1450657-24-5

Usage

Uses

Used in Pharmaceutical Industry:
(R)-3-ethoxy-4-methoxy-α-[(methylsulfonyl)methyl]benzyl alcohol is used as a potential compound for the development of new pharmaceuticals due to its complex molecular structure and the presence of various functional groups that may interact with biological targets.
Used in Organic Synthesis:
(R)-3-ethoxy-4-methoxy-α-[(methylsulfonyl)methyl]benzyl alcohol is used as a building block or intermediate in the synthesis of other organic molecules, potentially leading to the creation of novel compounds with specific applications in various fields.

Upstream product

• 1450657-28-9 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-one 
• 60758-86-3 3-ethoxy-4-methoxybenzenecarbonitrile 
• 31526-71-3 3-ethoxy-4-methoxy-acetophenone 
• 1131-52-8 3-ethoxy-4-methoxybenzaldehyde 
• 52805-46-6 2-methoxy-5-cyanophenol 
• 621-59-0 isovanillin 

Downstream Products

• 608141-43-1 (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine-(S)-2-acetamido-4-methylpentanoate 
• 608141-41-9 Apremilast 
• 608141-42-0 (S)-2-[1 (3-ethoxy-4-methoxyphenyl)]-1-methanesulfonyl-2-ethylamine 
• 608141-44-2 R-Apremilast 

Relevant academic research and scientific papers

Chemoenzymatic synthesis of apremilast: A study using ketoreductases and lipases

The key step in the chemoenzymatic synthesis of apremilast was to produce the chiral alcohol (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol, (R)-3. Two enzymatic approaches were evaluated to obtain (R)-3, one using ketoreductases and the other lipases. Bioreduction of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (2), using ketoreductase KRED.P2-D12, led to (R)-3 with 48% conversion and 93% enantiomeric excess (ee). Kinetic resolution of rac-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl acetate (rac-4), via hydrolysis reaction, with 20% of n-butanol, catalyzed by lipase from Aspergillus niger yielded (R)-3 with > 99% ee, 50% conversion and E-value (enantiomeric ratio) > 200. The reaction between enantiomerically pure (R)-3 and 4-acetylamino-isoindol-1,3-dione (8) afforded apremilast in 65% yield and 67% ee.

Chemoenzymatic Oxosulfonylation-Bioreduction Sequence for the Stereoselective Synthesis of β-Hydroxy Sulfones

A series of optically active β-hydroxy sulfones has been obtained through an oxosulfonylation-stereoselective reduction sequence in aqueous medium. Firstly, β-keto sulfones were synthesized from arylacetylenes and sodium sulfinates to subsequently develop the carbonyl reduction in a highly selective fashion using alcohol dehydrogenases as biocatalysts. Optimization of the chemical oxosulfonylation reaction was investigated, finding inexpensive iron(III) chloride hexahydrate (FeCl3 ? 6H2O) as the catalyst of choice. The selection of isopropanol in the alcohol-water media resulted in high compatibility with the enzymatic process for enzyme cofactor recycling purposes, providing a straightforward access to both (R)- and (S)-β-hydroxy sulfones. The practical usefulness of this transformation was illustrated by describing the synthesis of a chiral intermediate of Apremilast. Interestingly, the development of a chemoenzymatic cascade approach avoided the isolation of β-keto sulfone intermediates, which allowed the preparation of chiral β-hydroxy sulfones in high conversion values (83–94 %) and excellent optical purities (94 to >99 % ee).

Refining method of apremilast intermediate

The invention relates to a refining method of an apremilast intermediate. The refining method comprises the following steps: providing a crude product of the intermediate shown as a formula (I); refining the crude product of the intermediate shown in the formula (I) by adopting a refining solvent to prepare a refined product of the intermediate shown in the formula (I); the refining solvent being at least one of methyl isobutyl ketone, acetonitrile and butanone; and R1, R2, and R3 being each independently a C1-16 alkyl group, a 3 to 8-membered cycloalkyl group, a 5 to 10-membered aryl group, or a 5 to 10-membered heteroaryl group. The refining solvent is used for purifying the crude product of the intermediate shown in the formula (I), so that the purity of the intermediate shown in the formula (I) is effectively improved, and the residual quantity of process impurities can be controlled to be below 0.1% on the basis of keeping higher yield of the product.

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

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.

For treating psoriasis sexual arthritis disease apps is special synthetic method (by machine translation)

The invention discloses a method for treating psoriasis sexual arthritis disease apps is special synthetic method, the method to 3 - ethoxy - 4 - methoxybenzaldehyde as the starting material, by with the dimethyl sulfone, n-butyl reaction, to obtain 3 - ethoxy - 4 - methoxy - α - [(methylsulfonyl) methyl] - benzene methanol, through the oxidation reaction to obtain 1 - (3 - ethoxy - 4 - methoxyphenyl) - 2 - methyl-sulfonyl - ethanone, through the reduction reaction to obtain the R - 3 - ethoxy - 4 - methoxy - α - [(methylsulfonyl) methyl] - benzene methanol, finally with 3 - acetamide group ortho-phthalic acid imide by Mitsunobu reaction, to obtain the target product apps is special. The invention has mild reaction condition, the process is simple, the yield is good, easy industrialization and the like. (by machine translation)

A SYNTHETIC PATHWAY TOWARDS APREMILAST

The present invention relates to an asymmetric process for providing N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide (apremilast) or a pharmaceutically acceptable salt or solvate thereof.

A NOVEL SYNTHETIC PATHWAY TOWARDS APREMILAST

The present invention relates to a process for providing a chiral β-hydroxysulfone compound, an intermediate useful in the synthesis of the isoindoline-based compound apremilast.

Preparation method of chiral S/R-3-ethoxy-4-methoxy-alpha[(methylsulfonyl)methyl] benzyl alcohol

The invention relates to a preparation method of chiral S/R-3-ethoxy-4-methoxy-alpha[(methylsulfonyl)methyl] benzyl alcohol. The preparation method comprises the following steps: 3-hydroxy-4-methoxybenzaldehyde is taken as a starting material and reacts with hydroxylammonium hydrochloride to produce 3-hydroxy-4-methoxybenzonitrile; 3-hydroxy-4-methoxybenzonitrile reacts with bromoethane to produce 3-ethoxy-4-methoxybenzonitrile; 3-ethoxy-4-methoxybenzonitrile reacts with dimethyl sulfone under the action of n-butyllithium, a product is hydrolyzed in an aqueous hydrochloric acid solution, and 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone is obtained; finally, S-(-)-alpha,alpha-diphenyl-2-pyrrolidinemethanol or R-(+)-alpha,alpha-diphenyl-2-pyrrolidinemethanol is taken as a chiral catalyst, a borane dimethyl sulfide solution is taken as a reducing agent, carbonyl is reduced, and a product is obtained. The reaction conditions are mild, the product yield is higher, the technology level is increased, the operability is improved, and large-scale industrial production is facilitated.

A method for synthesizing intermediate apps special chiral amine

The invention relates to a synthetic method of an apremilast chiral amine intermediate (S)-2-[1-(3-ethoxyl-4-methoxylphenyl)]-1-methylsulfonyl-2-ethylamine (V). The synthetic method is characterized by including following steps: (1) with 1-(3-ethoxyl-4-methoxylphenyl)-2-(methylsulfonyl)ethyl ketone (I) as a raw material, performing asymmetric hydrogenation reduction to obtain methyl sulfonyl ethanol (II); (2) performing an esterification reaction to obtain methyl sulfonyl ester (III); (3) performing an azidation reaction to obtain an azide compound (IV); and (4) performing hydrogenation reduction to obtain the chiral amine intermediate (V) being high in chiral purity. The synthetic method is simple in process, is stable in reaction processes, and is environmental-protective and low-cost. In the synthetic method, the use amount of a catalyst during catalytic hydrogenation is less and the conversion rate reaches higher than 98%. The chiral amine can be prepared through chiral alcohol with very high yield and purity so that the synthetic method has a quite excellent commercial value and develops a new approach for synthesizing the apremilast chiral amine intermediate.

ASYMMETRIC SYNTHETIC PROCESSES FOR THE PREPARATION OF AMINOSULFONE COMPOUNDS

Processes for synthesizing aminosulfone compounds are provided. Aminosulfone compounds obtained using methods provided herein are useful in production or synthesis of sulfone group containing isoindoline based compounds.