JP2005525350A - Iodination of 4-fluoro-benzaldehyde - Google Patents
Iodination of 4-fluoro-benzaldehyde Download PDFInfo
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- JP2005525350A JP2005525350A JP2003569588A JP2003569588A JP2005525350A JP 2005525350 A JP2005525350 A JP 2005525350A JP 2003569588 A JP2003569588 A JP 2003569588A JP 2003569588 A JP2003569588 A JP 2003569588A JP 2005525350 A JP2005525350 A JP 2005525350A
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- Prior art keywords
- acid
- fluoro
- benzaldehyde
- iodination
- inorganic
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- OATOZCSPTSMOIY-UHFFFAOYSA-N Fc1ccc(C2OCCO2)cc1Br Chemical compound Fc1ccc(C2OCCO2)cc1Br OATOZCSPTSMOIY-UHFFFAOYSA-N 0.000 description 1
- FAHZIKXYYRGSHF-UHFFFAOYSA-N O=Cc(cc1)cc(Br)c1F Chemical compound O=Cc(cc1)cc(Br)c1F FAHZIKXYYRGSHF-UHFFFAOYSA-N 0.000 description 1
- DGUYWJGDFCRUHC-UHFFFAOYSA-N O=Cc(cc1I)ccc1F Chemical compound O=Cc(cc1I)ccc1F DGUYWJGDFCRUHC-UHFFFAOYSA-N 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
Abstract
本発明は、置換されたベンズアルデヒドをヨウ素化するための改良された方法に関する。The present invention relates to an improved process for iodination of substituted benzaldehydes.
Description
カリウムチャンネルは、細胞膜の興奮の調整において、重要な役割を果たす。カリウムチャンネルが開くときに、細胞膜を横切って電位に変化が生じ、その結果としてさらなる分極状態となる。多くの病気又は病状が、カリウムチャンネルを開く治療剤によって治療され得る；例えば、（Ｋ．Ｌａｗｓｏｎ，Ｐｈａｒｍａｃｏｌ．Ｔｈｅｒ．，第７０巻，３９−６３頁（１９９６））；（Ｄ．Ｒ．Ｇｅｈｌｅｒｔ等，Ｐｒｏｇ．Ｎｅｕｒｏ−Ｐｓｙｃｈｏｐｈａｒｍａｃｏｌ ＆ Ｂｉｏｌ．Ｐｓｙｃｈｉａｔ．，第１８巻，１０９３−１１０２頁（１９９４））；（Ｍ．Ｇｏｐａｌａｋｒｉｓｈｎａｎ等，Ｄｒｕｇ Ｄｅｖｅｌｏｐｍｅｎｔ Ｒｅｓｅｒｃｈ，第２８巻，９５−１２７頁（１９９３））；（Ｊ．Ｅ．Ｆｒｅｅｄｍａｎ等，Ｔｈｅ Ｎｅｕｒｏｓｃｉｅｎｔｉｓｔ，第２巻，１４５−１５２頁（１９９６））；（Ｄ．Ｅ．Ｎｕｒｓｅ等，Ｂｒ．Ｊ．Ｕｒｏｌ．，第６８巻 ２７−３１頁（１９９１））；（Ｂ．Ｂ．Ｈｏｗｅ等，Ｊ．Ｐｈａｒｍａｃｏｌ．Ｅｘｐ．Ｔｈｅｒ．，第２７４巻 ８８４−８９０頁（１９９５））；（Ｄ．Ｓｐａｎｓｗｉｃｋ等，Ｎａｔｕｒｅ，第３９０巻 ５２１−２５頁（１９９７年１２月４日））；（Ｄｏｍｐｅｌｉｎｇ Ｖａｓａ．Ｓｕｐｐｌｅｍｅｎｔｕｍ（１９９２）３４３４）；（ＷＯ９９３２４９５）；（Ｇｒｏｖｅｒ，Ｊ Ｍｏｌ Ｃｅｌｌ Ｃａｒｄｉｏｌ．（２０００）３２，６７７）；及び（Ｂｕｃｈｈｅｉｔ，Ｐｕｌｍｏｎａｒｙ Ｐｈａｒｍａｃｏｌｏｇｙ ＆ Ｔｈｅｒａｐｅｕｔｉｃｓ（１９９９）１２，１０３）を参照されたい。前記の病気又は病状には、喘息、癲癇、男性機能障害、女性機能障害、疼痛、膀胱過活動、脳卒中、レイノー現象及び間欠性跛行のような骨血流量の減少に伴う病気、摂食障害、機能性腸疾患、神経変性、良性前立腺過形成（ＢＰＨ）、月経困難症、早産、脱毛、心臓保護、冠動脈疾患、アンギナ、虚血、及び失禁が含まれる。 Potassium channels play an important role in regulating cell membrane excitation. When the potassium channel opens, a change in potential occurs across the cell membrane, resulting in a further polarization state. Many diseases or conditions can be treated with therapeutic agents that open potassium channels; for example, (K. Lawson, Pharmacol. Ther., 70, 39-63 (1996)); (DR Gehrert et al. , Prog. Neuro-Psychopharmacol & Biol. Psychiat., 18, pp. 1093-1102 (1994)); (E. Freeman et al., The Neuroscientist, Volume 2, pages 145-152 (1996)); (DE Nurse et al., Br. J. Urol., Volume 68 pages 27-31 (1991)); BB How , J. Pharmacol. Exp. Ther., 274, 884-890 (1995)); (D. Spanswick et al., Nature, 390, 521-25 (December 4, 1997)); Vasa.Supplementum (1992) 3434); (WO9932495); (Glover, J Mol Cell Cardiol. (2000) 32,677); and (Buchheit, Pulmonary Pharmacology & Therapeutics (see 1999) 12, 103). The above diseases or conditions include asthma, epilepsy, male dysfunction, female dysfunction, pain, bladder overactivity, stroke, Raynaud's phenomenon and intermittent claudication, bone loss, eating disorders, function Genital bowel disease, neurodegeneration, benign prostatic hyperplasia (BPH), dysmenorrhea, premature birth, hair loss, cardioprotection, coronary artery disease, angina, ischemia, and incontinence.
４−フルオロ−３−ヨード−ベンズアルデヒドは、これまでに、スキーム１に示される５工程で合成された。要約すれば、４−フルオロ安息香酸（１）を、４−フルオロ−３−ニトロ安息香酸（２）に変換して、その後、対応するアミン（３）に還元する。さらに還元してアルコール（４）にして、引き続いてヨウ素化（５）し、酸化して、最終的にヨウ素化ベンズアルデヒド（６）とする。 4-Fluoro-3-iodo-benzaldehyde has so far been synthesized in 5 steps as shown in Scheme 1. In summary, 4-fluorobenzoic acid (1) is converted to 4-fluoro-3-nitrobenzoic acid (2) and then reduced to the corresponding amine (3). Further reduction to alcohol (4), followed by iodination (5), oxidation, and finally iodinated benzaldehyde (6).
４−フルオロ−３−ヨードベンズアルデヒドの他の合成方法は、スキームＩＩに示される。４−フルオロ−３−ブロモ−ベンズアルデヒドが出発原料としては比較的高価であり、本方法が低温条件を必要とすることから、本方法は不利である。 Another method for the synthesis of 4-fluoro-3-iodobenzaldehyde is shown in Scheme II. This process is disadvantageous because 4-fluoro-3-bromo-benzaldehyde is relatively expensive as a starting material and the process requires low temperature conditions.
本発明は、カリウムチャンネル開口剤であるジヒドロピリジンの合成に有用な中間体の合成方法に関する。 The present invention relates to a method for synthesizing intermediates useful in the synthesis of dihydropyridine, a potassium channel opener.
（発明の詳細な説明）
本発明は、４−フルオロ−ベンズアルデヒドのヨウ素化による４−フルオロ−３−ヨード−ベンズアルデヒドの効率的な合成に関する。４−フルオロ−３−ヨード−ベンズアルデヒドは、カリウムチャンネル開口剤である５−（４−フルオロ−３−ヨードフェニル）−５，１０ジヒドロ−１Ｈ，３Ｈ−ジピラノ［３，４−ｂ：４，３−ｅ］ピリジン−４，６（７Ｈ，９Ｈ）ジオンの製造における鍵となる中間体である。
(Detailed description of the invention)
The present invention relates to an efficient synthesis of 4-fluoro-3-iodo-benzaldehyde by iodination of 4-fluoro-benzaldehyde. 4-Fluoro-3-iodo-benzaldehyde is a potassium channel opener 5- (4-fluoro-3-iodophenyl) -5,10 dihydro-1H, 3H-dipyrano [3,4-b: 4,3 -E] is a key intermediate in the production of pyridine-4,6 (7H, 9H) dione.
本発明は、ベンズアルデヒドのヨウ素化のための改良された方法に関する。スキームＩＩＩに示されるように、この改良された方法は、１工程の手順での４−フルオロ−３−ヨード−ベンズアルデヒドの合成を可能にする。４−フルオロ−３−ヨードベンズアルデヒドは、４−フルオロベンズアルデヒドとＮ−ヨードスクシンイミドとを酸媒体中で合わせることによって合成される。好ましくは、４−フルオロ−３−ヨードベンズアルデヒドとＮ−ヨードスクシンイミドは、それぞれ１：１．２の当量比にある。 The present invention relates to an improved process for iodination of benzaldehyde. As shown in Scheme III, this improved method allows the synthesis of 4-fluoro-3-iodo-benzaldehyde in a one-step procedure. 4-Fluoro-3-iodobenzaldehyde is synthesized by combining 4-fluorobenzaldehyde and N-iodosuccinimide in an acid medium. Preferably, 4-fluoro-3-iodobenzaldehyde and N-iodosuccinimide are each in an equivalent ratio of 1: 1.2.
本発明における使用に適した酸には、有機酸及び無機酸が含まれる。本発明における使用に適した有機酸の例には、トリフルオロメタンスルホン酸が含まれるがこれに限定されない。 Acids suitable for use in the present invention include organic and inorganic acids. Examples of organic acids suitable for use in the present invention include, but are not limited to, trifluoromethanesulfonic acid.
無機酸も同様に、本発明における使用に適している。本発明における使用に適した無機酸には、硝酸、硫酸、及び塩酸が含まれるがこれらに限定されない。 Inorganic acids are likewise suitable for use in the present invention. Inorganic acids suitable for use in the present invention include, but are not limited to, nitric acid, sulfuric acid, and hydrochloric acid.
上記無機酸は、また、酢酸と組み合わせて使用されてもよい。酢酸は溶解性の目的で使用される。強無機酸／酢酸の組み合わせが、本発明における使用に適している。好ましくは、無機酸／酢酸の組み合わせは、１：１の比率にある。 The inorganic acid may also be used in combination with acetic acid. Acetic acid is used for solubility purposes. Strong inorganic acid / acetic acid combinations are suitable for use in the present invention. Preferably, the inorganic acid / acetic acid combination is in a 1: 1 ratio.
４−フルオロベンズアルデヒド（４０．０ｇ）、Ｎ−ヨードスクシンイミド（８７．１ｇ）、及び酢酸（８０ｍＬ）をフラスコに添加した。４０℃より低い温度に維持して、硫酸（８０ｍＬ）をゆっくりと添加する。得られた混合物を４０℃で２．５時間攪拌して、その後、１０℃に冷却した後に、３５℃より低い温度に維持しながら、水（４００ｍＬ）を添加した。室温で３０分間攪拌した後、スラリーを濾過し、得られた固形物を水（８０ｍＬ）で洗浄した。ウエットケーキを３８０ｇの酢酸エチル／ヘプタン（１：１ｖ／ｖ ２５０ｐｐｍのＢＨＴを含有）に溶解し、溶液を、１０％チオ硫酸ナトリウム水溶液（２０４ｇ）で洗浄し、その後１０％炭酸ナトリウム水溶液（２１４ｇ）で洗浄し、続けて２００ｇの水で洗浄した。 4-Fluorobenzaldehyde (40.0 g), N-iodosuccinimide (87.1 g), and acetic acid (80 mL) were added to the flask. Sulfuric acid (80 mL) is added slowly, maintaining the temperature below 40 ° C. The resulting mixture was stirred at 40 ° C. for 2.5 hours, then cooled to 10 ° C. and then water (400 mL) was added while maintaining the temperature below 35 ° C. After stirring at room temperature for 30 minutes, the slurry was filtered and the resulting solid was washed with water (80 mL). The wet cake is dissolved in 380 g ethyl acetate / heptane (1: 1 v / v containing 250 ppm BHT) and the solution is washed with 10% aqueous sodium thiosulfate (204 g) followed by 10% aqueous sodium carbonate (214 g). Followed by 200 g of water.
溶液を濃縮して約４０ｍＬにして、１４８ｇのヘプタン（ＢＨＴを含有）を添加した。これを再び蒸留して約４０ｍＬにして、全ての酢酸エチルを除去した。ヘプタン（２６５ｇ）を添加して、得られた混合物を５５℃に加熱して、固形物を溶解させた。溶液を約４０℃に冷却し、種結晶を添加した。温度が５℃になるまで冷却を続け、その後、スラリーを濾過した。ウエットケーキを冷ヘプタンで洗浄し、その後、生成物を４０℃の真空オーブンで乾燥した。 The solution was concentrated to about 40 mL and 148 g heptane (containing BHT) was added. This was distilled again to about 40 mL to remove all ethyl acetate. Heptane (265 g) was added and the resulting mixture was heated to 55 ° C. to dissolve the solid. The solution was cooled to about 40 ° C. and seed crystals were added. Cooling was continued until the temperature reached 5 ° C., after which the slurry was filtered. The wet cake was washed with cold heptane, after which the product was dried in a vacuum oven at 40 ° C.
Claims (7)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
|---|---|
| JP2005525350A true JP2005525350A (en) | 2005-08-25 |
Family
ID=27752716
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2003569588A Withdrawn JP2005525350A (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) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008285473A (en) * | 2008-04-07 | 2008-11-27 | Nippo Kagaku Kk | Method for producing iodinated aromatic compound |
| JP5248489B2 (en) * | 2007-05-18 | 2013-07-31 | 日宝化学株式会社 | Method for producing halogenated aromatic compound |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2222000T3 (en) * | 1997-12-18 | 2005-01-16 | Abbott Laboratories | COMPOUNDS THAT OPEN THE POTASSIUM CHANNELS. |
-
2003
- 2003-02-03 WO PCT/US2003/003082 patent/WO2003070678A1/en not_active Application Discontinuation
- 2003-02-03 JP JP2003569588A patent/JP2005525350A/en not_active Withdrawn
- 2003-02-03 CA CA002476824A patent/CA2476824A1/en not_active Abandoned
- 2003-02-03 EP EP03742706A patent/EP1476415A1/en not_active Withdrawn
- 2003-02-03 MX MXPA04008072A patent/MXPA04008072A/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5248489B2 (en) * | 2007-05-18 | 2013-07-31 | 日宝化学株式会社 | Method for producing halogenated aromatic compound |
| JP2008285473A (en) * | 2008-04-07 | 2008-11-27 | Nippo Kagaku Kk | Method for producing iodinated aromatic compound |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2003070678A1 (en) | 2003-08-28 |
| MXPA04008072A (en) | 2004-11-26 |
| CA2476824A1 (en) | 2003-08-28 |
| EP1476415A1 (en) | 2004-11-17 |
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