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5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products308
Continuous flow synthesis avoided the side product and the yield of 2 was
improved to 91% [4].
Problem 123: Formation of a Dimer Impurity in the Development of
Delafloxacin
Delafloxacin is a 6-fluoroquinolone antibiotic with excellent antibacterial
activity against Gram-positive organisms, including both methicillin-susceptible
Staphylococcus aureus and methicillin-resistant S. aureus. It was approved by the
U.S. Food and Drug Administration in June 2017. A key step in the synthesis of dela-
floxacin is a selective chlorination on the 8-position of the functionalized quinolone
1. A new impurity up to 0.43 area% by HPLC was detected, and this new impurity is
difficult to purge during the final salt formation. The structure of the new impurity
was identified as a dimer 4 by comparison with synthetic standard [6].
Please propose a mechanism for the formation of 4.
Experimental Procedure (from Org. Process Res. Dev., 2009, 13, 54)
The dimer 4 was synthesized from 5, 6, and 7 in seven steps [6].
N
O
N
F
N
F
F
O
O
1
NCS, H
2
SO
4
EtOAc, MeOAc
17 °C
N
O
N
F
N
F
F
O
O
2
Cl
1. aq. KOH
2. AcOH
N
O
N
F
N
F
F
HO
3
Cl
N-methyl-D-
glucamine
N
O
N
F
N
F
F
HO
Delafloxacin
Cl
OH
H
HHO
OHH
OH
H
OH
N
O
N
F
N
H
F
F
4
Cl
O
OH
N
N
O
N
F
F
Cl
F
CO
2
Et
H
2
N
CO
2
H
H
2
N
HO
2
C
NH
2
H
2
N
CO
2
H
H
2
N
CO
2
−
N
+
H
2
H
2
N
CO
2
Et
N
O
N
F
N
H
F
F
4
Cl
O
OH
NN
O
N
F
F
Cl
F
OH
HN
HCl
5
N
O
CO
2
Et
N
F
F
F
Cl
6
7 steps
F
Cl
O
7
H
2
N
HO
2
C
NH
2
H
2
N
CO
2
H
5.1 Formation of Noncyclic Alkane and Derivatives 309
Compound 4. Yellow crystals. Mp 198–205 °C dec;
1
HNMR (300 MHz, DMSO-d
6
):
δ 3.28–3.45 (2H, m), 3.45–3.78 (2H, m), 3.79–3.88 (1H, m), 4.16–4.33 (3H, m),
4.61–4.75 (2H, m), 5.25 (1H, br s), 6.23–6.35 (1H, m), 6.76 (4H, s), 7.79 (1H, d, J =
13.7 Hz), 7.90 (1H, d, J = 13.8 Hz), 7.93 (2H, dd, J = 9.7, 2.4 Hz), 8.70 (1H, s), 8.71
(1H, s), 14.59 (2H, br s);
13
CNMR (75 MHz, CDCl
3
): δ 48.1 (d, J
F
= 11 Hz), 63.8, 68.4,
69.0 (d, J
F
= 5 Hz), 70.6 (d, J
F
= 6 Hz), 104.5 (d, J
F
= 6 Hz), 105.9 (d, J
F
= 7 Hz),
107.8, 108.2, 109.8 (d, J
F
= 23 Hz), 110.8 (d, J
F
= 23 Hz), 113.4 (d, J
F
= 23 Hz), 113.7
(d, J
F
= 23 Hz), 115.8 (d, J
F
= 8 Hz), 116.6 (d, J
F
= 8 Hz), 133.3 (dd, J
F
= 14, 3 Hz), 133.5
(dd, J
F
= 14, 4 Hz), 134.8, 135.9, 141.0 (d, J
F
= 12 Hz), 142.1 (d, J
F
= 12 Hz), 142.8 (dd,
J
F
= 249, 5 Hz), 143.3 (dd, J
F
= 249, 5 Hz), 145.1 (dd, J
F
= 259, 5 Hz), 145.4 (dd, J
F
=
260, 5 Hz), 145.6 (2×, d, J
F
= 15 Hz), 149.5 (d, J
F
= 248 Hz), 150.1 (2×), 150.2 (d, J
F
=
249 Hz), 164.7, 164.8, 175.8 (d, J
F
= 3 Hz), 175.9 (d, J
F
= 3 Hz); IR: (KBr) 1727, 1622,
1489, 1439 cm
−1
; ES-HRMS m/z: (M
+
+ H) calcd for C
36
H
25
Cl
2
F
6
N
8
O
8
881.1071, found
881.1090.
The Mechanism
The formation of impurity 4 may be initiated by an acid-catalyzed activation of
the azetidine ring, followed by an isobutyric ester-induced ring opening to gen-
erate species A. This reactive intermediate A could then undergo cleavage by chlo-
ride ions (Cl⁻) to form intermediate B. The chloride ions may be generated from
N-chlorosuccinimide (NCS) upon quenching the reaction with Na
2
SO
3
. Subsequently,
the chlorine in intermediate B could be displaced by the hydroxyl group of the ethyl
ester of compound 3, resulting in the formation of dimer C. Finally, hydrolysis of
dimer C by aqueous potassium hydroxide (KOH) would yield impurity 4.
N
O
CO
2
Et
N
F
N
F
F
O
O
2
Cl
N
O
N
F
F
F
O
O
Cl
H
Ar
N
OH
3, ethyl ester
Saponification
by KOH-H
2
O
4
N
O
N
F
N
H
F
FCl
O
O
NN
O
N
F
F
Cl
F
O
C
N
O
N
F
N
H
F
FCl
O
+
O
A
N
O
N
F
N
H
F
F
Cl
O
O
B
Cl
H
2
SO
4
H
2
N
CO
2
Et
H
2
N
HSO
4
–
CO
2
Et
H
2
N
CO
2
Et
CI
–
CI
–
H
2
N
EtO
2
C
H
2
N
NH
2
CO
2
Et
N
+
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products310
The mechanism for quenching NCS by Na
2
SO
3
is as follows. During this workup,
Cl
−
(NaCl) is produced.
There is another possibility for the formation of impurity 4. Species A could be
attacked by ethyl ester of 3 before the Na
2
SO
3
quenching, which would also lead to
intermediate C.
Problem 124: Formation of an Amidino-Diol Side Product
WAY-315193 (1) was identified as a progesterone receptor modulator. In a synthesis
of 1, treatment of the diol 2 by p-toluenesulfonyl chloride followed by methyl-
amine provided 1 in 34% yield. Meanwhile, a side amidino-diol product 3 was also
obtained [7].
Please suggest a mechanism for the formation of 3.
NaO
S
ONa
O
N
Cl
O
O
NaO
NaO
O
Cl
O
O
NH
O
O
NaO S
NaO
O
Cl
O
H
HCl
NaCl
+
NaHSO
3
S
+
N
–
H
2
O
HO
–
Na
2
SO
4
Na
2
SO
3
HO
–
Ar
N
OH
3, ethyl ester
Saponification
by KOH-H
2
O
4
N
O
N
F
N
H
F
FCl
O
O
NN
O
N
F
F
Cl
F
O
C
N
O
N
F
N
H
H
2
N
F
FCl
O
+
O
A
Ar
N
OH
CO
2
Et
EtO
2
C
NH
2
H
2
N
CO
2
Et
5.1 Formation of Noncyclic Alkane and Derivatives 311
Experimental Procedure (from Org. Process Res. Dev. 2009, 13, 880)
(2 S,3S)-3-((E)-7-Fluoro-3,3-dimethyl-2-(methylimino)indolin-1-yl)-
3-(3-fluorophenyl)propane-1,2-diol (3). To a solution of diol 2 (11.4 g, 32.9 mmol)
in dichloromethane (70 mL), were added Bu
2
SnO (0.164 g, 0.66 mmol, 2 mol%)
and triethylamine (13.7 mL, 98.7 mmol, 3 equiv). A solution of p-toluenesulfonyl
chloride (6.27 g, 32.9 mmol) in dichloromethane (30 mL) was added over 15 min
at 20 °C. The reaction mixture was stirred at ambient temperature for 3 h, at
which point HPLC analysis indicated 80:20 areas ratio of monotosylate : diol.
Diisopropylethylamine (5 mL, 28.7 mmol) was added, the reaction mixture was kept
at room temperature for 18 h, diluted with acetonitrile (150 mL), and stirred at 40 °C
for 7.5 h. Methylamine (41 mL of 8 M EtOH solution, 328 mmol) was added at 10 °C.
The reaction mixture was allowed to warm up to room temperature, stirred for 24 h,
and then concentrated in vacuum. Methyl tertiary-butyl ether (MTBE) (100 mL)
was added, followed by 2 N HCl (100 mL). The phases were separated. The aqueous
phase was washed with 50 mL of MTBE. The acidic aqueous phase was cooled to
10 °C. MTBE (100 mL) was added, followed by 5 N NaOH (40 mL). The precipitated
solids were filtered to afford 4.11 g of crude product. The solids were slurried in
12 mL of acetonitrile at 81 °C, cooled to room temperature, and filtered to afford
2.89 g of the title product. The remaining biphasic aqueous NaOH/MTBE system
was further processed to afford a second crop of product. The MTBE phase was
separated, the aqueous phase was extracted with 50 mL of MTBE. The combined
MTBE phase was dried over Na
2
SO
4
and concentrated to yield 2.81 g of crude
product, which was slurried in 5 mL of acetonitrile at 81 °C, cooled to room
temperature, and filtered to afford 1.608 g of the title product (38% combined
yield).
1
HNMR (400 MHz, CD
3
CN, 55 °C) δ: 7.30–7.19 (m, 3H), 6.98–6.90 (m, 2H),
6.86–6.76 (m, 2H), 5.67 (br, 1H), 4.40 (br, 1H), 3.58 (dd, J = 11, 5 Hz, 1H), 3.46–3.38
(m, 1H), 3.43 (s, 3H), 1.66 (s, 3H), 1.59 (s, 3H). For detailed 2D NMR studies, see
Supporting Information. MS (positive ESI, for M + H): m/z 361.
The Mechanism
Initially, the monotosylate A is formed. Subsequently, the carbon bearing the TsO
group is attacked by the adjacent hydroxyl group, leading to the formation of epoxide B
(
path A). This epoxide is then opened by methylamine to produce the desired product 1.
Alternatively, the carbon with the TsO group in A can undergo intramolecular attack
by the amide oxygen, generating the cationic intermediate C (path B). Methylamine
can react with C at the imidate carbon, displacing the imidate oxygen, opening the
N
NHMe
F
F
OH
O
N
OH
F
F
OH
O
N
OH
F
F
OH
N
+
2. MeNH
2
, EtOH
1 (WAY-315193)
2
3
1. TsCl, Et
3
N
Bu
2
SnO(cat)
DCM
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products312
six-membered ring, and yielding the corresponding amidino-diol 3. Additionally, the
reaction of C with water would regenerate the starting amido-diol 2.
5.1.2 Amine
Problem 125: Formation of Ketoamine During Semmler–Wolff Aromatization
Dasabuvir (ABT-133) is an antiviral medication for the treatment of hepatitis C.
Sulfonamide 1 is an intermediate for the preparation of ABT-333. In a process study
of the synthesis of 1, the Semmler–Wolff reaction was employed for the conversion
of oxime 2 to naphthylamine 3 [8]. The reaction is shown as below. Except the
desired product 3, a side product 4 was also obtained in around 14% yield.
Please provide a mechanism for the formation of 4.
Experimental Procedure (from Org. Process Res. Dev., 2014, 18, 1696)
6-Bromo-2-naphthylamine hydrochloride salt (3) and 6-bromo-1-oxo-
1,2,3,4-tetrahydronaphthalen-2-aminium chloride (4). A mixture of oxime of
6-bromo-2-tetralone 2 (97.3 kg, 405.5 mol) and 1 M HCl in glacial acetic acid (1122.0 kg,
1030.0 mol) was heated to 75 ± 5 °C. After heating at 75 ± 5 °C for 3.5 h, HPLC anal-
ysis indicated that 2 was <0.5 peak area %. The reaction mixture was cooled to 50 °C,
filtered, and washed sequentially with 220 kg of acetic acid and MTBE (700 kg).
F
F
OH
O
N
OH
F
F
OH
O
TsCl, Et
3
N
2
N
OTs
F
F
O
O
H
Path A
A
N
F
F
O
B
O
N
N
H
F
F
OH
O
1
Path B
TsO
–
N
F
F
OH
O
N
H
N
OH
F
F
OH
N
3
C
Et
3
N.HCI
Et
3
N.TsOH
Et
3
N
MeNH
2
2 MeNH
2
MeNH
2
. TsOH
H
2
N
H
2
O
N
+
H
N
S
O
O
O
N
H
NO O
Dasabuvir (ABT-133)
H
N
S
O
O
Br
1
N
Br
2
OH
1 M HCl in
HOAc (2.5 eq.)
80 °C, 2 h
Br
3 (85%)
Br
+
O
MsCl
Py
4 (14%)
NH
3
+
CI
–
NH
3
+
CI
–
5.1 Formation of Noncyclic Alkane and Derivatives 313
After being dried under vacuum at 50 °C for 5 h, 79.9 kg of the product was obtained
as off-white solids (76%). By-product ketoamine 4 (formed in ~14 mol% in the reac-
tion) partially precipitated overnight from the mother liquors as hydrochloride salt
and was filtered and washed with MTBE to provide an analytical sample for charac-
terization. HPLC (method B) retention times: 3 6.79 min, 4 2.12 min.
Analytical data for 3:
1
HNMR (400 MHz, DMSO-d
6
): δ 8.21 (d, J = 2 Hz, 1H), 7.98
(d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.65 (dd, J =
2, 8.8 Hz, 1H), 7.5 (dd, J = 2, 8.8 Hz, 1H).
13
CNMR (100 MHz, DMSO-d
6
): δ 132.0,
131.2, 130.9, 129.5, 129.2 (two peaks overlapping), 128.4, 122.0, 119.5, 118.8. Mp 281 °C
(decomp.). Anal. Calcd for C
10
H
9
BrClN (HCl salt): C, 46.46; H, 3.51; N 5.42. Found: C,
46.12; H, 3.19; N, 5.39. HRMS calcd for C
10
H
8
BrN 220.9840, obsd 220.9839.
Analytical data for 4:
1
H NMR (400 MHz, DMSO-d
6
): δ 8.77 (s, br, 3H), 7.81
(d, J = 8 Hz, 1H), 7.67 (d, J = 4, 1H), 7.60 (dd, J = 4, 12 Hz, 1H), 4.37 (d, J =
12 Hz, 1H), 3.18 (ddd, J = 4, 12, 16 Hz, 1H), 3.04 (ddd, J = 2, 4, 20 Hz, 1H), 2.52
(m, 1H), 2.16 (ddd, J = 4, 8, 26 Hz, 1H).
13
C NMR (100 MHz, DMSO-d
6
): δ 191.6,
145.8, 131.3, 129.7, 129.0, 128.3, 128.2, 54.4, 27.3, 26.8. Mp 254.4 °C. Anal. Calcd
for C
10
H
11.5
BrCl
1.5
NO (1.5 × HCl salt): C, 40.74; H, 3.93; N, 4.75; Cl, 18.04. Found:
C, 38.11; H, 3.74; N, 4.31; Cl, 18.91. HRMS calcd for C
10
H
10
BrNO 238.9946, obsd
238.9945.
The Mechanism
Under acidic condition, oxime 2 is protonated to give species 2a, which can pro-
ceed via two tautomerization pathways. Following pathway (a), tautomer 2b loses
water to give 2c, which then tautomerizes/aromatizes to provide desired product 3.
Alternatively, through pathway (b), 2a can tautomerize to 2d, which can then
undergo hydration while cleaving the N─O bond to afford 2e, which undergoes a
double tautomerization to generate side product 4.
According to this mechanism, water is added in pathway (b). Therefore, removal of
water from the reaction should have a positive impact on the formation of 3. Thus, by
adding 1.2 eq of acetic anhydride as a scavenger to remove water from the reaction,
the yield of 3 was improved to 94% and the yield of 4 was reduced to 2.4% [8].
N
Br
2
OH
Br
O
H
H
H
N
Br
H
H
H
a
b
Path a
H
Br
H
3
H
Path b
N
Br
H
H
H
Br
OH
H
Br
OH
4
2a
2b
2c
2d
2e
2f
Br
Br
O
H
2
O
H
+
O
+
N
+
O
+
H
2
N
+
H
2
O
H
2
N
+
H
3
N
+
NH
3
+
CI
–
NH
3
+
CI
–
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products314
In another report when oxime 5 was submitted to the Semmler-Wolff aro-
matization conditions (Ac
2
O, AcCl, refluxing), 4-diacetylamino-3-acetoxy-
1,2-dihydrophenanthrene 6 was obtained in 27% yield [9].
The mechanism for the formation of 6 should be as follows.
Problem 126: Formation of an Aniline Impurity by Smiles Rearrangement
In the synthesis of a novel renin inhibitor (5) for the treatment of hypertension,
one synthetic step involved the alkylation of phenol 1 with bromide 2. In addition
to the desired product 3, an impurity 4 was also identified. The percentage of 4 was
increased over the reaction time [10].
Please explain the mechanism for the formation of 4.
N
OH
5
Ac
2
O, AcCl
reflux
N
Ac
6 (27%)
OAc
Ac
N
OH
5
Cl
O
AcCl
OH
Ac
H
N
Ac
H H
O
O O
Ac
2
O
N
Ac
O O
O
O
H
HOAc
N
Ac
OAc
H
N
Ac
OAcAc
HOAc
6
Cl
–
Cl
–
H
2
O
Ac
2
O
Ac
2
O
Ac
2
O
Cl
–
N
+
O
+
O
+
Cl
HO
1
+
H
N
N
H
Br
O
O
2
t-BuONa
THF
H
N
N
H
O
O
O
3
Cl
H
N
N
H
O
4
Cl
Steps
N
O
N
O
H
N
O
NH
O
5
+
5.1 Formation of Noncyclic Alkane and Derivatives 315
Experimental Procedure (from Org. Process Res. Dev., 2019, 23, 499*)
1-(2-Chloro-5-methylphenoxy)-N-(2-propionamidoethyl)cyclobutane-1-
carboxamide (3). To a solution of tBuONa (14.2 kg, 147.3 mol, 1.2 equiv) in toluene
(523.0 kg) and 1-BuOH (187.0 kg) was added 1 (17.5 kg, 122.7 mol, 1.0 equiv) with
stirring under a nitrogen atmosphere. The mixture was stirred at 20 °C for 1 h. To
the mixture was added 2 (34.0 kg, 122.7 mol, 1.0 equiv) over 40 min and stirred at
the same temperature. The mixture was heated to 45 °C, and the reaction was mon-
itored by HPLC until completion (2.5 h). After cooling to 25 °C, water (250.0 kg)
was added with stirring for 15 min. The separated organic phase was washed with
water (84.0 kg) and concentrated to give a suspension (245.0 kg). The suspension
was heated to 45 °C and stirred at the same temperature for 30 min and then cooled
to 0 °C over 2 h. n-Heptane (84.0 kg) was added dropwise to the cooled suspension,
and the resulting suspension was stirred at the same temperature for 2.5 h. The pre-
cipitate was filtered, washed with a mixture of toluene and n-heptane twice, and
dried to give 3 (36.4 kg, 107.6 mol, 87.6% yield) as a white solid.
1
HNMR (400 MHz,
CDCl
3
) δ 7.22 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.0, 1.2 Hz, 1H), 6.59 (t, J = 5.6 Hz,
1H), 6.29 (d, J = 1.2 Hz, 1H), 5.81 (t, J = 5.6 Hz, 1H), 3.47–3.31 (m, 2H), 3. 25–3.19
(m, 2H), 2.73–2.65 (m, 2H), 2.41–2.32 (m, 2H), 2.21 (s, 3H), 2.03 (q, J = 8.0 Hz, 2H),
2.00–1.84 (m, 2H), 1.03 (t, J = 8.0 Hz, 3H);
13
CNMR (100 MHz, CDCl
3
) δ 174.2, 173.8,
150.1, 137.8, 130.2, 123.3, 120.7, 116.5, 81.9, 40.0, 39.1, 31.7 (2C), 29.4, 21.3, 13.7, 9.7;
HRMS (ESI) calcd for C
17
H
23
ClN
2
O
3
m/z 339.1470 [M + H]
+
, found 339.1471.
*The formation of the impurity 4 was discussed in the article [10]. However, the isolation and
identification of 4 was not disclosed.
The Mechanism
The formation of aniline 4 can be rationalized through a Smiles rearrangement, as
outlined below. Upon generation of the desired alkylation product 3, the amide NH
group is deprotonated by the excess base (initially, 1.2 equivalents of t-BuONa were
H
N
N
H
O
O
O
3
Cl
t-BuONa
t-BuOH
H
N
O
O
O Cl
Cl
O
N
O
NH
O
Cl
O
N
O
NH
O
H
H
N
N
H
O
4
Cl
O
O
A
B
C
Cl
N
O
NH
O
D
O
H
Na
+
H
3
+
O
H
3
+
O
Na
+
N
–
−
5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products316
added), yielding the sodium salt A. The nitrogen anion in A then acts as a nucle-
ophile, attacking the phenyl carbon adjacent to the ether linkage, resulting in the
formation of the five-membered spiro anion B. Under acidic aqueous conditions,
cleavage of the C─O bond produces the cyclobutanol amide C. This cyclobutanol
amide, activated by the acidic environment, undergoes a 1,2-alkyl migration accom-
panied by ring expansion to form the amino cyclopentanol D. Subsequent hydro-
lysis of D under acidic aqueous conditions leads to the formation of the impurity 4,
along with the co-production of cyclopentane-1,2-dione.
5.2 Formation of Cyclic Alkane and Derivatives
5.2.1 Cyclopropane
Problem 127: Formation of a Cyclopropane Impurity
GW641597X (1) was under development as a peroxisome proliferator-activated
receptor (PPAR)-α agonist for the treatment of dyslipidemia. During the synthesis of
compound 1, a series of steps were employed: deacetylation of acetate 2 using t-BuOK,
followed by alkylation of phenol 3 with chloromethyl oxadiazole 4, and finally hydro-
lysis of the ethyl ester to yield the desired product 2 in 76% yield. However, this process
also generated a cyclopropane impurity 5 in approximately 1% yield [11]. To improve
the reaction, a milder base, K
2
CO
3
, was used in ethanol, which resulted in the smooth
hydrolysis of 2 and subsequent coupling with alkyl chloride 4 was intrinsically cleaner.
Please suggest a mechanism for the formation of 5.
Experimental Procedure (from Org. Process Res. Dev., 2020, 24, 371)
2-(4-((3-(4-(tert-Butyl)phenyl)-1,2,4-oxadiazol-5-yl)-methoxy)-
2-methylphenoxy)-2-methylpropanoic Acid (1). Crude (GW641597X) via ethyl
2-(4-((3-(4-(tert-butyl)-phenyl)-1,2,4-oxadiazol-5-yl)methoxy)-2-methylphenoxy)-
2-methylpropanoic acid. Potassium carbonate (10.9 kg, 79.9 mol) was added to a
stirred solution of crude acetate 2 (ca. 25 kg) in absolute ethanol (125.0 kg), followed
OAc
O
OH
O
t-Bu
N
O
N
Cl
N
O
N
O O
1 (GW641597X) (71%)
2
3
4
K
2
CO
3
EtOH
reflux, 2 h
1.
2. NaOH, 40–45 °C, 2 h
N
O
N
N
O
N
N
O
N
5 (~1%)
Reflux, 19 h
t
-Bu
t-Bu
t-Bu
t-Bu
CO
2
H
CO
2
Et
CO
2
Et
5.2 Formation of Cyclic Alkane and Derivatives 317
by an ethanol (10.0 kg) wash, and the suspension was heated to reflux (76 °C) and
stirred at reflux for 2 h. A solution of crude alkyl chloride 4 (ca. 20.9 kg) in tetrahy-
drofuran (THF) (67.2 kg) was then added, with a 16.0 kg ethanol line wash, followed
by three “put and take” distillations with ethanol (3 × 53.9 kg) to remove THF.
The resulting solution was then stirred at reflux for ca. 19 h. The reaction mixture
was cooled to 43 °C, treated with aqueous sodium hydroxide (20.5 kg in 27.0 kg of
water), and stirred at 40–45 °C for ca. 2 h. The mixture was quenched with aqueous
hydrochloric acid (30.7 kg of concentrated hydrochloric acid in 25.6 kg of water) at
40–45 °C and cooled to 25 °C before being stirred for 2 h at that temperature. Crude
GW641597X was collected by centrifugation, washed once with ethanol (54.0 kg),
followed by twice with water (2 × 136.4 kg), and dried at 60–65 °C to give the title
compound 1 as a cream solid (22.1 kg, 71%).
2-(4-((3-(4-(tert-Butyl)phenyl)-1,2,4-oxadiazol-5-yl)-methoxy)-2-methyl-
phenoxy)-2-methylpropanoic Acid (1). Final or API Grade (GW641597X). Crude 1
(GW641597X) (22.1 kg, 52 mol) was diluted with denatured ethanol (122.2 kg), stirred,
and heated to reflux (76 °C) until dissolved. The hot solution was filtered into a sep-
arate vessel, followed by a 17.5 kg denatured ethanol wash, before being cooled to
20 °C over ca. 2 h. The slurry was stirred at ca. 18 °C for 2 h before being filtered, and
the cake was washed with 30.3 kg of denatured ethanol. The product was then dried
at 55–60 °C under vacuum and sieved through a 0.024 inch sieve screen to give API
grade 1 (GW641597X) as a white solid (18.3 kg, 81.9%).
1
HNMR (400 MHz, dimethyl
sulfoxide (DMSO)-d
6
): δ 12.95 (br s, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz,
2H), 6.94 (d, J = 3.1 Hz, 1H), 6.82 (dd, J = 8.8, 3.1 Hz, 1H), 6.73 (d, J = 8. Hz, 1H), 5.48
(s, 2H), 2.15 (s, 3H), 1.46 (s, 6H), 1.30 (s, 9H);
13
CNMR (101 MHz, DMSO-d
6
): δ 175.7,
175.3, 167.6, 154.5, 151.8, 148.4, 130.5, 126.9 (2C), 126.1 (2C), 123.1, 117.9, 117.4, 112.2,
78.7, 61.2, 34.7, 30.8 (3C), 25.0 (2C), 16.6; high-resolution mass spectrometry (HRMS)
[M + H]
+
: calcd for C
24
H
29
N
2
O
5
: 425.2076; found: 425.2057.
1,2,3-Tris(3-(4-(tert-butyl)phenyl)-1,2,4-oxadiazol-5-yl)-cyclopropane (5).
Sodium hydride (0.19 g, 4.8 mmol) was added in one portion to a stirred solution of
alkyl chloride 4 (1.0 g, 4.0 mmol) in THF (20 mL) and dimethylformamide (10 mL)
at 20 °C under nitrogen for 15.5 h. The reaction was quenched into water (150 mL),
and the off-brown precipitate was collected by filtration, washed twice with water
(20 mL), and dried. The crude product was slurried in methanol (20 mL) at 50 °C for
ca. 2 h and then filtered and washed twice with methanol (5 mL) to yield the title
compound 5 as a cream solid (0.58 g, 68%).
1
HNMR (400 MHz, CDCl
3
): δ 8.02 (d, J =
8.6 Hz, 2H), 7.90 (d, J = 8.5 Hz, 4H), 7.54 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.5 Hz, 4H),
4.16 (t, J = 5.9 Hz, 1H), 3.75 (d, J = 5.9 Hz, 2H), 1.38 (s, 9H), 1.34 (s, 18H); HRMS
[M + H]
+
: calcd for C
39
H
43
N
6
O
3
: 643.3396; found: 643.3422.
The Mechanism
The formation of 5 should be a result of trimerization of the chloromethyl oxadia-
zole 4 under the strong base conditions. In the presence of t-BuOK, the α-proton
in 4 could be trapped to form anion 4a. Then it would attack another chloromethyl
group followed by elimination of HCl to generate the alkene dimer 4b. Anion 4a
attacks the alkene and cyclizes to give 5. Indeed, treatment of 4 with NaH provided
5 in 68% yield [11]. Similar cyclopropanation was reported previously in the litera-
ture [12, 13, 14].