A method for synthesizing an intermediate of medroxyprogesterone acetate based on metal-organic synergistic catalysis

Abstract

This invention discloses a method for synthesizing medroxyprogesterone acetate intermediates based on a metal-organic synergistic catalysis. The method uses 17-acetyl-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopenta[a]phenanthrene-17-yl acetate as a starting material. Under the synergistic catalytic system composed of a chiral α-amino acid (such as L-proline) and a Lewis acid metal salt (such as zinc acetate), it reacts with a secondary amine and a formaldehyde source to selectively prepare a 6-methylene derivative. This invention utilizes the regio-directing effect of amino acids and the activating and stabilizing effect of metal ions to significantly suppress C2-position side reactions and dimer formation, resulting in a product yield exceeding 93% and a purity exceeding 99%. Column chromatography is not required, making it suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of steroidal drug chemical synthesis, specifically relating to a method for highly selectively synthesizing a key intermediate (6-methylene compound) of medroxyprogesterone acetate. Background Technology

[0002] Medroxyprogesterone acetate is a widely used progestin drug. A key step in its synthetic route is the introduction of a methylene group at the C6 position of the steroid backbone.

[0003] In existing technologies, the introduction of 6-methylene groups mainly faces the following challenges: Interference from the 3-keto carbonyl group: The 3-keto group on the A ring of a steroid is more reactive or competitive than the 6-keto group, and direct reaction easily leads to 3-condensation or multi-substituted byproducts. Therefore, traditional processes (such as the Vilsmeier reaction route) usually require the 3-keto group to be converted into an enol ether for protection before the reaction, followed by hydrolysis to remove the protection. This results in cumbersome steps, low overall yield, and large amounts of waste.

[0004] Side reaction control is difficult: Even when attempting to directly perform the Mannich reaction, the lack of effective regioselectivity control often results in the formation of large amounts of C2-substitution impurities and difficult-to-remove "bis-steroid methylene dimers" (two steroid molecules linked by a methylene group). These impurities are similar in nature to the products and must be separated by column chromatography, making industrialization difficult.

[0005] The catalytic system is singular: existing direct methods usually rely on simple acid-base adjustments (such as hydrochloric acid or acetic acid), failing to solve the problems of transition state stability and steric hindrance guidance at the molecular mechanism level.

[0006] Therefore, developing a one-step synthesis process that requires no protecting group, can precisely control the C6-position selectivity, and suppress dimer formation is an urgent need in this field. Summary of the Invention

[0007] The present invention aims to solve the above-mentioned technical problems and provide a synthesis method based on the "metal-organic synergistic catalysis" strategy.

[0008] The technical solution of the present invention is as follows: A method for synthesizing a high-purity medroxyprogesterone acetate intermediate includes the following steps: Using (8R,9S,10R,13S,14S,17R)-17-acetyl-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopenta[a]phenanthrene-17-yl acetate (compound A) as a starting material, in a reaction solvent and in the presence of a co-catalyst system, a Mannich condensation-elimination tandem reaction was carried out with a formaldehyde source and a secondary amine to prepare medroxyprogesterone acetate intermediate (compound B). The synergistic catalytic system consists of component I (chiral α-amino acid) and component II (Lewis acid metal salt).

[0009] Preferably, component I (chiral α-amino acid) is selected from L-proline, L-valine, L-phenylalanine, L-alanine or 4-hydroxy-L-proline; preferably L-proline.

[0010] Preferably, component II (Lewis acid metal salt) is selected from the acetate, chloride, bromide or trifluoromethanesulfonate of zinc (Zn), magnesium (Mg), calcium (Ca) or copper (Cu); preferably zinc acetate, zinc chloride, magnesium acetate or magnesium chloride; most preferably zinc acetate (Zn(OAc)2).

[0011] Preferably, the secondary amine is a cyclic secondary amine selected from pyrrolidine, piperidine, morpholine or 4-methylpiperazine; preferably pyrrolidine.

[0012] Preferably, the formaldehyde source is paraformaldehyde or triformaldehyde.

[0013] Preferably, the reaction solvent is a C1-C5 lower alcohol, acetonitrile, tetrahydrofuran, or a mixture thereof; more preferably, isopropanol or n-butanol.

[0014] Preferably, the pH of the reaction system is controlled at 4.0-5.5 during the reaction process by adding organic acid dropwise; the organic acid is preferably acetic acid or propionic acid.

[0015] Preferably, the reaction temperature is from 50°C to the solvent reflux temperature, and the reaction time is 2-6 hours.

[0016] Preferably, the obtained compound B has an HPLC purity greater than 99.0% and a dimer impurity content of less than 0.1%.

[0017] Compared with the prior art, the present invention has the following significant advantages: Significant synergistic catalytic effect: A pioneering synergistic system of "chiral α-amino acid + Lewis acid metal salt". Utilizing the stereodirecting effect of amino acids to precisely target the C6 reaction, combined with the activation and stabilization effect of metal salts on intermediates, the dimer formation pathway is effectively interrupted.

[0018] Extremely high yield and purity: The yield of the target product is increased from about 70% by traditional methods to over 93%, and the HPLC purity reaches over 99%. In particular, the extremely difficult-to-remove dimer impurities are controlled to below 0.05%, and the crude product can be obtained as a pharmaceutically pure product by simple crystallization without column chromatography.

[0019] The process is simple and environmentally friendly: it achieves efficient one-step conversion, avoiding the cumbersome "protection-deprotection" steps. The reaction conditions are mild, the catalyst is inexpensive and readily available, and there is little waste, significantly reducing production costs and making it highly valuable for industrial applications. Attached Figure Description

[0020] Figure 1 The synthetic route diagram for medroxyprogesterone acetate intermediate (B) provided in the embodiments of the present invention. Detailed Implementation

[0021] The following examples are used to further illustrate the present invention, and the detection method is HPLC (normalization method).

[0022] Example 1: 200 mL of isopropanol and 20.0 g (0.05 mol) of compound A were added to a 500 mL reaction flask. 5.33 g (1.5 eq) of secondary amine pyrrolidine were added. 4.5 g (3.0 eq) of formaldehyde source paraformaldehyde were added. 1.15 g (0.2 eq) of L-proline and 1.83 g (0.2 eq) of anhydrous zinc acetate were added as co-catalysts. Glacial acetic acid was added dropwise under stirring to adjust the pH to approximately 4.8. The mixture was heated to reflux (approximately 82 °C) and reacted for 3.5 hours. HPLC monitoring showed the starting material concentration to be <0.5%. The reaction solution was concentrated under reduced pressure to recover the solvent. The residue was slurried with 100 mL of water and filtered. The filter cake was washed with 5% NaHCO3 aqueous solution, then washed with water until neutral, and dried to obtain 18.8 g of a white solid compound B. Yield: 93.1%. HPLC purity: 99.4%. Dimer impurities were not detected (<0.05%), and C2-position isomers were 0.2%.

[0023] Example 2: The procedure was the same as in Example 1, except that anhydrous zinc acetate was replaced with an equimolar amount of magnesium chloride hexahydrate (MgCl2·6H2O). The reaction time was 4 hours. 18.2 g of solid was obtained. Yield: 90.1%. HPLC purity: 98.8%.

[0024] Example 3: The procedure was the same as in Example 1, except that "L-proline" was replaced with an equimolar amount of "L-valine". The reaction time was 5 hours. 17.5 g of solid was obtained. Yield: 86.6%. HPLC purity: 98.2%.

[0025] Comparative Example 1: Isopropanol, compound A, pyrrolidine, paraformaldehyde, and 1.15 g of L-proline were added to a reaction flask, and acetic acid was added dropwise to adjust the pH to 4.8. No zinc salt was added. The reaction was refluxed for 3.5 hours, with approximately 3% of the starting material remaining. The reaction was extended to 6 hours, and the starting material was almost completely reacted. Post-processing yielded 16.4 g of solid. Yield: 81.2%. HPLC purity: 96.5%. 1.2% dimer impurities and 0.8% C2-position isomer were detected.

[0026] Comparative Example 2: Isopropanol, compound A, pyrrolidine, paraformaldehyde, and 1.83 g of zinc acetate were added to a reaction flask. Acetic acid was added dropwise to adjust the pH to 4.8. L-proline was not added. The reaction was refluxed for 3.5 hours. The reaction solution was dark in color. HPLC showed that 15% of the starting material remained, and several unknown impurity peaks appeared. Post-processing yielded 14.5 g of solid. Yield: 71.8%. HPLC purity: 92.0%.

[0027] Comparative Example 3: Isopropanol, compound A, pyrrolidine, and paraformaldehyde were added to a reaction flask, and the pH was adjusted to 4.8 by adding acetic acid dropwise only. The reaction was refluxed for 6 hours. Post-treatment yielded 13.8 g of solid. Yield: 68.3%. HPLC purity: 88.5%.

Claims

1. A method for synthesizing a high-purity medroxyprogesterone acetate intermediate, characterized in that, Includes the following steps: Using (8R,9S,10R,13S,14S,17R)-17-acetyl-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecano-1H-cyclopenta[a]phenanthrene-17-yl acetate (compound A) as a starting material, in a reaction solvent and in the presence of a co-catalyst system, a Mannich condensation-elimination tandem reaction was carried out with a formaldehyde source and a secondary amine to prepare medroxyprogesterone acetate intermediate (compound B). The synergistic catalytic system consists of component I (chiral α-amino acid) and component II (Lewis acid metal salt).

2. The synthesis method according to claim 1, characterized in that, Component I (chiral α-amino acid) is selected from L-proline, L-valine, L-phenylalanine, L-alanine or 4-hydroxy-L-proline; preferably L-proline.

3. The synthesis method according to claim 1, characterized in that, Component II (Lewis acid metal salt) is selected from the acetate, chloride, bromide or trifluoromethanesulfonate of zinc (Zn), magnesium (Mg), calcium (Ca) or copper (Cu); preferably zinc acetate, zinc chloride, magnesium acetate or magnesium chloride; most preferably zinc acetate (Zn(OAc)2).

4. The synthesis method according to claim 1, characterized in that, The secondary amine is a cyclic secondary amine selected from pyrrolidine, piperidine, morpholine or 4-methylpiperazine; preferably pyrrolidine.

5. The synthesis method according to claim 1, characterized in that, The formaldehyde source is paraformaldehyde or triformaldehyde.

6. The synthesis method according to claim 1, characterized in that, The reaction solvent is a C1-C5 lower alcohol, acetonitrile, tetrahydrofuran, or a mixture thereof; preferably isopropanol or n-butanol.

7. The synthesis method according to claim 1, characterized in that, The molar ratio of compound A, secondary amine, formaldehyde source, component I, and component II is 1 : (1.2-2.5) : (1.5-4.0) : (0.05-0.3) : (0.05-0.3).

8. The synthesis method according to claim 1, characterized in that, The pH of the reaction system is controlled at 4.0-5.5 during the reaction process by adding organic acid dropwise; the organic acid is preferably acetic acid or propionic acid.

9. The synthesis method according to claim 1, characterized in that, The reaction temperature is from 50℃ to the solvent reflux temperature, and the reaction time is 2-6 hours.

10. The synthesis method according to any one of claims 1-9, characterized in that, The obtained compound B has an HPLC purity greater than 99.0% and a dimer impurity content of less than 0.1%.

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