JP3888914B2 - Highly fluorinated carboxylic acid derivatives and processes and intermediates thereof - Google Patents

Description

【０００５】
【発明の実施の形態】
以下、本発明を詳細に説明する。
【０００６】
まず、中間体の製造法を説明する。
【０００７】
式［ＩＩ］
【化９】

（式中、Ｒｆは、炭素数５〜１０のパーフルオロアルキル基を、Ｒはアルキル基、アラルキル基、アリール基を、ｌは１〜３の整数を、ｍは２または３を表す。）で表される中間体は、有機溶媒中、塩基存在下、アミノ酸エステルと、式［ＩＩＩ］
【化１０】

（式中、Ｙはアルキルスルホニルオキシ基、アリールスルホニルオキシ基、またはフッ素を除くハロゲンのいずれかを、Ｒｆはパーフルオロアルキル基を、ｎは整数を表す。）で表されるパーフルオロアルキル誘導体とを反応させ製造する。
【０００８】
原料となるアミノ酸エステルとしては、周知のアミノ酸エステルを用いることができる。アミノ酸としては、グリシン、Ｌ−アラニン、Ｄ−アラニン、β−アラニン、３−アミノプロピオン酸等のアミノカルボン酸を挙げることができる。エステル部分には、周知のカルボン酸の保護基を用いることができる。たとえば、メチルエステル、エチルエステル、第三ブチルエステルなどのアルキルエステル体、ベンジルエステル、ｐ−メトキシベンジルエステル、ｐ−ニトロベンジルエステルなどのアラルキルエステル体、フェニルエステル、ナフチルエステル、フェナシルエステルなどの芳香族エステルを挙げることができる。
【０００９】
もう一方の原料となる式［ＩＩＩ］（式中、Ｙはアルキルスルホニルオキシ基、アリールスルホニルオキシ基、またはフッ素を除くハロゲンのいずれかを、Ｒｆはパーフルオロアルキル基を、ｎは整数を表す。）で表されるパーフルオロアルキル誘導体は周知の誘導体を使用できる。
【００１０】
アルキルスルホニルオキシ基、アリールスルホニルオキシ基としては周知のスルホニルオキシ基を使用できる。たとえば、ｐ−トルエンスルホニルオキシ基、メタンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基などのスルホニルオキシ基を挙げることができる。また、フッ素を除くハロゲンとしては、塩素、臭素、ヨウ素など周知のハロゲンを挙げることができる。
【００１１】
パーフルオロアルキル基としては周知のパーフルオロアルキル基を用いることができる。たとえば、パーフルオロヘキシル基、パーフルオロヘプチル基、パーフルオロオクチル基、パーフルオロデシル基、パーフルオロテトラデシル基などを挙げることができる。さらに、分岐構造や立体異性体の有無などを問わないことは言うまでもない。フッ素原子の導入率を高めるにはパーフルオロアルキル基は長鎖の方が有効である。しかし、通常取り扱いや入手の容易さを考慮し、炭素数３から１６の範囲の誘導体を使用する。好ましくは炭素数５〜１０の範囲の誘導体である。
【００１２】
パーフルオロアルキル基に結合しているメチレン鎖は何ら制限はなく、通常炭素数１〜８のメチレン鎖である。特に、炭素数１〜４のメチレン鎖が好ましい。
【００１３】
有機溶媒としては、周知の溶媒を使用できる。ジクロロメタン、クロロホルム、ヘキサン、ベンゼン、トルエン、テトラヒドロフラン、エーテル、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、アセトニトリル、プロピオニトリル、酢酸エチル、ジメチルスルホキシド、メチルエチルケトン、パーフルオロヘキサン、パーフルオロカーボン（たとえば、フロリナート^TMＦＣ７２）などを挙げることができる。また、これらの混合物や含水物、あるいは、不均一系での反応ができることは言うまでもない。
【００１４】
塩基としては、何ら制限はない。たとえば、トリエチルアミン、トリブチルアミン、Ｎ，Ｎ−ジイソプロピルエチルアミン、ピリジン、ＤＢＵなどの有機塩基、炭酸カリウム、炭酸セシウム、水酸化ナトリウム、水酸化カリウムなどの無機塩基あるいは、ブチルリチウム、フェニルリチウムなどの有機金属化合物を挙げることができる。
【００１５】
用いる両原料、塩基の当量数にも何ら制限はない。いずれか１成分か２成分を過剰に用いることもできる。アミノ酸エステルに１当量〜１５当量の範囲の塩基と式［ＩＩＩ］（式中、Ｙはアルキルスルホニルオキシ基、アリールスルホニルオキシ基、またはフッ素を除くハロゲンのいずれかを、Ｒｆはパーフルオロアルキル基を、ｎは整数を表す。）で表されるパーフルオロアルキル誘導体を用いる。通常、直接本発明化合物である高度にフッ素化されたカルボン酸のエステル誘導体と中間体の混合物として得られる。両者は、シリカゲルカラムクロマトグラフィーなどの通常の精製手段で容易に分離することができる。両者の生成比は個々の誘導体によって異なるとともに当量数に依存している。従って、中間体を優先的に製造することも、後述する本発明化合物である高度にフッ素化されたカルボン酸のエステル誘導体を優先的に製造することも可能であることは言うまでもない。
【００１６】
反応時間、反応温度にも何ら制限はない。いずれも個々の誘導体によって異なり、また、塩基や溶媒によっても異なるが、通常、室温から溶媒の沸点までの範囲で、１時間から７日間の範囲である。
【００１７】
次に中間体から本発明化合物である高度にフッ素化されたカルボン酸およびカルボン酸誘導体の製造法について述べる。
【００１８】
有機溶媒中、塩基存在下、上記中間体に前述した式［ＩＩＩ］（式中、Ｙはアルキルスルホニルオキシ基、アリールスルホニルオキシ基、またはフッ素を除くハロゲンのいずれかを、Ｒｆはパーフルオロアルキル基を、ｎは整数を表す。）で示されるパーフルオロアルキル誘導体を反応させるか、もしくは式［ＩＶ］
【化１１】

（式中、Ｒｆはパーフルオロアルキル基を、ｎは整数を表す。）で表されるパーフルオロアルキルカルボン酸、または式［Ｖ］
【化１２】

（式中、Ｒｆはパーフルオロアルキル基を、Ｘはカルボニル基あるいはメチレン基を、ｌ、ｍ、ｎ、ｐは整数を表し、Ｒｆ、Ｘ、ｍ、ｎはその表示各位において同一である必要はない。）で示される高度にフッ素化されたカルボン酸を縮合させ、式［ＶＩ］
【化１３】

（式中、Ｒｆはパーフルオロアルキル基を、Ｒはアルキル基、アラルキル基、アリール基のいずれかを、Ｘはカルボニル基あるいはメチレン基を、ｌ、ｍ、ｎ、ｐは整数を表し、Ｒｆ、Ｘ、ｍ、ｎはその表示各位において同一である必要はない。）で表されるより高度にフッ素化させたカルボン酸誘導体（エステル体）を得たのち、エステル部分を常法に従いカルボン酸に変換し、高度にフッ素化されたカルボン酸を製造する。式［Ｉ］（式中、Ｒｆは、炭素数５〜１０のパーフルオロアルキル基を、Ｒは水素、アルキル基、アラルキル基、アリール基のいずれか、Ｘはカルボニル基あるいはメチレン基を、ｌは１〜３の整数を、ｍは２または３を、ｎは１または２、ｐは０〜４の整数を表し、Ｒｆ、Ｘ、ｍ、ｎはその表示各位において同一である必要はない。）で示される本発明化合物である高度にフッ素化されたカルボン酸およびカルボン酸誘導体は上記の方法で製造できる。
【００１９】
式［ＩＩＩ］で示されるパーフルオロアルキル誘導体、式［ＩＶ］で示されるパーフルオロアルキルカルボン酸のパーフルオロアルキル基としては、何ら制限はなく、前述のパーフルオロアルキル基を使用できる。
【００２０】
メチレン鎖の長さｎも何ら制限はなく、通常炭素数１〜８のメチレン鎖である。特に、炭素数１〜４のメチレン鎖が好ましい。
【００２１】
アルキルスルホニルオキシ基、アリールスルホニルオキシ基、フッ素を除くハロゲンについても前述と同様、何ら制限はない。
【００２２】
式［ＩＩＩ］で示されるパーフルオロアルキル誘導体を反応させる際の、有機溶媒、塩基についても、何ら制限はなく、具体的には、中間体の製造について述べた例と同じである。また、一度中間体を単離した後に反応させることも、前述したように二段階の反応を一挙に行うこともできることは言うまでもない。
【００２３】
式［ＩＶ］あるいは式［Ｖ］（式中、Ｒｆはパーフルオロアルキル基を、Ｘはカルボニル基あるいはメチレン基を、ｌ、ｍ、ｎ、ｐは整数を表し、Ｒｆ、Ｘ、ｍ、ｎはその表示各位において同一である必要はない。）で示されるパーフルオロアルキルカルボン酸を、式［ＩＩ］で示される中間体と反応させる方法についても何ら制限はない。反応させるパーフルオロカルボン酸を予め、酸ハロゲン化物、混合酸無水物、対称酸無水物、活性エステルに変換させて反応させる方法や、Ｎ，Ｎ−ジシクロヘキシルカルボジイミド（ＤＣＣ）などの縮合試薬と直接反応させる方法が挙げられる。いずれの誘導体も周知の誘導体を利用できる。具体的には、酸塩化物、酸臭化物、ピバル酸混合酸無水物、ペンタフルオロフェニルエステル、ｐ−ニトロフェニルエステル、コハク酸イミドエステルなど周知の誘導体を例示できる。また、縮合試薬としては前述のＤＣＣ、ＰｙＢＯＰ^TM（ベンゾトリアゾール−１−イル−オキシ−トリス−ピロリジノ−ホスホニウム ヘキサフルオロホスフェート）、ＢＯＰ（ベンゾトリアゾール−１−イル−オキシ−トリス（ジメチルアミノ）ホスホニウム ヘキサフルオロホスフェート）等を挙げることができる。上記の工程を繰り返すことにより、より高度にフッ素化されたカルボン酸を製造できる。繰り返し回数にも制限はないが、実質的には式［Ｉ］で示したｐの値は０〜４までが好ましく、さらに好ましくは０〜２である。
【００２４】
以上のようにして得られる本発明化合物である高度にフッ素化されたカルボン酸誘導体（エステル体）は通常の方法でカルボン酸へ変換できる。具体的には、エステルの種類に依存する。たとえば、メチルエステル、エチルエステルなどの場合には、水酸化ナトリウム水溶液を用いる方法などアルカリ加水分解で、第三ブチルエステルの場合にはトリフルオロ酢酸などの酸分解で、ベンジルエステルなどの場合には接触水素化分解で行うことができる。
【００２５】
こうして得られた本発明化合物であるカルボン酸誘導体はフルオラス合成に於ける目的化合物あるいは材料表面のアミノ基や官能基に高度にフッ素化されたアシル型保護基として導入できる。その導入は通常のアシル化の方法が適用できることは言うまでもない。本アシル基が導入された化合物はパーフルオロカーボン層へ抽出されやすくなり、精製操作が容易になる。式［Ｉ］で示される高度にフッ素化されたカルボン酸誘導体におけるpの値は本発明の大きな特徴であり、この価は、主反応生成物の分離能と、高度にフッ素化されたカルボン酸を産業界に供するその容易性とのバランスから定められる。特に、式［Ｉ］で示したｐが０の誘導体でパーフルオロカーボン層への抽出効率が低い場合にはｐが１または２の誘導体が有効である。また、水酸基に導入した本アシル基は、常法に従いナトリウムメトキシドや水酸化ナトリウムなどの塩基性条件下に容易に除去できる。従って、式［ＶII］
【化１４】

（式中、Ｒｆは、炭素数５〜１０のパーフルオロアルキル基を、Ｘはカルボニル基あるいはメチレン基を、ｌは１〜３の整数を、ｍは２または３を、ｎは１または２、ｐは０〜４の整数を表し、Ｒｆ、Ｘ、ｍ、ｎはその表示各位において同一である必要はない。）で示される高度にフッ素化されたアシル基を水酸基の保護基として使用する方法により、特にフルオラス合成における新規な保護基として実用性が高い。また、アミノ基に導入した本アシル基は塩酸や硫酸などの酸性条件下除去可能である。しかも、脱保護された後に本発明化合物もしくはその誘導体はパーフルオロカーボン層へ容易に抽出されるため、回収、再利用ができ、環境に優しい製造システムを確立できる。また、種々の材料表面にある水酸基、アミノ基などの官能基と反応させ、アシル型表面修飾基として導入すれば、撥水性、潤滑性の付与など表面特性改善などに応用できるなどその用途は極めて広い。この場合、式［Ｉ］で示したｐの値が大きい方が有利になることは自明である。加えて、本発明化合物のみをフルオラス有機プロトン酸触媒として利用できることも言うまでもない。
【００２６】
以下に実施例を挙げて本発明をさらに具体的に説明するが、その要旨を超えない限り、何ら制限を受けるものではない。
【００２７】
【実施例１】
β-アラニン エチルエステル塩酸塩 (0.71 g, 4.64 mmol) と式［ＩＩＩ］（但し、ＲｆはＣ₈Ｆ₁₇を、Ｙはｐ−トルエンスルホニルオキシ基を、ｎは２を示す。）で表されるパーフルオロ化合物 (6.02 g, 9.74 mmol) のプロピオニトリル (100 mL) 溶液に炭酸カリウム (3.84 g, 27.8 mmol) を加え、４日間加熱還流した。冷後、反応液を水中に加え、酢酸エチルで３回抽出した。酢酸エチル層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー (hexane : AcOEt = 8 : 1 〜 AcOEt)にて精製し、式［ＩＩ］（但し、ＲｆはＣ₈Ｆ₁₇を、Ｒはエチル基、ｌは２を、ｍは３を示す。）で表される中間体（無色油状）：¹H-NMR (CDCl₃):δ 1.27 (3H, t, J= 7.3 Hz), 1.77 (2H, m), 2.16 (2H, m), 2.50 (2H, t, J= 6.3 Hz), 2.70 (2H, t, J=6.8 Hz), 2.88 (2H, t, J=6.3 Hz), 4.15 (2H, q, J=7.3 Hz)を1.39 g（52 %)、および 式［Ｉ］（但し、ＲｆはＣ₈Ｆ₁₇を、Ｒはエチル基を、Ｘはメチレン基を、ｌは２を、ｍは３を、ｎは２、ｐは０を示す。）で表される高度にフッ素化されたカルボン酸のエチルエステル誘導体（無色油状）：¹H-NMR (CDCl₃):δ 1.24 (3H, t, J= 7.1 Hz), 1.73 (4H, m), 2.11 (4H, m), 2.40 (2H, t, J= 6.6 Hz), 2.48 (4H, t, J=6.1 Hz), 2.76 (2H, t, J=6.6 Hz), 4.12 (2H, q, J=7.1 Hz) を1.34 g（28 %)得た。
【００２８】
【実施例２】
実施例１で得た高度にフッ素化されたカルボン酸のエチルエステル誘導体(1.34 g, 1.29 mmol) のジオキサン (20 mL) 溶液に1M NaOH (10 mL) を加え、70 ℃で３時間撹拌した。冷後、2M HCl を加え、反応液の pH を３に調整し、酢酸エチルで３回抽出した。酢酸エチル層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去し、目的とする式［Ｉ］（但し、ＲｆはＣ₈Ｆ₁₇を、Ｒは水素を、Ｘはメチレン基を、ｌは２を、ｍは３を、ｎは２、ｐは０を示す。）で 表される高度にフッ素化されたカルボン酸（白色粉末）：¹H-NMR (CDCl₃-CD₃OD = 1 : 1):δ 2.01 (4H, m), 2.28 (4H, m), 2.70 (2H, t, J= 6.3 Hz), 3.04 (4H, t, J=7.9 Hz), 3.24 (2H, t, J=6.3 Hz)を1.22 g（94 %) 得た。
【００２９】
【実施例３】
実施例１で調製した中間体 (0.74g, 1.29mmol) と式［ＩＶ］（但し、ＲｆはＣ₈Ｆ₁₇を、ｎは２を示す。）で表されるパーフルオロアルキルカルボン酸誘導体(0.74g, 1.29mmol)の無水ジクロロメタン (20 mL) 溶液にトリエチルアミン (0.54 mL, 3.86 mmol) と PyBOP (0.80g, 1.54 mmol) を順次加え、室温で３時間撹拌した。反応液に5% クエン酸溶液を加え、酢酸エチルで３回抽出した。酢酸エチル層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー (hexane : AcOEt = 4 : 1)にて精製し、式［Ｉ］（但し、ＲｆはＣ₈Ｆ₁₇を、Ｒはエチル基、Ｘはカルボニル基を、ｌは２を、ｍは３を、ｎは２、ｐは０を示す。）で表される高度にフッ素化されたカルボン酸のエチルエステル誘導体（式［ＶＩＩＩ］で示されるBfp-OHのエチルエステル）（無色油状）：¹H-NMR (CDCl₃):δ 1.27 (3H, m), 1.87 (2H, m), 2.10 (2H, m), 2.61 (6H, m), 3.45 (2H, m), 3.64 (2H, m), 4.16 (2H, m)、 MALDI-TOF-MS: Calcd for C₂₇H₁₉F₃₄NO₃ (M⁺): 1051.1, Found: 1051. を1.27 g（93 %)得た。この高度にフッ素化されたカルボン酸エチルエステル（式［ＶＩＩＩ］で示されるBfp-OHのエチルエステル） (1.26 g, 1.20 mmol) のジオキサン (20 mL) 溶液に1M NaOH (10 mL) を加え、70 ℃ で4時間撹拌した。冷後、2M HCl を加え、反応液の pH を３に調整し、酢酸エチルで３回抽出した。酢酸エチル層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去し、高度にフッ素化されたカルボン酸（式［ＶＩＩＩ］で示されるBfp-OH）（白色粉末）：1H-NMR (CDCl₃-CD₃OD = 5 : 3)δ: 1.92 (2H, m), 2.15 (2H, m), 2.65 (6H, m), 3.49 (2H, m), 3.66 (2H, m). MALDI-TOF-MS: Calcd for C₂₅H₁₅F₃₄NO₃ (M⁺): 1023.1, Found: 1022.6. (1.21 g, 98 %) を得た。
【００３０】
【実施例４】
【化１５】

化合物１ (1.05 g, 1.03 mmol) と式［Ｉ］（但し、ＲｆはＣ₈Ｆ₁₇を、Ｒは水素を、Ｘはカルボニル基を、ｌは２を、ｍは３を、ｎは２、ｐは０を示す。）で表される高度にフッ素化されたカルボン酸 （式［ＶＩＩＩ］で示されるBfp-OH）(124 mg, 0.29 mmol)の無水ジクロロメタン (10 mL) 溶液に４−ジメチルアミノピリジン (139 mg, 1.14 mmol)とDCC (353 mg, 1.71 mmol)を順次加え、室温で2時間撹拌した。反応液をトルエン (30 mL) と パーフルオロカーボン（フロリナート^TMFC-72 ）(30 mL) で分配抽出し、FC-72層を減圧濃縮して当該アシル基で水酸基を保護された式［ＶＩＩＩ］の化合物２ (836 mg, 85 %) を得た。
【００３１】
【実施例５】
化合物３ (43 mg, 12.1 mmol) のエーテル (2 mL) とメタノール (2 mL) 混合溶液に5.2 M NaOMe (20 μＬ) を加え、室温で１時間撹拌し脱保護した。アンバーライト(IR-120; H⁺ form) を加えて中和し、ろ過した。ろ液の減圧濃縮残渣をFC-72 (10 mL) と メタノール (10 mL) で分配抽出し、メタノール層を減圧濃縮して式［IX］で示される化合物４ (4.1 mg, 95 %) を得た。一方、FC-72層を減圧濃縮して式［Ｉ］（但し、ＲｆはＣ₈Ｆ₁₇を、Ｒはメチル基を、Ｘはカルボニル基を、ｌは２を、ｍは３を、ｎは２、ｐは０を示す。）で表される式［IX］の化合物５（Bfp-OMe） (35 mg, 92 %) を得た。
【化１６】

【００３２】
【実施例６】
式［Ｉ］（但し、ＲｆはＣ₈Ｆ₁₇を、Ｒは水素を、Ｘはカルボニル基を、lは２を，ｍは３，ｎは２、ｐは０を示す。）で示される高度にフッ素化されたカルボン酸 (0.74g, 1.29mmol) と式［ＩＩ］（但し、ＲｆはＣ₈Ｆ₁₇を、lは２を，ｍは３を示す。）で表される中間体(10.0g, 9.8mmol)の無水ジクロロメタン (300 mL) 溶液にトリエチルアミン (4.1 mL, 29.3 mmol) と PyBOP (6.1g, 11.7 mmol) を順次加え、室温で３時間撹拌した。反応液に5% クエン酸溶液を加え、酢酸エチルで３回抽出した。酢酸エチル層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー (hexane : AcOEt = 3 : 2) にて精製し、式［Ｉ］（但し、ＲｆはＣ₈Ｆ₁₇を、Ｒはエチル基を、Ｘはカルボニル基を、ｌは２を、ｍは３を、ｎは２、ｐは１を示す。）で表される高度にフッ素化されたカルボン酸のエチルエステル（無色油状）：¹H-NMR (CDCl₃):δ 1.26 (3H, t, J = 7.1 Hz), 1.87 (4H, m), 2.08 (4H, m), 2.58 (6H, m), 2.73 (2H, m), 3.45 (4H, m), 3.63 (4H, m), 4.14 (2H, q, J = 7.1 Hz). MALDI-TOF-MS: Calcd for C₄₁H₃₀F₅₁N₂O₄ (M+H⁺): 1583.1, Found: 1581.6. を1.21 g（78 %）得た。得られた高度にフッ素化されたカルボン酸エチルエステル (5.20 g, 3.29 mmol) のジオキサン (70 mL) 溶液に1M NaOH (35 mL) を加え、50 ℃ で3時間撹拌した。冷後、2M HCl を加え、反応液の pH を３に調整し、酢酸エチル-EtOC₄F₉(1:2)の混合溶媒で３回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去し、式［Ｉ］（但し、ＲｆはＣ₈Ｆ₁₇を、Ｒは水素を、Ｘはカルボニル基を、ｌは２を、ｍは３を、ｎは２、ｐは１を示す。）で示される高度にフッ素化されたカルボン酸（白色粉末）MALDI-TOF-MS: Calcd for C₃₉H₂₆F₅₁N₂O₄ (M+H⁺): 1555.1, Found: 1553.2. (4.94 g, 97 %) を得た。
【００３３】
【実施例７】
実施例６で得た式［Ｉ］（但し、ＲｆはＣ₈Ｆ₁₇を、Ｒは水素を、Ｘはカルボニル基を、ｌは２を、ｍは３を、ｎは２、ｐは１を示す。）で示される高度にフッ素化されたカルボン酸 (0.76 g, 0.49 mmol) と式［ＩＩ］（但し、ＲｆはＣ₈Ｆ₁₇を、lは２を，ｍは３を示す。）で表される中間体(0.28 g, 0.49 mmol)の無水ジクロロメタン (30 mL) 溶液にトリエチルアミン (0.2 mL, 1.47 mmol) と PyBOP (0.31 g, 0.59 mmol) を順次加え、室温で１８時間撹拌した。反応液に5% クエン酸溶液を加え、酢酸エチルで３回抽出した。酢酸エチル層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー (hexane : AcOEt = 1 : 1) にて精製し、式［Ｉ］（但し、ＲｆはＣ₈Ｆ₁₇を、Ｒはエチル基を、Ｘはカルボニル基を、ｌは２を、ｍは３を、ｎは２、ｐは２を示す。）で表される高度にフッ素化されたカルボン酸のエチルエステル（無色油状）：¹H-NMR (CDCl₃):δ 1.26 (3H, m), 1.86 (6H, m), 2.09 (6H, m), 2.59 (6H, m), 2.73 (4H, m), 3.45 (6H, m), 3.65 (6H, m), 4.14 (2H, m). MALDI-TOF-MS: Calcd for C₅₅H₄₀F₆₈N₃O₅ (M+H⁺): 2114.2, Found: 2112.2. を 0.52 g（50 %）得た。得られた高度にフッ素化されたカルボン酸エチルエステル(388 mg, 0.16 mmol)のジオキサン(3.5 mL)溶液に1M NaOH (1.8 mL) を加え、70 ℃ で3時間撹拌した。冷後、2M HCl を加え、反応液の pH を３に調整し、EtOC₄F₉で３回抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去し、式［Ｉ］（但し、ＲｆはＣ₈Ｆ₁₇を、Ｒは水素を、Ｘはカルボニル基を、ｌは２を、ｍは３を、ｎは２、ｐは２を示す。）で示される高度にフッ素化されたカルボン酸（白色粉末）MALDI-TOF-MS: Calcd for C₅₃H₃₅F₆₈N₃NaO₅ (M+Na⁺): 2108.1, Found: 2106.9. (226 mg, 75 %)を得た。
【００３４】
【発明の効果】
本発明化合物を用いるフルオラス合成が、医薬や食品添加物、化粧品、液晶、電子材料、高分子材料モノマー、機能性材料、医療材料などのファインケミカルズの製造、ペプチド、糖鎖、核酸などの複雑な天然物やそのアナローグの製造を容易にすることは確実である。また、フルオラスプロトン酸触媒や材料表面の改質剤などとしても利用可能であり、本発明化合物の工業的価値や波及効果は極めて大である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to highly fluorinated carboxylic acid derivatives. Synthetic organic chemistry plays an extremely high role in the production of fine chemicals such as pharmaceuticals, food additives, cosmetics, liquid crystals, electronic materials, polymer material monomers, functional materials, and medical materials. Fluorous synthesis has been proposed as a technology that goes beyond the concept of conventional organic synthesis, and its development is desired. This is because perfluorocarbons do not dissolve in organic solvents and water, and the three parties can separate each other, and only highly fluorinated derivatives can be extracted into the perfluorocarbon layer to easily and safely purify compounds. It is a method. For example, prior to the step of reacting Compound A and Compound B, a highly fluorinated carboxylic acid (a reagent for introducing a highly fluorinated group) is reacted with Compound A, and the highly fluorinated group is converted to Compound A Specific functional groups such as amino groups. Thereafter, the reaction between the reaction product and compound B, which is the main reaction, is performed. This is the reaction of another functional group of Compound A, such as a carboxyl group, with Compound B, such as an amino group. Since the reaction product obtained in this way has a high fluorine content, when perfluorocarbon (solvent) is added to this reaction system, this reaction product easily migrates to the perfluorocarbon layer. Separation becomes extremely easy by the operation using. Thereafter, the highly fluorinated group added prior to the main reaction is removed from the reaction product by hydrolysis or the like, and the target reaction product can be obtained with high purity and efficiency. On the other hand, it is expected that water repellency, lubricity, etc. can be imparted by utilizing the characteristics of fluorine atoms and highly fluorinating the material surface. However, in any case, as a method for highly fluorinated, a reagent for introducing a highly fluorinated group is required.
[0002]
[Prior art]
Various attempts have been made to synthesize organic compounds using this attractive method of fluorous synthesis in the fields of medicines and food additives, but no results have been obtained yet. This is because there is no reagent that introduces a highly fluorinated group that is reacted with the compound A in advance to make the fluorous synthesis successful. As a highly fluorinated carboxylic acid, (Rf) ₃ Si—C ₆ H ₄ —CO—OH [Rf: C ₁₀ F ₂₁ (CH ₂ ) −, C ₆ F ₁₃ (CH ₂ ) −] (Journal of Organic Chemistry, 62, 2917, 1997), etc., all of which can be used as a reagent for introducing a highly fluorinated group into the fluorous synthesis. Highly versatile because the reaction to add to is difficult, and in addition, it is difficult to remove the highly fluorinated group added with the reagent from the reaction product by hydrolysis after the main reaction. It could not be used for fluorous synthesis.
[0003]
[Problems to be solved by the invention]
An object of the present invention is to address such conventional problems. That is, since the reaction of adding the above-described reagent to the compound A in the fluorous synthesis is difficult, and the operation of removing the added highly fluorinated group from the reaction product is difficult, the fluorous synthesis It is to solve the problem that was not available to you. This problem is to realize the high separation ability of the reaction product from the reaction system as described above, and to protect the functional group not involved in the reaction in the unit process, which is often used in an organic chemical reaction. It realizes a highly fluorinated protecting group. Another object of the present invention is to provide a specific surface modifier of a polymer material or a natural material and a specific fluorous organic protonic acid catalyst.
[0004]
[Means for Solving the Problems]
As a result of intensive studies, the present inventors have created the compound of the present invention and solved the above-mentioned conventional problems of introduction and removal of highly fluorinated groups in fluorous synthesis from the methylene group constituting the compound of the present invention. It was found that there was an effect to solve, and in addition, the introduction of sufficient fluorine atoms was successful and the present invention was completed. That is, the present invention relates to the formula [I] (wherein Rf is a C 5-10 perfluoroalkyl group, R is hydrogen, an alkyl group, an aralkyl group, or an aryl group, and X is a carbonyl group. Alternatively, a methylene group, l is an integer of 1 to 3, m is 2 or 3, n is 1 or 2, p is an integer of 0 to 4, and Rf, X, m, and n are the same in each position. A highly fluorinated carboxylic acid derivative characterized in that it is represented by the following formula:
[Chemical 8]

[0005]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in detail.
[0006]
First, a method for producing an intermediate will be described.
[0007]
Formula [II]
[Chemical 9]

(Wherein Rf represents a perfluoroalkyl group having 5 to 10 carbon atoms, R represents an alkyl group, an aralkyl group or an aryl group, l represents an integer of 1 to 3, and m represents 2 or 3). The intermediate represented is an amino acid ester in the presence of a base in an organic solvent and a compound of the formula [III]
[Chemical Formula 10]

(Wherein Y represents an alkylsulfonyloxy group, an arylsulfonyloxy group, or a halogen other than fluorine, Rf represents a perfluoroalkyl group, and n represents an integer) To react.
[0008]
As the amino acid ester used as a raw material, a known amino acid ester can be used. Examples of amino acids include aminocarboxylic acids such as glycine, L-alanine, D-alanine, β-alanine, and 3-aminopropionic acid. A well-known carboxylic acid protecting group can be used for the ester moiety. For example, alkyl esters such as methyl ester, ethyl ester and tert-butyl ester, aralkyl esters such as benzyl ester, p-methoxybenzyl ester and p-nitrobenzyl ester, fragrances such as phenyl ester, naphthyl ester and phenacyl ester Group esters can be mentioned.
[0009]
Formula [III] (wherein Y represents an alkylsulfonyloxy group, an arylsulfonyloxy group, or a halogen other than fluorine, Rf represents a perfluoroalkyl group, and n represents an integer. A well-known derivative can be used for the perfluoroalkyl derivative represented by).
[0010]
As the alkylsulfonyloxy group and arylsulfonyloxy group, known sulfonyloxy groups can be used. Examples thereof include sulfonyloxy groups such as p-toluenesulfonyloxy group, methanesulfonyloxy group, and trifluoromethanesulfonyloxy group. Examples of the halogen other than fluorine include well-known halogens such as chlorine, bromine and iodine.
[0011]
A well-known perfluoroalkyl group can be used as the perfluoroalkyl group. For example, a perfluorohexyl group, a perfluoroheptyl group, a perfluorooctyl group, a perfluorodecyl group, a perfluorotetradecyl group, and the like can be given. Furthermore, it goes without saying that it does not matter whether there is a branched structure or a stereoisomer. Longer chains of perfluoroalkyl groups are more effective for increasing the introduction rate of fluorine atoms. However, in consideration of easy handling and availability, derivatives having 3 to 16 carbon atoms are used. A derivative having 5 to 10 carbon atoms is preferred.
[0012]
There is no restriction | limiting in the methylene chain couple | bonded with the perfluoroalkyl group, and it is a C1-C8 methylene chain normally. In particular, a methylene chain having 1 to 4 carbon atoms is preferable.
[0013]
As the organic solvent, a known solvent can be used. Dichloromethane, chloroform, hexane, benzene, toluene, tetrahydrofuran, ether, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, propionitrile, ethyl acetate, dimethyl sulfoxide, methyl ethyl ketone, perfluorohexane, perfluorocarbon (e.g. And Fluorinert ^™ FC72). Needless to say, the reaction can be carried out in a mixture, hydrated product, or heterogeneous system.
[0014]
There is no limitation on the base. For example, organic bases such as triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine and DBU, inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide, or organic metals such as butyllithium and phenyllithium A compound can be mentioned.
[0015]
There are no restrictions on the number of equivalents of both raw materials and base used. Either one component or two components can be used in excess. In the amino acid ester, a base in the range of 1 to 15 equivalents and a formula [III] (wherein Y is an alkylsulfonyloxy group, an arylsulfonyloxy group, or a halogen excluding fluorine, and Rf is a perfluoroalkyl group. , N represents an integer)). Usually, it is obtained directly as a mixture of an ester derivative of a highly fluorinated carboxylic acid which is a compound of the present invention and an intermediate. Both can be easily separated by ordinary purification means such as silica gel column chromatography. The production ratio of the two differs depending on the individual derivatives and depends on the number of equivalents. Therefore, it goes without saying that it is possible to preferentially produce an intermediate or to preferentially produce an ester derivative of a highly fluorinated carboxylic acid which is a compound of the present invention described later.
[0016]
There is no limitation on reaction time and reaction temperature. Each of them varies depending on individual derivatives, and also varies depending on the base and the solvent, but is usually in the range from room temperature to the boiling point of the solvent and in the range of 1 hour to 7 days.
[0017]
Next, a method for producing a highly fluorinated carboxylic acid and carboxylic acid derivative, which is a compound of the present invention, from an intermediate will be described.
[0018]
In the presence of a base in an organic solvent, the above formula [III] (wherein Y represents an alkylsulfonyloxy group, an arylsulfonyloxy group, or a halogen other than fluorine, and Rf represents a perfluoroalkyl group). N represents an integer) or a perfluoroalkyl derivative represented by the formula [IV]
Embedded image

(Wherein Rf represents a perfluoroalkyl group and n represents an integer), or the formula [V]
Embedded image

(In the formula, Rf represents a perfluoroalkyl group, X represents a carbonyl group or a methylene group, l, m, n, and p represent integers, and Rf, X, m, and n need to be the same at each display position. A highly fluorinated carboxylic acid of the formula [VI]
Embedded image

(In the formula, Rf represents a perfluoroalkyl group, R represents an alkyl group, an aralkyl group, or an aryl group, X represents a carbonyl group or a methylene group, l, m, n, and p represent an integer, Rf, X, m and n do not have to be the same at each displayed position.) After obtaining a highly fluorinated carboxylic acid derivative (ester) represented by the following formula, the ester moiety is converted into a carboxylic acid according to a conventional method. Convert to produce highly fluorinated carboxylic acids. Formula [I] (wherein Rf is a C 5-10 perfluoroalkyl group, R is hydrogen, an alkyl group, an aralkyl group, or an aryl group, X is a carbonyl group or a methylene group, and l is An integer of 1 to 3, m is 2 or 3, n is 1 or 2, p is an integer of 0 to 4, and Rf, X, m, and n need not be the same in each display position. The highly fluorinated carboxylic acid and carboxylic acid derivative which is the compound of the present invention represented by the above can be produced by the above-mentioned method.
[0019]
The perfluoroalkyl derivative represented by the formula [III] and the perfluoroalkyl group of the perfluoroalkylcarboxylic acid represented by the formula [IV] are not particularly limited, and the above-mentioned perfluoroalkyl group can be used.
[0020]
The length n of the methylene chain is not limited at all, and is usually a methylene chain having 1 to 8 carbon atoms. In particular, a methylene chain having 1 to 4 carbon atoms is preferable.
[0021]
The alkylsulfonyloxy group, arylsulfonyloxy group, and halogen other than fluorine are not limited as described above.
[0022]
There are no limitations on the organic solvent and base used when the perfluoroalkyl derivative represented by the formula [III] is reacted, and specifically, the same as the example described for the production of the intermediate. Needless to say, the intermediate can be isolated and then reacted, or as described above, the two-step reaction can be performed at once.
[0023]
Formula [IV] or Formula [V] (wherein Rf is a perfluoroalkyl group, X is a carbonyl group or a methylene group, l, m, n, and p are integers, and Rf, X, m, and n are There is no limitation on the method of reacting the perfluoroalkylcarboxylic acid represented by the formula [II] with the intermediate represented by the formula [II]. The perfluorocarboxylic acid to be reacted is converted into an acid halide, mixed acid anhydride, symmetric acid anhydride, active ester in advance, or directly reacted with a condensation reagent such as N, N-dicyclohexylcarbodiimide (DCC). The method of letting it be mentioned. Any derivative may be a known derivative. Specific examples include well-known derivatives such as acid chlorides, acid bromides, pivalic acid mixed acid anhydrides, pentafluorophenyl esters, p-nitrophenyl esters, and succinimide esters. Examples of the condensation reagent include DCC, PyBOP ^™ (benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), BOP (benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexa Fluorophosphate) and the like. By repeating the above steps, a more highly fluorinated carboxylic acid can be produced. The number of repetitions is not limited, but substantially the value of p represented by the formula [I] is preferably 0 to 4, more preferably 0 to 2.
[0024]
The highly fluorinated carboxylic acid derivative (ester) that is the compound of the present invention obtained as described above can be converted to a carboxylic acid by a usual method. Specifically, it depends on the type of ester. For example, in the case of methyl ester, ethyl ester, etc., alkaline hydrolysis such as a method using an aqueous sodium hydroxide solution, in the case of tert-butyl ester, acid decomposition of trifluoroacetic acid, etc., in the case of benzyl ester, etc. It can be carried out by catalytic hydrogenolysis.
[0025]
The carboxylic acid derivative, which is the compound of the present invention thus obtained, can be introduced as an acyl-type protecting group highly fluorinated in the target compound or the amino group or functional group on the surface of the material in the fluorous synthesis. Needless to say, a conventional acylation method can be used for the introduction. The compound having the acyl group introduced is easily extracted into the perfluorocarbon layer, and the purification operation is facilitated. The value of p in the highly fluorinated carboxylic acid derivative represented by the formula [I] is a major feature of the present invention, and this value depends on the separation ability of the main reaction product and the highly fluorinated carboxylic acid. Is determined from the balance with its ease of use for industry. In particular, when the derivative represented by the formula [I] is p of 0 and the extraction efficiency into the perfluorocarbon layer is low, the derivative of p of 1 or 2 is effective. The acyl group introduced into the hydroxyl group can be easily removed under basic conditions such as sodium methoxide and sodium hydroxide according to a conventional method. Therefore, the formula [VII]
Embedded image

(In the formula, Rf represents a perfluoroalkyl group having 5 to 10 carbon atoms, X represents a carbonyl group or a methylene group, l represents an integer of 1 to 3, m represents 2 or 3, n represents 1 or 2, p represents an integer of 0 to 4, and Rf, X, m, and n do not have to be the same in each of the displayed positions.) A method using a highly fluorinated acyl group represented by Therefore, it is highly practical as a novel protecting group in fluorous synthesis. The acyl group introduced into the amino group can be removed under acidic conditions such as hydrochloric acid and sulfuric acid. Moreover, since the compound of the present invention or its derivative is easily extracted into the perfluorocarbon layer after being deprotected, it can be recovered and reused, and an environment-friendly production system can be established. In addition, by reacting with functional groups such as hydroxyl groups and amino groups on the surface of various materials and introducing them as acyl-type surface modifying groups, they can be applied to improve surface properties such as imparting water repellency and lubricity, etc. wide. In this case, it is obvious that the larger value of p shown in the formula [I] is more advantageous. In addition, it goes without saying that only the compound of the present invention can be used as a fluorous organic protonic acid catalyst.
[0026]
Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited at all unless it exceeds the gist.
[0027]
[Example 1]
β-alanine ethyl ester hydrochloride (0.71 g, 4.64 mmol) and formula [III] (where Rf represents C ₈ F ₁₇ , Y represents a p-toluenesulfonyloxy group, and n represents 2). To a solution of the perfluoro compound (6.02 g, 9.74 mmol) in propionitrile (100 mL) was added potassium carbonate (3.84 g, 27.8 mmol), and the mixture was heated to reflux for 4 days. After cooling, the reaction mixture was added to water and extracted three times with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 8: 1 to AcOEt), and the formula [II] (where Rf is C ₈ F ₁₇ , R is an ethyl group, l is 2, m is 3) Intermediate (colorless oil): ¹ H-NMR (CDCl ₃ ): δ 1.27 (3H, t, J = 7.3 Hz), 1.77 (2H, m), 2.16 (2H, m) , 2.50 (2H, t, J = 6.3 Hz), 2.70 (2H, t, J = 6.8 Hz), 2.88 (2H, t, J = 6.3 Hz), 4.15 (2H, q, J = 7.3 Hz) 1.39 g (52%), and formula [I] (where Rf is C ₈ F ₁₇ , R is an ethyl group, X is a methylene group, l is 2, m is 3, n is 2, p is The ethyl ester derivative of a highly fluorinated carboxylic acid (colorless oil) represented by: ¹ H-NMR (CDCl ₃ ): δ 1.24 (3H, t, J = 7.1 Hz), 1.73 ( 4H, m), 2.11 (4H, m), 2.40 (2H, t, J = 6.6 Hz), 2.48 (4H, t, J = 6.1 Hz), 2.76 (2H, t, J = 6.6 Hz), 4.12 ( 2H, q, J = 7.1 Hz) was obtained 1.34 g (28%).
[0028]
[Example 2]
1M NaOH (10 mL) was added to a dioxane (20 mL) solution of the ethyl ester derivative (1.34 g, 1.29 mmol) of the highly fluorinated carboxylic acid obtained in Example 1, and the mixture was stirred at 70 ° C. for 3 hours. After cooling, 2M HCl was added to adjust the pH of the reaction solution to 3, and extracted three times with ethyl acetate. The ethyl acetate layer is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain the desired formula [I] (where Rf is C ₈ F ₁₇ , R is hydrogen, X is A highly fluorinated carboxylic acid represented by a methylene group, l is 2, m is 3, n is 2, and p is 0.): ¹ H-NMR (CDCl ₃ − CD ₃ OD = 1: 1): δ 2.01 (4H, m), 2.28 (4H, m), 2.70 (2H, t, J = 6.3 Hz), 3.04 (4H, t, J = 7.9 Hz), 3.24 ( 2H, t, J = 6.3 Hz) was obtained 1.22 g (94%).
[0029]
[Example 3]
A perfluoroalkylcarboxylic acid derivative (0.74 g) represented by the intermediate (0.74 g, 1.29 mmol) prepared in Example 1 and the formula [IV] (where Rf represents C ₈ F ₁₇ and n represents 2). g, 1.29 mmol) in anhydrous dichloromethane (20 mL) were added triethylamine (0.54 mL, 3.86 mmol) and PyBOP (0.80 g, 1.54 mmol) sequentially, and the mixture was stirred at room temperature for 3 hours. A 5% citric acid solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 4: 1). Formula [I] (where Rf was C ₈ F ₁₇ , R was an ethyl group, X was a carbonyl group, and l was 2) , M represents 3, n represents 2, and p represents 0. A highly fluorinated ethyl ester derivative of a carboxylic acid (ethyl ester of Bfp-OH represented by the formula [VIII]) (colorless) Oily): ¹ H-NMR (CDCl ₃ ): δ 1.27 (3H, m), 1.87 (2H, m), 2.10 (2H, m), 2.61 (6H, m), 3.45 (2H, m), 3.64 ( 2H, m), 4.16 (2H, m), MALDI-TOF-MS: Calcd for C ₂₇ H ₁₉ F ₃₄ NO ₃ (M ⁺ ): 1051.1, Found: 1051. 1.27 g (93%) were obtained. To this highly fluorinated ethyl carboxylic acid ester (ethyl ester of Bfp-OH represented by the formula [VIII]) (1.26 g, 1.20 mmol) in dioxane (20 mL) was added 1M NaOH (10 mL). The mixture was stirred at 70 ° C. for 4 hours. After cooling, 2M HCl was added to adjust the pH of the reaction solution to 3, and extracted three times with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and a highly fluorinated carboxylic acid (Bfp-OH represented by the formula [VIII]) (white powder): 1H-NMR (CDCl ₃ -CD ₃ OD = 5: 3) δ: 1.92 (2H, m), 2.15 (2H, m), 2.65 (6H, m), 3.49 (2H, m), 3.66 (2H, m MALDI-TOF-MS: Calcd for C ₂₅ H ₁₅ F ₃₄ NO ₃ (M ⁺ ): 1023.1, Found: 1022.6. (1.21 g, 98%) was obtained.
[0030]
[Example 4]
Embedded image

Compound 1 (1.05 g, 1.03 mmol) and formula [I] (where Rf is C ₈ F ₁₇ , R is hydrogen, X is a carbonyl group, l is 2, m is 3, n is 2, p is 0.) A highly fluorinated carboxylic acid (Bfp-OH represented by the formula [VIII]) (124 mg, 0.29 mmol) in anhydrous dichloromethane (10 mL) was added to 4-dimethyl Aminopyridine (139 mg, 1.14 mmol) and DCC (353 mg, 1.71 mmol) were sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was partitioned and extracted with toluene (30 mL) and perfluorocarbon (Fluorinert ^™ FC-72) (30 mL), and the FC-72 layer was concentrated under reduced pressure to protect the hydroxyl group with the acyl group of formula [VIII]. Compound 2 (836 mg, 85%) was obtained.
[0031]
[Example 5]
5.2 M NaOMe (20 μL) was added to a mixed solution of compound 3 (43 mg, 12.1 mmol) in ether (2 mL) and methanol (2 mL), and the mixture was stirred at room temperature for 1 hour for deprotection. Amberlite (IR-120; H ⁺ form) was added to neutralize and filtered. The filtrate concentrated under reduced pressure was partitioned and extracted with FC-72 (10 mL) and methanol (10 mL), and the methanol layer was concentrated under reduced pressure to obtain Compound 4 (4.1 mg, 95%) represented by the formula [IX]. It was. On the other hand, the FC-72 layer was concentrated under reduced pressure to give the formula [I] (where Rf is C ₈ F ₁₇ , R is a methyl group, X is a carbonyl group, l is 2, m is 3, n is 2, p represents 0.) Compound 5 (Bfp-OMe) (35 mg, 92%) of the formula [IX] represented by formula (IX) was obtained.
Embedded image

[0032]
[Example 6]
An altitude represented by the formula [I] (where Rf represents C ₈ F ₁₇ , R represents hydrogen, X represents a carbonyl group, l represents 2, m represents 3, n represents 2, and p represents 0). Fluorinated carboxylic acid (0.74 g, 1.29 mmol) and an intermediate represented by the formula [II] (wherein Rf represents C ₈ F ₁₇ , l represents 2, m represents 3) (10.0 To a solution of g, 9.8 mmol) in anhydrous dichloromethane (300 mL), triethylamine (4.1 mL, 29.3 mmol) and PyBOP (6.1 g, 11.7 mmol) were sequentially added, and the mixture was stirred at room temperature for 3 hours. A 5% citric acid solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 3: 2). Formula [I] (where Rf was C ₈ F ₁₇ , R was an ethyl group, X was a carbonyl group, and l was 2) , M is 3, n is 2, and p is 1.) A highly fluorinated ethyl ester of a carboxylic acid (colorless oil): ¹ H-NMR (CDCl ₃ ): δ 1.26 ( 3H, t, J = 7.1 Hz), 1.87 (4H, m), 2.08 (4H, m), 2.58 (6H, m), 2.73 (2H, m), 3.45 (4H, m), 3.63 (4H, m ), 4.14 (2H, q, J = 7.1 Hz). MALDI-TOF-MS: Calcd for C ₄₁ H ₃₀ F ₅₁ N ₂ O ₄ (M + H ⁺ ): 1583.1, Found: 1581.6. %)Obtained. 1 M NaOH (35 mL) was added to a dioxane (70 mL) solution of the obtained highly fluorinated carboxylic acid ethyl ester (5.20 g, 3.29 mmol), and the mixture was stirred at 50 ° C. for 3 hours. After cooling, 2M HCl was added to adjust the pH of the reaction solution to 3, and the mixture was extracted 3 times with a mixed solvent of ethyl acetate-EtOC ₄ F ₉ (1: 2). The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to remove the formula [I] (where Rf is C ₈ F ₁₇ , R is hydrogen, X is a carbonyl group, 1 represents a highly fluorinated carboxylic acid (white powder) MALDI-TOF-MS: Calcd for C ₃₉ H ₂₆ F ₅₁ N ₂ O ₄ (M + H ⁺ ): 1555.1, Found: 1553.2. (4.94 g, 97%) was obtained.
[0033]
[Example 7]
Formula [I] obtained in Example 6 (where Rf is C ₈ F ₁₇ , R is hydrogen, X is a carbonyl group, 1 is 2, m is 3, n is 2, and p is 1) A highly fluorinated carboxylic acid (0.76 g, 0.49 mmol) and the formula [II] (wherein Rf represents C ₈ F ₁₇ , l represents 2 and m represents 3). Triethylamine (0.2 mL, 1.47 mmol) and PyBOP (0.31 g, 0.59 mmol) were sequentially added to a solution of the intermediate represented (0.28 g, 0.49 mmol) in anhydrous dichloromethane (30 mL), and the mixture was stirred at room temperature for 18 hours. A 5% citric acid solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 1: 1). Formula [I] (where Rf was C ₈ F ₁₇ , R was an ethyl group, X was a carbonyl group, and l was 2) , M is 3, n is 2, and p is 2. The ethyl ester of a highly fluorinated carboxylic acid represented by (colorless oil): ¹ H-NMR (CDCl ₃ ): δ 1.26 ( 3H, m), 1.86 (6H, m), 2.09 (6H, m), 2.59 (6H, m), 2.73 (4H, m), 3.45 (6H, m), 3.65 (6H, m), 4.14 (2H MALDI-TOF-MS: Calcd for C ₅₅ H ₄₀ F ₆₈ N ₃ O ₅ (M + H ⁺ ): 2114.2, Found: 2112.2. 0.52 g (50%) was obtained. 1M NaOH (1.8 mL) was added to a dioxane (3.5 mL) solution of the obtained highly fluorinated carboxylic acid ethyl ester (388 mg, 0.16 mmol), and the mixture was stirred at 70 ° C. for 3 hours. After cooling, 2M HCl was added to adjust the pH of the reaction solution to 3, followed by extraction with EtOC ₄ F ₉ three times. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to remove the formula [I] (where Rf is C ₈ F ₁₇ , R is hydrogen, X is a carbonyl group, 1 represents a highly fluorinated carboxylic acid (white powder) MALDI-TOF-MS: Calcd for C ₅₃ H ₃₅ F ₆₈ N ₃ NaO ₅ (M + Na ⁺ ): 2108.1, Found: 2106.9. (226 mg, 75%) was obtained.
[0034]
【The invention's effect】
Fluorous synthesis using the compounds of the present invention is a complex natural product such as pharmaceuticals, food additives, cosmetics, liquid crystals, electronic materials, polymer materials monomers, functional materials, production of fine chemicals such as medical materials, peptides, sugar chains, nucleic acids, etc. It is certain to facilitate the manufacture of objects and their analogs. Further, it can be used as a fluorous protonic acid catalyst or a material surface modifier, and the industrial value and ripple effect of the compound of the present invention are extremely large.

Claims (5)

The following formula [I]

(In the formula, Rf represents a perfluoroalkyl group having 5 to 10 carbon atoms, R represents hydrogen, an alkyl group, an aralkyl group, or an aryl group, X represents a carbonyl group or a methylene group, and l represents 1 to 3) , M represents 2 or 3, n represents 1 or 2, p represents an integer of 0 to 4, and Rf, X, m, and n need not be the same in each display position. A highly fluorinated carboxylic acid derivative characterized in that Rf is C ₈ F ₁₇ , R is hydrogen, a methyl group, or an ethyl group, X is a carbonyl group, l is 2, m is 3, n is 2, and p is an integer of 0 to 2, A highly fluorinated carboxylic acid derivative according to claim 1. In the presence of a base, the following formula [III]

(Wherein Y represents an alkylsulfonyloxy group, an arylsulfonyloxy group, or a halogen other than fluorine, Rf represents a perfluoroalkyl group having 5 to 10 carbon atoms , and n represents 1 or 2 ). reacting the perfluoroalkyl derivative represented, then the presence of a base, is reacted with perfluoroalkyl derivative represented by again formula [III], or formula [IV]

(Wherein Rf represents a perfluoroalkyl group having 5 to 10 carbon atoms , and n represents 1 or 2. ) or a formula [V]

(In the formula, Rf represents a perfluoroalkyl group having 5 to 10 carbon atoms , X represents a carbonyl group or a methylene group, l represents an integer of 1 to 3, m represents 2 or 3, n represents 1 or 2, p represents an integer of 0 to 3, and Rf, X, m, and n do not have to be the same at each display position.) and is condensed with a carboxylic acid represented by the formula [I]

(Wherein Rf is a perfluoroalkyl group having 5 to 10 carbon atoms , R is an alkyl group, aralkyl group or aryl group, X is a carbonyl group or methylene group, and l is an integer of 1 to 3) , M represents 2 or 3, n represents 1 or 2, p represents an integer of 0 to 4 , and Rf, X, m, and n do not have to be the same in each display position. A method for producing a fluorinated carboxylic acid derivative. The formula [I] according to claim 3 , wherein Rf represents a perfluoroalkyl group having 5 to 10 carbon atoms , R represents an alkyl group, an aralkyl group, or an aryl group, and X represents a carbonyl group or a methylene group. , L represents an integer of 1 to 3, m represents 2 or 3, n represents 1 or 2, p represents an integer of 0 to 4 , and Rf, X, m, and n must be the same in each display position And a method for producing a highly fluorinated carboxylic acid, which comprises a step of deriving from a highly fluorinated carboxylic acid derivative to a carboxylic acid. Formula [VII]

(In the formula, Rf represents a perfluoroalkyl group having 5 to 10 carbon atoms, X represents a carbonyl group or a methylene group, l represents an integer of 1 to 3, m represents 2 or 3, n represents 1 or 2, p Represents an integer of 0 to 4, and Rf, X, m, and n do not have to be the same in each position thereof.) A method of using a highly fluorinated acyl group represented by