Preparation method of steroid methyl ketone compound

Abstract

The invention discloses a preparation method of a steroid methyl ketone compound, belongs to the technical field of preparation of steroid hormone drugs, and particularly relates to a preparation method for preparing a methyl ketone compound shown as a formula II from a steroid corticoid intermediate chloro compound shown as a formula I through zinc powder dechlorination reduction. The solvent is alcohol, and performing dechlorination reduction to obtain the compound shown in the formula II. The method disclosed by the invention is thorough in reduction, wide in substrate applicability and good in safety, can greatly improve the purity and yield of the product in the step, does not need to use a large amount of acid as a solvent, is beneficial to synthesis of downstream corticoid and safe index control operation, and is particularly suitable for a corticoid synthesis process and industrial production thereof.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation of steroid hormone drug intermediates, and specifically relates to a preparation method of a steroid methyl ketone compound. Background Art

[0002] Steroidal methyl ketone compounds (Formula II) are important intermediates for the synthesis of various corticosteroid drugs. Using steroidal halogenated methyl ketone compounds Formula I to construct methyl ketone groups through dehalogenation reduction reactions, and then synthesizing target intermediates and corticosteroid drugs is an important method for the synthesis of steroid drugs. The synthesis route is as follows:

[0003]

[0004] The invention discloses a method for synthesizing a methyl ketone compound of formula II from a halogenated methyl ketone compound. The methyl ketone dehalogenation reduction technologies used in steroid compounds include: ① In the synthesis process of rimexolone intermediate reported in CN101041682A, glacial acetic acid is used as a solvent and sodium iodide is used to catalyze the reduction dehalogenation of insurance powder. Insurance powder has a high degree of danger and is not suitable for large-scale industrial production; ② In the synthesis process of methylprednisolone intermediate reported in CN110698528B, acetone is used as a solvent and glacial acetic acid zinc powder is used to reduce and dehalogenate to construct methyl ketone. This method cannot effectively reduce steroid compounds containing 1,2 double bonds; ③ In the synthesis process of pregnane-4-ene-17α-ol-3,11,20-trione reported in CN110684069B, dimethyl sulfoxide, N, N-dimethylformamide or tetrahydrofuran is used as solvent, organic acid is used as catalyst, zinc powder, aluminum powder or tin powder is used for reduction and dehalogenation to construct methyl ketone. This method is also unable to effectively reduce steroid compounds containing 1,2 double bonds. ④ In the synthesis process of nomegestrol reported in CN106866768A, glacial acetic acid is used as solvent, zinc powder or iron powder is used for dehalogenation and reduction to construct methyl ketone. The combination of glacial acetic acid and metal powder is unable to effectively reduce steroid compounds containing 1,2 double bonds. ⑤ Chirality (2013), 25 (9), 575-581 reported that 30% ammonia methanol solution is used as solvent, titanium sulfate is used for reduction and dehalogenation to construct methyl ketone. The reaction scale is milligram level and a large amount of ammonia is used. At the same time, a large amount of insoluble titanium dioxide is produced during the reaction process, which is not suitable for industrial production.

[0005] In view of the problems in the reductive dehalogenation step of the above reaction, it is necessary to provide a reductive dehalogenation synthesis method with a wide range of substrate applications, safe production, and convenient operation. Summary of the invention

[0006] The present invention aims at the problems existing in the reductive dehalogenation reaction of the above-mentioned corticosteroid intermediate halomethyl ketone compound I to construct the methyl ketone compound II, and provides another novel reductive dehalogenation scheme for constructing the methyl ketone, which can be simply summarized as follows: the halomethyl ketone compound I is used as a solvent, an acid salt is added, and zinc powder is used for reductive dehalogenation. After the reaction is completed, the target methyl ketone compound II is obtained by filtering, concentrating, and precipitating a simple post-treatment to obtain a high-purity and high-yield target methyl ketone compound II. The structures of the corticosteroid intermediate halomethyl ketone compound I and the methyl ketone compound II of the present invention refer to:

[0007]

[0008] Wherein, in the compounds of the above formula I and II of the present invention, R1 and R2 can be H at the same time, or form a carbon-carbon double bond; R 3、 R4 can be H at the same time, or form a carbon-carbon double bond; R 6、 R3 can be H at the same time, or form a carbon-carbon double bond; R5 is H or CH3; R6 is H or CH3.

[0009] In particular, the structure of the reactant compound of formula I involved in the present invention is selected from the following structures:

[0010]

[0011] Specifically, the preparation method of the compound of formula II comprises the following steps: dissolving the compound of formula I in a solvent, adding an appropriate amount of acidic salt and an appropriate amount of zinc powder at 10 to 50°C, controlling the temperature at 10 to 50°C to react for 2 to 12 hours, and monitoring the reaction by TLC until the reaction of the compound of formula I is complete; filtering the feed liquid, concentrating the filtrate under reduced pressure to about 2V of the mother liquor, adding water to 10V, and precipitating the material at room temperature; filtering, draining, and vacuum drying to obtain the compound of formula II, sampling and testing, and calculating the yield.

[0012] In the present invention, the C1-C3 alcohols are preferably methanol or ethanol. Based on the weight of the compound of formula I, when the compound I is 1W, the solvent is used at 10-50V. Preferably, the solvent can be selected at any volume of 20-35V.

[0013] The acidic salt of the present invention is one or two of ammonium chloride, potassium hydrogen sulfide, and potassium dihydrogen phosphate. As a preferred embodiment, one of ammonium chloride, potassium hydrogen sulfide, or potassium dihydrogen phosphate is used. Based on the weight of the compound of formula I, when the compound I is 1W, the acidic salt is used in an amount of 0.2 to 0.8W.

[0014] The reducing agent in the present invention is zinc powder. Based on the weight of the compound of formula I, when the compound I is 1W, the zinc powder is used in an amount of 0.2-0.5W.

[0015] Note: In the weight-to-volume ratio referred to in the present invention, W represents weight and V represents volume. When the unit of W is g, the unit of V is mL; when the unit of W is Kg, the unit of V is L.

[0016] The specific structures (1) and (2) of the above-mentioned compound of formula I are used to demonstrate the technical effect of the present invention. The compound of structure (1) or (2) of formula I is used as a reaction substrate for dehalogenation reduction. The applicability of the substrate in the prior art is poor, and the structural formula (1) cannot normally undergo a reduction dehalogenation reaction to obtain the corresponding methyl ketone. In some specific embodiments of the present invention, the total weight yield of the corresponding compound of formula II obtained by reducing and dehalogenating the structure (1) through the present invention is ≥90%, and the purity of the compound is greater than 95%, which is higher than the existing manufacturing level in the industry; the chromatographic purity of the corresponding compound of formula II obtained by structure (2) is greater than 95%, the reaction is thorough, the purity is high, and the yield is greatly improved, which provides a new path for the synthesis of such downstream drugs.

[0017] Compared with the prior art, the dehalogenation reduction scheme for preparing methyl ketone formula II compounds from steroidal corticosteroid intermediate halogenated ketone formula I compounds provided by the present invention has the following advantages: 1) The dehalogenation reduction of the present invention technology is thorough, and the target methyl ketone formula II compound can be stably obtained in this way with high yield and good purity. 2) The scheme of the present invention has simple steps, environmental protection and safety, a wide range of substrate applications, and the obtained methyl ketone formula II compound has high purity and light color, which is conducive to the synthesis and index control of downstream corticosteroids. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 HPLC chromatogram of compound II of Example 1

[0019] Figure 2 HPLC chromatogram of Example 5 Compound II

[0020] Figure 3 HPLC chromatogram of Example 6 Compound II

[0021] Figure 4 HPLC chromatogram of Comparative Example 1 Compound II DETAILED DESCRIPTION

[0022] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0023] It should be understood that the terms described in the present invention are only for describing special embodiments and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that the upper and lower limits of the scope and each intermediate value therebetween are specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0024] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art to which the invention belongs. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials related to the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0025] The reagents and materials used in the examples of the present invention are all commercially available, and their quality standards meet the research and development and production requirements and needs of the industry. To further illustrate the scheme of the present invention, a structure in the general formula of the compound of formula I is used as an example in the examples to explain the specific implementation process of the present invention.

[0026] Example 1

[0027] The starting compound I is sourced from Hunan Xinhexin Biopharmaceutical Co., Ltd., and the product of batch H2-231023 has a chromatographic purity of 98.9% after purification.

[0028]

[0029] In a reaction flask, add the compound of formula I (1W, 500g), methanol (30V, 1.5L), adjust the temperature to 20-25°C, stir and dissolve until completely dissolved, add ammonium chloride (0.2W, 100g), add zinc powder (0.2W, 100g), stir and react at 20-25°C for 5 hours; after the reaction is complete, filter, concentrate the filtrate at 50°C to about 2V of the mother liquor, add water 10V, stir at room temperature for 0.5 hours; filter, wash with water, and dry in vacuo at 50-60°C to obtain compound II of formula II, with a weight yield of 91.5% and a chromatographic purity of 98.04% ( ST-231128 )

[0030] Example 2

[0031] The starting compound I is sourced from Hunan Xinhexin Biopharmaceutical Co., Ltd., and the product of batch H2-231023 has a chromatographic purity of 98.9% after refinement.

[0032]

[0033] In a reaction flask, add the compound of formula I (1W, 500g) and methanol (30V, 1.5L), adjust the temperature to 40°C, stir and dissolve until completely dissolved, potassium hydrogen sulfate (0.8W, 400g), add zinc powder (0.5W, 250g) and stir at 40°C for 5 hours; after the reaction is complete, filter, concentrate the filtrate under reduced pressure to about 2V of the mother liquor, add water 10V, stir at room temperature for 0.5 hours; filter, wash with water, and dry in vacuo at 50-60°C to obtain compound II of formula II, with a weight yield of 92.8% and a chromatographic purity of 97.3% ( ST-231119 )

[0034] Example 3

[0035] The starting compound I is sourced from Hunan Xinhexin Biopharmaceutical Co., Ltd., and the product of batch H2-231023 has a chromatographic purity of 98.9% after refinement.

[0036]

[0037] In a reaction flask, add the compound of formula I (1W, 500g) and methanol (40V, 2L), adjust the temperature to 40°C, stir and dissolve until completely dissolved, potassium dihydrogen phosphate (0.4W, 200g), add zinc powder (0.3W, 150g), stir and react at 25°C for 5 hours; after the reaction is complete, filter, concentrate the filtrate under reduced pressure to about 2V of the mother liquor, add water 10V, stir at room temperature for 0.5 hour; filter, wash with water, and vacuum dry at 50-60°C to obtain compound II of formula II, with a weight yield of 92.8% and a chromatographic purity of 97.9% ( ST-231120 )

[0038] Example 4

[0039] The starting compound I is sourced from Hunan Xinhexin Biopharmaceutical Co., Ltd., and the product of batch H2-231023 has a chromatographic purity of 98.8% after refinement.

[0040]

[0041] In a reaction flask, add the compound of formula I (1W, 50g), methanol (30V, 150ml), adjust the temperature to 20-25°C, stir and dissolve until completely dissolved, add ammonium chloride (0.35W, 17.5g), add zinc powder (0.4W, 20g), stir and react at 20-25°C for 12 hours; after the reaction is complete, filter, concentrate the filtrate at 50°C to about 2V of the mother liquor, add 10V of water, stir at room temperature for 0.5 hour; filter, wash with water, and vacuum dry at 50-60°C to obtain compound II of formula II, with a weight yield of 92.9% and a chromatographic purity of 98.53% (ST-240505)

[0042] Example 5

[0043] The starting compound I was obtained from Taizhou Xianju Pharmaceutical Co., Ltd., batch 04.1527-240601, with a chromatographic purity of 99.34%.

[0044]

[0045] In a reaction flask, add the compound of formula I (1W, 150kg) and methanol (30V, 4500L), adjust the temperature to 20-25°C, stir and dissolve until completely dissolved, add potassium hydrogen sulfate (0.5W, 75kg), add zinc powder (0.4W, 60kg), stir and react at 25°C for 5 hours; after the reaction is complete, filter, concentrate the filtrate under reduced pressure to about 2V of the mother liquor, add water 10V, stir at room temperature for 0.5 hour; filter, wash with water, and vacuum dry at 50-60°C to obtain compound II of formula II, with a weight yield of 91.3% and a chromatographic purity of 98.2% (04.1557-240601)

[0046] Example 6

[0047] The starting compound 21-chloro-19-norprogesterone is from Zhejiang Xianju Pharmaceutical Co., Ltd., ST-230801 batch product, chromatographic purity 93.7%. The reaction of this example is as follows:

[0048]

[0049] In a reaction flask, add the compound of formula I (1W, 7g), methanol (20V, 140mlL), adjust the temperature to 40°C, stir and dissolve until completely dissolved, potassium hydrogen sulfate (0.5W, 3.5g), add zinc powder (0.4W, 2.8g) and stir at 40°C for 5 hours; after the reaction is complete, filter, concentrate the filtrate under reduced pressure to about 2V of the mother liquor, add 8V of water, stir at room temperature for 0.5 hour; filter, wash with water, and vacuum dry at 50-60°C to obtain compound II of formula II, with a weight yield of 92.3% and a chromatographic purity of 97.7% (ST-241201)

[0050] Comparative Example 1

[0051] The starting compound I was obtained from Hunan Xinhexin Biopharmaceutical Co., Ltd., batch H2-231023 product, with a chromatographic purity of 93.9%. The dehalogenation reduction reaction was carried out according to CN110698528B.

[0052]

[0053] In a reaction flask, add the compound of formula I (1W, 20g), acetone 7V, zinc powder 0.3W, glacial acetic acid 1.5V, reflux at 50-55℃ for 7h, cool the system to below 35℃, add 7V dichloromethane, filter, wash the filter cake with 1V dichloromethane, concentrate the filtrate to below 1V, add 5V water, stir for 1h, filter, wash the filter cake with water until neutral, and vacuum dry at 50-60℃ to obtain compound II of formula II, with a chromatographic purity of 55.4%, 36.0% of the raw materials are not completely reacted, and 2.7% of demethylation by-products and 4.2% of hydrogenation by-products are produced. (ST-231001)

[0054] Comparative Example 2

[0055] With reference to the same feed ratio as in Comparative Example 1, the reflux reaction time was extended to 22h to obtain compound II of formula II with a chromatographic purity of 34.4%. 3.6% of the raw materials were not completely reacted, and 33.7% of demethylation by-products and 34.9% of hydrogenation by-products were produced. (ST-231007)

[0056] Comparative Example 3

[0057] The starting compound I was obtained from Hunan Xinhexin Biopharmaceutical Co., Ltd., batch H2-231023 product, with a chromatographic purity of 93.9%. The dehalogenation reduction reaction was carried out according to CN110684069B.

[0058]

[0059] In a reaction flask, add the compound of formula I (1W, 20g), N,N-dimethylformamide 2.5V, zinc powder 0.4W, glacial acetic acid 1.5V, react at 35℃ for 5h, filter, add 6V water to the filtrate, stir for 1h, filter, wash the filter cake with water until neutral, and vacuum dry at 50-60℃ to obtain compound II of formula II, with a chromatographic purity of 27.7%, 5.3% of the raw materials are not completely reacted, and 16.8% of demethylation by-products and 45.9% of hydrogenation by-products are produced. (ST-231003)

[0060] Comparative Example 3

[0061] Referring to Comparative Example 3, the solvent was replaced with tetrahydrofuran.

[0062] In a reaction flask, add the compound of formula I (1W, 20g), tetrahydrofuran 8V, zinc powder 0.3W, glacial acetic acid 1.5V, reflux reaction for 7h, filter, add 6V water to the filtrate, stir for 1h, filter, wash the filter cake with water until neutral, and vacuum dry at 50-60℃ to obtain compound II of formula II, with a chromatographic purity of 27.7%, 5.3% of the raw materials are not completely reacted, and 16.8% of demethylation by-products and 45.9% of hydrogenation by-products are produced. (ST-231003)

[0063] Comparative Example 4

[0064] The starting compound I was obtained from Hunan Xinhexin Biopharmaceutical Co., Ltd., batch H2-231023 product, chromatographic purity 93.9%. The dehalogenation reduction reaction was carried out according to CN106866768A.

[0065]

[0066] In a reaction flask, add compound I (1W, 20g), glacial acetic acid (5V, 100ml), zinc powder (0.3W, 6g) and react at room temperature for 7h. Add (20V, 400ml) water to the filtrate, stir for 1h, filter, wash the filter cake with water until neutral, and dry it in vacuum at 50-60℃ to obtain compound II of formula II, with a chromatographic purity of 47.2%, 3.2% of the raw materials are not completely reacted, and 15.2% of isomer by-products and 14.1% of hydrogenation by-products are produced. (ST-231015)

[0067] Although the present invention has been described with reference to exemplary embodiments, it should be understood that the present invention is not limited to the disclosed exemplary embodiments. Various adjustments or changes may be made to the exemplary embodiments of the present specification without departing from the scope or spirit of the present invention. The scope of the claims should be based on the broadest interpretation to cover all modifications and equivalent structures and functions.

Claims

1. A method for preparing a steroidal methyl ketone compound, characterized in that: The preparation method comprises: under the protection of inert gas, adding an acid salt to a compound of formula I in an appropriate solvent and a reducing agent zinc powder to carry out a dehalogenation reduction reaction at a certain temperature; after the compound of formula I is completely reacted, filtering the reaction system, and obtaining a compound of formula II through post-treatment steps such as concentration and water separation. The synthesis route is as follows: Wherein, the reaction solvent refers to a C1-C3 alcohol solvent; the structure of the compound of formula I is selected from any one of the following structures:

2. The method for preparing the steroidal methyl ketone compound according to claim 1, characterized in that: The C1-C3 alcohol solvent used in the reaction is one or two of methanol, ethanol, n-propanol and isopropanol.

3. The method for preparing the steroidal methyl ketone compound according to claim 1, characterized in that: The acidic salt used in the reaction is one or two of ammonium chloride, potassium hydrogen sulfate and potassium dihydrogen phosphate.

4. The method for preparing the steroidal methyl ketone compound according to claim 1, characterized in that: The reaction temperature is 10-50°C, more preferably 20-40°C.

5. The method for preparing the steroidal methyl ketone compound according to claim 4, characterized in that: The weight-volume ratio of the compound of formula I to the reaction solvent, the acid salt and the zinc powder is 1W:10-50V:0.2-0.8W:0.2-0.5W.

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