CN116199637A - Preparation method of deferasirox - Google Patents

Abstract

The invention provides a preparation method of deferasirox, which comprises the following steps: the method comprises the steps of carrying out esterification reaction on aminobenzoic acid and 2-trisilylethanol, carrying out diazotization reaction on an obtained compound INT-1 and sodium nitrite in an acidic aqueous solution system to generate a diazonium salt intermediate, carrying out reduction reaction on the diazonium salt intermediate, carrying out cyclization reaction on the obtained phenylhydrazine compound INT-2 and 2- [2- (benzyloxy) phenyl ] -4H-benzo [ e ] [1,3] oxazin-4-one to obtain a compound INT-3, carrying out catalytic hydrogenation deprotection reaction, and then carrying out deprotection reaction in the presence of tetrabutylammonium fluoride to obtain deferaside. The preparation method disclosed by the invention is mild in condition, easy in raw material acquisition, low in cost and suitable for industrial production, application and popularization.

Description

Preparation method of deferasirox

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a preparation method of deferasirox.

Background

Deferasirox (Deferasirox), chemical name 4- [3, 5-di (2-hydroxyphenyl) -1H-1,2, 4-triazol-1-yl ] benzoic acid, trade name Exjade, is a novel iron ion chelating agent researched and developed by the pharmaceutical company of northwest, and can effectively improve the excretion of iron, reduce the content of iron in vivo and reduce tissue damage and functional damage of a plurality of organs caused by iron overload through combining with iron ions in vivo. Deferasirox is the first orally available iron-expelling agent approved by the U.S. FDA, the FDA awarding its orphan status for the treatment of iron overload in non-transfusion dependent thalassemia, deferasirox was approved in the european union for the treatment of chronic iron overload in non-transfusion dependent thalassemia syndrome patients over 10 years in need of chelation therapy due to contraindicated or insufficient administration of deferasirox mesylate, and has been currently marketed in more than 80 countries.

Regarding the preparation method of deferasirox, patent nos. WO2008094617, WO2009094956, WO2011070560 and WO2012131017 have reported that various process route methods are that a benzoxazolone intermediate or a benzoxazolone intermediate with a protecting group is prepared first and then reacted with 4-carboxyphenylhydrazine, and a ring opening rearrangement mechanism is involved to obtain deferasirox:

for example, salicylic acid is used as a raw material, thionyl chloride is used to obtain salicyloyl chloride, and the salicyloyl chloride and salicylamide are subjected to dehydration condensation and cyclization at a high temperature of 170 ℃ to obtain a benzoxazolone intermediate:

salicylic nitrile or benzyl protected salicylic nitrile, treated with methanolic hydrogen chloride solution, can give methyl o-benzyloxybenzimido acid, which dehydrates and cyclizes with salicyl chloride to give benzyl protected benzoxazolone intermediate:

if salicylic acid is used as a raw material to react with p-toluenesulfonyl chloride to generate mixed anhydride, and then the mixed anhydride is dehydrated and cyclized with salicylamide, the benzoxazolone intermediate is also obtained:

in the prior art, the quality control and the yield of the intermediate are both relatively difficult, and the 4-carboxyphenylhydrazine and the benzoxazolone intermediate have more reaction sites, so that various side reactions are generated, and complex reactions and process parameter control are required to be established, which is not beneficial to impurity control and production implementation of bulk drugs.

Aiming at the defects and the shortcomings existing in the prior art, the preparation technology of the deferasirox with concise process, economy and environmental protection is sought, and particularly, the process scheme which can adapt to industrial production is sought, thus having important practical significance for improving the economic and social benefits of the variety.

Disclosure of Invention

The invention aims to provide a preparation method of deferasirox, which has mild process conditions, is beneficial to controlling side reactions and impurity generation, improves yield, reduces preparation cost, and is efficient, green and environment-friendly so as to meet the requirement of industrial scale-up production.

The invention adopts the technical scheme that:

synthetic route of deferasirox:

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the preparation method of the deferasirox comprises the following specific steps:

(1) Carrying out esterification reaction on the para aminobenzoic acid and 2-trimethylsilyl ethanol to obtain a compound INT-1;

(2) Diazotizing a compound INT-1 and sodium nitrite in an acidic aqueous solution system to generate a diazonium salt intermediate, and carrying out a reduction reaction to obtain a phenylhydrazine compound INT-2;

(3) The phenylhydrazine compound INT-2 and 2- [2- (benzyloxy) phenyl ] -4H-benzo [ e ] [1,3] oxazin-4-one undergo a cyclization reaction in a solvent system to obtain a compound INT-3;

(4) Carrying out catalytic hydrogenation deprotection reaction on the compound INT-3 to obtain a compound INT-4;

(5) The compound INT-4 is subjected to deprotection reaction in the presence of tetrabutylammonium fluoride to obtain deferasirox.

Preferably, the molar ratio of the para-aminobenzoic acid to the 2-trimethylsilyl ethanol in the step (1) is 1:1.2-1.6;

preferably, the esterification reaction is carried out in the presence of a sulfonic acid derivative;

preferably, the sulfonic acid derivative is any one or a combination of at least two of p-toluenesulfonic acid, methanesulfonic acid, p-dodecylbenzenesulfonic acid, benzenesulfonic acid, 2,4, 6-triisopropylbenzenesulfonic acid or m-nitrobenzenesulfonic acid;

preferably, the molar ratio of the sulfonic acid derivative to the para-aminobenzoic acid is 0.005-0.05:1;

preferably, the solvent of the esterification reaction in the step (1) is one or a combination of toluene and xylene;

preferably, the temperature of the esterification reaction is 90-110 ℃ and the reaction time is 2-6 hours.

Preferably, the molar ratio of the compound INT-1 to the sodium nitrite in the step (2) is 1:1-1.1;

preferably, the reducing agent used in the reduction reaction is sodium sulfite;

preferably, the molar ratio of sodium sulfite to compound INT-1 is 3-5:1;

preferably, the temperature of the diazotization reaction is between-5 and 5 ℃ and the reaction time is between 0.5 and 1 hour;

preferably, the temperature of the reduction reaction is 70-90 ℃ and the reaction time is 2-6 hours.

Preferably, the molar ratio of phenylhydrazine compound INT-2 to 2- [2- (benzyloxy) phenyl ] -4H-benzo [ e ] [1,3] oxazin-4-one in step (3) is from 1:1 to 1.05;

preferably, the solvent is any one or a combination of at least two of ethanol, methanol, isopropanol, n-propanol, n-butanol or isobutanol;

preferably, the temperature of the cyclization reaction is 50-100 ℃ and the reaction time is 3-12 hours.

Preferably, the catalytic hydrogenation deprotection reaction in the step (4) is to react a compound INT-3 with hydrogen under the condition that palladium-carbon is used as a catalyst to obtain a compound INT-4;

preferably, the solvent for the catalytic hydrogenation deprotection reaction in the step (4) is any one or at least two of methanol, ethanol or isopropanol;

preferably, the temperature of the catalytic hydrogenation deprotection reaction is 30-60 ℃ and the time is 6-12 hours;

preferably, the catalytic hydrogenation deprotection reaction of step (4) is carried out at normal pressure.

Preferably, the molar ratio of tetrabutylammonium fluoride to compound INT-4 of step (5) is from 2 to 5:1;

preferably, the solvent for the deprotection reaction of step (5) is any one or a combination of at least two of tetrahydrofuran, methyl tert-butyl ether, 1, 4-dioxane or acetonitrile;

preferably, the temperature of the deprotection reaction in the step (5) is 40-80 ℃ and the reaction time is 2-6 hours.

As a preferable technical scheme, the preparation method of the deferasirox comprises the following steps:

(1) In the presence of sulfonic acid derivatives, carrying out esterification reaction on p-aminobenzoic acid and 2-trimethylsilyl ethanol at the molar ratio of 1:1.2-1.6 at the temperature of 90-110 ℃ for 2-6 hours to obtain a compound INT-1;

(2) In an acidic aqueous solution system, diazotizing a compound INT-1 and sodium nitrite for 0.5-1 hour at a temperature of between 5 ℃ below zero and 5 ℃ in a molar ratio of 1:1-1.1 to obtain a diazonium salt solution; adding pre-cooled sodium sulfite aqueous solution, heating to 70-90 ℃, and reacting for 2-6 hours to obtain phenylhydrazine compound INT-2

(3) The cyclization reaction of the phenylhydrazine compound INT-2 and 2- [2- (benzyloxy) phenyl ] -4H-benzo [ e ] [1,3] oxazin-4-one is carried out for 3-12 hours in a solvent system at 50-100 ℃, and the molar ratio of the phenylhydrazine compound INT-2 to the 2- [2- (benzyloxy) phenyl ] -4H-benzo [ e ] [1,3] oxazin-4-one is 1:1-1.05, so as to obtain a compound INT-3;

(4) Under the condition of taking palladium-carbon as a catalyst, carrying out catalytic hydrogenation deprotection reaction with hydrogen to obtain a compound INT-4;

(5) Deprotection of the compound INT-4 in the presence of tetrabutylammonium fluoride at 40-80℃for 2-6 hours afforded deferasirox.

According to the technical scheme, firstly, the low-cost and easily available para-aminobenzoic acid and 2-trimethylsilyl ethanol are used for carrying out esterification reaction, namely carboxyl is protected, diazotization and reduction are carried out in the next step to obtain phenylhydrazine compound INT-2, and then cyclization reaction is carried out to construct triazole mother nucleus, and as carboxylate radicals are extremely easy to produce side reaction, the carboxyl is protected at first, the whole synthesis process is relatively concise, and the reaction condition is relatively mild. Compared with the prior art, the invention has the following beneficial effects: the process condition is mild, toxic impurities and process impurities are avoided, and the quality control of the deferasirox bulk drug is facilitated; the method has the advantages of easy obtainment of the raw materials of the reagents used in the process route, higher yield, reasonable technical scheme, environmental friendliness, contribution to industrialized popularization and capability of mass production to meet the use requirements.

Detailed Description

The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.

Example 1:

(1) Preparation of Compound INT-1:

para aminobenzoic acid (10 g,72.9 mmol), 2-trimethylsilylethanol (11 g,93 mmol) and p-toluenesulfonic acid (0.1 g,0.6 mmol) are dissolved in toluene (200 mL), the temperature is raised to 110 ℃ for reaction for 2h, the organic solvent is removed by decompression concentration, dichloromethane extraction, common salt water washing, anhydrous sodium sulfate drying and decompression rotary evaporation to dryness are carried out, and the compound INT-1 (15 g) is obtained, the yield is 87 percent, and the HPLC purity is 95.6 percent; ¹ H NMR(400MHz,CDCl ₃ )δ0.07(s,9H),1.10(m,2H),4.07(br s,2H,NH),4.36,(m,2H),6.62(d,J＝8.6Hz,2H),7.84(d,J＝8.7Hz,2H)；EI-MS m/z:238[M+H] ⁺ 。

(2) Preparation of phenylhydrazine Compound INT-2:

compound INT-1 ]15g,63.2 mmol) and water (15 mL) are mixed and stirred, cooled to-5 ℃, concentrated hydrochloric acid (15 mL) is added, sodium nitrite (4.4 g,63.8 mmol) solution (10 mL) is added dropwise, stirring is carried out for 0.5h at-5 ℃, sodium sulfite (24 g,0.19 mol) solution (100 mL) is slowly added dropwise, the temperature is raised for 70 reaction for 6h, phenylhydrazine compound INT-2 (14 g) is obtained after acidification, crystallization, suction filtration and vacuum drying, the yield is 88%, EI-MS m/z:253[ M+H ]] ⁺ 。

(3) Preparation of Compound INT-3:

phenylhydrazine compound INT-2 (14 g,55.5 mmol), 2- [2- (benzyloxy) phenyl]-4H-benzo [ e ]][1,3]Oxazin-4-one (18.5 g,56.2 mmol) was dissolved in ethanol (150 mL), reacted at 80℃for 9h, cooled for 3h to crystallize, suction filtered, the filter cake was washed with frozen ethanol (50 mL), ethanol-water recrystallized, and vacuum dried to give compound INT-3 (28 g), yield 90%, EI-MS m/z 564[ M+H ]] ⁺ 。

(4) Preparation of Compound INT-4:

compound INT-3 (28 g,49.7 mol) was dissolved in methanol (250 mL), and palladium on charcoal (1.5 g) was added thereto and reacted at 30℃under normal pressure with hydrogen for 12 hours. The catalyst was removed by suction filtration through celite and the filtrate was concentrated to dryness by rotary evaporation to give the compound INT-4 (22 g) in 94% yield; HPLC purity>98.0％，EI-MS m/z:474[M+H] ⁺ 。

(5) Preparation of deferasirox:

compound INT-4 (22 g,46.5 mmol) was dissolved in tetrahydrofuran (200 mL), tetrabutylammonium fluoride (25 g,95.6 mol) was added, the temperature was raised to 40 ℃ for reaction for 6h, cooled to room temperature, the kieselguhr was filtered off, the filtrate was collected, concentrated under reduced pressure to remove the organic solvent, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and distilled to dryness under reduced pressure to give deferasirox (16 g), yield 92%, HPLC purity 99.3%; ¹ H NMR(400MHz,DMSO-d ₆ )δ6.85(d,J＝8.2Hz,1H),7.04-6.93(m,3H),7.37(m,2H),7.54(m,3H),7.98(d,J＝8.6Hz,2H),8.04(dd,J＝1.4,7.8Hz,1H),10.04(brs,1H),10.79(s,1H),13.18(brs,1H)；EI-MS m/z:374[M+H] ⁺ 。

example 2:

(1) Preparation of Compound INT-1:

para aminobenzoic acid (18 g,0.13 mol), 2-trimethylsilylethanol (22 g,0.19 mol), methanesulfonic acid (0.3 g,3.1 mmol) were dissolved in xylene (500 mL), reacted at 100℃for 4 hours, concentrated under reduced pressure to remove the organic solvent, extracted with methylene chloride, washed with brine, dried over anhydrous sodium sulfate, and distilled to dryness under reduced pressure to give Compound INT-1 (28 g) in 90% yield and 95.7% HPLC purity.

(2) Preparation of phenylhydrazine Compound INT-2:

the compound INT-1 (28 g,0.12 mol) and water (28 mL) are mixed, stirred, cooled to 0 ℃, concentrated hydrochloric acid (28 mL) is added, sodium nitrite (8.5 g,0.12 mol) solution (20 mL) is dropwise added, stirring is carried out for 0.5h at 0 ℃, sodium sulfite (60 g,0.48 mol) solution (250 mL) is slowly dropwise added, the temperature is raised to 80 ℃ for reaction for 4h, and phenylhydrazine compound INT-2 (26 g) is obtained through acidification, crystallization, suction filtration and vacuum drying, and the yield is 87%.

(3) Preparation of Compound INT-3:

phenylhydrazine compound INT-2 (26 g,0.1 mol), 2- [2- (benzyloxy) phenyl ] -4H-benzo [ e ] [1,3] oxazin-4-one (35 g,0.11 mol) was dissolved in isopropyl alcohol (300 mL), reacted at 80℃for 6 hours, cooled for 3 hours to crystallize, suction-filtered, the filter cake was washed with frozen ethanol (200 mL), ethanol-water recrystallized, and vacuum dried to give compound INT-3 (55 g) in 95% yield.

(4) Preparation of Compound INT-4:

compound INT-3 (55 g,97.6 mmol) was dissolved in ethanol (500 mL), palladium on charcoal (2.5 g) was added and reacted at 35℃under normal pressure with hydrogen for 10h. The catalyst was removed by suction filtration through celite and the filtrate was concentrated to dryness by rotary evaporation to give the compound INT-4 (44 g) in 95% yield; HPLC purity >98.0%.

(5) Preparation of deferasirox:

compound INT-4 (44 g,92.9 mmol) was dissolved in methyl tert-butyl ether (350 mL), tetrabutylammonium fluoride (75 g,0.29 mol) was added, the temperature was raised to 60℃for 4h, cooled to room temperature, the kieselguhr was filtered off with suction, the filtrate was collected, the organic solvent was removed by concentration under reduced pressure, extraction with methylene chloride was added, brine wash, dried over anhydrous sodium sulfate, and spin-evaporated to dryness under reduced pressure to give deferasirox (32 g), yield 92%, HPLC purity 98.3%.

Example 3:

(1) Preparation of Compound INT-1:

para aminobenzoic acid (55 g,0.4 mol), 2-trimethylsilylethanol (75 g,0.63 mol), p-dodecylbenzenesulfonic acid (6 g,18.4 mmol) were dissolved in toluene (1500 mL), reacted at 90℃for 6 hours, concentrated under reduced pressure to remove the organic solvent, extracted with methylene chloride, washed with brine, dried over anhydrous sodium sulfate, and distilled to dryness under reduced pressure to give compound INT-1 (85 g) in 89% yield and 95.5% HPLC purity.

(2) Preparation of phenylhydrazine Compound INT-2:

the compound INT-1 (85 g,0.36 mol) and water (85 mL) are mixed, stirred, cooled to 5 ℃, concentrated hydrochloric acid (85 mL) is added, sodium nitrite (27 g,0.39 mmol) solution (55 mL) is dropwise added, stirring is carried out for 0.5h at 5 ℃, sodium sulfite (225 g,1.79 mol) solution (700 mL) is slowly dropwise added, the temperature is raised to 90 ℃ for reaction for 2h, and phenylhydrazine compound INT-2 (82 g) is obtained through acidification, crystallization, suction filtration and vacuum drying, and the yield is 91%.

(3) Preparation of Compound INT-3:

phenylhydrazine compound INT-2 (82 g,0.33 mol), 2- [2- (benzyloxy) phenyl ] -4H-benzo [ e ] [1,3] oxazin-4-one (112 g,0.34 mol) were dissolved in n-butanol (1000 mL), reacted at 100℃for 3 hours, cooled for 3 hours for crystallization, suction filtered, the filter cake was washed with frozen ethanol (100 mL), ethanol-water recrystallized, and vacuum dried to give compound INT-3 (172 g) in 94% yield.

(4) Preparation of Compound INT-4:

compound INT-3 (172 g,0.31 mol) was dissolved in isopropanol (1500 mL), palladium on charcoal (8 g) was added, and the mixture was reacted at 25℃under normal pressure with hydrogen for 12 hours. The catalyst was removed by suction filtration through celite and the filtrate was concentrated to dryness by rotary evaporation to give the compound INT-4 (138 g) in 96% yield; HPLC purity >98.0%.

(5) Preparation of deferasirox:

compound INT-4 (138 g,0.29 mol) was dissolved in acetonitrile (1000 mL), tetrabutylammonium fluoride (380 g,1.45 mol) was added, the temperature was raised to 80℃for 2 hours, cooled to room temperature, the mixture was filtered through celite, the filtrate was collected, the organic solvent was removed by concentration under reduced pressure, extraction with methylene chloride was added, washing with common salt, drying over anhydrous sodium sulfate, and spin-evaporation to dryness under reduced pressure was performed to give deferasirox (102 g), yield 94%, HPLC purity 98.3%.

Claims (7)

1. A method for preparing deferasirox, comprising the steps of:

(1) Esterification reaction is carried out on aminobenzoic acid and 2-trimethylsilyl ethanol to obtain a compound INT-1:

(2) Diazotizing the compound INT-1 and sodium nitrite in an acidic aqueous solution system to generate a diazonium salt intermediate, and carrying out a reduction reaction to obtain a phenylhydrazine compound INT-2:

(3) The phenylhydrazine compound INT-2 and 2- [2- (benzyloxy) phenyl ] -4H-benzo [ e ] [1,3] oxazin-4-one undergo a cyclization reaction in a solvent system to obtain a compound INT-3:

(4) The compound INT-3 is subjected to catalytic hydrogenation deprotection reaction to obtain a compound INT-4:

(5) Deprotection of compound INT-4 in the presence of tetrabutylammonium fluoride gives deferasirox:

2. the process for preparing deferasirox according to claim 1, wherein the molar ratio of p-aminobenzoic acid to 2-trimethylsilyl alcohol in step (1) is 1:1.2-1.6;

the esterification reaction is carried out in the presence of a sulfonic acid derivative;

the sulfonic acid derivative is any one or a combination of at least two of p-toluenesulfonic acid, methanesulfonic acid, p-dodecylbenzenesulfonic acid, benzenesulfonic acid, 2,4, 6-triisopropylbenzenesulfonic acid or m-nitrobenzenesulfonic acid;

the molar ratio of the sulfonic acid derivative to the p-aminobenzoic acid is 0.005-0.05:1;

the solvent of the esterification reaction in the step (1) is one or a combination of toluene and xylene;

the temperature of the esterification reaction is 90-110 ℃, and the reaction time is 2-6 hours.

3. A process for the preparation of deferasirox according to claim 1 and/or 2, characterized in that the molar ratio of compound INT-1 to sodium nitrite in step (2) is 1:1-1.1;

the reducing agent used in the reduction reaction is sodium sulfite;

the molar ratio of the sodium sulfite to the compound INT-1 is 3-5:1;

the temperature of the diazotization reaction is between 5 ℃ below zero and 5 ℃, and the reaction time is between 0.5 and 1 hour;

the temperature of the reduction reaction is 70-90 ℃ and the reaction time is 2-6 hours.

4. A process for the preparation of deferasirox according to any of claims 1 to 3, characterized in that the molar ratio of phenylhydrazine compound INT-2 to 2- [2- (benzyloxy) phenyl ] -4H-benzo [ e ] [1,3] oxazin-4-one of step (3) is 1:1 to 1.05;

the solvent is any one or the combination of at least two of ethanol, methanol, isopropanol, n-propanol, n-butanol or isobutanol;

the temperature of the cyclization reaction is 50-100 ℃ and the reaction time is 3-12 hours.

5. The process for the preparation of deferasirox according to any of claims 1 to 4, characterized in that the catalytic hydrogenation deprotection reaction of step (4) is a reaction of compound INT-3 with hydrogen in the presence of palladium on charcoal as catalyst to give compound INT-4;

the solvent for the catalytic hydrogenation deprotection reaction in the step (4) is any one or at least two of methanol, ethanol and isopropanol;

the temperature of the catalytic hydrogenation deprotection reaction is 30-60 ℃ and the time is 6-12 hours;

the catalytic hydrogenation deprotection reaction in the step (4) is carried out under normal pressure.

6. A process for the preparation of deferasirox according to any of claims 1 to 5, characterized in that the molar ratio of tetrabutylammonium fluoride to compound INT-4 in step (5) is 2-5:1;

the solvent for the deprotection reaction in the step (5) is any one or a combination of at least two of tetrahydrofuran, methyl tertiary butyl ether, 1, 4-dioxane and acetonitrile;

the temperature of the deprotection reaction in the step (5) is 40-80 ℃, and the reaction time is 2-6 hours.

7. A process for the preparation of deferasirox according to any of claims 1-6, comprising the steps of:

(1) In the presence of sulfonic acid derivatives, carrying out esterification reaction on p-aminobenzoic acid and 2-trimethylsilyl ethanol at the molar ratio of 1:1.2-1.6 at the temperature of 90-110 ℃ for 2-6 hours to obtain a compound INT-1;

(2) In an acidic aqueous solution system, diazotizing a compound INT-1 and sodium nitrite for 0.5-1 hour at a temperature of between 5 ℃ below zero and 5 ℃ in a molar ratio of 1:1-1.1 to obtain a diazonium salt solution; adding pre-cooled sodium sulfite aqueous solution, heating to 70-90 ℃, and reacting for 2-6 hours to obtain phenylhydrazine compound INT-2

(3) The cyclization reaction of the phenylhydrazine compound INT-2 and 2- [2- (benzyloxy) phenyl ] -4H-benzo [ e ] [1,3] oxazin-4-one is carried out for 3-12 hours in a solvent system at 50-100 ℃, and the molar ratio of the phenylhydrazine compound INT-2 to the 2- [2- (benzyloxy) phenyl ] -4H-benzo [ e ] [1,3] oxazin-4-one is 1:1-1.05, so as to obtain a compound INT-3;

(4) Under the condition of taking palladium-carbon as a catalyst, carrying out catalytic hydrogenation deprotection reaction with hydrogen to obtain a compound INT-4;

(5) Deprotection of the compound INT-4 in the presence of tetrabutylammonium fluoride at 40-80℃for 2-6 hours afforded deferasirox.