JP2006232909A

JP2006232909A - Cyclic lactic acid oligomer

Info

Publication number: JP2006232909A
Application number: JP2005046885A
Authority: JP
Inventors: Mikio Watanabe; 幹夫渡邊; 二郎 ▲高▼野; Jiro Takano; Masahiro Murakami; 正裕村上; Shohei Kashimura; 昇平樫村; Okitaka Hashimoto; 興尚橋本
Original assignee: Tokai University
Current assignee: Tokai University
Priority date: 2005-02-23
Filing date: 2005-02-23
Publication date: 2006-09-07

Abstract

<P>PROBLEM TO BE SOLVED: To prepare and isolate each of cyclic lactic acid oligomers (heptamer to dodecamer) as a single compound. <P>SOLUTION: The single cyclic lactic acid heptamer represented by formula (1) and cyclic lactic acid multimers are provided. The cyclic lactic acid heptamer with no contamination of lactic acid oligomers other than the heptamer is prepared by subjecting a chain-like free lactic acid heptamer to a cyclization reaction via intramolecular dehydrocondensation in the presence of 2,4,6-trichlorobenzoyl chloride and 4-(N, N-dimethylamino)pyridine (DMAP). The single cyclic lactic acid oligomers (octamer to dodecamer) are each prepared through a similar reaction. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

本発明は、環状オリゴ乳酸、並びにその製造方法に関する。より詳細には、本発明は、単一の鎖長を有する単一の化合物として合成された７量体の環状オリゴ乳酸、並びに７から１２量体の環状オリゴ乳酸の製造方法に関する。 The present invention relates to cyclic oligolactic acid and a method for producing the same. More specifically, the present invention relates to a 7-mer cyclic oligolactic acid synthesized as a single compound having a single chain length, and a method for producing a 7 to 12-mer cyclic oligolactic acid.

縮合度３〜１９の環状及び／又は鎖状のポリＬ−乳酸混合物は、抗悪性腫瘍剤として（特開平９−２２７３８８号公報および特開平１０−１３０１５３号公報）、また癌患者のＱＯＬ改善剤として（特開２０００−２３９１７１号公報）有用であることが報告されている。また、縮合度３〜１９の環状及び／又は鎖状のポリ乳酸混合物が、血糖低下作用を有し、糖尿病又は糖尿病の合併症の予防及び／又は治療のための医薬として有用であることも判明している（国際公開ＷＯ０１／０１０４５１号公報）。また、上記のポリ乳酸混合物は、過剰な食欲の抑制、基礎代謝増進並びに肥満の改善及び／又は予防、のために有用であることも判明している。さらに、上記のポリ乳酸混合物は、免疫賦活、微生物感染の防御、抗アレルギー、抗ストレス、及び抗癌剤の副作用の軽減など多様な生理活性を示すことが実証されている。 A cyclic and / or chain poly L-lactic acid mixture having a condensation degree of 3 to 19 is used as an antineoplastic agent (Japanese Patent Laid-Open Nos. 9-227388 and 10-130153), and a QOL improving agent for cancer patients. (JP 2000-239171 A) are reported to be useful. It was also found that cyclic and / or chain polylactic acid mixtures having a condensation degree of 3 to 19 have a hypoglycemic effect and are useful as a medicament for the prevention and / or treatment of diabetes or diabetic complications. (International Publication WO01 / 010451). It has also been found that the polylactic acid mixture described above is useful for suppressing excessive appetite, promoting basal metabolism and improving and / or preventing obesity. Furthermore, the polylactic acid mixture described above has been demonstrated to exhibit various physiological activities such as immunostimulation, protection against microbial infection, antiallergy, antistress, and reduction of side effects of anticancer agents.

上記したように縮合度３〜１９の環状及び／又は鎖状のオリゴ乳酸混合物は、多種多様な薬効を示すことが実証されつつあり、今後も医薬品として開発されることが期待されている。オリゴ乳酸を医薬品として開発していくためには、異なる鎖長のポリ乳酸から成る混合物ではなく、特定の単一の鎖長を有するオリゴ乳酸を単一の化合物として単離することが望ましい。しかしながら、７量体の環状のオリゴ乳酸を単一の化合物として合成することについてはこれまでの所、報告がない。 As described above, cyclic and / or chain oligolactic acid mixtures having a condensation degree of 3 to 19 are being demonstrated to exhibit a wide variety of medicinal effects, and are expected to be developed as pharmaceuticals in the future. In order to develop oligolactic acid as a pharmaceutical product, it is desirable to isolate oligolactic acid having a specific single chain length as a single compound rather than a mixture of polylactic acids having different chain lengths. However, there has been no report so far about synthesizing a 7-mer cyclic oligolactic acid as a single compound.

特開平９−２２７３８８号公報JP-A-9-227388 特開平１０−１３０１５３号公報JP-A-10-130153 特開２０００−２３９１７１号公報JP 2000-239171 A 国際公開ＷＯ０１／０１０４５１号公報International Publication WO01 / 010451

本発明は、７量体の環状のオリゴ乳酸を単一の化合物として製造かつ単離することを解決すべき課題とした。本発明はまた、７量体から１２量体の環状オリゴ乳酸の製造方法を提供することを解決すべき課題とした。 An object of the present invention is to produce and isolate a 7-mer cyclic oligolactic acid as a single compound. Another object of the present invention is to provide a method for producing a cyclic oligolactic acid from a 7-mer to a 12-mer.

本発明者らは上記課題を解決するために鋭意検討した結果、-乳酸ラクトイルを出発材料として使用し、先ず７量体以上の単一の鎖長を有する直鎖オリゴ乳酸を単一の化合物として合成し、次いで、この直鎖リゴ乳酸を所定の条件下で分子内環化反応に供することによって、７量体の環状オリゴ乳酸を単一の化合物として合成し、また８量体以上の環状オリゴ乳酸混合物を製造することに成功した。本発明はこの知見に基づいて完成したものである。 As a result of intensive studies to solve the above problems, the present inventors have used -lactic acid lactoyl as a starting material, and firstly used a linear oligolactic acid having a single chain length of 7-mer or more as a single compound. Next, this linear ligigolactic acid is subjected to an intramolecular cyclization reaction under predetermined conditions, thereby synthesizing a heptamer cyclic oligolactic acid as a single compound, and an octamer or higher cyclic oligolactic acid. Succeeded in producing a lactic acid mixture. The present invention has been completed based on this finding.

即ち、本発明によれば、下記式（１）で表される単一の環状オリゴ乳酸が提供される。

That is, according to the present invention, a single cyclic oligolactic acid represented by the following formula (1) is provided.

本発明の別の側面によれば、下記式で表される化合物を分子内脱水縮合による環化反応に付することを特徴とする、上記の単一の環状オリゴ乳酸を製造する方法が提供される。

According to another aspect of the present invention, there is provided a method for producing the above single cyclic oligolactic acid, characterized by subjecting a compound represented by the following formula to a cyclization reaction by intramolecular dehydration condensation. The

好ましくは、分子内脱水縮合による環化反応を、ジイソプロピルエチルアミン、塩化2, 4, 6-トリクロロベンゾイル及び4-（N,N-ジメチルアミノ）ピリジン（ＤＭＡＰ）の存在下で行う。 Preferably, the cyclization reaction by intramolecular dehydration condensation is carried out in the presence of diisopropylethylamine, 2,4,6-trichlorobenzoyl chloride and 4- (N, N-dimethylamino) pyridine (DMAP).

本発明のさらに別の側面によれば、下記式（２）で表される化合物：

（式中、ｎは８から１２の整数を示す）
を分子内脱水縮合による環化反応に付することを特徴とする、下記式（３）で表される環状オリゴ乳酸を製造する方法が提供される。

（式中、ｎは式（２）のｎと同義であり、ｍは１以上の整数を示す。） According to still another aspect of the present invention, a compound represented by the following formula (2):

(Where n represents an integer of 8 to 12)
Is subjected to a cyclization reaction by intramolecular dehydration condensation, and a method for producing a cyclic oligolactic acid represented by the following formula (3) is provided.

(In the formula, n has the same meaning as n in formula (2), and m represents an integer of 1 or more.)

本発明のさらに別の側面によれば、上記した本発明の製造方法により製造される環状オリゴ乳酸が提供される。 According to still another aspect of the present invention, there is provided cyclic oligolactic acid produced by the production method of the present invention described above.

本発明により、７量体以上の環状のオリゴ乳酸を単一の化合物を単一の化合物として提供することが可能になった。本発明により提供される環状のオリゴ乳酸の単一化合物を利用することにより、医薬品、医薬品原料、食品添加物、香粧料原料、製剤原料、製剤添加物などを開発していくことが可能になる。 According to the present invention, it is possible to provide a cyclic oligolactic acid of 7-mer or more as a single compound as a single compound. By using a single compound of cyclic oligolactic acid provided by the present invention, it is possible to develop pharmaceuticals, pharmaceutical raw materials, food additives, cosmetic raw materials, pharmaceutical raw materials, pharmaceutical additives, etc. Become.

以下、本発明の実施態様及び実施方法について詳細に説明する。
本発明は、下記式（１）で表される単一の環状オリゴ乳酸に関する。

Hereinafter, embodiments and methods of the present invention will be described in detail.
The present invention relates to a single cyclic oligolactic acid represented by the following formula (1).

上記式（１）の環状オリゴ乳酸は、７量体の単一の環状オリゴ乳酸であり、７量体以外のオリゴ乳酸が混在しないことを特徴とするものである。 The cyclic oligolactic acid of the above formula (1) is a heptamer single cyclic oligolactic acid and is characterized in that no oligolactic acid other than the heptamer is mixed.

また、本発明の上記オリゴ乳酸の各種の水和物、溶媒和物や結晶多形の物質も全て本発明の範囲内のものである。 In addition, various hydrates, solvates and crystalline polymorphic substances of the above-mentioned oligolactic acid of the present invention are all within the scope of the present invention.

本発明の化合物には不斉炭素が含まれるため立体異性体が存在するが、全ての可能な異性体、並びに２種類以上の該異性体を任意の比率で含む混合物も本発明の範囲内のものである。即ち、本発明の化合物は、光学活性体、ラセミ体、ジアステレオマー等の各種光学異性体の混合物及びそれらの単離されたものを含む。 Since the compounds of the present invention contain asymmetric carbons, stereoisomers exist, but all possible isomers and mixtures containing two or more of these isomers in any ratio are also within the scope of the present invention. Is. That is, the compound of the present invention includes a mixture of various optical isomers such as an optically active substance, a racemate, a diastereomer and the like and an isolated product thereof.

本発明の化合物の立体配置は、原料として使用する化合物における乳酸単位の立体配置に依存する。即ち、原料として使用する化合物における乳酸単位としてＬ体、Ｄ体またはその混合物を使用するかにより、本発明の化合物の立体配置も多様なものとなる。本発明においては、乳酸単位の立体配置としてはＬ体を使用することが好ましい。 The configuration of the compound of the present invention depends on the configuration of the lactic acid unit in the compound used as a raw material. That is, the configuration of the compound of the present invention varies depending on whether L-form, D-form or a mixture thereof is used as the lactic acid unit in the compound used as a raw material. In the present invention, the L-form is preferably used as the steric configuration of the lactic acid unit.

即ち、式（１）で表される環状オリゴ乳酸の中でも好ましい化合物は、以下の式で表される化合物である。 That is, a preferable compound among the cyclic oligolactic acids represented by the formula (1) is a compound represented by the following formula.

次に、本発明の環状オリゴ乳酸の製造方法について説明する。本発明では、下記式（２）で表される化合物：

（式中、ｎは８から１２の整数を示す）
を分子内脱水縮合による環化反応に付することによって、下記式（３）で表される環状オリゴ乳酸を製造することができる。なお、上記式（２）においてｎが７である化合物を使用した場合には、ｎは８から１２の整数を示す場合と同様の反応により、上記した式（１）で表される７量体の環状オリゴ乳酸を単一の化合物として合成することができる。

（式中、ｎは式（２）のｎと同義であり、ｍは１以上の整数を示す。） Next, the manufacturing method of cyclic oligolactic acid of this invention is demonstrated. In the present invention, a compound represented by the following formula (2):

(Where n represents an integer of 8 to 12)
Is subjected to a cyclization reaction by intramolecular dehydration condensation, whereby a cyclic oligolactic acid represented by the following formula (3) can be produced. In addition, when the compound in which n is 7 in the above formula (2) is used, the heptamer represented by the above formula (1) is obtained by the same reaction as in the case where n represents an integer of 8 to 12. These cyclic oligolactic acids can be synthesized as a single compound.

ここで、分子内脱水縮合による環化反応は、分子内脱水反応を伴うエステル化反応が進行できる条件下であれば任意の条件下で行うことができるが、好ましくは、ジイソプロピルエチルアミン、塩化2, 4, 6-トリクロロベンゾイル及び4-（N,N-ジメチルアミノ）ピリジン（ＤＭＡＰ）の存在下で行うことができる。 Here, the cyclization reaction by intramolecular dehydration condensation can be carried out under any conditions as long as the esterification reaction accompanied with the intramolecular dehydration reaction can proceed, but preferably diisopropylethylamine, 2, The reaction can be carried out in the presence of 4,6-trichlorobenzoyl and 4- (N, N-dimethylamino) pyridine (DMAP).

反応温度は、反応が進行する限り特に限定されないが、好ましくは−５０℃〜室温である。
また、反応は、好ましくは反応溶媒の存在下で実施される。反応溶媒は反応に不活性な溶媒であれば特に制限されないが、好ましくは、ベンゼン、トルエン、キシレン、アルキルベンゼン等を用いることができる。
また、反応雰囲気としては、窒素ガスやアルゴンガス等の不活性ガス雰囲気を使用することができる。 The reaction temperature is not particularly limited as long as the reaction proceeds, but is preferably −50 ° C. to room temperature.
The reaction is preferably carried out in the presence of a reaction solvent. The reaction solvent is not particularly limited as long as it is inert to the reaction, but preferably, benzene, toluene, xylene, alkylbenzene, or the like can be used.
Moreover, as reaction atmosphere, inert gas atmosphere, such as nitrogen gas and argon gas, can be used.

上記反応の好ましい具体例としては、アルゴン雰囲気下などの不活性ガス雰囲気下において、室温で、上記式（２）で表される鎖状オリゴ乳酸の溶液（例えば、塩化メチレン溶液など）にジイソプロピルエチルアミンを含む溶液（例えば、ベンゼン溶液）を加え、さらに塩化2, 4, 6-トリクロロベンゾイルの溶液（例えば、ベンゼン溶液）を加え、数時間撹拌し、この混合物を4-（N,N-ジメチルアミノ）ピリジン（ＤＭＡＰ）の溶液（例えば、ベンゼン溶液）に一定の時間をかけて加え、撹拌する。反応後に溶媒を除去して、残渣をカラムクロマトグラフィー(シリカゲルなど)を用いて分離する。これにより、ベンゼン：酢酸エチル溶出部より、環状オリゴ乳酸の混合物（又は７量体のオリゴ乳酸の場合には、単一のオリゴ乳酸）を得ることができる。 A preferred specific example of the reaction is diisopropylethylamine in a solution of a chain oligolactic acid represented by the above formula (2) (for example, a methylene chloride solution) at room temperature in an inert gas atmosphere such as an argon atmosphere. A solution containing benzene (eg benzene solution) is added, then a solution of 2,4,6-trichlorobenzoyl chloride (eg benzene solution) is added and stirred for several hours, and the mixture is 4- (N, N-dimethylamino) ) Add to a solution of pyridine (DMAP) (eg benzene solution) over a period of time and stir. After the reaction, the solvent is removed, and the residue is separated using column chromatography (such as silica gel). Thereby, a mixture of cyclic oligolactic acid (or a single oligolactic acid in the case of a 7-mer oligolactic acid) can be obtained from the eluate of benzene: ethyl acetate.

上記した分子内エステル化反応において出発物質として使用する、鎖状オリゴ乳酸は公知化合物であり、例えば、特開平９−５９２１８号公報などに記載されている。あるいは、本明細書の以下の実施例に記載又はそれに準じた方法により合成することができる。
以下の実施例により本発明をより具体的に説明するが、本発明は実施例によって限定されることはない。 The chain oligolactic acid used as a starting material in the above intramolecular esterification reaction is a known compound, and is described, for example, in JP-A-9-59218. Or it can synthesize | combine by the method as described in the following Example of this specification, or according to it.
The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to the examples.

実施例１：(2S, 5S)-乳酸ラクトイルベンジルの合成(2)

Example 1: Synthesis of (2S, 5S) -lactoylbenzyl lactate (2)

窒素雰囲気下、室温にて、10.70mmolの乳酸ラクトイル(1)の塩化メチレン溶媒を10ml加え、トリエチルアミン1.727gと臭化ベンジル1.82ｍｌを加え6時間攪拌した。飽和塩化アンモニウム水溶液を20ml加え、飽和炭酸水素ナトリウム水溶液を20ml加え、酢酸エチルで3回抽出し、無水硫酸ナトリウムで一昼夜乾燥した。溶媒を除去し、残渣をカラムクロマトグラフィー(シリカゲル)を用いて分離し、ヘキサン:酢酸エチル(7:1)溶出部より無色油状の(2S, 5S)-乳酸ラクトイルベンジル（2）を3.76mmol(62%)で得た。 Under a nitrogen atmosphere, at room temperature, 10.70 mmol of methylene chloride solvent of lactoyl lactate (1) was added, 1.727 g of triethylamine and 1.82 ml of benzyl bromide were added, and the mixture was stirred for 6 hours. 20 ml of a saturated aqueous solution of ammonium chloride was added, 20 ml of a saturated aqueous solution of sodium bicarbonate was added, extracted three times with ethyl acetate, and dried over anhydrous sodium sulfate all day and night. The solvent was removed, and the residue was separated using column chromatography (silica gel). From the eluate of hexane: ethyl acetate (7: 1), colorless oil (2S, 5S) -lactoylbenzyl lactate (2) (3.76 mmol) was obtained. (62%).

¹H NMR(500MHz, CDCl₃)δ= 1.43 (d, 3H, J=6.9Hz), 1.54 (d, 3H, J=7.2Hz), 4.33 (ｑ, 1H, J=7.0Hz), 5.18 (dd, 2H, J=12.2 Hz, 12.7 Hz), 7.33-7.39 (ｍ, 5H)
¹³C NMR(125MHz, CDCl₃)δ=16.85, 20.47, 60.43, 67.28, 69.37, 69.43, 128.22, 128.28, 128.33, 128.58, 128.66, 135.07, 170.00, 175.16
IR(cm^-1): 3527(OH), 3035(Ph C-H), 1747(C=O), 1456(Ph C=C)
[α]²⁴ _D =-34.36°(c=1.62, CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.43 (d, 3H, J = 6.9Hz), 1.54 (d, 3H, J = 7.2Hz), 4.33 (q, 1H, J = 7.0Hz), 5.18 (dd , 2H, J = 12.2 Hz, 12.7 Hz), 7.33-7.39 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = 16.85, 20.47, 60.43, 67.28, 69.37, 69.43, 128.22, 128.28, 128.33, 128.58, 128.66, 135.07, 170.00, 175.16
IR (cm ^-1 ): 3527 (OH), 3035 (Ph CH), 1747 (C = O), 1456 (Ph C = C)
[α] ²⁴ _D = -34.36 ° (c = 1.62, CH ₂ Cl ₂ )

実施例２：tert-ブチルジメチルシリル乳酸3量体ベンジル(5)の合成

Example 2: Synthesis of tert-butyldimethylsilyl lactic acid trimer benzyl (5)

窒素雰囲気下、0℃にて、tert-ブチルジメチルシリル-(2S, 5S)-乳酸ラクトイル(3)9.27mmolの塩化メチレン溶液10mlを加え、(S)-(-)-乳酸ベンジル(4)1.8067gの塩化メチレン溶液10mlを加え、4-ジメチルアミノピリジン2.5729gの塩化メチレン溶液10mlを加え、N, N'-ジシクロへキシルカルボジイミド2.7779gの塩化メチレン溶液20mlを加え、5分間撹拌した。室温に戻し、2時間撹拌した。減圧ろ過し、飽和塩化アンモニウム溶液40ml、飽和炭酸水素ナトリウム50mlを順に加え。ジエチルエーテルで4回抽出し、無水硫酸マグネシウムで2時間乾燥した。溶媒を除去し、残渣をカラムクロマトグラフィー(シリカゲル)を用いて分離し、ヘキサン：ジエチルエーテル（5：1）溶出部より、無色透明油状のtert-ブチルジメチルシリル乳酸3量体ベンジル(5)を収率72％で得た。 Under a nitrogen atmosphere at 0 ° C., 10 ml of tert-butyldimethylsilyl- (2S, 5S) -lactoyl lactate (3) 9.27 mmol methylene chloride solution was added, and (S)-(−)-benzyl lactate (4) 1.8067 10 ml of m in methylene chloride was added, 10 ml of methylene chloride in 2.5729 g of 4-dimethylaminopyridine was added, 20 ml of methylene chloride in 2.7779 g of N, N'-dicyclohexylcarbodiimide was added, and the mixture was stirred for 5 minutes. It returned to room temperature and stirred for 2 hours. After filtration under reduced pressure, 40 ml of saturated ammonium chloride solution and 50 ml of saturated sodium bicarbonate were added in this order. The mixture was extracted 4 times with diethyl ether and dried over anhydrous magnesium sulfate for 2 hours. The solvent was removed, and the residue was separated using column chromatography (silica gel). From the eluate of hexane: diethyl ether (5: 1), tert-butyldimethylsilyl lactic acid trimer benzyl (5) was obtained as a colorless transparent oil. Obtained in 72% yield.

¹H NMR(500MHz, CDCl₃)δ= 0.090 (d, 6H J=11.5Hz), 0.91 (s, 9H), 1.44 (d, 3H, J=6.7Hz), 1.51 (d, 3H, J=7.1Hz), 1.52 (d, 3H, J=7.1Hz), 4.37 (q, 1H, J=7.0Hz), 5.12 (q, 1H, J=7.0Hz), 5.15 (dd, 2H, J=12.3Hz, 12.5Hz), 5.20 (q, 1H, J=7.0Hz), 7.31-7.38 (m, 5H)
¹³C NMR(125MHz, CDCl₃)δ= -5.30, -4.90, 16.69, 16.82, 18.30, 21.24, 68.03, 68.57, 68.83, 69.11, 128.28, 128.51, 128.63, 169.96
IR(cm^-1): 3035(Ph C-H), 1755(C=O), 1456(Ph C=C)
[α]²⁴ _D =-64.68°(c=1.71 CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 0.090 (d, 6H J = 11.5Hz), 0.91 (s, 9H), 1.44 (d, 3H, J = 6.7Hz), 1.51 (d, 3H, J = 7.1 Hz), 1.52 (d, 3H, J = 7.1Hz), 4.37 (q, 1H, J = 7.0Hz), 5.12 (q, 1H, J = 7.0Hz), 5.15 (dd, 2H, J = 12.3Hz, 12.5Hz), 5.20 (q, 1H, J = 7.0Hz), 7.31-7.38 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = -5.30, -4.90, 16.69, 16.82, 18.30, 21.24, 68.03, 68.57, 68.83, 69.11, 128.28, 128.51, 128.63, 169.96
IR (cm ^-1 ): 3035 (Ph CH), 1755 (C = O), 1456 (Ph C = C)
[α] ²⁴ _D = -64.68 ° (c = 1.71 CH ₂ Cl ₂ )

実施例３：tert-ブチルジメチルシリル乳酸4量体ベンジル(6)の合成

Example 3: Synthesis of tert-butyldimethylsilyl lactic acid tetramer benzyl (6)

窒素雰囲気下、0℃にて、tert-ブチルジメチルシリル-(2S, 5S)-乳酸ラクトイル(3)1.3mmolの塩化メチレン溶液10mlを加え、(2S, 5S)-乳酸ラクトイルベンジル(2) 1.43mmolの塩化メチレン溶液10mlを加え、4-ジメチルアミノピリジン1.3当量の塩化メチレン溶液10mlを加え、N, N'-ジシクロへキシルカルボジイミド2.6当量の塩化メチレン溶液20mlを加え、5分間撹拌した。室温に戻し、2時間撹拌した。減圧ろ過し、飽和塩化アンモニウム溶液40ml、飽和炭酸水素ナトリウム50mlを順に加え。ジエチルエーテルで4回抽出し、無水硫酸マグネシウムで2時間乾燥した。溶媒を除去し、残渣をカラムクロマトグラフィー(シリカゲル)を用いて分離し、ヘキサン：ジエチルエーテル（10：1）溶出部より、無色透明固体のtert-ブチルジメチルシリル乳酸4量体ベンジル(6)を収率88％で得た。 Under nitrogen atmosphere at 0 ° C., 10 ml of 1.3 mmol of tert-butyldimethylsilyl- (2S, 5S) -lactoyl lactate (3) 1.3 mmol in methylene chloride was added and (2S, 5S) -lactoylbenzyl lactate (2) 1.43 10 ml of a methylene chloride solution of mmol was added, 10 ml of a methylene chloride solution of 1.3 equivalent of 4-dimethylaminopyridine was added, and 20 ml of a methylene chloride solution of 2.6 equivalent of N, N′-dicyclohexylcarbodiimide was added and stirred for 5 minutes. It returned to room temperature and stirred for 2 hours. After filtration under reduced pressure, 40 ml of saturated ammonium chloride solution and 50 ml of saturated sodium bicarbonate were added in this order. The mixture was extracted 4 times with diethyl ether and dried over anhydrous magnesium sulfate for 2 hours. The solvent was removed, and the residue was separated using column chromatography (silica gel). From the eluate of hexane: diethyl ether (10: 1), tert-butyldimethylsilyl lactic acid tetramer benzyl (6) was obtained as a colorless transparent solid. The yield was 88%.

¹H NMR(500MHz, CDCl₃)δ= 0.12 (d, 6H J=10.9Hz), 0.91 (s, 9H), 1.45 (d, 3H, J=6.3Hz), 1.52 (d, 3H, J=7.1Hz), 1.53 (d, 3H, J=7.1Hz), 1.57 (d, 3H, J=7.1Hz), 4.39 (q, 1H, J=6.8Hz), 5.13 (q, 1H, J=7.1Hz), 5.16 (dd, 2H, J=12.2Hz, 18.0Hz), 5.17 (q, 1H, J=8.1Hz), 5.19 (q, 1H, J=6.9Hz), 7.31-7.39 (m, 5H)
¹³C NMR(125MHz, CDCl₃)δ= -5.29, -4.90, 16.62, 16.76, 18.30, 21.25, 67.22, 68.00, 68.56, 68.84, 69.25, 128.28, 128.54, 128.64, 135.09, 169.71, 169.99, 173.59
IR(cm^-1): 2991(Ph C-H), 1757(C=O), 1456(Ph C=C)
[α]²² _D＝ -72.61°(c=1.70 CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 0.12 (d, 6H J = 10.9Hz), 0.91 (s, 9H), 1.45 (d, 3H, J = 6.3Hz), 1.52 (d, 3H, J = 7.1 Hz), 1.53 (d, 3H, J = 7.1Hz), 1.57 (d, 3H, J = 7.1Hz), 4.39 (q, 1H, J = 6.8Hz), 5.13 (q, 1H, J = 7.1Hz) , 5.16 (dd, 2H, J = 12.2Hz, 18.0Hz), 5.17 (q, 1H, J = 8.1Hz), 5.19 (q, 1H, J = 6.9Hz), 7.31-7.39 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = -5.29, -4.90, 16.62, 16.76, 18.30, 21.25, 67.22, 68.00, 68.56, 68.84, 69.25, 128.28, 128.54, 128.64, 135.09, 169.71, 169.99, 173.59
IR (cm ^-1 ): 2991 (Ph CH), 1757 (C = O), 1456 (Ph C = C)
[α] ²² _D = -72.61 ° (c = 1.70 CH ₂ Cl ₂ )

実施例４：tert-ブチルジメチルシリル乳酸3量体(7)の合成

Example 4: Synthesis of tert-butyldimethylsilyl lactic acid trimer (7)

水素雰囲気下、2.8484gの5エタノール溶液10mlに、10％Pd/C 0.2859g加え、室温で1時間半撹拌した。溶媒を除去し、淡黄色油状のtert-ブチルジメチルシリル乳酸3量体(7)をほぼ定量的に得た。 Under hydrogen atmosphere, 0.2859 g of 10% Pd / C was added to 10 ml of 5 ethanol solution of 2.8484 g, and stirred at room temperature for 1.5 hours. The solvent was removed, and a pale yellow oily tert-butyldimethylsilyl lactic acid trimer (7) was obtained almost quantitatively.

¹H NMR(500MHz, CDCl₃)δ= 0.094 (d, 6H, J=11.5Hz), 0.90 (s, 9H), 1.44 (d, 3H, J=7.0Hz), 1.55 (d, 3H, J=7.0Hz), 1.56 (d, 3H, J=7.0Hz), 4.40 (q, 1H, J=7.0Hz), 5.14 (q, 1H, J=7.0Hz), 5.17 (q, 1H, J=7.0Hz)
¹³C NMR(125MHz, CDCl₃)δ= -5.32, -4.95, 16.66, 18.25, 21.27, 25.57, 25.67, 68.02, 68.57, 68.68, 169.94, 173.63, 175.23
IR(cm^-1): 1745(C=O), 3000-3500(broad, COOH)
[α]¹⁷ _D＝ -60.4°(c=0.816 CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 0.094 (d, 6H, J = 11.5Hz), 0.90 (s, 9H), 1.44 (d, 3H, J = 7.0Hz), 1.55 (d, 3H, J = 7.0Hz), 1.56 (d, 3H, J = 7.0Hz), 4.40 (q, 1H, J = 7.0Hz), 5.14 (q, 1H, J = 7.0Hz), 5.17 (q, 1H, J = 7.0Hz )
¹³ C NMR (125 MHz, CDCl ₃ ) δ = -5.32, -4.95, 16.66, 18.25, 21.27, 25.57, 25.67, 68.02, 68.57, 68.68, 169.94, 173.63, 175.23
IR (cm ^-1 ): 1745 (C = O), 3000-3500 (broad, COOH)
[α] ¹⁷ _D = -60.4 ° (c = 0.816 CH ₂ Cl ₂ )

実施例５：tert-ブチルジメチルシリル乳酸4量体(8)の合成

Example 5: Synthesis of tert-butyldimethylsilyl lactic acid tetramer (8)

水素雰囲気下、2.1176gの6エタノール溶液15mlに、10％Pd/C 0.2950g加え、室温で1時間半撹拌した。溶媒を除去し、無色油状のtert-ブチルジメチルシリル乳酸4量体(8)をほぼ定量的に得た。 Under a hydrogen atmosphere, 0.2950 g of 10% Pd / C was added to 15 ml of 2.1176 g of 6 ethanol solution, and stirred at room temperature for 1.5 hours. The solvent was removed, and colorless oily tert-butyldimethylsilyl lactic acid tetramer (8) was obtained almost quantitatively.

¹H NMR(500MHz, CDCl₃)δ= 0.097 (d, 6H, J=11.5Hz), 0.90 (s, 9H), 1.45 (d, 3H, J=7.0Hz), 1.56 (d, 3H, J=7.0Hz), 1.58 (d, 12H, J=7.0Hz), 4.40 (q, 1H, J=7.0Hz), 5.14 (q, 1H, J=7.0Hz), 5.17 (q, 1H, J=7.0Hz), 5.19 (q, 1H, J=7.0Hz)
¹³C NMR(125MHz, CDCl₃)δ= -5.30, -4.92, 16.61, 16.67, 16.72, 18.26, 21.20, 25.62, 25.69, 68.01, 68.58, 68.76, 67.84, 169.63, 170.03, 173.59, 174.43
IR(cm^-1): 1755(C=O), 3000-3650(broad, COOH)
[α]¹⁴ _D ＝ -65.43°(c=1.43 CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 0.097 (d, 6H, J = 11.5Hz), 0.90 (s, 9H), 1.45 (d, 3H, J = 7.0Hz), 1.56 (d, 3H, J = 7.0Hz), 1.58 (d, 12H, J = 7.0Hz), 4.40 (q, 1H, J = 7.0Hz), 5.14 (q, 1H, J = 7.0Hz), 5.17 (q, 1H, J = 7.0Hz ), 5.19 (q, 1H, J = 7.0Hz)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = -5.30, -4.92, 16.61, 16.67, 16.72, 18.26, 21.20, 25.62, 25.69, 68.01, 68.58, 68.76, 67.84, 169.63, 170.03, 173.59, 174.43
IR (cm ^-1 ): 1755 (C = O), 3000-3650 (broad, COOH)
[α] ¹⁴ _D = -65.43 ° (c = 1.43 CH ₂ Cl ₂ )

実施例６：乳酸3量体ベンジル(9)の合成

Example 6: Synthesis of lactic acid trimer benzyl (9)

tert-ブチルジメチルシリル乳酸3量体ベンジル(5) 0.3045g(0.69mmol)のアセトニトリル溶液30mlにフッ化水素酸水溶液30滴を加え3時間撹拌した。飽和炭酸水素ナトリウム溶液を加え中性とし、酢酸エチルで3回、抽出し、集めた有機層を飽和食塩水で２回洗浄した。無水硫酸マグネシウムで一昼夜乾燥し、溶媒を除去し、残渣をカラムクロマトグラフィー(シリカゲル)を用いて分離し、ヘキサン：ジエチルエーテル(2：1)溶出部より無色油状の乳酸3量体ベンジル(9)を0.6762mmol(98％)で得た。 30 drops of aqueous hydrofluoric acid solution was added to 30 ml of acetonitrile solution of 0.3045 g (0.69 mmol) of tert-butyldimethylsilyl lactic acid trimer benzyl (5) and stirred for 3 hours. Saturated sodium hydrogen carbonate solution was added to neutralize, extracted three times with ethyl acetate, and the collected organic layer was washed twice with saturated brine. Drying with anhydrous magnesium sulfate all day and night, removing the solvent, separating the residue using column chromatography (silica gel), elution with hexane: diethyl ether (2: 1), colorless oily lactic acid trimer benzyl (9) Of 0.6762 mmol (98%).

¹H NMR(500MHz, CDCl₃)δ= 1.49 (d, 3H, J=7.0Hz), 1.53 (d, 3H, J=7.1Hz), 1.54 (d, 3H, J=7.1Hz), 4.35 (q, 1H, J=6.9Hz), 5.17 (dd, 2H, J=12.2Hz, 16.5Hz), 5.21 (q, 2H, J=7.2Hz), 7.31-7.38 (m, 5H)
¹³C NMR(125MHz, CDCl₃)δ= 16.69, 16.80, 20.54, 66.72, 67.27, 69.14, 69.33, 128.30, 128.57, 128.65, 135.06, 169.62, 169.93, 175.17
IR(cm^-1): 3527(OH), 2991(Ph C-H), 1751(C=O), 1451(Ph C=C)
[α]²⁶ _D＝ -50.90°(c=1.51 CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.49 (d, 3H, J = 7.0Hz), 1.53 (d, 3H, J = 7.1Hz), 1.54 (d, 3H, J = 7.1Hz), 4.35 (q , 1H, J = 6.9Hz), 5.17 (dd, 2H, J = 12.2Hz, 16.5Hz), 5.21 (q, 2H, J = 7.2Hz), 7.31-7.38 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = 16.69, 16.80, 20.54, 66.72, 67.27, 69.14, 69.33, 128.30, 128.57, 128.65, 135.06, 169.62, 169.93, 175.17
IR (cm ^-1 ): 3527 (OH), 2991 (Ph CH), 1751 (C = O), 1451 (Ph C = C)
[α] ²⁶ _D = -50.90 ° (c = 1.51 CH ₂ Cl ₂ )

実施例７：乳酸4量体ベンジル(10)の合成

Example 7: Synthesis of lactic acid tetramer benzyl (10)

tert-ブチルジメチルシリル乳酸4量体ベンジル(6) 0.7238g(1.42mmol)のアセトニトリル溶液18mlにフッ化水素酸水溶液18滴を加え45分撹拌した。飽和炭酸水素ナトリウム溶液を加え中性とし、酢酸エチルで3回、抽出し、集めた有機層を飽和食塩水で２回洗浄した。無水硫酸マグネシウムで一昼夜乾燥し、溶媒を除去し、残渣をカラムクロマトグラフィー(シリカゲル)を用いて分離し、ヘキサン：ジエチルエーテル(2：1)溶出部より無色油状の乳酸4量体ベンジル(10)を0.5372g(94％)で得た。 18 drops of aqueous hydrofluoric acid solution was added to 18 ml of acetonitrile solution of 0.7238 g (1.42 mmol) of tert-butyldimethylsilyl lactic acid tetramer benzyl (6) and stirred for 45 minutes. Saturated sodium hydrogen carbonate solution was added to neutralize, extracted three times with ethyl acetate, and the collected organic layer was washed twice with saturated brine. Drying with anhydrous magnesium sulfate all day and night, the solvent was removed, the residue was separated using column chromatography (silica gel), and colorless oily lactic acid tetramer benzyl (10) was eluted from hexane: diethyl ether (2: 1) Of 0.5372 g (94%).

¹H NMR(500MHz, CDCl₃)δ= 1.47 (d, 3H, J=7.0Hz), 1.52 (d, 3H, J=7.6Hz), 1.54 (d, 3H, J=7.5Hz), 1.60 (d, 3H, J=7.1Hz), 4.36 (q, 1H, J=6.9Hz), 5.16 (dd, 2H, J=12.2Hz, 20.4Hz), 5.17 (q, 1H, J=6.9Hz), 5.19 (q, 1H, J=7.3Hz), 5.21 (q, 2H, J=7.3Hz), 7.31-7.39 (m, 5H)
¹³C NMR(125MHz, CDCl₃)δ= 16.62, 16.75, 16.78, 20.55, 66.72, 67.26, 69.08, 69.14, 69.22, 128.28, 128.56, 128.65, 135.06, 169.57, 169.68, 169.95, 175.19
IR(cm^-1): 3500(OH), 2993(Ph C-H), 1751(C=O), 1456(Ph C=C)
[α]²³ _D＝ -75.91°(c=1.64 CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.47 (d, 3H, J = 7.0Hz), 1.52 (d, 3H, J = 7.6Hz), 1.54 (d, 3H, J = 7.5Hz), 1.60 (d , 3H, J = 7.1Hz), 4.36 (q, 1H, J = 6.9Hz), 5.16 (dd, 2H, J = 12.2Hz, 20.4Hz), 5.17 (q, 1H, J = 6.9Hz), 5.19 ( q, 1H, J = 7.3Hz), 5.21 (q, 2H, J = 7.3Hz), 7.31-7.39 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = 16.62, 16.75, 16.78, 20.55, 66.72, 67.26, 69.08, 69.14, 69.22, 128.28, 128.56, 128.65, 135.06, 169.57, 169.68, 169.95, 175.19
IR (cm ^-1 ): 3500 (OH), 2993 (Ph CH), 1751 (C = O), 1456 (Ph C = C)
[α] ²³ _D = -75.91 ° (c = 1.64 CH ₂ Cl ₂ )

実施例８：tert-ブチルジメチルシリル乳酸5量体ベンジル(11)の合成

Example 8: Synthesis of tert-butyldimethylsilyl lactic acid pentamer benzyl (11)

窒素雰囲気下、0℃にて、tert-ブチルジメチルシリル乳酸3量体(7)1.5mmolの塩化メチレン溶液10mlを加え、(2S, 5S)-乳酸ラクトイルベンジル(2)0.8232ｇの塩化メチレン溶液10mlを加え、4-ジメチルアミノピリジン1当量の塩化メチレン溶液10mlを加え、N, N'-ジシクロへキシルカルボジイミド1.3当量の塩化メチレン溶液20mlを加え、5分間撹拌した。室温に戻し、5時間撹拌した。減圧ろ過し、飽和塩化アンモニウム溶液30ml、飽和炭酸水素ナトリウム50mlを順に加え。ジエチルエーテルで4回抽出し、無水硫酸マグネシウムで2時間乾燥した。溶媒を除去し、残渣をカラムクロマトグラフィー(シリカゲル)を用いて分離し、ヘキサン：ジエチルエーテル（5：1）溶出部より、無色油状のtert-ブチルジメチルシリル乳酸5量体ベンジル(11)を収率85％で得た。 Add 10ml of 1.5mmol of tert-butyldimethylsilyl lactic acid trimer (7) 1.5mmol of methylene chloride at 0 ° C under nitrogen atmosphere and add 0.82g of (2S, 5S) -Lactoylbenzyl lactate (2) 0.8232g of methylene chloride 10 ml was added, 10 ml of a methylene chloride solution of 1 equivalent of 4-dimethylaminopyridine was added, 20 ml of a methylene chloride solution of 1.3 equivalent of N, N′-dicyclohexylcarbodiimide was added, and the mixture was stirred for 5 minutes. It returned to room temperature and stirred for 5 hours. After filtration under reduced pressure, 30 ml of saturated ammonium chloride solution and 50 ml of saturated sodium bicarbonate were added in this order. The mixture was extracted 4 times with diethyl ether and dried over anhydrous magnesium sulfate for 2 hours. The solvent was removed, the residue was separated using column chromatography (silica gel), and colorless oily tert-butyldimethylsilyl lactic acid pentamer benzyl (11) was collected from the eluate of hexane: diethyl ether (5: 1). Obtained at a rate of 85%.

¹H NMR(500MHz, CDCl₃)δ= 0.094 (d, 6H J=11.9Hz), 0.90 (s, 9H), 1.45 (d, 3H, J=6.8Hz), 1.52 (d, 3H, J=7.1Hz), 1.52 (d, 3H, J=7.1Hz), 1.57 (d, 3H, J=7.1Hz), 1.58 (d, 3H, J=7.2Hz), 4.40 (q, 1H, J=6.8Hz), 5.13 (q, 1H, J=7.1Hz), 5.15 (q, 1H, J=7.2Hz), 5.16 (dd, 2H, J=12.2Hz, 18.6Hz), 5.17 (q, 1H, J=7.2Hz), 5.18 (q, 1H, J=6.3Hz), 7.31-7.38 (m, 5H)
¹³C NMR(125MHz, CDCl₃)δ= -5.29, -4.90, 16.59, 16.69, 16.77, 18.30, 21.25, 67.24, 68.00, 68.56, 68.83, 68.99, 69.27, 128.28, 128.55, 128.64, 169.62, 169.76, 169.96, 170.04, 173.59
IR(cm^-1): 2993(Ph C-H), 1745(C=O), 1454(Ph C=C)
[α]²² _D= -93.30°(C=1.02, CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 0.094 (d, 6H J = 11.9Hz), 0.90 (s, 9H), 1.45 (d, 3H, J = 6.8Hz), 1.52 (d, 3H, J = 7.1 Hz), 1.52 (d, 3H, J = 7.1Hz), 1.57 (d, 3H, J = 7.1Hz), 1.58 (d, 3H, J = 7.2Hz), 4.40 (q, 1H, J = 6.8Hz) , 5.13 (q, 1H, J = 7.1Hz), 5.15 (q, 1H, J = 7.2Hz), 5.16 (dd, 2H, J = 12.2Hz, 18.6Hz), 5.17 (q, 1H, J = 7.2Hz ), 5.18 (q, 1H, J = 6.3Hz), 7.31-7.38 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = -5.29, -4.90, 16.59, 16.69, 16.77, 18.30, 21.25, 67.24, 68.00, 68.56, 68.83, 68.99, 69.27, 128.28, 128.55, 128.64, 169.62, 169.76, 169.96 , 170.04, 173.59
IR (cm ^-1 ): 2993 (Ph CH), 1745 (C = O), 1454 (Ph C = C)
[α] ²² _D = -93.30 ° (C = 1.02, CH ₂ Cl ₂ )

実施例９：tert-ブチルジメチルシリル乳酸6量体ベンジル(12)の合成

Example 9: Synthesis of tert-butyldimethylsilyl lactic acid hexamer benzyl (12)

窒素雰囲気下、0℃にて、tert-ブチルジメチルシリル-(2S, 5S)-乳酸ラクトイル(3)6.1mmolの塩化メチレン溶液5mlを加え、乳酸4量体ベンジル(10) 6.0mmolの塩化メチレン溶液5mlを加え、4-ジメチルアミノピリジン0.2当量の塩化メチレン溶液5mlを加え、N, N'-ジシクロへキシルカルボジイミド1.3当量の塩化メチレン溶液15mlを加え、5分間撹拌した。室温に戻し、3時間撹拌した。減圧ろ過し、飽和塩化アンモニウム溶液30ml、飽和炭酸水素ナトリウム30mlを加え。ジエチルエーテルで4回抽出し、無水硫酸マグネシウムで2時間乾燥した。溶媒を除去し、残渣をカラムクロマトグラフィー(シリカゲル)を用いて分離し、ヘキサン：ジエチルエーテル（5：1）溶出部より、無色油状のtert-ブチルジメチルシリル乳酸6量体ベンジル(12)を収率58％で得た。 Under nitrogen atmosphere at 0 ° C, tert-butyldimethylsilyl- (2S, 5S) -lactoyl lactate (3) 6.1 mmol methylene chloride solution 5 ml was added, lactic acid tetramer benzyl (10) 6.0 mmol methylene chloride solution 5 ml was added, 5 ml of methylene chloride solution of 0.2 equivalent of 4-dimethylaminopyridine was added, and 15 ml of methylene chloride solution of 1.3 equivalent of N, N′-dicyclohexylcarbodiimide was added and stirred for 5 minutes. It returned to room temperature and stirred for 3 hours. After filtration under reduced pressure, 30 ml of saturated ammonium chloride solution and 30 ml of saturated sodium bicarbonate were added. The mixture was extracted 4 times with diethyl ether and dried over anhydrous magnesium sulfate for 2 hours. The solvent was removed, the residue was separated using column chromatography (silica gel), and colorless oily tert-butyldimethylsilyl lactic acid hexamer benzyl (12) was collected from the eluate of hexane: diethyl ether (5: 1). Obtained at a rate of 58%.

¹H NMR(500MHz, CDCl₃)δ= 0.094 (d, 6H, J=11.8Hz), 0.90 (s, 9H), 1.45 (d, 3H, J=6.8Hz), 1.52 (d, 3H, J=7.1Hz), 1.52 (d, 3H, J=7.1Hz), 1.57 (d, 3H, J=7.1Hz), 1.58 (d, 6H, J=7.1Hz), 4.40 (q, 1H, J=6.7Hz), 5.13 (q, 1H, J=7.2Hz), 5.16 (q, 1H, J=7.4Hz), 5.16 (dd, 2H, J=12.1Hz, 18.5Hz), 5.16 (q, 1H, J=7.4Hz), 5.17 (q, 1H, J=7.5Hz), 5.18 (q, 1H, J=6.7Hz), 7.31-7.38 (m, 5H)
¹³C NMR(125MHz, CDCl₃)δ= -5.26, -4.90, 16.59, 16.65, 16.70, 16.77, 18.30, 21.24, 67.24, 68.01, 68.55, 68.82, 68.98, 69.29, 128.28, 128.56, 128.64, 135.07, 169.58, 169.77, 169.95, 173.58
IR(cm^-1): 2992(Ph C-H), 1758(C=O), 1455(Ph C=C)
[α]²¹ _D＝ -85.45°(c=1.63 CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 0.094 (d, 6H, J = 11.8Hz), 0.90 (s, 9H), 1.45 (d, 3H, J = 6.8Hz), 1.52 (d, 3H, J = 7.1Hz), 1.52 (d, 3H, J = 7.1Hz), 1.57 (d, 3H, J = 7.1Hz), 1.58 (d, 6H, J = 7.1Hz), 4.40 (q, 1H, J = 6.7Hz ), 5.13 (q, 1H, J = 7.2Hz), 5.16 (q, 1H, J = 7.4Hz), 5.16 (dd, 2H, J = 12.1Hz, 18.5Hz), 5.16 (q, 1H, J = 7.4 Hz), 5.17 (q, 1H, J = 7.5Hz), 5.18 (q, 1H, J = 6.7Hz), 7.31-7.38 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = -5.26, -4.90, 16.59, 16.65, 16.70, 16.77, 18.30, 21.24, 67.24, 68.01, 68.55, 68.82, 68.98, 69.29, 128.28, 128.56, 128.64, 135.07, 169.58 , 169.77, 169.95, 173.58
IR (cm ^-1 ): 2992 (Ph CH), 1758 (C = O), 1455 (Ph C = C)
[α] ²¹ _D = -85.45 ° (c = 1.63 CH ₂ Cl ₂ )

実施例１０：tert-ブチルジメチルシリル乳酸7量体ベンジル(13)の合成

Example 10: Synthesis of tert-butyldimethylsilyl lactic acid heptamer benzyl (13)

窒素雰囲気下、0℃にて、tert-ブチルジメチルシリル乳酸3量体(3)2.2537ｇの塩化メチレン溶液5mlを加え、乳酸4量体ベンジル(10)5.17mmolの塩化メチレン溶液5mlを加え、4-ジメチルアミノピリジン1.0当量の塩化メチレン溶液5mlを加え、N, N'-ジシクロへキシルカルボジイミド1.3当量の塩化メチレン溶液15mlを加え、5分間撹拌した。室温に戻し、3時間撹拌した。減圧ろ過し、飽和塩化アンモニウム溶液40ml、飽和炭酸水素ナトリウム50mlを加え。ジエチルエーテルで4回抽出し、無水硫酸マグネシウムで2時間乾燥した。溶媒を除去し、残渣をカラムクロマトグラフィー(シリカゲル)を用いて分離し、ヘキサン：ジエチルエーテル（3：1）溶出部より、無色油状のtert-ブチルジメチルシリル乳酸7量体ベンジル(13)を収率69％で得た。 Under nitrogen atmosphere, at 0 ° C., add 5 ml of methylene chloride solution of 2.2537 g of tert-butyldimethylsilyl lactic acid trimer (3), add 5 ml of methylene chloride solution of 5.17 mmol of lactic acid tetramer benzyl (10), 4 -5 ml of methylene chloride solution of 1.0 equivalent of dimethylaminopyridine was added, and 15 ml of methylene chloride solution of 1.3 equivalent of N, N'-dicyclohexylcarbodiimide was added and stirred for 5 minutes. It returned to room temperature and stirred for 3 hours. After filtration under reduced pressure, 40 ml of saturated ammonium chloride solution and 50 ml of saturated sodium bicarbonate were added. The mixture was extracted 4 times with diethyl ether and dried over anhydrous magnesium sulfate for 2 hours. The solvent was removed, the residue was separated using column chromatography (silica gel), and colorless oily tert-butyldimethylsilyl lactic acid heptamer benzyl (13) was collected from the eluate of hexane: diethyl ether (3: 1). Obtained at a rate of 69%.

¹H NMR(500MHz, CDCl₃)δ= 0.093 (d, 6H, J=11.8Hz), 0.90 (s, 9H), 1.44 (d, 3H, J=6.9Hz), 1.52 (d, 3H, J=7.1Hz), 1.52 (d, 3H, J=7.2Hz), 1.57 (d, 3H, J=7.0Hz), 1.58 (d, 6H, J=7.1Hz), 1.58 (d, 3H, J=7.1 Hz)，4.39 (q, 1H, J=6.8Hz), 5.13 (q, 1H, J=7.1Hz), 5.15 (q, 1H, J=7.2Hz), 5.15 (dd, 2H, J=12.2Hz, 21.7Hz), 5.16 (q, 2H, J=7.0Hz), 5.17 (q, 1H, J=7.0Hz), 5.18 (q, 1H, J=6.9Hz), 7.31-7.38 (m, 5H)
¹³C NMR(125MHz, CDCl₃)δ= -5.33, -4.93, 16.62, 16.66, 16.73, 18.26, 21.21, 25.67, 67.21, 67.97, 68.52, 68.79, 68.95, 68.99, 69.26, 128.24, 128.52, 128.61, 169.55, 169.61, 169.65, 169.73, 169.99, 173.55
IR(cm^-1): 3068(Ph C-H), 1747(C=O), 1454(Ph C=C)
[α]²¹ _D＝ -120.00°(c=0.97 CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 0.093 (d, 6H, J = 11.8Hz), 0.90 (s, 9H), 1.44 (d, 3H, J = 6.9Hz), 1.52 (d, 3H, J = 7.1Hz), 1.52 (d, 3H, J = 7.2Hz), 1.57 (d, 3H, J = 7.0Hz), 1.58 (d, 6H, J = 7.1Hz), 1.58 (d, 3H, J = 7.1 Hz) ), 4.39 (q, 1H, J = 6.8Hz), 5.13 (q, 1H, J = 7.1Hz), 5.15 (q, 1H, J = 7.2Hz), 5.15 (dd, 2H, J = 12.2Hz, 21.7 Hz), 5.16 (q, 2H, J = 7.0Hz), 5.17 (q, 1H, J = 7.0Hz), 5.18 (q, 1H, J = 6.9Hz), 7.31-7.38 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = -5.33, -4.93, 16.62, 16.66, 16.73, 18.26, 21.21, 25.67, 67.21, 67.97, 68.52, 68.79, 68.95, 68.99, 69.26, 128.24, 128.52, 128.61, 169.55 , 169.61, 169.65, 169.73, 169.99, 173.55
IR (cm ^-1 ): 3068 (Ph CH), 1747 (C = O), 1454 (Ph C = C)
[α] ²¹ _D = -120.00 ° (c = 0.97 CH ₂ Cl ₂ )

実施例１１：tert-ブチルジメチルシリル乳酸8量体ベンジル(14)の合成

Example 11: Synthesis of tert-butyldimethylsilyl lactic acid octamer benzyl (14)

窒素雰囲気下、0℃にて、tert-ブチルジメチルシリル乳酸4量体(8)1.7176ｇの塩化メチレン溶液5mlを加え、乳酸4量体ベンジル(10)3.75mmolの塩化メチレン溶液5mlを加え、4-ジメチルアミノピリジン1.0当量の塩化メチレン溶液5mlを加え、N, N'-ジシクロへキシルカルボジイミド1.3当量の塩化メチレン溶液15mlを加え、5分間撹拌した。室温に戻し、3時間撹拌した。減圧ろ過し、飽和炭酸水素ナトリウム30mlを加え。ジエチルエーテルで4回抽出し、無水硫酸マグネシウムで2時間乾燥した。溶媒を除去し、残渣をカラムクロマトグラフィー(シリカゲル)を用いて分離し、ヘキサン：ジエチルエーテル（3：1）溶出部より、無色油状のtert-ブチルジメチルシリル乳酸8量体ベンジル(14)を収率69％で得た。 Under a nitrogen atmosphere, at 0 ° C., 5 ml of 1.7176 g of tert-butyldimethylsilyl lactic acid tetramer (8) (1.7176 g) was added, 5 ml of methylene chloride solution of 3.75 mmol of benzyl tetramer (10) was added, and 4 -5 ml of methylene chloride solution of 1.0 equivalent of dimethylaminopyridine was added, and 15 ml of methylene chloride solution of 1.3 equivalent of N, N'-dicyclohexylcarbodiimide was added and stirred for 5 minutes. It returned to room temperature and stirred for 3 hours. Filter under reduced pressure and add 30 ml of saturated sodium bicarbonate. The mixture was extracted 4 times with diethyl ether and dried over anhydrous magnesium sulfate for 2 hours. The solvent was removed, the residue was separated using column chromatography (silica gel), and colorless oily tert-butyldimethylsilyl lactic acid octamer benzyl (14) was collected from the eluate of hexane: diethyl ether (3: 1). Obtained at a rate of 69%.

¹H NMR(500MHz, CDCl₃)δ= 0.094 (d, 6H, J=11.8Hz), 0.90 (s, 9H), 1.45 (d, 3H, J=6.8Hz), 1.52 (d, 3H, J=7.1Hz), 1.52 (d, 3H, J=7.1Hz), 1.57 (d, 3H, J=7.1Hz), 1.58 (d, 12H, J=7.1Hz), 4.40 (q, 1H, J=6.8Hz), 5.13 (q, 1H, J=7.1Hz), 5.15 (q, 1H, J=7.1Hz), 5.16 (dd, 2H, J=12.3Hz, 18.8Hz), 5.16 (q, 2H, J=6.6Hz), 5.17 (q, 1H, J=7.0Hz), 5.18 (q, 1H, J=6.9Hz), 7.30-7.38 (m, 5H)
¹³C NMR(125MHz, CDCl₃)δ= -5.33, -4.93, 16.55, 16.62, 16.73, 18.26, 21.21, 25.67, 67.21, 67.97, 68.52, 68.79, 68.94, 68.99, 69.26, 128.24, 128.52, 128.61, 169.62, 169.73, 170.00
IR(cm^-1): 2994(Ph C-H), 1768(C=O), 1454(Ph C=C)
[α]²⁵ _D＝ -101.70°(c=0.94 CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 0.094 (d, 6H, J = 11.8Hz), 0.90 (s, 9H), 1.45 (d, 3H, J = 6.8Hz), 1.52 (d, 3H, J = 7.1Hz), 1.52 (d, 3H, J = 7.1Hz), 1.57 (d, 3H, J = 7.1Hz), 1.58 (d, 12H, J = 7.1Hz), 4.40 (q, 1H, J = 6.8Hz ), 5.13 (q, 1H, J = 7.1Hz), 5.15 (q, 1H, J = 7.1Hz), 5.16 (dd, 2H, J = 12.3Hz, 18.8Hz), 5.16 (q, 2H, J = 6.6 Hz), 5.17 (q, 1H, J = 7.0Hz), 5.18 (q, 1H, J = 6.9Hz), 7.30-7.38 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = -5.33, -4.93, 16.55, 16.62, 16.73, 18.26, 21.21, 25.67, 67.21, 67.97, 68.52, 68.79, 68.94, 68.99, 69.26, 128.24, 128.52, 128.61, 169.62 , 169.73, 170.00
IR (cm ^-1 ): 2994 (Ph CH), 1768 (C = O), 1454 (Ph C = C)
[α] ²⁵ _D = -101.70 ° (c = 0.94 CH ₂ Cl ₂ )

実施例１２：乳酸5量体ベンジル(15)の合成

Example 12: Synthesis of lactic acid pentamer benzyl (15)

tert-ブチルジメチルシリル乳酸5量体ベンジル(11) 1.15mmolのアセトニトリル溶液16.2mlにフッ化水素酸水溶液1.2mlを加え2時間撹拌した。飽和炭酸ナトリウム溶液を加え中性とし、酢酸エチルで4回、抽出し、集めた有機層を飽和食塩水で1回洗浄した。無水硫酸マグネシウムで一昼夜乾燥し、溶媒を除去し、無色油状の乳酸5量体ベンジル(15)を1.12mmol (97％)で得た。 To 16.2 ml of acetonitrile solution of tert-butyldimethylsilyl lactic acid pentamer benzyl (11) 1.15 mmol, 1.2 ml of aqueous hydrofluoric acid solution was added and stirred for 2 hours. Saturated sodium carbonate solution was added to neutralize, extracted four times with ethyl acetate, and the collected organic layer was washed once with saturated brine. After drying overnight with anhydrous magnesium sulfate, the solvent was removed to obtain 1.12 mmol (97%) of colorless oily lactic acid pentamer benzyl (15).

実施例１３：乳酸6量体ベンジル(16)の合成

Example 13: Synthesis of lactic acid hexamer benzyl (16)

tert-ブチルジメチルシリル乳酸6量体ベンジル(12) 3.586mmolのアセトニトリル溶液38mlにフッ化水素酸水溶液2.9mlを加え2時間半撹拌した。飽和炭酸ナトリウム溶液を加え中性とし、酢酸エチルで4回、抽出し、集めた有機層を飽和食塩水で1回洗浄した。無水硫酸マグネシウムで一昼夜乾燥し、溶媒を除去し、無色油状の乳酸6量体ベンジル(16)を3.44mmol (96％)で得た。 tert-Butyldimethylsilyl lactic acid hexamer benzyl (12) 2.9 ml of an aqueous hydrofluoric acid solution was added to 38 ml of an acetonitrile solution of 3.586 mmol, and the mixture was stirred for 2.5 hours. Saturated sodium carbonate solution was added to neutralize, extracted four times with ethyl acetate, and the collected organic layer was washed once with saturated brine. After drying overnight with anhydrous magnesium sulfate, the solvent was removed to obtain 3.44 mmol (96%) of lactic acid hexamer benzyl (16) as colorless oil.

¹H NMR(500MHz, CDCl₃)δ= 1.48 (d, 3H, J=6.9Hz), 1.51 (d, 3H, J=7.1Hz), 1.51 (d, 3H, J=7.1Hz), 1.57 (d, 3H, J=6.9Hz), 1.58 (d, 6H, J=7.1Hz), 4.34 (q, 1H, J=6.9Hz), 5.13 (q, 1H, J=7.0Hz), 5.14 (q, 1H, J=7.0Hz), 5.15 (dd, 2H, J=12.2Hz, 18.7Hz), 5.16 (q, 1H, J=6.6 Hz), 5.17 (q, 1H, J=6.8Hz), 5.19 (q, 1H, J=6.8Hz), 5.20 (q, 1H, J=7.1Hz), 7.31-7.38 (m, 5H)
¹³C NMR(125MHz, CDCl₃)δ= 16.58, 16.66, 16.76, 20.54, 66.72, 67.24, 69.04, 69.06, 69.10, 69.30, 128.27, 128.55, 128.64, 135.07, 169.56, 169.62, 169.69, 169.93, 175.16
IR(cm^-1): 3527(OH), 3000(Ph C-H), 1751(C=O), 1456(Ph C=C)
[α]²² _D＝ -77.61°(c=2.23 CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.48 (d, 3H, J = 6.9Hz), 1.51 (d, 3H, J = 7.1Hz), 1.51 (d, 3H, J = 7.1Hz), 1.57 (d , 3H, J = 6.9Hz), 1.58 (d, 6H, J = 7.1Hz), 4.34 (q, 1H, J = 6.9Hz), 5.13 (q, 1H, J = 7.0Hz), 5.14 (q, 1H , J = 7.0Hz), 5.15 (dd, 2H, J = 12.2Hz, 18.7Hz), 5.16 (q, 1H, J = 6.6 Hz), 5.17 (q, 1H, J = 6.8Hz), 5.19 (q, 1H, J = 6.8Hz), 5.20 (q, 1H, J = 7.1Hz), 7.31-7.38 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = 16.58, 16.66, 16.76, 20.54, 66.72, 67.24, 69.04, 69.06, 69.10, 69.30, 128.27, 128.55, 128.64, 135.07, 169.56, 169.62, 169.69, 169.93, 175.16
IR (cm ^-1 ): 3527 (OH), 3000 (Ph CH), 1751 (C = O), 1456 (Ph C = C)
[α] ²² _D = -77.61 ° (c = 2.23 CH ₂ Cl ₂ )

実施例１４：乳酸7量体ベンジル(17)の合成

Example 14: Synthesis of lactic acid heptamer benzyl (17)

tert-ブチルジメチルシリル乳酸7量体ベンジル(13) 2.44mmolのアセトニトリル溶液26mlにフッ化水素酸水溶液2.0mlを加え1時間半撹拌した。飽和炭酸ナトリウム溶液を加え中性とし、ジエチルエーテルで4回、抽出し、集めた有機層を飽和食塩水で1回洗浄した。無水硫酸マグネシウムで一昼夜乾燥し、溶媒を除去し、無色油状の乳酸7量体ベンジル(17)を2.3mmol (94％)で得た。 To 26 ml of acetonitrile solution of tert-butyldimethylsilyl lactic acid heptamer benzyl (13) 2.44 mmol was added 2.0 ml of hydrofluoric acid aqueous solution and stirred for 1.5 hours. Saturated sodium carbonate solution was added to neutralize, extracted four times with diethyl ether, and the collected organic layer was washed once with saturated brine. After drying overnight with anhydrous magnesium sulfate, the solvent was removed to obtain 2.3 mmol (94%) of a colorless oily lactic acid 7-mer benzyl (17).

¹H NMR(500MHz, CDCl₃)δ= 1.49 (d, 3H, J=7.0Hz), 1.52 (d, 3H, J=7.1Hz), 1.52 (d, 3H, J=7.2Hz), 1.58 (d, 3H, J=7.7Hz), 1.59 (d, 3H, J=7.3Hz), 1.60 (d, 3H, J=7.3Hz), 1.60 (d, 3H, J=7.4Hz), 4.35 (q, 1H, J=6.9Hz), 5.16 (q, 1H, J=7.1Hz), 5.16 (dd, 2H, J=12.3Hz, 18.2Hz), 5.16 (q, 1H, J=7.1Hz), 5.18 (q, 1H, J=7.1Hz), 5.19 (q, 1H, J=7.2Hz), 5.19 (q, 1H, J=7.3Hz), 5.22 (q, 1H, J=7.2Hz), 7.31-7.38 (m, 5H)
¹³C NMR(125MHz, CDCl₃)δ= 16.52, 16.63, 16.73, 20.51, 66.70, 67.22, 69.01, 69.09, 69.30, 128.24, 128.53, 128.61, 169.61, 175.15
IR(cm^-1): 3517(OH), 2994(Ph C-H), 1770(C=O), 1455(Ph C=C)
[α]²¹ _D＝ -119.62°(c=1.05 CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.49 (d, 3H, J = 7.0Hz), 1.52 (d, 3H, J = 7.1Hz), 1.52 (d, 3H, J = 7.2Hz), 1.58 (d , 3H, J = 7.7Hz), 1.59 (d, 3H, J = 7.3Hz), 1.60 (d, 3H, J = 7.3Hz), 1.60 (d, 3H, J = 7.4Hz), 4.35 (q, 1H , J = 6.9Hz), 5.16 (q, 1H, J = 7.1Hz), 5.16 (dd, 2H, J = 12.3Hz, 18.2Hz), 5.16 (q, 1H, J = 7.1Hz), 5.18 (q, 1H, J = 7.1Hz), 5.19 (q, 1H, J = 7.2Hz), 5.19 (q, 1H, J = 7.3Hz), 5.22 (q, 1H, J = 7.2Hz), 7.31-7.38 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = 16.52, 16.63, 16.73, 20.51, 66.70, 67.22, 69.01, 69.09, 69.30, 128.24, 128.53, 128.61, 169.61, 175.15
IR (cm ^-1 ): 3517 (OH), 2994 (Ph CH), 1770 (C = O), 1455 (Ph C = C)
[α] ²¹ _D = -119.62 ° (c = 1.05 CH ₂ Cl ₂ )

実施例１５：乳酸8量体ベンジル(18)の合成

Example 15: Synthesis of lactic acid octamer benzyl (18)

tert-ブチルジメチルシリル乳酸8量体ベンジル(14) 0.68mmolのアセトニトリル溶液8.2mlにフッ化水素酸水溶液8滴を加え45分撹拌した。飽和炭酸水素ナトリウム溶液を加え中性とし、酢酸エチルで3回、抽出し、集めた有機層を飽和食塩水で1回洗浄した。無水硫酸マグネシウムで一昼夜乾燥し、溶媒を除去し、無色油状の乳酸8量体ベンジル(18)を0.6725mmol (96％)で得た。 8 drops of aqueous hydrofluoric acid solution was added to 8.2 ml of acetonitrile solution of 0.68 mmol of tert-butyldimethylsilyl lactic acid octamer benzyl (14) and stirred for 45 minutes. Saturated sodium hydrogen carbonate solution was added to neutralize, extracted three times with ethyl acetate, and the collected organic layer was washed once with saturated brine. After drying overnight with anhydrous magnesium sulfate, the solvent was removed to obtain a colorless oily lactic acid octamer benzyl (18) at 0.6725 mmol (96%).

¹H NMR(500MHz, CDCl₃)δ= 1.49 (d, 3H, J=6.9Hz), 1.52 (d, 3H, J=7.2Hz), 1.52 (d, 3H, J=7.2Hz), 1.58 (d, 6H, J=7.2Hz), 1.59 (d, 3H, J=7.3Hz), 1.60 (d, 3H, J=8.1Hz), 1.60 (d, 3H, J=7.3Hz), 4.36 (q, 1H, J=6.9Hz), 5.15 (q, 1H, J=6.9 Hz), 5.15 (dd, 2H, J=13.6Hz, 17.6Hz), 5.16 (q, 1H, J=7.1Hz), 5.17 (q, 1H, J=7.3Hz), 5.17 (q, 1H, J=6.9Hz), 5.18 (q, 1H, J=7.0Hz), 5.18 (q, 1H, J=7.1Hz), 5.18 (q, 1H, J=7.1Hz), 5.22 (q, 1H, J=7.1Hz), 7.31-7.38 (m, 5H)
¹³C NMR(125MHz, CDCl₃)δ= 16.64, 16.74, 20.53, 66.70, 67.22, 69.01, 69.10, 69.27, 128.25, 128.53, 128.62, 169.60 ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.49 (d, 3H, J = 6.9Hz), 1.52 (d, 3H, J = 7.2Hz), 1.52 (d, 3H, J = 7.2Hz), 1.58 (d , 6H, J = 7.2Hz), 1.59 (d, 3H, J = 7.3Hz), 1.60 (d, 3H, J = 8.1Hz), 1.60 (d, 3H, J = 7.3Hz), 4.36 (q, 1H , J = 6.9Hz), 5.15 (q, 1H, J = 6.9 Hz), 5.15 (dd, 2H, J = 13.6Hz, 17.6Hz), 5.16 (q, 1H, J = 7.1Hz), 5.17 (q, 1H, J = 7.3Hz), 5.17 (q, 1H, J = 6.9Hz), 5.18 (q, 1H, J = 7.0Hz), 5.18 (q, 1H, J = 7.1Hz), 5.18 (q, 1H, J = 7.1Hz), 5.22 (q, 1H, J = 7.1Hz), 7.31-7.38 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = 16.64, 16.74, 20.53, 66.70, 67.22, 69.01, 69.10, 69.27, 128.25, 128.53, 128.62, 169.60

実施例１６：tert-ブチルジメチルシリル乳酸6量体(19)の合成

Example 16: Synthesis of tert-butyldimethylsilyl lactic acid hexamer (19)

水素雰囲気下、1.68mmolの12エタノール溶液7mlに、10％Pd/C 0.1227g加え、室温で1時間撹拌した。溶媒を除去し、淡黄色油状のtert-ブチルジメチルシリル乳酸6量体(19)を1.54mmol(91%)で得た。 Under a hydrogen atmosphere, 0.1227 g of 10% Pd / C was added to 7 ml of a 1.68 mmol 12 ethanol solution, and the mixture was stirred at room temperature for 1 hour. The solvent was removed to obtain 1.54 mmol (91%) of tert-butyldimethylsilyl lactic acid hexamer (19) as a pale yellow oil.

¹H NMR(500MHz, CDCl₃)δ= 0.093 (d, 6H, J=11.7Hz), 0.89 (s, 9H), 1.44 (d, 3H, J=6.8Hz), 1.56 (d, 3H, J=7.5Hz), 1.57 (d, 6H, J=7.0Hz), 1.59 (d, 6H, J=6.4Hz), 4.40 (q, 1H, J=6.8Hz), 5.13 (q, 1H, J=6.8Hz), 1.57 (d, 1H, J=7.0Hz), 1.57 (d, 1H, J=7.1Hz), 5.18 (q, 1H, J=6.9Hz) ¹ H NMR (500MHz, CDCl ₃ ) δ = 0.093 (d, 6H, J = 11.7Hz), 0.89 (s, 9H), 1.44 (d, 3H, J = 6.8Hz), 1.56 (d, 3H, J = 7.5Hz), 1.57 (d, 6H, J = 7.0Hz), 1.59 (d, 6H, J = 6.4Hz), 4.40 (q, 1H, J = 6.8Hz), 5.13 (q, 1H, J = 6.8Hz ), 1.57 (d, 1H, J = 7.0Hz), 1.57 (d, 1H, J = 7.1Hz), 5.18 (q, 1H, J = 6.9Hz)

実施例１７：tert-ブチルジメチルシリル乳酸9量体ベンジル(20)の合成

Example 17: Synthesis of tert-butyldimethylsilyl lactic acid 9-mer benzyl (20)

窒素雰囲気下、0℃にて、tert-ブチルジメチルシリル乳酸4量体(8)0.2990ｇの塩化メチレン溶液5mlを加え、乳酸5量体ベンジル(15)0.2353ｇの塩化メチレン溶液5mlを加え、4-ジメチルアミノピリジン1.0当量の塩化メチレン溶液5mlを加え、N, N'-ジシクロへキシルカルボジイミド1.3当量の塩化メチレン溶液15mlを加え、5分間撹拌した。室温に戻し、2時間半撹拌した。減圧ろ過し、飽和炭酸水素ナトリウム30mlを加え。酢酸エチルで4回抽出し、無水硫酸マグネシウムで2時間乾燥した。溶媒を除去し、残渣をカラムクロマトグラフィー(シリカゲル)を用いて分離し、(ヘキサン：ジエチルエーテル4：1）溶出部より、無色油状のtert-ブチルジメチルシリル乳酸9量体ベンジル(20)を収率86％で得た。 In a nitrogen atmosphere, at 0 ° C., 5 ml of 0.2990 g of methylene chloride solution of tert-butyldimethylsilyl lactic acid tetramer (8) was added, and 5 ml of methylene chloride solution of 0.2353 g of lactic acid pentamer benzyl (15) was added. -5 ml of methylene chloride solution of 1.0 equivalent of dimethylaminopyridine was added, and 15 ml of methylene chloride solution of 1.3 equivalent of N, N'-dicyclohexylcarbodiimide was added and stirred for 5 minutes. It returned to room temperature and stirred for 2.5 hours. Filter under reduced pressure and add 30 ml of saturated sodium bicarbonate. The mixture was extracted 4 times with ethyl acetate and dried over anhydrous magnesium sulfate for 2 hours. The solvent was removed, and the residue was separated using column chromatography (silica gel). From the eluate of (hexane: diethyl ether 4: 1), colorless oily tert-butyldimethylsilyl lactic acid 9-mer benzyl (20) was collected. Obtained at a rate of 86%.

¹H NMR(500MHz, CDCl₃)δ= 0.094 (d, 6H, J=11.7Hz), 0.90 (s, 9H), 1.44 (d, 3H, J=6.9Hz), 1.52 (d, 3H, J=7.1Hz), 1.52 (d, 3H, J=7.1Hz), 1.57 (d, 6H, J=7.3Hz), 1.58 (d, 12H, J=7.1Hz), 4.39 (q, 1H, J=6.7Hz), 5.13 (q, 1H, J=7.3Hz), 5.15 (q, 1H, J=7.2Hz), 5.16 (dd, 2H, J=12.2Hz, 17.9Hz), 5.16 (q, 3H, J=6.9Hz), 5.17 (q, 2H, J=6.9Hz), 5.18 (q, 1H, J=6.7Hz), 7.31-7.38 (m, 5H)
¹³C NMR(125MHz, CDCl₃)δ= -5.33, -4.96, 16.55, 16.63, 16.65, 16.74, 18.26, 21.21, 25.67, 67.21, 67.97, 68.52, 68.79, 68.99, 69.26, 128.24, 128.53, 128.61, 169.73
IR(cm^-1): 2993(Ph C-H), 1749(C=O), 1454(Ph C=C)
[α]²¹ _D＝ -104.55°(c=0.99 CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 0.094 (d, 6H, J = 11.7Hz), 0.90 (s, 9H), 1.44 (d, 3H, J = 6.9Hz), 1.52 (d, 3H, J = 7.1Hz), 1.52 (d, 3H, J = 7.1Hz), 1.57 (d, 6H, J = 7.3Hz), 1.58 (d, 12H, J = 7.1Hz), 4.39 (q, 1H, J = 6.7Hz ), 5.13 (q, 1H, J = 7.3Hz), 5.15 (q, 1H, J = 7.2Hz), 5.16 (dd, 2H, J = 12.2Hz, 17.9Hz), 5.16 (q, 3H, J = 6.9 Hz), 5.17 (q, 2H, J = 6.9Hz), 5.18 (q, 1H, J = 6.7Hz), 7.31-7.38 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = -5.33, -4.96, 16.55, 16.63, 16.65, 16.74, 18.26, 21.21, 25.67, 67.21, 67.97, 68.52, 68.79, 68.99, 69.26, 128.24, 128.53, 128.61, 169.73
IR (cm ^-1 ): 2993 (Ph CH), 1749 (C = O), 1454 (Ph C = C)
[α] ²¹ _D = -104.55 ° (c = 0.99 CH ₂ Cl ₂ )

実施例１８：tert-ブチルジメチルシリル乳酸10量体ベンジル(21)の合成

Example 18: Synthesis of tert-butyldimethylsilyl lactic acid decameric benzyl (21)

窒素雰囲気下、0℃にて、tert-ブチルジメチルシリル乳酸4量体(8)1.5633ｇの塩化メチレン溶液5mlを加え、乳酸6量体ベンジル(16)3.44mmolの塩化メチレン溶液5mlを加え、4-ジメチルアミノピリジン1.0当量の塩化メチレン溶液5mlを加え、N, N'-ジシクロへキシルカルボジイミド1.3当量の塩化メチレン溶液15mlを加え、5分間撹拌した。室温に戻し、3時間撹拌した。減圧ろ過し、飽和炭酸水素ナトリウム30mlを加え。酢酸エチルで4回抽出し、無水硫酸マグネシウムで2時間乾燥した。溶媒を除去し、残渣をカラムクロマトグラフィー(シリカゲル)を用いて分離し、(ヘキサン：ジエチルエーテル2：1）溶出部より、無色油状のtert-ブチルジメチルシリル乳酸10量体ベンジル(21)を収率82％で得た。 Under a nitrogen atmosphere, at 0 ° C., 5 ml of 1.5633 g of tert-butyldimethylsilyl lactic acid tetramer (8) 1.5633 g and 5 ml of methylene chloride solution of 3.44 mmol of lactic acid hexamer benzyl (16) were added. -5 ml of methylene chloride solution of 1.0 equivalent of dimethylaminopyridine was added, and 15 ml of methylene chloride solution of 1.3 equivalent of N, N'-dicyclohexylcarbodiimide was added and stirred for 5 minutes. It returned to room temperature and stirred for 3 hours. Filter under reduced pressure and add 30 ml of saturated sodium bicarbonate. The mixture was extracted 4 times with ethyl acetate and dried over anhydrous magnesium sulfate for 2 hours. The solvent was removed, and the residue was separated using column chromatography (silica gel). From the eluate of (hexane: diethyl ether 2: 1), colorless oily tert-butyldimethylsilyl lactic acid decameric benzyl (21) was collected. Obtained at a rate of 82%.

¹H NMR(500MHz, CDCl₃)δ= 0.094 (d, 6H, J=11.8Hz), 0.90 (s, 9H), 1.44 (d, 3H, J=6.8Hz), 1.52 (d, 3H, J=7.1Hz), 1.52 (d, 3H, J=7.1Hz), 1.57 (d, 3H, J=7.1Hz), 1.58 (d, 18H, J=7.1Hz), 4.39 (q, 1H, J=6.8Hz), 5.13 (q, 1H, J=7.1Hz), 5.15 (q, 1H, J=7.2Hz), 5.16 (dd, 2H, J=12.3Hz, 18.6Hz), 5.16 (q, 5H, J=6.9Hz), 5.17 (q, 1H, J=7.1Hz), 5.18 (q, 1H, J=7.0Hz), 7.31-7.38 (m, 5H)
¹³C NMR(125MHz, CDCl₃)δ= -5.32, -4.93, 16.56, 16.63, 16.74, 18.27, 21.21, 25.68, 67.22, 67.98, 68.52, 68.80, 68.99, 69.27, 128.24, 128.53, 128.62, 169.61
IR(cm^-1): 2993(Ph C-H), 1745(C=O), 1454(Ph C=C)
[α]²¹ _D＝ -106.58°(c=0.79 CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 0.094 (d, 6H, J = 11.8Hz), 0.90 (s, 9H), 1.44 (d, 3H, J = 6.8Hz), 1.52 (d, 3H, J = 7.1Hz), 1.52 (d, 3H, J = 7.1Hz), 1.57 (d, 3H, J = 7.1Hz), 1.58 (d, 18H, J = 7.1Hz), 4.39 (q, 1H, J = 6.8Hz ), 5.13 (q, 1H, J = 7.1Hz), 5.15 (q, 1H, J = 7.2Hz), 5.16 (dd, 2H, J = 12.3Hz, 18.6Hz), 5.16 (q, 5H, J = 6.9 Hz), 5.17 (q, 1H, J = 7.1Hz), 5.18 (q, 1H, J = 7.0Hz), 7.31-7.38 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = -5.32, -4.93, 16.56, 16.63, 16.74, 18.27, 21.21, 25.68, 67.22, 67.98, 68.52, 68.80, 68.99, 69.27, 128.24, 128.53, 128.62, 169.61
IR (cm ^-1 ): 2993 (Ph CH), 1745 (C = O), 1454 (Ph C = C)
[α] ²¹ _D = -106.58 ° (c = 0.79 CH ₂ Cl ₂ )

実施例１９：tert-ブチルジメチルシリル乳酸11量体ベンジル(22)の合成

Example 19 Synthesis of tert-butyldimethylsilyl lactic acid 11-mer benzyl (22)

窒素雰囲気下、0℃にて、tert-ブチルジメチルシリル乳酸6量体(19)0.72mmolの塩化メチレン溶液5mlを加え、乳酸6量体ベンジル(15)0.476mmolの塩化メチレン溶液5mlを加え、4-ジメチルアミノピリジン1.0当量の塩化メチレン溶液5mlを加え、N, N'-ジシクロへキシルカルボジイミド1.3当量の塩化メチレン溶液15mlを加え、5分間撹拌した。室温に戻し、2時間半撹拌した。減圧ろ過し、飽和炭酸水素ナトリウム30mlを加え。酢酸エチルで4回抽出し、無水硫酸マグネシウムで2時間乾燥した。溶媒を除去し、残渣をカラムクロマトグラフィー(シリカゲル)を用いて分離し、(ヘキサン：ジエチルエーテル1：1）溶出部より、無色油状のtert-ブチルジメチルシリル乳酸11量体ベンジル(22)を収率96％で得た。 Under a nitrogen atmosphere, at 0 ° C., 5 ml of 0.72 mmol of tert-butyldimethylsilyl lactic acid hexamer (19) 0.72 mmol was added, and 5 ml of methylene chloride solution of 0.476 mmol of lactic acid hexamer benzyl (15) was added. -5 ml of methylene chloride solution of 1.0 equivalent of dimethylaminopyridine was added, and 15 ml of methylene chloride solution of 1.3 equivalent of N, N'-dicyclohexylcarbodiimide was added and stirred for 5 minutes. It returned to room temperature and stirred for 2.5 hours. Filter under reduced pressure and add 30 ml of saturated sodium bicarbonate. The mixture was extracted 4 times with ethyl acetate and dried over anhydrous magnesium sulfate for 2 hours. The solvent was removed, the residue was separated using column chromatography (silica gel), and colorless oily tert-butyldimethylsilyl lactic acid 11-mer benzyl (22) was collected from the eluate of (hexane: diethyl ether 1: 1). Obtained at a rate of 96%.

¹H NMR(500MHz, CDCl₃)δ= 0.094 (d, 6H, J=11.8Hz), 0.90 (s, 9H), 1.45 (d, 3H, J=6.8Hz), 1.51 (d, 3H, J=7.2Hz), 1.52 (d, 3H, J=7.1Hz), 1.57 (d, 3H, J=7.1Hz), 1.58 (d, 21H, J=7.2Hz), 4.40 (q, 1H, J=6.8Hz), 5.13 (q, 1H, J=7.1Hz), 5.15 (q, 1H, J=7.2Hz), 5.16 (dd, 2H, J=12.4Hz, 18.6Hz), 5.16 (q, 7H, J=7.1Hz), 5.18 (q, 1H, J=7.3Hz), 7.31-7.38 (m, 5H)
¹³C NMR(125MHz, CDCl₃)δ= -5.32, -4.93, 16.56, 16.63, 16.74, 18.27, 21.21, 25.68, 67.98, 68.52, 68.80, 68.99, 69.27, 128.24, 128.53, 128.62, 169.61
IR(cm^-1): 2997(Ph C-H), 1756(C=O), 1454(Ph C=C)
[α]²³ _D＝ -121.71°(c=1.05 CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 0.094 (d, 6H, J = 11.8Hz), 0.90 (s, 9H), 1.45 (d, 3H, J = 6.8Hz), 1.51 (d, 3H, J = 7.2Hz), 1.52 (d, 3H, J = 7.1Hz), 1.57 (d, 3H, J = 7.1Hz), 1.58 (d, 21H, J = 7.2Hz), 4.40 (q, 1H, J = 6.8Hz ), 5.13 (q, 1H, J = 7.1Hz), 5.15 (q, 1H, J = 7.2Hz), 5.16 (dd, 2H, J = 12.4Hz, 18.6Hz), 5.16 (q, 7H, J = 7.1 Hz), 5.18 (q, 1H, J = 7.3Hz), 7.31-7.38 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = -5.32, -4.93, 16.56, 16.63, 16.74, 18.27, 21.21, 25.68, 67.98, 68.52, 68.80, 68.99, 69.27, 128.24, 128.53, 128.62, 169.61
IR (cm ^-1 ): 2997 (Ph CH), 1756 (C = O), 1454 (Ph C = C)
[α] ²³ _D = -121.71 ° (c = 1.05 CH ₂ Cl ₂ )

実施例２０：tert-ブチルジメチルシリル乳酸12量体ベンジル(23)の合成

Example 20: Synthesis of tert-butyldimethylsilyl lactic acid 12-mer benzyl (23)

窒素雰囲気下、0℃にて、tert-ブチルジメチルシリル乳酸6量体(19)0.79mmolの塩化メチレン溶液5mlを加え、乳酸6量体ベンジル(16)0.94mmolの塩化メチレン溶液5mlを加え、4-ジメチルアミノピリジン1.0当量の塩化メチレン溶液5mlを加え、N, N'-ジシクロへキシルカルボジイミド1.3当量の塩化メチレン溶液15mlを加え、5分間撹拌した。室温に戻し、2時間半撹拌した。減圧ろ過し、飽和炭酸水素ナトリウム30mlを加え。酢酸エチルで4回抽出し、無水硫酸マグネシウムで2時間乾燥した。溶媒を除去し、残渣をカラムクロマトグラフィー(シリカゲル)を用いて分離し、(ヘキサン：ジエチルエーテル1：1）溶出部より、白色固体のtert-ブチルジメチルシリル乳酸12量体ベンジル(23)を収率73％で得た。 Under a nitrogen atmosphere, at 0 ° C., 5 ml of a tert-butyldimethylsilyl lactic acid hexamer (19) 0.79 mmol methylene chloride solution was added, and a lactic acid hexamer benzyl (16) 0.94 mmol methylene chloride solution 5 ml was added. -5 ml of methylene chloride solution of 1.0 equivalent of dimethylaminopyridine was added, and 15 ml of methylene chloride solution of 1.3 equivalent of N, N'-dicyclohexylcarbodiimide was added and stirred for 5 minutes. It returned to room temperature and stirred for 2.5 hours. Filter under reduced pressure and add 30 ml of saturated sodium bicarbonate. The mixture was extracted 4 times with ethyl acetate and dried over anhydrous magnesium sulfate for 2 hours. The solvent was removed, and the residue was separated using column chromatography (silica gel). From the eluate of (hexane: diethyl ether 1: 1), tert-butyldimethylsilyl lactic acid 12-mer benzyl (23) was collected as a white solid. Obtained at a rate of 73%.

¹H NMR(500MHz, CDCl₃)δ= 0.093 (d, 6H, J=11.8Hz), 0.90 (s, 9H), 1.44 (d, 3H, J=6.7Hz), 1.52 (d, 3H, J=7.1Hz), 1.52 (d, 3H, J=7.1Hz), 1.57 (d, 6H, J=7.1Hz), 1.58 (d, 21H, J=7.2Hz), 4.39 (q, 1H, J=6.8Hz), 5.13 (q, 1H, J=7.1Hz), 5.15 (q, 1H, J=7.2Hz), 5.16 (dd, 2H, J=12.3Hz, 18.4Hz), 5.16 (q, 6H, J=7.1Hz), 5.17 (q, 1H, J=7.1Hz), 5.18 (q, 1H, J=6.8Hz), 7.31-7.38 (m, 5H)
¹³C NMR(125MHz, CDCl₃)δ= -5.33, -4.93, 16.55, 16.63, 16.73, 18.26, 21.20, 25.67, 67.21, 67.97, 68.52, 68.79, 68.98, 69.26, 128.24, 128.52, 128.61, 169.60, 173.53
IR(cm^-1): 2994(Ph C-H), 1759(C=O), 1454(Ph C=C)
[α]²² _D＝ -115.16°(c=0.95 CH₂Cl₂)
mp= 63.5℃（uncorrected） ¹ H NMR (500MHz, CDCl ₃ ) δ = 0.093 (d, 6H, J = 11.8Hz), 0.90 (s, 9H), 1.44 (d, 3H, J = 6.7Hz), 1.52 (d, 3H, J = 7.1Hz), 1.52 (d, 3H, J = 7.1Hz), 1.57 (d, 6H, J = 7.1Hz), 1.58 (d, 21H, J = 7.2Hz), 4.39 (q, 1H, J = 6.8Hz ), 5.13 (q, 1H, J = 7.1Hz), 5.15 (q, 1H, J = 7.2Hz), 5.16 (dd, 2H, J = 12.3Hz, 18.4Hz), 5.16 (q, 6H, J = 7.1 Hz), 5.17 (q, 1H, J = 7.1Hz), 5.18 (q, 1H, J = 6.8Hz), 7.31-7.38 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = -5.33, -4.93, 16.55, 16.63, 16.73, 18.26, 21.20, 25.67, 67.21, 67.97, 68.52, 68.79, 68.98, 69.26, 128.24, 128.52, 128.61, 169.60, 173.53
IR (cm ^-1 ): 2994 (Ph CH), 1759 (C = O), 1454 (Ph C = C)
[α] ²² _D = -115.16 ° (c = 0.95 CH ₂ Cl ₂ )
mp = 63.5 ℃ (uncorrected)

実施例２１：乳酸9量体ベンジル(24)の合成

Example 21: Synthesis of lactate 9-mer benzyl (24)

tert-ブチルジメチルシリル乳酸9量体ベンジル(20) 0.2940g(0.337mmol)のアセトニトリル溶液18mlにフッ化水素酸水溶液1.4mlを加え1時間撹拌した。飽和炭酸ナトリウム溶液を加え中性とし、酢酸エチルで4回、抽出し、集めた有機層を飽和食塩水で1回洗浄した。無水硫酸マグネシウムで一昼夜乾燥し、溶媒を除去し無色油状の乳酸9量体ベンジル(24)を0.2497g、収率98％で得た。 1.4 ml of an aqueous hydrofluoric acid solution was added to 18 ml of acetonitrile solution of 0.2940 g (0.337 mmol) of tert-butyldimethylsilyl lactic acid 9-mer benzyl (20) and stirred for 1 hour. Saturated sodium carbonate solution was added to neutralize, extracted four times with ethyl acetate, and the collected organic layer was washed once with saturated brine. After drying overnight with anhydrous magnesium sulfate, the solvent was removed to obtain 0.2497 g of lactic acid 9-mer benzyl (24) as colorless oil in a yield of 98%.

¹H NMR(500MHz, CDCl₃)δ= 1.49 (d, 3H, J=7.0Hz), 1.52 (d, 3H, J=7.1Hz), 1.52 (d, 3H, J=7.2Hz), 1.58 (d, 12H, J=7.3Hz), 1.60 (d, 6H, J=8.7Hz), 4.36 (q, 1H, J=7.0Hz), 5.15 (q, 1H, J=7.0Hz), 5.16 (dd, 2H, J=12.3Hz, 24.0Hz), 5.17 (q, 3H, J=7.2Hz), 5.17 (q, 1H, J=7.0Hz), 5.18 (q, 1H, J=7.0Hz), 5.19 (q, 1H, J=7.0Hz), 5.20 (q, 1H, J=7.2Hz), 7.30-7.38 (m, 5H)
¹³C NMR(125MHz, CDCl₃)δ= 16.63, 16.73, 69.26, 70.00, 128.24, 169.60
IR(cm^-1): 3512(OH), 2993(Ph C-H), 1757(C=O), 1454(Ph C=C)
[α]²⁰ _D＝ -128.50°(c=0.20 CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.49 (d, 3H, J = 7.0Hz), 1.52 (d, 3H, J = 7.1Hz), 1.52 (d, 3H, J = 7.2Hz), 1.58 (d , 12H, J = 7.3Hz), 1.60 (d, 6H, J = 8.7Hz), 4.36 (q, 1H, J = 7.0Hz), 5.15 (q, 1H, J = 7.0Hz), 5.16 (dd, 2H , J = 12.3Hz, 24.0Hz), 5.17 (q, 3H, J = 7.2Hz), 5.17 (q, 1H, J = 7.0Hz), 5.18 (q, 1H, J = 7.0Hz), 5.19 (q, 1H, J = 7.0Hz), 5.20 (q, 1H, J = 7.2Hz), 7.30-7.38 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = 16.63, 16.73, 69.26, 70.00, 128.24, 169.60
IR (cm ^-1 ): 3512 (OH), 2993 (Ph CH), 1757 (C = O), 1454 (Ph C = C)
[α] ²⁰ _D = -128.50 ° (c = 0.20 CH ₂ Cl ₂ )

実施例２２：乳酸10量体ベンジル(25)の合成

Example 22: Synthesis of lactic acid decameric benzyl (25)

tert-ブチルジメチルシリル乳酸10量体ベンジル(21) 0.9126g(0.9677mmol)のアセトニトリル溶液51mlにフッ化水素酸水溶液3.9mlを加え3時間撹拌した。飽和炭酸ナトリウム溶液を加え中性とし、酢酸エチルで4回、抽出し、集めた有機層を飽和食塩水で1回洗浄した。無水硫酸マグネシウムで一昼夜乾燥し、溶媒を除去し無色油状の乳酸10量体ベンジル(25)を0.7950g、収率99％で得た。 To 51 ml of acetonitrile solution of 0.9126 g (0.9677 mmol) of tert-butyldimethylsilyl lactic acid 10-mer benzyl (21), 3.9 ml of aqueous hydrofluoric acid solution was added and stirred for 3 hours. Saturated sodium carbonate solution was added to neutralize, extracted four times with ethyl acetate, and the collected organic layer was washed once with saturated brine. After drying overnight with anhydrous magnesium sulfate, the solvent was removed to obtain 0.7950 g of lactic acid 10-mer benzyl (25) as colorless oil in a yield of 99%.

¹H NMR(500MHz, CDCl₃)δ= 1.49 (d, 3H, J=6.9Hz), 1.52 (d, 3H, J=7.1Hz), 1.52 (d, 3H, J=7.1Hz), 1.58 (d, 12H, J=7.2Hz), 1.59 (d, 3H, J=7.3Hz), 1.60 (d, 3H, J=8.7Hz), 1.60 (d, 3H, J=7.4 Hz), 4.36 (dq, 1H, J=6.9Hz, J=6.9Hz), 5.15 (q, 1H, J=7.0Hz), 5.16 (dd, 2H, J=12.3Hz, 17.4Hz), 5.16 (q, 1H, J=7.1Hz), 5.16 (q, 1H, J=7.1Hz), 5.17 (q, 1H, J=7.5Hz), 5.18 (q, 1H, J=7.1Hz), 5.19 (q, 1H, J=7.2Hz), 5.21 (q, 1H, J=7.2Hz), 7.31-7.34 (m, 5H)
¹³C NMR(125MHz, CDCl₃)δ= 16.63, 16.74, 69.00, 128.25, 128.62, 169.60
IR(cm^-1): 3508(OH), 2995(Ph C-H), 1765(C=O), 1454(Ph C=C) ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.49 (d, 3H, J = 6.9Hz), 1.52 (d, 3H, J = 7.1Hz), 1.52 (d, 3H, J = 7.1Hz), 1.58 (d , 12H, J = 7.2Hz), 1.59 (d, 3H, J = 7.3Hz), 1.60 (d, 3H, J = 8.7Hz), 1.60 (d, 3H, J = 7.4 Hz), 4.36 (dq, 1H , J = 6.9Hz, J = 6.9Hz), 5.15 (q, 1H, J = 7.0Hz), 5.16 (dd, 2H, J = 12.3Hz, 17.4Hz), 5.16 (q, 1H, J = 7.1Hz) , 5.16 (q, 1H, J = 7.1Hz), 5.17 (q, 1H, J = 7.5Hz), 5.18 (q, 1H, J = 7.1Hz), 5.19 (q, 1H, J = 7.2Hz), 5.21 (q, 1H, J = 7.2Hz), 7.31-7.34 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = 16.63, 16.74, 69.00, 128.25, 128.62, 169.60
IR (cm ^-1 ): 3508 (OH), 2995 (Ph CH), 1765 (C = O), 1454 (Ph C = C)

実施例２３：乳酸11量体ベンジル(26)の合成

Example 23: Synthesis of lactic acid 11-mer benzyl (26)

tert-ブチルジメチルシリル乳酸11量体ベンジル(22) 0.4145g(0.408mmol)のアセトニトリル溶液22mlにフッ化水素酸水溶液1.6mlを加え2時間撹拌した。飽和炭酸ナトリウム溶液を加え中性とし、酢酸エチルで4回、抽出し、集めた有機層を飽和食塩水で1回洗浄した。無水硫酸マグネシウムで一昼夜乾燥し、溶媒を除去し無色油状の乳酸11量体ベンジル(26)を0.3514g、収率96％で得た。 1.6 ml of hydrofluoric acid aqueous solution was added to 22 ml of acetonitrile solution of 0.4145 g (0.408 mmol) of tert-butyldimethylsilyl lactic acid 11-mer benzyl (22) and stirred for 2 hours. Saturated sodium carbonate solution was added to neutralize, extracted four times with ethyl acetate, and the collected organic layer was washed once with saturated brine. It was dried overnight with anhydrous magnesium sulfate, and the solvent was removed to obtain 0.3514 g of a colorless oily lactic acid 11-mer benzyl (26) in a yield of 96%.

¹H NMR(500MHz, CDCl₃)δ= 1.49 (d, 3H, J=7.0Hz), 1.52 (d, 3H, J=7.1Hz), 1.52 (d, 3H, J=7.1Hz), 1.58 (d, 15H, J=7.1Hz), 1.59 (d, 3H, J=7.4Hz), 1.60 (d, 3H, J=8.9Hz), 1.60 (d, 3H, J=7.4Hz), 2.64 (d, 1H, J=6.1Hz), 4.36 (q, 1H, J=6.7Hz), 5.15 (q, 1H, J=7.2Hz), 5.16 (dd, 2H, J=12.6Hz, 18.9Hz), 5.16 (q, 4H, J=7.1Hz), 5.17 (q, 1H, J=6.7Hz), 5.18 (q, 1H, J=7.1Hz), 5.18 (q, 1H, J=7.2Hz), 5.18 (q, 1H, J=7.0Hz), 5.22 (q, 1H, J=7.1Hz), 7.31-7.38 (m, 5H)
¹³C NMR(125MHz, CDCl₃)δ= 16.63, 16.74, 20.53, 66.69, 67.22, 69.00, 69.10, 69.27, 128.25, 128.54, 128.62, 169.61
IR(cm^-1): 3512(OH), 2995(Ph C-H), 1757(C=O), 1454(Ph C=C)
[α]²³ _D＝ -110.75°(c=0.93 CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.49 (d, 3H, J = 7.0Hz), 1.52 (d, 3H, J = 7.1Hz), 1.52 (d, 3H, J = 7.1Hz), 1.58 (d , 15H, J = 7.1Hz), 1.59 (d, 3H, J = 7.4Hz), 1.60 (d, 3H, J = 8.9Hz), 1.60 (d, 3H, J = 7.4Hz), 2.64 (d, 1H , J = 6.1Hz), 4.36 (q, 1H, J = 6.7Hz), 5.15 (q, 1H, J = 7.2Hz), 5.16 (dd, 2H, J = 12.6Hz, 18.9Hz), 5.16 (q, 4H, J = 7.1Hz), 5.17 (q, 1H, J = 6.7Hz), 5.18 (q, 1H, J = 7.1Hz), 5.18 (q, 1H, J = 7.2Hz), 5.18 (q, 1H, J = 7.0Hz), 5.22 (q, 1H, J = 7.1Hz), 7.31-7.38 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = 16.63, 16.74, 20.53, 66.69, 67.22, 69.00, 69.10, 69.27, 128.25, 128.54, 128.62, 169.61
IR (cm ^-1 ): 3512 (OH), 2995 (Ph CH), 1757 (C = O), 1454 (Ph C = C)
[α] ²³ _D = -110.75 ° (c = 0.93 CH ₂ Cl ₂ )

実施例２４：乳酸12量体ベンジル(27)の合成

Example 24: Synthesis of lactic acid 12-mer benzyl (27)

tert-ブチルジメチルシリル乳酸12量体ベンジル(23) 0.4444g(0.4088mmol)のアセトニトリル溶液22mlにフッ化水素酸水溶液1.6mlを加え1時間撹拌した。飽和炭酸ナトリウム溶液を加え中性とし、酢酸エチルで4回、抽出し、集めた有機層を飽和食塩水で1回洗浄した。無水硫酸マグネシウムで一昼夜乾燥し、溶媒を除去し白色固体の乳酸12量体ベンジル (27)を0.3777g、収率95％で得た。 1.6 ml of hydrofluoric acid aqueous solution was added to 22 ml of acetonitrile solution of 0.4444 g (0.4088 mmol) of tert-butyldimethylsilyl lactic acid 12-mer benzyl (23) and stirred for 1 hour. Saturated sodium carbonate solution was added to neutralize, extracted four times with ethyl acetate, and the collected organic layer was washed once with saturated brine. It was dried overnight with anhydrous magnesium sulfate, and the solvent was removed to obtain 0.3777 g of white solid lactic acid 12-mer benzyl (27) in a yield of 95%.

¹H NMR(500MHz, CDCl₃)δ= 1.49 (d, 3H, J=7.0Hz), 1.52 (d, 3H, J=7.1Hz), 1.52 (d, 3H, J=7.2Hz), 1.58 (d, 18H, J=7.1Hz), 1.59 (d, 3H, J=6.9Hz), 1.60 (d, 6H, J=7.4Hz), 4.36 (dq, 1H, J=6.5Hz, 6.5Hz), 5.15 (q, 1H, J=7.1Hz), 5.16 (dd, 2H, J=12.6Hz, 18.7Hz), 5.16 (q, 5H, J=7.1Hz), 5.17 (q, 1H, J=7.1Hz), 5.18 (q, 1H, J=7.0Hz), 5.18 (q, 1H, J=7.0Hz), 5.19 (q, 1H, J=7.0Hz), 5.22 (q, 1H, J=7.1Hz), 7.31-7.38 (m, 5H)
¹³C NMR(125MHz, CDCl₃)δ= 16.63, 16.74, 69.00, 128.24, 128.61, 169.60
IR(cm^-1): 3512(OH), 2995(Ph C-H), 1757(C=O), 1454(Ph C=C)
[α]²⁰ _D＝ -125.21°(c=0.71 CH₂Cl₂)
mp= 48.0-54.5℃（uncorrected） ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.49 (d, 3H, J = 7.0Hz), 1.52 (d, 3H, J = 7.1Hz), 1.52 (d, 3H, J = 7.2Hz), 1.58 (d , 18H, J = 7.1Hz), 1.59 (d, 3H, J = 6.9Hz), 1.60 (d, 6H, J = 7.4Hz), 4.36 (dq, 1H, J = 6.5Hz, 6.5Hz), 5.15 ( q, 1H, J = 7.1Hz), 5.16 (dd, 2H, J = 12.6Hz, 18.7Hz), 5.16 (q, 5H, J = 7.1Hz), 5.17 (q, 1H, J = 7.1Hz), 5.18 (q, 1H, J = 7.0Hz), 5.18 (q, 1H, J = 7.0Hz), 5.19 (q, 1H, J = 7.0Hz), 5.22 (q, 1H, J = 7.1Hz), 7.31-7.38 (m, 5H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = 16.63, 16.74, 69.00, 128.24, 128.61, 169.60
IR (cm ^-1 ): 3512 (OH), 2995 (Ph CH), 1757 (C = O), 1454 (Ph C = C)
[α] ²⁰ _D = -125.21 ° (c = 0.71 CH ₂ Cl ₂ )
mp = 48.0-54.5 ℃ (uncorrected)

実施例２５：遊離乳酸7量体(28)の合成

Example 25: Synthesis of free lactic acid heptamer (28)

水素雰囲気下、0.215mmolの17エタノール溶液10mlに、10％Pd/C 0.0120g加え、室温で30分撹拌した。溶媒を除去し、無色油状の遊離乳酸7量体(28)をほぼ定量的に得た。 Under hydrogen atmosphere, 0.0120 g of 10% Pd / C was added to 10 ml of 0.215 mmol of 17 ethanol solution, and the mixture was stirred at room temperature for 30 minutes. The solvent was removed, and a colorless oily free lactic acid heptamer (28) was obtained almost quantitatively.

¹H NMR(500MHz, CDCl₃)δ= 1.49 (d, 3H, J=7.0Hz), 1.56 (d, 3H, J=7.1Hz), 1.58 (d, 3H, J=7.0Hz), 1.59 (d, 6H, J=7.1Hz), 1.60 (d, 3H, J=7.0Hz), 1.60 (d, 3H, J=7.2Hz), 4.36 (q, 1H, J=6.9Hz), 5.18 (q, 1H, J=7.2Hz), 5.18 (q, 2H, J=7.1Hz), 5.19 (q, 2H, J=7.1Hz), 5.22 (q, 1H, J=7.1Hz)
¹³C NMR(125MHz, CDCl₃)δ= 16.60, 16.68, 16.75, 20.51, 66.74, 68.71, 69.04, 69.14, 169.63
IR(cm^-1): 3511(OH), 1747(C=O) ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.49 (d, 3H, J = 7.0Hz), 1.56 (d, 3H, J = 7.1Hz), 1.58 (d, 3H, J = 7.0Hz), 1.59 (d , 6H, J = 7.1Hz), 1.60 (d, 3H, J = 7.0Hz), 1.60 (d, 3H, J = 7.2Hz), 4.36 (q, 1H, J = 6.9Hz), 5.18 (q, 1H , J = 7.2Hz), 5.18 (q, 2H, J = 7.1Hz), 5.19 (q, 2H, J = 7.1Hz), 5.22 (q, 1H, J = 7.1Hz)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = 16.60, 16.68, 16.75, 20.51, 66.74, 68.71, 69.04, 69.14, 169.63
IR (cm ^-1 ): 3511 (OH), 1747 (C = O)

実施例２６：遊離乳酸8量体(29)の合成

Example 26: Synthesis of free lactic acid octamer (29)

水素雰囲気下、4.99mmolの18エタノール溶液10mlに、10％Pd/C 0.1g加え、室温で30分撹拌した。溶媒を除去し、無色油状の遊離乳酸8量体(29)を0.2765g、収率93％で得た。 Under a hydrogen atmosphere, 0.1 g of 10% Pd / C was added to 10 ml of a 4.99 mmol 18 ethanol solution, and the mixture was stirred at room temperature for 30 minutes. The solvent was removed to obtain 0.2765 g of a colorless oily free lactic acid octamer (29) in a yield of 93%.

¹H NMR(500MHz, CDCl₃)δ= 1.49 (d, 3H, J=6.9Hz), 1.55 (d, 3H, J=7.1Hz), 1.58 (d, 12H, J=6.0Hz), 1.59 (d, 3H, J=7.1Hz), 1.60 (d, 3H, J=6.9Hz), 4.37 (q, 1H, J=6.9Hz), 5.16 (q, 1H, J=7.1Hz), 5.18 (q, 1H, J=7.2Hz), 5.18 (q, 2H, J=7.0Hz), 5.19 (q, 2H, J=8.4Hz), 5.21 (q, 1H, J=7.1Hz), 5.22 (q, 1H, J=7.1Hz) ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.49 (d, 3H, J = 6.9Hz), 1.55 (d, 3H, J = 7.1Hz), 1.58 (d, 12H, J = 6.0Hz), 1.59 (d , 3H, J = 7.1Hz), 1.60 (d, 3H, J = 6.9Hz), 4.37 (q, 1H, J = 6.9Hz), 5.16 (q, 1H, J = 7.1Hz), 5.18 (q, 1H , J = 7.2Hz), 5.18 (q, 2H, J = 7.0Hz), 5.19 (q, 2H, J = 8.4Hz), 5.21 (q, 1H, J = 7.1Hz), 5.22 (q, 1H, J = 7.1Hz)

実施例２７：遊離乳酸9量体(24)の合成

Example 27: Synthesis of free lactic acid 9-mer (24)

水素雰囲気下、0.1836mmolの24エタノール溶液10mlに、10％Pd/C 0.0371g加え、室温で30分撹拌した。溶媒を除去し、無色油状の遊離乳酸9量体(30)を0.1619mmol、収率88％で得た。 Under hydrogen atmosphere, 0.0371 g of 10% Pd / C was added to 10 ml of 0.1836 mmol of 24 ethanol solution, and the mixture was stirred at room temperature for 30 minutes. The solvent was removed to obtain 0.1619 mmol of a colorless oily free lactic acid 9-mer (30) in a yield of 88%.

¹H NMR(500MHz, CDCl₃)δ= 1.49 (d, 3H, J=6.9Hz), 1.55 (d, 3H, J=7.2Hz), 1.57 (d, 3H, J=7.1Hz), 1.58 (d, 6H, J=7.1Hz), 1.58 (d, 6H, J=6.9Hz), 1.59 (d, 3H, J=7.0Hz), 1.60 (d, 3H, J=7.1Hz), 4.36 (q, 1H, J=6.9Hz), 5.15 (q, 1H, J=7.1Hz), 5.16 (q, 1H, J=7.2Hz), 5.17 (q, 2H, J=7.1Hz), 5.17 (q, 1H, J=7.2Hz), 5.17 (q, 1H, J=7.1Hz), 5.18 (q, 1H, J=7.1Hz), 5.21 (q, 1H, J=7.1Hz)
¹³C NMR(125MHz, CDCl₃)δ= 16.56, 16.62, 16.65, 16.72, 20.49, 66.69, 69.01, 69.11, 169.60, 175.18 ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.49 (d, 3H, J = 6.9Hz), 1.55 (d, 3H, J = 7.2Hz), 1.57 (d, 3H, J = 7.1Hz), 1.58 (d , 6H, J = 7.1Hz), 1.58 (d, 6H, J = 6.9Hz), 1.59 (d, 3H, J = 7.0Hz), 1.60 (d, 3H, J = 7.1Hz), 4.36 (q, 1H , J = 6.9Hz), 5.15 (q, 1H, J = 7.1Hz), 5.16 (q, 1H, J = 7.2Hz), 5.17 (q, 2H, J = 7.1Hz), 5.17 (q, 1H, J = 7.2Hz), 5.17 (q, 1H, J = 7.1Hz), 5.18 (q, 1H, J = 7.1Hz), 5.21 (q, 1H, J = 7.1Hz)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = 16.56, 16.62, 16.65, 16.72, 20.49, 66.69, 69.01, 69.11, 169.60, 175.18

実施例２８：遊離乳酸10量体(31)の合成

Example 28: Synthesis of free lactic acid decamer (31)

水素雰囲気下、0.199mmolの25エタノール溶液5mlに、10％Pd/C 0.0118g加え、室温で30分撹拌した。溶媒を除去し、無色油状の遊離乳酸10量体(31)を0.185mmol、収率93％で得た。 Under a hydrogen atmosphere, 0.0118 g of 10% Pd / C was added to 5 ml of a 0.199 mmol 25 ethanol solution, and the mixture was stirred at room temperature for 30 minutes. The solvent was removed to obtain 0.185 mmol of a colorless oily free lactic acid decamer (31) in a yield of 93%.

¹H NMR(500MHz, CDCl₃)δ= 1.49 (d, 3H, J=7.0Hz), 1.56 (d, 3H, J=7.2Hz), 1.58 (d, 6H, J=7.4Hz), 1.59 (d, 6H, J=7.1Hz), 1.60 (d, 6H, J=7.5Hz), 1.60 (d, 6H, J=7.2Hz), 4.36 (q, 1H, J=7.0Hz), 5.17 (q, 5H, J=7.1Hz), 5.17 (q, 3H, J=7.2Hz)
¹³C NMR(125MHz, CDCl₃)δ= 16.63, 69.00, 169.60
IR(cm^-1): 3514(OH), 1741(C=O) ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.49 (d, 3H, J = 7.0Hz), 1.56 (d, 3H, J = 7.2Hz), 1.58 (d, 6H, J = 7.4Hz), 1.59 (d , 6H, J = 7.1Hz), 1.60 (d, 6H, J = 7.5Hz), 1.60 (d, 6H, J = 7.2Hz), 4.36 (q, 1H, J = 7.0Hz), 5.17 (q, 5H , J = 7.1Hz), 5.17 (q, 3H, J = 7.2Hz)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = 16.63, 69.00, 169.60
IR (cm ^-1 ): 3514 (OH), 1741 (C = O)

実施例２９：遊離乳酸11量体(32)の合成

Example 29: Synthesis of free lactic acid 11-mer (32)

水素雰囲気下、0.2123mmolの26エタノール溶液5mlに、10％Pd/C 0.0270g加え、室温で1時間撹拌した。溶媒を除去し、無色油状の遊離乳酸11量体(32)を0.1966mmol、収率93％で得た。 Under hydrogen atmosphere, 0.0270 g of 10% Pd / C was added to 5 ml of 0.2123 mmol of 26 ethanol solution, and the mixture was stirred at room temperature for 1 hour. The solvent was removed to obtain a colorless oily free lactic acid 11mer (32) in 0.1966 mmol in a yield of 93%.

¹H NMR(500MHz, CDCl₃)δ= 1.49 (d, 3H, J=7.0Hz), 1.56 (d, 3H, J=7.1Hz), 1.58 (d, 21H, J=7.3Hz), 1.60 (d, 6H, J=8.2Hz), 4.36 (q, 1H, J=7.0Hz), 5.15 (q, 1H, J=7.2Hz), 5.16 (q, 1H, J=7.1Hz), 5.17 (q, 2H, J=7.1Hz), 5.17 (q, 2H, J=6.9Hz), 5.18 (q, 1H, J=6.9Hz), 5.18 (q, 2H, J=6.8Hz), 5.21 (q, 1H, J=7.3Hz)
¹³C NMR(125MHz, CDCl₃)δ= 16.63, 69.00, 169.60
IR(cm^-1): 3566(OH), 1755(C=O)
[α]²⁰ _D＝ -153.16°(c=0.23 CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.49 (d, 3H, J = 7.0Hz), 1.56 (d, 3H, J = 7.1Hz), 1.58 (d, 21H, J = 7.3Hz), 1.60 (d , 6H, J = 8.2Hz), 4.36 (q, 1H, J = 7.0Hz), 5.15 (q, 1H, J = 7.2Hz), 5.16 (q, 1H, J = 7.1Hz), 5.17 (q, 2H , J = 7.1Hz), 5.17 (q, 2H, J = 6.9Hz), 5.18 (q, 1H, J = 6.9Hz), 5.18 (q, 2H, J = 6.8Hz), 5.21 (q, 1H, J = 7.3Hz)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = 16.63, 69.00, 169.60
IR (cm ^-1 ): 3566 (OH), 1755 (C = O)
[α] ²⁰ _D = -153.16 ° (c = 0.23 CH ₂ Cl ₂ )

実施例３０：遊離乳酸12量体(33)の合成

Example 30: Synthesis of free lactic acid 12-mer (33)

水素雰囲気下、0.2039mmolの27エタノール溶液5mlに、10％Pd/C 0.0200g加え、室温で30分撹拌した。溶媒を除去し、無色油状の遊離乳酸12量体(33)を0.1855mmol、収率91％で得た。 Under hydrogen atmosphere, 0.0200 g of 10% Pd / C was added to 5 ml of 0.2039 mmol of 27 ethanol solution, and stirred at room temperature for 30 minutes. The solvent was removed to obtain a colorless oily free lactic acid 12mer (33) in 0.1855 mmol in a yield of 91%.

¹H NMR(500MHz, CDCl₃)δ= 1.49 (d, 3H, J=7.0Hz), 1.56 (d, 3H, J=7.2Hz), 1.58 (d, 21H, J=7.2Hz), 1.58 (d, 6H, J=7.2Hz), 1.59 (d, 3H, J=8.3Hz), 1.60 (d, 3H, J=7.2Hz), 4.36 (q, 1H, J=7.0Hz), 5.15 (q, 1H, J=7.1Hz), 5.17 (q, 4H, J=7.1Hz), 5.17 (q, 2H, J=7.1Hz), 5.18 (q, 2H, J=7.0Hz), 5.18 (q, 1H, J=6.4Hz), 5.19 (q, 1H, J=7.1Hz), 5.21 (q, 1H, J=7.2Hz)
¹³C NMR(125MHz, CDCl₃)δ= 16.63, 69.00, 169.60
IR(cm^-1): 3525(OH), 1757(C=O)
[α]²⁰ _D＝ -153.91°(c=0.23 CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.49 (d, 3H, J = 7.0Hz), 1.56 (d, 3H, J = 7.2Hz), 1.58 (d, 21H, J = 7.2Hz), 1.58 (d , 6H, J = 7.2Hz), 1.59 (d, 3H, J = 8.3Hz), 1.60 (d, 3H, J = 7.2Hz), 4.36 (q, 1H, J = 7.0Hz), 5.15 (q, 1H , J = 7.1Hz), 5.17 (q, 4H, J = 7.1Hz), 5.17 (q, 2H, J = 7.1Hz), 5.18 (q, 2H, J = 7.0Hz), 5.18 (q, 1H, J = 6.4Hz), 5.19 (q, 1H, J = 7.1Hz), 5.21 (q, 1H, J = 7.2Hz)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = 16.63, 69.00, 169.60
IR (cm ^-1 ): 3525 (OH), 1757 (C = O)
[α] ²⁰ _D = -153.91 ° (c = 0.23 CH ₂ Cl ₂ )

実施例３１：遊離の鎖状乳酸7量体(28)の環化反応合成(1.8mM, 室温, DIPEA, 2,4,6-TCBCl, ベンゼン)

Example 31: Cyclization synthesis of free chain lactic acid heptamer (28) (1.8 mM, room temperature, DIPEA, 2,4,6-TCBCl, benzene)

アルゴン雰囲気下、室温で、28 0.3500mmolの塩化メチレン溶液4mlにジイソプロピルエチルアミン(3eq)のベンゼン溶液48.6mlを加え、塩化2, 4, 6-トリクロロベンゾイル(2eq)のベンゼン溶液48.6mlを加え2時間撹拌した。これを4等量のDMAPの97.2mlベンゼン溶液に16時間かけて加え1時間撹拌した。溶媒を除去し、残渣をカラムクロマトグラフィー(シリカゲル)を用いて分離し、ベンゼン：酢酸エチル(2：1)溶出部より環状乳酸7量体(39)を0.1112g(0.2210mmol, 62％)得た。 Add 48.6 ml of benzene solution of diisopropylethylamine (3 eq) to 4 ml of 28 0.3500 mmol methylene chloride at room temperature under argon atmosphere, add 48.6 ml of benzene solution of 2,4,6-trichlorobenzoyl chloride (2 eq) for 2 hours Stir. This was added to 4 equivalents of a 97.2 ml benzene solution of DMAP over 16 hours and stirred for 1 hour. The solvent was removed, and the residue was separated using column chromatography (silica gel). From the eluate of benzene: ethyl acetate (2: 1), 0.1112 g (0.2210 mmol, 62%) of cyclic lactic acid heptamer (39) was obtained. It was.

¹H NMR(500MHz, CDCl₃)δ= 1.55 (d, J=7.1, 21H), 5.23 (q, J=7.1, 7H)
¹³C NMR(125MHz, CDCl₃)δ= 16.61, 69.21, 168.57
IR(cm^-1): 1749(C=O)
[α]²² _D =-100.7060(c=0.425, CH₂Cl₂) ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.55 (d, J = 7.1, 21H), 5.23 (q, J = 7.1, 7H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = 16.61, 69.21, 168.57
IR (cm ^-1 ): 1749 (C = O)
[α] ²² _D = -100.7060 (c = 0.425, CH ₂ Cl ₂ )

実施例３２：遊離の鎖状乳酸8量体(29)の環化反応合成(1.8mM, 室温, DIPEA, 2,4,6-TCBCl, ベンゼン)

Example 32: Cyclization synthesis of free chain lactic acid octamer (29) (1.8 mM, room temperature, DIPEA, 2,4,6-TCBCl, benzene)

窒素雰囲気下、室温で、0.465mmolの29の4ml塩化メチレン溶液に3等量のジイソプロピルエチルアミンの65mlベンゼン溶液を加え、2等量の塩化2, 4, 6-トリクロロベンゾイルの65mlベンゼン溶液を加え2時間撹拌した。これを4等量のDMAPの130mlベンゼン溶液に16時間かけて加え1時間撹拌した。溶媒を除去し、残渣をカラムクロマトグラフィーにて分離し、ベンゼン：酢酸エチル(2：1)溶出部より環状乳酸8n量体を0.1088g(0.189mmol, 60％)得、ESI-MS(ポジティブモード)により測定したところ、分子内脱水縮合した環状乳酸8量体と2倍体である環状乳酸16量体が生成比91：9で得たことを確認した。 Add 3 equivalents of 65 ml benzene solution of diisopropylethylamine to 0.465 mmol 29 4 ml methylene chloride solution at room temperature under nitrogen atmosphere and add 2 equivalents of 65 ml benzene solution of 2,4,6-trichlorobenzoyl chloride 2 Stir for hours. This was added to 4 equivalents of a 130 ml benzene solution of DMAP over 16 hours and stirred for 1 hour. The solvent was removed and the residue was separated by column chromatography. 0.1088 g (0.189 mmol, 60%) of cyclic lactic acid 8n was obtained from the eluate of benzene: ethyl acetate (2: 1), and ESI-MS (positive mode) ), It was confirmed that an intramolecular dehydration-condensed cyclic lactic acid octamer and a diploid cyclic lactic acid 16mer were obtained at a production ratio of 91: 9.

¹H NMR(500MHz, CDCl₃)δ= 1.55 (d, J=7.1, 21H), 5.28 (q, J=7.1, 7H)
¹³C NMR(125MHz, CDCl₃)δ= 16.70, 69.25, 168.81 ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.55 (d, J = 7.1, 21H), 5.28 (q, J = 7.1, 7H)
¹³ C NMR (125 MHz, CDCl ₃ ) δ = 16.70, 69.25, 168.81

実施例３３：遊離の鎖状乳酸9量体(30)の環化反応合成(1.8mM, 室温, DIPEA, 2,4,6-TCBCl, ベンゼン)

Example 33: Cyclization synthesis of free chain lactic acid 9-mer (30) (1.8 mM, room temperature, DIPEA, 2,4,6-TCBCl, benzene)

アルゴン囲気下、室温で、30 0.1215mmolの塩化メチレン溶液2mlにジイソプロピルエチルアミン(3eq)のベンゼン溶液16.85mlを加え、塩化2, 4, 6-トリクロロベンゾイル(2eq)のベンゼン溶液16.85mlを加え2時間撹拌した。これを4等量のDMAPの50mlベンゼン溶液に16時間かけて加え2時間撹拌した。溶媒を除去し、残渣をカラムクロマトグラフィー(シリカゲル)を用いて分離し、ベンゼン：酢酸エチル(15：4)溶出部より環状9n乳酸量体の混合物を0.0352g(0.0543mmol, 45％)得、¹H-NMRにおけるメチンプロトンのケミカルシフトより分子内脱水縮合した環状乳酸9量体が93％の割合で得たことを確認した。 At room temperature under an argon atmosphere, add 16.85 ml of a benzene solution of diisopropylethylamine (3 eq) to 2 ml of 30 0.1215 mmol of methylene chloride, and then add 16.85 ml of a benzene solution of 2,4,6-trichlorobenzoyl chloride (2 eq) for 2 hours. Stir. This was added to a solution of 4 equivalents of DMAP in 50 ml of benzene over 16 hours and stirred for 2 hours. The solvent was removed, and the residue was separated using column chromatography (silica gel). From the eluate of benzene: ethyl acetate (15: 4), 0.0352 g (0.0543 mmol, 45%) of a cyclic 9n lactic acid monomer mixture was obtained, ^From the chemical shift of methine proton in ¹ H-NMR, it was confirmed that 93% of cyclic lactic acid 9-mer obtained by intramolecular dehydration condensation was obtained.

¹H NMR(500MHz, CDCl₃)δ(ppm)= 1.54 (d, J=7.1Hz), 1.56 (d, J=7.4Hz), 5.19 (q, J=7.0Hz), 5.23 (q, J=7.0Hz) ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm) = 1.54 (d, J = 7.1 Hz), 1.56 (d, J = 7.4 Hz), 5.19 (q, J = 7.0 Hz), 5.23 (q, J = 7.0Hz)

実施例３４：遊離の鎖状乳酸10量体(31)の環化反応合成(1.8mM, 室温, DIPEA, 2,4,6-TCBCl, ベンゼン)

Example 34: Cyclization synthesis of free chain lactic acid decamer (31) (1.8 mM, room temperature, DIPEA, 2,4,6-TCBCl, benzene)

窒素雰囲気下、室温で、31 0.1750mmolの塩化メチレン溶液4mlにジイソプロピルエチルアミン(3eq)のベンゼン溶液24.3mlを加え、塩化2, 4, 6-トリクロロベンゾイル(2eq)のベンゼン溶液24.3mlを加え2時間撹拌した。これを4等量のDMAPの48.6mlベンゼン溶液に16時間かけて加え2時間撹拌した。溶媒を除去し、残渣をカラムクロマトグラフィー(シリカゲル)を用いて分離し、ベンゼン：酢酸エチル(15：4)溶出部より環状10n乳酸量体の混合物を0.0863g(0.118mmol, 68％)得、¹H-NMRにおけるメチンプロトンのケミカルシフトより分子内脱水縮合した環状乳酸10量体が76％の割合で得られること確認した。 At room temperature under nitrogen atmosphere, add 24.3 ml of benzene solution of diisopropylethylamine (3 eq) to 4 ml of 31 0.1750 mmol methylene chloride solution, add 24.3 ml of benzene solution of 2,4,6-trichlorobenzoyl chloride (2 eq) for 2 hours Stir. This was added to a 48.6 ml benzene solution of 4 equivalents of DMAP over 16 hours and stirred for 2 hours. The solvent was removed, the residue was separated using column chromatography (silica gel), and 0.0863 g (0.118 mmol, 68%) of a cyclic 10n lactic acid monomer mixture was obtained from the eluate of benzene: ethyl acetate (15: 4). ^From the chemical shift of methine proton in ¹ H-NMR, it was confirmed that a cyclic lactic acid decamer obtained by intramolecular dehydration condensation was obtained at a ratio of 76%.

¹H NMR(500MHz, CDCl₃)δ= 1.52 (d, J=7.2Hz), 1.55 (d, J=7.1Hz), 1.57 (d, J=7.1Hz), 5.19 (q, J=7.1Hz), 5.22 (q, J=7.1Hz), 5.25 (q, J=7.0Hz) ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.52 (d, J = 7.2Hz), 1.55 (d, J = 7.1Hz), 1.57 (d, J = 7.1Hz), 5.19 (q, J = 7.1Hz) , 5.22 (q, J = 7.1Hz), 5.25 (q, J = 7.0Hz)

実施例３５：遊離の鎖状乳酸11量体(32)の環化反応合成(1.8mM, 室温, DIPEA, 2,4,6-TCBCl, ベンゼン)

Example 35: Cyclization synthesis of free chain lactic acid 11-mer (32) (1.8 mM, room temperature, DIPEA, 2,4,6-TCBCl, benzene)

アルゴン囲気下、室温で、32 0.1798mmolの塩化メチレン溶液3mlにジイソプロピルエチルアミン(3eq)のベンゼン溶液25mlを加え、塩化2, 4, 6-トリクロロベンゾイル(2eq)のベンゼン溶液25mlを加え2時間撹拌した。これを4等量のDMAPの50mlベンゼン溶液に16時間かけて加え2時間撹拌した。溶媒を除去し、残渣をカラムクロマトグラフィー(シリカゲル)を用いて分離し、ベンゼン：酢酸エチル(4.25：1)溶出部より環状11n乳酸量体の混合物を0.0862g(0.1087mmol, 61％)で得た。 At room temperature under an argon atmosphere, 25 ml of a benzene solution of diisopropylethylamine (3 eq) was added to 3 ml of 32 0.1798 mmol of methylene chloride, and 25 ml of a benzene solution of 2,4,6-trichlorobenzoyl chloride (2 eq) was added and stirred for 2 hours. . This was added to a solution of 4 equivalents of DMAP in 50 ml of benzene over 16 hours and stirred for 2 hours. The solvent was removed, and the residue was separated using column chromatography (silica gel). A cyclic 11n lactic acid monomer mixture was obtained as 0.0862 g (0.1087 mmol, 61%) from the eluate of benzene: ethyl acetate (4.25: 1). It was.

¹H NMR(500MHz, CDCl₃)δ= 1.52 (d, J=7.2Hz), 1.55 (d, J=7.1Hz), 1.57 (d, J=7.2Hz), 1.57 (d, J=7.1Hz), 1.59 (d, J=7.1Hz), 5.15 (q, J=7.1Hz), 5.16 (q, J=6.9Hz), 5.17 (q, J=7.2Hz), 5.21 (q, J=7.1Hz), 5.23 (q, J=7.1Hz) ¹ H NMR (500MHz, CDCl ₃ ) δ = 1.52 (d, J = 7.2Hz), 1.55 (d, J = 7.1Hz), 1.57 (d, J = 7.2Hz), 1.57 (d, J = 7.1Hz) , 1.59 (d, J = 7.1Hz), 5.15 (q, J = 7.1Hz), 5.16 (q, J = 6.9Hz), 5.17 (q, J = 7.2Hz), 5.21 (q, J = 7.1Hz) , 5.23 (q, J = 7.1Hz)

実施例３６：遊離の鎖状乳酸12量体(33)の環化反応合成(1.8mM, 室温, DIPEA, 2,4,6-TCBCl, ベンゼン)

Example 36: Cyclization synthesis of free chain lactic acid 12-mer (33) (1.8 mM, room temperature, DIPEA, 2,4,6-TCBCl, benzene)

アルゴン雰囲気下、室温で、33 0.15825mmolの塩化メチレン溶液2mlにジイソプロピルエチルアミン(3eq)のベンゼン溶液21.95mlを加え、塩化2, 4, 6-トリクロロベンゾイル(2eq)のベンゼン溶液21.95mlを加え2時間撹拌した。これを4等量のDMAPの43.9mlベンゼン溶液に16時間かけて加え2時間撹拌した。溶媒を除去し、残渣をカラムクロマトグラフィー(シリカゲル)を用いて分離し、ベンゼン：酢酸エチル(4.25：1)溶出部より環状12n乳酸量体の混合物を0.0728g(0.08419mmol, 53％)得、¹H-NMRにおけるメチンプロトンのケミカルシフトより分子内脱水縮合した環状乳酸12量体が83％の割合で得られること確認した。 Under argon atmosphere, at room temperature, add 21.95 ml of benzene solution of diisopropylethylamine (3 eq) to 2 ml of 33 0.15825 mmol methylene chloride, add 21.95 ml of benzene solution of 2,4,6-trichlorobenzoyl chloride (2 eq) for 2 hours Stir. This was added to a 43.9 ml benzene solution of 4 equivalents of DMAP over 16 hours and stirred for 2 hours. The solvent was removed, the residue was separated using column chromatography (silica gel), and 0.0728 g (0.08419 mmol, 53%) of a cyclic 12n lactic acid monomer mixture was obtained from the eluate of benzene: ethyl acetate (4.25: 1). ^From the chemical shift of methine proton in ¹ H-NMR, it was confirmed that 83% of cyclic lactic acid 12-mer dehydrated by intramolecular condensation was obtained.

¹H NMR(500MHz, CDCl₃)δ= 1.53 (d, J=7.1Hz), 1.55 (d, J=7.1Hz), 1.58 (d, J=7.1Hz), 5.17 (q, J=6.9Hz), 5.19 (q, J=7.1Hz), 5.23 (q, J=7.1Hz)

¹ H NMR (500MHz, CDCl ₃ ) δ = 1.53 (d, J = 7.1Hz), 1.55 (d, J = 7.1Hz), 1.58 (d, J = 7.1Hz), 5.17 (q, J = 6.9Hz) , 5.19 (q, J = 7.1Hz), 5.23 (q, J = 7.1Hz)

Claims

A single cyclic oligolactic acid represented by the following formula (1).

The method for producing a single cyclic oligolactic acid according to claim 1, wherein the compound represented by the following formula is subjected to a cyclization reaction by intramolecular dehydration condensation.

The production according to claim 2, wherein the cyclization reaction by intramolecular dehydration condensation is carried out in the presence of diisopropylethylamine, 2,4,6-trichlorobenzoyl chloride and 4- (N, N-dimethylamino) pyridine (DMAP). Method.

Compound represented by the following formula (2):

(Where n represents an integer of 8 to 12)
Is subjected to a cyclization reaction by intramolecular dehydration condensation, and a method for producing a cyclic oligolactic acid represented by the following formula (3):

The production according to claim 4, wherein the cyclization reaction by intramolecular dehydration condensation is carried out in the presence of diisopropylethylamine, 2,4,6-trichlorobenzoyl chloride and 4- (N, N-dimethylamino) pyridine (DMAP). Method.

Cyclic oligolactic acid produced by the production method according to claim 4 or 5.