An improved method for synthesis of 4,4-dimethylpyrazolone and application to dihydropyridazinone ring formation

Article abstract of DOI:10.1248/cpb.60.267

An improved method for 4,4-dimethylpyrazolone synthesis with t-butylcarbazate was described. The applicability of this method to dihydropyridazinone formation was demonstrated. This method is useful for suppressing the side reaction caused by the high nuc

Full text of DOI:10.1248/cpb.60.267

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February 2012
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Chem. Pharm. Bull. 60(2) 267 269 (2012)
267
An Improved Method for Synthesis of 4,4-Dimethylpyrazolone and
Application to Dihydropyridazinone Ring Formation
Koji Ochiai, Akihiko Kojima, and Yasushi Kohno*
Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd.; 2399–1 Nogi, Nogi-machi, Shimotsuga-gun,
Tochigi 329–0114, Japan.
Received October 6, 2011; accepted November 24, 2011; published online November 29, 2011
An improved method for 4,4-dimethylpyrazolone synthesis with t-butylcarbazate was described. The
applicability of this method to dihydropyridazinone formation was demonstrated. This method is useful for
suppressing the side reaction caused by the high nucleophilicity of hydrazine.
Key words 4,4-dimethylpyrazolone; t-butylcarbazate; dihydropyridazinone
We have been searching for dual phosphodiesterase (PDE) ply the other method. Kobayashi et al. reported that Sc(OTf)3
3/4 inhibitors and found that dihydropyridazinone derivative catalyzed a Mannich-type reaction of acylhydrazones with si-
3a has unique biological activity.1,2) On the other hand, pyr- lyl enolates followed by cyclization to give pyrazolone deriva-
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9)
azolone is also known as an attractive structure in medicinal tives in an excellent yield.7 We utilized Kobayashi s method
chemistry.3,4) We therefore attempted to synthesize 4,4-dimeth- for the synthesis of 5 (Chart 2). Contrary to our expectation,
ylpyrazolone derivative 5, in which a 4,4-dimethylpyrazolone 4,4-dimethylpyrazolone precursor 9 was obtained in a low
ring was introduced instead of a dihydropyridazinone ring.5) yield even if excess amounts of 8 or Sc(OTf)3 were employed,
However, 5 was obtained in an insufficient yield under the the reaction temperature was increased, or the solvent was
same conditions as for dihydropyridazinone ring formation, changed.
’
’
Application of Kobayashi s method to the synthesis of our
because a nucleophilic attack of hydrazine to the 7-position of
pyrazolo[1,5-a]pyridine occurred, generating mainly undesired target compound was a failure, however, it was found that
byproduct 5′ (Chart 1). In the case of dihydropyridazinone benzoylhydrazone 7 was obtained without the occurrence
ring formation, no such side reaction was observed, even in of a nucleophilic attack of BzNHNH2 to the 7-position of
the synthesis of dimethyldihydropyridazinone derivative 3b. pyrazolo[1,5-a]pyridine. This shows that some acylhydra-
The difference in yield between 3a and b can be explained zines might have a potential to attack a ketone selectively.
by steric hindrance at the α-position of a ketone. But we can- Based on this finding, we carefully examined the formation
not explain why the yield of 5 is very low. Calculation of the of hydrazone, which was a pyrazolone precursor, without in-
lowest unoccupied molecular orbitals (LUMOs) of 2a,b, and 4 ducing a side reaction (Table 1). We selected t-butylcarbazate
suggested that the 7-position of pyrazolo[1,5-a]pyridine can be (BocNHNH2) as a hydrazine source because the Boc group
more reactive for a nucleophile than a ketone in 4,4-dimeth- could be easily removed under acidic conditions after di-
ylpyrazolone formation. However, in dihydropyridazinone methylpyrazolone formation. As a result, an undesired side
formation, a ketone is more reactive, even in the case of 2b.6) reaction, nucleophilic substitution at the 7-position, was sup-
Therefore, it was presumed that hydrazine attacked the 7-posi- pressed (Entry 1). However, the desired compound 10 was not
tion of pyrazolo[1,5-a]pyridine prior to a ketone.
obtained under this condition. Although the reaction tempera-
By considering the result of calculation of the LUMOs, it ture was increased by changing the solvent from EtOH to tol-
was supposed that 4,4-dimethylpyrazolone formation from 4 uene, 10 was not observed (Entry 2). Surprisingly, when 0.1eq
with hydrazine was very difficult, and we attempted to ap- of pyridinium p-toluenesulfonate (PPTS) was added under
Chart 1. Syntheses of Dihydropyridazinone and 4,4-Dimethylpyrazolone
in the General Method
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Chart 2. 4,4-Dimethylpyrazolone Formation under Kobayashi s Con-
dition
*To whom correspondence should be addressed. e-mail: yasushi.kohno@mb.kyorin-pharm.co.jp
© 2012 The Pharmaceutical Society of Japan

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Vol. 60, No. 2
Table 1. Hydrazone Formation with t-Butylcarbazate
Entry
Solvent
Additive
Yield of 10 (%)a)
Yield of 5″ (%)a)
Yield of 5 (%)a)
1
2
3c)
EtOH
None
None
PPTSd)
NRb)
NRb)
0
NRb)
NRb)
15
NRb)
NRb)
Trace
Toluene
Toluene
a) Isolated yield. b) NR=no reaction. c) Dean–Stark trap was used to remove water. d) 0.1eq of PPTS was used.
Table 2. Optimization of Reaction Conditions
Yield of
Entry
X (eq)
Solvent
Additive
5 (%)a)
1
1.1
3
Xylene
Xylene
Xylene
Xylene
EtOH
PPTS
PPTS
PTSA
PPTS
PPTS
37
46
2
3
3
41
4
5b)
10
3
51
Trace
a) Isolated yield. b) Molecular sieves 3A (powder) was added to the reaction
mixture instead of using the Dean–Stark trap.
dehydration conditions with a Dean-Stark trap, we obtained
4,4-dimethylpyrazolone 5″ in a low yield, not hydrazone 10.
In addition, we observed a trace amount of 5. Thus, since we
could produce the desired pyrazolone 5 directly from ketoester
4, the reaction conditions for the synthesis of 5 were further
optimized (Table 2).
Chart. 3. Application to Dihydropyridazinone Formation
When the solvent was changed from toluene to xylene and
the reaction temperature was increased, the yield of 5 im-
proved (Entry 1). Treatment of 4 with 3eq of BocNHNH2 gave dual PDE3/4 inhibitor project. In the case of the synthesis of
5 in 46% yield (Entry 2). The yield of 5 was not influenced by 2-trifluoromethyl-benzoxazole derivative 14, the nucleophilic
the change of the acid (p-toluenesulfonic acid (PTSA) instead attack of hydrazine to the 2-position of the benzoxazole core
of PPTS) (Entry 3). Moreover, when 10eq of BocNHNH2 was as well as dihydropyridazinone ring formation was observed
employed, the yield of 5 was slightly increased to give the under the same conditions as the synthesis of 3, and we could
best result (Entry 4). On the other hand, the use of a polar not obtain the desired 14 (Chart 3). Then, we applied the
solvent such as EtOH, which was reacted under general condi- optimized condition for 4,4-dimethylpyrazolone synthesis to
tions, was ineffective even under dehydration conditions by the formation of a dihydropyridazinone ring. As expected,
the addition of molecular sieves (Entry 5). It was presumed the desired compound 14 was obtained in a moderate yield
that the reaction between a sterically hindered ketone 4 and without an undesired side reaction. We demonstrated that the
BocNHNH2, which is less nucleophilic than hydrazine, re- optimized condition for 4,4-dimethylpyrazolone synthesis was
quired a high temperature, and that the cyclization of the applicable to dihydropyridazinone ring formation.
resultant hydrazone 10 was very fast. In addition, it seems
In conclusion, we have found an improved method for
that the Boc group is thermally removed after the construction synthesis of 4,4-dimethylpyrazolone with BocNHNH2 and
of the 4,4-dimethylpyrazolone ring. As mentioned above, we for dramatically increasing the yield of 5, from 7 to 51%. In
have found the reaction conditions for 4,4-dimethylpyrazolone addition, we demonstrated the applicability of this method to
synthesis without an undesired side reaction.
the formation of the dihydropyridazinone ring. This method
At around the same time, we faced another problem on the is useful for suppressing the side reaction caused by the high

February 2012
269
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nucleophilicity of hydrazine.
(1H, brs), 6.27 (1H, d, J=7.3Hz), 7.06 (1H, brs), 7.28 7.53
(7H, m). FAB-MS m/z: 465 (M+H+).
Preparation of 14 To a stirred solution of t-butyl malo-
Experimental
General 1H-NMR spectra were measured with a JEOL nate (1.08g, 4.99mmol) in N,N-dimethylformamide (DMF)
JNM-ECA-400 or -ECX-400 (400MHz) spectrometer. The (20mL) was added NaH (60% in oil, 150mg, 3.75mmol) at
°
chemical shifts are expressed in parts per million (δ value) 0 C. After stirring for 0.5h at room temperature, a solution
downfield from tetramethylsilane, using tetramethylsilane of 11 (684mg, 1.94mmol) in DMF (5mL) was added and
(δ=0) and/or residual solvents such as chloroform (δ=7.26) as the reaction mixture was stirred for 1h. The reaction was
an internal standard. Splitting patterns are indicated as s, sin- quenched with sat. NH4Cl aq. and the resultant mixture was
glet; d, doublet; t, triplet; q, quartet; m, multiplet; brs, broad extracted with EtOAc. The organic layer was washed with
singlet. Measurements of mass spectra were performed with H2O, brine, dried over Na2SO4, and concentrated in vacuo.
a JEOL JMS-SX102X mass spectrometer. Data for elemental The residue was purified by silica gel column chromatography
analyses are within 0.3% of the theoretical values, and were (n-hexane:EtOAc=4:1) to give diester (793mg). The resultant
determined by a Yanaco CHN-corder MT-6. The melting diester (793mg) was dissolved in CH2Cl2 (10mL) and treated
points were determined on a TOKYO INSTRUMENTS, INC., with trifluoroacetic acid (TFA) (5mL). After stirring for 0.5h
Japan, OptiMelt Automated Melting Point System and are at room temperature, the reaction mixture was concentrated
uncorrected. Unless otherwise noted, all the experiments were in vacuo. The residue was dissolved in xylene (30mL) and the
°
carried out using anhydrous solvents under an atmosphere of mixture was stirred for 2h at 150 C. t-Butylcarbazate (646mg,
argon. Throughout this study, Merck precoated TLC plates 4.89mmol) and p-toluenesulfonic acid monohydrate (310mg,
(Silica gel 60 F254, 0.25mm) were used for thin layer chro- 1.63mmol) were added, and the reaction mixture was stirred
matographic (TLC) analysis, and all of the spots were visual- for 2h under reflux conditions with a Dean–Stark trap. The
ized using UV light followed by coloring with phosphomolyb- resultant mixture was directly purified by silica gel column
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dic acid or anisaldehyde. Silica gel 60N (40 50μm, neutral; chromatography (n-hexane:EtOAc=2:3) to give 14 (285mg,
Kanto Chemical Co., Inc., Tokyo, Japan) or Chromatorex® NH 0.871mmol, 45% in 4 steps) as a white solid. 1H-NMR
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DM2035 (200 350 mesh; Fuji Silysia Chemical, Ltd., Aichi, (CDCl3) δ: 1.27 (3H, d, J=7.3Hz), 2.53 (1H, dd, J=17.1,
—
1.2Hz), 2.82 (1H, dd, J=17.1, 7.3Hz), 4.06 4.16 (1H, m), 4.09
Japan) was used for the flash column chromatography.
Preparation of 5 To a stirred solution of 4 (1.15g, (3H, s), 7.06 (1H, d, J=8.6Hz), 7.91 (1H, d, J=8.6Hz), 8.65
3.34mmol) in xylene (30.0mL) were added t-butylcarbazate (1H, s). EI-MS m/z: 327 (M+). Anal. Calcd for C14H12F3N3O:
(1.32g, 10.0mmol) and PPTS (100mg, 0.398mmol), and the C, 51.38; H, 3.70; N, 12.84. Found: C, 51.54; H, 3.65; N, 12.88.
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°
reaction mixture was stirred for 16h under reflux condi- mp 155 156 C.
tions with a Dean–Stark trap. The resultant solution was
directly purified by silica gel column chromatography (n-
Acknowledgment We are grateful to Mr. Kazuhiko Iwase
hexane:EtOAc=1:1) to give 5 (501mg, 1.54mmol, 46%) as for his many valuable suggestions and calculations of LUMOs.
1
a white solid. H-NMR (CDCl3) δ: 1.59 (6H, s), 4.24 (3H, s),
6.30 (1H, d, J=8.0Hz), 7.58 (1H, d, J=8.0Hz), 7.68 (1H, s),
8.89 (1H, brs). Anal. Calcd for C14H13F3N4O2: C, 51.54; H,
References and Notes
1) Ochiai K., Ando N., Iwase K., Kishi T., Fukuchi K., Ohinata A.,
Zushi H., Yasue T., Adams D. R., Kohno Y., Bioorg. Med. Chem.
°
4.02; N, 17.17. Found: C, 51.33; H, 4.10; N, 17.10. mp >170 C
—
Lett., 21, 5451 5456 (2011).
(decomp.).
2) Allcock R. W., Blakli H., Jiang Z., Johnston K. A., Morgan K. M.,
Preparation of 7 To a stirred solution of 6 (500mg,
2.05mmol) was added BzNHNH2 (279mg, 2.05mmol). After
stirring for 3.5h under reflux conditions, solvent was removed
under reduced pressure. The resultant solid was triturated with
diisopropyl ether, filtered, and recrystallized from MeCN to
Rosair G. M., Iwase K., Kohno Y., Adams D. R., Bioorg. Med.
—
Chem. Lett., 21, 3307 3312 (2011).
3) Edmondson S. D., Mastracchio A., He J., Chung C. C., Forrest M.
’
J., Hofsess S., MacIntyre E., Metzger J., O Connor N., Patel K.,
Tong X., Tota M. R., Van der Ploeg L.-H. T., Varnerin J. P., Fisher
M. H., Wyvratt M. J., Weber A. E., Parmee E. R., Bioorg. Med.
1
give 7 (513mg, 1.42mmol, 69%) as a white solid. H-NMR
—
(DMSO-d6) δ: 4.20 (3H, s), 6.74 (1H, d, J=8.0Hz), 7.53 7.61
—
Chem. Lett., 13, 3983 3987 (2003).
—
4) Sircar I., Morrison G. C., Burke S. E., Skeean R., Weishaar R. E., J.
(3H, m), 7.75 (1H, d, J=8.0Hz), 7.81 (1H, s), 7.94 7.95
—
Med. Chem., 30, 1724 1728 (1987).
(2H, m), 8.55 (1H, s), 12.00 (1H, s). Electron ionization-high
resolution-mass spectra (EI-HR-MS) m/z: 362.0997 (Calcd for
C17H13F3N4O2: 362.0991). Anal. Calcd for C17H13F3N4O2: C,
56.36; H, 3.62; N, 15.46. Found: C, 56.26; H, 3.71; N, 15.32.
5) Kohno Y., Ando N., Ochiai K., PCT Int. Patent WO 2008129624
(2008).
6) Initial 3D structures of compounds 2a, 2b, and 4 were generated
using a protocol of CAESAR Generate Conformations and opti-
mized using a protocol of CHARMm (version 35.1) Minimization
available within Discovery Studio software (version 2.5.5; Accelrys
Inc:2009;2009). LUMOs of equilibrium geometry of 2a, 2b, and 4
—
°
mp 273 274 C.
Preparation of 9 To a stirred solution of 7 (50.0mg,
0.138mmol) in MeCN (3mL) were added Sc(OTf)3 (6.80mg,
13.8μmol) and 8 (42.0mL, 0.207mmol) at 0 C. After stirring
°
—
’
were calculated using the HF 3 21G(*) method of SPARTAN 04
°
for 1.5h at 0 C, the reaction was quenched with sat. NaHCO3
software (version 1.0.3; Wavefunction Inc.: 2005).
aq. and the resultant mixture was extracted with CH2Cl2. The
organic layer was washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by preparative
thin-layer chromatography (n-hexane:EtOAc=1:1) to give 9
7) Okitsu O., Oyamada H., Furuta T., Kobayashi S., Heterocycles, 52,
—
1143 1162 (2000).
8) Kobayashi S., Furuta T., Sugita K., Oyamada H., Synlett, 1998,
—
1019 1021 (1998).
—
9) Oyamada H., Kobayashi S., Synlett, 1998, 249 250 (1998).
1
(9.20mg, 19.8μmol, 14%) as a white solid. H-NMR (CDCl3)
δ: 1.16 (3H, s), 1.36 (3H, s), 4.18 (3H, s), 4.75 (1H, brs), 5.52