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Pomalidomide impurity synthesis method

A technology of pomalidomide and a synthesis method, which is applied in the field of chemical pharmacy and achieves the effects of simple operation, improved accurate positioning and qualitative, and easy availability of raw materials

Active Publication Date: 2017-02-22
SHENZHEN NEPTUNUS PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After retrieval, there is no bibliographical report about the synthesis of this impurity, therefore, it is of great practical significance to provide a synthetic method of pomalidomide impurity M10 for the preparation of impurity standard

Method used

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  • Pomalidomide impurity synthesis method
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  • Pomalidomide impurity synthesis method

Examples

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Effect test

Embodiment 1

[0023] Example 1: Pomalidomide impurity M10: Synthesis of (S)-5-amino-4-(4-amino-1,3-dioxoisoindol-2-yl)-5-oxopentanoic acid

[0024] Combine 3-nitrophthalic anhydride (1) (25.0g, 129mmol), L-isoglutamine (18.5g, 126mmol), molecular sieve 92g) was mixed in N,N-dimethylformamide (400mL), and heated at 90°C for 16 hours. After the reaction is complete, the reaction solution is brought to room temperature, and the molecular sieve is filtered out. The filtrate was concentrated and concentrated to obtain a yellow solid, which was placed in a mixed solvent of methanol and water (V / V=3:26, 232ml) and stirred at room temperature overnight, and then filtered. The filtered solid was washed with water (100ml), and then dried in a vacuum oven (55°C) for 6 hours to obtain (S)-5-nitro-4-(4-amino-1,3-dioxoindole-2) -Yl)-5-oxopentanoic acid (2) (21.0 g, pale yellow solid, yield 53.0%). LC / MS=344.2[M+Na] + ,1H NMR(400MHz,DMSO-d 6 ): δ12.06(s,1H), 8.29(d,1H), 8.18(d,1H), 8.07(t,1H), 7.62(s,1H),...

Embodiment 2

[0029] Example 2: Pomalidomide impurity M10: Synthesis of (S)-5-amino-4-(4-amino-1,3-dioxoisoindol-2-yl)-5-oxopentanoic acid

[0030] Combine 3-nitrophthalic anhydride (1) (25.0g, 129mmol), L-isoglutamine (17.5g, 119mmol), molecular sieve ( 50g) was mixed in N,N-dimethylformamide (266 mL), and heated at 80°C for 15 hours. After the reaction is complete, the reaction solution is brought to room temperature, and the molecular sieve is filtered out. The filtrate was concentrated and concentrated to obtain a yellow solid, which was placed in a mixed solvent of methanol and water (V / V=3:26, 232ml) and stirred at room temperature overnight, and then filtered. The filtered solid was washed with water (100ml), and then dried in a vacuum oven (50°C) for 4 hours to obtain (S)-5-nitro-4-(4-amino-1,3-dioxoindole-2) -Yl)-5-oxopentanoic acid (2) (20.0 g, pale yellow solid, yield 50.5%).

[0031] The above (S)-5-nitro-4-(4-amino-1,3-dioxoisoindol-2-yl)-5-oxopentanoic acid (2) (21.0g, 65.5mmol)...

Embodiment 3

[0032] Example 3: Pomalidomide Impurity M10: Synthesis of (S)-5-amino-4-(4-amino-1,3-dioxoisoindol-2-yl)-5-oxopentanoic acid

[0033] Combine 3-nitrophthalic anhydride (1) (25.0g, 129mmol), L-isoglutamine (37.5g, 255mmol), molecular sieve ( 125g) was mixed in N,N-dimethylformamide (798 mL), and heated at 120°C for 20 hours. After the reaction is complete, the reaction solution is brought to room temperature, and the molecular sieve is filtered out. The filtrate was concentrated and concentrated to obtain a yellow solid, which was placed in a mixed solvent of methanol and water (V / V=3:26, 232ml) and stirred at room temperature overnight, and then filtered. The filtered solid was washed with water (100ml) and then dried in a vacuum oven (60°C) for 8 hours to obtain (S)-5-nitro-4-(4-amino-1,3-dioxoindole-2) -Yl)-5-oxopentanoic acid (2) (20.5 g, pale yellow solid, yield 51.8%).

[0034] The above (S)-5-nitro-4-(4-amino-1,3-dioxoisoindol-2-yl)-5-oxopentanoic acid (2) (21.0g, 65.5mmol...

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Abstract

The invention discloses a pomalidomide impurity (S)-5-amino-4-(4-amino-1,3-dioxo-isoindole-2-yl)-5-oxopentanoic acid synthesis method. The method includes: S1, acylation reaction, to be more specific, adding 3-nitrophthalic anhydride (1), L-isoglutamine, molecular sieves and N,N-dimethyl formamide into a reaction bottle, performing reaction for 15-20h at 80-120 DEG C, and treating reaction liquid to obtain (S)-5-nitro-4-(4-amino-1,3-dioxo-isoindole-2-yl)-5-oxopentanoic acid (2); S2, hydrogenation reduction, to be more specific, adding the (S)-5-nitro-4-(4-amino-1,3-dioxo-isoindole-2-yl)-5-oxopentanoic acid (2) into the reaction bottle, then adding palladium charcoal and methyl alcohol, performing room-temperature stirring reaction for 12-20h in existence of hydrogen, and carrying out vacuum concentration to obtain a product. The synthesis method has advantages of simplicity in operation, high yield and high purity, and accuracy of pomalidomide product detection and analysis for quantitative determination of impurity M10 is improved.

Description

Technical field [0001] The invention belongs to the technical field of chemical pharmacy, and specifically relates to a pomalidomide impurity M10: (S)-5-amino-4-(4-amino-1,3-dioxoisoindol-2-yl)-5 -Synthesis method of oxovaleric acid. Background technique [0002] Multiple myeloma (MM) can be treated effectively but not cured. 97% of patients were over 40 years old at diagnosis, and only 3% of cases were younger than 40 years old. 80% of cases occur after the age of 60, and China is rapidly entering an aging society. The population aged 60 and above accounts for 13.26% of the total population of the country, close to 180 million people. As the base of the elderly population grows, the incidence of multiple myeloma will show an upward trend. [0003] The chemical name of pomalidomide is: 4-amino-2-(2,6-dioxo-piperidin-3-yl)-isoindoline-1,3-dione. Pomalidomide is a kind of Thalidomide analog is an immunomodulator with anti-tumor activity. In the in vitro cytology test, pomalidomi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/48
CPCC07D209/48
Inventor 唐田彭江华吴婧王彦青黎万杨经安佘琴冯汉林
Owner SHENZHEN NEPTUNUS PHARMA RES INST CO LTD
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