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Preparation method for synthesizing apremilast intermediate

A technology for intermediates and compounds, which is applied in the field of simple preparation of synthesizing apremilast intermediate-1-phenyl-2-methanesulfonylethylamine, can solve the problem of no industrial value, reduced molecular utilization, difficult operation, etc. problem, to achieve the effect of stable nature and low price, conducive to operation and reducing waste water discharge

Active Publication Date: 2015-03-25
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] The above reaction scheme 5 uses dimethyl sulfone monolithium salt in the addition reaction, and the monolithium salt is prepared from dimethyl sulfone and butyllithium in an aprotic solvent, and butyllithium, etc. are inevitably used Lively lithium compound, not easy to handle
At the same time, the use of macromolecular and highly selective chiral amines reduces the utilization rate of molecules and has no industrial value

Method used

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  • Preparation method for synthesizing apremilast intermediate
  • Preparation method for synthesizing apremilast intermediate
  • Preparation method for synthesizing apremilast intermediate

Examples

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Embodiment 1

[0064] Example 1: Preparation of 1-(3-ethoxy-4-methoxy)phenyl-2-methanesulfonyl ethyl ketone (II)

[0065] Under the protection of nitrogen, add 200 grams of normal hexane and 24 grams (0.6 moles) of 60% solid sodium hydride successively in a dry 1000 milliliter glass flask, cool, keep the internal temperature between 15 ° C and 25 ° C, dropwise add 188 grams (2 mol) dimethyl sulfone, the dropwise addition is completed in about 2 hours, and then the temperature is raised to 35° C. for 1-2 hours (activation reaction). Then keep the internal temperature between 30°C and 35°C, add dropwise a mixed solution of 126.6 grams of 3-ethoxy-4-methoxybenzoic acid methyl ester (0.6 mole) and 200 grams of n-hexane, and drop it in about 2 hours. After dropping, react at 35°C for 4 hours. Cool down to 20°C, add 110 grams of saturated ammonium chloride aqueous solution dropwise, statically separate layers, extract the aqueous layer with 100 grams of ethyl acetate three times, combine the orga...

Embodiment 2

[0066] Example 2: Preparation of 1-(3-ethoxy-4-methoxy)phenyl-2-methanesulfonyl ethyl ketone (II)

[0067] Under the protection of nitrogen, add 200 g dimethyl sulfoxide, 200 g dimethyl sulfone, and 89.6 g (0.8 mole) potassium tert-butoxide to a dry 1000 ml glass flask in sequence, cool and keep the inner temperature between 10°C and 20°C After 2 hours, the temperature was raised to 30°C and the reaction was kept for 1 to 2 hours. Then keep the internal temperature between 33°C and 35°C, add 126.6 g of methyl 3-ethoxy-4-methoxybenzoate (0.6 mol) in batches, and react at 35°C for 4 hours after the addition. Cool down to 20°C, add 118 grams of saturated ammonium chloride aqueous solution dropwise, statically separate layers, extract the aqueous layer with 100 grams of ethyl acetate three times, combine the organic phases, dry with 30 grams of anhydrous sodium sulfate for 4 hours, filter, and recover the solvent from the filtrate 147.7 g of off-white solid 1-(3-ethoxy-4-methoxy)...

Embodiment 3

[0068] Example 3: Preparation of 1-(3-ethoxy-4-methoxy)phenyl-2-methanesulfonyl ethyl ketone (II)

[0069] Under the protection of nitrogen, add 180 grams of cyclohexane and 36 grams (0.9 moles) of 60% solid sodium hydride successively in a dry 1000 milliliter glass flask, cool, keep the internal temperature between 20°C and 25°C, and add dropwise 141 grams ( 1.5 moles) of dimethyl sulfone, the dropwise addition was completed in about 2 hours, and then the temperature was raised to 35°C and the reaction was kept for 1 to 2 hours. Then keep the internal temperature at 34-35°C, add dropwise a mixed solution of 134.4 grams of 3-ethoxy-4-methoxyethyl benzoate (0.6 moles) and 200 grams of cyclohexane, and drop it in about 2 hours. React at 35°C for 4 hours. Cool down to 20°C, add 165 grams of saturated ammonium chloride aqueous solution dropwise, statically separate layers, extract the aqueous layer with 150 grams of ethyl acetate three times, combine the organic phases, dry with ...

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Abstract

The invention relates to a preparation method for synthesizing an apremilast intermediate. The preparation method comprises the following steps of: carrying out condensation reaction on 3-ethoxyl-4-methoxyl-benzoate and dimethyl sulfone under an alkaline condition to generate 2-(3-ethoxy-4-methoxyphenyl)-1-methylsulfonyl acetone; reacting the compound II and chiral amine in the presence of an acidic catalyst to obtain 1-N-substituted amino-1-(3-ethoxyl-4-methoxyl) phenyl-2-methylsulfonyl ethylene (III), and directly hydrogenating the obtained compound III in the presence of a hydrogenation catalyst without separating the compound III to obtain a product (S)-1-(3-ethoxyl-4-methoxyl) phenyl-2-methanesulfonyl ethylamine (I), namely the apremilast intermediate, wherein the apremilast intermediate can be further prepared into N-acetyl L-leucinate. The invention also provides a preparation method of apremilast. The preparation method disclosed by the invention has the advantages of simple process flow, safety, environmental friendliness and low cost and is favorable to clean industrialized production.

Description

technical field [0001] The invention relates to a convenient preparation method for synthesizing a premilast intermediate (S)-1-(3-ethoxy-4-methoxy)phenyl-2-methanesulfonylethylamine, which belongs to the pharmaceutical biochemical industry field. Background technique [0002] (S)-1-(3-ethoxy-4-methoxy)phenyl-2-methanesulfonylethylamine (I) is the key intermediate for the preparation of apremilast. Apremilast (Apremilast) is an oral drug for the treatment of active psoriatic arthritis, the chemical name is (S)-2-[1-(3-ethoxy-4-methoxy)phenyl-2- Methanesulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, CAS No. 608141-41-9. The drug, which was approved by the FDA under the brand name Otezla (Apremilast) in March 2014, is the first and only FDA-approved oral, selective phosphodiesterase 4 (PDE4) inhibitor for the treatment of plaque psoriasis agent. [0003] U.S. Patent US6962940 first reported the synthesis method of Apremilast, which is obtained by condensation of two key...

Claims

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Application Information

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IPC IPC(8): C07C317/28C07C315/04C07D209/48
Inventor 周立山戚聿新陈军宋春鹏王宝昌王凯李新发
Owner XINFA PHARMA
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