A method for synthesizing steroidal drug intermediates using pyridine trifluoroacetate catalysis

Abstract

This disclosure discloses a method for synthesizing steroidal drug intermediates using trifluoroacetic acid pyridinium salt catalysis, comprising the following steps: in an organic solvent, in the presence of trifluoroacetic acid pyridinium salt, reacting a compound of formula A with compound R. 2 C(OR 3 )3 undergoes a cyclization reaction to generate a compound as shown in Formula B. This method avoids the risk of generating genotoxic impurities such as sulfonate esters, complies with ICH M7 and CDE control requirements for genotoxic impurities, significantly reduces the risk of supplementary information requests during drug registration, and improves catalytic efficiency, process stability and controllability, making it suitable for large-scale production.

Description

Technical Field

[0001] This disclosure relates to the field of chemistry, and more specifically to a method for synthesizing steroidal drug intermediates using pyridine trifluoroacetate catalysis. Background Technology

[0002] 17α,21-Dihydroxypregn-4-ene-3,20-dione-17α,21-ethyl orthopropionate is a key pharmaceutical intermediate in the synthesis of corateron. In existing synthetic processes, the target compound is generated by a cyclization reaction between 17α,21-dihydroxypregn-4-ene-3,20-dione and triethyl orthopropionate under acid catalysis. Traditional processes typically use p-toluenesulfonic acid (PTSA) as the acid catalyst, which readily generates sulfonate impurities such as methyl p-toluenesulfonate, ethyl p-toluenesulfonate, and isopropyl p-toluenesulfonate. According to ICH M7 guidelines, sulfonate impurities are explicitly classified as Group 2 genotoxic impurities, possessing mutagenic and potential carcinogenic properties.

[0003] The core defects of the existing process are: (1) Risk of genotoxic impurities: The reaction of alcohol with PTSA in the reaction system generates sulfonate impurities such as methyl p-toluenesulfonate, ethyl p-toluenesulfonate, and isopropyl p-toluenesulfonate. These impurities are clearly listed as Category 2 genotoxic impurities by ICH M7, which have mutagenicity and potential carcinogenicity; (2) High registration compliance risk: According to ICH specifications, the maximum daily intake of genotoxic impurities is ≤1.5 μg / d. Combined with the maximum daily dose of 20 mg / day for cloasterol cream, the impurity limit is estimated to be only 75 ppm. In order to control genotoxic impurities, a special inspection item needs to be set in the quality standard, which increases the quality control cost and the risk of registration supplementation; (3) Process limitations: The existing process cannot eliminate the risk of genotoxicity from the source. It can only reduce the impurity content through subsequent purification. The process controllability and safety are insufficient. Summary of the Invention

[0004] The technical problems to be solved by this disclosure are: 1) When p-toluenesulfonic acid is used as a catalyst in the existing synthesis process, sulfonate ester genotoxic impurities are easily generated, which leads to a significant risk of genotoxic impurities in drug registration; 2) The process has poor stability and is not suitable for industrial applications; 3) The reaction yield and purity are low.

[0005] The present disclosure adopts the following technical solution to solve the above-mentioned technical problems: This disclosure provides a method for synthesizing a steroidal drug intermediate, comprising the following steps: in an organic solvent, in the presence of pyridine trifluoroacetate, reacting a compound of formula A with compound R. 2 C(OR 3 )3 undergoes a cyclization reaction to produce a compound as shown in formula B; ; Among them, R 1It is H or hydroxyl; R 2 For H or C 1-4 alkyl; R 3 C 1-4 alkyl.

[0006] In some of the technical solutions disclosed herein, R 1 For H.

[0007] In some of the technical solutions disclosed herein, R 1 It is a hydroxyl group.

[0008] In some of the technical solutions disclosed herein, R 2 It can be H, methyl, or ethyl; for example, ethyl.

[0009] In some of the technical solutions disclosed herein, R 3 It can be methyl or ethyl; for example, ethyl.

[0010] In some technical solutions of this disclosure, the molar ratio of the compound represented by Formula A to pyridinium trifluoroacetate is 1:(0.001-2); preferably 1:(0.005-1.5); for example 1:0.01, 1:0.05, 1:0.1, 1:0.2, 1:0.3, 1:0.5 or 1:1.

[0011] In some of the technical solutions disclosed herein, the reaction weight of the compound represented by Formula A is at least 150g; for example, at least 500g; and for example, at least 1000g.

[0012] In some technical solutions of this disclosure, the compound represented by formula A and compound R 2 C(OR 3 The molar ratio of 3 is 1:(1-10); preferably 1:(1-5); for example 1:2.

[0013] In some of the technical solutions disclosed herein, the compound represented by Formula A is 17α,21-dihydroxypregn-4-ene-3,20-dione.

[0014] In some of the technical solutions disclosed herein, the compound represented by Formula A is hydrocortisone.

[0015] In some technical solutions of this disclosure, the compound R 2 C(OR 3 )3 is triethyl orthopropionate, trimethyl orthopropionate, triethyl orthoformate, or triethyl orthoacetate.

[0016] In some technical solutions of this disclosure, the compound R 2 C(OR 3 )3 is triethyl propionate.

[0017] In some of the technical solutions disclosed herein, the organic solvent is a haloalkane solvent or an aromatic hydrocarbon solvent; for example, dichloromethane or toluene.

[0018] In some technical solutions of this disclosure, the temperature of the cyclization reaction is the temperature at which the reaction system is refluxed, for example, 20-50°C or 100-130°C; preferably 30-40°C or 110-120°C.

[0019] In some technical solutions of this disclosure, the reactants for the cyclization reaction consist of a compound represented by formula A, a pyridinium trifluoroacetate salt, and compound R. 2 C(OR 3 It consists of 3 components.

[0020] In some of the technical solutions disclosed herein, the cyclization reaction includes the following post-processing steps: extraction (e.g., dichloromethane extraction), washing (e.g., water washing and saturated brine washing; preferably water washing followed by saturated brine washing), and concentration.

[0021] Terminology Explanation

[0022] Unless otherwise specified, the terms used in this disclosure have the following meanings: The term “C1-4 alkyl” refers to a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples include, but are not limited to: methyl (-CH3), ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), and n-butyl (-CH2CH2CH2CH3).

[0023] The positive and progressive effects of this disclosure are as follows: (1) Completely eliminate genotoxic impurities: Trifluoroacetic acid pyridine salt does not contain sulfonic acid structure, eliminating the risk of genotoxic impurities generated by sulfonate esters from the source of the process. It fully complies with the control requirements of ICH M7 and CDE on genotoxic impurities, and there is no need to set genotoxicity test items in the quality standard, which significantly reduces the risk of drug registration and supplementary information.

[0024] (2) The catalytic efficiency is comparable or even better: in the 100-gram scale-up experiment, the yield can reach 95.0% and the HPLC purity can reach 99.5%, which is better than the level of traditional process (PTSA).

[0025] (3) Strong process stability: good repeatability of batches at the 100-gram level, stable purity, and controllable impurities.

[0026] (4) Cost controllable: Trifluoroacetic acid pyridine salt is used in small quantities, is cheap and readily available, and is suitable for large-scale production. Detailed Implementation

[0027] The present disclosure is further illustrated below by way of embodiments, but the present disclosure is not limited to the scope of the embodiments described herein.

[0028]

[0029] The structures of the products of Examples 1-9 and Comparative Examples 1-5 were confirmed by proton NMR and carbon NMR spectroscopy, and the characterization data are as follows: 1 H NMR (600 MHz, Chloroform- d ) δ 5.72 (s, 1H), 4.16 (d, J = 16.6 Hz, 1H), 3.93 (d, J = 16.6 Hz, 1H), 3.54 – 3.47 (m, 1H), 3.44 (p, J = 7.1 Hz,1H), 2.72 – 2.65 (m, 1H), 2.40 (dd, J = 14.5, 5.0 Hz, 2H), 2.37 – 2.31 (m,2H), 2.28 (d, J = 14.1 Hz, 1H), 2.06 – 1.95 (m, 2H), 1.87 (dd, J = 11.4, 4.5Hz, 1H), 1.83 (q, J = 7.5 Hz, 2H), 1.78 – 1.71 (m, 3H), 1.70 (dd, J = 6.3, 3.2 Hz, 1H), 1.64 (dt, J = 13.9, 3.9 Hz, 1H), 1.59 (dt, J = 10.4, 5.2 Hz,1H), 1.49 – 1.43 (m, 1H), 1.41 (dd, J = 13.1, 4.0 Hz, 1H), 1.24 (q, J = 7.1,6.4 Hz, 1H), 1.18 (s, 4H), 1.12 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H), 0.65 (s, 3H). 13 C NMR (151 MHz, Chloroform-d ) δ 205.87, 199.60, 171.15, 124.04,113.33, 92.38, 77.37, 77.16, 76.95, 68.48, 59.00, 53.34, 50.91, 48.99, 38.71,35.99, 35.82, 34.09, 33.63, 32.97, 32.11, 31.62, 27.66, 24.15, 20.90, 17.55,15.30, 14.83, 7.93, 0.12. The HPLC purity analysis conditions are as follows: Instrument: High-performance liquid chromatograph; Detector: Ultraviolet detector; Column: Waters CORTECS C18, 4.6 mm × 150 mm, 2.7 μm or equivalent column; Mobile phase: Mobile phase A was 1 mmol / L ammonium acetate aqueous solution (adjusted to pH=7.0 with ammonia):acetonitrile = 8:2; Mobile phase B was 1 mmol / L ammonium acetate aqueous solution (adjusted to pH=7.0 with ammonia):acetonitrile = 2:8. Gradient elution procedure:

[0030] Column temperature: 35℃; flow rate: 1.0 mL / min; detection wavelength: 245 nm and 288 nm; injection volume: 5 μL.

[0031] Example 1

[0032] 5 g of 17α,21-dihydroxypregn-4-ene-3,20-dione, 0.56 g of pyridinium trifluoroacetate, and 5 g of triethyl orthopropionate were added to a reaction flask. The mixture was then refluxed and stirred. After the reaction was completed, the mixture was extracted with dichloromethane, washed with water and saturated brine, and concentrated to obtain 5.76 g of the target compound 17α,21-dihydroxypregn-4-ene-3,20-dione-17α,21-ethyl orthopropionate, with a yield of 93.0% and an HPLC purity of 99.0%.

[0033] Example 2

[0034] 5 g of 17α,21-dihydroxypregn-4-ene-3,20-dione, 0.03 g of pyridinium trifluoroacetate (0.01 equivalent), and 5 g of triethyl orthopropionate were added to a reaction flask. The mixture was refluxed and stirred until the reaction was complete. The mixture was then extracted with dichloromethane, washed with water and saturated brine, and concentrated to obtain 5.67 g of the target compound 17α,21-dihydroxypregn-4-ene-3,20-dione-17α,21-ethyl orthopropionate, with a yield of 91.5% and an HPLC purity of 98.3%.

[0035] Example 3

[0036] 5 g of 17α,21-dihydroxypregn-4-ene-3,20-dione, 0.14 g of pyridinium trifluoroacetate (0.05 equivalent), and 5 g of triethyl orthopropionate were added to a reaction flask. The mixture was refluxed and stirred until the reaction was complete. The mixture was then extracted with dichloromethane, washed with water and saturated brine, and concentrated to obtain 5.71 g of the target compound 17α,21-dihydroxypregn-4-ene-3,20-dione-17α,21-ethyl orthopropionate, with a yield of 92.1% and an HPLC purity of 98.5%.

[0037] Example 4

[0038] 5 g of 17α,21-dihydroxypregn-4-ene-3,20-dione, 0.28 g of pyridinium trifluoroacetate (0.1 equivalent), and 5 g of triethyl orthopropionate were added to a reaction flask. The mixture was refluxed and stirred until the reaction was complete. The mixture was then extracted with dichloromethane, washed with water and saturated brine, and concentrated to obtain 5.89 g of the target compound 17α,21-dihydroxypregn-4-ene-3,20-dione-17α,21-ethyl orthopropionate, with a yield of 95.0% and an HPLC purity of 99.4%.

[0039] Example 5

[0040] 5 g of 17α,21-dihydroxypregn-4-ene-3,20-dione, 0.56 g of pyridinium trifluoroacetate (0.2 equivalents), and 5 g of triethyl orthopropionate were added to a reaction flask. The mixture was refluxed and stirred until the reaction was complete. The mixture was then extracted with dichloromethane, washed with water and saturated brine, and concentrated to obtain 5.82 g of the target compound 17α,21-dihydroxypregn-4-ene-3,20-dione-17α,21-ethyl orthopropionate, with a yield of 93.9% and an HPLC purity of 98.9%.

[0041] Example 6

[0042] 5 g of 17α,21-dihydroxypregn-4-ene-3,20-dione, 0.84 g of pyridinium trifluoroacetate (0.3 equivalent), and 5 g of triethyl orthopropionate were added to a reaction flask. The mixture was refluxed and stirred until the reaction was complete. The mixture was then extracted with dichloromethane, washed with water and saturated brine, and concentrated to obtain 5.74 g of the target compound 17α,21-dihydroxypregn-4-ene-3,20-dione-17α,21-ethyl orthopropionate, with a yield of 92.6% and an HPLC purity of 98.7%.

[0043] Example 7

[0044] 5 g of 17α,21-dihydroxypregn-4-ene-3,20-dione, 1.4 g of pyridinium trifluoroacetate (0.5 equivalent), and 5 g of triethyl orthopropionate were added to a reaction flask. The mixture was refluxed and stirred until the reaction was complete. The mixture was then extracted with dichloromethane, washed with water and saturated brine, and concentrated to obtain 5.70 g of the target compound 17α,21-dihydroxypregn-4-ene-3,20-dione-17α,21-ethyl orthopropionate, with a yield of 92.0% and an HPLC purity of 98.7%.

[0045] Example 8

[0046] 5 g of 17α,21-dihydroxypregn-4-ene-3,20-dione, 2.8 g of pyridinium trifluoroacetate (1.0 equivalent), and 5 g of triethyl orthopropionate were added to a reaction flask. The mixture was refluxed and stirred until the reaction was complete. The mixture was then extracted with dichloromethane, washed with water and saturated brine, and concentrated to obtain 5.71 g of the target compound 17α,21-dihydroxypregn-4-ene-3,20-dione-17α,21-ethyl orthopropionate, with a yield of 92.1% and an HPLC purity of 98.5%.

[0047] Example 9

[0048] 150 g of 17α,21-dihydroxypregn-4-ene-3,20-dione, 8.35 g of pyridinium trifluoroacetate, and 152.61 g of triethyl orthopropionate were added to a reaction vessel. The mixture was then dissolved in toluene, refluxed, and stirred. After the reaction was complete, the mixture was extracted with dichloromethane, washed with water, washed with saturated brine, and concentrated to obtain 177.0 g of the target compound, 17α,21-dihydroxypregn-4-ene-3,20-dione-17α,21-ethyl orthopropionate, with a yield of 95.0% and an HPLC purity of 99.5%. HRMS: m / z: [M+H] + 431.2787.

[0049] Example 10

[0050] Add 5g of hydrocortisone, 0.53g of pyridinium trifluoroacetate, and 4.78g of triethyl orthopropionate to a reaction flask. Add toluene to dissolve the compound, reflux and stir. After the reaction is complete, extract with dichloromethane, wash with water and saturated brine, and concentrate to obtain 5.72g of the target compound, with a yield of 92.9% and an HPLC purity of 99.0%.

[0051] Comparative Example 1

[0052] Add 5g of 17α,21-dihydroxypregn-4-ene-3,20-dione to a reaction flask, add 14.4mL of 0.1NHCl and 5g of triethyl orthopropionate, add toluene solvent, reflux and stir, no target compound is formed.

[0053] Comparative Example 2

[0054] 5 g of 17α,21-dihydroxypregn-4-ene-3,20-dione, 0.17 g of acetic acid, and 5 g of triethyl orthopropionate were added to a reaction flask. The mixture was then refluxed and stirred. After the reaction was completed, the mixture was extracted with dichloromethane, washed with water and saturated brine, and concentrated to obtain the target compound 17α,21-dihydroxypregn-4-ene-3,20-dione-17α,21-ethyl orthopropionate with an HPLC purity of 20.47%.

[0055] Comparative Example 3

[0056] 5 g of 17α,21-dihydroxypregn-4-ene-3,20-dione, 0.13 g of formic acid, and 5 g of triethyl orthopropionate were added to a reaction flask. The mixture was then refluxed and stirred. After the reaction was completed, the mixture was extracted with dichloromethane, washed with water and saturated brine, and concentrated to obtain the target compound 17α,21-dihydroxypregn-4-ene-3,20-dione-17α,21-ethyl orthopropionate with an HPLC purity of 34.87%.

[0057] Comparative Example 4

[0058] 5 g of 17α,21-dihydroxypregn-4-ene-3,20-dione, 0.23 g of hydrobromic acid, 5 g of triethyl orthopropionate were added to a reaction flask, and toluene was added to dissolve the compound. The mixture was refluxed and stirred. After the reaction was completed, the compound was extracted with dichloromethane, washed with water and saturated brine, and concentrated to obtain the target compound 17α,21-dihydroxypregn-4-ene-3,20-dione-17α,21-ethyl orthopropionate with an HPLC purity of 57.60%.

[0059] Comparative Example 5

[0060] 5 g of 17α,21-dihydroxypregn-4-ene-3,20-dione, 0.33 g of trifluoroacetic acid, and 5 g of triethyl orthopropionate were added to a reaction flask. Toluene was added to dissolve the compound, and the mixture was refluxed and stirred. After the reaction was completed, the mixture was extracted with dichloromethane, washed with water and saturated brine, and concentrated to obtain 5.58 g of the target compound 17α,21-dihydroxypregn-4-ene-3,20-dione-17α,21-ethyl orthopropionate, with a yield of 90.0% and an HPLC purity of 96.5%.

Claims

1. A method for synthesizing a steroidal drug intermediate, comprising the following steps: In an organic solvent, in the presence of pyridinium trifluoroacetate, the compound shown in Formula A reacts with compound R. 2 C(OR 3 )3 undergoes a cyclization reaction to produce a compound as shown in formula B; ； Wherein, R1 is H or a hydroxyl group; R 2 For H or C 1-4 Alkyl; R 3 C 1-4 alkyl.

2. The method for synthesizing the steroidal drug intermediate as described in claim 1, characterized in that, It satisfies any one or more of the following conditions: (1) R 1 It is H or hydroxyl; (2) R 2 It is H, methyl, or ethyl, for example, R 2 For ethyl; and (3) R 3 It is methyl or ethyl, for example, R 3 It is an ethyl group.

3. The method for synthesizing the steroidal drug intermediate as described in claim 1, characterized in that, It satisfies any one or more of the following conditions: (1) The compound represented by formula A is 17α,21-dihydroxypregn-4-ene-3,20-dione or hydrocortisone; and (2) The compound R 2 C(OR 3 )3 is triethyl orthopropionate, trimethyl orthopropionate, triethyl orthoformate, or triethyl orthoacetate, for example, compound R. 2 C(OR 3 )3 is triethyl propionate.

4. The method for synthesizing the steroidal drug intermediate as described in claim 1, characterized in that, It satisfies any one or more of the following conditions: (1) The molar ratio of the compound represented by formula A to pyridinium trifluoroacetate is 1:(0.001-2); (2) The reaction weight of the compound represented by formula A is at least 150 g; and (3) The compound represented by formula A and compound R 2 C(OR 3 The molar ratio of 3 is 1:(1-10).

5. The method for synthesizing the steroidal drug intermediate as described in claim 1, characterized in that, It satisfies any one or more of the following conditions: (1) The molar ratio of the compound represented by formula A to pyridinium trifluoroacetate is 1:(0.005-1.5); (2) The reaction weight of the compound represented by formula A is at least 500 g; and (3) The compound represented by formula A and compound R 2 C(OR 3 The molar ratio of 3 is 1:(1-5).

6. The method for synthesizing the steroidal drug intermediate as described in claim 1, characterized in that, It meets one or more of the following conditions: (1) The molar ratio of the compound represented by formula A to pyridinium trifluoroacetate is 1:0.01, 1:0.05, 1:0.1, 1:0.2, 1:0.3, 1:0.5 or 1:1; (2) The reaction weight of the compound represented by formula A is at least 1000 g; and (3) The compound represented by formula A and compound R 2 C(OR 3 The molar ratio of 3 is 1:

2.

7. The method for synthesizing the steroidal drug intermediate as described in claim 1, characterized in that, It meets one or more of the following conditions: (1) The organic solvent is a haloalkane solvent or an aromatic hydrocarbon solvent; (2) The cyclization reaction temperature is the temperature at which the system of the reaction is refluxed; and (3) The cyclization reaction includes the following post-processing steps: extraction, washing and concentration.

8. The method for synthesizing the steroidal drug intermediate as described in claim 1, characterized in that, It meets one or more of the following conditions: (1) The organic solvent is dichloromethane or toluene; and (2) The cyclization reaction is carried out at a temperature of 20-50℃ or 100-130℃.

9. The method for synthesizing the steroidal drug intermediate as described in claim 1, characterized in that, The cyclization reaction is carried out at a temperature of 30-40℃ or 110-120℃.

10. The method for synthesizing the steroidal drug intermediate as described in claim 1, characterized in that: The reactants for the cyclization reaction consist of the compound represented by formula A, pyridinium trifluoroacetate, and compound R. 2 C(OR 3 It consists of 3 components.

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