Synthetic method of (s)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine

A technology of methoxyphenyl and methanesulfonyl, which is applied in the field of synthesis of -1--2-ethylamine, can solve the problems of high synthesis cost and low yield of chiral amine intermediates, and achieve simple treatment of three wastes Easy to operate, easy to separate and purify, and environmentally friendly

Active Publication Date: 2022-03-22
ENANTIOTECH CORP +1
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

This synthesis method has the problem that the yield of chiral amine intermediate is on the low side, and the synthetic cost of Apremilast is on the high side.

Method used

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  • Synthetic method of (s)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine
  • Synthetic method of (s)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine
  • Synthetic method of (s)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine

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preparation example Construction

[0037] A synthetic method of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine, comprising the steps of:

[0038] Mix 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyleneamine, chiral catalyst, acid and solvent, and react;

[0039] The structural formula of the chiral catalyst is shown in formula (I):

[0040]

[0041]R is selected from a hydrogen atom, a straight-chain alkyl group with 1-20 carbon atoms, a branched-chain alkyl group with 3-20 carbon atoms, a cycloalkyl group with 3-10 carbon atoms, a cycloalkyl group with 3-10 ring atoms Heterocyclyl, alkoxy with 1-20 carbon atoms, trifluoromethyl, halogen, amino, cyano, hydroxyl, nitro, ester, amido, substituted or unsubstituted with 6-20 rings Atomic aryl, substituted or unsubstituted heteroaryl having 5-20 ring atoms.

[0042] The invention provides a synthetic method of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine, which uses 1-(3-ethoxy Base-4-methoxyphenyl)-2-(methylsulfonyl)vinylam...

Embodiment 1

[0078] This example provides a synthesis method of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine.

[0079] (1) Preparation of Chiral Catalyst I:

[0080] 2,2,6-Trimethyl-1,3-dioxin-4-one (142.2 mg, 1 mmol) was added dropwise to (S)-α-hydroxy-N-methyl-2-phenylacetamide ( 165.1mg, 1mmol) in toluene (0.5mL) solution. After stirring at reflux overnight, the reaction mixture was cooled to 50°C and the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography (the volume ratio of n-hexane:ethyl acetate was 20:1) to obtain 187.0 mg of white solid compound with a yield of 75%.

[0081] The above white solid compound (498.6mg, 2mmol), ammonium acetate (77.1mg, 1mmol) and hexamethylenetetramine (140.2mg) were dissolved in 5mL of dioxane, and heated at 100°C for 30 minutes. Cool to room temperature, add water, extract with dichloromethane, and collect the organic phase. After the organic phase was concentrated, it was purified by...

Embodiment 2

[0086]In this embodiment, a synthetic method of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine, the steps are the same as in Example 1, the difference is that: The chiral catalyst for is Catalyst II.

[0087] (1) Preparation of Chiral Catalyst II:

[0088] 2,2,6-Trimethyl-1,3-dioxin-4-one (142.2 mg, 1 mmol) was added dropwise to (S)-α-hydroxy-N-ethyl-2-phenylacetamide ( 179.2mg, 1mmol) in toluene (0.5mL) solution. After stirring at reflux overnight, the reaction mixture was cooled to 50°C and the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography (the volume ratio of n-hexane:ethyl acetate was 20:1) to obtain 243.0 mg of white solid compound with a yield of 82%.

[0089] The above white solid compound (526.6mg, 2mmol), ammonium acetate (77.1mg, 1mmol) and hexamethylenetetramine (140.2mg) were dissolved in 5mL of dioxane, and heated at 100°C for 30 minutes. Cool to room temperature, add water, extract with dichlor...

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Abstract

The invention relates to a synthesis method of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine. The method comprises the steps of: mixing 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) vinylamine, a chiral catalyst, an acid and a solvent, and reacting; the chiral catalyst The structural formula is shown in formula (I), R is selected from hydrogen atom, alkyl, aromatic ring, alkoxy, halogen atom, amino, cyano, hydroxyl, trifluoromethyl, nitro, ester or amido. (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine with high chiral purity can be generated in one step, and the product is easy to separate and purify with high yield. In addition, the reaction condition is mild, the process is stable, the reaction operation is simple and safe, the production cost is low, the three wastes are easy to handle, the environment is friendly, the raw materials are easily available, the production cost is low, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a synthesis method of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine. Background technique [0002] Apremilast, chemical name (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylamino Isoindoline-1,3-dione, whose structure is shown in the following formula (1), is a selective PDE4 inhibitor developed by Celgene, which was approved by the US FDA in March 2014 as a treatment for psoriatic Oral drugs for arthritis are on the market, and in September 2014, they were approved by the US FDA for the treatment of moderate to severe psoriasis (also known as plaque psoriasis). [0003] [0004] The synthetic method of Apremilast is usually based on (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethylamine (formula (2), hereinafter referred to as hand amine intermediate) and acid anhydride intermediate (formula (3)) as raw materials, the pro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07B53/00C07C315/04C07C317/28B01J31/02C07D211/90
CPCC07B53/00C07C315/04C07D211/90B01J31/0245C07B2200/07B01J2231/645C07C317/28
Inventor 李彦雄徐亮蒙发明于永海
Owner ENANTIOTECH CORP
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