Chemical Properties
White to Off-White Crystalline Solid
Originator
Emory University (US)
Definition
ChEBI: An organofluorine compound that is 5-fluorocytosine substituted at the 1 position by a 2-(hydroxymethyl)-1,3-oxathiolan-5-yl group (2R,5S configuration). It is used in combination therapy for the treatment of HIV-1 infect
on.
Brand name
Emtriva (Gilead
Sciences) [Note—Emtricitabine has appeared in the
literature with the trivial names, (-)-FTC and FTC-(-).].
Acquired resistance
Resistance is associated with a substitution in the HIV-1 reverse
transcriptase gene at codon 184 (M184V/I). Emtricitabineresistant
isolates are cross-resistant to lamivudine. HIV-1 isolates
with the K65R substitution in the reverse transcriptase
coding region have reduced susceptibility.
General Description
Emtricitabine is an orally active NRTI whose pharmacokineticsare favorable for once-daily administration.
Pharmaceutical Applications
A synthetic nucleoside analog of cytosine, formulated for oral use.
Clinical Use
Treatment of HIV infection (in combination with other antiretroviral drugs)
Synthesis
Emcitritabine (VII) was discovered by
researchers at Emory University and licensed to Triangle
Pharmaceuticals, which started the development work before
being acquired by Gilead. Because emcitritabine (VII)
belongs to an important structural class of nucleosides with
marketed drugs, such as 3TC, several processes for the
manufacture of this class of oxathiolane nucleosides have
appeared in patents and scientific literature.
However, only the synthesis described in the latest patent
filed for the manufacture of emcitritabine (VII) and one other
efficient synthesis from the Liotta group will be described . The synthesis started with diacylation
with butyryl chloride (62) of the 2-butene-1,4-diol (61) in
methyl t-butylether at 0??C to room temperature in the presence of triethylamine to give diacylated product 63 in
95% yield. Ozonolysis followed by reduction with thiourea
provided a mixture of hemiacetal 64 mixed with acetals,
dimers and trimers in 97% yield, which was used in the next
step directly. The hemiacetal mixture was reacted with
thioacetic acid in toluene at 85??C for 3 hr to give the crude
keto oxathiolane mixture, which was purified by vacuum
distillation in a 2-in Pope Scientific wiped film still to
remove impurities and collect about 92% pure 66 in 54%
yield. Also mentioned in the patent is the potential use of
enzymatic resolution of the isomers as reported previously. This keto oxathiolane 66 was reduced at 5??C with
lithium aluminum t-butoxide, which was prepared in situ
via reaction of LAH and t-butanol, and the resulting lactol
was trapped with acetic anhydride in the presence of DMAP
in the same reaction vessel to give, after workup, 87% yield
of the key intermediate acetate 67. The bis-silyl protected 5-
fluorocytosine 68, prepared in situ by reacting 5-
fluorocytosine (71) with HMDS, was reacted with acetate 67
in the presence of trimethylsilyliodide at 0??C to room
temperature to give a 1:1 mixture of alpha and beta-anomers
69 and 70. Pure 69 could be isolated by recrystallization
from toluene. Cleavage of the butyryl group with a strongly
basic DOWEX SBR resin in methanol at room temperature
gave emcitritabine (VII) in 81% yield. An alternate concise
synthesis reported by Liotta et al is worth mentioning.
This synthetic route accessed the key thioxalane acetate 76 as
the TBDMS ether in four steps from allyl alcohol 72. The key step to the preparation of the final compound was the
coupling of the bis-silyl 5-fluorocytosine (68) with acetate
76 with tin tetrachloride in a stereoselective manner, after
cleavage of the silyl groups and recrystallization, to give
pure cis isomer emcitritabine (VII) in excellent yield.
Drug interactions
Potentially hazardous interactions with other drugs
Antivirals: avoid concomitant use with lamivudine.
Orlistat: absorption of emtricitabine possibly
reduced.
Metabolism
There is limited metabolism of emtricitabine. The
biotransformation of emtricitabine includes oxidation of
the thiol moiety to form the 3'-sulphoxide diastereomers
(approximately 9% of dose) and conjugation with glucuronic
acid to form 2'-O-glucuronide (approximately 4% of dose).
Emtricitabine is primarily excreted by the kidneys
with complete recovery of the dose achieved in urine
(approximately 86%) and faeces (approximately 14%).
13% of the emtricitabine dose was recovered in urine as
three metabolites
References
[1] Patent: CN106478618, 2017, A. Location in patent: Paragraph 0071; 0072; 0073-0074
[2] Patent: WO2009/84033, 2009, A2. Location in patent: Page/Page column 10
[3] Patent: WO2011/107920, 2011, A1. Location in patent: Page/Page column 13
[4] Organic Process Research and Development, 2006, vol. 10, # 3, p. 670 - 672
