JP5321936B2 - Ester-type dendrimer, production method thereof, and monomer for ester-type dendrimer synthesis - Google Patents

Description

The present invention relates to an ester-type dendrimer in which a multi-branched structure is formed by an ester bond, a method for producing the ester-type dendrimer, and a monomer for synthesizing an ester-type dendrimer that is a raw material for producing them.

  In recent years, a dendritic polymer having a highly branched structure has attracted attention. Because of its unique molecular structure, dendritic polymers are amorphous, have high solubility in organic solvents, have extremely low viscosity, and have many chain ends into which functional groups can be introduced. It has characteristics different from those of glassy polymers, is expected to be applied in various fields, and has been actively researched in recent years.

  Dendritic polymers include a dendrimer that forms a regular branched structure by chemically reacting a monomer having a polyfunctional group one step at a time, and a highly branched polymer that forms a branched structure at once by polycondensation of ABx type monomers. It has been known. Among these, a dendrimer is produced by chemically reacting a monomer having a polyfunctional group step by step, so that the molecular weight can be accurately defined and a polymer having excellent monodispersibility can be obtained. For example, Non-Patent Document 1 reports a polyester dendrimer composed of glycerol and succinic acid. This synthetic route is shown below.

M.A.Carnahan, M.W.Grinstaff, Macromolecules, 34, 7648 (2001).

However, the ester-type dendrimer described in Non-Patent Document 1 has a problem in that it is difficult to synthesize a homogeneous dendrimer because the terminal rearrangement reaction shown in the following chemical reaction formula occurs simultaneously in the deprotection process in the synthesis route. was there.

The starting material 1,3-O-benzylideneglycerol (d) can be synthesized by the reaction of benzaldehyde and glycerin, but 4-hydroxymethyl-2-phenyl-1, which is represented by the following formula as a by-product, Since 3-dioxolane (e) was produced, there was a problem that purification took time and production cost was increased.

  The present invention has been made in view of the above-described conventional circumstances, and does not cause a rearrangement reaction in the synthesis process, and is easy to manufacture and low in manufacturing cost, its manufacturing method, and its ester type Providing a monomer for dendrimer synthesis is an issue to be solved.

The inventors speculated that the rearrangement reaction occurs in the synthesis of the ester dendrimer based on the following reaction formula.

  Furthermore, if this assumption is correct, if a symmetric triol having three equivalent hydroxyl groups is used instead of glycerin as a raw material, the rearrangement results in exactly the same compound, and a homogeneous ester dendrimer is easily obtained. In addition, the present invention was completed because it was considered to be obtained in a high yield.

That is, the ester-type dendrimer of the present invention has a triol represented by the general formula (a) (wherein R ₁ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms) starting from the functional group of the core molecule. It is characterized by forming a regular branched structure by alternately esterifying dicarboxylic acids.

The ester-type dendrimer of the present invention has a rule in which triols represented by the general formula (a) (wherein R ₁ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms) and dicarboxylic acid are alternately ester-bonded. Has a bifurcated structure. Since the hydroxyl groups of this triol are in an equivalent relationship with each other, even if rearrangement occurs upon elimination of the benzylidene protecting group in the synthesis of the dendrimer of the present invention, the result is exactly the same compound. For example, the reaction formula when the dicarboxylic acid is succinic acid and the triol is 1,1,1-tris (hydroxymethyl) ethane is as follows. For this reason, the homogeneous ester-type dendrimer of this invention can be obtained easily and with a high yield.

The dendrimer of the present invention can be produced as follows.
That is, the method for producing an ester-type dendrimer of the present invention includes a core molecule modification step in which a core molecule is modified via a hydroxyl group of a benzylidene-protected triol derivative in which a benzylidene protecting group is introduced into two of the three hydroxyl groups of the triol. ,
A core molecule deprotecting step of generating a plurality of hydroxyl groups by removing the benzylidene protecting group introduced by the core molecule modifying step;
A dendrimer step having a regular branched structure by alternately esterifying triols and dicarboxylic acids starting from a plurality of hydroxyl groups generated by the core molecule deprotection step,
The dendrimer step includes an esterification step in which a benzylidene-protected monoester, which is a monoester of a benzylidene-protected triol derivative in which a benzylidene-protecting group is introduced into two of the three hydroxyl groups of the triol, is esterified to a hydroxyl group; An ester-type dendrimer by removing the benzylidene protecting group introduced by the esterification step to form a plurality of hydroxyl groups, and repeating the esterification step and the deprotection step once or each time In the method for producing a dendrimer,
The triol is represented by the general formula (a) (wherein R ₁ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms).

Here, the benzylidene protecting group means a protecting group having the following structure.

  The dicarboxylic acid used as the raw material of the ester dendrimer of the present invention is, for example, succinic acid or malonic acid of a dicarboxylic acid having a carboxyl group bonded to both ends of an alkylene group, or phthalic acid having a carboxyl group bonded to both ends of a phenylene group. A dicarboxylic acid such as can be used.

このようなモノマーを原料としてデンドリマーを合成した場合、ベンジリデン保護基の脱離に際して転位反応が生じたとしても、結果として転位前と同じ化合物となるため、転位反応による副生成物は生じることがない。このため、均質なエステル型デンドリマーが容易かつ高収率で得ることができる。 The ester-type dendrimer synthesis monomer used as the raw material of the ester-type dendrimer of the present invention is that one carboxyl group of dicarboxylic acid and the hydroxyl group of the benzylidene-protected triol derivative represented by the general formula (c) are ester-bonded. It is characterized (in the formula, R ₁ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and φ represents an aryl group which may be substituted).

When a dendrimer is synthesized using such a monomer as a raw material, even if a rearrangement reaction occurs upon elimination of the benzylidene protecting group, the resulting compound is the same as that before the rearrangement, so that no by-product due to the rearrangement reaction is generated. . For this reason, a homogeneous ester type dendrimer can be obtained easily and in high yield.

<Synthesis of benzylidene-protected triol derivative (1)>
As shown in the following formula, 1,1,1-tris (hydroxymethyl) ethane was reacted with benzaldehyde to synthesize a benzylidene-protected triol derivative (1).

That is, in a 200 mL eggplant flask equipped with a Dimroth condenser, Dean-Stark water separator, magnetic stirrer, 5.00 g (47.1 mmol) benzaldehyde, 5.77 g (48.0 mmol) 1,1,1-tris (hydroxymethyl) ethane , And 50 mL of toluene were taken and heated to reflux with stirring for 4 hours. After completion of the reaction, diethyl ether was added to the reaction mixture, washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a pale yellow transparent oil. Recrystallization from chloroform / hexane gave 9.51 g (yield 97%) of a benzylidene-protected triol derivative (1) as a white solid. The benzylidene protected triol derivative (1) was a mixture of cis and trans 5.8: 1. This is a compound for introducing a protecting group in the process of synthesizing a dendrimer. Since the benzylidene protecting group is eliminated at the time of dendrimer formation and the stereoisomerism disappears, it can be used in the next step as a mixture of cis and trans.
¹ H NMR
(CDCl ₃ , δppm)
cis body: 7.53 to 7.46 (m, 2H, Ph-), 7.41 to 7.33 (m, 3H, Ph-), 5.44 (s, 1H, -OC H (Ph) -O-), 4.06 (d, J = 11.88 Hz, 2H, -OC H ₂ -C (Me) (CH ₂ OH) -C H ₂ -O-), 3.91 (d, J = 5.61 Hz, 2H, -C H ₂ -OH), 3.66 (d , J = 11.88 Hz, 2H, -OC H ₂ -C (Me) (CH ₂ OH) -C H ₂ -O-), 1.76 (t, J = 5.61 Hz, 1H, -O H ), 0.81 (s , 3H, -Me)
trans form: 7.53-7.46 (m, 2H, Ph-), 7.41-7.33 (m, 3H, Ph-), 5.42 (s, 1H, -OC H (Ph) -O-), 3.92 (d, J = 11.22 Hz, 2H, -OC H ₂ -C (Me) (CH ₂ OH) -C H ₂ -O-), 3.84 (d, J = 10.89 Hz, 2H, -OC H ₂ -C (Me) (CH ₂ OH) -C H ₂ -O-), 3.41 (d, J = 5.27 Hz, 2H, -C H ₂ -OH), 1.46 (t, J = 5.28 Hz, 1H, -O H ), 1.31 (s , 3H, -Me)

<Core molecule modification process>
Synthesis of benzylidene protected dicarboxylic acid diester (2) Next, the benzylidene protected triol derivative (1) was reacted with succinic acid to obtain a benzylidene protected dicarboxylic acid diester (2) (see the following reaction formula).

That is, benzylidene protected triol derivative (1) (3.02 g, 14.5 mmol), succinic acid (0.9 g, 7.6 mmol) and 4-dimethylaminopyridine (0.18 g, 1.5 mmol) were stirred in 60 mL of dichloromethane with a magnetic stirrer. 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide
Hydrochloride (3.05 g, 15.9 mmol) was added and the reaction vessel was purged with nitrogen. After stirring at 0 ° C. (ice cooling) for 3 hours, the mixture was stirred overnight at room temperature. The reaction solution was washed 3 times with 1 / 20N hydrochloric acid, then twice with 100 mL of saturated aqueous sodium carbonate solution, and further once with 100 mL of water, and then the organic solvent phase was dried over anhydrous sodium sulfate. Thereafter, sodium sulfate was removed by decantation, and the solvent was distilled off under reduced pressure. The white solid thus obtained was recrystallized and purified with a chloroform / methanol mixed solution. The precipitated white crystals were taken out by suction filtration and dried under vacuum to obtain first crystals. Further, the solvent was distilled off from the filtrate, and the obtained white solid was recrystallized and purified in the same manner to obtain second to fourth crystals. Further, the residue was purified by silica gel column chromatography to obtain a total of 3.1 g of benzylidene-protected dicarboxylic acid diester (2) consisting of white crystals in a yield of 87.0%. Since (1) was a mixture of cis and trans, the generated (2) was a cis isomer at both ends, one was a cis isomer, the other was a trans isomer, and both ends were trans isomers. As a mixture. The stereoisomers could not be clearly separated in each crystal, and the cis-cis isomer was the main component, followed by the cis-trans isomer followed by the trans-trans isomer. FIG. 1 shows the ¹ HNMR spectrum of the portion relating to the methyl groups of the first to fourth crystals obtained when the benzylidene-protected dicarboxylic acid diester (2) is purified by recrystallization.
¹ H NMR (CDCl ₃ , δppm)
cis-cis form: 7.57-7.42 (m, 4H, Ph-), 7.41-7.30 (m, 6H, Ph-), 5.4122 (s, 2H, -OC H (Ph) -O-), 4.40 (s, 4H, -C H ₂ -OCOCH ₂ CH ₂ COO-C H _2- ),
4.04 (d, J = 11.94 Hz, 4H, -OC H ₂ -C (Me) (CH ₂ COO-)-C H ₂ -O-), 3.65 (d, J = 11.94 Hz, 4H, -OC H ₂ -C (Me) (CH ₂ COO-)-C H ₂ -O-), 2.69 (s, 4H, -OCO-C H ₂ C H ₂ -COO-), 0.79 (s, 6H, -Me)
cis-trans: 7.57-7.42 (m, 4H, Ph-), 7.41-7.30 (m, 6H, Ph-), 5.4263 (s, 1H, -OC H (Ph) -O-, cis or trans), 5.3951 (s, 1H, -OC H (Ph) -O-, cis ortrans), 4.05 (d, J = 11.94 Hz, 2H, -OC H ₂ -C (Me) (CH ₂ COO-)-C H ₂ -O-, cis), 3.67 (d, J = 11.94 Hz, 2H, -OC H ₂ -C (Me) (CH ₂ COO-)-C H ₂ -O-, cis),
3.89-3.83 (m, 4H, -OC H ₂ -C (Me) (CH ₂ COO-)-C H ₂ -O-, trans),
2.69 (s, 4H, -OCO-C H ₂ C H ₂ -COO-), 1.33 (s, 3H, -Me, trans), 0.82 (s, 3H, -Me, cis)
trans-trans: 7.57 to 7.42 (m, 4H, Ph-), 7.41 to 7.30 (m, 6H, Ph-), 5.4153 (s, 2H, -OC H (Ph) -O-), 3.91 to 3.84 ( m, 8H, -OC H ₂ -C (Me) (CH ₂ COO-)-C H ₂ -O-), 2.69 (s, 4H, -OCO-C H ₂ C H ₂ -COO-), 1.34 ( s, 6H, -Me)

すなわち、吸引栓を備えたナス型フラスコに、ベンジリデン保護ジカルボン酸ジエステル（２）を0.25ｇ（0.50mmol）入れ、脱水テトラヒドロフラン10mLを加えて溶解した。次いでこの溶液に10％Pd/Cを0.05g加え、さらに、濃塩酸50μLをメタノール2mLに溶解させた溶液を20μL加えた。そして、窒素を満たしたバルーンを三方コックを介してナス型フラスコに接続し、三方コックの残った口をアスピレーターに接続した。アスピレーターでフラスコ内を減圧した後、窒素を導入する操作を３回繰り返し、フラスコ内を窒素で置換した。次に窒素バルーンを水素で満たしたバルーンと交換し、同様の操作によってフラスコ内を水素で置換した。その後、室温下、マグネティックスターラーで溶液を１．５時間激しく撹拌した。その後、吸引濾過によってＰｄ／Ｃを除去し、濾液の溶媒を減圧下留去し、真空ポンプで乾燥させることにより、白色固体のジカルボン酸ジエステル（３）を定量的に得た。^１H-NMRは以下の通りであり、芳香族プロトンが消失している事からベンジリデン保護基が脱離している事が容易に確認できた。それによって生成したヒドロキシル基のプロトンは溶媒などの影響で観察できないが、このものは転位が起こっても同じ構造をとる為、4種類のプロトンしか示さない非常に単純なスペクトルとなった。
¹H NMR
(CD₃OD,δppm)
4.00 (s, 4H, -CH ₂ -OCOCH₂CH₂COO-CH ₂ -)、3.46〜3.42 (m, 8H, -CH ₂ OH)、2.65 (s, 4H, -OCO-CH ₂ CH ₂ -COO-)、0.90 (s, 6H, -Me) <Core molecule deprotection process>
The benzylidene protecting group was removed from the benzylidene protected dicarboxylic acid diester (2) thus obtained to obtain a dicarboxylic acid diester (3).

That is, 0.25 g (0.50 mmol) of benzylidene-protected dicarboxylic acid diester (2) was placed in an eggplant-shaped flask equipped with a suction stopper, and 10 mL of dehydrated tetrahydrofuran was added and dissolved. Next, 0.05 g of 10% Pd / C was added to this solution, and 20 μL of a solution prepared by dissolving 50 μL of concentrated hydrochloric acid in 2 mL of methanol was added. Then, a balloon filled with nitrogen was connected to the eggplant-shaped flask through a three-way cock, and the remaining mouth of the three-way cock was connected to an aspirator. After reducing the pressure inside the flask with an aspirator, the operation of introducing nitrogen was repeated three times to replace the inside of the flask with nitrogen. Next, the nitrogen balloon was replaced with a balloon filled with hydrogen, and the inside of the flask was replaced with hydrogen by the same operation. Thereafter, the solution was vigorously stirred at room temperature with a magnetic stirrer for 1.5 hours. Then, Pd / C was removed by suction filtration, the solvent of the filtrate was distilled off under reduced pressure, and the white dicarboxylic acid diester (3) was quantitatively obtained by drying with a vacuum pump. ¹ H-NMR is as follows. From the disappearance of the aromatic proton, it was easily confirmed that the benzylidene protecting group was eliminated. The protons of the hydroxyl group thus generated cannot be observed due to the influence of the solvent, etc., but since this has the same structure even when rearrangement occurs, it has a very simple spectrum showing only four types of protons.
¹ H NMR
(CD ₃ OD, δppm)
4.00 (s, 4H, -C H ₂ -OCOCH ₂ CH ₂ COO-C H _2- ), 3.46 to 3.42 (m, 8H, -C H ₂ OH), 2.65 (s, 4H, -OCO-C H ₂ C H ₂ -COO-), 0.90 (s, 6H, -Me)

すなわち、ジムロート冷却器およびマグネティックスターラーを装備した50 ml二口ナスフラスコに5.00 g (27.7mmol)のベンジリデン保護トリオール誘導体（１）、ピリジン24 mL、無水コハク酸2.76 g (27.6 mmol)の順に取り、窒素下室温で一晩攪拌した。反応終了後、溶媒を減圧留去し、淡黄色オイルを得た。酢酸エチル/ヘキサン混合溶媒で再結晶することにより白色固体としてベンジリデン保護ジカルボン酸モノエステル（４）を6.17g（収率83.4％）得た。
¹H NMR
(CDCl₃,δppm)
cis体：7.52〜7.42 (m, 2H, Ph-)、7.41〜7.32 (m, 3H, Ph-)、5.42 (s, 1H, -O-CH(Ph)-O-)、
4.42 (s, 2H, -CH ₂ -OCOCH₂CH₂COOH)、
4.04 (d, J = 11.87Hz, 2H, -O-CH ₂ -C(Me)(CH₂COO-)-CH ₂ -O-)、3.66 (d, J = 11.88 Hz, 2H, -O-CH ₂ -C(Me)(CH₂COO-)-CH ₂ -O-)、2.68 (s, 4H, -OCOCH ₂ CH ₂ COOH)、0.80 (s, 3H,-Me)
trans体：7.52〜7.42 (m, 2H, Ph-)、7.41〜7.32 (m, 3H, Ph-)、5.41 (s,1H, -O-CH(Ph)-O-)、3.89 (s, 2H, -CH ₂ -OCOCH₂CH₂COOH)、
3.86〜3.84 (m, 4H, -O-CH ₂ -C(Me)(CH₂COO-)-CH ₂ -O-)、2.68 (s, 4H, -OCOCH ₂ CH ₂ COOH)、1.33 (s, 3H, -Me) <Synthesis of ester-type dendrimer synthesis monomer>
Synthesis of benzylidene-protected dicarboxylic acid monoester (4) By reacting benzylidene-protected triol derivative (1) with succinic anhydride, benzylidene-protected dicarboxylic acid monoester (4) as a monomer for ester-type dendrimer synthesis was obtained ( Refer to the following reaction formula).

That is, in a 50 ml two-necked eggplant flask equipped with a Dimroth condenser and a magnetic stirrer, 5.00 g (27.7 mmol) of benzylidene-protected triol derivative (1), pyridine 24 mL, and succinic anhydride 2.76 g (27.6 mmol) were taken in this order. Stir overnight at room temperature under nitrogen. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain a pale yellow oil. Recrystallization from a mixed solvent of ethyl acetate / hexane gave 6.17 g (yield 83.4%) of benzylidene-protected dicarboxylic acid monoester (4) as a white solid.
¹ H NMR
(CDCl ₃ , δppm)
cis body: 7.52-7.42 (m, 2H, Ph-), 7.41-7.32 (m, 3H, Ph-), 5.42 (s, 1H, -OC H (Ph) -O-),
4.42 (s, 2H, -C H ₂ -OCOCH ₂ CH ₂ COOH),
4.04 (d, J = 11.87Hz, 2H, -OC H ₂ -C (Me) (CH ₂ COO-)-C H ₂ -O-), 3.66 (d, J = 11.88 Hz, 2H, -OC H ₂ -C (Me) (CH ₂ COO-)-C H ₂ -O-), 2.68 (s, 4H, -OCOC H ₂ C H ₂ COOH), 0.80 (s, 3H, -Me)
trans form: 7.52-7.42 (m, 2H, Ph-), 7.41-7.32 (m, 3H, Ph-), 5.41 (s, 1H, -OC H (Ph) -O-), 3.89 (s, 2H, -C H ₂ -OCOCH ₂ CH ₂ COOH),
3.86 to 3.84 (m, 4H, -OC H ₂ -C (Me) (CH ₂ COO-)-C H ₂ -O-), 2.68 (s, 4H, -OCOC H ₂ C H ₂ COOH), 1.33 ( s, 3H, -Me)

すなわち、ジカルボン酸ジエステル（３）(0.1g,0.31mmol)と、ベンジリデン保護ジカルボン酸モノエステル（４）(0.40g,1.3mmol)と、4-ジメチルアミノピリジン(0.016g,0.13mmol)とを12mLのジクロロメタンに加え、マグネティックスターラーにて撹拌して溶解させた。さらに、1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
Hydrochloride(0.27g,1.4mmol)を加え、反応容器内を窒素置換した。そして、0℃(氷冷)で1時間撹拌した後、室温で一晩撹拌した後、反応液を1/20Nの塩酸で3回洗浄し、次いで飽和炭酸ナトリウム水溶液100mLで2回洗浄し、さらに水100mLで1回洗浄した後、有機溶媒相を無水硫酸ナトリウムで乾燥させた。その後、デカンテーションで硫酸ナトリウムを除去し、減圧下で溶媒留去し、無色透明粘性固体のベンジリデン保護デンドリマー（５）を0.43g（収率92％）得た。
¹H NMR
(CDCl₃,δppm)
7.51〜7.41 (m, 8H, k)、7.39〜7.30 (m, 12H, j)、5.44 (s, 4H, i, trans)、5.41 (s, 4H, i, cis)、4.42 (bs, 8H, f, trans)、4.40 (bs, 8H, f, cis)、4.03 (d, J= 11.76 Hz, 8H, h, cis)、4.00 (s, 4H, b, 8H, d)、3.88〜3.82 (m, 16H, h, trans)、3.65 (d, J = 11.76 Hz, 8H, h, cis)、2.69〜2.58 (m, 16H, e, 4H, a)、1.32 (s, 12H, g, trans)、0.99 (s, 6H, c)、0.80 (s, 12H, g, cis)

<Esterification process>
Synthesis of benzylidene-protected dendrimer (5) The carboxyl group of the benzylidene-protected dicarboxylic acid monoester (4) was ester-bonded to the four hydroxyl groups of the dicarboxylic acid diester (3) to obtain the benzylidene-protected dendrimer (5) See formula).

That is, 12 mL of dicarboxylic acid diester (3) (0.1 g, 0.31 mmol), benzylidene-protected dicarboxylic acid monoester (4) (0.40 g, 1.3 mmol), and 4-dimethylaminopyridine (0.016 g, 0.13 mmol). In addition to dichloromethane, the mixture was dissolved by stirring with a magnetic stirrer. In addition, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide
Hydrochloride (0.27 g, 1.4 mmol) was added, and the inside of the reaction vessel was purged with nitrogen. Then, after stirring at 0 ° C. (ice cooling) for 1 hour and stirring overnight at room temperature, the reaction solution was washed with 1 / 20N hydrochloric acid three times, and then washed with 100 mL of saturated aqueous sodium carbonate solution twice, and further After washing once with 100 mL of water, the organic solvent phase was dried over anhydrous sodium sulfate. Thereafter, sodium sulfate was removed by decantation, and the solvent was distilled off under reduced pressure to obtain 0.43 g (yield 92%) of a benzylidene-protected dendrimer (5) as a colorless transparent viscous solid.
¹ H NMR
(CDCl ₃ , δppm)
7.51 to 7.41 (m, 8H, k), 7.39 to 7.30 (m, 12H, j), 5.44 (s, 4H, i, trans), 5.41 (s, 4H, i, cis), 4.42 (bs, 8H, f, trans), 4.40 (bs, 8H, f, cis), 4.03 (d, J = 11.76 Hz, 8H, h, cis), 4.00 (s, 4H, b, 8H, d), 3.88 to 3.82 (m , 16H, h, trans), 3.65 (d, J = 11.76 Hz, 8H, h, cis), 2.69 to 2.58 (m, 16H, e, 4H, a), 1.32 (s, 12H, g, trans), 0.99 (s, 6H, c), 0.80 (s, 12H, g, cis)

すなわち、吸引栓を備えたナス型フラスコにベンジリデン保護デンドリマー（５）(0.25ｇ,0.17mmol)を脱水テトラヒドロフラン10mLに溶解し、10％Pd/Cを0.05g加え、さらに濃塩酸50μLをメタノール2mLに溶解させた溶液を20μL加えた。窒素を満たしたバルーンを三方コックを介してナス型フラスコに接続し、三方コックの残った口をアスピレーターに接続した。アスピレーターにてフラスコ内を減圧、その後窒素を導入する操作を3回繰り返し、フラスコ内を窒素で置換した。次に水素で満たしたバルーンに置き換え、同様の操作によってフラスコ内を水素で置換した。その後室温で反応液をマグネティックスターラーで1.5時間激しく撹拌した。反応後、吸引濾過でPd/Cを除去し、濾液を減圧下で溶媒留去し、真空ポンプで乾燥させ、無色粘性液体のエステル型デンドリマー（６）を定量的に得た。
¹H NMR
(CD₃OD,δppm)
4.03 (s, 4H, b, 8H, d)、4.00 (s, 8H, f)、3.43 (s, 16H, h)、2.64 (s, 16H, e, 4H, a)、1.02 (s, 6H, c)、0.88 (s, 12H, g)

<Deprotection process>
Synthesis of Dendrimer (6) Then, the benzylidene protecting group was removed from the benzylidene protected dendrimer (5) to obtain an ester dendrimer (6).

That is, benzylidene-protected dendrimer (5) (0.25 g, 0.17 mmol) was dissolved in 10 mL of dehydrated tetrahydrofuran in an eggplant-shaped flask equipped with a suction stopper, 0.05 g of 10% Pd / C was added, and 50 μL of concentrated hydrochloric acid was added to 2 mL of methanol. 20 μL of the dissolved solution was added. A balloon filled with nitrogen was connected to the eggplant-shaped flask through a three-way cock, and the remaining mouth of the three-way cock was connected to an aspirator. The operation of depressurizing the inside of the flask with an aspirator and then introducing nitrogen was repeated three times to replace the inside of the flask with nitrogen. Next, the balloon was replaced with hydrogen, and the flask was replaced with hydrogen by the same operation. Thereafter, the reaction solution was vigorously stirred at room temperature with a magnetic stirrer for 1.5 hours. After the reaction, Pd / C was removed by suction filtration, the solvent was distilled off from the filtrate under reduced pressure, and the residue was dried with a vacuum pump to quantitatively obtain the ester-type dendrimer (6) as a colorless viscous liquid.
¹ H NMR
(CD ₃ OD, δppm)
4.03 (s, 4H, b, 8H, d), 4.00 (s, 8H, f), 3.43 (s, 16H, h), 2.64 (s, 16H, e, 4H, a), 1.02 (s, 6H, c), 0.88 (s, 12H, g)

＜脱保護工程＞
デンドリマー（８）の合成
吸引栓を備えたナス型フラスコにベンジリデン保護デンドリマー（７）(0.13ｇ,0.038mmol)を脱水テトラヒドロフラン10mLに溶解し、10％Pd/Cを0.03g加え、さらに濃塩酸50μLをメタノール2mLに溶解させた溶液を40μL加えた。窒素を満たしたバルーンを三方コックを介してナス型フラスコに接続し、三方コックの残った口をアスピレーターに接続した。アスピレーターにてフラスコ内を減圧、その後窒素を導入する操作を3回繰り返し、フラスコ内を窒素で置換した。次に水素で満たしたバルーンに置き換え、同様の操作によってフラスコ内を水素で置換した。その後室温で反応液をマグネティックスターラーで1.5時間激しく撹拌した。反応後、吸引濾過でPd/Cを除去し、濾液を減圧下で溶媒留去し、真空ポンプで乾燥させ、無色粘性液体を定量的に得た。
¹H NMR
(CD₃OD,δppm)
4.05 (bs, 4H, b, 8H, d, 8H, f, 16H, h)、4.00 (s, 16H, j)、3.47〜3.43 (m, 32H, l)、2.70〜2.64 (m, 32H, i, 16H, e,4H, a)、1.03(s, 6H, c, 12H, g)、0.90 (s, 24H, k)

＜エステル化工程＞
ベンジリデン保護デンドリマー（９）の合成
デンドリマー（８）(0.079g,0.029mmol)と、ベンジリデン保護ジカルボン酸モノエステル（４）(0.18g,0.58mmol)と、4-ジメチルアミノピリジン(0.0071g,0.058mmol)とを15mLのジクロロメタンに加え、マグネティックスターラーにて撹拌して溶解させた。さらに、1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
Hydrochloride(0.13g,0.69mmol)を加え、反応容器内を窒素置換した。そして、0℃(氷冷)で1時間撹拌した後、室温で一晩撹拌した後、反応液を1/20Nの塩酸で3回洗浄し、次いで飽和炭酸ナトリウム水溶液50mLで3回洗浄し、有機溶媒相を無水硫酸ナトリウムで乾燥させた。その後、デカンテーションで硫酸ナトリウムを除去し、減圧下で溶媒留去し、白色固体のベンジリデン保護デンドリマー（９）を0.22g（定量的）得た。
¹H NMR
(CDCl₃,δppm)
7.52〜7.41 (m, 32H, s)、7.40〜7.29 (m, 48H, r)、5.42 (s, 16H, q, trans)、5.41 (s, 16H, q, cis)、4.41 (s, 32H,n, trans)、4.39 (s, 32H, n, cis)、4.03 (d, J = 11.94 Hz, 32H, p, cis)、4.00 (s, 4H, b, 8H, d, 8H, f, 16H, h, 16H, j, 32H, l)、3.90〜3.82 (m, 64H, p, trans)、3.65 (d, J = 11.94 Hz, 32H, p, cis)、2.71〜2.56 (m, 64H, m, 32H, i, 16H, e, 4H, a)、1.32 (s, 48H, o, trans)、0.99 (bs, 6H,c, 12H, g, 24H, k)、0.80 (s, 48H, o, cis)

＜脱保護工程＞
デンドリマー（１０）の合成
吸引栓を備えたナス型フラスコにベンジリデン保護デンドリマー（９）(0.19ｇ,0.026mmol)を脱水テトラヒドロフラン10mLに溶解し、10％Pd/Cを0.04g加え、さらに濃塩酸50μLをメタノール2mLに溶解させた溶液を80μL加えた。窒素を満たしたバルーンを三方コックを介してナス型フラスコに接続し、三方コックの残った口をアスピレーターに接続した。アスピレーターにてフラスコ内を減圧、その後窒素を導入する操作を3回繰り返し、フラスコ内を窒素で置換した。次に水素で満たしたバルーンに置き換え、同様の操作によってフラスコ内を水素で置換した。その後室温で反応液をマグネティックスターラーで1.5時間激しく撹拌した。反応後、吸引濾過でPd/Cを除去し、濾液を減圧下で溶媒留去し、真空ポンプで乾燥させ、無色粘性固体を定量的に得た。
¹H NMR
(CD₃OD,δppm)
4.04 (bs, 4H, b, 8H, d, 8H, f, 16H, h, 16H,j, 32H, l)、4.01(s, 32H, n)、3.45(bs, 64H, p)、2.71〜2.63 (m, 64H, m,32H, i,16H, e, 4H, a)、1.04 (s, 6H, c, 12H, g, 24H, k)、0.90 (s, 48H, o)

<Esterification process>
Synthesis of benzylidene protected dendrimer (7) Dendrimer (6) (0.13 g, 0.11 mmol), benzylidene protected dicarboxylic acid monoester (4) (0.35 g, 1.14 mmol), and 4-dimethylaminopyridine (0.014 g, 0.11 mmol) ) Was added to 15 mL of dichloromethane and dissolved by stirring with a magnetic stirrer. In addition, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide
Hydrochloride (0.26 g, 1.4 mmol) was added, and the inside of the reaction vessel was purged with nitrogen. The mixture was stirred at 0 ° C. (ice cooling) for 1 hour and then at room temperature overnight, and then the reaction solution was washed 3 times with 1 / 20N hydrochloric acid and then 3 times with 50 mL of saturated aqueous sodium carbonate solution. The solvent phase was dried over anhydrous sodium sulfate. Thereafter, sodium sulfate was removed by decantation, and the solvent was distilled off under reduced pressure to obtain 0.38 g (yield 97%) of a white solid benzylidene-protected dendrimer (7).
¹ H NMR
(CDCl ₃ , δppm)
7.51 to 7.42 (m, 16H, o), 7.40 to 7.31 (m, 24H, n), 5.42 (bs, 8H, m, cis
and trans), 4.42 (bs, 16H, j, trans), 4.40 (bs, 16H, j, cis), 4.04 (d, J
= 11.94 Hz, 16H, l, cis), 4.00 (s, 4H, b, 8H, d, 8H, f, 16H, h), 3.89 to 3.83 (m, 32H, l, trans), 3.66 (d, J = 11.94 Hz, 16H, l, cis), 2.74 to 2.57 (m, 32H, i, 16H, e, 4H, a), 1.33 (s, 24H, k, trans), 1.08 to 0.94 (m, 6H, c , 12H, g), 0.80 (s, 24H, k, cis)

<Deprotection process>
Dissolve benzylidene-protected dendrimer (7) (0.13 g, 0.038 mmol) in 10 mL of dehydrated tetrahydrofuran, add 0.03 g of 10% Pd / C, and add 50 μL of concentrated hydrochloric acid to an eggplant-shaped flask equipped with a synthetic suction stopper for dendrimer (8). 40 μL of a solution in which was dissolved in 2 mL of methanol was added. A balloon filled with nitrogen was connected to the eggplant-shaped flask through a three-way cock, and the remaining mouth of the three-way cock was connected to an aspirator. The operation of depressurizing the inside of the flask with an aspirator and then introducing nitrogen was repeated three times to replace the inside of the flask with nitrogen. Next, the balloon was replaced with hydrogen, and the flask was replaced with hydrogen by the same operation. Thereafter, the reaction solution was vigorously stirred at room temperature with a magnetic stirrer for 1.5 hours. After the reaction, Pd / C was removed by suction filtration, and the filtrate was evaporated under reduced pressure and dried with a vacuum pump to quantitatively obtain a colorless viscous liquid.
¹ H NMR
(CD ₃ OD, δppm)
4.05 (bs, 4H, b, 8H, d, 8H, f, 16H, h), 4.00 (s, 16H, j), 3.47 to 3.43 (m, 32H, l), 2.70 to 2.64 (m, 32H, i , 16H, e, 4H, a), 1.03 (s, 6H, c, 12H, g), 0.90 (s, 24H, k)

<Esterification process>
Synthesis of benzylidene protected dendrimer (9) Dendrimer (8) (0.079 g, 0.029 mmol), benzylidene protected dicarboxylic acid monoester (4) (0.18 g, 0.58 mmol), and 4-dimethylaminopyridine (0.0071 g, 0.058 mmol) ) Was added to 15 mL of dichloromethane and dissolved by stirring with a magnetic stirrer. In addition, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide
Hydrochloride (0.13 g, 0.69 mmol) was added, and the inside of the reaction vessel was purged with nitrogen. The mixture was stirred at 0 ° C. (ice cooling) for 1 hour and then at room temperature overnight, and then the reaction solution was washed 3 times with 1 / 20N hydrochloric acid and then 3 times with 50 mL of saturated aqueous sodium carbonate solution. The solvent phase was dried over anhydrous sodium sulfate. Thereafter, sodium sulfate was removed by decantation, and the solvent was distilled off under reduced pressure to obtain 0.22 g (quantitative) of a benzylidene-protected dendrimer (9) as a white solid.
¹ H NMR
(CDCl ₃ , δppm)
7.52 to 7.41 (m, 32H, s), 7.40 to 7.29 (m, 48H, r), 5.42 (s, 16H, q, trans), 5.41 (s, 16H, q, cis), 4.41 (s, 32H, n, trans), 4.39 (s, 32H, n, cis), 4.03 (d, J = 11.94 Hz, 32H, p, cis), 4.00 (s, 4H, b, 8H, d, 8H, f, 16H, h, 16H, j, 32H, l), 3.90 to 3.82 (m, 64H, p, trans), 3.65 (d, J = 11.94 Hz, 32H, p, cis), 2.71 to 2.56 (m, 64H, m, 32H, i, 16H, e, 4H, a), 1.32 (s, 48H, o, trans), 0.99 (bs, 6H, c, 12H, g, 24H, k), 0.80 (s, 48H, o, cis )

<Deprotection process>
Dissolve benzylidene-protected dendrimer (9) (0.19 g, 0.026 mmol) in 10 mL of dehydrated tetrahydrofuran in an eggplant-shaped flask equipped with a synthetic suction stopper of dendrimer (10), add 0.04 g of 10% Pd / C, and add 50 μL of concentrated hydrochloric acid. 80 μL of a solution in which was dissolved in 2 mL of methanol was added. A balloon filled with nitrogen was connected to the eggplant-shaped flask through a three-way cock, and the remaining mouth of the three-way cock was connected to an aspirator. The operation of depressurizing the inside of the flask with an aspirator and then introducing nitrogen was repeated three times to replace the inside of the flask with nitrogen. Next, the balloon was replaced with hydrogen, and the flask was replaced with hydrogen by the same operation. Thereafter, the reaction solution was vigorously stirred at room temperature with a magnetic stirrer for 1.5 hours. After the reaction, Pd / C was removed by suction filtration, and the solvent was distilled off from the filtrate under reduced pressure, followed by drying with a vacuum pump to obtain a colorless viscous solid quantitatively.
¹ H NMR
(CD ₃ OD, δppm)
4.04 (bs, 4H, b, 8H, d, 8H, f, 16H, h, 16H, j, 32H, l), 4.01 (s, 32H, n), 3.45 (bs, 64H, p), 2.71 to 2.63 (m, 64H, m, 32H, i, 16H, e, 4H, a), 1.04 (s, 6H, c, 12H, g, 24H, k), 0.90 (s, 48H, o)

<Esterification process>
Synthesis of benzylidene protected dendrimer (11) Dendrimer (10) (0.12 g, 0.021 mmol), benzylidene protected dicarboxylic acid monoester (4) (0.26 g, 0.83 mmol), and 4-dimethylaminopyridine (0.010 g, 0.083 mmol) ) Was added to 15 mL of dichloromethane and dissolved by stirring with a magnetic stirrer. In addition, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide
Hydrochloride (0.19 g, 1.0 mmol) was added, and the inside of the reaction vessel was purged with nitrogen. The mixture was stirred at 0 ° C. (ice cooling) for 1 hour and then at room temperature overnight, and then the reaction solution was washed 3 times with 1 / 20N hydrochloric acid and then 3 times with 50 mL of saturated aqueous sodium carbonate solution. The solvent phase was dried over anhydrous sodium sulfate. Thereafter, sodium sulfate was removed by decantation, and the solvent was distilled off under reduced pressure to obtain 0.30 g (yield 96%) of a benzylidene-protected dendrimer (11) as a white solid.
¹ H NMR
(CDCl ₃ , δppm)
7.51-7.42 (m, 64H, w), 7.40-7.30 (m, 96H, v), 5.43-5.40 (m, 32H, u, cis and trans), 4.43 (s, 64H, r, trans), 4.39 ( s, 64H, r, cis), 4.03 (d, J
= 11.94 Hz, 64H, t, cis), 4.00 (s, 4H, b, 8H, d, 8H, f, 16H, h, 16H, j, 32H, l, 32H, n, 64H, p), 3.88 ~ 3.82 (m, 128H, t, trans), 3.65 (d, J = 11.94 Hz, 64H, t, cis), 2.71 to 2.59 (m, q, 128H, 64H, m, 32H, i, 16H, e, 4H , a), 1.32 (s, 96H, s, trans), 1.05-0.95 (m, 6H, c, 12H, g, 24H, k, 48H, o), 0.79 (bs, 96H, s, cis)

<Deprotection process>
Dissolve benzylidene-protected dendrimer (11) (0.28 g, 0.018 mmol) in 10 mL of dehydrated tetrahydrofuran in an eggplant-shaped flask equipped with a synthetic suction stopper of dendrimer (12), add 0.10 g of 10% Pd / C, and add 50 μL of concentrated hydrochloric acid. 80 μL of a solution in which was dissolved in 2 mL of methanol was added. A balloon filled with nitrogen was connected to the eggplant-shaped flask through a three-way cock, and the remaining mouth of the three-way cock was connected to an aspirator. The operation of depressurizing the inside of the flask with an aspirator and then introducing nitrogen was repeated three times to replace the inside of the flask with nitrogen. Next, the balloon was replaced with hydrogen, and the flask was replaced with hydrogen by the same operation. Thereafter, the reaction solution was vigorously stirred at room temperature with a magnetic stirrer for 1.5 hours. After the reaction, Pd / C was removed by suction filtration, and the solvent was distilled off from the filtrate under reduced pressure, followed by drying with a vacuum pump to obtain a colorless viscous solid quantitatively.
¹ H NMR
(CD ₃ OD, δppm)
4.05 (bs, 4H, b, 8H, d, 8H, f, 16H, h, 16H,
j, 32H, l, 32H, n, 64H, p), 4.01 (s, 64H, r), 3.44 (s, 128H, t), 2.71 to 2.63 (m, 128H, q, 64H, m, 32H, i , 16H, e, 4H, a), 1.04 (s, 6H, c, 12H, g,
24H, k, 48H, o), 0.89 (s, 96H, s)

  The present invention is not limited to the description of the embodiments of the invention. Various modifications may be included in the present invention as long as those skilled in the art can easily conceive without departing from the description of the scope of claims.

  The present invention can be applied to an ester-type dendrimer that is a functional polymer and a method for producing the same.

A ¹ H NMR spectrum of the portion of the first crystallization-methyl fourth crystal obtained in purifying by recrystallization benzylidene protected dicarboxylic acid diester (2).

Claims (4)

Starting from the functional group of the core molecule, triols represented by the general formula (a) (wherein R ₁ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms) and dicarboxylic acid are alternately ester-bonded. It has a regular branch structure ,
The dicarboxylic acid is an ester-type dendrimer represented by the general formula (b) (wherein R ₂ represents an alkylene group having 0 to 10 carbon atoms or a phenylene group) .

The ester dendrimer according to claim _1, wherein R ₁ is any one of a hydrogen atom, a methyl group, and an ethyl group. A core molecule modification step of modifying the core molecule via a hydroxyl group of a benzylidene-protected triol derivative in which a benzylidene protecting group is introduced into two of the three hydroxyl groups of the triol;
A core molecule deprotecting step of generating a plurality of hydroxyl groups by removing the benzylidene protecting group introduced by the core molecule modifying step;
A dendrimer step having a regular branched structure by alternately esterifying triols and dicarboxylic acids starting from a plurality of hydroxyl groups generated by the core molecule deprotection step,
The dendrimer step includes an esterification step in which a benzylidene-protected monoester, which is a monoester of a benzylidene-protected triol derivative in which a benzylidene-protecting group is introduced into two of the three hydroxyl groups of the triol, is esterified to a hydroxyl group; The deprotection step in which the benzylidene protecting group introduced by the esterification step is eliminated to form a plurality of hydroxyl groups, and the esterification step and the deprotection step are each performed once or repeatedly to form an ester type In the method of producing a dendrimer to obtain a dendrimer,
The triol is represented by the general formula (a) (wherein R ₁ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms), and a method for producing an ester-type dendrimer.

The benzylidene-protected monoester is a compound in which one carboxyl group of the dicarboxylic acid and a hydroxyl group of a benzylidene-protected triol derivative represented by the general formula (c) are ester-bonded ( wherein R ₁ is a hydrogen atom or a carbon number) 4 represents an alkyl group of 1 to 5, and φ represents an aryl group which may be substituted). 5. The method for producing an ester dendrimer according to claim 3, wherein

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