Application of the tisler triazolopyrimidine cyclization to the synthesis of a crop protection agent and an intermediate

Article abstract of DOI:10.1021/op0601518

A new synthetic route to the Dow AgroSciences early stage sulfonamide herbicide 3-(2-methoxy-4-trifluoromethyl)-N-(5,7-dimethoxy[1,2,4]triazolo[1,5-a] pyrimidin-2-yl)pyridinesulfonamide (pyroxsulam) has been developed. The synthesis is based on formation of the triazole ring as the final step, utilizing the Tisler triazolopyrimidine cyclization. A Tisler cyclization route to 2-amino-5,7-dimethoxy-1,2,4-trazolo[1,5-a]pyrimidine starting with 2-chloro-4,6-dimethoxypyrimidine has also been demonstrated.

Full text of DOI:10.1021/op0601518

Organic Process Research & Development 2006, 10, 1167−1171
Application of the Tisler Triazolopyrimidine Cyclization to the Synthesis of a
Crop Protection Agent and an Intermediate
†
§
‡
,⊥
Bruce M. Bell, Phillip E. Fanwick, Paul R. Graupner, and Gary A. Roth*
Dow Chemical Company, Analytical Sciences, 1897 Building, Midland, Michigan 48674, U.S.A., Purdue UniVersity,
Department of Chemistry, West Lafayette, Indiana 47907, U.S.A., Dow AgroSciences LLC, DiscoVery Research,
3
06 Building, Indianapolis, Indiana 46268, U.S.A., and Dow Chemical Company, Process Sciences, 1710 Building,
Midland, Michigan 48674, U.S.A.
Abstract:
Scheme 1
A new synthetic route to the Dow AgroSciences early stage
sulfonamide herbicide 3-(2-methoxy-4-trifluoromethyl)-N-(5,7-
dimethoxy[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)pyridinesulfona-
mide (pyroxsulam) has been developed. The synthesis is based
on formation of the triazole ring as the final step, utilizing the
Tisler triazolopyrimidine cyclization. A Tisler cyclization route
to 2-amino-5,7-dimethoxy-1,2,4-trazolo[1,5-a]pyrimidine start-
ing with 2-chloro-4,6-dimethoxypyrimidine has also been dem-
onstrated.
A preface on the Tisler triazolopyrimidine cyclization is
appropriate at this point.
Certain sulfonamides make up a class of compounds that
are highly efficacious against a variety of weed species in a
number of important agricultural crops. A general synthetic
Tisler and co-workers have found that the thermal
1
cyclization of substituted 1,2,4-oxadiazol-5-ones can provide
entry into these materials has been the coupling of an
appropriate sulfonyl chloride with a substituted amine. In
the event of a stubborn coupling, sulfilimine catalysis can
3
2
-amino-s-triazolo[1,5-a]pyrimidines in moderate yields.
4
The original preparation of triazolopyrimidine 3 within Dow
AgroSciences laboratories was based on Tisler’s cyclization
2
be very useful. During the course of process research on
5
reaction. Thus, commercially available amino pyrimidine
the sulfonamide herbicide 3-(2-methoxy-4-trifluoromethyl)-
N-(5,7-dimethoxy[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)py-
ridinesulfonamide (1), we encountered what originally
appeared to be one of these difficult coupling reactions
4
was treated with N-carboethoxyisothiocyanate (5) providing
N-ethoxycarbonyl thiourea 6. Reaction of 6 with hydroxy-
lamine in ethanol followed by heating the reaction mixture
afforded the desired triazolopyrimidine 3 via the intermedi-
ates (7 and 8) depicted in Scheme 2.
(Scheme 1).
Even with sulfilimine catalysis, yields of 55-75% were
Although this preparation of heterocycle 3 worked well,
thiourea 9 was inevitably formed as a side-product (2-4%
by HPLC analysis). Under reaction conditions in which the
liberated hydrogen sulfide is not efficiently removed from
the system, another impurity was formed in substantial
quantities (up to 4 area % via HPLC) and was tentatively
identified as guanidine 10. An alternate synthesis of 3, again
based on the work of Tisler, is presented in Scheme 3.
Reaction of chloropyrimidine 11 with sodium cyanamide
common, depending on the quality of the starting materials.
Earlier work from these laboratories showed that sulfonyl
chloride 2 could be induced to undergo coupling with other
amino-heterocycles in yields approaching 90%. These results
suggested that the lack of nucleophilicity of amine 3 may
be a contributing problem in the present coupling. On the
basis of this rationalization, we set out to devise an alternate
synthetic route in which the sulfonyl chloride (2) coupling
reaction would be conducted, using what we anticipated
would be a more nucleophilic system. The final steps of the
synthesis would then form the triazolopyrimidine ring system.
6
gave cyanoaminopyrimidine 12. Treatment of 12 with
6
hydroxylamine afforded N-hydroxyguanidine 13, which then
was O-acylated by reaction with ethylchloroformate to give
7
1
4. Spectral and chromatographic data for 14 were much
*
To whom correspondence should be addressed. E-mail: garoth@dow.com.
different than the same data obtained for 7. Heating 14 in
Telephone: 989-638-6132.
†
Dow Chemical Company, Analytical Sciences.
Purdue University.
Dow AgroSciences LLC.
Dow Chemical Company, Process Sciences.
§
(3) Vercek, B.; Ogoreve, B.; Stanovnik, B.; Tisler, M. Monatsh. Chem. 1983,
114, 789-798.
(4) For an earlier preparation of 3, see: Bee, M. A.; Rose, F. J. Chem. Soc. C
1966, 2031.
(5) Johnson, T. C.; Van Heertum, J. C.; Ouse, D. G.; Arndt, K. E.; Pobanz, M.
A.; Walker, D. K. N-(5,7-Dimethoxy[1,2,]triazolo[1,5-a]pyrimidin-2-yl)-
aryl Sulfonamide Coupounds and Their Uses as Herbicides. U.S. Patent
6,559,101 B2, May 6, 2003.
(6) Diehr, H. J.; Pest, C.; Kirsten, R.; Kluth, J.; Mueller, K. H.; Pfister, T.;
Priesnitz, U.; Rieble, H. J.; Roy, W. EP 173321, 1986.
‡
⊥
(
(
1) Kleschick, W. A. Chem. Plant Prot. 1994, 10, 119-143; CAN 122:153980.
2) Ringer, J. W.; Scott, C. A.; Pearson, D. L.; Wallin, A. P. N-Arylsulfilimine
Compounds and Their Use as Catalysts in the Preparation of N-Arylaryl-
sufonamide Compounds. U.S. Patent 5,973,148, October 26, 1999. Ringer,
J. W.; Pearson, D. L.; Scott, C. A.; Wallin, A. P. N-Arylsufilimine
Compounds and Their Use as Catalysts in the Preparation of N-Arylaryl-
sulfonamide Compounds. U.S. Patent 6,114,580, September 5, 2000.
1
0.1021/op0601518 CCC: $33.50 © 2006 American Chemical Society
Vol. 10, No. 6, 2006 / Organic Process Research & Development
•
1167
Published on Web 10/24/2006

Scheme 2
Scheme 4
NMR and mass spectrum were consistent with the desired
product 16 (or imine isomer). We speculated, in conjunction
10
with a literature reference, that we had the desired material
6 (or a tautomer or imine isomer). However, on the basis
Scheme 3
1
of our spectroscopic data, we could not completely rule out
that we had formed a regioisomer of 16 as a result of
sulfonylation at the amine group connected to the pyrimidine
ring. This issue is not readily resolved by NMR studies due
to the absence of protons in the molecule. However, advances
1
5
in the use of N NMR at natural abundance has given rise
to the use of two-dimensional heteronuclear multiple bond
correlation spectroscopy (HMBC) experiments in solving
1
1
15
similar problems. In this case, the N chemical shift of
the protonated nitrogen should indicate the site of sulfony-
lation. For example imine nitrogen atoms resonate at about
3
3
00 ppm (wrt NH at 0 ppm) and secondary amines at about
ethanol at reflux provided the desired heterocycle 3 via the
intermediate 8 (Scheme 2), as determined by following the
reaction using HPLC. This route provided material of higher
quality than did the previous synthesis, and the byproducts
1
5
1
00 ppm. A single N HMBC optimized for 4 Hz indicated
a protonated nitrogen at 139 ppm. Additionally, a correlation
was found from this proton to a nitrogen at 213 ppm, which
also indicated a correlation to the pyrimidine proton. Thus,
it was possible to assign the structure as tautomer 16 and
neither of the other two possibilities. Final structural proof
was established by X-ray diffraction analysis of compound
9
or 10 were avoided.
As stated previously, aminotriazolopyrimidine 3 seemed
to be unreactive toward coupling with the desired sulfonyl
chloride 2, providing only moderate yields of sulfonamide
1
6 (Figure 1). It is interesting to note that the sulfone group
1. Therefore, we devised an alternative route to 1 in which
of the sulfonamide and the NH of the thioimidate are in a
syn relationship across the imine double bond (N9dC8). This
stereochemistry is likely a result of the six centered hydrogen-
bonding arrangement that these two functional groups can
attain.
Treatment of thioimidate 16 with hydroxylamine hydro-
chloride and a tertiary amine base (e.g., Hunigs base,
triethylamine) in methanol or acetonitrile resulted in forma-
the coupling reaction would be conducted using the better
nucleophile 15 as the free base, (Scheme 4). The final steps
of the synthesis would then be directed at triazole ring
formation.
Methylation of thiourea 9 using a literature method
provided thioimidate 158,9 which when reacted with 2
1
(
Scheme 4) provided good yield of a compound whose H
(
7) D’Alo, G.; Perghum, M.; Grunanger, P. Ann. Chim. (Rome) 1963, 53, 1405-
410; Gross, M.; Held, P.; Schubert, H. J. Prakt. Chem. 1974, 316, 434.
1
(10) Gesing, E. R.; Fest, C.; Kirsten, R.; Kluth, J.; Mueller, K. H.; Helmut, K.;
Riebel, H. J.; Santel, H. J.; Luerssen, K. S.; Rober, T. EP 413221, 1991;
CAN:115:87494.
(
8) The intermediate S-methylisothiourea 15 could be isolated; however, it was
more convenient to use the acetonitrile solution of the intermediate in the
following step.
(11) For a review of 2D inverse NMR spectrosopy for 15N see: Martin, G. E.;
Hadden, C. E. J. Nat. Prod. 2000, 63, 543.
(
9) Riedel, H. J. EP 533012, 1993; CAN 119:72622.
1168
•
Vol. 10, No. 6, 2006 / Organic Process Research & Development

Experimental Section
High performance liquid chromatography (HPLC) was
performed on a Zorbax RX-C8 (4.6 mm × 250 mm) column
3
using varying concentrations of CH CN and water as the
eluent (0.1% formic acid) at 1.0 mL/min flow rate. Detection
was accomplished at 250 nm. NMR spectra were obtained
with a Bruker 300 FT-NMR. Additional NMR experiments
were performed on a Bruker DRX600 spectrometer operating
1
15
at 600.13 MHz ( H) and 60.8 MHz ( N). HPLC/MS analyses
were conducted on a Waters Alliance 2690 (chromatography
conditions as above)/Micromass QTOF2 quadrupole/time-
of-flight MS/MS system via a Micromass Z-spray electro-
spray (ESI) interface, operating in the positive ion mode.
Combustion analyses were performed at Galbraith Labora-
tories, Knoxville, TN. The X-ray cystallographic analysis
was performed by Phil Fanwick, Department of Chemistry,
Purdue University, West Lafayette, IN. All reported yields
were determined by weight, assuming a product purity of
100%, unless stated otherwise.
Figure 1. ORTEP plot of 16.
tion of 17; however, this was accompanied by formation of
significant quantities of 13 (Scheme 3). Use of sodium
acetate as the base efficiently suppressed formation of 13;
however, under these conditions significant amounts of
sulfonamide 20 and oxime 19 resulted. The reaction of 16
with hydroxylamine hydrochloride/triethylamine in methyl-
ene chloride gave the desired oxime 17 in good yield.
Treatment of 17 with ethyl chloroformate in the presence of
base provided the O-acylated oxime 18. However, all
attempts at cyclization of 18 to 1 resulted in very low yields
and the formation of two major products as determined by
LC/MS analysis. These products were identified (LC/MS)
as an isomer of 1 and a reduction product of 17 in which a
hydrogen atom had replaced the hydroxyl group of the
oxime. It was at this point that we began to doubt our
structural assignment of 16 and the previously described
HMBC and X-ray studies were initiated. Eventually we found
that treatment of a acetonitrile solution of 17 with phosgene
in the presence of potassium carbonate rapidly produced
oxadiazolone 21 (Scheme 5).
2-Cyanamino-4,6-dimethoxypyrimidine (12). A 125-mL
three-neck vessel was purged with N and then fitted with a
2
thermometer, condenser/N inlet, a stopper, and a stir bar.
2
To the pot was added the chloropyrimindine 11 (10.0 g, 57.3
mmol) and NMP (50 mL). The resulting solution was treated
with sodium cyanamide (8.3 g, 0.13 mol) and the mixture
stirred at room temperature until the reaction was complete
as determined by HPLC (several days). To the thin slurry
was added water (100 mL), causing complete dissolution of
all solids. Concentrated HCl was added dropwise with stirring
to a pH of 6. The resulting thick slurry was treated with ice
(97 g) and the mixture stirred until all the ice had melted.
The precipitate was collected by filtration, and the solid
was washed with 1 cake volume of water. The material was
air-dried overnight and then dried to a constant weight (55
°
C/5 mmHg), providing the product as a fluffy, white solid
Scheme 5
1
(9.4 g, 91%): mp 195 °C; H NMR (DMSO-d
6
) 3.86 (s,
+
6
1
H), 5.86 (s, 1H),11.46 (bs, 1H); MS (LC, ESI) 181 (M ,
00).
N-4,6-Dimethoxy-2-pyrimidinyl-N′-hydroxyguani-
dine (13). A 100-mL three-neck vessel was flushed with N
and then fitted with a thermometer, reflux condenser/N inlet,
a stopper, and a stir bar. The cyanamino-pyrimidine 12 (4.9
g, 27.2 mmol), CH OH (30 mL), and hydroxylamine
2
2
Compound 21 (only characterized via LC/MS) could be
isolated; however, even upon standing as a solid at room
temperature the material slowly cyclized to the desired
product (1). The best method of operation was to con-
tinue stirring the phosgenation reaction at room temperature
or slightly above, thus producing 1 in the same reaction
vessel.
3
hydrochloride (2.0 g, 29 mmol) were charged into the vessel.
Triethylamine (4.2 mL, 30 mmol) was added, and the mixture
was stirred at room temperature for 5 h. The reaction was
warmed to 45 °C and stirred overnight. After stirring an
additional 3 h at 45 °C, HPLC analysis indicated no change.
Hydroxylamine hydrochloride (0.5 g) and triethylamine (1
mL) were added, and the mixture was stirred at 45 °C
overnight. The off-white slurry was treated with water (30
mL) and stirred for 20 min. The resulting solid was collected
by filtration and washed with 1 cake volume of water. The
material was dried to a constant weight (60 °C/5 mmHg),
Conclusions
A new synthetic route to the sulfonamide herbicide
pyroxsulam (1) has been developed. This route relies on
coupling of the appropriate pyridine sulfonyl chloride (2)
with a nucleophilic thioimidate (15) followed by a Tisler
triazolopyrimidine cyclization reaction. In addition, an
alternative synthetic route to 2-amino-5,7-methoxy-1,2,4-
trazolo[1,5-a]pyrimidine (3) starting with 2-chloro-4,6-
dimethoxypyrimidine (11) has been demonstrated.
providing the product as a white solid (4.7 g, 81%): mp
1
180-185 °C (dec, gassing); H NMR (DMSO-d
6
) 3.81 (s,
6H), 5.62 (s,1H), 6.27 (bs, 2H), 8.65 (bd, 2H); HRMS
(LC/ESI) calcd for C , 213.0862; found, 213.0847.
7 11 5 3
H N O
Vol. 10, No. 6, 2006 / Organic Process Research & Development
•
1169

N-4,6-Dimethoxy-2-pyrimidinyl-N′-ethoxycar-
bonyloxy guanidine (14). A 50-mL three-neck vessel was
467.0545; found, 467.0557. Anal. Calcd for: C, 38.54; H,
3.45; N, 14.98. Found: C, 38.62; H, 3.48; N, 14.99.
N-[N-(4,6-Dimethoxypyrimidin-2-yl)-N′-hydroxycar-
bamimidoyl]-2-methoxy-4-(trifluoromethyl)pyridine-3-
sulfonamide (17). A 100-mL single-neck flask was purged
purged with N
inlet, a stir bar, and a stopper. To the reactor was added
3 (1.0 g, 4.7 mmol) and CH CN (15 mL). The slurry was
2
and then fitted with a thermometer, condenser/
N
2
1
3
treated with ethyl chloroformate (0.66 mL, 6.9 mmol)
followed by triethylamine (0.96 mol, 6.9 mmol). At first the
slurry thinned and then became very thick while exotherming
to 35 °C. The thick slurry was stirred at ambient temperature
for 30 min, and then water (20 mL) was added. The aqueous
slurry was stirred for 15 min, and the solid was collected by
filtration. The cake was washed with a little water, and the
with N
inlet. To the vessel was added 16 (5.5 g, 11.8 mmol) and
CH Cl (40 mL). To the slurry was added NH OH hydro-
chloride (1.56 g, 22 mmol) followed by triethylamine (3.1
mL, 22 mmol). The mixture was stirred at room temperature
for a total of 3 h at which time HPLC analysis indicated the
reaction was complete. Water (15 mL) was added, and then
2 2
and then fitted with a stir bar and a condenser/N
2
2
2
material was air-dried to a constant weight, affording 14 as
the vessel was fitted with a N
connected to a bleach scrubber. The two-phase mixture was
sparged with N , causing most of the CH Cl to evaporate
2
sparge tube which was
1
a fluffy, white solid (0.8 g, 60%): H NMR (DMSO-d
6
) 1.24
(t, J ) 7.5 Hz, 3H), 3.82 (s, 6H), 4.16 (q, J ) 7.5 Hz, 2H),
2
2
2
5
.75 (s, 1H), 7.27 (bs, 2H), 9.65 (s, 1H); MS (LC/ESI) 286
: C, 42.10; H, 5.30;
N, 24.55. Found: C, 41.92; H, 5.27; N, 24.32.
-Amino-5,7-methoxy-1,2,4-triazolo[1,5-a]pyrimidine
3) by Cyclization of 14. The guanidine 14 was slurried in
and a solid to precipitate. Methanol (25 mL) was added, and
sparging was continued for 30 min to ensure that all the
CH Cl had been removed. The white precipitate was
2 2
collected and washed with water, leaving 5.8 g of wet solid.
The material was allowed to air-dry overnight, providing 4.7
g of white crystals. The solid was dissolved in 150 mL of
boiling methanol and then concentrated to a total volume of
50 mL. After cooling in an ice bath the product was collected
by filtration and washed with a little methanol. The solid
was dried to a constant weight (5 mmHg/room temperature)
15 5 5
(M + H); Anal. Calcd for C10H N O
2
(
ethanol (7 mL) and the mixture heated to reflux under
nitrogen. All solids went into solution, and then a precipitate
soon began to form. The slurry was heated at reflux a total
of 5.5 h at which time HPLC analysis indicated that the
reaction was complete. The slurry was cooled to room
temperature, and the precipitate was collected by filtration
and washed with ethanol (5 mL). The material was dried to
providing 17 as white crystals (4.1 g, 77%): mp 186-187
1
°C (dec, off-gassing); H NMR (DMSO-d
6
) 3.23 (s, 3H),
a constant weight at 60 °C/5 mmHg providing 3 as a white
3.89 (s, 3H), 3.92 (s, 3H), 6.07 (s, 1H), 7.51 (d, J Hz, 1 H),
8.59 (d, J ) 5.1 Hz, 1H), 10.08 (bs, 2H), 11.46 (bs, 1H);
1
solid (240 mg, 88%). H NMR (DMSO-d
6
) 3.33 (s, H
2
O),
3.90 (s, 3H), 4.07 (s, 3H), 5.94 (bs, 2H), 6.07 (s, 1H).
15 3 6 6
HRMS (LC/ESI) calcd for C14H F N O S, 452.07259;
N-[N-(4,6-Dimethoxypyrimidin-2-yl)-S-methylthio-
found, 452.0729.
carbamoyl]-2-methoxy-4-(trifluoromethyl)pyridine-3-sul-
fonamide (16) via a One-Pot Process from 9. A 250-mL
(3-(2-Methoxy-4-trifluoromethyl)-N-(5,7-dimethoxy-
[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)pyridinesulfon-
amide) (1). Hydroxyguanidine 17 (2.0 g, 4.4 mmol) was
three-neck vessel was flushed with N
a condenser/N inlet, a thermometer, and a stopper. The
thiourea (9, 11.6 g, 54.5 mmol), CH CN (60 mL), and
2
and then fitted with
2
3 2
slurried in CH CN (20 mL) and cooled to -5 °C under N .
3
Potassium carbonate (1.38 g, 10 mmol) was added, followed
by dropwise addition of phosgene in toluene (ca. 20%, 2.6
mL, ca. 4.9 mmol). The reaction was stirred at this temper-
ature for 40 min at which time HPLC analysis indicated 15%
of 17 remained. After stirring an additional 30 min HPLC
analysis indicated 15% of 17 still remained. Additional
phosgene/toluene (0.25 mL) was added and the reaction
stirred at -5 °C for 30 min at which time HPLC indicated
that less than 2% of 17 remained. The white slurry was
warmed to room temperature and allowed to stir overnight.
HPLC analysis indicated that 9% of oxadiazolone 21
remained. The white slurry was warmed to 35 °C and was
held there for 30 min at which time HPLC indicated the
cyclization was complete. The slurry was cooled to room
temperature and then treated with water (15 mL). The pH
was adjusted to 2 by dropwise addition of concentrated
HCl. The volatiles were removed on the rotary evaporator
(35 °C/25 mmHg), leaving a white slurry. The solid was
collected by filtration and washed with a little water to give
2.74 g of crude wet material. HPLC analysis of the wet
material revealed three major peaks: (1) rt 3.07 min, 7.9%;
HRMS indicated this impurity is an isomer of 1; (2) rt 3.52
min, 79.5% 1; (3) rt 5.84 min, 10.9%, toluene. The wet solid
dimethyl sulfate (5.8 mL, 61.3 mmol) were added, and the
slurry was heated to reflux. After 2 h most of the solid had
gone into solution. The mixture was allowed to reflux an
additional 0.5 h, and then was cooled to room temperature
and allowed to stir overnight. The reaction had set up into a
3
white mass, and thus CH CN (40 mL) was added which
allowed stirring. To the white slurry was added 2 (18 g, 65
mmol) and triethylamine (23 g, 0.23 mol). All solids went
into solution over 5 min, and the temperature rose to 30 °C.
The mixture was warmed to 45 °C and allowed to stir
overnight. The amber slurry was transferred to a 500-mL
flask and then chilled in an ice bath. To the slurry was added
2
M HCl (116 mL) in portions. After the addition was
complete, the slurry was stirred in an ice bath for 45 min (6
C). The solid was collected by filtration and washed with
cake volumes of water. The material was dried to a constant
weight (60 °C/5 mmHg), providing 16 as light-beige crystals
17.1 g, 67%). A small sample was recrystallized from ethyl
°
2
(
1
acetate, providing an analytical sample: mp 184-85 °C; H
NMR (CDCl ) 2.18 (s, 3H), 3.97 (s, 6H), 4.04 (s, 3H), 5.83
s, 1H), 7.35 (d, J ) 5.2 Hz, 1H), 8.44 (d, J ) 5.2 Hz, 1H),
3
(
1
16
3 5 5 2
1.02 (bs, 1H); HRMS (LC/ESI) calcd for C15H F N O S ,
1170
•
Vol. 10, No. 6, 2006 / Organic Process Research & Development

was dried to a constant weight (80 °C/ 25 mmHg), providing
the product as a white solid (1.84 g). A 1.0 g sample was
sample contained 2.3 area % of an isomer of 1 and 6.6 wt
% CH CN.
3
3 3
dissolved in boiling CH OH/CH CN (60 mL/10 mL) and
then concentrated to a total volume of 15 mL. The mixture
was cooled in an ice bath, and the resulting crystals were
Acknowledgment
We thank Dr. William H. Pearson, Dr. M. V. M. Emonds,
and Mr. Chris Hamilton for helpful discussions throughout
the course of this work. We thank Dr. Scott Thornburgh for
his aid in obtaining the X-ray crystal structure of 16.
3
collected and washed with a little CH OH. The material was
dried to a constant weight (5 mmHg/room temperature)
providing 1 as white needles (944 mg, 91.1% purity via
external standard HPLC analysis, 83% yield based on
recrystallization of all of the 1.84 g of crude material). This
Received July 26, 2006.
OP0601518
Vol. 10, No. 6, 2006 / Organic Process Research & Development
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1171