Development of a practical route for the manufacture of N-[5-(3-lmidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]acetamide

Article abstract of DOI:10.1021/op700222r

An efficient synthesis of a potent candidate in our respiratory program is described. The synthesis based on a key Darzens condensation-α,β- epoxide rearrangement circumvented the toxicity and safety issues encountered in the original synthesis route. Sub

Full text of DOI:10.1021/op700222r

Organic Process Research & Development 2008, 12, 111–115
Development of a Practical Route for the Manufacture of N-[5-(3-Imidazol-1-yl-4-
methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]acetamide
Hans Hirt, Ruedi Haenggi, Jesus Reyes, Manuela Seeger-Weibel, and Fabrice Gallou*
NoVartis Pharma AG, Chemical and Analytical DeVelopment, CH-4002 Basel, Switzerland
Scheme 1. Retrosynthetic analysis
Abstract:
An efficient synthesis of a potent candidate in our respiratory
program is described. The synthesis based on a key Darzens
condensation-r,ꢀ-epoxide rearrangement circumvented the toxic-
ity and safety issues encountered in the original synthesis route.
Subsequent functionalization and formation of an heterocyclic
moiety is presented with a particular emphasis on the practicality,
robustness, and streamlining of the process.
Introduction
Asthma is a chronic inflammatory disease characterized by
recurrent attacks of breathlessness and wheezing, responsible
for over 255,000 deaths in 2005 according to the World Health
Organization (WHO).1 If no urgent action is taken, WHO
predicts an alarming increase of almost 20% in the next 10
years. Today, although more than 300 million people have been
diagnosed as suffering from asthma, it is still considered to be
under-diagnosed and under-treated, creating a substantial burden
to individuals and families and possibly restricting individuals’
activities for a lifetime. Although asthma cannot be cured,
appropriate management could control the disorder and enable
people to enjoy a better quality of life.
Scheme 2. Original manufacturing of 2a
In the course of our respiratory program, a potent candidate
(1) was discovered.2 In the mild-persistent to moderate asthma
patient segment, the introduction of a successful nonsteroidal
oral therapy would offer numerous benefits for the patients.
Multikilogram quantities of the drug substance were needed
for the development of 1. The present paper describes the
evolution of the synthetic approach from the early route to the
long-term development route.
In a retrosynthetic plan, a sequential approach was designed
where the imidazole would be introduced last via an SNAr on
the activated aryl fluoride 2 (see Scheme 1). The thiazole subunit
could come from the keto intermediate 3 and thiourea after
R-halogenation and condensation. Compound 3 could in turn
come from an SNAr reaction of 3,4-difluorobenzaldehyde 4 with
sodium thiomethoxide or more directly with the corresponding
sulfinate anion, followed by Henry condensation with nitroet-
hane and subsequent reduction of the nitro compound. These
disconnections offered us the advantage to define compound 2
as a very advanced API starting material, which would facilitate
our outsourcing strategy.
a Reagent and conditions: (a) CH3SO2Na, DMSO, 75 °C, 3 h; (b) EtNO2,
NH4OAc, 105 °C, 6 h; (c) Fe, AcOH, 100 °C, 2 h; (d) Br2, dioxane, 10 °C,
2.5 h; (e) N-acetyl-thiourea, 5-ethyl-2-methyl-pyridine, CH3CN, 50 °C, 1 h then
80 °C, 2.5 h.
The original synthesis started from the readily available
3,4-difluorobenzaldehyde (4), which was reacted with a
slight excess of sodium methylsulfinate in dimethyl
sulfoxide in an SNAr process (see Scheme 2). A rapid
temperature study and optimization of the amount of
sodium methylsulfinate showed that formation of the bis-
sulfonylated product 8 was the major process impurity
(see Figure 1). It could be minimized to below 6% by
reducing the reaction temperature to ca. 75 °C and using
1.1 equiv of sodium methylsulfinate. A single recrystal-
lization from DMSO/water then allowed for isolation of
the desired product 5 in 80% yield and purity higher than
98%. Interestingly, the quality of sodium methylsulfinate
appeared to be critical for the robustness of the reaction.
Various supplies with supposedly nearly identical purity
* To whom correspondence should be addressed. E-mail: fabrice.gallou@
novartis.com.
(1) See World Health Organization asthma web page at http://www.
who.int/mediacentre/factsheets/fs307/en/.
(2) Bruce, I.; Cuenoud, B.; Keller, T. H.; Pilgrim, G. E.; Press, N.; Le
Grand, D. M.; Ritchie, C.; Valade, B.; Hayler, J.; Budd, E. PCT Int.
Appl. (2004) WO 2004096797.
10.1021/op700222r CCC: $40.75
Published on Web 01/03/2008
2008 American Chemical Society
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Figure 1. By-products in 7 and 2.
levels indeed resulted in significant variations in the yield
and amount of bis-sulfonylated product 8.
occurred once again promoted by the acid generated in the
process, whereby the deacetylated compound (11) was indeed
identified as a major side-product. The hydrobromic acid
liberated in the course of the thiazole formation was therefore
trapped with an acid scavenger, 5-ethyl-2-methylpyridine, to
avoid an additional re-acetylation step. The product precipitated
in the course of the reaction and was recrystallized from DMSO/
water to provide material of high purity (>98%) in an overall
44% isolated yield for the two steps.
This initial approach allowed us to produce the first few
hundred grams of material, but numerous process issues had
been identified. The high cost of methylsulfinate and its varying
quality, safety issues with the formation of the nitro alkene 6
and subsequent reduction, toxicological concerns with the
mutagenic intermediate 6, poor overall yield, and complex
operations were major issues that prompted us to look for an
alternative approach.
In an attempt to identify a more practical and scalable route,
we turned our attention to the key intermediate ketone 3 and to
an approach that utilized a Darzens condensation and subsequent
R,ꢀ-epoxyester rearrangement.7 This approach had the benefit
over other proposals that it would afford the previously used
key intermediate 3 and therefore it would not change our overall
development strategy (same raw material and API starting
material).
As previously, the readily available 3,4-difluorobenzaldehyde
4 was used as the precursor. It was first reacted with sodium
thiomethoxide (21% in water) in an SNAr reaction (see Scheme
3).8 The mercaptan was used as a solution in water to minimize
the discomfort caused by the malodorous reagent. The displace-
ment proceeded almost quantitatively to 12 in 1 h. The crude
reaction mixture was then used directly in the subsequent
Darzens condensation with methyl-R-chloropropionate, which
resulted in the formation of a diasteoisomeric mixture in more
than 98% yield. The crude mixture was directly saponified,
decarboxylated, and rearranged to the desired product 13 as a
single product in high yield. Oxidation of the sulfide to the
sulfone using the conditions developed by Noyori9 led to the
key intermediate 3 in an overall 75% yield. Interestingly, when
the Darzens condensation-epoxide rearrangement sequence
was attempted on 3-fluoro-4-methylsulfonebenzaldehyde, al-
most no Darzens condensation product was observed. We are
currently investigating in more detail this electronic effect.
The key keto intermediate 3 was then prepared in a two-
step process. Nitroethane was first reacted with the aldehyde 5
at 105 °C to generate the nitro alkene product 6,3 reduced to
the corresponding enamine and hydrolyzed to ketone 3.4 Several
critical process issues became apparent from this sequence. The
addition of nitroethane to the aldehyde 5 was carried out at
elevated temperature (more than 100 °C), and an important
exothermic decomposition (>3000 J/g) was observed with a
relatively low onset temperature (ca. 159 °C) compared to the
reaction temperature. Our concern with this relatively low safety
margin was further reinforced when the nitro alkene intermedi-
ate 6 was found to be Ames positive. A cumbersome process
therefore had to be designed to minimize contact with the
mutagenic intermediate 6. In addition, although the chemical
yield for this transformation had proven robust, the crude
product required column chromatography to provide an accept-
able quality of product 6. The subsequent reduction step was
carried out with iron in acetic acid at 40 °C. An endothermic
decomposition with low onset temperature was again observed
(ca. 95 °C), although with a moderate enthalpy of decomposition
as observed by DSC of the reaction mixture. The purification
process also proved tedious, requiring both column chroma-
tography and recrystallization to obtain high quality material
with no metal contamination. The overall isolated yield for these
two steps was therefore low (32% overall).
The thiazole ring was then built in a two-step process:
regioselective benzylic bromination followed by reaction with
N-acetyl-thiourea led to the desired heterocyclic moiety. The
halogenation proved challenging, resulting in the terminal
bromide 9, dibrominated species 10, and the back-reaction to
3 under acid catalysis from the released hydrobromic acid (see
Figure 1).5 After extensive screening, a preformed complex of
bromine-dioxane used at low temperature (ca. 10 °C) was
found to minimize the extent of side-reaction.6 We also
attempted to remove the hydrobromic acid generated in the
process, to minimize the amount of back-reaction, by running
the reaction under slight vacuum (150–200 mbar), and to our
delight, a much improved chemical yield was obtained (from
ca. 60% to ca. 85%). At completion, the reaction mixture was
concentrated, diluted with acetonitrile, and heated in the
presence of N-acetyl-thiourea for 3 h. A major side-reaction
(3) (a) Henry, L. C.R. Acad. Sci. Ser. C 1895, 120, 1265. (b) Henry, C.
Bull. Soc. Chim. France 1895, 13, 999. (c) see latest review and
references therein Luzzio, F. A. Tetrahedron 2001, 57, 915.
(4) (a) Konovalov, M. J. Russ. Phys. Chem. Soc. 1893, 25, 509. (b) Nef,
J. U. Liebigs Ann. Chem. 1894, 280, 263. (c) see latest review and
references therein Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017.
(5) (a) Brewster, K.; Pinder, R. M. Synthesis 1971, 307. (b) Choi, H. Y.;
Chi, D. Y. Org. Lett. 2003, 5, 411.
(7) (a) Darzens, G. Compt. Rend 1904, 139, 1214. (b) Darzens; G., Compt.
Rend 1906, 141, 214. (c) Rosen, T. In ComprehensiVe Organic
Synthesis; Trost, B. M.; Fleming, I., Ed. Pergamon: Oxford, 1991,
vol. 2, pp 409–439.
(8) Chianelli, D.; Testaferri, L.; Tiecco, M.; Tingoli, M. Synthesis 1982,
475.
(6) (a) Schneider, J. A.; Mills, Jack F. U.S. (1973), US 3755444; (b)
Schneider, J. A.; Mills, Jack F. U.S. (1971), US 3607883.
(9) Sato, K.; Hyodo, M.; Aoki, M.; Zheng, X.-Q.; Noyori, R. Tetrahedron
2001, 57, 2469.
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Scheme 3. Manufacturing process of 3a
a Reagent and conditions: (a) NaSCH3(aq), CH3CN, rt, 1 h; (b) methyl-R-chloropropionate, NaOCH3, toluene, 0 °C to rt, 4 h; (c) NaOH; then HCl; (d) H2O2 30%,
Na2WO4, n-BuOAc/H2O, 50 °C, 12 h.
Scheme 4. Manufacturing of the drug substance 1a
a Reagent and conditions: (a) SO2Cl2, CH3CN, 0–5 °C, 1 h; (b) N-acetyl-thiourea, 5-ethyl-2-methyl-pyridine, CH3CN, 50 °C, 1 h then 80 °C, 3 h; (c) imidazole,
K2CO3, NMP, 100 °C, then Ac2O.
Table 1. Attempted purification of the drug substance 1
Further optimization of the process led to a more streamlined
and practical process with a single purification throughout the
sequence.
solvent system
purity (%) recovery (%)
DMSO/water (4:1), 100 °C
N-methylpyrrolidone/water, 60 °C
DMSO/water (4:1), 60 °C
(slurry conversion)
>98
>98
>98
ca. 95
ca. 80
ca. 95
A more straightforward selective benzylic chlorination
process was also identified as an alternative to the previously
used bromination (see Scheme 4). The keto intermediate 3 was
reacted with sulfuryl chloride in acetonitrile at ca. 0 °C for 1 h,
concentrated, and directly submitted to the subsequent thiazole
ring formation as previously developed.10 The desired product
2 was isolated by crystallization from water in an overall 90%
yield and purity higher than 95% after recrystallization from
acetonitrile/water.
The original final SNAr reaction proceeded smoothly in
DMSO with cesium carbonate and gave the crude drug
substance along with a significant amount of hydrolyzed amide.
Both the base and solvent could be substituted by the more
practical N-methylpyrrolidone and potassium carbonate with no
impact on the outcome of the nucleophilic displacement.
However, the amount of hydrolyzed amide remained above
15%. An in situ functionalization was therefore introduced as
a second step. Eventually a one-pot protocol was designed
wherein an excess of acetic anhydride was added at the end of
the SNAr to convert the amine back to the amide 1. The crude
material was then isolated by direct precipitation from N-
methylpyrrolidone/water and recrystallized from DMSO/water
to result in high quality material (>99%) and good overall yield
(85%). Due to the potential autocatalytic decomposition of
DMSO at elevated temperatures,11 alternative solvent systems
and conditions were evaluated. Direct slurry conversion at 60
°C was first attempted and proved sufficient to provide material
of similar purity (>98%), high recovery (>95%) and good
overall yield (85%). DMSO could eventually be completely
removed and the recrystallization carried out in N-methylpyr-
rolidone/water. However, more dilute conditions were required
to reject the process impurities and to meet the specifications.
It followed that a slightly lower yield was achieved (ca. 80%,
see Table 1).
In summary, we have described here an efficient, practical
and robust process to the target drug substance (1). The overall
process was streamlined, and the overall yield for the sequence
was improved from 7% to 45% from readily available 3,4-
difluorobenzaldehyde 4 to the free base. The newly developed
approach allowed us to circumvent the toxicity and safety issues
originally encountered. In addition, it gave us the opportunity
(11) (a) Bollyn, M. Org. Proc. Res. DeV 2006, 10, 1299. (b) Lam, T. T.;
Vickery, T. Tuma, Linda. J. Therm. Anal. Calorim 2006, 85, 25.
(10) McPhee, W. D.; Klingsberg, E. J. Am. Chem. Soc. 1944, 66, 1132.
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to develop a robust and practical protocol for the homologation
of aromatic aldehydes after revisiting the Darzens condensation.
Further efforts on the subject will be reported shortly.
1-(3-Fluoro-4-methanesulfonyl-phenyl)propan-2-one (3).
Sodium tungstate dihydrate (0.25 g, 0.75 mmol) and phe-
nylphosphonic acid (0.12 g, 0.75 mmol) were added to water
(15 mL) at room temperature and stirred until a clear solution
was formed. To this solution were added methyltrioctylammo-
nium hydrogen sulfate (0.37 g, 0.75 mmol) and then hydrogen
peroxide (51.0 g, 450 mmol, 30% in water), followed by
n-butylacetate (180 mL) at room temperature. The clear biphasic
mixture was stirred rapidly for 10 min. The mixture was then
heated to 50 °C, and the crude solution of 13 in toluene (60 g,
50% w/w, ca. 150 mmol) was added slowly over 30 min at a
rate such that the temperature remained below 50 °C. The
biphasic mixture was stirred vigorously for 12 h at 50 °C. At
completion, the mixture was cooled to room temperature, and
a half-saturated sodium chloride solution (255 mL) was added.
The phases were separated, and the aqueous phase extracted
with n-butylacetate (60 mL). The combined organic phases were
washed with sodium hydrogen sulfite solution (15 mL; ca. 20%
w/w). A saturated sodium chloride solution (255 mL) was added
at room temperature with vigorous stirring, and then sodium
hydrogen carbonate was added until pH ) ca. 6.5 (4.6 g was
required). The phases were separated, and the organic phase
was partially concentrated under vacuum (e50 mbar, ca. 60
°C) to afford 25% w/w of solution (ca. 138 g). The concentrate
was warmed to 60 °C and subjected to a rapid hot-filtration to
remove precipitated inorganic salts. The cake was washed
portion-wise with warm n-butylacetate (60 mL). The clear
filtrate was partially concentrated under vacuum to afford a 50%
w/w solution (ca. 69 g). This concentrate was stirred at 60 °C
for 10 min and then allowed to cool to -20 °C over 2 h with
seeding at ca. 50 °C. The mixture was held at -20 °C for 1 h,
and the solid was collected by filtration. The cake was washed
with cold n-butylacetate/TBME mixture (24 mL, 1:1 v/v), and
the solid was dried in a vacuum oven overnight (20 mbar, 40
°C) to afford 3 as a pale yellow solid (25.2 g, 72.9% (5 steps),
Experimental Section
3-Fluoro-4-methylsulfanylbenzaldehyde (12). To a well-
stirred solution of 3,4-difluorobenzaldehyde 4 (33.6 mL, 300.0
mmol) in acetonitrile (330 mL) at room temperature was added
sodium methanethiolate solution (105.2 g, 315 mmol; 21% in
water) over a period of 1 h. The suspension was stirred for an
additional 1 h at room temperature. Saturated sodium hydrogen
carbonate solution (120 mL) and water (120 mL) were added,
and acetonitrile was removed under vacuum (g100 mbar, ET
50 °C). The mixture was extracted with toluene (300 mL). The
organic phase containing the product was washed once with
water (150 mL) and partially concentrated under vacuum (to
ca. 50% w/w; giving ca. 102 g) to afford a yellow-brown clear
solution of 12 in toluene (103.7 g; concentration, ca. 50% w/w;
purity, 98.8%; theoretical yield, 51.0 g, 300 mmol). The crude
solution was used as such in the next step; 1H NMR (400 MHz,
CDCl3) δ 10.1 (d, J ) 1.25 Hz, 1H), 8.11 (t, J ) 7.5 Hz, 1H),
7.98–8.01 (m, 2H), 3.41 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 191.2, 159.4, 158.9, 134.9, 134.0, 126.7, 126.2, 113.6, 13.1;
HRMS (M + H) calcd 171.02016, obsd 171.02742.
1-(3-Fluoro-4-methylsulfanyl-phenyl)propan-2-one (13).
To the solution of 12 in toluene (103.7 g, ca. 50% w/w, ca.
300 mmol) was added methyl-R-chloropropionate (45.5 g, 360
mmol) over 10 min at room temperature. The solution was
cooled to 0–5 °C, and a solution of sodium methoxide in
methanol (62.6 g, 30% w/w, 348 mmol) was added over 20
min (exothermic) at a rate such that the temperature remained
below 10 °C. The resulting suspension was stirred for an
additional 30 min at 0–5 °C and then warmed to room
temperature. The yellow suspension was stirred at room
temperature until reaction completion (4 h). The mixture was
diluted with toluene (150 mL) and warmed to 35–40 °C. A
30% solution of sodium hydroxide (34.5 mL, 345 mmol) was
added over 45 min, and the suspension was allowed to stir for
1 h. At completion of the hydrolysis, water (450 mL) was added,
the mixture was cooled to room temperature, and the two phases
were separated. The water phase containing the product was
washed an additional time with toluene (150 mL). To the water
phase was added toluene (180 mL). The resulting triphasic
mixture was heated to 60 °C, and concentrated hydrochloric
acid (ca. 32 mL, ca. 385 mmol, 37%) was added over 30 min,
to reach pH 2.5 (exothermic; CO2 evolution). The mixture was
stirred for 1 h at 60 °C and for an additional 4 h at 95 °C. The
colourless biphasic mixture was then cooled to room temper-
ature, and the phases were separated. The organic phase was
washed with water (150 mL) and partially concentrated under
vacuum (ca. 50% w/w; ca. 120 g; at ca. 50 °C) to afford a
yellow-grey clear solution of 13 in toluene (120.0 g; concentra-
tion, ca. 50% w/w; purity, 87.7%; theoretical yield, 59.5 g, 300
mmol). The crude solution was used as such in the next step;
1H NMR (400 MHz, CDCl3) δ 8.11 (t, J ) 7.53 Hz, 1H), 8.01
(s, 1H), 7.98 (s, 1H), 3.41 (s, 3H), 3.22 (s, 3H), 2.26 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 191.5, 160.3, 157.7, 142.1,
132.6, 130.3, 125.9, 117.3, 51.4, 43.9, 28.9.
1
109.4 mmol; purity, 99.5%); H NMR (400 MHz, CDCl3) δ
7.91 (t, J ) 7.83 Hz, 1H), 7.16 (dd, J ) 11.3, 1.3 Hz, 1H),
7.12 (dd, J ) 11.3, 1.3 Hz,, 1H), 3.84 (s, 2H), 3.22 (s, 3H),
2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 204.6, 159.6,
157.1, 144.8, 128.8, 126.7, 126.6, 118.4, 48.6, 43.6, 29.9;
HRMS (M + H) calcd 231.04129, obsd 231.04850.
1-Chloro-1-(3-fluoro-4-methanesulfonyl-phenyl)propan-
2-one (3). The intermediate 3 (23.0 g, 100 mmol) was dissolved
in dry acetonitrile (50 mL) at room temperature, and the clear
solution obtained was cooled to 0–5 °C. Sulfuryl chloride (13.9
g, 102 mmol) was added over 1 h (exothermic; HCl and SO2
gas evolved), and the reaction mixture was stirred for 30 min
at 0–5 °C. The mixture was warmed slowly to 45 °C (gas
evolution) and subjected to distillation (100 mbar, ca. 45 °C,
ca. 8 mL acetonitrile removed) to afford a pale yellow solution
of 13 in acetonitrile (57.1 g; concentration, ca. 46% w/w; purity,
96.7%; theoretical yield, 26.5 g, 100 mmol) used as such in
the next step.
N-[5-(3-Fluoro-4-methanelsulfonyl-phenyl)-4-methyl-thi-
azol-2-yl]acetamide (2). N-Acetyl-thiourea (8.45 g, 110 mmol)
and 5-ethyl-2-methylpyridine (27.2 mL, 200 mmol) were added
to dry acetonitrile (100 mL) at room temperature to provide a
free-flowing suspension. The mixture was warmed to 50 °C,
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and a solution of 13 in acetonitrile (57.1 g, ca. 100 mmol) was
added over 15 min. The reaction mixture was stirred for 1 h at
50 °C. Water (200 mL) was added over ca. 20 min at this
temperature, and the resulting suspension was cooled to room
temperature over ca. 1 h. The precipitate was collected by
filtration after a 1 h hold, and the cake was washed with a
mixture of water/acetonitrile (100 mL, 2:1 v/v). The solid was
dried in a vacuum oven (20 mbar, 50 °C) to obtain 2 as an
off-white powder (29.3 g, 89.2% (over 3 steps), 89.2 mmol;
purity, 99.8%); 1H NMR (400 MHz, CDCl3) δ 12.31 (s, 1H),
7.88 (t, J ) 8.0 Hz, 1H), 7.62 (dd, J ) 11.5, 1.5 Hz, 1H), 7.54
(dd, J ) 8.2, 1.5 Hz, 1H), 3.36 (s, 3H), 2.43 (s, 3H), 2,16 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 168.7, 160.1, 157.5, 156.6,
145.2, 140.6, 129.7, 126.1, 124.6, 121.2, 116.1, 43.7, 22.4, 16.5;
HRMS (M + H) calcd 329.03516, obsd 329.04235.
N-[5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-meth-
yl-thiazol-2-yl]acetamide (1). N-Methylpyrrolidine (160 mL)
was charged to a vessel containing intermediate 2 (26.3 g, 80
mmol), imidazole (10.9 g, 160 mmol), and potassium carbonate
(22.1 g, 160 mmol). The suspension was heated to 145 °C and
stirred overnight. The suspension was cooled to an internal
temperature of 90 °C, and acetic anhydride (4.9 g, 48 mmol)
was added over ca. 5 min. The mixture was stirred for an
additional 30 min at 90 °C, and water (320 mL) was added
over ca. 20 min at a rate such that the temperature remained
between 70 and 90 °C. The mixture was cooled to room
temperature over 1 h and stirred for 1 h. The precipitate was
collected by filtration and washed, portion-wise, with water (180
mL) and ethanol (100 mL). The solid was dried in a vacuum
oven (20 mbar, 50 °C) to obtain the crude free base 1 as a
brown powder (26.5 g, ca. 88.0%, ca. 70.4 mmol; purity,
98.9%). Mp 293 °C. Anal. Calcd for C16H16N4O3S2: C, 51.05;
H, 4.28; O, 12.75. Found: C, 50.92; H, 4.27; O, 12.93. 1H NMR
(400 MHz, CDCl3) δ 12.33 (m, 1H), 9.50 (s, 1H), 8.22 (d, J )
8.0 Hz, 1H), 8.14 (s, 1H), 8.05–8.02 (m, 1H), 7.98 (dd, J )
11.5, 1.5 Hz, 1H), 7.88 (s, 1H), 3.26 (s, 3H), 2.47 (s, 3H), 2.17
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.8, 157.0, 145.9,
139.1, 138.1, 134.1, 133.1, 131.1, 130.6, 129.3, 124.8, 120.7,
119.8, 43.7, 22.4, 16.5; HRMS (M + H) calcd 377.06638, obsd
377.07359.
A suspension of crude free base 1 (26.4 g, 70 mmol) in
dimethylsulfoxide (105 mL) was heated to 60 °C and stirred
for 30 min. To the suspension was added water (26 mL) over
15 min at a rate such that the temperature remained constant.
The mixture was cooled to room temperature over 1 h and
stirred for an additional 1 h. The suspension was filtered, and
the cake was washed successively with a water/DMSO mixture
(93 mL, 1:1 v/v) and with water (10 mL). The solid was dried
in a vacuum oven (20 mbar, 50 °C) to provide the pure free
base 1 as an off-white powder (25.4 g, 96.4%, 67.5 mmol;
purity, 99.5%).
Received for review October 4, 2007.
OP700222R
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