Note: Descriptions are shown in the official language in which they were submitted.
CA 02476824 2004-08-19
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S IODINATION OF 4-FLUORO-BENZALDEHYDE
Background of the Invention
Potassium channels play an important role in regulating cell membrane
excitability.
When the potassium channels open, changes in the electrical potential across
the cell membrane
occur and result in a more polarized state. A number of diseases or conditions
may be treated
with therapeutic agents that open potassium channels; see for example (K.
Lawson, Pharmacol.
Ther., v. 70, pp. 39-63 (1996)); (D.R. Gehlert et al., Prog. Neuro-
Psychopharmacol & Biol.
Psychiat., v. 18, pp. 1093-1102 (1994)); (M. Gopalakrishnan et al., Drug
Development Research,
v. 28, pp. 95-127 (1993)); (J.E. Freedman et al., The Neuroscientist, v. 2,
pp. 145-152 (1996));
(D. E. Nurse et al., Br. J. Urol., v. 68 pp. 27-31 (1991)); (B. B. Howe et
al., J. Pharmacol. Exp.
Ther., v. 274 pp. 884-890 (1995)); (D. Spanswick et al., Nature, v. 390 pp.
521-25 (December 4,
1997)); (Dompeling Vasa. Supplementum (1992) 3434); (W09932495); (Grover, J
Mol Cell
Cardiol. (2000) 32, 677); and (Buchheit, Pulmonary Pharmacology & Therapeutics
(1999) 12,
103). Such diseases or conditions include asthma, epilepsy, male sexual
dysfunction, female
sexual dysfunction, pain, bladder overactivity, stroke, diseases associated
with decreased skeletal
blood flow such as Raynaud's phenomenon and intermittent claudication, eating
disorders,
functional bowel disorders, neurodegeneration, benign prostatic hyperplasia
(BPH),
dysmenorrhea, premature labor, alopecia, cardioprotection, coronary artery
disease, angina,
ischemia, and incontinence.
4-fluoro-3-iodo-benzaldehyde was previously synthesized in five steps as shown
in
Scheme 1. In summary, 4-fluorobenzoic acid (1) is converted to 4-fluoro-3-
nitrobenzoic acid (2)
which is then reduced to the corresponding amine (3). Further reduction
results in the alcohol
(4) and subsequent iodination (5) and oxidation ultimately leads to the
iodinated benzaldehyde
(6).
CA 02476824 2004-08-19
WO 03/070678 PCT/US03/03082
F F F
F
NOp ~ NHy ~ NHz
COZH COyH COpH
HO 4
2
F F
F
NHz ~ I I
HO 4 HO 5 CHO 6
Another process for producing 4-fluoro-3-iodobenzaldehyde is shown in Scheme
II.
There are disadvantages to this process as 4-fluoro-3-bromo-benzaldehyde is
relatively
expensive as a starting material and the process requires low temperature
conditions.
Scheme II
F
F F
Br ~ Br ~ I
CHO ~ 8 6
CHO
O
O
2
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The present invention relates to a process for producing an intermediate that
is used to
make a dihydropyridine potassium channel opener.
Detailed Description of the Invention
The present invention relates to an efficient synthesis of 4-fluoro-3-iodo-
benzaldehyde by
iodinating 4-fluoro-benzaldehyde. 4-Fluoro-3-iodo-benzaldehyde is a key
intermediate in the
manufacture of the potassium channel opener, 5-(4-fluoro-3-iodophenyl)-5,10
dihydro-1H,3H-
dipyrano[3,4-b:4,3-a]pyridine-4,6(7H,9H) dione.
The present invention relates to an improved process for iodinating
benzaldehydes. As
shown in Scheme III, the improved process allows for a one- step procedure for
synthesizing 4-
fluoro-3-iodo-benzaldehyde. 4-Fluoro-3-iodobenzaldehyde is synthesized by
combining 4-
fluorobenzaldehyde and N-iodosuccinimide in an acid medium. Preferably, the 4-
Fluoro-3-
iodobenzaldehyde and N-iodosuccinimide are in a 1:1.2 equivalents ratio
respectively.
Suitable acids for use in the present invention include organic acids and
inorganic acids.
An example of organic acids suitable for use in the present invention
includes, but is not
intended to be limited to, trifluoromethanesulfonic acid.
Inorganic acids are suitable for use in the present invention as well.
Inorganic acids
suitable for use in the present invention include, but is not intended to be
limited to, nitric acid,
sulfuric acid, and hydrochloride acid.
The inorganic acid may be used in combination with acetic acid as well. Acetic
acid is
used for solubility purposes. A strong inorganic acid/acetic acid combination
is suitable for use
in the present invention. Preferably, the inorganic acid/acetic acid
combination is in a 1:1 ratio.
Scheme III
F F
I
( N-Iodosuccinimide
Acid
10 CHO 6 CHO
3
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Example 1
4-Fluorobenzaldehyde (40.0 g), N-iodosuccinimide (87.1 g) and acetic acid (80
mL) were
added to a flask. Sulfuric acid (80 mL) is added slowly, maintaining the
temperature below
40°C. The resulting mixture was stirred for 2.5 h at 40 °C and
then after cooling to 10 °C, water
(400 mL) was added, maintaining the temperature below 35 °C. After
stirnng for 30 min at
room temperature the slurry was filtered and the resulting solid washed with
water (80 mL). The
wetcake was dissolved in 380 g ethyl acetate / heptane (1:1 v/v containing 250
ppm BHT) and
the solution was washed with 10% aqueous sodium thiosulfate (204 g), then with
10% aqueous
sodium carbonate (214 g), followed by 200 g water.
1 S The solution was concentrated to approximately 40 mL, and 148 g heptane
(containing
BHT) was added. This was distilled again to approximately 40 mL, to remove all
of the ethyl
acetate. Heptane (265 g) was added and the resulting mixture heated to 55
°C to dissolve the
solids The solution was cooled to approximately 40 °C and seed crystals
were added. Cooling
was continued until the temperature reached 5 °C and then the slurry
was filtered. After washing
the wetcake with cold heptane, the product was dried in a vacuum oven at 40
°C.
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