Preparation method of pitavastatin calcium key intermediate

Abstract

The invention provides a preparation method of a pitavastatin calcium key intermediate, and relates to the technical field of medicine preparation. The method specifically comprises the following steps: sequentially adding a first solvent, fluorobenzene and Lewis acid into a container under the protection of nitrogen, cooling to-10 DEG C to-5 DEG C, adding an anhydride reagent, reacting the fluorobenzene and the anhydride reagent at the ambient temperature under the catalysis of the Lewis acid, and then quenching, pickling, adjusting alkali and concentrating to obtain the pitavastatin calcium key intermediate 2-amino-4 '-fluoro-benzophenone. The synthetic route is short, the operation is simple, the used raw material reagents are easy to obtain, the used reagents are dangerous, small in pollution, safe and environment-friendly, the reaction conditions are mild, the operation is convenient and controllable, and the prepared 2-amino-4 '-fluoro-benzophenone is good in purity and high in yield.

Description

Technical Field

[0001] The invention relates to the technical field of drug preparation, and in particular to a method for preparing a key intermediate of pitavastatin calcium. Background Art

[0002] Pitavastatin calcium is a third-generation statin and one of the statins with the best lipid-lowering effect in international clinical applications. It is highly effective, safe, and well tolerated. 2-Amino-4'-fluoro-benzophenone is a key intermediate used in the production of pitavastatin calcium.

[0003] At present, there are mainly the following methods for the synthesis of 2-amino-4'-fluoro-benzophenone:

[0004] Route 1, using o-nitrobenzoic acid as the starting material, the product is obtained through chlorination reaction, Friedel-Crafts acylation, and reduction. This route is relatively long, and the chlorination reaction uses sulfonyl chloride and other polluting byproducts, which leads to environmental problems in the industrial scale-up of the reaction. In addition, the clean method for nitro reduction is Pd-C catalytic hydrogen reduction, but palladium is expensive. The economical method is iron powder reduction, but there is a problem that the post-treatment of iron mud requires a large amount of acid water washing, which is seriously polluting and limits the industrial application of this route;

[0005] Route 2, using phthalic anhydride as the starting material, first undergoing Friedel-Crafts acylation with fluorobenzene to obtain p-fluorobenzoylbenzoic acid, and then undergoing chlorination reaction, amidation reaction, and Hofmann degradation to obtain 2-amino-4'-fluoro-benzophenone. This reaction uses too many types of reagents and a long route, which is not conducive to industrial production;

[0006] Route 3, using anisole as a raw material, firstly protecting the amino group with p-toluenesulfonyl chloride, then chlorinating to obtain the acyl chloride, and then performing Friedel-Crafts reaction with fluorobenzene to deprotect the group to obtain 2-amino-4'-fluoro-benzophenone. This route is long and has a low overall yield.

[0007] In summary, the current synthesis route of the key intermediate of pitavastatin calcium, 2-amino-4'-fluoro-benzophenone, is difficult to industrialize due to the disadvantages of high raw material cost, long route, complex operation, low yield, and large environmental pollution. Therefore, it is urgent to develop a green, environmentally friendly, and highly operable synthesis process of the key intermediate of pitavastatin calcium, 2-amino-4'-fluoro-benzophenone, and it has broad prospects. Summary of the invention

[0008] 1. Technical issues to be solved

[0009] In view of the deficiencies of the prior art, the present invention provides a method for preparing a key intermediate of pitavastatin calcium, which solves the technical problems of the prior art preparation method, such as high environmental pollution and low yield.

[0010] (II) Technical solution

[0011] To achieve the above objectives, the present invention is implemented through the following technical solutions:

[0012] The present invention provides a method for preparing 2-amino-4'-fluoro-benzophenone, a key intermediate of pitavastatin calcium. The synthetic route is as follows:

[0013]

[0014] Wherein, R is selected from H, Boc Fmoc One of them.

[0015] The specific steps include:

[0016] Under nitrogen protection, the first solvent, fluorobenzene and Lewis acid are added to the container in sequence, the temperature is lowered to -10°C to -5°C, an anhydride reagent is added, and under the catalysis of Lewis acid, fluorobenzene and the anhydride reagent react at ambient temperature, and then quenched, acid washed, alkali adjusted and concentrated to obtain the key intermediate of pitavastatin calcium 2-amino-4'-fluoro-benzophenone.

[0017] Further, the first solvent is selected from dichloromethane or dichloroethane, preferably, the first solvent is dichloromethane;

[0018] Further, the Lewis acid is selected from one of ferric chloride, aluminum chloride and zinc chloride, preferably, the Lewis acid is aluminum chloride;

[0019] Further, the acid anhydride is selected from one of isatoic anhydride, N-Boc-isatoic anhydride and N-Fmoc-isatoic anhydride, preferably, the acid anhydride is isatoic anhydride;

[0020] Further, the molar ratio of isatoic anhydride, fluorobenzene and Lewis acid is 1:1-100:2-8, preferably, the molar ratio is 1:1.2-1.5; 3-6;

[0021] Further, the ambient temperature is 20-30°C, preferably, the temperature is 25-28°C;

[0022] Further, the quenching is pouring into ice water and stirring;

[0023] Furthermore, the pickling is washing with 12N hydrochloric acid;

[0024] Furthermore, the alkali washing is washing the organic layer with aqueous ammonia, sodium carbonate, and triethylamine solution until the pH of the organic layer is 8 to 10, preferably, the alkali is aqueous ammonia;

[0025] Furthermore, the preparation method of the key intermediate of pitavastatin calcium also includes post-treatment, which specifically includes the following steps: adding a second solvent to 2-amino-4'-fluoro-benzophenone, then heating, dissolving, cooling and crystallizing, filtering, and drying to obtain the key intermediate of pitavastatin calcium 2-amino-4'-fluoro-benzophenone.

[0026] Furthermore, the second solvent is selected from one of methanol, ethanol and isopropanol. Preferably, the second solvent is methanol.

[0027] (III) Beneficial effects

[0028] The present invention provides a method for preparing a key intermediate of pitavastatin calcium. Compared with the prior art, the method has the following beneficial effects:

[0029] The invention discloses a method for preparing 2-amino-4'-fluoro-benzophenone, a key intermediate of pitavastatin calcium, wherein fluorobenzene, an anhydride reagent and Lewis acid are selected, and under the catalytic action of Lewis acid, fluorobenzene and the anhydride reagent react to obtain 2-amino-4'-fluoro-benzophenone. The invention has a short synthesis route, simple operation, easy acquisition of raw materials and reagents, low hazard and pollution of reagents, safety and environmental protection, mild reaction conditions, convenient and controllable operation, and the prepared 2-amino-4'-fluoro-benzophenone has good purity and high yield. DETAILED DESCRIPTION

[0030] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0031] In order to better understand the above technical solution, the above technical solution will be described in detail below in conjunction with specific implementation methods.

[0032] Example 1

[0033] This embodiment provides a method for preparing 2-amino-4'-fluoro-benzophenone, a key intermediate of pitavastatin calcium, comprising the following steps:

[0034]

[0035] Under nitrogen protection, dichloromethane (500 mL), fluorobenzene (57.7 g, 0.6 mol), aluminum chloride (378 g, 2.5 mol) were added in sequence, the temperature was lowered to -5 ° C, 50% isatoic anhydride-dichloromethane solution (163.1 g, 0.5 mol) was added dropwise, after the dropwise addition, stirring was completed for 30 min, the temperature was raised to 25 ° C, the reaction was performed for 5 h, the mixture was poured into ice water, 12N hydrochloric acid 300 mL was added, stirring was performed for 1 h, filtered, ammonia water was added, the pH was adjusted to 10, the organic layer was separated, concentrated to substantially no fraction, methanol 200 mL was added, the temperature was raised to dissolve, the temperature was lowered to 0 ° C, filtered, and dried to obtain 93.7 g of solid 2-amino-4'-fluoro-benzophenone with a yield of 87% and a purity of 99.7%.

[0036] The prepared 2-amino-4'-fluoro-benzophenone was tested, and the results were as follows:

[0037] 1 HNMR (400MHz, CDCl3) δ = 7.75-7.60 (m, 2H), 7.45 (d, J = 8.4Hz, 1H), 7.26 (t, J = 8.4Hz, 1H ),7.15(t,J=8.4Hz,2H),6.79(d,J=8.4Hz,1H),6.65(t,J=7.5Hz,1H),6.23(s,2H)ppm;

[0038] 13 CNMR (150MHz, CDCl3) δ = 195.3, 168.7, 165.9, 152.4, 138.2, 135.4, 132.7, 131.2, 124.5, 118.0, 116.2ppm.

[0039] Example 2

[0040] This embodiment provides a method for preparing 2-amino-4'-fluoro-benzophenone, a key intermediate of pitavastatin calcium, comprising the following steps:

[0041]

[0042] Under nitrogen protection, dichloroethane (500 mL), fluorobenzene (72.1 g, 0.75 mol), and ferric chloride (324.4 g, 2.0 mol) were added in sequence, the temperature was lowered to -10 ° C, and 43% N-Boc-isatoic anhydride-dichloroethane solution (306.1 g, 0.5 mol) was added dropwise. After the dropwise addition, the mixture was stirred for 30 min, the temperature was raised to 28 ° C, and the reaction was carried out for 6 h. The mixture was poured into ice water, 12N hydrochloric acid 200 mL was added, the mixture was stirred for 1 h, filtered, triethylamine was added, the pH was adjusted to 10, the organic layer was separated, and the mixture was concentrated to substantially no fraction. 200 mL of ethanol was added, the temperature was raised to dissolve, the temperature was lowered to 0 ° C, filtered, and dried to obtain 91.5 g of solid 2-amino-4'-fluoro-benzophenone with a yield of 85% and a purity of 99.2%.

[0043] Example 3

[0044] This embodiment provides a method for preparing 2-amino-4'-fluoro-benzophenone, a key intermediate of pitavastatin calcium, comprising the following steps:

[0045]

[0046] Under nitrogen protection, dichloromethane (500 mL), fluorobenzene (67.3 g, 0.70 mol), zinc chloride (300 g, 2.2 mol) were added in sequence, the temperature was lowered to -5 ° C, 45% N-Fmoc-isatoic anhydride-dichloromethane solution (428.2 g, 0.5 mol) was added dropwise, and the mixture was stirred for 1 h. The mixture was heated to 26 ° C. The reaction was performed for 7 h, and the mixture was poured into ice water. 200 mL of 12N hydrochloric acid was added, and the mixture was stirred for 2 h. The mixture was filtered and sodium bicarbonate solution was added to adjust the pH to 10. The organic layer was separated and concentrated until there was almost no fraction. 150 mL of isopropanol was added, the mixture was heated to dissolve, the temperature was lowered to -5 ° C., the mixture was filtered and dried to obtain 87.2 g of solid 2-amino-4'-fluoro-benzophenone with a yield of 81% and a purity of 99.4%.

[0047] In summary, compared with the prior art, the present invention has the following beneficial effects:

[0048] The preparation method of 2-amino-4'-fluoro-benzophenone provided by the invention has the advantages of short synthesis route, simple operation, easy acquisition of raw materials and reagents, low hazard and pollution of reagents, safety and environmental protection, short synthesis route, mild reaction conditions, convenient and controllable operation, and the prepared 2-amino-4'-fluoro-benzophenone has good purity and high yield.

[0049] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the sentence "comprise a ..." do not exclude the existence of other identical elements in the process, method, article or device including the elements.

[0050] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a key intermediate of pitavastatin calcium, characterized in that: The synthetic route is as follows: Wherein, R is selected from H, Boc Fmoc One of The specific steps include: Under nitrogen protection, the first solvent, fluorobenzene and Lewis acid are added to the container in sequence, the temperature is lowered to -10°C to -5°C, an anhydride reagent is added, and under the catalysis of Lewis acid, fluorobenzene and the anhydride reagent react at ambient temperature, and then quenched, acid washed, alkali adjusted and concentrated to obtain the key intermediate of pitavastatin calcium 2-amino-4'-fluoro-benzophenone.

2. The preparation method according to claim 1, characterized in that The first solvent is selected from dichloromethane or dichloroethane.

3. The preparation method according to claim 1, characterized in that: The Lewis acid is selected from one of ferric chloride, aluminum chloride and zinc chloride.

4. The preparation method according to claim 1, characterized in that: The acid anhydride is selected from one of isatoic anhydride, N-Boc-isatoic anhydride and N-Fmoc-isatoic anhydride.

5. The preparation method according to claim 1, characterized in that: The molar ratio of isatoic anhydride, fluorobenzene and Lewis acid is 1:1-100:2-8.

6. The preparation method according to claim 1, characterized in that: The ambient temperature is 20-30°C.

7. The preparation method according to claim 1, characterized in that: The quenching step is pouring into ice water and stirring.

8. The preparation method according to claim 1, characterized in that: The acid washing is washing with 12N hydrochloric acid.

9. The preparation method according to claim 1, characterized in that: The alkaline washing is to wash the organic layer with aqueous ammonia, sodium carbonate and triethylamine solution until the pH of the organic layer is 8-10.

10. The preparation method according to claim 1, characterized in that: The method also includes post-processing, which specifically includes the following steps: adding a second solvent to 2-amino-4'-fluoro-benzophenone, then heating, dissolving, cooling, crystallizing, filtering, and drying to obtain 2-amino-4'-fluoro-benzophenone, a key intermediate of pitavastatin calcium; The second solvent is selected from one of methanol, ethanol and isopropanol.

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