Preparation of (s)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonylethylamine and preparation method of apremilast

A technology of methylsulfonylethylamine and methylsulfonylacetonitrile, which is applied in the preparation of organic compounds, chemical instruments and methods, organic chemistry, etc., can solve the problems of large discharge of "three wastes", unfavorable environmental protection, and high price, and achieve waste liquid discharge The effect of less, strong operability, and low product cost

A technology of methylsulfonylethylamine and methylsulfonylacetonitrile, which is applied in the preparation of organic compounds, chemical instruments and methods, organic chemistry, etc., can solve the problems of large discharge of "three wastes", unfavorable environmental protection, and high price, and achieve waste liquid discharge The effect of less, strong operability, and low product cost

CN105348172BActive Publication Date: 2017-11-14XINFA PHARMA
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  • Preparation of (s)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonylethylamine and preparation method of apremilast
  • Preparation of (s)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonylethylamine and preparation method of apremilast
  • Preparation of (s)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonylethylamine and preparation method of apremilast

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1: Preparation of racemate III (R, S)-1-(4-methoxy-3-ethoxy)phenyl-2-methanesulfonylethylamine (Ⅲ)

[0053] Add 100 grams of tetrahydrofuran, 3.0 grams of magnesium, 1 grain of iodine (about 10-20 mg), 0.5 grams of 4-methoxy-3-ethoxybromobenzene to a dry 500-ml glass flask, and initiate at 45-50 ° C. Reaction, then dropwise add a solution of 22.6 grams (0.1 moles in total) of 4-methoxy-3-ethoxybromobenzene and 150 grams of tetrahydrofuran between 45-50°C, and drop it for about 50 minutes. After that, 55-60°C The reaction time between them was 3 hours.

[0054] After cooling to -5-0°C, 12.0 g (0.11 mole) of methanesulfonyl acetonitrile was added dropwise for about 40 minutes, and then reacted at -5-0°C for 3 hours. Add 20 grams of 30% ammonium chloride aqueous solution to adjust the pH value of the system to 6-7, and transfer it to a stainless steel pressure kettle after reacting at 20-25 ° C for 3 hours, then add 1.0 grams of 50% Raney nickel (water content 50%...

Embodiment 2

[0055] Example 2: Preparation of (R,S)-1-(4-methoxy-3-ethoxy)phenyl-2-methanesulfonylethylamine (Ⅲ)

[0056] Into a dry 500 ml glass flask, add 100 g of ethoxymethyl ether, 3.0 g of magnesium, 1 grain of iodine (about 10-20 mg), 0.5 g of 4-methoxy-3-ethoxybromobenzene, Initiate the reaction at 50-55°C, then add 22.6 grams (0.1 moles in total) of 4-methoxy-3-ethoxybromobenzene and 160 grams of ethoxymethyl ether solution dropwise between 55-60°C for about 50 minutes After dropping, the reaction time is 2 hours at 55-60°C. Cool to -5-0°C, add 12.0 g (0.11 mol) methanesulfonyl acetonitrile dropwise, and drop it in about 40 minutes, then react at 0-5°C for 3 hours. Add 20 grams of 30% ammonium chloride aqueous solution to adjust the pH value of the system to 6-7, and transfer it to a stainless steel pressure kettle after reacting at 20-25 ° C for 3 hours, then add 0.6 grams of 5% palladium carbon, and replace it with nitrogen for 3 times. The inner temperature is 20-25°C, and th...

Embodiment 3

[0057] Example 3: Preparation of (R,S)-1-(4-methoxy-3-ethoxy)phenyl-2-methanesulfonylethylamine (Ⅲ)

[0058] Add 100 grams of cyclopentyl methyl ether, 3.1 grams of magnesium, 1 grain of iodine, and 0.5 grams of 4-methoxy-3-ethoxybromobenzene to a dry 500-milliliter glass flask, and initiate the reaction at 45-50 ° C, then A solution of 22.6 grams (0.1 moles in total) of 4-methoxy-3-ethoxybromobenzene and 150 grams of cyclopentyl methyl ether was added dropwise between 45-50 ° C, and the drop was completed in about 40 minutes. After that, 55-60 The reaction time between °C was 2 hours. After cooling to -5-0°C, 12.0 g (0.11 mole) of methanesulfonyl acetonitrile was added dropwise for about 40 minutes, and then reacted at -5-0°C for 3 hours. Add 20 grams of 30% ammonium chloride aqueous solution to adjust the pH value of the system to 6-7, and transfer it to a stainless steel pressure kettle after reacting at 20-25 ° C for 3 hours, then add 1.0 grams of 50% Raney nickel (water ...

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Abstract

The invention relates to preparation of (S)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonyl ethylamine and a preparation method of apremilast. 4-methoxy-3-ethoxy phenylmagnesium bromide is prepared from 4-methoxy-3-ethoxy bromobenzene through Grignard reaction; 4-methoxy-3-ethoxy phenylmagnesium bromide is in addition reaction with methylsulfonyl acetonitrile, and then hydrolysis and reduction are carried out, so that (R,S)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonyl ethylamine (III) is obtained; separation and filtering are carried out, so that (S)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonyl ethylamine N-acetyl-L-leucine salt (IV) is obtained; through neutralization, (S)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonyl ethylamine (II) is obtained; the compound (II) is subjected to imidization, so that apremilast (1) is obtained. The mother liquor obtained after separation is recycled and converted into a compound IV, so that discharge of waste liquid is reduced, environment friendliness is realized and the cost is reduced.

Description

technical field [0001] The present invention relates to the preparation of a premilast intermediate (S)-1-(4-methoxy-3-ethoxy)phenyl-2-methanesulfonylethylamine and the preparation method of apremilast , belonging to the field of pharmaceutical biochemical industry. Background technique [0002] (S)-1-(4-methoxy-3-ethoxy)phenyl-2-methanesulfonylethylamine is a key intermediate for the preparation of apremilast. Apremilast is the first and only FDA-approved oral, selective phosphodiesterase 4 (PDE4) inhibitor developed by Celgene for the treatment of plaque psoriasis. The CAS number of Apremilast (Ⅰ) is 608141-41-9, and the chemical name is (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl Ethyl]-4-acetylaminoisoindoline-1,3-dione, the structural formula is as follows Formula I: [0003] [0004] The preparation of Apremilast intermediate (S)-1-(4-methoxy-3-ethoxy)phenyl-2-(methylsulfonyl)ethylamine (Ⅱ) mainly involves enantiomer resolution Division and asymmetric s...

Claims

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Application Information

Patent Timeline
14 Nov 2017
Publication
CN105348172B
IPC
C07D209/48; C07C317/28; C07C315/04; C07C315/06
CPC
C07C315/04; C07C315/06; C07D209/48; C07C317/28
Inventors
戚聿新; 陈军