Hydrocodone

1H-NMR & 13C-NMR of hydrocodone (1)


 hydrocodone as a pale-yellow solid. 
1H NMR (300 MHz, CDCl3) δ 6.72 (d, J = 8.2 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 4.68 (s, 1H), 3.92 (s, 3H), 3.20 (m, 1H), 3.04 (d, J = 18.5 Hz, 1H), 2.59 (m, 2H), 2.49–2.27 (m, 6H), 2.21 (td, J = 11.9, 3.3 Hz, 1H), 2.08 (td, J = 12.0, 4.5 Hz, 1H), 1.86–1.79 (m, 2H), 1.35–1.19 (m, 1H). 

13C NMR (75 MHz, CDCl3) δ 207.89, 145.39, 142.82, 127.24, 126.28, 119.76, 114.47, 91.39, 59.19, 56.75, 56.71, 46.89, 46.83, 42.88, 42.70, 40.23, 35.52, 25.57, 19.95.


HYDROCODONE

Hydrocodone, a high value active pharmaceutical ingredient (API), is usually produced in a semisynthetic pathway from morphine, codeine or thebaine. The latter alkaloid is an attractive precursor as it is not used as a remedy itself. The key step in this production route is a selective olefin reduction forming 8,14-dihydrothebaine which can be subsequently hydrolyzed to yield hydrocodone. Unfortunately, standard hydrogenation procedures cannot be applied due to severe selectivity problems. A transfer hydrogenation using in situ generated diimide is the only known alternative to achieve a selective transformation. The most (atom) economic generation of this highly unstable reducing agent is by oxidizing hydrazine hydrate (N2H4·H2O) with O2. In the past, this route was “forbidden” on an industrial scale due to its enormous explosion potential in batch. A continuous high-temperature/high-pressure methodology allows an efficient, safe, and scalable processing of the hazardous reaction mixture. The industrially relevant reduction was achieved by using four consecutive liquid feeds (of N2H4·H2O) and residence time units, resulting in a highly selective reduction within less than 1 h.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00370

Selective Olefin Reduction in Thebaine Using Hydrazine Hydrate and O2under Intensified Continuous Flow Conditions

Bartholomäus Pieber†, D. Phillip Cox‡, and C. Oliver Kappe*†

† Institute of Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria

‡ Noramco, Inc., 503 Carr Road, Suite 200, Wilmington, Delaware 19809, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.5b00370

Publication Date (Web): December 15, 2015

Copyright © 2015 American Chemical Society

*E-mail: oliver.kappe@uni-graz.at.

Hydrocodone

Systematic (IUPAC) name
4,5α-epoxy-3-methoxy-17-methylmorphinan-6-one
Clinical data
Trade names	Zohydro ER
AHFS/Drugs.com	Micromedex Detailed Consumer Information
MedlinePlus	a601006
Pregnancy category	US: C (Risk not ruled out)
Legal status	AU: S8 (Controlled) CA: Schedule I DE: Anlage III UK: Class A US: Schedule II
Dependence liability	severe / high
Routes of administration	oral, intranasal, rectal
Pharmacokinetic data
Bioavailability	High
Metabolism	Hepatic: CYP2D6 (minor; converts tohydromorphone), CYP3A4(major; converts tonorhydrocodone)
Biological half-life	3.8–6 hours
Excretion	Renal
Identifiers
CAS Number	125-29-1
ATC code	R05DA03
PubChem	CID: 5284569
IUPHAR/BPS	7081
DrugBank	DB00956
ChemSpider	4447623
UNII	6YKS4Y3WQ7
KEGG	D08045
ChEBI	CHEBI:5779
ChEMBL	CHEMBL1457
Synonyms	dihydrocodeinone
Chemical data
Formula	C18H21NO3
Molecular mass	299.368 g/mol
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