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Preparation method of pomalidomide

A technology of pomalidomide and reaction temperature, which is applied in the field of pomalidomide preparation, achieves the effects of high yield, simple post-treatment, and easy-to-obtain raw materials

Active Publication Date: 2014-04-16
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In summary, the reported synthetic methods of pomalidomide all have defects in varying degrees, which need to be further improved.

Method used

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  • Preparation method of pomalidomide
  • Preparation method of pomalidomide
  • Preparation method of pomalidomide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] The preparation of compound III-1, wherein R is H;

[0037] 3-Nitrophthalic anhydride (I, 44.0g, 0.23mol), 3-amino-2,6-piperidinedione hydrochloride (II, 37.9g, 0.23mol), dissolved in 600mL tetrahydrofuran (THF ), then slowly add triethylamine (23.27g, 0.23mol) dropwise to the system, control the temperature of the system 1 H-NMR (DMSO-D 6 )δ: 1.88 (-*CHC H a h b CH c h d -, 1H, m), 2.21 (-*CHCH a h b C H c h d -, 1H, m), 2.53 (-*CHCH a H b CH c h d -, 1H, m), 2.72 (-*CHCH a h b CH c H d -, 1H, m), 4.74 (-* CH CH a h b CH c h d -, 1H, m), 7.76 (-ArH, 1H, t), 8.16 (-ArH, 1H, d), 8.18 (-ArH, 1H, d), 8.99 (-COOH, 1H, d), 10.85 (- CO-NH-, 1H, s), 13.60 (-CO-NH-CO-, 1H, s); ESI-MS(m / z)=322.03[M+H] + .

Embodiment 2

[0039] Compounds III-2, III-3 and III-4 are prepared from compound III-1.

[0040] Preparation of compound Ⅲ-2: wherein: R is CH 3

[0041]Compound Ⅲ-1 (32.16g, 0.10mol), methanol (3.84g, 0.12mol), dissolved in 100mL of dichloromethane, cooled in an ice bath, slowly added thionyl chloride (11.75g, 0.12mol) dropwise to the system , control the temperature of the system <5°C during the dropwise addition. After the dropwise addition is completed, raise the temperature to room temperature and react for 3.0 hours. After the reaction is complete as detected by TLC, concentrate, and add saturated sodium bicarbonate solution to the residue. Solids are precipitated, and filtered. The target compound III-2 was obtained, 30.83 g, 92%.

[0042] Preparation of compound Ⅲ-3: wherein, R is C 2 h 5

[0043] Compound Ⅲ-1 (32.16g, 0.10mol), ethanol (5.52g, 0.12mol), dissolved in 100mL of dichloromethane, cooled in an ice bath, slowly added thionyl chloride (11.75g, 0.12mol) dropwise to the...

Embodiment 3

[0047] Preparation of compound Ⅳ-1

[0048] Compound Ⅲ-1 (32.10g, 0.10mol), 10%Pd / C (50%, 16.05g) and toluene (6.42L) were added to the hydrogenation kettle, filled with a pressure of 0.1MPa, and reacted at 100°C. After the reaction was detected by TLC, it was filtered, washed with methanol (20 mL×3), the filtrate was concentrated, and dried in vacuo to obtain 27.65 g of compound IV, with a yield of 95.0%. 1 H-NMR (DMSO-D 6 )δ: 1.89 (-*CHC H a h b CH c h d -, 1H, m), 2.16 (-*CHCH a h b C H c h d -, 1H, m), 2.51 (-*CHCH a H b CH c h d -, 1H, m), 2.78 (-*CHCH a h b CH c H d -, 1H, m), 4.65 (-* CH CH a h b CH c h d -, 1H, m), 5.51 (-NH2, 2H, s), 6.86 (-ArH, 1H, t), 7.02 (-ArH, 1H, t), 7.13 (-ArH, 1H, d), 8.61 (- COOH, 1H, d), 10.92 (-CO-NH-, 1H, s), 13.62 (-CO-NH-CO-, 1H, s); ESI-MS(m / z)=292.09[M+H] + .

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Abstract

The invention discloses a preparation method of pomalidomide as a medicament for resisting multiple myeloma. The preparation method comprises the following steps: dissolving a compound as shown in a formula IV in a solvent, carrying out self cyclization reaction without adding any catalyst, then cooling, separating solid out, and collecting the solid, namely the target product pomalidomide. Compared with a publically reported method, the preparation method disclosed by the invention has the advantages that raw materials are easily obtained, fewer reaction steps are adopted, the conditions are mild, the posttreatment is simple and the yield is high; in addition, the target product does not contain heavy metal residues; the preparation method is suitable for large-scale industrial product. The general formula is described in the specification.

Description

technical field [0001] The invention relates to a preparation method of an anti-multiple myeloma drug pomalidomide (3-amino-(2,6-dioxo-3-piperidinyl)-phthalimide). Background technique [0002] Multiple myeloma (MM) is a malignant plasma cell disease, and its tumor cells originate from plasma cells in the bone marrow, and plasma cells are cells that develop into the final functional stage of B lymphocytes, and are currently classified as B-cell lymphocytes by WHO. A type of tumor called plasma cell myeloma / plasma cell tumor. It is characterized by abnormal proliferation of bone marrow plasma cells with overproduction of monoclonal immunoglobulins or light chains (M protein), and in rare cases can be non-secretory MM that does not produce M protein. Multiple myeloma is often accompanied by multiple osteolytic lesions, hypercalcemia, anemia, and kidney damage. Due to the suppression of normal immunoglobulin production, it is prone to various bacterial infections. The incide...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 李建其黄道伟周爱南刘育朱梅誉
Owner SHANGHAI INST OF PHARMA IND CO LTD