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Preparation method of Apremilast

A molar ratio, ethoxy technology, applied in the direction of organic chemistry, etc., can solve problems such as unfavorable industrial production, high production cost, expensive catalyst, etc., and achieve the effects of easy industrial production, low cost, and short reaction route.

Inactive Publication Date: 2016-02-17
DONGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] The catalysts used in the above synthesis methods are expensive and require strict anhydrous and oxygen-free operations. 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 Apremilast
  • Preparation method of Apremilast
  • Preparation method of Apremilast

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] In a 100mL three-neck flask, add 10.04g (65.99mmol) of 3-hydroxy-4-methoxybenzaldehyde, 45mL of formic acid, and 13.75g (132.16mmol) 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 (88.07 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

[0058] In a 100mL single-necked flask, add 10g (67.11mmol) of 3-hydroxy-4-methoxybenzonitrile, 25mL (335.2mmol) of ethyl bromide, 10.25g of potassium carbonate, and 50mL of dimethylformamide in sequence, and heat and stir until 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

[0060] Add 2.6g (28.3mmol) of dimethyl sulfone and 10mL of tetrahydrofuran to the reactor, cool down to 0-10°C under the protection of nitrogen, add 20mL of 1.6M n-butyllithium n-hexane solution to the reactor, and control the temperature at Stir at 0-10°C for 3h, then dissolve 4.0g (22.60mmol) of the obtained 3-ethoxy-4-methoxybenzonitrile in 10mL of tetrahydrofuran and add dropwise to the above reaction solution at 0-10°C. After the addition, the temperature of the reaction system was raised to room temperature, stirred for 6 hours, until the reaction was complete, then hydrochloric acid solution was added dropwise to quench the reaction, after stirring for 30 minutes, the solvent was spin-dried, and water was added for suction filtration to obtain 4.96 g of white solid 1-(3- Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone, yield 81%, mp: 118-120°C. 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....

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Abstract

The invention relates to a preparation method of Apremilast, comprising the following steps: by taking 3-hydroxy-4-methoxybenzaldehyde as a staring material, reacting with hydroxylamine hydrochloride to obtain 3-hydroxy-4-methoxy cyanobenzene, reacting with bromoethane to obtain 3-ethyoxyl-4-methoxy cyanobenzene, and then reacting with dimethyl sulfone under the action of n-butyllithium, and hydrolyzing in aqueous hydrochloric acid solution to obtain 1-(3-ethyoxyl-4-methoxyphenyl)-2-(mesyl)ketol); finally by taking S-(-)-alpha, alpha-diphenyl-2-pyrrolidine methanol as a chiral catalyst and taking borane dimethyl sulfide complex solution as a reductant, obtaining chirality S-3-ethyoxyl-4-methoxy group-alpha[(mesyl)benzyl alcohol], and then reacting with 3-acetamido-phthalimide under the action of triphenylphosphine and diethyl azodicarboxylate, thus obtaining the Apremilast. According to the preparation method, the process is effectively simplified, the reaction conditions are mild, the product yield and purity are relatively high, and large-scale industrial production is benefited.

Description

technical field [0001] The invention belongs to the field of medicine preparation for psoriatic arthritis, in particular to a preparation method of apremilast. Background technique [0002] Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis, with a psoriatic rash accompanied by pain, swelling, tenderness, stiffness, and movement disturbances in the joints and surrounding soft tissues. Some patients may have sacroiliitis and (or) spondylitis, the course of the disease is protracted and easy to relapse. In the late stage, there may be joint stiffness. In about 75% of patients, the rash appeared before arthritis, in about 15% of patients at the same time, and in about 10% of patients after arthritis. The disease can occur at any age, and the peak age is 30 to 50 years old. There is no gender difference, but the spine is more involved in men. PsA is a form of arthritis that affects some people with psoriasis. Most people are diagnosed with P...

Claims

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Application Information

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IPC IPC(8): C07D209/48
CPCC07D209/48
Inventor 赵圣印黄强
Owner DONGHUA UNIV
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