Development of practical syntheses of potent non-nucleoside reverse transcriptase inhibitors

Article abstract of DOI:10.1016/j.tet.2009.03.084

The development of practical and efficient syntheses of the potent non-nucleoside reverse transcriptase inhibitors 1 and 2 is described. The preparation of 1 proceeded in four synthetic steps and in 48% overall yield from 3. The long-term synthesis of 2 proceeded in nine synthetic steps and in 47% overall yield from commercially available 2,6-diflurorpyridine. The route to 2 was highlighted by the three-step synthesis of intermediate 22 and the high yielding coupling between 18 and phenol 8. The overall sequence required no chromatography and has successfully been utilized for the manufacture of 2 on large scale.

Full text of DOI:10.1016/j.tet.2009.03.084

Tetrahedron 65 (2009) 5013–5023
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Development of practical syntheses of potent non-nucleoside reverse
transcriptase inhibitors
,
a
,
b
b
a
Jeffrey T. Kuethe a , Yong-Li Zhong , Mahbub Alam , Anthony D. Alorati , Gregory L. Beutner ,
Dongwei Cai a, Fred J. Fleitz a, Andrew D. Gibb b, Amude Kassim a, Kathleen Linn a, Danny Mancheno a,
Benjamin Marcune a, Philip J. Pye a, Jeremy P. Scott b, David M. Tellers a, Bangping Xiang a,
*
*
Nobuyoshi Yasuda a, Jingjun Yin a, Ian W. Davies a
,
b
a Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA
b Department of Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The development of practical and efficient syntheses of the potent non-nucleoside reverse transcriptase
inhibitors 1 and 2 is described. The preparation of 1 proceeded in four synthetic steps and in 48% overall
yield from 3. The long-term synthesis of 2 proceeded in nine synthetic steps and in 47% overall yield from
commercially available 2,6-diflurorpyridine. The route to 2 was highlighted by the three-step synthesis of
intermediate 22 and the high yielding coupling between 18 and phenol 8. The overall sequence required
no chromatography and has successfully been utilized for the manufacture of 2 on large scale.
Ó 2009 Published by Elsevier Ltd.
Received 15 January 2009
Received in revised form 23 March 2009
Accepted 26 March 2009
Available online 1 April 2009
1. Introduction
not initially obvious in the deceptively simple structure of 2. Herein,
the preparation of 1 and the evolution of a robust and long-term
Representing a key component of highly active antiretroviral
therapy, non-nucleoside reverse transcriptase inhibitors (NNRTIs)
target an allosteric binding pocket on the reverse transcriptase
enzyme giving rise to a broad spectrum of activity against HIV RT
mutations. Although there are currently three marketed NNRTIs
(efavirenz, nevirapine, and delavirdine) that demonstrate clinical
efficacy against HIV-1 RT mutations,1 treatment-related failure due
to the emergence of clinical resistance remains a recurring issue
with these therapies. The discovery of second generation NNRTIs,
such as the very recently approved etravirine,2 that have a broader
spectrum of activity against mutant viruses and have a high genetic
barrier to the selection of new resistant strains, has been an in-
tensive area of investigation. As part of a program to develop po-
tent, orally active NNRTIs possessing a broader spectrum of activity
against HIV RT mutations, Merck has recently reported the dis-
covery of a novel class of second generation NNRTIs from which
both 1 and 2 were brought forward for development.3 The key
structural features of these molecules are the pyrazolo[3,4-b]pyri-
dine fragment and the pendant biaryl ether moiety. In particular,
the amino substituent on the pyrazolo[3,4-b]pyridine fragment of
compound 2 presented formidable synthetic challenges that were
scaleable synthesis of 2 will be discussed.
NC
Cl
H
N
N
N
O
O
R
Cl
1 R = H
2 R = NH2
2. Results and discussion
2.1. Preparation of compound 1
Compound 1 was the first second generation NNRTI that Merck
brought forward for development. The synthesis of 1 closely paral-
leled the initial synthesis and began with the known 3-methyl-pyr-
azolo[3,4-b]pyridine 3 (Scheme 1).4 Conversion of 3 to 45 was
effected by reaction of 3 with Boc2O in the presence of 20 mol %
DMAP in MeCN at 45 ꢀC for 6 h. In the initial stages of the reaction,
formation of intermediate 5 was observed byHPLC. However, further
heating led to the nearly complete conversion of 5 to 4 (99.5:0.5).
Althoughcompound 4 couldbeisolated, it wasfoundthatisolationof
4 was not necessary. Crude 4 was carried forward in the next step
without further purification after an acidic aqueous workup with 1 N
* Corresponding authors. Tel.: þ1 732 594 9522; fax: þ1 732 594 5170.
E-mail addresses: jeffrey_kuethe@merck.com (J.T. Kuethe), yongli_zhong@
merck.com (Y.-L. Zhong).
0040-4020/$ – see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tet.2009.03.084

5014
J.T. Kuethe et al. / Tetrahedron 65 (2009) 5013–5023
1 equiv of 6 and 1 equiv of 8 in the presence of 6 equiv of CsF as the
Me
N
Me
N
Me
N
base and 1.5 equiv of KI as an additive afforded 9 in 70–78% yield
(Scheme 2). The mass balance of the reaction was found to contain
up to 10% of over-alkylated by-product 10 and approximately 8% of
a mixture of unidentified by-products 11. The formation of 10 and
other by-products 11 arise from the fact that bromide 6 was un-
stable to the reaction conditions, presumably due to the presence of
adventitious water, which competitively cleaves the Boc group. This
was confirmed in subsequent experiments where treatment of
bromide 6 under the identical reaction conditions in the absence of
phenol 8 led to extensive decomposition of bromide 6. The addition
of KI to the reaction resulted in a dramatic increase in the rate of
reaction where the rapid formation of iodide intermediate 12 could
be observed by HPLC. However, the use of super-stoichiometric
amounts of KI also resulted in extremely thick reaction mixtures,
which were difficult to stir. After extensive optimization of the
initial reaction parameters, better conditions for the alkylation in-
volved the portion-wise addition of 1.08 equiv of bromide 6 to
a preformed mixture of 1 equiv of 8 and 3.00 equiv of CsF in DMF at
room temperature and stirring for 2 h. Analysis of the crude re-
action mixture by HPLC after workup revealed that 9 was obtained
in 90% yield with <9% combined amounts of both 10 and 11 pres-
ent. Elimination of KI from the initial conditions was found to
slightly decrease the reaction rate, but also gave stirrable reaction
slurries. Intermediate 9 was not isolated but was directly used in
the deprotection step without further purification.
Deprotection of crude 9 to 1 was effected at 35–40 ꢀC in aqueous
THF using 2.5 equiv of concd H2SO4 for 2.5 h to give quantitative
conversion to 1 (Scheme 3). Direct filtration of the crude reaction
mixture provided 1 as a crystalline hemi sulfate salt. The freebase of
1 was obtained by distilling the THF from the crude reaction mix-
ture prior to filtration followed by the addition of water. Alterna-
tively, neutralization with NEt3 to a pH of 8–9 also provided the
freebase of 1. The purity of 1 was upgraded by recrystallization from
1:1 MeOH/MeCN to provide analytically pure 1 in 78% overall yield
from 8.
Boc2O, DMAP
Boc
+
MeCN, 45 °C
6 h
N
N
N
N
N
N
H
Boc
3
4
5
100%
99.5:0.5
NBS, AIBN (cat.)
C6H5CF3
80 °C, 1 h
Br
Br
Br
+
4 ( 24%)
+
N
N
N
N
Boc
N
N
Boc
7 (14%)
Scheme 1.
6 (61%)
KH2PO4, which effectively removed all traces of DMAP from the or-
ganic layer. After the solvent was switched to trifluorotoluene, re-
action of crude 4 with NBS in the presence of catalytic amount of
AIBN at 80 ꢀC for 1 h gave a statistical ratio of the desired bromide 6
(61%), dibromide 7 (14%), and starting material 4 (24%). All efforts to
drive the reaction to completion led to significant amounts of
dibromide7 and substantial degradation of both 6 and 7. Fortunately,
bromide 6 could be isolated in 42% yield from 3 after purification by
silica gel chromatography followed by recrystallization from MTBE/
heptane. It should be noted that storage of bromide 6 at room tem-
perature for prolonged periods of time led to significant degradation
and the formation of multiple unidentifiable products. This was
mitigatedbystorage of6at0–5 ꢀCwhereithadgoodstabilitywithno
loss of chemical purity for up to 2 years.
The preparation of 1 from bromide 6 and phenol 83 required
considerable optimization of the initial route due to both the in-
stability of 6 at room temperature and the use of NaH. The initial
route involved deprotonation of 8 with NaH followed by reaction
with 6 in DMF. Subsequent Boc deprotection with TFA gave 1 in 67%
yield for the two-step procedure. The use of NaH in conjunction
with DMF raised serious concerns in terms of safety associated with
scale-up since reports of thermal runaway in large-scale processes,
the pyrophoric nature of NaH, and issues associated with rapid
release of hydrogen gas upon deprotonation.6 Therefore our efforts
were focused on alternative safer reaction conditions for the cou-
pling of 6 and 8. Our initial experiments revealed that reaction of
2.2. Preparation of compound 2 (first generation synthesis)
Pre-clinical evaluation of compound 1 revealed that compound
1 was only orally bioavailable when dosed as a solution. Given the
low solubility of 1 and the higher doses/exposures needed to sup-
port dosing in safety assessment and clinical studies, the de-
velopment of compound 1 was halted. Compound 2 was ultimately
brought forward for development as it was equally as potent and
compound 1 displayed excellent pharmacokinetic properties and
NH
N
NC
Cl
NC
Cl
Boc
CsF, DMF
NC
6
N
N
N
N
N
Cl
N
O
O
O
O
Cl
+
Cl
O
OH
9
10
Cl
8
11 (Unidentified by-products)
With additive KI: 9:10:11 (78%:10%:8%)
No additive : 9:10:11 (91%: 6%:3%)
I
N
N
Boc
12
N
Scheme 2.

J.T. Kuethe et al. / Tetrahedron 65 (2009) 5013–5023
5015
NC
Cl
NC
Cl
Boc
N
H
N
1. H2SO4 (conc.)
N
N
N
N
THF, 5 v% H2O
40 °C, 2.5 h
O
O
O
O
2. NEt3
3. MeOH/MeCN (1:1)
60 °C to rt
Cl
Cl
9
1
Scheme 3.
was several orders of magnitude more soluble at relevant pH. With
sufficient quantities of compound 1 in hand, the first generation
synthesis of 2 was focused on conversion of 1 to 2. It was reasoned
that appropriate activation of the pyridine nitrogen toward nucle-
ophilic addition of a protected amine would allow for the rapid
preparation of 2. A recent report from these laboratories has
demonstrated that reaction of pyridine N-oxides with Ts2O in the
presence of tert-butylamine followed by cleavage of the tert-butyl
group with TFA is an attractive method for preparation of 2-ami-
nopyridines and 2-aminoquinolines.7 Therefore, we elected to fully
investigate this approach for the preparation of 2.
Oxidation of the pyridine nitrogen of 1 was conducted with
MCPBA (1.7 equiv) in EtOAc at 55 ꢀC (Scheme 4). While the reaction
mixture was a slurry throughout the course of the reaction, near
complete conversion to 13 was observed. Upon cooling and filtra-
tion, 13 was isolated in analytically pure form and essentially
quantitative yield. While these conditions appeared to perform
well on small scale, they were found to be unacceptable upon scale-
up leading to incomplete conversion of 1 to 13. It was believed that
entrainment of 1 by the product was the source of incomplete re-
action. Solubility experiments were conducted in order to find an
effective solvent where the starting material 1 was soluble and the
product was not. It was finally established that AcOH was the op-
timal solvent for conducting the oxidation. The optimal conditions
involved addition of an AcOH solution of MCPBA to a solution of 1 in
AcOH at 55 ꢀC over 1 h and stirring for an additional 3 h at 55 ꢀC.
Upon cooling the reaction mixture was diluted with aqueous so-
dium bisulfite, which not only quenched remaining MCPBA but also
aided in the removal of 3-chlorobenzoic acid. The product was fil-
tered providing 13 in 98% isolated yield.
Installation of the amino substituent on the pyridine ring was
next examined. Treatment of 13 with Ts2O in the presence of tert-
butylamine resulted in complex reaction mixtures due to
competitive tosylation of the pyrazole nitrogen atom. Therefore,
protection of the pyrazole nitrogen atom was required prior to
amination. Due to the lability of the Boc group seen in bromide 6,
the use of a more robust protecting group was required. After
evaluation of several common protecting groups, the THP-pro-
tected pyrazole 14 was selected for further development.
Compound 14 was prepared by reaction of 13 with 4.7 equiv of 3,4-
dihydro-2H-pyran (DHP) in toluene at 80 ꢀC in the presence of
catalytic TsOH. After cooling to room temperature, crystalline 14
was isolated in 80% yield. Addition of a preformed mixture of 14
and 4 equiv of tert-butylamine in CH2Cl2 to a solution of 2.1 equiv of
Ts2O in CH2Cl2 keeping the internal temperature between 0 and
5 ꢀC afforded 15 and tert-butylsulfonamide 16 as a reaction by-
product. Compound 16 was insoluble in CH2Cl2 and was easily re-
moved by filtration upon completion of the reaction. The filtrate
containing 15 was washed with water and the solvent switched to
MeCN for global deprotection of both the THP and tert-butyl
groups. Since compound 15 was not a crystalline intermediate, it
was not isolated and was used crude in the deprotection step
without purification.
It was envisioned that removal of the THP group of 15 would be
trivial and that cleavage of the tert-butyl group from the amino-
pyridine nitrogen would require more forcing conditions.8 It was
initially discovered that deprotection of 15 in the presence of
a combination of 5 equiv of dry TsOH and 25 equiv of TFA in MeCN
at 70 ꢀC for 3 h afforded tosylate salt 2a, which crystallized from the
crude reaction mixture and was isolated in 55–60% yield for the
one-pot process (Scheme 5). However, these investigations also
revealed that the product 2a appeared to be decomposing over
NC
Cl
H
N
O
N
N
MCPBA
AcOH, 55 °C
98%
1
O
O
Cl
13
NC
Cl
H
N
O
NC
Cl
N
Ts2O, H2N
TsOH
MeCN
N
O
N
15
N
O
O
DHP
N
NH
CH2Cl2, 0 °C
O
O
toluene, 80 °C
80%
Cl
Cl
17
14
NC
Cl
H
N
TFA
TsO
NH3
O
NC
Cl
N
65 °C
N
O
O
O2
N
N
S
N
N
H
O
O
Cl
+
NH
2a
63% overall
Cl
16
15
Scheme 4.
Scheme 5.

5016
J.T. Kuethe et al. / Tetrahedron 65 (2009) 5013–5023
time. For example, treatment of crude 15 with TsOH$H2O at room
temperature resulted in rapid cleavage for the THP group giving
intermediate 17. The rapid removal of the THP group also resulted
in the formation of an extremely dark reaction mixture, presumably
due to the formation/polymerization of the THP by-products. In
order to prevent potential hydrolysis of the cyano group under the
extremely acidic reaction conditions, water from the TsOH was
azeotropically removed prior to the addition of TFA (25 equiv) and
the reaction mixture heated to 70 ꢀC for 3.5 h. The course of the
reaction was monitored by HPLC analysis. Conversion of the des-
THP intermediate 17 to 2 stalled at 90% at the end of 3.5 h. As shown
in Figure 1, maximum HPLC assay yield9 of 65% was achieved after
2.5 h and the yield of 2a dropped to 60% after prolong heating.
Attempts to either lower the reaction temperature to 50–55 ꢀC or
number of equivalents of TFA did not improve the reaction profile. It
is also important to note, that the use of TsOH or TFA alone only
resulted in the formation of 17 and failed to proceed to 2a.
For further scale-up of the reaction, it was estimated that
azeotropic distillation of water after the addition of TsOH$H2O to 15
would take several hours. Due to the instability of the reaction
intermediates, it was decided to examine azeotropic drying the
TsOH prior to addition of 15. In addition, the reaction was further
refined in terms of reaction time and number of equivalents of
TsOH employed. The conditions that were finally selected involved
addition of 4 equiv of dry TsOH in MeCN to a solution of 15 in MeCN
followed by the addition of 25 equiv of TFA. The reaction mixture
was stirred at 65 ꢀC for 4 h and monitored by HPLC. As outlined in
Figure 2, a dramatic increase in HPLC assay yield to near 80% was
realized. Although these slightly improved conditions were bene-
ficial, conversion of 17 to 2a still stalled at 90% conversion. After 4 h,
the reaction mixture was cooled to room temperature and seeded
with pure tosylate salt 2a resulting in the crystallization of 2a from
the crude reaction mixture. After addition of water, 2a was isolated
in 63% overall yield from 15. The first generation synthesis of 2
including the preparation of 310 required nine linear steps and
proceeded in 13% overall yield.
90
80
70
60
50
40
30
20
10
0
0
2
4
6
Time (hrs)
Figure 2.
with improved overall yield and efficiency was required. Key lia-
bilities that needed to be addressed included elimination of the
unstable bromide 6, which was only obtained in 42% yield from 3,
and streamlining the final deprotection step. It was reasoned that
installation of the amino group at an early stage of the synthesis
would allow for a more convergent synthesis of 2. Our retro-
synthetic approach was centered on preparation of alcohol 18
(Scheme 6). It was reasoned that appropriate activation of the fully
elaborated benzylic alcohol 18 would eliminate the low-yielding
transformations of the previous route and shorten the synthesis.
Since THP-protection of the pyrazole nitrogen proved successful in
the first generation synthesis, retention of this protecting group
became a key design feature and imparted a significant degree of
stability to synthetic intermediates.
2.3. Preparation of compound 18 (second generation
synthesis)
The first generation synthesis of 2 described above was only
suitable for the short-term. In order to support further clinical trials
with this drug candidate, a longer-term route for the synthesis of 2
NC
Cl
OH
H
N
70
60
50
40
30
N
N
N
+ 8
O
O
NH2
N
N
H
N
O
Cl
2
18
Scheme 6.
The second generation synthesis of 18 began with pyrazole 20.
Recently we outlined an effective strategy for the preparation of 20
from 2-fluoropyridine, which proceeded in 50% overall yield.11
N-Oxidation of 20 was accomplished by treating 20 with 1.3 equiv
of MCPBA in isopropyl acetate (IPAc) at 35 ꢀC for 2 h (Scheme 7).
Due to the increased solubility of 20 in IPAc at 35 ꢀC, the compli-
cations encountered in the first generation synthesis for the con-
version of 1 to 13 were not observed. Compound 21 began to
crystallize from the reaction mixture during the oxidation, and
upon cooling to room temperature, compound 21 was isolated by
direct filtration of the crude reaction mixture in 82% yield.
20
10
0
0
2
Times (hrs)
4
THP-protection of pyrazole 21 and subsequent conversion to
tert-butylamine 22 was developed as a one-pot procedure. Reaction
of 21 with 5 equiv of DHP in the presence of catalytic amount of
Figure 1.

J.T. Kuethe et al. / Tetrahedron 65 (2009) 5013–5023
5017
pyridine p-toluenesulfonate (PPTS) at 80 ꢀC in trifluorotoluene for
5 h gave crude THP-protected pyrazole in near quantitative yield.
Conversion of the THP-protected N-oxide intermediate to 22 was
initially conducted in trifluorotoluene. Cooling the crude reaction
mixture to ꢁ15 to ꢁ10 ꢀC and adding 5.6 equiv of tert-butylamine
was followed by the portion-wise addition of 2.5 equiv of Ts2O
while keeping the internal temperature <ꢁ5 ꢀC. Analysis of the
crude reaction mixture by both HPLC and NMR revealed that the
undesired 4-regioisomer 23 was also formed. The ratio of 22/23
was w6.5:1 as determined by NMR. After warming to 0 ꢀC the re-
action mixture was diluted with heptane and filtered to remove
precipitated 16. The filtrate was then treated with 10 N NaOH to
precipitate the remaining sulfonamide 16 as a sodium salt that was
removed by filtration. The use of an aqueous NaOH workup to
remove 16 was found to be ineffective as little of 16 was found in
the aqueous layer. The organic layer was then concentrated under
reduced pressure and purified by silica gel chromatography to give
the desired regioisomer 22 in 65–67% isolated yield.
the hydrogenation was repeated with crude 22 that contained both
regioisomer 23 and sulfonamide 16. Unfortunately, all attempts to
hydrogenate the crude mixture were unsuccessful. To understand
the lack of reactivity and identify the source of the catalyst poison,
the reaction was repeated with pure 22 that was spiked with either
16 or 23. It was established that the amount of residual 16 in iso-
lated 22 could be up to 8% and was not detrimental to the hydro-
genation of 22 as this experiment gave quantitative conversion to
18. However, spiking with regioisomer 23 resulted in a complete
shut-down of the hydrogenation. It was concluded that 23 was
acting as a catalyst poison in the hydrogenation and all traces of this
isomer needed to be removed prior to hydrogenation of 22.12 Un-
like bromide 6, which needed to be stored at low temperature to
prevent decomposition, alcohol 18 was indefinitely stable at room
temperature. Conversion of 18 to 2 was successful (vida infra) and
will be discussed in detail in the third generation synthesis.
2.4. Preparation of compound 2 (third generation synthesis)
In an effort to improve the regioselectivity of this step, the re-
action was further investigated in terms of solvent, temperature,
and order of addition of reagents. It was found that formation of the
THP intermediate was best performed in trifluorotoluene and
subsequent conversion of 22 was done in THF. After THP-protection
in trifluorotoluene, the reaction solvent was switched to THF by
distillation under reduced pressure. To the solution was directly
added 10 equiv of tert-butylamine. The resulting solution was then
added drop-wise to a cold slurry (ꢁ10 to ꢁ15 ꢀC) of 5 equiv of Ts2O
in THF. After stirring for 1 h at ꢁ10 ꢀC, the reaction was worked up
as described above to give a 10.5:1 mixture of 22/23. Unfortunately,
all attempts to completely remove both 16 and regioisomer 23
without recourse to chromatography were unsuccessful. Purifica-
tion by silica gel afforded 22 in 91% yield for the improved ami-
nation step.
The second generation synthesis of 2 established that benzylic
alcohol 18 was the key intermediate required for the final and
optimal manufacture of 2. However, the route needed to be com-
pletely overhauled. The obvious liabilities in the synthesis of alco-
hol 18 would necessitate elimination of both the N-oxidation step
and the amination step that required chromatographic removal of
the undesired 4-regioisomer 23. The third generation synthesis of 2
began with 2,6-difluoropyridine 24 (Scheme 8).13 Lithiation of 24
with 1.1 equiv of BuLi (2.5 M BuLi in hexanes) occurred smoothly
below ꢁ65 ꢀC and was complete within 60 min. While LDA could
also be employed, the use of BuLi was found to be more practical
and avoided the use of diisopropylamine. The direct addition of
a pre-cooled solution of Weinreb amide 2514 in THF to the resulting
lithiate and warming to ꢁ10 ꢀC was followed by an aqueous
workup and gave crude 26 in 81% HPLC assay yield. Also detected in
the crude reaction mixture was unreacted 24, 25, and amide 27.15
Ketone 26 could be isolated in analytically pure form by crystalli-
zation from EtOAc/heptane. However, it was found that purification
of this intermediate was unnecessary. A one-step process for con-
version of crude 26 to pyrazole 30 was developed where the
Removal of the benzyl protecting group to give the key alcohol
intermediate 18 was next examined. Catalytic hydrogenation of 22
was accomplished under a balloon pressure of hydrogen in the
presence of catalytic amount of 5% Pd/C at room temperature for
6 h and gave 18 as a crystalline solid in 95% isolated yield. In an
effort to remove the chromatography step for the purification of 22,
OBn
OBn
MCPBA
N
50%
see ref 11
N
IPAc, 35 °C
82%
N
N
H
N
O
N
F
N
H
19
21
20
OBn
NH
OBn
1. DHP, TsOH (cat.)
C6H5CF3
N
+
16
N
+
N
N
N
N
N
H
O
Ts2O,
H2N
2.
O
THF, 0 °C
22
23
91%
Pd/C, H2
95%
OH
N
N
N
N
H
O
18
Scheme 7.

5018
J.T. Kuethe et al. / Tetrahedron 65 (2009) 5013–5023
O
O
OBn
1. BuLi, THF
tert-Butylamine
Me
OBn
+
N
H
NMP
O
2.
F
N
F
F
N
F
O
OBn
27
26
N
24
81% assay
25
O
O
OBn
OBn
NH2NH2
OBn
N
NMP, one pot
+
N
H
F
N
NH
N
H
N
N
H
N
F
~ 10:1
30
81% assay
28
29
OH
OBn
N
5% Pd/C
DHP, toluene
PPTs (cat.)
N
N
N
H
N
N
EtOH, H2
N
N
H
O
O
99%
22
61% overall from 24
95%
18
Scheme 8.
presence of impurities 24, 25, and 27 was found not to be detri-
mental to the reaction conditions. Reaction of crude 26 in NMP with
5 equiv of tert-butylamine at 0–5 ꢀC afforded a mixture of the de-
sired addition product 28 and the undesired regioisomer 29 as
a w10:1 (determined by 1H NMR) mixture of 28/29.16 The reaction
mixture was degassed and 5 equiv of 64% hydrazine hydrate was
added to the reaction mixture. The mixture was stirred at room
temperature until complete consumption of 28 was observed and
the formation of 30 was complete. The pH of the reaction mixture
was adjusted to 5 with 5 N sulfuric acid and 30 was extracted into
MTBE. The solvent was then switched to toluene for use in the next
reaction without further purification giving pyrazole 30 in 81%
HPLC assay yield from 26. The exact fate of regioisomer 29 was not
rigorously determined and only impurities 25 and 27 were still
present at this stage.
remove the PPTS catalyst, solvent switching to cyclohexane, and
cooling to 10 ꢀC. Under these conditions, crystalline 22 was isolated
in 61% overall yield from difluoropyridine 24. Catalytic hydroge-
nation of 22 with 5 mol % Pd/C in EtOH at 20 psi H2 was complete
within 18 h at room temperature and provided 18 in quantitative
yield. Compound 18 was isolated in analytically pure form after
filtration of the catalyst and concentration to remove the toluene,
formed during the removal of the benzyl group, followed by the
direct addition of water to give 18 in 95% isolated yield (58% overall
yield from 24).
The conversion of 18 to intermediate 15 was extensively ex-
amined. For example, activation of alcohol 7 as mesylate 31 was
conducted in 2-MeTHF in the presence of 1.10 equiv of Hu¨nig’s base
by the drop-wise addition of 1.05 equiv of MsCl while maintaining
the internal temperature <8 ꢀC (Scheme 9). Also observed in the
crude reaction mixture was chloride 32 (3–5%). When the reaction
mixture was allowed to warm to room temperature, conversion of
mesylate 31 to chloride 32 increased to 20–25%. Interestingly, when
NEt3 was utilized as a base in the mesylation step, the formation of
Conversion of crude 30 to THP-pyrazole 22 was carried out in
toluene at 80–85 ꢀC in the presence of 5 equiv of DHP and 5 mol %
of PPTS to give nearly quantitative conversion to THP-pyrazole 22.17
Isolation of 22 was accomplished following an aqueous workup to
OMs
+
Cl
MsCl, Hunigs base, 2-MeTHF
N
N
18
N
N
N
N
N
H
N
H
THP
THP
31
32
O
NC
Cl
NEt3
Cl
KI, DMAc, CsF
Cl
N
N
N
N
N
N
H
N
O
O
NH
Cl
THP
33
Cl
HO
O
CN
15
8
93% from 18
Scheme 9.

J.T. Kuethe et al. / Tetrahedron 65 (2009) 5013–5023
5019
chloride 32 was suppressed; however, the formation of ammonium
NC
Cl
salt 33 was observed during the subsequent alkylation step. Am-
monium salt 33 was unreactive toward displacement and resulted
in lower conversion to 15. The use of Hu¨nig’s base completely
suppressed the formation of ammonium salts in the alkylation step.
Mesylate 31 was unstable to aqueous workup and readily converted
back to alcohol 18 when exposed to water. Therefore, the crude
reaction mixture was filtered to remove the precipitated ammo-
nium salts and the solvent was removed under reduced pressure.
The crude mesylate was dissolved in DMAc and 1.7 equiv of KI,
0.93 equiv of phenol 8, and 5 equiv of CsF were added and the
mixture stirred at room temperature for 12 h to give 15 in 93% HPLC
assay yield. As described in Scheme 2, the reaction proceeded via
the in situ formation of the iodide intermediate, which was ob-
served by HPLC. Chloride 32 reacted at a much slower rate with 8
than the iodide intermediate and required longer reaction times in
order to obtain complete conversion to 15. When KI was eliminated
from the reaction, the coupling proceeded to 15; however, the
formation of a number of unidentified impurities resulted in a less
desirable reaction profile.
H
N
H2SO4 (2.2 equiv)
• 2 H2SO4
N
1-octanethiol (2.2 equiv)
N
15
O
O
NH
MeCN, rt, 30 min
95%
Cl
34
NC
Cl
H2SO4 (7 equiv)
H2O (4 vol%)
H
N
N
N
MeCN, 70 °C, 2 h
92%
O
O
HSO4
NH3
Cl
2b
Scheme 11.
which was used in the final deprotection without further
purification.
Although the conditions outlined in Scheme 9 for the prepara-
tion of 15 were successful, the reaction needed further refinement
in order to streamline the approach and allow for a more robust
process. Since mesylate 31 was unstable and readily converted to
chloride 32, the decision was made to form 32 quantitatively prior
to reaction with 8 (Scheme 10). Reaction of 18 with 1.05 equiv of
MsCl in the presence of 1.10 equiv of Hunig’s base in 2-MeTHF at
room temperature followed by warming the reaction mixture to
55–60 ꢀC for 3–3.5 h resulted in the quantitative conversion to
chloride 32. Upon cooling, the ammonium salts were removed by
filtration and the filtrate containing 32 was used in the alkylation
step without purification. Chloride 32 was indefinitely stable as a 2-
MeTHF solution and as concentrated foam with no apparent loss of
purity. The alkylation step was then fully optimized in terms of
solvent, base, temperature, and amount of KI using the crude 2-
MeTHF solution of 32. Due to the expense and hygroscopic nature
of CsF, a number of other bases were examined with optimal results
being obtained with 5 equiv of powdered K2CO3 when MeCN was
used as the solvent. The use of catalytic amount of KI for the al-
kylation was also examined where it was found that 10 mol % of KI
led to smooth conversion to 15 when the alkylation was performed
at 55–60 ꢀC. The alkylation of crude 32 with phenol 8 was con-
ducted by the addition of the 2-MeTHF solution of 32 to a mixture
of 1 equiv of 8, 5 equiv of K2CO3, and 0.1 equiv of KI in MeCN at 55–
60 ꢀC. After 7–8 h, complete conversion to 15 was observed. Fol-
lowing an aqueous workup, HPLC assay yield of crude 15 was 98%,
The deprotection of 15 and conversion to 2 was thoroughly
optimized with the aid of high throughput experimentation (HTE)
coupled with DOE optimization (Scheme 11).8 Screening results
found that removal of both the THP and tert-butyl groups could be
effected in a one-pot procedure employing sulfuric acid in MeCN at
70 ꢀC eliminating the use of a combination of TsOH and TFA. Un-
fortunately, the HPLC assay yields of 2 remained <70%. It was
rapidly established that the by-products of the THP cleavage were
the cause of the low yields and a two-step protocol was imple-
mented for the final preparation of 2. The optimized procedure
involved treatment of 15 at room temperature with 2.2 equiv of
concd sulfuric acid in MeCN in the presence of 1-octanethiol. The
use of 1-octanethiol was crucial as it effectively trapped the THP by-
products associated with THP removal. During the course of the
reaction, des-THP intermediate 34 began to crystallize from the
reaction mixture. After dilution with MTBE and then heptane to
maximize the recovery, compound 34 was isolated as the bis-sul-
fate salt in 95% yield. Removal of the tert-butyl group was accom-
plished by reaction of 34 with 7 equiv of concd sulfuric acid in
MeCN in the presence of 4 vol % of water at 70 ꢀC for 2 h. During the
course of the reaction, sulfate salt 2b crystallized from the reaction
mixture. After being cooled to room temperature, the slurry of 2b
was diluted with water and was filtered to give 2b in 92% isolated
yield. The crystalline freebase of 2 could be obtained by neutrali-
zation of either 2a/b with NaHCO3 in EtOAc at 50 ꢀC and subsequent
crystallization from EtOH to give 2 in >95% yield.
In conclusion, we have developed a practical, efficient route for
the synthesis of the potent non-nucleoside reverse transcriptase
inhibitor 2 in 47% overall yield from 2,6-difluoropyridine. The
synthetic route is highlighted by a three-step synthesis of the in-
termediate 22 that does not require isolation of any intermediates,
and a high yielding coupling reaction between 18 with phenol 8.
This chromatography-free and scalable route has been used suc-
cessfully to prepare large quantities of 2. Furthermore, two other
routes for the synthesis of compound 2 and an optimized initial
synthesis of compound 1 were discussed.
Cl
1. MsCl (1.05 equiv)
Hunigs base (1.10 equiv)
2-MeTHF, 55-60 °C
N
18
N
N
H
N
THP
2. Filter
32
KI (0.1 equiv)
NC
O
N
Cl
K2CO3 (5 eqviv)
MeCN
N
3. Experimental section
3.1. General
N
Cl
Cl
O
O
NH
Cl
HO
O
CN
Melting points are uncorrected. All solvents and reagents were
used as received from commercial sources. Analytical samples were
obtained by chromatography on silica gel using an ethyl acetate–
hexane mixture as the eluent unless specified otherwise. Water
15
98% from 18
8
Scheme 10.

5020
J.T. Kuethe et al. / Tetrahedron 65 (2009) 5013–5023
content (KF) was determined by Karl Fisher titration on a Metrohm
737 KF coulometer.
117.4, 119.5, 122.2, 127.1, 130.1, 131.7, 135.7, 140.5, 149.6, 150.5, 152.8,
158.2, 159.0. Anal. Calcd for C20H12Cl2N4O2: C, 58.41; H, 2.94; N,
13.62. Found: C, 58.29; H, 2.75; N, 13.55.
3.2. Preparation of 3-bromomethyl-pyrazolo[3,4-b]-
pyridine-1-carboxylic acid tert-butyl ester (6)
3.4. Preparation of 3-chloro-5-[2-chloro-5-(7-oxy-
1H-pyrazolo[3,4-b]pyridine-3-ylmethoxy)-phenoxy]-
benzonitrile (13)
In a 100 L round bottom flask equipped with a mechanical
stirrer, thermocouple, and reflux condenser was added 6.64 kg
(29.3 mol) of 4 and 73 L of trifluorotoluene and the mixture heated
to 75 ꢀC. To the mixture was added 2.60 kg (29.3 mol) of NBS as
a solid. After 15 min, 481 g (2.93 mol) of AIBN was added and the
mixture was heated between 75 and 80 ꢀC for 1 h. The reaction
mixture was allowed to slowly cool to room temperature overnight.
The resulting slurry was filtered and the solids were washed with
15 L of toluene. The filtrate containing a mixture of 4 (24%), desired
product 6 (61%), and dibromide 7 (14%) was concentrated under
reduced pressure and diluted to a final volume of w19 L with tol-
uene. The crude mixture was purified on a 45 (diameter)ꢂ100
(height) cm silica gel column (EMD Sciences silica gel 60 40–63 um)
using a 42:58 (v/v) mixture of EtOAc/heptane. The fractions con-
taining the desired bromide 6 were combined and concentrated
under reduced pressure to give a solid, which was slurried in 18 L of
MTBE and 18 L of heptane. The slurry was heated to 55 ꢀC to dis-
solve all the solids and allowed to cool to room temperature
overnight. To the slurry was then added 20 L of heptane and the
slurry was stirred for 4 h and filtered. The wet cake was washed
with 10 L of heptane/MTBE (4:1) and the solid was dried under
vacuum/N2 sweep to afford 3.84 kg (42%) of 6 as an off-white
crystalline solid. Mp 85–86 ꢀC;18 1H NMR (DMSO-d6, 400 MHz)
In a 400 L reaction vessel was added 27.1 kg (110 mol) of MCPBA
and 198 L of AcOH. The resulting solution was stirred at room
temperature for 20 min to fully dissolve the MCPBA. In a separate
1000 L reaction vessel was added 28.3 kg (68.8 mol) of 1 and 425 L
of AcOH and the mixture was heated to 55 ꢀC. To the solution was
added the AcOH solution containing MCPBA while maintaining the
internal temperature at 55 ꢀC. The reaction mixture was stirred at
this temperature for 3 h and was cooled to 30 ꢀC. To the reaction
mixture was added aqueous sodium bisulfite (prepared by dis-
solving 5.01 kg of sodium bisulfite in 8 L of water) over 30 min
while maintaining the internal temperature w30 ꢀC. The reaction
mixture was then diluted with 550 L of water and the slurry was
stirred for 30 min and filtered. The wet cake was washed with 225 L
of EtOH/water (3:2) and dried under vacuum/N2 sweep at 40 ꢀC for
18 h to afford 32.2 kg (98%) of 13 as an off-white solid. Mp 197–
198 ꢀC; 1H NMR (DMSO-d6, 400 MHz)
d 5.49 (s, 2H), 7.09 (dd, 1H,
J¼8.8, 2.8 Hz), 7.12 (d, 1H, J¼2.7 Hz), 7.19 (dd, 1H, J¼8.0, 6.0 Hz), 7.35
(t, 1H, J¼2.2 Hz), 7.45 (dd, 1H, J¼2.2, 1.4 Hz), 7.55 (d, 1H, J¼8.8 Hz),
7.78 (t, 1H, J¼1.4 Hz), 7.89 (d, 1H, J¼8.0 Hz), 8.40 (d, 1H, J¼6.0 Hz);
13C NMR (DMSO-d6, 100 MHz)
d 64.1, 110.0, 114.5, 114.6, 117.4, 117.5,
118.5, 118.6, 119.6, 120.1, 122.2, 127.1, 131.8, 135.8, 136.0, 150.5, 152.2,
158.5. Anal. Calcd for C20H12Cl2N4O3: C, 56.22; H, 2.83; N, 13.11.
Found: C, 56.14; H, 2.79; N, 12.99.
d
1.62 (s, 9H), 5.05 (s, 2H), 7.48 (dd, 1H, J¼8.0, 4.5 Hz), 8.42 (dd, 1H,
J¼8.0, 1.5 Hz), 8.74 (dd, 1H, J¼4.5, 1.5 Hz); 13C NMR (DMSO-d6,
100 MHz)
152.2.
d 24.2, 31.1, 85.0, 116.2, 120.2, 131.1, 146.2, 147.3, 151.4,
3.5. Preparation of 3-chloro-5-{2-chloro-5-[7-oxy-1-
(tetrahydro-pyran-2yl)-1H-pyrazolo[3,4-b]pyridine-3-
ylmethoxy]-phenoxy}-benzonitrile (14)
3.3. Preparation of 3-chloro-5-[2-chloro-5-(1H-pyrazolo-
[3,4-b]pyridine-3-ylmethoxy)-phenoxy]-benzonitrile (1)
In a 400 L reaction vessel was added 28.4 kg (66.5 mol) of 13 and
284 L of toluene. The slurry was heated to 50 ꢀC and the solvent
concentrated under reduced pressure to a final volume of w200 L
to remove residual water. The slurry was re-diluted with 80 L of
toluene and 252 g (1.33 mol) of TsOH$H2O was added followed by
30.8 kg (366 mol) of 3,4-dihydro-2H-pyran. The reaction temper-
ature was raised to 80 ꢀC and stirred at this temperature for 2.5 h.
The reaction mixture was cooled to 60 ꢀC and seeded with pure 14
(2 g). The resulting slurry was cooled to room temperature over 4 h
and filtered. The wet cake was washed with 60 L of toluene and
dried under vacuum/N2 sweep for 18 h at 50 ꢀC to give 27.3 kg (80%)
of 14 as a colorless solid. Mp 162–163 ꢀC; 1H NMR (DMSO-d6,
In a 400 L reaction vessel was charged 24.9 kg (89.0 mol) of 8
and 33 kg (217 mol) of CsF and 75 L of DMF. The resulting suspen-
sion as stirred at room temperature for 15 min followed by the
portion-wise addition of 30.0 kg (96.1 mol) of 6 over 30 min. After
20 min post addition of 6, a final 6.7 kg (46 mol) of CsF was added.
After 2 h, the reaction mixture was diluted with 175 L of MTBE and
aqueous NaHCO3 (prepared by dissolving 4.5 kg NaHCO3 in 145 L of
water). The layers were separated and the organic layer was
washed with water (2ꢂ100 L). The solvent was concentrated under
reduced pressure and solvent switched to THF and a final volume of
250 L. To the crude solution of 9 was added 7.5 L of water and the
mixture was warmed to 30 ꢀC. To the solution was added 21.8 kg
(62.5 mol) of concd sulfuric acid over 30 min and the mixture was
stirred at <40 ꢀC for 2 h. To the reaction mixture was added 130 L of
water and the solvent was concentrated under reduced pressure to
a final volume of w90 L. The thick suspension was diluted with 15 L
of THF and 150 L of water and the pH of the mixture adjusted to 8–9
by the addition of NEt3 and warming to 40 ꢀC. The slurry was cooled
to room temperature and was filtered. The wet cake was washed
with 100 L of 10:1 water/THF and dried under vacuum/N2 sweep.
The crude product was slurried in 223 L of MeCN and 200 L of
MeOH and the slurry warmed to 60 ꢀC for 45 min and then cooled
to room temperature over 3 h. The slurry was filtered and the wet
cake washed with 120 L of 1:1 MeCN/MeOH. The solid was dried
under vacuum/N2 sweep to give 28.6 kg (78%) of 1 as a colorless
400 MHz)
d 1.51 (m, 2H), 1.67 (m, 1H), 1.97 (m, 2H), 2.35 (m, 1H),
3.61 (m, 1H), 3.89 (m, 1H), 5.45 (d, 1H, J¼12.5 Hz), 5.50 (d, 1H,
J¼12.5 Hz), 7.06 (m, 2H), 7.13 (m, 1H), 7.24 (dd, 1H, J¼8.3, 6.2 Hz),
7.36 (s, 1H), 7.45 (s, 1H), 7.54 (d, 1H, J¼8.8 Hz), 7.78 (s, 1H), 7.91 (d,
1H, J¼8.3 Hz), 8.40 (d, 1H, J¼6.2 Hz); 13C NMR (DMSO-d6, 100 MHz)
d
22.9, 25.1, 29.4, 63.9, 67.4, 85.0, 109.9, 114.5, 114.6, 117.4, 117.5,
119.5, 119.6, 120.4, 120.7, 122.2, 127.1, 131.7, 135.8, 138.5, 141.3, 142.8,
150.5, 158.2, 158.8. Anal. Calcd for C25H20Cl2N4O4: C, 58.72; H, 3.94;
N, 10.96. Found: C, 58.47; H, 4.03; N, 10.99.
3.6. Preparation of 3-{5-(6-amino-1H-pyrazolo[3,4-b]-
pyridine-3-ylmethoxy)-2-chloro-phenoxy}-5-chloro-
benzonitrile p-toluenesulfonate salt (2a)
solid. Mp 164–165 ꢀC; 1H NMR (DMSO-d6, 400 MHz)
d
5.47 (s, 2H),
In a 400 L reaction vessel was added 27.2 kg (53.2 mol) of 14,
408 L of CH2Cl2, and 22.4 L of tert-butylamine and the mixture was
cooled to 15 ꢀC. In a separate 1000 L reaction vessel was added
36.5 kg (112 mol) of Ts2O and 136 L of CH2Cl2 and the mixture was
7.08 (m, 2H), 7.20 (s, 1H), 7.36 (s, 1H), 7.45 (s, 1H), 7.54 (d, 1H,
J¼8.8 Hz), 7.78 (s, 1H), 8.29 (s, 1H), 8.54 (s, 1H), 13.73 (br s, 1H); 13C
NMR (DMSO-d6, 100 MHz)
d 64.4, 109.9, 113.8, 114.5, 114.6, 117.2,

J.T. Kuethe et al. / Tetrahedron 65 (2009) 5013–5023
5021
cooled to ꢁ5 ꢀC. The mixture containing 14 was transferred to the
Ts2O solution over 1 h keeping the internal temperature <5 ꢀC. The
reaction mixture was stirred at this temperature for w30 min at
which point HPLC analysis confirmed the completion of the re-
action. The resulting slurry was filtered to remove insoluble 16
rinsing with 55 L of CH2Cl2. The filtrate was washed with 82 L of
water and the solvent was switched to a final volume of 165 L of
MeCN by concentration under reduced pressure. To the crude so-
lution of 15 was added 40.5 kg (212.8 mol) of TsOH$H2O followed
by 243 L of MeCN and 162 L of toluene. The solvent was removed by
atmospheric distillation and a final volume of 150 L and KF of
<900 ppm water. To the cooled reaction mixture was added 151 kg
(1324 mol) of TFA and the mixture was heated to 67 ꢀC for 4 h and
was cooled to 5 ꢀC. The black reaction mixture was seeded with
pure 2a and 10 L of water was added and the slurry stirred for
30 min. To the slurry was added 99 L of water over 45 min and the
mixture was stirred overnight at room temperature. The slurry was
filtered and the wet cake was washed with 100 L of MeCN and was
dried under vacuum/N2 sweep at 45 ꢀC to give 20.2 kg (60%) of 2a
as an off-white solid. Mp 219 ꢀC (decomp.); 1H NMR (DMSO-d6,
stirring at 0 ꢀC for 30 min, the solids were filtered and washed with
1:1 heptane/THF. The solvent was removed under reduced pressure
and the residue purified by silica gel chromatography. The first
product to elute from the column was identified as compound 22
and was obtained as a colorless solid. mMp 69–70 ꢀC; 1H NMR
(CDCl3, 400 MHz) d 1.53 (s, 9H), 1.59 (m, 1H), 1.73–1.86 (m, 2H), 1.95
(m, 1H), 2.12 (m, 1H), 2.66 (m, 1H), 3.76 (m, 1H), 4.14 (m, 1H), 4.54
(d, 1H, J¼11.9 Hz), 4.57 (d, 1H, J¼11.9 Hz), 4.62 (br s, 1H), 4.81 (d, 1H,
J¼12.7 Hz), 4.84 (d, 1H, J¼12.7 Hz), 5.87 (dd, 1H, J¼12.3, 1.9 Hz), 6.19
(d, 1H, J¼8.7 Hz), 7.28–7.35 (m, 5H), 7.72 (d, 1H, J¼8.7 Hz); 13C NMR
(100 MHz, CDCl3) d 23.5, 25.2, 29.3, 29.7, 51.6, 66.5, 68.4, 72.2, 82.6,
106.8, 107.4, 127.6, 128.0, 128.4, 130.4, 138.4, 142.9, 151.6, 157.8.
HRMS (ESI) calculated for C23H30N4O2 (MþH) 395.2447, found
395.2431.
The second product to elute from the column was identified as
[3-benzyloxymethyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-
b]pyridine-4-yl]-tert-butylamine 23, which was obtained as an oil.
1H NMR (400 MHz, CDCl3)
d 1.29 (s, 9H), 1.53 (m, 1H), 1.80 (m, 2H),
1.92 (m, 1H), 2.10 (m, 1H), 3.83 (m, 1H), 4.14 (m, 1H), 4.57 (s, 2H),
4.96 (s, 2H), 6.03 (dd, 1H, J¼10.8, 2.2 Hz), 6.33 (d, 1H, J¼5.8 Hz), 6.93
(br s, 1H), 7.32 (m, 5H), 8.11 (d, 1H, J¼5.8 Hz); 13C NMR (100 MHz,
400 MHz)
d
2.30 (s, 3H), 5.45 (s, 2H), 6.65 (d, 1H, J¼9.2 Hz), 7.07 (m,
2H), 7.13 (d, 2H, J¼7.9 Hz), 7.36 (d, 1H, J¼1.7 Hz), 7.47 (s, 1H), 7.53 (d,
2H, J¼7.9 Hz), 7.58 (d, 1H, J¼8.5 Hz), 7.80 (s, 1H), 8.27 (d, 1H,
CDCl3) d 23.3, 25.1, 29.9, 51.2, 67.6, 68.6, 72.3, 81.9, 99.1, 105.5, 128.1,
128.4, 137.0, 142.1, 148.6, 149.8, 153.2. HRMS (ESI) calculated for
C23H30N4O2 (MþH) 395.2447, found 395.2441.
J¼9.2 Hz); 13C NMR (DMSO-d6, 100 MHz)
d
21.3, 106.7, 109.0, 114.6,
114.7, 117.4, 117.7, 119.7, 122.3, 126.0, 127.2, 128.7, 131.9, 135.8, 138.4,
145.7, 150.6, 156.3, 158.2, 158.5. Anal. Calcd for C27H21Cl2N5O5S: C,
54.19; H, 3.54; N, 11.70. Found: C, 53.89; H, 3.22; N, 11.49.
3.9. Preparation of [6-tert-butylamino-1-(tetrahydro-pyran-
2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-methanol (18)
3.7. Preparation of 3-benzyloxymethyl-1H-pyrazolo[3,4-b]-
pyridine 7-oxide (21)
To a solution of 8.50 g (21.6 mmol) of THP-pyrazole 22 in 40 mL
of EtOH was added 1.96 g of 10% Pd/C (w50% wet Degussa type
E101 NE/W). The stirred solution was placed under an atmosphere
of hydrogen (10 psi) and stirred at room temperature for 18 h. The
reaction mixture was filtered through a pad of Solka floc (filter
agent) eluting with w40 mL of EtOAc. The filtrate was concentrated
under reduced pressure flushing with w35 mL of EtOH and the
final volume adjusted to 30 mL. To the EtOH solution containing 18
was added drop-wise 40 mL of water and the mixture seeded with
pure 18. The slurry was stirred at room temperature for 30 min and
35 mL of water was added over 30 min. The slurry was cooled to 2–
5 ꢀC and was filtered. The wet cake was washed with water
(2ꢂ30 mL) and dried under vacuum/N2 sweep for 12 h to give
6.23 g (95%) of 18 as a white to off-white crystalline solid. Mp 146–
In a 500 mL three-neck round bottom flask equipped with
a mechanical stirrer, and a thermocouple was added 4.49 g
(18.8 mmol) of pyrazole 20 and 67 mL of IPAc. To the solution was
added 6.01 g (24.4 mmol) of 70–77 wt % MCPBA and the sides of the
flask were rinsed with 5 mL of IPAc. The reaction mixture was
warmed to 35–40 ꢀC and stirred at this temperature for 2 h. During
the course of the reaction a thick, yellow slurry of the product
formed. After heating for 2 h, the reaction mixture was slowly
cooled (5 ꢀC/h) to room temperature. The slurry was filtered and
the wet cake washed with 70 mL of IPAc. The solid was dried for 3–
12 h under vacuum/N2 sweep to give 4.47 g (82%) of 21 as a mon-
ohydrate and a fluffy white solid that was sufficiently pure for use
in subsequent transformations. Mp 210–211 ꢀC; 1H NMR (DMSO-d6,
147 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 1.51 (s, 9H), 1.59 (m, 1H), 1.76
(m, 2H), 1.91 (m, 1H), 2.11 (m, 1H), 2.20–2.50 (br m, 1H), 2.61 (m,
1H), 3.73 (t, 1H, J¼10.8 Hz), 4.12 (d, 1H, J¼11.4 Hz), 4.66 (br s, 1H),
4.87 (s, 2H), 5.83 (d, 1H, J¼10.8 Hz), 6.19 (d, 1H, J¼8.6 Hz), 7.67 (d,
400 MHz)
d
4.54 (s, 2H), 4.83 (s, 2H), 7.18 (dd, 1H, J¼8.0, 4.8 Hz),
7.21–7.35 (m, 5H), 7.82 (d, 1H, J¼8.0 Hz), 8.39 (d, 1H, J¼4.8 Hz); 13C
NMR (DMSO-d6, 100 MHz)
d
64.7, 71.6, 117.8, 118.3, 119.7, 127.6,
1H, J¼8.6 Hz); 13C NMR (CDCl3, 100 MHz)
d 23.4, 25.2, 29.3, 29.6,
127.7, 128.3, 135.4, 138.0, 143.6, 144.4. Anal. Calcd for C14H13N3O2: C,
65.87; H, 5.13; N, 16.46. Found: C, 66.03; H, 5.24; N, 16.49.
51.6, 59.1, 68.4, 82.5, 106.0, 107.4, 130.0, 145.1, 151.6, 157.8. Anal.
Calcd for C16H24N4O2: C, 63.13; H, 7.95; N, 18.41. Found: C, 62.91; H,
7.86; N, 18.21.
3.8. Preparation of [6-tert-butylamino-1-(tetrahydro-
pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-methylene
benzyl ether (22)
3.10. Preparation of 2-benzyloxy-1-(2,6-difluoro-pyridin-
3-yl)-ethanone (26)
In a 100 mL round bottom flask was added 3.06 g (12.0 mmol) of
21, 5.05 g (60 mmol) of DHP, 60 mg (0.24 mmol) of pyridinium p-
toluenesulfonate, and 30 mL of trifluorotoluene. The mixture was
heated to 85 ꢀC for 4 h, cooled to room temperature, and concen-
trated under reduced pressure while switching the solvent to THF
and a final volume of 20 mL. To the resulting solution was added
4.40 g (60.0 mmol) of tert-butylamine. In a separate 250 mL round
bottom flask was added 9.81 g (30.0 mmol) of Ts2O and 50 mL of
THF. The solution was cooled to ꢁ10 ꢀC, and the above mixture was
added over 30 min. The reaction mixture was diluted with 70 mL of
heptane and the reaction mixture was filtered. The filtrate was
cooled to 0 ꢀC and 6 mL of 10 N NaOH solution was added. After
To a 2 L round bottom flask, equipped with an overhead stirrer,
thermocouple, addition funnel, and nitrogen inlet, was charged
51.6 g (448 mmol) of 2,6-difluoropyridine 1 and 616 mL of anhy-
drous THF and the solution was cooled to wꢁ70 ꢀC. To the mixture
was added drop-wise 185 mL (461 mmol) of n-butyllithium (2.5 M
in hexane) through the addition funnel while maintaining the in-
ternal temperature <ꢁ65 ꢀC. After the addition of butyllithium was
complete, the resulting mixture was stirred at ꢁ65 ꢀC for 1 h. In
a separate flask was placed 93.7 g (448 mmol) of Weinreb amide 25
in 175 mL of 2-MeTHF and this solution was pre-cooled to ꢁ60 to
ꢁ55 ꢀC. The solution containing 25 was rapidly charged to the
lithiate difluoropyridine solution and the resulting reaction

5022
J.T. Kuethe et al. / Tetrahedron 65 (2009) 5013–5023
mixture was stirred at ꢁ65 ꢀC for 1 h, and slowly warmed to ꢁ10 ꢀC
over 4 h. The reaction mixture was inversely quenched into a so-
lution of 293 mL of 5 N HCl and 175 mL of THF at ꢁ15 to ꢁ5 ꢀC. The
mixture was extracted with 516 mL of MTBE. The layers were
separated and the organic layer was washed with water
(2ꢂ258 mL) and concentrated under reduced pressure while
azeotropically drying to a final KF <250 ppm and then the solvent
switched under reduced pressure to a final volume of 266 mL of
NMP and used in the next reaction without further purification.
HPLC assay yield of 26 was 88.7 g (81%). An analytical sample was
obtained by concentration of the crude reaction mixture and
crystallized from EtOAc/heptane (1:4) at ꢁ10 ꢀC to give pure 26 as
colorless needles. Mp 52.3–52.8 ꢀC; 1H NMR (CDCl3, 400 MHz)
and with 200 mL of water. HPLC assay yield of the organic layer
gave 106 g (99%) of crude 22. The organic layer was concentrated
under reduced pressure, and the solvent switched to cyclohexane
and a final volume of 330 mL by distillation at 50 ꢀC. The resulting
solution was cooled to 30 ꢀC, and seeded with a few crystals of pure
22. The resulting slurry was stirred at room temperature for 5 h,
and at 10 ꢀC for 1 h. The crystalline solid was filtered, washed with
80 mL of cold cyclohexane, and 150 mL of cold cyclohexane/hep-
tane (2:1) and dried under vacuum/N2 sweep to afford 99.1 g (93%)
of 22 as an off-white solid that was identical to that obtained above.
3.13. Preparation of 3-{5-[6-tert-butylamino-1-]tetrahydro-
pyran-2-yl}-1H-pyrazolo[3,4-b]pyridine-3-ylmethoxy]-2-
chloro-phenoxy}-5-chloro-benzonitrile (15)
d
4.69 (d, 2H, J¼3.0 Hz), 4.70 (s, 2H), 6.89 (dd, 1H, J¼8.4, 1.9 Hz),
7.31–7.52 (m, 5H), 8.54 (dd, 1H, J¼16.5, 8.4 Hz); 13C NMR (CDCl3,
100 MHz)
d
73.8, 75.3 (d, J¼10 Hz), 107.7 (dd, J¼33, 9 Hz), 115.5 (d,
In a 1 L round bottomed flask equipped with a mechanical
stirrer and thermocouple was added the 75 g (241 mmol) of 18 and
300 mL of 2-MeTHF. The resulting heterogeneous mixture was
cooled to an internal temperature of w5 ꢀC and 46.3 mL
(266 mmol) of Hunig’s base was added in one portion. To the slurry
was added drop-wise 19.8 mL (254 mmol) MsCl at such a rate that
the internal temperature was maintained <30 ꢀC. The resulting
mixture was then heated to an internal temperature of 50–55 ꢀC
and stirred at this temperature for 3 h. The resulting hot mixture
was cooled in an ice bath to 5 ꢀC and stirred at this temperature for
30 min and filtered. The flask and filter cake were rinsed with
300 mL of 2-MeTHF. The resulting filtrate was concentrated to
a final volume of w300 mL and used in the next step ‘as is’. An
analytical sample of 3-chloromethyl-pyrazolo[3,4-b]pyridine-1-
carboxylic acid tert-butyl ester 32 was obtained by purification on
silica gel to give 32 as a colorless oil. 1H NMR (CDCl3, 400 MHz)
J¼33 Hz), 128.1, 128.2, 128.6, 137.0, 146.9 (d, J¼9 Hz), 160.3 (dd,
J¼251, 16 Hz), 163.7 (dd, J¼254, 16 Hz), 192.2 (d, J¼8 Hz). HRMS
(ESI) calculated for C14H11F2NO2 (MþH) 264.0836, found 264.0807.
3.11. Preparation of (3-benzyloxymethyl-1H-pyrazolo-
[3,4-b]pyridine-6-yl)-tert-butylamine (30)
To a 1 L round bottom flask, equipped with an overhead stirrer,
thermocouple, addition funnel, and nitrogen inlet, was charged
179 mL (1.68 mol) of tert-butylamine and 532 mL of anhydrous
NMP. To the resulting solution was slowly added via the addition
funnel 88.7 g (337 mmol) of 2,6-difluoropyridine ketone 26 in
266 mL of NMP while maintaining the internal temperature be-
tween 0 and 5 ꢀC over 1 h and the mixture as stirred at the same
temperature for 2–3 h. The reaction mixture was degassed under
vacuum and then placed under an atmosphere of nitrogen. To the
resulting mixture was added 83.3 mL (1.68 mol) of hydrazine
monohydrate slowly while maintaining the internal temperature
between 0 and 5 ꢀC. After complete addition, the reaction mixture
was stirred at 0–5 ꢀC for 5 h, and at room temperature for 3–5 h.
The reaction mixture was cooled to 0 ꢀC, and the pH was adjusted to
5 by the addition of 5 N sulfuric acid while keeping the internal
temperature <20 ꢀC. To the solution was added 700 mL of water
and 800 mL of MTBE and the layers were allowed to separate. The
aqueous layer was extracted with MTBE (2ꢂ300 mL). The combined
organic extracts were washed with water (4ꢂ300 mL), concen-
trated under reduced pressure while solvent switching to toluene
and azeotropically drying to a final volume of 600 mL of toluene
and a KF <150 ppm water. To resulting solution was used as is in the
next step without further purification. HPLC assay yield of 30 was
84.7 g (81%). An analytical sample of 30 was obtained by silica gel
chromatography (EtOAc/heptane¼1:4) to give pure 30 as colorless
d
1.47 (s, 9H), 1.56 (m, 2H), 1.75 (m, 2H), 1.94 (m, 1H), 2.10 (m, 1H),
2.58 (m, 1H), 3.76 (m, 1H), 4.12 (m, 1H), 4.60 (s, 2H), 5.87 (dd, 1H,
J¼10.6, 2.3 Hz), 6.28 (d, 1H, J 8.8 Hz), 7.71 (d, 1H, J¼8.8 Hz); 13C NMR
(CDCl3, 100 MHz) d 23.2, 25.3, 28.9, 29.3, 38.9, 51.8, 68.2, 86.7, 106.1,
107.7, 129.8, 141.6, 151.4, 157.6. Anal. Calcd for: C16H23ClN4O: C,
59.53; H, 7.18; N, 17.35. Found: C, 59.21; H, 6.89; N, 17.01.
In a separate 3 L round bottom flask equipped with a mechanical
stirrer and thermocouple, was added the 67.6 g (241 mmol) of
phenol 8, 4.00 g (24.1 mmol) of KI, 133 g (966 mmol) of K2CO3, and
450 mL of MeCN. The resulting mixture was heated to an internal
temperature of 55–60 ꢀC and the above solution containing crude
chloride 31 in 2-MeTHF was added over 20 min. The reaction
mixture was stirred at 55–60 ꢀC for 7–10 h and allowed to cool to
room temperature and stirred overnight at room temperature. The
reaction mixture was diluted with 600 mL of IPAc and 600 mL of
water and the layers well mixed for 15 min and allowed to separate.
The organic layer was washed with 375 mL of water and 375 mL of
brine. The solvent was concentrated under reduced pressure
flushing first with IPAc to bring the KF down and then MeCN to
a final volume of 400 mL of MeCN and a KF w200 ppm. HPLC assay
yield of 15 was 133 g (97%). The MeCN solution containing 15 was
used in the next reaction without further purification. An analytical
sample of 3-{5-[6-tert-butylamino-1-(tetrahydro-pyran-2-yl)-1H-
pyrazolo[3,4-b]pyridin-3-ylmethoxy]-2-chlorophenoxy}-5-chloro-
benzonitrile 15 was obtained by purification on silica gel to give 15
oil. 1H NMR (CDCl3, 400 MHz)
d 1.51 (s, 9H), 4.57 (s, 2H), 4.72 (br s,
1H), 4.83 (s, 2H), 6.22 (d, 1H, J¼8.9 Hz), 7.27–7.36 (m, 5H), 7.56 (d,
1H, J¼8.9 Hz), 10.24 (br s, 1H); 13C NMR (CDCl3, 100 MHz)
d 29.3,
51.7, 66.1, 72.1, 105.9, 107.4, 127.7, 128.0, 128.4, 130.4, 138.2, 143.5,
152.8, 158.1. HRMS (ESI) calculated for C18H22N4O (MþH) 311.1872,
found 311.1854.
3.12. Preparation of [6-tert-butylamino-1-(tetrahydro-
pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-methylene
benzyl ether (22)
as a colorless foam. 1H NMR (CDCl3, 400 MHz)
d 1.53 (s, 9H),1.62 (m,
1H), 1.78 (m, 2H), 1.92 (m, 1H), 2.14 (m, 1H), 2.57 (m, 1H), 3.76 (m,
1H), 4.15 (m, 1H), 4.71 (br s, 1H), 5.29 (s, 2H), 5.88 (dd, 1H, J¼10.6,
2.4 Hz), 6.22 (d, 1H, J¼8.8 Hz), 6.83 (d, 1H, J¼2.9 Hz), 6.94 (dd, 1H,
J¼8.8, 2.9 Hz), 7.02 (dd, 1H, J¼2.4, 1.4 Hz), 7.13 (m, 1H), 7.34 (m, 1H),
7.45 (d, 1H, J¼10.6 Hz), 7.66 (d, 1H, J¼8.8 Hz); 13C NMR (CDCl3,
To a 1 L round bottom flask, equipped with an overhead stirrer,
thermocouple, addition funnel, and nitrogen inlet, was sequentially
charged 84.6 g (273 mmol) of crude 30 in 600 mL of dry toluene–
toluene, 126 mL (1.36 mol) of 3,4-dihydro-2H-pyran, and 2.35 g
(13.6 mmol) of pyridinium p-toluenesulfonate. The resulting mix-
ture was heated at 80–85 ꢀC for 18 h. The reaction mixture was
cooled to room temperature, washed with 100 mL of 5% NaHCO3
100 MHz)
d 14.1, 23.3, 25.1, 29.6, 51.7, 65.2, 68.4, 82.5, 106.3, 108.0,
109.7, 113.6, 114.6, 117.0, 118.1, 118.2, 121.7, 126.1, 129.7, 131.4, 136.4,
140.5,150.3,151.5,157.8,158.4,158.7. Anal. Calcd for C29H29Cl2N5O3:
C, 61.49; H, 5.16; N, 12.36. Found: C, 61.57; H, 5.29; N, 12.29.

J.T. Kuethe et al. / Tetrahedron 65 (2009) 5013–5023
5023
3.14. Preparation of 3-{5-(6-tert-butylamino-1H-pyrazolo-
[3,4-b]pyridine-3-ylmethoxy)-2-chloro-phenoxy}-5-chloro-
benzonitrile bisulfate (34)
C20H15Cl2N5O6S2: C, 45.81; H, 2.88; N, 13.36. Found: C, 45.97; H,
2.98; N, 13.33.
Acknowledgements
In a 1 L flask three-neck round bottom flask equipped with
a
mechanical stirrer and thermocouple was added 35.9 g
The authors wish to thank John Edwards, Faye Sheen, Sophie
Strickfuss, Adrian Goodyear, and Thomas Vickery of Merck & Co.,
Inc. for their valuable contributions to this work.
(63.4 mmol) of 15 in 100 mL of MeCN and 20.4 g (139 mmol) of 1-
octanethiol in one portion. The reaction mixture was cooled to
15 ꢀC and 7.43 mL (139 mmol) of concd sulfuric acid was added
drop-wise over 30 min while maintaining the internal temperature
<25 ꢀC. The resulting homogeneous solution was stirred at room
temperature for 30 min during which time 34 began to crystallize
from the crude reaction mixture. The resulting slurry was stirred at
room temperature for 30 min at and MTBE (130 mL) was added
drop-wise over 45 min. The resulting slurry was stirred at room
temperature for an additional 30 min and heptane (65 mL) was
added drop-wise over 45 min and the slurry stirred for 3 h and
filtered. The wet cake was washed with 125 mL of MTBE and dried
under vacuum/N2 sweep for 8 h to give 40.9 g (95%) of 34 as a col-
References and notes
1. Tarby, C. M. Curr. Top. Med. Chem. 2004, 4, 1045–1057.
2. http://www.tibotec.com/bgdisplay.jhtml?itemname¼HIV_tmc125.
3. (a) Tucker, T. J.; Saggar, S.; Sisko, J. T.; Tynebor, R. M.; Williams, T. M.; Felock, P.
J.; Flynn, J. A.; Lai, M.-T.; Liang, Y.; McGaughey, G.; Liu, M.; Miller, M.; Moyer, G.;
Munshi, V.; Perlow-Poehnelt, R.; Prasad, S.; Sanchez, R.; Torrent, M.; Vacca, J. P.;
Wan, B. L.; Yan, Y. Bioorg. Med. Chem. Lett. 2008, 18, 2959–2966; (b) Tucker, T. J.;
Sisko, J. T.; Tynebor, R. M.; Williams, T. M.; Felock, P. J.; Flynn, J. A.; Lai, M.-T.;
Liang, Y.; McGaughey, G.; Liu, M.; Miller, M.; Moyer, G.; Munshi, V.; Perlow-
Poehnelt, R.; Prasad, S.; Reid, J. C.; Sanchez, R.; Torrent, M.; Vacca, J. P.; Wan, B.
L.; Yan, W. J. Med. Chem. 2008, 51, 6503–6511.
4. Lynch, B. M.; Khan, M. A.; Teo, H. C.; Pedrotti, F. Can. J. Chem. 1988, 66, 420–
428.
5. Henke, B. R.; Aquino, C. J.; Birkemo, L. S.; Croom, D. K.; Dougherty, R. W., Jr.;
Ervin, G. N.; Grizzle, M. K.; Hirst, G. C.; James, M. K.; Johnson, M. F.; Queen, K. L.;
Sherrill, R. G.; Sugg, E. E.; Suh, E. M.; Szewczyk, J. W.; Unwalla, R. J.; Yingling, J.;
Willson, T. M. J. Med. Chem. 1997, 40, 2706–2725.
6. UK Chemical Reaction Hazards Forum. http://www.crhf.org.uk/incident101.
html (accessed April 2007).
7. Yin, J.; Xiang, B.; Huffman, M. A.; Raab, C. E.; Davies, I. W. J. Org. Chem. 2007, 72,
4554–4557.
8. For a preliminary account of our work involving the deprotection of in-
termediate 15 leading to final product 2, see: Kuethe, J. T.; Tellers, D. M.;
Weissman, S. A.; Yasuda, N. Org. Process Res. Dev. 2009, 13. doi:10.1021/
op8002739
9. HPLC assay yield refers to quantitative HPLC analysis of the crude reaction
mixture using an analytically pure standard.
orless solid. Mp 140 ꢀC (DSC); 1H NMR (DMSO-d6, 400 MHz)
d 1.25
(s, 9H), 4.67 (s, 2H), 6.08 (d, 1H, J¼9.4 Hz), 6.17 (d, 1H, J¼2.8 Hz),
6.27 (dd, 1H, J¼8.9, 2.8 Hz), 6.32 (m, 1H), 6.36 (m, 1H), 6.69 (m, 2H),
7.44 (d, 1H, J¼9.4 Hz); 13C NMR (DMSO-d6, 100 MHz)
d 26.5, 52.7,
60.7, 105.5, 108.6, 113.0, 113.7, 115.7, 117.4, 120.5, 125.2, 130.6, 135.3,
137.1, 144.9, 149.7, 152.4, 157.4, 157.6. Anal. Calcd for
C24H25Cl2N5O10S2: C, 42.48; H, 3.71; N, 10.32. Found: C, 42.06; H,
3.66; N, 10.21.
3.15. Preparation of 3-{5-(6-amino-1H-pyrazolo[3,4-b]-
pyridine-3-ylmethoxy)-2-chloro-phenoxy}-5-chloro-
benzonitrile sulfate (2b)
10. Compound 3 was prepared in two steps from chloronicotinoyl chloride in 70%
yield, also see Ref. 5.
11. Beutner, G. L.; Kuethe, J. T.; Kim, M.; Yasuda, N. J. Org. Chem. 2009, 74, 789–794.
12. For the effect of amines on the O-benzyl hydrogenolysis, see: Czech, B. P.;
Bartsch, R. A. J. Org. Chem. 1984, 49, 4076–4078.
13. We have previously outlined a strategy for the preparation of amino-1H-pyr-
azolo[3,4-b]pyridines, see: Zhong, Y.-L.; Lindale, M. G.; Yasuda, N. Tetrahedron
Lett. 2009, 50, 2293–2297.
To a 1 L round bottom flask equipped with a mechanical stirrer,
thermocouple, and reflux condenser was added 53.9 g (79 mmol)
of 34 and 350 L of 96:4 mixture of MeCN/water (by volume). To the
solution was added 4.23 mL (556 mmol) of concd sulfuric acid and
the reaction mixture was heated to 70 ꢀC for 2 h during which point
the product begins to crystallize from the crude reaction mixture.
The slurry was cooled to room temperature and diluted with
190 mL of water. The slurry was stirred for 3 h and filtered. The wet
cake was washed with 150 mL of MeCN/water (2:1, 2ꢂ) and dried
under vacuum/N2 sweep for 12 h to give 38.2 g (92%) of 2b as
a colorless solid. Mp 225 ꢀC (DSC); 1H NMR (DMSO-d6, 400 MHz)
14. Williams, R. M.; Ehrlich, P. P.; Zhai, W.; Hendrix, J. J. Org. Chem. 1987, 52, 2615–
2617.
15. Graham, S. L.; Scholz, T. H. Tetrahedron Lett. 1990, 31, 6269–6272.
16. For a discussion on the addition of methylamine to 2,6-difluoropyridine-3-
carbozylic esters in various solvents, see: (a) Hirokawa, Y.; Horikawa, T.; Kato, S.
Chem. Pharm. Bull. 2000, 48, 1847–1853; (b) Hirokawa, Y.; Yoshida, N.; Kato, S.
Bioorg. Med. Chem. Lett. 1998, 8, 1551–1554; (c) Hirokawa, Y.; Fujiwara, I.; Su-
zuki, K.; Harada, H.; Yoshikawa, T.; Yoshida, N.; Kato, S. J. Med. Chem. 2003, 46,
702–715.
17. In similar fashion as described for the preparation of compound 4, Scheme
1, the intermediate regioisomeric THP-protected pyrazole could be ob-
served by HPLC. This intermediate converts to THP-pyrazole 22 upon
heating.
d
5.45 (s, 2H), 6.64 (d,1H, J¼9.2 Hz), 7.07 (m, 2H), 7.37 (dd,1H, J¼2.3,
1.2 Hz), 7.47 (dd, 1H, J¼2.3, 1.2 Hz), 7.59 (m, 1H), 7.81 (s, 1H), 8.27 (d,
1H, J¼9.2 Hz); 13C NMR (DMSO-d6, 100 MHz)
d 61.5, 106.7, 109.2,
109.9, 114.5, 114.6, 117.4, 117.7, 119.7, 122.3, 127.2, 131.9, 135.8,
136.9, 137.7, 145.8, 150.6, 156.1, 158.2, 158.4. Anal. Calcd for
18. Satisfactory elemental analysis could not be obtained for bromide 6 due to the
instability of this intermediate.