New short synthesis of (5)-2,3-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl] -5-iodobenzamide: Dopamine D2 receptor

Article abstract of DOI:10.1080/00397910701771199

A new short and highly efficient synthesis of (5)-2,3-dimethoxy-N[(1-ethyl- 2-pyrrolidinyl)methyl]-5-iodobenzamide (epidepride, 1) from 3-methoxy- salicylaldehyde (o-vanillin, 2) and 3-methoxysalicyclic acid (6) was achieved by employing a new iodination

Full text of DOI:10.1080/00397910701771199

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New Short Synthesis of
(5)‐2,3‐Dimethoxy‐N‐[(1‐ethyl‐2‐pyrrolidinyl)met
Dopamine D2 Receptor
Alummoottil V. Joshua a b , Sanjay K. Sharma a b & Douglas N. Abrams a b
a Department of Oncology , University of Alberta , Edmonton, Canada
b Edmonton Radiopharmaceutical Centre , Edmonton, Canada
Published online: 28 Jan 2008.
To cite this article: Alummoottil V. Joshua , Sanjay K. Sharma & Douglas N. Abrams (2008) New Short
Synthesis of (5)‐2,3‐Dimethoxy‐N‐[(1‐ethyl‐2‐pyrrolidinyl)methyl]‐5‐iodobenzamide: Dopamine D2 Receptor,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
38:3, 434-440, DOI: 10.1080/00397910701771199
To link to this article: http://dx.doi.org/10.1080/00397910701771199
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Synthetic Communicationsw, 38: 434–440, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701771199
New Short Synthesis of (5)-2,3-Dimethoxy-
N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-
iodobenzamide: Dopamine D2 Receptor
Alummoottil V. Joshua,1,2 Sanjay K. Sharma,1,2
and Douglas N. Abrams1,2
1Department of Oncology, University of Alberta, Edmonton, Canada
2Edmonton Radiopharmaceutical Centre, Edmonton, Canada
Abstract: A new short and highly efficient synthesis of (5)-2,3-dimethoxy-N[(1-ethyl-2-
pyrrolidinyl)methyl]-5-iodobenzamide (epidepride, 1) from 3-methoxy-salicylaldehyde
(o-vanillin, 2) and 3-methoxysalicyclic acid (6) was achieved by employing a new iodina-
tion method with iodine monochloride and iodine nitrate under basic conditions.
Keywords: dopamine D2 receptor, epidepride, iodine monochloride, iodine nitrate
INTRODUCTION
Epidepride [(5)-2,3-dimethoxy–N[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodoben-
zamide] (1) is a neuroleptic possessing selective and high binding affinity
toward dopamine D2 receptor sites in vitro.[1] The 123I-labeled form of 1
combined with single-photon emission computed tomography (SPECT) can
serve as a superior in vivo imaging agent for the dopamine D2 receptors in the
human brain.[2] Several syntheses of 1 have been reported, all in low to
moderate yieds.[3–5] These methods involve low-yielding direct iodination of a
salicyl-type phenol precursor[3] and the anion-mediated exchange of bromine
to iodine at the 5-position at some stage in the synthetic sequence.[3a,5] The
latter method suffers from the rather unreactive nature of iodine toward 5-lithio
Received in the USA August 2, 2007
Address correspondence to Alummoottil V. Joshua, Edmonton Radiopharmaceuti-
cal Centre, Edmonton 11560, AB, Canada T6G 1Z2. E-mail: alummott@cancerboard.
ab.ca
434

Dopamine D2 Receptor Synthesis
435
Scheme 1. Reagent and conditions: (a) MeI, K2CO3, DMF, 608C, 16 h, 98%; (b) Br2,
64%; (c) CH2(CH2OH)2, Hþ; (d) t-BuLi, I2; (e) HCl; (f) KMnO4, K2HPO4; (g)
(COCl)2, DMF; (h) (S)-2-aminomethyl-1-ethylpyrrolidine, CH2Cl2, 1 h, 63%.
derivatives and the propensity of the pyrrolidine fragment to undergo decompo-
sition. The overall yield (54%) of epidepride (1) by this approach has been
somewhat improved by the use of 5-bromo-2,3-dimethoxy-1-(1,3-dioxacin-2-yl)
benzene as a substrate (Scheme 1).[5,6] Although methods involving aryltin inter-
mediates are satisfactory for the preparation of labeled epidepride, they are less
than satisfactory for the preparation of unlabeled 1, because the procedures are
too long with low overall yields.
Thus, a shorter and more efficient synthesis of epidepride (1) is highly
desirable. A major problem in the synthesis of epidepride and related
iodinated compounds has been the lack of suitable methods for the direct iodi-
nation of salicyl-type phenol substrates. Yue et al.[5] investigated the reaction
of several known iodinating agents with 3-methoxysalicylaldehyde and
methyl-3-methoxysalicylate and found that none gave satisfactory yields of
the desired iodinated products. Thus, a good and high-yielding iodination
method for salicyl-type phenol compounds would greatly simplify the
synthesis of these compounds. Such a method and its applications to the
synthesis of epidepride (1) are the subjects of this communication.
RESULTS AND DISCUSSION
Reactionof3-methoxysalicylaldehyde(o-vanillin, 2) with pyridine complexes of
iodine monochloride[6] or iodine nitrate[7] (generated in situ from iodine mono-
chloride and silver nitrate in chloroform-pyridine) at room temperature
proceeded cleanly and efficiently to yield 5-iodo-3-methoxysalicylaldehyde (3,
yield 96%) (Scheme 2). It is to be noted that the reaction of iodine
monochloride in acetic acid with o-vanillin gave predominantly 5-chloro-3-

436
A. V. Joshua, S. K. Sharma, and D. N. Abrams
Scheme 2. Reagent and conditions: (a) AgNO3, ICl, pyridine, CHCl3, rt, 2 h, 96%;
(b) MeI, K2CO3, DMF, 608C, 16 h, 98%; (c) KMnO4, K2HPO4, t-BuOH, rt, 1.5 h;
(d) NaOH, THF, H2O, 20 h, reflux, 98%; (e) (S)-2-aminomethyl-1-ethylpyrrolidine,
CDI, CH2Cl2, rt, 20 h, 99%.
methoxysalicylaldehyde.[5] For the conversion of 3 to the methoxy derivative 4,
the reported methods[3,8,9] for the corresponding bromoaldehyde and bromo acid
was unsatisfactory because a very large excess (,25 molar excess) of dimethyl
sulfate was required, and the reaction never went to completion. On the other
hand reaction of 3 with methyl iodide and anhydrous potassium carbonate in
anhydrous DMF at 608C for 16 h gave the dimethoxy derivative 4[5] in 98%
yield. Masamune oxidation [5,9] (KMnO4, t-BuOH, K2HPO4) gave 5-iodo-2,3-
dimethoxybenzoic acid (5) [5] in 98% yield after chromatographic purification.
Alternatively, reaction of 3-methoxysalicyclic acid (6) with either iodine mono-
chloride in pyridine or iodine nitrate gave 5-iodo-3-methoxy salicylic acid (7) in
quantitative yield. Methylation of 7 (CH3I, K2CO3, DMF) to 8 proceeded
smoothly in 98% yield. Hydrolysis of 5 (NaOH, H2O, THF) provided 5-iodo-
2,3-dimethoxy benzoic acid (8) in 98% yield.
Both iodine nitrate-pyridine and iodine monochloride-pyridine
complexes gave comparable yields of the iodoaldehyde 3 and the iodo acid
7. The iodine nitrate-pyridine complex is considerably faster (2 h) than with
iodine monochloride-pyridine complex (20 h).

Dopamine D2 Receptor Synthesis
437
The acid chloride coupling method[5,10] on 5 (oxalyl or thionyl chloride
followed by reaction with (S)-2-aminomethyl-1-ethylpyrrolidine) gives
excellent yield of epidepride (1), but it involves the use of a relatively large
excess of the chiral diamine. We have used a more convenient and less
wasteful procedure without any sacrifice in yield by using carbonyldiimidazole
as the coupling agent.[11] Thus treatment of 5 with carbonyldiimidazole (1.05
equivalent) to generate the imidazole derivative in situ and subsequent reaction
with(S)-2-aminomethyl-1-ethylpyrrolidine[10] (1.05equivalent) gaveepidepride
1, homogeneous by thin-layer chromatography (TLC) in 99% yield.
CONCLUSION
The use of iodine monochloride-pyridine complex or iodine nitrate-pyridine
complex for the key iodination step of o-vanillin (2) or 3-methoxysalicylic
acid (6) has yielded a three-step synthesis of 5-iodo-2,3-dimethoxybenzoic
acid 5 in 98% overall yield. Using carbonyldiimidazole as a coupling agent
we have achieved the shortest and most efficient (95% overall) synthesis of
epidepride (1) to date.
EXPERIMENTAL
Method A
To a solution of silver nitrate (7.14 g, 42 mmol) dissolved in a mixture of CHCl3
(50 mL) and pyridine (20 mL), iodine monochloride (6.82 g, 42 mmol) in CHCl3
(10 mL)wasaddeddropwiseovera periodof5 minwithconstantstirringatroom
temperature. The stirring was continued for another 10 min, and to this solution
o-vanillin (2, 6.08 g, 40 mmol) dissolved in CHCl3 (10 mL) was added dropwise
with stirring. The reaction mixture was stirred at room temperature for 2 h and
then diluted with ether (50 mL). The mixture was filtered, the residue was
washed with a mixture of CHCl3–ether (1:1), and the combinedfiltratewas evap-
oratedat308C, resultingina whiteresidue. Theresiduewas redissolved inCHCl3
(50 mL), and washed successively with 5% HCl (50 mL), 5% sodium thiosulfate
(50 mL), and finally water (50 mL). The organic layer was separated, collected,
dried over sodium sulfate, and filtered, and the solvent was evaporated at 308C.
The residual solid was purified by passing through a short silica-gel column
(CHCl3) to give compound 3, which was crystallized from ethylacetate hexane
(50 mL, 40:10) to give 10.68 g (96%) of 3. The mixture of 2 (3.39 g,
12.2 mmol), anhydrous K2CO3 (8.42 g, 61 mmol), and methyl iodide (8.66 g,
61 mmol) in anhydrous DMF (30 mL) was heated at 688C with continuous
stirring under nitrogen for 16 h. The solvent was removed; the residue was
taken up in dichloromethane (3 ꢀ 30 mL) and washed with water (50 mL).
The organic layer was collected and dried over Na2SO4, filtered, and

438
A. V. Joshua, S. K. Sharma, and D. N. Abrams
concentrated. The residue was passed through a column of neutral alumina (in
EtOAc) and eluted by the same to give 4 as a white solid (3.63 g, yield 90%),
with mp 100–1018C (lit. 100–1018C).[10] The oxidation of 4 to give 5-iodo-
2,3-dimethoxybenzoic acid (5) was achieved by Masamune oxidation.[5,10] The
aldehyde 4 (1.22 g, 4.18 mmol) was dissolved in tert. butanol (30 mL), and dipo-
tassium hydrogen phosphate (1.25 M, 16.5 mL) and potassium permanganate
(1 M, 25.5 mL) were added. The mixture was stirred at room temperature for
90 min. The reaction was quenched with saturated Na2SO3, and the pH of the
reaction mixture was adjusted to 1–2 with a few drops of conc. HCl, extracted
with CHCl3 (5 ꢀ 25 mL). The combined organic extract was dried over
Na2SO4, filtered, and evaporated in vacuo. The resulting solid was purified on
a silica-gel column; pure compound 5 came in 5% MeOH–CHCl3 as a white
solid (1.26 g, yield 98%), with mp 126–1288C.
Method B
Iodine monochloride (1.95 g, 12 mmol) in CHCl3 (5 mL) was added dropwise
to pyridine (20 mL) with stirring. After stirring for another 15 min, the
resulting brownish-yellow solution was added to a solution of o-vanillin (2,
1.52 g, 10 mmol) in CHCl3 (10 mL) and stirred at room temperature for
20 h. The reaction mixture was concentrated in vacuo. The residue was redis-
solved in CHCl3 (50 mL) and washed successively with 5% HCl (50 mL), 5%
sodium thiosulfate (50 mL), and finally with water (50 mL). The organic layer
was separated and collected, dried over sodium sulfate, and filtered, and the
solvent was evaporated at 308C. The residual solid was purified by passing
through a short silica-gel column (20 cm packed length to remove the color
impurity) (CHCl3) to give compound 3, which was crystallized from ethyl
acetate hexane (50 mL, 40:10) to give 2.665 g of 3 in 96% yield.
Selected Data for Compound 3
Mp 124–1268C (sharp), anal. calcd. for C8H7IO3 C, 34.56; H, 2.54. Found C,
34.74; H, 2.54. H NMR (DMSO-d6) d (ppm): 10.20 (s, 1H, OH, exchanged
1
with D2O), 10.16 (s, 1H, CHO, exchanged with D2O), 7.48 and 7.43 (dd,
2H, Ar-H), 3.85 (S, 3H, OCH3). EI (mass) [M þ 1] 278.
Synthesis of Epidepride (1)
To a stirred suspension of 5-iodo-2,3-dimethoxybenzoic acid (5, 308 mg,
1.0 mmol) in dichloromethane (5 mL), 1,1-carbonyldiimidazole (170 mg,
1.05 mmol) was added, and the mixture was stirred at room temperature for
1.5 h. To this, (S)-2-aminomethyl-1-ethylpyrrolidine (141 mg, 1.1 mmol) was
added. The stirring was continued at room temperature for 20 h. The reaction

Dopamine D2 Receptor Synthesis
439
mixture was washed with 1 N sodium hydroxide solution (10 mL) and water
(20 mL). The organic layer was dried over sodium sulphate and filtered, and the
solvent was evaporated at 308C. The residual solid was purified by silica-gel
column (20 cm); pure compound was eluted in CHCl3–MeOH (9:1), as yellow
oil (415 mg, 99.3% yield). Anal. calcd. for C16H23IN2O3: C, 45.94; H, 5.54; N,
1
6.70. Found: C, 45.98; H, 5.59; N, 7.78. H NMR (DMSO-d6) d (ppm): 8.58
(s, 1H, NH, exchanged with D2O), 7.29 and 7.78 (dd, 2H, Ar-H), 3.85 and 3.73
(S, 3H, OCH3), 1.64–2.80 (m, 7H, PyrrolidineH) EI (mass) [M þ 1] 419.
ACKNOWLEDGMENT
This work was supported by the grants from Edmonton Radiopharmaceutical
Centre and Alberta Cancer Foundation.
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