Preparation method of eltrombopag medicine for treating idiopathic thrombocytopenic purpura

Abstract

The invention discloses a preparation method of Eltrombopag used for treating idiopathic thrombocytopenic purpura. The chemical name of Eltrombopag is 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-amino ethanol salt; the preparation process of the present invention is simple, the raw material is easy to get, avoids the use of highly toxic methyl iodide, is economical and environmentally friendly, is conducive to the realization of industrialization, can promote the economic and technological development of Eltrombopag raw material medicine, and reduces the production cost. cost, suitable for mass production.

Description

Technical field

[0001] The invention relates to the technical field of medicine, in particular to a preparation method of Eltrombopag used for treating idiopathic thrombocytopenic purpura. Background technique

[0002] Idiopathic thrombocytopenic purpura (ITP for short) is a clinical syndrome in which the immune mechanism causes increased platelet destruction, also known as autoimmune thrombocytopenic purpura (AITP for short), which is a relatively common It is also the most common type of thrombocytopenic purpura, characterized by peripheral thrombocytopenia, shortened platelet lifespan, normal or increased bone marrow megakaryocytes, and accelerated platelet turnover rate. According to clinical manifestations, age of onset, duration of thrombocytopenia and treatment effect, it can be divided into acute type and chronic type. The acute type is more common in children and is often self-limited, while the chronic type is more common in young women.

[0003] Eltrombopag (Eltr...

Examples

Embodiment 1

[0027] The chemical name of Eltrombopag is 3-{(2Z)-2-[1-(3,4-xylyl)-3-methyl-5-oxo-1,5-dihydro-4H -pyrazole-4-ylidene]hydrazine group}-2-hydroxyl-3-biphenylcarboxylic acid-2-aminoethanol salt, the preparation method of making said Eltrombopag comprises the following processing steps:

[0028] (1) Mix (10.9g, 50mmol) 2-nitro-6-bromophenol (I), (9g, 52mmol) benzyl bromide (II) and potassium carbonate (7.6g, 55mmol) in acetonitrile (120ml) Reflux for 3 hours, cool to room temperature, filter, concentrate to dryness, add ethyl acetate (100ml) to the concentrate to dissolve, wash with water (50ml) and saturated sodium chloride solution (50ml) successively, wash with anhydrous sulfuric acid After drying with sodium, filter, filter and concentrate to dryness to obtain yellow crystal 2-benzyloxy-1-bromo-3-nitrobenzene (III);

[0029] Its chemical reaction formula is:

[0030] .

[0031] (2) (12.32g, 40mmol) 2-benzyloxy-1-bromo-3-nitrobenzene (III), (7.97g, 48mmol) 3-carboxyphenyl...

Embodiment 2

[0041] The chemical name of Eltrombopag is 3-{(2Z)-2-[1-(3,4-xylyl)-3-methyl-5-oxo-1,5-dihydro-4H -pyrazole-4-ylidene]hydrazine group}-2-hydroxyl-3-biphenylcarboxylic acid-2-aminoethanol salt, the preparation method of making said Eltrombopag comprises the following processing steps:

[0042](1) Mix (21.8g, 100mmol) 2-nitro-6-bromophenol (I), (27g, 156mmol) benzyl bromide (II) and potassium carbonate (7.6g, 55mmol) in acetonitrile (200ml) Reflux for 3 hours, cool to room temperature, filter, concentrate to dryness, add ethyl acetate (150ml) to the concentrate to dissolve, wash with water (100ml) and saturated sodium chloride solution (75ml) successively, wash with anhydrous sulfuric acid After drying with sodium, filter, filter and concentrate to dryness to obtain yellow crystal 2-benzyloxy-1-bromo-3-nitrobenzene (III);

[0043] Its chemical reaction formula is as described in Example 1.

[0044] (2) (24.64g, 40mmol) 2-benzyloxy-1-bromo-3-nitrobenzene (III), (11.97g, 72mmol)...

Technical field

[0001] The invention relates to the technical field of medicine, in particular to a preparation method of Eltrombopag used for treating idiopathic thrombocytopenic purpura. Background technique

[0002] Idiopathic thrombocytopenic purpura (ITP for short) is a clinical syndrome in which the immune mechanism causes increased platelet destruction, also known as autoimmune thrombocytopenic purpura (AITP for short), which is a relatively common It is also the most common type of thrombocytopenic purpura, characterized by peripheral thrombocytopenia, shortened platelet lifespan, normal or increased bone marrow megakaryocytes, and accelerated platelet turnover rate. According to clinical manifestations, age of onset, duration of thrombocytopenia and treatment effect, it can be divided into acute type and chronic type. The acute type is more common in children and is often self-limited, while the chronic type is more common in young women.

[0003] Eltrombopag (Eltr...

Examples

Embodiment 1

[0027] The chemical name of Eltrombopag is 3-{(2Z)-2-[1-(3,4-xylyl)-3-methyl-5-oxo-1,5-dihydro-4H -pyrazole-4-ylidene]hydrazine group}-2-hydroxyl-3-biphenylcarboxylic acid-2-aminoethanol salt, the preparation method of making said Eltrombopag comprises the following processing steps:

[0028] (1) Mix (10.9g, 50mmol) 2-nitro-6-bromophenol (I), (9g, 52mmol) benzyl bromide (II) and potassium carbonate (7.6g, 55mmol) in acetonitrile (120ml) Reflux for 3 hours, cool to room temperature, filter, concentrate to dryness, add ethyl acetate (100ml) to the concentrate to dissolve, wash with water (50ml) and saturated sodium chloride solution (50ml) successively, wash with anhydrous sulfuric acid After drying with sodium, filter, filter and concentrate to dryness to obtain yellow crystal 2-benzyloxy-1-bromo-3-nitrobenzene (III);

[0029] Its chemical reaction formula is:

[0030] .

[0031] (2) (12.32g, 40mmol) 2-benzyloxy-1-bromo-3-nitrobenzene (III), (7.97g, 48mmol) 3-carboxyphenyl...

Embodiment 2

[0041] The chemical name of Eltrombopag is 3-{(2Z)-2-[1-(3,4-xylyl)-3-methyl-5-oxo-1,5-dihydro-4H -pyrazole-4-ylidene]hydrazine group}-2-hydroxyl-3-biphenylcarboxylic acid-2-aminoethanol salt, the preparation method of making said Eltrombopag comprises the following processing steps:

[0042](1) Mix (21.8g, 100mmol) 2-nitro-6-bromophenol (I), (27g, 156mmol) benzyl bromide (II) and potassium carbonate (7.6g, 55mmol) in acetonitrile (200ml) Reflux for 3 hours, cool to room temperature, filter, concentrate to dryness, add ethyl acetate (150ml) to the concentrate to dissolve, wash with water (100ml) and saturated sodium chloride solution (75ml) successively, wash with anhydrous sulfuric acid After drying with sodium, filter, filter and concentrate to dryness to obtain yellow crystal 2-benzyloxy-1-bromo-3-nitrobenzene (III);

[0043] Its chemical reaction formula is as described in Example 1.

[0044] (2) (24.64g, 40mmol) 2-benzyloxy-1-bromo-3-nitrobenzene (III), (11.97g, 72mmol)...