Development of Scalable Processes for the Preparation of N-Methyl-3-Bromo-5-Methyl Pyrazole

Article abstract of DOI:10.1021/acs.oprd.7b00091

The development and optimization of two scalable routes to N-methyl-3-bromo-5-methyl pyrazole is described. The initial Sandmeyer route entailed a three-step sequence from crotonitrile and methyl hydrazine, proceeding through the 3-amino pyrazole intermediate. Due to the GTI liability of the 3-amino pyrazole intermediate, a tedious steam-distillation, and <30% overall yield, we developed a second-generation Sandmeyer-free approach from methyl crotonate and methyl hydrazine which leveraged a condensation, bromination, and oxidation sequence. Process development led to the improved preparation of N-methyl-3-bromo-5-methyl pyrazole with increased efficiency and overall yield. The isolation, handling, and storage of the final product was greatly improved through the generation of the triflic acid salt, and salt form studies are also discussed.

Full text of DOI:10.1021/acs.oprd.7b00091

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Full Paper
Development of Scalable Processes for the
Preparation of N-Methyl-3-Bromo-5-Methyl Pyrazole
Richard J. Fox, Chester A Markwalter, Michael Lawler, Keming
Zhu, Jacob Albrecht, Joseph Payack, and Martin Eastgate
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00091 • Publication Date (Web): 12 Apr 2017
Downloaded from http://pubs.acs.org on April 12, 2017
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Development of Scalable Processes for the Preparation of N-
Methyl-3-Bromo-5-Methyl Pyrazole
Richard J. Fox,* Chester E. Markwalter, Michael Lawler, Keming Zhu, Jacob Albrecht, Joseph Payack
and Martin D. Eastgate
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Chemical & Synthetic Development
Bristol-Myers Squibb Company
P. O. Box 191
New Brunswick, NJ 08903-0191
*To whom correspondence should be addressed. E-mail: richard.fox@bms.com
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Table of Contents Graphic
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Me
N
Me
HX
3 HCl, X = Cl
3 steps
3 steps
Me
Me
NC
N
MeO2C
Sandmeyer avoided
Robust 3 TfOH isolation
38-42% overall yield
Sandmeyer approach
3 HCl salt sublimation
19-28% overall yield
Br
1
4
9
3 TfOH, X = OTf
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Abstract
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The development and optimization of two scalable routes to N-methyl-3-bromo-5-methyl pyrazole
is described. The initial Sandmeyer route entailed a 3-step sequence from crotonitrile and methyl
hydrazine, proceeding through the 3-amino pyrazole intermediate. Due to the GTI liability of the 3-amino
pyrazole intermediate, a tedious steam-distillation, and <30% overall yield, we developed a second-
generation Sandmeyer-free approach from methyl crotonate and methyl hydrazine which leveraged a
condensation, bromination, oxidation sequence. Process development led to the improved preparation of
N-methyl-3-bromo-5-methyl pyrazole with increased efficiency and overall yield. The isolation, handling
and storage of the final product was greatly improved through the generation of the triflic acid salt, and
salt form studies are also discussed.
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Keywords: N-methyl-3-bromo-5-methyl pyrazole, bromopyrazole, Sandmeyer halogenation,
regioselective methyl hydrazine addition, dihydropyrazole oxidation
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Introduction
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Halogenated pyrazoles represent an important class of heterocycles due to their presence in
biologically active compounds,1 as well as their synthetic utility as starting materials for further
functionalization.2 A variety of methods have been reported for the formation of 3, 4, and 5-halogenated
pyrazoles, with 3-halopyrazoles most often prepared via: (1) direct electrophilic bromination when the
C(4) substituent is not hydrogen, (2) dehydroxyhalogenation of 3-hydroxypyrazoles, (3) bromination of
N-oxides,3 (4) Hunsdiecker decarboxylation/halogenation, (5) N-1 alkylation, (6) cycloaddition
methodologies, (7) Pd-catalyzed coupling via C(5) nonaflates and (8) diazoniation of 3-aminopyrazoles
(i.e., Sandmeyer) (Figure 1).4 While these approaches have been successful for a variety of targets, the
synthesis of N-methyl-3-bromo-5-methyl pyrazole (i.e., R1 = R2 = Me and R3 = H, Figure 1) had not been
reported.
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Figure 1. Known Approaches to 3-Bromopyrazoles
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Herein we describe our efforts towards developing two scalable processes for the preparation of
N-methyl-3-bromo-5-methyl pyrazole (3) (Scheme 1). The initial Sandmeyer route entailed a 3-step
telescoped process from crotonitrile and methyl hydrazine and proceeded through 3-aminopyrazole 2. An
improved second-generation approach was then developed from methyl crotonate and methyl hydrazine
which leveraged a sequence consisting of condensation, followed by bromination and oxidation. Salt form
studies for N-methyl-3-bromo-5-methyl pyrazole (3) are also presented.
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Scheme 1. Routes to N-methyl-3-bromo-5-methyl pyrazole (3)
Results and Discussion
For a recent program we needed to prepare multi kilogram amounts of N-methyl-3-bromo-5-
methyl pyrazole (3). We initially investigated the preparation of 3 utilizing a variety of known
methodologies for 3-bromopyrazoles, but these approaches were unsuccessful. For example, bromination
of 6 is known to lead to bromide 7,5 6 was resistant to oxidation,6 and N-methylation of 14 led to a mixture
of regioisomers. Likewise, C(3) bromination of 9 led to undesired decarboxylation/bromination to afford
11,6 while attempted Hunsdiecker decarboxylation/halogenation of 12 led to bromide 13. C(3)
bromination of 9 led to undesired decarboxylation/bromination to afford 11,7 while 12 did not undergo
the desired decarboxylation, but instead led to bromide 13 (Figure 2).
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Figure 2. Unsuccessful Approaches to 3
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Based on our previous report8 that described both the unsuccessful conversion of hydroxypyrazole
15 to either 3 or the chloro derivative 16, along with the preparation of iodopyrazole 17 from known
aminopyrazole 2,9 we selected a Sandmeyer strategy for our initial route to 3 (Scheme 2).
Scheme 2. Previous Attempts to 3 and Sandmeyer Route to 17
The first-generation synthesis of 3 began with bromination of commercially available
crotononitrile (1) (Table 1). During our process development, we found that the two most important
variables for the bromination were the addition of catalytic acid and addition order. Specifically, while
the reaction of 1 with bromine in DCM was slow, addition of 0.05 equiv of HBr dramatically increased
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the reaction rate. Reaction calorimetry also indicated that addition of HBr to the mixture of 1 and bromine
in DCM, followed by heating to 30°C, had both an adiabatic temperature rise of 84.3°C, and a sharp spike
in the heat liberation rate to 88 W/kg shortly after reaching 30 °C. On the other hand, controlled addition
of 1 in DCM to a solution of bromine and HBr in DCM reduced the peak heat liberation rate to 57 W/kg,
with 98% of heat liberation occurring over the course of the addition. Control during this addition was
important as a strong exotherm could lead to loss of bromine and significant unreacted 1. The optimized
reaction conditions entailed addition of a solution of 1 in 2 L/kg DCM over 4 h to a mixture of 1.0 equiv
Br2 and 5 mole% 33% HBr in acetic acid in 13 L/kg DCM to maintain the internal temperature <35 oC.
Following aqueous workup, concentration of the DCM solution under vacuum led to 18 as a neat oil.10
This procedure was successfully executed on 3 x 145 kg batches to afford 18 in 84% average corrected
yield with 93.9 liquid chromatography area percent (LCAP), 2.5-2.6 LCAP unreacted 1, and 91-95 wt%.
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Table 1. Preparation of 2
Entry MeNHNH2 source (equiv)
Base (equiv)
K2CO3 (3.0)
Solvent (L/kg)
Isolated 2
88-93 LCAP, 59-73 wt%
2.1-5.0 LCAP 19
Water (30)
1
2
3
H2SO4 salt (3.0)
H2SO4 salt (1.25)
freebase (1.25)
MeOH (8.0)
36-47% yield from 18
93-95 LCAP, 78-86 wt%
<1 LCAP 19
10 N NaOH (5.2)
10 N NaOH (8.0)
Water (4.2)
Water (4.2)
77-84% yield from 18
97 LCAP, 98 wt%
<1 LCAP 19
83% yield from 18
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With respect to the conversion of 18 to 2, the initial conditions utilized 3.0 equivalents of both
MeNHNH2•H2SO4 and K2CO3 in water/MeOH and led to 2 in only modest yield and potency, along with
up to 5.0 LCAP of undesired isomer 19 (Table 1, entry 1). Fortunately we found that highly basic reaction
conditions (pH >13) minimized the formation of 19, and the conditions in entry 2 were successfully
executed on 250-350 kg scale to afford 2 in 77-84% corrected yield with 93-95 LCAP (<1 LCAP 19) and
78-86 wt%. While these conditions were scalable, the initial neutralization of the sulfate salt with sodium
hydroxide was highly exothermic. For this reason, commercially available methylhydrazine freebase was
also examined, and the modified conditions in entry 3 afforded 2 in 83% yield with 97 LCAP and 98 wt%
on 500 g scale.
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As 2 was found to be an AMES positive genotoxic intermediate (GTI), it was also desirable to
develop a workup protocol that would eliminate the isolation of neat 2. Towards this end, following the
addition of 1 L/kg toluene at the end of the reaction, the layers could be split, and the resulting product-
rich aqueous layer washed with 6 x 1.5 L/kg DCM. The combined DCM layers could then be solvent
swapped into 5 L/kg CH3CN, assayed for potency, and telescoped into the Sandmeyer chemistry.11
The final optimized process for the conversion of 2 to 3•HCl is shown in Scheme 3. Some of the
key process development knowledge entailed: (1) Cu(I)Br12 was critical, as use of Cu(II) bromide led to
an undesired regioisomer; (2) conducting the reaction with 30% water in acetonitrile, versus 100%
CH3CN, increased the end of reaction purity from ~50 to 80 LCAP; (3) slow addition (>1 h) of
isoamylnitrite was required to minimize the rate of N2-offgasing; and (4) the concentrated reaction mixture
was found to be unstable in the presence of unreacted isoamylnitrite and copper salts.13 To address this
last observation, 10 volumes of water were charged at the end of reaction, and the stream was filtered
through celite to remove copper salts prior to initiating a constant-volume steam distillation.14
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Scheme 3. Preparation of 3•HCl from 2
The constant-volume steam-distillation was conducted at atmospheric pressure, charging a total of
40 L/kg water.15 The distillate collected between 80-100 oC afforded 3 with ~90 LCAP, along with ~10
LCAP des-bromide 6. While this distillation was an effective clean-up strategy, it required 4 days of
continuous processing on 100 kg scale. Fortunately, we confirmed prior to the scale-up that no safety or
quality liabilities were observed during the analysis of both batch and distillate samples taken over the
course of 10 days.
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To complete the isolation, the aqueous distillate of 3 was extracted with MTBE/1 N HCl. Using
this protocol, des-bromide 6 was selectively protonated and extracted into aqueous layer. The organic
phase was then dried and concentrated to 5 L/kg. Reduction of the water content of the organic stream
was critical to control losses to the mother liquor during the crystallization. Typical yields at this stage
were 35-45%, with the main source of process variability resulting from batch-to-batch differences in the
steam distillation of 3. Controlled addition of 2 equiv of 5-6 N HCl in isopropanol then furnished 3•HCl.
Using this process, 196 kg 3•HCl was prepared in 26-39% yield with excellent purity [99.9 LCAP, < 4ppm
2 (GTI)].
Concurrent with the efforts associated with the development and scale-up of the Sandmeyer route,
we identified both shipping and stability liabilities of 3•HCl.16 Differential Scanning Calorimetry (DSC),
Thermogravimetric Analysis (TGA) and materials compatibility testing with Armorflex (AF110) bags
confirmed that 3•HCl began to sublime at temperatures as low as 40 oC. Additionally, 3•HCl was observed
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to deliquesce upon exposure to elevated humidity, and Moisture Sorption Analysis indicated complete
sublimation by 85% relative humidity. Thus, there was a risk of significant mass loss during shipment
and storage of kilogram quantities of 3•HCl. As a stop-gap measure, the material generated during the
initial scale-up was shipped and stored cold. However, to reduce or eliminate these shipping and storage
concerns in future batches, alternative salt forms of 3 were investigated.
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As shown in Table 2, a broad screen supported that use of acids weaker than HCl led to either no
crystallization or highly hygroscopic solids. The theoretical pKa of the conjugate acid of 3 was estimated
to be ~0.5,17 indicating that bromopyrazole 3 was significantly less basic than des-Br pyrazole 6, which
had an experimental pKa value of 2.5.18 This observation suggested that acids stronger than HCl might
be required to protonate 3.19 To our delight, the triflate salt of 3 was a highly crystalline solid with no
sublimation liabilities and only mild hygroscopic character that was easily addressed by the addition of
desiccant during shipment and storage.
Table 2: Acid Salt Screen of 3
Entry
Acid
Tartaric acid
Succinic acid
4-NO2 benzoic acid
Fumaric acid
TFA
Acid pKa
4
Observations
no solids
1
2
4
no solids
3
3.4
no solids
4
3.0
no solids
5
0.25
-2.5
-2.6
-3.0
-3.0
-8.0
no solids
6
CSA
solids deliquesce
solids deliquesce
solids deliquesce
solids deliquesce
sublimes at 40 oC
7
MSA
8
H2SO4
9
benzenesulfonic acid
HCl
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HBr
-9.0
sublimes at 70 oC
mp = 145 oC
TfOH
-14.0
Having identified the triflate salt form of 3, we turned our attention to the development of an
alternative route to 3•TfOH that would eliminate both the GTI liabilities associated with 2, and tedious
steam-distillation, as well as improve the overall yield. Towards this end, we were attracted to a synthetic
strategy in which the 3-bromo moiety would be introduced at an earlier stage in the process, followed by
a final oxidation step of the corresponding dihydropyrazole intermediate to furnish 3.20
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Our efforts towards a second-generation route to N-methyl-3-bromo-5-methyl pyrazole (3) began
with the condensation of methyl hydrazine and methyl crotonate (4). While this transformation had not
been reported,21 literature precedent supported that 20 would be the favored regioisomer.22 As shown in
Table 3, while our initial studies (entries 1-4) demonstrated that the use of water or methanol led to the
highest (i.e., 8-15:1) in-process (IP) regioselectivity, the high solubility (i.e., >100 mg/mL) of 20•HBr,
which was the ideal salt form to minimize halogen exchange in the subsequent bromination, in these
solvents made a direct drop isolation challenging. On the other hand, while the low (i.e., <5 mg/mL)
solubility of 20•HBr in IPA was attractive with respect to isolation, both the rate and regioselectivity for
the condensation were not optimal. Entries 5 and 6 demonstrated that running at higher concentrations
and adding 5 mole% NaOH increased both the reaction rate and regioselectivity; variable dissolution of
NaOH in IPA was the presumed cause of the selectivity range from 7-11:1. Due to the increased solubility
of KOH in IPA, our optimized process utilized 5 mole% KOH in 2.3 L/kg IPA at ambient temperature,
and reproducibly led to a 13:1 in-process ratio of 20:21 (entry 7).23 Following seeding with 20•HBr,
addition of 1.1 equiv of HBr in IPA (prepared from 1.1 equiv acetyl bromide in 9.3 L/kg IPA) led to
20•HBr in 90% isolated yield with >99.5 LCAP purity and 99 wt% on 40 g scale. Pleasingly, this
chemistry was successfully conducted on 72 kg scale to produce 20•HBr with >99 LCAP in 85% yield.
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Table 3. Preparation of 20•HBr
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Me
N
Me
H
N
Me
O
i. solvent
HN
N
NHMe
NH2
MeO
Me
+
+
Me
O
O
4
1.05 equiv 1.0 equiv
20
21
ii. AcBr/IPA
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20 HBr
Entry
Solvent
(L/kg)a
Additive
Conversion IP ratio
after 4 hb
>95%
>95%
>95%
85%
20:21b
1
2
3
4
5
6
7
neat
water (10)
none
none
5:1
15:1
8:1
MeOH (10) none
IPA (10)
IPA (2.3)
IPA (2.3)
IPA (2.3)
none
none
4:1
>95%
3:1
0.05 eq NaOH >95%
0.05 eq KOH >95%
7-11:1
13:1
a L/kg based on methyl hydrazine. b Determined by HPLC.
Turning to the conversion of 20•HBr to 5, a brief screen of conditions supported: (1) POBr3 was
uniquely effective for this transformation, (2) reaction rates were comparable in DCM and CH3CN, (3)
base was required, and (4) while Et3N, DIPEA and 2,6-lutidine were all acceptable, K2CO3 led to low
conversion.24 Due to the anticipated need for an aqueous workup to both quench the excess POBr3 and
remove the organic base, the combination of DCM and Et3N was selected for further development.
As summarized in Table 4, further optimization led to two key findings: (1) 0.9 equiv Et3N was
optimal (entries 1-4), and (2) while catalytic DMF, N-methyl morpholine (NMM) and DABCO25 were not
beneficial (entries 5-7), addition of 0.3 equiv Et4NBr significantly increased the reaction rate (entry 8).
This rate enhancement correlated well with FTIR data that supported 20•HBr rapidly converted to 22 upon
addition of POBr3, and conversion of 22 to 5 was rate-determining.26 Final optimization of concentration
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and temperature decreased the time needed to reach >95% conversion from approximately 20 h to 5 h
(entry 9).
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Table 4. Optimizing Conversion of 20•HBr to 5
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Me
N
Me
N
Me
N
1.3 equiv POBr3
Et3N, DCM
HN
N
Br-
O
P
N
Me
HBr
Me
Me
SLOW
O
O
Br
Br
Br
22
5
20 HBr
Entry
L/kg
DCM
10
Et3N
equiv
Additive
(equiv)
none
Temp
(oC)
20
LCAP
5a
1
2
3
4
5
6
7
8
9
0.7
0.9
1.1
2.2
0.9
0.9
0.9
0.9
0.9
56
71
63
2
10
none
20
10
none
20
10
none
20
10
DMF (0.1)
NMM (0.1)
20
55
73
69
81
95
10
20
10
DABCO (0.1)
Et4NBr (0.3)
Et4NBr (0.3)
20
10
20
6
30
a After 7 h at 20 oC for entries 1-8 and 5 h at 30 oC for entry 9
For the aqueous workup,27 initial experimentation revealed the partitioning of 5 into aqueous
solution was highly dependent on pH, with ~15% yield loss observed at pH 1.5, but <3% yield loss at pH
>4.5. As shown in Table 5, in order to remove both the residual Et3N and Et4NBr prior to the subsequent
oxidation, our initial workup entailed addition of aqueous KOH to the reaction mixture to obtain a final
pH of 4-5 (entry 1). Unfortunately, this led to a challenging emulsion. Based on the higher water solubility
of NaH2PO4 vs KH2PO4, presumably the major phosphate salt present at pH 4-5 after quenching the excess
POBr3,28 we replaced KOH with NaOH. This led to a clean phase split, removal of both the Et3N and
Et4NBr, and 5 in 74% in-process yield (entry 2). Switching to an inverse aqueous NaOH quench not only
led to a more controlled exotherm, but further improved the IP yield, presumably due to maintaining the
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pH >4 throughout the quench (entry 3). Overall, the final workup protocol involved addition of the
bromination reaction mixture into 4.5 equiv NaOH in 19 L/kg water at 0 oC, followed by warming to 20
oC, and washing the resulting DCM layer sequentially with 5 L/kg 0.1 M Na2HPO4 and 5 L/kg water.
Under these conditions, 5 was isolated in 93% solution yield with excellent purity on 30 g scale. This
chemistry proved extremely robust, leading to 5 in 97% solution yield on 73 kg scale.
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Table 5. Investigating POBr3 Workup Protocol
Entry Quench
solution
Addition Final
Emulsion Et3N in
Et4NBr in
IP
mode
pH
4-5
observed
org layera
org layera
yieldb
NDc
74%
93%
1
2
3
aq KOH
aq NaOH
aq NaOH
normal
normal
inverse
Y
N
N
N
N
N
N
N
N
4-5
4-5
a Determined by 1H NMR. b Determined by 1H NMR of final 5/DCM solution using 1,2-
dichloroethane as internal standard. c ND = not determined.
Continuing with the proposed telescope, an extensive screen of oxidants supported that NaOCl, t-
BuOOH/VO(acac)2 and MnO2 were most effective in converting 5 to 3.24 Due to the scale-up challenges
of MnO2, and minimal purity profile differences between NaOCl and t-BuOOH/VO(acac)2,29 NaOCl was
selected for further optimization. Our initial trials were conducted by adding 1 equiv of aqueous NaOCl
o
to a biphasic solution of 5 in DCM and 1 equiv K3PO4 in 5 L/kg water at 0-5 C. Unexpectedly, we
observed a significant induction period under these conditions (Figure 3). Based on the well-precedented
impact of bromide additives in TEMPO/bleach oxidations,30 we next charged 0.1 equiv of KBr at the start
of the reaction. With the addition of KBr, we observed the expected near addition controlled kinetics.
Taken together, these results supported that HOBr was the active oxidant, and the induction period
observed in the absence of KBr was likely due to the time needed to induce some hydrolysis of 5 to release
bromide into the reaction mixture.
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Figure 3. Impact of KBr on Oxidation Kinetics
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60
50
40
30
20
10
0
0
5
10
15
20
Time (h)
Control (no KBr)
with 0.1 equiv KBr
Further optimization led to our final oxidation conditions which entailed the slow addition of 1.75
equiv of aqueous NaOCl to a biphasic mixture of 5 in DCM and 2 equiv K3PO4 and 0.5 equiv KBr in 2
o
L/kg water at 0-5 C (Table 6). The use of 2 equiv K3PO4 was critical to maintain the pH >12 and
minimize formation of dibromide 24. For example, subjecting 3 to the reaction conditions with pH 12
buffer led to <2 LCAP 24 after 3 h, while use of pH 10 buffer led to 40 AP 24.31 Additional HPLC,
HRMS and NMR studies supported that in addition to the 65% yield of 3, the end of reaction mixture also
contained 12 AP (15% molar yield) of N,N dimer 23.32 After an aqueous Na2S2O3 wash to quench the
excess bleach, we subjected the resulting product-rich DCM layer to a variety of workup/isolation
protocols to determine the fate of dimer 23. While direct addition of stoichiometric TfOH led to the rapid
conversion of 23 to desmethyl pyrazole 14, the observation of ~10 LCAP dibromide 24 suggested that the
strongly acidic conditions also led to the formation of an electrophilic bromide source, and the isolated
3•TfOH was only 55 LCAP (entry 2). In line with these results, while charging only 0.3 equiv HCl in IPA
led to more controlled conversion of 23 to 14, ~4% over-bromination was still observed (entry 3).
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Fortunately, the conversion of 23 to 14 also occurred upon addition of 0.5 equiv Et3N, and under the basic
conditions, no over-bromination was detected (entry 4). Based on our previous learnings from the
Sandmeyer process that desmethyl 14 can selectively partition into aqueous HCl, we next performed 2 x
2 N HCl washes, followed by addition of TfOH and heptane as antisolvent to isolate 3•TfOH in 50% yield
and 99.8 LCAP on 50 g scale. Utilizing this improved process, 182 kg 3•TfOH was prepared in 46-50%
yield with excellent purity (99.8 LCAP).
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Table 6. Investigating Oxidation Workup Protocol
2 L/mole water, 0-5 oC
Br
Me
2 eq K3PO4, 0.5 eq KBr
1.75 eq NaOCl
Me
N
Me
N
N
N
N
N
N
Me
Me
+
N
Br
Br
Me
crude 5
in DCM
Br
3
23
Me
N
N
H
N
H
N
i. aq Na2S2O3
ii. conditions
N
N
Me
Me
Me
+
+
3
Br
Br
Br
Br
Br
24
14
25
Entry
Workup
Sample
3
23
12.1
55.2 <0.05 10.3
63.0 <0.05 4.2
24
14
25
Yield 3
65%a
NDb
1
2
3
end of reaction
isolated 3•TfOH
DCM layer
85.1
0.29 <0.05 <0.05
TfOH addition to DCM layer
0.3 equiv HCl to DCM layer
0.5 equiv Et3N to DCM layer
after 2 x 2 N HCl washes
22.6
24.3
0.72
0.75
57%a
65%a
61%a
50%c
DCM layer
68.1 <0.05 0.30
90.4 <0.05 0.43
30.2 <0.05
6.6 0.72
4
final DCM layer
isolated 3•TfOH
TfOH addition then heptane
99.8 <0.05 <0.05 0.16 <0.05
c
a In-process yield determined by HPLC. b ND = not determined. Isolated yield.
Mechanistically, the formation of 14 is proposed to be due to competitive elimination pathways in
N-halo intermediate 26, with desired Ha elimination leading to 3, and undesired Hb elimination affording
iminium 28, which upon hydrolysis and oxidative dimerization generates 23 (Scheme 4a). Addition of
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Et3N during the workup then would lead to deprotonation/N-N bond cleavage to afford 1 equiv of both 14
and 28, the latter of which would undergo further oxidation to afford 2 equiv 14 per mole of 23. Deuterium
labeling studies supported the proposed competitive deprotonations of Ha leading to 3 versus Hb leading
to 14. As shown in Scheme 4B, by replacing the N-CH3 group in 5 with N-CD3 (29), which would have
been expected to decrease the acidity of Hb versus Ha and favor the desired elimination pathway,33 the
ratio of product:des-methyl impurity increased dramatically from 2.3:1 3:14 (starting from 5) to >20:1
30:14 (starting from 29), and 30 was isolated in 86% isolated yield.
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Scheme 4. Proposed Oxidation Pathways
A
Br
Me
N
Me
Me
N
N
N
Et3N
H
N
N
Me
28
[O]
Me
+
N
N
Br
Br
Me
crude 5
in DCM
- Ha
desired
Br
N
N
3
23
Me
Br
dimerization
14
(2 equiv)
Hb
- Hb
undesired
X
H
N
H2O
N
N
N
N
N
Me
Ha
Me
Me
Br
Br
Br
26
27
28
X = Br, Cl
B
D
D
D
CD3
N
H
N
(Hb)
i. aq NaOCl, KBr, K3PO4
N
N
N
N
Me
Me
+
Me
Ha
ii. Et3N
Br
Br
Br
iii. 2 N HCl
30
crude 29
in DCM
14
>20 : 1
(86%)
In conclusion, we have developed two scalable routes to N-methyl-3-bromo-5-methyl pyrazole
(3). First, a Sandmeyer route involving a 3-step telescope from crotonitrile and methyl hydrazine, which
proceeded through 3-amino pyrazole intermediate 2, led to 3•HCl with 99.9% HPLC purity in 19-28%
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overall yield. Due to the genotoxic nature of 2, long-cycle time during the steam distillation of 3, low
overall yield and sublimation challenges involving 3•HCl, we developed a second-generation route which
leveraged a condensation, bromination, oxidation sequence starting from methyl crotonate and methyl
hydrazine, as well as a crystallization protocol with triflic acid, to afford 3 as the higher melting 3•TfOH
salt with 99.8% HPLC purity in an improved 38-42% overall yield.
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Experimental section
General. The reactions were performed under a nitrogen atmosphere. All reagents were commercially
available and used as received. GC or HPLC was used to monitor reaction progress. NMR analysis was
performed on a Bruker DRX-400 or DRX-500 instrument.
Preparation of 18. To dichloromethane (1885 L, 13 L/kg) at ambient temperature was added bromine
(346 kg, 2161 moles, 1.0 equiv). The resulting solution was then charged with HBr in acetic acid (33%,
26.1 L, 108 moles, 0.05 equiv) slowly over 2.5 h to maintain the internal temperature below 30 °C. A
solution of crotonitrile (145 kg, 2161 moles, 1.0 equiv) in dichloromethane (290 L, 2 L/kg) was then added
over 4-5 h maintaining the internal temperature between 30−35 °C. The reaction mixture was then aged
for an additional 4-5 h before checking reaction conversion by HPLC (dilute 100 mg reaction mixture to
10 mL CH3CN and analyze at 210 nm). Target conversion was <2.0% unreacted crotonitrile. Cooled
reaction mixture to 25−30 °C and sequentially washed DCM layer with 10% aqueous sodium thiosulfate
(580 L, 4 L/kg), 10% aqueous sodium bicarbonate (580 L, 4 L/kg) and water (870 L, 6 L/kg). The product-
rich organic layer was then concentrated under vacuum at 40-45°C to dryness to afford 428 kg (91 wt%)
of 18 as a crude clear yellow oil in 83 wt% corrected yield which was used without further purification.
Preparation of 2. Note: Nitrogen inertion should be utilized throughout all operations to prevent
darkening of 2. However, darkening of 2 does not affect its’ downstream reactivity. To a 0 °C solution of
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water (2.0 L, 4.16 L/kg) was sequentially charged 10 N NaOH (670 mL, 6.70 moles, 3.16 equiv) and
methyl hydrazine (120 g, 2.61 moles, 1.23 equiv). Crude 18 (480.2 g, 2.12 moles, 1.0 equiv) was then
added in portions over at least 2 h to maintain the internal temperature <10 °C. Checked pH after addition
was complete. If pH was <12.5 charged additional 10 N NaOH. Checked reaction progress by HPLC
after aging an additional 16 h at 0 °C. Target relative area percent was 18/2 < 2.0%. Charged toluene
(500 mL, ~1 L/kg). Agitated for 15 min and then separated the phases. Extracted the product rich aqueous
layer six times with DCM (6 x 750 mL, 6 x ~1.5 L/kg). Dried the combined product-rich DCM layers
over Na2SO4, filtered and concentrated under vacuum to dryness to afford 196.4 g (97 LCAP, 98 wt%) of
2 as a yellow solid in 83% wt% corrected yield. The spectral data were consistent with previous reports.34
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Preparation of 3•HCl. To a solution of water (609 L, 5 L/kg) and acetonitrile (1218 L, 10 L/kg) was
charged copper(I) bromide (188.7 kg, 1315 moles, 1.2 equiv), followed by a solution of 2 (121.8 kg, 1096
moles, 1.0 equiv) in acetonitrile (609 L, 5 L/kg). The reaction mixture was cooled to 0-5 °C and charged
with isoamylnitrite (192.6 kg, 1644 moles, 1.5 equiv) over 8 h, keeping the internal temperature below 5
°C. Note: slow addition was required to minimize exotherm and allow venting of nitrogen gas. After an
additional 30 min, reaction progress was checked by HPLC. Target relative area percent was 2/3 < 1.0%.
The reaction mixture was then charged with water 1218 L (10 L/kg), agitated for at least 30 min at 20-25
°C, followed by celite (188.8 kg, 1.55 kg/kg). After agitating for 30 min, the layers were allowed to settle
and the upper liquid layer was decanted into a new vessel. This washing/decanting of the celite residue
was repeated two more times with 1:1 CH3CN:water (2 x 731 L, 2 x 6.0 L/kg). The celite mixture was
then filtered and washed with water (243 L, 2.0 L/kg) and acetonitrile (122 L, 1.0 L/kg). Safety Note:
testing showed that if the reaction slurry was concentrated without first adding water, a strong run-
away exothermic event was possible. The combined CH3CN:water solutions were then subjected to
constant-volume distillation, adding 5481 L (45 L/kg) water, under atmospheric pressure and collected
product in aqueous distillate between 90-101 °C. Once distillation was complete, cooled to 20-25 °C and
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washed combined aqueous distillates with MTBE (3 x 1219 L, 3 x 10 L/kg). Combined product-rich
MTBE layers were then charged with Na2SO4, filtered, and washed with MTBE (50 L, 0.4 L/kg). The
combined MTBE filtrates were then sequentially washed with 1 N aqueous HCl (600 L, ~5 L/kg), water
(600 L, ~5 L/kg), concentrated to ~600 L (~5 L/kg) under atmospheric distillation conditions, and
quantified to determine the in-process yield of 3 (31%). The final solution was then polish filtered and
charged with 5 N HCl in IPA (136 L, 680 moles, 2.0 equiv with respect to in-process level of 3) over at
least 1 h to maintain the internal temperature between 20-25 °C. After an additional 2-3 h, the resulting
slurry was filtered, washed with MTBE (244 L, 2 L/kg) and dried under vacuum at 25-30 °C to afford
46.5 kg (99.9 LCAP, >99 wt%) of 3•HCl as a white solid in 27% yield; sublimes at 40 oC; 1H NMR (500
MHz, DMSO-d6) δ 11.88 (s, 1 H), 6.07 (s, 1 H), 3.62 (s, 3 H), 2.16 (s, 3 H); 13C NMR (125 MHz, DMSO-
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d6) δ 141.7, 123.0, 107.5, 36.5, 10.9; HRMS-ESI (m/z) calcd for C5H8N2Br [M + H]+ 174.9864, found
174.9864.
Preparation of 20•HBr. To a mixture of isopropanol (46.5 L, 2.3 L/kg), and KOH (1.2 kg, 21.9 moles,
0.05 equiv) at 20-25 °C was charged methyl hydrazine (20.2 kg, 438 moles, 1.0 equiv). Reaction mass
was then heated to 60-65 °C and visually checked to confirm all KOH had dissolved. Reaction mass was
then cooled to 5-10 °C and slowly charged with trans-methyl crotonate (4, 46.1 kg, 460 moles, 1.05 equiv)
over 2 h to maintain the internal temperature <25 °C. Note: strong exotherm observed. The reaction
mixture was then agitated at 20-25 °C for 5 h before checking for reaction conversion by HPLC. Target
relative area percent was 4/4+20+21 < 11.0%. To a second reactor was charged isopropanol (188 L, 9.3
L/kg), cooled to 0-5°C and slowly charged acetyl bromide (59.3 kg, 482 moles, 1.1 equiv) over 2 h to
maintain the internal temperature < 25 °C. Note: strong exotherm observed. After an additional 15 min,
charged seeds of 20•HBr (808 g, 0.04 kg/kg) to 1st reactor and aged for 30 min. Charged HBr/IPA solution
in 2nd reactor to 1st reactor over 2 h, maintaining the internal temperature in 1st reactor between 20‐25 °C.
Rinsed 2nd reactor with isopropanol (10 L, 0.5 L/kg) and transferred to 1st reactor. Aged resulting slurry
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at 20‐25 °C for 2 h and checked for desaturation. Target was <13 mg/mL or <1.5 wt% 20•HBr in mother
liquor. Filtered slurry, sequentially washed cake with isopropanol (162 L, 8.0 L/kg) and MTBE (2 x 162
L, 2 x 8.0 L/kg) and dried under vacuum at 40 °C until LOD <1 wt% to afford 72.6 kg (99.9 LCAP, 99.8
8
9
1
wt%) of 20•HBr as a white solid in 85% yield; mp = 150-160oC; H NMR (400 MHz, D2O) 4.15 (m, 1
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H), 3.15 (s, 3 H), 3.06 (dd, J=8.0, 16.0 Hz, 1 H), 2.63 (dd, J= 8.0, 16.0 Hz, 1 H), 1.52 (d, J= 4.0 Hz, 3 H);
13C NMR (100 MHz, D2O) δ 174.2, 65.9, 43.5, 36.0, 15.0; HRMS-ESI (m/z) calcd for C5H11ON2 [M +
H]+ 115.0866, found 115.0869.
Preparation of 5. To a mixture of 20•HBr (72.7 kg, 373 moles, 1.0 equiv) and tetraethylammonium
bromide (23.3 kg, 111 moles, 0.3 equiv) in dichloromethane (218 L, 3.0 L/kg) at 20‐25 °C was charged
triethylamine (33.6 kg, 332 moles, 0.90 equiv) over 1 h maintaining the internal temperature <35 °C. The
resulting reaction mixture was then cooled to 0‐5 °C and charged with a solution of POBr3 in
dichloromethane [prepared with 137.8 kg (481 moles, 1.3 equiv) POBr3 and 145 L (2.0 L/kg)
dichloromethane] over 0.5 h, maintaining the internal temperature <15 °C. The reaction mixture was then
warmed to 30 °C. The reaction mixture was then agitated at 30 °C for 6.5 h before checking for reaction
conversion by HPLC. Note: HPLC analysis should utilize 0.10 M Me4NOAc in MeOH as the sample
prep diluent, as inconsistent results were observed using unbuffered CH3CN or water. Target relative area
percent was 20/20+5 < 2.0%. To a separate reactor containing a 0-5 °C solution of water (1368 L, 19
L/kg) and NaOH (66.5 kg, 1663 moles, 4.5 equiv) was slowly charged the bulk reaction mixture,
maintaining the internal temperature <20 °C, followed by a dichloromethane rinse (37 L, 0.5 L/kg). The
resulting biphasic mixture was then warmed to 20‐25 °C, agitated for 0.5 h, and the aqueous layer checked
by pH. Target was 4 < pH < 5. If pH was <4, adjusted with 2 N aqueous NaOH; if pH was >5, adjusted
with 2 N aqueous H3PO4. Split layers, and washed lower product-rich organic layer sequentially with 0.1
M NaH2PO4 (364 L, 5.0 L/kg) and water (364 L, 5.0 L/kg). Isolated 590 kg of final 5/DCM solution.
Quantified wt% of DCM solution by 1H QNMR (d1 = 5 sec) using 1,2-dichloroethane as internal standard.
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For 72.7 kg scale batch, final 5/DCM solution = 97.4 LCAP, 10.9 wt% and in‐process yield = 97.6%. H
NMR (500 MHz, CDCl3) 3.16-3.07 (m, 1 H), 2.93 (dd, J= 9.4, 16.4 Hz, 1 H), 2.3 (s, 3 H), 2.62 (dd, J=
13.9, 16.1 Hz, 1 H), 1.27 (d, J= 6.3 Hz, 3 H).
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Preparation of 3•TfOH. To a 0‐5 °C solution of potassium phosphate tribasic (265.7 kg, 1252 moles,
2.0 equiv), potassium bromide (37.3 kg, 313 moles, 0.5 equiv) and water (1253 L, 2.0 L/mole 5) was
charged crude 5/DCM solution (1167 kg solution, 9.50 wt% 5 in DCM, 110.9 kg 5, 626 moles, 1.0 equiv).
Aqueous bleach (770 kg, 10.6 wt% in water, 1096 moles, 1.75 equiv) was then added over 4-5 h,
maintaining reaction mixture at 0‐5 °C. The reaction mixture was then agitated at 0-5 °C for an additional
3 h before checking lower DCM layer for reaction conversion by HPLC. Target relative area percent was
5/3 < 1.0%. The layers were split and the lower organic layer was then charged into a solution of sodium
thiosulfate (198 kg, 1252 moles, 2.0 equiv) in purified water (1253 kg , 2.0 L/mole 5), maintaining the
internal temperature between 0-5 °C. The layers were split, and the lower DCM layer was charged with
triethylamine (31.7 kg, 313 moles, 0.5 equiv) over 0.5 h, warmed to 30-35 °C, and checked for reaction
conversion by HPLC after 7 h. Target relative area percent was 23/23+3 <0.08. Note: relative response
time (rrt) 23 = 1.50 with respect to 3. Cooled reaction mixture to 0‐5 °C and charged 2 N HCl (438 L, 0.7
L/mole 5), maintaining the internal temperature between 0‐10 °C. After agitating for 0.5 h, the layers
were separated. The resulting product-rich lower organic layer was then washed with additional 2 x 2 N
HCl (2 x 438 L, 2 x 0.7 L/mole 5), followed by water (438 L, 0.7 L/mole 5), all between 0‐10 °C. Final
DCM solution was then analyzed by HPLC to quantity in-process level of 3 to determine endpoint for
concentration, and both TfOH and heptane charges. On 110.9 kg scale, total mass = 1017 kg; 91.31
LCAP; wt% = 5.74%; 58.4 kg 3; 334 moles; 53% in-process yield. Note: all remaining equivalents and
volumes based on in-process level of 3. Concentrated DCM solution to ~290 L (5 L/kg) under atmospheric
pressure. Charged dichloromethane (146 L, 2.5 L/kg) and concentrated under atmospheric pressure to
~290 L. After the concentration was complete, the reaction was sampled to ensure the water content (KF)
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was <200 ppm. If KF >200 ppm, charged additional dichloromethane and concentrated to ~290 L. Cooled
solution to 20‐25 °C and charged triflic acid (15.0 kg, 99.9 moles, 0.3 equiv), followed by 3•TfOH seeds
(1.1 kg, 1.9 wt%). After aging for 0.5 h, the remaining triflic acid (35.0 kg, 233 moles, 0.7 equiv) was
charged over 3-4 h. After an additional 0.5.h, heptane (99 L, 1.7 L/kg) was charged over 1-1.5 h, and after
2 h, the slurry was checked for desaturation. Target was <2.0 wt% 3•TfOH in mother liquor. If wt% was
>2.0%, aged longer and resampled. Filtered slurry and washed reactor/cake with 30 volume % heptane
in dichloromethane (117 L, 2 L/kg). Washed wet cake directly with 30 volume % heptane in
dichloromethane (175 L, 3 L/kg) and then heptane (175 L, 3 L/kg), and dried under vacuum at 30 °C until
loss-on-drying (LOD) <1 wt%. Isolated 93.2 kg (99.8 LCAP, 100 wt%, 46% yield) of 3•TfOH as an off-
white solid; mp = 145oC; 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1 H), 6.06 (s, 1 H), 3.62 (s, 3 H),
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2.16 (s, 3 H); 13C NMR (100 MHz, DMSO-d6) δ 141.9, 123.2, 121.2 (q, J = 320 Hz), 107.6, 36.5, 10.9;
HRMS-ESI (m/z) calcd for C5H8N2Br [M + H]+ 174.9864, found 174.9865.
Acknowledgment
We thank Dr. Antonio Ramirez for assistance with pKa modeling, Shella Tameze for conducting the
Moisture Sorption Analysis, Dan Roberts for collecting pXRD data, Michael Peddicord and Jon Marshall
for collecting high resolution mass spectra of all new compounds and NMR data for 22, Dr. Michael
Schmidt for editorial comments, and the Chemical & Synthetic Development senior management for
support during the preparation of the manuscript.
Current address for C.E.M. Princeton University School of Engineering and Applied Science, Engineering
Quadrangle, 41 Olden St. Princeton, NJ 08540
Current address for M.L. Arrowhead Pharmaceuticals, 502 South Rosa Road Madison, WI 53719
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The authors declare no competing financial interest
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Supporting Information Available
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Further screening results for the bromination and oxidation sequence, characterization data for dimer 23,
1
experimental details for the preparation of CD3 derivative 30, and H/13C NMR data for all compounds
can be found in the Supporting Information. This information is available free of charge via the Internet
at http://pubs.acs.org/.
References and Notes
1 (a) Lamberth, C. Heterocycles 2007, 71, 1467. (b) Kramer, W.; Schirmer, U.; Jeschke, P.; Witschel, M.
Modern Crop Protection Compounds; Wiley-VCH: Weinham, 2012. (c) Rouse, M.; Seefeld, M. A. WO
2010093885, 2010. (d) Le-Brun, A.; Thompson, F.; Tiraboschi, G.; Salvino, J. M.; Maillet, P. US
20050130989, 2005.
2 Zhang, J.; Didierlaurent, S.; Fortin, M.; Lefrancois, D.; Uridat, E.; Vevert, J.P. Bioorganic & Med. Chem.
Lett. 2000, 10, 2575.
3 For examples using pyridine N-oxides, see Wengryniuk, S. E.; Weickgenannt, A.; Reiher, C.;
Strotman, N. A.; Chen, K.; Eastgate, M. D.; Baran, P. S. Org. Lett. 2013, 15, 792.
4 (a) Janin, Y. L. Chem. Rev. 2012, 117, 3924. (b) Bourrain, S.; Ridgill, M.; Collins, I. Synlett 2004, 5,
795.
5 Andreeva, M. A.; Bolotov, M. I.; Isaev, Sh. G.; Mushii, R. Y.; Perevalov, V. P.; Seraya, V. I.;
Stepanov, B. I. Zhurnal Obshchei Khimii 1980, 50, 2116.
6 (a) Herrmann, W. A.; Kratzer, R. M.; Ding, H.; Thiel, W. R.; Glas, H. J. Organometallic Chem. 1998,
555, 293. (b) Adolfsson, H.; Converso, A.; Sharpless, K. B. Tet. Lett. 1999, 40, 3991.
7 Attaryan, O. S.; Akopyan, G. A.; Badalyan, K. S.; Asratyan, G. V. Russian Journal of General
Chemistry 2007, 77, 307.
8
For the synthesis of N-methyl-3-iodo-5-methyl pyrazole, see Fitzgerald, M. A.; Soltani, O.; Wei, C.;
Skliar, D.; Zheng, B.; Li, J.; Albrecht, J.; Schmidt, M.; Mahoney, M.; Fox, R. J.; Tran, K.; Zhu, K.;
Eastgate, M. D. J. Org. Chem. 2015, 80, 6001.
9 (a) Ege, G.; Franz, H. J. Heterocycl. Chem. 1982, 19, 1267. (b) Ege, G.; Franz, H. J. Heterocycl. Chem.
1984, 21, 689.
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Complete removal of DCM was important as it can cause reaction stalling in the subsequent step.
Isolated oil can also be dissolved in 1 L/kg toluene for use in subsequent cyclization.
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11 As 2 was observed to slowly react with DCM, we also investigated extractions with CH3CN. However,
high salt loads were required to achieve phase splits, and only 40% of 2 was extracted.
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12 While use of Cu(I)Br was critical, specific source of Cu(I)Br did not appear to impact reaction.
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13 Without removing copper salts, concentrated reaction mass showed onset of major exotherm at 65-70
oC (ΔTad >300 oC) with an estimated ADT 24 and ADT 8 of 28 oC and 38 oC, respectively.
14 Scale-up attempts that excluded the celite filtration resulted in binding of the agitator and higher losses
at the completion of the steam distillation.
15
Needed to run at atmospheric pressure. Much poorer recovery of 3 at lower pressures. While the
acetonitrile/water distillation resulted in high concentrations of 3 in the distillate (on the order of 35
mg/mL), other solvent systems yielded similar outcomes. For example, both MTBE/water and a
mesitylene system have been shown to distill the product.
16 For additional examples of HCl salt stability challenges, see Handbook of Pharmaceutical Salts:
Properties Selection and Use; Stahl, P. H.; Vermuth, C. G., Eds.; Wiley-VCH: Zurich; 2008.
17 pKa calculations were performed using a first-principles approach at the B3LYP/6-31G+(d) level of
theory incorporating PCM corrections for water as the solvent. The pyrazoliyum-pyrazole acid-base pair
was used as the experimental reference system. For leading references see: Ding, F.; Smith, J. M.; Wang,
H. J. Org. Chem. 2009, 74, 2679.
18 Elguero, J.; Gonzalez, E.; Jacquier, R. Bull. Soc. Chim. Fr. 1968, 5009.
19
All calculations were executed using Gaussian 09, Revision B.01: Frisch, M. J.; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng,
G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.;
Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.;
Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega,
N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts,
R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels,
A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian, Inc., Wallingford CT,
2010.
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(a) Foti, F.; Grassi, G.; Risitano, F. Tetrahedron Lett. 1999, 40, 2605. (b) Lahm, G. P.; Selby, T. P.;
Stevenson, T. M. WO 2003015519, 2003. (c) Berger, R. A.; Flexner, J. L. WO 2003024222, 2003. (d)
Badiger, S.; Behnke, D.; Betschart, C.; Chaudhari, V.; Chebrolu, M.; Costesta, S.; Hintermann, S.; Pandit,
C. WO 2011076744, 2011. (e) Yang, Q.; Lorsbach, B.; Roth, G.; Niyaz, N. M.; Nissen, J.; Ross, R. Jr.;
Whiteker, G.; Deamicis, C.; Gray, K.; Zhang, Y. WO 2015058028, 2015.
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For the asymmetric preparation of 20, see Sibi, M. P.; Soeta, Takahiro. J. Am. Chem. Soc. 2007, 129,
4522.
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(a) Pawelczyk, A.; Zaprutko, L. Eur. J. Med. Chem. 2006, 41, 586-591. (b) Pawelczyk, A.; Zaprutko,
L. Eur. J. Med. Chem. 2009, 44, 3032. (c) Chouhan, G.; Alper, H. J. Org. Chem. 2009, 74, 6181. (d) Aoki,
S.; Kawasaki-Takasuka, T.; Yamazaki, T. Tetrahedron 2011, 67, 4845.
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23 The root cause for the increased regioselectivity using KOH
24
See Supporting Information for screening details.
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Zheng, B.; Conlon, D. A.; Corbett, R. M.; Chau, M.; Hsieh, D.-M.; Yeboah, A.; Hsieh, D.;
Müslehiddinoğlu, J.; Gallagher, W. P.; Simon, J. N.; Burt, J. Org. Process Res. Dev. 2012, 16, 1846.
26 In analogy to reactions with POCl3, intermediates other than 22 may also be possible, see Arnott, E.
A.; Chan, L. C.; Cox, B. G.; Meyrick, B.; Phillips, A. J. Org. Chem. 2011, 76, 1653.
27 Quenching of POCl3 with water is known to be autocatalytic, and similar safety precautions should be
taken during the quenching of POBr3. See Achmatowicz, M. M.; Thiel, O. R.; Colyer, J. T.; Hu,
J.; Elipe, M. V. S.; Tomaskevitch, J.; Tedrow, J. S.; Larsen, R. D. Org. Process Res. Dev. 2010, 14, 1490.
28
Solubilites of NaH2PO4 and KH2PO4 in water = 86.9 g/100 mL and 22.6 g/100 mL, respectively. See
http://en.wikipedia.org/wiki/Solubility_table
29
Avoiding the use of VO(acac)2 also prevented the need to control and quantitate vanadium levels, a
Class 2A elemental metal.
30 Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem. 1987, 52, 2559.
31 For references describing the pH dependent decomposition of hypohalites (HOX) to mixtures containing
X2, see (a) Chapin, R. M. J. Am. Chem. Soc. 1934, 56, 2211. (b) Adam, L. C.; Fábián, I.; Susuki, K.;
Gordon, G. Inorg. Chem. 1992, 31, 3534.
32 See Supporting Information for complete analytical data.
33 For a reference describing isotope effects on acidity, see Streitwieser, A., Jr; Klein, H. S. J. Am. Chem.
Soc. 1963, 85, 2759
34 Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6984.
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