JP2004035572A - セミフルオロアルカン及びその使用 - Google Patents
セミフルオロアルカン及びその使用 Download PDFInfo
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Abstract
【解決手段】
本発明は、一般式RFRHおよびRFRHRF(式中、RFは、線形または分岐ペルフルオロアルキル基を表し、RHは、線形または分岐飽和(炭化水素)アルキル基を表す)で表されるセミフルオロアルカンを含む皮膚剤に関する。
【選択図】なし
Description
[1] H.Meinert, A.Knoblich, Biomat.Art.Cells & Immob.Biotech., 21(1993)583
[2] H.Meinert, Fluorine in Medicine in the 21st Century, Manchester (1994),paper 23
[3] R.J.Twieg 等, Marcomolecules, 18(1985)1361
[4] J.Hopkin 等, Marcomol.Chem., 189(1988) 911
[5] K.von Werner, DE 39 25 525 A1 (1989)
[6] Organikum, Autorenkollektiv, Dtsch. Verlag der Wissenschaft, Berlin (1977) 363
[7] H.Meinert, DE 42 05 341 A1 (1992) / WO93/16974A1(1993)
[8] L.C.Clark, US Pat.4,490,351 (1984) / EP 0 112 658 A2 (1984)
[9] H.Meinert,US Pat. A-5,397,805 (1995) / EP 0 493 677 A3 (1991)/DE 41 00 059 A (1994)
[10] H.Meinert, DE 42 11 958 A1 (1992) / EP 0 563 446 A1 (1992)
[11] S.Chang 等, Am.J.Ophthalmol., 103 (1987) 29
S.Chang 等, Am.J.Ophthalmol., 103 (1987) 38
S.Chang 等, Ophthalmology 96 (1989) 785
[12] G.A.Peyman 等, Internal Tamponade in Vitreoretinal Surgery,Ravenna (1994) paper 33
[13] D.C.White, US Pat. A-4366169
[14] R.E.Moore, GB 2087882 A (1982)
[15] E.Borgarello, EP 29 66 61 A
[16] U.Gross, DE 41 27 442 (1991)
[17] U.Gross, DE 42 21 255 (1992)
[18] D.Prescher等, DD 207310 A3 (1985)
[19] P.A.Thiessen等, DD 289424 A7 (1991)
[20] R.C. Bowers等, Lubric Engng., 12 (1956) 245
[21] V.S.Isakovich等, Trenie Iznos, 13 (1992) 306
[22] E.R.Jones等, NASA-Report, TM-87284 (1986)
[23] S.Mori, W.Morales, Wear 132 (1989) 111
[24] K.von Werner, EP 0 545 174 A1 (1993)
[25] D.L.Cho, H.Yasuda, J.Appl.Polymer Sci.: Appl.Polymer Symp., 42(1988) 139
RFRHおよびRFRHRF
(式中,RFは、線形または分岐ペルフルオロアルキル基を表し、RHは、線形または分岐飽和(炭化水素)アルキル基を表す)
のセミフルオロアルカンに関する。
F(CF2)n(CH2)mH
F(CF2)n(CH2)m(CF2)nF
(式中、n=1−20,m=3−20)
を有する。
F(CF2)n(CH2)mH
F(CF2)n(CH2)m(CF2)nF
(式中、n=3−20,m=3−20)の化合物およびその分岐異性体は、更に広い用途に使用される。なぜならば、分子のRF成分およびRH成分の延長とともにペルフルオロカーボン系および炭化水素系の溶解度が有意に拡大されるからである。典型的な液状セミフルオロアルカン(表1、2参照)は、その優れた物理的性質にもとづき、網膜の展開に直接に使用でき、特にレーザ凝固時に極めて安定な無色液体として好適である。なぜならば、レーザ照射時に分解生成物が生じないからである。
セミフルオロ二ブロックおよび三ブロックアルカンの調製
実施例1
[5]にもとづき、(圧力補償のためのバイパスを備えた)滴下濾斗、翼形撹拌機、温度計および逆止め弁を備えた還流冷却器を装備しアルゴン1.82g(0.0075モル)を含む内容積250cm3の四つ口フラスコに、無水ジ−n−プロピルエーテル10cm3に導入したマグネシウム切削屑を装入し、数滴のヨウ化メチルを加え、若干加熱して賦活した。温度を80℃に昇温し、23.7g(0.05モル)のC6F13CH2CH2Iと60cm3の無水ジ−n−プロピルエーテルとの混合物を激しく撹拌しながら1h以内に滴下した。次いで、混合物を9h還流させ、次いで、10℃に冷却し、5%塩酸100cm3で加水分解して、過剰のマグネシウムを溶解した。次いで、エーテル相を分離し、回転蒸発器によって濃縮した。かくして得られた油状残渣をクロロホルム30cm3と混合し、0℃に1h放置した。混合物から沈殿した固形生成物を吸引し、デシケータ中で乾燥した。融点48℃の無色結晶のC6F13(CH2)4C6F1311.0gが得られた。収率は、理論値の63.2%であった。(内部標準としてテトラメチルシランを含むCDCl3溶液中で)核共鳴分光分析によって下記数値を求めた:
1H−NMR:2.11ppm(CF2CH 2),1.72ppm(CH2CH 2)
[5]にもとづき、実施例1と同様に操作した。但し、下記物質を使用した:
1.82g(0.075モル)マグネシウム切削屑
28.7g(0.05モル)C8F17CH2CH2I
70cm3無水ジ−n−プロピルエーテル
希塩酸で加水分解後、混合物を濾過し、粗生成物を水洗し、デシケータ中で乾燥し、次いで、クロロホルム中から結晶化させ、真空乾燥した。融点92〜93℃の化合物C8F17(CH2)4C8F17の無色小片14.9gが得られた。収率は、理論値の66.8%であった。核共鳴分光分析によって下記数値を求めた:
1H−NMR:2.12ppm[CF2CH 2,3J(HF)=18.2Hz]、
1.73ppm(CH2CH 2)
13C−NMR:31.17ppm[CF2CH 2,2J(CF)=22.6Hz]、
20.37ppm(CH2CH 2)
[5]にもとづき、実施例2と同様に操作した。但し、ヨウ化メチルでマグネシウム切削屑を賦活した後、化合物[(C6H5)3P]2CoCl293.6mg(0.143mmol)を触媒として反応生成物に加えた。実施例2と同様にクロロホルムから反応生成物を結晶化させ冷却した後、融点92〜93℃の化合物C8F17(CH2)4C8F1716.6gが得られた。得られた量は、理論値の74.1%であった。核共鳴分光分析の数値は、実施例2の場合と同様である。
実施例2と同様に操作した。但し、マグネシウム切削屑の賦活後、化合物C8F17CH=CH22.2g[0.005mol=使用した化合物C8F17CH2CH2Iに対して10モル%]を無水ジ−n−プロピルエーテルと化合物C8F17CH2CH2Iとの混合物とともに反応生成物に添加した。クロロホルムから反応生成物を結晶化させ真空乾燥した後、融点92〜93℃の化合物C8F17(CH2)4C8F1717.5gが得られた。得られた量は、理論値の78.1%であった。核共鳴分光分析の数値は、実施例2の場合と同一である。
[5]にもとづき、実施例1と同様に操作した。但し、下記物質を使用した:
1.82g(0.075モル)マグネシウム切削屑
30.1g(0.05モル)C8F17(CH2)4I
70cm3無水ジ−n−プロピルエーテル
希塩酸で加水分解後、混合物を濾過し、粗生成物を水洗し、デシケータ中で乾燥した。クロロホルム中から結晶化させ、真空乾燥した後、融点84.5℃の化合物C8F17(CH2)8C8F1714,3gが無色小片として得られた。得られた量は、理論値の60.1%であった。
核共鳴分光分析において下記数値が得られた:
配列:C8F17−CH2−CH2−CH2−CH2−CH2−CH2−CH2−CH2−C8F17
1H−NMR:(1)/(8)2.01ppm,(2)/(7)1,62ppm,
(3)/(4)/(5)及び(6)1,38ppm
13C−NMR:(1)/(8)31.21ppm、[2J(CF)=22.1Hz]、
(2)/(7)20.34ppm、(3)/(4)/(5)及び
(6)29.17ppm
[5]にもとづき、実施例5と同様に操作した。但し、マグネシウム切削屑の賦活後、化合物C8F17CH=CH2の代わりに化合物C8F17(CH2)2CH=CH21.2g[0.005mol=使用した化合物C8F17(CH2)4に対して5モル%]を触媒として添加した。処理後、融点84,5℃の化合物C8F17(CH2)8C8F1716.2gが得られた。得られた量は、理論値の68.2%であった。
[1]にもとづくセミフルオロアルカンの調製
ペルフルオロアルキルハロゲン化物2mmolおよびアルケン(I)4mmolをオクタン15mlに溶解し、アルゴンを排気し、90℃に加熱した。次いで、アゾイソブチロニトリル150mgを複数部分に分けて30分以内に添加した。この場合、溶液は淡黄色を呈した。次いで、混合物を分溜した。<0,5mbarの減圧下で所望の種類の化合物RF−CHI−CH2−RFを蒸留した。収率は、ペルフルオロアルキルハロゲン化物の使用量に関して、ヨウ化物の場合は85−90%であり、臭化物の場合は22%であった。
ペルフルオロアルキルハロゲン化物の還元
ペルフルオロアルキルハロゲン化物6.6mmolをジエチルエーテル15mlに溶解し、酢酸5mlを加えた。混合物を50℃に加熱し、スズ4mmolをゆっくり加えた。冷却後、水を加え、相を分離した。有機相を乾燥、蒸留した。この場合、セミフルオロアルカン/アルケン(5:1)混合物最大68%と二量化体約10%とが分離された。
[1]にもとづくセミフルオロ三ブロックアルカンの調製
60℃において、n−ジブチルエーテル30cm3およびマグネシウム4gに、C6F13C2H34gを加え、温度を120℃に昇温した。次いで、n−ジブチルエーテルに溶解したC6F13C2H4I40gを加えた。約90分後、溶液は、真黒色を呈し、若干時間後、再び無色となった。次いで、混合物を濾過し、慎重に水を加え、分離された有機相を乾燥、濾過した。高沸点分画を、一晩、冷蔵庫中で−20℃に保持した。この際、C6F13C4H8C6F13が白色の沈殿物として沈殿した。
リチウムブチルによる調製
C6F13C2H43gおよびヘキサン中の1.6mリチウムブチル4mlをヘキサン5ml中に加え、60℃に加熱した。約10分後、白色沈殿物が生成した。次いで、慎重に水を加え、有機相を分離した。次いで、同様に、マグネシウムと反応させた。GCによって、生成物比RFRHRHRF/RFRH−Buを求めた。ペルフルオロデカリンを標準として使用した。総合収量は3.1g(85%)であった。
GC、MSおよび1H−NMRによって既知物質と比較して化合物を特定した。
[4]にもとづき、F(CF2)12(CH2)nH(n=4,5,8,10,12,14,16,18,20),F(CF2)10(CH2)8(CF2)10FおよびF(CF2)12(CH2)10(CF2)12Fの合成を行った。この場合、ラジカルを添加して、ペルフルオロヨウ化デシルまたはペルフルオロヨウ化ドデシルを対応するアルケンまたはジアルケンと反応させ、次いで、トルオール中でトリブチル水素化スズおよびAIBNで還元した。
[6]にもとづき、実施例9と同様に、まず、ペルフルオロヨウ化アルキルを形成し、次いで、オートクレーブ中で4barにおいて、触媒としてパラジウムカーボンまたは酸化白金を使用してセミフルオロアルカン,即ち、RFRHまたはRFRHRFに還元した。
Claims (5)
- 下記一般式:
RFRH 及び RFRHRF
(式中、RFは、線形または分岐ペルフルオロアルキル基を表し、RHは、線形または分岐飽和(炭化水素)アルキル基を表す)のセミフルオロアルカンであって、
−非分岐セミフルオロアルカンが、下記一般式:
F(CF2)n(CH2)mH
F(CF2)n(CH2)m(CF2)nF
(式中,n=3−20,m=3−20)を有し、
−分岐セミフルオロアルカンが、ペルフルオロアルキル基内に、−FCX−単位(但し、X=C2F5,C3F7またはC4F9)をさらに含み、アルキル基内に、−HCY−単位(但し、Y=C2H5,C3H7またはC4H9)を含み、
−全ての異性体(すなわち線形または分岐ペルフルオロアルカン)において、1つまたは複数のペルフルオロアルキル部分の炭素原子の総数が、常にn=3−20の範囲内に保持され、更に、アルキル部分の炭素原子数が、m=3−20の範囲内に保持されるセミフルオロアルカンを特徴とする皮膚剤。 - ペルフルオロアルキル鎖内に、−CX2−基がさらに含まれ、アルキル鎖内に、−CY2−基がさらに含まれていることを特徴とする請求項1記載の皮膚剤。
- 分子末端に、ペルフルオロアルキル基F3C−の代わりに、FCX2−基またはF2CX−基が結合し、同様に、分子末端に、アルキル基H3C−の代わりに、HCY2−基またはH2CY−基が結合することを特徴とする請求項1または2記載の皮膚剤。
- 前記セミフルオロアルカンが、生体調和性乳化剤とともに、ガス溶解度の大きい水性エマルジョンを形成することを特徴とする請求項1から3のいずれかに記載の皮膚剤。
- 浸透圧活性剤及び膨張圧活性剤を特徴とする、請求項4記載の皮膚剤。
Applications Claiming Priority (2)
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DE19536504A DE19536504C2 (de) | 1995-09-29 | 1995-09-29 | Verwendung fluorierter Alkane |
DE19536504.6 | 1995-09-29 |
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JP09513914A Division JP2000511157A (ja) | 1995-09-29 | 1996-08-09 | セミフルオロアルカン及びその使用 |
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JP09513914A Pending JP2000511157A (ja) | 1995-09-29 | 1996-08-09 | セミフルオロアルカン及びその使用 |
JP2003344963A Pending JP2004083593A (ja) | 1995-09-29 | 2003-10-02 | セミフルオロアルカン及びその使用 |
JP2003344962A Expired - Fee Related JP4731801B2 (ja) | 1995-09-29 | 2003-10-02 | セミフルオロアルカン及びその使用 |
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JP09513914A Pending JP2000511157A (ja) | 1995-09-29 | 1996-08-09 | セミフルオロアルカン及びその使用 |
JP2003344963A Pending JP2004083593A (ja) | 1995-09-29 | 2003-10-02 | セミフルオロアルカン及びその使用 |
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US (3) | US6262126B1 (ja) |
EP (3) | EP0965329B1 (ja) |
JP (3) | JP2000511157A (ja) |
KR (3) | KR100497874B1 (ja) |
AT (3) | ATE214270T1 (ja) |
CA (3) | CA2473394C (ja) |
DE (4) | DE19536504C2 (ja) |
ES (3) | ES2174551T3 (ja) |
WO (1) | WO1997012852A1 (ja) |
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JP2016515553A (ja) * | 2013-03-25 | 2016-05-30 | ビー.ブラウン メルズンゲン アーゲーB.Braun Melsungen Ag | セミフッ化炭素化合物含有造影剤 |
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1995
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1996
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- 1996-08-09 ES ES99111588T patent/ES2174554T3/es not_active Expired - Lifetime
- 1996-08-09 AT AT96927711T patent/ATE188958T1/de active
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2001
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2016515553A (ja) * | 2013-03-25 | 2016-05-30 | ビー.ブラウン メルズンゲン アーゲーB.Braun Melsungen Ag | セミフッ化炭素化合物含有造影剤 |
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