The Boulton-Katritzky rearrangement of isocarboxazid

Article abstract of DOI:10.1002/jhet.163

(Chemical Equation Presented) Isocarboxazid rearranges on heating to 5-acetonyl-2-benzyl-4-hydroxy-1,2,3-triazole in DMF at 150°C, in the ionic liquid, [bmin]HSO₄^- at 100°C or as a melt at 105°C. This is the first reported example of the Boulton-Katritzky rearrangement of an acyl hydrazide.

Full text of DOI:10.1002/jhet.163

September 2009
The Boulton–Katritzky Rearrangement of Isocarboxazid
909
Susan D. Van Arnum and Henry J. Niemczyk*
API, Inc., 12 Spielman Road, Fairfield, New Jersey 07004
*E-mail: henryniemczyk@apacpharma.com
Received November 21, 2008
DOI 10.1002/jhet.163
Published online 2 September 2009 in Wiley InterScience (www.interscience.wiley.com).
Isocarboxazid rearranges on heating to 5-acetonyl-2-benzyl-4-hydroxy-1,2,3-triazole in DMF at
150ꢀC, in the ionic liquid, [bmin]HSOꢁ4 at 100ꢀC or as a melt at 105ꢀC. This is the first reported exam-
ple of the Boulton–Katritzky rearrangement of an acyl hydrazide.
J. Heterocyclic Chem., 46, 909 (2009).
INTRODUCTION
way by which pyrazole 6 was formed, some interesting
results on the thermolysis of isocarboxazid (1) were
obtained. We wish to report on these findings.
Control of process impurity formation is a critical as-
pect of pharmaceutical process research and develop-
ment. Current guidelines by the ICH (International
Committee on Harmonization) state that known impur-
ities in the drug substance are acceptable at levels of
0.2%. Satisfactory levels of unknown impurities are
0.1% [1]. The melding of a mechanistic knowledge of
impurity pathways coupled with solid process develop-
ment has led to a generalized approach for statistical
process control and control of impurity formation [2].
The necessity to characterize impurities and to synthe-
size quantities for analytical method development has
afforded new synthetic methodology [3]. When an
understanding of reactivity is required to elucidate
potential degradation pathways in the drug product, ex-
perimental and computational methods have proven to
be useful to accomplish this goal [4].
RESULTS AND DISCUSSION
Although b-ketonitriles are known to have a propen-
sity to dimerize and trimerize [10] and we are speculat-
ing about possible ways to form pyrazole 6, we envi-
sioned that a likely path for the formation of pyrazole 6
would be by loss of N-(benzylamino)isocyanate from
the acidic a nitrogen of isocarboxazid (1) followed by
isoxazole ring opening and formation of 3-oxobutaneni-
trile (4). Reaction of nitrile 4 with benzylhydrazine (3)
would afford pyrazole 6 via the intermediacy of hydra-
zone 5 (Scheme 2). Many years ago, Gardener has com-
mented on the formation of pyrazoles from isoxazole
hydrazides and has indicated that their formation can be
mitigated if the hydrazide-forming reaction is done at
room temperature or under conditions by which the
hydrazides will crystallize [11]. Alternatively, the route
for the preparation of isocarboxazid (1) might be funda-
mentally flawed and the route could involve elimination
of 3-oxobutanenitrile (4) in competition with loss of
methanol.
Isocarboxazid (1) is a monoamine oxidase inhibitor
[5] and is used in the treatment of clinical depression
[6]. The use of this compound in treatment is limited by
side effects and its incompatibility with certain foods
and the manifestation of the so-called ‘‘cheese effect’’
[7]. In the USP (United States Pharmacopoeia), the iso-
carboxazid (1) monograph requires a TLC test at a limit
of 0.5% of two impurities: methyl 5-methylisoxazole-3-
carboxylate (2) and 5-amino-1-benzyl-3-methylpyrazole
(6). The respective visualization of these substances is
done by short-wavelength ultraviolet light and by a
spray of ferric chloride and potassium ferricycanide [8].
Isocarboxazid (1) is prepared by the reaction of the is-
oxazole ester 2 with benzylhydrazine (3) (Scheme 1)
[9]. As a result of our efforts to characterize the path-
Facile isoxazole ring opening of 3-acylisoxazoles is
evident in the fact that when 3-acetyl-5-methylisoxazole
(7) is reacted with sodium methoxide, nitrile 4 is
formed. Nitrogen–oxygen bond cleavage of the isoxa-
zole ring is initiated by the elimination of a neutral mol-
ecule, methyl acetate [12]. This chemistry parallels
established behavior of isoxazole-3-yl lithium intermedi-
ates [13]. The enolate of nitrile 4 can be trapped with
C
V
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910
S. D. Van Arnum and H. J. Niemczyk
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Scheme 1. Synthesis of isocarboxazid (1).
Scheme 3. Base-catalyzed ring opening of isoxazole 7.
at 105ꢀC in a reaction vial for 2 h. For this drug sub-
stance, a validated HPLC method showed limits of
detection (LOD) of 15 lg for the triazole 9 and 7.5 lg
for the pyrazole 6 and no triazole 9 or pyrazole 6 was
detected in the crude isocarboxazid (1).
acetyl chloride and this route was used to prepare the
(E) and (Z) isomers of 3-acetoxybut-2-ene nitrile (8)
(Scheme 3) [14].
By analogy with the Boulton–Katritzky rearrangement
of monoazoles, the driving force for this reaction would
be the formation of the more aromatic triazole ring as
opposed to the isoxazole ring [17]. In general, 1,2,4-
oxadiazoles are the heterocycle involved in this rear-
rangement, although it has been observed in the case of
an isoxazole [18]. Because of the increased acidity of
the a-hydrogens of the hydrazide as opposed to an am-
ide [19], we favor that the rearrangement occurs from
the enol or imidic acid tautomer of the hydrazide. The
rate acceleration that is observed in the ionic liquid as
opposed to the nonpolar solvent toluene would support
such an assertation. Nucleophilic attack of nitrogen on
nitrogen followed by isoxazole nitrogen–oxygen bond
cleavage would afford triazole 9.
The expired Roche patent for the preparation of iso-
carboxazid (1) involves a purification of isocarboxazid
(1) by the formation of a hydrochloride salt. Free-basing
of the salt yields isocarboxazid (1) [9]. In a control
experiment, we have found that isocarboxazid (1) is
unstable in base and we would offer that pyrazole 6
originates, when isocarboxazid (1) is regenerated by
treatment of the hydrochloride with base. For our cur-
rent process, which is the result of additional develop-
ment studies, the process has been refined and does not
involve the formation of a hydrochloride salt.
Unimolecular reactions of isocarboxazid (1) are
known. As reported in the patent literature, isocarboxa-
zid (1) rearranges to 5-acetonyl-2-benzyl-4-hydroxy-1,2-
3-triazole (9) in refluxing toluene after an overnight
hold in a 64% yield. No spectral data or purity assess-
ment of the triazole 9 was reported [15]. We have
repeated this experiment and found that the reaction fol-
lows first-order kinetics with t1/2 of ꢂ29 h (Scheme 4).
A significantly better conversion is observed when the
rearrangement is conducted in DMF or in an ionic liquid
at 150ꢀC [16]. At 100ꢀC in the ionic liquid,
[bmin]HSOꢁ4 , close to the temperature of refluxing tolu-
ene, the reaction is essentially complete in 3 h as deter-
mined by HPLC analysis. Isocarboxazid (1) melts
between 103 and 107ꢀC and a 24% conversion to tria-
zole 9 was observed when isocarboxazid (1) was heated
Scheme 2. Thermal degradation of isocarboxazid (1) to nitrile 4.
Scheme 4. Thermolysis of isocarboxazid (1).
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The Boulton–Katritzky Rearrangement of Isocarboxazid
911
Scheme 5. Synthesis of isoxazole acid (10).
rangement of monoazoles, the reaction would appear to
proceed through the enol tautomer of the hydrazide.
There is increased interest in monoamine oxidase inhibi-
tors [24] and the crystal structures of monoamine oxi-
dase A [25] and monoamine oxidase B [26] as well as
the crystal structure of isocarboxazid (1) [27] have been
solved. Combinatorial routes to 3-acylisoxazoles have
been described [12,28]. The unmasking of a ketone
functionality in this pericyclic rearrangement may have
biochemical implications. The recent work of Edmonson
and others have suggested that an aldehyde group may
play a role in the inhibition of monoamine oxidase by
arylalkylhydrazine-based therapeutics [26].
3-Oxobutanenitrile (4) or any precursors are not pres-
ent in the starting ester 2 as both the isoxazole ester 2
and 5-methylisoxazole-3-carboxylic acid (10) are of
exceptional quality [9,20]. Isoxazole acid (10) was pre-
pared by the nitric acid oxidation of 2,5-hexanedione
[20]. We have found that the violent exotherm of this
oxidation [12] can be tempered when 3-acetyl-5-methyl-
isoxazole (7) is prepared in situ by a heteropoly acid-
catalyzed nitrosation with nitrous acid. When nitric acid
is added to this reaction mixture, no uncontrolled exo-
therm is observed (Scheme 5). No yield improvement
has yet been realized, however, as the heteropolyacid
may also catalyze an aldol reaction or cyclization to
2,5-dimethylfuran.
EXPERIMENTAL
Isocarboxazid (1) was a product of internal manufacture. An
authentic sample of 5-amino-1-benzyl-3-methylpyrazole hydro-
chloride (6a) was obtained form the U.S. Pharmacopoeia,
Rockville, MD [29]. The validated HPLC method consisted of
gradient elution with a variable composition of 25 mM phos-
phate buffer and acetonitrile. The flow rate was 1.0 mL per
minute. The initial conditions of the method consisted of 80%
aqueous buffer and 20% acetonitrile. This condition was main-
tained for 10 min and over a 10 min period was changed to
60% buffer and 40% acetonitrile. After a further 10 min pe-
riod, the conditions were changed to 50% aqueous buffer and
50% acetonitrile. The column temperature was maintained at
40ꢀC and the wavelength was 232 nm. The buffer was pre-
pared by dissolving 3.40 g of potassium hydrogen phosphate
in 1 L of distilled water and by adjusting the pH to 2.5 with
phosphoric acid. The column had dimensions of 250 mm ꢃ
An authentic sample of 5-amino-1-benzyl-3-methyl-
pyrazole (6) was prepared by an adaptation of the Mag-
nus b-ketonitrile process for the synthesis of 3-oxobuta-
nenitrile (4) [21]. The procedure entails the reaction of
b-ketonitrile 4 with benzylhydrazine (3), followed by
ring closure of hydrazone 5 in a mixture of ethanol and
hydrochloric acid [22]. The basis of this nitrile 4 process
involves reaction of the enolate of acetonitrile with ethyl
acetate and an inverse addition of the enolate suspension
to an acetic acid solution of benzylhydrazine (3) [21].
Magnus’ laboratory procedure involves the use of
DMSO to solubilize the enolate. However, we found
that stiff plastic tubing outfitted with standard adapters
could accomplish this transfer in much the same way as
the enolate suspension was transferred in the Magnus
plant process. Although the yield was only 25%, by-
products could be readily removed from the relatively
soluble pyrazole 6 and the pyrazole 6 was isolated as its
hydrochloride salt 6a. For comparison’s sake, chroma-
tography of the reaction mixture afforded the free base
and the 1H NMR spectrum agreed with the published
values for this compound [23].
˚
4.6 mm and contained Luna C18(2), 5 l, 100 A packing. The
column manufacturer was Phenomenex. The injection volume
was 10 lL.
The respective retention times are 19.4 min for isocarboxazid
(1), 15.9 min for the triazole 9, 10.9 min for the isoxazole ester
2, 6.9 min for the pyrazole 6, 5.6 min for the isoxazole acid 10,
and 3.5 min for 5-methylisoxazole-3-carboxylic acid hydrazide
(11). Similar retention time behavior is observed when 0.1% tri-
fluoroacetic acid (v/v) is used as the aqueous phase.
For the validated method, 20 mg of isocarboxazid (1) was
dissolved in 5.0 mL of acetonitrile in a 100 mL volumetric
flask. The diluent was 0.1% trifluoracetic acid (v/v) and the so-
lution was diluted to volume with diluent. Serial dilutions of
this solution allowed for the determination of the LOD from
six replicate injections. The LOD of the known compounds
was determined in a similar manner. The LOD for isocarboxa-
zid (1), triazole 9, isoxazole ester 2, pyrazole 6, isoxazole acid
10, and isoxazole hydrazide 11 was 30, 15, 15, 7.5, 15, and
15 lg, respectively.
5-Acetonyl-2-benzyl-4-hydroxy-1,2,3-triazole (9). Under a
nitrogen purge, isocarboxazid (1) (50.00 g) and 150 mL of anhy-
drous DMF were combined and heated to 150ꢀC. When first at
temperature, HPLC analysis showed the reaction to be 85%
complete. After 2 h at 150ꢀC, the conversion was essentially
100% and the triazole 9 was the only component present by
HPLC. The reaction mixture was cooled and was added to 2.5 L
of distilled water. Gummy material, which was associated with a
In conclusion, our requirement to control the forma-
tion of pyrazole 6 led to a more detailed investigation
of the thermal rearrangement of isocarboxazid (1) to tri-
azole 9. By analogy with the Boulton–Katritzky rear-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

912
S. D. Van Arnum and H. J. Niemczyk
Vol 46
white solid formed and the solution was decanted. The solid was
washed with water. The solid was dissolved in 500 mL of iso-
propanol (IPA) and the IPA was evaporated to a minimum vol-
ume and was filtered. There was obtained 13.86 g of the triazole
9 as a pale yellow solid in a 27.4% yield and the solid was 100%
pure by HPLC analysis. The crude solid was recrystallized from
a 10:1 mixture of cyclohexane and IPA. Pure triazole 9 as a
white solid was obtained in a 90.2% yield. The triazole 9 had
melting point 95–96ꢀC; IR (potassium bromide): 3033–2983 (br,
OH), 1717 (C¼¼O), 1226, 1180 cmꢁ1; 1H NMR (deuteriochloro-
form) d 2.29 (s, 3H, CH3), 3.85 (s, 2H, CH2), 5.32 (s, 2H, CH2),
7.27–7.36 (m, 5H aromatic), 9.24 (b, 1H, OH); ms: m/z 232 (M
droxide was added to a separate 3 L flask. Glacial acetic acid
(225 mL) was added. The pH of the solution was 5 by paper
and the suspension was cooled to 30ꢀC. Under vacuum, the
enolate suspension was transferred to the flask containing ben-
zylhydrazine (3) with 1.0 cm (outer diameter) stiff plastic tub-
ing, which had fitted into two standard 29/42 tubing adapters.
The addition time was <5 min and the temperature was main-
tained at <30ꢀC. The vessel was rinsed with 150 mL of THF.
The suspension was stirred at room temperature for 22.5 h.
The solvent was removed under 10 mm of vacuum and a
temperature of <45ꢀC. Ethanol (500 mL) was added and this
was followed by the addition of 120 mL of concentrated hy-
drochloric acid. The reaction mixture was refluxed for 24 h
[22]. The reaction mixture was cooled and sodium carbonate
was added. The pH of the solution was 5 to wet paper. The
batch was filtered and washed with ethanol (2 ꢃ 300 mL).
The filtrate was evaporated at 40–45ꢀC under vacuum. After
500 mL of ethanol was removed, a white solid formed. The
suspension was filtered and washed with ethanol. The concen-
tration and filtration was repeated twice. To the residue was
added 550 mL of isopropanol. The slurry was cooled, filtered,
and washed with 2 ꢃ 50 mL of IPA. Concentrated hydrochlor-
ide acid (25 mL) was added. The slurry was cooled in an ice-
bath, filtered, and dried. There was obtained in two crops,
16.16 g of 5-amino-1-benzy-3-methylpyrazole hydrochloride
(6a) as a white solid in a 25.3% yield. Pyrazole hydrochloride
6a had mp 221–223ꢀC and the purity by HPLC was 100%.The
melting point of the USP reference standard was 223–227ꢀC
[29].
þ
1), 175 (M þ1-CH3COCH2), 132; Anal. Calcd for
C12H13N3O2 (231.26): C, 62.33; H, 5.67; N, 18.17. Found: C,
62.44; H, 5.74; N, 18.32.
Thermolysis
of
isocarboxazid
(1)
in
[bmin]
HSOꢁ4 . Isocarboxazid (1) (21.55 g) and 67.55 g of 1-butyl-3-
methylimidazolium hydrogen sulfate were combined and
heated to 150ꢀC. At temperature, the reaction was essentially
complete as evident by HPLC analysis. The reaction was
cooled and the product was extracted with 5 ꢃ 150 mL of
MTBE. The MTBE layer was isolated by vacuum decantation
using a suction flask and the ionic liquid remained in the flask.
After evaporation, there was obtained 11.41 g of the triazole 9
as a white solid in a 52.9% yield. The ionic liquid phase was
extracted with 2 ꢃ 150 mL of ethyl acetate and 6.96 g of the
remaining 10.14 g of triazole 9 was obtained. 20% IPA in
ethyl acetate (150 mL) was used to extract the remaining
amount of triazole 9. After evaporation, 4.30 g of solid was
obtained. The total mass balance was 105% with the overage
being the ionic liquid, which was extracted when ethyl acetate
or a mixture of IPA and ethyl acetate was used. No triazole 9
was detected in the ionic liquid phase. The ionic liquid was
heated at 100ꢀC for an overnight hold to remove solvent.
The ionic liquid was used in a recycle with 20.00 g of iso-
carboxazid (1) at 100ꢀC. The reaction was monitored by
HPLC once the reaction mixture reached temperature and ev-
ery hour afterward. The reaction was 100% complete in 3 h.
Thermolysis of isocarboxaxzid (1) in toluene. Isocarboxazid
(1) (50.00 g) and 150 mL of anhydrous toluene were combined
under a nitrogen purge and the batch was heated to reflux. The
solution was monitored periodically by HPLC over a time pe-
riod of 60 h and the disappearance of isocarboxazid (1) was
ascertained by this method. At an 88% conversion to triazole
9, there was 4.6% of a polar impurity present along with
<2.0% of other components.
5-Amino-1-benzyl-3-methylpyrazole (6). Using a similar
protocol, the free base 6 was isolated in a 29% yield after
chromatography on silica gel and with an eluent consisting of
a mixture of 60% ethyl acetate and 40% heptane. Pyrazole 6
1
had mp 64–66ꢀC (lit mp 67–70.5ꢀC [23]) and H NMR (deu-
teriochloroform) d 2.14 (s, 3H), 3.46 (b, 2H), 4.92 (s, 2H),
5.40 (s, 1H), 7.15–7.36 (m, 5H, aromatic). The 1H NMR
agrees with the reported values [23]. Pyrazole 6 was freely
soluble in IPA, the recrystallization solvent for isocarboxazid
(1). The addition of hydrochloric acid causes the hydrochloride
6a to precipitate from solution. Pyrazole 6a had mp 223–
227ꢀC.
5-Methylisoxazole-3-carboxylic acid (10). 2,5-Hexanedione
(42.8 g; 0.375 mol), 0.54 g (0.05 mol %) of silicotungstic
acid, 17.9 mL (0.34 mol) of concentrated sulfuric acid, and
80 mL of water were combined and cooled to 5ꢀC. Sodium ni-
trite (65.0; 0.94 mol) was added over a 100 min period and
the temperature was maintained below 40ꢀC. Copious gas evo-
lution was observed with some nitrogen dioxide vapors. The
mixture was held overnight. The reaction mixture was filtered
and washed with ꢂ5 mL of water. The filtrate contained two
phases.
Thermolysis of neat isocarboxazid (1). 20 mg of isocarbox-
azid (1) was heated at 105ꢀC in a reaction vial for 2 h. The
extent of the rearrangement was determined by HPLC. Tria-
zole 9 was present to the extent of 24.4% by HPLC and trace
levels (<0.2%) were observed for five unknowns.
5-Amino-1-benyzl-3-methylpyrazole hydrochloride (6a). Under
a nitrogen purge, potassium tert-butoxide (87.90 g, 0.783 mol)
and 825 mL of anhydrous tetrahydrofuran were combined in a
2 L flask with a mechanical stirrer. A mixture of 69.0 mL
(62.2 g, 0.706 mol) of ethyl acetate and 45.0 mL (35.4 g,
0.862 mol) of acetonitrile was added over a 30 min period and
the temperature was maintained below 30ꢀC. The light beige
suspension was stirred for 1 h at room temperature.
The reaction mixture was heated to between 75 and 80ꢀC.
70% Nitric acid (85 mL, 1.3 mol) was added slowly over a
1 h period. The heat was shut off after the addition of 15 mL
nitric acid. The batch temperature was maintained at 100–
102ꢀC for 19.5 h. The reaction was cooled to 15ꢀC and the
product was isolated by filtration. After drying to a constant
weight, there was obtained 21.33 g of 5-methylisoxazole-3-car-
boxylic acid (10) as a white solid in a 45% yield. The purity
by HPLC was 99% (Zorbax-SC-Cyano column, eluent: 95%
25 mM phosphate buffer and 5% methanol, flow rate: 1.0 mL
Benzylhydrazine dihydrochloride (3a) (55.65 g, 0.285 mol),
150 mL of ethanol, and 75 mL of concentrated ammonium hy-
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September 2009
The Boulton–Katritzky Rearrangement of Isocarboxazid
913
per min) and the melting point was 171–173ꢀC (decomposi-
tion). A reference standard, which was prepared by the Cus-
mano method [20] and was recrystallized from acetone had a
melting point of 172–173ꢀC with decomposition.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet