Scale-up synthesis of a TRPV1 antagonist featuring a facile thiazolo[5,4-d]pyrimidine formation

Article abstract of DOI:10.1021/op1002984

An efficient and practical synthesis of a TRPV1 inhibitor bearing a thiazolo[5,4-d]pyrimidine core was developed. The initial synthesis was modified to facilitate acylation of 5-aminopyrimidine and subsequent thiazole formation. The synthesis features an efficient two-pot, five-step process for the construction of the thiazolo[5,4-d]pyrimidine ring. The new route is concise, chromatography-free, and amenable to large-scale preparation.

Full text of DOI:10.1021/op1002984

ARTICLE
pubs.acs.org/OPRD
Scale-Up Synthesis of a TRPV1 Antagonist Featuring a Facile
Thiazolo[5,4-d]pyrimidine Formation
Jing Liu,* Anne E. Fitzgerald, Alec D. Lebsack, and Neelakandha S. Mani
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121,
United States
S Supporting Information
b
ABSTRACT: An efficient and practical synthesis of a TRPV1 inhibitor bearing a thiazolo[5,4-d]pyrimidine core was developed.
The initial synthesis was modified to facilitate acylation of 5-aminopyrimidine and subsequent thiazole formation. The synthesis
features an efficient two-pot, five-step process for the construction of the thiazolo[5,4-d]pyrimidine ring. The new route is concise,
chromatography-free, and amenable to large-scale preparation.
’ INTRODUCTION
The transient receptor potential vanilloid, subtype I (TRPV1
or VR1) receptor is the best characterized member of the tran-
sient receptor potential family of ion channels.1 TRPV1 is
believed to play an important role in transmitting inflammatory
pain signals. It has become an attractive therapeutic target for the
treatment of various neuroinflammatory disorders, and several
small-molecule TRPV1 antagonists are currently in early clinical
trials.2 Our discovery team identified thiazolopyrimidine 1
(Figure 1) as an important lead compound.3
Figure 1. Structure of TRPV1 inhibitor 1.
common problem in the synthesis of thiazolo[5,4-d]pyrimidines
and was a major cause for low yields in the preparation of 2 and 3
(Figure 2). In our case, the transformation could only be
accomplished as a neat reaction at high temperature, which
would pose safety hazards and operational difficulty on larger
scale. Second, thiazole formation from 9 was accompanied by
undesired hydrolysis of the chloropyrimidine functionality,
which necessitated a subsequent rechlorination step. Product
11 was obtained in low overall yield after chromatographic
purification. The process mass intensity (PMI)8 value for the
overall route was well over 1000, indicating significant adverse
environmental impact if the process were to be adopted on large
scale. It was clear that an improved route was highly desirable.
Route Scouting. We started by briefly investigating a differ-
ent strategy that involved the coupling of thioamide 13 with
various substituted pyrimidines (Table 1). Thioamide 13 was
easily prepared in quantitative yield from commercially available
2,6-dichlorophenyl acetonitrile (14).9 The coupling reaction was
first tested with 5-amino-4,6-dichloropyrimidine (8) (entries
1-3). No reaction was observed under Pd-mediated coupling
conditions. In the presence of acid or base after prolonged
heating, nitrile 14 became the main product.10 The coupling
with aniline-substituted pyrimidine 15 gave similar results
(entries 4-6). Finally, coupling with 4,5,6-trichloropyrimidine
(16) was also examined but again failed to afford desired product
(entries 7-8). The difficulty we encountered was in agreement
The key structural feature of 1 is the thiazolo[5,4-d]pyrimi-
dine core, a close analogue of purine. This core is found in a
variety of pharmacologically relevant molecules with potential
indications for diabetes, cancer, and other diseases (2-5,
Figure 2).4-7 Examination of the syntheses of 2-5 shows that
the assembly of 2-alkyl-thiazolo[5,4-d]pyrimidines is a nontrivial
challenge. The syntheses typically involve thiolation/acylation of
5-aminopyrimidine followed by intramolecular ring closure.
Unfortunately, these steps often require very harsh conditions
and the use of highly malodorous reagents and suffer from
unsatisfactory yields (5%, 10%, and 24% yield over two steps
for 24, 35, and 46, respectively). Here we report the development
of an efficient and scalable synthesis of thiazolopyrimidine 1.
’ RESULTS AND DISCUSSION
Initial Synthesis. The first synthesis of compound 1 was
developed by our medicinal chemistry colleagues (Scheme 1).3
Commercially available phenylacetic acid 6 was treated with
thionyl chloride to give acid chloride 7. Acylation of 5-amino-4,
6-dichloropyrimidine (8) by 7 afforded amide 9, which then
underwent thiolation and intramolecular cyclization to provide
thiazolopyrimidine 10. After chlorination by POCl3, the resulting
chloropyrimidine 11 reacted with aniline 12 to give final product
1. This synthesis was successfully completed on 10-g scale.
We analyzed the initial synthesis in Scheme 1 from a process
chemistry perspective and identified two potential issues. First,
the acylation of 5-aminopyrimidine 8 was very difficult. This is a
Received: November 8, 2010
Published: January 24, 2011
r
2011 American Chemical Society
382
dx.doi.org/10.1021/op1002984 Org. Process Res. Dev. 2011, 15, 382–388
|

Organic Process Research & Development
ARTICLE
Figure 2. Several 2-alkyl-thiazolo[5,4-d]pyrimidines of clinical interest.
Scheme 1. Initial synthesis of 1
with the paucity of literature precedence for such transforma-
tions. Despite the prevalence of thiazole-fused heterocycles in the
literature, formations of thiazoles via the coupling of thioamide
and aromatic vicinal dihalides are rarely reported.11
Next, we examined the transformation of 17 to final product 1
via thiolation and intramolecular ring closure (Table 2). In the
literature, similar sequences often suffer from unpleasant re-
agents, harsh conditions, and low yield. There are two possible
pathways: electrophilic thiolation of the amide functionality to
give thioamide 18, or nucleophilic thiolation of chloropyrimidine
We then turned our attention to the redesign of the original
synthetic route. The difficult acylation of 5-aminopyrimidine 8
with acyl chloride 7 was first studied. Literature survey revealed
that acylations of 5-aminopyrimidines are the most difficult when
multiple electron-withdrawing substituents are present.12 In the
case of 8, the 4,6-dichloro groups were the likely culprit for the
sluggish acylation. We reasoned that if the aniline moiety was
installed first to give 15 (Scheme 2), it should increase the
electron density and facilitate acylation. Gratifyingly, the reaction
between 15 and acyl chloride 7 in N,N-dimethylacetamide
(DMA) was completed in only 1 h at room temperature,
confirming that the reactivity was indeed significantly enhanced
thanks to the electron-donating effect of the aniline substituent.13
to give thiopyrimidine 19. Intramolecular cyclization of 18 or
4,14
19 then affords 1. For electrophilic thiolation, P2S5
and
Lawesson’s reagent6,15 are commonly employed. Indeed, reac-
tion of 17 with Lawesson’s reagent gave final product 1 directly
(entry 1). However, the strong stench and moisture sensitivity of
Lawesson’s reagent are potential problems on large scale. On the
other hand, nucleophilic thiolations of chloropyrimidines in the
literature utilize either alkali sulfides16 or thiourea,17 the latter
clearly the reagent of choice on large scale. We were pleased to
find that reaction of 17 with thiourea gave 19 in moderate yield
(entry 3). For the subsequent intramolecular cyclization step, we
383
dx.doi.org/10.1021/op1002984 |Org. Process Res. Dev. 2011, 15, 382–388

Organic Process Research & Development
ARTICLE
Table 1. Thiazole formation with thioamide 13
Scheme 2. Acylation of pyrimidine 15
screened both basic and acidic conditions18 and found the reaction
took place in the presence of excess HCl to afford 1 (entry 5).
Thus, an improved synthetic route was developed for the
preparation of thiazolopyrimidine 1 (Scheme 3). The acylation
of aminopyrimidine 8 was greatly facilitated by prior installation
of the aniline moiety. The feasibility of subsequent thiolation and
cyclization was also demonstrated. Compared to the original
synthesis, the overall yield increased from 15% to 28%. The new
synthesis also had a much lower PMI value of 188, a reduction of
over 80%. Most importantly, this route served as a good starting
point for further optimization and scale-up synthesis.
Route Optimization. To adapt the preliminary route for
large-scale synthesis, several problems needed to be solved.
The yields for acylation and thiolation were still relatively low.
Several intermediates such as 17 and 19 have very poor solubility
in most solvents, rendering the corresponding reactions highly
heterogeneous and difficult to handle on large scale. Facile isolation
and purification protocols also needed to be established. Finally, we
believed if conditions were chosen strategically, it might be possible
to combine two or more steps into a single reaction/operation and
increase the overall efficiency.
We first examined the aniline substitution reaction and
screened solvents, equivalents of reagents, and concentration.19
The crude product 15 that precipitated out was collected and
analyzed for yield and purity. The results showed that EtOH was
the best solvent and that only a catalytic amount of HCl was
needed. A slight excess of aniline 12 (1.1 equiv) was important
to ensure complete consumption of pyrimidine 8 and higher yield
of 15. It is worth noting that no 4,6-disubstituted aniline was observed
in the crude product of any reaction.13 Finally, reactions at higher
concentrations gave more solid precipitate, but at 2.0 M the crude
product was contaminated with the HCl salt of aniline 12. For the
synthesis on larger scale, we decided to use HCl salt of aniline 12,
because it is a stable solid that can be easily stored and handled, and
the commercial supply has higher purity. We were pleased to find that
the yield increased to 76% on 140-g scale.20
384
dx.doi.org/10.1021/op1002984 |Org. Process Res. Dev. 2011, 15, 382–388

Organic Process Research & Development
ARTICLE
Table 2. Thiolation and cyclization
a Under microwave irradiation.
Scheme 3. Modified synthetic route
The next step was formation of acid chloride 7 from acid 6
(Scheme 4). Both thionyl chloride and oxalyl chloride could be
successfully employed. Oxalyl chloride led to a faster reaction but
also more off-gassing and a more substantial exotherm. In both
cases, the reaction rate was significantly enhanced by the addition
of a small amount of DMF.
complete acylation could be accomplished in CH2Cl2, CH3CN,
or DMA solvent with no need for a base or catalyst. However,
both starting material 15 and product 17 were sparingly soluble
in CH2Cl2 and CH3CN, leading to sluggish reactions and highly
heterogeneous reaction mixtures that would be difficult to handle
on large scale. In contrast, the reaction in DMA was much more
facile and remained homogeneous throughout. Product 17 was
easily isolated by filtration upon addition of EtOH.
The crude acid chloride formed was directly used as a solution
in toluene in the subsequent acylation reaction. We found that
385
dx.doi.org/10.1021/op1002984 |Org. Process Res. Dev. 2011, 15, 382–388

Organic Process Research & Development
ARTICLE
Scheme 4. Acylation of 5-aminopyrimidine 17
Scheme 5. One-pot thiazole formation
With compound 17 in hand, the thiolation/cyclization se-
quence was then studied. The thiolation step (thiourea, H2O,
EtOH, 80 °C) gave only moderate yield, in part due to the
extremely poor solubility of starting material 17, intermediate 19,
and product 1 in EtOH. Once again, this problem was solved by
using DMA as solvent. It completely solublized the starting
material 17 and led to a much faster and cleaner reaction. In this
step, a nucleophilic additive was required to release thiol 19 from
initial thiourea adduct 20. EtOH and 2-propanol were found to be
more efficient than water. Finally, since we had already established
that the ensuing cyclization could occur in DMA under acidic
conditions, the two steps were successfully combined. Thus, pyrimi-
dine 17 was dissolved in DMA and treated with thiourea and HCl/
2-propanol at 80 °Ctodirectlygiveproduct1(Scheme5). Commer-
cially available 5-6 M HCl in 2-propanol was chosen to serve dual
purposes: 2-propanol as the nucleophilic additive for the formation of
thiol 19 from 20, and HCl as the catalyst for the cyclization step.
Taking advantage of the fact that all solvents and byproducts
(DMA, 2-propanol, HCl, and isopropyl carbamimidate) were
water soluble, we developed a simple procedure to isolate pro-
duct 1 by water trituration. Upon reaction completion, water was
slowly added at 80 °C, and the resulting suspension was slowly
cooled to give product 1 as a crystalline precipitate. Performing
the trituration at elevated temperature and maintaining con-
trolled slow cooling were found to be very important for
achieving an acceptable filtration speed on large scale.
(∼1.3 wt %). Solubility screening showed that 1 was sparingly
i
soluble in alcohol but more soluble in EtOAc, PrOAc, and
acetone. Under the optimized final purification protocol, crude 1
was dissolved in hot acetone and filtered to remove thiol impurity
19. The filtrate was heated to reflux again and triturated with
water to afford pure 1 as a highly crystalline solid. Once again,
performing trituration at elevated temperature and slow cooling
were key to obtaining an acceptable rate of filtration. Using this
route, the first batch of API 1 was prepared on 20-g scale.
Compared to the preliminary synthesis (Scheme 2), the number
of steps/operations was reduced, and the overall yield based on
acid 6 was increased from 28% to 59%. The PMI value was again
lowered to 77, a 60% reduction.
For the synthesis of the second and larger batch, we identified
an interesting opportunity to further streamline the synthesis.
Since acylation, thiolation, and cyclization all used DMA as
solvent, we speculated that it might be possible to combine them
into a one-pot operation. Gratifyingly, this was accomplished
after optimization (Scheme 6). Thus, acyl chloride 7 was
prepared from acid 6 and the reaction mixture in toluene was
directly added to a solution of pyrimidine 15 in DMA. After
complete acylation, thiourea and HCl/2-propanol were added,
and the reaction was heated to 80 °C to give 1. Once again, using
DMA as the main solvent allowed the product to be easily
isolated via water trituration. Overall, acid chloride formation,
acylation, thiourea addition, thiol formation, and cyclization
occurred sequentially in this easy two-pot operation to generate
final product 1 from commercially available starting material 6.
Crude product 1 from the above reaction contained residual
solvents and small amounts of impurities including thiol 19
386
dx.doi.org/10.1021/op1002984 |Org. Process Res. Dev. 2011, 15, 382–388

Organic Process Research & Development
ARTICLE
Scheme 6. Scale-Up Synthesis of 1
0.61 mol, 1.00 equiv), ethanol (500 mL), and 4-aminobenzotrifluo-
ride hydrochloride (12 HCl, 120 g, 0.61 mol, 1.00 equiv) was
3
stirred at reflux temperature for 24 h and slowly cooled to room
temperature. The resulting precipitate was collected by filtration,
washed with ethanol (250 mL), and dried in a vacuum oven at
80 °C for 4 d to give 15 as a light-pink solid (141 g, 76%). 1H NMR
(600 MHz, d6-DMSO, δ): 9.34 (s, 1H), 8.03 (d, J = 8.5 Hz, 2H),
7.96 (s, 1H), 7.68 (d, J = 8.6 Hz, 2H), 6.59 (br s, 3H); 13C NMR
(151 MHz, d6-DMSO, δ): 148.0, 144.1, 143.6, 138.7, 125.7, 125.7
(q, J = 4.0 Hz), 124.5 (q, J = 271.4 Hz), 122.1 (q, J = 34.2 Hz),
119.8; MS (ESIþ): calculated for C11H9ClF3N4 [M þ Hþ], 289.0;
m/z found, 289.0; HPLC retention time: 4.383 min. Based on
elemental analysis results, the compound existed as a ∼1:1 mixture
of free base and HCl salt. Anal. Calculated for C11H8.5Cl1.5F3N4: C,
43.05; H, 2.79; N, 18.26; Cl, 17.33; found: C, 43.31; H, 2.31; N,
18.31; Cl, 17.07.
2-(2,6-Dichlorobenzyl)-N-(4-(trifluoromethyl)phenyl)thi-
azolo[5,4-d]pyrimidin-7-amine (1). 2,6-Dichlorophenylacetic
acid (6, 62.5 g, 0.305 mol, 1.17 equiv) and DMF (1.60 mL) were
dissolved in toluene (160 mL). Thionyl chloride (26.6 mL, 0.36
mol, 1.38 equiv) was added slowly over 10 min. The reaction
mixture was stirred at 20 °C for 18 h, then added over 1.5 h to a
solution of 6-chloro-N4-(4-trifluoromethyl-phenyl)pyrimidine-
4,5-diamine hemihydrochloride (15, 80.0 g, 0.261 mol, 1.00
equiv) in DMA (80 mL). The reaction was stirred at 20 °C for
2 h. Thiourea (31.6 g, 0.416 mol, 1.60 equiv) was added in
one batch, followed by HCl in 2-propanol (5-6 M, 504 mL,
∼2.77 mol, ∼10.6 equiv) over 1 h via an addition funnel. The
resulting solution was heated to 80 °C for 4 h. Water (340 mL)
was added over 20 min and the resulting suspension was cooled
to room temperature. The precipitate was collected by filtration
and washed with ethanol (500 mL) to afford crude 1 (90 g, 76%)
as a light-pink solid.
All four intermediates 7, 17, 20, and 19 could be monitored by
HPLC, which enabled convenient and precise in-process control.
This new protocol not only increased operational efficiency but
also enhanced overall yield from 59% to 76%. The optimizations
further reduced the PMI value by another 40% to 44. The second
batch of API was prepared on 90-g scale and used to support
several pharmacokinetic and toxicology studies.
Final Purification of 1. A suspension of crude 2-(2,6-dich-
lorobenzyl)-N-(4-(trifluoromethyl)phenyl)thiazolo[5,4-d]pyri-
midin-7-amine (1, 98.0 g, 0.215 mol) in acetone (1.55 L) was
heated to reflux and filtered. The filtrate was heated to reflux
again. Water (620 mL) was added over 5 min, and the suspension
was cooled to 20 °C over 4 h. The solid was collected by filtration
and dried in a vacuum oven at 50 °C overnight to give 1 as a
white crystalline solid (91.5 g, 93% yield). 1H NMR (400 MHz,
d6-DMSO, δ): 10.43 (s, 1H), 8.58 (s, 1H), 8.19 (d, J = 8.4 Hz,
2H), 7.71 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.48 (t, J =
8.1 Hz, 1H), 4.83 (s, 2H); 13C NMR (126 MHz, d6-DMSO, δ):
165.7, 162.8, 153.5, 152.4, 142.7, 135.4, 132.4, 130.8, 130.8,
128.9, 125.6 (q, J = 3.7 Hz), 124.4 (q, J = 271.2 Hz), 123.0 (q, J =
37.0 Hz), 121.1, 36.0; MS (ESIþ): calculated for C19H12-
Cl2F3N4S [M þ H]þ, 455.0; m/z found, 455.1; HPLC retention
time: 6.076 min; Anal. Calculated for C19H11Cl2F3N4S: C, 50.12;
H, 2.44; N, 12.31; found: C, 49.92; H, 2.27; N, 12.23.
’ CONCLUSION
In summary, a scalable and concise synthesis of TRPV1
antagonist 1 was developed (Scheme 6). A key element in the
route design was the installation of the electron-donating aniline
moiety in the first step to facilitate acylation and thiazole forma-
tion. The initial route was then optimized to accommodate
intermediates with limited solubility, allow expedient product
isolation, and enable telescoping processes. The final synthesis
featured an efficient two-pot, five-step process for the construc-
tion of the thiazolo[5,4-d]pyrimidine ring. The optimization
greatly reduced adverse environmental impact, as evidenced by
a 95% reduction in PMI value. These results should not only
facilitate future preparation of 1 on larger scale, but also be of
value to syntheses of other biologically active compounds bearing
a similar thiazolopyrimidine core.
’ ASSOCIATED CONTENT
’ EXPERIMENTAL SECTION
S
Supporting Information. Optimizations for the synthe-
b
General Methods. Toluene, CH3CN, DMF, CH2Cl2, Me-
OH, and N,N-dimethylacetamide (DMA) were dried via passage
through two alumina columns. All reactions were monitored by
HPLC (Hewlett-Packard; Zorbax Eclipse XDB-C18, 5 μm,
4.6 mm ꢀ 150 mm column; gradient used: CH3CN in H2O,
5%-99% 5.0 min, 99% 1.0 min, 99%-5% 12 s, 5% 1.0 min; flow
rate 2.0 mL/min; 35 °C).
sis of 15; 1H NMR and 13C NMR spectra for compounds 15 and
1. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
6-Chloro-N4-(4-trifluoromethyl-phenyl)pyrimidine-4,
5-diamine (15). 5-Amino-4,6-dichloropyrimidine (8, 100 g,
Corresponding Author
jliu30@its.jnj.com.
387
dx.doi.org/10.1021/op1002984 |Org. Process Res. Dev. 2011, 15, 382–388

Organic Process Research & Development
ARTICLE
’ REFERENCES
(1) Szallasi, A.; Cortright, D. N.; Blum, C. A.; Eid, S. R. Nat. Rev.
Drug Discovery 2007, 6, 357.
(2) (a) Wong, G. Y.; Gavva, N. R. Brain Res. Rev. 2009, 60, 267 and
references therein. (b) Kym, P. R.; Kort, M. E.; Hutchins, C. W. Biochem.
Pharmacol. 2009, 78, 211.
(3) Branstetter, B. J.; Breitenbucher, J. G.; Lebsack, A. D.; Liu, J.;
Rech, J. C.; Xiao, W. U.S. Patent 20090156599, 2009, CAN 151:56868.
(4) Luke, R. W. A.; Ballard, P.; Buttar, D.; Campbell, L.; Curwen, J.;
Emery, S. C.; Griffen, A. M.; Hassall, L.; Hayter, B. R.; Jones, C. D.;
McCoull, W.; Mellor, M.; Swain, M. L.; Tucker, J. A. Bioorg. Med. Chem.
Lett. 2009, 19, 6670.
(5) Baettig, U.; Brown, L.; Brundish, D.; Dell, C.; Furzer, A.;
Garman, S.; Janus, D.; Kane, P. D.; Smith, G.; Walker, C. V.; Cockcroft,
X.; Ambler, J.; Mitchelson, A.; Talbot, M. D.; Tweed, M.; Wills, N.
Bioorg. Med. Chem. Lett. 2000, 10, 1563.
(6) Yoshida, S.; Kobayashi, K.; Mochiduki, N.; Yamakawa, T.;
Kobayashi, T.; Shinohara, Y. U.S. Patent 20070293512, 2007, CAN
144:69842.
(7) Pei, Z.; von Geldern, T.; Madar, D. J.; Li, X.; Basha, F.; Yong, H.;
Longenecker, K. L.; Backes, B. J.; Judd, A. S.; Mulhern, M. M.; Stewart,
K. D. U.S. Patent 20070049596, 2007, CAN 146:273992.
(8) Process Mass Intensity (PMI) is defined as the total mass of raw
materials input divided by the mass of final Active Pharmaceutical
Ingredient (API) output. It is adopted by the ACS Green Chemistry
Institute as one of the benchmarks to measure the environmental impact
and sustainability of chemical processes. For a review of PMI and other
similar benchmarks, see: Constable, D. J. C.; Curzons, A. D.; Cunning-
ham, V. L. Green Chem. 2002, 4, 521.
(9) Diethyl dithiophosphate, H2O, 80 °C, 2 h, 100% yield. See
Yousif, N. M. Tetrahedron 1989, 45, 4599.
(10) For an example of using chloropyrimidine as desulfhydrating
reagent, see Kondo, K.; Komamura, C.; Murakami, M.; Takemoto, K.
Synth. Commun. 1985, 15, 171.
(11) To the best of our knowledge, such couplings have only been
reported with 2,3-dihalo-quinoxaline and quinones. See (a) Katritzky,
A. R.; Fan, W. Q. J. Heterocycl. Chem. 1988, 25, 901. (b) Phadke, R. C.;
Rangnekar, D. W. Bull. Chem. Soc. Jpn. 1986, 59, 1245. (c) Chadha, V. K.;
Saxena, V. K. J. Ind. Chem. Soc. 1980, 57, 946.
(12) (a) Cavalla, D.; Chasin, M.; Hofer, P. PCT 9931103, 1999. (b)
Li, X.; Shocron, E.; Song, A.; Patel, N.; Sun, C. L. Bioorg. Med. Chem. Lett.
2009, 19, 2860.
(13) Ragan, J. A.; Bourassa, D. E.; Blunt, J.; Breen, D.; Busch, F. R.;
Cordi, E. M.; Damon, D. B.; Do, N.; Engtrakul, A.; Lynch, D.;
McDermott, R. E.; Mongillo, J. A.; O’Sullivan, M. M.; Rose, P. R.;
Vanderplas, B. C. Org. Process Res. Dev. 2009, 13, 186.
(14) Falco, E. A.; Hitchings, G. H. J. Am. Chem. Soc. 1950, 72, 3203.
(15) (a) Hirano, M.; Yamakawa, T.; Ishikawa, T.; Saito, H. EP
2036561, 2009, CAN 148:45810. (b) Koehler, M. F. T.; Gazzard, L.;
Tsui, V. H.-W. U.S. Patent 20090221630, 2009, CAN 147:386251.
(16) Ali, A.; Aster, S. D.; Graham, D. W.; Patel, G. F.; Taylor, G. E.;
Tolman, R. L.; Painter, R. E.; Silver, L. L.; Young, K.; Ellsworth, K.;
Geissler, W.; Harris, G. S. Bioorg. Med. Chem. Lett. 2001, 11, 2185.
ꢁ
(17) (a) Dolꢀakovꢀa, P.; Draꢁcínskꢀy, M.; Masojídkovꢀa, M.; Solínovꢀa, V.;
Kaꢁsiꢁcka, V.; Holꢀy, A. Eur. J. Med. Chem. 2009, 44, 2408. (b) Boarland,
M. P. V.; McOmie, J. F. W. J. Chem. Soc. 1951, 1218. (c) Polonovski, M.;
Schmitt, H. Bull. Soc. Chim. Fr. 1950, 616.
(18) For such cyclizations in polyphosphoric acid (PPA), see ref 7
and Fu, S.-C. J.; Chinoporos, E.; Terzian, H. J. Org. Chem. 1965, 30,
1916.
(19) See Supporting Information for more details.
(20) The isolated product was found to contain ∼0.5 equiv of HCl
based on elemental analysis. See Experimental Section for details.
388
dx.doi.org/10.1021/op1002984 |Org. Process Res. Dev. 2011, 15, 382–388