Triamcinolone intermediate isomer impurity as well as preparation method and process control method thereof

Abstract

The invention provides a triamcinolone intermediate isomer impurity as well as a preparation method and a process control method thereof, and the structure of the isomer impurity is as follows: the preparation method comprises the following steps: dissolving a compound A in an organic solvent at the temperature of-10 to-5 DEG C, and then adding an oxidant solution for oxidation reaction to obtain the isomer impurity, wherein the structure of the compound A is shown in the specification, and the intermediate isomer impurity in the process of preparing triamcinolone under the technological process can be prepared through the preparation method, so that the intermediate isomer impurity is detected and effectively controlled in the technological process; and the generation of isomer impurities of the triamcinolone is controlled and reduced by controlling a reaction means, so that the quality and the yield of the triamcinolone product are controlled.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and more particularly to a triamcinolone intermediate isomer impurity and a preparation method thereof, and a method for inhibiting the generation of the triamcinolone intermediate isomer impurity. Background Art

[0002] Triamcinolone, its C 21 H 27 FO6 molecular weight: 394.44 Its structural formula is as follows: Triamcinolone is a glucocorticoid drug indicated for its potent immunosuppressive effects in the treatment of various allergic inflammatory conditions and autoimmune diseases. Because its primary pharmacological action is identical to that of prednisone acetate (prednisone), its indications are largely the same as those of prednisone, primarily including: 1. Connective tissue diseases such as systemic lupus erythematosus; 2. Immune kidney diseases such as nephrotic syndrome; 3. Immune diseases such as idiopathic thrombocytopenic purpura; and 4. Other conditions for which prednisone acetate is indicated.

[0003] The existing technology for preparing triamcinolone mainly adopts the following methods: Figure 1 The synthetic route shown is as follows: Compound 3TR reacts with a high-valent manganese salt and an acid to produce TA-1; TA-1 reacts with dibromohydantoin via addition to produce YXTC-1, which undergoes epoxidation and hydrolysis under alkaline conditions to produce YXTC-2; YXTC-2 reacts with HF to produce the target compound, triamcinolone. However, this route contains an important isomeric impurity, namely ethyl 2-[(8S,10S,13S,14S,16R,17S)-16,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthrene-17-yl]-2-oxyacetate. This impurity is produced during the reaction from compound 3TR to compound TA-1 and is an isomeric impurity of TA-1. Liquid chromatography analysis of the crude TA-1 obtained after oxidation of compound 3TR reveals the following results: Figure 2 As shown, the peak of RRT: 0.569 is the peak of the isomeric impurity of TA-1, and the purity by area normalization method is 32.272%. The impurity accounts for a large proportion. If it is not detected and controlled, directly feeding TA-1 into production will directly affect the quality and yield of the finished product, and purification will be difficult. Therefore, it is necessary to control the isomeric impurities generated in the process of preparing TA-1 by the reaction of compound 3TR to achieve quality control of triamcinolone and ensure that the triamcinolone product meets the quality control requirements.

[0004] The production of triamcinolone requires the detection and control of this isomer impurity, so a pure product of this process impurity is needed as a reference, but there is currently a lack of a simple preparation process for this impurity. Summary of the Invention

[0005] In view of the above-mentioned technical problems existing in the prior art, the present invention provides a method for preparing isomeric impurities of a triamcinolone intermediate. The preparation method can be used to prepare the intermediate isomeric impurities in the process of preparing triamcinolone under the process flow, so as to detect the intermediate isomeric impurities and effectively control them in the process flow, thereby reducing the isomeric impurities in triamcinolone and achieving quality control of the triamcinolone product.

[0006] In order to achieve the above object, the technical solution of the present invention is as follows:

[0007] A triamcinolone intermediate isomeric impurity, characterized by having the following structure:

[0008]

[0009] The preparation method of the above-mentioned triamcinolone intermediate isomer impurity comprises the following steps:

[0010] At a temperature of -10 to -5°C, compound A is dissolved in an organic solvent, and then an oxidant solution is added to carry out an oxidation reaction to obtain the isomeric impurity; wherein the structure of compound A is:

[0011] In some embodiments, the oxidant is a high-valent manganese compound and / or a high-valent chromium compound.

[0012] In some embodiments, the high-valent manganese compound is at least one of potassium permanganate, manganese dioxide, manganese trioxide, manganese monoxide, manganous anhydride, manganic anhydride, and permanganic anhydride.

[0013] In some embodiments, the organic solvent is at least one of methanol, ethanol, ethyl acetate, acetone, and tetrahydrofuran.

[0014] In some embodiments, the method for preparing the isomeric impurity comprises the following steps:

[0015] Under the protection of inert gas and at -10°C to 5°C, compound A is added to an organic solvent, stirred to dissolve, an oxidant solution is added dropwise, and then an acid is added to react to obtain the isomeric impurity.

[0016] In some embodiments, the acid is at least one of hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, formic acid, acetic acid, propionic acid, and methanesulfonic acid.

[0017] The present invention also provides a method for inhibiting the generation of the above-mentioned triamcinolone intermediate isomer impurities, the method comprising the following steps:

[0018] Under the protection of inert gas and at -10°C to -5°C, compound A is added to an organic solvent, stirred to dissolve, acid is added first and stirred, and then an oxidant solution is added dropwise to carry out the reaction.

[0019] In some embodiments, the method comprises the following steps:

[0020] Under inert gas protection and at 0°C to 5°C, compound A is added to an organic solvent, stirred to dissolve, and then acid is added and stirred for 30-60 minutes, and then an oxidant solution is added dropwise to carry out the reaction.

[0021] In some embodiments, the acid is at least one of hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, formic acid, acetic acid, propionic acid, and methanesulfonic acid.

[0022] In some embodiments, the oxidant is a high-valent manganese compound and / or a high-valent chromium compound.

[0023] In some embodiments, the high-valent manganese compound is at least one of potassium permanganate, manganese dioxide, manganese trioxide, manganese monoxide, manganous anhydride, manganic anhydride, and permanganic anhydride.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] The method of the present invention can effectively prepare the isomeric impurities of the intermediate obtained in the triamcinolone process. The obtained impurities can be used to control the quality of the triamcinolone product. By optimizing the process, avoiding the generation of the impurities plays an important role in the quality control and process optimization of triamcinolone.

[0026] The method for inhibiting the generation of isomer impurities of a triamcinolone intermediate provided by the present invention can improve the purity and yield of the triamcinolone intermediate, thereby improving the yield of the triamcinolone product. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is a flow chart of the preparation process of triamcinolone in the prior art;

[0028] Figure 2 This is a liquid chromatogram of the crude product obtained by preparing TA-1 using compound 3TR in the existing triamcinolone process;

[0029] Figure 3 This is a process flow chart for the isomeric impurities of the triamcinolone intermediate in this application;

[0030] Figure 4 This is a liquid chromatogram of the crude triamcinolone intermediate isomer impurity obtained in Example 1;

[0031] Figure 5is a liquid chromatogram of the refined product obtained in Example 1;

[0032] Figure 6 The mass spectrum of the triamcinolone intermediate isomeric impurity 2-[(8S,10S,13S,14S,16R,17S)-16,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthrene-17-yl]-2-oxyacetic acid ethyl ester obtained in Example 1 is shown;

[0033] Figure 7 The hydrogen spectrum of the triamcinolone intermediate isomeric impurity 2-[(8S,10S,13S,14S,16R,17S)-16,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthrene-17-yl]-2-oxyacetic acid ethyl ester obtained in Example 1;

[0034] Figure 8 This is the carbon spectrum of the triamcinolone intermediate isomer impurity 2-[(8S,10S,13S,14S,16R,17S)-16,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthrene-17-yl]-2-oxyethyl acetate obtained in Example 1.

[0035] Figure 9 This is a liquid chromatogram of the triamcinolone intermediate TA-1 product obtained in Example 2;

[0036] Figure 10 The figure is a liquid chromatogram of the triamcinolone intermediate TA-1 product prepared by the process of Example 2. DETAILED DESCRIPTION

[0037] The following description sets forth numerous specific details to facilitate a thorough understanding of the present invention. However, the present invention can be implemented in many other ways than those described herein, and those skilled in the art may make similar modifications without departing from the scope of the present invention. Therefore, the present invention is not limited to the specific implementations disclosed below.

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in this specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0039] Example 1

[0040] like Figure 3 As shown, a method for preparing an isomeric impurity of a triamcinolone intermediate comprises the following steps:

[0041] Add 10.0g of compound A and 300.0g of acetone to the reactor, stir at room temperature to dissolve, replace with nitrogen twice, cool to -5°C, continue to maintain the temperature at -5°C, add 200.0g (concentration: 0.025g / mL) of potassium permanganate solution dropwise, and control the temperature at -10 to -5°C; after the addition is complete, add 3.6g of acetic acid, keep the temperature at -10 to -5°C for 5 to 10 minutes, and take a TLC sample; after the reaction is basically completed, control the temperature below 0°C, and add 50.0g (concentration 0.12g / mL) of sodium metabisulfite aqueous solution dropwise The reaction mixture was added dropwise, stirred at -5 to 0 ° C for 20 minutes, then heated to 25 ° C, and kept at 25 ° C for 1 hour; the material was discarded, the filtrate was retained, the filter cake was washed twice with anhydrous ethanol (each time for half an hour), the material was discarded, the filtrate was combined, and the acetone was concentrated under negative pressure at 40 ° C until no droplets were distilled out; after concentration, it was cooled to 15 to 20 ° C, kept at 15 to 20 ° C, and stirred for crystallization for 1 to 2 hours; after the crystallization was completed, the material was discharged, centrifuged and filtered, and dried. The filter cake was washed with water and dried to obtain 7.0 g of crude product of the intermediate isomer of the compound triamcinolone (C 23 H 28 O6, molecular weight 400.47), the crude purity is as Figure 4 As shown; the crude product was separated and purified by main layer chromatography to obtain 1.5g of refined product, as shown Figure 5 As shown, the yield is 15% and the purity is 97.93%.

[0042] The refined product obtained in this example was subjected to structural identification, and the identification results were as follows: Figure 6-8 As shown;

[0043] in:

[0044] Figure 6 is the mass spectrum of the compound;

[0045] Figure 7 is the hydrogen spectrum of the compound;

[0046] Figure 8 is the carbon spectrum of the compound.

[0047] The identification results showed that the compound prepared in this example was ethyl 2-[(8S,10S,13S,14S,16R,17S)-16,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthrene-17-yl]-2-oxyacetate, and its structure was as follows:

[0048] Example 2

[0049] like Figure 1 As shown, a method for preparing triamcinolone intermediate TA-1 comprises the following steps:

[0050] Add 10.0g of compound 3TR and 300.0g of acetone to the reactor, stir at room temperature to dissolve, replace with nitrogen twice, cool to -5°C, add 3.6g of acetic acid, continue to cool to maintain the temperature at -5°C after addition, add 200.0g (concentration: 0.025g / mL) of potassium permanganate solution dropwise, control the temperature at -10 to -5°C, and add dropwise; after addition, keep the temperature at -10 to -5°C for 5 to 10 minutes, take TLC samples; after the reaction is basically completed, control the temperature below 0°C, and add 50.0g (concentration 0.12g / mL) of sodium metabisulfite The aqueous solution was added dropwise to the reaction solution. After the addition was complete, the mixture was stirred at -5 to 0°C for 20 minutes, then heated to 25°C and kept at 25°C for 1 hour. The material was discarded, the filtrate was retained, and the filter cake was washed twice with anhydrous ethanol (each time for half an hour), the material was discarded, the filtrate was combined, and the acetone was concentrated under negative pressure at 40°C until no droplets were evaporated. After concentration, the mixture was cooled to 15 to 20°C, kept at 15 to 20°C, and stirred for crystallization for 1 to 2 hours. After the crystallization was completed, the material was discharged, centrifuged and filtered, and the filter cake was washed with water and dried to obtain 10.1 g of intermediate TA-1 of the compound triamcinolone.

[0051] The intermediate TA-1 product obtained was tested, and the results were as follows Figure 9 As shown. Figure 9 The intermediate TA-1 prepared in this example has a yield of 101% and a purity of 98.87%; the isomer impurity is 0.21%.

[0052] Three batches of triamcinolone intermediate TA-1 were produced continuously using the process of Example 2. Figure 10 As shown, the yield is above 100%, the purity is above 98.5%, and the isomer impurities are all controlled below 0.2%, indicating that the impurities are effectively controlled.

[0053] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0054] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be determined by the appended claims.

Claims

1. A triamcinolone intermediate isomer impurity, characterized in that: Has the following structure:

2. The method for preparing the isomeric impurities of the triamcinolone intermediate according to claim 1, characterized in that: The following steps are involved: At a temperature of -10 to -5°C, compound A is dissolved in an organic solvent, and then an oxidant solution is added to carry out an oxidation reaction to obtain the isomeric impurity; wherein the structure of compound A is:

3. The method for preparing the triamcinolone intermediate isomer impurity according to claim 2, wherein: The oxidant is a high-valent manganese compound and / or a high-valent chromium compound.

4. The method for preparing triamcinolone intermediate isomer impurities according to claim 3, wherein The high-valent manganese compound is at least one of potassium permanganate, manganese dioxide, manganese trioxide, manganese monoxide, manganous anhydride, manganic anhydride, and permanganic anhydride.

5. The method for preparing triamcinolone intermediate isomer impurities according to claim 2, wherein: The organic solvent is at least one of methanol, ethanol, ethyl acetate, acetone and tetrahydrofuran.

6. The method for preparing the triamcinolone intermediate isomer impurity according to any one of claims 1 to 5, characterized in that: The preparation method of the isomeric impurity comprises the following steps: Under the protection of inert gas and at -10°C to -5°C, compound A is added to an organic solvent, stirred to dissolve, an oxidant solution is added dropwise, and then an acid is added to react to obtain the isomeric impurity.

7. The method for preparing triamcinolone intermediate isomer impurities according to claim 6, characterized in that: The acid is at least one of hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, formic acid, acetic acid, propionic acid, and methanesulfonic acid.

8. The method for inhibiting the formation of isomeric impurities in the triamcinolone intermediate according to claim 1, characterized in that: The following steps are involved: Under the protection of inert gas and at -10°C to -5°C, compound A is added to an organic solvent, stirred to dissolve, acid is added first and stirred, and then an oxidant solution is added dropwise to carry out the reaction.

9. The method for inhibiting the formation of isomeric impurities in a triamcinolone intermediate according to claim 8, wherein: The following steps are involved: Under inert gas protection and at 0°C to 5°C, compound A is added to an organic solvent, stirred to dissolve, and then acid is added and stirred for 30-60 minutes, and then an oxidant solution is added dropwise to carry out the reaction.

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