US 12,291,505 B2
Methods for the synthesis of deuterated dextromethorphan
Matt Johnson, Morrisville, NC (US); Cunxiang Zhao, Tianjin (CN); Weihua Meng, Tianjin (CN); Zhijun Lu, Tianjin (CN); and Yan Li, Tianjin (CN)
Assigned to AVANIR PHARMACEUTICALS, INC., Aliso Viejo, CA (US)
Filed by AVANIR PHARMACEUTICALS, INC., Aliso Viejo, CA (US)
Filed on Nov. 8, 2023, as Appl. No. 18/388,041.
Application 18/388,041 is a division of application No. 17/095,026, filed on Nov. 11, 2020, granted, now 11,845,731.
Application 17/095,026 is a division of application No. 16/910,353, filed on Jun. 24, 2020, granted, now 10,865,187, issued on Dec. 15, 2020.
Application 16/910,353 is a division of application No. 16/312,439, granted, now 10,730,841, issued on Aug. 4, 2020, previously published as PCT/US2017/040623, filed on Jul. 3, 2017.
Claims priority of application No. PCT/CN2016/088414 (WO), filed on Jul. 4, 2016.
Prior Publication US 2024/0067608 A1, Feb. 29, 2024
Int. Cl. C07D 221/28 (2006.01); C07B 59/00 (2006.01); A61P 25/24 (2006.01); A61P 25/28 (2006.01)
CPC C07D 221/28 (2013.01) [C07B 59/002 (2013.01); A61P 25/24 (2018.01); A61P 25/28 (2018.01); C07B 2200/05 (2013.01)] 6 Claims
 
1. A method for synthesizing a deuterated dextromethorphan of Formula (I)

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the method comprising:
(i)O-demethylating the methoxy group of a dextromethorphan compound of Formula (II)

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to a compound of Formula (VIII)

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isolating the compound of Formula (VIII);
(ii) deuterating the O-demethylated compound of Formula (VIII) to a compound of Formula (VII)

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by O-methylation in the presence of a base and iodomethane-D3 at temperatures in the range of −10° C. to 10° C. inclusive;
(iii)N-demethylating the tertiary amine of a dextromethorphan compound of Formula (VII) to a compound of Formula (IX);

OG Complex Work Unit Chemistry
isolating the compound of Formula (IX);
and
(iv) deuterating the N-demethylated compound of Formula (IX) to the compound of Formula (I) by N-methylation in the presence of a base and iodomethane-D3 at a temperature in the range of −90° C. to 90° C. inclusive.