WO1993025531A1 - Type a crystal of naphthol derivative - Google Patents
Type a crystal of naphthol derivative Download PDFInfo
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- WO1993025531A1 WO1993025531A1 PCT/JP1993/000733 JP9300733W WO9325531A1 WO 1993025531 A1 WO1993025531 A1 WO 1993025531A1 JP 9300733 W JP9300733 W JP 9300733W WO 9325531 A1 WO9325531 A1 WO 9325531A1
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- crystal
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- naphthol
- quinolylmethoxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
Definitions
- the present invention provides a naphthol derivative having a 5-lipoxygenase inhibitory activity and useful as an anti-inflammatory agent, for example, (+)-2,2-dibutyl-1-5- (2-quinolylmethoxy) -1,1,2,3 It relates to a new type A crystal of 4-tetrahydro-11-naphthol.
- (+) — 2,2-Dibutyl-1- (2-quinolylmethoxy) -1,1,2,3,4-tetrahydro-1-naphthol is known as a substance having an inhibitory action on 5-lipoxygenase (for example, see JP-A-63-
- this known crystal is relatively unstable, such as being slightly colored or slightly decomposed by light. For this reason, there has been a problem in producing a more stable crystal form free of such defects.
- the type A crystal of the novel crystal of the present invention ie, (+)-2,2-dibutyl-5- (2-quinolylmethoxy) -1,2,3,4-tetrahydro-1-naphthol has the following physical properties. These physical properties are different from those of known crystals (the physical properties of other A-type crystals are the same as those of known crystals).
- B-type crystals 1,2,3,4-tetrahydro-1-naphthol
- the A-type crystal of the present invention can be produced, for example, by using the B-type crystal with n-hexane, n-heptane, isopropanol, hydrated isopropanol, or the like, for example, by the method described in Examples below.
- FIG. 1 is an X-ray diffraction chart of the A-type crystal according to the present invention
- FIG. 2 is an infrared absorption spectrum of the A-type crystal according to the present invention.
- irradiation was performed at an illuminance of about 30000 lux for 5 days.
- Freshly distilled tetrahydrofuran of lithium aluminum hydride (3.80 g) A freshly distilled tetrahydrofuran (60 ml) solution of (S)-(-) 4-anilinol 3-methylbutanol (1.96 g) in a suspension in orchid (120 ml) Is added dropwise over 1.5 hours in a nitrogen gas atmosphere while cooling in an ice bath. The suspension is stirred at room temperature for 1 hour and then cooled to 163 ° C.
- the crude B-type crystal (100 g) obtained by the method of Production Example 1 was dissolved in n-heptane (800 ml) at 60 to 70 ° C, and charcoal powder (5 g) was added. Stir for a minute and filter out the charcoal dust. The charcoal powder etc. which has been filtered off is washed with n-heptane (700 ml). The filtrate and washing solution are combined, cooled to 40 ° C, and seed crystals (0.1 g) are added to precipitate crystals. After cooling to 30 ° C, raise the temperature again to 38-40 ° C to improve scaling and fluidity. Thereafter, the mixture is cooled to 10 ° C or less, and aged for 1 hour or more, and the precipitated crystals are collected by filtration.
- the crude B-type crystal (100 g) obtained by the method of Production Example 1 is dissolved in isopropanol (400 ml) at 30 to 40 ° C, and then clarified and filtered through a filter. Wash the filter with isopropanol (200 ml). The filtrate and washing solution are combined, cooled to 5 ° C, seed crystals (0.1 g) are added to precipitate crystals, and the mixture is further stirred and aged at the same temperature for 3 hours.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
Abstract
Description
明細書 ナフトール誘導体の A型結晶 技術分野 Description A-type crystal of naphthol derivative
この発明は、 5—リポキシゲナーゼ阻害作用を有し、 例えば抗炎症剤として有 用なナフトール誘導体、 (+ ) - 2, 2—ジブチル一 5— （2—キノリルメ トキ シ） 一 1， 2, 3, 4ーテトラヒドロ— 1一ナフトールの A型結晶の新規な結晶 に関するものである。 背景技術 The present invention provides a naphthol derivative having a 5-lipoxygenase inhibitory activity and useful as an anti-inflammatory agent, for example, (+)-2,2-dibutyl-1-5- (2-quinolylmethoxy) -1,1,2,3 It relates to a new type A crystal of 4-tetrahydro-11-naphthol. Background art
(+ ) — 2, 2—ジブチル一 5— (2—キノリルメ トキシ） 一 1， 2， 3， 4 ーテトラヒドロー 1—ナフトールは 5—リポキシゲナーゼ阻害作用を有する物質 として公知である （例えば特開昭 63 - 301840号公報参照) が、 この公知 の結晶は、 光りに対してやや着色するとか、 やや分解する等、 比較的不安定であ る。 このためこのような欠点のないより安定な結晶型の製造が課題であった。 (+) — 2,2-Dibutyl-1- (2-quinolylmethoxy) -1,1,2,3,4-tetrahydro-1-naphthol is known as a substance having an inhibitory action on 5-lipoxygenase (for example, see JP-A-63- However, this known crystal is relatively unstable, such as being slightly colored or slightly decomposed by light. For this reason, there has been a problem in producing a more stable crystal form free of such defects.
発明の開示 Disclosure of the invention
この発明の新規結晶すなわち （+ ) — 2， 2—ジブチルー 5— (2—キノリル メ トキシ） — 1， 2, 3, 4—テトラヒ ドロ— 1一ナフ トールの A型結晶は以下 の物性値を有し、 これらの物性値は公知の結晶の物性値と異なる （他の A型結晶 の物性値は公知のそれと同じ） 。 The type A crystal of the novel crystal of the present invention, ie, (+)-2,2-dibutyl-5- (2-quinolylmethoxy) -1,2,3,4-tetrahydro-1-naphthol has the following physical properties. These physical properties are different from those of known crystals (the physical properties of other A-type crystals are the same as those of known crystals).
( 1 ) mp ：約 85 °C (1) mp: about 85 ° C
( 2 ) 粉末 X線回折：図 1に示す通り (2) X-ray powder diffraction: as shown in Figure 1
(3) 赤外線吸収スぺク トル：図 2に示す通り (3) Infrared absorption spectrum: As shown in Fig. 2
(4) 溶解度： 5。C 70%イソプロパノール 12. 9mg/m 1 (4) Solubility: 5. C 70% isopropanol 12.9mg / m 1
5°C 60%イソプロパノール 4. 6mg/m 1 この発明の原料化合物 （+ ) — 2， 2—ジブチル— 5— （2—キノリルメ トキ シ） — 1 , 2， 3， 4 —テトラヒ ドロ— 1 一ナフ トールの粉末、 結晶は （以下 B 型結晶という） は例えば後記の製造例により製造することができる。 5 ° C 60% isopropanol 4.6 mg / m 1 Raw material compound of the present invention (+) — 2,2-dibutyl-5- (2-quinolylmethoxy B) Powders and crystals of 1,2,3,4-tetrahydro-1-naphthol (hereinafter referred to as B-type crystals) can be produced, for example, by the following production example.
この発明の A型結晶は、 例えば B型結晶を n—へキサン、 n—ヘプタン、 イソ プロパノール、 含水ィソプロパノ一ル等を用いて例えば後述の実施例の方法によ り製造することができる。 図面の簡単な説明 The A-type crystal of the present invention can be produced, for example, by using the B-type crystal with n-hexane, n-heptane, isopropanol, hydrated isopropanol, or the like, for example, by the method described in Examples below. BRIEF DESCRIPTION OF THE FIGURES
第 1図は、 この発明にかかる A型結晶の X線回折チャー トであり、 第 2図は、 こ の発明にかかる A型結晶の赤外線吸収スベク トルである。 FIG. 1 is an X-ray diffraction chart of the A-type crystal according to the present invention, and FIG. 2 is an infrared absorption spectrum of the A-type crystal according to the present invention.
A型結晶の有用性を示すために、 光照射による A型結晶の安定性についての試 験を行った。 In order to demonstrate the usefulness of A-type crystals, we conducted tests on the stability of A-type crystals by light irradiation.
試験法 Test method
メタルハライ ドランプを使用し、 照度約 3 0 0 0 0ルクスで 5日間照射を行つ た。 一 Using a metal halide lamp, irradiation was performed at an illuminance of about 30000 lux for 5 days. One
試^ Try ^
HPLC ： 高速液体ク口マトグラフィ— HPLC: High performance liquid mouth chromatography
実施例 Example
以下、 実施例によりこの発明を説明する。 Hereinafter, the present invention will be described with reference to examples.
製造例 1 Production Example 1
水素化アルミニウムリチウム （3 . 8 0 g ) の新たに蒸留したテトラヒドロフ ラン （120m l) 中懸濁液に、 （S) — (-) 一 4一ァニリノー 3—メチルァ ミノ一 1ーブタノ一ル （ 19. 96 g) の新たに蒸留したテ トラヒ ドロフラン (60m l ) 溶液を、 氷浴中冷却下窒素ガス雰囲気中 1時間半かけて滴下する。 懸濁液を常温で 1時間攪拌し、 次いで一 63°Cに冷却する。 懸濁液に 2, 2—ジ プチルー 3， 4ージヒ ドロー 5— (2—キノ リルメ トキシ） 一 1一 （2 H) —ナ フタレノン （13. 84 g) の新たに蒸留したテトラヒ ドロフラン （60m l) 溶液を同温で半時間かけて滴下する。 混合物を- 61°C〜- 63 °Cで 2時間攪拌 し、 0°Cに加温する。 混合物に塩化アンモニゥム飽和水溶液 （250m l) を、 氷浴中反応温度を 12 °C未満に保ちながら注意して加え、 これにジェチルェ一テ ノレ （100m 1 ) を加える。 Freshly distilled tetrahydrofuran of lithium aluminum hydride (3.80 g) A freshly distilled tetrahydrofuran (60 ml) solution of (S)-(-) 4-anilinol 3-methylbutanol (1.96 g) in a suspension in orchid (120 ml) Is added dropwise over 1.5 hours in a nitrogen gas atmosphere while cooling in an ice bath. The suspension is stirred at room temperature for 1 hour and then cooled to 163 ° C. Add 2,2-dibutyl-3,4-dihydro-5- (2-quinolylmethoxy) -111 (2H) -naphthalenone (13.84 g) to the suspension in freshly distilled tetrahydrofuran (60 ml). ) The solution is added dropwise at the same temperature over half an hour. The mixture is stirred at -61 ° C to -63 ° C for 2 hours and warmed to 0 ° C. A saturated aqueous solution of ammonium chloride (250 ml) is carefully added to the mixture while keeping the reaction temperature below 12 ° C in an ice bath, and to this is added the ethyl acetate (100 ml).
分離する水層をジェチルエーテルで 3回抽出する。 有機層を合わせて 1 Nクェ ン酸水溶液、 食塩水、 炭酸水素ナトリウム水溶液および食塩水で洗浄する。 有機 層を硫酸マグネシゥムで乾燥し、 減圧濃縮して得られる無定形固体をメタノール から結晶化させて、 （+ ) —2， 2—ジブチル— 5— （2—キノ リルメ トキシ） 一 1， 2， 3, 4ーテドラヒ ドロー 1—ナフ トール （13. 81 g) を白 (粗 B型結晶） を得る。 実施例 1 Extract the separated aqueous layer three times with getyl ether. Combine the organic layers and wash with 1N aqueous citric acid, brine, aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the resulting amorphous solid was crystallized from methanol to give (+)-2,2-dibutyl-5- (2-quinolylmethoxy) 1-1,2, 3,4-Tedrahedro 1-naphthol (13.81 g) was obtained as white (crude B-type crystal). Example 1
製造例 1の方法により得られた粗 B型結晶 （ 1 00 g) を n—ヘプタ ン (800m 1 ) に 60〜70°Cで溶解後、 炭末 （5 g) を加え、 同温で 15分間 攪拌し、 炭末を濾去する。 濾去した炭末等は n—ヘプタン （700m l) で洗浄 する。 濾液と洗液を合わせ、 40°Cまで冷却し、 種晶 （0. 1 g) を加え、 結晶 を析出させる。 30°Cまで冷却した後、 スケーリ ング、 流動性等を改善するた め、 再度 38〜40°Cまで昇温する。 その後、 10°C以下まで冷却、 1時間以上 熟成後、 析出結晶を濾取する。 濾取した結晶は、 n—ヘプタン （200m l ) で 洗浄後、 一夜真空乾燥し、 （ + ) —2， 2—ジブチルー 5— （2—キノ リルメ ト キシ） 一 1， 2， 3， 4—テトラヒ ドロ一 1一ナフ トールの粗 A型結晶 （91. 5 g) を得る。 The crude B-type crystal (100 g) obtained by the method of Production Example 1 was dissolved in n-heptane (800 ml) at 60 to 70 ° C, and charcoal powder (5 g) was added. Stir for a minute and filter out the charcoal dust. The charcoal powder etc. which has been filtered off is washed with n-heptane (700 ml). The filtrate and washing solution are combined, cooled to 40 ° C, and seed crystals (0.1 g) are added to precipitate crystals. After cooling to 30 ° C, raise the temperature again to 38-40 ° C to improve scaling and fluidity. Thereafter, the mixture is cooled to 10 ° C or less, and aged for 1 hour or more, and the precipitated crystals are collected by filtration. The collected crystals were washed with n-heptane (200 ml), dried in vacuum overnight, and (+)-2,2-dibutyl-5- (2-quinolylmethoxy) -1,2,3,4- Crude Form A crystals of tetrahydro-11-naphthol (91.5 g) are obtained.
融点：約 85 C IR(Nu〕'ol)cm一1 ： 3590, 1588, 1262, 1096, 819, 782 Melting point: approx. 85 C IR (Nu) 'ol) cm- 1 : 3590, 1588, 1262, 1096, 819, 782
h NMR( δ , ppm) ： 0.6-1. Km, 6H), 1.0-2. Km, 14H), 1.79(d, IH), 2.4-3.2(m, 2H)， 4.37 (d, IH), 5.37(s, 2H), 6.7-8.3(m, 9H) 実施例 2 h NMR (δ, ppm): 0.6-1. Km, 6H), 1.0-2. Km, 14H), 1.79 (d, IH), 2.4-3.2 (m, 2H), 4.37 (d, IH), 5.37 (s, 2H), 6.7-8.3 (m, 9H) Example 2
製造例 1の方法により得られた粗 B型結晶 （100 g) をイソプロパノール (400m l) に 30〜40°Cで溶解後、 フィルタ一で清澄濾過を行う。 フィル ター等はイソプロパノール （200m l) で洗浄する。 濾液と洗液を合わせ、 5 °Cまで冷却し、 種晶 （0. 1 g) を加え、 結晶を析出させ、 さらに同温で 3時間 攪拌、 熟成させる。 あらかじめ 5 °C付近まで冷却した 33. 3%イソプロパノ一 ル水溶液 （900ml) を 0〜5°Cで 10分間を要して滴下させ、 結晶を更に析 出させる。 滴下後、 10分間攪拌し、 静置後、 析出結晶を濾取する。 濾取した結 晶は 50%イソプロパノール水溶液 （300ml) で洗浄後、 一夜真空乾燥し、 (+ ) — 2， 2—ジブチルー 5— (2—キノ リルメ トキシ） 一 1， 2， 3, 4一 テトラヒドロ— 1—ナフトールの粗 A型結晶 （91. 5 g) を得る。 The crude B-type crystal (100 g) obtained by the method of Production Example 1 is dissolved in isopropanol (400 ml) at 30 to 40 ° C, and then clarified and filtered through a filter. Wash the filter with isopropanol (200 ml). The filtrate and washing solution are combined, cooled to 5 ° C, seed crystals (0.1 g) are added to precipitate crystals, and the mixture is further stirred and aged at the same temperature for 3 hours. A 33.3% isopropanol aqueous solution (900 ml), which has been cooled to around 5 ° C in advance, is added dropwise at 0 to 5 ° C over 10 minutes to further precipitate crystals. After the dropwise addition, the mixture is stirred for 10 minutes, allowed to stand, and the precipitated crystals are collected by filtration. The crystals collected by filtration were washed with a 50% aqueous solution of isopropanol (300 ml), dried in vacuo overnight, and (+)-2,2-dibutyl-5- (2-quinolylmethoxy) -1,2,3,4-tetrahydrofuran — Obtain crude A-form crystals of 1-naphthol (91.5 g).
融点、 I R、 1 HNMR、 X線の値は実施例 1で得られる粗 A型結晶の場合と 同じ。 The melting point, IR, 1 HNMR, and X-ray values are the same as those of the crude A-type crystal obtained in Example 1.
Claims
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17928192 | 1992-06-13 | ||
| JP4/179281 | 1992-06-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1993025531A1 true WO1993025531A1 (en) | 1993-12-23 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1993/000733 Ceased WO1993025531A1 (en) | 1992-06-13 | 1993-05-31 | Type a crystal of naphthol derivative |
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| Country | Link |
|---|---|
| WO (1) | WO1993025531A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63301840A (en) * | 1987-04-28 | 1988-12-08 | Fujisawa Pharmaceut Co Ltd | Novel bicyclic compound, method for producing the same, and pharmaceutical composition containing the same |
-
1993
- 1993-05-31 WO PCT/JP1993/000733 patent/WO1993025531A1/en not_active Ceased
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63301840A (en) * | 1987-04-28 | 1988-12-08 | Fujisawa Pharmaceut Co Ltd | Novel bicyclic compound, method for producing the same, and pharmaceutical composition containing the same |
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