1478 Gilbile et al.
Asian J. Chem.
1
oilseeds [9]. Flupyrsulfuron methyl-sodium which was reported
as a new 5-substituted sulfonylurea herbicide used to control
grasses and broadleaf weeds in cereals [10] it has less than
one month residual life [11]. Since then, several other 5-substi-
tuted sulfonylureas which show similar characteristics have
been reported [12-14].
59 °C. H NMR (300 MHz, CDCl3): δ 3.85 (s, 3H, -OMe),
3.82 (s, 3H,-NMe); ESI-MS: m/z, 209 (M+1)+.
Step-2: Preparation of methyl 3-chloro-5-mercapto-
1-methyl-1H-pyrazole-4-carboxylate (3): To a solution of
compound 2 (5 g, 23.92 mol) in DMF (11 mL) was added
portion wide 70 % sodium hydrogen sulphide (4.78 g, 59.79
mmol) at room temperature.After stirring for 30 min at 60 °C,
the mixture was cooled to room temperature, poured into water
(90 mL) and the insoluble solid was filtered off. The filtrate
was acidified with 35 % HCl (6 mL). The resultant solid was
gathered, washed with water and dried in vaccuo to obtain
compound 3. Off white solid; Yield: 4.74 g, 96 %; m.p.: 84-
85 °C; 1H NMR (300 MHz, CDCl3): δ 6.64 (s, 1H,-SH), 3.88
(s, 3H, -OMe), 3.74 (s, 3H,-NMe); ESI-MS: m/z, 207 (M+1)+.
Step-3: Preparation of methyl 3-chloro-1-methyl-5-
sulfamoyl pyrazole-4-carboxylate (4): To a stirred mixture
of compound 3 (4g, 19.35 mmol), tetrabutyl ammonium
chloride (21.5 g, 77.36 mmol) and water (0.87 g, 48.33 mmol)
in MeCN (25 mL) at 0 °C, N-chloro succinimide (7.75 g, 58.04
mmol) was added as a solid in portions over 1-2 min. After 30
min, ammonium carbonate (1.95g, 20.30 mmol) was added to
the mixture over 1-2 min. The resulting mixture was stirred at
room temperature for 12 h (until TLC showed complete
disappearance of starting material). The mixture was filtered
and rinsed with acetonitrile (20 mL). The filtrate was evapo-
rated to obtain compound 4. Recrystallization from a mixture
of EtOH and water resulted in pure product. White solid,Yield:
Attempts and efforts to decrease the environmental crash
of a synthetic process should begin in the initial stage of the
product/process development. Some tools have been estab-
lished and further developed to tolerate fewer argumentative
processes [15-23], such as choosing of solvents considering
environmental, health and safety feature as well as the life
cycle assessment (LCA) and economic measure. Kralisch and
co-workers [24,25] evaluated and optimized an approach
considering ecological and economic aspects of the production
of some reactants and solvents used in synthesis, workup,
recycling and disposal. To appraise the greenness of a product
or process the authors used three main criteria: energy factor
(EF), environmental and human health factor (EHF) and cost
factor (CF). Such criteria describe the energy demand, toxicity
and the cost of chemicals, auxiliaries and equipment used
during a product or process of life cycle stages. There are some
other metrics which can also be used such as atom economy
(AE) [26,27], reaction mass efficiency (RME) [28], environ-
mental factor (E-factor) [29-32], effective mass yield [33],
mass intensity [34] and the process profile [35].
Thus, the present aim of this study was to evaluate the atom
economy, reaction mass efficiency and environmental factor
of the improved synthesis of methyl 3-chloro-5-(4,6-dimethoxy-
pyrimidin-2-ylcarbamoylsulfamoyl)-1-methylpyrazole-4-
carboxylate (Halosulphuron) using green metrics.
1
4.41 g, 90 %; m.p.: 125-126 °C; H NMR (DMSO-d6, 300
MHz): δ 8.10 (brs, 2H, NH2), 4.05 (s, 3H, NMe), 3.88 (s, 3H);
ESI-MS: m/z, 254 (M+1);
Step-4: Preparation of phenyl 4,6-dimethoxypyrimidin-
2-yl carbamate (6): To a stirred solution of compound 5 (1g,
6.45 mmol) in acetonitrile (10 mL) was added triethylamine
(0.85 g, 8.40 mmol) followed by phenyl chloroformate (1.31
g, 8.37 mmol) at room temperature. The reaction mixture was
heated to 60 °C for 6 h. The reaction mixture was cooled to
room temperature and diluted with water (6 mL) and the
precipitated solids were filtered and dried under vacuum to
obtain compound 6. White solid, Yield: 1.48 g, 83 %; m.p.:
119 °C; 1H NMR (400 MHz, DMSO-d6): δ 7.65 (s, 1H), 7.42-
7.40 (m, 2H), 7.18-7.14 (m, 3H), 5.80 (s, 1H), 3.96 (s, 6H);
ESI-MS: m/z, 276.1 (M+1);
Step-5: Preparation of methyl 3-chloro-5-(4,6-dimethoxy-
pyrimidin-2-yl carbamoylsulfamoyl)-1-methylpyrazole-4-
carboxylate (7): A mixture of compound 6 (0.32 g, 1.16
mmol), compound 4 (0.25 g, 0.98 mmol) and triethylamine
(0.12 g, 1.18 mmol) in acetonitrile (5 mL) was irradiated in a
microwave at 60 °C for 10 min.After completion of the reaction
(checked by TLC), the reaction mixture was diluted with water
(10 mL) and extracted with dichloromethane (10 mL). The
organic layer was washed with 1 M HCl (2 × 5 mL) and then
with water (20 mL) followed by brine solution (10 mL). The
organic layer was dried over anhydrous sodium sulphate (6.2
g), filtered and evaporated under reduced pressure to obtain
the crude product. The crude product was re-crystallized in
acetonitrile (10 mL) to obtain the pure compound 7. Off-white
powder;Yield: 0.410 g, 96 %); m.p.: 176 °C (Lit. m.p.: 175.5-
177.2 °C); 1H NMR (400 MHz, CDCl3): δ 7.56 (s, 1H), 5.64
EXPERIMENTAL
The uncorrected melting points of compounds were taken
in an open capillary in a paraffin bath. All reagents used were
commercial and laboratory grade, melting points were
determined in open capillaries and are uncorrected. IR spectra
were recorded on potassium bromide disks on a Perkin-Elmer
1
383 spectrophotometer. H NMR spectra were obtained on
Varian 400 MHz instrument and Varian 300 MHz, with TMS
as internal Standard and chemical shifts are expressed in δ
ppm solvent used in CDCl3 and DMSO-d6 and mass spectrum
on a Hewelett Packard mass spectrometer operating at 70 eV,
purity of the compounds were checked by TLC, which is
performed with E. Merck pre coated silica gel plates (60 F-
254) with iodine as a developing agent.
Step-1: Preparation of methyl 3,5-dichloro-1-methyl-
1H-pyrazole-4-carboxylate (2): Sulphuryl chloride (14.4 mL,
178.35 mmol) was added to a solution of compound 1 (5 g,
35.68 mmol) in dichloromethane (100 mL) and the resulting
mixture was stirred at room temperature for 12 h. The reaction
mixture was poured into saturated aqueous solution of sodium
bicarbonate (40 mL) and extracted with dichloromethane (2 ×
20 mL). The combined extracts were washed with brine solution
(3 × 25 mL), dried over sodium sulphate (22 g), filtered and
evaporated in vacuo to obtain the crude product. The crude
compound was crystallized using cyclohexane (30 mL) to
afford compound 1. White powder;Yield: 7g, 94 %; m.p.: 58-