Application of flow photochemical bromination in the synthesis of a 5-bromomethylpyrimidine precursor of rosuvastatin: Improvement of productivity and product purity

Article abstract of DOI:10.1021/op300248y

In this report we present a flow photochemical bromination of a 5-methyl-substituted pyrimidine precursor of rosuvastatin. The study demonstrated that the reaction productivity can be increased markedly with a flow-mode approach compared to a batch-mode synthesis. Indeed, reaction times can be significantly shortened from a range of hours to a range of minutes. Moreover, in addition to process intensification, the study demonstrated that significantly lower overall levels of side products are obtained when photochemical bromination is conducted in a flow mode.

Full text of DOI:10.1021/op300248y

Technical Note
pubs.acs.org/OPRD
Application of Flow Photochemical Bromination in the Synthesis of a
5‑Bromomethylpyrimidine Precursor of Rosuvastatin: Improvement
of Productivity and Product Purity
‡
§
,‡,§,⊥
̌
̌
Damjan Sterk, Marko Jukic, and Zdenko Casar*
̌
‡Sandoz Development Center Slovenia, API Development, Organic Synthesis Department, Lek Pharmaceuticals, d.d., Kolodvorska
27, 1234 Menges, Slovenia
̌
§Faculty of Pharmacy, University of Ljubljana, Ask
̌ ̌
erceva 7, 1000 Ljubljana, Slovenia
⊥Global Portfolio Management API, Sandoz GmbH, Biochemiestrasse 10, 6250 Kundl, Austria
ABSTRACT: In this report we present a flow photochemical bromination of a 5-methyl-substituted pyrimidine precursor of
rosuvastatin. The study demonstrated that the reaction productivity can be increased markedly with a flow-mode approach
compared to a batch-mode synthesis. Indeed, reaction times can be significantly shortened from a range of hours to a range of
minutes. Moreover, in addition to process intensification, the study demonstrated that significantly lower overall levels of side
products are obtained when photochemical bromination is conducted in a flow mode.
This would enable us to distinguish whether the predominant
side-reaction pathways proceed via bromination of benzylic
positions or via bromination of the aryl substituent on position
4 of the pyrimidine ring. Furthermore, although 5-bromome-
thylpyrimidine 1 was obtained as a principal product in the
batch-mode reaction during our primary study and could be
obtained as NMR pure material (impurities below ∼2% were
not observed) after simple workup by precipitation with water
and consecutive aqueous MeOH wash of precipitate,11 the
batch reaction was not completely regioselective, and impurities
1. INTRODUCTION
Superstatins1,2 have recently attracted our attention as
interesting synthetic targets due the fact that they maintain a
leadership position in high cholesterol management and rank
among the most valued pharmaceuticals within the cardiovas-
cular therapeutic category.3,4 In particular, rosuvastatin5 has
shown some interesting therapeutic advantages over previously
known members of the superstatin family.6,7 Therefore, we
have recently developed a lactone pathway to superstatins,
exemplified by assembly of rosuvastatin8 and pitavastatin9 via a
lactonized statin side-chain precursor.10 Afterwards, we focused
our attention on the heterocyclic part of the rosuvastatin
molecule and developed a highly efficient four-step procedure
to 5-bromomethylpyrimidine 1.11 This important rosuvastatin
precursor12−14 was accessed from simple starting materials via
photochemical bromination of 5-methylpyrimidine 2 (Scheme
1).11
1
could indeed already be detected by H NMR in the crude
product. These impurities were responsible for a lower, 74%
yield (4 W low-pressure Hg lamp) to 80% yield (150 W
medium-pressure Hg lamp), which is not acceptable for such a
simple transformation when the industrial process is consid-
ered. Moreover, batch-mode reactions were relatively long
(16−64 h) already on millimolar scale (12 mmol).11
Furthermore, undesirable carryover to the product of impurities
such as 3, 4 and 5 might be possible in the remaining short
three to four sequences to the final API.2 Alternatively, 3 and 4
might partially react with phosphorus precursors (e.g.,
phosphine or phosphite) in the ensuing step and further in
Wittig or HWE coupling with the formyl-substituted side-chain
precursors to provide similarly problematic impurity products.
Therefore, the objective of the present study was to elaborate
an improved process of the key photochemical bromination
step in the preparation of 5-bromomethylpyrimidine 1, which
would enable industrial use and provide superior productivity
as well as the improved impurity profile of 1. In addition, this
work provides basic understanding about the formation of
alkylbromide impurities during the photochemical bromination
of the highly substituted pyrimidine core and their influence on
the quality of the product.
However, 5-methylpyrimidine 211 has a relatively complex
structure for the application of photochemical halogenation
approaches when functionalization of the 5-methyl position is
attempted. A closer look at the structure of 2 reveals a benzylic
isopropyl moiety located at position 6 of the pyrimidine core
that might also be susceptible to photochemical bromination.
This could result in the formation of other regioisomers of the
desired intermediate and its analogues with multiple bromi-
nated sites such as 3, 4 and 5 (Scheme 1).15 In addition,
photochemical bromination of the aromatic part of the skeleton
is also viable16 which could provide, in combination with
bromination of the benzylic positions, various regiobrominated
derivatives 6 (lighter grey-colored brominated positions denote
lower likelihood of bromination, Scheme 1). Compounds 3, 4
and 5 are, due to the bromoalkyl fragment, known to trigger
concerns in relation to genotoxic potential, while compounds 6
are less problematic in drug production.17,18 Therefore, we
were prompted to investigate possible formation of these side
products in crude 1 after batch photochemical bromination.
Received: September 6, 2012
© XXXX American Chemical Society
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Scheme 1. Application of 5-bromomethylpyrimidine in the synthesis of rosuvastatin and possible impurities formed during its
preparation via photochemical bromination of 5-methylpyrimidine
Scheme 2. Flow vs batch photochemical bromination of 5-methylpyrimidine 2
a
Table 1. Comparison of flow and batch photobromination of 2
d
,
e
d,
e
d,e
entry
reaction type
time
3 h
remaining 2 in 1 [area %]
purity of 1 [area %]
Σ impurities in 1 [area %]
productivity [mmol/h]
b
1
2
3
4
5
6
small batch
0.5
2.0
88.0
80.4
88.6
89.1
89.4
11.5
17.6
11.4
10.9
10.6
10.0
8.1
13.6
9.7
c
large batch
13 h
flow
flow
flow
flow
30 min
15 min
10 min
5 min
<0.2
<0.2
<0.2
19.4
29.2
2.0
88.0
58.3
a
b
c
d
e
In all cases the temperature of reaction was 22 °C. 28 mmol scale based on starting 2. 203 mmol scale based on starting 2. HPLC purity. Values
refer to crude product obtained after precipitation with water (see the Experimental Section).
dissipation.20,21 Therefore, we constructed an 18-mL flow
2. RESULTS AND DISCUSSION
reactor coupled to an HPLC pump as described by Hook et
al.,22 which enabled us to vary the residence time by controlling
the reaction mixture flow and to achieve better controlled
irradiation conditions. The reactor was constructed from a
fluorinated polyethylene tube (FEP) of 0.8-mm inner diameter
and 36-m length on a quartz cooling jacket support holding the
150 W medium-pressure Hg lamp.
In the quest for more controlled reaction conditions,
homogeneous irradiation of the entire volume of the reaction
mixture, and simpler scale-up, we attempted to perform the
photobromination of 2 in a flow mode.19 Indeed, flow reactors
usually provide better mass transfer through more efficient
mixing along with many other advantages including better light
B
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1
Figure 1. Comparison of impurity profiles by H NMR in batch- vs flow-mode photochemical reactions.
For comparison reasons, we started our experiments of
bromination with a small-scale batch reaction (28 mmol of 2),
using the 150 W medium-pressure Hg lamp (Scheme 2; Table
1, entry 1). Reaction was completed in 3 h, giving 0.5 area % of
the remaining starting material 2 in the reaction mixture (99.5%
conversion). Crude product 1, after precipitation triggered by
water addition, had 88 area % purity. When the scale of the
reaction was increased to 203 mmol of the starting bromide 2
(7.25-fold increase), the reaction took a significantly longer
time to reach near completion under the same reaction
conditions. Indeed, 13 h were required to reach 98 area %
conversion (2 area % of starting 2 remained in the mixture;
Scheme 2; Table 1, entry 2).23 Moreover, the prolonged
reaction time had a markedly deteriorative effect on the product
quality. Notably, the crude product obtained after precipitation
triggered by water addition was only 80.4 area % pure and
contained, in addition to unreacted 2, a total 17.6 area % of
other impurities (highest individual impurity was on the level of
∼2 area %). Recrystallization from THF/heptane (1/3, v/v)
provided bromide 1 in 88% overall yield with only 82 area %
purity, which did not meet our requirements for subsequent
transformations. Moreover, this indicated that the formed
impurities are similar in nature and consequently difficult to
remove using crystallization as the prime purification method.
These results implied that scale-up would be a difficult task to
achieve. Because of the prolonged reaction time, the product
quality would obviously further decrease significantly beneath
the acceptable level. These findings demonstrated that the
batch reaction was scale dependent, whereas millimolar
experiments produced up to ∼8% fewer impurities and were
completed 4.3 times faster in comparison to larger batches
already on the lab scale.24
Therefore, we turned our attention to flow-mode reactions
under identical reaction conditions (same solvent, lamp, and
applied temperature). Flow reactions with 10−30 min
residence times performed similarly, giving practically full
conversion (<0.2 area % of 2 remaining in the reaction
mixture) and comparable crude product quality after
precipitation with water: 88.6−89.4 area % purity of crude 1
(Scheme 2; Table 1, entries 3−5). The thus obtained quality of
1 was similar to that of small batch-type reactions (88.0 area %,
Table 1, entry 1). Nevertheless, productivity of flow reactions
was up to 3.6 times higher than that of small-scale batch
reaction (Scheme 2, Table 1, entry 1 vs entry 5). When the
residence time in the flow reaction was shortened to 5 min
(Scheme 2; Table 1, entry 6), a borderline performance of the
system was reached, demonstrated by a drop of conversion to
98% (2 area % of 2 remaining in the reaction mixture).
Nevertheless, reaction was clean and gave product 1 of 88 area
% purity after precipitation with water, which contained the
lowest sum of all impurities among all performed reactions. In
this case the highest 58.3 mmol/h productivity was obtained.
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The crude bromide 1 was purified by recrystallization from
THF/heptane (1/3, v/v) and was recovered in 86% yield as an
off-white crystalline solid with chromatographic purity of 93
area %. The largest individual impurity remaining in the
recrystallized 1 was 2 at a level of 1.5 area %. Since 2 cannot
undergo transformation in the subsequent phosphonium salt
formation step12a,14,25 and can be easily depleted by
crystallization, product 1 obtained from the largest flow
experiment met our specification requirements.
both cases these types of impurities can be considered as typical
ICH-type impurities and, at formed levels below 1%, do not
represent any quality concerns since they can easily be depleted
to acceptable levels in the ensuing steps (e.g., phosphonium salt
preparation and crystallization) towards the API.8
3. CONCLUSION
In summary, we presented a flow photochemical bromination
of a 5-methylpyrimidine rosuvastatin precursor. To our
knowledge this represents the first report on benzylic
bromination performed in a flow mode.20,21 Our investigation
shows favorable effects of the flow-mode reaction on the
productivity of the reaction. Moreover, the flow approach
proved to be cleaner and provided the desired product with
considerably lowers levels of impurities. These are apparently
formed by photochemical bromination of an aromatic
substituent16 or photochemical degradation, while benzylic
positions within the molecule are less affected by side reactions.
Interestingly, no overbromination of the 5-benzylic position
was observed,15 while the 6-isopropyl moiety was prone to
bromination to a slight extent. The formed impurities proved to
be of no concern for the product quality. We believe that the
demonstrated flow approach to the title compound will be
suitable for easy scale-up. Due to these facts, we trust that our
results will promote the application of flow-mode photo-
chemical brominations in the pharmaceutical industry.
An interesting feature of both batch- and flow-mode
1
reactions can be observed in Figure 1, where H NMR spectra
of independently prepared possible benzylic bromination
impurities 3, 4, and 5 (Scheme 1) are compared with those
of crude mixtures of batch- and flow-mode reactions.
Compound 3 was obtained by the method of Strekowski et
al.,15 where 1 was heated with NBS at reflux in CCl4 in the
presence benzoyl peroxide followed by chromatographic
isolation. Similarly, 4 was obtained by the same approach
using 2 as a starting material. The monobrominated derivative
5 was obtained by irradiation of MeCN solution of 2 and NBS
with less selective irradiation ranging from 250 to 650 nm.
Figure 1 shows that this improved impurity profile is obtained
in flow-mode photochemical bromination. Moreover, it
suggests that the 5-benzylic site in 2 was not susceptible to
additional photochemical overbromination at the applied
conditions since 5,5-dibromo derivative 3 is not detectable
either in batch- or flow-type photochemical bromination.
Similarly, monobromide 5 also could not be observed in the
flow reaction. This was confirmed when the batch- and flow-
mode products were analyzed by different HPLC or UPLC
methods, where 3 and 5 were not clearly distinguished down to
the detection limit (verified also with control samples
containing pure 3 and 5). This is a favorable fact since it
indicates that potentially genotoxic benzylic bromides 3 and 5
are not present in the product 1. On the other hand Figure 1
indicates that impurity 4 might be present in both batch and
flow reactions (detected as a specific broad singlet at 5.01
ppm). This was also observed by HPLC and UPLC analysis,
which revealed 4 in levels up to 2 area % (confirmed also with a
control sample containing pure 4) in the crude product.
Therefore, we have assessed the depletion power of this
impurity in the subsequent step of the rosuvastatin synthesis
where phosphonium salt derivatives, used in Wittig coupling,
are formed. For this purpose, we have reacted pure 4 with PBu3
in THF at 50 °C for 90 min,25 which resulted in full conversion.
LC−MS analysis of the mixture revealed that two compounds
in 1:2 ratio were formed. HRMS analysis of these two
compounds indicated that neither contains an alkylbromide
fragment26 and can be considered as typical ICH impurities.
This data suggest that impurity 4, albeit being formed in the
photochemical bromination step on detectable level, is easily
transformed/depleted in the subsequent synthetic steps
towards API and is therefore not critical to the quality of the
product. Furthermore, the above findings suggest that if the
compounds 3 and 5 were not formed there is even a lower
likelihood that their analogues with brominated aromatic ring 6
are generated (Scheme 1). On the other hand, analogues of 4
with brominated aromatic moieties, if present, could be easily
depleted in the subsequent synthetic steps as was shown in the
case of 4. These findings imply that a majority of formed
impurities observed on NMR, HPLC, and UPLC originate
either from bromination of different positions of the p-F-phenyl
substituent16 or from photochemical degradation products. In
4. EXPERIMENTAL SECTION
4.1. General Considerations. Reagents and solvents were
used as purchased. NMR spectra were recorded at 298 K on a
Bruker Avance III 500 spectrometer operating at 500 MHz
(1H), 125 MHz (13C) respectively. Proton and carbon spectra
were referenced to TMS as internal standard or residual solvent
signals. Chemical shifts are given on the δ scale (ppm).
Coupling constants (J) are given in Hz. Multiplicities are
indicated as follows: s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), or br (broadened). High-resolution
mass spectra were obtained with Agilent 6224 Accurate Mass
TOF LC/MS system. Infrared spectra were recorded on a
Thermo Nicolet Nexus spectrometer using samples in
potassium bromide disks. Melting points were determined on
a Mettler Toledo DSC apparatus 822e (heating rate 10 °C
min−1). For flash chromatography, Fluka silica gel 60, 220−440
mesh was used. HPLC analyses were performed on a Waters
2487 instrument with dual λ absorbance detector and a Waters
XTerra RP-18 3.5 μm 250 mm × 4.6 mm column was used.
HPLC conditions: 40 °C, 0.8 mL min−1, 240 nm, aqueous pH
4.5 buffer (TFA/NH3)/acetonitrile = 2:8. HPLC analyses were
alternatively performed on a Waters 2487 instrument with dual
λ absorbance detector and a Waters Symmetry Shield RP-18 5
μm 150 mm × 4.6 mm column. HPLC conditions: 30 °C, 1.0
mL min−1, 220 nm, 0.1% trifluoroacetic acid in water/0.1%
trifluoroacetic acid in acetonitrile = 10:0 → 0:10. UPLC
analyses were performed on a Waters Acquity instrument and a
Waters Acquity HHS T3 1.8 μm 100 mm × 2.1 mm column.
UPLC conditions: 25 °C, 0.4 mL min−1, 265 nm, aqueous pH
4.5 buffer (AcOH/NH3)/acetonitrile = 7:3. Batch photo-
chemical reactions were conducted in an immersion-type
reactor consisting of a reactor body fabricated of borosilicate
glass with an inserted double-walled quartz immersion well
obtained from UV-Consulting Peschl. A medium-pressure Hg
lamp TQ 150 from UV-Consulting Peschl (P = 150 W, λ =
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Organic Process Research & Development
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predominantly >300 nm) was inserted into a vertically arranged
double-walled, water-cooled immersion well. Flow reactions
were conducted in a photochemical reactor as described by
Hook et al.22 with the same lamp as used for the batch
reactions.
4.4. Preparation of N-(5-(Bromomethyl)-4-(2-bromo-
propan-2-yl)-6-(4-fluorophenyl)pyrimidin-2-yl)-N-meth-
ylmethanesulfonamide (4). To a stirred suspension of N-(4-
(4-fluorophenyl)-6-isopropyl-5-methylpyrimidin-2-yl)-N-meth-
ylmethanesulfonamide (2) (1.68 g, 5.0 mmol, 1 equiv) in
tetrachloromethane (35 mL) were added N-bromosuccinimide
(NBS) (1.78 g, 10.0 mmol, 2 equiv) and benzoyl peroxide (125
mg, 0.5 mmol, 0.1 equiv) at room temperature. Reaction
mixture was heated to reflux, stirred for 15 h, and left to cool to
room temperature. Solids were filtered off and filtrate was
concentrated under reduced pressure to afford residual oil.
Product was purified by column chromatography (silica gel;
hexane/EtOAc = 90:10 → 70:30; Rf = 0.39 in hexane/EtOAc =
80:20) to afford 0.5 g (21% yield) of compound 4 as a white
4.2. Preparation of N-(4-(4-Fluorophenyl)-5-(bromo-
methyl)-6-isopropylpyrimidin-2-yl)-N-methylmethane-
sulfonamide (1). 4.2.1. Batch Mode. A photochemical reactor
with 150 W medium-pressure Hg lamp reactor was equilibrated
before reaction for 30 min at 22 °C. Starting N-(4-(4-
fluorophenyl)-6-isopropyl-5-methylpyrimidin-2-yl)-N-methyl-
methanesulfonamide (2)11 (68.4 g, 0.203 mol, 1.0 equiv) and
N-bromosuccinimide (NBS) (76.2 g, 0.426 mol, 2.1 equiv)
were dissolved in acetonitrile (650 mL) resulting in a 0.27 M
solution of 2. The resulting solution was irradiated in
photochemical reactor for 13 h and water (1.3 L) was added.
The resulting precipitate was filtered off, washed with water
(0.38 L) and dried under reduced pressure to yield 86.5 g of
crude 1 that was recrystallized from THF (140 mL) and
heptane (420 mL) by evaporation of THF to give 73.9 g (88%
yield) of 1 (82 area % HPLC purity) as white powder.
4.2.2. Flow Mode. The flow reactor was equilibrated before
reaction for 30 min at 22 °C. Starting N-(4-(4-fluorophenyl)-6-
isopropyl-5-methylpyrimidin-2-yl)-N-methylmethanesulfona-
mide (2)11 (31.5 g, 93.5 mmol, 1.0 equiv) and N-
bromosuccinimide (NBS) (35.0 g, 196 mmol, 2.1 equiv)
were dissolved in acetonitrile (300 mL), resulting in a 0.27 M
solution of 2. The resulting solution was pumped via a syringe
pump through the flow reactor with the flow rate of 3.60 mL
min−1 (5 min retention time); 50 mL of reaction mixture was
collected, and water (100 mL) was added. The resulting
precipitate was filtered off, washed with water (20 mL), and
dried under reduced pressure to yield 5.53 g of crude 1 that was
recrystallized from THF (10 mL) and heptane (30 mL) by
evaporation of THF to give 4.80 g (86% yield) of 1 (93 area %
HPLC purity) as white powder.
1
solid. Mp = 146 °C (DSC onset). H NMR (CDCl3): δ 2.31
(6H, s, CH3), 3.45 (3H, s, CH3N), 3.55 (3H, s, CH3SO2), 5.01
(2H, br s, CH2), 7.18−7.26 (2H, m, CHAr), 7.56−7.59 (2H, m,
CHAr). 13C NMR (CDCl3): δ 27.3, 33.4, 34.5, 42.2, 62.1, 115.7
(d, JCF = 21.8 Hz), 122.1, 130.4(d, JCF = 8.4 Hz), 133.6, 156.0,
163.4 (d, (d, JCF = 249.9 Hz), 169.9, 170.4. IR (KBr) ν 575,
844, 954, 969, 1113, 1155, 1332, 1379, 1442, 1509, 1548, 1606,
3445 cm−1. HRMS (ESI+) calcd for C16H19Br2FN3O2S+([M +
H]+): 493.9543; found: 493.9540.
4.5. Preparation of N-(4-(2-Bromopropan-2-yl)-6-(4-
fluorophenyl)-5-methylpyrimidin-2-yl)-N-methylmetha-
nesulfonamide (5). Starting N-(4-(4-fluorophenyl)-6-iso-
propyl-5-methylpyrimidin-2-yl)-N-methylmethanesulfonamide
(2) (3.37 g, 10.0 mmol, 1 equiv) and bromosuccinimide (NBS)
(3.73 g, 21.0 mmol, 2.1 equiv) were dissolved in acetonitrile
(70 mL) and transferred to the photoreactor. The reactor was
sealed and flushed with nitrogen for 10 min. The mixture was
stirred and irradiated with a doped medium-pressure Hg lamp,
TQ 150 Z3, from UV-Consulting Peschl (P = 150 W,
polychromatic emission spectra between 250 and 650 nm)
for 4 h. Medium-pressure Hg lamp was in a quartz immersion
jacket cooled with water and stabilized at 40 − 45 °C. The
obtained solution was diluted with H2O/methanol = 9:1 (100
mL). Precipitate was filtered off and filtrate collected. Volatiles
were evaporated under reduced pressure, and residual water
phase was thoroughly extracted with dichloromethane (2 × 10
mL). Organic phases were combined, acetonitrile (10 mL) and
CF3CO2NH4 buffer (pH = 4.5, 15 mL) were added, and the
mixture was stirred at room temperature for 24 h. Volatiles
were evaporated under reduced pressure, and the water phase
was again thoroughly extracted with dichloromethane (2 × 10
mL). Organic phases were combined, washed with brine (10
mL), dried over MgSO4, and evaporated under reduced
pressure to afford residual oil. The product was purified by
reverse phase column chromatography (C18; aqueous pH 4.5
buffer (TFA/NH3)/acetonitrile = 2:8; Rf = 0.38 in hexane/
EtOAc = 80:20) to afford 80 mg (2% yield) of 5 as a yellowish
This is a known compound with spectroscopic and physical
properties in accordance with those reported in the literature.11
Rf = 0.45 in hexane/EtOAc = 80:20.
4.3. Preparation of N-(5-(Dibromomethyl)-4-(4-fluo-
rophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmetha-
nesulfonamide (3). To a stirred solution of N-(4-(4-
fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-
methylmethanesulfonamide (1) (2.08 g, 5.0 mmol, 1 equiv) in
tetrachloromethane (35 mL) were added N-bromosuccinimide
(NBS) (1.78 g, 10.0 mmol, 2 equiv) and benzoyl peroxide (125
mg, 0.5 mmol, 0.1 equiv) at room temperature. Reaction
mixture was heated to reflux, stirred for 5 h, and left to cool to
room temperature. Solids were filtered off and filtrate was
concentrated under reduced pressure to afford oily residue.
Product was purified by column chromatography (silica gel;
hexane/EtOAc = 90:10 → 70:30; Rf = 0.49 in hexane/EtOAc =
80:20) to afford 0.15 g (6% yield) of compound 3 as a white
1
solid. Mp = 145 °C (DSC onset). H NMR (CDCl3): δ 2.25
(6H, s, CH3), 2.56 (3H, s, CH3), 3.46 (3H, s, CH3N), 3.55
(3H, s, CH3SO2), 7.14−7.19 (2H, m, CHAr), 7.53−7.57 (2H,
m, CHAr). 13C NMR (CDCl3): δ 17.5, 33.3, 33.7, 42.0, 62.2,
115.3 (d, JCF = 21.6 Hz), 120.7, 131.3 (d, JCF = 8.4 Hz), 134.6,
155.3, 163.3 (d, JCF = 249.8 Hz), 168.12, 169.3. IR (KBr) ν 575,
1113, 1150, 1229, 1332, 1389, 1512, 1546, 2923, 3437 cm−1.
HRMS (ESI+) calcd for C16H20BrFN3O2S+([M + H]+):
416.0438; found: 416.0441.
1
solid. Mp = 154 °C (DSC onset). H NMR (CDCl3): δ 1.39
(6H, d, J = 6.6 Hz, CH3), 3.45 (3H, s, CH3N), 3.50 (3H, s,
CH3SO2), 4.16 (1H, h, J = 6.5 Hz, CH), 6.80 (1H, s, CH),
7.17−7.20 (2H, m, CHAr), 7.54−7.57 (2H, m, CHAr). 13C
NMR (CDCl3): δ 21.8, 32.5, 33.1, 33.3, 42.6, 116.2 (d, JCF
=
21.8 Hz), 123.9, 130.4 (d, JCF = 8.5 Hz), 133.2, 157.8, 161.6,
163.8 (d, JCF = 251.5 Hz), 179.8. IR (KBr) ν 522, 543, 575,
773, 820, 964, 1152, 1118, 1153, 1236, 1338, 1388, 1540, 1553,
4.6. Reaction of N-(5-(Bromomethyl)-4-(2-bromopro-
pan-2-yl)-6-(4-fluorophenyl)pyrimidin-2-yl)-N-methyl-
methanesulfonamide (4) with Tributylphosphine. To a
1 9 6 7 , 3 4 4 4 c m − 1
.
H R M S ( E S I + ) c a l c d f o r
C16H19Br2FN3O2S+([M + H]+): 493.9543; found: 493.9549.
E
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(12) For the synthesis of rosuvastatin from bromide 1 via
phosphonium salt derivatives, see: (a) Mei, G.; Cai, Q. Chin. Pat.
Appl. CN 1687087 A, 2005, Chem. Abstr. 2005, 145, 188893;
(b) Joshi, N.; Bhirud, S. B.; Chandrasekhar, B.; Rao, K. E.; Damle, S.
U.S. Pat. Appl. 2005 0124639 A1, 2005; Chem. Abstr. 2005, 143,
26633.
(13) For the synthesis of rosuvastatin from bromide 1 via
phosphonate ester derivatives, see: Saka, Y.; Nishiyama, A. PCT Pat.
Appl. WO/2010/047296 A1, 2010; Chem. Abstr. 2010, 152, 477137.
(14) For the synthesis of rosuvastatin from bromide (1) via
phosphine oxide derivatives, see: Ju, H.; Joung, S.-S.; Yi, H.-J.; Khoo,
J.-H.; Lim, J.-C.; Kim, J.-G. PCT Pat. Appl. WO/2012/002741 A2,
2012; Chem. Abstr. 2012, 156, 122219.
solution of N-(5-(bromomethyl)-4-(2-bromopropan-2-yl)-6-(4-
fluorophenyl)pyrimidin-2-yl)-N-methylmethanesulfonamide
(4) (49 mg, 0.1 mmol) in dry THF under nitrogen atmosphere
was added tributylphosphine (55 μL, 0.22 mmol) at 50 °C.25
The resulting colorless solution was stirred at 50 °C, and after
90 min the HPLC analysis indicated complete conversion of
the starting material. The reaction was very clean, and two
products were formed: bis- and monophosphonium salts in the
ratio of 1:2.26 The structures of the products were determined
by LC−HRMS analysis, and that of monophosphonium salt
was determined by comparison of the retention time with with
that of an authentic sample.12a,14,25 Monophosphonium salt
might originate from bis-phosphonium salt via hydrolysis with
water during sample preparation. Monophosphonium salt:
HRMS (ESI+) calcd for C28H45FN3O2PS+([M + H]+):
538.3027; found: 538.3026. Bis-phosphonium salt: HRMS
(ESI+) calcd for C40H70FN3O2P2S2+([M + 2H]2+): 369.7397;
found: 369.7404. Note that the calculated mass for the
phosphonium salt is lower for one hydrogen and that for the
bis-phosphonium salt is lower for two hydrogens than the
actual mass due to the fact that the MS software assumes that
the ion is formed by ionization with an additional proton while
the compound is already in an ionic form.
(15) Strekowski, L.; Wydra, L. R.; Janda, L.; Harden, D. B. J. Org.
Chem. 1991, 56, 5610−5614.
(16) (a) Chhattise, P. K.; Ramaswamy, A. V.; Waghmode, S. B.
Tetrahedron Lett. 2008, 49, 189−194. (b) Zysman-Colman, E.; Arias,
K.; Siegel, J. S. Can. J. Chem. 2009, 87, 440−447.
(17) Robinson, D. I. Org. Process Res. Dev. 2010, 14, 946−959 and
references therein.
(18) Anderson, N. G. Practical Process Research and Development, 2nd
ed.; Academic Press Inc.: San Diego, 2012; pp 365−395.
(19) A reference to a key photochemical reaction step, which appears
here in the form of an article, is based on our recently published patent
̌
applications: (a) Casar, Z.; Kosm
̌
rlj J. PCT Int. Appl. WO/2010/
̌
086438 A1, 2010; Chem. Abstr. 2010, 153, 232607; (b) Casar, Z.;
Sterk, D.; Jukic, M. PCT Int. Appl. WO/2012/013325 A1, 2012;
̌
Chem. Abstr. 2012, 156, 230344.
̌
AUTHOR INFORMATION
Corresponding Author
■
(20) For recent reviews on flow chemistry, see: (a) Wegner, J.;
Ceylan, S.; Kirschning, A. Adv. Synth. Catal. 2012, 354, 17−57.
(b) Baraldi, P. T.; Hessel, V. Green Process. Synth. 2012, 1, 149−167.
(c) Anderson, N. G. Org. Process Res. Dev. 2012, 16, 852−869.
(d) Wegner, J.; Ceylan, S.; Kirschning, A. Chem. Commun. 2011, 47,
4583−4592. (e) Ralph, M. J. Curr. Org. Chem. 2011, 15, 2658−2672.
(f) Kirschning, A. Beilstein J. Org. Chem. 2011, 7, 1046−1047 and the
ensuing articles of this thematic issue on “Chemistry in Flow Systems
*E-mail: zdenko.casar@sandoz.com. Telephone: +43 5338 200
3747. Fax: +43 5338 200 418.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
̋
́
II”. (g) Keseru, G. M.; Dorman, G. Mol. Diversity 2011, 15, 603−604
We gratefully acknowledge Lek Pharmaceuticals, d.d., for
support of this work. L. Kolenc, S. Borise
and the ensuing articles of this thematic issue: “Special Issue in Flow
Chemistry”. (h) Razzaq, T.; Kappe, C. O. Chem.Asian J. 2010, 5,
1274−1289 and references therein. (i) Kirschning, A. Beilstein J. Org.
Chem. 2009, 5, (No. 15) and the ensuing articles of this thematic issue
on “Chemistry in Flow Systems”.
̌
̌
k, M. Borisek, and
M. Ust
̌
ar are acknowledged for assistance in some analytical
̌
work. Dr. M. Crnugelj is gratefully acknowledged for
acquisition of NMR spectra as well as Dr. D. Urankar
(University of Ljubljana) for HRMS analysis and Prof. J.
(21) For recent reviews and selected articles on flow photochemistry,
̌
Kosmrlj (University of Ljubljana) for valuable discussions.
see: (a) Oelgemoller, M. Chem. Eng. Technol. 2012, 35, 1144−1152.
̈
́
(b) Andrews, R. S.; Becker, J. J.; Gagne, M. R. Angew. Chem., Int. Ed.
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F
dx.doi.org/10.1021/op300248y | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Technical Note
which are the reacting species in a photochemical reaction, the
progress of the photochemical reaction depends essentially on the
concentration of such excited molecules. Moreover, photochemical
reactions are only apparently homogeneous, since the concentration of
excited molecules varies throughout the volume of reaction mixture
and decreases according to the distance from the UV lamp immersion
unit. This means that photochemical reaction in batch mode is very
dependent on the thickness of the irradiated layer and efficiency of the
stirring, which is usually far from ideal in any batch vessel. Thus, the
energy is not equally adsorbed in the medium, and the excited species
are not homogeneously distributed throughout batch vessel volume.
Consequently, the photochemical reaction is significantly more intense
near the walls of the UV lamp immersion unit than it is near the walls
of the batch vessel where the effect of the stirring is usually the least
pronounced. Therefore, in a small batch vessel, as in the case of our
millimolar reactions, the majority of the reaction mixture is in close
proximity to the walls of the UV lamp immersion unit, which assures
that reaction conditions are close to being homogeneous and
consequently that the yields are the highest. On the other hand,
with the increasing batch/vessels size, as in the case of our larger lab-
scale reactions (up to 0.2 mol), where the thickness of the layer of the
reaction mixture exposed to light increases, nonhomogenous
conditions are created, leading to nonhomogenous irradiation in the
reaction mixture more distant from the UV lamp immersion unit. This
results in lower yields and/or prolonged reaction times. The latter can
lead to overexposing the substrate and/or the product to light and
consequently can lead to overreaction on less active or more hindered
sites, resulting in regiobrominated and degradation side products.
̌
̌
(25) Zlicar, M. PCT Pat. Appl. WO/2007/017117 A1, 2007; Chem.
Abstr. 2007, 146, 251655.
(26) Structures of the products, obtained in the reaction between N-
(5-(bromomethyl)-4-(2-bromopropan-2-yl)-6-(4-fluorophenyl)pyrimi-
din-2-yl)-N-methylmethanesulfonamide (4) and tributylphosphi-
ne12a,14,25 proposed on the basis of HRMS analysis and also by
comparison of HPLC retention time with authentic sample in the case
of monophosphonium salt:
G
dx.doi.org/10.1021/op300248y | Org. Process Res. Dev. XXXX, XXX, XXX−XXX