* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With hydrogenchloride; nitromethane In water at 30℃; for 5 h; Inert atmosphere
Into a 100 mL three-necked flask equipped with a thermometer, a three-way cock, and a stirring bar, under a nitrogen stream, 3.96 g (0.03 mol) of 4-hydroxybenzyl alcohol (manufactured by Tokyo Chemical Industry Co., Ltd.), 21 g of methanol (manufactured by Nacalai Tesque, Inc.), two drops of nitromethane (manufactured by Nacalai Tesque, Inc.) were added. While stirring at room temperature, 0.2 g of hydrochloric acid (manufactured by Nacalai Tesque, Inc.) was added dropwise, followed by stirring at 30 ° C. for 5 hours.The area percentage of HPLC at the end of the reaction was 95percent. 0.28 g of pyridine (manufactured by Nacalai Tesque, Inc.) and 8 g of toluene (manufactured by Nacalai Tesque, Inc.) were added and neutralized, methanol was concentrated under reduced pressure, 31 g of toluene and 6 g of water were added to extract And the organic layer was washed with 5 g of water. The obtained organic layer was concentrated, cooled to 10 ° C. or less, and the precipitated crystals were filtered and dried to obtain 3.53 g (yield: 80percent) of colorless 4-methoxymethylphenol. The HPLC purity was 99percent (excluding solvent toluene).
Reference：
[1] Journal of Chemical Research - Part S, 2000, # 6, p. 266 - 268
[2] Journal of Chemical Research - Part S, 2000, # 6, p. 266 - 268
[3] Chemical and pharmaceutical bulletin, 2002, vol. 50, # 3, p. 380 - 383
[4] Patent: JP5747348, 2015, B2, . Location in patent: Paragraph 0058-0062; 0066-0070
[5] Journal of Organic Chemistry, 1988, vol. 53, # 18, p. 4263 - 4273
[6] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1448,1452
[7] Helvetica Chimica Acta, 1977, vol. 60, p. 1304 - 1311
[8] Tetrahedron Letters, 1987, vol. 28, # 45, p. 5551 - 5554
[9] Molecular Crystals and Liquid Crystals (1969-1991), 1985, vol. 130, p. 231 - 248
[10] Molecular crystals and liquid crystals, 1984, vol. 112, # 3-4, p. 319 - 324
[11] Organic Process Research and Development, 2005, vol. 9, # 1, p. 62 - 69
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 13, p. 4462 - 4465
5
[ 67-56-1 ]
[ 106-44-5 ]
[ 623-05-2 ]
[ 5355-17-9 ]
[ 123-08-0 ]
Reference：
[1] Organic Process Research and Development, 2005, vol. 9, # 1, p. 62 - 69
6
[ 67-56-1 ]
[ 106-44-5 ]
[ 623-05-2 ]
[ 5355-17-9 ]
[ 15519-73-0 ]
[ 123-08-0 ]
Reference：
[1] Organic Process Research and Development, 2004, vol. 8, # 6, p. 873 - 878
7
[ 67-56-1 ]
[ 106-44-5 ]
[ 623-05-2 ]
[ 5355-17-9 ]
[ 123-08-0 ]
[ 99-96-7 ]
Reference：
[1] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 1999, vol. 38, # 8, p. 792 - 796
8
[ 107-31-3 ]
[ 623-05-2 ]
[ 14191-95-8 ]
Yield
Reaction Conditions
Operation in experiment
96%
With sulfuric acid In methanol; dichloromethane; water
EXAMPLE 1 Preparation of para-hydroxybenzyl cyanide A mixture of 4.96 para-hydroxybenzyl alcohol 2.8 g. sodium cyanide 18 ml. methanol and 6 ml. of methyl formate is heated with stirring under reflux for a period of 70 minutes. The reaction mixture is distilled under partial vacuum to recover starting material, and the residue stirred with 20 ml. water and sulphuric acid added until the mixture is no longer alkaline. The product is now isolated by extracting 3 times each time with 15 ml. methylene chloride. The combined solvent extracts are washed with 10 ml. aqueous sodium bicarbonate and solvent evaporated finally under vacuum at a temperature of 60° C. There is obtained 5.11 g. of crude para-hydroxybenzyl cyanide corresponding to a weight yield of 96percent of theory. On simple distillation under oil pump vacuum there is obtained a pale yellow fraction m.pt. 65° C. corresponding to a weight yield equivalent to 93percent of theory. Melting point data indicates that this material has an absolute purity of 97percent.
Reference：
[1] Patent: US4378319, 1983, A,
9
[ 623-05-2 ]
[ 109-94-4 ]
[ 14191-95-8 ]
Reference：
[1] Patent: US4378319, 1983, A,
10
[ 110-74-7 ]
[ 623-05-2 ]
[ 14191-95-8 ]
Reference：
[1] Patent: US4317781, 1982, A,
11
[ 773837-37-9 ]
[ 623-05-2 ]
[ 14191-95-8 ]
Reference：
[1] Organic Process Research and Development, 1998, vol. 2, # 4, p. 274 - 276
[2] Journal of Natural Medicines, 2010, vol. 64, # 3, p. 245 - 251
[3] Organic Process Research and Development, 2016, vol. 20, # 7, p. 1354 - 1362
12
[ 623-05-2 ]
[ 14191-95-8 ]
Reference：
[1] Patent: US3983160, 1976, A,
13
[ 623-05-2 ]
[ 17194-82-0 ]
Reference：
[1] Organic Process Research and Development, 1998, vol. 2, # 4, p. 274 - 276
14
[ 623-05-2 ]
[ 52727-95-4 ]
Reference：
[1] Journal of the American Chemical Society, 1999, vol. 121, # 24, p. 5835 - 5836
[2] Patent: CN105503747, 2016, A,
[3] Patent: CN105481835, 2016, A,
15
[ 64-17-5 ]
[ 623-05-2 ]
[ 57726-26-8 ]
Yield
Reaction Conditions
Operation in experiment
75%
With hydrogenchloride In water at 35℃; for 3 h;
Regarding Example 2, instead of methanol, the same operation as in Example 2 was carried out except that ethanol was used. The residue was purified under reduced pressure distillation (boiling point: 110-119 ° C./1.5 Torr) to give 4-ethoxymethylphenol. Yield is 75percent. HPLC purity was 98percent. In a 200 mL three-necked flask equipped with thermometer, three way cock, stirrer, under a nitrogen stream, 15.0 g (0.12 mol) of 4-hydroxybenzyl alcohol, 69 g of methanol, 0.06 g of nitromethane were added. While stirring at room temperature, a mixed solution of 0.45 g of hydrochloric acid and 3.0 g of methanol was added dropwise, and the mixture was stirred at 35 ° C. for 3 hours. The area percentage of HPLC at the end of the reaction was 99percent. A mixed solution of 0.38 g of imidazole (manufactured by Aldrich Co., Ltd.) and 1.1 g of methanol was added dropwise to neutralize, and methanol was concentrated under reduced pressure. 60 g of isopropyl ether (manufactured by Nacalai Tesque, Inc.) and 22.5 g of water were added and extracted, and 27 g of water and 0.26 g of acetic acid (manufactured by Nacalai Tesque) were added to the organic layer and washed. After washing the organic layer twice with water, the organic layer was concentrated and seed crystals were added and the mixture was slowly cooled to about 8 ° C. The precipitated crystals were filtered and dried to obtain 12.0 g (yield: 72percent) of colorless 4-methoxymethylphenol. HPLC purity was 99percent.
Reference：
[1] Patent: JP5747348, 2015, B2, . Location in patent: Paragraph 0060; 0063-0065
[2] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1448,1452
[3] Molecular Crystals and Liquid Crystals (1969-1991), 1985, vol. 130, p. 231 - 248
[4] Molecular crystals and liquid crystals, 1984, vol. 112, # 3-4, p. 319 - 324
16
[ 623-05-2 ]
[ 78-39-7 ]
[ 57726-26-8 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1988, # 5, p. 901 - 904
Reference：
[1] Journal of the American Chemical Society, 1936, vol. 58, p. 1565,1566
21
[ 623-05-2 ]
[ 29122-68-7 ]
Reference：
[1] Organic Process Research and Development, 1998, vol. 2, # 4, p. 274 - 276
[2] Organic Process Research and Development, 1998, vol. 2, # 4, p. 274 - 276
With triethylamine In tetrahydrofuran at 20℃; for 1 h; Inert atmosphere
4-Pivaloyloxybenzyl alcohol (Compound Ml)._:To a stirred solution of 4-hydroxybenzyl alcohol (6.21 g, 50 mmol) in anhydrous THF (50 mL) containing triethylamine (10.43 mL, 75 mmol) pivaloyl chloride (6.79 mL, 55 mmol) was added drop wise at room temperature under argon atmosphere. After being stirred for 60 min, the reaction mixture was quenched with water (0.2 mL) and left overnight. It was then diluted with EtOAc (-400 mL) and washed with saturated NaHC03 (3 x 100 mL) and brine (100 mL), It was then dried over Na2S04, filtered and concentrated. The product (TLC: Rf~0.4 in ethyl acetate/hexanes (4:6)) was isolated using flash chromatography on silica gel column (4 x 20 cm) eluting with ethyl acetate/hexanes (4:6). Pure fractions were pooled, concentrated and dried in vacuum to give 7.75 g (74percent) of colorless oil. 'H NMR (0374) (DMSO-de): δ 7.35 (d, 2H, J=8.6 Hz), 7.04 (d, 2H, J=8.6 Hz), 5.22 (t, 1H), 4.50 (d, 2H), 1.31
74%
With triethylamine In tetrahydrofuran at 20℃; for 1 h; Inert atmosphere
[00201] To a stirred solution of 4-hydroxybenzyl alcohol (6.21 g, 50 mmol) in anhydrous THF (50 mL) containing triethylamine (10.43 mL, 75 mmol) pivaloyl chloride (6.79 mL, 55 mmol) was added drop wise at room temperature under argon atmosphere. After being stirred for 60 min, the reaction mixture was quenched with water (0.2 mL) and left overnight. It was then diluted with EtOAc (-400 mL) and washed with saturated NaHC03 (3 x 100 mL) and brine (100 mL). It was then dried over Na2S04, filtered and concentrated. The product (TLC: Rf~0.4 in ethyl acetate/hexanes (4:6)) was isolated using flash chromatography on silica gel column (4 x 20 cm) eluting with ethyl acetate/hexanes (4:6). Pure fractions were pooled, concentrated and dried in vacuum to give 7.75 g (74percent) of colorless oil. XH NMR (DMSO-d6): δ 7.35 (d, 2H, J=8.6 Hz), 7.04 (d, 2H, J=8.6 Hz), 5.22 (t, 1H), 4.50 (d, 2H), 1.31 (s, 9H).
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 23, p. 9470 - 9479
[2] Journal of Organic Chemistry, 2006, vol. 71, # 22, p. 8651 - 8654
[3] Chemical Communications, 2018, vol. 54, # 61, p. 8466 - 8469
[4] Patent: WO2015/153496, 2015, A1, . Location in patent: Paragraph 00201
[5] Patent: WO2015/153510, 2015, A1, . Location in patent: Paragraph 00201
[6] Angewandte Chemie - International Edition, 2008, vol. 47, # 45, p. 8719 - 8722
[7] Journal of Natural Products, 2004, vol. 67, # 9, p. 1557 - 1564
30
[ 623-05-2 ]
[ 122320-73-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 924 - 928
With lithium perchlorate In acetonitrile at 20℃; Electrochemical reaction
General procedure: A 40 cm3 acetonitrile solution of alcohols 1a–1i(1 mmol) in LiClO4 (0.05 g) was electrolyzed at the2.0 V versus SCE. After completion of the electro-oxidationof alcohols to their corresponding aldehydes,indoles 2a, 2b (2 mmol) were added and electrolyzed at-0.9 V versus SCE. In the two mentioned stages, electrosynthesisreactions were done in an undivided cellequipped with graphite rods as the cathode and Pt-anodeat room temperature. The electrolysis was terminatedwhen the current decreased by more than 95 percent. Amagnetic stirrer was employed during the electrolysis.The process was interrupted several times during theelectrolysis and the graphite rod was washed in acetonein order to reactivate it. After completion of the electrocondensation,the solvent was evaporated and theresulting crude product was purified by preparative thinlayerchromatography on silica gel (eluent: n-hexane–EtOAc, 4:1) to afford 3,30-di(indolyl)methanes 3a–3k.All the products were characterized by comparison oftheir melting points and also spectroscopic data (IR, 1HNMR and mass spectra) with those of the authenticsamples in literature
With ytterbium(III) triflate In acetonitrile at 80℃; for 5h;
80%
With hydrogenchloride; nitromethane In water at 30℃; for 5h; Inert atmosphere;
1 Example 1 4-methoxymethylphenol
Into a 100 mL three-necked flask equipped with a thermometer, a three-way cock, and a stirring bar, under a nitrogen stream, 3.96 g (0.03 mol) of 4-hydroxybenzyl alcohol (manufactured by Tokyo Chemical Industry Co., Ltd.), 21 g of methanol (manufactured by Nacalai Tesque, Inc.), two drops of nitromethane (manufactured by Nacalai Tesque, Inc.) were added. While stirring at room temperature, 0.2 g of hydrochloric acid (manufactured by Nacalai Tesque, Inc.) was added dropwise, followed by stirring at 30 ° C. for 5 hours.The area percentage of HPLC at the end of the reaction was 95%. 0.28 g of pyridine (manufactured by Nacalai Tesque, Inc.) and 8 g of toluene (manufactured by Nacalai Tesque, Inc.) were added and neutralized, methanol was concentrated under reduced pressure, 31 g of toluene and 6 g of water were added to extract And the organic layer was washed with 5 g of water. The obtained organic layer was concentrated, cooled to 10 ° C. or less, and the precipitated crystals were filtered and dried to obtain 3.53 g (yield: 80%) of colorless 4-methoxymethylphenol. The HPLC purity was 99% (excluding solvent toluene).
66%
With toluene-4-sulfonic acid for 6h; Ambient temperature;
at 150℃;
With hydrogenchloride Heating;
68.7 g
With hydrogenchloride In water for 1h; Ambient temperature;
With hydrogenchloride; In water; at 35.0℃; for 3.0h;
Regarding Example 2, instead of methanol, the same operation as in Example 2 was carried out except that ethanol was used. The residue was purified under reduced pressure distillation (boiling point: 110-119 C./1.5 Torr) to give 4-ethoxymethylphenol. Yield is 75%. HPLC purity was 98%.In a 200 mL three-necked flask equipped with thermometer, three way cock, stirrer, under a nitrogen stream, 15.0 g (0.12 mol) of 4-hydroxybenzyl alcohol, 69 g of methanol, 0.06 g of nitromethane were added. While stirring at room temperature, a mixed solution of 0.45 g of hydrochloric acid and 3.0 g of methanol was added dropwise, and the mixture was stirred at 35 C. for 3 hours. The area percentage of HPLC at the end of the reaction was 99%. A mixed solution of 0.38 g of imidazole (manufactured by Aldrich Co., Ltd.) and 1.1 g of methanol was added dropwise to neutralize, and methanol was concentrated under reduced pressure. 60 g of isopropyl ether (manufactured by Nacalai Tesque, Inc.) and 22.5 g of water were added and extracted, and 27 g of water and 0.26 g of acetic acid (manufactured by Nacalai Tesque) were added to the organic layer and washed. After washing the organic layer twice with water, the organic layer was concentrated and seed crystals were added and the mixture was slowly cooled to about 8 C. The precipitated crystals were filtered and dried to obtain 12.0 g (yield: 72%) of colorless 4-methoxymethylphenol. HPLC purity was 99%.
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 0.75h;
Imidazole (85.1 mg, 1.25 mmol) and tert-butyl(chloro)dimethylsilane (TBSC1, 90.4 mg, 0.600 mmol) were added to a solution of 4-hydroxybenzyl alcohol (XLVI) (62.1 mg, 0.500 mmol) in DMF (4 mL) and the mixture stirred at rt for 45 minutes. The reaction was diluted with ethyl acetate (30 mL) and the organic phase washed with water (30 mL), sat. aq. NaHCCO3 (30 mL) and brine (30 mL), dried (MgS04) and concentrated under reduced pressure to give TBS ether XL VII (119 mg, quant.) as a colourless oil that was used without purification.1H NMR (400 MHz, CDC13) δ 7.21 - 7.15 (m, 2H), 6.83 - 6.78 (m, 2H), 4.66 (s, 2H), 0.93 (s, 9H), 0.08 (s, 6H).
94%
12 g of 4-hydroxymethyl-phenol, 180 ml of dichloromethane and 14 g of imidazole are introduced into a 250 ml flask. The mixture is cooled to 0 C. and a solution constituted by 32 g of t-butyl-dimethyl silyl chloride in 30 ml of dichloromethane are added thereto in about one hour. After adding it is left to recover at ambient temperature and such conditions are maintained for two hours. Thus the disappearance of the initial product is verified under TLC; if positive, 200 ml of a saturated NaCl solution are added, the mixture is stirred vigorously for 10′, then the two phases are left to decant; the lower organic phase is washed using 200 ml of the saturated NaCl solution and 200 ml of deionised water, then concentrated under vacuum at 40 C. to obtain 34.1 g of a pale yellow oil. 340 ml of DMF and 34 ml of deionised water followed by 15.3 g of cesium carbonate are added to such residue. The mixture is stirred for two hours at 25 C., then it is diluted with 100 ml of deionised water and 170 ml of saturated NaCl solution and the mixture is extracted using 205 ml of toluene. The organic phase is washed using 100 ml of saturated NaCl solution and two 135 ml portions of deionised water, then evaporated to residue obtaining 22 g of an oil constituted by the desired product (94% yield)
92.8%
With 1H-imidazole; In dichloromethane; at 20℃; for 2.5h;
P-hydroxybenzyl alcohol (50) (5.00 g) was dissolved in N, N-dimethylformamide (40 mL), and under ice cooling,Imidazole (3.02 g, 44.4 mmol) and tert-butyldimethylchlorosilane (6.68 g) were added, and the mixture was stirred at room temperature for 2.5 hours.The reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.The obtained residue was purified by silica gel flash column chromatography (developing solvent n-hexane: ethyl acetate = 9: 1 to 1: 1) to give the title compound (51) (8.91 g, yield 92.8%) as a colorless oil .
92%
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere;
To a solution of 4-hydroxybenzyl alcohol (1.24 g, 0.01 mole) in DMF (15 mL) were added tert-butyldimethylsilyl chloride (1.8 g, 0.012 mmol) and imidazole (1.7 g, 0.025 mmol) at room temperature under nitrogen. After the reaction mixture was stirred for 16 hours, H2O (30 mL) was added to the mixture. The resulting mixture was extracted with EA (2 x 30 mL). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to provide compound Int- A1 (2.19 g, 92 %). 1H-NMR (400 MHz, CDCl3) d 7.16 (d, J = 6.9 Hz, 2H), 6.74 (d, J = 6.9 Hz, 2H), 5.69 (s, 1H), 4.66 (s, 2H), 0.93 (s, 9H), 0.09 (s, 6H)
89%
With pyridine; at 0℃; for 3h;
EXAMPLE 1; This example demonstrates the synthesis of N-{2-[4-(isopropylcarbonyl- oxy)benzylthio]benzoyl}-p-alaninamide. The reaction scheme is depicted in FIG. 1.; The synthesis of 4-(isopropylcarbonyl-oxy)benzyl iodide 5a was carried out on the basis of Iyer et al. [Bioorg. Med. Chem., 6, 1917-1922 (1996)]. 4-hydroxybenzyl alcohol 1 (20.0 mmol, 2.48 g) was dissolved in pyridine (40 ml), and the solution was cooled to 0 C. To the solution TBDMS-C1 (20.0 mmol, 3.01 g) was added at 0 C. The mixture was stirred for 3 hours at 0 C. The solvent was removed by using a rotary evaporator. EtOAc (400 ml) was added to the residue obtained. The organic layer was washed with brine and IN hydrogen chloride (aq) and then was dried over anhydrous sodium sulfate. After filtration, the solvent was removed. The residue obtained was purified by flash chromatography (n- hexane-EtOAc = 5:1) to give TBDMS-protected compound 2 (4.22 g, 89%, oil). Rf = 0.36 (n-hexane-EtOAc = 5:1).
86.7%
With 1H-imidazole; In tetrahydrofuran; at 0 - 20℃; for 2.16667h;Inert atmosphere;
4-hydroxy-benzyl alcohol (214.5 mg, 1.7279 mmol) THF (4 mL) solution in imidazole (258.8 mg, 3.8014 mmol) of the reaction solution obtained by the addition of, THF of TBSCl (286.5 mg, 1.9007 mmol) (2 mL) solution under argon, was added at 0 C.. The reaction solution was stirred for 10 minutes at 0 C, and the mixture was stirred for 2 hours at room temperature. The resulting solution to terminate the water (7 mL) was added the reaction, the aqueous layer was separated and extracted three times with dichloromethane (7 mL x 3). The combined organic layers were dried over magnesium sulfate, the solvent was distilled off. The residue was purified by column chromatography (hexane: ethyl acetate = 4: 1-0: 1) to give the title compound (357.0 mg, 1.4975 mmol, 86.7%, colorless oil).
81.2%
With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃;
(4) Add 4-hydroxybenzyl alcohol (0.5g, 4.03mmol) and imidazole (0.274g, 4.03mmol) to 5mL DMF, cool to 0 C, and add tert-butyldiphenylchlorosilane (0.6g, 4.03) mmol) and stirred at room temperature overnight.The reaction solution was washed with brine, extracted with ethyl acetate (3 × 20 mL), the organic phase was dried, the solvent was removed under reduced pressure, and compound 4 was obtained by column chromatography (0.78 g, yield: 81.2%).
75%
With 1H-imidazole; In tetrahydrofuran; at 0 - 20℃; for 3h;
4-Hydroxymethylphenol (600 mg, 4.83 mmol) was dissolved in well-dried THF (5 mL) and cooled to 0 C in ice-bath. Then imidazole (658 mg, 9.67 mmol) was added. After stirring for 10 min, tert-butylchlorodimethylsilane (TBDMSCl, 729 mg, 4.83 mmol) was added. The reaction was stirred at room temperature for 3 h. The mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (V(EA)/V(Hexane) = 1:15) to give the desired compound 7 (860 mg, 75%). 1H NMR (300 MHz, CDCl3): δ = 7.08 (d, J = 8.08 Hz, 2H), 6.66 (d, J = 8.10 Hz, 2H), 5.18 (s, 1H), 4.57 (s, 1H), 0.84 (s, 9H), 0.7 (s, 6H). 13C NMR (75 MHz, CDCl3): δ = 155.01, 132.89, 128.13, 115.37, 65.16, 26.11, 18.58, -5.03. ESI-MS: Calcd for C13H21O2Si 237.1. Found 237.1 [M-H]-.
71%
In an inert 100 mL three-necked flask 6.02 g (88.6 mmol, 2.19 eq) imidazole and 6.76 g (44.8 mmol, 1.11 eq) tert- butyl(chloro)dimethylsilane were placed. After evacuating and flooding with argon twice, 40.0 mL dry DMF were added and stirred for 10 minutes at room temperature. Afterwards 5.00 g (40.3 mmol, 1.00 eq) 4-(hydroxymethyl)phenol were added. The stirring was continued for 2.5 hours. The suspension was mixed with 150 mL brine and extracted twice with 100 mL ethyl acetate. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica g (28.5 mmol, 71 %).
70%
With 1H-imidazole; In tetrahydrofuran; at 20℃; for 2h;Cooling with ice;
To a dry flask, 4-hydroxymethylphenol (5 g, 40.28 mmol, 1 eq.) was dissolved in dry THF (42 ml_) and cooled in an ice-bath. Imidazole (5.48 g, 80.56 mmol, 2 eq.) was added and the reaction mixture was left stirring for 10 minutes. Then tert- butylchlorodimethylsilane (7.28 g, 48.33 mmol, 1.2 eq) was added. The reaction stirred at room temperature for 2 hours until LCMS showed full consumption of the starting material. The mixture was quenched with ammonium chloride (15 ml_) and extracted with ethyl acetate (3x 60 ml_). The combined organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product was purified by column chromatography on silica gel using 4:1 heptane/EtOAc as eluent to give the desired product 1 in 70% yield. (0414) 1H-NMR (400 MHz, CDCh): d = 7.21 (dd, J = 21.4, 8.0 Hz, 2H), 6.80 (d, 1 H), 4.69 (s, 2H), 0.96 (s, 9H), 0.12 (s, 6H). 13C-NMR (101 MHz, CDCh): d = 154.62, 133.50, 127.87, 115.11 , 64.83, 26.00, 18.46, 5.15. UPLC-MS (ESI): m/z found 237.0 [M-H] , required 237.1 [C13H2i02Si]-.
68%
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 2h;
[00783] To a solution of 4-(hydroxymethyl)phenol (2 g, 16.1 mmol) in DMF (20 mL) was added TBSC1 (2.7 g, 17.9 mmol) and imidazole (2.2 g, 32.3 mmol). The reaction was stilTed at room temperature for 2 hr. The reaction was diluted with EtOAc (100 mL) and washed with 0.1 N HC1 (50 mLx3). The organic phase was dried over Na2SO4 and concentrated. Column chromatography gave 4-(((tert-butyldimethylsilyl)oxy)methyl)phenol (2.6 g, 68%).
68%
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 2h;
To a solution of 4-(hydroxymethyl)phenol (2 g, 16.1 mmol) in DMF (20 mL) was added TBSCl (2.7 g, 17.9 mmol) and imidazole (2.2 g, 32.3 mmol). The reaction was stirred at room temperature for 2 hr. The reaction was diluted with EtOAc (100 mL) and washed with 0.1 N HC1 (50 mLx3). The organic phase was dried over Na2S04 and concentrated. Column chromatography gave 4-(((tert-butyldimethylsilyl)oxy)methyl)phenol (2.6 g, 68%).
68%
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 2h;
[00787] SDC-TRAP-0 171[00788] 4-((((2- (2,6-dioxopiperidin-3-yl)- 1 -oxoisoindolin-4-yl)carbamoyl)oxy) methyl)phenyl-4- (4- (3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H- 1 ,2,4-triazol-4-yl)-2-fluorobenzyl)piperazine- 1 -carboxylateHOTBSCIYOH DMF[00789] To a solution of 4-(hydroxymethyl)phenol (2 g, 16.1 mmol) in DMF (20 mL) was added TBSC1 (2.7 g, 17.9 mmol) and imidazole (2.2 g, 32.3 mmol). The reaction was stirred at room temperature for 2 hr. The reaction was diluted with EtOAc (100 mL) and washed with 0.1 N HC1 (50 mLx3). The organic phase was dried over Na2SO4 and concentrated. Column chromatography gave4- (((tert-butyldimethylsilyl)oxy)methyl)phenol (2.6 g, 68%).
68%
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 2h;
To a solution of 4-(hydroxymethyl)phenol (2 g, 16.1 mmol) in DMF (20 mL) was added TBSC1 (2.7 g, 17.9 mmol) and imidazole (2.2 g, 32.3 mmol). The reaction was stirred at room temperature for 2 hr. The reaction was diluted with EtOAc (100 mL) and washed with 0.1 N HC1 (50 mLx3). The organic phase was dried over Na2SO4 and concentrated. Column chromatography gave 4-(((tert-butyldimethylsilyl)oxy)methyl)phenol (2.6 g, 68%).
3.67 g
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 16h;Cooling with ice; Inert atmosphere;
The Reference Example 1-(g) was also prepared as follows. To a solution of 4-hydroxybenzenemethanol (2.00 g) in dehydrated dimethylformamide (10 mL) in a 100 mL round-bottom flask were added tert-butylchlorodimethylsilane (2.67 g) and imidazole (2.20 g) under ice-cooling under argon atmosphere with stirring, and the resulting mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, 0.1 M hydrochloric acid was added thereto, and the resulting mixed solution was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residues were purified by medium pressure preparative chromatography (silica gel, elution solvent; hexane : ethyl acetate) to give 4-(((tert-butyldimethylsilyl)oxy)methyl)phenol (3.67 g) as a colorless oil.
4-Hydroxybenzyl alcohol (17, 4.0 g, 32 mmol) and anhyd K2CO3 (22.3 g, 161 mmol, 5 equiv) were dissolved in anhyd DMF (80 mL) in a 250-mL round-bottom flask. The suspension was purged with argon and stirred for 30 min at r.t. Then BnBr (13.8 g, 80.6 mmol, 2.5 equiv) was added by syringe to the suspension and the mixture was stirred for 20 h at r.t. Then mixture was filtered through celite and the celite cake was washed with Et2O (100 mL). The filtrate was washed with H2O (3 × 60 mL), followed by sat. brine (2 × 50 mL). The Et2O solution was dried (anhyd MgSO4), and the solvent was evaporated using a rotary evaporator and then under high vacuum to give pure 18 (5.982 g, 27.95 mmol, 87%) as a white solid; Rf = 0.75 (silica gel, EtOAc-n-hexane, 1:1); mp 73-75 C.
In a 30 ml autoclave fitted with a dropping funnel, a solution of 0.01 mmol of Rh[(dppb)COD]BF4 in 5 ml of methanol was hydrogenated at room temperature and a hydrogen pressure of 50 bar for 15 minutes. A solution of 5 mmol of 4-hydroxybenzaldehyde and 10 mmol of piperidine in 10 ml of methanol was subsequently added from the dropping funnel and hydrogenation was continued for a further 2 hours. After evaporation of the solvent, the residue was examined by NMR spectroscopy. At a conversion of above 99%, the ratio of: N-(4-hydroxybenzyl)piperidine to 4-hydroxybenzyl alcohol was found to be 94/1.
With triethylamine; In tetrahydrofuran; at 20℃; for 1h;Inert atmosphere;
4-Pivaloyloxybenzyl alcohol (Compound Ml)._:To a stirred solution of 4-hydroxybenzyl alcohol (6.21 g, 50 mmol) in anhydrous THF (50 mL) containing triethylamine (10.43 mL, 75 mmol) pivaloyl chloride (6.79 mL, 55 mmol) was added drop wise at room temperature under argon atmosphere. After being stirred for 60 min, the reaction mixture was quenched with water (0.2 mL) and left overnight. It was then diluted with EtOAc (-400 mL) and washed with saturated NaHC03 (3 x 100 mL) and brine (100 mL), It was then dried over Na2S04, filtered and concentrated. The product (TLC: Rf~0.4 in ethyl acetate/hexanes (4:6)) was isolated using flash chromatography on silica gel column (4 x 20 cm) eluting with ethyl acetate/hexanes (4:6). Pure fractions were pooled, concentrated and dried in vacuum to give 7.75 g (74%) of colorless oil. 'H NMR (0374) (DMSO-de): delta 7.35 (d, 2H, J=8.6 Hz), 7.04 (d, 2H, J=8.6 Hz), 5.22 (t, 1H), 4.50 (d, 2H), 1.31
74%
With triethylamine; In tetrahydrofuran; at 20℃; for 1h;Inert atmosphere;
[00201] To a stirred solution of 4-hydroxybenzyl alcohol (6.21 g, 50 mmol) in anhydrous THF (50 mL) containing triethylamine (10.43 mL, 75 mmol) pivaloyl chloride (6.79 mL, 55 mmol) was added drop wise at room temperature under argon atmosphere. After being stirred for 60 min, the reaction mixture was quenched with water (0.2 mL) and left overnight. It was then diluted with EtOAc (-400 mL) and washed with saturated NaHC03 (3 x 100 mL) and brine (100 mL). It was then dried over Na2S04, filtered and concentrated. The product (TLC: Rf~0.4 in ethyl acetate/hexanes (4:6)) was isolated using flash chromatography on silica gel column (4 x 20 cm) eluting with ethyl acetate/hexanes (4:6). Pure fractions were pooled, concentrated and dried in vacuum to give 7.75 g (74%) of colorless oil. XH NMR (DMSO-d6): delta 7.35 (d, 2H, J=8.6 Hz), 7.04 (d, 2H, J=8.6 Hz), 5.22 (t, 1H), 4.50 (d, 2H), 1.31 (s, 9H).
In toluene; for 12h;Heating / reflux;Product distribution / selectivity;
Example 13Synthesis of (2-Hydroxy-4-phenyl-3 ,4-dihydro-2H-chromen-6-yl)methanolN-methylpiperazine 1) Toluene, reflux, 10h2) Toluene, EtOAc, HCi 2M wash 3) Toluene, EtOAc, Crystallisation4-(Hydroxymethyl)phenol trans-Cinnamaldehyde (2-Hydroxy-4-phenyl-3,4- dihydro-2H-chromen-6- yl)methanol 4-(Hydroxymethyl)phenol (2.515kg, 20.26mol, leq) was stirred with TV-methylpiperazine (5.06kg, 50.52mol, 2.5eq) in toluene (17.74kg, 20.5L, 8.15mL/g) and then heated to reflux. trans-Cinnamaldehyde (3.35kg, 25.35mol, 1.25eq) was then added over 2 hours maintaining the reaction mixture at reflux. The transfer line was washed with toluene (0.9Kg, 0.35ml/g). Once the addition was complete the reaction mixture continued to be heated at reflux for 19h. Then some toluene was distilled off, reducing the volume to approximately 18.5L. The mixture was then allowed to cool to room temperature and EtOAc was added (13.5Kg 15L, 6mL/g). The organic phase was washed with HCl 2M <n="24"/>(46.4kg, 46.4L 18.5mL/g). The phases were separated, and ethyl acetate (27.1kg, 3OL, 12ml/g) was added to dilute the organic layer. The organic phase was washed with IM HCl (17.75kg, 17.75L 7.1mL/g), 5% w/w NaHCO3 (17.5L, 7mL/g) and water (25L, lOmL/g). The phases were separated, and toluene (6.5Kg, 7.5L, 3ml/g) was added to the organic layer, and the mixture was distilled to approximately 8L. Additional toluene (7kg) was charged followed by ethyl acetate (3.9L). The mixture was heated to reflux then cooled to 220C at lC/minute, then stirred for 20hrs. The suspension was cooled to 20C and granulated for 2hrs. The slurry was filtered and the cake was washed with cold toluene (2x4.3Kg, 5L). The resulting pale tan solid was dried in vacuum for 68h at 40C, to provide 2.76Kg of product (2-hydroxy-4-phenyl-3,4-dihydro-2H-chromen-6- yl)methanol (53.4% yield) which was used in the following example without purification: 1H NMR 300MHz d6 DMSO delta ppm (mixture of isomers, 10:1): 1.95-2.10 (m, 2H), 2.15- 2.35 (m, minor isomer), 3.25-3.35 (m, IH), 4.15-4.35 ( m, 3H), 4.80-4.95 (m, IH), 5.35- 5.45 (m, minor isomer), 5.46-5.55 (m, IH), 6.51-6.54 (m, minor isomer), 6.58-6.63 (m, IH), 6.75 (d J=8.2Hz, IH), 6.98-7.40 (m, 6H).; Example 19 Synthesis of r2-(4-Methylpiperazin- 1 -yl)-4-phenyl-2H-chroman-6-vn-methanol4-(Hydroxymethyl)phenol tra?s-Cinnamaldehyde [2 (4-Methylpiperazin-1 -yl)-4-phenyl- 3,4-dihydro-2H-chromen-6-yl]methanol tra«5-Cinnamaldehyde (66.5g, 0.66mol, 1.25eq) was diluted with toluene (10OmL, 2mL/g based on 4-(hydroxymethyl)phenol), and was washed twice with a saturated solution of sodium hydrogen carbonate (2x10OmL) and once with water (10OmL). This toluene solution of cinnamaldehyde was then added over 2 hours to a mixture of 4- (hydroxymethyl)phenol (5Og, 0.40mol, leq) and N-methylpiperazine (113mL, l.Omol, 2.5eq) in toluene (35OmL, 7mL/g) heated to reflux under Dean-Stark conditions. Once the addition was complete the reaction mixture continued to be heated at reflux under Dean- Stark conditions for 1Oh. The mixture was then cooled to room temperature and a sample was evaporated to dryness under reduced pressure for analytical purposes. The dark oil contains crude [2-(4-methylpiperazin- 1 -yl)-4-phenyl-2H-chroman-6-yl]methanol (mixture of diastereoisomers) and impurities.EI-GC-MS (Agilent), column: ZB-5etaT, Temperature program: 5O0C (0.5min), 20C/min to 32O0C (2min) obtained: RT=24.4min, MW: 338.1H NMR (DMSO) (crude mixture) 30OmHz delta (ppm): 7.40-7.00 (28H, m); 6.89 (IH, d, J=2.0 Hz); 6.81 (IH, d, J=8.3 Hz); 6.75 (IH, d, J=8.2 Hz); 6.54 (IH, d, J=LO Hz); 4.87 (IH, d, J=10.2 Hz); 4.45 (IH, d, J=10.0 Hz); 4.40-4.20 (3H, m); 4.36 (2H, s); 4.23 (1.8H, s); 2.86 (4H, m); 2.80-2.50 (14H, m); 2.50-2.00 (50H, m) including 2.31 (s); 2.17 (s); 2.14 (s); 2.11 (s).
With potassium hydroxide; In water; dimethyl sulfoxide;
(i) Synthesis of 4-n-propyloxybenzyl alcohol 4-hydroxybenzyl alcohol (12.4 g: 100.0 mmol) was dissolved in 100 ml of dimethylsulfoxide (DMSO), and an aqueous solution of potassium hydroxide (KOH/H2O: 6.6 g/15 ml) was added to the mixture. After the resultant mixture was dissolved homogeneously by stirring, n-propyl bromide (12.3 g:100.0 mmol) was added thereto, and the reaction was carried out at a room temperature for 24 hours. The reaction mixture was poured into 1L of an iced water and a solid was formed by stirring. The resultant solid was collected by filtration, dried, and recrystallized from toluene to provide 15.8 g (95.2 mmol) of 4-n-propyloxybenzyl alcohol.
With sodium hydroxide; sodium chloride; potassium carbonate; In water; acetone;
Reference Example 118 A mixture (50 ml) of 4-hydroxybenzyl alcohol (1.5 g), 1-bromopropane (1.3 ml), potassium carbonate (2.5 g) and acetone (50 ml) was stirred at 60 C. for 8 hours. After concentration under reduced pressure, the residue was mixed with water and was extracted with ethyl acetate. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. The resulting organic layer was concentrated under reduced pressure to obtain 4-propoxybenzyl alcohol (1.37 g) as a yellow oily substance. 1H-NMR (200 MHz, CDCl3) delta1.04 (3H, t, J=7.3 Hz), 1.52 (1H, t, J=5.4 Hz), 1.72-1.90 (2H, m), 3.93 (2H, t, J=6.6 Hz), 4.62 (2H, d, J=5.4 Hz), 6.89 (2H, d, J=8.8 Hz), 7.29 (2H, d, J=8.8 Hz).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; for 3h;Heating / reflux;
A 4-Hydroxybenzyl alcohol (1 g, 0.0081 mol, A) was suspended in acetonitrile (2 ml), to which 2-methoxydimethyl malonate (0.0161 mol, 2.61 g, 2.2 ml, B) and DBU (0.0041 mol, 0.62 g, 0.61 ml, C) were added. The suspension was refluxed for 3 hours. The reaction mixture was cooled and the solvent evaporated. 20 ml water were added to the residue and the emulsion obtained was extracted with 3 x 20 ml ethyl acetate. The collected organic phases were dried over MGS04. After removal of the solvent by distillation a yellowish oil (1.92 g, 88 %) was obtained, which crystallised after being left to stand.
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20 - 70℃; for 6 - 8h;
A) To a solution of 4-hydroxy benzaldehyde (0.213 g, 0.0023 M) and 2,3, 5,6- <strong>[2402-79-1]tetrachloropyridine</strong> (0.493 g, 0.0023 M) in DMF (8 ml) was added cesium carbonate (0.740 g, 0.0023 M) at room temperature. The reaction mixture was stirred at 70 oC for 4-6 h. The solvent was removed from reaction mixture under vacum and crude mixture was taken into chloroform and washed with water, dried over sodium sulfate and concentrated. The pure product was obtained by column chromatography in 80% yield. B) To a solution of 4-hydroxy benzyl alcohol (0.218 mg, 0.0023 mmol) and 2,3, 5,6- <strong>[2402-79-1]tetrachloropyridine</strong> (0.493 mg, 0.0023mmol) in DMF (8 ML) was added cesium carbonate (0.740 mg, 0.0023 mmol) at room temperature. The reaction mixture was heated at 70 o C for 6-8 h. At the end of the reaction the solvent was distilled off and the residue was taken up into chloroform and washed with water, dried over sodium sulfate and concentrated. The pure product was obtained by column chromatography in almost 85 % yield.
With 8-quinolinol; potassium carbonate In 1,3-dimethyl-2-imidazolidinone at 170℃; for 20h;
105
Reference Example 105 (4-Phenoxyphenyl)methanol A solution of iodobenzene (2.0 g, 9.7 mmol), 4-hydroxybenzyl alcohol (1.0 g, 8.1 mmol), potassium carbonate (0.67 g, 4.8 mmol), copper chloride(I) (0.016 g, 0.16 mmol) and 8-quinolinol (0.023 g, 0.16 mmol) in 1,3-dimethyl-2-imidazolidinone (5 mL) was stirred at 170°C for 20 hours. The reaction solution was filtered, extracted with ethyl acetate, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate = 7: 3) to give the title compound (0.12 g, yield 7%) as an oily matter. 1H NMR: 1.60 (1H, t, J=5.8), 4.68 (2H, d, J=5.8), 6.95-7.16 (5H, m), 7.30-7.37 (4H, m).
EXAMPLE 5 4-(2-piperidine-1-yl-ethoxy)-benzyl alcohol (3a) 4-hydroxybenzyl alcohol (6.2 g, 0.0.05 mol) was dissolved in aqueus sodium hydroxide (SN, 30 mL). Toluene (30 mL) was added followed by 1-(2-chloroethyl) piperidine hydrochloride (9.29 g, 0.05 mol) and <strong>[5197-95-5]benzyltriethylammonium bromide</strong> (0.3 g). The reaction mixture was heated with vigorous stirring for 1.5 h. The layers were separated, the aqueous layer was extracted with toluene (2*15 mL). Combined organic extracts and organic layer was washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and concentrated on a rotary evaporator to give 8.725 g (75%) of alcohol (3a) as a yellowish brown oil.
With potassium iodide; potassium carbonate; In acetone; Petroleum ether;
b) 4-(alpha-Ethoxycarbonyl-benzyloxy)benzyl alcohol 41.8 g (0.172 mol) of ethyl 2-bromo-phenylacetate and 21.3 g (0.172 mol) of 4-hydroxybenzyl alcohol are dissolved in 850 ml of acetone and 24.8 g (0.18 mol) of potassium carbonate and 5.0 g (0.03 mol) of potassium iodide are added thereto. The reaction mixture is refluxed for 60 hours with stirring. Then the inorganic salts are filtered off and the residue is washed with hot acetone. The filtrate is evaporated down and the residue is purified over a silica gel column (particle size: 0.063-0.02 mm), initially using petroleum ether as eluant and then using mixtures of petroleum ether and ethyl acetate of increasing polarity (9:1, 8:2 and 7:3). The unified fractions are evaporated down in vacuo. Yield: 30.65 g (62.5% of theory), Rf value: 0.40 (silica gel; eluant: ethyl acetate/petroleum ether=3:7)
F. 4-Tert-butyldimethylsiloxymethylphenol A mixture of 1.24 g (0.01 mole) of 4-hydroxymethylphenol, 1.8 g (0.012 mole) of tert-butyldimethylsilyl chloride, 1.7 g (0.025 mole) of imidazole and 3 ml of dimethylformamide was stirred under nitrogen at room temperature for 12 h. The reaction mixture was poured into water and extracted with three portions of ether. Ether extracts were combined and washed successively with water and saturated NaCl solution and then dried (Na2 SO4). The ether solution was concentrated in-vacuo and the resultant crude product was purified by flash chromatography (silica; 10% ethyl acetate in hexanes) to give the title compound as a colorless oil. PMR (CDCl3): δ 0.09 (6H, s), 0.93 (9H, s), 4.66 (2H, s), 5.69 (1H, broad s), 6.74 (2H, d, J~6.9 Hz), 7.16 (2H, d, J~6.9 Hz).
With water;penicillin-G-amidase; In Chremephor EL; dimethyl sulfoxide; at 37℃;pH 7.4;Enzymatic reaction; Aqueous phosphate buffer;Kinetics;
Compounds 1 and 2 (2 mul of a 10 mM stock solution in DMSO) were dissolved in 98 mul of PBS (pH 7.4) to give a final concentration of 200 muM. Compound 3 (2 muL of a 10 mM stock solution in DMSO: Chremephor EL (1:1)) was dissolved in 98 mul of PBS (pH 7.4) to give a final concentration of 200 muM. All solutions were kept at 37 C. A PGA stock solution in PBS (pH 7.4) was used to activate the dendritic compounds. The UV-Visible spectra of p-nitrophenol and of the tested solutions of Compound 1 and 2 in PBS (pH 7.4) were measured in order to determine the optimal wavelength which will be indicative for following the appearance of released p-nitrophenol and the results are depicted in FIG. 5. As shown in FIG. 5, a wavelength of 405 nm, in which p-nitrophenol has a maximal absorption and the dendritic compounds have minimal absorption was found as indicative for the appearance of a released p-nitrophenol. Thus, Compounds 1-3 were incubated with or without PGA in PBS pH 7.4 at 37 C. and the biodegradation of the tested compounds was conveniently monitored by following the formation of 4-nitrophenol with visible spectroscopy at a wavelength of 405 nm. The kinetics of the release of 4-nitrophenol from Compounds 1-3 is shown in FIG. 6. Upon addition of PGA to Compounds 1-3, free 4-nitrophenol was gradually formed, indicating a PGA-induced cleavage of the phenylacetamide substrate and a following degradation that occurs as was predicted. In the absence of PDA, no p-nitrophenol was detected. Expectedly, 4-nitrophenol was released from the G1-dendritic compound (Compound 2) faster then from the G0-dendritic compounds (Compound 1), while the G2-dendritic compound (Compound 3) released it relatively slower. The kinetic constants K(obs) for the three reactions were calculated by linear correlation with the measured plots (e.g., Kobs was calculated as the slop of the linear area of the graphs), and are presented in Table 1 below. Without being bound to any particular theory, it is suggested that the phenomenon of Compound 2 releasing its reporter group faster than Compound 1 occurs since the enzymatic substrate concentration in Compound 2 is twice higher than Compound 1. The following self-cyclization step is relatively fast and therefore, the rate-limiting step is the cleavage of the enzymatic substrate. In Compound 3, additional self-immolative reactions occur in order to complete the release of the reporter group (another intra-cyclization and 1,6-quinone-methide elimination). The overall rate of these reactions is slower than the rate of the enzymatic substrate cleavage and therefore the K(obs) for Compound 3 is relatively smaller.
4a A mixture of 4-hydroxybenzyl alcohol (2.7 g, 21.7 mmol) <strong>[288399-19-9]2-methyl-4-chloromethylquinoline</strong> (4.5 g, 23.5 mmol) and potassium carbonate (9.0 g, 65 mmol) in 50 mL acetonitrile was heated to reflux for 12 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with brine and concentrated on a rotary evaporator to give 4-[(2-methyl-4-quinolinyl)methoxy]benzyl alcohol which was carried to the next step crude. MS found: (M+H)+=280.
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;
Example 144; 5-[4-(6-Fluoro-benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid amideStep A: [4-(6-Fluoro-benzothiazol-2-yloxy)-phenyl]-methanol. A mixture of <strong>[154327-27-2]2-chloro-5-fluorobenzthiazole</strong> (2.2 g, 12.0 mmol), 4-hydroxylbenzyl alcohol (1.48 g, 12.0 mmol) and Cs2CO3 (8.6 g, 26.4 mmol) in DMF (30 mL) was stirred at rt overnight. The reaction was filtered and diluted with CH2Cl2 (200 mL) and concentrated. The crude mixture was purified via silica gel column chromatography (1% to 15% CH3OH/CH2Cl2) to afford the title compound (1.1 g, 34%). MS (ESI): Mass calcd for C14H10NO2SF, 275.0; m/z found, 276.1 [M+H]+
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 14h;
Intermediate 21: [4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenyl]methanol To a solution of <strong>[91524-96-8]2-chloro[1,3]thiazolo[5,4-b]pyridine</strong> (103 mg, 0.604 mmol) in DMF (2.0 mL) was added 4-hydroxymethyl-phenol (75 mg, 0.604 mmol, 1.0 equiv.) and Cs2CO3 (221 mg, 0.628 mmol, 1.04 equiv.). The reaction was allowed to stir at rt for 14 h. The reaction mixture was then filtered through diatomaceous earth, diluted with EtOAc (15 mL), washed with water (4*50 mL) and dried. After filtration and concentration, the desired product was obtained as a cream-colored solid (140 mg, 90%). MS (ESI): mass calcd. for C13H10N2O2S, 258.1; m/z found, 259.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 8.46-8.44 (m, 1H), 8.11-8.08 (m, 1H), 7.51 (dd, J=8.2, 4.7, 1H), 7.48-7.42 (m, 4H), 5.32 (t, J=5.8, 1H), 4.55 (d, J=5.8, 2H).
POTASSIUM TERT. -BUTYLATE (5.387 G, 0.0480 MOL) WAS suspended in 2-methyl-2-butanol (30 ml). Then methoxymethyl acetate (0.0480 mol, 5.000 g, 4.8 ml) and dimethyl oxalate (0.0480 mol, 5.668 g) were added. The suspension was stirred for 1 hour at room temperature under an N2 atmosphere. 4-Hydroxybenzyl alcohol (0.0408 mol, 5.065 g) was added in one portion and the reaction mixture refluxed for 30 minutes (oil bath 120 C). The thick suspension was cooled in an ice bath to 5 C. 100 ml MTBE were added. The insoluble solid was filtered off and the filter cake washed with 30 ml MTBE. The filtrate was concentrated to dry it and the residue dried to constant weight in an oil pump vacuum. After evaporation and drying, A-METHOXY-ss-(P- hydroxyphenyl) methyl propionate was obtained as an orange- coloured oil (8.0 g, 79 %). The methyl ester group was hydrolysed under the same conditions as in EXAMPLE 2.
With sodium hydrogen sulfate; for 0.0833333h;Neat (no solvent); Microwave irradiation;
Equivalent hydroxyphenylmethanol and multihydroxybenzoic acid (1 mmol both) were mixed with NaHSO4 and grinded in mortar. The mixture was then transferred to an evaporation pan and put into the microwave oven. After irradiated for a few minutes the solid was afford with high yield. It should be noted that all yields below are isolated yield.
With sodium hydroxide;tetrabutylammomium bromide; In water; toluene;Reflux;
4-Hydroxybenzyl alcohol (10 g) is added to a solution of sodium hydroxide (7.73 g) in water (150 mL). The mixture is stirred to obtain a clear solution, and then toluene (100 mL), 2-chloroethylazepan hydrochloride (20.74 g), and tetrabutylammonium bromide (0.519 g) are added. The mixture is refluxed for completion of the reaction (1 -1.5 hours), as verified using TLC. The mixture is cooled to 25-35°C and the organic layer is separated and washed with 10percent NaCI solution (100 mL) at 500C. The organic layer is distilled completely under vacuum, and then dichloromethane (200 mL) is added to the residue. The mixture is stirred for dissolution under a nitrogen atmosphere. Dry HCI gas is passed through the solution for 30-60 minutes at 25-35°C and the mixture is stirred for 1 -1.5 hours at the same temperature. About 85-90percent of the solvent is distilled from the mixture, then acetone (60 mL) is added, and 85-90percent of the solvent is distilled. This addition and distillation step is repeated twice with acetone (60 mL). To the residue, acetone (60 mL) is added and mixture is cooled to 0-50C and further stirred at same temperature for 4-4.5 hours. The solid obtained is filtered under a nitrogen atmosphere, washed with chilled acetone (40 mL) under a nitrogen atmosphere, and dried under vacuum at 50-550C for 4-5 hours to afford the title compound in 61.2percent yield.
With Escherichia coli penicillin-G-amidase; water; In dimethyl sulfoxide; at 37℃; for 4h;pH 7.4;aq. phosphate buffer; Enzymatic reaction;
PGA (penicillin-G-amidase, 1 U/muL) was purchased from Zhejiang Shunfeng Haider Co. Ltd. Compound 1 was dissolved in DMSO (not more than 10%, V/V) and further diluted with 0.1 M PBS (pH 7.4) to give the final stock solution, followed by treating with PGA. The incubation was kept at 37 C and the fluorescence spectra were measured every 30 min by RF-5301PC spectroscopy.
With iron(III) chloride; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; hydroxylamine hydrochloride; iodine; potassium carbonate In 1,2-dichloro-ethane at 90℃; for 16h;
With dihydrogen peroxide; In water-d2;pH 7.4;Kinetics;
3.4 Hydrogen peroxide triggered conversion of TIP to deferasirox The unmasking reaction of TIP with H2O2 is anticipated to occur as shown in Scheme 2, where oxidation of the boronic acid by H2O2 gives a phenol intermediate that undergoes spontaneous 1,6 elimination to release deferasirox and quinone methide, which converts to 4-hydroxybenzyl alcohol in water [27]. Fig. 8 shows the aromatic region of a 1H NMR spectrum of a 250-muM sample of TIP in D2O after reaction with excess H2O2. The expected products deferasirox and 4-hydroxybenzyl alcohol are clearly identified. The clean conversion of TIP to deferasirox was also observed by LC/MS, as shown by the chromatograms in Fig. 9. The rate of the unmasking reaction was assessed by UV-Vis spectrophotometry. As can be seen in Fig. 10, the UV-Vis spectrum of 20 muM TIP in PBS buffer pH 7.4 changes upon exposure to H2O2. The increase in absorbance at 273 nm versus time for solutions of TIP under pseudo first-order conditions of excess of H2O2 was used to obtain observed rate constants kobs. The second-order rate constant for this reaction was then obtained from the data shown in Fig. 10 to be 1.4 M-1s-1, a value that is similar to that found for prochelator BHAPI, which also contains a self-immolative boronate protecting group [27].
With lithium perchlorate; In acetonitrile; at 20℃;Electrochemical reaction;
General procedure: A 40 cm3 acetonitrile solution of alcohols 1a?1i(1 mmol) in LiClO4 (0.05 g) was electrolyzed at the2.0 V versus SCE. After completion of the electro-oxidationof alcohols to their corresponding aldehydes,indoles 2a, 2b (2 mmol) were added and electrolyzed at-0.9 V versus SCE. In the two mentioned stages, electrosynthesisreactions were done in an undivided cellequipped with graphite rods as the cathode and Pt-anodeat room temperature. The electrolysis was terminatedwhen the current decreased by more than 95 percent. Amagnetic stirrer was employed during the electrolysis.The process was interrupted several times during theelectrolysis and the graphite rod was washed in acetonein order to reactivate it. After completion of the electrocondensation,the solvent was evaporated and theresulting crude product was purified by preparative thinlayerchromatography on silica gel (eluent: n-hexane?EtOAc, 4:1) to afford 3,30-di(indolyl)methanes 3a?3k.All the products were characterized by comparison oftheir melting points and also spectroscopic data (IR, 1HNMR and mass spectra) with those of the authenticsamples in literature
With 18-crown-6 ether; potassium carbonate; In acetone; for 72.0h;Reflux;
2.34g (20mmol) was dissolved in methanol paraben 50mL of acetone, stirred successively added 2-bromoethyl methyl ether3.31g (24mmol), 40mg of 18-crown-6, potassium carbonate 8.29g (60mmol), refluxed for 72h. Inorganic salt was removed by suction,The acetone mother liquor was removed under reduced pressure, dissolved in ethyl acetate was added, extracted with saturated brine, the organic layer was dried over anhydrous sodium sulfate,Silica gel column chromatography (PE: EA = 10: 1 (v / v)), to give a colorless liquid ((4- (2-methoxyethoxy) benzyl alcohol), a yield of 58.6%
9-(4-(hydroxymethyl)phenoxy)-1,6,6-trimethyl-6,7,8,9-tetrahydrophenanthro[1,2-b]furan-10,11-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In chlorobenzene at 120℃; for 36h; Sealed tube; regioselective reaction;
Typical experimental procedure for the catalyst-free Aromatic ethers reaction.
General procedure: A 10 mL sealed tube was charged with Tan-IIA substrates (0.1 mmol), various phenol (0.17 mmol), and TEMPO (0.2 mmol). PhCl (1 mL) was added, and the resulting mixture was stirred at 120°C. The reaction was monitored by TLC until the starting material disappeared. Then the solvent was removed under vacuum, and the resulting residue was purified by chromatography on a silica gel column to furnish the desired compound 4 as red solids.
With beta-galactosidase from Bacillus megaterium YZ08; magnesium chloride; In aq. phosphate buffer; dimethyl sulfoxide; at 35℃; for 12h;pH 7.4;Enzymatic reaction;
General procedure: The reaction mixture (70 mL Na2PO4/KH2PO4 buffer (50 mM, pH 7.4) + 30 mL DMSO) containing MgCl2 (5 mM), <strong>[63-42-3]lactose</strong> (50 mmol), aromatic alcohols (30-40 mmol), crude enzyme solution (100 U) was prepared in a 250 mL Erlenmeyer flask. The reaction was conducted at 35 C with shaking at 200 rpm for 12 h. AB-8 macroporous resin column and flash column chromatography were used to purify the products. The procedure is detailed in supplementary material. The product structure was determined by NMR (Bruker AV-400 spectrometer, Switzerland).
2-(4-hydroxybenzyl)-4-O-(4-phenol)-1,4-benzenediol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19%
With toluene-4-sulfonic acid In 1,4-dioxane; toluene at 60℃; for 3h;
2.5.4. Compounds 16 and 17
General procedure: To a stirred solution of 4,4′-oxybisphenol (404 mg, 2 mmol) or 4,4′-thiobisphenol (437 mg, 2 mmol) in 1,4-dioxane (7.5 mL) and toluene (2.5 mL) at room temperature was added sequentially p-hydroxybenzylalcohol (124 mg, 1 mmol) and TsOH (0.4 mg, 0.2 mmol). The mixture was heated at 60 °C for 3 h. The reaction mixture was quenched with saturated sodium bicarbonate and extracted with EtOAc (10 mL×3).The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residues were purified by silica gel CC (EtOAc-petroleum ether, 10:90) and delivered compounds 16 and 17.
With toluene-4-sulfonic acid In 1,4-dioxane; toluene at 60℃; for 3h;
1 Synthesis method of 2-(4-hydroxybenzyl)-4-O-(4-phenol)-1,4-benzenediol:
The raw material 4,4'-oxybisphenol (404.2 mg, 2 mmol) was dissolved in a mixed solution of 1,4-dioxane/toluene (3:1, 10 mL). p-hydroxybenzyl alcohol (124.14 mg, 1 mmol) and p-toluenesulfonic acid (0.38 mg, 0.2 mmol) were added in that order, and the mixture was heated to 60 °C, and the reaction was stopped after 3 hours. Add the saturated sodium hydrogencarbonate solution to adjust the pH to neutrality, and dissolve the ethyl acetate (10 mL × 3). The organic phase is combined, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give purified crystals of compound 8.
2-(4-hydroxybenzyl)-4-S-(4-phenol)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13%
With toluene-4-sulfonic acid In 1,4-dioxane; toluene at 60℃; for 3h;
2.5.4. Compounds 16 and 17
General procedure: To a stirred solution of 4,4′-oxybisphenol (404 mg, 2 mmol) or 4,4′-thiobisphenol (437 mg, 2 mmol) in 1,4-dioxane (7.5 mL) and toluene (2.5 mL) at room temperature was added sequentially p-hydroxybenzylalcohol (124 mg, 1 mmol) and TsOH (0.4 mg, 0.2 mmol). The mixture was heated at 60 °C for 3 h. The reaction mixture was quenched with saturated sodium bicarbonate and extracted with EtOAc (10 mL×3).The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residues were purified by silica gel CC (EtOAc-petroleum ether, 10:90) and delivered compounds 16 and 17.
With toluene-4-sulfonic acid In 1,4-dioxane; toluene at 60℃; for 3h;
1 2-(4-Hydroxybenzyl)-4-S-(4-phenol)phenol:
The raw material 4,4'-thiobisphenol (436.5 mg, 2 mmol) was dissolved in a mixed solution of 1,4-dioxane/toluene (3:1, 10 mL). p-Hydroxybenzyl alcohol (124.14 mg, 1 mmol) and p-toluenesulfonic acid (0.38 mg, 0.2 mmol) were added in that order, and the mixture was heated to 60 °C, and the reaction was stopped after 3 hours. Add the saturated sodium hydrogencarbonate solution to adjust the pH to neutrality, and dissolve the ethyl acetate (10 mL × 3). The organic phase is combined, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give purified crystals.
With hydrogenchloride; In water; for 0.25h;pH 5.25;
General procedure: Proper amount of fresh RGE slices were ground in a mortar. The pH value of fresh RGE juicewas 5.25 measured by pH meter. The above 10 monomer compounds were precisely weighed 1.0 mg, dissolved by 1.0 mL hydrochloric acid solution of pH 5.25, and placed in a vial. The sample solution of 1.0 mg/mL was obtained. The vials of 10 samples were steamed in the steamer simulating the steaming process of RGE. The timing started after the round vapor. After 15 min, the vials were taken out. After cooling to room temperature, the analysis was carried out under the condition of Section 3.5, PA was analyzed by HPLC-ESI-TOF/MS and the other nine compounds were analyzed by HPLC.
3-hydroxy-5-oxo-5-[[4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]methoxy]-3-[[4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]methoxycarbonyl]pentanoic acid[ No CAS ]
[ 623-05-2 ]
[ 952068-57-4 ]
[ 952283-93-1 ]
[ 62499-27-8 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In water; for 0.25h;pH 5.25;
General procedure: Proper amount of fresh RGE slices were ground in a mortar. The pH value of fresh RGE juicewas 5.25 measured by pH meter. The above 10 monomer compounds were precisely weighed 1.0 mg, dissolved by 1.0 mL hydrochloric acid solution of pH 5.25, and placed in a vial. The sample solution of 1.0 mg/mL was obtained. The vials of 10 samples were steamed in the steamer simulating the steaming process of RGE. The timing started after the round vapor. After 15 min, the vials were taken out. After cooling to room temperature, the analysis was carried out under the condition of Section 3.5, PA was analyzed by HPLC-ESI-TOF/MS and the other nine compounds were analyzed by HPLC.
With hydrogenchloride; In water; for 0.25h;pH 5.25;
General procedure: Proper amount of fresh RGE slices were ground in a mortar. The pH value of fresh RGE juicewas 5.25 measured by pH meter. The above 10 monomer compounds were precisely weighed 1.0 mg, dissolved by 1.0 mL hydrochloric acid solution of pH 5.25, and placed in a vial. The sample solution of 1.0 mg/mL was obtained. The vials of 10 samples were steamed in the steamer simulating the steaming process of RGE. The timing started after the round vapor. After 15 min, the vials were taken out. After cooling to room temperature, the analysis was carried out under the condition of Section 3.5, PA was analyzed by HPLC-ESI-TOF/MS and the other nine compounds were analyzed by HPLC.
3-hydroxy-5-oxo-5-[[4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]methoxy]-3-[[4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]methoxycarbonyl]pentanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In water; for 0.25h;pH 5.25;
General procedure: Proper amount of fresh RGE slices were ground in a mortar. The pH value of fresh RGE juicewas 5.25 measured by pH meter. The above 10 monomer compounds were precisely weighed 1.0 mg, dissolved by 1.0 mL hydrochloric acid solution of pH 5.25, and placed in a vial. The sample solution of 1.0 mg/mL was obtained. The vials of 10 samples were steamed in the steamer simulating the steaming process of RGE. The timing started after the round vapor. After 15 min, the vials were taken out. After cooling to room temperature, the analysis was carried out under the condition of Section 3.5, PA was analyzed by HPLC-ESI-TOF/MS and the other nine compounds were analyzed by HPLC.
With hydrogenchloride; In water; for 0.25h;pH 5.25;
General procedure: Proper amount of fresh RGE slices were ground in a mortar. The pH value of fresh RGE juicewas 5.25 measured by pH meter. The above 10 monomer compounds were precisely weighed 1.0 mg, dissolved by 1.0 mL hydrochloric acid solution of pH 5.25, and placed in a vial. The sample solution of 1.0 mg/mL was obtained. The vials of 10 samples were steamed in the steamer simulating the steaming process of RGE. The timing started after the round vapor. After 15 min, the vials were taken out. After cooling to room temperature, the analysis was carried out under the condition of Section 3.5, PA was analyzed by HPLC-ESI-TOF/MS and the other nine compounds were analyzed by HPLC.
With hydrogenchloride; beta-D-glucosidase; In water; at 35℃; for 2h;pH 5.25;Enzymatic reaction;
GAS (0.591 mg/mL) and beta-D-glucosidase (1.24 mg/mL) were dissolved in hydrochloric acidsolution of pH 5.25 in a vial. Two copies of the above samples were prepared. One was steamed on a steamer for 15 min, and the other was incubated in water bath at 35 C for 2 h. A 10 L aliquot was injected for HPLC analysis.
4-(((E)-3-(3,4-dimethoxyphenyl)acryloyl)oxy)benzyl (E)-3-(3,4-dimethoxyphenyl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane;
General procedure: General experimental procedure for the synthesis of vanillyl cinnamate derivatives (1-8 and 19-26): a mixture containing substituted cinnamic acids (4.0mmol, 1.0 equiv.), 1-(3-Dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDCI, 4.0mmol, 1.0equiv.), 4-(dimethylamino)-pyridin (DMAP, 1.0mmol, 0.25 equiv.) and vanillyl alcohol or 4-hydroxybenzyl alcohol (1.5mmol, 0.375 equiv.) in the presence of anhydrous dichloromethane (30mL) was thoroughly stirred at room temperature for 6-10h till the completion of reaction. The obtained product was extracted with sodium bicarbonate water solution and diluted hydrochloric acid. The organic layer was dried over anhydrous sodium sulphate and evaporated to dryness to give the crude product. The obtained residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (6:1, v:v) as original eluent to give the pure compounds 1-8 and 21-26 (Scheme 1).
4-hydroxybenzyl (E)-3-(3,4-dimethoxyphenyl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane;
General procedure: General experimental procedure for the synthesis of vanillyl cinnamate derivatives (1-8 and 19-26): a mixture containing substituted cinnamic acids (4.0mmol, 1.0 equiv.), 1-(3-Dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDCI, 4.0mmol, 1.0equiv.), 4-(dimethylamino)-pyridin (DMAP, 1.0mmol, 0.25 equiv.) and vanillyl alcohol or 4-hydroxybenzyl alcohol (1.5mmol, 0.375 equiv.) in the presence of anhydrous dichloromethane (30mL) was thoroughly stirred at room temperature for 6-10h till the completion of reaction. The obtained product was extracted with sodium bicarbonate water solution and diluted hydrochloric acid. The organic layer was dried over anhydrous sodium sulphate and evaporated to dryness to give the crude product. The obtained residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (6:1, v:v) as original eluent to give the pure compounds 1-8 and 21-26 (Scheme 1).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane
1 Example 1: Preparation method of compound of formula 2
1.0 g of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide was added to a suspension of 1.0 g of erdosteine, 226 mg of 4-hydroxybenzyl alcohol, and 89 mg of dimethylaminopyridine in 23 ml of dichloromethane, followed by stirring overnight. It was extracted by dilution with dichloromethane and water. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by eluting with a column packed with silica gel (methanol : dichloromethane = 1 : 20). The fractions were concentrated under reduced pressure to obtain 0.46 g of the title compound.
4-((E)-4-methoxy-4-oxobut-2-enoyloxy)benzyl methyl fumarate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 8h;
1
1.0 g of monomethyl fumarate was suspended in 20 ml of tetrahydrofuran, and 0.48 g (0.5 eq.) of 4-hydroxybenzyl alcohol, 3.68 g (2.5 eq.) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and 0.94 g (1.0 eq.) of 4-dimethylaminopyridine were added. After stirring at room temperature for 8 hours, the mixture was concentrated and diluted with 20 ml of dichloromethane. After washing with 20 ml of water, drying over anhydrous magnesium sulfate, concentration, and crystallization with a mixed solvent of ethyl acetate and n-hexane (1:2, v/v), 0.66 g of the title compound as a white solid was obtained. (Yield: 49%) 1H NMR (400 MHz, DMSO-d6) δ 3.71 (s, 3H), 3.75 (s, 3H), 5.22 (s, 2H), 6.80 (s, 2H), 6.95 (s, 2H), 7.21 (d, 2H), 7.46 (d, 2H)
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