CA2476824A1 - Iodination of 4-fluoro-benzaldehyde - Google Patents
Iodination of 4-fluoro-benzaldehyde Download PDFInfo
- Publication number
- CA2476824A1 CA2476824A1 CA002476824A CA2476824A CA2476824A1 CA 2476824 A1 CA2476824 A1 CA 2476824A1 CA 002476824 A CA002476824 A CA 002476824A CA 2476824 A CA2476824 A CA 2476824A CA 2476824 A1 CA2476824 A1 CA 2476824A1
- Authority
- CA
- Canada
- Prior art keywords
- acid
- fluoro
- benzaldehyde
- inorganic
- iodination
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to an improved process for iodinating a substituted benzaldehyde
Description
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).
F F F
F
NOp ~ NHy ~ NHz COZH COyH COpH
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).
F F F
F
NOp ~ NHy ~ NHz COZH COyH COpH
F F
F
NHz ~ I I
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
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 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.
F
NHz ~ I I
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
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 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.
Claims (7)
1. A process for producing 4-fluoro-3-iodobenzaldehyde by combining 4-fluorobenzaldehyde, N-iodosuccinimide in an acid medium.
2. A process of claim 1 wherein said acid is an organic acid.
3. A process of claim 2 wherein said organic acid is trifluoromethanesulfonic acid.
4. A process of claim 1 wherein said acid is an inorganic acid.
5. A process of claim 4 wherein said inorganic acid is selected from the group consisting of nitric, sulfuric, and hydrochloric acid.
6. A process of claim 1 wherein said acid is an inorganic acid in combination with acetic acid.
7. A process of claim 4 herein said inorganic acid/acetic acid combination is in a 1:1 ratio.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7861702A | 2002-02-19 | 2002-02-19 | |
| US10/078,617 | 2002-02-19 | ||
| PCT/US2003/003082 WO2003070678A1 (en) | 2002-02-19 | 2003-02-03 | Iodination of 4-fluoro-benzaldehyde |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2476824A1 true CA2476824A1 (en) | 2003-08-28 |
Family
ID=27752716
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002476824A Abandoned CA2476824A1 (en) | 2002-02-19 | 2003-02-03 | Iodination of 4-fluoro-benzaldehyde |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1476415A1 (en) |
| JP (1) | JP2005525350A (en) |
| CA (1) | CA2476824A1 (en) |
| MX (1) | MXPA04008072A (en) |
| WO (1) | WO2003070678A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008143141A1 (en) * | 2007-05-18 | 2008-11-27 | Nippoh Chemicals Co., Ltd. | Method for producing halogenated aromatic compound |
| JP5295613B2 (en) * | 2008-04-07 | 2013-09-18 | 日宝化学株式会社 | Process for producing iodinated aromatic compounds |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1040097B1 (en) * | 1997-12-18 | 2004-04-14 | Abbott Laboratories | Potassium channel openers |
-
2003
- 2003-02-03 MX MXPA04008072A patent/MXPA04008072A/en unknown
- 2003-02-03 CA CA002476824A patent/CA2476824A1/en not_active Abandoned
- 2003-02-03 JP JP2003569588A patent/JP2005525350A/en not_active Withdrawn
- 2003-02-03 WO PCT/US2003/003082 patent/WO2003070678A1/en not_active Application Discontinuation
- 2003-02-03 EP EP03742706A patent/EP1476415A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| WO2003070678A1 (en) | 2003-08-28 |
| MXPA04008072A (en) | 2004-11-26 |
| JP2005525350A (en) | 2005-08-25 |
| EP1476415A1 (en) | 2004-11-17 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |