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Preparation method of (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol

A technology of alkoxyphenyl and alkylsulfonyl, applied in the field of preparation of -1--2-ethanol), which can solve problems such as failure to meet drug quality standards and multiple metals

Active Publication Date: 2020-08-11
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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  • Preparation method of (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol
  • Preparation method of (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol
  • 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 t...

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 gas to degas by bubbling, and continue bubbling for 1h. Degassing is complete. Add 0.2g catalyst to the feeding port Wherein n is 12), and the feeding port is closed rapidly. 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 gas to degas by bubbling, and continue bubbling for 1h. Degassing is complete. Add 0.2g catalyst ( Wherein n is 16), and the feeding port is closed rapidly. 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 invention relates to a preparation method of (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol. The preparation method comprises the following steps: providing a compound with a structureshown as a formula (II); carrying out a catalytic hydrogenation reaction on the compound with the structure shown in the formula (II) to prepare a compound shown in a formula (I), wherein a catalystadopted in the catalytic hydrogenation reaction has a structure as shown in a formula (A) which is described in the specification. In the formula (A), X and Y are halogen independently; n ranges from12 to 65; a fragment as described in the specification is a diphosphorus ligand; R1, R2 and R3 are each independently selected from a group consisting of C1-16 alkyl groups, three-to-eight-membered cycloalkyl groups, five-to-ten-membered aryl groups and five-to-ten-membered heteroaryl groups; and R4 is H or a C1-8 alkyl group. The method can effectively reduce heavy metal residues while improvingan asymmetric conversion rate, and lays a foundation for 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, can specifically act on cyclic adenosine monophosphate (cAMP), and PDE4 inhibition leads to intracellular cAMP levels Increase, and produce anti-inflammatory activity by preventing rheumatoid synoviocytes from secreting tu...

Claims

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Application Information

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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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