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The preparation method of (r)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol

A technology of alkoxyphenyl and alkylsulfonyl, which is applied in the field of preparation of -1--2-ethanol, can solve the problems of inability to meet drug quality standards, heavy metals and the like

Active Publication Date: 2021-11-30
ENANTIOTECH CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method introduces heavy metals due to the catalytic hydrogenation step, which leads to more heavy metals remaining in the raw material of Apremilast, which cannot meet the drug quality standards

Method used

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  • The preparation method of (r)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol
  • The preparation method of (r)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol
  • The preparation method of (r)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol

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preparation example Construction

[0047] The preparation method of (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol according to one embodiment of the present invention comprises the following steps:

[0048] S101: providing a compound of the structure shown in formula (II);

[0049]

[0050] Among them, R 1 , R 2 and R 3 each independently for C 1-16 Alkyl, 3-8 membered cycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl; further, R 1 , R 2 and R 3 each independently for C 1-6 Alkyl, 3-6 membered cycloalkyl, 6 membered aryl or 6 membered heteroaryl; further, R 1 , R 2 and R 3 each independently for C 1-4 Alkyl or phenyl.

[0051] The structural compound represented by formula (II) can be obtained by using commercially available raw materials, or can be synthesized by existing methods, and is not particularly limited here. For example: Synthesize using the following method:

[0052]

[0053] Remove the ketone carbonyl α-position active wave hydrogen of the compound shown in th...

Embodiment 1

[0103]

[0104] In a 5L autoclave, under an argon atmosphere, add 100g of compound 1 from the feeding port, then add 1.5L of toluene to fully dissolve the raw material, stir fully and continuously pass in argon to degas by bubbling, and continue bubbling for 1h. Degassing is complete. Add 0.2g catalyst ( Where n is 12), quickly close the feeding port. Replace the argon with hydrogen, slowly introduce hydrogen to 3.0Mpa, and close the inflation valve. Rapidly stirred reactions were carried out at 25-40°C. When the pressure drops to remain constant, the reaction is considered to stop. Sampling was sent for liquid phase analysis to confirm the conversion rate. After the reaction, the system was filtered with suction. The catalyst was removed, and the filtrate was concentrated under reduced pressure to obtain an off-white solid, which was tested for residual heavy metals, chiral purity, catalyst recovery, and absolute configuration.

Embodiment 2

[0106]

[0107] In a 5L autoclave, under an argon atmosphere, add 100g of compound 1 from the feeding port, then add 1.5L of toluene to fully dissolve the raw material, stir fully and continuously pass in argon to degas by bubbling, and continue bubbling for 1h. Degassing is complete. Add 0.2g catalyst ( Where n is 16), quickly close the feeding port. Replace the argon with hydrogen, slowly introduce hydrogen to 3.0Mpa, and close the inflation valve. Rapidly stirred reactions were carried out at 25-40°C. When the pressure drops to remain constant, the reaction is considered to stop. Sampling was sent for liquid phase analysis to confirm the conversion rate. After the reaction, the system was filtered with suction. The catalyst was removed, and the filtrate was concentrated under reduced pressure to obtain an off-white solid, which was tested for residual heavy metals, chiral purity, catalyst recovery, and absolute configuration.

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Abstract

The present invention relates to the preparation method of (R)-1-(3-alkoxy-4-alkoxyphenyl)-2-(alkylsulfonyl)ethanol, comprising the following steps: providing the structure shown in formula (II) Compound; make the structural compound shown in formula (II) carry out catalytic hydrogenation reaction, make the compound shown in formula (I); Wherein, the catalyst that adopts in the described catalytic hydrogenation reaction has the structure shown in following formula (A): X, Y is each independently a halogen; n is 12‑65; represents a diphosphorus ligand; R 1 , R 2 and R 3 each independently for C 1‑16 Alkyl, 3‑8 membered cycloalkyl, 5‑10 membered aryl or 5‑10 membered heteroaryl; R 4 for H or C 1‑8 alkyl. The synthesis method can effectively reduce heavy metal residues while increasing the asymmetric conversion rate, and lays the foundation for the industrial production of apremilast.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol. 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 and can specifically act on cyclic adenosine monophosphate (cAMP), PDE4 inhibition leads to intracellular cAMP levels Increase, and produce anti-inflammatory activity by preventing rheumatoid synoviocytes from secreting tumo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C315/04C07C317/18B01J31/22B01J31/24
CPCB01J31/1815B01J31/2414B01J2231/643B01J2531/821C07C315/04C07C317/18
Inventor 毛波李彦雄蒙发明徐亮张伟鹏
Owner ENANTIOTECH CORP
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