A rapid microwave assisted synthesis of [U-14C]isosorbide and dimethyl[U-14C]isosorbide from D-[U-14C]glucose

Article abstract of DOI:10.1002/jlcr.1047

[U-¹⁴C]Isosorbide and [U-¹⁴C]dimethyl isosorbide with a specific activity of 462MBq/ mmol was prepared from D-[U-¹⁴C] glucose, in an overall yield of 79%, under microwave heating conditions. Copyright

Full text of DOI:10.1002/jlcr.1047

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2006; 49: 333–337.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.1047
Research Article
A rapid microwave assisted synthesis of
[U-14C]isosorbide and Dimethyl[U-14C]isosorbide
from d-[U-14C]glucose
K. M. Mathew*, S. Ravi, 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
[U-14C]Isosorbide and [U-14C]dimethyl isosorbide with a specific activity of 462 MBq/
mmol was prepared from d-[U-14C]glucose, in an overall yield of 79%, under
microwave heating conditions. Copyright # 2006 John Wiley & Sons, Ltd.
Key Words: d-[U-14C]glucose; [U-14C]isosorbide; dimethyl[U-14C]isosorbide
Introduction
Isosorbide is a key synthetic intermediate for the synthesis of (i) perfluor-
oalkylated monoesters used as new surfactants in biomedical application,1 (ii)
mono and dinitro isosorbide,2 (iii) monobenzylated3 and octylated isosorbide4
(iv) chiral auxiliary for the asymmetric synthesis5 and (v) dimethyl isosorbide.6
The 14C-labelled analogues of these compounds are required to study their
mode of action and usefulness. For this purpose, a suitable method was
developed for its preparation and the procedure was standardized using
microwave heating technique.
In recent times, microwave (MW) induced organic reaction enhancement
(MORE) chemistry has taken an undeniable place in chemical laboratory
practice as a very effective method of activating reactions. Microwave heating
is especially useful for reactions using radioisotopes because of its capability to
bring about significant decrease in the reaction time which often results in
substantial increase of the radiochemical yield. Examples of the use of this
technology in organic synthesis are numerous.7 Better yields of products are
*Correspondence to: K. M. Mathew, Labelled Compounds Radiopharmaceuticals, Immunoassay, Labelled
Compounds and Jonaki Board of Radiation and Isotope Technology, BARC Vashi Complex, Navi
Mumbai 400705, India. Email: lcbrit@rediffmail.com
Copyright # 2006 John Wiley & Sons, Ltd.
Received 9 December 2005
Revised 22 December 2005
Accepted 22 December 2005

334
K. M. MATHEW ET AL.
obtained when compared to those obtained with conventional heating under
the same conditions, in spite of similar profiles of rise in temperature.
Results and discussion
In our approach d-[U-14C]glucose 1 was quantitatively converted to d-[U-14C]
sorbitol 2 by sodium borohydride reduction under microwavey (1300 W)
heating for 2 min. Alternatively, d-[U-14C]sorbitol was also prepared by simple
mixing of d-[U-14C]glucose with (10%) NaBH4–alumina in solid state and
heating the mixture in an alumina bath for 40 s using a domestic microwave
oven (520 W). The product formation was confirmed by TLC and also by the
absence of bands at 2725 cmꢀ1 and 1700 cmꢀ1 due to aldehydic group in IR
spectra. Optical rotation values further confirmed the formation. The acid
catalyzed dehydration of d-[U-14C]sorbitol under microwave heating for 3 min
yielded [U-14C]isosorbide 3. TLC (silica, ethyl acetate: methanol 5:1). Rf for
d-sorbitol was found to be 0.25 and for isosorbide 0.5. Optical rotation was
observed to be ½aꢁD30 þ 448 (H2O) . This on methylation with methyl iodide in
presence of a phase transfer catalyst tetrabutylammonium bromide (TBAB)
under microwave (520 W) irradiation for 4 min (8 ꢂ 30 s) yielded [U-14C]
dimethyl isosorbide
4 in an overall yield of 79% starting from
d-[U-14C]glucose. TLC (silica, ethyl acetate: methanol 5:1). The Rf for
dimethyl isosorbide was 0.8 and for isosorbide 0.5. Optical rotation was found
to be ½aꢁD30 þ 968 (C2, CHCl3). It was further confirmed by HPLC analysis and
by comparison with the authentic sample. The results obtained were found to
be in good agreement (dimethyl isosorbide eluted out at Rf 1.95 min, and
isosorbide at 3.5 min) (Scheme 1).
Thus the microwave irradiation technique has been efficiently employed for
the radiosynthesis of [U-14C]dimethyl isosorbide 4 in an overall yield of 79%
starting from d-[U-14C]glucose.
Experimental
d-[U-14C]Sorbitol ð2Þ. A mixture of d-[U-14C ]glucose 1 (0.2 mmol, 36 mg,
specific activity 462 MBq/mmol), sodium borohydride (9.5 mg, 0.25 mmol),
Dowex 1 ꢂ 8 anion exchange resin (10 mg, Clꢀ form, 100–200 mesh) and THF
(500 ml) was heated in a borosilicate glass tube using a domestic microwave
oven (BPL make with different power setting) (1300 W,) for 2 min (4 ꢂ 30 s).
The reaction mixture was then de-ionized by passing through a column
containing a mixture of Dowex 1 ꢂ 8 (OHꢀ, 50–100 mesh) and Dowex 50 ꢂ 8
(H+, 50–100 mesh). The eluate was rotary evaporated several times with
y The domestic microwave oven (LG make, model MS 257PL) with variable power setting was used through
the experiment.
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RAPID MICROWAVE ASSISTED SYNTHESIS
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Scheme 1. (i) NaBH4/Dowex 1 ꢂ 8, MW; (ii) H2SO4, Undecane, MW; (iii)
CH3l, KOH, TBAB, MW; (iv) Alumina-NaBH4, MW
methanol to give d-[U-14C ]sorbitol in quantitative yield. The reaction mixture
was analyzed by TLC followed by radiochromatogram scanning.
TLC (silica, isopropanol: benzene: water 20:1:1). Rf for d-glucose was
found to be 0.5 and for d-sorbitol 0.35. Optical rotation was observed to be
½aꢁD25 ꢀ 2:28 (H2O) (Reported ½aꢁD20 ꢀ 2:08 (H2O))8.
Alternate method
d-[U-14C]Sorbitol ð2Þ. Freshly prepared NaBH4–aluminaz (54 mg, 0.168
mmol NaBH4) was thoroughly mixed with d-[U-14C]-glucose (30 mg,
0.166 mmol, specific activity 462 MBq/mmol) in a test tube and placed in an
alumina bath (see footnote z) inside the microwave oven (520 W) and
irradiated for 40 s. Water was added to the reaction mixture and filtered. The
filtrate was concentrated to give quantitative yield of d-[U-14C]sorbitol.
The reaction mixture was analyzed as above.
[U-14C]Isosorbide ð3Þ. A mixture of d-[U-14C]sorbitol 2 (34 mg, 0.2 mmol,
specific activity 462 MBq/mmol), sulfuric acid (5 ml) and undecane (500 ml) was
heated in a domestic microwave (1300 W) oven for 3 min (6 ꢂ 30 s). The
reaction mixture was then de-ionized by passing through a column of anion
z 10% Sodium borohydride supported on alumina was prepared by mixing alumina (5 g) thoroughly with
sodium borohydride (0.565 g) using a pestle and mortar. Alumina bath (50 g in 100 ml breaker) was used for
the uniform heating of the reaction mixture, thereby preventing its charring.
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K. M. MATHEW ET AL.
exchange resin (Dowex 1 ꢂ 8, OHꢀ) and the eluate was concentrated under
reduced pressure. It was purified by column chromatography (silica, ethyl
acetate: methanol, 5:1). The product was analyzed by TLC followed by
radiochromatogram scanning.
TLC (silica, ethyl acetate: methanol 5:1). Rf for d-sorbitol was found to be
0.25 and for isosorbide 0.5. Optical rotation ½aꢁD25 þ 458 (C3, H2O) ( reported
value +448).8 Yield >80%.
[U-14C]Dimethyl isosorbide ð4Þ. [U-14C]Isosorbide (0.067 mmol, 9.78 mg,
specific activity 462 MBq/mmol), methyl iodide (0.2 mmol,12.5 ml), TBAB
(3 mg), powdered KOH (0.12 g, 0.23 mmol) and undecane (300 ml) were taken
in a borosilicate glass ampoule and was sealed. The reaction mixture was then
homogenized and submitted to microwave irradiation using a domestic
microwave oven (520 W) for 6 min (30 s ꢂ 12). It was cooled to room
temperature and the contents dissolved in methylene chloride. The reaction
mixture was filtered and the filtrate was concentrated under reduced pressure.
The pure products were isolated by column chromatography (silica, ethyl
acetate: methanol, 5:1) and analyzed by TLC (silica, ethyl acetate: methanol
5:1). Rf for dimethyl isosorbide was found to be 0.8 and for isosorbide 0.5.
Optical rotation: ½aꢁD30 þ 968 (C2, CHCl3).} Yield: 99%.
HPLC (mobile phase: acetonitrile, Column ODS (SS Exsil(SGE),
4 mm ꢂ 250 mm)5 m, detector UV 210 nm, flow rate 1 ml/min). The retention
time for dimethyl isosorbide and isosorbide was 1.95 and 3.5 min respectively.
The fraction corresponding to the dimethyl isosorbide was collected and
assayed by liquid scintillation counter for radioactive content. (A product
having radioactivity 10 000 dpm was injected and the fraction at Rt 1.95
contained 9870 dpm). Radiochemical purity was 98.70%.
Acknowledgements
The authors wish to express their thanks to Mr J.K. Ghosh, Chief Executive,
BRIT for his keen interest in this work.
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Copyright # 2006 John Wiley & Sons, Ltd.
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J Label Compd Radiopharm 2006; 49: 333–337