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Synthetic method of apremilast chiral amine intermediate

A synthetic method and intermediate technology, applied in the field of pharmaceutical and chemical intermediate synthesis, can solve the problems of difficult industrialization, long process cycle, high reagent price, etc., and achieve the effect of simple synthetic route, stable reaction process and low cost

Active Publication Date: 2015-07-08
ENANTIOTECH CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with the resolution, the above chiral synthesis method has the advantages of lower cost, higher yield, economical and environmental protection, but also has certain limitations, such as long process cycle, difficult to realize industrialization or relatively high price of reagents used, etc.

Method used

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  • Synthetic method of apremilast chiral amine intermediate
  • Synthetic method of apremilast chiral amine intermediate
  • Synthetic method of apremilast chiral amine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] In a 250ml dry Shrek bottle, 2.72g (10mmol) of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone was dissolved in 30ml of anhydrous toluene, After bubbling with argon for 15 min, transfer to a 100 mL hydrogenation tube, add 10 mg of DIOP-RuCl 2 -Me-BIMAH catalyst and 70mg (0.6mmol) of potassium tert-butoxide, passed through 3MPa of hydrogen, stirred at 25°C for 16h. Filtrate, and remove the solvent by rotary evaporation to obtain 2.70 g of off-white solid (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol, the reaction yield is 99.4% , the enantiomeric excess value was 98.2%, and it was directly carried out to the next reaction without purification.

[0038] After dissolving 2.74g (10mmol) (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol in 30ml of dichloromethane, transfer it to a 100mL three-necked flask 4.0 mL (30 mmol) of triethylamine was added, and a solution of 1.16 mL of methanesulfonyl chloride dissolved in 10 mL of dichloromethane was...

Embodiment 2

[0042] In a 250ml dry Shrek bottle, 5.45g (20mmol) of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone was dissolved in 60ml of anhydrous toluene, After bubbling with argon for 15 min, transfer to a 250 mL hydrogenation tube, add 17 mg of DIOP-RuCl 2 -Me-BIMAH catalyst and 135 mg (1.2 mmol) of potassium tert-butoxide, passed through 1 MPa of hydrogen, stirred at 45° C. for 10 h. Filtrate, and remove the solvent by rotary evaporation to obtain 5.42 g of off-white solid (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol, with a reaction yield of 98.8% , the enantiomeric excess value was 98.0%, and it was directly carried out to the next reaction without purification.

[0043] After dissolving 2.74g (10mmol) (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol in 30ml of dichloromethane, transfer it to a 100mL three-necked flask 6.0 mL (40 mmol) of pyridine was added, and a solution of 2.2 mL of benzenesulfonyl chloride dissolved in 10 mL of dichloromethane...

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Abstract

The invention relates to a synthetic method of an apremilast chiral amine intermediate (S)-2-[1-(3-ethoxyl-4-methoxylphenyl)]-1-methylsulfonyl-2-ethylamine (V). The synthetic method is characterized by including following steps: (1) with 1-(3-ethoxyl-4-methoxylphenyl)-2-(methylsulfonyl)ethyl ketone (I) as a raw material, performing asymmetric hydrogenation reduction to obtain methyl sulfonyl ethanol (II); (2) performing an esterification reaction to obtain methyl sulfonyl ester (III); (3) performing an azidation reaction to obtain an azide compound (IV); and (4) performing hydrogenation reduction to obtain the chiral amine intermediate (V) being high in chiral purity. The synthetic method is simple in process, is stable in reaction processes, and is environmental-protective and low-cost. In the synthetic method, the use amount of a catalyst during catalytic hydrogenation is less and the conversion rate reaches higher than 98%. The chiral amine can be prepared through chiral alcohol with very high yield and purity so that the synthetic method has a quite excellent commercial value and develops a new approach for synthesizing the apremilast chiral amine intermediate.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical and chemical intermediates, and mainly provides a chiral amine intermediate (S)-2-[1-(3-ethoxy-4-methoxyphenyl)]- Synthetic method of 1-methylsulfonyl-2-ethylamine. Background technique [0002] Apremilast, chemical name (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylamino Isoindoline-1,3-dione, a selective PDE4 inhibitor developed by Celgene, was approved by the US FDA in March 2014 as an oral drug for the treatment of psoriatic arthritis. In 2014 In September, it was approved by the US FDA for the treatment of moderate to severe psoriasis (also known as plaque psoriasis), and the trade name is Otezla. As an oral small molecule phosphodiesterase 4 (PDE4) inhibitor, apremilast can selectively inhibit PDE4, can specifically act on cyclic adenosine monophosphate (cAMP), and PDE4 inhibition leads to intracellular cAMP levels Increase, and produce anti-inflammatory act...

Claims

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Application Information

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IPC IPC(8): C07C315/04C07C317/28
Inventor 徐亮蒙发明陈汝婷杨尉穆罕默德·马卡
Owner ENANTIOTECH CORP
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