JP4437223B2 - Fluorine-containing unsaturated lipid derivatives - Google Patents

Description

  The present invention relates to a novel fluorine-containing lipid derivative.

  Lipids such as saturated and unsaturated fatty acids, and lipids esterified with one and two glycerol saturated or unsaturated fatty acids have surface activity and are used for mining, metalworking, surface finishing, and cleaning. It is widely used as various industrial treatment agents, household cleaning agents and detergents, pharmaceuticals, cosmetics and food additives. Among these uses, they are particularly useful as emulsifiers, demulsifiers, detergents, dispersants, hydrotropes and the like.

Conventionally, in this type of unsaturated fatty acid glycerol ester, an acyclic phospholipid compound in which one molecule of glycerol and two molecules of saturated or unsaturated fatty acid are ester-bonded and the remaining hydroxyl group is bonded to a phosphate group in vivo. And have been synthesized by human means. These materials are under investigation to improve their properties. Among these, in the case of having a cyclic portion, it is considered that the characteristics of molecular rigidity are improved, and synthesis of cyclic phospholipids is performed.
The introduction of fluorine atoms is used as a surface improvement material using its water repellency. Furthermore, since the carbon-fluorine bond is stronger (block effect) than the carbon-hydrogen bond, introduction of fluorine atoms increases the stability of the compound. Since the fluorine atom has almost the same van der Waals radius as the hydrogen atom (mimic effect), the physical property of the compound can be changed without a structural change.

  Vierling et al. Report the synthesis of fluorinated glycerophospholipids. Glycerol has been combined with fluorinated unsaturated alcohols and esters, and a phosphocholine group, phosphoethanolamine group, or polyethylene glycol (methyl ether end) of phosphoethanolamine has been successfully introduced as a hydrophilic group. As for the unsaturation of glycerophospholipid, synthesis of only ene and diene in the ether form and only ene in the ester form has been reported (see Non-Patent Documents 1 and 2). However, in these compounds, the secondary hydroxyl group of glycerol is a racemic form (mixture of R and S forms), and chiral ethers and esters of glycerol have not been obtained. Furthermore, synthesis of ester derivatives of diene and fluorine derivatives having a triple bond have not been performed.

Lu et al. Have succeeded in synthesizing Rf—C≡C—R and Rf— (CH═CH) ₂ —R. As an example, Rf is Cl (CF ₂ ) _n (n = 2, 4, 8), CF ₃ and C ₂ F ₅ , R is n-C _n H _m (n, m = 3, 7; 5, 11 Only 6,6,13; 8,17) and (CH ₂ ) _n OH (n = 6, 9) have been reported (see Non-Patent Document 3). However, synthesis of Z-form, introduction of hydrophilic groups, and synthesis of glycerol derivatives are not performed.

In addition, Prestwich has synthesized (Z) -5-decenyl acetate partially fluorinated and has succeeded in introducing a triple bond, but is limited to a compound having 10 carbon atoms. Furthermore, only the introduction of a deprotectable functional group (acetyl group, methoxymethyl group or t-butylmethylsilyl group) into the hydroxyl group (see Non-Patent Document 4). Synthesis of E-form, introduction of hydrophilic group, and synthesis of glycerol derivative were not performed.
Buchanan et al. (Z) -11, 11, 12, 12, 13, 13, 14, 14, 15, 15, 16, 16, 17, 17, 18, 18-heptadecafluoro- partially fluorinated The synthesis of octadec-8-enoic acid and its alcohol is reported. Only the introduction of a deprotectable tetrahydropyranyl group has been reported for the hydroxyl group (see Non-Patent Document 5). However, the synthesis of triple bonds, synthesis of E isomers, introduction of hydrophilic groups, and synthesis of glycerol derivatives have not been achieved.

Helvetica Chimica Acta, 79, 405-425 (1996) J. et al. Fluorine Chem. 107, 337-354 (2001) Tetrahedron, 51 (43), 11765-11774 (1995) J. et al. Org. Chem. , 57 (1), 132-137 (1992) J. et al. Fluorine Chem. , 119, 207-209 (2003)

The present invention has been made in view of the above-described actual situation in the prior art. That is, an object of the present invention is to provide a fluorine-containing alcohol derivative having a carbon-carbon unsaturated bond of in (C≡C), or a novel fluorine-containing compound obtained by binding one chiral glycerol molecule to two ether bonds. It is to provide unsaturated lipid derivatives.

As a result of intensive research on the above problems, the present inventors have found that fluorine-containing unsaturated alcohol derivatives can be synthesized . It has been found that a novel fluorine-containing unsaturated lipid derivative bonded to ether can be synthesized. Further, at that time, it was found that a chiral compound group can be selectively produced by using a compound represented by the sexual formula HOCH ₂ CH (OH) CH ₂ OH, which is a chiral compound, as a raw material, and the present invention. It came to complete. That is, in the present invention, chiral glycerol or glycerol protected at the 1-position or 2-position, or the hydroxyl group at the 1-position and 2-position is obtained by optical resolution or resolution using an enzyme, or (S)- (+)-2,2-dimethyl-1,3-dioxolane-4-methanol or (R)-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol or (R)- (+)-3-Benzyloxy-1,2-propanediol or (S)-(−)-3-benzyloxy-1,2-propanediol is used.

（式中、Ｒ ^１ とＲ ^３ は、パーフルオロアルキル基、Ｒ ^２ とＲ ^４ はアルキレン基である。またＲ ^１ とＲ ^３ 、Ｒ ^２ とＲ ^４ は、それぞれ同一であっても異なっていても良い。Ｒ ^５ は水素原子またはリン酸基とアミノアルコールが結合した基を示す。Ｘ ^１ 及びＸ ^２ は、それぞれＣ≡Ｃを示す。）で表される含フッ素脂質誘導体。
〈２〉下記一般式（２）

（式中、Ｒ ^１ 〜Ｒ ^５ 、及びＸ ^１ 、Ｘ ^２ 前記したと同じ意味である。）で表される含フッ素脂質誘導体。 That is, this application provides the following inventions.
<1> The following general formula (1)

(In the formula, R ¹ and R ³ are perfluoroalkyl groups, R ² and R ⁴ are alkylene groups, and R ¹ and R ³ , R ² and R ⁴ are the same or different. R ⁵ represents a hydrogen atom or a group in which a phosphoric acid group and an amino alcohol are bonded, and X ¹ and X ² each represents C≡C .
<2> The following general formula (2)

(Wherein R ^{1 to} R ⁵ and X ¹ and X ² have the same meaning as described above) .

The present invention provides a novel compound in which a fluorine-containing organic group and chiral glycerol are ether-bonded in the same molecule. These compounds are surface-active and are used as emulsifiers in industry and household, for example in the fields of metal processing, mining, surface finishing, cleaning and cleaning, cosmetics, medicine, food processing and cooking. , Demulsifiers, detergents, dispersants or hydrotropes.

In the fluorine-containing unsaturated lipid derivative represented by the general formulas (1) to (2) of the present invention, first, the group R ¹ ~ R ⁵ The contents will be specifically described.
  R ¹ And R ³ Is a perfluoroalkyl group, R ² And R ⁴ Is an alkylene group. Also R ¹ And R ³ , R ² And R ⁴ May be the same or different.
  Next, X ¹ And X ² Is C≡C.

R ⁵ in the above general formula represents a group in which a group containing a hydrogen atom or a phosphorus atom and an amino alcohol are bonded. Examples of the group containing a phosphorus atom include P, PO, PO ₂ , and PO ₃ . Examples of amino alcohols include choline, ethanolamine, and serine.

The steric configuration of the compounds represented by the general formulas (1) to (2) can be expressed according to the secondary hydroxyl group of glycerol. That is, the secondary hydroxyl group of glycerol is indicated by the R configuration and the S configuration.

Hereinafter, the production method including the compound of the present invention will be specifically described with reference to examples including intermediate synthesis examples, but the present invention is not limited to these examples. The compound numbers shown below are the same as those shown in FIGS.

８−ブロモオクタン−１−オールの無水エーテル溶液に３，４−ジヒドロ−２Ｈ−ピラン（１．６当量）とパラトルエンスルホン酸・１水和物（０．１当量）加え、室温で１８時間攪拌した。炭酸カリウムを加え、濾過後、減圧下溶媒を留去し、化合物１を得た。（ＴＨＰは、テトラヒドロピラニル基を示す） [Example]
<Synthesis of Compounds 17 and 18>
[Synthesis of Compound 1]

3,4-Dihydro-2H-pyran (1.6 eq) and paratoluenesulfonic acid monohydrate (0.1 eq) were added to an anhydrous ether solution of 8-bromooctane-1-ol, and 18 hours at room temperature. Stir. Potassium carbonate was added, and after filtration, the solvent was distilled off under reduced pressure to obtain Compound 1. (THP represents a tetrahydropyranyl group)

氷冷下、リチウムアセチリド・エチレンジアミン（１．１当量）の無水ジメチルスルホキシド懸濁液に化合物１の無水ジメチルスルホキシド溶液を加え、室温で１８時間攪拌した。氷水を加え、ヘキサンで抽出後、減圧下溶媒を留去し、減圧蒸留により化合物２を５５〜７５％で得た。 [Synthesis of Compound 2]

Under ice cooling, an anhydrous dimethyl sulfoxide solution of Compound 1 was added to an anhydrous dimethyl sulfoxide suspension of lithium acetylide · ethylenediamine (1.1 equivalents), and the mixture was stirred at room temperature for 18 hours. After adding ice water and extraction with hexane, the solvent was distilled off under reduced pressure, and Compound 2 was obtained at 55 to 75% by distillation under reduced pressure.

化合物２のアセトニトリル−水溶液にペルフルオロオクチルヨーダイド（１．２当量）、炭酸水素ナトリウム（０．５当量）、ハイドロサルファナトリウム（０．５当量）を順に加え、室温で４時間撹拌した。水を加えて希釈し、エーテルで抽出後、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。濾過後、減圧下溶媒を留去し、残査をシリカゲルカラムクロマトグラフィー（１％酢酸エチル／ｎ−ヘキサン）にて精製し、化合物３を６１〜８１％で得た。 [Synthesis of Compound 3]

To the acetonitrile-water solution of Compound 2 were added perfluorooctyl iodide (1.2 eq), sodium bicarbonate (0.5 eq), and hydrosulfur sodium (0.5 eq) in this order, and the mixture was stirred at room temperature for 4 hours. The mixture was diluted with water, extracted with ether, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (1% ethyl acetate / n-hexane) to obtain Compound 3 at 61-81%.

−２０℃のカリウムｔ−ブトキシド（２．５当量）の無水エーテル溶液に化合物３の無水エーテル溶液を滴下し、−２０℃〜０℃で２〜３時間攪拌した。３Ｍの塩酸水溶液を加え、エーテルで抽出後、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。濾過後、減圧下溶媒を留去し、残査をシリカゲルカラムクロマトグラフィー（１％酢酸エチル／ｎ−ヘキサン）にて精製し、化合物４を７７〜９７％で得た。 [Synthesis of Compound 4]

An anhydrous ether solution of compound 3 was added dropwise to an anhydrous ether solution of potassium t-butoxide (2.5 equivalents) at −20 ° C., and the mixture was stirred at −20 ° C. to 0 ° C. for 2 to 3 hours. 3M aqueous hydrochloric acid solution was added, extracted with ether, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (1% ethyl acetate / n-hexane) to obtain Compound 4 at 77 to 97%.

氷冷下、化合物４のアセトン溶液にジョーンズ試薬を反応溶液が褐色を保持するまで滴下後、室温で１．５時間攪拌した。２−プロパノールを加え、濾過後、減圧下溶媒を留去した。残査を酢酸エチルで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥させた。濾過後、減圧下溶媒を留去し、残査をシリカゲルカラムクロマトグラフィー（１５〜２５％酢酸エチル／ｎ−ヘキサン）にて精製し、化合物５を７２〜９２％で得た。 [Synthesis of Compound 5]

Under ice-cooling, Jones reagent was added dropwise to an acetone solution of compound 4 until the reaction solution kept brown, and then stirred at room temperature for 1.5 hours. 2-Propanol was added, and after filtration, the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (15-25% ethyl acetate / n-hexane) to obtain Compound 5 at 72-92%.

化合物４のエタノール溶液にｐ−トルエンスルホン酸ピリジニウム（０．５当量）を加え、５５℃で１時間加熱した。冷後、氷水を加え、酢酸エチルで抽出後、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。濾過後、減圧下溶媒を留去し、シリカゲルカラムグラフィー（１５％酢酸エチル／ｎ−ヘキサン）にて精製し、化合物６を８８〜１００％で得た。 [Synthesis of Compound 6]

Pyridinium p-toluenesulfonate (0.5 equivalent) was added to the ethanol solution of compound 4 and heated at 55 ° C. for 1 hour. After cooling, ice water was added, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (15% ethyl acetate / n-hexane) to obtain Compound 6 at 88 to 100%.

化合物６のトルエン溶液に当量の無水酢酸、酢酸、トリフェニルホスフィンと触媒料のビスベンジリデンアセトンパラジウムを順に加え、１１０℃で１５〜１８時間加熱した。冷後、濾過し、減圧下溶媒留去後、シリカゲルカラムクロマトグラフィー（５％ 酢酸エチル／ｎ−ヘキサン）のより精製し、化合物７を５５−７５％で得た。（Ａｃは、アセチル基を示す） [Synthesis of Compound 7]

An equivalent amount of acetic anhydride, acetic acid, triphenylphosphine, and bisbenzylideneacetone palladium as a catalyst were sequentially added to a toluene solution of Compound 6 and heated at 110 ° C. for 15 to 18 hours. After cooling, the mixture was filtered and the solvent was distilled off under reduced pressure. The residue was further purified by silica gel column chromatography (5% ethyl acetate / n-hexane) to obtain Compound 7 at 55-75%. (Ac represents an acetyl group)

化合物７のメタノール溶液に炭酸ナトリウムを加え、室温で１８時間攪拌し後、減圧下、溶媒を留去した。水を加えて希釈し、エーテルで抽出後、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。濾過後、減圧下溶媒を留去し、シリカゲルカラムクロマトグラフィー（１５％ 酢酸エチル／ｎ−ヘキサン）にて精製し、化合物８を８０−９５％で得た。 [Synthesis of Compound 8]

Sodium carbonate was added to the methanol solution of compound 7 and stirred at room temperature for 18 hours, and then the solvent was distilled off under reduced pressure. The mixture was diluted with water, extracted with ether, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (15% ethyl acetate / n-hexane) to obtain Compound 8 at 80-95%.

氷冷下、化合物８のアセトン溶液にジョーンズ試薬を反応溶液が褐色を保持するまで滴下した後、室温で１．５時間攪拌した。２−プロパノールを加え、濾過後、減圧下溶媒を留去した。残査を酢酸エチルで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥させた。濾過後、減圧下溶媒を留去し、残査をシリカゲルカラムクロマトグラフィー（（１５〜２５％ 酢酸エチル／ｎ−ヘキサン）にて精製し、化合物９を７０〜９０％で得た。 [Synthesis of Compound 9]

Under ice cooling, Jones reagent was added dropwise to an acetone solution of compound 8 until the reaction solution kept brown, and then stirred at room temperature for 1.5 hours. 2-Propanol was added, and after filtration, the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography ((15-25% ethyl acetate / n-hexane) to obtain Compound 9 at 70-90%.

化合物３のメタノール溶液にパラトルエンスルホン酸・１水和物（０．１当量）を加え、室温で１８時間攪拌し後、減圧下、溶媒を留去した。水を加えて希釈し、エーテルで抽出後、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。濾過後、減圧下溶媒を留去し、シリカゲルカラムグラフィー１５％ 酢酸エチル／ｎ−ヘキサン）にて精製し、化合物１０ａと１０ｂを８８〜１００％で得た。 [Synthesis of Compounds 10a and 10b]

Paratoluenesulfonic acid monohydrate (0.1 equivalent) was added to a methanol solution of compound 3, and the mixture was stirred at room temperature for 18 hours, and then the solvent was distilled off under reduced pressure. The mixture was diluted with water, extracted with ether, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography 15% ethyl acetate / n-hexane) to obtain compounds 10a and 10b at 88 to 100%.

−７８℃に冷却した化合物１０ａの無水テトラヒドロフラン溶液に１．６Ｍのｎ−ブチルリチウムのヘキサン溶液（４〜５当量）を加えた。１時間後、メタノールを加え、０℃までゆっくりと温度を上昇させた後、飽和塩化アンモニウム水溶液を加え酢酸エチルで抽出し、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥させた。濾過後，減圧下溶媒を留去し、シリカゲルカラムクロマトグラフィー（１５％ 酢酸エチル／ｎ−ヘキサン）で精製し、化合物１１ａを７１〜９１％で得た。 [Synthesis of Compound 11a]

A 1.6 M n-butyllithium hexane solution (4 to 5 equivalents) was added to an anhydrous tetrahydrofuran solution of compound 10a cooled to −78 ° C. After 1 hour, methanol was added and the temperature was slowly raised to 0 ° C., then a saturated aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (15% ethyl acetate / n-hexane) to obtain compound 11a at 71 to 91%.

−７８℃に冷却した化合物１０ｂの無水テトラヒドロフラン溶液に１．６Ｍのｎ−ブチルリチウムのヘキサン溶液（４〜５当量）を加えた。１時間後、メタノールを加え、０℃までゆっくりと温度を上昇させた後、飽和塩化アンモニウム水溶液を加え酢酸エチルで抽出し、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥させた。濾過後，減圧下溶媒を留去し、シリカゲルカラムクロマトグラフィー（１５％ 酢酸エチル／ｎ−ヘキサン）で精製し、化合物１１ｂを７１〜９１％で得た。 [Synthesis of Compound 11b]

A 1.6 M n-butyllithium hexane solution (4 to 5 equivalents) was added to an anhydrous tetrahydrofuran solution of compound 10b cooled to −78 ° C. After 1 hour, methanol was added and the temperature was slowly raised to 0 ° C., then a saturated aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (15% ethyl acetate / n-hexane) to obtain compound 11b at 71 to 91%.

氷冷下、化合物１１ａのアセトン溶液にジョーンズ試薬を反応溶液が褐色を保持するまで滴下後、室温で１．５時間攪拌した。２−プロパノールを加え、濾過後、減圧下溶媒を留去した。残査を酢酸エチルで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥させた。濾過後、減圧下溶媒を留去し、残査をシリカゲルカラムクロマトグラフィー（１５〜２５％ 酢酸エチル／ｎ−ヘキサン）にて精製し、化合物１２ａを７２〜９２％で得た。 [Synthesis of Compound 12a]

Under ice-cooling, Jones reagent was added dropwise to an acetone solution of compound 11a until the reaction solution kept brown, and then stirred at room temperature for 1.5 hours. 2-Propanol was added, and after filtration, the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (15-25% ethyl acetate / n-hexane) to obtain Compound 12a at 72-92%.

氷冷下、化合物１１ｂのアセトン溶液にジョーンズ試薬を反応溶液が褐色を保持するまで滴下後、室温で１．５時間攪拌した。２−プロパノールを加え、濾過後、減圧下溶媒を留去した。残査を酢酸エチルで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥させた。濾過後、減圧下溶媒を留去し、残査をシリカゲルカラムクロマトグラフィー（１５〜２５％ 酢酸エチル／ｎ−ヘキサン）にて精製し、化合物１２ｂを７２〜９２％で得た。 [Synthesis of Compound 12b]

Under ice-cooling, Jones reagent was added dropwise to an acetone solution of compound 11b until the reaction solution kept brown, and then stirred at room temperature for 1.5 hours. 2-Propanol was added, and after filtration, the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (15-25% ethyl acetate / n-hexane) to obtain Compound 12b at 72-92%.

氷冷下、２．５当量の２−ブロモエチルジクロロホスフェートのクロロホルム溶液に、２．５当量のトリエチルアミン、化合物６のクロロホルム溶液を滴下し、同温にて4時間撹拌した後、０．１Ｎ塩化カリウム水溶液を加え、室温にて１時間攪拌した。クロロホルムで抽出し、減圧下溶媒を留去した後、アセトニトリル：クロロホルム：イソプロパノール＝１：１：１混合溶媒と３０％トリエチルアミン水溶液を加え、７０℃で２時間加熱した。冷後、減圧下溶媒を留去し、残査をシリカゲルカラムクロマトグラフィー（６５：２５：４〜６５：３５：８＝クロロホルム：メタノール：水）にて精製し、化合物１３を収率４９〜６９％で得た。（ＰＣは、ホスホコリン基を示す） [Synthesis of Compound 13]

Under ice cooling, 2.5 equivalents of triethylamine and a chloroform solution of Compound 6 were added dropwise to a solution of 2.5 equivalents of 2-bromoethyldichlorophosphate in chloroform, stirred at the same temperature for 4 hours, and then 0.1N chloride. A potassium aqueous solution was added, and the mixture was stirred at room temperature for 1 hour. After extracting with chloroform and evaporating the solvent under reduced pressure, a mixed solvent of acetonitrile: chloroform: isopropanol = 1: 1: 1 and 30% aqueous triethylamine were added, and the mixture was heated at 70 ° C. for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (65: 25: 4-65: 35: 8 = chloroform: methanol: water) to obtain compound 13 in a yield of 49-69. %. (PC represents a phosphocholine group)

Compound 13 was identified by ¹ H-NMR and ¹⁹ F-NMR spectra. The results are as follows.
¹ H-NMR (TMS, CDCl ₃ -CD ₃ OD): 1.25-1.43 (m, 8H), 1.53-1.62 (m, 4H), 2.35 (m, 2H), 3.29 (s, 9H), 3.71 (bs, 2H), 3.84 (q, J = 6.7 Hz, 2H), 4.27 (bs, 2H).
¹⁹ F-NMR (CFCl ₃ , CDCl ₃ -CD ₃ OD): −80.71 (t, J = 10.04 Hz, 3F), −96.05 (m, 2F), −121.1 (m, 2F) ), -121.8 (m, 4F), -122.5 to -122.7 (m, 4F), -126.0 (m, 2F).

アルゴン雰囲気下、細かく砕いた３０当量の水酸化カリウムにジメチルスルホキシドを加え、懸濁状とした。水冷下、（Ｓ）−（＋）−２，２−ジメチル−１，３−ジオキソラン−４−メタノールのジメチルスルホキシド溶液を滴下した。次に３．５当量のベンジルブロミドを滴下した。室温で３時間撹拌させた後、氷水を加えて反応を止め、酢酸エチルで抽出し、氷水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥させた。濾過後、減圧下溶媒を留去し、残査をシリカゲルカラムクロマトグラフィー（５％ 酢酸エチル／ｎ−ヘキサン）に通して精製して得られた化合物に１０％酢酸水溶液を加え、９０度で３時間加熱した。冷後、酢酸エチルで抽出し、水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。濾過後、減圧下溶媒を留去し、残査をシリカゲルカラムクロマトグラフィー（８０〜１００％ 酢酸エチル／ｎ−ヘキサン）に通して精製し、化合物１４ａを７０〜９０％で得た。 [Synthesis of Compound 14a]

Under an argon atmosphere, dimethyl sulfoxide was added to 30 equivalents of finely pulverized potassium hydroxide to form a suspension. Under water cooling, a dimethyl sulfoxide solution of (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol was added dropwise. Next, 3.5 equivalents of benzyl bromide were added dropwise. After stirring at room temperature for 3 hours, the reaction was stopped by adding ice water, extracted with ethyl acetate, washed with ice water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by passing through silica gel column chromatography (5% ethyl acetate / n-hexane). A 10% acetic acid aqueous solution was added to the compound obtained by adding 3% at 90 ° C. Heated for hours. After cooling, the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by passing through silica gel column chromatography (80 to 100% ethyl acetate / n-hexane) to obtain Compound 14a at 70 to 90%.

アルゴン雰囲気下、細かく砕いた３０当量の水酸化カリウムにジメチルスルホキシドを加え、懸濁状とした。水冷下、（Ｒ）−（＋）−２，２−ジメチル−１，３−ジオキソラン−４−メタノールのジメチルスルホキシド溶液を滴下した。次に３．５当量のベンジルブロミドを滴下した。室温で３時間撹拌させた後、氷水を加えて反応を止め、酢酸エチルで抽出し、氷水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥させた。濾過後、減圧下溶媒を留去し、残査をシリカゲルカラムクロマトグラフィー（５％ 酢酸エチル／ｎ−ヘキサン）に通して精製して得られた化合物に１０％酢酸水溶液を加え、９０度で３時間加熱した。冷後、酢酸エチルで抽出し、水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。濾過後、減圧下溶媒を留去し、残査をシリカゲルカラムクロマトグラフィー（８０〜１００％ 酢酸エチル／ｎ−ヘキサン）に通して精製し、化合物１４ｂを７０〜９０％で得た。 [Synthesis of Compound 14b]

Under an argon atmosphere, dimethyl sulfoxide was added to 30 equivalents of finely pulverized potassium hydroxide to form a suspension. Under water cooling, a dimethyl sulfoxide solution of (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol was added dropwise. Next, 3.5 equivalents of benzyl bromide were added dropwise. After stirring at room temperature for 3 hours, the reaction was stopped by adding ice water, extracted with ethyl acetate, washed with ice water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by passing through silica gel column chromatography (5% ethyl acetate / n-hexane). A 10% acetic acid aqueous solution was added to the compound obtained by adding 3% at 90 ° C. Heated for hours. After cooling, the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by passing through silica gel column chromatography (80 to 100% ethyl acetate / n-hexane) to obtain Compound 14b at 70 to 90%.

氷冷下、化合物６の無水塩化メチレン溶液にトリエチルアミン（２当量）、メタンスルホニルクロリド（１当量）を加えた。１〜２時間攪拌後、氷水を加え、塩化メチレンで抽出し、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。濾過後、減圧下溶媒を留去し、残査をシリカゲルカラムクロマトグラフィー（３０％ 酢酸エチル／ｎ−ヘキサン）に通して精製し、化合物１４ｂを７０〜９０％で得た。（Ｍｓは、メタンスルホニル基を示す） [Synthesis of Compound 15]

Under ice-cooling, triethylamine (2 equivalents) and methanesulfonyl chloride (1 equivalent) were added to an anhydrous methylene chloride solution of Compound 6. After stirring for 1-2 hours, ice water was added, extracted with methylene chloride, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by passing through silica gel column chromatography (30% ethyl acetate / n-hexane) to obtain Compound 14b at 70 to 90%. (Ms represents a methanesulfonyl group)

水素化ナトリウムの無水テトラヒドロフラン溶液に化合物１４ａを加え、室温で４時間攪拌し、さらに６５℃で１時間加熱した。そこに化合物１５の無水テトラヒドロフラン溶液に化合物を加え、３日間加熱還流した。冷後、氷水を加え、エーテルで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥させた。濾過後、減圧下溶媒を留去し、残査をシリカゲルカラムクロマトグラフィー（１０％ 酢酸エチル／ｎ−ヘキサン） に通して精製し、化合物１６を５８−７８％で得た。 [Synthesis of Compound 16]

Compound 14a was added to an anhydrous tetrahydrofuran solution of sodium hydride, stirred at room temperature for 4 hours, and further heated at 65 ° C. for 1 hour. The compound was added to the anhydrous tetrahydrofuran solution of the compound 15 there, and it heated and refluxed for 3 days. After cooling, ice water was added, extracted with ether, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by passing through silica gel column chromatography (10% ethyl acetate / n-hexane) to obtain Compound 16 at 58-78%.

Compound 16 was identified by ¹ H-NMR and ¹⁹ F-NMR spectra. The results are as follows.
¹ H-NMR (CDCl ₃ , TMS): 7.23 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 4.46 (s, 2H), 3.79 (s, 3H), 3.39-3.60 (m, 9H), 2.35 (m, 4H), 1.54-1.64 (m, 8H), 1.28-1. 47 (m, 16H).
¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ): −80.64 (t, J = 9.71 Hz, 6F), −95.58 (m, 4F), −120.49 (m, 4F), −121 .88 (m, 8F), −122.55 to −122.74 (m, 8F), −126.03 (m, 4F).

氷冷下、化合物１６の塩化メチレン溶液にリン酸緩衝液（ｐＨ７．０）を加えた後、少量の２，３−ジクロロ−５，６−ジシアノ−１，４−ベンゾキノンを加え、８時間攪拌した。飽和炭酸水素ナトリウム水溶液を加え、濾過後、塩化メチレンで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥させた。濾過後、減圧下溶媒を留去し、残査をシリカゲルカラムクロマトグラフィー（３０％ 酢酸エチル／ｎ−ヘキサン）に通して精製し、化合物１７を５８−７８％で得た。 [Synthesis of Compound 17]

A phosphate buffer solution (pH 7.0) was added to a methylene chloride solution of Compound 16 under ice cooling, and then a small amount of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was added and stirred for 8 hours. did. Saturated aqueous sodium hydrogen carbonate solution was added, filtered, extracted with methylene chloride, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by passing through silica gel column chromatography (30% ethyl acetate / n-hexane) to obtain Compound 17 at 58-78%.

Compound 17 was identified by ¹ H-NMR and ¹⁹ F-NMR spectra. The results are as follows.
¹ H-NMR (CDCl ₃ , TMS): 3.39-3.60 (m, 9H), 2.35 (m, 4H), 2.17 (bs, 2H), 1.54-1.64 ( m, 8H), 1.28-1.47 (m, 16H).
¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ): −80.64 (t, J = 9.71 Hz, 6F), −95.58 (m, 4F), −120.49 (m, 4F), −121 .88 (m, 8F), −122.55 to −122.74 (m, 8F), −126.03 (m, 4F).

氷冷下、２．５当量の２−ブロモエチルジクロロホスフェートのクロロホルム溶液に、２．５当量のトリエチルアミン、化合物１７のクロロホルム溶液を滴下し、同温にて4時間撹拌した後、０．１Ｎ塩化カリウム水溶液を加え、室温にて１時間攪拌した。クロロホルムで抽出し、減圧下溶媒を留去した後、アセトニトリル：クロロホルム：イソプロパノール＝１：１：１混合溶媒と３０％トリエチルアミン水溶液を加え、７０℃で２時間加熱した。冷後、減圧下溶媒を留去し、残査をシリカゲルカラムクロマトグラフィー（６５：２５：４〜６５：３５：８＝クロロホルム：メタノール：水）にて精製し、化合物１８を４９−６９％で得た。 [Synthesis of Compound 18]

Under ice-cooling, 2.5 equivalents of a solution of 2-bromoethyldichlorophosphate in chloroform was added dropwise with 2.5 equivalents of a solution of triethylamine and compound 17 in chloroform, and the mixture was stirred at the same temperature for 4 hours. A potassium aqueous solution was added, and the mixture was stirred at room temperature for 1 hour. After extracting with chloroform and evaporating the solvent under reduced pressure, a mixed solvent of acetonitrile: chloroform: isopropanol = 1: 1: 1 and 30% aqueous triethylamine were added, and the mixture was heated at 70 ° C. for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (65: 25: 4-65: 35: 8 = chloroform: methanol: water) to obtain compound 18 at 49-69%. Obtained.

Compound 18 was identified by ¹ H-NMR and ¹⁹ F-NMR spectra. The results are as follows.
¹ H-NMR (CDCl ₃ , TMS): 4.00-4.21 (m, 2H), 3.78 (bs, 2H), 3.25-3.65 (m, 9H), 3.09 ( s, 9H), 2.35 (m, 4H), 1.54-1.64 (m, 8H), 1.28-1.47 (m, 16H).
¹⁹ F-NMR (CDCl ₃ , CFCl ₃ ): −80.64 (t, J = 9.71 Hz, 6F), −95.58 (m, 4F), −120.49 (m, 4F), −121 .88 (m, 8F), −122.55 to −122.74 (m, 8F), −126.03 (m, 4F).

化合物１２ａと化合物１４ｂのジメチルホルムアミド溶液に１．２当量の４−ジメチルアミノピリジンおよび１，３−ジシクロヘキシルカルボジイミドを加え、室温で２４時間攪拌した。氷水を加えて反応を止め、塩化メチレンで抽出し、冷１０％塩酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥させた。濾過後、減圧下溶媒を留去し、残査をシリカゲルカラムクロマトグラフィー（１５％酢酸エチル／ヘキサン）に通して精製し、化合物１９を得た。 [Reference example]
<Synthesis of Compounds 20 and 21>
[Synthesis of Compound 19]

1.2 equivalents of 4-dimethylaminopyridine and 1,3-dicyclohexylcarbodiimide were added to a dimethylformamide solution of compound 12a and compound 14b, and the mixture was stirred at room temperature for 24 hours. Ice water was added to stop the reaction, and the mixture was extracted with methylene chloride, washed sequentially with a cold 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by passing through silica gel column chromatography (15% ethyl acetate / hexane) to obtain Compound 19.

氷冷下、化合物１９の塩化メチレン溶液にリン酸緩衝液（ｐＨ７．０）を加えた後、少量の２，３−ジクロロ−５，６−ジシアノ−１，４−ベンゾキノンを加え、８時間攪拌した。飽和炭酸水素ナトリウム水溶液を加え、濾過後、塩化メチレンで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥させた。濾過後、減圧下溶媒を留去し、残査をシリカゲルカラムクロマトグラフィー（３０％酢酸エチル／ｎ−ヘキサン）に通して精製し、化合物２０を得た。 [Synthesis of Compound 20]

A phosphate buffer solution (pH 7.0) was added to a methylene chloride solution of compound 19 under ice cooling, a small amount of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was added, and the mixture was stirred for 8 hours. did. Saturated aqueous sodium hydrogen carbonate solution was added, filtered, extracted with methylene chloride, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by passing through silica gel column chromatography (30% ethyl acetate / n-hexane) to obtain Compound 20.

氷冷下、２．５当量の２−ブロモエチルジクロロホスフェートのクロロホルム溶液に、２．５当量のトリエチルアミン、化合物２０のクロロホルム溶液を滴下し、同温にて4時間撹拌した後、０．１Ｎ塩化カリウム水溶液を加え、室温にて１時間攪拌した。クロロホルムで抽出し、減圧下溶媒を留去した後、アセトニトリル：クロロホルム：イソプロパノール＝１：１：１混合溶媒と３０％トリエチルアミン水溶液を加え、７０℃で２時間加熱した。冷後、減圧下溶媒を留去し、残査をシリカゲルカラムクロマトグラフィー（６５：２５：４〜６５：３５：８＝クロロホルム：メタノール：水）にて精製し、化合物２１を得た。 [Synthesis of Compound 21]

Under ice-cooling, 2.5 equivalent of triethylamine and a chloroform solution of compound 20 were added dropwise to 2.5 equivalent of 2-bromoethyldichlorophosphate in chloroform, and the mixture was stirred at the same temperature for 4 hours, and then 0.1N chloride. A potassium aqueous solution was added, and the mixture was stirred at room temperature for 1 hour. After extracting with chloroform and evaporating the solvent under reduced pressure, a mixed solvent of acetonitrile: chloroform: isopropanol = 1: 1: 1 and 30% aqueous triethylamine were added, and the mixture was heated at 70 ° C. for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (65: 25: 4 to 65: 35: 8 = chloroform: methanol: water) to obtain Compound 21.

The fluorinated lipid derivative of the present invention is a novel compound having a fluorinated organic group and an ether bond in the same molecule, and has surface activity , so it can be used as a surfactant used in a wide range of technical fields. It can be done.

2 is a chemical reaction formula showing a synthetic route of an example of a synthetic intermediate of a fluorinated lipid derivative in the present invention. 2 is a chemical reaction formula showing a synthesis route of an example of a fluorinated lipid derivative in the present invention. It is a chemical reaction formula showing a synthetic route of an example of a fluorine-containing lipid derivative of a reference example .

Claims (2)

The following general formula (1)

(In the formula, R ¹ and R ³ are perfluoroalkyl groups, R ² and R ⁴ are alkylene groups, and R ¹ and R ³ , R ² and R ⁴ are the same or different. R ⁵ represents a hydrogen atom or a group in which a phosphoric acid group and an amino alcohol are bonded, and X ¹ and X ² each represents C≡C . The following general formula (2)

(Wherein R ^{1 to} R ⁵ and X ¹ and X ² have the same meaning as described above) .

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