Preparation method of 3-(4-amino-1,3-dihydro-1-oxo-2h-isoindol-2-yl)-2,6-piperidinedione

A technology of methylpyrrolidone and dimethyl sulfoxide, which is applied in the field of synthesis of 3--2,6-piperidinedione, can solve the problems of high risk factor, difficult purification, and high equipment requirements, and achieve low equipment requirements, The effect of low cost and easy industrial production

Active Publication Date: 2019-03-01
JIANGSU HANSOH PHARMA CO LTD
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

This method has the disadvantages of high risk factor, high equipment requirements and difficult purification

Method used

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  • Preparation method of 3-(4-amino-1,3-dihydro-1-oxo-2h-isoindol-2-yl)-2,6-piperidinedione
  • Preparation method of 3-(4-amino-1,3-dihydro-1-oxo-2h-isoindol-2-yl)-2,6-piperidinedione
  • Preparation method of 3-(4-amino-1,3-dihydro-1-oxo-2h-isoindol-2-yl)-2,6-piperidinedione

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Experimental program
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Effect test

Embodiment 1

[0022]

[0023] Compound II (3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindol-2-yl)piperidine-2,6-dione) (28.9g, 0.1mol ), 10% palladium carbon (10.0g), and ammonium formate (15.8g, 0.25mol) were added to dimethyl sulfoxide (500ml), kept at a temperature of 30-40°C, reacted for 7-8h, filtered while hot, and the filtrate was added dropwise Put it into water (1500ml), stir and crystallize, filter with suction, wash the filter cake with water, and dry the filter cake in vacuum at room temperature for 14-16 hours to obtain compound I (light yellow solid, 24.2g), molar yield: 93.4%. Melting point: 269-271°C, HPLC: 99.94%. LC / MS (m / c): 260.10 (MH + ), the product was determined to be compound I after NMR structure analysis, and its hydrogen spectrum was as follows figure 1 As shown, the carbon spectrum as figure 2 shown.

Embodiment 2

[0025] Compound II (3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindol-2-yl)piperidine-2,6-dione) (14.5g, 0.05mol ), 10% palladium carbon (5.0g), and ammonium formate (7.88g, 0.125mol) were added to methanol (700ml), kept at a temperature of 30-40°C, reacted for 7-8h, filtered while hot, concentrated the filtrate to 100ml, added water (500ml) was beaten for 1 hour, filtered, and the filter cake was vacuum-dried at room temperature for 14-16 hours to obtain compound I (yellow solid, 8.43g), molar yield: 65%. The product was identified as compound I after NMR structure analysis.

Embodiment 3

[0027] Compound II (3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindol-2-yl)piperidine-2,6-dione) (14.5g, 0.05mol ), 10% palladium carbon (5.0g), and ammonium formate (7.88g, 0.125mol) were added to N-methylpyrrolidone (200ml), kept at a temperature of 30-40°C, reacted for 7-8h, filtered while hot, and the filtrate dripped Add it into water (1000ml), stir and crystallize, filter with suction, wash the filter cake with water, and dry the filter cake under vacuum at room temperature for 14-16 hours to obtain compound I (light yellow solid, 11.8g), molar yield: 90.8%. The product was identified as compound I after NMR structure analysis.

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Abstract

The present invention relates to 3-(4-amino-1, 3-dihydro-1-oxo-2 H-isoindole-2-yl)-2, 6-piperidinedione preparation method. The method is as follows: in the presence of reducing system, a target product is prepared by reaction of formula (II) compound in an organic solvent. The method provided by the present invention has no need to use hydrogen as a reducing agent, and is safe, low in cost, high in yield, easy in purification and easy in industrialization.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and specifically relates to a low-cost, green and environmentally friendly preparation of 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2 , The synthetic method of 6-piperidinedione. Background technique [0002] Lenalidomide (Revlimid) is used in the treatment of myelodysplastic syndrome, which affects various biological pathways in cells. Celgene is still evaluating the hematology and oncology treatment of this product, including multiple myeloma, myelodysplastic syndrome, chronic lymphocytic leukemia and solid tumors. Myelodysplastic syndrome is a hematologic malignancy affecting approximately 300,000 patients worldwide. MDS occurs when blood cells in the bone marrow remain immature and cannot perform their necessary functions. The bone marrow fills with these immature cells, inhibiting the development of normal cells. Patients with myelodysplastic syndrome must often rely on blood...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 刘学良徐士伟仇伟强
Owner JIANGSU HANSOH PHARMA CO LTD
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