Rapid synthesis of tetrahydro-4H-pyrazolo[1,5-a]diazepine-2-carboxylate

Article abstract of DOI:10.1016/S0040-4039(03)01417-5

Hydrazines condense with dimethyl 2-pyrrolidino-4-oxo-2-pentenedioate in the presence of aq. HCl to form N-substituted pyrazole-3,5-dicarboxylates 2. Complex bicyclic derivatives, such as pyrazolo-oxazine 3a, pyrazolo-oxazepine 3b, pyrazolo-pyrazine 4a, and pyrazolo-diazepine 4b, were generated using 2-hydrazinoethanol, 3-hydrazinopropanol, 2-hydrazinoethylamine, and 3-hydrazinopropylamine.

Full text of DOI:10.1016/S0040-4039(03)01417-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5867–5870
Rapid synthesis of
tetrahydro-4H-pyrazolo[1,5-a]diazepine-2-carboxylateꢀ
Raymond J. Cvetovich,* Brenda Pipik, Frederick W. Hartner and Edward J. J. Grabowski
Department of Process Research, Merck Research Laboratories, Merck & Co., PO Box 2000, Rahway, NJ 07065, USA
Received 13 May 2003; revised 3 June 2003; accepted 3 June 2003
Abstract—Hydrazines condense with dimethyl 2-pyrrolidino-4-oxo-2-pentenedioate in the presence of aq. HCl to form N-substi-
tuted pyrazole-3,5-dicarboxylates 2. Complex bicyclic derivatives, such as pyrazolo-oxazine 3a, pyrazolo-oxazepine 3b, pyrazolo-
pyrazine 4a, and pyrazolo-diazepine 4b, were generated using 2-hydrazinoethanol, 3-hydrazinopropanol, 2-hydrazinoethylamine,
and 3-hydrazinopropylamine.
© 2003 Elsevier Ltd. All rights reserved.
synthesis of substituted N-substituted pyrazole dicar-
boxylates 2 or more complex bicyclic derivatives such
as pyrazolo-oxazine 3a, pyrazolo-pyrazine 3b, pyrazolo-
oxazepine 4a, or pyrazolo-diazepine 4b (see Fig. 2) was
highly desirable,2 with pyrazolo-diazepin 4b being the
prize goal as a key intermediate for the synthesis of oral
fibrinogen antagonist 1.1b
1. Introduction
The incorporation of heterocyclic rings into prospective
pharmaceutical candidates is a major tactic to gain
activity and safety advantages. Pyrazole-3,5-dicarboxyl-
ate offers linkage opportunities via the carbonyl groups
as well as the pyrazole nitrogens, and is an important
feature of oral fibrinogen antagonist 1 (see Fig. 1).1 An
alternate approach that allows an efficient and flexible
2. Results and discussion
The ease of condensation of hydrazines with b-
dicarbonyls3a and b-enaminones3b is well documented.
A study to extend this condensation to dimethyl 2,4-di-
oxo-pentanedioate, 6, for the preparation of a variety
of N-substituted-3,5-dicarboxy-pyrazoles was initiated.
The synthesis of diketone 6 has been previously
reported.4 The dimethylamino enamine of methyl pyru-
vate was prepared using stoichiometric amounts of
Figure 1. Oral fibrinogen antagonist 1.
Figure 2. Substituted pyrazole dicarboxylates.
Keywords: aminohydrazines; hydroxyhydrazines; pyrazole formation; pyrazolo-diazepine.
ꢀ Supplementary data associated with this article can be found at doi:10.1016/S0040-4039(03)01417-5
* Corresponding author. E-mail: raymond cvetovich@merck.com
–
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01417-5

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Figure 3. Synthesis of dimethyl 2,4-di-oxo-pentanedioate (6).
Table 1. Hydrazines 7 used in condensations
AsCl3, then treated with methyl oxalyl chloride and
hydrolyzed to the diketone. The replacement of AsCl3,
an environmentally unsatisfactory reagent, was
achieved with the use of more benign trimethylborate,
B(OMe)3, in tert-butyl methylether (MTBE) or methyl-
ene chloride for the formation of the pyrrolidine enam-
ine. Treatment of the reaction solution with
triethylamine and methyl oxalylchloride produced crys-
talline enaminoketone 5 in ꢀ50% overall yield (see Fig.
3).5
It was found that condensations of hydrazines with
enaminoketone 5 were facile and obviated the need to
convert the stabile crystalline enaminoketone into dike-
tone 6, an unstable oil. Condensations of hydrazines
with enaminoketone 5 were carried out in methanol at
25–50°C, in the presence of a small amount of aq HCl.6
Simple alkyl hydrazines 7a–f (Table 1) gave pyrazoles
2a–f as crystalline solids in yields of 70–90%. Hydrazine
7g failed to cyclize, and the corresponding hydrazone
was isolated.
Hydrazines 7h–k were prepared by displacement of the
corresponding chloride or bromide with hydrazine
hydrate.7,8 Isolation and purification was achieved by
crystallization of the hydrazines as bis-p-toluenesul-
fonic acid salts, which were stable and non-hygro-
scopic.9 Condensation of enaminoketone 5 with the
hydrazines 7h–k (as the Tosic acid salts) in methanol,
Figure 4. Pyrazole lactone and amide syntheses.

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5869
ethanol or water failed. In the presence of sodium
acetate decomposition occurred with little or no desired
product formation. In the presence of 1N HCl rapid
formation of pyrazoles occurred.
borate (8.0 ml, 0.071 mol) was added dropwise over 2
min and the solution was stirred for 2 h at −10°C. The
solution was treated with triethylamine (55 ml, 395
mmol), forming a precipitate, then a solution of methyl
oxalylchloride (24.6 ml, 0.267 mol) in MTBE (50 mL)
was added dropwise over 30 min to form a thick slurry.
The resulting slurry was stirred for 30 min, treated with
saturated sodium bicarbonate (250 mL) and methylene
chloride (200 ml) and the phases separated. The aqueous
phase was extracted with methylene chloride (2×100 ml).
The combined organic phases were evaporated in vacuo
to give an oil which was triturated with MTBE to pro-
duce 15.75 g of yellowish solids (45% yield). A sample
was recrystallized from toluene/cyclohexane. Mp 80.3–
Condensation with hydrazino-alcohols 7h and 7i pro-
duced the corresponding alcohols 8 and 9, which were
converted to lactones 3a and 4a, respectively. Alcohol 8
readily lactonized to pyrazolo-oxazine 3a using DBU in
THF. Alcohol 9, however, failed to cyclize under acidic
or basic conditions. When treated with potassium
hydroxide in THF at 2°C,10 ester hydrolysis produced
acid 10, which cyclized upon subsequent treatment with
EDC and HOBt (see Fig. 4).11
1
82.0°C. H NMR (400.13 MHz, CDCl3): l 5.70 (s, 1H),
Aminohydrazines 7j and 7k produced the bicyclic pyra-
zole-pyrazine 3b and pyrazolo-diazepine 4b directly.
Thus, in a two-step synthesis, the key bicyclic interme-
diate 4b used in the synthesis of oral fibrinogen antago-
nist 1 was achieved in 40% overall yield.
3.90 (s, 3H), 3.77 (s, 3H), 3.46 (br t, J=6.5, 2H), 3.32 (br
t, J=6.7, 2H), 2.04–1.90 (m, 4H). 13C NMR (100.613
MHz, CDCl3): l 175.8, 165.2, 163.9, 154.9, 90.8, 53.2,
52.4, 49.0, 48.7, 25.1, 24.5. Anal. calcd for C11H15NO5: C,
54.77; H, 6.27; N, 5.81. Found: C, 54.73; H, 6.27; N,
5.74.
The need to add 1N HCl to effect hydrazine condensa-
tion to enaminoketone 5 suggested the intermediacy of
diketone 6. When the pyrrolidine enamine of methyl
pyruvate was reacted with ethyl oxalyl chloride, the
mixed ester enaminoketone 11 was isolated. Addition
of hydrazine 7k produced a 1:1 mixture of isomeric
esters 4b and 12. It was otherwise anticipated that a
differentiation between a 1,4- and 1,2-addition would
have resulted in a biased ratio.
6. NMR and analytical data for compounds 2b–f can be
found in Supplementary Data. The supplementary data is
available online with the paper in ScienceDirect.
7. Showalter, H. D. H.; Johnson, J. L.; Hoftiezer, J. M. J.
Heterocyclic Chem. 1986, 23, 1491, described 3-hydra-
zino-propanamine and 2-hydrazino-ethanamine as
liquids.
8. Gever, G. J. Am. Chem. Soc. 1954, 76, 1283.
9. Typical procedure: 3-Hydrazino-1-propanol bis-tosic acid
salt (7i). A solution of 3-bromo-1-propanol (13.9 g, 0.10
mol) in ethanol (20 mL) was added to hydrazine hydrate
(40 mL) at 65°C dropwise over 2 h, then stirred for 2 h.
The mixture was concentrated in vacuo (27 in Hg, 90°C
bath), dissolved in water (200 mL), and passed through a
column of IRA-400 resin (285 mL, on base cycle). The
column was eluted with water (4 bed volumes) and the
eluate was concentrated in vacuo to an oil (7.3 g). The oil
was evaporatively dried with ethanol (2×100 mL), dis-
solved with ethanol (100 mL) and p-TsOH hydrate (26 g)
was added. After stirring for 1 h, crystalline product was
filtered, washed with cold EtOH, and dried to give 18.6 g
of off-white crystals of the bis-p-toluenesulfonic acid salt.
Thus, complex N-substituted pyrazole dicarboxylates 2
and bicyclic pyrazoles 3 and 4 were rapidly formed by
the addition of hydrazines to enaminoketone 5 in typi-
cally 70–90% yields.
References
1. (a) Askew, B. C.; Bednar, R. A.; Bednar, B.; Claremon,
D. A.; Cook, J. J.; McIntyre, C. J.; Hunt, C. A.; Gould,
R. J.; Lynch, R. J.; Lynch, J. J., Jr.; Gaul, S. L.;
Stranieri, M. T.; Sitko, G. R.; Holahan, M. A.; Glass, J.
D.; Hamill, T.; Gorham, L. M.; Prueksaritanont, T.;
Baldwin, J. J.; Hartman, G. D. J. Med. Chem. 1997, 40,
1779; (b) Hartner, F. W.; Cvetovich, R. J.; Tsay, F.-R.;
Amato, J. S.; Pipik, B.; Grabowski, E. J. J.; Reider, P. J.
J. Org. Chem. 1999, 64, 7751.
2. For reviews of pyrazole syntheses, see: (a) Makino, K.;
Kim, H. S.; Kurasawa, Y. J. Heterocycl. Chem. 1999, 36,
321; (b) Makino, K.; Kim, H. S.; Kurasawa, Y. J.
Heterocycl. Chem. 1998, 35, 489.
1
Mp 125.0–126.1°C. H NMR (400.13 MHz, D2O): l 7.54
(td, J=8.3, 2.0, 4H), 7.20 (td, J=8.3, 2.0, 4H), 4.71 (s,
6H), 3.53 (t, J=6.1, 2H), 3.08 (t, J=7.3, 2H), 2.21 (s,
6H), 1.75 (m, 2H). 13C NMR (100.61 MHz, D2O): l
142.3, 139.3, 129.3, 125.2, 58.8, 49.0, 26.6, 20.3. Anal.
calcd for C17H26N2S2O7: C, 46.99; H, 6.03; N, 6.45; S,
14.76. Found: C, 47.00; H, 5.92; N, 6.23; S, 14.86. NMR
and analytical data for compounds 7h, 7j, and 7k can be
found in the Supplementary Data.
10. (a) Lee, H. H.; Cain, B. F.; Denny, W. A. J. Org. Chem.
1989, 54, 428; (b) Chambers, D.; Denny, W. A.; Buckle-
ton, J. S.; Clark, G. R. J. Org. Chem. 1985, 50, 4736.
11. Methyl 4-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]-
diazepine-2-carboxylate (4b). Enaminoketone 5 (1.22 g,
5.0 mm) was dissolved in methanol (10 mL) and added
3-hydrazino-1-propylamine bis-Tosic acid salt (7k) (2.22
g, 5.1 mm). 2N aq HCl (0.5 mL) was added and the
mixture was stirred 8 h. This was partitioned between
methylene chloride (20 mL) and aq bicarbonate (20 mL).
The aqueous phase was extracted with methylene chloride
3. (a) For a recent review, see: Zelenin, K. N. Org. Prep.
Proc. Int. 1995, 27, 519; (b) Dannhardt, G.; Geyer, Y.;
Mayer, K. K.; Obergrusberger, R. Arch. Pharm. (Wein-
heim) 1988, 321, 17.
4. Arnold, Z. Synthesis 1990, 39.
5. Dimethyl 2-pyrrolidino-4-oxo-2-pentenedioate (5). A solu-
tion of pyrrolidine (12.6 ml, 0.151 mol) in MTBE (100
ml) was cooled to −10°C. A solution of methyl pyruvate
(13.6 ml, 0.151 mol) in MTBE (100 ml) was added
dropwise over 30 min and stirred for 15 min. Trimethyl-

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(3×20 mL), and the extracts were evaporated to solids
(0.80 g). The solids were dissolved into acetonitrile at
60°C and DBU (10 ml) was added to complete cycliza-
tion. After evaporation, lactam 4b was isolated and
found to be identical to known lactam. Additional
experimental, NMR and Analytical data for compounds
3a,b, 4a, 8, 9, and 10 can be found in the Supplementary
Data.