EP1476415A1 - Iodination of 4-fluoro-benzaldehyde - Google Patents
Iodination of 4-fluoro-benzaldehydeInfo
- Publication number
- EP1476415A1 EP1476415A1 EP03742706A EP03742706A EP1476415A1 EP 1476415 A1 EP1476415 A1 EP 1476415A1 EP 03742706 A EP03742706 A EP 03742706A EP 03742706 A EP03742706 A EP 03742706A EP 1476415 A1 EP1476415 A1 EP 1476415A1
- Authority
- EP
- European Patent Office
- 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.)
- Withdrawn
Links
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 title claims description 6
- 230000026045 iodination Effects 0.000 title description 3
- 238000006192 iodination reaction Methods 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- 150000007522 mineralic acids Chemical class 0.000 claims description 10
- DGUYWJGDFCRUHC-UHFFFAOYSA-N 4-fluoro-3-iodobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1I DGUYWJGDFCRUHC-UHFFFAOYSA-N 0.000 claims description 8
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 150000007524 organic acids Chemical class 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 150000003935 benzaldehydes Chemical class 0.000 abstract description 3
- 230000002083 iodinating effect Effects 0.000 abstract description 3
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 abstract 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 abstract 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- BBYDXOIZLAWGSL-UHFFFAOYSA-N 4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1 BBYDXOIZLAWGSL-UHFFFAOYSA-N 0.000 description 3
- 102000004257 Potassium Channel Human genes 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 108020001213 potassium channel Proteins 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- BOJWTAQWPVBIPG-UHFFFAOYSA-N 4-fluoro-3-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C([N+]([O-])=O)=C1 BOJWTAQWPVBIPG-UHFFFAOYSA-N 0.000 description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 2
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000004036 potassium channel stimulating agent Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- FAHZIKXYYRGSHF-UHFFFAOYSA-N 3-bromo-4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1Br FAHZIKXYYRGSHF-UHFFFAOYSA-N 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 208000030814 Eating disease Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000019454 Feeding and Eating disease Diseases 0.000 description 1
- 206010057671 Female sexual dysfunction Diseases 0.000 description 1
- 206010021639 Incontinence Diseases 0.000 description 1
- 206010022562 Intermittent claudication Diseases 0.000 description 1
- 206010057672 Male sexual dysfunction Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000006399 Premature Obstetric Labor Diseases 0.000 description 1
- 206010036600 Premature labour Diseases 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 208000012322 Raynaud phenomenon Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000005961 cardioprotection Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 235000014632 disordered eating Nutrition 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 208000021156 intermittent vascular claudication Diseases 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000010915 one-step procedure Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 208000026440 premature labor Diseases 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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
Definitions
- Potassium channels play an important role in regulating cell membrane excitability.
- 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.
- 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.
- BPH benign prostatic hyperplasia
- dysmenorrhea premature labor
- alopecia
- 4-fluoro-3-iodo-benzaldehyde was previously synthesized in five steps as shown in Scheme 1.
- 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).
- the present invention relates to a process for producing an intermediate that is used to make a dihydropyridine potassium channel opener.
- 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-lH,3H- dipyrano[3,4-b:4,3-e]pyridine-4,6(7H,9H) dione.
- the present invention relates to an improved process for iodinating benzaldehydes.
- 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.
- 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.
- the inorganic acid/acetic acid combination is in a 1:1 ratio.
- 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.
- the solution was concentrated to approximately 40 mL, and 148 g heptane (containing
Landscapes
- 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
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); (WO9932495); (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).
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
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-lH,3H- dipyrano[3,4-b:4,3-e]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
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 stirring 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. 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
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 |
|---|---|---|---|
| US78617 | 1987-07-28 | ||
| US7861702A | 2002-02-19 | 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 |
|---|---|
| EP1476415A1 true EP1476415A1 (en) | 2004-11-17 |
Family
ID=27752716
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP03742706A Withdrawn EP1476415A1 (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 |
|---|---|---|---|---|
| CN1158259C (en) * | 1997-12-18 | 2004-07-21 | 艾博特公司 | potassium channel blocker |
-
2003
- 2003-02-03 CA CA002476824A patent/CA2476824A1/en not_active Abandoned
- 2003-02-03 WO PCT/US2003/003082 patent/WO2003070678A1/en not_active Ceased
- 2003-02-03 MX MXPA04008072A patent/MXPA04008072A/en unknown
- 2003-02-03 EP EP03742706A patent/EP1476415A1/en not_active Withdrawn
- 2003-02-03 JP JP2003569588A patent/JP2005525350A/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO03070678A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2476824A1 (en) | 2003-08-28 |
| WO2003070678A1 (en) | 2003-08-28 |
| MXPA04008072A (en) | 2004-11-26 |
| JP2005525350A (en) | 2005-08-25 |
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