The initial discovery of the drug
and SAR studies were published in 2007, including the initial discovery
patent applications. Since then, a number of patents
have been published with various improvements made for largescale
synthesis of the drug. While the molecule has been
synthesized using various modifications of the common intermediates,
the large-scale preparation proceeds via a convergent strategy
involving the coupling of three key intermediates as shown in the Scheme below.
Several routes to the synthesis of cyclopentyl amino alcohol 235
have been reported. Most of these routes are based on reaction of
cyclopentene acetate 238 with the appropriate amine, which is
commercially available. Interestingly, one route targeting
deuterated ticagrelor used a nitroxide Diels–Alder reaction with
cyclopentadiene to incorporate the amine into the ring system.
The most likely process-scale preparation of the key cyclopentyl
amine required for ticagrelor is highlighted in the scheme below.
Commercially available enantiopure acetate 238 was reacted
with sodium di-tert-butyloxy diimide under catalytic palladiummediated
amination conditions to give bis-Boc amide 239 in 92%
yield. Dihydroxylation of cyclopentene 239 using catalytic osmium
tetraoxide and N-methyl morpholine N-oxide (NMO) in THF/water
quantatively resulted in the cis-diol 240. The free amine was liberated
with 6 N HCl followed by in situ ketalizaion of the cis-diol
hydrochloride salt 241 in 92% yield. Cbz carbamate 242 was quantitatively
synthesized from 241 under standard conditions. Alcohol
242 was treated with potassium t-butoxide and bromoethyl acetate
(243), the ester intermediate of which was reduced in situ
with lithium borohydride to alcohol 244 in 86% overall yield (two steps). Hydrogenolysis at 1.2 bar of hydrogen pressure with
5% Pd/C gave amino alcohol intermediate 235 in 83% yield. This
amine (235) was mixed with oxalic acid to provide the oxalate salt
in 82% yield, which was subsequently used for the final synthesis of
ticagrelor.
The large-scale preparation of ticagrelor necessitated the synthesis
of dichloroamino pyrimidine thioether 236, for which there
are several reported routes. The synthesis is initiated with
the construction of thiol barbituric acid 247 (Scheme below). This
intermediate was formed from the reaction of dimethyl malonate
(245) with thiourea (246) in the presence of sodium methoxide.
These conditions provided the sodium salt of the pyrimidone thiol
247 in 83% yield, which was isolated via filtration from the reaction
mixture. Salt 247 was then reacted with propyliodide in aqueous
methanolic sodium hydroxide followed by HCl quench to provide
the desired thioether 248 in 76% yield. Nitration of pyrimidinol thioether
248 was achieved by treatment with fuming nitric acid in
acetic acid, furnishing the nitro pyrimidinol 249 in 75% yield. Subsequent
bis-chlorination with POCl3 converted 249 to dichloropyrimidine
thioether 250 in near quantitative yield. In an earlier
publication, a selective reduction of the nitro dichloropyrimide thioether
250 was demonstrated by hydrogenation at 3 bar hydrogen
pressure using 3%Pt/0.6%V/C catalyst to provide the amino dichloropyrimidine
thioether 236 in 95% yield. It is also of note that
for the larger kilo-scale reaction, selective hydrogenation was
accomplished with Pt/V/C (2% Pt; 1% V on carbon) catalyst with
8 bar of hydrogen pressure to give the crude amino dichloropyrimidine
thioether 236.
While a number of routes have been described for the preparation
of cyclopropyl amine intermediate 237,184–187,193–196 the large
scale route used is described (Scheme below).195 Condensation of
malonic acid and 3,4-difluorobenzaldehyde (251) with piperidine
in pyridine gave acid 252 in 88% yield after acidic work-up. Acid
chloride 253 was prepared using thionyl chloride, which was
followed by esterification with L-menthol and pyridine to give Lmenthol
ester 254 in 93% over 2 steps. Cyclopropanation with
dimethylsulfoxonium methylide in DMSO gave desired trans cyclopropane
255 in 40% yield and 92% ee after recrystallization.
Hydrolysis of the ester followed by reaction with thionyl chloride
gave acid chloride 257 in 61% overall yield in two steps. Acid chloride 257 was then reacted with sodium azide in the presence
of sodium carbonate and tetrabutyl ammonium bromide in a biphasic
mixture of toluene and water to give the acyl azide intermediate,
which was immediately subjected to warm toluene to
furnish, after acidic workup, the key intermediate cyclopropyl
amine 237 in 88% yield and 92% ee. This enantioenriched intermediate was then mixed with R-(-)-mandelic acid to provide the
mandelic acid salt of amine 237 (258).
With all three intermediates available from the above mentioned
routes, the final assembly of ticagrelor was accomplished
as outlined in the scheme below. First, oxalate salt of cyclopentyl amine
235 was coupled with dichloroaminopyrimidine thioether 236 in the presence of triethylamine and at elevated temperature to give
diamine intermediate 259 in 88% yield after crystallization. Diamine
259 was then subjected to diazotization with sodium nitrite
in acetic acid and toluene at ~30°C, leading to the formation of triazole
260. This intermediate was immediately reacted with 258
(madelic acid salt of cyclopropyl amine 237) to give intermediate
261, which was subsequently taken forward to the final deprotection
step. Reaction of ketal 261 with concentrated HCl in methanol
and toluene at 15°C provided ticagrelor (XXII) in 82–90% yield
over the 3 steps.