A practical synthetic method of O -(2-(Pyrazol-1-yl)pyridin-5-yl) methylhydroxylamine as a component of modithromycin

Article abstract of DOI:10.1021/op200311q

A practical synthesis of O-(2-(pyrazol-1-yl)pyridin-5-yl) methylhydroxylamine was achieved from the inexpensive raw materials, 2-chloro-5-chloromethylpyridine, pyrazole, and acetone oxime, using common reagents such as aq NaOH and sulfuric acid.

Full text of DOI:10.1021/op200311q

Article
pubs.acs.org/OPRD
A Practical Synthetic Method of O-(2-(Pyrazol-1-yl)pyridin-5-
yl)methylhydroxylamine as a Component of Modithromycin
Sumio Shimizu,*,† Toshikazu Hakogi,‡ Naomi Umesako,§ Yutaka Yokota,† and Tatsuo Ueki†
†Chemical Development Center, CMC Development Laboratories, Shionogi & Co., Ltd., 1-3, Kuise Terajima 2-Chome, Amagasaki,
Hyogo 660-0813, Japan
ABSTRACT: A practical synthesis of O-(2-(pyrazol-1-yl)pyridin-5-yl)methylhydroxylamine was achieved from the inexpensive
raw materials, 2-chloro-5-chloromethylpyridine, pyrazole, and acetone oxime, using common reagents such as aq NaOH and
sulfuric acid.
of 6b to give acetone oxime derivative 5b in good yield. As a
result, using acetone oxime as a hydroxylamine precursor offers
the most convenient and economical route (Scheme 3).
Reaction Conditions and Procedure. After choosing the
synthetic route, we examined the reaction conditions and
procedure. The selection of reagents for scaling up is
determined by reactivity/selectivity, cost, availability, ease of
scale-up operations. We tried to develop the reaction using a
cheap and convenient reagent. Fortunately, in the presence of
aq 48% NaOH,7 chloromethylpyridine 7a readily reacted with
acetone oxime (9) in 1-methyl-2-pyrrolidinone (NMP) at room
temperature to give oxime derivative 6b in good yield.8 Next,
water was added to the reaction mixture to crystallize the oxime
derivative 6b, which was isolated by centrifugation to obtain
wet crystals of 6b without further purification.
Reactions of pyrazole anion 11 with 6b were examined under
various conditions (Table 1). Although amide solvents were
superior to toluene and other nonpolar solvents for the reaction
rate, in amide solvents pyrazole anion 11 reacted not only with
6b but also with amide solvents to give a messy reaction
mixture (entries 1−3). The pyrazole anion 11 was found to
successfully react with 6b in diethyleneglycol dimethyl ether
(diglyme) to give 5b in good yield (entry 4).
INTRODUCTION
■
The novel bicyclolide agent modithromycin (1, EP-013420,
EDP-420, S-013420)1 was discovered by Enanta Pharmaceut-
icals and semi-synthesized from erythromycin A 9-oxime (2)
and two synthetic fragments (3, 4) of the side chain (Scheme
1).2 To develop modithromycin in Japan, we needed a low-cost
and reliable synthetic method by which modithromycin could
be prepared on a large scale. We tried to find convenient
synthetic methods of 1.3 In this paper, we describe developing
the synthesis of O-(2-(pyrazol-1-yl)pyridin-5-yl)-
methylhydroxylamine (4) focusing on cost economy, process
safety, and selection of common reagents as acids and bases.3b
RESULTS AND DISCUSSION
■
Selection of Raw Material and Route. Retrosynthetic
analysis of O-substituted hydroxylamine derivative 4 shows that
2-chloro-5-chloromethylpyridine (7a) and 2-chloro-5-hydrox-
ymethylpyridine (7b) are the best starting materials for the
synthesis of hydroxylamine 4 (Scheme 2), because the synthetic
routes are convenient and inexpensive. These inexpensive
pyridines 7 are widely used as raw materials of chloronicotinyl
insecticides which represented nearly 17% of the global
insecticide market in 2006.4
Nonsubstituted pyrazole in the 1-position shows NH acidity.
The pKa value of pyrazole is ∼14 and equals that of water,9
which led us to examine the preparation of pyrazole anion 11
by 28% sodium methoxide in MeOH and aq 48% NaOH
instead of the expensive and hazardous NaH (entries 5−6). As
a result, we selected aq 48% NaOH7 for the preparation of
pyrazole sodium salt 11, although azeotropic dehydration is a
time-consuming procedure.
To a solution of pyrazole (10) in diglyme were added aq
48% NaOH and toluene, and then the mixture was distilled
under reduced pressure to remove toluene and water as an
azeotropic mixture. The azeotropic dehydration was repeated
until the distillate was clear. The obtained diglyme solution of
pyrazole salt 11 was added to the diglyme solution of 6b which
was also dehydrated by azeotropic removal of toluene and
water. Then the solvent was exchanged from toluene to
Two hydroxylamine precursors are typically used to
synthesize O-substituted hydroxylamine. One of the most
conventional precursors is N-hydroxyphthalimide derivative
5a.5 It is well-known that the phthaloyl moiety, present in 5a,
can be deprotected by hydrazines under mild conditions.5
However, this protecting group was not suitable to have in the
precursor intermediate 6a, because it might lead to an
undesirable cross-reactivity with the pyrazole anion in the
nucleophilic substitution process with the chloropyridine. Thus,
the phathalimide derivative 5a was alternatively prepared from
the hydroxymethylpyridine 7b in sequence steps that involved
the intermediate 8 with protection, deprotection, and
chlorination of the hydroxyl group. As the phthaloyl group
involves a lack of atomic economy, we examined other
precursors.
Another possible precursor is oximes,6 the most inexpensive
example being acetone oxime derivative 5b. Fortunately,
pyrazole anion 11 does not react with the oxime moiety of
6b but selectively reacts with the chloride on the pyridine ring
Received: November 1, 2011
Published: December 8, 2011
© 2011 American Chemical Society
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Scheme 1. Semi-synthesis of modithromycin
Scheme 2. Retro-synthetic analysis of O-substituted hydroxylamine 4
Scheme 3. Synthetic route of O-substituted hydroxylamine 4
diglyme. The obtained anhydrous diglyme solution of 11 and
6b was heated at 115−135 °C for 13 h to give compound 5b.
After the reaction was completed, water was added to the
reaction mixture to crystallize 5b, which was isolated by
centrifugation.
Usually acetone oximes are hydrolyzed on a laboratory scale
by hydrochloric acid,6 which generates volatile hydrogen
chloride and causes the threat of rusting if used in the plant.
To avoid rusting, nonvolatile sulfuric acid was used instead of
hydrochloric acid. Acetone oxime 5b was hydrolyzed in
aqueous sulfuric acid at reflux by removing acetone to obtain 4.
Safety Assessment of Hydroxylamine Derivatives.
Because hydroxylamine derivatives are high-energy com-
pounds,10 their handling was evaluated with respect to thermal
stability by DSC (Table 2). The decomposition energies of the
hydroxylamine derivatives greatly depend on the material of the
DSC pans (entries 5−9). Therefore, to prevent the
decomposition reaction, contamination with metal ion must
be avoided. Furthermore, it was found that hydroxylamine 4 in
aqueous sulfuric acid, the hydrolytic reaction mixture of 5b and
sulfuric acid, had considerable exothermic energy with a
considerable low onset at 160 °C (entry 7). The hydroxylamine
4 in aqueous sulfuric acid must be exposed to heat aging at
reflux for long periods of time to complete the hydrolysis of 5b.
The potential instability of the hydroxylamine 4 in aqueous
sulfuric acid was examined using an advanced reactive system
screening tool (ARSST) on a sample of the reaction mixture,
which showed that the hydroxylamine 4 in aqueous sulfuric acid
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Table 1. Preparation of pyrazole anion 11 and reaction of 11 with 6b
a
entry
base
solvents
results yields of 5b
b
1
2
3
4
5
6
55% NaH
55% NaH
55% NaH
55% NaH
toluene
DMF
slow
messy
messy
88%
b
b
b
NMP
diglyme
diglyme
diglyme
c
28% NaOMe in MeOH
75%
d
aq 48% NaOH
80%
a
b
c
Pyrazole anion 11 was reacted with chloropyridine 6b at 120 °C for 7 h. Dispersion in mineral oil. Salt 11 was prepared by distillation to remove
d
MeOH. Salt 11 was prepared by distillation to remove H2O.
Table 2. Thermal analysis study of hydroxylamine
derivatives by DSC
decomposition-
onset temp
decomposition materials of
entry
cmpds
[°C]
energy [J/g]
pan
1
2
9
>200
283
−
274
aluminum
6b
stainless
steel
3
reaction mixture of
6b with pyrazole
214
36
stainless
steel
4
5
5b
>300
241
−
454
gold
4·1/2H2SO4
stainless
steel
Figure 2. Temperature rate and pressure rate profile for 4 in aqueous
sulfuric acid determined with ARSST.
6
7
4·1/2H2SO4
4 in aq H2SO4
(Reaction
mixture of
hydrolyzed 5b)
216
160
637
229
aluminum
gold
pressure, can suppress the decomposition reaction of 4. If the
decomposition reaction occurs, boiling at the heat of the
decomposition reaction can be suppressed by raising the
pressure. Moreover, if the capacity of the condenser is enough
to cool the heat of the decomposition reaction, accidents can be
avoided.
8
9
4·CF3COOH
246
179
168
stainless
steel
4·CF3COOH
1143
aluminum
On a laboratory scale (1 L), 5b was hydrolyzed with aqueous
sulfuric acid at reflux by removing acetone to obtain 4.11 In the
case of production in a plant, twice the appropriate amount of
ethanol was added to a two-phase mixture of 5b and aqueous
sulfuric acid to increase the affinity of the two phases. The two-
phase mixture was then distilled under reduced pressure at 70−
100 °C for 9 h, with continuous addition of water to maintain
volume of the mixture, to obtain 4.
is stable at 30−220 °C. A 5-g sample of the reaction mixture
was loaded into the ARSST 10-mL glass test cell, which was
sealed in a 350-mL vessel and pressurized with 410 psi
nitrogen. The sample was heated from 30 to 220 °C at 2 °C/
min polynomial control condition. Figure 1 and Figure 2 show
the temperature and pressure profiles from the ARSST.
The obtained hydroxylamine 4 was used to prepare the
bridge oxime of modithromycin 1, which has an E-oxime
configuration.2b Other researchers in our company found that
the highest E/Z ratio (7/1) of 1 could be achieved by using
trifluoroacetic acid for the acid-catalyzed oximation reaction.3a
Thus, a trifluoroacetic acid salt of hydroxylamine 4 became one
of the starting materials for modithromycin 1 synthesis.
CONCLUSION
■
Figure 1. Temperature and pressure profile for 4 in aqueous sulfuric
acid determined with ARSST.
We have developed a convenient, economical, and safe
synthetic method of 4 starting from the inexpensive compound
7a and using common and operator-friendly reagents (aq 48%
NaOH and sulfuric acid). Use of this method led to the
successful manufacturing of hydroxylamine 4·CF3COOH by
our outsourcing companies on a 33−36 kg/lot scale.
To enhance the safety of the hydrolytic reaction of 5b, we
adopted distillation under reduced pressure for the following
three reasons. Lowering the operation temperature by reducing
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reaction with an activated carbon treatment. The yield was
EXPERIMENTAL SECTION
■
estimated at ∼92% by HPLC analysis.
General. The 1H and 13C NMR spectra were measured on a
Varian Gemini 300 MHz FT NMR spectrometer and/or Varian
Inova 500 MHz FT NMR spectrometer. The FT-IR spectra
were recorded on a Bruker Vertex 70 spectrometer. Mp was
1
5b: mp 60.8−60.9 °C. H NMR (300 MHz, CDCl3) δ 1.87
(3H, s), 1.88 (3H, s), 5.08 (2H, s), 6.46 (1H, dd, J = 1.5 and
2.7 Hz), 7.72−7.75 (1H, m), 7.81 (1H, dd, J = 2.3 and 8.7 Hz),
7.96 (1H, dd, J = 0.6 and 8.7 Hz), 8.38−8.42 (1H, m), 8.56
(1H, dd, J = 0.6 and 2.7 Hz). 13C NMR (75 MHz, CDCl3) δ
15.7, 21.8, 72.0, 107.5, 111.8, 126.7, 131.4, 138.5, 141.7, 147.4,
150.8, 155.5.
measured on Buchi melting point apparatus B-545. DSC
̈
measurements were run on a Perkin-Elmer Pyris 1 and a
Mettler Toledo DSC 822e, and the scanning rate was 10 °C/
min, with a temperature range up to 300 °C.
O-(2-(Pyrazol-1-yl)pyridin-5-yl)methylhydroxylamine
Trifluoroacetic Acid Salt (4·CF3COOH). Under nitrogen
atmosphere, a slurry of the obtained wet 5b (35.5 kg), activated
carbon (1.7 kg), and ethyl acetate (30.7 kg) was stirred for 30
min at 20−30 °C. Then heptane (186 kg) was added, and the
slurry was stirred for 30 min. The slurry was filtered, and the
removed activated carbon was washed three times with mixed
solutions of ethyl acetate (10 kg) and heptane (62 kg). The
obtained filtrate and rinse were combined and concentrated
under reduced pressure at 30−80 °C until the ethyl acetate and
heptane content was as little as possible.
A mixture of the concentrated residue, ethanol (26 kg), water
(157 kg), and sulfuric acid (43 kg) was distilled under reduced
pressure (0.005−0.007 MPa) at 70−100 °C for 60 min.
Ethanol (26 kg) and water (22 kg) were added, and the
distillation was continued for 8 h at 70−90 °C under reduced
pressure (0.001−0.005 MPa), while adding water to maintain
the volume of the mixture.
After the reaction completing, the reaction mixture was
cooled to 60 °C, and toluene (57.2 kg) and water (66 kg) were
added and stirred at 55−65 °C. The toluene layer was
separated to remove insoluble material in the aqueous layer. To
the separated aqueous layer, toluene (85.7 kg) and 48% NaOH
(72.8 kg) were added at 15−35 °C with stirring; the mixture
was filtered with Celite (1.7 kg) and washed with toluene (5.7
kg).
Layers were separated, and the aqueous layer was extracted
with toluene (42.9 kg). The combined toluene layer was
dehydrated by distillation under reduced pressure at 40−80 °C
with addition of toluene until the distillate was clear, and the
water content of the toluene solution of 4 was 0.5% or less.
Toluene was added to adjust the weight of the solution of 4 to
170 kg.
O-(2-Chloropyridin-5-yl)methyl Acetone Oxime (6b).
Under nitrogen atmosphere, into a solution of 2-chloro-5-
chloromethylpyridine (7a) (30.0 kg, 185 mol) and acetone
oxime (9) (15.3 kg, 210 mol) in NMP (61.8 kg) and water (7.5
kg), was added aq 48% NaOH (17.1 kg, 205 mol) dropwise at
27−40 °C for 1 h with stirring. After reaction completion, the
reaction mixture was cooled to 13−17 °C. The seed crystals of
6b were added; then water (253.5 kg) was added at 13−17 °C
for 150 min with stirring. The obtained slurry was separated by
centrifugation, and the crystals of 6b were washed twice with
water (120 kg). The obtained wet crystals of 6b were used in
the next reaction without further purification. The yield was
estimated at ∼87% by HPLC analysis.
1
6b: mp 38.9−39.0 °C. H NMR (300 MHz, CDCl3) δ 1.86
(3H, s), 1.87 (3H, s), 5.03 (2H, s), 7.30 (1H, d, J = 8.1 Hz),
7.64 (1H, dd, J = 2.3 and 8.1 Hz), 8.36 (1H, d, J = 2.3 Hz). 13C
NMR (75 MHz, CDCl3) δ 15.7, 21.7, 71.6, 123.7, 132.7, 138.3,
149.0, 150.4, 155.8. IR (CHCl3) 3025, 2994, 1590, 1462, 1213,
1106, 1075, 1020 cm−1. Anal. Calcd for C9H12ClN2O: C, 54.42;
H, 5.58; Cl, 17.85; N, 14.10. Found: C, 54.06; H, 5.42; Cl,
17.46; N, 14.09.
O-(2-(Pyrazol-1-yl)pyridin-5-yl)methyl Acetone Oxime
(5b). A mixture of the wet crystals 6b (33.2 kg) and toluene
(104 kg) was distilled under reduced pressure at 40−80 °C
until 52 kg of toluene was removed by the distillation; toluene
(52 kg) was added and distilled under reduced pressure. The
above distillation was repeated until the distillate was clear. The
dehydration was verified by a Karl Fischer titration test until the
water content of toluene solution of 6b was 0.1% or less.
Under nitrogen atmosphere, a mixture of pyrazole (14.4 kg),
diethyleneglycol dimethyl ether (diglyme, 85.1 kg), 48% aq
NaOH (16.4 kg), and toluene (52 kg) was distilled under
reduced pressure at 40−80 °C. After 26 kg of distillate was
removed by the distillation, toluene (26 kg) was added and
then distilled under reduced pressure. The above distillation
was repeated until the distillate was clear and the water content
of diglyme solution of 11 was 0.2% or less.
The dehydrated toluene solution of 6b was added to the
diglyme solution of 11, the combined solution was distilled
under reduced pressure until the toluene content was 2% or
less. Diglyme was added to adjust the volume of the solution to
102 L. The obtained diglyme solution was heated with stirring
at 115−135 °C for 13 h.
After the reaction completion, the reaction mixture was
cooled at 20 °C, and water (90 kg) was added dropwise for 20
min at 20−30 °C. After the beginning of crystallization, the
slurry was stirred for 30 min at 20 °C, water (135 kg) was
added dropwise for 30 min at 20−30 °C, and then the obtained
slurry was cooled at −5 °C for 30 min. After completion of
crystallization, the slurry was separated by centrifugation, and
the obtained crystals were washed with 60 kg of water at 3−5
°C. The obtained wet crystals of 5b were used in the next
To a solution of trifluoroacetic acid (3.44 kg), 2-propanol
(2.6 kg), and toluene (11.4 kg), the obtained toluene solution
of 4 was added dropwise at 20−30 °C, and then toluene (40
kg) was added. The slurry was cooled at 0 °C for 30 min,
filtered, and washed with a solution of 2-propanol (0.3 kg) and
toluene (11 kg). The obtained wet 4·CF3COOH was dried
under reduced pressure at 25−55 °C to afford 36.1 kg of
4·CF3COOH (77.0% yield) .
4 CF3COOH: mp 112.6−112.7 °C dec. 1H NMR (300 MHz,
DMSO-d6) δ 4.99 (2H, s), 6.60 (1H, dd, J = 0.9 and 1.5 Hz),
7.85 (1H, t, J = 0.9 Hz), 7.95−8.10 (2H, m), 8.48−8.52 (1H,
m), 8.64 (1H, dd, J = 0.6 and 1.5 Hz). Anal. Calcd for
C9H10N4O·C2HF3O2: C, 43.43; H, 3.64; F, 18.73; N, 18.42.
Found: C, 43.45; H, 3.71; F, 18.69; N, 18.55. FAB-MS (NBA)
m/z 191 [M + H]+. FAB-MS (NBA + Na) m/z 213 [M + Na]+.
4 1/2 H2SO4: mp 188.6−189.2 °C dec. 1H NMR (300 MHz,
DMSO-d6) δ 4.85 (2H, s), 6.59 (1H, dd, J = 1.8 and 2.4 Hz),
7.83 (1H, dd, J = 0.6 and 1.5 Hz), 7.94 (1H, dd, J = 0.8 and 8.5
Hz), 8.00 (1H, dd, J = 2.4 and 8.5 Hz), 8.467 (1H, d, J = 1.5
Hz), 8.62 (1H, dd, J = 0.8 and 2.4 Hz). Anal. Calcd for
C9H10N4O·1/2H2SO4: C, 45.18; H, 4.63; N, 23.42; S, 6.70.
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(10) (a) Boyles, D. C.; Curran, T. T.; Parlett, R. V. IV Org. Process
Found: C, 45.09; H, 4.70; N, 23.31; S, 6.75. FAB-MS (NBA)
m/z 191 [M + H]+. FAB-MS (NBA + Na) m/z 213 [M + Na]+.
Res. Dev. 2002, 6, 230. (b) Hett, R.; Krahmer, R.; Vaulont, I.;
̈
Leschinsky, K.; Snyder, J. S.; Kleine, P. H. Org. Process Res. Dev. 2002,
́
6, 896. (c) Mendiola, J.; Rincon, J. A.; Mateos, C.; Soriano, J. F.; de
AUTHOR INFORMATION
■
Frutos, o.; Niemeier, J. K.; Davis, E. M. Org. Process Res. Dev. 2009, 13,
263.
Corresponding Author
sumio.shimizu@shionogi.co.jp
(11) The preliminary experiment using the actually used materials
was conducted prior to the scale-up as a quality test.
Present Addresses
‡Shanghai Office, Shionogi & Co., Ltd., 318A, 3F, Building A,
Far East International Plaza, No. 319, Xianxia Road, Shanghai
200051, China.
§Discovery Research Laboratories, Shionogi & Co., Ltd., 12-4,
Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan.
ACKNOWLEDGMENTS
■
We are grateful to Dr. T. Konoike, Mr. M. Hajima, Mr. H.
Nakanishi, Mr. M. Kabaki, Mr. N. Keshi, Mr. Y. Kitaura, Mr. Y.
Nishino, and Dr. Y. Araki for their helpful discussion and
support; to Dr. Y. Kan and Ms. I. Fujisaka for spectral analysis
and support; to Mr. R. Ikenishi and Ms. Y. Takagi for elemental
analysis and support.
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