Preparation method of Apremilast and intermediate

A compound and reaction technology, applied in the field of medicine and chemical industry, can solve problems such as inconvenient operation, low yield of 3-acetamidophthalic anhydride, great danger, etc., to facilitate the operation process, reduce production costs, and improve safety sexual effect

Active Publication Date: 2016-06-01
NANJING ANYUAN BIO PHARMA TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] There are certain defects in this method: the synthesis process needs to use n-butyllithium n-hexane solution, which is inconvenient to operate and has greater danger; meanwhile, the yield of 3-acetamidophthalic anhydride is low, only 61%

Method used

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  • Preparation method of Apremilast and intermediate
  • Preparation method of Apremilast and intermediate
  • Preparation method of Apremilast and intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] The synthesis of embodiment 1 formula II compound

[0045]

[0046] Add 0.25mol of the compound of formula I, 400mL of DMF, 0.25mol of potassium carbonate and 0.30mol of 1-bromoethane into a 1L four-neck flask, and react at 25°C for 4h. The reaction solution was poured into 600 mL of water, stirred, extracted with EA (100 mL×3), the organic phases were combined, washed with saturated brine (100 mL×1), dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a white solid . Slurry with 100 mL of n-hexane for 10 min, filter, and vacuum-dry the filter cake at 40° C. for 5 h to obtain 42 g of white solid with a yield of 86.5%.

[0047] 1 HNMR (400MHz, DMSO) δ: 7.62(dd, J=8.4, 2.0Hz, 1H), 7.43(d, J=1.9Hz, 1H), 7.07(d, J=8.4Hz, 1H), 4.07(q, J=7.0Hz, 2H), 3.85(s, 3H), 2.53(s, 3H), 1.35(t, J=7.0Hz, 3H).

Embodiment 2

[0048] Synthesis of embodiment 2 formula Ⅲ-1 compound

[0049]

[0050] Add 25mmol of the compound of formula II, 25mmol of phenyltrimethylammonium tribromide, 10mL of tetrahydrofuran and 10mL of methanol into the reaction flask, react at 20°C for 1h, evaporate the solvent under reduced pressure, add 50mL of water and 50mL of EA to the residue, extract and separate , extracted with EA (50mL×2), combined the organic phases, washed once with an appropriate amount of 2M aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was vacuum-dried at 40°C for 5h , to obtain 6.0 g of white solid with a yield of 88.2%.

[0051] 1 HNMR (400MHz, CDCl 3 )δ: 7.62(dd, J=8.4, 2.0Hz, 1H), 7.56(d, J=2.0Hz, 1H), 6.93(d, J=8.4Hz, 1H), 4.42(s, 2H), 4.19( q,J=7.0Hz, 2H), 3.97(s,3H), 1.51(t,J=7.0Hz, 3H).

Embodiment 3

[0052] Synthesis of embodiment 3 formula Ⅲ-2 compound

[0053]

[0054] Add 50mmol of the compound of formula II, 100mL of methanol and 25mmol of p-toluenesulfonic acid into a 250mL four-neck flask. The ice-water bath is lower than 5°C. Dichlorohydantoin is added in 3 batches, totaling 37.5mmol, and the temperature is controlled below 10°C. After the addition was completed, the temperature was naturally raised to 25°C, the system became clear, and a white solid was precipitated after reacting for 15 hours. The solvent was evaporated under reduced pressure, and the residue was added with 100 mL each of water and EA, shaken to separate the liquid, and extracted with EA (50 mL×3). The organic phases were combined, washed with saturated brine (100 mL×1), dried over anhydrous magnesium sulfate, filtered, and the filtrate was distilled off the solvent under reduced pressure to obtain a light yellow solid. Wash with 2 mL of EA, filter, and vacuum-dry the filter cake at 40° C. for...

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Abstract

The invention provides a preparation method of Apremilast and its intermediate. The invention provides an Apremilast intermediate as shown in the formula III. According to the preparation method, the compound as shown in the formula III reacts with methanesulfinate to obtain a compound as shown in the formula IV; the compound as shown in the formula IV undergoes reductive amination to obtain a compound as shown in the formula V; the compound as shown in the formula V and asymmetry acid undergo salifying to obtain a compound as shown in the formula VI; and the compound as shown in the formula VI reacts with 3-acetamido-phthalic anhydride to obtain Apremilast. By the method for synthesizing Apremilast, usage of an n-butyllithium hexane solution can be avoided. Production cost is reduced, and operation process is convenient. In addition, safety in the industrial production is raised to a great extent, and the preparation method is more suitable for industrial continuous production. According to the preparation method of 3-acetamido-phthalic anhydride, yield is raised to 81%. As the yield is high, the method provided by the invention is extremely suitable for industrial production of Apremilast.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a synthesis method of apremilast. Background technique [0002] Apremilast is a PDE4 inhibitor developed by Celgene, and its chemical name is 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4 - Acetylaminoisoindoline-1,3-dione, having a structure as shown in Formula A. Apremilast was approved by the US FDA on March 25, 2014, and has been clinically developed for rheumatoid arthritis, psoriatic arthritis, Crohn's disease, ulcerative colitis and other indications; the first FDA-approved The first indication is active psoriatic arthritis (psoriaticarthritis, PsA) in adults. Apremilast is different from the anti-TNF monoclonal antibody commonly used in clinical practice. It is an oral anti-rheumatic drug with a new mechanism of action and has huge market potential. [0003] [0004] US2013 / 0217919Al discloses the synthetic method of Apremilast, and route is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C49/84C07C45/63C07D209/48
CPCC07C45/63C07C49/80C07C49/84C07D209/48
Inventor 王小龙李鑫源李志亚刘彦龙张喜全
Owner NANJING ANYUAN BIO PHARMA TECH CO LTD
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