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Preparation method of N-(2, 6-dioxo-3-piperidyl) phthalimide compound

A technology of nitrophthalic acid and aminoglutarimide, applied in the field of pomalidomide preparation, can solve the problems of easy moisture absorption, short preparation route, instability, etc.

Inactive Publication Date: 2014-05-28
NANJING HUAWE MEDICINE TECH DEV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Method 1 and method 2 have sufficient market supply of raw materials, guaranteed sources and quality, and short preparation routes. Each step of the reaction is a mature chemical reaction, simple to operate, and easy to industrialized production. However, due to the influence of the adjacent nitro , 3-nitrophthalic anhydride is very unstable, it is easy to absorb moisture, hydrolyzed into 3-nitrophthalic acid and formic acid

Method used

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  • Preparation method of N-(2, 6-dioxo-3-piperidyl) phthalimide compound
  • Preparation method of N-(2, 6-dioxo-3-piperidyl) phthalimide compound
  • Preparation method of N-(2, 6-dioxo-3-piperidyl) phthalimide compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1: Preparation of 3-nitro-N-(2,6-dioxo-3-piperidinyl)-phthalimide

[0049] In a 2L reaction flask, add 3-nitrophthalic acid (150g, 0.7mol), 3-amino-2,6-piperidinedione hydrochloride (90g, 0.55mol), 100g molecular sieve and 1.6L For glacial acetic acid, add anhydrous sodium acetate (50 g, 0.37 mol) after heating to 105-115 °C, keep the temperature at this temperature for 3-4 hours, and stop the reaction after TLC detects that the reaction is complete. Suction filtration and thorough drying gave off-white solid (154 g, 93%), mp 282-283°C.

[0050] 1 H NMR (DMSO-d 6 )δ: 11.19 (s, 1H, CONHCO), 8.32 (d, 1H, CHCNO 2 ), 8.24 (d, 1H, CHCCO), 8.10 (d, 1H, CHC H CH), 5.14~5.21(m, 1H, COC H CH a h b ), 2.81~2.86 (m, 1H, C H a h b CO), 2.55~2.60(m, 1H, COCHC H a h b ), 2.43~2.51 (m, 1H, CH a H b CO), 2.02~2.06(m, 1H, COCHCH a H b ).

Embodiment 2

[0051] Embodiment 2: the preparation of pomalidomide

[0052] Thoroughly dissolve 3-nitro-N-(2,6-dioxo-3-piperidinyl)-phthalimide (80 g, 0.26 mol) in 1.2 L of N, N-dimethyl Add 10 g of palladium on carbon to the formamide, transfer to a hydrogenation kettle, and react for 12 hours at a hydrogen pressure of 0.5-1.0 MPa. After the reaction was completed, the palladium-carbon was filtered off, 120 g of activated carbon was added to the filtrate, stirred for 0.5 h, and filtered with suction, an appropriate amount of pure water was added dropwise to the filtrate, stirred for 1 h, filtered with suction, and fully dried to obtain the crude product (68 g, 95%). After beating and washing with hot water, a yellow solid was obtained, mp>300°C.

[0053] 1 HNMR (DMSO-d 6 )δ.1112(s, 1H, CONHCO), 745(t, 1H, CHC H CH), 7.01(d, 1H, CHCCO), 7.01(d, 1H, C H CNH 2 ), 6.54 (s, 2H, NH 2 ), 5.03~5.08 (m, 1H, COC H CH a h b ), 2.85~2.89 (m, 1H, C H a h b CO), 2.59~2.63(m, 1H, COCHC H a...

Embodiment 3

[0055] Embodiment 3: the preparation of compound 2

[0056]

[0057] Add 0.8mol of 3-nitrophthalic acid, 0.55mol of compound 1 and 1.5L of N,N-dimethylformamide to a 2L reaction flask in sequence, add 70g of anhydrous sodium acetate after heating to 120°C, and keep the The reaction was carried out at high temperature for 5 h, and the reaction was stopped after the completion of the reaction detected by TLC. Suction filtration, fully dried to obtain off-white solid (yield 80%).

[0058] 1 H NMR (DMSO-d 6 )δ: 11.19 (s, 1H, CONHCO), 8.32 (d, 1H, CHCNO 2 ), 8.24 (d, 1H, CHCCO), 8.10 (d, 1H, CHC H CH), 7.30~7.40(m, 5H, CHCHCHCHCH ), 5.14~5.21(m, 1H, COC H CH a h b ), 4.32(d, 2H, CC H 2 C), 2.81 ~ 2.86 (m, 1H, C H a h b CO), 2.55~2.60(m, 1H, COCHC H a h b ), 2.43~2.51 (m, 1H, CH a H b CO), 2.02~2.06(m, 1H, COCHCH a H b ).

[0059] LC-MS(ESI)(m / z):394[M+H] + .

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Abstract

The invention relates to a method for preparing a compound represented as a formula (I) or pharmaceutically acceptable salt, solvate, polymorphic substance or stereoisomer, wherein the method has the advantages of short reaction period, simplicity in operation, low production cost, good product quality and suitability of industrial production, raw materials are easy to obtain, and an R group is hydrogen, halogen, benzyl, (C1-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical production, and in particular relates to a preparation method of unsubstituted and substituted N-(2,6-dioxo-3-piperidinyl)phthalimide compounds, especially pomadol Methods for the preparation of amines. Background technique [0002] 3-Amino-N-(2,6-dioxo-3-piperidinyl) phthalimide, namely pomalidomide, was developed by Celgene Crop, USA An oral immunomodulator, trade name Pomalyst. The drug was approved by the U.S. Food and Drug Administration (FDA) on February 8, 2013 for the treatment of relapsed and refractory multiple myeloma, and its racemic mixture is used clinically. The structural formula is as follows: [0003] [0004] Currently, there are six methods for preparing 3-amino-N-(2,6-dioxo-3-piperidinyl)phthalimine compounds reported in the literature. [0005] Method 1: Using 3-nitrophthalic acid as the starting material, dehydration in acetic anhydride to obtain 3-nitrophthalic...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 包金远徐峰蒋玉伟张孝清
Owner NANJING HUAWE MEDICINE TECH DEV
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