A facile synthesis of [14C]pyrithiobac-sodium

Article abstract of DOI:10.1002/jlcr.1048

Condensation of thiourea 1 with diethyl malonate 2 in the presence of sodium methoxide furnished 4,6-dihydroxy-2-mercaptopyrimidine 3. Compound 3 on methylation with diazomethane followed by oxidation with H₅IO ₆/CrO₃ in ethyl acetate gave 4,6-dimethoxy-2- methylsulphonylpyrimidine 5. Compound 5 on condensation with 2-mercapto-6-chlorobenzoic acid in the presence of a phase transfer catalyst, tetrabutylammonium bromide and sodium carbonate gave the title compound - pyrithiobac-sodium 6 with an overall yield of > 35% starting from thiourea. Following the above standardized procedure, using [¹⁴C]-thiourea in lieu of thiourea, ¹⁴C labelled product 6, was synthesized with an overall radiochemical yield > 30% (with respect to [¹⁴C]-thiourea) for further evaluations of environmental fate of 6, in soils and plants. Copyright

Full text of DOI:10.1002/jlcr.1048

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2006; 49: 339–343.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.1048
Research Article
A facile synthesis of [14C]pyrithiobac-sodium
S. Ravi*, K. M. Mathew, D. Padmanabhan, V. K. P. Unny and N. Sivaprasad
Labelled Compounds Radiopharmaceuticals, Immunoassay, Labelled Compounds, and
Jonaki Board of Radiation and Isotope Technology, BARC Vashi Complex, Navi
Mumbai 400705, India
Summary
Condensation of thiourea 1 with diethyl malonate 2 in the presence of sodium
methoxide furnished 4,6-dihydroxy-2-mercaptopyrimidine 3. Compound 3 on
methylation with diazomethane followed by oxidation with H5IO6/CrO3 in ethyl
acetate gave 4,6-dimethoxy-2-methylsulphonylpyrimidine 5. Compound
5 on
condensation with 2-mercapto-6-chlorobenzoic acid in the presence of a phase
transfer catalyst, tetrabutylammonium bromide and sodium carbonate gave the title
compound – pyrithiobac-sodium 6 with an overall yield of >35% starting from
thiourea. Following the above standardized procedure, using [14C]-thiourea in lieu of
thiourea, 14C labelled product 6, was synthesized with an overall radiochemical yield
>30% (with respect to [14C]-thiourea) for further evaluations of environmental fate
of 6, in soils and plants. Copyright # 2006 John Wiley & Sons, Ltd.
Key Words: [14C]-Thiourea; 4,6-dihydroxy-2-mercaptopyrimidine; 4,6-dimethoxy-
2-methylsulphonyl-pyrimidine; [14C]-pyrithiobac-sodium; [14C]sodium 2-chloro-6-
(4,6-dimethoxy-2-pyrimidinylthio)benzoate
Introduction
Pyrithiobac-sodium (sodium-2-chloro-6-(4,6-dimethoxy-2-pyrimidinylthio)-
benzoate) belongs to the group of acetolactate synthase (ALS) inhibiting
herbicides. It inhibits the synthesis of the essential branched chain amino acids
(leucine, iso-leucine and valine).1–3 This herbicide acts against a broad
spectrum of weeds associated with the cotton crop. It is used at low rates, as
soil or foliar applied, at both pre- and post-emergence stages of the cotton
crop. The said herbicide is highly selective for cotton.
*Correspondence to: S. Ravi, Labelled Compounds Radiopharmaceuticals, Immunoassay, Labelled
Compounds and Jonaki Board of Radiation and Isotope Technology, BARC Vashi Complex, Navi
Mumbai 400705, India. E-mail: lcbrit@rediffmail.com
Copyright # 2006 John Wiley & Sons, Ltd.
Received 9 December 2005
Revised 22 December 2005
Accepted 22 December 2005

340
S. RAVI ET AL.
Results and discussion
Condensation of thiourea 1 with diethyl malonate 2 in the presence of sodium
methoxide gave 4,6-dihydroxy-2-mercaptopyrimidine 3. The product 3 showed
a characteristic –SH band at 2570 cmꢀ1 and bands due to hydroxyl group at
3500–3300 and 1050 cmꢀ1 in the IR spectrum. Also, product exhibited, PMR
signal at d ¼ 5:525:7, which on integration accounted for single proton and
thus confirmed the formation of 3. Methylation of 3 with diazomethane4
furnished 4,6-dimethoxy-2-methylmercaptopyrimidine 4. The structure was
confirmed by the absence of band at 2570 cmꢀ1 due to –SH group and by the
absence of bands at 3500–3300 and 1050 cmꢀ1 due to hydroxyl group in IR
spectrum. The structure was additionally confirmed by the presence of
methoxyl group band at 1250 cmꢀ1. Further, it was evident from the presence
of PMR signal at d ¼ 3:8, (integrating for six protons) that two methoxyl
groups were present. In addition, presence of PMR signal at d ¼ 3:5 was
observed. On integration the signal accounted for three protons due to –SCH3
group, which in turn confirmed the formation of 4. Oxidation of 4 with H5IO6/
CrO3 in ethyl acetate5 gave 4,6-dimethoxy-2-methylsulphonylpyrimdine 5. The
formation of 5 was confirmed by HPLC analysis, by comparison with the
authentic sample. The results obtained were in good agreement (the product
eluted out at 4.980 min, mobile phase was 30% acetonitrile in water, column
ODS 5 m). Presence of bands at 1350–1300 cmꢀ1 and at 1160–1110 cmꢀ1
(sulphonyl group bands) in IR spectrum confirmed the formation of 5. The
compound 5 on condensation with 2-mercapto-6-chlorobenzoic acid in the
presence of tetrabutylammonium bromide in dry acetone medium gave the
required product 6.6 The product formation was confirmed by HPLC analysis.
The results obtained were in good agreement with the authentic sample. The
spectral data was compared with that of the authentic sample and was found
to be in good agreement [IR: (KBr film) 2835, 1680, 1250, 680 cmꢀ1, PMR:
(D2O), d ¼ 3:75 (6H, s), d ¼ 5:92 (1H, s), d ¼ 7:3227:58 (3H, m)]. We
standardized this method for the synthesis of 14C labelled product 6, for
further evaluations of environmental fate of 6, in soils and plants (Scheme 1).
Experimental
4,6-Dihydroxy-2-mercaptopyrimidine 3. Sodium methoxide was generated in
situ by adding metallic sodium (55 mg) to dry methanol (1 ml) followed by
stirring for 10 min. The temperature of the reaction mixture was raised to 608C
and added thiourea (1 mmol, 76.12 mg). The reaction mixture was stirred for
5 min at 608C. To this reaction mass, diethyl malonate (1.2 mmol, 182 ml) was
added and the reaction mixture was stirred continuously for 30 min at 608C.
The product formation was confirmed by TLC (silica, solvent: ethyl acetate).
Thiourea Rf ¼ 0:26 and 4,6-dihydroxy-2-mercaptopyrimidine Rf ¼ 0:06.
Copyright # 2006 John Wiley & Sons, Ltd.
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FACILE SYNTHESIS OF [14C]PYRITHIOBAC-SODIUM
341
Scheme 1. (i) Sodium, methanol; (ii) diazomethane; (iii) periodic acid/chromium
trioxide; (iv) 2-mercapto-6-chlorobenzoic acid, sodium carbonate, tetrabutylam-
monium bromide
The reaction mixture was loaded on cation exchanger column (Dowex – 50 ꢁ 8,
50–100 mesh) in H+ form and was eluted with water to elute 4,6-dihydroxy-2-
mercaptopyrimidine 3. Yield: 80%, IR: (KBr film) 3500–3300, 2530,
1050 cmꢀ1 PMR (CD3C(O)CD3) d ¼ 6:4 ppm (1H, s).
4,6-dimethoxy-2-mercaptomethylpyrimidine 4. To a cooled solution of N-
methyl-N-nitrosotoluene-p-sulphonamide (6 mmol, 1.28 gm) in 30 ml ether,
alcoholic NaOH solution (0.4 gm in 96% ethanol (10 ml)) was added dropwise
and stirred for 5 min. The resulting etheral solution of diazomethane was
distilled into the flask containing 4,6-dihydroxy-2-mercaptopyrimidine
(0.5 mmol, 72 mg) in dry methanol (6 ml) and the reaction mixture was stirred
at 48C for 30 min. Reaction mixture was evaporated to dryness under reduced
pressure and loaded on a silica column. The column was eluted with ethyl
acetate to elute 4,6-dimethoxy-2-mercaptomethylpyrimidine. Yield 85%, TLC
(silica, solvent: ethyl acetate) 4,6-dimethoxy-2-mercaptomethylpyrimidine Rf
¼ 0:9 and 4,6-dihydroxy-2-mercaptopyrimidine Rf ¼ 0:06. IR: (KBr film)
2835, 1250, 717–625 cmꢀ1 PMR (CD3C(O)CD3) d ¼ 3:5 (3H, s), d ¼ 3:024:0
(6H, s) d ¼ 6:1 (1H, s).
4,6-dimethoxy-2-methylsulphonylpyrimidine 5. Periodic acid (2.63 mmol,
600 mg) was dissolved in acetonitrile (6 ml) by stirring at room temperature
for 60 min. To this solution, chromium trioxide (0.125 mmol, 12.5 mg) was
added and stirred for 5 min, to give clear orange solution. H5IO6/CrO3
solution (1.7 ml) was added to solution of 4,6-dimethoxy-2-methylmercapto-
pyrimidine (0.23 mmol, 42.8 mg) in ethyl acetate and was stirred at room
temperature for 30 min. The reaction mixture was quenched with saturated
sodium thiosulphate and was loaded on silica column. The column was eluted
Copyright # 2006 John Wiley & Sons, Ltd.
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S. RAVI ET AL.
with acetone to obtain 4,6-dimethoxy-2-methylsulphonylpyrimidine. The
product was analyzed by HPLC, (30% acetonitrile in water, Column ODS
5 m, Rt 4.980). Yield 75%. TLC: (silica, solvent: chloroform) 4,6-dimethoxy-2-
mercaptomethylpyrimidine Rf ¼ 0:8 and 4,6-dimethoxy-2-methylsulphonyl-
pyrimidine Rf ¼ 0:56, IR: (KBr film) 2835, 1350–1300, 1250, 1160–1110 cmꢀ1
PMR (CD3C(O)CD3), d ¼ 3:5 (3H, s), d ¼ 3:824:0 (6H, s), d ¼ 6:3 (1H, s).
,
Pyrithiobac sodium (sodium 2-chloro-6-(4,6-dimethoxy-2-pyrimidinylthio)
benzoate) 6. Acetone (3 ml) was added to a flask containing 2-mercapto-
6-chlorobenzoic acid (0.119 mmol, 22.5 mg), 4,6-dimethoxy-2-methylsulpho-
nylpyrimidine (0.117 mmol, 25.5 mg), sodium carbonate (0.2 mmol, 21.2 mg)
and tetrabutylammonium bromide. The reaction mixture was stirred at room
temperature for 4 h. Acetone was evaporated and the residue was dissolved in
water. The compound was purified on silica column. The compound was
eluted with 10% methanol in chloroform to separate pyrithiobac sodium 6:
Yield 70%, HPLC (solvent 30% acetonitrile in water, Column ODS 5 m, Rt
19.92), TLC (silica, solvent: chloroform : methanol 95 : 5 v/v) 4,6-dimethoxy-
2-methylsulphonylpyrimidine Rf ¼ 0:56 and pyrithiobac-sodium Rf ¼ 0:2,
IR (KBr film) 2835, 1680, 1250, 680 cmꢀ1, PMR: (D2O), d ¼ 3:75 (6H, s),
d ¼ 5:92 (1H, s), d ¼ 7:3227:58 (3H, m).
[14C] Pyrithiobac-sodium. Following the above standardized procedure
[14C]-pyrithiobac-sodium was synthesized using [14C]-thiourea in lieu of
thiourea, with an overall radiochemical yield 33% (with respect to [14C]-
thiourea) having a specific radioactivity 5 mCi/mmol and radiochemical purity
>98% (assayed by HPLC followed by liquid scintillation counting of the
fraction eluting at 19.9 min and also by TLC followed radiochromatogram
scanning).
Acknowledgements
The authors wish to express their thanks to Mr J. K. Ghosh, Chief Executive,
BRIT for his support and encouragement in the work and to all the colleagues
from Labelled Compounds, BRIT for their help.
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