* 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.
Stage #1: With sodium hydrogensulfide In water at 20℃; for 0.5 h; Stage #2: at 70℃; for 5.91667 - 6 h;
A mixture of 4-Cyanophenol (50.0 g, 0.42 mol), and NaSH (15.5 g, 0.21 mol) in distilled water (125 mL) was stirred at room temperature for 30 minutes. The mixture was then put under a vacuum, flushed with H2S, and the pressure was brought to 40-50 psi for a period of a few minutes. The mixture was then heated to 70° C. and stirred for 40-45 minutes. The mixture was stirred vigorously at 70° C. under constant pressure of 56 psi for 5 hours and 15 minutes. The H2S pressure was removed and the reaction was cooled to room temperature. The reaction was neutralized to pH 5-7 with 2 M HCl (66 mL). The product was filtered, and the filter cake washed with distilled water (2*50 mL), and dried under a vacuum at 80-85° C. for 22 hours to provide 62.74 g (97.57percent) desired product.
94%
With sodium monohydrogen sulfide x-hydrate; ammonium chloride In water; N,N-dimethyl-formamide at 40℃; for 22 h;
To a solution of a sodium hydrogen sulfide hydrate (2.35 g), N,N-dimethylformamide (3 ml) and water (0.5 ml) were added 4-hydroxybenzonitrile (1.0 g) and ammonium chloride (2.25 g) while stirring. After the mixture was stirred at 40° C. for 22 hours, 2N hydrochloric acid (9.5 ml) was added followed by the addition of water (2.0 ml) to the mixture. A solid formed under ice cooling and stirring was filtered and then dried to afford 4-hydroxybenzothioamide (1.21 g) (yield 94percent).
92%
With sodium hydrogen sulfide; triethylamine hydrochloride; triethylamine In ethanol at 5 - 50℃; for 12 h;
11 g of sodium hydrosulfide,6 g of p-hydroxybenzonitrile,6.9 mL of triethylamine,40 mL of ethanol was added to a 100 mL three-necked flask, ice bath temperature control 5 ~ 10 °C, A solution of 27.5 g of triethylamine hydrochloride was added in portions, Add the elevated temperature to 50 °C ,Stirring under the insulation for 12 hours, TLC monitoring reaction is complete, liquid phase control shows the conversion rate of 95percent or more, the final yield of 92percent.After the end of the reaction, the ethanol recovered by distillation can be directly applied. Distilled by adding 40 mL of ethanol to beat at 50 ° C for 0.5 hour and filtering to obtain a higher purity sodium chloride solid salt.The ethanol filtrate was concentrated to dryness, and 25 mL of water was added to the beater, filtered and dried to give 7.32 g of a yellowish solid. Liquid content of more than 97percent, the yield of 92percent.The filtered aqueous phase can be repeatedly applied in multiple batches and finally concentrated to dryness, resulting in triethylamine hydrogen sulfide and triethylamine hydrochloride, which can be recycled to the reaction. The whole process is basically no waste generated.
87.5%
With O,O-Diethyl hydrogen phosphorodithioate In water at 50℃; for 3 h;
EXAMPLE- 1 (preparation of 4-hydroxythiobenzamide) 0.23 moles of diethyldithiophosphoric acid was added to 1.66 moles of water followed by addition of 0.21 moles of 4-cyanophenol. The reaction mixture was heated to 50°C and was maintained at this temperature with stirring for 3 hrs. The reaction mass was then cooled to 25-30°C. 100 ml of dichloromethane was added to the mixture and it was maintained at 25-30°C for 30 min. It was then filtered and the solid product was washed with saturated sodium carbonate solution followed by 70 ml water. It was dried at 75oC to obtain 4-hydroxythiobenzamide in 87,5percent yield.
70%
With tetraphosphorus decasulfide In ethanol at 70℃; for 12 h;
P2S5 (0.37 g, 16.8 mmol) was dissolved in ethanol (10 mL) and stirred at rt for 1 h. Then the solution became clear. To this reaction mixture, 4-hydroxy-benzonitrile (1) (1 g, 8.4 mmol) was added. The RM was then heated at 70 °C for 12 h. The RM was evaporated to dryness and the resultant crude mixture was purified by column chromatography on silica, product eluted with 50percent EA/Hex to afford 4-hydroxy benzamide (2) (800 mg, 70percent) as white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.08 (s, 1H), 9.52 (s, 1H), 9.20 (s, 1H), 7.86 (d, J = 8.56 Hz, 2H), 6.74 (d, J = 8.6 Hz, 2H). MS (ESI): m/z calc. for C7H7NOS+: 153.0; found: 154.1 [M+H]+.
97.57%
With hydrogenchloride; NaSH In water
EXAMPLE 1 4-hydroxybenzene carbothioamide A mixture of 4-Cyanophenol (50.0 g, 0.42 mol), and NaSH (15.5 g, 0.21 mol) in distilled water (125 mL) was stirred at room temperature for 30 minutes. The mixture was then put under a vacuum, flushed with H2S, and the pressure was brought to 40-50 psi for a period of a few minutes. The mixture was then heated to 70° C. and stirred for 40-45 minutes. The mixture was stirred vigorously at 70° C. under constant pressure of 56 psi for 5 hours and 15 minutes. The H2S pressure was removed and the reaction was cooled to room temperature. The reaction was neutralized to pH 5-7 with 2 M HCl (66 mL). The product was filtered, and the filter cake washed with distilled water (2*50 mL), and dried under a vacuum at 80-85° C. for 22 hours to provide 62.74 g (97.57percent) desired product.
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[3] Patent: CN106928108, 2017, A, . Location in patent: Paragraph 0043; 0044; 0046; 0048; 0063; 0065; 0067; 0071
[4] Patent: WO2016/46836, 2016, A2, . Location in patent: Page/Page column 3
[5] Synthetic Communications, 2000, vol. 30, # 6, p. 1083 - 1094
[6] Tetrahedron, 1989, vol. 45, # 14, p. 4599 - 4604
[7] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 10, p. 904 - 908
[8] Journal of Photochemistry and Photobiology A: Chemistry, 2017, vol. 334, p. 1 - 12
[9] Chemical and Pharmaceutical Bulletin, 2005, vol. 53, # 4, p. 410 - 418
[10] Collection of Czechoslovak Chemical Communications, 1991, vol. 56, # 12, p. 2964 - 2968
[11] Journal of the American Chemical Society, 1972, vol. 94, p. 3153 - 3159
[12] Synlett, 2004, # 14, p. 2615 - 2617
[13] Patent: US2005/27128, 2005, A1,
[14] New Journal of Chemistry, 2018, vol. 42, # 1, p. 76 - 84
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[1] Phosphorus and Sulfur and the Related Elements, 1985, vol. 25, p. 297 - 306
6
[ 128886-86-2 ]
[ 73901-01-6 ]
[ 767-00-0 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2015, vol. 36, # 5, p. 1360 - 1365
7
[ 767-00-0 ]
[ 7153-22-2 ]
Reference：
[1] Synlett, 1998, # 2, p. 183 - 185
[2] Advanced Synthesis and Catalysis, 2017, vol. 359, # 3, p. 419 - 425
[3] Chemistry - An Asian Journal, 2017, vol. 12, # 17, p. 2323 - 2331
8
[ 767-00-0 ]
[ 35794-84-4 ]
Reference：
[1] Letters in Drug Design and Discovery, 2010, vol. 7, # 6, p. 415 - 420
[2] ChemMedChem, 2013, vol. 8, # 6, p. 914 - 918
[3] Medicinal Chemistry Research, 2015, vol. 24, # 7, p. 3008 - 3020
9
[ 1740-74-5 ]
[ 767-00-0 ]
[ 33143-29-2 ]
Yield
Reaction Conditions
Operation in experiment
87%
With 3-Methylpyridine In para-xylene for 24 h; Reflux
1,1-Diethoxy-3-methylbut-2-ene 17 (1.74 g,11.0 mmol), 4-cyanophenol (2.65 g, 22.0 mmol) and 3-picoline(0.27 mL, 2.75 mmol) were dissolved in p-xylene (20 mL/g ofphenol). The mixture was heated under reflux for 24 h, and thereaction mixture allowed to cool to ambient temperature. The clear,golden mixture was diluted with EtOAc (50 mL) and washed withHCl (1 N, 2 25 mL). The aqueous layers were combined andwashed with EtOAc (2 25 mL). The combined organic layers werewashed with NaOH (1 N, 25 mL), brine (25 mL), dried over anhydrousMgSO4 and filtered. The solvents were removed underreduced pressure to give a bright yellow solid. The yellow solid wasrecrystallized from light petroleumto give the title compound 16 asa yellow powder (1.78 g, 87percent).
35%
With Mo11O40PV*4H(1+)*3C5H5N In para-xylene at 20 - 120℃; for 6 h; Green chemistry
Py3-Mo11V was used as catalyst for the preparation of 6-CN-2,2-DMB. 1,1-diethoxy-3-methyl-2-butene (17 mmol), 4-cyanophenol (13 mmol), and the catalyst (Py3-PMo11V, 1 mmol percent) were added to p-xylene (20 mL) as solvent at 20° C. The progress of the reaction was monitored by TLC and GC analysis. The reaction mixture was heated and stirred at 120° C. After 6 h, the reaction mixture was cooled down to room temperature. The clear, yellow solution was diluted with p-xylene (10 mL) and the catalyst was recovered by centrifugation, washed with p-xylene (5 mL), dried in vacuum, and reused. The organic phases were washed with HCl(1 M, 2 × 7 mL), NaOH (1 M, 2 × 7 mL), saturated solution of NaCl(10 mL), H2O (10 mL), dried (anhydrous Na2SO4), and concentrated.The crude product was crystallized from hexanes. The crystals were recovered by filtration, washed with hexanes, and dried to give 35percent yield, mp 46-47° C, lit147° C. 1H NMR (200 MHz, CDCl3) = 7.36 (dd,J = 8 Hz, J = 2 Hz, 1 H), 7.24 (d, J = 2 Hz, 1 H), 6.80 (d, J = 8 Hz, 1 H), 6.31(d, J = 10 Hz, 1 H), 5.72 (d, J = 10 Hz, 1 H), and 1.46 (s, 6H).13C NMR(50 MHz, CDCl3) = 156.7, 133.3, 132.2, 130.2, 121.5, 120.6, 119.1,117.2, 103.5, 77.8, and 28.2.
Reference：
[1] Tetrahedron, 2016, vol. 72, # 51, p. 8406 - 8416
[2] Journal of Organic Chemistry, 1995, vol. 60, # 11, p. 3397 - 3400
[3] Journal of Molecular Catalysis A: Chemical, 2015, vol. 398, p. 11 - 16
10
[ 108-99-6 ]
[ 767-00-0 ]
[ 33143-29-2 ]
Reference：
[1] Patent: US5502220, 1996, A,
11
[ 1111-97-3 ]
[ 767-00-0 ]
[ 33143-29-2 ]
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[1] Patent: US4391815, 1983, A,
12
[ 767-00-0 ]
[ 33143-29-2 ]
Reference：
[1] Letters in Drug Design and Discovery, 2010, vol. 7, # 6, p. 415 - 420
[2] Organic Letters, 2013, vol. 15, # 16, p. 4138 - 4141
[3] Medicinal Chemistry Research, 2015, vol. 24, # 7, p. 3008 - 3020
[4] Tetrahedron, 2016, vol. 72, # 51, p. 8406 - 8416
13
[ 1111-97-3 ]
[ 767-00-0 ]
[ 100-85-6 ]
[ 33143-29-2 ]
Reference：
[1] Patent: US4251537, 1981, A,
14
[ 767-00-0 ]
[ 115-19-5 ]
[ 33143-29-2 ]
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15
[ 267877-40-7 ]
[ 14191-95-8 ]
[ 103-90-2 ]
[ 767-00-0 ]
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[1] Australian Journal of Chemistry, 1999, vol. 52, # 11, p. 1029 - 1033
16
[ 767-00-0 ]
[ 2315-81-3 ]
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[1] Journal of the Chemical Society, 1949, p. 642,645
17
[ 767-00-0 ]
[ 163685-01-6 ]
[ 491-11-2 ]
Reference：
[1] Journal of the American Chemical Society, 1995, vol. 117, # 20, p. 5484 - 5491
18
[ 767-00-0 ]
[ 23795-02-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 5, p. 1278 - 1283
19
[ 100-47-0 ]
[ 611-20-1 ]
[ 873-62-1 ]
[ 767-00-0 ]
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[1] Inorganica Chimica Acta, 2016, vol. 444, p. 159 - 165
[2] Tetrahedron Letters, 1982, vol. 23, # 25, p. 2605 - 2608
[3] Chemical Communications, 2006, # 9, p. 1012 - 1014
[4] Chemistry - A European Journal, 2010, vol. 16, # 47, p. 13995 - 14006
[5] Chemistry - A European Journal, 2015, vol. 21, # 7, p. 2855 - 2861
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[7] Catalysis Letters, 2015, vol. 145, # 4, p. 1014 - 1021
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[ 460-19-5 ]
[ 108-95-2 ]
[ 611-20-1 ]
[ 873-62-1 ]
[ 767-00-0 ]
[ 100-47-0 ]
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[1] Journal of the American Chemical Society, 1981, vol. 103, # 14, p. 4204 - 4209
21
[ 100-47-0 ]
[ 611-20-1 ]
[ 4096-34-8 ]
[ 873-62-1 ]
[ 767-00-0 ]
[ 71-43-2 ]
[ 108-95-2 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1985, p. 1135 - 1142
22
[ 460-19-5 ]
[ 108-95-2 ]
[ 611-20-1 ]
[ 74-90-8 ]
[ 873-62-1 ]
[ 767-00-0 ]
[ 100-47-0 ]
[ 108-88-3 ]
Reference：
[1] Journal of the American Chemical Society, 1980, vol. 102, # 23, p. 7119 - 7120
23
[ 767-00-0 ]
[ 3272-08-0 ]
Yield
Reaction Conditions
Operation in experiment
94.5%
at 45 - 50℃; for 1.5 h;
11.9 g of p-hydroxybenzonitrile (0.1 mol) and 50 mL glacial acetic acid were added to a 250 mL three-necked flask, added dropwise with the mixture of 8 mL concentrated nitric acid and 12 mL glacial acetic acid. After dripping, the solution was slowly heated to 45-50° C. to react 1.5 hours, tested by TLC, the starting materials were reacted completely; then cooled down, added with dichloromethane, standing, to separate the upper organic layer, and then washed by water, 5percent sodium bicarbonate solution and saturated brine, 50 mL each. Solvent was recovered under reduced pressure to get 15.5 g of light yellow solid 3-nitro-4-hydroxybenzonitrile (VII), with a yield of 94.5percent.
79%
at 40 - 60℃; for 0.333333 h;
Step A:4-Hydroxy-3-nitrobenzonitrile; <n="62"/>A mixture of nitric acid (1.16 g, 12 mmol) and glacial acetic acid (1 mL) was heated to 40 0C. To this mixture was added rapidly a solution of 4-hydroxybenzonitrile (1 g, 8.4 mmol) in glacial acetic acid (4 mL) until the flask temperature rose to 50 0C. Then the solution was added at a rate such that the temperature was maintained at 50-60 0C. When addition was complete the mixture was stirred for another 20 min at 55 0C, and then poured into ice-water (24 mL). The mixture was filtered and the solid was washed with water to give 4-hydroxy-3-nitro- benzonitrile 1.09 g (79 percent) as a solid.1H NMR (300 MHz, CDCI3): δ 10.91 (s, 1 H), 8.48 (d, 1 H), 7.82 (dd, 1 H), 7.28 (dd, 1 H).
67%
With copper(II) nitrate trihydrate In tetrahydrofuran for 3 h; Reflux
General procedure: A suspension of 2-methylphenol(18.5 mmol, 1.0 eq) and Cu(NO3)2.3H2O (27.7 mmol, 1.5 eq) in THF was stirred magnetically at 60°C or reflux for several hours. Then after the solvent was removed under vacuum, the mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (5mL), dried over anhydrous MgSO4 and concentrated under vacuum. The crude residue was purified by column chromatography to afford the product (67-90percent).
67%
at 40 - 55℃; for 0.333333 h;
To a mixture of HNO3 (2.7mL, 63.Ommol) and AcOH (5mL) was added 4- hydroxybenzonitrile (5g, 42mmol) in AcOH (5mL) dropwise at 40 00. The reaction mixture was heated at 55 00 for 20 mm. The TLC showed reaction to be complete. The reaction mixture was poured into ice-water (lOOmL). The precipitated solid was filtered, washed with water (200mL) and dried under vacuum to afford 4-hydroxy-3- nitrobenzonitrile as a yellow solid. Yield: 2.5g (67percent); 1H NMR (400 MHz, DMSO-d612.34 (bs, 1H), 8.43 (5, 1H), 7.94 (d, J= 10.5 Hz, 1H), 7.24 (d, J= 8.7 Hz, 1H); MS (ESl+) for CHNOS m/z 163.03 [M+H].
55%
With uronium nitrate In water; acetonitrile at 80℃; for 1 h; Microwave irradiation
General procedure: Phenol (10 mmol) and urea nitrate (10 mmol)were mixed together in acetonitrile–water (95:5, 5 ml) in a 25 ml round bottomed flask and placed in a Milestone’s Start SYNTH microwave reactor. The reaction mixture was heated at 80°C for 40–50 min. At the end of the reaction, the reaction mixture was allowed to cool at room temperature,treated with water, and extracted with dichloromethane. After removing the solvent under reduced pressure, the residue was purified by column chromatography on silica gel to give the corresponding nitrophenol. In allcases ortho-nitrophenols were obtained selectively without any evidence forthe formation of the para-substituted nitrophenols. All the compoundsobtained were characterized by 1H NMR, 13C NMR, mp (for solids), GC–MSand in comparison with authentic samples.
Reference：
[1] Chinese Chemical Letters, 2011, vol. 22, # 7, p. 827 - 830
[2] Phosphorus, Sulfur and Silicon and the Related Elements, 2003, vol. 178, # 9, p. 2019 - 2025
[3] Turkish Journal of Chemistry, 2010, vol. 34, # 5, p. 753 - 759
[4] Patent: US2016/83373, 2016, A1, . Location in patent: Paragraph 0043; 0044
[5] Journal of Organic Chemistry, 1996, vol. 61, # 10, p. 3289 - 3297
[6] Mendeleev Communications, 2006, vol. 16, # 1, p. 41 - 42
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[8] Molecules, 2001, vol. 6, # 7, p. 614 - 620
[9] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2001, vol. 40, # 12, p. 1191 - 1195
[10] Synlett, 2003, # 2, p. 191 - 194
[11] South African Journal of Chemistry, 2007, vol. 60, p. 109 - 112
[12] Bulletin des Societes Chimiques Belges, 1984, vol. 93, # 11, p. 961 - 972
[13] Synthetic Communications, 2008, vol. 38, # 19, p. 3366 - 3374
[14] Molecules, 2002, vol. 7, # 10, p. 734 - 742
[15] Patent: WO2007/110364, 2007, A1, . Location in patent: Page/Page column 60-61
[16] Arkivoc, 2014, vol. 2014, # 5, p. 64 - 71
[17] Patent: WO2018/37223, 2018, A1, . Location in patent: Page/Page column 77
[18] Journal of Chemical Research - Part S, 2001, # 4, p. 140 - 142
[19] Tetrahedron Letters, 2014, vol. 55, # 7, p. 1320 - 1322
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[21] Proceedings of the Royal Society of London, Series B: Biological Sciences, 1946, vol. 133, p. 20,30
[22] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 22, p. 6842 - 6851
Example 1; 3-Bromo-4-hydroxybenzonitrile (IV)4-Cyanophenol (III) (5.0 g, 0.042 mol) was dissolved in acetonitrile (50 mL), under a nitrogen atmosphere. The mixture was cooled to -15°C, and CF3SO3H was added (3.7 mL, 6.3 g, 0.042 mol). The temperature was kept under 100C and NBS (8.2 g, 0.046 mol) was added in 6 portions. The reaction mixture was brought at room temperature and was stirred for 4 hours under a nitrogen atmosphere, monitoring by TLC (Hexane/EtOAc 75:25, UV, KMnψ4). When the starting material was completely consumed, the mixture was diluted with an aqueous solution OfNa2CO3 and extracted with MTBE (3 x 50 mL). The combined organic layers were dried over sodium sulphate and the solvent was removed under reduced pressure to afford the title compound, as a white solid (7.7 g, 93percent).1H NMR (DMSO, 300 MHz, 300 K): δ= 8.04 ppm (d, J=2.2 Hz, IH), 7.63 (dd, J=2.2 Hz, J=8.5 Hz, IH), 7.04 (d, J=8.5, IH).
89.1%
Stage #1: With iodine In dichloromethane at -5℃; for 0.166667 h; Stage #2: With bromine In dichloromethane at 20℃; for 24 h;
Intermediate 13-bromo-4-hydroxy benzonitrile preparation For 1000 ml in three-necked bottle, adding 50g (0.420mol) to p-hydroxybenzonitrile, 1.5g (0.006mol) iodine, 200 ml dichloromethane, -5 ° C of the lower mechanical stirring 10 min. The 43.4 ml (0.840mol) bromine and 200 ml methylene chloride mixed solution into the above-mentioned reaction solution, the drop finishes, room temperature reaction 24h. the response finishes, the above-mentioned reaction solution slowly poured into 550 ml (16percent) in aqueous solution of sodium bisulfite, stirring 30 min then, filtering, washing, drying, the white solid obtained 74.1g, yield: 89.1percent
Reference：
[1] Patent: US9181298, 2015, B2, . Location in patent: Page/Page column 33; Sheet 8
[2] Journal of Organic Chemistry, 2005, vol. 70, # 11, p. 4267 - 4271
[3] Patent: WO2010/142653, 2010, A1, . Location in patent: Page/Page column 14
[4] Patent: CN103333134, 2016, B, . Location in patent: Paragraph 0101; 0102
[5] RSC Advances, 2014, vol. 4, # 49, p. 25898 - 25903
[6] Tetrahedron Letters, 2015, vol. 56, # 41, p. 5646 - 5650
[7] Synthetic Communications, 2011, vol. 41, # 1, p. 147 - 155
[8] Journal of the Chemical Society, 1949, p. 642,645
[9] Patent: WO2010/92043, 2010, A1, . Location in patent: Page/Page column 78-79
[10] Patent: WO2011/141933, 2011, A2, . Location in patent: Page/Page column 44
[11] Journal of Organic Chemistry, 2018, vol. 83, # 15, p. 7867 - 7877
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[ 1689-84-5 ]
[ 2315-86-8 ]
[ 767-00-0 ]
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[1] Journal of Photochemistry and Photobiology A: Chemistry, 2018, vol. 365, p. 151 - 156
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[ 1689-84-5 ]
[ 17345-61-8 ]
[ 2315-86-8 ]
[ 767-00-0 ]
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[1] Journal of Photochemistry and Photobiology A: Chemistry, 2018, vol. 365, p. 151 - 156
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[ 2315-86-8 ]
[ 1689-84-5 ]
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[1] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506
[2] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506
[3] Journal of the Chemical Society, 1949, p. 642,645
[4] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506
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[ 767-00-0 ]
[ 3032-92-6 ]
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[ 767-00-0 ]
[ 188998-64-3 ]
[ 6508-04-9 ]
[ 79370-78-8 ]
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[ 767-00-0 ]
[ 696-60-6 ]
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[1] Patent: EP696593, 1996, A2,
[2] Bulletin des Societes Chimiques Belges, 1996, vol. 105, # 10-11, p. 721 - 727
[3] Journal of Chemical Research, 2009, # 1, p. 5 - 7
[4] Tetrahedron, 1992, vol. 48, # 21, p. 4301 - 4312
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[ 767-00-0 ]
[ 14543-43-2 ]
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[2] Proceedings of the Royal Society of London, Series B: Biological Sciences, 1946, vol. 133, p. 20,30
[3] Patent: WO2018/37223, 2018, A1,
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[1] Journal of Organic Chemistry, 2007, vol. 72, # 18, p. 6905 - 6917
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[ 767-00-0 ]
[ 117011-70-8 ]
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[ 767-00-0 ]
[ 22171-15-9 ]
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[3] Journal of the American Chemical Society, 1984, vol. 106, # 11, p. 3344 - 3353
39
[ 100-97-0 ]
[ 767-00-0 ]
[ 74901-29-4 ]
Yield
Reaction Conditions
Operation in experiment
19%
at 0 - 100℃; for 16 h;
Step l:3-Formyl-4-hydroxybenzonitrile (3_29_2) [00235] Hexamethylenetetramine (HMTA, 117.6 g, 840 mmol) was added to a cooled (0°C) solution of 4-cyanophenol 3_29_1 (50 g, 420 mmol) in trifluoroacetic acid (TFA, 340 mL). After the addition, the mixture was heated at 100°C for 16 hours, cooled to room temperature, quenched with 50 percent sulfuric acid (210 mL) and water (1260 mL), extracted with ethyl acetate, dried and concentrated. The residue was purified by chromatography to give compound 3_29_2 (12 g, 19 percent yield) as an off- white solid.
Reference：
[1] Chemical & Pharmaceutical Bulletin, 1983, vol. 31, # 5, p. 1751 - 1753
[2] Patent: WO2013/110643, 2013, A1, . Location in patent: Paragraph 00235
[3] Journal of Organic Chemistry, 2016, vol. 81, # 19, p. 8744 - 8758
40
[ 767-00-0 ]
[ 141-78-6 ]
[ 74901-29-4 ]
Yield
Reaction Conditions
Operation in experiment
13%
With hexamethylenetetramine; sulfuric acid In dichloromethane; water; trifluoroacetic acid
Reference Example 84 5-Cyano-2-hydroxybenzaldehyde To a solution of 4-cyanophenol (25.0 g) in trifluoroacetic acid (150 ml) was added hexamethylenetetramine (50.0 g) and the mixture was stirred at 100° C. for 9 hours. After cooling to room temperature, sulfuric acid (50 ml) and water (300 ml) were added to the reaction mixture. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with dichloromethane. The extract was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/ethyl acetate=19/1 as an eluant to give the desired compound (4.3 g, yield 13percent) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ ppm: 7.11 (1H, d, J=9.0), 7.78 (1H, dd, J=9.0, 2.0), 7.94 (1H, d, J=2.0), 9.93 (1H, s).
Reference：
[1] Journal of Medicinal Chemistry, 1990, vol. 33, # 4, p. 1252 - 1257
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 2, p. 592 - 608
44
[ 767-00-0 ]
[ 405-04-9 ]
[ 2967-54-6 ]
Reference：
[1] Journal of Fluorine Chemistry, 2000, vol. 102, # 1-2, p. 169 - 173
45
[ 767-00-0 ]
[ 38148-63-9 ]
Reference：
[1] Journal of Materials Chemistry, 2012, vol. 22, # 41, p. 21987 - 21997,11
[2] Journal of Materials Chemistry, 2012, vol. 22, # 41, p. 21987 - 21997
[3] Journal of the American Chemical Society, 1988, vol. 110, p. 244
46
[ 87199-16-4 ]
[ 767-00-0 ]
[ 90178-72-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6384 - 6399
47
[ 767-00-0 ]
[ 81005-00-7 ]
[ 81930-17-8 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1983, vol. 19, p. 1479 - 1483[2] Zhurnal Organicheskoi Khimii, 1983, vol. 19, # 8, p. 1669 - 1674
[3] Molecular crystals and liquid crystals, 1984, vol. 107, # 3-4, p. 411 - 443
48
[ 767-00-0 ]
[ 73011-79-7 ]
[ 72928-55-3 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1983, vol. 19, p. 1479 - 1483[2] Zhurnal Organicheskoi Khimii, 1983, vol. 19, # 8, p. 1669 - 1674
[3] Molecular crystals and liquid crystals, 1984, vol. 107, # 3-4, p. 411 - 443
Reference：
[1] Journal of Fluorine Chemistry, 2000, vol. 102, # 1-2, p. 169 - 173
51
[ 767-00-0 ]
[ 118811-07-7 ]
[ 333954-86-2 ]
Yield
Reaction Conditions
Operation in experiment
55.8%
With potassium carbonate In N,N-dimethyl-formamide at 100℃;
Step (i): Preparation of 4-(4-Cyano phenoxy) piperidine-l-carboxylic acid tert-butyl esterA solution of 4-hydroxy benzonitrile (15 g, 0.126 moles), potassium carbonate (28.89 g, 0.208 moles) and 4-(Toluene-4-sulfonyloxy) piperidine-l-carboxylic acid tert-butyl ester (57.62 g, 0.162 moles) in dimethylformamide (150 mL) was stirred at 100 °C while monitoring the progress of the reaction by thin layer chromatography. After completion of reaction, the reaction mass was quenched on to water (400 mL) and extracted with ethyl acetate (3 x 300 mL). The resulting ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude residue, which was further purified by flash chromatography using (ethyl acetate: hexane,l :9) to afford the title compound 21.25 g (Yield: 55.8 percent). - NMR (δ ppm): 1.47 (9H, s), 1.74 - 1.80 (2H, m), 1.91 - 1.96 (2H, m) 3.33 - 3.40 (2H, m), 3.66 - 3.72 (2H, m), 4.53 - 4.57 (1H, m), 6.94 - 6.96 (2H, d, J = 8.78 Hz), 7.57 - 7.59 (2H, d, J = 8.76 Hz);Mass (m/z): 303.4 (M+H)+.
55.8%
With potassium carbonate In N,N-dimethyl-formamide at 100℃;
Step (i): Preparation of 4-(4-Cyano phenoxy)piperidine-1-carboxylic acid tert-butyl ester A solution of 4-hydroxy benzonitrile (15 g, 0.126 moles), potassium carbonate (28.89 g, 0.208 moles) and 4-(Toluene-4-sulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester (57.62 g, 0.162 moles) in dimethylformamide (150 mL) was stirred at 100° C. while monitoring the progress of the reaction by thin layer chromatography. After completion of reaction, the reaction mass was quenched on to water (400 mL) and extracted with ethyl acetate (3*300 mL). The resulting ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude residue, which was further purified by flash chromatography using (ethyl acetate:hexane, 1:9) to afford the title compound 21.25 g (Yield: 55.8percent). 1H-NMR (δ ppm): 1.47 (9H, s), 1.74-1.80 (2H, m), 1.91-1.96 (2H, m) 3.33-3.40 (2H, m), 3.66-3.72 (2H, m), 4.53-4.57 (1H, m), 6.94-6.96 (2H, d, J=8.78 Hz), 7.57-7.59 (2H, d, J=8.76 Hz); Mass (m/z): 303.4 (M+H)+.
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 25℃; for 4 h;
Tert-butyl-4-hydroxypiperidine-1-carboxylate (4.5 g, 22.4 mmol)4-hydroxybenzonitrile (2.7 g, 22.7 mmol)And triphenylphosphine(8.8 g, 33.5 mmol) was dissolved in tetrahydrofuran (80 mL)Cooled to 0 ° C,Diethyl azodicarboxylate (5.8 g, 33.3 mmol) was added.25 ° C for 4 hours,LC-MS detection reaction is completed,Concentrated, ethyl acetate (150 mL) and water (50 mL) were added,The aqueous phase was extracted with ethyl acetate (50 mL)Combined organic phase,The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the product (4.6 g, 67.6percent yield).
Reference：
[1] Patent: CN107226807, 2017, A, . Location in patent: Paragraph 0264-0266
53
[ 767-00-0 ]
[ 609-15-4 ]
[ 161797-99-5 ]
Reference：
[1] Patent: CN106928108, 2017, A, . Location in patent: Paragraph 0068; 0069
54
[ 767-00-0 ]
[ 161797-99-5 ]
Yield
Reaction Conditions
Operation in experiment
84.2%
With hydrogenchloride; sodium hydroxide In ethanol
EXAMPLE 2 Ethyl 2-(4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate A mixture of 4-Cyanophenol (23.82 g, 0.2 mol), NaOH (8 g, 0.2 mol), and 200 mL ethanol were mixed in a pressure bottle while heated to 80° C. Hydrogen sulfide gas was then introduced and the pressure increased to 30-60 psi until the thioamidation was determined to be complete by HPLC. Without isolating the thioamide product, HCl was added to the bottle until the pH was below 3.5, the H2S gas was removed, and the bottle was placed under a vacuum for 20 minutes at 30-40° C. The reaction was then heated to 70° C. and ethyl 2-chloroacetoacetate(1.1 eq.) was added to the reaction solution. The reaction was mixed under reflux for 2-3 hours, treated with enough H2O to dissolve the NaCl salt in the reaction mixture, cooled to room temperature, treated with enough water to precipitate the product, and the solid was collected by filtration. The precipitate was washed with water and dried at 80° C. with nitrogen bleeding to provide 50.50 g (84.2percent) of desired product.
Reference：
[1] Patent: US2005/27128, 2005, A1,
55
[ 767-00-0 ]
[ 161797-99-5 ]
Reference：
[1] Patent: WO2016/46836, 2016, A2,
[2] Journal of Photochemistry and Photobiology A: Chemistry, 2017, vol. 334, p. 1 - 12
[3] Patent: CN104529935, 2017, B,
56
[ 767-00-0 ]
[ 161798-01-2 ]
Reference：
[1] Journal of Photochemistry and Photobiology A: Chemistry, 2017, vol. 334, p. 1 - 12
[2] Patent: CN104529935, 2017, B,
A mixture of 4-Cyanophenol (50.0 g, 0.42 mol), and NaSH (15.5 g, 0.21 mol) in distilled water (125 mL) was stirred at room temperature for 30 minutes. The mixture was then put under a vacuum, flushed with H2S, and the pressure was brought to 40-50 psi for a period of a few minutes. The mixture was then heated to 70 C. and stirred for 40-45 minutes. The mixture was stirred vigorously at 70 C. under constant pressure of 56 psi for 5 hours and 15 minutes. The H2S pressure was removed and the reaction was cooled to room temperature. The reaction was neutralized to pH 5-7 with 2 M HCl (66 mL). The product was filtered, and the filter cake washed with distilled water (2*50 mL), and dried under a vacuum at 80-85 C. for 22 hours to provide 62.74 g (97.57%) desired product.
94%
With sodium monohydrogen sulfide x-hydrate; ammonium chloride; In water; N,N-dimethyl-formamide; at 40℃; for 22h;Product distribution / selectivity;
To a solution of a sodium hydrogen sulfide hydrate (2.35 g), N,N-dimethylformamide (3 ml) and water (0.5 ml) were added 4-hydroxybenzonitrile (1.0 g) and ammonium chloride (2.25 g) while stirring. After the mixture was stirred at 40 C. for 22 hours, 2N hydrochloric acid (9.5 ml) was added followed by the addition of water (2.0 ml) to the mixture. A solid formed under ice cooling and stirring was filtered and then dried to afford 4-hydroxybenzothioamide (1.21 g) (yield 94%).
92%
With sodium hydrogen sulfide; triethylamine hydrochloride; triethylamine; In ethanol; at 5 - 50℃; for 12h;
11 g of sodium hydrosulfide,6 g of p-hydroxybenzonitrile,6.9 mL of triethylamine,40 mL of ethanol was added to a 100 mL three-necked flask, ice bath temperature control 5 ~ 10 C, A solution of 27.5 g of triethylamine hydrochloride was added in portions, Add the elevated temperature to 50 C ,Stirring under the insulation for 12 hours, TLC monitoring reaction is complete, liquid phase control shows the conversion rate of 95% or more, the final yield of 92%.After the end of the reaction, the ethanol recovered by distillation can be directly applied. Distilled by adding 40 mL of ethanol to beat at 50 C for 0.5 hour and filtering to obtain a higher purity sodium chloride solid salt.The ethanol filtrate was concentrated to dryness, and 25 mL of water was added to the beater, filtered and dried to give 7.32 g of a yellowish solid. Liquid content of more than 97%, the yield of 92%.The filtered aqueous phase can be repeatedly applied in multiple batches and finally concentrated to dryness, resulting in triethylamine hydrogen sulfide and triethylamine hydrochloride, which can be recycled to the reaction. The whole process is basically no waste generated.
90%
With sodium monohydrogen sulfide x-hydrate; ammonium chloride; In water; N,N-dimethyl-formamide; at 40℃; for 22h;
To a solution of sodium hydrosulfide hydrate in dimethylformamide (1.8 mL) and water (0.25 mL) is added 4-hydroxybenzonitrile and NH4Cl with stirring. The reaction mixture is stirred for 22 hours at 40 C. To this reaction mixture under ice cooling is added 5 mL of 5N HCl followed by water and allowed to stir for a while. Solid formed after stirring is filtered, dried and used as such for thiazole synthesis. (0408) [00337] To a solution of 4,4-Dimethoxybenzoin (1 equivalent) in dichloromethane at 0 C is added 4-Toluenesulfonyl chloride (1 equivalent) followed by trimethylamine (2 equivalents) and catalytic N,N-dimethylaminopyridine with constant stirring. The reaction mixture is stirred at room temperature overnight. After completion of reaction, the crude product is partitioned between ethyl acetate and water. The ethyl acetate layer is washed with brine and then dried over Na2SO4 and evaporated under reduced pressure. The crude reaction mixture is purified by column chromatography using ethyl acetate/hexane. (0409) [00338] In the next step, the tosylated-4,4-dimethoxybenzoin (1.0 mmol) and thiobenzamide (1.2 mmol) are added to 1-butyl-3-methylimidazolium hexafluorophosphate (BMIM-PF6) (2 mL). The resulting mixture is heated at 110 C for 3-4 hours. Subsequently, the reaction mixture is extracted with diethylether multiple times. The combined etheral solution is vacuum evaporated. The residue is chromatographed on silica gel column using (0410) methanol/dichloromethane to provide the product in 55 % yield. [00339] 4,5-bis(4-methoxyphenyl)-2-(4-(2-(piperidin-1-yl)ethoxy)phenyl)thiazole (TSI-14- 17) (0411) [00340] 1H NMR (500 MHz, Chloroform-d) 7.92 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.19 (t, J = 5.8 Hz, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 2.84 (t, J = 5.3 Hz, 2H), 2.58 (s, 4H), 1.70- 1.62 (m, 4H), 1.48 (s, 2H).13C NMR (126 MHz, CDCl3) 164.8, 160.5, 159.6, 159.3, 150.0, 134.2131.0, 130.5, 128.1, 128.0, 127.2, 124.9, 115.1, 114.4, 113.9, 66.3, 58.1, 55.6, 55.5, 55.47, 55.3, 26.1, 24.4. HRMS-ESI: m/z [M+H]+ for C30H33N2O3S, calculated 501.2212; (0412) observed 501.2211.
87.5%
With O,O-Diethyl hydrogen phosphorodithioate; In water; at 50℃; for 3h;
EXAMPLE- 1 (preparation of 4-hydroxythiobenzamide) 0.23 moles of diethyldithiophosphoric acid was added to 1.66 moles of water followed by addition of 0.21 moles of 4-cyanophenol. The reaction mixture was heated to 50C and was maintained at this temperature with stirring for 3 hrs. The reaction mass was then cooled to 25-30C. 100 ml of dichloromethane was added to the mixture and it was maintained at 25-30C for 30 min. It was then filtered and the solid product was washed with saturated sodium carbonate solution followed by 70 ml water. It was dried at 75oC to obtain 4-hydroxythiobenzamide in 87,5% yield.
70%
With tetraphosphorus decasulfide; In ethanol; at 70℃; for 12h;
P2S5 (0.37 g, 16.8 mmol) was dissolved in ethanol (10 mL) and stirred at rt for 1 h. Then the solution became clear. To this reaction mixture, 4-hydroxy-benzonitrile (1) (1 g, 8.4 mmol) was added. The RM was then heated at 70 C for 12 h. The RM was evaporated to dryness and the resultant crude mixture was purified by column chromatography on silica, product eluted with 50% EA/Hex to afford 4-hydroxy benzamide (2) (800 mg, 70%) as white solid. 1H NMR (400 MHz, DMSO-d6) delta (ppm): 10.08 (s, 1H), 9.52 (s, 1H), 9.20 (s, 1H), 7.86 (d, J = 8.56 Hz, 2H), 6.74 (d, J = 8.6 Hz, 2H). MS (ESI): m/z calc. for C7H7NOS+: 153.0; found: 154.1 [M+H]+.
68.4%
With hydrogen sulfide; ammonium chloride; In N,N-dimethyl-formamide; at 50 - 95℃; under 1520.1 - 3040.2 Torr;Autoclave; Inert atmosphere;
Add 300 g of DMF to the autoclave; add 150 g (1.259 mol) of p-hydroxybenzonitrile (RS160-00); add 10 g (0.187 mol) of ammonium chloride, replace the air in the tank with nitrogen 2 to 3 times, and empty, Under stirring, hydrogen sulfide gas was passed in to make the pressure in the kettle be 2 to 3 atm; heated to 50 to 60 C, hydrogen sulfide gas was intermittently passed in to keep the pressure in the kettle between 2 to 4 atm and the temperature in the kettle was maintained at 85 ~ 95 ; keep stirring for 8 ~ 16hr until the pressure in the kettle does not change significantly; after the reaction is completed, reduce the temperature to 30 ~ 40 , replace the hydrogen sulfide gas in the kettle with nitrogen, and then press out the reaction solution with nitrogen , Transfer to a fume hood, dilute the reaction solution with 1500g of water; cool to 0 ~ 5 C, stir and crystallize thoroughly; filter, filter cake rinse with water, collect solids; add the obtained solids to 240g of absolute ethanol, heat Completely dissolve the solids to 70 80 , heat filter to remove mechanical impurities; collect the filtrate, cool to 0 5 , and keep crystallization for about 3 5hr; filter, filter cake rinse with 90% ethanol / water, collect Solid; blast drying at 75 85 to obtain about 132g of 152A1-00 dry product (theoretical amount: 192.9g) . One-way yield: 68.4%.
62.74 g (97.57%)
With hydrogenchloride; NaSH; In water;
EXAMPLE 1 4-hydroxybenzene carbothioamide A mixture of 4-Cyanophenol (50.0 g, 0.42 mol), and NaSH (15.5 g, 0.21 mol) in distilled water (125 mL) was stirred at room temperature for 30 minutes. The mixture was then put under a vacuum, flushed with H2S, and the pressure was brought to 40-50 psi for a period of a few minutes. The mixture was then heated to 70 C. and stirred for 40-45 minutes. The mixture was stirred vigorously at 70 C. under constant pressure of 56 psi for 5 hours and 15 minutes. The H2S pressure was removed and the reaction was cooled to room temperature. The reaction was neutralized to pH 5-7 with 2 M HCl (66 mL). The product was filtered, and the filter cake washed with distilled water (2*50 mL), and dried under a vacuum at 80-85 C. for 22 hours to provide 62.74 g (97.57%) desired product.
With ammonium hydroxide; iodine; potassium iodide; In water; at 20℃; for 16h;Inert atmosphere;
To a solution of 4-hydroxy-benzonitrile (5 g, CAS: 767-00-0) in NH4OH (225 mL) was added a solution of KI (34.14 g, CAS: 7681-11-0) and ?2(10.65 g, CAS: 7553-56-2) in H20 (50 mL). The reaction mixture was stirred at rt for 16 hours. The reaction mixture was filtered andthe filtrate was evaporated. The residue was dissolved in DCM (250 mL) and was washed with H20 (2x150 mL), saturated aqueous Na5203 solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2504, filtered and concentrated under reduced pressure to give the title compound (8.44 g, 82%) that was used in the next step without further purification. LC-MS: (ESI): mlz = 244.0 [M-H]
80%
With ammonium hydroxide; iodine; potassium iodide; In water; for 6h;
To a solution of A- hydroxybenzonitrile (0.5 g; 4.18 mmol) in 25% NH4OH (22 ml) a solution of I2 (1.06 g; 4.18 mmol) and Kl (3.41 g; 20.54 mmol) in H2O (5 ml) was added at once with stirring. The stirring was continued for 6 h, during which time the mixture turn from black into colourless. The precipitate formed was filtered off and filtrate was evaporated to dryness under reduced pressure. The residue was treated with H2O (3 ml). The precipitate formed was filtered off, washed with cold H2O (3 x 2 ml), and dried in vacuo to give the title compound (0.82 g; 80%), as colourless solid. 1H-NMR (CDCI3) 7.96 (d, 1 H, 1 .9 Hz); 7. 53 (dd, 1 H, J = 1 .9 Hz, 8.5 Hz); 7.03 (d, 1 H, J = 8.5 Hz); 6.03 (s, 1 H);
80%
With ammonia; iodine; potassium iodide; In water; for 6h;
To a solution of 4- hydroxybenzonitrile (0.5 g; 4.18 mmol) in 25% NH4OH (22 ml) a solution of I2 (1.06 g; 4.18 mmol) and Kl (3.41 g; 20.54 mmol) in H2O (5 ml) was added at once with stirring. The stirring was continued for 6 h, during which time the mixture turn from black into colourless. The precipitate formed was filtered off and filtrate was evaporated to dryness under reduced pressure. The residue was treated with H2O (3 ml). The precipitate formed was filtered off, washed with cold H2O (3 x 2 ml), and dried in vacuo to give the title compound (0.82 g; 80%), as colourless solid. 1 H-NMR (CDCI3 ) 6.03 (s, 1 H); 7.03 (d, 1 H, J = 8.5 Hz); 7. 53 (dd, 1 H, J = 1 .9 Hz, 8.5 Hz); 7.96 (d, 1 H, 1 .9 Hz).
80%
With ammonium hydroxide; iodine; potassium iodide; In water; for 6h;
To a solution of 4- hydroxybenzonitrile (0.5 g; 4.18 mmol) in 25% NH4OH (22 ml) a solution of l2 (1 .06 g; 4.18 mmol) and Kl (3.41 g; 20.54 mmol) in H20 (5 ml) was added at once with stirring. The stirring was continued for 6 h, during which time the mixture turn from black into colourless. The precipitate formed was filtered off and filtrate was evaporated to dryness under reduced pressure. The residue was treated with H20 (3 ml). The precipitate formed was filtered off, washed with cold H20 (3 x 2 ml), and dried in vacuo to give the title compound (0.82 g; 80%), as colourless solid. 1 H-NMR (CDCI3) 7.96 (d, 1 H, 1 .9 Hz) ; 7. 53 (dd, 1 H, J = 1 .9 Hz, 8.5 Hz) ; 7.03 (d, 1 H, J = 8.5 Hz); 6.03 (s, 1 H) ;
With ammonia; iodine; In methanol; water; at 20℃; for 2h;
A. 3-Iodo-4-hydroxybenzonitrile 11.9 g (0.1 mol) of 4-hydroxybenzonitrile are dissolved in 250 ml of methanol and 250 ml of 20% aqueous ammonia are added. A solution of 31.75 g of iodine in 250 ml of methanol is then added dropwise, with care, due to the explosive nature of the reaction. After addition, the mixture is stirred for 2 hours at ambient temperature. The methanol is evaporated off, dilution is carried out in water and acidification with a hydrochloric acid solution is performed until pH=2 to 3 is obtained. Extraction with ethyl acetate and washing with water, a sodium thiosulfate solution and a saturated sodium chloride solution are subsequently carried out. In this way, 24.73 g of desired compound are obtained. M.p.: 144-146 C. The compound below was prepared using the same process as above:
With 3-Methylpyridine; In para-xylene; for 24h;Reflux;
1,1-Diethoxy-3-methylbut-2-ene 17 (1.74 g,11.0 mmol), 4-cyanophenol (2.65 g, 22.0 mmol) and 3-picoline(0.27 mL, 2.75 mmol) were dissolved in p-xylene (20 mL/g ofphenol). The mixture was heated under reflux for 24 h, and thereaction mixture allowed to cool to ambient temperature. The clear,golden mixture was diluted with EtOAc (50 mL) and washed withHCl (1 N, 2 25 mL). The aqueous layers were combined andwashed with EtOAc (2 25 mL). The combined organic layers werewashed with NaOH (1 N, 25 mL), brine (25 mL), dried over anhydrousMgSO4 and filtered. The solvents were removed underreduced pressure to give a bright yellow solid. The yellow solid wasrecrystallized from light petroleumto give the title compound 16 asa yellow powder (1.78 g, 87%).
35%
With Mo11O40PV*4H(1+)*3C5H5N; In para-xylene; at 20 - 120℃; for 6h;Green chemistry;Catalytic behavior;
Py3-Mo11V was used as catalyst for the preparation of 6-CN-2,2-DMB. 1,1-diethoxy-3-methyl-2-butene (17 mmol), 4-cyanophenol (13 mmol), and the catalyst (Py3-PMo11V, 1 mmol %) were added to p-xylene (20 mL) as solvent at 20 C. The progress of the reaction was monitored by TLC and GC analysis. The reaction mixture was heated and stirred at 120 C. After 6 h, the reaction mixture was cooled down to room temperature. The clear, yellow solution was diluted with p-xylene (10 mL) and the catalyst was recovered by centrifugation, washed with p-xylene (5 mL), dried in vacuum, and reused. The organic phases were washed with HCl(1 M, 2 × 7 mL), NaOH (1 M, 2 × 7 mL), saturated solution of NaCl(10 mL), H2O (10 mL), dried (anhydrous Na2SO4), and concentrated.The crude product was crystallized from hexanes. The crystals were recovered by filtration, washed with hexanes, and dried to give 35% yield, mp 46-47 C, lit147 C. 1H NMR (200 MHz, CDCl3) = 7.36 (dd,J = 8 Hz, J = 2 Hz, 1 H), 7.24 (d, J = 2 Hz, 1 H), 6.80 (d, J = 8 Hz, 1 H), 6.31(d, J = 10 Hz, 1 H), 5.72 (d, J = 10 Hz, 1 H), and 1.46 (s, 6H).13C NMR(50 MHz, CDCl3) = 156.7, 133.3, 132.2, 130.2, 121.5, 120.6, 119.1,117.2, 103.5, 77.8, and 28.2.
4-[2-(4-Cyanophenoxy)ethyl]-1H-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium iodide; potassium carbonate; In N-methyl-acetamide;
EXAMPLE 112 4-[2-(4-Cyanophenoxy)ethyl]-1H-imidazole 360 mg (3 mmol) of 4-cyanophenol, 251 mg (1.5 mmol) of 4-[2-chloroethyl]imidazole hydrochloride, 500 mg (3.6 mmol) of potassium carbonate and sodium iodide (catalyst) are stirred at 80 C. for 5 days in 5 ml of dimethylformamide. The mixture is cooled and filtered. The filtrate is evaporated under reduced pressure to give an oily residue. The unreacted 4-cyanophenol is precipitated with a methanol/diethyl ether (1/10) fixture. After filtration, the filtrate is evaporated under reduced pressure to give the title compound which is crystallized from a methanol/water (10/3) mixture, M.p.: 181-183 C.
With potassium carbonate; In butanone; for 4h;Heating / reflux;
4.91 g of tert-butyl 4-(2-bromoethyl)-1-piperidinecarboxylate was dissolved in 50 ml of 2-butanone, and then, 2.00 g of 4-cyanophenol and 4.64 g of potassium carbonate were added thereto, followed by heating to reflux for 4 hours. After cooling to room temperature, 50 ml of water and 50 ml of ethyl acetate were added to the reaction mixture, so that the organic layer was separated. The separated organic layer was washed with saturated aqueous solution of sodium chloride dried over anhydrous magnesium sulfate, and the solvent was then removed under a reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; n-hexane: ethyl acetate = 2: 1] to obtain 3.61 g of a colorless oil product, tert-butyl 4-[2-(4-cyanophenoxy)ethyl]-1-piperidinecarboxylate. 1H-NMR (CDCl3) delta: 1.00-1.30 (2H, m), 1.46 (9H, s), 1.50-2.04 (5H, m), 2.62-2.76 (2H, m), 4.05 (2H, t, J = 6.2 Hz), 4.00-4.18 (2H, m), 6.93 (2H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.5 Hz)
With potassium carbonate; In acetone; for 4h;Reflux;
General procedure: A solution mixture of benzylbromide derivative, 4cyanophenol (1.0-1.2 equiv) and K2CO3 (4.0 equiv) was heated in acetone (200-400 mL) at 5060 C of reflux (4 h). The reaction mixture was evaporated in vacuo, and the resulted residue was diluted in CH2Cl2 (300 mL), then extracted with distilled H2O (300 mL × 2). The combined organic layer was dried (Na2SO4) and evaporated in vacuo. Using Method A, 4-cyanophenol (4.00 g, 33.6 mmol), 3-fluorobenzyl bromide (4.18 mL, 33.6 mmol), and K2CO3 (18.60 g, 134.3 mmol) gave 6f as a white solid (7.25 g, 95%): Rf = 0.47 (EtOAc 1 : n-hexane 5): 1H NMR (DMSO-d6, 400 MHz) d 5.23 (s, OCH2),7.14-7.22 (m, 3 ArH), 7.28-7.32 (m, 2 ArH), 7.45 (q, J = 7.6 Hz, 14.1 Hz, 1 ArH), 7.79 (d, J = 8.8 Hz, 2 ArH); 13C NMR (DMSO-d6, 100 MHz) d 68.8 (OCH2), 103.2 (ArC-CN), 114.4, 114.6, 114.9 (d, JC-F = 20.9 Hz), 115.9, 119.1 (CN), 123.8, 130.6 (d, JC-F = 8.3 Hz), 134.3, 139.1 (10 ArC), 161.6 (OArC), 162.2 (d, JC-F = 242.4 Hz).
93%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1h;
Preparation Example 6. 4-(3-Fluorobenzyloxy)-benzylamine To a solution of 4-cyanophenol (3.0g, 25.2mmol) and 3-fluorobenzyl bromide (3.1mL, 25.2mmol) in N,N-dimethylformamide (30mL) was added potassium carbonate (8.71g, 63.0mmol), and the mixture was stirred for 1 hour at room temperature. Ethyl acetate and water were added to the reaction mixture, which was then partitioned, the organic layer was washed with water, then, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain 4-(3-fluorobenzyloxy)-benzonitrile (5.31 g, 93%) as a colorless solid. Next, to a solution of lithium aluminum hydride (1.25g, 133.0mmol) in tetrahydrofuran (15mL) was added a solution of 4-(3-fluorobenzyloxy)-benzonitrile (218mg, 0.615mmol) in tetrahydrofuran (12mL) on an ice bath, and the solution was stirred at room temperature for 19 hours. A mixture solvent of methanol and water (9:1) was added to the reaction solution, an aqueous solution of saturated ammonium chloride was further added, and the solution was stirred on an ice bath for 30 minutes. This solution was filtered through Celite pad, and insoluble matter was removed. The filtrate was partitioned, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the title compound (1.33g, 44%) was obtained as a yellow solid. This was used in the next reaction without further purification.
93%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1h;
To a solution of 4-cyanophenol (3.0g, 25.2mmol) and 3-fluorobenzyl bromide (3.1mL, 25.2mmol) in N,N-dimethylformamide (30mL) was added potassium carbonate (8.71g, 63.0mmol), and the mixture was stirred for 1 hour at room temperature. Ethyl acetate and water were added to the reaction mixture, which was then partitioned, the organic layer was washed with water, then, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain 4-(3-fluorobenzyloxy)-benzonitrile (5.31g, 93%) as a colorless solid. Next, to a solution of lithium aluminum hydride (1.25g, 133.0mmol) in tetrahydrofuran (15mL) was added a solution of 4-(3-fluorobenzyloxy)-benzonitrile (218mg, 0.615mmol) in tetrahydrofuran (12mL) on an ice bath, and the solution was stirred at room temperature for 19 hours. A mixture solvent of methanol and water (9:1) was added to the reaction solution, an aqueous solution of saturated ammonium chloride was further added, and the solution was stirred on an ice bath for 30 minutes. This solution was filtered through Celite pad, and insoluble matter was removed. The filtrate was partitioned, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the title compound (1.33g, 44%) was obtained as a yellow solid. This was used in the next reaction without further purification.
87%
With potassium carbonate; In acetone; for 5h;Reflux;
Scheme 1. Preparation pf (R)-3 and (S)-Z.; Preparation of 4-(3-Fluorobenzyloxy)benzonitrile. (Nakamoto, Kazutaka;Tsukada, Itaru; Tanaka, Keigo; Matsukura, Masayuki; Haneda, Tom; Inoue, Satoshi; Ueda, Norihiro; Abe, Shinya; Hata, Katsura; Watanabe, Naoaki, WO 2005033079 (2005)).; A mixture of 4-cyanophenol (11.91 g, 100.0 mmol), K2CO3 (55.20 g, 400.0 mmol), and 3-fluorobenzylbromide (22.68 g, 120.0 mmol) were heated in acetone (400 ml_) at reflux (5 h). The volatiles were evaporated and the residue was diluted in CH2CI2 (300 mL), and then washed with H2O (500 mL), dried (MgSO4), and concentrated in vacuo to give white needles (19.81 g, 87%): Rf = 0.45 (hexanes/EtOAc 9/1); mp 104-105 0C; 1H NMR (CDCI3) delta 5.11 (s, CH2O), 6.98-7.20 (m, 5 ArH), 7.33-7.41 (m, 1 ArH), 7.59 (d, J = 8.7 Hz, 2 ArH); HRMS (M+Na+)(ESI+) 250.0641 [M + Na+] (calcd for C14H10NONa+ 250.0641).
75%
With sodium carbonate; In acetone; for 16h;Reflux;
General procedure: 4-Cyanophenol (12) (1.54 g, 12.8 mmol) and Na2CO3 (4.96 g,46.8 mmol) were mixed in acetone (120 mL) and benzyl bromide (13) (2.00 g, 11.6 mmol) was added. The resulting mixture was stirred (16 h) atreflux and evaporated in vacuo. The resulting residue was diluted in CH2Cl2(120 mL), washed with H2O (2 × 120 mL), dried (Na2SO4),and concentrated in vacuo to give 22(2.43 g, 100%) as a white solid. If it was necessary, the substitutedbenzonitrile was further purified by flash chromatography (hexanes/EtOAc 7/1).
Example 3 4-Hydroxy-thiobenzamide In a round bottomed flask, 4-hydroxybenzonitrile (5.00 g, 41.9 mmol), diethylthiophosphoric acid (7.02 g, 41.9 mmol), and water (8 ml) were heated with stirring to about 80 C. for about thirty minutes. An additional 10 ml of water was then added to the suspension, and the reaction was heated for about another one hour. The mixture was then allowed to stir for about sixteen hours at room temperature and was then extracted with water and 1:1 ether/ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (silica gel; hexanes to ethyl acetate). The product was isolated as a yellow solid (5.54 g, 87% yield). 1H NMR (CD3OD): delta6.74 (d, 2H, J=9.1 Hz), 7.83 (d, 2H, J=8.7 Hz).
3-(2,6-dibutyl-4-methylphenoxy)-4,5-bis(4-cyanophenoxy)-6-fluorophthalonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78.3 mol%
With potassium fluoride; In acetone;
SYNTHESIS EXAMPLE 4 Synthesis of 3-(2,6-dibutyl-4-methylphenoxy)-4,5-bis(4-cyanophenoxy)-6-fluorophthalonitrile In a four-neck separable flask having an inner volume of 500 ml, 60 g (0.30 mol) of <strong>[1835-65-0]tetrafluorophthalonitrile</strong>, 41.8 g (0.72 mol) of potassium fluoride, and 160 ml of acetone. Further, to a dropping funnel attached thereto, 71.5 g (0.60 mol) of 4-cyanophenol and 110 ml of acetone were placed. The 4-cyalophenol/acetone mixed solution was added dropwise from the dropping funnel to the flask over a period of about two hours while kept stirred at -1° C. The stirring was subsequently continued for about two hours. Thereafter, the contents of the flask were stirred overnight, with the reaction temperature thereof slowly raised to room temperature. Then, to this flask, 79.8 g (0.30 mol) of 2,6-dibutyl-4-methylphenol, 20.9 g (0.36 mol) of potassium fluoride, and 15.0 mol of acetone were charged and the mixture was kept stirred at 40° C. for 10 hours. The reaction solution was cooled and filtered. The filtrate was distilled by a rotary evaporator to expel the acetone and was recrystallized from methanol. The produced crystals were separated by filtration and vacuum dried to afford 151.3 g of 3-(2,6-dibutyl-4-methylphenoxy)-4,5-bis(4-cyanophenoxy)-6-fluorophthalonitrile (yield: 78.3 mol percent).
3-(2,6-dimethylphenoxy)-4,5-bis(4-cyanophenoxy)-6-fluorophthalonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77.5 mol%
With potassium fluoride; In acetone;
SYNTHESIS EXAMPLE 5 Synthesis of 3-(2,6-dimethylphenoxy)-4,5-bis(4-cyanophenoxy)-6-fluorophthalonitrile In a four-neck separable flask having an inner volume of 500 ml, 60 g (0.30 mol) of <strong>[1835-65-0]tetrafluorophthalonitrile</strong>, 41.8 g (0.72 mol) of potassium fluoride, and 160 ml of acetone. Further, in a dropping funnel attached thereto, 71.5 g (0.60 mol) of 4-cyanophenol and 110 ml of acetone were placed. The 4-cyalophenol/acetone mixed solution was added dropwise from the dropping funnel to the flask over a period of about two hours while kept stirred at -1° C. The stirring was subsequently continued for about two hours. Thereafter, the contents of the flask were stirred overnight, with the reaction temperature thereof slowly raised to room temperature. Then, to this flask, 36.7 g (0.30 mol) of 2,6-dimethylphenol, 20.9 g (0.36 mol) of potassium fluoride, and 15.0 ml of acetone were charged and the mixture was kept stirred at 40° C. for 10 hours. The reaction solution was cooled and filtered. The filtrate was distilled by a rotary evaporator to expel the acetone and was recrystallized from methanol. The produced crystals were separated by filtration and vacuum dried to afford 116.3 g of 3-(2,6-dimethylphenoxy)-4,5-bis(4-cyanophenoxy)-6-fluorophthalonitrile (yield: 77.5 mol percent).
With hydrogenchloride; In ethanol; para-xylene; ethyl acetate;
B. 2,2-Dimethyl-2H-1-benzopyran-6-carbonitrile A 500-mL, 3-necked, round-bottomed flask topped with a distilling head, internal temperature probe/argon inlet, and an overhead stirrer was sequentially charged with the title A compound, 1,1-diethoxy-3-methyl-2-butene (26.59 g, 168.00 mmol), p-xylene (300 mL), 4-cyanophenol (15.00 g, 125.92 mmol), and 3-picoline (3.0 mL, 2.870 g, 30.83 mmol). The reaction mixture was rapidly stirred. The internal temperature was rapidly brought up to 115 C. and then slowly raised in order to distill off the ethanol formed during the reaction. After 24 hours the reaction mixture was a clear, golden yellow solution. The distillate collected was a clear, colorless liquid (4.96 g) and was determined to be ~98% ethanol and ~2% p-xylene by 1 H NMR analysis. The reaction was cooled to room temperature, poured into a mixture of ethyl acetate (150 mL) and 1N hydrochloric acid (400 mL), and after mixing vigorously the layers were separated. The organic phase was washed again with 1N hydrochloric acid (200 mL). The acidic, aqueous layers were combined and extracted with ethyl acetate (100 mL). The organic solutions were combined and washed with 1N sodium hydroxide (1*400 mL, 1*200 mL). The basic, aqueous layers were combined and extracted with ethyl acetate (100 mL). The organic solutions were combined, washed with saturated sodium chloride solution (300 mL), dried (magnesium sulfate), filtered, and concentrated to a golden yellow liquid that contained a small amount of solid (20.85 g, 89% crude yield). To a portion of this material (20.22 g) was added hexanes (20.0 mL). The very cloudy, yellow mixture was heated to a reflux (hazy, yellow), cooled to room temperature, seeded, and then allowed to stand undisturbed for nine hours. The mixture was then cooled to, and maintained at, 5 C. for 14 hours. The supernatant liquor was decanted and filtered. The crystals were removed, placed atop the same filter, and washed quickly with 0 C. hexanes (1*6 mL, 2*7 mL). The crystals were air-dried (30 minutes), then placed under high vacuum (<1 mm Hg until a constant weight was attained) to yield the products as off-white crystals (14.91 g).
In methanol; dichloromethane; water; N,N-diethylaniline;
EXAMPLE 7 The intermediate cyano compounds of Example 5 may be prepared as follows: 4-Cyanophenol (19.6 g), sodium hydroxide pellets (9.9 g), 3-chloro-3-methylbut-1-yne (40.83 g) and benzyltrimethyl-ammonium hydroxide (34.5 g, 40% in methanol) were stirred in methylene chloride (150 ml) and water (150 ml) at room temperature for 4 days. After separation of the layers, the aqueous layer was extracted twice with chloroform. The combined organic extracts were evaporated and the residue taken up in ether and washed with water and 2N sodium hydroxide solution before drying over anhydrous sodium sulphate. Removal of solvent and drying agent gave an oil (15.72 g). Distillation at 0.5 mm Hg gave the analytical material as the fraction boiling at 96-102 C. (10.13 g). Cyclisation of the 3-(p-cyanophenoxy)-3-methybut-1-yne (9.77 g) was accomplished by heating in diethylaniline at 210-220 C. under nitrogen. Purification by distillation, and extraction with dilute hydrochloric acid gave 2,2-dimethyl-6-cyano-2H-benzo[b]pyran as a colourless oil (6.84 g), which slowly crystallized on standing, having a nmr spectrum showing signals at delta1.46, 6.25 (d, J=10), 5.67 (d, J=10), 6.74 (d, J=8), 7.18 (d, J=2), 7.34 (q, J=8,2)
trans-2,2-dimethyl-4-piperidino-6-cyano-3,4-dihydro-2H-benzo[b]pyran-3-ol[ No CAS ]
[ 33143-29-2 ]
Yield
Reaction Conditions
Operation in experiment
With N-benzyl-trimethylammonium hydroxide; In methanol; dichloromethane; water; N,N-diethylaniline;
EXAMPLE 1 Trans-2,2-dimethyl-4-piperidino-6-cyano-3,4-dihydro-2H-benzo[b]pyran-3-ol 4-Cyanophenol (19.6 g), sodium hydroxide pellets (9.9 g), 3-chloro-3-methylbut-1-yne (40.85 g) and benzyltrimethylammonium hydroxide (34.5 g, 40% in methanol) were stirred in methylene chloride (150 ml) and water (150 ml) at room temperature for 4 days. After separation of the layers, the aqueous layer was extracted twice with chloroform. The combined organic extracts were evaporated and the residue taken up in ether and washed with water and 2 N sodium hydroxide solution before drying over anhydrous sodium sulphate. Removal of solvent and drying agent gave an oil (15.72 g). Distillation at 0.5 mm Hg gave the analytic material as the fraction boiling at 96-102 C. (10.13 g). Cyclisation of the 3-(p-cyanophenoxy)-3-methybut-1-yne (9.77 g) was accomplished by heating in diethylaniline at 210-220 C. under nitrogen. Purification by distillation, and extraction with dilute hydrochloric acid gave 2,2-dimethyl-6-cyano-2H-benzo[b]pyran as a colourless oil (6.84 g), which slowly crystallized on standing, having a nmr spectrum showing signals at delta146, 6.25 (d, J=10), 5.67 (d, J=10), 6.74 (d, J=8), 7.18 (d, J=2), 7.34 (q, J=8,2).
With potassium hydroxide; In methanol; ethanol; water; dimethyl sulfoxide;
EXAMPLE 3 Some of the starting materials to be employed could be prepared as follows: STR26 50 g (0.42 mol) of 4-hydroxybenzonitrile were dissolved in 300 ml of dimethylsulphoxide and a solution of 27 g of potassium hydroxide in 30 ml of water was added. 150 ml of distillate were stripped off in vacuo. 72 g (0.3 mol) of 3-bromo-4-chloro-1-nitrobenzene were added to the residue and the batch was heated for 1 hour at 80 C. and for a further hour at 100 C. After it had cooled, the product was precipitated by means of ice-water, while adding methanol, and was then filtered off. After washing with water and recrystallizing from ethanol, 63 g of the pure compound of melting point 115-116 C. were obtained. STR27 151 g (0.475 mol) of the 2-bromo-4-nitro-4'-cyanodiphenyl ether obtained under (a) were dissolved in 700 ml of ethanol and after adding 40 g of Raney nickel/iron and 10 g of sodium bicarbonate the compound was hydrogenated at 20 C.
With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; for 1h;
A mixture of <strong>[926293-55-2]6-bromo-2-methylpyridine-3-carboxaldehyde</strong> (1.00 g, 5.00 mmol), 4- hydroxy-benzonitrile (0.596 g, 5.00 mmol) and K2CO3 (0.414 g, 3.00 mmol) in DMF (10 mL) was heated at 130 C for 1 h. The mixture was cooled to room temperature and DMF was removed. Aqueous work-up and purification by flash chromatography on silica gel (EtOAc/hexanes, 2:3 in v/v) afforded 4-(5-formyl-6-methyl-pyridin-2-yloxy)-benzonitrile as a white solid (0.497 g, 41%). 1H NMR (CDCl3) delta 2.72 (s, 3H), 6.92 (d, IH, J= 8.4 Hz), 7.28-7.31 (m, 2H), 7.69-7.73 (m, 2H), 8.17 (d, IH, J= 8.4 Hz), 10.26 (s, IH).
With hydrogenchloride; sodium hydroxide; In ethanol;
EXAMPLE 2 Ethyl 2-(4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate A mixture of 4-Cyanophenol (23.82 g, 0.2 mol), NaOH (8 g, 0.2 mol), and 200 mL ethanol were mixed in a pressure bottle while heated to 80 C. Hydrogen sulfide gas was then introduced and the pressure increased to 30-60 psi until the thioamidation was determined to be complete by HPLC. Without isolating the thioamide product, HCl was added to the bottle until the pH was below 3.5, the H2S gas was removed, and the bottle was placed under a vacuum for 20 minutes at 30-40 C. The reaction was then heated to 70 C. and ethyl 2-chloroacetoacetate(1.1 eq.) was added to the reaction solution. The reaction was mixed under reflux for 2-3 hours, treated with enough H2O to dissolve the NaCl salt in the reaction mixture, cooled to room temperature, treated with enough water to precipitate the product, and the solid was collected by filtration. The precipitate was washed with water and dried at 80 C. with nitrogen bleeding to provide 50.50 g (84.2%) of desired product.
With potassium carbonate; In acetonitrile; at 70.0℃; for 1.5h;
4-cyanophenol (1.32 g, 11 mmol), 2-methyl bromoacetate (2 g, 13 mmol), potassium carbonate (4.15 g, 33 mmol), and acetonitrile (25 mL) were added to a 50 mL single-mouth bottle one by one, and heated to react at 70 C for 1.5 hours. After completion of the reaction, the reaction mixture was cooled, and filtered, and the solvent was dried with rotation under vacuum to give the product of 2-(4-cyanophenoxyl)methyl acetate (white solid, 2.28 g), with a yield of 100%. H1 NMR (400 MHz, CDCl3) delta 7.62-7.60 (d, J= 8.9 Hz, 2H), 6.97-6.96 (d, J= 8.9 Hz, 2H), 4.69 (s, 2H), 3.82 (s, 3H).
With potassium carbonate; In acetonitrile; at 20.0℃;
EXAMPLE 149 Preparation of 2-(4-(1-benzyl-1H-tetrazol-5-yl)phenoxy-N-(isoquinolin-6-yl)acetamide (E149) A mixture of 4-cyanophenol and methyl bromoacetate in CH3CN was treated with K2CO3 and refluxed for 18 hours. Then the reaction was cooled to room temperature and concentrated. The residue was partitioned between EtOAc and H2O and the organic layer was washed with brine, driend (Na2SO4), filtered and evaporated. Flash chromatography (SiO2, hexanes/EtOAc) gave pure methyl 2-(4-cyanophenoxy)acetate.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
Example 174-[5-[4-(2-aminoethyl)-piperidine-1-carbonyl]-6-(4-trifluoromethoxy-phenoxy)-pyridine-2-yloxy]benzamidinea) 2-Chloro-6-(4-cyano phenoxy)nicotinic Acid Ethyl Ester96.7 mg (0.7 mmol) of potassium carbonate was added to a stirred solution of 2,6-dichloro nicotinic acid ethyl ester 0.15 g (0.7 mmol) in 10 ml of N,N-dimethyl-formamide (DMF) cooled to 5 C. This was followed by dropwise addition (over a period of 10 min) of 4-cyano phenol 80 mg (0.68 mmol) dissolved in 2 ml of DMF. The reaction mixture was allowed to stir at RT for 2 h, concentrated under reduced pressure and the residue was dissolved in 100 ml of ethylacetate. The organic layer was washed with water and dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane:ethylacetate (8:2) as eluants to afford 0.13 g of the required product. 1H NMR (DMSO-d6): delta 1.3 (3H, t), 4.3 (2H, q), 7.26 (1H, s), 7.38 (1H, s), 7.48 (2H, d), 7.96 (2H, d).
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3h;
Example 12(2-{1-[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-4-carbonyl]-piperidin-4-yl}-ethylaminea) 2,6-bis(4-Cyano phenoxy)-isonicotinic Acid Ethyl EsterPotassium carbonate 3.17 g (23.0 mmol) was added to <strong>[1604-14-4]2,6-dichloro-isonicotinic acid ethyl ester</strong> 1.0 g (4.6 mmol), dissolved in 5 ml of DMF, and stirred for 10 min. This was followed by the dropwise addition of 4-hydroxy-benzonitirle 1.64 g (13.8 mmol), dissolved in 5 ml of DMF, followed by stirring at 100 C. for 3 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic phase was washed with 1 M Na2CO3 and saturated brine solution, dried over sodium sulphate and concentrated. The crude oily residue was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 0.4 g of the required product. Percentage purity (LCMS): 87.4%. (M+1)=385.1+1. 1H NMR (DMSO-d6): delta 1.42 (3H, t), 4.44 (2H, q), 7.16 (4H, d), 7.27 (2H, d), 7.64 (4H, d).
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;
Example 52-(1-{2,6-Bis-[4-carbamimidoyl-phenoxy]-pyridine-3-carbonyl}-piperidin-4-yl)-ethylaminea) 2,6-Bis(4-Cyano Phenoxy)-nicotinic Acid Ethyl EsterPotassium carbonate 1.58 g (11.5 mmol) was added to a stirred solution of <strong>[58584-86-4]2,6-dichloro-nicotinic acid ethyl ester</strong> 1.0 g (4.6 mmol) in 5 ml of DMF and stirred for 10 min. 4-Hydroxy-benzonitrile 1.36 g (11.5 mmol), dissolved in 5 ml of DMF, was added dropwise to the stirred DMF solution and the flask was stirred at 80 C. for 4 h. The reaction mixture was poured into ice-cold water and the result was partitioned using ethyl acetate. The organic phase was washed with 1 M of Na2CO3 and saturated brine solution, dried over sodium sulphate and concentrated. The oily residue was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 1.6 g of the required product. Percentage purity: 84.8%, (M+1)=385.1. 1H NMR (DMSO-d6): 1.36 (3H, t), 4.22 (214, q), 6.78 (1H, d), 7.06 (4H, d), 7.58 (4H, d), 8.21 (1H, d).
With potassium carbonate; In ethanol; water; at 80℃; for 16h;
A mixture of 1-chloro-2-methyl-propan-2-ol (10 mL ), 4-hydroxybenzonitrile (2 g, 16.8 mmol), K2CO3 (9.3 g, 67.3 mmol) in water (6 mL) and ethanol (60 mL) was heated at 80 °C for 16 hours. The reaction mixture was cooled and the solvent was concentrated in vacuo. The residue was diluted with ether (200 mL) and filtered and the filtrate was washed sequentially with water (50 mL) and brine solution (50 mL). The organics were separated and dried over MgSO4 and solvent was removed in vacuo to give a residue which was purified by silica gel column chromatography using (0-100percent) EtOAc/DCM as eluent to give 4-(2-hydroxy- 2-methyl-propoxy)benzonitrile (3.0 g, 94 percent) as a yellow solid. ESI-MS m/z calc. 191.1, found 192.3 (M+1)+; Retention time: 1.05 minutes (3 min run).
methyl 4-(1-(4-cyanophenoxy)ethyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 12h;
Methyl 4-(l-(4-cyanophenoxy)ethyl)benzoate. Methyl 4-(l -hydroxy ethyl)benzoate (540 mg, 3 mmol), 3-hydroxybenzonitrile (360 mg, 3 mmol), triphenylphosphine (1.04 mg, 4 mmol), azodicarboxylic acid diisopropyl ester (800 mg, 4 mmol) in tetrahydrofuran (130 mL) were stirred at 20C for 12 hours. Water was added and the mixture was extracted with ethyl acetate (150 mL x 3), the combined organic phase was dried by sodium sulfate, then filtered. The filtrate was evaporated in vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 3: 1) to give methyl 4-(l-(4- cyanophenoxy)ethyl)benzoate (370 mg, 45%) as colorless oil. LRMS (M + H+) m/z: calcd 281.11; found 281.).
With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; under 2400.24 Torr; for 0.5h;Microwave irradiation;
Tert-butyl 4-(4-cyanophenoxy)benzoate. To a solution of tert-butyl 4- fluorobenzoate (392 mg, 2 mmol) in dimethyl formamide (20 mL) was added 4- hydroxybenzonitrile (240 mg, 2 mmol) and potassium carbonate (552 mg, 4 mmol), the mixture was heated to 130C for 0.5 hour by microwave (pressure: 3.2 bar, equipment power : 150W). The solvent was evaporated in vacuo and purified by column chromatography (silica gel, dichloromethane/methanol = 20: 1) to give tert-butyl 4-(4-cyanophenoxy)benzoate (80 mg, 14%). LRMS (M + H+) m/z: calcd 295.12; found 295.
14%
With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; under 2400.24 Torr; for 0.5h;Microwave irradiation;
To a solution of <strong>[58656-98-7]ter<strong>[58656-98-7]t-butyl 4-fluorobenzoate</strong></strong> (392 mg, 2 mmol) in dimethyl formamide (20 mL) was added 4-hydroxybenzonitrile (240 mg, 2 mmol) and potassium carbonate (552 mg, 4 mmol), the mixture was heated to 130 C. for 0.5 hour by microwave (pressure: 3.2 bar, equipment power: 150 W). The solvent was evaporated in vacuo and purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give tert-butyl 4-(4-cyanophenoxy)benzoate (80 mg, 14%). LRMS (M+H+) m/z: calcd 295.12. found 295.
With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; for 4h;Inert atmosphere; Schlenk technique;
General procedure: To a round-bottom flask (25 mL) equipped with a spherical condenser (40 cm length) were added amidine hydrochloride 1s or 1t (1.0 mmol), Cu(OAc)2 (0.2 equiv), K2CO3 (2.0equiv), 1,10-phenanthroline (0.1 equiv) and anhyd DMF (2.0 mL). Then the mixture was well stirred at 130C under an inert atmosphere. After cooling off, the mixture was filtered through a pad of celite eluting with CH2Cl2 (3 × 6mL). The volatiles were removed under reduced pressure and the residue was purified by a short flash silica gel column chromatography to give compound 3a or 3b.
(R)-4-(3-(1,3-dioxoisoindolin-2-yl)-2-hydroxypropoxy)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 16h;
Step 1. Preparation of (R)-4-(3-(1,3-dioxoisoindolin-2-yl)-2-hydroxypropoxy)benzonitrile To a 500-ml flask, 5 g (24.6 mmol) of (R)-N-glycidylphthalimide was added and 150 ml of N,N-dimethylformamide was added, followed by stirring. 2.93 g (24.6 mmol, 1 eq) of 4-cyanophenol was added, and 10.2 g (73.8 mmol, 3 eq) of K2CO3 was added, followed by stirring at 120C for 16 hours. After completion of the reaction, the reaction product was diluted with ethyl acetate (200 ml), and washed with water (200 ml). After separation of layers, an organic layer was washed with a saturated NH4Cl aqueous solution, and then washed with water. The organic layer was separated and then washed with a NaCl aqueous solution, dehydrated and dried over MgSO4 and concentrated under reduced pressure. A concentrate was subjected to column chromatography to obtain 3.37 g (43%) of a title compound. 1H NMR (CDCl3, 400MHz) delta 7.87~7.85(m, 2H), 7.75~7.73(m, 2H), 7.57(d, 2H), 6.94(d, 2H), 4.31(q, 1H), 4.29~3.96(m, 4H), 2.87(d, 1H) Mass[M+H] : 323.10
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 5 - 20℃; for 16h;
4-Cyanophenol (8.3 g, 69 mmol) is dissolved in a stirred solution of Dichloromethane (75 ml) together with Undecandioic acid (15 g, 15.7 mmol) and Dimethyl aminopyridine (0.24 g, 1.9 mmol). After cooling to a temperature of 5 C. in Ice/water, a solution of Dicyclohexyl-carbodiimide (3.2 g, 15.6 mmol) in Dichloromethane (25 ml) is added drop wise. The reaction is stirred for 16 h and then allowed to warm up to room temperature. The reaction mixture is filtered in vacuo and the filtrate is concentrated to afford the crude product. Purification is carried out by column chromatography through silica gel, eluting with ethyl acetate/petroleum ether mixture (gradient elution from 2% to 20% ethyl acetate). A white powder is obtained and used without further purification.
4-((5-chloro-3-fluoropyridin-2-yl)oxy)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 18h;
A solution of 4-hydroxybenzonitrile (6.55 g, 55.0 mmol)2-chlorobenzothiazole (6.51 mL, 50.0 mmol)And K2CO3 (7.60 g, 55.0 mmol)In DMF (20 mL)The suspension is heated to120 ° CAnd keep it for 18 hours.The reaction mixture was allowed to cool to rt,With heptane:EtOAc (1: 1,300 mL)Diluted with 0.2 N NaOH (200 mL),Saturated Na2CO3 (50 mL) and brine (50 mL).Dried by Na2SO4,Filtered and concentrated to dryness,The crude product was purified, purified by crystallization (heptane: EtOAc)To give the desired beige solid ether 3a.Nitrile 3c was prepared starting from nitrile 3a from <strong>[89402-43-7]5-chloro-2,3-difluoropyridine</strong> and 4-hydroxybenzonitrile at a reaction temperature of 90 ° C.The title compound was obtained as a colorless solid containing about 7percent of the by-product, and the by-product was transferred to the next step and removed in that step.
With sodium hydroxide catalyzed,hydrogen sulfide pressure 2 ~ 4kg pressure in ethanol solvent at 80 and p-hydroxybenzonitrile reaction,reaction is not separated at the end, hydrochloric acid to adjust the pH below 3.5, 30 ~ 40 ,negative pressure to maintain half an hour, heated to 70 C, adding ethyl 2-chloroacetoacetate,Refluxed for 2 to 3 hours, treated with water to give ethyl 2- (4-hydroxyphenyl) -4-methyl-5-thiazole, yield 84%
With p-cyanophenol and thioacetamide as starting materials,Sulfonylation reaction first, in a clean reaction flask,Put 70g polyphosphoric acid,1.5g water,Preparation of anhydrous phosphoric acid system,The system was added 12.7g of thioacetamide and20g of p-cyanophenol,Stirring heated to 40-80 ,Reaction time 2-8 hours;The reaction was completely detected by HPLC to give 4-hydroxythiobenzamide (Formula II)
With hydrogenchloride; In water; at 60℃; for 2h;Green chemistry;
12.2 g (0.1 mol) of p-hydroxybenzaldehyde, 9.0 g (0.13 mol) of hydroxylamine hydrochloride, 8.8 g (0.13 mol) of sodium formate and 100 mL of formic acid were added to the reaction flask.The mixture was gradually heated to 105 C, stirred under reflux, and the reaction was monitored by TLC.After about 2 hours, the reaction was completed and the reaction solution was cooled to room temperature.Then add 12 mol/L concentrated hydrochloric acid (100 mL) and13.5g (0.18mol) of thioacetamide, the reaction system is heated to 60 C for reaction,The progress of the reaction was monitored by TLC. After the reaction for 2 hours, it basically ends.The reaction solution was cooled to room temperature, and 100 mL of ethanol was added thereto.24.7 g (0.15 mol) of ethyl 2-chloroacetoacetate was added dropwise under stirring.Then, the temperature was raised to 80 C by heating, and the mixture was stirred under reflux for 3 hours. After the TLC test determines that the reaction is complete,The reaction solution was cooled to below 10 C and suction filtered.The ethanol and formic acid obtained by treating the filtrate by distillation or the like can be recycled and applied.The filter cake was washed three times with 50 mL of water and then rinsed once with 10 mL of ice ethanol.After drying, the yellow crystalline powder can be obtained.Ethyl 2-(4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate 24.0 g,The yield was 91% and the purity was 99.2%.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;
To a solution of diisopropyl azodicarboxylate (DIAD) (0.35?mL, 1.76?mmol) in dry THF (10?mL), Ph3P (1.3?g, 5.20?mmol) was added at 0?C under N2 atmosphere. The mixture was stirred until there was a white precipitate. Then, 4-hydroxybenzonitrile (0.2?g, 1.67?mmol) and 4-(hydroxymethyl)benzonitrile (0.23?g, 1.76?mmol) were added and the reaction mixture was maintained to room temperature overnight. The mixture was then poured into ice/water, yielding a precipitate that was filtered and treated with Et2O, to give 44 (0.17?g, 44%) as white solid. 1H NMR (400?MHz, DMSO-d6): delta 5.25 (s, 2H, CH2), 7.15 and 7.75 (d, J?=?8.6?Hz, each 2H, aromatic CH), 7.65 and 7.85 (d, J?=?8.0?Hz, each 2H, aromatic CH).
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