Synthetic method of promacta key intermediate

Abstract

The invention discloses a synthetic method of a promacta key intermediate. The Eltrombopag olamine key intermediate is 3'-nitryl-2'-methoxyl-[1, 1'-biphenyl]-3-formic acid shown in a formula (I). The synthetic method comprises the following steps of: performing a reaction on 3-carboxyl phenylboronic acid or 3-carboxyl phenylboronic acid pinacol ester shown in a formula (III) and 2-halogen-6-nitrobenzene methyl ether shown in a formula (II) at the temperature of 40-100 DEG C under functions of alkali substances and a heterogeneous catalyst such as palladium carbon under the inert atmosphere protection in a mixed solvent which is prepared by methanol and water in volume ratio of 1:(0.5-6.0); filtering, washing and recovering the catalyst after the reaction is completed; regulating a pH value of filter liquid to be between 1 and 9 by using acid; separating out a product, and filtering to obtain c3'-nitryl-2'-methoxyl-[1, 1'-biphenyl]-3-formic acid shown in the formula (I); the alkali substances are sodium carbonate or potassium carbonate. The synthetic method is low in cost, suitable for industrial production, and easy to operate; moreover, the product is high in yield and high in purity.

Description

technical field

[0001] The invention discloses a key intermediate of Eltrombopag 3'-nitro-2'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (CAS No.: 376591-94-5) The synthetic method relates to the field of organic synthesis. Background technique

[0002] Eltrombopag-2-aminoethanol salt, chemical name 3'-{(2Z)-2-[1-(3,4-xylyl)-3-methyl-5-oxo-1,5 -Dihydro-4H-pyrazole-4-ylidene]hydrazino}-2'-hydroxy-3-biphenylcarboxylic acid-2-aminoethanolate, the structural formula is as follows:

[0003]

[0004] US FDA approves GlaxoSmithKline's Eltrombopag tablets (Promacta) for the treatment of chronic idiopathic thrombocytopenic purpura (ITP) after glucocorticoids, immunoglobulin therapy or splenectomy Thrombocytopenia in patients.

[0005] Eltrombopag is the first oral non-peptide thrombopoietin receptor agonist approved for the treatment of adults with chronic ITP. Preclinical and clinical studies have shown that stimulating this product can increase the proliferation and differentia...

Examples

Embodiment 1

[0065] Synthesis of 3'-nitro-2'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (compound Ⅰ)

[0066] In a 500mL three-necked flask, sodium carbonate (7.63g, 72.0mmol), water (100mL), 3-carboxyphenylboronic acid (14.30g, 86.0mmol), methanol (100mL), 2-bromo-6-nitro Phenoxymethyl ether (10.01 g, 43.0 mmol) was stirred for 10 min, and palladium on carbon (5%, 0.50 g, ω=10%) was added. Under the protection of helium atmosphere, the reaction was carried out at 60°C for 4.5 hours. It was detected by TLC (PE:EA=1:1) that the reaction was complete, and the catalyst was recovered by filtration, and the catalyst was washed with water (100 mL). The filtrates were combined, and 6M hydrochloric acid was added dropwise with stirring until the pH was about 3, then the dropwise addition of hydrochloric acid was stopped and the stirring was carried out for 30 min, and the solid was obtained by filtration, washed with water (100 mL), and dried by air at 60°C for 10 h to obtain 11.58 g of the product...

Embodiment 2

[0069] Synthesis of 3'-nitro-2'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (compound Ⅰ)

[0070] In a 500mL three-necked flask, sodium carbonate (7.63g, 72.0mmol), water (100mL), 3-carboxyphenylboronic acid (14.30g, 86.0mmol), methanol (100mL), 2-bromo-6-nitro Phenoxymethyl ether (10.01 g, 43.0 mmol) was stirred for 10 min, and palladium on carbon (3%, 0.30 g, ω=10%) was added. N 2 The atmosphere was protected and reacted at 60°C for 7.5 hours. TLC (PE:EA=1:1) detected that the reaction was complete, and the catalyst was recovered by filtration, and the catalyst was washed with water (100 mL). The filtrates were combined, and 6M hydrochloric acid was added dropwise with stirring until the pH was about 7. Stop adding the hydrochloric acid and stir for 30 minutes, and filtered to obtain a solid, which was washed with water (100 mL), and dried at 60°C for 10 hours to obtain 11.36 g of the product, with a yield of 98.7%. HPLC purity 99.36%.

[0071] 1 H NMR (500MHz, DMSO) δ13.1...

Embodiment 3

[0073] Synthesis of 3'-nitro-2'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (compound Ⅰ)

[0074] In a 500mL three-necked flask, sodium carbonate (7.63g, 72.0mmol), water (100mL), 3-carboxyphenylboronic acid (14.30g, 86.0mmol), methanol (100mL), 2-bromo-6-nitro Phenoxymethyl ether (10.01 g, 43.0 mmol) was stirred for 10 min, and palladium on carbon (8%, 0.80 g, ω=10%) was added. N 2 The atmosphere was protected and reacted at 60°C for 4.0 hours. TLC (PE:EA=1:1) detected that the reaction was complete, and the catalyst was recovered by filtration, and the catalyst was washed with water (100 mL). The filtrates were combined, and 6M hydrochloric acid was added dropwise with stirring until the pH was about 8. Stop adding the hydrochloric acid and stir for 30 minutes, and filtered to obtain a solid, which was washed with water (100 mL), and dried at 60° C. for 10 hours to obtain 10.62 g of the product, with a yield of 90.1%. HPLC purity 99.36%.

[0075] 1 H NMR (500MHz, DMSO) δ13...

technical field

[0001] The invention discloses a key intermediate of Eltrombopag 3'-nitro-2'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (CAS No.: 376591-94-5) The synthetic method relates to the field of organic synthesis. Background technique

[0002] Eltrombopag-2-aminoethanol salt, chemical name 3'-{(2Z)-2-[1-(3,4-xylyl)-3-methyl-5-oxo-1,5 -Dihydro-4H-pyrazole-4-ylidene]hydrazino}-2'-hydroxy-3-biphenylcarboxylic acid-2-aminoethanolate, the structural formula is as follows:

[0003]

[0004] US FDA approves GlaxoSmithKline's Eltrombopag tablets (Promacta) for the treatment of chronic idiopathic thrombocytopenic purpura (ITP) after glucocorticoids, immunoglobulin therapy or splenectomy Thrombocytopenia in patients.

[0005] Eltrombopag is the first oral non-peptide thrombopoietin receptor agonist approved for the treatment of adults with chronic ITP. Preclinical and clinical studies have shown that stimulating this product can increase the proliferation and differentia...

Examples

Embodiment 1

[0065] Synthesis of 3'-nitro-2'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (compound Ⅰ)

[0066] In a 500mL three-necked flask, sodium carbonate (7.63g, 72.0mmol), water (100mL), 3-carboxyphenylboronic acid (14.30g, 86.0mmol), methanol (100mL), 2-bromo-6-nitro Phenoxymethyl ether (10.01 g, 43.0 mmol) was stirred for 10 min, and palladium on carbon (5%, 0.50 g, ω=10%) was added. Under the protection of helium atmosphere, the reaction was carried out at 60°C for 4.5 hours. It was detected by TLC (PE:EA=1:1) that the reaction was complete, and the catalyst was recovered by filtration, and the catalyst was washed with water (100 mL). The filtrates were combined, and 6M hydrochloric acid was added dropwise with stirring until the pH was about 3, then the dropwise addition of hydrochloric acid was stopped and the stirring was carried out for 30 min, and the solid was obtained by filtration, washed with water (100 mL), and dried by air at 60°C for 10 h to obtain 11.58 g of the product...

Embodiment 2

[0069] Synthesis of 3'-nitro-2'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (compound Ⅰ)

[0070] In a 500mL three-necked flask, sodium carbonate (7.63g, 72.0mmol), water (100mL), 3-carboxyphenylboronic acid (14.30g, 86.0mmol), methanol (100mL), 2-bromo-6-nitro Phenoxymethyl ether (10.01 g, 43.0 mmol) was stirred for 10 min, and palladium on carbon (3%, 0.30 g, ω=10%) was added. N 2 The atmosphere was protected and reacted at 60°C for 7.5 hours. TLC (PE:EA=1:1) detected that the reaction was complete, and the catalyst was recovered by filtration, and the catalyst was washed with water (100 mL). The filtrates were combined, and 6M hydrochloric acid was added dropwise with stirring until the pH was about 7. Stop adding the hydrochloric acid and stir for 30 minutes, and filtered to obtain a solid, which was washed with water (100 mL), and dried at 60°C for 10 hours to obtain 11.36 g of the product, with a yield of 98.7%. HPLC purity 99.36%.

[0071] 1 H NMR (500MHz, DMSO) δ13.1...

Embodiment 3

[0073] Synthesis of 3'-nitro-2'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (compound Ⅰ)

[0074] In a 500mL three-necked flask, sodium carbonate (7.63g, 72.0mmol), water (100mL), 3-carboxyphenylboronic acid (14.30g, 86.0mmol), methanol (100mL), 2-bromo-6-nitro Phenoxymethyl ether (10.01 g, 43.0 mmol) was stirred for 10 min, and palladium on carbon (8%, 0.80 g, ω=10%) was added. N 2 The atmosphere was protected and reacted at 60°C for 4.0 hours. TLC (PE:EA=1:1) detected that the reaction was complete, and the catalyst was recovered by filtration, and the catalyst was washed with water (100 mL). The filtrates were combined, and 6M hydrochloric acid was added dropwise with stirring until the pH was about 8. Stop adding the hydrochloric acid and stir for 30 minutes, and filtered to obtain a solid, which was washed with water (100 mL), and dried at 60° C. for 10 hours to obtain 10.62 g of the product, with a yield of 90.1%. HPLC purity 99.36%.

[0075] 1 H NMR (500MHz, DMSO) δ13...

Images