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2',6'-dimethyltyrosine derivative and C-H activation methylation synthesis method thereof

A compound, alkoxymethyl technology, applied in the field of designing drug synthesis, can solve the problems of low efficiency, lengthy steps, harsh hydrogenation conditions, etc.

Active Publication Date: 2018-01-09
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

For example, the hydrogenation asymmetric synthesis reaction requires complex and expensive chiral rhodium catalysts, and the hydrogenation conditions are harsh; the de novo synthesis requires lengthy steps, and sometimes specific ligands are required to control the chirality; chemical resolution can only obtain half of the DMT in the S configuration , the efficiency is not high, and it does not conform to the principle of atom economy

Method used

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  • 2',6'-dimethyltyrosine derivative and C-H activation methylation synthesis method thereof
  • 2',6'-dimethyltyrosine derivative and C-H activation methylation synthesis method thereof
  • 2',6'-dimethyltyrosine derivative and C-H activation methylation synthesis method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0222] Embodiment 1: Synthesis of methylation raw material 2a (using synthetic method one)

[0223]

[0224] Dissolve L-tyrosine (50mmol) in 50mL of dry methanol, cool the reaction to 0°C, then add SOCl dropwise 2 (75mmol). After the addition was complete, the reaction mixture was refluxed for 8 hours. The reaction was stopped, the reaction was cooled to room temperature, and the excess solvent was spun off to obtain the crude compound 4a as a white solid. The crude product of the compound can be directly subjected to the next reaction without separation by column chromatography.

[0225] Compound 4a (50 mmol) was dissolved in 70 mL of dry acetonitrile, and the reaction solution was cooled to 0° C., then TBDMSCl (75 mmol) and DBU (100 mmol) were successively added to the system. After the addition was complete, the reaction was left at room temperature for 12 hours. Determined by TLC that the reaction was complete, adding H 2 O (50 mL) quenched the reaction and extract...

Embodiment 2

[0234] Embodiment 2: the synthesis of methylation raw material 2b, 2u (using synthetic method two)

[0235]

[0236] Compound 2a (50 mmol) was dissolved in 50 mL of dry tetrahydrofuran, and the reaction solution was cooled to 0° C., and 1 N TBAF solution in THF (60 mL) was slowly added dropwise to the system. After the addition was complete, the reaction was left at room temperature for 12 hours. Determined by TLC that the reaction was complete, adding H 2 The reaction was quenched with O (50 mL) and extracted with ethyl acetate (3 x 100 mL). Combine the organic phases, wash with saturated NaCl solution, anhydrous Na 2 SO 4 Dry and spin off excess solvent. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1-2:1) to obtain the target product 2b (14.4 g, 96%). 1 H NMR (400M Hz, CDCl 3 )δ8.55-8.52 (m, 2H), 8.13 (d, J = 7.8Hz, IH), 7.82 (td, J = 1.6, 7.7Hz, IH), 7.42-7.39 (m, 1H), 7.01-6.99 (m, 3H), 6.73(d, J=8.5Hz, ...

Embodiment 3

[0240] Embodiment 3: the synthesis of methylation raw material 2 (synthetic method three)

[0241]

[0242] Operation steps: put 2m (5mmol) in a Schlenk reaction flask, add palladium acetate (10%) and dppp (10%). After the reaction bottle was pumped and ventilated under argon protection, ROH (4.0mL), DMF (8.0mL) and triethylamine (15mmol) were added in sequence. The reaction bottle was first placed at room temperature and stirred until the raw materials were completely dissolved, and then introduced into the system Gas CO and the reaction temperature was raised to 70 ° C for 6 hours. The reaction was confirmed to be complete by TLC, the reaction was cooled to room temperature, and H 2 O (20mL) quenched the reaction, and the R"OH in the system was rotated. Extracted with ethyl acetate (3 × 30mL). The organic phases were combined, washed with saturated sodium chloride solution, anhydrous NaCl 2 SO 4 Dry and spin off excess solvent. The crude product was separated by silica...

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Abstract

The present invention provides a 2',6'-dimethyltyrosine derivative and a C-H activation methylation synthesis method thereof, specifically a compound represented by the following formula I, wherein each group is defined in the specification. The invention further provides a preparation method of the compound. The formula I is defined in the specification.

Description

technical field [0001] The present invention designs the field of drug synthesis, specifically, the present invention provides a C-H activated methylation synthesis of 2',6'-dimethyltyrosine derivatives and a preparation method thereof. Background technique [0002] Peptides and proteins are important physiological regulators of the human body, which can fully regulate the physiological functions of the human body, enhance and exert the physiological activities of the human body, and have important biological functions. Peptides are important for human cell activity, functional activities, and life existence. The introduction of non-natural amino acids into polypeptides can significantly change the properties of polypeptides, including biological activity, solubility, and metabolic stability. DMT (2',6'-dimethyl-L-tyrosine) is a very important specialty amino acid, especially in the de novo design of variable synthetic peptides. This unnatural amino acid is a constituent o...

Claims

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Application Information

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IPC IPC(8): C07D213/81C07D215/48C07C269/00C07C271/22C07C227/20C07C229/36
CPCY02P20/55
Inventor 马大为徐兰婷王绪宁
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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