CN111675672A

CN111675672A - Method for preparing astallurens

Info

Publication number: CN111675672A
Application number: CN202010397868.5A
Authority: CN
Inventors: 方瑜; 杜玉民
Original assignee: Shijiazhuang Duzhi Pharmaceutical Technology Co ltd
Current assignee: Shijiazhuang Duzhi Pharmaceutical Technology Co ltd
Priority date: 2020-05-12
Filing date: 2020-05-12
Publication date: 2020-09-18

Abstract

The invention discloses a method for preparing atraurone (Ataluren, PTC124, trade name Translarna), belonging to the field of organic synthesis. Methyl m-cyanobenzoate and hydroxylamine hydrochloride react in lower alcohol or a mixed solvent of the lower alcohol and water to generate 3- (N-hydroxyamidino) -methyl benzoate; o-acylation reaction of methyl 3- (N-hydroxycarbamimidoyl) -benzoate and O-fluorobenzoyl chloride in organic solvent to obtain methyl 3- ((5- (2-fluorophenyl)) -3- (1,2, 4-oxadiazolyl)) -benzoate; carrying out cyclization under the catalytic action of tetraalkylammonium halide to obtain 3- ((5- (2-fluorophenyl)) -3- (1,2, 4-oxadiazolyl)) -methyl benzoate; fourthly, hydrolyzing to obtain the atractylen. The invention is a simple and high-efficiency synthesis method of the astallurens.

Description

Method for preparing astallurens

Technical Field

The invention relates to a method for preparing atraumatic, belonging to the field of organic synthesis.

Background

Attulellan, english name: ataluren, trade name: (Translarna), chemical name: 3- ((5- (2-fluorophenyl)) - (1,2, 4-oxadiazol-3-yl)) -benzoic acid. Is a small molecule oral drug developed by PTC in the united states for the treatment of nonsense-mutated Duchenne muscular dystrophy (Duchenne and Becker) and cystic fibrosis, and is currently marketed in europe and in phase iii in the united states. During translation of mRNA, ribosomes are allowed to pass over the stop codon that appears prematurely in the mRNA, allowing normal genetic information to be read and the synthesis of a fully functional protein. The structure of astallurone is as follows:

in the prior art, the methyl m-cyanobenzoate is generally reacted with hydroxylamine hydrochloride to produce the methyl 3- (N-hydroxyamidino) -benzoate. The ester is subjected to O-acylation reaction with O-fluorobenzoyl chloride to obtain 3- (N- (2-fluorobenzoyloxy) amidino) -methyl benzoate, and cyclization is carried out to obtain 3- ((5- (2-fluorophenyl)) -3- (1,2, 4-oxadiazolyl)) -methyl benzoate. Hydrolyzing under alkaline condition to obtain the alpha-gulen.

The method for synthesizing the atraumatic in the patent CN101535284A comprises the following steps: the method comprises the steps of adopting a one-pot method to prepare alpha-methyl cyanobenzoate as an initial raw material, carrying out a reaction with hydroxylamine hydrochloride, carrying out an O-acylation reaction on O-fluorobenzoyl chloride, cyclizing to obtain 3- ((5- (2-fluorophenyl)) -3- (1,2, 4-oxadiazolyl)) -methyl benzoate, and hydrolyzing under an acidic condition to obtain alpha-lulan. The reaction time was about 63 hours, with 32 hours for the cyclization reaction to proceed, and the overall yield was 67%. The reaction time is long, the intermediate is not separated, and impurities in the final product are complex.

WO2004091502A/US6992096 is similar to CN101535284A, but the reaction is carried out step by step, O-acylation and cyclization are carried out on O-fluorobenzoyl chloride by taking toluene as a solvent, a water separation device is arranged, reflux is carried out for 4 hours at 130 ℃, and then stirring is carried out for 18 hours at 5 ℃.

Laura Lentini, Raffaella Melfi, Aldo Di Leonardo et al published in molecular pharmaceuticals (2014, 11, 653-664) introduced the synthesis of Altaluron by using 3-cyanobenzoyl chloride as raw material, esterification, acylation-cyclization, and catalytic hydrolysis of boron trifluoride as solvent to obtain Altaluron with a total yield of 40%.

There are generally two methods by which the basic parent 1,2, 4-oxadiazole in the molecular structure of arabinls can be obtained. Firstly, the 1, 3-dipolar cycloaddition between cyano group of nitrile compound and cyano oxide is difficult to obtain raw material, the specificity of reaction is poor, and the product is complex. Another method is the cyclization of aminooxime derivatives. Aminooxime derivatives are readily prepared by reacting a cyano group with hydroxylamine followed by acylation with carboxylic acids and their derivatives. Therefore, the latter method is often used for the synthesis of astallurens.

The existing synthetic technical route of the atralon is analyzed, so that the amino oxime derivative synthesized in the first step and the second step is relatively mature reaction, and the yield is relatively high. The cyclization reaction is the technical key of the whole synthesis process. The reaction type of the step belongs to nucleophilic addition-elimination reaction, the reaction speed is low, the efficiency is low along with the rise of the reaction temperature and the extension of the reaction time, the purification is not easy, and the side products generated by cyclization with the amino oxime are increased, so that the yield and the purity of the final product are influenced. The invention adopts the catalyst to catalyze and make the cyclization reaction of the amidoxime O-acylated derivative easy to carry out.

Disclosure of Invention

The invention aims to solve the technical problem of providing a method for preparing the atraumatic, and the invention is a simple and efficient atraumatic synthesis method.

The technical scheme adopted by the invention is as follows: a method of preparing artoluron, comprising the steps of:

(1) adding methyl m-cyanobenzoate and hydroxylamine hydrochloride into a low molecular alcohol or a low molecular alcohol aqueous solution, and reacting in the presence of alkali to generate 3- (N-hydroxyamidino) -methyl benzoate;

(2) putting the ester obtained in the step (1) and O-fluorobenzoyl chloride into an organic solvent for O-acylation reaction to obtain 3- (N- (2-fluorobenzoyloxy) amidino) -methyl benzoate;

(3) cyclizing the ester obtained in the step (2) under the action of a quaternary ammonium salt catalyst to obtain 3- ((5- (2-fluorophenyl)) -3- (1,2, 4-oxadiazolyl)) -methyl benzoate;

(4) hydrolyzing the ester obtained in the step (3) under an alkaline condition to obtain the aliskiren.

Preferred catalysts are quaternary ammonium salts of the formula R₄N⁺X^-R is C₁-C₁₆In chain hydrocarbon radicals

And X is one of Cl, Br, I or F.

The preferred catalyst is one of quaternary ammonium salts tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide or tetrabutylammonium fluoride.

The preferred catalyst is the quaternary ammonium salt tetrabutylammonium fluoride.

The preferred lower alcohol is one of methanol, ethanol or isopropanol.

The preferable molar ratio of the catalyst to the methyl m-cyanobenzoate is 0.05-1: 1.

In a preferable mixed solvent of lower alcohol and water, the ratio of alcohol to water is 10-1: 1.

The preferred base is one of sodium carbonate, potassium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, triethylamine or diisopropylethylamine.

The preferable organic solvent is one of dichloromethane, tetrahydrofuran, dimethylformamide, acetonitrile, ethylene glycol dimethyl ether or acetone.

In the preparation process of the important intermediate 3- ((5- (2-fluorophenyl)) -3- (1,2, 4-oxadiazolyl)) -methyl benzoate of the alpha-toluron, methyl m-cyanobenzoate is used as a raw material to react with hydroxylamine hydrochloride to generate the methyl 3- (N-hydroxyamidino) -benzoate. Followed by O-acylation with O-fluorobenzoyl chloride to give methyl 3- (N- (2-fluorobenzoyloxy) amidino) -benzoate. At room temperature, the methyl 3- ((5- (2-fluorophenyl)) -3- (1,2, 4-oxadiazolyl)) -benzoate is obtained through catalytic cyclization. Hydrolyzing under alkaline condition to obtain the alpha-gulen.

The synthetic route is as follows:

adopt the produced beneficial effect of above-mentioned technical scheme to lie in: the method is simple and efficient, and can obviously shorten the reaction time on the premise of ensuring the product yield. The total yield of the preparation method of the atractylen can reach 68%, and the purity of the prepared atractylen can reach more than 99.0% after once crystallization.

The specific implementation mode is as follows:

preparation of methyl 3- (N-hydroxycarbamimidoyl) -benzoate

(1) Methyl m-cyanobenzoate (80.1 g, 0.5 mol) in ethanol (800 mL) was added hydroxylamine hydrochloride (68.5 g, 1.0 mol) and sodium ethoxide (68.05 g, 1.0 mol). The reaction was stirred at room temperature for 20 h and the solvent was evaporated under reduced pressure. Ethyl acetate (500 mL) was added to the residue, which was filtered and evaporated under reduced pressure to give a crude product, which was slurried with water, filtered and dried to give 92.5 g of methyl 3- (N-hydroxycarbamimidoyl) -benzoate as a white solid with a yield of 95% and mp.101-102.1 ℃. MS (M/z): 195[ M + H]⁺。

¹H-NMR(400 MHz，DMSO-d ₆)： 9.83 (s，1H)，8.41 (d，1H；J= 0.9 Hz)，8.01(t，1H；J= 7.5 Hz)，7.56 (t，1H；J= 7.5 Hz)，6.02 (s，2H)，3.95 (s，3H)。

(2) Methyl m-cyanobenzoate (12 g, 74.4 mmol) was dissolved in methanol (240 mL), and hydroxylamine hydrochloride (12.8 g, 186 mmol) was added with stirring. A solution of sodium methoxide (11.8 g, 186 mmol) in methanol (240 mL) was added dropwise to the reaction mixture, the mixture was reacted at room temperature for 20 hours, methanol was distilled off under reduced pressure, ethyl acetate (300 mL) was added, the mixture was filtered, and ethyl acetate was distilled off under reduced pressure to obtain a crude product, which was slurried with water, filtered, and dried to obtain methyl 3- (N-hydroxycarbamimidoyl) -benzoate as a white solid in a yield of 87%.

(3) Hydroxylamine hydrochloride (32.1 g, 0.468 mol) and sodium carbonate (32.6 g, 0.31 mol) were added to a solution of methyl m-cyanobenzoate (50.0 g, 0.31 mol) in ethanol (500 mL), stirred at room temperature, water (200 mL) was added, and stirring was continued for 16 h. The reaction mixture was poured into 500mL of ice water, filtered to give the crude product, which was recrystallized from ethyl acetate-N-hexane to give methyl 3- (N-hydroxycarbamimidoyl) -benzoate as a white solid, 43.95g, 73%.

Preparation of methyl 3- (N-2-fluorobenzoyloxyamidyl) benzoate

(1) 3- (N-hydroxycarbamimidoyl) -benzoic acid methyl ester (120 g, 620 mmol) is dissolved in anhydrous tetrahydrofuran (400 mL), diisopropylethylamine (150 mL, 868 mmol) is added, 2-fluorobenzoyl chloride (96.2 mL, 806 mmol) is added dropwise at 5 deg.C, the mixture is stirred at room temperature for 1h, filtered, concentrated under reduced pressure, the residue is dissolved in ethyl acetate (800 mL), washed with water (250 mL × 3), dried over anhydrous sodium sulfate, the solvent is evaporated under reduced pressure and recrystallized from ethyl acetate and N-hexane (6: 4) to give a white solid, 3- (N-2-fluorobenzoyloxyamidino) benzoic acid methyl ester 175g, 89.2%.¹H-NMR(400 MHz，CDCl₃)： 8.18（1H），8.03（2H），7.48（2H），7.18（2H），5.61（2H），3.82（3H）。

(2) Methyl 3- (N-hydroxycarbamimidoyl) -benzoate (10 g, 51.5 mmol) was dissolved in acetone (180 mL), stirred at room temperature, potassium carbonate (8.55 g, 61.87 mmol) and o-fluorobenzoyl chloride (9.81 g, 61.87 mmol) were added, stirred at room temperature for 1h, and acetone was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (80 mL), washed with water (25 mL. times.3), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate and N-hexane (6: 4) to give a white solid, methyl 3- (N-2-fluorobenzoyloxyamidino) benzoate 14 g, 86.2%.

Preparation of fluorophenyl)) -3- (1,2, 4-oxadiazolyl)) -methyl benzoate

Methyl 3- (N-2-fluorobenzoyloxyamidyl) benzoate (63.5g, 0.2 mol) was dissolved in THF (500 mL) and tetrabutylammonium fluoride (1 mol/L in THF, 20 mL, 0.02 mol) was added dropwise at room temperature and stirred for 24 h. The mixture was poured into ethyl acetate, and washed with water and saturated brine, respectively. Drying with anhydrous sodium sulfate, decompressing to obtain a solvent, and recrystallizing with ethyl acetate-n-hexane to obtain 54.28g of white solid 3- ((5- (2-fluorophenyl)) -3- (1,2, 4-oxadiazolyl)) -methyl benzoate and 91 percent. mp.133.8-136.4 ℃. MS (M/z) 299[ M + H ] +.

¹H-NMR (400 MHz，DMSO-d ₆): 8.78 (t，1H，J= 1.8 Hz)，8.31 (dt，1H，J ₁=7.8 Hz，J ₂= 1.4 Hz)，8.18−8.12 (m，2H)，7.59−7.52 (m，2H)，7.32−7.20 (m，2H)，3.91(s，3H)。

Preparation of fluorophenyl)) -3- (1,2, 4-oxadiazolyl)) -benzoic acid

Methyl 3- ((5- (2-fluorophenyl)) -3- (1,2, 4-oxadiazolyl)) -benzoate (80 g, 0.268 mol) was added to a tetrahydrofuran-water (2: 1) mixed solvent (800 mL), lithium hydroxide (38.5 g) was added, the mixture was stirred at room temperature for 24 hours, the solvent was evaporated under reduced pressure, water was added for dilution, acidification was performed with hydrochloric acid to precipitate a white precipitate, and filtration and drying were performed to obtain 63.8 g, 88% of 3- ((5- (2-fluorophenyl)) -3- (1,2, 4-oxadiazolyl)) -benzoic acid as a white solid. mp.239.5-241.6 ℃. And (3) HPLC detection result: chemical purity of 99.8%, SunFere^TMC₁₈Chromatography column (150 mm × 4.6.6 mm, 5 μ M) with mobile phase of acetonitrile-0.1% formic acid (50: 50), MS (M/z): 285[ M + H]+。¹H-NMR (400 MHz，DMSO-d ₆) : 7.51(t，2H，Ar，J= 8.9 Hz)，7.56(d，2H，Ar，J= 8.8Hz)，8.07(m，1H，Ar)，8.17-8.34 (d，2H，Ar，J= 8.9Hz)，8.68 (s，1H，Ar)，13.36 (brs，1 H，OH)。

Claims

1. A method for preparing atraulon, which is characterized by comprising the following steps:

(1) adding methyl m-cyanobenzoate and hydroxylamine hydrochloride into lower alcohol or a mixed solvent of the lower alcohol and water, and reacting under an alkaline condition to generate methyl 3- (N-hydroxycarbamimidoyl) -benzoate;

(2) dissolving the methyl 3- (N-hydroxycarbamimidoyl) -benzoate obtained in the step (1) and o-fluorobenzoyl chloride in an organic solvent

Carrying out O-acylation reaction in a medium to obtain 3- ((5- (2-fluorophenyl)) -3- (1,2, 4-oxadiazolyl)) -methyl benzoate;

(3) under the catalytic action of tetraalkylammonium halide, 3- ((5- (2-fluorophenyl)) -3- (1,2,4-

Oxadiazolyl)) -benzoic acid methyl ester;

(4) 3- ((5- (2-fluorophenyl)) -3- (1,2, 4-oxadiazolyl)) -methyl benzoate are hydrolyzed to obtain the aliskiren.

2. The process for preparing arturin according to claim 1, characterized in that said tetrahydrocarbon is

Based on the formula of the ammonium halide catalyst R₄N⁺X^-R is C₁～C₁₆One or more than two kinds of chain alkyl, X is one of Cl, Br, I or F.

3. The method for preparing attulellan according to claim 2, wherein the quaternary ammonium salt catalyst is one of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide or tetrabutylammonium fluoride.

4. The method for preparing attulellan according to claim 3, wherein the quaternary ammonium salt catalyst is tetrabutylammonium fluoride.

5. The method for preparing aliskiren according to claim 1, wherein the lower alcohol is one of methanol, ethanol, or isopropanol.

6. The method for preparing atralone according to claim 1, wherein the molar ratio of the catalyst to the methyl m-cyanobenzoate is 0.05-1: 1.

7. The method for preparing arturin according to claim 1, wherein the lower alcohol is water

The ratio of the alcohol to the water in the mixed solvent of (1) to (10).

8. A process according to claim 1, wherein the base used is an alkali

Sodium carbonate, potassium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, triethylamine

Or diisopropylethylamine.

9. A process for preparing aliskiren according to claim 1, wherein the organic solvent used is

The medium is one of dichloromethane, tetrahydrofuran, dimethylformamide, acetonitrile, ethylene glycol dimethyl ether or acetone.