 1-10 hours. The dehydration reaction time can be adjusted according to the specific reaction conditions.

[0042] In some examples, the reducing catalyst is selected from any one of sodium borohydride, potassium borohydride, lithium borohydride.

[0043] In some examples, the reducing reaction temperature is 0-30°C. The reaction temperature can be adjusted according to the reaction conditions to obtain a satisfactory reaction rate while producing as few impurities as possible.

[0044] In some examples, the molar amount of sodium hydroxide used in the hydrolysis reaction is 0.9-1.2 times that of compound 2.

[0045] In some examples, the hydrolysis reaction temperature is 40-60°C. The reaction temperature can be adjusted according to the reaction conditions to obtain a satisfactory reaction rate while producing as few impurities as possible.

[0046] The following disclosure provides many different embodiments or examples for implementing the various aspects of the present application.

[0047] Example 1

[0048] 1) Preparation of compound 1

[0049] 30 g of fluvoxamine was dissolved in 75 ml of acetonitrile, 15 ml of water and 0.75 ml of hydrochloric acid were added, and the temperature was raised to 70°C and stirred for 3 hours. After the reaction was completed, it was concentrated to dryness to obtain a brown solid;

[0050] 150 ml of ethyl acetate was added, the temperature was raised to 70°C to dissolve, and the temperature was lowered to crystallize. After filtration and drying, 16.1 g of compound 1 was obtained (yield 55.9%, purity 98.3%), and the standard data was: ESI-MS: 448 [M+H + ]; 1H-NMR: (500MHz, DMSO-d6) δ 7.67 (d 1H), 7.43 (s, 2H), 7.39 (d, 2H), 7.29 (t, 2H), 7.19 (t, 2H), 7.05 (d, 1H), 6.42-6.32 (m, 1H), 5.99 (d, 1H), 5.15 (s, 1H), 5.00-4.93 (m, 1H), 1.62 (s, 6H), 1.46 (s, 9H).

[0051] 2) Preparation of compound 2

[0052] 9g of compound 1 was dissolved in 90ml of tetrahydrofuran, 2.3g of sodium borohydride was added in batches under ice bath, and the temperature was raised to 20°C for stirring for 7h. After being concentrated to dryness, an oil was obtained. Purification was carried out by silica gel column to obtain 7.5g of compound 2 (yield 83%).

[0053] 3) Preparation of sodium fluvastatin impurity F

[0054] 1g of compound 2 was dissolved in 10ml of methanol, 1ml of water and 0.09g of sodium hydroxide were added, and the temperature was raised to 50°C for stirring for 4h. TLC showed that the reaction was complete. After being concentrated to dryness, 15ml of acetone was added for recrystallization. Filtration obtained 620mg of yellow solid (yield 67%), which was sodium fluvastatin impurity F. Its nuclear magnetic resonance hydrogen spectrum is shown in Figure 1 , mass spectrum is shown in Figure 2 , and high performance liquid chromatogram is shown in Figure 3 .

[0055] Example 2

[0056] 1) Preparation of compound 1 was the same as example 1.

[0057] 2) Preparation of compound 2

[0058] 7g of compound 1 was dissolved in 70ml of tetrahydrofuran, 2.5g of potassium borohydride was added in batches under ice bath, and the temperature was raised to 20°C for stirring for 7h. After being concentrated to dryness, an oil was obtained. Purification was carried out by silica gel column to obtain 6.0g of compound 2 (yield 85%).

[0059] 3) Preparation of sodium fluvastatin impurity F

[0060] 6g of compound 2 was dissolved in 60ml of methanol, 6ml of water and 0.54g of sodium hydroxide were added, and the temperature was raised to 50°C for stirring for 5h. TLC showed that the reaction was complete. After being concentrated to dryness, 90ml of acetone was added for recrystallization. Filtration obtained 4.5g of yellow solid (yield 82%), which was sodium fluvastatin impurity F.

[0061] Example 3

[0062] 1) Preparation of compound 1

[0063] 10g of fluvastatin ketone was dissolved in 50ml of toluene, 2ml of hydrochloric acid was added, and the temperature was raised to 70°C for stirring for 9h. After being concentrated to dryness, brown solid was obtained. 50ml of isopropyl acetate was added, the temperature was raised to 70°C for stirring, and the temperature was lowered for crystallization. Filtration and drying obtained 6.2g of compound 1 (yield 64.5%).

[0064] 2) Preparation of compound 2

[0065] 5g of compound 1 was dissolved in 50ml of tetrahydrofuran, 1.3g of sodium borohydride was added in batches under ice bath, and the temperature was raised to 20°C for stirring for 6h. After concentration to dryness, 3.8g of compound 2 was obtained (yield 76%) in the form of oil, which was purified by silica gel column.

[0066] 3) Preparation of fluvastatin sodium impurity F

[0067] 1g of compound 2 was dissolved in 10ml of methanol, 1ml of water and 0.1g of sodium hydroxide were added, and the temperature was raised to 50°C for stirring for 4h. TLC showed that the reaction was complete. After concentration to dryness, 15ml of acetonitrile was added for recrystallization, and 550mg of yellow solid (yield 60%) was obtained by filtration, which was fluvastatin sodium impurity F.

[0068] Comparative Example 1

[0069] Compound 1 was prepared as follows: 10g of fluvastatin ketone was dissolved in 50ml of toluene, 2ml of hydrochloric acid was added, and the temperature was raised to 110°C for stirring for 3h. After concentration to dryness, black oil was obtained, and the target compound 1 was not detected.

[0070] Comparative Example 2

[0071] Compound 1 was prepared as follows: 10g of fluvastatin ketone was dissolved in 50ml of toluene, 1.5g of p-toluenesulfonic acid monohydrate was added, and the temperature was raised to 110°C for heating for 3h. After concentration to dryness, black oil was obtained, and the target compound 1 was not detected.

[0072] The preparation methods of compound 1 in Example 1 and Comparative Examples 1-2 are listed in Table 1. As can be seen from Table 1, the dehydration step of fluvastatin ketone is explored in the present application, and suitable dehydration solvents and inorganic acid catalysts are selected. At the same time, solvents such as ethyl acetate and isopropyl acetate are used, and high-purity compound 1 can be obtained by simple recrystallization.

[0073] Table 1

[0074]

[0075] The above is a further detailed description of the present application, which cannot be regarded as a specific implementation of the present application. For ordinary skilled persons in the technical field to which the present application belongs, simple deduction or replacement without departing from the concept of the present application is within the protection scope of the present application.

Claims

1. A method for preparing fluvastatin sodium impurity F, characterized in that, Includes the following steps: 1) Fluvafluvanone was dissolved in an acidic solvent, subjected to a dehydration reaction, and concentrated and recrystallized to obtain compound 1. The acidic solvent is a mixed solution of an organic solvent and an inorganic acid, wherein the organic solvent is selected from any one of acetonitrile, methanol, and toluene, and the inorganic acid is selected from any one of hydrochloric acid and sulfuric acid. The volume ratio of the organic solvent to the inorganic acid is (1-40):1, the volume ratio of the acidic solvent to fluvastatin is (2-10):1, the dehydration reaction temperature is 20-80°C, and the dehydration reaction time is 1-10 hours. 2) Compound 1 was dissolved in an organic solvent and reduced under reducing catalytic conditions to obtain compound 2. ； 3) Compound 2 was hydrolyzed with sodium hydroxide to give fluvastatin sodium impurity F. 。 2. The preparation method according to claim 1, characterized in that, The reducing catalyst is selected from any one of sodium borohydride, potassium borohydride, and lithium borohydride.

3. The preparation method according to claim 1, characterized in that, The reduction reaction temperature is 0–30°C.

4. The preparation method according to claim 1, characterized in that, The molar amount of sodium hydroxide used in the hydrolysis reaction is 0.9 to 1.2 times that of compound 2.

5. The preparation method according to claim 1, characterized in that, The hydrolysis reaction temperature is 40–60°C.

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