Practical and scalable process for the preparation of 4-Amino-1,3- dimethylpyrazole hydrochloride

Article abstract of DOI:10.1021/op900296p

A practical and scalable process for the preparation of 4-amino-1,3-dimethylpyrazole hydrochloride 1 is described. Compound 1 is a useful starting material; its preparation is achieved via a three-step sequence from methyl hydrazine and technical grade acetaldehyde dimethylacetal. The target molecule is isolated in high chemical and isomeric purity (≥99.0% with respect to 4-amino-1,5-dimethylpyrazole).

Full text of DOI:10.1021/op900296p

Organic Process Research & Development 2010, 14, 242–243
Practical and Scalable Process for the Preparation of 4-Amino-1,3-dimethylpyrazole
Hydrochloride
Stephen R. Graham,*,† Peter J. Brown,† and J. Gair Ford*,‡
SAFC Pharma, Synergy House, Manchester Science Park, Manchester, U.K. M15 6SY, and Process R&D, AstraZeneca, Silk
Road Business Park, Charter Way, Macclesfield, U.K. SK10 2NA
Abstract:
A practical and scalable process for the preparation of
4-amino-1,3-dimethylpyrazole hydrochloride 1 is described.
Compound 1 is a useful starting material; its preparation is
achieved Wia a three-step sequence from methyl hydrazine
and technical grade acetaldehyde dimethylacetal. The target
molecule is isolated in high chemical and isomeric purity
(>99.0% with respect to 4-amino-1,5-dimethylpyrazole).
Figure 1. 4-Amino-1,3-dimethylpyrazole hydrochloride, 1, and
regioisomer 4-amino-1,5-dimethylpyrazole, 1a.
Introduction
The ability to rapidly prepare multikilogram quantities of
starting material, 4-amino-1,3-dimethylpyrazole hydrochloride,
1, would be advantageous. In order to achieve this, we have
developed a safe, robust and scalable synthesis. While the
material is commercially available, it is expensive, available in
only gram quantities, and although processes have been
reported, none are convenient to carry out on a large scale.
Herein we report development of a robust, practical and scalable
process for the preparation of 1.
Figure 2. Selective alkylation approach to 4-amino-1,3-dim-
ethylpyrazole.
Adopting the AADMA approach towards preparation of 1,
we successfully generated a mixture of 1,3- and 1,5-dimeth-
ylpyrazole, 2 and 2a, largely free of byproduct. The ratio of
1,3- to 1,5- regioisomers was 2.5:1 (1H NMR analysis).3 Having
isolated the crude reaction mixture and demonstrated through
user trial that the crude mixture of isomers did not lead to
isolation of 1 in the required isomeric purity, we turned our
attention toward purification strategies. The reported boiling
points4 of 1,3-dimethylpyrazole and 1,5-dimethylpyrazole in-
dicated that fractional distillation of the desired isomer might
be possible. Although enrichment of the desired regioisomer
was observed, isolation of isomerically pure material was not
possible in our hands by distillation alone. Nevertheless,
distillation of the crude reaction mixture under reduced pressure
(50-60 °C @ 45 mmHg) allowed efficient separation of a
mixture of 1,3- and 1,5-dimethylpyrazoles, free from residual
starting materials and water. The ratio of this purified pyrazole
fraction (1,3- to 1,5-) was found to be 2.8:1.0. Subsequent
distillation of the purified mixture of pyrazoles at ambient
pressure (138-143 °C @ 760 mmHg), through a packed bed
allowed significant enrichment of the mixture to an isomeric
purity level of >95% (1H NMR analysis). Processing of the
enriched isomeric mixture through user trial of the subsequent
nitration step gave rise to crystalline material which afforded
the possibility of further regioisomeric upgrade Via recrystal-
lisation (4:1, methyl tert-butyl ether/heptanes) to >99.0%.
Further investigations revealed that isomeric purity of the
pyrazole mixture must be >85% to allow isolation of >99.0%
(GC analysis) isomerically pure nitro compound, 3. During
development of a nitration procedure suitable for preparation
Results and Discussion
Initial attempts toward preparation of 1 were based on
methylation1 of the commercially available 3-methylpyrazole
(Figure 2). Although the desired regioisomer was formed, the
synthesis was unsuitable for the following reasons: (1) Reactions
failed to go to completion; (2) large proportions of regioisomer
were produced; (3) several byproduct were generated over the
course of the reaction.
Given the lack of success encountered using this route, we
turned our attention to methodology that would construct the
pyrazole ring. Previous reports2 indicated that reaction of methyl
hydrazine and acetylacetaldehyde dimethylacetal (AADMA)
gives a mixture of regioisomers. However, isolation of the
required 1,3 isomer was achieved Via crystallisation of the
picrate salt. Due to the inherent stability issues surrounding
picrates, an alternative mode of purification was necessary.
* Authors for correspondence. E-mail: stephen.graham@sial.com;
peter.brown@sial.com; gair.ford@astrazeneca.com.
† SAFC Pharma.
‡ AstraZeneca.
(1) Plate, R.; Plaum, M. J. M.; de Boer, T.; Andrews, J. S.; Rae, D. R.;
Gibson, S. Bioorg. Med. Chem. 1996, 4, 227. (a) Padwa, A.; Filip-
kowski, M. A.; Kline, D. N.; Murphree, S. S.; Yeske, P. E. J. Org.
Chem. 1993, 58, 2061. Yang, J.; Gharagozloo, P.; Yao, J.; Ilyin, V. I.;
Carter, R. B.; Nguyen, P.; Robledo, S.; Woodward, R. M.; Hogenkamp,
D. J. J. Med. Chem. 2004, 47, 1547. (c) Papesch, V.; Dodson, R. M. J.
Org. Chem. 1965, 30, 199.
(2) Burness, D. M. J. Org. Chem. 1956, 21, 97. Elguero, J.; Jacquier, R.;
Tarrago, G.; Tien Duc, H. C. N. Bull. Soc. Chim. Fr. 1965, 293.
(3) Holzer, W. Tetrahedron 1991, 47, 1393.
(4) Butler, A. J. Org. Chem. 1972, 37, 215.
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Vol. 14, No. 1, 2010 / Organic Process Research & Development
10.1021/op900296p  2010 American Chemical Society
Published on Web 12/28/2009

Scheme 1. AADMA approach towards dimethylpyrazoles 2
and 2a
Scheme 2. Preparation of 1 from 1,3-dimethylpyrazole 2
of 3, thermal hazard evaluation was performed and indicated
that a feed-controlled reaction could be safely carried out below
70 °C, with no evidence of accumulation. In the subsequent
reduction of 3 by heterogeneous catalysis it was found
convenient to have hydrochloric acid in the reaction mixture
to allow in situ formation of 1. All attempts to isolate the free
base of 1 were unsuccessful.
added dropwise to a mixture of nitric acid (190 mL, 4.50 mol)
and sulfuric acid (190 mL, 3.55 mol), maintaining the temper-
ature between 50-60 °C. The reaction mixture was stirred at
60 °C for 1.5 h. The mixture was cooled to room temperature
and quenched into water (1.9 L). The aqueous mixture was
basified (pH 14) by addition of potassium hydroxide solution
(40%, 2.0 kg). The aqueous mixture was extracted with methyl
tert-butyl ether (3 × 1 L). The combined organics were dried
(MgSO4), filtered, partially concentrated until a thick slurry was
observed. The resultant mixture was diluted with heptanes
(1 L) and partially concentrated again. The slurry was filtered
to give the crude product as a white solid (240 g). The crude
material was recrystallised from methyl tert-butyl ether/heptanes
(5 vol, 4:1) to give 3 (158.2 g, 69%, LC purity 99.8% a/a).
The mother liquors were reprocessed Via concentration and
solvent switched to heptanes, and the solids were recrystallised
from methyl tert-butyl ether/heptanes (5 vol, 4:1) to give a
second crop of 3 (40.7 g, 15%, LC purity 99.6% a/a).
Conclusion
An efficient, practical and scaleable process for the controlled
production of 4-amino-1,3-dimethylpyrazole bis-hydrochloride,
1, has been demonstrated. By adopting a procedurally simple
distillation/crystallization sequence the use of picrate salts is
avoided. The described process allows the target molecule to
be isolated in high chemical purity and isomeric purity. The
route has proven itself reliable and convenient for the prepara-
tion of multimolar quantities of 1. We acknowledge that scale-
up to significantly larger quantities would require further
optimization.
4-Amino-1,3-dimethylpyrazole Hydrochloride (1). A mix-
ture of 3 (76.7 g, 540 mmol), Pd/C (7.7 g, 10% loading,
50% wet) and hydrochloric acid (100 mL, 37%) in methanol
(760 mL) was stirred under hydrogen (120 psi) at 50 °C. After
3 days a process test (NMR) showed a 4:1 mixture of product:
intermediate. A further portion of Pd/C (3.8 g) was charged to
the vessel and the mixture stirred overnight under hydrogen
(120 psi) at 50 °C. After a further 24 h, analysis (NMR) showed
no intermediate. The mixture was filtered (Whatman GF/F) and
the solvent switched for industrial methylated spirit (3 × 500
mL) (some precipitation occurred). The resultant mixture was
solvent switched to isopropyl acetate (3 × 500 mL), and the
solids were isolated by filtration and dried to constant weight
in Vacuo to give 1 (88.5 g, 88%, NMR purity 98% w/w).
Experimental Section
General. All reagents and solvents were used directly as
purchased from commercial suppliers. All reactions were
conducted under nitrogen unless otherwise stated. NMR spectra
were obtained on a Bruker Avance-400 spectrometer.
1,3-Dimethylpyrazole (2). Methyl hydrazine (497.4 g, 10.79
mol) was added to acetylacetaldehyde dimethylacetal (AAD-
MA) (1425.0 g, 10.78 mol) at 90 °C over 1 h (an exotherm to
106 °C was observed). The mixture was stirred at 90 °C for
1.5 h. The reaction mixture was cooled to room temperature.
The resultant solution of crude hydrazone was added to 3 N
hydrochloric acid (2.87 L) at 68 °C over 30 min (an exotherm
to 96 °C was observed). The resulting solution was stirred at
70 °C for 1 h. The mixture was cooled to 30 °C and basified
(pH 14) by addition of sodium hydroxide solution (1070 g, 50%
aq.) The mixture was extracted with methyl tert-butyl ether (3
× 1.5 L), and the combined extracts were dried (MgSO4). The
mixture was filtered and the solvent removed under reduced
pressure to give the crude mixture of pyrazoles (crude mass
1241 g).
Acknowledgment
We thank the Hazards Evaluation Laboratory at SAFC
Pharma, Gillingham for providing calorimetric data. We also
thank Graham Robinson, Anne O’Kearney-McMullan and
Lorraine Graham for their suggestions and expertise throughout
the project.
Distillations. The crude mixture of dimethylpyrazoles was
distilled under reduced pressure (50-60 °C, @ 45 mmHg),
typical wt/wt (with respect to crude mass of 2) recovery for
distillations was in the region of 60%. The mixture from reduced
pressure distillation was redistilled through a packed column
(Fenske helices) (bp 138-143 °C @ 760 mmHg) to furnish
1,3-dimethylpyrazole 2. Typical overall yield of 2 was in the
region of 40%.
Supporting Information Available
1H NMR spectra for all stages, GC data for stage 1, HPLC
data for stages 2 and 3, hazard evaluation data and distillation
data for compound 2. This material is available free of charge
via the Internet at http://pubs.acs.org.
Received for review November 11, 2009.
OP900296P
1,3-Dimethyl-4-nitropyrazole (3). A solution of 2 (190 g,
2.0 mol) in concentrated sulfuric acid (190 mL, 3.55 mol) was
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