CN116199637A - A kind of preparation method of deferasirox - Google Patents

Abstract

The invention provides a preparation method of deferasirox, the preparation method comprising the following steps: p-aminobenzoic acid and 2-trimethylsilyl ethanol are subjected to an esterification reaction, and the obtained compound INT-1 is mixed with sodium nitrite in an acidic aqueous solution In the system, a diazotization reaction is carried out to generate a diazonium salt intermediate, which undergoes a reduction reaction, and the obtained phenylhydrazine compound INT‑2 and 2‑[2‑(benzyloxy)phenyl]‑4H‑benzo[e ][1,3]Oxazin‑4‑one undergoes cyclization reaction to obtain compound INT‑3, which undergoes catalytic hydrogenation deprotection reaction followed by deprotection reaction in the presence of tetrabutylammonium fluoride to obtain diazepam Ross. The preparation method of the invention has mild conditions, easy-to-obtain raw materials and low cost, and is suitable for industrial production, application and popularization.

Description

A preparation method of Deferasirox

Technical Field

The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a method for preparing deferasirox.

Background Art

Deferasirox, chemical name 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid, trade name Exjade, is a new type of iron ion chelator developed by Novartis Pharmaceuticals of Switzerland. It effectively improves iron excretion and reduces the iron content in the body by binding to iron ions in the body, which can reduce tissue damage and functional damage of multiple organs caused by iron overload. Deferasirox is the first oral iron-removing agent approved by the US FDA for routine use. The FDA has granted it orphan drug status for the treatment of iron overload in non-transfusion-dependent thalassemia. In 2012, Deferasirox was approved in the European Union for the treatment of chronic iron overload in patients with non-transfusion-dependent thalassemia syndrome aged 10 years and above who require chelation therapy because deferoxamine mesylate therapy is contraindicated or insufficient. It is currently available in more than 80 countries.

There are patents WO2008094617, WO2009094956, WO2011070560, and WO2012131017 reporting on the preparation method of Deferasirox. The different process routes all involve first preparing a benzoxazolone intermediate or a benzoxazolone intermediate with a protecting group, and then reacting it with 4-carboxyphenylhydrazine, involving a ring-opening rearrangement mechanism, to obtain Deferasirox:

For example, salicylic acid is used as a raw material and chlorinated with dichlorothionyl to obtain salicylic acid chloride, which is then dehydrated, condensed and cyclized with salicylamide at a high temperature of 170°C to obtain a benzoxazolone intermediate:

Salicylonitrile or benzyl-protected salicylonitrile can be treated with methanolic hydrogen chloride to obtain o-benzyloxyphenylimine acid methyl ester, which is dehydrated and cyclized with salicylic acid chloride to obtain a benzyl-protected benzoxazolone intermediate:

If salicylic acid is used as the raw material, it reacts with p-toluenesulfonyl chloride to generate a mixed anhydride, which is then dehydrated and cyclized with salicylamide to obtain a benzoxazolone intermediate:

In the existing process, the quality control and yield of intermediates are both major problems. Both 4-carboxyphenylhydrazine and benzoxazolone intermediates have many reaction sites, which produce various side reactions. It is necessary to establish complex reaction and process parameter controls, which is not conducive to the impurity control and production implementation of raw materials.

In view of the defects and shortcomings in the existing process methods, efforts are made to develop a simple, economical and environmentally friendly preparation technology for deferasirox, especially to seek a process solution that can be adapted to industrial production, which has important practical significance for improving the economic and social benefits of this product.

Summary of the invention

The object of the present invention is to provide a method for preparing Deferasirox, which has mild process conditions, helps to control side reactions and impurity generation, improves yield, reduces preparation cost, and is highly efficient, green and environmentally friendly to meet the requirements of industrialized scale-up production.

The technical solution adopted by the present invention is:

The synthetic route of Deferasirox:

The specific steps of the preparation method of Deferasirox are as follows:

(1) esterification reaction between p-aminobenzoic acid and 2-trimethylsilylethanol to obtain compound INT-1;

(2) Compound INT-1 is subjected to a diazotization reaction with sodium nitrite in an acidic aqueous solution system to generate a diazonium salt intermediate, which is then subjected to a reduction reaction to obtain a phenylhydrazine compound INT-2;

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

(4) subjecting compound INT-3 to catalytic hydrogenation deprotection reaction to obtain compound INT-4;

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

Preferably, the molar ratio of p-aminobenzoic acid to 2-trimethylsilylethanol in 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 of p-toluenesulfonic acid, methanesulfonic acid, p-dodecylbenzenesulfonic acid, benzenesulfonic acid, 2,4,6-triisopropylbenzenesulfonic acid or m-nitrobenzenesulfonic acid, or a combination of at least two thereof;

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

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

Preferably, the esterification reaction temperature is 90-110° C., and the reaction time is 2-6 hours.

Preferably, the molar ratio of the compound INT-1 to sodium nitrite in 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 -5 to 5°C, and the reaction time is 0.5 to 1 hour;

Preferably, the reduction reaction temperature is 70-90° C., and the reaction time is 2-6 hours.

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

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

Preferably, the temperature of the cyclization reaction is 50-100° C., and the reaction time is 3-12 hours.

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

Preferably, the solvent for the catalytic hydrogenation deprotection reaction in 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° C. and the time is 6-12 hours;

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

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

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

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

As a preferred technical solution, a method for preparing Deferasirox according to the present invention comprises the following steps:

(1) In the presence of a sulfonic acid derivative, p-aminobenzoic acid and 2-trimethylsilylethanol are reacted at a molar ratio of 1:1.2-1.6 at 90-110° C. for 2-6 hours to obtain compound INT-1;

(2) In an acidic aqueous solution system, compound INT-1 and sodium nitrite are reacted at a molar ratio of 1:1-1.1 at -5 to 5°C for 0.5 to 1 hour to obtain a diazonium salt solution; a pre-cooled sodium sulfite aqueous solution is added, the temperature is raised to 70 to 90°C, and the reaction is carried out for 2 to 6 hours to obtain a phenylhydrazine compound INT-2

(3) a phenylhydrazine compound INT-2 and 2-[2-(benzyloxy)phenyl]-4H-benzo[e][1,3]oxazine-4-one are subjected to a cyclization reaction in a solvent system at 50-100° C. for 3-12 hours, wherein the molar ratio of the phenylhydrazine compound INT-2 to 2-[2-(benzyloxy)phenyl]-4H-benzo[e][1,3]oxazine-4-one is 1:1-1.05, to obtain a compound INT-3;

(4) performing a catalytic hydrogenation deprotection reaction with hydrogen in the presence of palladium on carbon as a catalyst to obtain compound INT-4;

(5) In the presence of tetrabutylammonium fluoride, compound INT-4 is subjected to a deprotection reaction at 40-80° C. for 2-6 hours to obtain deferasirox.

The technical solution of the present invention first uses cheap and readily available p-aminobenzoic acid and 2-trimethylsilylethanol to carry out an esterification reaction, that is, to protect the carboxyl group, and then performs diazotization and reduction to obtain a phenylhydrazine compound INT-2, and then performs a cyclization reaction to construct a triazole mother nucleus. Since the carboxylate radical is very likely to produce side reactions, it is very important to first protect the carboxyl group. The entire synthesis process is relatively simple and the reaction conditions are relatively mild. Therefore, relative to the prior art, the present invention has the following beneficial effects: the process conditions are mild, the appearance of toxic impurities and process impurities is avoided, and it is beneficial to the quality control of the bulk drug of Deferasirox; secondly, the reagent raw materials used in the process route of the present invention are easy to obtain, and the yield is high, the technical solution is reasonable and environmentally friendly, which is conducive to industrialization and promotion, and can be mass-produced to meet the use needs.

DETAILED DESCRIPTION

The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only used to help understand the present invention and should not be regarded as specific limitations of the present invention.

Embodiment 1:

(1) Preparation of compound INT-1:

p-Aminobenzoic acid (10 g, 72.9 mmol), 2-trimethylsilylethanol (11 g, 93 mmol) and p-toluenesulfonic acid (0.1 g, 0.6 mmol) were dissolved in toluene (200 mL), heated to 110°C for reaction for 2 h, concentrated under reduced pressure to remove the organic solvent, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain compound INT-1 (15 g) with a yield of 87% and a HPLC purity of 95.6%; ¹ H NMR (400 MHz, CDCl ₃ )δ0.07(s,9H),1.10(m,2H),4.07(br s,2H,NH),4.36,(m,2H),6.62(d,J＝8.6 Hz,2H),7.84(d,J＝8.7 Hz,2H); EI-MS m/z:238[M+H] ⁺ .

(2) Preparation of phenylhydrazine compound INT-2:

Compound INT-1 (15 g, 63.2 mmol) and water (15 mL) were mixed and stirred, cooled to -5°C, concentrated hydrochloric acid (15 mL) was added, sodium nitrite (4.4 g, 63.8 mmol) solution (10 mL) was added dropwise, stirred at -5°C for 0.5 h, sodium sulfite (24 g, 0.19 mol) solution (100 mL) was slowly added dropwise, the temperature was raised to 70°C and reacted for 6 h. After acidification, crystallization, suction filtration and vacuum drying, phenylhydrazine compound INT-2 (14 g) was obtained with a yield of 88%, EI-MS m/z: 253 [M+H] ⁺ .

(3) Preparation of compound INT-3:

Phenylhydrazine compound INT-2 (14 g, 55.5 mmol) and 2-[2-(benzyloxy)phenyl]-4H-benzo[e][1,3]oxazin-4-one (18.5 g, 56.2 mmol) were dissolved in ethanol (150 mL), heated to 80°C for 9 h, cooled for 3 h to crystallize, filtered, and the filter cake was washed with chilled ethanol (50 mL). Recrystallized from ethanol-water and dried in vacuo to obtain compound INT-3 (28 g) with a yield of 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), palladium carbon (1.5 g) was added, and hydrogen was introduced at 30°C under normal pressure for 12 h. The catalyst was removed by suction through diatomaceous earth, and the filtrate was concentrated to dryness by rotary evaporation to obtain compound INT-4 (22 g) with a yield of 94%; 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°C for reaction for 6 h, the temperature was lowered to room temperature, filtered through diatomaceous earth, the filtrate was collected, and the organic solvent was removed by concentration under reduced pressure. Dichloromethane was added for extraction, the product was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain deferasirox (16 g), with a yield of 92% and a HPLC purity of 99.3%; ¹ H NMR (400 MHz, 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] ⁺ .

Embodiment 2:

(1) Preparation of compound INT-1:

p-Aminobenzoic acid (18 g, 0.13 mol), 2-trimethylsilylethanol (22 g, 0.19 mol), and methanesulfonic acid (0.3 g, 3.1 mmol) were dissolved in xylene (500 mL), heated to 100 °C for 4 h, and concentrated under reduced pressure to remove the organic solvent. Dichloromethane was added for extraction, washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain compound INT-1 (28 g) with a yield of 90% and an HPLC purity of 95.7%.

(2) Preparation of phenylhydrazine compound INT-2:

Compound INT-1 (28 g, 0.12 mol) and water (28 mL) were mixed and stirred, cooled to 0°C, concentrated hydrochloric acid (28 mL) was added, sodium nitrite (8.5 g, 0.12 mol) solution (20 mL) was added dropwise, stirred at 0°C for 0.5 h, sodium sulfite (60 g, 0.48 mol) solution (250 mL) was slowly added dropwise, the temperature was raised to 80°C for 4 h, and phenylhydrazine compound INT-2 (26 g) was obtained after acidification, crystallization, suction filtration and vacuum drying, with a yield of 87%.

(3) Preparation of compound INT-3:

Phenylhydrazine compound INT-2 (26 g, 0.1 mol) and 2-[2-(benzyloxy)phenyl]-4H-benzo[e][1,3]oxazine-4-one (35 g, 0.11 mol) were dissolved in isopropanol (300 mL), heated to 80°C for 6 h, cooled for 3 h to crystallize, filtered, and the filter cake was washed with chilled ethanol (200 mL), recrystallized from ethanol-water, and dried in vacuo to obtain compound INT-3 (55 g) with a yield of 95%.

(4) Preparation of compound INT-4:

Compound INT-3 (55 g, 97.6 mmol) was dissolved in ethanol (500 mL), palladium carbon (2.5 g) was added, and hydrogen was introduced at 35°C under normal pressure for 10 h. The catalyst was removed by suction through diatomaceous earth, and the filtrate was concentrated to dryness by rotary evaporation to obtain compound INT-4 (44 g) with a yield of 95%; 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 ° C for 4 h, the temperature was lowered to room temperature, filtered through diatomaceous earth, the filtrate was collected, and the organic solvent was removed by concentration under reduced pressure. Dichloromethane was added for extraction, the mixture was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain Deferasirox (32 g) with a yield of 92% and a HPLC purity of 98.3%.

Embodiment 3:

(1) Preparation of compound INT-1:

p-Aminobenzoic acid (55 g, 0.4 mol), 2-trimethylsilylethanol (75 g, 0.63 mol), and p-dodecylbenzenesulfonic acid (6 g, 18.4 mmol) were dissolved in toluene (1500 mL), heated to 90 °C for 6 h, concentrated under reduced pressure to remove the organic solvent, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain compound INT-1 (85 g) with a yield of 89% and an HPLC purity of 95.5%.

(2) Preparation of phenylhydrazine compound INT-2:

Compound INT-1 (85 g, 0.36 mol) and water (85 mL) were mixed and stirred, cooled to 5°C, concentrated hydrochloric acid (85 mL) was added, sodium nitrite (27 g, 0.39 mmol) solution (55 mL) was added dropwise, stirred at 5°C for 0.5 h, sodium sulfite (225 g, 1.79 mol) solution (700 mL) was slowly added dropwise, the temperature was raised to 90°C for 2 h, and the phenylhydrazine compound INT-2 (82 g) was obtained after acidification, crystallization, suction filtration and vacuum drying. The yield was 91%.

(3) Preparation of compound INT-3:

Phenylhydrazine compound INT-2 (82 g, 0.33 mol) and 2-[2-(benzyloxy)phenyl]-4H-benzo[e][1,3]oxazin-4-one (112 g, 0.34 mol) were dissolved in n-butanol (1000 mL), heated to 100°C for 3 h, cooled for 3 h to crystallize, filtered, and the filter cake was washed with chilled ethanol (100 mL), recrystallized from ethanol-water, and dried in vacuo to obtain compound INT-3 (172 g) with a yield of 94%.

(4) Preparation of compound INT-4:

Compound INT-3 (172 g, 0.31 mol) was dissolved in isopropanol (1500 mL), palladium carbon (8 g) was added, and hydrogen was introduced at 25°C under normal pressure for 12 h. The catalyst was removed by suction through diatomaceous earth, and the filtrate was concentrated to dryness by rotary evaporation to obtain compound INT-4 (138 g) with a yield of 96%; 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 ° C for reaction for 2 h, the temperature was lowered to room temperature, filtered through diatomaceous earth, the filtrate was collected, and the organic solvent was removed by concentration under reduced pressure. Dichloromethane was added for extraction, the mixture was washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain Deferasirox (102 g) with a yield of 94% and a HPLC purity of 98.3%.

Claims (7)

1. a preparation method of deferasirox, is characterized in that, comprises the following steps: (1) Esterification of p-aminobenzoic acid and 2-trimethylsilyl ethanol to obtain compound INT-1:

(2) Compound INT-1 and sodium nitrite are subjected to a diazotization reaction in an acidic aqueous solution to generate a diazonium salt intermediate, which undergoes a reduction reaction to obtain the phenylhydrazine compound INT-2:

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

(4) Compound INT-3 undergoes catalytic hydrogenation deprotection reaction to obtain compound INT-4:

(5) In the presence of tetrabutylammonium fluoride, compound INT-4 undergoes a deprotection reaction to obtain deferasirox:

2. the preparation method of a kind of deferasirox according to claim 1, is characterized in that, the mol ratio of p-aminobenzoic acid and 2-trimethylsilyl ethanol described in step (1) is 1:1.2-1.6; The esterification reaction is carried out in the presence of sulfonic acid derivatives; The sulfonic acid derivative is p-toluenesulfonic acid, methanesulfonic acid, p-dodecylbenzenesulfonic acid, benzenesulfonic acid, 2,4,6-triisopropylbenzenesulfonic acid or m-nitrobenzenesulfonic acid Any one or a combination of at least two of them; The mol ratio of described sulfonic acid derivative and p-aminobenzoic acid is 0.005-0.05:1; The solvent of the esterification reaction described in step (1) is one or a combination in toluene or xylene; The temperature of the esterification reaction is 90-110° C., and the reaction time is 2-6 hours. 3. according to the preparation method of a kind of deferasirox described in claim 1 and/or 2, it is characterized in that, the mol ratio of step (2) described compound INT-1 and sodium nitrite is 1:1-1.1 ; The reducing agent used in the reduction reaction is sodium sulfite; The mol ratio of the sodium sulfite to the compound INT-1 is 3-5:1; The temperature of the diazotization reaction is -5-5°C, and the reaction time is 0.5-1 hour; The temperature of the reduction reaction is 70-90° C., and the reaction time is 2-6 hours. 4. according to the preparation method of a kind of deferasirox described in any one of claim 1-3, it is characterized in that, step (3) described phenylhydrazine compound INT-2 and 2-[2-(benzyloxy Base) phenyl]-4H-benzo[e][1,3]oxazin-4-one molar ratio is 1:1-1.05; The solvent is any one or a combination of at least two of ethanol, methanol, isopropanol, n-propanol, n-butanol or isobutanol; The temperature of the cyclization reaction is 50-100° C., and the reaction time is 3-12 hours. 5. according to the preparation method of a kind of deferasirox described in any one of claim 1-4, it is characterized in that, the catalytic hydrogenation deprotection reaction described in step (4) is to use compound INT-3 on palladium charcoal as In the case of catalyst, react with hydrogen to obtain compound INT-4; The solvent of the catalytic hydrogenation deprotection reaction in step (4) is any one or at least two of methanol, ethanol or isopropanol; The temperature of the catalytic hydrogenation deprotection reaction is 30-60°C, and the time is 6-12 hours; The catalytic hydrogenation deprotection reaction in step (4) is carried out under normal pressure. 6. according to the preparation method of a kind of deferasirox described in any one of claim 1-5, it is characterized in that, the mol ratio of tetrabutylammonium fluoride and compound INT-4 described in step (5) is 2-5:1; The solvent for the deprotection reaction in step (5) is any one or a combination of at least two of tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane or acetonitrile; The temperature of the deprotection reaction in step (5) is 40-80° C., and the reaction time is 2-6 hours. 7. according to the preparation method of a kind of deferasirox described in any one in claim 1-6, it is characterized in that, comprises the following steps: (1) In the presence of sulfonic acid derivatives, the molar ratio of p-aminobenzoic acid and 2-trimethylsilyl ethanol is 1:1.2-1.6 at 90-110°C for 2-6 hours to obtain the compound INT- 1; (2) In the acidic aqueous solution system, the molar ratio of compound INT-1 and sodium nitrite is 1:1-1.1, and the diazotization reaction is carried out at -5～5°C for 0.5-1 hour to obtain the diazonium salt solution; add Pre-cooled aqueous sodium sulfite solution, heated up to 70-90°C, reacted for 2-6 hours to obtain phenylhydrazine compound INT-2 (3) phenylhydrazine compound INT-2 and 2-[2-(benzyloxy)phenyl]-4H-benzo[e][1,3]oxazin-4-one in a solvent system, at 50- The cyclization reaction was carried out at 100°C for 3-12 hours, and the phenylhydrazine compound INT-2 and 2-[2-(benzyloxy)phenyl]-4H-benzo[e][1,3]oxazine-4 -The molar ratio of ketone is 1:1-1.05, obtains compound INT-3; (4) Under the situation of palladium charcoal as catalyst, carry out catalytic hydrogenation deprotection reaction with hydrogen, obtain compound INT-4; (5) In the presence of tetrabutylammonium fluoride, compound INT-4 was deprotected at 40-80° C. for 2-6 hours to obtain deferasirox.