JP5282200B2 - Transparent hydrogelator - Google Patents
Transparent hydrogelator Download PDFInfo
- Publication number
- JP5282200B2 JP5282200B2 JP2008227274A JP2008227274A JP5282200B2 JP 5282200 B2 JP5282200 B2 JP 5282200B2 JP 2008227274 A JP2008227274 A JP 2008227274A JP 2008227274 A JP2008227274 A JP 2008227274A JP 5282200 B2 JP5282200 B2 JP 5282200B2
- Authority
- JP
- Japan
- Prior art keywords
- hydrocarbon group
- formula
- oxygen atom
- integer
- carbon atoms
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Compositions Of Macromolecular Compounds (AREA)
- Polyethers (AREA)
Abstract
Description
本発明は、新規な化学構造を有するヒドロゲル化剤、及びヒドロゲルに関するものである。 The present invention relates to a hydrogelator having a novel chemical structure and a hydrogel.
低分子ゲルは、低分子化合物が分子間力による自己組織化により３次元ネットワークを形成することによって、溶媒分子を捕捉したゲルである（例えば、非特許文献１参照）。 A low molecular gel is a gel in which solvent molecules are captured by forming a three-dimensional network by self-assembly of low molecular compounds by intermolecular forces (see, for example, Non-Patent Document 1).
低分子ゲルは、ゲルを形成する低分子化合物の分子設計が可能なことから、分離膜、センサー、触媒、電子材料、バイオ素材等、様々な分野への応用が期待されている（例えば、非特許文献２参照）。 Low molecular gels are expected to be applied to various fields such as separation membranes, sensors, catalysts, electronic materials, biomaterials, etc., since molecular design of low molecular compounds that form gels is possible. Patent Document 2).
我々も、新規な構造を有する３，４，５−長鎖アルキルオキシベンズアミド誘導体を合成し（特許文献１参照）、その一部の化合物が有機溶媒をゲル化することを見出し、さらに高いゲル化能を有する化合物を提供した（特許文献２参照）。 We have also synthesized 3,4,5-long-chain alkyloxybenzamide derivatives having a novel structure (see Patent Document 1), and found that some of these compounds gel organic solvents. The compound which has the ability was provided (refer patent document 2).
しかし、バイオ素材への応用を考えた場合、有機溶媒をゲル化したオルガノゲルよりも、水をゲル化したヒドロゲルが望ましいことは明らかであるが、低分子が形成するヒドロゲルの報告は少ない（例えば、非特許文献３参照）。また、得られたヒドロゲルをバイオ素材として利用する場合、ヒドロゲル自体が生体適合性を持つことが望ましいが、こうした観点からの報告はほとんど無かった。 However, when considering application to biomaterials, it is clear that water gelled hydrogels are preferable to organogel gels, but there are few reports of low molecular hydrogels (for example, Non-Patent Document 3). Further, when the obtained hydrogel is used as a biomaterial, it is desirable that the hydrogel itself has biocompatibility, but there has been almost no report from this viewpoint.
我々は、これまでに、エチレングリコールのオリゴマー又はポリマー誘導体を結合した３，４，５−長鎖アルキルオキシベンズアミド誘導体を合成し、これらの化合物が医療用材料等に生体適合性を付与する目的で使用できること（特許文献３参照）、また、これらの化合物が有機溶媒をゲル化すること（特許文献４参照）を開示したばかりでなく、さらに、これらの化合物がヒドロゲルを形成することを見出した（特許文献５参照）。しかし、目的や用途に応じてヒドロゲルの物性や調製法等を最適化するために、さらに新規な分子構造を有するヒドロゲル化剤の開発が望まれている。また、光学材料、電子材料、バイオ素材等への応用では、ヒドロゲルの透明性が高いことが望ましい。 We have synthesized 3,4,5-long chain alkyloxybenzamide derivatives to which oligomers or polymer derivatives of ethylene glycol have been bound so far, and these compounds are intended to impart biocompatibility to medical materials. It has been disclosed that these compounds can be used (see Patent Document 3), and that these compounds gel organic solvents (see Patent Document 4), and further, these compounds have been found to form hydrogels ( (See Patent Document 5). However, development of a hydrogelator having a new molecular structure is desired in order to optimize the properties and preparation methods of the hydrogel according to the purpose and application. In addition, in application to optical materials, electronic materials, biomaterials, etc., it is desirable that the hydrogel has high transparency.
本発明の課題は、新規な化学構造を有するヒドロゲル化剤、及びヒドロゲルを提供することにある。 An object of the present invention is to provide a hydrogelator having a novel chemical structure and a hydrogel.
上記課題に関して鋭意検討した結果、本発明者らは、式（１）で示されるエチレングリコールのオリゴマー又はポリマー誘導体を結合し、酸素原子を介して結合した炭化水素基に不飽和結合を含む新規なベンズアミド誘導体が、これまでに検討した飽和のアルキルオキシ基を有するベンズアミド誘導体と同様に、親水性のオリゴエチレングリコール部分の長さ、疎水性の炭化水素基の長さ、及び、ゲル化の条件の適切な選択によって、ヒドロゲルを形成し、加えて、対応する飽和のアルキルオキシ基を有するベンズアミド誘導体より透明性の高いヒドロゲルを与えることを見出し、本発明を完成するに至った。 As a result of intensive studies on the above problems, the present inventors have synthesized a novel ethylene glycol oligomer or polymer derivative represented by formula (1) and containing an unsaturated bond to a hydrocarbon group bonded via an oxygen atom. Similar to the benzamide derivatives having a saturated alkyloxy group investigated so far, the length of the hydrophilic oligoethylene glycol moiety, the length of the hydrophobic hydrocarbon group, and the gelation conditions of the benzamide derivative Appropriate selection has been found to form hydrogels and, in addition, provide hydrogels that are more transparent than benzamide derivatives having the corresponding saturated alkyloxy groups, and have completed the present invention.
すなわち、本発明は、式（１）で示されるベンズアミド誘導体、式（１）で示されるベンズアミド誘導体を有効成分として含み、ヒドロゲルを形成するヒドロゲル化剤、及び、式（１）で示されるベンズアミド誘導体と水とを含んでなるヒドロゲルを提供する。
That is, the present invention includes a benzamide derivative represented by the formula (1), a benzamide derivative represented by the formula (1) as an active ingredient, a hydrogelator that forms a hydrogel, and a benzamide derivative represented by the formula (1) And a hydrogel comprising water.
本発明は、分子の自己組織化により、エチレングリコールのオリゴマー又はポリマーを部分構造とする化合物がヒドロゲル化する希な分子種に、新たな分子構造の多様性を加えるものである。 The present invention adds a variety of new molecular structures to a rare molecular species in which a compound having an ethylene glycol oligomer or polymer as a partial structure hydrogels by molecular self-assembly.
本発明のベンズアミド誘導体は、式（１）で表される化合物である。
なお、室温付近でのヒドロゲル形成の観点からｍは７以上、Ｒ１の炭素数は１２から１８まで、Ｒ２とＲ３の炭素数は１８以下が好ましく、合成工程の観点からｎは２以上が好ましい。
式（１）で示されるベンズアミド誘導体は、例えば、エチレングリコールのオリゴマー又はポリマーのアミン誘導体と、相当する酸素原子を介して結合した炭化水素基を有する安息香酸誘導体とのアミド縮合によって得られる（特開２００５−２３２０６１号公報）。また、末端のＸとエチレングリコールのオリゴマー又はポリマーの間のアルキル鎖長、及び、ベンズアミドとエチレングリコールのオリゴマー又はポリマーの間のアルキル鎖長は、下に記載のエチレングリコールのオリゴマー又はポリマーのアミン誘導体の合成法に準じて、適当な末端修飾を施すことによって得られる。
The benzamide derivative of the present invention is a compound represented by the formula (1).
In addition, m is preferably 7 or more from the viewpoint of hydrogel formation near room temperature, R 1 has 12 to 18 carbon atoms, R 2 and R 3 have 18 or less carbon atoms, and n is 2 or more from the viewpoint of the synthesis step. Is preferred.
The benzamide derivative represented by the formula (1) is obtained, for example, by amide condensation between an ethylene glycol oligomer or polymer amine derivative and a benzoic acid derivative having a hydrocarbon group bonded via the corresponding oxygen atom (special feature). No. 2005-232061). The alkyl chain length between the terminal X and the ethylene glycol oligomer or polymer and the alkyl chain length between the benzamide and ethylene glycol oligomer or polymer are the amine derivatives of the ethylene glycol oligomer or polymer described below. According to the synthesis method of (2), it can be obtained by applying an appropriate terminal modification.
エチレングリコールのオリゴマー又はポリマーのアミン誘導体は、例えば、市販のエチレングリコールのオリゴマー又はポリマーの一端、又は、両端を、順次、トシル化、トシル基のヨウ素化、ヨウ素基のフタルイミドへの変換、ヒドラジンによる脱保護によって得られる。また、市販で入手できない長さのオリゴマーについては、オリゴエチレングリコールの一端を保護し、他の一端をトシル化して、合計が必要な長さとなるオリゴエチレングリコールと縮合の後、脱保護して得られる化合物（ジャーナル・オブ・オーガニック・ケミストリー（Ｊ．Ｏｒｇ．Ｃｈｅｍ．）２００４年、６９巻、ｐ．６３９−６４７）の一端、又は、両端を、順次、トシル化、トシル基のヨウ素化、ヨウ素基のフタルイミドへの変換、ヒドラジンによる脱保護によって得られる（バイオケミストリー（Ｂｉｏｃｈｅｍｉｓｔｒｙ）１９８０年、１９巻、ｐ．４５９５−４６００）。あるいは、トシル化に続いて、トシル基のアジド化、それに引き続く還元によっても同様の化合物が得られる。 The ethylene glycol oligomer or polymer amine derivative is obtained by, for example, sequentially tosylating, iodination of tosyl group, conversion of iodine group to phthalimide, hydrazine by one end or both ends of commercially available ethylene glycol oligomer or polymer. Obtained by deprotection. For oligomers with lengths that are not commercially available, one end of oligoethylene glycol is protected, the other end is tosylated, and condensed with oligoethylene glycol, the total length of which is required, followed by deprotection. One or both ends of a compound (J. Org. Chem. 2004, 69, p.639-647), which is tosylated, iodinated tosyl group, iodine Obtained by conversion of the group to phthalimide, deprotection with hydrazine (Biochemistry 1980, 19, p. 4595-4600). Alternatively, a similar compound can be obtained by tosylation followed by azidation of the tosyl group and subsequent reduction.
不飽和の長鎖のアルキルオキシ基を有する安息香酸誘導体は、以下に記載する、各種の安息香酸誘導体合成の側鎖エーテル化のステップで、不飽和結合を含む炭化水素基を導入する部位に不飽和炭化水素化剤を用いることによって合成される。 A benzoic acid derivative having an unsaturated long-chain alkyloxy group is not present at a site where a hydrocarbon group containing an unsaturated bond is introduced in the side chain etherification step of synthesis of various benzoic acid derivatives described below. It is synthesized by using a saturated hydrocarbon agent.
３、４、５位に酸素原子を介して同じ炭化水素基を結合した安息香酸誘導体は、３，４，５−トリヒドロキシ安息香酸エステルをエーテル化の後、エステルを加水分解することによって得られる。 A benzoic acid derivative having the same hydrocarbon group bonded to the 3, 4, 5 position via an oxygen atom is obtained by etherifying 3,4,5-trihydroxybenzoic acid ester and then hydrolyzing the ester. .
５位が水素で、３位と４位に酸素原子を介して同じ炭化水素基を結合した安息香酸誘導体は、３，４−ジヒドロキシ安息香酸エステルを原料に、３位と４位を同時にエーテル化した後、エステルを加水分解することによって得られる。また、３位と４位に酸素原子を介して異なる炭化水素基を持つ安息香酸誘導体は、例えば、３位と４位の反応性の違いを利用して、４位を選択的にエーテル化し、続いて、３位を４位とは異なる炭化水素化剤によってエーテル化した後、エステルを加水分解することによって得られる。 A benzoic acid derivative in which the 5-position is hydrogen and the same hydrocarbon group is bonded to the 3-position and 4-position via an oxygen atom, and 3- and 4-positions are simultaneously etherified using 3,4-dihydroxybenzoate as a raw material. And then obtained by hydrolyzing the ester. In addition, benzoic acid derivatives having different hydrocarbon groups at the 3-position and 4-position via an oxygen atom, for example, selectively etherify the 4-position using the difference in reactivity between the 3-position and 4-position, Subsequently, it is obtained by etherifying the 3-position with a hydrocarbonating agent different from the 4-position and then hydrolyzing the ester.
５位に酸素原子を介して３位と４位とは異なる炭化水素基を有する安息香酸誘導体は、例えば、３，４，５−トリヒドロキシ安息香酸エステルの３位と４位をボロン酸誘導体の選択的な架橋を用いて保護し、５位をエーテル化の後、該ボロン酸誘導体を脱保護し、上記と同様の方法で、３位と４位のエーテル化と、それに続くエステルの加水分解によって得られる。 A benzoic acid derivative having a hydrocarbon group different from the 3rd and 4th positions through an oxygen atom at the 5th position is, for example, the 3rd and 4th positions of the 3,4,5-trihydroxybenzoic acid ester of the boronic acid derivative. Protection with selective crosslinking, etherification at the 5-position followed by deprotection of the boronic acid derivative, etherification at the 3- and 4-positions followed by hydrolysis of the ester in the same manner as above Obtained by.
４位が水素で、３位と５位に酸素原子を介して同じ炭化水素基を結合した安息香酸誘導体は、３，５−ジヒドロキシ安息香酸エステルを原料に、３位と５位を同時にエーテル化した後、エステルを加水分解することによって得られる。また、３位と５位に酸素原子を介して異なる炭化水素基を有する安息香酸誘導体は、例えば、エーテル化の際の炭化水素化剤の当量を抑えて、片側がエーテル化されたものを単離し、残りの水酸基を異なる炭化水素化剤でエーテル化した後、エステルを加水分解することによって得られる。 A benzoic acid derivative in which the 4-position is hydrogen and the same hydrocarbon group is bonded to the 3-position and 5-position via an oxygen atom, and 3- and 5-positions are simultaneously etherified using 3,5-dihydroxybenzoate as a raw material. And then obtained by hydrolyzing the ester. In addition, a benzoic acid derivative having different hydrocarbon groups at the 3-position and 5-position via an oxygen atom, for example, can be obtained by reducing the equivalent of a hydrocarbonating agent during etherification and by simply converting one etherified. And the remaining hydroxyl group is etherified with a different hydrocarbonating agent and then the ester is hydrolyzed.
４位に酸素原子を介して３位と５位とは異なる炭化水素基を結合した安息香酸誘導体は、例えば、３，４，５−トリヒドロキシ安息香酸エステルの４位の反応性の差を利用して、まず、４位をエーテル化の後、上記と同様の方法で、３位と５位のエーテル化と、それに続くエステルの加水分解によって得られる。 A benzoic acid derivative in which a hydrocarbon group different from the 3rd and 5th positions is bonded to the 4th position through an oxygen atom, for example, utilizes the difference in reactivity at the 4th position of 3,4,5-trihydroxybenzoic acid ester. Then, after etherification at the 4-position, it is obtained by etherification at the 3-position and 5-position and subsequent hydrolysis of the ester in the same manner as described above.
式（１）で示されるベンズアミド誘導体は、そのまま単独で、あるいは、そのヒドロゲル化を妨げない物質との混合物として、ヒドロゲル化剤として用いることができる。 The benzamide derivative represented by the formula (1) can be used as a hydrogelator alone as it is or as a mixture with a substance that does not hinder its hydrogelation.
ヒドロゲルは、式（１）で示されるベンズアミド誘導体を有効成分として含むヒドロゲル化剤を、適当量、水に懸濁させ、そのままヒドロゲルを用いる温度まで加熱するか、又は、一旦、ヒドロゲル化剤が溶解する温度まで加熱の後、室温まで冷却するか、該冷却後再度加熱するか、若しくは、該冷却後さらに低い温度まで冷却することによって製造する。 The hydrogel is prepared by suspending an appropriate amount of a hydrogelator containing a benzamide derivative represented by the formula (1) as an active ingredient in water and heating it to a temperature at which the hydrogel is used as it is, or once the hydrogelator is dissolved. It is manufactured by heating to a temperature after cooling, cooling to room temperature, heating again after the cooling, or cooling to a lower temperature after the cooling.
以下に、本発明をさらに詳細に説明するが、本発明は以下の記述に限定されるものではない。なお、以下において、ＥＤＣ・ＨＣｌは水溶性カルボジイミド塩酸塩の、ＨＯＢｔは１−ヒドロキシベンゾトリアゾール水和物の、ＰＥＧはポリエチレングリコールの略号である。 The present invention will be described in more detail below, but the present invention is not limited to the following description. In the following, EDC.HCl is an abbreviation for water-soluble carbodiimide hydrochloride, HOBt is an abbreviation for 1-hydroxybenzotriazole hydrate, and PEG is an abbreviation for polyethylene glycol.
＜実施例１＞
（式（１）で、Ｘ＝ＯＨ、ｋ＝０、ｍ＝２９〜３２、ｎ＝２、Ｒ１＝Ｒ３＝オレイルオキシ基、Ｒ２＝ＯＣＨ３であるベンズアミド誘導体の合成）
没食子酸メチル(4.16 g, 21.6 mmol) をアセトン (100 ml) に溶解し、炭酸カリウム(3.60 g, 34.0 mmol)とジメチル硫酸 (2.06 ml, 21.6 mmol) を加え、室温で24時間撹拌させたのち、オイルバスを使い56℃で4時間加熱還流した。反応終了後室温に戻し、少量の水を反応溶液に加え、酢酸エチルで抽出を行い、飽和NaCl水溶液で洗った。無水硫酸ナトリウムを加え反応溶液を脱水した。シリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=2:1)で精製し、3,5-ジヒドロキシ-4-メトキシ安息香酸メチル(2.320 g, 11.71 mmol, 54%) を得た。
<Example 1>
(Synthesis of benzamide derivative where X = OH, k = 0, m = 29 to 32, n = 2, R 1 = R 3 = oleyloxy group, R 2 = OCH 3 in formula (1))
Dissolve methyl gallate (4.16 g, 21.6 mmol) in acetone (100 ml), add potassium carbonate (3.60 g, 34.0 mmol) and dimethyl sulfate (2.06 ml, 21.6 mmol), and stir at room temperature for 24 hours. The mixture was heated to reflux at 56 ° C. for 4 hours using an oil bath. After completion of the reaction, the temperature was returned to room temperature, a small amount of water was added to the reaction solution, extracted with ethyl acetate, and washed with a saturated aqueous NaCl solution. Anhydrous sodium sulfate was added to dehydrate the reaction solution. Purification by silica gel column chromatography (hexane: ethyl acetate = 2: 1) gave methyl 3,5-dihydroxy-4-methoxybenzoate (2.320 g, 11.71 mmol, 54%).
3,5-ジヒドロキシ-4-メトキシ安息香酸メチル(0.985 g, 4.97 mmol) をDMF (150 ml) に溶解し、オレイル塩化物(5.70 g, 20.0 mmol)、K2CO3 (10 g) を加え、65℃に熱しN2気流下で一晩撹拌した。反応終了後室温に戻し、5%HCl水溶液(200 ml)を加え撹拌した。ヘキサン(200 ml) を加え撹拌し、有機相を抽出し、4%NaHCO3水溶液と飽和NaCl水溶液で洗った。抽出した反応溶液を無水硫酸ナトリウムで脱水し、シリカゲルカラムクロマトグラフィー(ヘキサン:ジクロロメタン=1:1)で精製し、3,5-ビス（オレイルオキシ）-4-メトキシ安息香酸メチル(1.79 g, 2.55 mmol, 51%) を得た。 Dissolve methyl 3,5-dihydroxy-4-methoxybenzoate (0.985 g, 4.97 mmol) in DMF (150 ml) and add oleyl chloride (5.70 g, 20.0 mmol) and K 2 CO 3 (10 g). The mixture was heated to 65 ° C. and stirred overnight under a N 2 stream. After completion of the reaction, the temperature was returned to room temperature, and 5% aqueous HCl (200 ml) was added and stirred. Hexane (200 ml) was added and stirred, and the organic phase was extracted and washed with 4% aqueous NaHCO 3 and saturated aqueous NaCl. The extracted reaction solution was dehydrated with anhydrous sodium sulfate, purified by silica gel column chromatography (hexane: dichloromethane = 1: 1), and methyl 3,5-bis (oleyloxy) -4-methoxybenzoate (1.79 g, 2.55 mmol, 51%).
1H-NMR (CDCl3) δ = 7.30 (2H, s, 2,6-H), 4.03 (4H, t, J = 7 Hz, 3,5-OCH2), 3.892, 3.886 (each 3H, s, 4-OCH3, COOCH3), 1.82 (4H, quintet, J = 7 Hz, 3,5-OCCH2), 1.47 (4H, quintet, J = 7 Hz, 3,5-OC2CH2), 1.31, 1.26 (54H, m, 3,5-OC3C14H26), 0.88 (6H, t, J = 7 Hz, 3,5-OC17CH3).
3,5-ビス（オレイルオキシ）-4-メトキシ安息香酸メチル(0.893 g, 1.28 mmol) をエタノール(30 ml)と水(10 ml) に溶解し、水酸化カリウム(1.2 g) を加え、78℃で一晩加熱還流した。反応溶液を室温に戻し、2% HCl水溶液(50 ml) 、ジクロロメタン(30 ml) を加えさらに50時間撹拌した。反応終了後、溶媒を留去し、メタノールを加え粗結晶を得た。乾燥させた粗結晶を1-プロパノールに加え、55℃に熱して溶解させた。反応溶液を室温に戻し、さらに冷却すると結晶が析出した。メタノールで結晶を洗い、3,5-ビス（オレイルオキシ）-4-メトキシ安息香酸(0.78 g, 1.14 mmol, 89%) を得た。
1 H-NMR (CDCl 3 ) δ = 7.30 (2H, s, 2,6-H), 4.03 (4H, t, J = 7 Hz, 3,5-OCH 2 ), 3.892, 3.886 (each 3H, s , 4-OCH 3 , COOCH 3 ), 1.82 (4H, quintet, J = 7 Hz, 3,5-OCCH 2 ), 1.47 (4H, quintet, J = 7 Hz, 3,5-OC 2 CH 2 ), 1.31, 1.26 (54H, m, 3,5-OC 3 C 14 H 26 ), 0.88 (6H, t, J = 7 Hz, 3,5-OC 17 CH 3 ).
Methyl 3,5-bis (oleyloxy) -4-methoxybenzoate (0.893 g, 1.28 mmol) was dissolved in ethanol (30 ml) and water (10 ml), potassium hydroxide (1.2 g) was added, and 78 The mixture was heated at reflux overnight at ° C. The reaction solution was returned to room temperature, 2% aqueous HCl (50 ml) and dichloromethane (30 ml) were added, and the mixture was further stirred for 50 hr. After completion of the reaction, the solvent was distilled off and methanol was added to obtain crude crystals. The dried crude crystals were added to 1-propanol and dissolved by heating to 55 ° C. When the reaction solution was returned to room temperature and further cooled, crystals were precipitated. The crystal was washed with methanol to obtain 3,5-bis (oleyloxy) -4-methoxybenzoic acid (0.78 g, 1.14 mmol, 89%).
1H-NMR (CDCl3) δ = 7.31 (2H, s, 2,6-H), 4.04 (4H, t, J = 7 Hz, 3,5-OCH2), 3.91 (3H, s, 4-OCH3), 1.83 (4H, quintet, J = 7 Hz, 3,5-OCCH2), 1.47 (4H, quintet, J = 7 Hz, 3,5-OC2CH2), 1.31, 1.25 (54H, m, 3,5-OC3C14H26), 0.87 (6H, t, J = 7 Hz, 3,5-OC17CH3).
3,5-ビス（オレイルオキシ）-4-メトキシ安息香酸(0.368 g, 0.537 mmol) をジクロロメタン(10 ml) に溶解し、HOBt (0.092 g, 0.650 mmol)とEDC・HCl (0.125 g, 0.650 mmol) を加え、室温で1時間撹拌した。ジクロロメタン(5 ml) にPEG 1540 mono-amineを溶解し、滴下ロートを用いて反応溶液に滴下しながら、さらに2時間撹拌した。反応終了後、有機相を4%NaHCO3水溶液、飽和NaCl水溶液の順で洗浄し、無水硫酸ナトリウムで脱水した。乾燥剤をろ別して、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(クロロホルム：メタノール＝9：1)で精製し、実施例１のベンズアミド誘導体(0.802 g, 0.383 mmol, 71%) を得た。
1 H-NMR (CDCl 3 ) δ = 7.31 (2H, s, 2,6-H), 4.04 (4H, t, J = 7 Hz, 3,5-OCH 2 ), 3.91 (3H, s, 4- OCH 3 ), 1.83 (4H, quintet, J = 7 Hz, 3,5-OCCH 2 ), 1.47 (4H, quintet, J = 7 Hz, 3,5-OC 2 CH 2 ), 1.31, 1.25 (54H, m, 3,5-OC 3 C 14 H 26 ), 0.87 (6H, t, J = 7 Hz, 3,5-OC 17 CH 3 ).
Dissolve 3,5-bis (oleyloxy) -4-methoxybenzoic acid (0.368 g, 0.537 mmol) in dichloromethane (10 ml) and add HOBt (0.092 g, 0.650 mmol) and EDC · HCl (0.125 g, 0.650 mmol) ) Was added and stirred at room temperature for 1 hour. PEG 1540 mono-amine was dissolved in dichloromethane (5 ml), and the mixture was further stirred for 2 hours while dropping into the reaction solution using a dropping funnel. After completion of the reaction, the organic phase was washed with 4% NaHCO 3 aqueous solution and saturated NaCl aqueous solution in this order, and dehydrated with anhydrous sodium sulfate. The desiccant was filtered off and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to obtain the benzamide derivative of Example 1 (0.802 g, 0.383 mmol, 71%).
1H-NMR (CDCl3) δ = 7.03 (2H, s, 2,6-H), 4.03 (4H, t, J = 7 Hz, 3,5-OCH2), 3.85 (3H, s, 4-OCH3), 3.72-3.49 (128H, m, OCH2CH2 × 32), 1.82 (4H, quintet, J = 7 Hz, 3,5-OCCH2), 1.46 (4H, quintet, J = 7 Hz, 3,5-OC2CH2), 1.31, 1.26 (54H, m, 3,5-OC3C14H26), 0.87 (6H, t, J = 7 Hz, 3,5-OC17CH3).
＜実施例２＞
（ヒドロゲル形成）
実施例１で合成したベンズアミド誘導体を、６０ｍＭの濃度になるように、純水中に分散させ、一端、１００度に加熱の後、室温に戻した。
1 H-NMR (CDCl 3 ) δ = 7.03 (2H, s, 2,6-H), 4.03 (4H, t, J = 7 Hz, 3,5-OCH 2 ), 3.85 (3H, s, 4- OCH 3 ), 3.72-3.49 (128H, m, OCH 2 CH 2 × 32), 1.82 (4H, quintet, J = 7 Hz, 3,5-OCCH 2 ), 1.46 (4H, quintet, J = 7 Hz, 3,5-OC 2 CH 2 ), 1.31, 1.26 (54H, m, 3,5-OC 3 C 14 H 26 ), 0.87 (6H, t, J = 7 Hz, 3,5-OC 17 CH 3 ) .
<Example 2>
(Hydrogel formation)
The benzamide derivative synthesized in Example 1 was dispersed in pure water to a concentration of 60 mM, heated to 100 ° C., and returned to room temperature.
室温では溶液状態だったが、昇温によって、５８℃で目視にて透明なヒドロゲルを与えることが倒置法により確認された。なお、倒置法とは、溶液がゲル状態になったことを、サンプル容器を倒置することによって確認する方法である。
＜参考例１＞
（式（１）で、Ｘ＝ＯＨ、ｋ＝０、ｍ＝２９〜３２、ｎ＝２、Ｒ１＝Ｒ３＝オクタデシルオキシ基、Ｒ２＝ＯＣＨ３であるベンズアミド誘導体のヒドロゲル形成）
実施例１と同様の方法で合成した、式（１）で、Ｘ＝ＯＨ、ｋ＝０、ｍ＝２９〜３２、ｎ＝２、Ｒ１＝Ｒ３＝オクタデシルオキシ基、Ｒ２＝ＯＣＨ３であるベンズアミド誘導体のヒドロゲル形成を、実施例２と同様の方法で検討した。その結果、この化合物は、室温で白濁したヒドロゲルを与えることが観察された。
Although it was in a solution state at room temperature, it was confirmed by an inversion method that a transparent hydrogel was visually observed at 58 ° C. by raising the temperature. The inversion method is a method for confirming that the solution is in a gel state by inverting the sample container.
<Reference Example 1>
(Hydrogel formation of a benzamide derivative where X = OH, k = 0, m = 29 to 32, n = 2, R 1 = R 3 = octadecyloxy group, R 2 = OCH 3 in formula (1))
In the formula (1) synthesized by the same method as in Example 1, X = OH, k = 0, m = 29 to 32, n = 2, R 1 = R 3 = octadecyloxy group, R 2 = OCH 3 The hydrogel formation of the benzamide derivative was examined in the same manner as in Example 2. As a result, this compound was observed to give a hydrogel that became cloudy at room temperature.
本発明が提供するヒドロゲルは、生体適合性が知られるエチレングリコールのオリゴマーまたはポリマー構造を有し、３次元細胞培養、細胞や蛋白質の分離・精製、蛋白質医薬品の徐放等に利用することができる。 The hydrogel provided by the present invention has an ethylene glycol oligomer or polymer structure known to be biocompatible, and can be used for three-dimensional cell culture, separation and purification of cells and proteins, sustained release of protein pharmaceuticals, and the like. .
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2008227274A JP5282200B2 (en) | 2008-09-04 | 2008-09-04 | Transparent hydrogelator |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2008227274A JP5282200B2 (en) | 2008-09-04 | 2008-09-04 | Transparent hydrogelator |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2010059324A JP2010059324A (en) | 2010-03-18 |
| JP5282200B2 true JP5282200B2 (en) | 2013-09-04 |
Family
ID=42186493
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2008227274A Expired - Fee Related JP5282200B2 (en) | 2008-09-04 | 2008-09-04 | Transparent hydrogelator |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP5282200B2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5352810B2 (en) * | 2008-09-04 | 2013-11-27 | 学校法人立命館 | Asymmetric hydrogelator |
| JP5343282B2 (en) * | 2008-09-04 | 2013-11-13 | 学校法人立命館 | Double-chain hydrogelator |
| JP2010083859A (en) * | 2008-09-04 | 2010-04-15 | Ritsumeikan | Diamide type hydro-gelling agent |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5637121A (en) * | 1994-12-30 | 1997-06-10 | Chevron Chemical Company | Poly(oxyalkylene) aromatic amides and fuel compositions containing the same |
| JP4141772B2 (en) * | 2002-09-06 | 2008-08-27 | 財団法人野口研究所 | Gelling agent that polymerizes |
| JP4526832B2 (en) * | 2004-02-18 | 2010-08-18 | 財団法人野口研究所 | Biocompatibility imparting agent |
| JP2005232278A (en) * | 2004-02-18 | 2005-09-02 | Noguchi Inst | Gellant for preparing mold |
| JP4947512B2 (en) * | 2006-02-16 | 2012-06-06 | 公益財団法人野口研究所 | Biocompatible hydrogel |
-
2008
- 2008-09-04 JP JP2008227274A patent/JP5282200B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP2010059324A (en) | 2010-03-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4947512B2 (en) | Biocompatible hydrogel | |
| JP6545159B2 (en) | 2-oxo-1,3-dioxolane-4-acyl halides, their preparation and use | |
| CN110078644B (en) | preparation method of [2- [1- (Fmoc-amino) ethoxy ] acetic acid | |
| JP5282200B2 (en) | Transparent hydrogelator | |
| EP2088140B1 (en) | Dihydrazide compounds, preparation and uses thereof | |
| JP5352810B2 (en) | Asymmetric hydrogelator | |
| JP2009084272A (en) | Benzamide derivative, hydrogelling agent and hydrogel | |
| JP5612467B2 (en) | Method for preparing a hydrolyzable linker based on Fmoc | |
| JP5604714B2 (en) | Double-ended amide-type hydrogelator | |
| JP5343282B2 (en) | Double-chain hydrogelator | |
| JP5282227B2 (en) | Both-end diamide type hydrogelator | |
| JP2010083859A (en) | Diamide type hydro-gelling agent | |
| JP2005232278A (en) | Gellant for preparing mold | |
| JP6925579B2 (en) | Biodegradable hydrogel with cyclic benzylidene acetal structure | |
| JP5097900B2 (en) | Method for producing active ester of organic acid or derivative thereof | |
| RU2795091C2 (en) | Method for obtaining yomeprol,the contrast agent | |
| WO2006121234A1 (en) | Biotin-amino acid conjugate useful as a hydrogelator and hydrogel prepared therefrom | |
| JP3569788B2 (en) | Method for producing fluorinated quaternary ammonium salt | |
| JP2013185086A (en) | Urea type hydrogelling agent | |
| CN109705372B (en) | Supramolecular material, hydrogel and preparation method thereof | |
| JP3787611B2 (en) | Carboxylic acid-type glycolipid derivative and method for producing the same | |
| JP4141772B2 (en) | Gelling agent that polymerizes | |
| JP2019135220A (en) | Manufacturing method of l-carnosine and derivative thereof | |
| JP2004182695A (en) | Isoleucine derivative and thickening gelatinizing agent | |
| CN116217917A (en) | Polyethylene glycol derivative, preparation method thereof, polyethylene glycol hydrogel and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20110901 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20130212 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20130215 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20130315 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20130319 |
|
| S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
| LAPS | Cancellation because of no payment of annual fees |