Conclusion
A process to generate RO3203546 was developed and
76.9 kg, 150.5 mol, 1.8 equiv) was added. The resulting
mixture was heated at 90-100 °C until in-process analysis
(GC) showed the absence of starting glycine ester (3.5 h).
The reactor contents were cooled to ca. 5 °C, and acetic acid
(9 kg, 151.9 mol, 1.8 equiv) was added over 10 min while
the temperature was maintained below 10 °C. Water (70 kg)
was added, and the resulting mixture stirred for 45 min. The
reactor contents were allowed to settle, and the lower aqueous
layer was removed. The organic layer was concentrated under
vacuum to ca. 100 L. Vacuum was released on the reactor,
and toluene (140 kg) was added to the concentrate. A solution
of HCl (3.1 kg, 114 mol, 1.4 equiv) in ethanol (88 kg) was
added, and the resulting mixture was stirred at ca. 22 °C for
30 min. The reactor contents were concentrated using an
isolated vacuum source equipped with a caustic scrubber to
a volume of ca. 200 L. Heptane (130 kg) was added, and
the temperature was adjusted to 22 °C. The mixture was left
overnight with slow stirring. The reactor contents were
cooled to ca. 5 °C, and after 1 h, the slurry was filtered and
rinsed with heptane (74 kg). The solid was dried on the filter
until in-process analysis showed the loss on drying to be
less than 1%. Total product discharged from the filter: 18.8
kg (76.8% yield). Mass spectrum: m/z 262 (M++1); wt %
chloride calcd, 11.91%; found, 11.76%; mp 162-165 °C.
7-Benzyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-
4-one (3): Formamidine acetate (11.4 kg, 10 mol, 1.5 equiv),
keto-ester 2 (22.0 kg, 73.9 mol, 1.0 equiv), ethanol (55 kg),
and sodium ethoxide (84 kg, 21 wt % in ethanol, 297 mol,
3.5 equiv) were combined, and the mixture was adjusted to
reflux. After 2.5 h, in-process analysis indicated the reaction
was complete. Toluene (97 kg) was added, and the mixture
was concentrated under vacuum from an initial volume of
ca. 310 L to a final volume of ca. 150 L. Toluene was added
as necessary to maintain a reactor volume of ca. 150 L, and
the distillation continued until in-process analysis (NMR)
indicated that the majority of the ethanol was removed.
Vacuum was released from the system, water (125 L) was
added, and the contents were adjusted to <30 °C. Sodium
hydroxide (4.4 kg, 50% solution in water, 36.3 mol, 0.7
equiv) was charged, and the lines were rinsed forward to
the reactor with ca. 7 kg of water. The biphasic mixture was
stirred for ca. 1.5 h. The layers were separated glacial acetic
acid was added to aqueous layer until the pH was 7. The
reactor contents were adjusted to 85-95 °C and allowed to
stir at this temperature for 1-2 h, then cooled to 5-10 °C
demonstrated in two pilot plant campaigns. In the first pilot
plant campaign, a debenzylation process was developed that
used transfer hydrogenation rather than a medium pressure
hydrogenation. Eliminating the need for the specialized
equipment required to safely perform hydrogenations on a
large scale made the process more amenable to further scale-
up. Replacing dioxane and methoxyethanol with solvents that
are more acceptable in the pharmaceutical industry was also
a significant achievement. Most importantly, a highly
crystalline, nonsolvated form of the API was discovered, and
a method to purify the compound and ensure that extraneous
material was removed from the drug substance was demon-
strated.
The second pilot plant campaign integrated enhancements
in the early stages of the process. Pyrimidinone 3 was
generated with formamidine acetate and isolated as a free
base. Generation of 3 as a free base simplified the analytics,
since 3 did not need to be assayed for sodium chloride
content. Free base 3 reacted more smoothly in the chlorina-
tion sequence with POCl3 than did the hydrochloride salt.
The charge of POCl3 was greatly reduced, and an in situ
quench with KOH was developed. Although the quench was
very exothermic, evaluation with a reaction calorimeter
showed that the reaction was instantaneous and could be
safely scaled as long as control of the addition rate of KOH
was maintained. The quenched reaction mixture was coupled
directly with morpholine and led to the production of 5 with
excellent throughput and an acceptable cycle time.
Processes that led to required reagents 2 and 7 were also
demonstrated on-scale. Modification of a published procedure
allowed 2 to be generated in-house which dramatically
accelerated the development of RO3202546. Although the
modifications made to the synthesis of 2 resulted in a slightly
lower yield than that reported in the literature, the cycle time
of the process was improved. Since the goal of the in-house
synthesis was to generate material within weeks rather than
wait months for an outside vendor, the marginally lower yield
was acceptable.
Experimental Section
General: All reactions were conducted in glass-lined
reactors under a nitrogen atmosphere. All equipment and
lines were checked for leaks by pressuring the system with
nitrogen prior to use.
23
and stirred for 1-2 h. The product was filtered, rinsed
Ethyl N-Benzyl-3-oxo-piperidine-4-carboxylate Hy-
drochloride (2): N-Benzylglycine ethyl ester (15.9 kg, 82.8
mol, 1.0 equiv), triethylamine (15.2 kg, 126.5 mol, 1.5 equiv),
and toluene (110 kg) were combined and heated to 95 °C.
Ethyl 4-bromobutyrate (31.2 kg, 155.8 mol, 1.9 equiv) was
added over 10 min, and the reaction mixture was adjusted
to reflux. After 5 h, in-process analysis indicated that the
reaction was complete (<1% starting material by area
normalized GC). The reaction mixture was cooled to 50 °C
and filtered. The reaction vessel and filter were rinsed with
toluene (22 kg), and the combined filtrate was transferred
to another reactor. The reactor contents were adjusted to ca.
90 °C, and potassium tert-amylate (25% solution in toluene,
with water (ca. 34 L), then dried. Yield: 14.0 kg of 3, purity
100% (area normalized HPLC), water content 0.3% (Karl-
Fisher method). Mass spectrum: m/z ) 242 (M++1), mp:
195-197 °C.
7-Benzyl-4-morpholin-4-yl-5,6,7,8-tetrahydro-pyrido-
[3,4-d]pyrimidine (5): Pyrimidinone 3 (14.0 kg, 5.8 mol, 1
equiv) and acetonitrile (77 kg) were combined and heated
to 50-60 °C. Phosphorus oxychloride (15 kg, 9.8 mol, 1.7
equiv) was charged over 15 min, and the reaction mixture
was adjusted to ca. 80 °C. The reaction mixture was kept at
(23) An agitated filter dryer was used for this filtration because the cake will
pull away from the walls of the filter.
86
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Vol. 9, No. 1, 2005 / Organic Process Research & Development