JP5651291B2 - Polyethylene glycol derivative and process for producing the intermediate - Google Patents

Description

  The present invention relates to a method for producing a polyethylene glycol derivative and an intermediate thereof.

  Various compounds are known as compounds that induce cell death or compounds that enhance the action of compounds that induce cell death, and studies on their use as active ingredients in drugs for the prevention or treatment of various diseases It is actively performed.

  For a polyethylene glycol derivative (for example, polyoxyethylene (2,4-diisooctylphenyl) ether) that can be used as an active ingredient of a cell death inducer and an anticancer agent, and a method for producing the same, WO 2006/043338 (A1) pamphlet, It is described in WO2006 / 043353 (A1) pamphlet and WO2006 / 134648 (A1) pamphlet.

Furthermore, the synthesis of such polyethylene glycol derivatives is described in Org. Lett., 2002, 4, 2329-2332.
WO2006 / 043338 pamphlet, WO2006 / 043353 pamphlet WO2006 / 134648 pamphlet Org. Lett., 2002, 4, 2329-2332

  In the production process of the intermediate for producing the polyethylene glycol derivative, there is a problem that an expensive metal reagent and strict anhydrous conditions are required. An object of the present invention is to solve such problems and provide many compounds useful as an active ingredient of an antitumor agent, and to provide a simpler method for producing synthetic intermediates of these compounds.

  The polyethylene glycol monoether compound of the present invention is a compound represented by the following formula (1).

(R in the above formula (1) represents a hydrocarbon group which may have a substituent, and n represents a positive integer.)
The compound of the above (1) can be efficiently produced using a compound of the following formula (2) as an intermediate.

(N in the above formula (2) represents a positive integer.)
This intermediate compound has the following formula (3):

(N in the above formula (3) represents a positive integer.)
It can obtain by carrying out the paratoluenesulfonyl esterification of only one hydroxyl group of the polyethyleneglycol compound represented by these.

  According to the present invention, a compound useful as an active ingredient such as an antitumor agent can be provided. In addition, the above efficient production method of an intermediate compound enables efficient production of such a useful compound.

  Examples of R in the above formula (1) include various saturated or unsaturated hydrocarbon groups such as aliphatic, alicyclic, aromatic and araliphatic. Specific examples include an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, an alkenyl group, and an arylalkenyl group. As the substituent in the case where R is substituted with a substituent, the above-described hydrocarbon group, and further, a nitrogen-containing substituent such as an alkoxy group, an acyl group, a cyano group, a carbamate group, a urea group, a hydrogen atom, Examples thereof include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom. Examples of the preferable substituent include the substituents described in Examples described later. Suitable numbers for n include the numbers described in the examples described later.

  Some compounds of the above formula (1) and salts thereof (for example, pharmacologically acceptable salts) have antitumor activity, and typical examples thereof are shown in the Examples, but the present invention is limited to the Examples. It is not something.

  The compound of the above formula (1) can be synthesized by substituting R for the paratoluenesulfonyl group of the intermediate compound (the compound represented by the formula (2)).

  The reaction can be carried out in an air atmosphere in the presence of water, a solvent immiscible with water in any proportion, and a basic metal salt that is water-soluble. In addition to those used in the examples, dichloromethane can be used as the solvent. Examples of the basic metal salt include sodium carbonate, sodium hydrogen carbonate, lithium hydride, potassium hydroxide and the like in addition to those used in the examples. Examples of the catalyst include quaternary ammonium salts such as tetrabutylammonium bromide, tetrabutylammonium iodide, cetyltrimethylammonium bromide in addition to those used in the examples. The reaction temperature can be appropriately set from a range including room temperature. After completion of the reaction, the desired compound represented by the formula (1) is recovered from the reaction solution. For this recovery, conventional methods such as filtration and separation methods using various chromatographies can be used.

  Further, this intermediate compound (compound represented by formula (2)) is prepared by mixing polyethylene glycol of formula (3) and paratoluenesulfonyl chloride with an alkaline aqueous solution such as sodium hydroxide and benzyl chloride in an inert solvent such as toluene. It can be obtained by reacting in the presence of a phase transfer catalyst such as triethylammonium. The reaction temperature can be appropriately set from a range including room temperature. After completion of the reaction, the desired compound represented by the formula (2) is recovered from the reaction solution. For this recovery, conventional methods such as filtration and separation methods using various chromatographies can be used.

  The route in the above synthesis is shown as the following reaction scheme.

  Hereinafter, the present invention will be described in detail by way of examples.

Example 1
Nonaethylene glycol mono (p-toluenesulfonyl) ester (5)

Nonaethylene glycol 2 (1.00 g, 2.41 mmol) was dissolved in toluene (10 mL). To this, benzyltriethylammonium chloride (0.05 g, 0.24 mmol) and 20% aqueous sodium hydroxide solution (10 mL) were added and stirred. To this was added a solution of p-toluenesulfonyl chloride (0.53 g, 2.75 mmol) in toluene (5.0 mL), and stirring was continued at room temperature for 18 hours. Thereafter, 10% hydrochloric acid (25 mL) was added, and the toluene layer and the aqueous layer were separated. The aqueous layer was extracted with ethyl acetate (25 mL × 3). The toluene layer and the ethyl acetate layer were combined and washed successively with water (20 mL), saturated aqueous sodium hydrogen carbonate (20 mL), and saturated brine (20 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 20 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 200 to 1 → 16 to 1), and colorless liquid 5 (0.88 g, 1.55 mmol) Yield 64%). IR (ATR) v max cm ^-1 : 3433. ¹ H-NMR (CDCl ₃ ) δ: 2.27 (3H, s), 2.93 (1H, br), 3.56-3.64 (34H, br), 4,14 (2H, t, J = 5.0 Hz), 7.34 (2H , d, J = 8.4 Hz), 7.79 (2H, d, J = 8.4 Hz).

  Nonaethylene glycol monophenyl ether (9b)

7b (100 mg, 1.07 mmol) was dissolved in THF (1.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 50 mg, 1.25 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (206 mg, 0.36 mmol) in THF (1.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 6 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 15 to 1), 9b (99 mg, 0.20 mmol, yield 56%) Got. ¹ H-NMR (CDCl ₃ ) δ: 1.78 (1H, br), 3.58-3.74 (32H, br), 3.85 (2H, t, J = 5.2 Hz), 4,12 (2H, t, J = 5.2 Hz ), 6.89-6.95 (2H, m), 7.23-7.29 (3H, m).

  Nonaethylene glycol mono (2,6-dimethylphenyl) ether (9c)

7c (130 mg, 1.07 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 52 mg, 1.30 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (192 mg, 0.34 mmol) in THF (1.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 6 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 15 to 1), and 9c (146 mg, 0.28 mmol, 83% yield) Got. ¹ H-NMR (CDCl ₃ ) δ: 2.16 (1H, br), 2.27 (6H, s), 3.58-3.75 (32H, br), 3.81 (2H, t, J = 5.0 Hz), 3.93 (2H, t , J = 5.0 Hz) 6.87-7.00 (3H, m).

  Nonaethylene glycol mono (3-bromophenyl) ether (9f)

7f (76 mg, 0.44 mmol) was dissolved in THF (1.0 mL). Sodium hydride (mineral oil suspension, purity 60%, 22 mg, 0.55 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 5 (95 mg, 0.17 mmol) in THF (1.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 10 to 1), and 9f (87 mg, 0.15 mmol, yield 91%) Got. ¹ H-NMR (CDCl ₃ ) δ: 1.87 (1H, br), 3.58-3.72 (32H, br), 3.84 (2H, t, J = 4.8 Hz), 4,10 (2H, t, J = 4.8 Hz ), 6.84 (1H, m), 7.05-7.14 (3H, m).

  Nonaethylene glycol mono (2,4-bis (1,1-dimethylethyl) phenyl) ether (9g)

7 g (130 mg, 0.63 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 30 mg, 0.75 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (123 mg, 0.22 mmol) in THF (1.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 15 to 1), and 9 g (120 mg, 0.20 mmol, yield 92%) Got. ¹ H-NMR (CDCl ₃ ) δ: 1.29 (9H, s), 1.38 (9H, s), 2.22 (1H, br), 3.58-3.72 (32H, br), 3.88 (2H, t, J = 5.1 Hz ), 4.11 (2H, t, J = 5.1 Hz), 6.76 (1H, d, J = 8.3 Hz), 7.14 (1H, dd, J = 8.3 Hz, 2.7 Hz), 7.30 (1H, d, J = 2.7 Hz).

  Nonaethylene glycol mono (4-methoxyphenyl) ether (9h)

7h (85 mg, 0.68 mmol) was dissolved in THF (1.5 mL). To this was added sodium hydride (mineral oil suspension, purity 60%, 35 mg, 0.87 mmol), and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 5 (197 mg, 0.35 mmol) in THF (1.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 10 to 1), 9h (106 mg, 0.20 mmol, yield 59%) Got. ¹ H-NMR (CDCl ₃ ) δ: 2.91 (1H, br), 3.56-3.72 (32H, br), 3.75 (3H, s), 3.81 (2H, t, J = 4.8 Hz), 4.06 (2H, t , J = 4.8 Hz), 6.80 (2H, d, J = 9.4 Hz), 6.84 (2H, d, J = 9.2 Hz).

  Nonaethylene glycol mono (4-bromophenyl) ether (9j)

7j (126 mg, 0.73 mmol) was dissolved in THF (1.0 mL). To this was added sodium hydride (mineral oil suspension, purity 60%, 36 mg, 0.90 mmol), and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 5 (192 mg, 0.34 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 10 to 1), 9j (130 mg, 0.23 mmol, yield 68%) Got. ¹ H-NMR (CDCl ₃ ) δ: 2.78 (1H, br), 3.59-3.74 (32H, br), 3.83 (2H, t, J = 4.8 Hz), 4.09 (2H, t, J = 4.6 Hz), 6.79 (2H, d, J = 9.2 Hz), 7.35 (2H, d, J = 9.2 Hz).

  Nonaethylene glycol mono (4-methoxycarbonylphenyl) ether (9k)

7k (93 mg, 0.61 mmol) was dissolved in THF (1.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 31 mg, 0.78 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (162 mg, 0.28 mmol) in THF (1.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 9 to 1), and 9k (36 mg, 0.07 mmol, yield 20%) Got. ¹ H-NMR (CDCl ₃ ) δ: 2.84 (1H, br), 3.59-3.73 (32H, br), 3.86 (2H, t, J = 4.6 Hz), 3.87 (3H, s), 4.17 (2H, t , J = 4.6 Hz), 6.92 (2H, d, J = 8.9 Hz), 7.97 (2H, d, J = 8.9 Hz).

  Nonaethylene glycol mono (4-carboxyphenyl) ether (9k ')

9k (285 mg, 0.52 mmol) was dissolved in methanol (2.0 mL). To this was added 20% aqueous sodium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 24 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (5 mL × 3). To the aqueous layer was added 10% hydrochloric acid (5.0 mL), and the mixture was extracted with dichloromethane (5 mL × 3). The dichloromethane layer was washed successively with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated by an evaporator to obtain 9k ′ (110 mg, 0.21 mmol, yield 38%). ¹ H-NMR (CDCl ₃ ) δ: 3.52-3.74 (34H, br), 3.86 (2H, t, J = 4.8 Hz), 4.20 (2H, t, J = 4.8 Hz), 6.94 (2H, d, J = 8.7 Hz), 8.01 (2H, d, J = 8.7 Hz).

  Nonaethylene glycol mono (4-acetylphenyl) ether (9l)

7l (102 mg, 0.75 mmol) was dissolved in THF (1.0 mL). To this was added sodium hydride (mineral oil suspension, purity 60%, 34 mg, 0.85 mmol), and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 5 (195 mg, 0.34 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 10 to 1), and 10 to 1 of 9 l and 5 from ¹ H-NMR integration ratio. A mixture (74 mg) was obtained. (Equivalent yield of 9l 62 mg, 0.12 mmol, Equivalent yield 34%) ¹ H-NMR (CDCl ₃ ) δ: 2.54 (3H, s), 2.84 (1H, br), 3.56-3.73 (32H, br), 3.87 (2H, t, J = 4.7 Hz), 4.18 (2H, t, J = 4.7 Hz), 6.93 (2H, d, J = 8.7 Hz), 7.91 (2H, d, J = 8.7 Hz).

  Nonaethylene glycol mono (4-tert-butoxycarboxamidophenyl) ether (9m)

7m (380 mg, 1.82 mmol) was dissolved in THF (3.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 75 mg, 1.86 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (400 mg, 0.70 mmol) in THF (4.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (15 mL), and washed successively with water (15 mL) and saturated brine (15 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 8 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 50 to 1 → 10 to 1), and 9 m (370 mg, 0.61 mmol, yield) Rate 86%). ¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.74 (1H, br), 3.58-3.72 (32H, br), 3.82 (3H, t, J = 4.8 Hz), 4.08 (2H, t , J = 4.8 Hz), 6.45 (1H, br), 6.83 (2H, d, J = 9.2 Hz), 7.24 (2H, d, J = 9.2 Hz).

  Nonaethylene glycol mono (4-aminophenyl) ether (9m ')

9m (250 mg, 0.41 mmol) was dissolved in methanol (1.5 mL). To this was added 10% hydrochloric acid (1.0 mL), and the mixture was stirred at room temperature for 24 hours. The reaction solution was diluted with water (10 mL) and extracted with toluene (5 mL × 4). To the aqueous layer was added 20% aqueous sodium hydroxide solution (5.0 mL), and the mixture was extracted with dichloromethane (5 mL × 4). The dichloromethane layer was washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 5 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 4 to 1), 9m '(169 mg, 0.33 mmol, yield 80% ) ¹ H-NMR (CDCl ₃ ) δ: 2.70 (2H, br), 2.95 (1H, br), 3.58-3.73 (32H, br), 3.85 (2H, t, J = 4.8 Hz), 4.11 (2H, t , J = 4.8 Hz), 6.86 (2H, d, J = 8.3 Hz), 7.11 (2H, d, J = 8.3 Hz).

  Nonaethylene glycol mono (4-fluorophenyl) ether (9n)

7n (95 mg, 0.85 mmol) was dissolved in THF (1.5 mL). Sodium hydride (mineral oil suspension, purity 60%, 42 mg, 1.05 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. To this was added 5 (197 mg, 0.35 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 8 to 1), and 9n (117 mg, 0.23 mmol, yield 66%) Got. ¹ H-NMR (CDCl ₃ ) δ: 2.73 (1H, br), 3.58-3.72 (32H, br), 3.83 (2H, t, J = 4.8 Hz), 4.07 (2H, t, J = 4.8 Hz), 6.85 (2H, d, J = 8.2 Hz), 6.94 (2H, d, J = 8.2 Hz).

  Nonaethylene glycol mono (4-trifluoromethylphenyl) ether (9o)

7o (170 mg, 1.05 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 50 mg, 1.25 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (200 mg, 0.35 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 8 to 1), 9o (99 mg, 0.18 mmol, yield 49%) Got. ¹ H-NMR (CDCl ₃ ) δ: 2.73 (1H, br), 3.57-3.73 (32H, br), 3.86 (2H, t, J = 4.8 Hz), 4.16 (2H, t, J = 4.8 Hz), 6.97 (2H, d, J = 8.7 Hz), 7.52 (2H, d, J = 8.7 Hz).

  Nonaethylene glycol mono (3-pyridyl) ether (9q)

7q (195 mg, 2.05 mmol) was dissolved in THF (2.5 mL). To this was added sodium hydride (mineral oil suspension, purity 60%, 100 mg, 2.50 mmol), and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 5 (270 mg, 0.47 mmol) in THF (2.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 5 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 16 to 1 → 4 to 1), and 9q (15 mg, 0.03 mmol, yield) Rate 7%). ¹ H-NMR (CDCl ₃ ) δ: 2.31 (1H, s), 3.57-3.72 (32H, br), 3.87 (2H, t, J = 4.7 Hz), 4.15 (2H, t, J = 4.7 Hz), 7.11 (1H, d, J = 7.7 Hz), 7.21 (1H, d, J = 2.3 Hz), 8.21 (1H, br), 8.32 (1H, br).

  Nonaethylene glycol mono (4-cyanophenyl) ether (9r)

7r (200 mg, 1.68 mmol) was dissolved in THF (3.0 mL). Sodium hydride (mineral oil suspension, purity 60%, 82 mg, 2.05 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 5 (240 mg, 0.42 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 5 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 100 to 1 → 8 to 1), and 9r (82 mg, 0.16 mmol, collected) Rate 38%). ¹ H-NMR (CDCl ₃ ) δ: 2.64 (1H, br), 3.59-3.74 (32H, br), 3.86 (2H, t, J = 4.8 Hz), 4.16 (2H, t, J = 4.8 Hz), 6.96 (2H, t, J = 8.9 Hz), 7.57 (2H, d, J = 8.9 Hz).

  Nonaethylene glycol mono (6-quinolyl) ether (9s)

7s (200 mg, 1.38 mmol) and benzyltriethylammonium chloride (30 mg, 0.13 mmol) were dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 60 mg, 1.50 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (180 mg, 0.32 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with water (10 mL) and extracted with chloroform (10 mL × 4). The chloroform layer was washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 16 to 1 → 8 to 1 → 7 to 2), and 9s (103 mg, 0.19 mmol, 60% yield). ¹ H-NMR (CDCl ₃ ) δ: 2.89 (1H, br), 3.58-3.79 (32H, br), 3.94 (2H, t, J = 4.9 Hz), 4.26 (2H, t, J = 4.9 Hz), 7.09 (1H, d, J = 2.7 Hz), 7.36 (1H, dd, J = 8.2 Hz, 4.1 Hz), 7.41 (1H, dd, J = 9.4 Hz, 2.7 Hz), 8.00 (1H, d, J = 9.4 Hz), 8.04 (1H, dd, J = 8.2 Hz, 1.7 Hz), 8.77 (1H, dd, J = 4.1 Hz, 1.7 Hz).

  Nonaethylene glycol mono (2-naphthyl) ether (9t)

7t (125 mg, 0.87 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 50 mg, 1.25 mmol) was added and stirred at room temperature for 1 hour. A solution of 5 (212 mg, 0.37 mmol) in THF (2.0 mL) was added to this, and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 8 to 1), and 9t (26 mg, 0.05 mmol, 13% yield) Got. ¹ H-NMR (CDCl ₃ ) δ: 2.74 (1H, br), 3.58-3.76 (32H, br), 3.92 (2H, t, J = 4.9 Hz), 4.25 (2H, t, J = 4.9 Hz), 7.13-7.18 (2H, m), 7.30-7.44 (2H, m), 7.71-7.80 (3H, m).

  Nonaethylene glycol mono (1-naphthyl) ether (9u)

7u (130 mg, 0.90 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 48 mg, 1.20 mmol) was added and stirred at room temperature for 1 hour. To this was added 5 (197 mg, 0.35 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 100 to 1 → 6 to 1), and 9u (101 mg, 0.19 mmol, collected) The rate was 54%). ¹ H-NMR (CDCl ₃ ) δ: 2.68 (1H, br), 3.64-3.79 (30H, br), 3.81 (2H, t, J = 4.7 Hz), 4.01 (2H, t, J = 4.9 Hz), 4.32 (2H, t, J = 4.9 Hz), 6.82 (1H, d, J = 7.6 Hz), 7.33-7.50 (4H, m), 7.79 (1H, dd, J = 7.1 Hz, 2.3 Hz), 8.28 ( 1H, d, J = 7.6 Hz).

  Nonaethylene glycol mono (4-formylphenyl) ether (9v)

7v (120 mg, 0.98 mmol) was dissolved in DMF (1.0 mL). To this was added potassium carbonate (140 mg, 1.01 mmol), and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 5 (160 mg, 0.28 mmol) in DMF (2.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 4). The ethyl acetate layer was washed successively with water (10 mL × 3) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate - methanol mixed solvent pair 0 → 45: 1 → 8: 1) was separated by, ¹ H-NMR integral ratio than 9v and 5 A 6: 1 mixture of (28 mg) was obtained. (9v conversion yield 24 mg, 0.05 mmol, conversion yield 16%) ¹ H-NMR (CDCl ₃ ) δ: 2.79 (1H, br), 3.58-3.74 (32H, br), 3.89 (2H, t, J = 4.7 Hz), 4.22 (2H, t, J = 4.7 Hz), 7.02 (1H, d, J = 8.9 Hz), 7.83 (1H, d, J = 8.9 Hz), 9.89 (1H, s).

  Nonaethylene glycol mono (4- (2-tert-butoxycarboxamidoethyl) phenyl) ether (9w)

7w (250 mg, 1.05 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 50 mg, 1.25 mmol) was added and stirred at room temperature for 1 hour. To this was added 5 (250 mg, 0.44 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 6 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 60 to 1 → 8 to 1 → 4 to 1), and 9w (230 mg, 0.36 mmol, yield 82%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.73 (2H, t, J = 7.1 Hz), 3.33 (3H, br), 3.57-3.74 (32H, br), 3.85 (2H, t , J = 4.8 Hz), 4.11 (2H, t, J = 4.8 Hz), 4.21 (1H, br), 4.54 (1H, br), 6.85 (1H, d, J = 8.5 Hz), 7.09 (1H, d , J = 8.5 Hz).

  Nonaethylene glycol mono (4- (2-aminoethyl) phenyl) ether (9w ')

9w (185 mg, 0.29 mmol) was dissolved in methanol (1.0 mL). To this was added 10% hydrochloric acid (1.0 mL), and the mixture was stirred at room temperature for 24 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (5 mL × 4). To the aqueous layer was added 20% aqueous sodium hydroxide solution (5.0 mL), and the mixture was extracted with dichloromethane (5 mL × 4). The dichloromethane layer was washed successively with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated by an evaporator to obtain 9w ′ (152 mg, 0.28 mmol, yield 97%). ¹ H-NMR (CDCl ₃ ) δ: 2.64-3.13 (4H, br), 3.58-3.74 (32H, br), 3.84 (2H, t, J = 4.7 Hz), 4.11 (2H, t, J = 4.7 Hz ), 6.87 (1H, d, J = 8.8 Hz), 7.12 (1H, d, J = 8.8 Hz).

  Nonaethylene glycol mono (2,4-dimethylphenyl) ether (9x)

7x (121 mg, 0.99 mmol) was dissolved in THF (1.5 mL). Sodium hydride (mineral oil suspension, purity 60%, 51 mg, 1.28 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 5 (214 mg, 0.38 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 50 to 1 → 8 to 1 → 4 to 1), and 9x (71 mg, 0.14 mmol, yield 36%). ¹ H-NMR (CDCl ₃ ) δ: 2.19 (3H, s), 2.25 (3H, s), 2.86 (1H, br), 3.60-3.75 (32H, br), 3.85 (2H, t, J = 5.0 Hz ), 4.09 (2H, t, J = 5.0 Hz), 6.71 (1H, d, J = 7.8 Hz), 6.92 (2H, m).

  Nonaethylene glycol mono (2-isopropyl-5-methylphenyl) ether (9y)

7y (180 mg, 1.20 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 55 mg, 1.38 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (215 mg, 0.38 mmol) in THF (1.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 50 to 1 → 8 to 1 → 4 to 1), and 9y (153 mg, 0.28 mmol, yield 74%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 7.0 Hz), 2.31 (3H, s), 2.73 (1H, br), 3.28 (1H, septet, J = 7.0 Hz), 3.59- 3.75 (32H, br), 3.86 (2H, t, J = 5.0 Hz), 4.11 (2H, t, J = 5.0 Hz), 6.66 (1H, s), 6.74 (1H, d, J = 7.8 Hz), 7.08 (1H, d, J = 7.8 Hz).

  Nonaethylene glycol mono (2,4-bis (1,1-dimethylpropyl) phenyl) ether (9z)

7z (222 mg, 0.95 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 50 mg, 1.25 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (220 mg, 0.39 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 50 to 1 → 8 to 1 → 4 to 1), and 9z (134 mg, 0.21 mmol, yield 55%). ¹ H-NMR (CDCl ₃ ) δ: 0.60 (3H, t, J = 7.3 Hz), 0.66 (3H, t, J = 7.3 Hz), 1.25 (6H, s), 1.34 (6H, s), 1.59 ( 2H, q, J = 7.3 Hz), 1.83 (2H, q, J = 7.3 Hz), 2.843 (1H, br), 3.58-3.74 (32H, br), 3.87 (2H, t, J = 5.2 Hz), 4.10 (2H, t, J = 4.8 Hz), 6.75 (1H, d, J = 8.2 Hz), 7.07 (1H, dd, J = 8.2 Hz, 2.3 Hz), 7.16 (1H, d, J = 2.3 Hz) .

  Nonaethylene glycol mono (4-methylphenyl) ether (9aa)

7aa (150 mg, 1.02 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 70 mg, 1.75 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (235 mg, 0.41 mmol) in THF (1.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 5 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 50 to 1 → 8 to 1 → 4 to 1), and 9aa (80 mg, 0.16 mmol, 39% yield). ¹ H-NMR (CDCl ₃ ) δ: 2.28 (3H, s), 2.86 (1H, br), 3.60-3.73 (32H, br), 3.84 (2H, t, J = 4.9 Hz), 4.10 (2H, t , J = 4.9 z), 6.81 (2H, d, J = 8.2 Hz), 7.07 (2H, d, J = 8.2 Hz).

  Nonaethylene glycol mono (3-trifluoromethylphenyl) ether (9ab)

7ab (160 mg, 0.99 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 50 mg, 1.25 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (230 mg, 0.40 mmol) in THF (1.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 5 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 60 to 1 → 8 to 1 → 4 to 1), and 9ab (145 mg, 0.26 mmol, yield 64%). ¹ H-NMR (CDCl ₃ ) δ: 2.92 (1H, br), 3.59-3.74 (32H, br), 3.88 (2H, t, J = 4.9 Hz), 4.17 (2H, t, J = 4.9 Hz), 7.09 (1H, dd, J = 8.3 Hz, 2.3 Hz), 7.15 (1H, br), 7.20 (1H, d, J = 7.8 Hz), 7.38 (1H, dd, J = 8.3 Hz, J = 7.8 Hz) .

  Nonaethylene glycol mono (2-trifluoromethylphenyl) ether (9ac)

7ac (159 mg, 0.98 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 59 mg, 1.48 mmol) was added and stirred at room temperature for 1 hour. To this was added 5 (250 mg, 0.44 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residues were separated by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 100 to 1 → 8 to 1 → 4 to 1), and ¹ H-NMR integration ratio As a result, a 9 to 1 mixture of 9ac and 5 (151 mg) was obtained. (Converted yield of 9ac 136 mg, 0.24 mmol, converted yield 55%) ¹ H-NMR (CDCl ₃ ) δ: 2.58 (1H, br), 3.58-3.76 (32H, br), 3.89 (2H, t, J = 4.6 Hz), 4.21 (2H, t, J = 4.6 Hz), 7.01 (2H, d, J = 7.8 Hz), 7.47 (1H, t, J = 7.8 Hz), 7.56 (1H, d, J = 7.8 Hz).

  Nonaethylene glycol mono (3,5-bis (trifluoromethyl) phenyl) ether (9ad)

7ad (230 mg, 0.99 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 52 mg, 1.30 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (245 mg, 0.43 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 30 to 1 → 8 to 1), and 9ad (128 mg, 0.20 mmol, yield) Rate 47%). ¹ H-NMR (CDCl ₃ ) δ: 2.73 (1H, br), 3.57-3.73 (32H, br), 3.89 (2H, t, J = 4.8 Hz), 4.21 (2H, t, J = 4.8 Hz), 7.34 (2H, s), 7.45 (1H, s).

  Nonaethylene glycol mono (8-quinolyl) ether (9ae)

7ae (270 mg, 1.86 mmol) and benzyltriethylammonium chloride (45 mg, 0.20 mmol) were dissolved in THF (3.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 88 mg, 2.20 mmol) was added and stirred at room temperature for 1 hour. To this was added 5 (255 mg, 0.45 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with water (10 mL) and extracted with chloroform (10 mL × 4). The chloroform layer was washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 16 to 1 → 8 to 1 → 7 to 2), and 9ae (185 mg, 0.34 mmol, yield 76%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.60 (1H, br), 3.60-3.78 (32H, br), 4.06 (2H, t, J = 5.5 Hz), 4.44 (2H, t, J = 5.5 Hz), 7.14 (1H, dd, J = 7.6 Hz, 1.2 Hz), 7.41 (3H, m), 8.12 (1H, dd, J = 8.2 Hz, 1.7 Hz), 8.94 (1H, dd, J = 4.4 Hz, 1.7 Hz ).

  Nonaethylene glycol mono (7-coumaryl) ether (9af)

7af (202 mg, 1.25 mmol) and benzyltriethylammonium chloride (66 mg, 0.29 mmol) were dissolved in THF (2.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 58 mg, 1.45 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (190 mg, 0.33 mmol) in THF (5.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with water (10 mL) and extracted with chloroform (10 mL × 4). The chloroform layer was washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 90 to 1 → 12 to 1 → 4 to 1), and ¹ H-NMR integration ratio A 9: 1 mixture of 9af and 5 (158 mg) was obtained. (Converted yield of 9af 138 mg, 0.25 mmol, converted yield 74%) ¹ H-NMR (CDCl ₃ ) δ: 2.63 (1H, br), 3.58-3.74 (32H, br), 3.89 (2H, t, J = 4.8 Hz), 4.19 (2H, t, J = 4.8 Hz), 6.24 (1H, d, J = 9.4 Hz), 6.86 (1H, dd, J = 8.7 Hz, 2.3 Hz), 6.87 (1H, d, J = 2.3 Hz), 7.36 (1H, d, J = 8.7 Hz), 7.62 (1H, d, J = 9.4 Hz).

  Nonaethylene glycol mono (5-isoquinolyl) ether (9ag)

7ag (136 mg, 0.94 mmol) and benzyltriethylammonium chloride (25 mg, 0.11 mmol) were dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 46 mg, 1.15 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (196 mg, 0.34 mmol) in THF (2.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with water (10 mL) and extracted with chloroform (10 mL × 4). The chloroform layer was washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 60 to 1 → 12 to 1 → 4 to 1), and 9ag (136 mg, 0.25 mmol, yield 73%). ¹ H-NMR (CDCl ₃ ) δ: 2.73 (1H, br), 3.59-3.73 (30H, br), 3.79 (2H, t, J = 4.6 Hz), 4.00 (2H, t, J = 4.8 Hz), 4.32 (2H, t, J = 4.8 Hz), 7.02 (1H, dd, J = 7.8 Hz, 0.9 Hz), 7.51 (2H, m), 8.03 (1H, d, J = 6.0 Hz), 8.52 (1H, d, J = 6.0 Hz), 9.20 (1H, s).

  Nonaethylene glycol mono (4-iodophenyl) ether (9ah)

7ah (230 mg, 1.05 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 49 mg, 1.23 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (210 mg, 0.37 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 90 to 1 → 12 to 1 → 4 to 1), and 9ah (154 mg, 0.25 mmol, yield 68%). ¹ H-NMR (CDCl ₃ ) δ: 2.61 (1H, br), 3.57-3.73 (32H, br), 3.84 (2H, t, J = 4.8 Hz), 4.09 (2H, t, J = 4.8 Hz), 6.69 (2H, d, J = 9.2 Hz), 7.54 (2H, d, J = 9.2 Hz).

  Nonaethylene glycol mono (4-chlorophenyl) ether (9ai)

7ai (120 mg, 0.93 mmol) was dissolved in THF (1.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 44 mg, 1.10 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (207 mg, 0.36 mmol) in THF (1.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 90 to 1 → 10 to 1 → 4 to 1), and 9ai (123 mg, 0.23 mmol, yield 64%). ¹ H-NMR (CDCl ₃ ) δ: 2.56 (1H, br), 3.59-3.74 (32H, br), 3.84 (2H, t, J = 4.8 Hz), 4.10 (2H, t, J = 4.8 Hz), 6.84 (2H, d, J = 8.9 Hz), 7.22 (2H, d, J = 8.9 Hz).

  Nonaethylene glycol mono (p-biphenyl) ether (9aj)

7aj (170 mg, 1.00 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 44 mg, 1.10 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (205 mg, 0.36 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 90 to 1 → 12 to 1 → 4 to 1), and 9aj (172 mg, 0.30 mmol, yield 84%). ¹ H-NMR (CDCl ₃ ) δ: 2.77 (1H, t, J = 6.0 Hz), 3.59-3.75 (32H, br), 3.88 (2H, t, J = 5.4 Hz), 4.18 (2H, t, J = 5.4 Hz), 6.98 (2H, d, J = 8.7 Hz), 7.30-7.56 (7H, m).

  Nonaethylene glycol mono (5-quinolyl) ether (9ak)

7ak (140 mg, 0.96 mmol) and benzyltriethylammonium chloride (24 mg, 0.11 mmol) were dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 46 mg, 1.15 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (210 mg, 0.37 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with water (10 mL) and extracted with chloroform (10 mL × 4). The chloroform layer was washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 16 to 1 → 8 to 1 → 4 to 1), and 9ak (126 mg, 0.23 mmol, yield 63%). ¹ H-NMR (CDCl ₃ ) δ: 2.98 (1H, br), 3.59-3.71 (30H, br), 3.79 (2H, t, J = 4.8 Hz), 4.00 (2H, t, J = 4.8 Hz), 4.32 (2H, t, J = 4.8 Hz), 6.87 (1H, d, J = 7.8 Hz), 7.38 (1H, dd, J = 8.6 Hz, 4.4 Hz), 7.60 (1H, dd, J = 8.5 Hz, 7.8 Hz), 7.70 (1H, d, J = 8.5 Hz), 8.62 (1H, d, J = 8.6 Hz), 8.91 (1H, dd, J = 4.4 Hz, 1.2 Hz).

  Nonaethylene glycol mono (4-indolyl) ether (9al)

7al (150 mg, 1.13 mmol) and benzyltriethylammonium chloride (24 mg, 0.11 mmol) were dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 50 mg, 1.25 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (200 mg, 0.35 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with water (10 mL) and extracted with chloroform (10 mL × 4). The chloroform layer was washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 8 to 1 → 4 to 1), and 9al (73 mg, 0.14 mmol, yield 39%). ¹ H-NMR (CDCl ₃ ) δ: 2.68 (1H, br), 3.59-3.80 (32H, br), 3.95 (2H, t, J = 5.1 Hz), 4.30 (2H, t, J = 5.1 Hz), 6.52 (1H, d, J = 7.3 Hz), 6.66 (1H, br), 7.02-7.13 (3H, m), 8.39 (1H, br).

  Nonaethylene glycol mono (5-indolyl) ether (9am)

7am (130 mg, 0.98 mmol) and benzyltriethylammonium chloride (22 mg, 0.10 mmol) were dissolved in THF (1.5 mL). Sodium hydride (mineral oil suspension, purity 60%, 38 mg, 0.95 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 5 (185 mg, 0.33 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with water (10 mL) and extracted with chloroform (10 mL × 4). The chloroform layer was washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 8 to 1 → 4 to 1), and 9am (142 mg, 0.27 mmol, yield 83%). ¹ H-NMR (CDCl ₃ ) δ: 2.82 (1H, br), 3.58-3.75 (32H, br), 3.87 (2H, t, J = 4.8 Hz), 4.18 (2H, t, J = 4.8 Hz), 6.45 (1H, br), 6.88 (1H, dd, J = 8.7 Hz, 2.6 Hz), 7.11 (1H, d, J = 2.3 Hz), 7.18 (1H, t, J = 2.8 Hz), 7.28 (1H, d, J = 8.7 Hz), 8.33 (1H, br).

  Nonaethylene glycol mono (3-estronyl) ether (9an)

7an (265 mg, 0.98 mmol) was dissolved in THF (2.0 mL). Sodium hydride (mineral oil suspension, purity 60%, 42 mg, 1.05 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 5 (200 mg, 0.35 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 90 to 1 → 45 to 1 → 30 to 1 → 8 to 1 → 4 to 1) Purification gave 9an (208 mg, 0.31 mmol, 89% yield). ¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, s), 1.38-1.73 (6H, m), 194-2.19 (4H, m), 2.24-2.54 (3H, m), 2.87 (3H, m) , 3.59-3.73 (32H, br), 3.84 (2H, t, J = 4.9 Hz), 4.10 (2H, t, J = 4.9 Hz), 6.66 (1H, d, J = 2.6 Hz), 6.72 (1H, dd, J = 8.6 Hz, 2.6 Hz), 7.18 (1H, t, J = 8.6 Hz).

  Nonaethylene glycol mono (3,4-methylenedioxyphenyl) ether (9ao)

7ao (135 mg, 0.98 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 46 mg, 1.15 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (186 mg, 0.35 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 60 to 1 → 8 to 1 → 4 to 1), and 9ao (109 mg, 0.20 mmol, 62% yield). ¹ H-NMR (CDCl ₃ ) δ: 2.86 (1H, br), 3.59-3.72 (32H, br), 3.82 (2H, t, J = 4.8 Hz), 4.05 (2H, t, J = 4.8 Hz), 5.91 (2H, s), 6.33 (1H, dd, J = 8.5 Hz, 2.6 Hz), 6.51 (1H, d, J = 2.6 Hz), 6.69 (1H, t, J = 8.5 Hz).

  Nonaethylene glycol mono (5,6,7,8-tetrahydro-2-naphthyl) ether (9ap)

7ap (160 mg, 1.08 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 49 mg, 1.23 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (210 mg, 0.37 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 5 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 90 to 1 → 8 to 1 → 4 to 1), and 9ap (105 mg, 0.19 mmol, yield 52%). ¹ H-NMR (CDCl ₃ ) δ: 1.77 (4H, m), 2.70 (4H, m), 2.81 (1H, br), 3.59-3.73 (32H, br), 3.83 (2H, t, J = 5.1 Hz ), 4.09 (2H, t, J = 5.1 Hz), 6.62 (1H, d, J = 2.8 Hz), 6.67 (1H, dd, J = 8.5 Hz, 2.8 Hz), 6.95 (1H, t, J = 8.5 Hz).

Nonaethylene glycol mono (4-acetamidophenyl) ether (9aq)
< Synthesis from 7aq >

7aq (145 mg, 0.96 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 49 mg, 1.23 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (200 mg, 0.35 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. Separation of the resulting residue by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 45 to 2 → 16 to 1 → 8 to 1 → 4 to 1) The product was purified and a 2.3 to 1 mixture (19 mg) of 9aq and 5 was obtained from ¹ H-NMR integration ratio. (Equivalent yield of 9aq 13 mg, 0.02 mmol, Equivalent yield 7%)
<Synthesis from 9m ' >

9m '(42 mg, 0.08 mmol) was dissolved in dichloromethane (1.0 mL). Triethylamine (0.10 mL, 0.72 mmol) and acetic anhydride (0.05 mL, 0.53 mmol) were added thereto, and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with water (5 mL) and extracted with chloroform (5 mL × 4). The chloroform layer was washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was dissolved in methanol (1.0 mL), potassium carbonate (16 mg, 0.12 mmol) was added, and the mixture was stirred at room temperature for 3 hr. The reaction solution was diluted with water (5 mL) and extracted with chloroform (5 mL × 4). The chloroform layer was washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 4 to 1), and pale yellow liquid 9aq (9 mg, 0.02 mmol, yield) 19%). ¹ H-NMR (CDCl ₃ ) δ: 2.14 (3H, s), 3.20-3.50 (1H, br), 3.58-3.73 (33H, br), 3.83 (2H, t, J = 4.9 Hz), 4.11 (2H , t, J = 4.9 Hz), 6.86 (2H, d, J = 9.0 Hz), 7.41 (2H, d, J = 9.0 Hz), 7.58 (1H, br).

  Nonaethylene glycol mono (4-benzoylphenyl) ether (9ar)

7ar (192 mg, 0.97 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 44 mg, 1.10 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (198 mg, 0.35 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 60 to 1 → 8 to 1 → 4 to 1), and 9ar (133 mg, 0. mmol, yield 64%). ¹ H-NMR (CDCl ₃ ) δ: 2.92 (1H, br), 3.59-3.75 (32H, br), 3.89 (2H, t, J = 4.8 Hz), 4.22 (2H, t, J = 4.8 Hz), 6.98 (2H, d, J = 8.7 Hz), 7.47 (2H, m), 7.57 (1H, m), 7.75 (2H, dd, J = 8.2 Hz, 1.4 Hz), 7.81 (2H, d, J = 9.2 Hz).

  Nonaethylene glycol mono (5-indanyl) ether (9as)

7as (132 mg, 0.98 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 44 mg, 1.10 mmol) was added and stirred at room temperature for 1 hour. To this was added 5 (190 mg, 0.33 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 90 to 1 → 8 to 1 → 4 to 1), and 9as (125 mg, 0. mmol, 71% yield). ¹ H-NMR (CDCl ₃ ) δ: 2.06 (2H, m), 2.85 (5H, br), 3.59-3.74 (32H, br), 3.84 (2H, t, J = 4.9 Hz), 4.10 (2H, t , J = 4.9 Hz), 6.70 (1H, dd, J = 8.0 Hz, 2.6 Hz), 6.80 (1H, d, J = 2.6 Hz), 7.19 (1H, t, J = 8.0 Hz).

  Nonaethylene glycol mono (3-methoxyphenyl) ether (9av)

7av (148 mg, 1.19 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 50 mg, 1.25 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (147 mg, 0.26 mmol) in THF (1.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 90 to 1 → 45 to 1 → 8 to 1 → 4 to 1). (93 mg, 0.18 mmol, 69% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.07 (1H, br), 3.59-3.74 (32H, br), 3.78 (3H, s), 3.85 (2H, t, J = 5.0 Hz), 4.11 (2H, t , J = 5.0 Hz), 6.50 (3H, m), 7.17 (1H, m).

  Nonaethylene glycol mono (3,4-dihydro-2 (1H) -quinolon-6-yl) ether (9aw)

7aw (156 mg, 0.96 mmol) was dissolved in THF (1.5 mL). To this was added sodium hydride (mineral oil suspension, purity 60%, 43 mg, 1.08 mmol), and the mixture was stirred at room temperature for 1 hour. To this was added 5 (190 mg, 0.33 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with water (10 mL) and extracted with chloroform (10 mL × 4). The chloroform layer was washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 16 to 1 → 8 to 1 → 4 to 1), and ¹ H -9: 1 mixture (30 mg) of 9aw and 5 was obtained from the NMR integration ratio. (9aw conversion yield 27 mg, 0.05 mmol, conversion yield 14%)
¹ H-NMR (CDCl ₃ ) δ: 2.60 (2H, m), 2.92 (3H, m), 3.58-3.73 (33H, br), 3.83 (2H, t, J = 4.9 Hz), 4.09 (2H, t , J = 4.9 Hz), 6.65 (1H, d, J = 8.5 Hz), 6.74 (2H, m).

  Nonaethylene glycol mono (4-carbomethoxymethylphenyl) ether (9ax)

7ax (156 mg, 0.94 mmol) was dissolved in THF (1.5 mL). To this was added sodium hydride (mineral oil suspension, purity 60%, 40 mg, 1.00 mmol), and the mixture was stirred at room temperature for 1 hour. To this was added 5 (190 mg, 0.33 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with water (10 mL) and extracted with chloroform (10 mL × 4). The chloroform layer was washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 20 to 1 → 4 to 1), and 9ax (90 mg, 0.16 mmol, 48% yield). ¹ H-NMR (CDCl ₃ ) δ: 2.88 (1H, br), 3.56-3.73 (34H, br), 3.68 (3H, s), 3.84 (2H, t, J = 5.0 Hz), 4.11 (2H, t , J = 5.0 Hz), 6.87 (2H, d, J = 8.7 Hz), 7.18 (2H, d, J = 8.7 Hz).

  Nonaethylene glycol mono (3-fluorophenyl) ether (9ay)

7ay (110 mg, 0.98 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 45 mg, 1.13 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (208 mg, 0.37 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 50 to 1 → 8 to 1 → 4 to 1), and 9ay (110 mg, 0.22 mmol, yield 59%). ¹ H-NMR (CDCl ₃ ) δ: 2.76 (1H, br), 3.59-3.73 (32H, br), 3.85 (2H, t, J = 4.8 Hz), 4.11 (2H, t, J = 4.8 Hz), 6.61-6.71 (3H, m), 7.22 (1H, m).

  Nonaethylene glycol mono (4-cyclohexylphenyl) ether (9az)

7az (173 mg, 0.98 mmol) was dissolved in THF (1.5 mL). To this was added sodium hydride (mineral oil suspension, purity 60%, 43 mg, 1.08 mmol), and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 5 (200 mg, 0.35 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 90 to 1 → 45 to 1 → 8 to 1 → 4 to 1). (114 mg, 0.20 mmol, 57% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.37 (4H, br), 1.73 (2H, br), 1.83 (4H, br), 2.43 (1H, br), 2.77 (1H, br), 3.59-3.73 (32H , br), 3.84 (2H, t, J = 4.9 Hz), 4.10 (2H, t, J = 4.9 Hz), 6.84 (2H, d, J = 8.7 Hz), 7.10 (2H, d, J = 8.7 Hz) ).

  Nonaethylene glycol mono (4-isopropoxycarbonylphenyl) ether (9ba)

7ba (174 mg, 0.95 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 44 mg, 1.10 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (202 mg, 0.36 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 90 to 1 → 45 to 1 → 8 to 1 → 4 to 1). (151 mg, 0.26 mmol, 78% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.35 (6H, d, J = 6.4 Hz) 2.76 (1H, br), 3.59-3.74 (32H, br), 3.87 (2H, t, J = 4.8 Hz), 4.18 (2H, t, J = 4.8 Hz), 5.22 (1H, septet, J = 6.4 Hz), 6.92 (2H, d, J = 8.7 Hz), 7.97 (2H, d, J = 8.7 Hz).

  Nonaethylene glycol mono (2-methoxy-4- (2-propenyl) phenyl) ether (9bb)

7bb (180 mg, 1.10 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 50 mg, 1.25 mmol) was added and stirred at room temperature for 1 hour. To this was added 5 (188 mg, 0.33 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 90 to 1 → 45 to 1 → 8 to 1 → 4 to 1), 9bb (140 mg, 0.25 mmol, yield 76%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.84 (1H, br), 3.33 (2H, d, J = 6.9 Hz), 3.59-3.73 (32H, br), 3.84 (3H, s), 3.86 (2H, t , J = 5.3 Hz), 4.16 (2H, t, J = 5.3 Hz), 5.07 (2H, m), 5.94 (1H, m), 6.69 (2H, m), 6.85 (1H, d, J = 8.7 Hz ).

  Nonaethylene glycol mono (3,4-dihydro-2 (1H) -quinolon-7-yl) ether (9bc)

7bc (163 mg, 1.00 mmol) was dissolved in THF (2.0 mL). To this was added sodium hydride (mineral oil suspension, purity 60%, 43 mg, 1.08 mmol), and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 5 (195 mg, 0.34 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with water (10 mL) and extracted with chloroform (10 mL × 4). The chloroform layer was washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 16 to 1 → 8 to 1 → 4 to 1), and ¹ H-NMR integration ratio From this, an 8.3 to 1 mixture of 9bc and 5 (93 mg) was obtained. (Converted yield of 9bc 83 mg, 0.15 mmol, converted yield 43%) ¹ H-NMR (CDCl ₃ ) δ: 2.60 (2H, t, J = 7.3 Hz), 2.89 (2H, t, J = 7.3 Hz) , 2.94 (1H, m), 3.58-3.73 (32H, br), 3.84 (2H, t, J = 4.8 Hz), 4.10 (2H, t, J = 4.8 Hz), 6.38 (1H, d, J = 2.3 Hz), 6.53 (1H, dd, J = 8.3 Hz, 2.3 Hz), 7.03 (1H, d, J = 8.3 Hz), 7.79 (1H, br).

  Nonaethylene glycol mono (4-phenylmethylphenyl) ether (9bd)

7bd (200 mg, 1.10 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 48 mg, 1.20 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (196 mg, 0.34 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 120 to 1 → 90 to 1 → 16 to 1), and 9bd (123 mg, 0.21 mmol, yield 62%). ¹ H-NMR (CDCl ₃ ) δ: 2.71 (1H, br), 3.59-3.72 (32H, br), 3.83 (2H, t, J = 5.0 Hz), 3.92 (2H, s), 4.10 (2H, t , J = 5.0 Hz), 6.83 (2H, d, J = 8.7 Hz), 7.08 (2H, d, J = 8.7 Hz), 7.18 (3H, m), 7.27 (2H, m).

  Nonaethylene glycol mono (2-tert-butyl-4-ethylphenyl) ether (9bf)

7bf (182 mg, 1.02 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 48 mg, 1.20 mmol) was added and stirred at room temperature for 1 hour. To this was added 5 (197 mg, 0.35 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 120 to 1 → 45 to 1 → 16 to 1 → 4 to 1), and 9bf (119 mg, 0.21 mmol, 60% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.6 Hz), 1.38 (9H, s), 2.58 (2H, q, J = 7.6 Hz), 2.72 (1H, br), 3.59- 3.72 (32H, br), 3.88 (2H, t, J = 5.0 Hz), 4.12 (2H, t, J = 5.0 Hz), 6.78 (1H, d, J = 8.3 Hz), 6.98 (1H, dd, J = 8.3 Hz, 2.3 Hz), 7.09 (1H, d, J = 2.3 Hz).

  Nonaethylene glycol mono (2,3-dihydro-2,2-dimethylbenzofuran-7-yl) ether (9bg)

7bg (162 mg, 0.99 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 48 mg, 1.20 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (184 mg, 0.32 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 120 to 1 → 90 to 1 → 45 to 1 → 8 to 1 → 4 to 1) Purification gave 9bg (126 mg, 0.22 mmol, 70% yield). ¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.91 (1H, br), 3.01 (2H, s), 3.59-3.73 (32H, br), 3.84 (2H, t, J = 5.4 Hz ), 4.22 (2H, t, J = 5.4 Hz), 6.75 (3H, m).

  Nonaethylene glycol mono (4- (1-adamantyl) phenyl) ether (9bh)

7bh (226 mg, 0.99 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 44 mg, 1.10 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (196 mg, 0.34 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 150 to 1 → 90 to 1 → 45 to 1 → 16 to 1 → 4 to 1) Purification gave 9bh (177 mg, 0.28 mmol, 82% yield). ¹ H-NMR (CDCl ₃ ) δ: 1.77 (6H, m), 1.88 (6H, br), 2.79 (1H, br), 3.59-3.73 (32H, br), 3.84 (2H, t, J = 5.0 Hz ), 4.11 (2H, t, J = 5.0 Hz), 6.86 (2H, d, J = 8.7 Hz), 7.26 (2H, d, J = 8.7 Hz).

  Nonaethylene glycol mono (4-ethylphenyl) ether (9bi)

7bi (122 mg, 1.00 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 45 mg, 1.13 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (191 mg, 0.34 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 90 to 1 → 8 to 1 → 4 to 1), and 9bi (151 mg, 0.29 mmol, yield 87%). ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7.6 Hz), 2.58 (2H, q, J = 7.6 Hz), 2.77 (1H, br), 3.59-3.73 (32H, br), 3.84 (2H, t, J = 4.9 Hz), 4.11 (2H, t, J = 4.9 Hz), 6.84 (2H, d, J = 8.7 Hz), 7.10 (2H, d, J = 8.7 Hz).

  Nonaethylene glycol mono (4- (1-methyl-1-phenylethyl) phenyl) ether (9bj)

7bj (222 mg, 1.05 mmol) was dissolved in THF (2.0 mL). Sodium hydride (mineral oil suspension, purity 60%, 51 mg, 1.28 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 5 (195 mg, 0.34 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 150 to 1 → 8 to 1 → 4 to 1), and 9bj (152 mg, 0.25 mmol, yield 73%). ¹ H-NMR (CDCl ₃ ) δ: 1.67 (6H, s), 2.89 (1H, br), 3.59-3.73 (32H, br), 3.83 (2H, t, J = 4.8 Hz), 4.10 (2H, t , J = 4.8 Hz), 6.81 (2H, d, J = 8.7 Hz), 7.14 (3H, m), 7.24 (4H, m).

  Nonaethylene glycol mono (4-ethoxycarbonylphenyl) ether (9bk)

7bk (176 mg, 1.06 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 50 mg, 1.25 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (181 mg, 0.32 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 90 to 1 → 8 to 1 → 4 to 1), and 9bk (122 mg, 0.22 mmol, yield 68%). ¹ H-NMR (CDCl ₃ ) δ: 1.38 (3H, t, J = 6.9 Hz), 2.80 (1H, br), 3.59-3.73 (32H, br), 3.87 (2H, t, J = 4.8 Hz), 4.18 (2H, t, J = 4.8 Hz), 4.33 (2H, q, J = 6.9 Hz), 6.93 (2H, d, J = 9.2 Hz), 7.98 (2H, d, J = 9.2 Hz).

  Nonaethylene glycol mono (4,6-di-tert-butyl-3-methylphenyl) ether (9bl)

7bl (226 mg, 1.03 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 50 mg, 1.25 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (160 mg, 0.28 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 150 to 1 → 90 to 1 → 8 to 1 → 4 to 1). (109 mg, 0.18 mmol, 61% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.37 (9H, s), 1.38 (9H, s), 2.48 (3H, s), 2.97 (1H, br), 3.59-3.72 (32H, br), 3.88 (2H , t, J = 5.3 Hz), 4.12 (2H, t, J = 5.3 Hz), 6.60 (1H, s), 7.28 (1H, s).

  Nonaethylene glycol mono (2- (1-adamantyl) -4-methylphenyl) ether (9bm)

7bm (234 mg, 0.97 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 50 mg, 1.25 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (182 mg, 0.32 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 150 to 1 → 90 to 1 → 8 to 1 → 4 to 1), 9bm (94 mg, 0.15 mmol, 46% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.76 (6H, br), 2.05 (3H, br), 2.11 (6H, br), 2.27 (3H, s), 2.93 (1H, br), 3.59-3.73 (32H , br), 3.89 (2H, t, J = 5.0 Hz), 4.10 (2H, t, J = 5.0 Hz), 6.74 (1H, d, J = 8.2 Hz), 6.94 (1H, dd, J = 8.2 Hz) , 2.3 Hz), 7.01 (1H, d, J = 2.3 Hz).

  Nonaethylene glycol mono (2-n-dodecyl-4-methylphenyl) ether (9bn)

7bn (274 mg, 0.99 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 46 mg, 1.15 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (168 mg, 0.30 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 300 to 1 → 90 to 1 → 8 to 1), and 9bn (97 mg, 0.14 mmol, yield 49%). ¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t, J = 7.3 Hz), 1.26 (18H, br), 1.55 (2H, m), 2.26 (3H, s), 2.56 (2H, t, J = 7.3 Hz), 2.91 (1H, br), 3.59-3.74 (32H, br), 3.84 (2H, t, J = 5.0 Hz), 4.09 (2H, t, J = 5.0 Hz), 6.72 (1H, d , J = 8.7 Hz), 6.93 (2H, m).

  Nonaethylene glycol mono (2-tert-butyl-4-methoxyphenyl) ether (9bo)

7bo (186 mg, 1.03 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 48 mg, 1.20 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (164 mg, 0.29 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 120 to 1 → 45 to 1 → 8 to 1), and 9bo (150 mg, 0.26 mmol, yield 90%). ¹ H-NMR (CDCl ₃ ) δ: 1.37 (9H, s), 2.96 (1H, br), 3.59-3.73 (32H, br), 3.76 (3H, s), 3.88 (2H, t, J = 5.0 Hz ), 4.09 (2H, t, J = 5.0 Hz), 6.67 (1H, dd, J = 8.7 Hz, 3.1 Hz), 6.78 (1H, d, J = 8.7 Hz), 6.88 (1H, d, J = 3.1 Hz).

  Nonaethylene glycol mono (4-phenoxyphenyl) ether (9bp)

7bp (185 mg, 0.99 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 46 mg, 1.15 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (164 mg, 0.29 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 180 to 1 → 45 to 1 → 8 to 1), and 9 bp (151 mg, 0.26 mmol, yield 90%). ¹ H-NMR (CDCl ₃ ) δ: 2.88 (1H, br), 3.59-3.75 (32H, br), 3.86 (2H, t, J = 4.8 Hz), 4.12 (2H, t, J = 4.8 Hz), 6.95 (6H, m), 7.04 (1H, d, J = 7.3 Hz), 7.30 (2H, m).

  Nonaethylene glycol mono (4-trifluoromethoxyphenyl) ether (9bq)

7bq (170 mg, 0.95 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 46 mg, 1.15 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (184 mg, 0.32 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 8 to 1 → 4 to 1), and 9bq (179 mg, 0.31 mmol, yield) Rate 96%). ¹ H-NMR (CDCl ₃ ) δ: 2.89 (1H, br), 3.59-3.73 (32H, br), 3.85 (2H, t, J = 4.8 Hz), 4.12 (2H, t, J = 4.8 Hz), 6.90 (2H, d, J = 9.2 Hz), 7.13 (2H, d, J = 9.2 Hz).

  Nonaethylene glycol mono (4-tritylphenyl) ether (9br)

7br (322 mg, 0.96 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 46 mg, 1.15 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (181 mg, 0.32 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 200 to 1 → 30 to 1 → 8 to 1 → 4 to 1). (186 mg, 0.25 mmol, 80% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.84 (1H, br), 3.59 -3.72 (32H, br), 3.84 (2H, t, J = 4.8 Hz), 4.10 (2H, t, J = 4.8 Hz), 6.78 (2H, d, J = 9.2 Hz), 7.08 (2H, d, J = 9.2 Hz), 7.15-7.24 (15H, br).

  Nonaethylene glycol mono (2,4-diisopropylphenyl) ether (9bs)

7bs (162 mg, 0.91 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 46 mg, 1.15 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (180 mg, 0.32 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 180 to 1 → 90 to 1 → 8 to 1 → 4 to 1), 9bs (106 mg, 0.19 mmol, yield 59%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.12 (6H, d, J = 6.9 Hz), 1.22 (6H, d, J = 6.9 Hz), 2.85 (1H, septet, J = 6.9 Hz), 2.93 (1H, br), 3.30 (1H, septet, J = 6.9 Hz), 3.59-3.74 (32H, br), 3.86 (2H, t, J = 5.0 Hz), 4.10 (2H, t, J = 5.0 Hz), 6.76 ( 1H, d, J = 8.3 Hz), 6.98 (1H, dd, J = 8.3 Hz, 2.3 Hz), 7.05 (1H, d, J = 2.3 Hz).

  Nonaethylene glycol mono (2- (benzotriazol-2-yl) -4- (2,2,4,4-tetramethylbutyl) phenyl) ether (9bu)

7bu (322 mg, 1.00 mmol) was dissolved in THF (2.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 45 mg, 1.13 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (177 mg, 0.31 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated by silica gel column chromatography (silica gel: 4 g, eluent: ethyl acetate-methanol mixed solvent 1 to 0 → 8 to 1 → 4 to 1). From the ¹ H-NMR integration ratio, 9bu and 5 Of 10.3 to 1 mixture (210 mg). (Equivalent yield of 9bu 195 mg, 0.27 mmol, 87% equivalent yield) ¹ H-NMR (CDCl ₃ ) δ: 0.77 (9H, s), 1.39 (6H, s), 1.75 (2H, s), 2.85 ( 1H, br), 3.30 (1H, septet, J = 6.9 Hz), 3.41-3.73 (34H, br), 4.18 (2H, t, J = 5.0 Hz), 7.08 (1H, d, J = 8.7 Hz), 7.44 (3H, m), 7.63 (1H, d, J = 2.3 Hz), 7.96 (2H, m).

  Nonaethylene glycol mono (2,4-bis (a, a-dimethylbenzyl) phenyl) ether (9bv)

7bv (330 mg, 1.00 mmol) was dissolved in THF (2.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 50 mg, 1.25 mmol) was added and stirred at room temperature for 1 hour. To this was added 5 (190 mg, 0.33 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 180 to 1 → 45 to 1 → 8 to 1 → 3 to 1), and 9bv (140 mg, 0.19 mmol, 58% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.59 (6H, s), 1.71 (6H, s), 2.86 (1H, br), 3.18 (2H, t, J = 5.2 Hz), 3.45 (2H, t, J = 5.2 Hz), 3.55-3.72 (32H, br), 6.66 (1H, d, J = 8.2 Hz), 7.03-7.29 (11H, m), 7.32 (1H, d, J = 2.3 Hz).

  Nonaethylene glycol mono (4'-iodo-4-biphenyl) ether (9bw)

7bw (296 mg, 1.00 mmol) was dissolved in THF (5.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 46 mg, 1.15 mmol) was added and stirred at room temperature for 1 hour. To this was added 5 (176 mg, 0.31 mmol) in THF (3.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 8 to 1 → 7 to 2), and 9 bw (119 mg, 0.17 mmol, yield) Rate 55%). ¹ H-NMR (CDCl ₃ ) δ: 2.64 (1H, br), 3.56-3.64 (32H, br), 3.88 (2H, t, J = 4.9 Hz), 4.17 (2H, t, J = 4.9 Hz), 6.98 (2H, d, J = 8.6 Hz), 7.29 (2H, d, J = 8.6 Hz), 7.47 (2H, d, J = 8.6 Hz), 7.73 (2H, d, J = 8.6 Hz).

  Nonaethylene glycol mono (2-biphenyl) ether (9by)

7by (167 mg, 0.98 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 45 mg, 1.13 mmol) was added and stirred at room temperature for 1 hour. To this was added 5 (202 mg, 0.36 mmol) in THF (2.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. Silica gel column chromatography (silica gel: 4 g, eluent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 30 to 1 → 45 to 2 → 8 to 1 → 7 to 2 → 2 pairs Separation and purification in 1) gave 9by (135 mg, 0.24 mmol, yield 67%). ¹ H-NMR (CDCl ₃ ) δ: 2.93 (1H, br), 3.59-3.73 (32H, br), 3.77 (2H, t, J = 5.0 Hz), 4.12 (2H, t, J = 5.0 Hz), 6.98 (2H, m), 7.27-7.40 (5H, m), 7.56 (2H, d, J = 8.2 Hz).

  Nonaethylene glycol mono (4- (1,1,3,3-tetramethylbutyl) phenyl) ether (9cb)

7cb (200 mg, 0.97 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 46 mg, 1.15 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (175 mg, 0.31 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 30 to 1 → 45 to 2 → 8 to 1 → 7 to 2) Purification gave 9cb (105 mg, 0.17 mmol, 57% yield). ¹ H-NMR (CDCl ₃ ) δ: 0.70 (9H, s), 1.33 (6H, s), 1.69 (2H, s), 2.76 (1H, br), 3.59-3.74 (32H, br), 3.84 (2H , t, J = 4.8 Hz), 4.11 (2H, t, J = 4.8 Hz), 6.82 (2H, d, J = 8.5 Hz), 7.25 (1H, d, J = 8.5 Hz).

  Nonaethylene glycol mono (2-iodo-4-biphenyl) ether (9cc)

7cc (299 mg, 1.01 mmol) was dissolved in THF (3.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 44 mg, 1.10 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (195 mg, 0.34 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 5 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 2 → 8 to 1 → 7 to 2), and 9 cc (142 mg, 142 mg, 0.21 mmol, yield 60%). ¹ H-NMR (CDCl ₃ ) δ: 2.86 (1H, br), 3.58-3.73 (30H, br), 3.82 (2H, t, J = 4.8 Hz), 3.95 (2H, t, J = 5.2 Hz), 4.21 (2H, t, J = 5.2 Hz), 6.90 (1H, d, J = 8.7 Hz), 7.30-7.53 (6H, m), 8.01 (1H, d, J = 2.3 Hz).

  Nonaethylene glycol mono (4-n-dodecylphenyl) ether (9cf)

7cf (300 mg, 1.14 mmol) was dissolved in THF (2.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 52 mg, 1.30 mmol) was added and stirred at room temperature for 1 hour. To this was added 5 (215 mg, 0.38 mmol) in THF (2.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 5 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 45 to 2 → 8 to 1 → 2 to 1), 9cf (168 mg, 0.25 mmol, 67% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.64-0.90 (13H, m), 1.09-1.34 (12H, m), 2.75 (1H, br), 3.59-3.73 (32H, r), 3.84 (2H, t, J = 4.9 Hz), 4.11 (2H, t, J = 4.9 Hz), 6.82-6.84 (2H, br), 7.12-7.24 (2H, m).

  Nonaethylene glycol mono (4-n-dodecyl-2-methylphenyl) ether (9cg)

7cg (296 mg, 1.07 mmol) was dissolved in THF (2.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 55 mg, 1.38 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (203 mg, 0.36 mmol) in THF (2.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 5 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 120 to 1 → 45 to 2 → 8 to 1 → 7 to 2), and 9 cg (129 mg, 0.19 mmol, 53% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t, J = 6.8 Hz), 1.25-1.30 (18H, br), 1.55 (2H, m), 2.49 (2H, m), 2.73 (1H, br ), 3.59-3.75 (32H, br), 3.85 (2H, t, J = 5.0 Hz), 4.10 (2H, t, J = 5.0 Hz), 6.72 (1H, d, J = 8.2 Hz), 6.92 (2H , m).

  Nonaethylene glycol mono (4'-fluoro-4-biphenyl) ether (9ch)

7ch (190 mg, 1.01 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 46 mg, 1.15 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (195 mg, 0.31 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 6 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 90 to 1 → 8 to 1 → 2 to 1), and 9ch (133 mg, 0.23 mmol, yield 66%). ¹ H-NMR (CDCl ₃ ) δ: 2.69 (1H, br), 3.59-3.74 (32H, br), 3.88 (2H, t, J = 4.9 Hz), 4.17 (2H, t, J = 4.9 Hz), 6.98 (2H, d, J = 8.7 Hz), 7.09 (2H, d, J = 8.7 Hz), 7.44-7.51 (4H, m).

  Nonaethylene glycol mono (4'-cyano-4-biphenyl) ether (9ci)

7ci (199 mg, 1.02 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 49 mg, 1.23 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (203 mg, 0.36 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 6 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 2 → 8 to 1 → 2 to 1), and 9ci (165 mg, 0.28 mmol, yield 78%). ¹ H-NMR (CDCl ₃ ) δ: 2.81 (1H, br), 3.59-3.75 (32H, br), 3.89 (2H, t, J = 4.8 Hz), 4.19 (2H, t, J = 4.8 Hz), 7.02 (2H, d, J = 9.2 Hz), 7.53 (2H, d, J = 9.2 Hz), 7.64 (2H, d, J = 8.7 Hz), 7.70 (2H, d, J = 8.7 Hz).

  Nonaethylene glycol mono (4-cyclopentyl) ether (9cj)

7cj (170 mg, 1.05 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 52 mg, 1.30 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (207 mg, 0.34 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 5 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 30 to 1 → 45 to 2 → 8 to 1 → 7 to 2), and 9cj (136 mg, 0.24 mmol, 60% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.54 (2H, m), 1.67 (2H, m), 1.78 (2H, m), 2.02 (2H, br), 2.74 (1H, br), 2.93 (1H, m ), 3.59-3.73 (32H, br), 3.84 (2H, t, J = 4.9 Hz), 4.11 (2H, t, J = 4.9 Hz), 6.84 (2H, d, J = 8.7 Hz), 7.14 (2H , d, J = 8.7 Hz).

  Nonaethylene glycol mono (4- (4'-tert-butoxycarbonypiperazin-1'-yl) -phenyl) ether (9ck)

7ck (342 mg, 1.23 mmol) was dissolved in THF (3.0 mL). To this was added sodium hydride (mineral oil suspension, purity 60%, 62 mg, 1.55 mmol), and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 5 (290 mg, 0.51 mmol) in THF (3.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 5 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 40 to 1 → 30 to 1 → 7 to 2), and 9ck (242 mg, 0.36 mmol, yield 70%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 2.75 (1H, br), 3.00 (2H, t, J = 5.1 Hz), 3.57 (2H, t, J = 5.1 Hz), 3.59- 3.73 (32H, br), 3.83 (2H, t, J = 5.1 Hz), 4.08 (2H, t, J = 5.1 Hz), 6.85 (2H, d, J = 9.5 Hz), 6.88 (2H, d, J = 9.5 Hz).

  Nonaethylene glycol mono (4- (piperazin-1'-yl) -phenyl) ether (9ck ')

9ck (47 mg, 0.07 mmol) was dissolved in methanol (0.5 mL). To this was added 10% hydrochloric acid (1.0 mL), and the mixture was stirred at room temperature for 24 hours. The reaction solution was diluted with water (10 mL) and extracted with toluene (5 mL × 4). To the aqueous layer was added 20% aqueous sodium hydroxide solution (5.0 mL), and the mixture was extracted with dichloromethane (5 mL × 4). The dichloromethane layer was washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator to obtain 9ck ′ (37 mg, 0.06 mmol, yield 93%). ¹ H-NMR (CDCl ₃ ) δ: 1.81 (2H, br), 3.58-3.73 (36H, br), 3.83 (2H, t, J = 4.8 Hz), 4.08 (2H, t, J = 4.8 Hz), 6.85 (2H, d, J = 9.2 Hz), 6.88 (2H, d, J = 9.2 Hz).

  Nonaethylene glycol mono (2,2,5,7,8-pentamethylchroman-6-yl) ether (9cl)

7cl (222 mg, 1.01 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 48 mg, 1.20 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (200 mg, 0.35 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 5 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 30 to 1 → 10 to 1 → 7 to 2), and 9cl (162 mg, 0.26 mmol, 75% yield). ¹ H-NMR (CDCl ₃ ) δ: 1.29 (6H, s), 1.78 (2H, t, J = 6.9 Hz), 2.07 (3H, s), 2.13 (3H, s), 2.17 (3H, s), 2.58 (2H, t, J = 6.9 Hz), 2.73 (1H, br), 3.58-3.81 (36H, br).

  Nonaethylene glycol mono (4'-methoxy-4-biphenyl) ether (9cm)

7 cm (201 mg, 1.00 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 46 mg, 1.15 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (206 mg, 0.36 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 5 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 4 to 1 → 2 to 1), and 9 cm (161 mg, 0.27 mmol, yield 74%). ¹ H-NMR (CDCl ₃ ) δ: 2.73 (1H, br), 3.59-3.75 (32H, br), 3.84 (3H, s), 3.88 (2H, t, J = 4.9 Hz), 4.17 (2H, t , J = 4.9 Hz), 6.95 (2H, d, J = 8.7 Hz), 6.96 (2H, d, J = 8.7 Hz), 7.46 (2H, d, J = 9.1 Hz), 7.47 (2H, d, J = 9.1 Hz).

  Nonaethylene glycol mono (2-bromo-4,6-difluorophenyl) ether (9cp)

7cp (212 mg, 1.01 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 48 mg, 1.20 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (202 mg, 0.36 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 6 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 20 to 1 → 8 to 1 → 1 to 1), 9 cp (85 mg, 0.14 mmol, 40% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.75 (1H, br), 3.59-3.73 (32H, br), 3.85 (2H, t, J = 4.5 Hz), 4.20 (2H, t, J = 4.5 Hz), 6.84 (1H, m), 7.09 (1H, m).

  Nonaethylene glycol mono (dl-a-tocopherolyl) ether (9cq)

7cq (450 mg, 1.04 mmol) was dissolved in THF (4.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 54 mg, 1.35 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 5 (204 mg, 0.36 mmol) in THF (3.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 5 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 8 to 1 → 7 to 2), and 9cq (272 mg, 0.32 mmol, yield 91%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.29 (12H, m), 1.07-1.81 (23H, br), 1.22 (3H, s), 2.07 (3H, s), 2.13 (3H, s), 2.17 (3H , s), 2.56 (2H, t, J = 6.8 Hz), 3.60-3.81 (36H, br).

  Dodecaethylene glycol mono (p-toluenesulfonyl) ester (3)

Dodecaethylene glycol 1 (1.00 g, 1.83 mmol) was dissolved in toluene (10 mL). To this, benzyltriethylammonium chloride (0.04 g, 0.19 mmol) and 20% aqueous sodium hydroxide solution (10 mL) were added and stirred. To this was added a solution of p-toluenesulfonyl chloride (0.36 g, 1.90 mmol) in toluene (5.0 mL), and stirring was continued at room temperature for 18 hours. Thereafter, 10% hydrochloric acid (25 mL) was added, and the toluene layer and the aqueous layer were separated. The aqueous layer was extracted with ethyl acetate (25 mL × 3). The toluene layer and the ethyl acetate layer were combined, and washed successively with water (20 mL), saturated aqueous sodium bicarbonate (20 mL), and saturated brine (20 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 16 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 60 to 1 → 8 to 1), and colorless liquid 3 (0.76 g, 1.08 mmol) , Yield 60%). IR (ATR) v max cm ^-1 : 3462. ¹ H-NMR (CDCl ₃ ) δ: 2.03 (1H, br), 2.27 (3H, s), 3.56-3.64 (46H, br), 4.14 (2H, t, J = 5.0 Hz), 7.34 (2H, d , J = 8.4 Hz), 7.79 (2H, d, J = 8.4 Hz).

  Dodecaethylene glycol monophenyl ether (8b)

7b (60 mg, 0.64 mmol) was dissolved in THF (1.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 31 mg, 0.78 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 3 (160 mg, 0.23 mmol) in THF (1.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 8 to 1), and 8b (30 mg, 0.05 mmol, yield 21%) Got. ¹ H-NMR (CDCl ₃ ) δ: 2.77 (1H, br), 3.58-3.63 (44H, br), 3.85 (2H, t, J = 4.8 Hz), 4.12 (2H, t, J = 4.8 Hz), 6.88-6.95 (2H, m), 7.24-7.29 (3H, m).

  Dodecaethylene glycol mono (2,6-dimethylphenyl) ether (8c)

7c (83 mg, 0.68 mmol) was dissolved in THF (1.0 mL). To this was added sodium hydride (mineral oil suspension, purity 60%, 35 mg, 0.87 mmol), and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 3 (140 mg, 0.20 mmol) in THF (1.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 12 to 1), and 8c (91 mg, 0.14 mmol, yield 70%) Got. ¹ H-NMR (CDCl ₃ ) δ: 2.28 (6H, s), 2.77 (1H, br), 3.58-3.66 (44H, br), 3.82 (2H, t, J = 4.9 Hz), 3.93 (2H, t , J = 4.9 Hz), 6.88-7.00 (3H, m).

  Dodecaethylene glycol mono (3-bromophenyl) ether (8f)

7f (89 mg, 0.51 mmol) was dissolved in THF (1.0 mL). To this was added sodium hydride (mineral oil suspension, purity 60%, 25 mg, 0.63 mmol), and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 3 (150 mg, 0.21 mmol) in THF (1.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 8 to 1), and 8f (126 mg, 0.18 mmol, 84% yield) Got. ¹ H-NMR (CDCl ₃ ) δ: 2.75 (1H, br), 3.57-3.64 (44H, br), 3.83 (2H, t, J = 4.8 Hz), 4.10 (2H, t, J = 4.8 Hz), 6.84 (1H, m), 7.05-7.14 (3H, m).

  Dodecaethylene glycol mono (2,4-bis (1,1-dimethylethyl) phenyl) ether (8g)

7 g (174 mg, 0.84 mmol) was dissolved in THF (1.5 mL). To this was added sodium hydride (mineral oil suspension, purity 60%, 40 mg, 1.00 mmol), and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 3 (200 mg, 0.29 mmol) in THF (1.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 12 to 1), and 8 g (174 mg, 0.24 mmol, yield 83%) Got. ¹ H-NMR (CDCl ₃ ) δ: 1.29 (9H, s), 1.38 (9H, s), 1.88 (1H, br), 3.58-3.64 (44H, br), 3.88 (2H, t, J = 5.1 Hz ), 4.11 (2H, t, J = 5.1 Hz), 6.76 (1H, d, J = 8.6 Hz), 7.14 (1H, dd, J = 8.6 Hz, 2.5 Hz), 7.30 (1H, d, J = 2.5 Hz).

  Dodecaethylene glycol mono (4-bromophenyl) ether (8j)

7j (169 mg, 0.98 mmol) was dissolved in THF (1.5 mL). Sodium hydride (mineral oil suspension, purity 60%, 47 mg, 1.18 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. A solution of 3 (215 mg, 0.31 mmol) in THF (2.0 mL) was added to this, and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 30 to 1 → 8 to 1 → 7 to 2), and 8j (44 mg, 0.06 mmol, yield 20%). ¹ H-NMR (CDCl ₃ ) δ: 2.78 (1H, br), 3.58-3.65 (44H, br), 3.83 (2H, t, J = 4.6 Hz), 4.08 (2H, t, J = 4.6 Hz), 6.79 (2H, d, J = 9.2 Hz), 7.35 (2H, d, J = 9.2 Hz).

  Dodecaethylene glycol mono (4-methoxycarbonylphenyl) ether (8k)

7k (152 mg, 1.00 mmol) was dissolved in THF (1.5 mL). Sodium hydride (mineral oil suspension, purity 60%, 47 mg, 1.18 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 3 (181 mg, 0.26 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with water (10 mL) and extracted with chloroform (10 mL × 4). The chloroform layer was washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 30 to 1 → 8 to 1 → 7 to 2), and 8k (115 mg, 0.17 mmol, yield 65%). ¹ H-NMR (CDCl ₃ ) δ: 2.77 (1H, br), 3.59-3.75 (44H, br), 3.86 (2H, t, J = 4.5 Hz), 3.88 (3H, s), 4.18 (2H, t , J = 4.5 Hz), 6.93 (2H, d, J = 9.0 Hz), 7.98 (2H, d, J = 9.0 Hz).

  Dodecaethylene glycol mono (4-tert-butoxycarboxamidophenyl) ether (8m)

7m (210 mg, 1.00 mmol) was dissolved in THF (2.0 mL). To this was added sodium hydride (mineral oil suspension, purity 60%, 43 mg, 1.08 mmol), and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 3 (204 mg, 0.29 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 30 to 1 → 8 to 1 → 4 to 1), 8 m (131 mg, 0.18 mmol, 61% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.51 (9H, s), 2.81 (1H, br), 3.60-3.74 (44H, br), 3.83 (2H, t, J = 4.9 Hz), 4.09 (2H, t , J = 4.9 Hz), 6.44 (1H, br), 6.85 (2H, d, J = 9.2 Hz), 7.25 (2H, d, J = 9.2 Hz).

  Dodecaethylene glycol mono (4-trifluoromethylphenyl) ether (8o)

7o (162 mg, 1.00 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 65 mg, 1.63 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 3 (250 mg, 0.36 mmol) in THF (1.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 5 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 8 to 1), and 8o (54 mg, 0.08 mmol, collected) Rate 22%). ¹ H-NMR (CDCl ₃ ) δ: 2.75 (1H, br), 3.57-3.73 (44H, br), 3.87 (2H, t, J = 4.8 Hz), 4.17 (2H, t, J = 4.8 Hz), 6.98 (2H, d, J = 8.5 Hz), 7.53 (2H, d, J = 8.5 Hz).

  Dodecaethylene glycol mono (4-cyanophenyl) ether (8r)

7r (118 mg, 1.00 mmol) and benzyltriethylammonium chloride (26 mg, 0.11 mmol) were dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 52 mg, 1.30 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 3 (200 mg, 0.29 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 60 to 1 → 11 to 2 → 7 to 2), and 8r (38 mg, 0.06 mmol, yield 20%). ¹ H-NMR (CDCl ₃ ) δ: 2.93 (1H, br), 3.59-3.74 (44H, br), 3.86 (2H, t, J = 4.8 Hz), 4.18 (2H, t, J = 4.8 Hz), 6.97 (2H, d, J = 9.2 Hz), 7.58 (2H, d, J = 9.2 Hz).

  Dodecaethylene glycol mono (6-quinolyl) ether (8s)

7s (140 mg, 0.96 mmol) and benzyltriethylammonium chloride (22 mg, 0.10 mmol) were dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 44 mg, 1.10 mmol) was added and stirred at room temperature for 1 hour. A solution of 3 (175 mg, 0.25 mmol) in THF (2.0 mL) was added to this, and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with water (10 mL) and extracted with chloroform (10 mL × 4). The chloroform layer was washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 16 to 1 → 4 to 1), and 8s (132 mg, 0.20 mmol, collected) Rate 79%). ¹ H-NMR (CDCl ₃ ) δ: 2.80 (1H, br), 3.58-3.79 (44H, br), 3.94 (2H, t, J = 4.8 Hz), 4.26 (2H, t, J = 4.8 Hz), 7.08 (1H, d, J = 2.7 Hz), 7.35 (1H, dd, J = 8.3 Hz, 3.3 Hz), 7.40 (1H, dd, J = 9.2 Hz, 2.7 Hz), 7.99 (1H, d, J = 9.2 Hz), 8.04 (1H, d, J = 8.3 Hz), 8.77 (1H, d, J = 3.3 Hz).

  Dodecaethylene glycol mono (1-naphthyl) ether (8t)

7t (141 mg, 0.98 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 53 mg, 1.33 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 3 (206 mg, 0.29 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 30 to 1 → 8 to 1 → 4 to 1) (68 mg, 0.10 mmol, 34% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.93 (1H, br), 3.59-3.66 (44H, br), 3.93 (2H, t, J = 4.8 Hz), 4.26 (2H, t, J = 4.8 Hz), 7.13-7.18 (2H, m), 7.30-7.46 (2H, m), 7.71-7.78 (3H, m).

  Dodecaethylene glycol mono (1-naphthyl) ether (8u)

7u (180 mg, 1.25 mmol) was dissolved in THF (1.5 mL). Sodium hydride (mineral oil suspension, purity 60%, 56 mg, 1.40 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 3 (240 mg, 0.34 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 5 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 50 to 1 → 8 to 1 → 4 to 1), and 8u (131 mg, 0.19 mmol, 57% yield). ¹ H-NMR (CDCl ₃ ) δ: 2.72 (1H, br), 3.58-3.65 (44H, br), 3.81 (2H, t, J = 4.9 Hz), 4.01 (2H, t, J = 4.9 Hz), 6.82 (1H, d, J = 8.1 Hz), 7.33-7.49 (4H, m), 7.79 (1H, dd, J = 6.7 Hz, 2.5 Hz), 8.28 (1H, d, J = 8.1 Hz).

  Dodecaethylene glycol mono (4-formylphenyl) ether (8v)

7v (120 mg, 0.98 mmol) was dissolved in THF (1.5 mL). To this was added sodium hydride (mineral oil suspension, purity 60%, 40 mg, 1.00 mmol), and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 3 (180 mg, 0.26 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 30 to 1 → 8 to 1 → 4 to 1), and ¹ H-NMR integration ratio Thus, a 1 to 1.3 mixture (50 mg) of 8v and 3 was obtained. (8v conversion yield 21 mg, 0.03 mmol, conversion yield 12%) ¹ H-NMR (CDCl ₃ ) δ: 2.90 (1H, br), 3.58-3.65 (44H, br), 3.89 (2H, t, J = 5.0 Hz), 4.22 (2H, t, J = 5.0 Hz), 7.02 (1H, d, J = 8.7 Hz), 7.83 (1H, d, J = 8.7 Hz), 9.89 (1H, s).

  Dodecaethylene glycol mono (2-isopropyl-5-methylphenyl) ether (8y)

7y (160 mg, 1.07 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 45 mg, 1.13 mmol) was added and stirred at room temperature for 1 hour. A solution of 3 (220 mg, 0.31 mmol) in THF (2.0 mL) was added to this, and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. Separation of the obtained residue by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 90 to 1 → 45 to 1 → 45 to 2 → 8 to 1 → 4 to 1) Purification gave 8y (101 mg, 0.15 mmol, 47% yield). ¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 7.0 Hz), 2.31 (1H, s), 2.88 (1H, br), 3.28 (1H, septet, J = 7.0 Hz), 3.58- 3.65 (44H, br), 3.86 (2H, t, J = 5.1 Hz), 4.12 (2H, t, J = 5.1 Hz), 6.66 (1H, s), 6.74 (1H, d, J = 7.8 Hz), 7.08 (1H, d, J = 7.8 Hz).

  Dodecaethylene glycol mono (2,4-bis (1,1-dimethylpropyl) phenyl) ether (8z)

7z (240 mg, 1.02 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 53 mg, 1.33 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 3 (225 mg, 0.32 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 60 to 1 → 30 to 1 → 4 to 1), and 8z (192 mg, 0.25 mmol, yield 79%). ¹ H-NMR (CDCl ₃ ) δ: 0.61 (3H, t, J = 7.5 Hz), 0.66 (3H, t, J = 7.5 Hz), 1.25 (6H, s), 1.34 (6H, s), 1.59 ( 2H, q, J = 7.5 Hz), 1.83 (2H, q, J = 7.5 Hz), 2.73 (1H, br), 3.59-3.74 (44H, br), 3.86 (2H, t, J = 5.2 Hz), 4.10 (2H, t, J = 4.8 Hz), 6.75 (1H, d, J = 8.4 Hz), 7.07 (1H, dd, J = 8.4 Hz, 2.4 Hz), 7.16 (1H, d, J = 2.4 Hz) .

  Dodecaethylene glycol mono (4-methylphenyl) ether (8aa)

7aa (110 mg, 1.02 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 50 mg, 1.25 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 3 (250 mg, 0.36 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 8 to 1 → 4 to 1) to obtain 8aa (85 mg, 0.13 mmol, yield 37%). ¹ H-NMR (CDCl ₃ ) δ: 2.28 (3H, s), 2.80 (1H, br), 3.59-3.66 (44H, br), 3.84 (2H, t, J = 4.8 Hz), 4.10 (2H, t , J = 4.8 Hz), 6.81 (2H, d, J = 8.3 Hz), 7.06 (2H, d, J = 8.3 Hz).

  Dodecaethylene glycol mono (3-trifluoromethylphenyl) ether (8ab)

7ab (180 mg, 1.12 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 58 mg, 1.45 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 3 (250 mg, 0.36 mmol) in THF (1.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 5 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 8 to 1 → 4 to 1), and 8ab (187 mg, 0.27 mmol, yield 76%). ¹ H-NMR (CDCl ₃ ) δ: 2.76 (1H, br), 3.59-3.64 (44H, br), 3.87 (2H, t, J = 4.8 Hz), 4.17 (2H, t, J = 4.8 Hz), 7.09 (1H, dd, J = 8.3 Hz, 2.3 Hz), 7.15 (1H, br), 7.20 (2H, d, J = 7.8 Hz), 7.38 (1H, dd, J = 8.3 Hz, 7.8 Hz).

  Dodecaethylene glycol mono (2-trifluoromethylphenyl) ether (8ac)

7ac (170 mg, 0.98 mmol) was dissolved in THF (1.5 mL). Sodium hydride (mineral oil suspension, purity 60%, 51 mg, 1.28 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 3 (204 mg, 0.29 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 8 to 1 → 4 to 1), and ¹ H-NMR integration ratio As a result, an 11 to 1 mixture (90 mg) of 8ac and 3 was obtained. (Equivalent yield of 8ac 82 mg, 0.12 mmol, Equivalent yield 41%) ¹ H-NMR (CDCl ₃ ) δ: 2.82 (1H, br), 3.59-3.64 (44H, br), 3.89 (2H, t, J = 5.1 Hz), 4.21 (2H, t, J = 5.1 Hz), 7.01 (2H, d, J = 7.8 Hz), 7.47 (1H, m), 7.56 (1H, d, J = 7.8 Hz).

  Dodecaethylene glycol mono (3,5-bis (trifluoromethyl) phenyl) ether (8ad)

7ad (225 mg, 0.98 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 45 mg, 1.13 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 3 (200 mg, 0.29 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 30 to 1 → 8 to 1 → 7 to 2), and 8ad (126 mg, 0.17 mmol, 58% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.94 (1H, br), 3.57-3.63 (44H, br), 3.89 (2H, t, J = 4.6 Hz), 4.22 (2H, t, J = 4.6 Hz), 7.35 (2H, s), 7.45 (1H, s).

  Dodecaethylene glycol mono (4-iodophenyl) ether (8ah)

7ah (216 mg, 0.98 mmol) was dissolved in THF (2.0 mL). Sodium hydride (mineral oil suspension, purity 60%, 51 mg, 1.28 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 3 (172 mg, 0.25 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 45 to 2 → 8 to 1), and 8ah (74 mg, 0.10 mmol, 40% yield). ¹ H-NMR (CDCl ₃ ) δ: 2.70 (1H, br), 3.59-3.73 (44H, br), 3.84 (2H, t, J = 4.8 Hz), 4.09 (2H, t, J = 4.8 Hz), 6.70 (2H, d, J = 8.9 Hz), 7.54 (2H, d, J = 8.9 Hz).

  Dodecaethylene glycol mono (p-biphenyl) ether (8aj)

7aj (173 mg, 1.02 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 45 mg, 1.13 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 3 (216 mg, 0.31 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 30 to 1 → 45 to 2 → 8 to 1 → 7 to 2) Purification was performed to obtain 8aj (105 mg, 0.15 mmol, yield 49%). ¹ H-NMR (CDCl ₃ ) δ: 3.57 (1H, t, J = 6.0 Hz), 3.59-3.75 (44H, br), 3.88 (2H, t, J = 4.9 Hz), 4.18 (2H, t, J = 4.9 Hz), 6.99 (2H, d, J = 8.7 Hz), 7.30-7.57 (7H, m).

  Dodecaethylene glycol mono (5,6,7,8-tetrahydro-2-naphthyl) ether (8ap)

7ap (144 mg, 0.97 mmol) was dissolved in THF (1.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 52 mg, 1.30 mmol) was added and stirred at room temperature for 1 hour. A solution of 3 (175 mg, 0.25 mmol) in THF (2.0 mL) was added to this, and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 30 to 1 → 4 to 1), and 8 ap (83 mg, 0.12 mmol, collected) Rate 49%). ¹ H-NMR (CDCl ₃ ) δ: 1.76 (4H, m), 2.70 (4H, m), 3.46 (1H, br), 3.59-3.74 (42H, br), 3.83 (2H, t, J = 5.6 Hz ), 4.09 (2H, t, J = 4.9 Hz), 4.22 (2H, t, J = 4.9 Hz), 6.62 (1H, d, J = 2.6 Hz), 6.67 (1H, dd, J = 8.5 Hz, 2.6 Hz), 6.95 (1H, d, J = 8.5 Hz).

  Dodecaethylene glycol mono (4'-iodo-4-biphenyl) ether (8bw)

7bw (310 mg, 1.05 mmol) was dissolved in THF (5.0 mL). Sodium hydride (mineral oil suspension, purity 60%, 51 mg, 1.28 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. To this was added a solution of 3 (200 mg, 0.29 mmol) in THF (2.0 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated by silica gel column chromatography (silica gel: 5 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 45 to 1 → 45 to 2 → 8 to 1 → 7 to 2), 8 bw (52 mg, 0.06 mmol, 22% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.75 (1H, br), 3.56-3.64 (44H, br), 3.88 (2H, t, J = 4.9 Hz), 4.17 (2H, t, J = 4.9 Hz), 6.98 (2H, d, J = 8.6 Hz), 7.29 (2H, d, J = 8.6 Hz), 7.47 (2H, d, J = 8.6 Hz), 7.73 (2H, d, J = 8.6 Hz).

  Dodecaethylene glycol mono (4- (1,1,3,3-tetramethylbutyl) phenyl) ether (8cb)

8cb (202 mg, 0.98 mmol) was dissolved in THF (2.0 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 46 mg, 1.15 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 3 (203 mg, 0.29 mmol) in THF (2.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The resulting residue was separated and purified by silica gel column chromatography (silica gel: 4 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 30 to 1 → 8 to 1 → 4 to 1), and 8cb (81 mg, 0.11 mmol, yield 38%). ¹ H-NMR (CDCl ₃ ) δ: 0.70 (9H, s), 1.33 (6H, s), 1.69 (2H, s), 2.81 (1H, br), 3.59-3.72 (44H, br), 3.84 (2H , t, J = 5.0 Hz), 4.11 (2H, t, J = 5.0 Hz), 6.82 (2H, d, J = 8.7 Hz), 7.25 (1H, d, J = 8.7 Hz).

  Dodecaethylene glycol mono (2-iodo-4-biphenyl) ether (8cc)

7cc (297 mg, 1.00 mmol) was dissolved in THF (2.5 mL). To this, sodium hydride (mineral oil suspension, purity 60%, 46 mg, 1.15 mmol) was added and stirred at room temperature for 1 hour. To this was added a solution of 3 (212 mg, 0.30 mmol) in THF (2.5 mL) and stirring was continued at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 mL). After drying over anhydrous sodium sulfate, this was filtered and concentrated with an evaporator. The obtained residue was separated and purified by silica gel column chromatography (silica gel: 5 g, developing solvent: ethyl acetate-methanol mixed solvent 1 to 0 → 15 to 2 → 8 to 1 → 7 to 2), and 8 cc (46 mg, 0.06 mmol, 19% yield). ¹ H-NMR (CDCl ₃ ) δ: 2.75 (1H, br), 3.60-3.74 (42H, br), 3.83 (2H, t, J = 4.8 Hz), 3.95 (2H, t, J = 4.8 Hz), 4.22 (2H, t, J = 4.8 Hz), 6.90 (1H, d, J = 8.3 Hz), 7.30-7.53 (6H, m), 8.01 (1H, d, J = 2.3 Hz).

(Test Example 1)
Bioassay at the cellular level
The cytotoxicity against tumor cells was measured using the MTT method. The MTT method is a kind of specific touch method. MTT reagent [3- (4,5-Dimethylthioazol-2-thiazolyl) -2,5-diphenyl-2H-tetrazolium bromide] is converted into insoluble MTT formazan (dark blue) by mitochondrial dehydrogenase in living cells Is done. The amount of MTT formazn produced is measured and expressed as relative cell viability.

Procedure 1. Pre-culture of cells: Hela cell (uterine cancer-derived) suspension adjusted to have an initial cell density of 2 × 10 ⁴ cells / cm ² was dispensed into each well of a 96-well culture plate at 50 μl. The cells were cultured for 24 hours using a CO ₂ incubator (37 ° C., CO ₂ concentration 5%).
2. Dissolution of assay compound: Dissolved in ultrapure water to 333 μg / ml For those which were hardly soluble and clouded, it was considered that the melting operation was completed by continuing stirring with a magnetic stirrer for 2 hours or more. After mixing with an equal volume of double concentration cell culture, it was dispensed into a 48-well culture plate simultaneously with filter sterilization in a clean bench.
3. Preparation of dilution series of test compound: A series of concentrations was prepared by diluting 5 times aseptically using a 48-well culture plate in a clean bench. The following two concentration ranges were prepared according to the strength of cytotoxic activity.
1) 100, 20, 4, 0.8 and O (ppm) (final concentration during main culture)
2) 4, 0.8, 0.16, 0.032 and O (ppm) (final concentration during main culture)
4). Main culture: 75 μl of a culture solution containing a predetermined concentration of test compound was added to each well to initiate main culture (the total volume of the culture solution is 125 μl, so the concentration of the test compound is diluted to 60%. 333 μg / ml (when assay compound is dissolved) → 166.5 μg / ml (when mixed with double concentration culture medium) → 99.9 μg / ml (when main culture is started)). The culture period was 3 days.
5. MTT reaction: a 0.5% MTT reagent into each well of the culture plate after completion of the culture was added 12.5 [mu] l, and allowed to stand for 4 hours in a C0 ₂ incubator base Ta. After stopping the reaction by adding 137.5 μl of 0.04N HCl dissolved in isopropanol to each well, pipetting was sufficiently performed until the blue particles were dissolved.
6). Absorbance measurement: The difference in absorbance at 570 nm (peak) and 630 nm (bottom) was measured with a plate reader.
7). Calculation of cell viability: A relative value with respect to the value in the 0 ppm action group (survival rate 100%) was calculated and used as the cell viability (%) in the concentration action group. In addition, when this value became negative, it was considered that the uniform cell viability was 0%.

  Assays are performed in triplicate and numerical calculations are performed using a simple average of the three values obtained.

(Test results)
The results obtained by the bioassay at the cellular level are shown below. The compound numbers tested are listed on the table. PEG9 is compound 2.

Claims (1)

One polyethylene glycol monoether compound or a salt thereof selected from the group consisting of the following compounds.

(In the above formula, Me represents a methyl group, Boc represents a tert-butoxycarbonyl group, Ac represents an acetyl group, iPr represents an isopropyl group, Et represents an ethyl group, and Ph represents a phenyl group.)