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

A technology of methoxybenzonitrile and methanesulfonyl, which is applied in the field of synthesis of pharmaceutical and chemical intermediates, can solve the problems of unfavorable industrialized production, expensive catalyst and high production cost, and achieves easy industrialized production, low cost and short reaction route. Effect

Active Publication Date: 2016-04-06
DONGHUA UNIV
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

[0016] Chiral alcohol S or R-3-ethoxy-4-methoxy-α-[(methylsulfonyl) methyl] benzyl alcohol is a key important intermediate in the above-mentioned synthetic method, and in its asymmetric synthesis The catalyst used is expensive and requires strict anhydrous and oxygen-free operation. The hydrogenation reaction requires a hydrogenation device, which has high production costs and is not conducive to industrial production.

Method used

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

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] In a 100mL three-neck flask, add 10.04g (65.9mmol) of 3-hydroxy-4-methoxybenzaldehyde, 45mL of formic acid, and 13.75g (132.1mmol) of sodium formate in sequence, heat and stir to 85°C, and all the reactants have been dissolved in formic acid middle. At 85° C., 6.12 g (88.1 mmol) of hydroxylamine hydrochloride was added, and the reaction was monitored by TLC, and the reaction ended after 5 hours. Stop heating, cool to room temperature, add the reaction solution into 200mL saturated brine, stir for 30min; suction filter, wash the solid with water until neutral, dry to obtain 9.04g of white solid, yield 92%, mp: 129~132°C. IR (cm -1 ,KBr): 3320, 2930, 2280, 1611, 1578, 1510cm -1 ; 1 HNMR (400MHz, CDCl 3 ): δ3.98(s,3H),5.78(s,1H),6.92(d,J=8.3Hz,1H),7.26–7.17(m,2H); 13 CNMR (101MHz, CDCl 3 ): δ56.16, 104.64, 110.77, 117.64, 119.01, 125.63, 145.95, 150.24; EI-MS: 149[M + ].

Embodiment 2

[0052] In a 100mL single-necked flask, add 10.0g (67.1mmol) of 3-hydroxy-4-methoxybenzonitrile, 12.5mL (0.168mol) of bromoethane, 10.25g (74.3mmol) of potassium carbonate, and Amide 50mL, heated and stirred to 100°C. TLC monitored the reaction, reacted for 8h, and stopped heating. Naturally cooled to room temperature, added 100 mL of water, extracted with ethyl acetate, dried the organic phase with anhydrous sodium sulfate, and spin-dried the solvent ethyl acetate to obtain 11.09 g of a white solid with a yield of 94%, mp: 68-70°C. 1 HNMR (400MHz, CDCl 3 )δ: 1.49(t, J=6.9Hz, 3H), 3.92(s, 3H), 4.10(dd, J=13.6, 6.7Hz, 2H), 6.91(d, J=8.3Hz, 1H), 7.08( s,1H),7.27(d,J=6.9Hz,1H); 13 CNMR (101MHz, CDCl 3 ): δ14.48, 56.04, 64.75, 103.94, 111.51, 115.40, 119.26, 126.31, 148.43, 153.06; EI-MS: 177[M + ].

Embodiment 3

[0054] Add 2.6g (28.3mmol) of dimethyl sulfone and 10mL of tetrahydrofuran to the reactor. Under nitrogen protection, cool down to 0-10°C, add 20.0mL of 1.6M n-butyllithium-n-hexane solution to the reactor, and control Stir at 0-10°C for 3 hours, then dissolve 4.0 g (22.6 mmol) of the obtained 3-ethoxy-4-methoxybenzonitrile in 10 mL of tetrahydrofuran at 0-10°C and add dropwise to the above reaction solution , after the dropwise addition, the temperature of the reaction system was raised to room temperature, stirred for 6h, until the reaction was complete, then a solution of hydrochloric acid was added dropwise to quench the reaction, after stirring for 30min, the solvent was spin-dried, and water was added for suction filtration to obtain 4.96g white solid 1-( 3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone, the yield is 81%, mp: 118~120℃. 1 HNMR (400MHz, CDCl 3 )δ1.52(t, J=7.0Hz, 3H), 3.16(s, 3H), 3.99(s, 3H), 4.19(q, J=7.0Hz, 2H), 4.57(s, 2H), 6.98( t, J=13.8Hz, 1H),...

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Abstract

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.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical and chemical intermediates, in particular to a method for preparing chiral S or R-3-ethoxy-4-methoxy-α-[(methylsulfonyl)methyl]benzyl alcohol. Background technique [0002] Apremilast (Apremilast) is a drug for the treatment of psoriatic arthritis researched and developed by Celgene Biotechnology Company of the United States. Clinically used for the treatment of psoriatic arthritis oral drug, the drug is a phosphodiesterase inhibitor, which can reduce joint swelling and improve the physiological function of joint parts. The drugs currently on the market for treating psoriatic arthritis are generally anti-TNF (tumor necrosis factor) drugs, such as Humira produced by AbbVie, which has a lot of side effects and can lead to serious adverse reactions in patients. However, Apremilast has no major side effects and has expanded the applicable population, so Apremilast has a broad market space f...

Claims

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Application Information

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IPC IPC(8): C07C317/18C07C315/04
CPCC07B2200/07C07C253/00C07C253/30C07C315/04C07C317/18C07C317/24C07C255/54
Inventor 赵圣印黄强
Owner DONGHUA UNIV
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