CN110734443B - Preparation method of tadalafil-related substance I - Google Patents

Preparation method of tadalafil-related substance I Download PDF

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Publication number
CN110734443B
CN110734443B CN201911226277.5A CN201911226277A CN110734443B CN 110734443 B CN110734443 B CN 110734443B CN 201911226277 A CN201911226277 A CN 201911226277A CN 110734443 B CN110734443 B CN 110734443B
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tadalafil
organic solvent
related substance
acid
preparation
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CN110734443A (en
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崔波
肖光林
黄超民
严紫薇
邓祥林
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Chongqing Liujiang Pharmatech Co ltd
Zhien Biotechnology Co ltd
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Chongqing Liujiang Pharmatech Co ltd
Zhien Biotechnology Co ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00
    • C07D487/12Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/20Spiro-condensed systems

Abstract

The invention discloses a preparation method of tadalafil related substance I. The preparation method takes tadalafil as a starting material, and the tadalafil and peroxy acid undergo oxidation reaction in an organic solvent, and the tadalafil related substance I is obtained through alkali rearrangement and column chromatography purification.

Description

Preparation method of tadalafil-related substance I
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a tadalafil related substance I.
Background
Chemical name of Tadalafil (Tadalafil): (6R,12aR) -6- (1, 3-benzodioxolan-5-yl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione, having the following structural formula:
tadalafil, a phosphodiesterase v (PDE-5) inhibitor, was marketed in the united states in 2003 under the trade name sielier (Cialis) and is a drug used for the treatment of male Erectile Dysfunction (ED). Compared with other anti-ED medicaments, tadalafil has quick response and longest duration of efficacy, and is the only medicament which is not influenced by high fat diet and alcohol intake in the four anti-ED medicaments at present. In addition to the ED indications, tadalafil was approved for Pulmonary Arterial Hypertension (PAH) 5 months in 2009 followed by Benign Prostatic Hyperplasia (BPH) 10 months in 2011.
Tadalafil has been collected in pharmacopoeias such as USP, EP, BP, etc., EP9.0 contains nine tadalafil-related substances: A. b, C, D, E, F, G, H, I are provided. Only two documents currently report methods for preparing tadalafil-related substance I: CN109796461A reports a method for obtaining a tadalafil-related substance I through peroxidation rearrangement of tadalafil in N-halogenated diimide, glacial acetic acid, tetrahydrofuran and a water system, wherein the method has relatively long reaction time, a large amount of sodium carbonate is required for neutralizing glacial acetic acid in post-treatment, and the yield is low; the paper (qianpeng flying, "synthesis of tadalafil and related substance research [ D ], suzhou university, 2016) mentioned a process for preparing tadalafil related substance I by oxidation of D-tryptophan methyl ester hydrochloride, with a total yield of only 11.7% in 4 steps. Therefore, it is necessary to develop a synthetic method which is simple and feasible. The tadalafil related substance I has the following structural formula:
disclosure of Invention
The invention provides a preparation method of a tadalafil related substance I, which has the advantages of easily obtained raw materials, simple operation and high product purity and provides a high-quality impurity reference substance for the quality research of tadalafil.
The invention provides a preparation method of a tadalafil related substance I, which comprises the following steps:
(1) the tadalafil reacts with peroxy acid in an organic solvent 1, and is quenched by a reducing agent and concentrated to obtain a compound shown as a formula II;
(2) dissolving the compound shown in the formula II obtained in the step (1) in an organic solvent 2 to react with alkali for rearrangement, and concentrating and extracting reaction liquid to obtain crude products of tadalafil related substances I;
(3) and (3) purifying the crude product of the tadalafil related substance I obtained in the step (2) to obtain the tadalafil related substance I.
In the above preparation method, wherein the reaction of steps (1) and (2) may be monitored by TLC.
In the above preparation method, the organic solvent 1 in the step (1) is one or more of dichloromethane, chloroform, carbon tetrachloride and tetrahydrofuran, preferably, dichloromethane. The peroxy acid is peroxyacetic acid, peroxytrifluoroacetic acid, peroxybenzoic acid, 3-chloroperoxybenzoic acid or peroxysulfuric acid, and preferably is 3-chloroperoxybenzoic acid. The reducing agent is: sodium thiosulfate, sodium sulfite, or dimethyl sulfide.
In the preparation method, the reaction temperature of the reaction in the step (1) is-30-40 ℃, and the reaction is preferably 15-30 ℃; the reaction time is 5 minutes to 1.5 hours.
In the above preparation method, the organic solvent 2 in step (2) is one or more of ethanol, isopropanol, n-butanol and methanol, preferably methanol. The alkali is one or more of sodium ethoxide, sodium methoxide, sodium hydroxide and potassium hydroxide, and preferably sodium methoxide.
In the preparation method, the reaction temperature of the reaction in the step (2) is 30-85 ℃, and the reaction time is 10 minutes-2 hours.
In the above preparation method, the purification in step (3) is a column chromatography purification method, and elution is performed using a single solvent or a mixed solvent of ethyl acetate, petroleum ether, n-hexane, n-heptane, dichloromethane, methanol, and the like.
The invention has the advantages that: the preparation method of the tadalafil related substance I is brand new, raw materials are easy to obtain, the operation is simple, the product purity is high, and a high-quality impurity reference substance is provided for tadalafil quality research.
The specific implementation mode is as follows:
the invention will be further illustrated with reference to the following examples for better understanding of the contents of the invention in its version, without however limiting the invention in any way.
Example 1
A50 ml three-necked flask was charged with 10ml of dichloromethane, 390mg of tadalafil and 224mg of 3-chloroperoxybenzoic acid, reacted at room temperature for 40min, and monitored by TLC (dichloromethane/methanol, 10: 1). After the reaction, 1ml of dimethyl sulfide was added dropwise to quench, and the organic layer was concentrated to dryness under reduced pressure to obtain a concentrate (a compound represented by formula II).
The concentrate was dissolved in 20ml of 1M sodium methoxide/methanol solution, heated at reflux for 40min and monitored by TLC (dichloromethane/methanol, 10: 1). After the reaction is finished, concentrating under reduced pressure to remove the methanol, adding water/ethyl acetate for extraction, and concentrating the organic layer under reduced pressure to be dry to obtain a crude product of the tadalafil related substance I.
And (3) purifying the crude product by using a 300-400-mesh silica gel column chromatography, wherein an eluent is dichloromethane, methanol and 10:1, and the tadalafil related substance I is 310mg, the yield is 59.5%, and the HPLC purity is 96.4%.
Example 2 was carried out:
10ml of chloroform, 390mg of tadalafil and 193mg of perbenzoic acid were added to a 50ml three-necked flask, and the mixture was reacted at room temperature for 60min with TLC monitoring (dichloromethane/methanol, 10: 1). After the reaction is finished, 5ml of 5% sodium thiosulfate is dripped at 0-5 ℃ for quenching, liquid separation is carried out, 5ml of saturated sodium bicarbonate is extracted and washed in an organic layer, and the organic layer is decompressed and concentrated to be dry, so that a concentrate (the compound shown in the formula II) is obtained.
The concentrate was dissolved in 20ml of 1M sodium ethoxide/ethanol solution, heated to reflux for 60min and monitored by TLC (dichloromethane/methanol, 10: 1). After the reaction is finished, concentrating under reduced pressure to remove ethanol, adding water/ethyl acetate for extraction, and concentrating the organic layer under reduced pressure to be dry to obtain a crude product of the tadalafil related substance I.
And (3) purifying the crude product by using a 300-400-mesh silica gel column chromatography, wherein an eluent is ethyl acetate and n-hexane which is 1:1, 295mg of tadalafil related substance I is obtained, the yield is 56.7%, and the HPLC purity is 95.6%.
Example 3 of implementation:
a50 ml three-necked flask was charged with 10ml of tetrahydrofuran, 390mg of tadalafil and 336mg of peroxosulfuric acid, and reacted at room temperature for 60min with TLC monitoring (dichloromethane/methanol, 10: 1). After the reaction is finished, 5ml of 5% sodium sulfite is dripped at 0-5 ℃ for quenching, liquid separation is carried out, 5ml of saturated sodium bicarbonate is extracted and washed in an organic layer, and the organic layer is decompressed and concentrated to be dry, so as to obtain a concentrate (the compound shown in the formula II).
The concentrate was dissolved in 20ml of 1M sodium methoxide/methanol solution, heated to reflux for 40min and monitored by TLC (dichloromethane/methanol, 10: 1). After the reaction is finished, concentrating under reduced pressure to remove the methanol, adding water/ethyl acetate for extraction, and concentrating the organic layer under reduced pressure to be dry to obtain a crude product of the tadalafil related substance I.
And (3) purifying the crude product by silica gel column chromatography with 300-400 meshes, wherein an eluent dichloromethane and methanol are 10:1, so that the tadalafil related substance I is 235mg, the yield is 45.1%, and the HPLC purity is 97.0%.
The detection conditions for HPLC were as follows:
chromatographic conditions are as follows: a flow chromatography column: c8250mm X4.6 mm 5 μm packing L7
Mobile phase A: taking 1ml of trifluoroacetic acid, and adding water to dilute the trifluoroacetic acid to 1000 ml; mobile phase B of acetonitrile
Column flow rate: 1.0ml/min detection wavelength: 285nm
Sample introduction amount: 20 μ l column temperature: 40 deg.C
Diluent agent: acetonitrile-mobile phase a ═ 1:1 mobile phase: linear gradient elution:

Claims (2)

1. the preparation method of the tadalafil-related substance I comprises the following steps:
(1) the tadalafil reacts with peroxy acid in an organic solvent 1, and is quenched by a reducing agent and concentrated to obtain a compound shown as a formula II;
(2) dissolving the compound shown in the formula II obtained in the step (1) in an organic solvent 2 to react with alkali for rearrangement, and concentrating and extracting reaction liquid to obtain crude products of tadalafil related substances I;
(3) purifying the crude product of the tadalafil related substance I obtained in the step (2) by column chromatography to obtain a tadalafil related substance I; wherein the organic solvent 1 in the step (1) is dichloromethane; the peroxy acid is 3-chloroperoxybenzoic acid; the reducing agent is dimethyl sulfide; or, the organic solvent 1 in the step (1) is chloroform; the peroxy acid is peroxybenzoic acid; the reducing agent is sodium thiosulfate; alternatively, the organic solvent 1 in the step (1) is tetrahydrofuran; said peroxyacid is peroxysulfuric acid; the reducing agent is sodium sulfite;
the reaction temperature in the step (1) is 15-30 ℃;
the reaction time in the step (1) is as follows: 5 minutes to 1.5 hours;
the alkali in the step (2) is sodium methoxide; the organic solvent 2 is methanol;
the reaction temperature in the step (2): 30-85 ℃;
the reaction time in the step (2) is as follows: 10 minutes to 2 hours.
2. The preparation method according to claim 1, wherein the column chromatography purification method of step (3) is eluted using a single solvent or a mixture of any two solvents selected from ethyl acetate, petroleum ether, n-hexane, n-heptane, dichloromethane and methanol.
CN201911226277.5A 2019-12-04 2019-12-04 Preparation method of tadalafil-related substance I Active CN110734443B (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017165738A1 (en) * 2016-03-25 2017-09-28 The Trustees Of Columbia University In The City Of New York Mitragynine alkaloids as opioid receptor modulators
CN109053724A (en) * 2018-08-22 2018-12-21 上海青平药业有限公司 The purification process and purposes of the preparation method and Tadalafei of a kind of impurity prepared during Tadalafei and the impurity
CN109796461A (en) * 2018-12-30 2019-05-24 杭州康本医药科技有限公司 A kind of preparation process of Tadalafei impurity I

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017165738A1 (en) * 2016-03-25 2017-09-28 The Trustees Of Columbia University In The City Of New York Mitragynine alkaloids as opioid receptor modulators
CN109053724A (en) * 2018-08-22 2018-12-21 上海青平药业有限公司 The purification process and purposes of the preparation method and Tadalafei of a kind of impurity prepared during Tadalafei and the impurity
CN109796461A (en) * 2018-12-30 2019-05-24 杭州康本医药科技有限公司 A kind of preparation process of Tadalafei impurity I

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
他达拉非的合成及有关物质研究;钱彭飞;《中国优秀硕士学位论文全文数据库》;20160115(第01期);正文第35页 *

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