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Synthesis method and intermediate of 3-(substituted dihydroisoindolinone-2-group)-2, 6-piperadinedione

A technology for intermediates and compounds, applied in the field of medicinal chemistry, can solve problems such as low product purity, insufficient total yield, and difficulty in environmental protection treatment

Active Publication Date: 2013-02-13
NANJING CAVENDISH BIO ENG TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The high-temperature reflux for a long time makes the purity of the product low, making separation and purification difficult
[0015] On the other hand, the total yield recorded in U.S. patent application US2006052609A1 is less than 20%; the yield recorded in Chinese patent ZL97180299.8 is less than 18%
Carbon tetrachloride has a serious effect on the destruction of the ozone layer. It is now a chemical banned by the United Nations Environment Agency. It is difficult to deal with environmental protection in industrial production, and it is highly toxic and extremely harmful to the environment.

Method used

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  • Synthesis method and intermediate of 3-(substituted dihydroisoindolinone-2-group)-2, 6-piperadinedione
  • Synthesis method and intermediate of 3-(substituted dihydroisoindolinone-2-group)-2, 6-piperadinedione
  • Synthesis method and intermediate of 3-(substituted dihydroisoindolinone-2-group)-2, 6-piperadinedione

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0172] Example 1: Preparation of 4-nitro-2,3-dihydro-1-hydro-isoindol-1-one:

[0173] Add 20 g of 2-bromomethyl-3-nitrobenzoic acid methyl ester and 200 ml of methanol into the reaction flask, blow ammonia gas at room temperature for 30 min while stirring, and keep the reaction for 2 hours. The crystals were grown in ice bath for 2 hours, filtered by suction, and dried to obtain 11.7 g of light yellow crystals. Yield: 90%. mp: 235.4-236.7°C.

[0174] 1 H-NMR: (300MHz, DMSO-d 6 )δ: 4.78 (s, 2H), 7.79 (t, 1H), 8.10 (d, 1H), 8.41 (d, 1H), 8.90 (S, 1H).

[0175] 1 H-NMR: (300MHz, DMSO-d 6 / D 2 O) δ: 4.76 (s, 2H), 7.77 (t, 1H), 8.08 (d, 1H), 8.39 (d, 1H).

[0176] FAB (M+1): 179

[0177] Elemental analysis: theoretical value: C 53.94%, H 3.39%, N 15.72%

[0178] Found values: C 54.08%, H 3.49%, N 15.81%

[0179] HPLC test conditions: column model and specification: phenomenonex Luna 5u C18

[0180] 250mm×4.6mm; flow rate: 1.0ml / min; λ=230...

Embodiment 2

[0184] Example 2: Preparation of 4-amino-2,3-dihydro-1-hydro-isoindol-1-one

[0185] Add 20 g of 4-nitro-2,3-dihydro-1-hydro-isoindol-1-one, 60 ml of methanol, 35 g of ammonium formate, 0.6 g of 7.5% Pd / C into the reaction flask, and heat up to 35 °C for 2 hours. Filter to remove Pd / C. The filtrate was concentrated to dryness under reduced pressure. Recrystallized from water to obtain 15.3 g of light yellow solid. Yield: 92%. mp: 195.6-197°C.

[0186] 1 H-NMR: (300MHz, DMSO-d 6 )δ: 4.31(s, 2H), 6.76(d, 1H), 7.14(t, 1H), 6.86(d, 1H), 5.30(s, 2H), 8.26(s, 1H)

[0187] 1 H-NMR: (300MHz, DMSO-d 6 / D 2 O)δ: 4.14(s, 2H), 6.79(d, 1H), 6.93(d, 1H), 7.16(t, 1H)

[0188] FAB(M+1): 149

[0189] Elemental analysis: theoretical value: C 64.85%, H 5.44%, N 18.91%

[0190] Found values: C 64.96%, H 5.61%, N 19.02%

[0191] HPLC test conditions: column model and specification: phenomenonex Luna 5u C18

[0192] 250mm×4.6mm; flow rate: 1.0ml / min; λ...

Embodiment 3

[0197] Embodiment 3: the preparation of α-bromoglutaric acid dimethyl ester:

[0198] Add 30 g of glutaric acid and 90 ml of chloroform into the dry reaction flask, and start stirring. Under reflux, 36 ml of thionyl chloride was added dropwise and reacted for 2 hours. Add 36 g of liquid bromine, and reflux with stirring for more than 16 hours. After cooling, 75ml of methanol was added dropwise under an ice bath, and the mixture was kept stirring for 2 hours. Wash with 150ml 5% sodium bisulfite, 150ml saturated sodium bicarbonate and 150ml saturated sodium chloride successively. The organic phase was dried over anhydrous sodium sulfate. Sodium sulfate was filtered off, the mother liquor was concentrated to dryness, and the fraction at 110-115°C / 5mmHg was collected by vacuum distillation. The target object is a colorless liquid. Weighs 41.3g. Yield: 76%.

[0199] FAB(M+1): 240

[0200] HPLC test conditions: column model and specification: phenomenonex Luna 5u C18

[020...

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Abstract

The invention discloses a synthesis method and an intermediate of 3-(substituted dihydroisoindolinone-2-group)-2, 6-piperadinedione, namely a synthesis method of a compound of the formula (I). The detailed definition of each substituent is shown in the specifications. The synthesis method has the advantages of high yield, small environmental effect, easy acquirement for raw materials and the like and is applicable to industrial production.

Description

[0001] This application is submitted on June 1, 2009. The application number is 200910142160.9, and the invention name is "3-(substituted dihydroisoindolinone-2-yl)-2,6-piperidinedione synthetic method and its intermediate divisional application of the "body" application. technical field [0002] The invention belongs to the field of medicinal chemistry, and more specifically relates to a synthesis method of 3-(substituted dihydroisoindolinone-2-yl)-2,6-piperidinedione and an intermediate thereof. Background technique [0003] Lenalidomide, a thalidomide analogue, is an immunomodulator with antiangiogenic and antineoplastic properties, and its chemical name is 3-(4-amino-1-oxo-1,3-dihydro-isoindol Indol-2-yl)-2,6-piperidinedione, its chemical structural formula is as follows: [0004] [0005] Lenalidomide has dione piperidine and indoline residues, and there is an asymmetric center in the structure. The currently approved lenalidomide is a racemic compound. [0006] Mu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/46C07D209/48C07D405/04
Inventor 杨浩严荣许永翔
Owner NANJING CAVENDISH BIO ENG TECH