* 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.
Reference：
[1] Angewandte Chemie, International Edition, 2009, vol. 48, # 33, p. 6097 - 6100[2] Angewandte Chemie, 2009, vol. 121, # 33, p. 6213 - 6216
2
[ 1679-64-7 ]
[ 7377-26-6 ]
Yield
Reaction Conditions
Operation in experiment
95%
for 15 h; Heating / reflux
4-Chlorocarbonyl-benzoic acid methyl ester (2).; To a mixture of Terephtalic acid monomethyl ester, compound 1 (lo.oog, 0.056 mol) and SOCl2 (somL) was added a drop of DMF and the mixture was boiled at refluxed for 15I1. The excess SOCl2 was removed in vacuo to afford compound 2 (io.57g) as a white solid in 95percent yield. This compound was used for the next step without further purification.
93%
for 1 h; Reflux
Reaction conditions to obtain compound 49 (4-Chlorocarbonyl-benzoic acid methyl ester): Terephthalic acid monomethyl ester (0.25 g, 1.4 mmol) was dissolved in thionyl chloride (5 ml) and refluxed for 1 hour. Excess thionyl chloride was removed in vacuo to give an off-white solid. The solid was dissolved in anhydrous benzene (7 ml), and the solvent was evaporated. The procedure was repeated 3 times, and the solid was dried at high temperatures to remove residual solvent. 273 mg was obtained at 93percent yield.
Reference：
[1] Journal of the American Chemical Society, 1995, vol. 117, # 27, p. 7041 - 7047
[2] Patent: WO2009/37302, 2009, A1, . Location in patent: Page/Page column 24
[3] Organic Letters, 2017, vol. 19, # 15, p. 4142 - 4145
[4] Patent: US2015/158888, 2015, A1, . Location in patent: Paragraph 0114
[5] Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2763 - 2770
[6] Journal of Medicinal Chemistry, 2011, vol. 54, # 23, p. 8099 - 8109
[7] Journal of Organic Chemistry, 1974, vol. 39, # 23, p. 3384 - 3387
[8] Makromolekulare Chemie, 1957, vol. 23, p. 31,51[9] Angewandte Chemie, 1955, vol. 67, p. 108
[10] Journal of Medicinal Chemistry, 1983, vol. 26, # 8, p. 1164 - 1168
[11] Bulletin of the Chemical Society of Japan, 1992, vol. 65, # 10, p. 2807 - 2813
[12] Magnetic Resonance in Chemistry, 1989, vol. 27, # 6, p. 585 - 591
[13] Journal of Physical Chemistry, 1988, vol. 92, # 16, p. 4801 - 4806
[14] Gazzetta Chimica Italiana, 1987, vol. 117, # 9, p. 529 - 532
[15] Canadian Journal of Chemistry, 1994, vol. 72, # 1, p. 142 - 145
[16] Journal of Medicinal Chemistry, 1995, vol. 38, # 1, p. 58 - 67
[17] Journal of Medicinal Chemistry, 1994, vol. 37, # 26, p. 4538 - 4553
[18] Journal of Organic Chemistry, 1996, vol. 61, # 4, p. 1297 - 1301
[19] Journal of Organic Chemistry USSR (English Translation), 1986, vol. 22, p. 620 - 627[20] Zhurnal Organicheskoi Khimii, 1986, vol. 22, # 4, p. 694 - 701
[21] J. Gen. Chem. USSR (Engl. Transl.), 1983, vol. 53, # 11, p. 2258 - 2262[22] Zhurnal Obshchei Khimii, 1983, vol. 53, # 11, p. 2505 - 2510
[23] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 2, p. 227 - 232
[24] Archiv der Pharmazie, 2002, vol. 335, # 2-3, p. 83 - 88
[25] Journal of Medicinal Chemistry, 2004, vol. 47, # 18, p. 4360 - 4372
[26] Archiv der Pharmazie, 2006, vol. 339, # 3, p. 115 - 122
[27] Journal of Medicinal Chemistry, 2006, vol. 49, # 2, p. 748 - 759
[28] Synthesis, 2006, # 3, p. 509 - 513
[29] Journal of the American Chemical Society, 2001, vol. 123, # 20, p. 4849 - 4850
[30] Chemistry - A European Journal, 2002, vol. 8, # 5, p. 1015 - 1023
[31] Angewandte Chemie - International Edition, 2007, vol. 46, # 4, p. 576 - 579
[32] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 24, p. 8590 - 8598
[33] Patent: US2005/85512, 2005, A1, . Location in patent: Page/Page column 13
[34] Patent: EP1541549, 2005, A1, . Location in patent: Page/Page column 15
[35] Patent: US5324859, 1994, A,
[36] Patent: US5534531, 1996, A,
[37] Patent: WO2007/67836, 2007, A2, . Location in patent: Page/Page column 142
[38] Chemistry - A European Journal, 2008, vol. 14, # 4, p. 1238 - 1252
[39] Chemistry - A European Journal, 2008, vol. 14, # 10, p. 3146 - 3153
[40] Patent: US2009/131468, 2009, A1, . Location in patent: Page/Page column 25-26
[41] Patent: WO2009/64251, 2009, A1, . Location in patent: Page/Page column 36-37
[42] Patent: WO2009/64251, 2009, A1, . Location in patent: Page/Page column 38-39
[43] Chemistry - A European Journal, 2009, vol. 15, # 7, p. 1637 - 1648
[44] Journal of the American Chemical Society, [45] Journal of the American Chemical Society, 2009, vol. 131, p. 6898 - 6899
[46] Patent: WO2004/89916, 2004, A1, . Location in patent: Page 26
[47] Journal of Medicinal Chemistry, 2009, vol. 52, # 19, p. 5950 - 5966
[48] Patent: EP2189450, 2010, A1, . Location in patent: Page/Page column 14
[49] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 24, p. 6882 - 6889
[50] Patent: EP2202229, 2010, A1, . Location in patent: Page/Page column 26
[51] Angewandte Chemie - International Edition, 2011, vol. 50, # 28, p. 6379 - 6382
[52] Patent: WO2011/73231, 2011, A1, . Location in patent: Page/Page column 98
[53] Journal of Materials Chemistry, 2011, vol. 21, # 16, p. 5916 - 5922
[54] Patent: WO2011/141928, 2011, A1, . Location in patent: Page/Page column 18-19
[55] Organic Letters, 2012, vol. 14, # 2, p. 656 - 659
[56] Organic Letters, 2012, vol. 14, # 1, p. 354 - 357
[57] Molecular Crystals and Liquid Crystals, 2011, vol. 551, p. 60 - 68
[58] Journal of the American Chemical Society, 2012, vol. 134, # 20, p. 8298 - 8301
[59] Organic Letters, 2012, vol. 14, # 12, p. 3044 - 3047
[60] Angewandte Chemie - International Edition, 2012, vol. 51, # 29, p. 7318 - 7322
[61] Journal of the American Chemical Society, 2012, vol. 134, # 29, p. 11948 - 11951
[62] Organic and Biomolecular Chemistry, 2013, vol. 11, # 6, p. 881 - 885
[63] Patent: WO2012/171903, 2012, A1, . Location in patent: Page/Page column 50
[64] Chemistry - A European Journal, 2013, vol. 19, # 4, p. 1373 - 1384
[65] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 97 - 105
[66] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 8, p. 2313 - 2318
[67] Journal of the American Chemical Society, 2013, vol. 135, # 12, p. 4628 - 4631
[68] Synthesis (Germany), 2013, vol. 45, # 16, p. 2234 - 2240
[69] Medicinal Chemistry Research, 2013, vol. 22, # 8, p. 3857 - 3862
[70] European Journal of Organic Chemistry, 2013, # 27, p. 6137 - 6145
[71] Organic Letters, 2014, vol. 16, # 2, p. 390 - 393
[72] Journal of Materials Chemistry C, 2014, vol. 2, # 34, p. 7029 - 7038
[73] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 19, p. 5487 - 5505
[74] Tetrahedron Letters, 2014, vol. 55, # 44, p. 6044 - 6047
[75] Chemical Communications, 2015, vol. 51, # 1, p. 77 - 80
[76] Organic Letters, 2014, vol. 16, # 24, p. 6412 - 6415
[77] Journal of Medicinal Chemistry, 2015, vol. 58, # 3, p. 1380 - 1389
[78] Chemical Communications, 2015, vol. 51, # 24, p. 5089 - 5092
[79] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 127 - 135
[80] Chemical Communications, 2014, vol. 50, # 84, p. 12718 - 12721
[81] Journal of Organometallic Chemistry, 2015, vol. 794, p. 136 - 145
[82] Chemistry - A European Journal, 2015, vol. 21, # 30, p. 10851 - 10869
[83] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 19, p. 6510 - 6519
[84] Patent: US2015/238558, 2015, A1, . Location in patent: Paragraph 0413
[85] Patent: US2015/329556, 2015, A1, . Location in patent: Paragraph 2069-2072
[86] Organic and Biomolecular Chemistry, 2016, vol. 14, # 5, p. 1599 - 1610
[87] Advanced Synthesis and Catalysis, 2016, vol. 358, # 5, p. 746 - 751
[88] Patent: WO2016/34673, 2016, A1, . Location in patent: Page/Page column 69-70
[89] Journal of Organic Chemistry, 2016, vol. 81, # 5, p. 2166 - 2173
[90] Letters in Drug Design and Discovery, 2016, vol. 13, # 8, p. 729 - 733
[91] Molecules, 2017, vol. 22, # 1,
[92] Journal of the American Chemical Society, 2017, vol. 139, # 5, p. 1762 - 1765
[93] Patent: US2016/333004, 2016, A1, . Location in patent: Paragraph 0314; 0319
[94] Angewandte Chemie - International Edition, 2017, vol. 56, # 9, p. 2482 - 2486[95] Angew. Chem., 2017, vol. 129, # 9, p. 2522 - 2526,5
[96] Organic Letters, 2017, vol. 19, # 6, p. 1294 - 1297
[97] Journal of Organic Chemistry, 2017, vol. 82, # 1, p. 420 - 430
[98] European Journal of Organic Chemistry, 2017, vol. 2017, # 20, p. 2866 - 2870
[99] Journal of Organic Chemistry, 2017, vol. 82, # 10, p. 5046 - 5067
[100] Organic Letters, 2017, vol. 19, # 12, p. 3091 - 3094
[101] Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6205 - 6219
[102] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 20, p. 4770 - 4776
[103] Organic Letters, 2017, vol. 19, # 19, p. 5304 - 5307
[104] Chemical Communications, 2017, vol. 53, # 93, p. 12584 - 12587
[105] Organic Process Research and Development, 2017, vol. 21, # 5, p. 748 - 753
[106] Synlett, 2017, vol. 28, # 19, p. 2594 - 2598
3
[ 1679-64-7 ]
[ 1147550-11-5 ]
[ 7377-26-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 7, p. 3331 - 3341
4
[ 1679-64-7 ]
[ 32529-79-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 6, p. 1564 - 1568
Reference：
[1] Patent: US7115750, 2006, B1, . Location in patent: Page/Page column 77
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 4, p. 1772 - 1776
[3] Chemistry - A European Journal, 2013, vol. 19, # 45, p. 15101 - 15104
7
[ 1679-64-7 ]
[ 39895-56-2 ]
Reference：
[1] Journal of the American Chemical Society, 1957, vol. 79, p. 672,674
8
[ 1679-64-7 ]
[ 94497-51-5 ]
Reference：
[1] Letters in Drug Design and Discovery, 2016, vol. 13, # 8, p. 729 - 733
[2] Organic Process Research and Development, 2017, vol. 21, # 5, p. 748 - 753
9
[ 1679-64-7 ]
[ 56893-25-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 1983, vol. 26, # 8, p. 1164 - 1168
With potassium peroxomonosulfate; potassium bromide In dichloromethane; lithium hydroxide monohydrate at 20℃; for 24h; visible light irradiation;
95%
With oxygen; sodium trifluoro-methanesulfinate In acetonitrile at 25℃; for 12h; Irradiation; Green chemistry;
91%
With pyridine; potassium peroxodisulfate; oxygen In acetonitrile at 80℃; for 16h; Green chemistry;
4. Typical procedure for oxidation of alkylbenzenes and toluene
General procedure: Ethylbenzene (3a) (0.0531 g, 0.5 mmol), K2S2O8 (0.2703 g, 1.0 mmol), pyridine (0.0158 g, 0.2 mmol) and CH3CN (1.0 mL) were added to an oven-dried pressure vessel with a magnetic stir bar. Then the pressure vessel was filled with dioxygen and the reaction mixture was stirred at 80 °C for 16 hours (oil bath). After the completion of the reaction, the solvent was evaporated and the reaction mixture was purified with column chromatography (eluenet: ethyl acetate/PE = 1/10) to give acetophenone (4a) (0.0535 g yield 89%).
70.9%
With air at 150℃; for 4h; other catalyst, time, temperature; in presence of p-xylene.;
With air; fatty acid cobalt-salts
93 % Chromat.
With N-hydroxyphthalimide; air In glacial acetic acid at 150℃; for 3h;
With oxygen In lithium hydroxide monohydrate at 150℃; for 5h;
4
Example 4; The reaction was conducted in the same manner as in Example 3 except that 300 g (2.0 mol) of methyl p-toluate was used instead of 300 g of p-xylene and that the pressure of the reaction system was raised to 0.2 MPa. The conversion of the substrate and the amount of the product were determined. As the results, the conversion of methyl p-toluate was 30%, the amounts of the products were as follows: 110 g of monomethyl terephthalate, 3.5 g of terephthalic acid, and 1 g of methyl benzoate as a by-product. Incidentally, 7 g of p-toluic acid remained in the reaction mixture.
With oxygen; Co(OAc)2.4H2O; glacial acetic acid; N,N′,N″-trihydroxyisocyanuric acid at 100℃; for 6h;
5 Example 5) Preparation of methyl terephthalate
4 g (26.6 mmol) methyl p-toluate in 44 ml_ acetic acid (9% by weight of methyl p-toluate) was placed in a 100 ml_ glass round bottom flask, which was equipped with a stirring bar, thermometer, reflux condenser and gas inlet. After addition of 47 mg THICA (0.266 mmol, 1 mol% based on methyl p-toluate) and 133 mg Co(OAc)2 x 4 H2O (molar ratio of Co : THICA is 2:1) the reaction mixture was heated to 100°C under oxygen at 100 kPa. Complete conversion to the title compound was detected after a reaction time of 6 hours with a selectivity of 100%.
With hydrogenchloride; tetrakis(tetrabutylammonium)decatungstate(VI); oxygen In lithium hydroxide monohydrate; acetonitrile at 20℃; for 24h; Irradiation;
15 Example 15: Preparation of Compound III-9
Methyl p-toluate (75.1 mg, 0.5 mmol) was dissolved in acetonitrile (1.5 mL) and 1 M aqueous hydrochloric acid (1.5 mL) at room temperature, TBADT (33.0 mg, 0.01 mmol) was added, Then the reaction system was connected to an oxygen balloon, and the reaction system was placed under 2×3W purple LED lamp irradiation and stirred for 24 hours.After the reaction of the raw materials is completed, the solvent is removed under reduced pressure to obtain a crude product.The crude product V-9 was dissolved in benzene (2.4 mL) and methanol (0.6 mL), TMSCHN2(171.33 mg, 1.5 mmol) was added, stirred at room temperature for 4 hours, and the reaction system was mixed with Vpetroleum ether/Vethyl acetate. Ester=50:1 column chromatography gave 69.9 mg of III-9 target product in 72% yield.
With methanol; potassium hydroxide at 65℃; for 4h;
1.1 (1) Preparation of monomethyl terephthalate
Add 1.35L of methanol and 56g (1mol) of KOH to the reaction flask, raise the temperature to dissolve all the KOH, then add 194.2g (1mol) of dimethyl terephthalate, and continue to raise the temperature to reflux reaction (the temperature is 65±1) , TLC monitors the progress of the reaction. After the reaction is kept for 4 hours, the methanol is recovered by distillation under reduced pressure. The obtained white solid was dissolved in water, stirred for 30 minutes and filtered, and about 11 g of unreacted raw material was recovered. The filtrate was acidified with hydrochloric acid (36% by mass) to a pH of about 4, and the product precipitated, stirred for 1h, filtered, and washed with water to obtain monomethyl terephthalate. The one-step reaction yield was 95.3% (yield after excluding the recovered raw materials), purity 98.0%.
86%
With potassium hydroxide In methanol Reflux;
Mono-methyl terephatalate (IIa)
A methanol (60 mL) solution ofIa (4.0 g, 20.6 mmol) and KOH (1.2 g, 21.6 mmol) was refluxed overnightand then evaporated. Then 80 mL of water was added and thesolution was extracted three times with 10 mL of CH2Cl2. Adjusting pHof the water solution to 1 with HCl resulted in precipitation of a whitesolid which after filtration, washing with water and drying yielded pureIIa.
86%
With potassium hydroxide In methanol Reflux;
Mono-methyl terephatalate (IIa)
A methanol (60 mL) solution ofIa (4.0 g, 20.6 mmol) and KOH (1.2 g, 21.6 mmol) was refluxed overnightand then evaporated. Then 80 mL of water was added and thesolution was extracted three times with 10 mL of CH2Cl2. Adjusting pHof the water solution to 1 with HCl resulted in precipitation of a whitesolid which after filtration, washing with water and drying yielded pureIIa. White solid. Yield 86 %. EA (calc.) for C9H8O4 (180.16): C,60.00; H, 4.48 %; found: C, 60.01; H, 4.45 %. 1H NMR (400 MHz,DMSO-d6, 298 K, ppm): δ 8.06 (s, 4H), 3.88 (s, 3H).
80%
With potassium hydroxide In methanol for 3.5h; Reflux;
78%
With potassium hydroxide In methanol at 80 - 120℃; for 5h;
77%
With potassium hydroxide In methanol for 3.5h; Heating;
73%
With potassium hydroxide In methanol; diethyl ether; water monomer for 21h;
56%
With potassium hydroxide In methanol; diethyl ether; water monomer at 20℃; for 24h;
4-(Methoxycarbonyl)benzoic acid (33)
To a solution of 32 (2.0 g, 10.0 mmol) in methanol and ether(methanol:ether = 1:1, 20 mL), a solution of KOH (0.58 g, 10.0 mmol) in methanol and water(methanol:water = 10:1, 10 mL) was added dropwise at 0 C. The mixture was stirred at roomtemperature for 24 h. After adding water (50 mL), the mixture was partitioned between waterand ether. Then treating the aqueous layer successively with 1 N HCl until pH = 1. The mixturewas partitioned between water and EtOAc. The organic layer was washed with a saturated aqueoussolution of brine, dried over anhydrous Na2SO4, and concentrated under vacuum to give 33 (1.0 g,56%) as a white solid. m.p. 188~192°C.
With methanol; potassium hydroxide; benzene
With potassium hydroxide
With sulfuric acid; acetic acid
With potassium carbonate
With potassium hydroxide In methanol
With sodium hydroxide In methanol; acetone Heating;
With water monomer
7.86 g
Stage #1: 1,4-benzenedicarboxylic acid dimethyl ester In methanol at 20℃; for 0.5h; Reflux; Inert atmosphere;
Stage #2: With potassium hydroxide In deuteromethanol Reflux; Inert atmosphere;
With lithium hydroxide monohydrate In methanol; water monomer for 4h;
7.05 g
With potassium hydroxide In methanol Reflux;
4.2. 4-(Methoxycarbonyl)benzoic acid (11)
A solution of terephthalic acid 6 (15.0 g, 90.3 mmol, 1.0 equiv.) andmethanol (375 mL) was refluxed for 30 min, after which thionylchloride (26 mL, 42.3 g, 3.97 equiv.) was added dropwise and themixture was maintained overnight at reflux. After being cooled to roomtemperature, the solvent was removed under reduced pressure. Themixture was extracted twice with diethyl ether (100×4) and washedwith KOH (0.1 M) solution. The combined organic layers were driedover anhydrous MgSO4, filtered and concentrated in vacuo to give abrown solid. To a portion of the dimethyl ester (8.95 g, 43.0 mmol, 1equiv.), methanol (150 mL) was added and the mixture was heated at40 °C for 15 min. Potassium hydroxide pellets (2.41 g, 43.0 mmol, 1equiv.) were then added and the mixture was refluxed overnight. Themixture was cooled and the alcohol evaporated. The resulting crudeproduct was dissolved in water and extracted with EtOAc (100×1 mL). The aqueous layer was acidified with HCl solution (1 M) and the precipitatewas filtered. The precipitate was then extracted with diethylether, dried over anhydrous MgSO4, concentrated under reducedpressure to give monoester 11 (7.05 g, 36.4 mmol, 85% over two steps)as a white solid. This product was used without further purification. 1HNMR (500 MHz, CDCl3) δ 7.91 (m, 4H, HAr), 3.76 (3, 3H, OMe); 13CNMR (125 MHz, CDCl3) δ 166.1 (C]O), 165.0 (C]O), 132.9 (CAr),132.4 (CAr), 128.4 (CAr), 128.2 (CAr), 51.2 (OMe); HRMS (ESI) m/zcalcd. for [C9H7O4]-: 179.0339, obsd.: 179.0339.
With potassium 2-(difluoro(trifluoromethoxy)methoxy)-2,2-difluoroacetate In acetonitrile at 80℃; for 1h; Schlenk technique; Sealed tube; Inert atmosphere;
75%
With pyridine; thionyl fluoride In acetonitrile at 20℃; for 0.5h;
51%
With pyridine; trifluoro-[1,3,5]triazine In acetonitrile at 20℃; for 16h; Inert atmosphere;
40%
With tetramethylammonium trifluoromethanethiolate In dichloromethane Inert atmosphere;
1-3. Procedures of preparation of acyl fluoride 1
General procedure: Method AS3: Under N2 atmosphere, the corresponding carboxylic acid (3.00 mmol) was transferredto a PFA bottle equipped with a stirrer bar. After addition of CH2Cl2 (5.00 mL) to the bottle, the reactionmixture was cooled at 0 °C in ice bath. Then, Deoxo-fluor (0.560 mL, 3.04 mmol) was added to thesolution. The bottle was capped, and the reaction mixture was stirred at 0 °C for 5-30 min (written ateach substrate in parentheses). The reaction was quenched by addition of aqueous NaHCO3. Themixture was extracted with CH2Cl2 (10.0 mL) three times. The combined organic layer was dried overNa2SO4. Solvents were removed under reduced pressure. The crude material was purified by silica gelcolumn chromatography (hexane/AcOEt = 97:3) to give the corresponding acid fluoride.Method BS4: Under N2 atmosphere, the corresponding carboxylic acid (1.00 mmol) was transferredto a PFA bottle equipped with a stirrer bar. To the reaction vessel, Me4N•SCF3 (230 mg, 1.31 mmol)and CH2Cl2 (5.00 mL) were added. Then, the reaction mixture was stirred until completelyconsumption of Me4N•SCF3. The resulting suspension was filtered through a silica gel pad. Solventswere removed under reduced pressure. The crude material was purified by silica gel columnchromatography (hexane/AcOEt = 97:3) to give the corresponding acid fluoride.
With sulfur tetrafluoride at 130℃; for 7h;
With N,N,N',N'-tetramethyl-1,8-diaminonaphthalene; fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate In tetrahydrofuran at 20℃; for 0.25h;
With N,N,N',N'-tetramethyl-1,8-diaminonaphthalene; fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate In tetrahydrofuran at 20℃; Inert atmosphere; Glovebox;
78 %Spectr.
With potassium fluoride; Tetrafluorophthalonitrile In acetonitrile at 80 - 90℃; for 24h; Glovebox; Inert atmosphere; Sealed tube;
Stage #1: Monomethyl terephthalate With thionyl chloride; N,N-dimethyl-formamide at 80℃; for 2h;
Stage #2: 2-amino-phenol With methanesulfonic acid In 1,4-dioxane for 18h; Reflux;
4.1 Step 1. Methyl 4-(benzo[d]oxazol-2-yl)benzoate
Thionyl chloride (10 mL, 137 mmol) was added to mono-methyl terephthalate (5.00 g, 27.8 mmol). A drop of DMF was added, and the mixture was heated at 80 °C for 2 h. The excess thionyl chloride was removed, and the residue was treated with 2- aminophenol (3.03 g, 27.8 mmol) and dioxane (60 mL). Methanesulfonic acid (5.59 mL, 86 mmol) was added and the reaction mixture was heated at reflux for 18 h. The solution was concentrated and the residue was partitioned between dichloromethane and satd. aq. sodium bicarbonate solution. The aqueous phase was separated and washed with dichloromethane and the combined organic phases were washed with brine, filtered, and concentrated to afford a brown solid. This material was triturated with methanol, filtered, and dried to afford methyl 4-(benzo[d]oxazol-2-yl)benzoate (4.827 g, 19.06 mmol, 69 % yield) as an off-white solid. MS (ESI, pos. ion) m/z: 254 (M + 1).
Stage #1: Monomethyl terephthalate With trimethylphenylsilane; C69H55ClP3Ru In tetrahydrofuran at 60℃; for 16h; Glovebox;
Stage #2: With hydrogenchloride In tetrahydrofuran; water monomer at 20℃; for 1h; Glovebox; chemoselective reaction;
75%
Stage #1: Monomethyl terephthalate With phenylsilane; potassium-t-butoxide; C22H30ClN2RuS2(1+)*Cl(1-) In tetrahydrofuran; 1,4-dioxane at 100℃; for 18h; Inert atmosphere;
Stage #2: With water monomer; caesium fluoride In tert-butyl methyl ether at 20℃; for 3h; Inert atmosphere; chemoselective reaction;
4-Hydroxymethyl-benzoic acid methyl ester (4a):
To a stirred suspension of terephthalicacid monomethyl ester 3a (500mg, 2.7753 mmol, 1equiv.) in degassed 1,4-dioxane (10 V) was added ARP-03 (29.0mg, 0.0555 mmol, 2 mol%) and again degassed for 10 minutes. After 10 minutes ofdegassing, PhSiH3 (1.72 mL, 13.8765 mmol, 5 equiv.) and t-BuOK (1 Min THF) (0.28 mL, 0.2775 mmol, 10 mol%) were added dropwise to reaction mixtureat RT. The reaction mixture was heated to 100°C and stirred for 18 h. Thereaction mixture was then evaporated to remove volatiles, then suspended inMTBE and stirred with aq. CsF solution (10%, 10 V) for 3 h. The organic layerwas then separated and concentrated in vacuum to furnish the crude, which was purified by column chromatography on silica gel(eluent: Ethyl acetate / n-hexane = 1/4) to afford 4-hydroxymethyl-benzoic acidmethyl ester (4a) (345 mg, 75%) as acolourless oil.1H NMR (300 MHz, DMSO- d6): δ 7.92 (d, J = 8.1 Hz, 2H),7.46 (d, J = 8.1 Hz, 2H), 5.37 (t, J = 5.4 Hz, 1H), 4.58 (d, J = 5.4 Hz, 2H), 3.84 (s, 3H).13C NMR (100 MHz, DEPT -135, CDCl3): δ 167.10 (CO), 146.10(C), 129.98 (CH×2), 129.46 (C), 126.60 (CH×2), 64.83 (CH2), 52.25(CH3).LCMS (EI, m/z) calcd for C8H10O3[M + H]: 167.18 Found: 167.1
72%
With Benzyltriethylammonium borohydride In dichloromethane Heating;
67%
With C25H42N6Rh(1+)*CF3O3S(1-); phenylsilane In tetrahydrofuran at 30℃; for 20h; Inert atmosphere;
43%
With tributylphosphine; diphenylsilane; C45H25F12N7Ni2O9 In 1,4-dioxane at 100℃; for 16h;
Multi-step reaction with 2 steps
1: 79 percent / dicyclohexylcarbodi-imide / ethyl acetate / 24 h / Ambient temperature
2: 95 percent / NaBH4, H2O / tetrahydrofuran / 0.08 h / Ambient temperature
With sodium borohydride; boron trifluoride-diethyl ether complex In tetrahydrofuran; water monomer
1 Preparation of Methyl p-Hydroxymethylbenzoate (Me pHMB).
EXAMPLE 1 Preparation of Methyl p-Hydroxymethylbenzoate (Me pHMB). To a stirred suspension of monomethylterephthalate (513.0 g., 2.85 moles) and sodium borohydride (94.0 g., 2.47 moles) in 4.0 liters of tetrahydrofuran, was added boron trifluoride etherate (465 g., 3.28 moles) at a rate to maintain a gentle reflux. The mixture was stirred for 2 hours at 20° C. Water (200 ml.) was added slowly, and the solvents were removed on a rotary evaporator. The residue was taken up in 3.5 liters of water and 1.5 liters of dichloromethane, the layers were separated, and the aqueous portion was extracted with dichloromethane (three 400 ml. portions). The combined organic portions were extracted with 2.5% sodium bicarbonate (1.0 liter), then dried over anhydrous sodium sulfate. Removal of solvent in vacuo left 466.5 g. (98.6%) Me pHMB; m.p. 47°-48° C. Distillation at 125°-127° C./0.4 torr and recrystallization from two parts carbon tetrachloride and one-half part hexane at 47° C. gave a purified product: m.p. 48.5°-49.5° C; ir (nujol) 3400-3200, 1725, 1290, 1115, 1050, 1020, and 760 cm.-1; nmr (CDCl3) 7.82 and 7.23 (AB quartet, JAB =9Hz, 4H), 4.58 (S, 2H), 3.80 (S, 3H), and 3.67 (broad S, 1H); mass spectrum m/e 166 (parent ion), 107 (base peak ion); acetylation gc, 99.91% Me pHMB. Analysis Calculated for C9 H10 O3: C, 65.1; H, 6.1; Found: C, 65.0; H, 6.2.
Multi-step reaction with 2 steps
1: (4-Me)Triaz(NHP<SUP>i</SUP>Pr<SUB>2</SUB>)<SUB>2</SUB>Mn(CO)<SUB>2</SUB>Br / toluene / 6 h / 25 °C / Inert atmosphere
2: mesoporous silica; water monomer / methanol / 60 °C / Inert atmosphere
Stage #1: Monomethyl terephthalate With di(succinimido) carbonate; sodium carbonate; tricyclohexylphosphine In tetrahydrofuran at 60℃;
Stage #2: phenylboronic acid In tetrahydrofuran at 60℃; for 20h; Further stages.;
51%
With P(p-CH3OC6H4)3; 2,2-dimethylpropanoic anhydride In tetrahydrofuran; water at 60℃; for 16h;
With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 18h;
S-23: Methyl 4- (Pyrrolidine-1-carbonyl)benzoate
Pyrrolidine (100 jtL, 1.11 nunol) andmonomethyl terephthalate (200 mg, 1.11 rnmol) were dissolved in anhydrous DMF (5.5 mL) at room temperature. i-Pr2NEt (0.58 mL, 3.33 nunol) and PyBrOP (518 mg, 1.11 rnrnol) were added. After 18 hours, the reaction mixture was diluted with EtOAc (75 mL) and washed with aqueous 1 N HC1 (2 x 50 ml), saturated aqueous NaC1 (25 ml), saturated aqueous NaHCO3 (50 ml) and saturated aqueous NaC1 (25 ml) . The organic phase was dried over Na2SO4, filtered and concentrated. Flash column chromatography (50-75%EtOAc/hexanes gradient) gave 205 mg (80%) of S-23. ‘HNMR (500 MHz, acetone-d6) 8.04 (d, J = 8.3 Hz, 2H),7.63 (d, J = 8.4 Hz, 2H), 3.90 (s, 3H), 3.54 (t, J =6.9 Hz, 2H), 3.41 (t, J= 6.5 Hz, 2H), 1.98 - 1.83(m, 4H)
67%
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 23℃; for 18h;
36%
Stage #1: Monomethyl terephthalate With pivaloyl chloride; triethylamine In dichloromethane at 0℃; for 1h;
Stage #2: pyrrolidine With triethylamine In dichloromethane at 20℃;
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 17h;
63
Description 63Methyl 4-[(1 -[5-chloro-2-(1 -methylethyl)-1 -benzofuran-7-yl]methyl}-5-methyl-1 H- pyrazol-3-yl)amino]carbonyl}benzoate (D63) A mixture of 1-[5-chloro-2-(1-methylethyl)-1-benzofuran-7-yl]methyl}-5-methyl-1 H-pyrazol-3- amine (0.334 g, 1.10 mmol), EDAC (0.254 g, 1.32 mmol), HOBt (0.179 g, 1.32 mmol) and 4- [(methyloxy)carbonyl]benzoic acid (0.238 g, 1.32 mmol) in dry DMF (4 ml) was stirred at room temperature under an atmosphere of argon for 17 hours (overnight). The reaction was monitored by LC-MS. The reaction mixture was partitioned between EtOAc and NaHCO3 (sat. aq solution). The organics were washed with water (3 x 20 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a colourless oil. The residue was chromatographed [SiO2, EtOAc:Hexane 10-50%] to give methyl 4-[(1-[5- chloro-2-(1 -methylethyl)-1 -benzofuran-7-yl]methyl}-5-methyl-1 H-pyrazol-3- yl)amino]carbonyl}benzoate (0.465 g, 91 %) LC/MS Rt = 3.60 min, [MH+] 466,468
(R)-{N-[1-(4-tert-butoxycarbonylamino-phenylcarbamoyl)-2-phenyl-ethyl]-terephthalamic acid methyl ester}[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94.8%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 16h;
A (R)-{N-[1-(4-Amino-phenylcarbamoyl)-2-phenyl-ethyl]-terephthalamic acid methyl ester}
Then mono-methyl terephthalate (0.51 g, 2.8 mmol) was allowed to react with (R)-[4-(2-amino-3-phenyl-propionylamino)-phenyl]-carbamic acid tert-butyl ester} (1.00 g, 2.8 mmol), HOBt (0.38 g, 2.8 mmol), Et3N (0.34 g, 3.4 mmol), and EDCI (0.54 g, 2.8 mmol) in anhydrous CH2Cl2 (20 mL) according to the General Procedure A. The volatile materials were removed in a rotary evaporator and the residue was stirred with water (15 mL) at rt for 15 min. The heterogeneous mixture were filtered, washed with water (3×25 mL) and dried to afford the desired amide (R)-{N-[1-(4-tert-butoxycarbonylamino-phenylcarbamoyl)-2-phenyl-ethyl]-terephthalamic acid methyl ester} (1.38 g, 94.8%) as pale-yellow solid.
(S)-{N-[1-(4-nitro-phenylcarbamoyl)-2-biphenyl-4-yl-ethyl]-terephthalamic acid methyl ester}[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 16h;
A
Then mono-methyl terephthalate (0.90 g, 5.02 mmol) was allowed to react with the above amine (1.65 g, 4.56 mmol), HOBt (0.68 g, 5.02 mmol), Et3N (0.55 g, 5.48 mmol), and EDCI (0.96 g, 5.02 mmol) in anhydrous CH2Cl2 (20 mL) according to the General Procedure A. The volatile materials were removed in a rotary evaporator and the residue was stirred with water (15 mL) at rt for 15 min. The heterogeneous mixture were filtered, washed with water (3×25 mL) and dried to afford (S)-{N-[1-(4-nitro-phenylcarbamoyl)-2-biphenyl-4-yl-ethyl]-terephthalamic acid methyl ester} (2.23 g, 93%) as light-yellow solid.
methyl 4-((2-(isopropylcarbamoyl)-4-phenoxyphenyl)carbamoyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20 - 65℃; for 16.25h;
34.D
34D. Preparation of methyl 4-((2-(isopropylcarbamoyl)-4-phenoxyphenyl)carbamoyl)benzoate A solution of 34C (72 mg, 0.27 mmol) in DMF (4 mL) was treated with 4-(methoxycarbonyl)benzoic acid (78 mg, 0.43 mmol), HOBt (66 mg, 0.43 mmol) and triethylamine (100 mg, 1.0 mmol). The solution was treated with EDCI (96 mg, 0.5 mmol) at room temperature for 15 minutes, and then warmed to 65° C. for 16 hours. The reaction mixture was partitioned between EtOAc (20 mL) and 1 M HCl (20 mL). The organic layer was washed with 1 N HCl (20 mL), 1 N NaOH (20 mL) and brine (20 mL). The reaction was dried (Na2SO4), filtered, and concentrated to a solid. The crude material was purified by chromatography (SiO2, 1:2 EtOAc in heptane) to afford 34D (99 mg, 85%).
With triethylamine; In oxalyl dichloride; dichloromethane; ethyl acetate;
Example 1 Synthesis of Compound 20 Preparation of Phenylmethyl 4-[4-(methoxycarbonyl)phenyl]carbonylamino}benzoate (compound 8). A solution of mono-methyl terephthalate (4.00 g, 22 mmol) in ethyl acetate (25 mL) and DMF (0.1 mL) was cooled in an ice bath and treated with oxalyl chloride (11 mL, 2N in CH2Cl2, 22 mmol) over 30 minutes. After stirring 2 hours at room temperature the solvent was removed on a rotary evaporator and the residue dissolved in CH2Cl2 (20 mL) and added to a solution of <strong>[19008-43-6]benzyl 4-aminobenzoate</strong> (5.00 g, 22 mmol) in CH2Cl2 (25 mL) and triethylamine (4.3 mL, 31 mmol) at -60 C. The reaction mixture was warmed to room temperature for 1 hour and then partitioned between water and ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered, and evaporated. The residue was recrystallized from t-butyl methyl ether to give 5.85 g of compound 8. Preparation of 4-[4-(methoxycarbonyl)phenyl]carbonylamino}benzoic acid (compound 9).
EXAMPLE 2 Synthesis of mono-tert-butyl terephthalate In the same manner as in Example 1, 10 g (0.056 mol) of monomethyl terephthalate and 200 ml (2.081 mols) of tert-butyl alcohol were charged, and 8.10 g (0.070 mol, 1.3 equivalent) of potassium-tert-butoxide was poured thereinto little by little at room temperature. As a result, the reaction mixture generated heat to result in rising of the temperature to 35 C., and white crystals were precipitated in the reaction mixture. Thereafter, the reaction mixture was heated to 83 C. and the reaction was carried out for 17 hours, during which methyl alcohol produced by the transesterification was distilled off together with tert-butyl alcohol, and tert-butyl alcohol in the same amount as the amount of the distilled tert-butyl alcohol was continuously added through the dropping funnel. After completion of the transesterification, tert-butyl alcohol was distilled off under normal pressure, and the residue was allowed to stand for cooling. Then, 80 ml of ice water was added to the residue, followed by separation washing twice with 100 ml of n-hexane. To the resulting aqueous phase was added 3.85 g (0.036 mol, 1.4 equivalent) of sulfuric acid diluted with 20 ml of cold water to liberate the acid. The components in the aqueous phase were analyzed by GC to obtain a peak area ratio of 66:34 of the starting monomethyl terephthalate and the product mono-tert-butyl terephthalate. This aqueous phase was subjected to extraction twice with 100 ml of n-hexane, and then the n-hexane phase extracted twice was washed thrice with 10 ml of pure water and thereafter subjected to concentration under reduced pressure. As a result, 2.99 g of mono-tert-butyl terephthalate of 94% in purity containing no monomethyl terephthalate was obtained. The yield in this case was 23%. Spectrum data of 1H-NMR on the product were as follows. 1H-NMR(CDCl3) 1.62 (9H, s), 8.08 (2H, d, J=8.1 Hz), 8.16 (2H, d, J=8.1 Hz).
21
[ 1679-64-7 ]
[ 87394-48-7 ]
[ 3282-30-2 ]
4-[1-(3-nitro-pyridin-2-yl)piperazin-4-yl-carbonyl]benzoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane;
PREPARATION EXAMPLE 2 Preparation of 4-[1-(3-nitro-2-pyridyl)piperazin-4-yl-carbonyl]benzoic acid methyl ester To the solution of mono-methyl terephthalate (20 g) in methylene chloride (380 ml), triethylamine (18.2 ml) was added and cooled. Then, pivaloyl chloride (15 ml) was added to the solution at 0~5 C. and stirred at 5 C. for 2 hours. 1-(3-Nitro-2-pyridyl)piperazine (21.3 g) and triethylamine (18.6 ml) were added to the reaction mixture in order and the mixture was stirred at 5~10 C. for 2 hours. The reaction mixture was washed with aqueous sodium bicarbonate and water twice and the separated organic layers were concentrated under reduced pressure. The precipitated yellow solid was treated with ether (250 ml) for 1 hour, filtered and dried to give 17.2 g (yield:
With pyridine; In methanol; dichloromethane; benzene;
EXAMPLE 27 STR31 4-(Methylaminocarbonyl)benzoic acid. Monomethylterephthalate (Aldrich, 5.0 g, 0.028 mol) was added to 80 mL of dry benzene in a 250-mL round-bottom flask under argon and fitted with a calcium chloride drying tube. Dry pyridine (4.4 g, 0.056 mol) was added and the mixture was stirred for 15 min. Oxalyl chloride (3.66 g, 0.029 mol) was added by drop over 10 min. The mixture bubbled vigorously during the addition and a heavy white precipitate formed. The mixture was vigorously stirred for 40 min and followed by TLC (three solvent systems: dichloromethane, 2% methanol, and 5% methanol). Anhydrous methylamine was bubbled into the mixture for 10 min. The precipitate dissipated somewhat and the solution color changed from colorless to green and finally to yellow. The mixture was then stirred overnight. The remaining white precipitate was collected on a filter and washed with benzene. The filtrate was washed with water and dried over sodium sulfate. The drying agent was removed by filtration, washed with benzene, and the solvent concentrated to give a white solid. The solids were combined and dissolved in 300 mL dichloromethane. The solution was washed 3 times with 5% HCl, 3*5% sodium bicarbonate, 3*water, 1*brine, and then dried over sodium sulfate. The drying agent was removed by filtration and the filtrate concentrated to give a white solid which was dried in vacuo. This white solid was recrystallized from methanol to give 2 g (37%) of methyl 4-(methylaminocarbonyl)benzoate, mp 126 C. Analysis: Calculated for C10 H11 NO3 (193.202): C, 62.17; H, 5.74; N, 7.25 Found: C, 62.16; H, 5.74: N, 7.25
General procedure: The respective carboxylic acid derivative (2mmol) was added into a flask with dry CH2Cl2 (5mL) and was put on ice. EDCI (2.4mmol) and HOBt (0.8mmol) were then added into the mixture and the reaction was stirred on ice for 15min. Then Et3N (2.0mmol) was added into the mixture, followed the amine (2.0mmol). Subsequently, the mixture was stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. The residue was purified by flash chromatography using Petroleum ether: EtOAc 5:1 (v/v) as eluent, to obtain the final product.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20℃; for 20h;
REFERENCE EXAMPLE 43Methyl 4-anilinocarbonylbenzoate; 4-Methoxycarbonyl benzoic acid (540 mg), aniline (0.27 ml), WSC (863 mg) and triethylamine (0.84 ml) were added to THF (20 ml). After the reaction mixture was stirred at room temperature for 20 hours, the reaction mixture was placed in water, and extraction was conducted using ethyl acetate-THF (1:1). The organic layer was washed with water, saturated sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried, and then concentrated. The resulting crude crystals were recrystallized from ethyl acetate-hexane to give the titled compound (659 mg).Melting point: 189-190 C.
With oxone||potassium monopersulfate triple salt; 2-iodo-N-isopropyl-5-methoxybenzamide; tetra(n-butyl)ammonium hydrogensulfate In nitromethane; water at 25℃; for 16h; Green chemistry;
Typical experimental procedure for oxidation of primary alcohols 14g-k [7]
General procedure: Primary alcohol 14 (0.50 mmol) was added to a solution of the catalyst (0.15 mmol) and Bu4NHSO4 (170 mg, 0.50mmol) in a mixture of MeNO2 (1.6 mL) and water (0.6 mL), followed by Oxone (768 mg. 1.25 mmol) at room temperature (25 °C). After 14 were completely consumed as indicated by TLC, the resulting mixture was diluted with EtOAc, water, and saturated aqueous Na2S2O3. The organic layer was then washed with saturated aqueous Na2S2O3, saturated aqueous NaHCO3, and brine; dried over MgSO4; filtered; and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the catalyst. The combined aqueous layers were acidified with 10% HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give pure carboxylic acid 26. All carboxylic acids 26 were directly identified by comparison with the commercial samples.
94%
With diethylene glycol dimethyl ether at 70℃; for 0.5h; Sonication;
30 Example 30: Preparation of monomethyl terephthalate:
In a 10 mL round bottom flask, 0.83 g of methyl 4-(hydroxymethyl)benzoate and 2 g of diethylene glycol dimethyl ether were added in sequence.The resulting mixture is in an ultrasonic reaction device,40KHz/30W/70°C ultrasonic radiation was opened for 30 minutes.The diethylene glycol dimethyl ether was removed under reduced pressure, and recrystallized to obtain 0.85 g of monomethyl terephthalate in a yield of 94%.
91%
With Iron(III) nitrate nonahydrate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium chloride; oxygen In 1,2-dichloro-ethane at 25℃; for 48h; Schlenk technique;
General procedure: To a Schlenk tube were added Fe(NO3)3·9H2O (40.6 mg, 0.1 mmol), TEMPO (15.8 mg, 0.1 mmol), KCl (7.5 mg, 0.1 mmol), 1a (108.5 mg, 1.0 mmol), and DCE (4.0 mL) sequentially under an atmosphere of oxygen (gas bag, commercial size: 2 L, which could be expanded to 5 L). The mixture was then stirred at 25 °C until completion of the reaction as monitored by TLC (petroleum ether/EtOAc = 5:1) (48h). The crude reaction mixture was filtered through a short column of silica gel (height: 2 cm, diameter: 3 cm) eluting with Et2O (3 × 25 mL). After evaporation, the residue was purified by chromatography on silica gel [petroleum ether/EtOAc = 15:1 (500 mL) to 2:1 (300 mL)] to afford benzoic acid (2a)14 (69.9 mg, 57%) as a pale yellow solid. Yields of 57% of 2a and 38% of benzaldehyde (3a)15 were observed by NMR analysisof the crude product using CH2Br2 as an internal standard and by comparison with spectra reported in the literature.
85%
With oxygen at 120℃; for 16h; Green chemistry;
83%
With oxygen In water; <i>tert</i>-butyl alcohol at 100℃; for 0.533333h; Flow reactor; Green chemistry;
94.6 g (94%)
With sulfuric acid In water; acetone
84.a a.
a. 4Methoxycarbonylbenzenecarboxylic acid Concentrated sulfuric acid (277.5 ml, 5.2 mol) was added dropwise over 1/2 hr to a stirred solution of chromium (VI) oxide (299.25 g, 2.99 mol) and water (925 ml) at 0°. The resulting solution was added dropwise over 1 hr to a stirred solution of methyl-4-(hydroxymethyl)benzoate (92.5 g, 0.564 mol) and acetone (4.6 l) at 0°. The reaction mixture was allowed to warm to room temperature and stirred overnight. The supernatant was decanted before the black tar-like residue was extracted with acetone. The decanted supernatant and acetone extracts were combined and concentrated under vacuum to leave a dark brown residue which was triturated with cold water (4 liter). The precipitate which formed was collected, washed three times with water (1 liter), and dried to give 94.6 g (94%) of the title compound as white crystals, m.p. 218°-221° C.
94.6 g (94%)
With sulfuric acid In water; acetone
14.a a.
a. 4-Methoxycarbonylbenzenecarboxylic acid or 1,4-benzenedicarboxylic acid monomethyl ester Concentrated sulfuric acid (277.5 ml, 5.2 mol) was added dropwise over 1/2 hr to a stirred solution of chromium (VI) oxide (299.25 g, 2.99 mol) and water (925 ml) at 0°. The resulting solution was added dropwise over 1 hr to a stirred solution of methyl-4-(hydroxymethyl)benzoate (92.5 g, 0.564 mol) and acetone (4.6l) at 0°. The reaction mixture was allowed to warm to room temperature and stirred overnight. The supernatant was decanted before the black tar-like residue was extracted with acetone. The decanted supernatant and acetone extracts were combined and concentrated under vacuum to leave a dark brown residue which was triturated with cold water (4 liters). The precipitate which formed was collected, washed three times with water (1 liter), and dried to give 94.6 g (94%) of the compound as white crystals, m.p. 218°-221° C.
With sulfuric acid In water; acetone
11.a a.
a. 4-Methoxycarbonylbenzenecarboxylic acid or 1,4-benzenedicarboxylic acid monomethyl ester Concentrated sulfuric acid (277.5 ml, 5.2 mol) was added dropwise over 1/2 hr to a stirred solution of chromium (VI) oxide (299.25 g, 2.99 mol) and water (925 ml) at 0°. The resulting solution was added dropwise over 1 hr to a stirred solution of methyl-4-(hydroxymethyl)benzoate (92.5 g, 0.564 mol) and acetone (4.6 l) at 0°. The reaction mixture was allowed to warm to room temperature and stirred overnight. The supernatant was decanted before the black tar-like residue was extracted with acetone. The decanted supernatant and acetone extracts were combined and concentrated under vacuum to leave a dark brown residue which was triturated with cold water (4 liters). The precipitate which formed was collected, washed three times with water (1 liter), and dried to give 94.6 g (94%) of the title compound as white crystals, m.p. 218°-221° C. STR51 Using the method of Example 6c, a product prepared according to Example 11a was allowed to react with the product prepared according to Example 3d to afford the final productproduct (83%); TLC, Rf =0.45, silica gel, CHCl3:MeOH (95:5).
77 %Chromat.
With sodium hypochlorite In 1,2-dimethoxyethane; water at 20℃;
81 %Chromat.
With [2,2]bipyridinyl; Iron(III) nitrate nonahydrate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen; acetic acid at 80℃; for 4h;
94.6 g (94%)
With sulfuric acid In water; acetone
8.a a.
a. 4-Methoxycarbonylbenzenecarboxylic acid. Concentrated sulfuric acid (277.5 ml, 5.2 mol) was added dropwise over 1/2 hr to a stirred solution of chromium (VI) oxide (299.25 g, 2.99 mol) and water (925 ml) at 0°. The resulting solution of added dropwise over 1 hr to a stirred solution was methyl-4-(hydroxymethyl)benzoate (92.5 g, 0.564 mol) and acetone (4.6 l) at 0°. The reaction mixture was allowed to warm to room temperature and stirred overnight. The supernatant was decanted before the black tar-like residue was extracted with acetone. The decanted supernatant and acetone extracts were combined and concentrated under vacuum to leave a dark brown residue which was triturated with cold water (4 l). The precipitate which formed was collected, washed three times with water (1 l), and dried to give 94.6 g (94%) of the title compound as white crystals, m.p. 218-221°C.
Stage #1: 2,3-Diaminopyridine; Monomethyl terephthalate With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 1h;
Stage #2: With acetic acid at 200℃; for 0.0833333h; Microwave irradiation;
5.5a
Example 5 (a) Methyl 4-(3H-imidazo[4,5-b]pyridin-2-yl)benzoateDIPEA (24 niL, 138 mmol) was added to a suspension of pyridine-2,3-diamine (5.0 g, 45.9 mmol), terephtalic acid monomethyl ester (8.26 g, 45.9 mmol) and HBTU (20.9 g, 55.0 mmol) in MeCN (200 niL) and the reaction mixture was stirred at r.t. for 1 h. A precipitate that formed was collected and washed with MeCN. The solid was distributed into microwave vials with HOAc (4 mL) and heated to +200 0C for 5 minutes. The product precipitated at r.t. and was filtered, washed with HOAc and MeCN and dried to afford 9.6 g (83% yield) of the title compound. MS (ESI) m/z 254 (M+l).
83%
Stage #1: 2,3-Diaminopyridine; Monomethyl terephthalate With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 1h;
Stage #2: With acetic acid at 200℃; for 0.0833333h; Microwave irradiation;
5.5a
Example 5 (a) Methyl 4-(3H-imidazo[4,5-b]pyridin-2-yl)benzoate(i-Pr)2NEt (24 mL, 138 mmol) was added to a suspension of pyridine-2,3-diamine (5.0 g, 45.9 mmol), terephtalic acid monomethyl ester (8.26 g, 45.9 mmol) and HBTU (20.9 0 g, 55.0 mmol) in MeCN (200 mL) and the reaction mixture was stirred at r.t. for 1 h. A precipitate that formed was collected and washed with MeCN. The solid was distributed into microwave vials with HOAc (4 mL) and heated to +200 0C for 5 minutes. The product precipitated at r.t., filtered, washed with HOAc and MeCN and dried to afford 9.6 g (83% yield) of the title compound. 5 MS (ESI) m/z 254 (M+l).
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine at 20℃; for 24h;
III
The respective methoxycarbonyl aroylic acid {10.0 mmol) (62, 63, 74, 75 or 57a and 57b) was dissolved in dry THF (50.0 mL) or DMF (20.0 mL) and 1.1 eq. BOP (benzotriazolyloxy-tris- (dimetiiylamino)phosphomumhexafluoroρhosphate), 2.2 eq, NEt3, and 1.1 eq. of the respective amine (64 or NH2OTHP) were added. After stirring at room temperature for 24h, the mixture was poured into water by stirring, the precipitating product filtered off, dried in vacuum and purified by cc (CH2Cl2MeOH = 10/1).6-methyl- methyl 4-(2-(terf-butoxycarbonyIainino)phenylcarbamoyl)-benzoate (65):(Delorme et al. Preparation of triazinyl and other carboxamides as inhibitors of histone deacetylase. US 2005/288282 Al, 2005): Yield: 31.05 mmol (94 %), colorless crystals; m.p. 145.5-146.5 0C; IR 1H-NMR (DMSO-[D6]): δ (ppm) - 1.44 (s, 9H), 3.91 (s, 3H), 7.22 (dt, IH, J = 1.8 Hz, J = 7.7 Hz), 7.15 (dt, IH, J = 1.7 Hz, J = 7.6 Hz), 7.55 (m, 2H), 8.10 (m, 4H), 8.71 (s, IH), 9.98 (s, IH).
94%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 24h;
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine In N,N-dimethyl-formamide
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 24h;
Stage #1: 5-bromo-pyridine-2,3-diamine; Monomethyl terephthalate With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 1h;
Stage #2: With acetic acid at 200℃; for 0.0833333h; Microwave irradiation;
1
Example 1; Methyl 4-(6-bromo-3H-imidazo [4,5-6] pyridin-2-yl)benzoate; DIPEA (16.6 mL, 95.7 mmol) was added to a suspension of 5-bromo pyridine-2, 3 -diamine (6.0 g, 31.9 mmol), terepthalic acid monomethyl ester (6.89 g, 38.3 mmol) and ηBTU(14.5 g, 38.3 mmol) in MeCN (100 mL) and the reaction mixture was stirred at r.t. for 1 h. A precipitate that formed was collected and washed with MeCN. The solid was distributed into microwave vials with HO Ac (4 mL) and heated to +200 0C for 5 minutes. The product precipitated at r.t. and was filtered, washed with HOAc and MeCN and dried to afford 8.58 g (81% yield) of the title compound.1U NMR (CDCl3) δ ppm ); 8.15 (d, J=1.52 Hz, 1 H), 8.07 - 8.09 (m, 2 H), 7.97 (d, J=8.84 Hz, 2 H), 7.59 (d, J=I.52 Hz, 1 H), 3.75 (s, 3 H); MS (APPI) m/z (M+ 1) 332, 334.
81%
Stage #1: 5-bromo-pyridine-2,3-diamine; Monomethyl terephthalate With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 1h;
Stage #2: With acetic acid at 200℃; for 0.0833333h; Microwave irradiation;
1
Example 1; Methyl 4-(6-bromo-3H-imidazo [4,5-6] pyridin-2-yl)benzoate; DIPEA (16.6 mL, 95.7 mmol) was added to a suspension of 5-bromo pyridine-2, 3 -diamine (6.0 g, 31.9 mmol), terepthalic acid monomethyl ester (6.89 g, 38.3 mmol) and ηBTU (14.5 g, 38.3 mmol) in MeCN (100 mL) and the reaction mixture was stirred at r.t. for 1 h. A precipitate that formed was collected and washed with MeCN. The solid was distributed into microwave vials with HO Ac (4 mL) and heated to +200 0C for 5 minutes. The product precipitated at r.t. and was filtered, washed with HOAc and MeCN and dried to afford 8.58 g (81% yield) of the title compound.1U NMR (CDCl3) δ ppm ); 8.15 (d, J=1.52 Hz, 1 H), 8.07 - 8.09 (m, 2 H), 7.97 (d, J=8.84 Hz, 2 H), 7.59 (d, J=I.52 Hz, 1 H), 3.75 (s, 3 H); MS (APPI) m/z (M+l) 332, 334.
Stage #1: 5-chloro-2,3-diaminopyridine; Monomethyl terephthalate With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 1h;
Stage #2: With acetic acid at 200℃; for 0.166667h; Microwave irradiation;
2
Example 2; Methyl 4-(6-chloro-3H-imidazo [4,5-6] pyridin-2-yl)benzoate; DIPEA (21.9 mL, 126 mmol) was added to a suspension of 5-chloro pyridine -2, 3-diamine (6.0 g, 42.0 mmol), terephtalic acid monomethyl ester (9.06 g 50.3 mmol) and ηBTU (19.1 g 50.3mmol) in MeCN (100 mL) and the reaction mixture was stirred at r.t. for 1 h. A precipitate that formed was collected and washed with MeCN. The solid was distributed into microwave vials with HO Ac (4 mL) and heated to +200 0C for 10 minutes. The product precipitated at r.t. and was filtered, washed with HOAc and MeCN and dried to afford 10.3g (85% yield) of the title compound. 1U NMR (CDCl3) δ ppm ); 7.92 - 7.98 (m, 3 H), 7.84 (d, J=8.84 Hz, 2 H), 7.38 (d, J=I.77 Hz, 1 H), 3.59 - 3.63 (m, 3 H); MS (APPI) m/z (M+ 1) 288, 290.
85%
Stage #1: 5-chloro-2,3-diaminopyridine; Monomethyl terephthalate With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 1h;
Stage #2: With acetic acid at 200℃; for 0.166667h; Microwave irradiation;
2
Example 2; Methyl 4-(6-chloro-3H-imidazo [4,5-6] pyridin-2-yl)benzoate; DIPEA (21.9 mL, 126 mmol) was added to a suspension of 5-chloro pyridine -2, 3-diamine (6.0 g, 42.0 mmol), terepthalic acid monomethyl ester (9.06 g 50.3 mmol) and ηBTU (19.1 g 50.3mmol) in MeCN (100 mL) and the reaction mixture was stirred at r.t. for 1 h. A precipitatethat formed was collected and washed with MeCN. The solid was distributed intomicrowave vials with HO Ac (4 mL) and heated to +200 0C for 10 minutes. The productprecipitated at r.t. and was filtered, washed with HOAc and MeCN and dried to afford 10.3g (85% yield) of the title compound.1R NMR (CDCl3) δ ppm ); 7.92 - 7.98 (m, 3 H), 7.84 (d, J=8.84 Hz, 2 H), 7.38 (d, J=I.77 Hz, 1 H), 3.59 - 3.63 (m, 3 H); MS (APPI) m/z (M+ 1) 288, 290.
Stage #1: 5-fluoro-2,3-pyridinediamine; Monomethyl terephthalate With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In acetonitrile at 20℃; for 1h;
Stage #2: With acetic acid at 200℃; for 0.0833333h; Microwave irradiation;
13
Example 13; Methyl 4-(6-fluoro-3H-imidazo [4,5-b] pyridin-2-yl)benzoate; Triethylamine (2.412 mL, 17.31 mmol) was added to a suspension of 5-fluoropyridine-2,3- diamine (2.2 g, 17.31 mmol), 4-(methoxycarbonyl)benzoic acid (3.12 g, 17.31 mmol) and O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (6.56 g, 17.31 mmol) in acetonitrile (15 mL) and the reaction mixture was stirred at r.t. for 1 h.The precipitate that formed was collected and washed with MeCN. The solid was distributed into microwave vials with HOAc (4 mL) and heated to +200 0C for 5 minutes. The product precipitated at r.t. and was filtered, washed with HOAc and MeCN and dried to afford methyl 4-(6-fluoro- 3H-imidazo[4,5-b]pyridin-2-yl)benzoate (3.70 g, 79 %) MS ESI m/z 272 M+
79%
Stage #1: 5-fluoro-2,3-pyridinediamine; Monomethyl terephthalate With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In acetonitrile at 20℃; for 1h;
Stage #2: With acetic acid at 200℃; for 0.0833333h; Microwave irradiation;
15
Example 15; Methyl 4-(6-fluoro-3H-imidazo [4,5-b] pyridin-2-yl)benzoate; Triethylamine (2.412 mL, 17.31 mmol) was added to a suspension of 5-fluoropyridine-2,3- diamine (2.2 g, 17.31 mmol), 4-(methoxycarbonyl)benzoic acid (3.12 g, 17.31 mmol) and O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (6.56 g, 17.31 mmol) in acetonitrile (15 mL) and the reaction mixture was stirred at r.t. for 1 h.The precipitate that formed was collected and washed with MeCN. The solid was distributed into microwave vials with ηOAc (4 mL) and heated to 200 0C for 5 minutes. The product precipitated at r.t. and was filtered, washed with ηOAc and MeCN and dried to afford methyl 4-(6-fluoro- 3η-imidazo[4,5-b]pyridin-2-yl)benzoate (3.70 g, 79 %). MS ESI m/z 272 M+
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 15℃; for 2h;
111
To a solution of 71 (1.8 g, 10 mmol) in DMF (15 mL) was added HATU (5.7 g, 15 mmol), TEA(3.04 g, 30 mmol) and 1-methylpiperazine (1.0 g, 10 mmol). The mixture was stirred at 15 C for2 h.The reaction mixture was partitioned between water (30 mL) and EtOAc (60 mL). The organic phase was separated, washed with brine (2OmL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give 72 (2.1 g, 80%) as a brown oil. 1H NMR (400 MHz, DMSO-d6) 7.99 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 3.86 (s, 3H), 3.61 (s, 2H), 3.25 (s, 2H), 2.37 (s, 2H), 2.19 (s, 2H), 1.97(s, 3H). To a mixture of 72 (1.54 g, 5.87 mmol) in THF (20 mL) was added LiAIH4 (334 mg, 8.81 mmol) at 0 C, and then the mixture was stirred at 0 C for 1 h under N2 atmosphere. The reaction mixture was quenched by sat. sodium potassium tartrate (1 .2 mL), filtered and concentrated under reduced pressure to give 73 (1.2 g, crude) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6) 7.26-7.21 (m, 4H), 5.10 (t, J= 6.0 Hz, 1H), 4.46 (d, J= 5.6 Hz, 2H), 3.41 (s, 2H), 2.32 (s, 8H), 2.13 (s, 3H).
61.1%
Stage #1: Monomethyl terephthalate With oxalyl dichloride In dichloromethane at 20℃; for 0.5h;
Stage #2: In dichloromethane for 1.5h;
Stage #3: 1-methyl-piperazine With pyridine In dichloromethane at 0 - 20℃; for 4h;
86
Oxalyl chloride (0.533 mL, 6.11 mmol) was added dropwise to a stirred suspension of 4-(methoxycarbonyl)benzoic acid (1 g, 5.55 mmol) in DCM (20 mL) under nitrogen. The resulting suspension was stirred at room temperature for 30 mins. DMF (0.05 mL) was added dropwise under nitrogen. The resulting suspension was stirred for 90 mins. A solution of 1-methylpiperazine (0.554 mL, 5.00 mmol) and pyridine (1.211 mL, 14.99 mmol) in DCM (15 mL) was added dropwise at 0° C., over a period of 60 mins under nitrogen. The resulting solution was stirred at room temperature for 3 h. The reaction mixture was evaporated to dryness to afford the crude product (1.791 g) as a dark orange solid. The solid was redissolved in DCM and washed with NaHCO3. The organic layer was evaporated to dryness to afford methyl 4-(4-methylpiperazine-1-carbonyl)benzoate (0.890 g, 61.1%) as an orange gum, which solidified on standing. Used without further purification. 1H NMR (399.9 MHz, CDCl3) δ 2.78 (4H, s), 3.43 (4H, s), 7.42-7.45 (2H, m), 8.04-8.06 (2H, m) MS: m/z 263 (MH+)
Stage #1: Monomethyl terephthalate With phosgene In dichloromethane at 20℃; for 2h;
Stage #2: 1-methyl-piperazine In tetrahydrofuran at 0 - 20℃; for 3h;
dimethyl [1,1'-biphenyl]-2,4-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
Stage #1: Monomethyl terephthalate; chlorobenzene With caesium carbonate In N,N-dimethyl-formamide at 20 - 145℃; for 26h; sealed vial; Molecular sieve;
Stage #2: With hydrogenchloride In water; N,N-dimethyl-formamide at 20℃;
Stage #3: diazomethyl-trimethyl-silane In methanol; hexanes at 0℃; for 5h;
III.12; II
Palladium acetate (5.6 mg, 0.025 mmol), mono-methyl isophthalate (90 mg, 0.5 mmol) and chlorobenzene (283 mg, 2.5 mmol), butyldi-1-adamantylphosphine (19.2 mg, 0.05 mmol), Cs2CO3 (358 mg, 1.1 mmol), molecular sieves 3 (155 mg) and anhydrous DMF (2.5 mL). After the reaction and workup the residue was dissolved in methanol (10 mL) and cooled to 0° C. (Trimethylsilyl)diazomethane in hexanes (5.0 ml of a 2.0M solution, 1 mmol) was added dropwise, the cooling bath was removed and the mixture stirred for 5 h. The solvent was removed under reduced pressure. Purification by preparative HPLC afforded 101 mg (75%) of a colorless oil. Analytical data are consistent with that of previously reported data.4 1H NMR (300 MHz, CDCl3) δ 3.67 (s, 3H), 3.95 (s, 3H), 7.30-7.47 (m, 6H), 8.15-8.18 (m, 1H), 8.5 (br s, 1H). The 1H NMR spectrum is shown in FIG. 38.
dimethyl 2,6-bis(4-trifluoromethylphenyl)-1,4-benzenedicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
Stage #1: Monomethyl terephthalate; 3-Chloroacetanilide With caesium carbonate In N,N-dimethyl-formamide at 29 - 145℃; for 26h; sealed vial; Molecular sieve;
Stage #2: With hydrogenchloride In water; N,N-dimethyl-formamide at 20℃;
Stage #3: diazomethyl-trimethyl-silane In methanol; hexanes at 0℃; for 5h;
III.3; II
Palladium acetate (5.6 mg, 0.025 mmol), monomethyl terephthalate (90 mg, 0.5 mmol), 4-chlorobenzo-trifluoride (271.5 mg, 1.5 mmol), butyldi-1-adamantylphosphine (19.2 mg, 0.05 mmol), Cs2CO3 (358 mg, 1.1 mmol), molecular sieves 3 (155 mg) and anhydrous DMF (2.5 mL). After the reaction and workup the residue was dissolved in methanol (10 nL) and cooled to 0° C. (Trimethylsilyl)diazomethane in hexanes (5.0 mL of a 2.0M solution, 1 mmol) was added dropwise, the cooling bath was removed and the mixture stirred for 5 h. The solvent was removed under reduced pressure. Purification by flash chromatography (hexanes then dichloromethane-ethylacetate 95:5) afforded 190 mg (79%) of a white solid, mp 158-160° C. (isooctane). Rf-0.36 (1/9 ethyl acetate-hexanes). 1H NMR (300 MHz, CD2Cl2) δ3.41 (s, 3H), 3.94 (s, 3H), 7.55-7.57 (m, 4H), 7.71-7.74 (m, 4H), 8.11 (s, 2H). 13C NMR (75 MHz, CD2Cl2) δ52.7, 53.1, 124.7 (q, J-272.95 Hz), 125.9 (q, J-3.9 Hz), 129.4, 130.5 (q, J-32.1 Hz), 130.8, 132.1, 136.9, 140.0, 143.6, 166.1, 168.9. FT-IR (neat, cm1) υ 1731, 1326, 1120. Anal. calcd for C24H16F6O4, (482.37 g/mol): C, 59.76; H, 3.34. Found: C, 59.62; H, 3.29. The 1H NMR and 13C NMR spectra are shown in FIGS. 36A&B, respectively.
With [bis(acetoxy)iodo]benzene; iodine; palladium diacetate In N,N-dimethyl-formamide at 100℃; for 24h; Sealed tube;
General Procedure for ortho-Diiodination of Benzoic Acid Derivatives
General procedure: In a flame-dried 100 mL round-bottom flask, benzoic acid starting material (16.4 mmol, 1.0 equiv.), palladium acetate (0.05 equiv.), iodobenzene diacetate (1.5 equiv.), and iodine (1.5 equiv.) were dissolved in anhydrous DMF (40 mL) under atmospheric air. The flask was then sealed with a septum and the reaction mixture was stirred at 100 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and then washed with 0.5 N HCl (420 mL). The organic phase was washed with brine, dried over Na2SO4, and concentrated in a rotary evaporator. The residue was purified by column chromatography on silica gel (3 : 1 hexane/EtOAc) to give the desired iodinated product.
74%
With [bis(acetoxy)iodo]benzene; iodine; palladium diacetate In N,N-dimethyl-formamide at 100℃; for 24h;
tert-butyl 2-(4-(methoxycarbonyl)benzoyl)hydrazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20 - 30℃; for 20h; Inert atmosphere;
8.1 Step 1: Preparation of tert-butyl 2-(4-(methoxycarbonyl)benzoyl)hydrazine-1-carboxylate (8B)
Monomethyl terephthalate (5.00 g, 27.8 mmol), dichloromethane (80 mL), tert-butyl carbazate (4.50 g, 34.4 mmol), DMAP (13.5 g, 111 mmol) and EDCI (7.50 g, 38.9 mmol) were added to a reaction flask, and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was extracted with 100 mL of water and 100 mL of dichloromethane. The organic phase was washed with water and saturated brine once, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 16.30 g of the title product as a light yellow solid, which was used directly in the next step, yield: 100%.
100%
With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20 - 30℃; for 20h; Inert atmosphere;
8.1 Step 1: Preparation of tert-butyl 2-(4-(methoxycarbonyl)benzoyl)hydrazine-1-carboxylate (8B)
Monomethyl terephthalate (5.00 g, 27.8 mmol), dichloromethane (80 mL), tert-butyl carbazate (4.50 g, 34.4 mmol), DMAP (13.5 g, 111 mmol) and EDCI (7.50 g, 38.9 mmol) were added to a reaction flask, and stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was extracted with 100 mL of water and 100 mL of dichloromethane. The organic phase was washed with water and saturated brine once, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 16.30 g of the title product as a light yellow solid, which was used directly in the next step, yield: 100%.
90%
With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃;
1
4-Methoxycarbonylbenzoic acid (1.54 g, 8.55 mmol), tert-butyl N-aminocarbamate (1.40 g, 10.6 mmol) and DMAP (4.2 g, 34.4 mmol) were mixed in DCM (30 mL) and EDCI (2.3 g, 12.0 mmol) was added. The reaction mixture was a slurry from the beginning but dissolved during stirring at rt overnight. The reaction mixture was diluted with EtOAc (150 mL) and was washed with KHSO4 (1 M, 2×50 mL), saturated NaHCO3 (50 mL), water (50 mL) and dried (MgSO4) to give the title compound (2.26 g, 90%) which was used without further purification.1H NMR (400 MHz, CDCl3) δ 8.25 (br s, 1H), 8.05 (d, 2H), 7.82 (d, 2H), 6.76 (br s, 1H), 3.92 (s, 3H), 1.47 (s, 9H).
86.4%
With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃;
Synthesis of methyl 4-(hydrazinecarbonyl)benzoate (3f)
Step A. To the solution of 4-(methoxycarbonyl)benzoic acid (0.5 g, 2.7 mmol) dissolved in dichloromethane, tert-butoxycarbonyl hydrazide (0.37 g, 2.8 mmol), DMAP (1.4 g, 11.4 mmol) and EDCI (0.8 g, 3.8 mmol) were added and stirred at room temperature overnight. The reaction completion was monitored by LC-MS analysis. The reaction was diluted with ethyl acetate (25 mL), washed with 1 M KHSO4 (aq, 20 mL), saturated NaHCO3 (aq, 20 mL) and water (25 mL). Combined organic layers were dried (MgSO4) and concentrated in vacuo to give t-butyl 2-(4-(methoxycarbonyl)benzoyl)hydrazine-1-carboxylate 12as yellow solid (0.7 g, 86.4%) MS (ESI) m/z (%): 194.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.7 (s, 1H), δ 9.96 (s, 1H), 8.04-8.00 (m, 2H), 7.95-7.91 (m, 2H), 3.88 (s, 3H), 1.91 (s, 9H).
With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃; for 3h;
[003651 To a stirred solution of Compound AC12 (1 g, 5.55 mmol) and Compound AC12-1 (0.88 g, 6.66 mmol) in DCM (15 mL) was added EDCI (1.49 g, 7.77mmol) and DMAP (0.95 g, 7.77 mmol) in one portion at r.t., then the mixture was stirred at r.t. for 3 h. TLC showed the reaction was completed. The reaction mixture was concentrated and purified by column to afford the Compound AC13 (1.2 g, purity : 90% on TLC). ‘H NMR (400 MHz; CDC13) 3 ppm 8.31 (s, 1 H), 8.06 (d, J = 8.4 Hz, 2 H), 7.84 (d, J = 8.4 Hz, 2 H), 6.80 (s, 1 H), 3.93 (s, 3 H), 1.49 (s, 9 H) ppm.
With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 0 - 20℃;
To a solution of monomethyl terephthalate (850 mg, 4.72 mmol) and tert-butyl carbazate (686 mg, 5.19 mmol) in DCM (12 mL) were added EDCI (1.4 g, 7.08 mmol) and DMAP (865 mg, 7.08 mmol) in one portion at 0C, then the mixture was stirred at room temperature overnight. The saturated NaHCO3solution was added andextracted with EtOAc. The combined organic phase was dried over Na2SO4. The crude product33was used for the next reaction without purification. To a solution of crude product33(1.4 g, 0.05 mol) in EtOAc (22 mL) was slowly added concentrated HCl (2 mL) at 0 C and the reaction mixture was stirred at room temperature for 2 h, neutralized with saturated NaHCO3to pH 8. The resulting solid was filtered to afford the compound34(870 mg, 93% in 2 steps).The compound36was prepared according to the procedure described in 4.1.1.1 to yield 1,3,4-oxadiazin-5(6H)-onefrom the hydrazide34(light pink solid500 mg, yield 55% in 2 steps).To a suspension ofLiAlH4(100 mg, 2.56 mmol) in dry THF (20 mL) was added dropwise compound36(300 mg, 1.28 mmol) in dry THF (5 mL) at 0C. The reaction was stirredat 0C for 3 h, quenched with EtOAc, and treated with H2O. The product wasextracted with EtOAc, and dried overNa2SO4. The precipitated solid in MeOH was filtered to afford the compound37(150 mg, 60%). To a solution of the compound37(150 mg, 0.7 mmol) in DMF (3.5 mL) was added MnO2(600 mg, 7.0 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through the celite pad and washed with EtOAc. The filtrate was washed with H2O, and dried over Na2SO4. The pure product38was obtained by filtration of the precipitate in MeOH. White solid (80 mg, yield 55%).
With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 30℃; for 2h;
1
Step 1: To a mixture of 4-(methoxycarbonyl)benzoic acid (5.0 g, 28 mmol), tert-butyl hydrazinecarboxylate (4.4 g, 33 mmol), and DMAP (13.6 g, 111 mmol) was added DCM (70 mL) and EDC (6.9 g, 36 mmol). The reaction mixture was stirred at 30°C for 2 h. The mixture was washed with saturated aqueous sodium bicarbonate (50 mL) and water (50 mL), and then the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-30% EtOAc/petroleum ether) to afford tert-butyl 2-(4- (methoxycarbonyl)benzoyl)hydrazinecarboxylate as a solid.
With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane
With N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃;
methyl 4-(2-(5-bromopyridin-2-yl)hydrazine-1-carbonyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h;
21 Synthesis of Methyl 4-(2-(5-bromopyridin-2-yl)hydrazine-l-carbonyl)benzoate
To a solution of 5-bromo-2-hydrazinylpyridine (500 mg, 2.66 mmol), 4- (methoxycarbonyl)benzoic acid (599 mg, 3.32 mmol) and DIPEA (1.39 mL, 7.98 mmol) in DMF (5.00 mL) was added a 50% solution of propylphosphonic anhydride (T3P) in DMF (2.33 mL, 3.99 mmol). The resulting reaction mixture was allowed to stir at room temperature for 1 h, after which LCMS analysis showed completion. Reaction mixture was poured over ice H2O, stirred for 10 min, product collected by filtration, rinsed generously with H2O and allowed to air dry to afford methyl 4-(2-(5-bromopyridin-2-yl)hydrazine-l-carbonyl)benzoate (906 mg, 2.59 mmol, 97 % yield) as a tan solid, which was used without further purification. 1 H NMR (400 MHz, DMSO-ifc) d 10.61 (d, / = 1.9 Hz, 1H), 8.80 (d, J= 1.9 Hz, 1H), 8.15 (dd, / = 2.5, 0.7 Hz, 1H), 8.10 - 8.05 (m, 2H), 8.05 - 8.00 (m, 2H), 7.71 (dd, /= 8.9, 2.5 Hz, 1H), 6.66 (dd, J = 8.9, 0.7 Hz, 1H), 3.89 (d, J = 2.5 Hz, 3H). LCMS RT (Method 2) = 2.863 min, m/z 352.3 [M+H+]
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane
Stage #1: Monomethyl terephthalate With oxalyl dichloride In dichloromethane at 20℃; for 2h;
Stage #2: 2-pyridin-3-ylethylamine With 4-methyl-morpholine In dichloromethane for 0.333333h;
Intermediate 13; N-(2-Pyridin-3-yI-ethyl)-terephthalamic acid methyl ester; Procedure M:; EPO To a stirring solution of terephthalic acid monomethyl ester (500 mg, 2.5 mmol) and oxalyl chloride (0.44 rnL, 5.03 mmol) in dichloromethane (20 mL), is added 3 drops of dimethylformamide and the reaction is stirred for 2 h at room temperature. The reaction is concentrated in vacuo and then redissolved in dichloromethane. The solution is slowly added to a stirring solution of 3-(2-arninoethyl)pyridine (308 mg, 2.5 2mmol) and n-methylmorpholine (0.28 mL, 2.52 mmol) in dichloromethane (20 mL). After 20 min, the reaction is washed with saturated aqueous sodium bicarbonate while extracting with 10% isopropanol/dichloromethane. The organic portion is dried with sodium sulfate, filtered, and concentrated in vacuo. The resulting residue is purified using radial chromatography, eluting with methanol and dichloromethane to obtain 613 mg (86%) of the title compound. MS (ES+) m/e 285.1 (M+l)+.
methyl 4-(1-ethoxy-3-hydroxy-1-oxopropan-2-ylcarbamoyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane;Inert atmosphere;
General procedure: L-Serine methyl ester hydrochloride 6a,b (1.0 equiv) was dissolved in CH2Cl2 together with acids 7a,b (1.1 equiv), Et3N (1.1 equiv) and EDC (1.1 equiv). After stirring overnight, the solution was washed with H2O, NaHCO3 satd sol and brine, then dried over Na2SO4. Evaporation of the solvent gave amide 8a-d, which were used without further purification.
methyl 4-(1-(benzyloxy)-3-hydroxy-1-oxopropan-2-ylcarbamoyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane;Inert atmosphere;
General procedure: L-Serine methyl ester hydrochloride 6a,b (1.0 equiv) was dissolved in CH2Cl2 together with acids 7a,b (1.1 equiv), Et3N (1.1 equiv) and EDC (1.1 equiv). After stirring overnight, the solution was washed with H2O, NaHCO3 satd sol and brine, then dried over Na2SO4. Evaporation of the solvent gave amide 8a-d, which were used without further purification.
Synthesis 12i-Dichloro-4-ethoxyphenylcarbamoyl)benzoic acid (AAA-013)ii) LiOH, THF/H20Step (i): 4-(3,5-Dichloro-4-hydroxyphenylcarbamoyl)benzoic acid (4)ii) LiOH, THF/H20A mixture of 4-(chlorocarbonyl)benzoic acid methyl ester (1) (600 mg, ca. 3.02 mmol) contaminated with 4-(methoxycarbonyl)benzoic acid was suspended in DCM (5 mL) and cooled to 0°C. The mixture was treated with oxalyl chloride (529 pL, 6.04 mmol) and DMF (1 drop). The resultant mixture was warmed to RT, stirred for 2 h, and then concentrated in vacuo. The residue was dissolved in DCM (3 mL) and a suspension of 4- amino-2,6-dichlorophenol (2) (51 1 mg, 2.9 mmol) in DCM (18 mL) was added. The resultant suspension was treated with DIPEA (1.58 mL, 9.06 mmol) and was stirred at RT overnight. The solvent was removed in vacuo and the residue partitioned between EtOAc/DCM and aqueous HCl (1 M). The layers were separated and the organic layer was washed with water and brine. The organic layer was dried over MgS04l filtered and then the solvent evaporated in vacuo to afford a pale brown solid (930 mg), which was triturated in hot acetonitrile/methanol (9: 1 ) and filtered. The precipitate and filtrate were recombined, the solvent was evaporated in vacuo and then the residue was dissolved in THF (40 mL). Water (10 mL) was added and the mixture treated with lithium hydroxide (340 mg, 14.2 mmol). The mixture was stirred overnight and then partitioned between EtOAc and aqueous HCl (1 M). The organic layer was washed successively with water (2 x 50 mL), brine, dried over MgS04, filtered and then concentrated in vacuo to afford crude 4-(3,5-dichloro-4-hydroxyphenylcarbamoyl)benzoic acid (3) as a pale brown solid. This material was used in the subsequent reaction step without purification.
A mixture of 4-(chlorocarbonyl)benzoic acid methyl ester (1) (600 mg, ca. 3.02 mmol) contaminated with 4-(methoxycarbonyl)benzoic acid was suspended in DCM (5 mL) and cooled to 0° C. The mixture was treated with oxalyl chloride (529 muL, 6.04 mmol) and DMF (1 drop). The resultant mixture was warmed to RT, stirred for 2 h, and then concentrated in vacuo. The residue was dissolved in DCM (3 mL) and a suspension of <strong>[5930-28-9]4-amino-2,6-dichlorophenol</strong> (2) (511 mg, 2.9 mmol) in DCM (18 mL) was added. The resultant suspension was treated with DIPEA (1.58 mL, 9.06 mmol) and was stirred at RT overnight. The solvent was removed in vacuo and the residue partitioned between EtOAc/DCM and aqueous HCl (1 M). The layers were separated and the organic layer was washed with water and brine. The organic layer was dried over MgSO4, filtered and then the solvent evaporated in vacuo to afford a pale brown solid (930 mg), which was triturated in hot acetonitrile/methanol (9:1) and filtered. The precipitate and filtrate were recombined, the solvent was evaporated in vacuo and then the residue was dissolved in THF (40 mL). Water (10 mL) was added and the mixture treated with lithium hydroxide (340 mg, 14.2 mmol). The mixture was stirred overnight and then partitioned between EtOAc and aqueous HCl (1 M). The organic layer was washed successively with water (2.x.50 mL), brine, dried over MgSO4, filtered and then concentrated in vacuo to afford crude 4-(3,5-dichloro-4-hydroxyphenylcarbamoyl)benzoic acid (3) as a pale brown solid. This material was used in the subsequent reaction step without purification.
Stage #1: Monomethyl terephthalate With trichlorophosphate In 1,4-dioxane at 20℃; for 0.5h;
Stage #2: 4-butyl-3-thiosemicarbazide In 1,4-dioxane at 80℃;
59
PREPARATION 59Methyl 4-(5-(butylamino)-1,3,4-thiadiazol-2-yl)benzoateTo a stirred solution of the 4-(methoxycarbonyl)benzoic acid (5 g, 27.17 mmol, Aldrich) in dioxane (40 ml), POCl3 (5.2 ml, 55.96 mmol) was added drop wise and the mixture was stirred at rt for 30min. Then, the title compound of Preparation 3 (4 g, 27.75 mmol) was added portion wise and then let to react at 80° overnight. Solvent was removed in vacuum and the solid thus obtained was suspended in water, then it was basified to pH 8-9 and filtered. The precipitate thus obtained was dried in vacuum to yield a solid. 6.77 g (81 % yield) of the title compound were obtained. LRMS: m/z 292 (M+1)+ Retention time: 3.26 min (method A) 1H NMR (200 MHz, CDCl3) δ ppm 0.92 (t, J=7.03 Hz, 3 H) 1.27 - 1.50 (m, 2 H) 1.50 - 1.73 (m, 2 H) 3.24 - 3.46 (m, 2 H) 3.88 (s, 3 H) 7.85 - 7.97 (m, 2 H) 8.03 (m, 2 H) 8.13 (t, J=5.08 Hz, 1 H)
81%
Stage #1: Monomethyl terephthalate With trichlorophosphate In 1,4-dioxane at 20℃; for 0.5h;
Stage #2: 4-butyl-3-thiosemicarbazide In 1,4-dioxane at 80℃;
59
To a stirred solution of the 4-(methoxycarbonyl)benzoic acid (5 g, 27.17 mmol, Aldrich) in dioxane (40 ml), POCI3 (5.2 ml, 55.96 mmol) was added drop wise and the mixture was stirred at rt for 30min. Then, the title compound of Preparation 3 (4 g, 27.75 mmol) was added portion wise and then let to react at 80° overnight. Solvent was removed in vacuum and the solid thus obtained was suspended in water, then it was basified to pH 8-9 and filtered. The precipitate thus obtained was dried in vacuum to yield a solid. 6.77 g (81% yield) of the title compound were obtained.LRMS: m/z 292 (M+1)+ Retention time: 3.26 min (method A)1H NMR (200 MHz, CDCI3) δ ppm 0.92 (t, .7=7.03 Hz, 3 H) 1.27 - 1.50 (m, 2 H) 1.50 - 1.73 (m, 2 H) 3.24 - 3.46 (m, 2 H) 3.88 (s, 3 H) 7.85 - 7.97 (m, 2 H) 8.03 (m, 2 H) 8.13 (t, J=5.08 Hz, 1 H)
Example 1: Preparation of methyl [4-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2- naphthalenyl)carbonyl]benzoateTo a solution of 4-carboxy benzoic acid (100 g) in dichloromethane (800 ml) under nitrogen gas atmosphere, phosphorous pentachloride (200 g) was added at 25-30 C and temperature was slowly raised to 38-44 C. After completion of the reaction (monitored by GC), the reaction mass was cooled to -5 to -10 C. Thereafter aluminium chloride (340g) and l,2,3,4,-tetrahydro-l-l,4,4,6-pentamethyl naphthalene (120 g) were successively added to the reaction mixture and heated slowly to 38-44C and refluxed for 1 hour. After completion of reaction (monitored by TLC), the reaction mass was cooled to 15-20 C and poured into 5N hydrochloric acid (1L). Layers were separated and aqueous layer was extracted with dichloromethane (600 ml). The combined organic layer was washed successively with demineralized water (2 L) and sodium bicarbonate solution (8 % solution, 1600 ml)) The resulting organic layer was distilled off at atmospheric pressure to give residue which was dried to give title compound having purity 98.58 %, impurity A: 0.52 % and keto acid impurity B: 0.22 % by HPLC. Purification:n-Heptane (400 ml) was added to the resulting product and stirred for 30 minutes. The mixture is then cooled to 5-10 C, stirred for 1 hour and filtered. The solid, thus obtained, is slurry washed with cold n- heptane (200 ml) and dried at 65C to give 173 g of title compound as white to off white crystalline powder having purity 99.75%, impurity A: 0.14 % and keto acid impurity B: 0.02% by HPLC.
Stage #1: Monomethyl terephthalate; 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h;
Stage #2: With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 96h;
5.3
A solution of 5-(3-aminopyrrolidin-l-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4- +, tR = 1.48 min.
190 mg
Stage #1: Monomethyl terephthalate; 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h;
Stage #2: With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 96h;
Intermediate 74 Methyl 4-(3-ethoxy-3-oxopropanoyl)benzoate A solution of 4-(methoxycarbonyl)benzoic acid (3 g, 16.65 mmol) and 1,1'-carbonyldiimidazole (3.2 g, 19.73 mmol) in THF (50 ml) was stirred for 3 hours at 50 C. Then, a solution of the magnesium salt of malonic acid monoethyl ester (prepared via the addition of Et3N (4.3 g, 42.49 mmol) and MgCl2 (5.2 g, 58.51 mmol) to a solution of potassium 3-ethoxy-3-oxopropanoate (7.8 g, 45.88 mmol) in acetonitrile (100 ml) stirred at room temperature for 2.5 h) was added at 0 C. The resulting solution was stirred overnight at 85 C., quenched by the addition of water (100 ml) and adjusted to pH 7 with HCl (3N). The resulting solution was extracted with ethyl acetate (3*100 ml), and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography with 2%-10% ethyl acetate in petroleum ether to afford methyl 4-(3-ethoxy-3-oxopropanoyl)benzoate as a white solid (2.6 g, 62%). LC/MS (ES, m/z): [M+H]+ 251.0 1H-NMR (300 MHz, CDCl3): delta 12.56 (s, 1H), 7.99-8.16 (m, 6H), 7.83-7.90 (m, 2H), 5.74 (s, 1H), 4.25-4.32 (m, 4H), 4.02-4.23 (m, 2H), 3.97 (s, 6H), 1.26-1.37 (m, 6H).
With Bronsted acidic, ionic liquid containing, heteropolyanion functionalized polysiloxane network POS-HPA-IL for 6h; Reflux; Green chemistry; chemoselective reaction;
85%
With bromobenzene at 55 - 60℃; for 8h; Autoclave;
General procedure for the esterification
General procedure: benzoic acid (Table 3, entry 1) (1.0 g,0.0081 mol), bromobenzene (0.125 g, 0.0081 mol), 10% palladium on carbon(50% wet) (0.2 g) and methanol (3 mL) were placed in autoclave vessel. Autoclave was pressurized with 1-2 bar of nitrogen followed by 1-2 bar of hydrogen gas and then put under the desired pressure of hydrogen (5-6 bar).The reaction mixtures are then warmed to 55-60 C temperature and stirredfor 4 h at 300 rpm. After reaction, the catalyst was filtered through celite bed.Filtrate was added with water (30 mL). The reaction mixture was extracted with isopropyl acetate (2 15 mL). The combined organic layers were washedwith 5% aqueous sodium bicarbonate solution (2 15 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated under vacuum togive of methyl benzoate product
With chloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]copper(I); In tetrahydrofuran; at 70℃; for 16h;Inert atmosphere; Sealed tube;
General procedure: In a glovebox, Cu(IPr)Cl catalyst and PMC (62.8 mg, 0.55 mmol,1.1 equiv) were charged to a glass reaction tube. A solution of 3(0.50 mmol) in THF (1.5 mL) was added, the tube was sealed, taken out of the glovebox, and heated at 70 C for 16 h. After cooling tor.t., H2O (2 mL) was added and the reaction mixture was acidified with aqueous HCl (1 M), and saturated with sodium chloride. After extraction with EtOAc (3 × 5 mL), the organic phase was dried overanhydrous sodium sulfate and concentrated under vacuo. The product was purified by silica gel column chromatography.
With chloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]copper(I) In tetrahydrofuran at 70℃; for 16h; Inert atmosphere; Sealed tube;
Carboxylation of Arylboronic Esters with PMC; Typical Procedure
General procedure: In a glovebox, Cu(IPr)Cl catalyst and PMC (62.8 mg, 0.55 mmol,1.1 equiv) were charged to a glass reaction tube. A solution of 3(0.50 mmol) in THF (1.5 mL) was added, the tube was sealed, taken out of the glovebox, and heated at 70 °C for 16 h. After cooling tor.t., H2O (2 mL) was added and the reaction mixture was acidified with aqueous HCl (1 M), and saturated with sodium chloride. After extraction with EtOAc (3 × 5 mL), the organic phase was dried overanhydrous sodium sulfate and concentrated under vacuo. The product was purified by silica gel column chromatography.
With di-tert-butyl peroxide; copper(II) bis(trifluoromethanesulfonate) In 1,2-dichloro-ethane at 130℃; for 12h; Sealed tube;
General procedure for the amidation of benzoic acids:
General procedure: A 50 mL sealed tube (with a Teflon high pressure valve) equipped with a magnetic stir bar was charged with Cu(OTf)2 (0.05 mmol), followed by carboxylic acid (0.5 mmol), formamide (2.0 mmol), tert-butyl peroxide (DTBP, 1 mmol), and DCE (1 mL). After the reaction mixture was stirred at 130 °C for 12 h, it was allowed to cool to ambient temperature. The reaction mixture was diluted with ethyl acetate, and then filtered through a small pad of Celite. The filtrate was washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL, twice). The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel preparative TLC to give the corresponding product.
methyl 4-((6-hydroxybenzo[d]thiazol-2-yl)carbamoyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 16h;
Example 60 : N 1 -(6-hydroxybenzo [d]thiazol-2-yl)-N4-(prop-2-yn- 1 -yl)terephthalamide. To a vial equipped with a magnetic stir bar was added 2-aminobenzo[d]thiazol-6-ol (500 mg, 3.0 mmol), mono-methyl terephthalate (597 mg, 3.3 mmol), HATU (1.38 g, 3.6 mmol), and DMF (6 ml). The resulting solution was treated with N,N-diisopropylethyl amine (1.0 ml, 6.0 mmol), and the mixture was allowed to stir for 16 h at ambient temperature. Water was added to the mixture, and the resulting precipitate was washed with water and dried by aspiration to give methyl 4-((6- hydroxybenzo[d]thiazol-2-yl)carbamoyl)benzoate (907 mg, 92%): LCMS (ESI) m/z 329.2 [M+l]+.
With water; sodium formate; palladium diacetate at 20℃; for 30h;
4-Nitrobenzoic Acid (2a)
General procedure: A 25-mL flask was charged with Pd(OAc)2 (1.2 mg, 0.005 mmol), 1-iodo-4-nitrobenzene (1a, 127.0 mg, 0.5 mmol), K2CO3 (141.0 mg, 1.0 mmol), H2O (0.5 mL), and PEG 400 (2.0 mL); the flask was subjected to standard cycles (3 ×) of evacuation and back-filling with dry and pure CO. The mixture was stirred at r.t. for the indicated time. The mixture was poured into sat. aq NaCl (15 mL), acidified to pH 3 with 3 M aq HCl, and extracted with EtOAc (3 × 15 mL). The solvent was removed from the combined organic phases on a rotary evaporator. The crude product was purified by column chromatography (silica gel, PE-EtOAc-HCO2H, 25:1:1) to afford 2a as a light yellow solid; yield: 75mg (90%); mp 238.0-239.3 °C. 1H NMR (400 MHz, DMSO-d6): δ = 13.68 (br s, 1 H), 8.30 (d, J = 8.0 Hz,2 H), 8.14 (d, J = 8.0 Hz, 2 H). 13C NMR (100 MHz, DMSO-d6): δ = 165.9, 150.0, 136.4, 130.7, 123.8.
52%
With water; caesium carbonate at 95℃; for 20h; Microwave irradiation; Sealed tube;
methyl 4-((2-(pyridin-2-yl)propan-2-yl)carbamoyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: To a round bottom flask was added the acid (5 mmol)and anhydrous CH2Cl2 (20 mL). Then the flask was submergedin an ice bath, N-methylmorpholine (6 mmol) wasadded via syringe and the solution stirred for 15 min. Isobutylchloroformate(5.5 mmol) was added dropwise over 20min. After that, 20 mL anhydrous CH2Cl2 solution containingPIP-NH2 (5 mmol) and N-methylmorpholine (NMM, 5mmol) was added to the solution. After stirring for 6 h atambient temperature, the resulting mixture was washed withsat. Na2CO3, and brine, dried over MgSO4, filtered andconcentrated under reduced pressure. The residue was purifiedby flash chromatography to give the desired product.
Stage #1: morpholine; Monomethyl terephthalate With dmap; triethylamine In tetrahydrofuran for 0.5h; Inert atmosphere;
Stage #2: With 9,9-dichloro-9-silafluorene In tetrahydrofuran at 20 - 60℃; Inert atmosphere;
83%
With dichloro(dimethylglyoxime)(dimethylglyoximato)cobalt(III); [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate; triphenylphosphine In dichloromethane at 20℃; for 6h; Inert atmosphere; Sealed tube; Irradiation;
12 Example 12
First weigh (36.0mg, 0.2mmol), [Ir(dF(CF3)ppy)2(dtbbpy)]PF6(2.3mg, 0.002mmol), PPh3(52.5mg, 0.2mmol) and Co(dmgH)(dmgH2) Cl2 (3.6mg, 0.01mmol) was added to the reaction tube, sealed with a stopper, and vented through the vacuum line three times. Under a nitrogen atmosphere, dichloromethane (6.0mL) was added, and then slowly added (26.1μL, 0.3mmol) , And then placed under blue LEDs, reacted at room temperature for 6 hours, and the stirring speed is 1200r/min. After the reaction was monitored by TLC, the solvent was removed by rotary evaporation, and the product was separated by column chromatography (300-400 mesh chromatography silica gel, eluent: petroleum ether-ethyl acetate) to obtain 41.5 mg of the product, with a yield of 83%.
83%
With dichloro(dimethylglyoxime)(dimethylglyoximato)cobalt(III); [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate; triphenylphosphine In dichloromethane at 20℃; Inert atmosphere; Sealed tube; Irradiation;
63%
With diphenylsilane In acetonitrile at 80℃; for 16h; Inert atmosphere; Sealed tube; Green chemistry;
Stage #1: Monomethyl terephthalate With phosgene In dichloromethane at 20℃; for 2h;
Stage #2: morpholine In tetrahydrofuran at 0 - 20℃; for 3h;
2.76 g
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0 - 20℃; for 1h;
6.a Step a
To a stirred suspension of morpholine (CAS Number 1 10-91 -8, available from Spectrochem) (1 .06 ml, 12.210 mmol) and mono methyl terephthalate (CAS Number 1679- 64-7, available from Combi Blocks) (2.00 g, 1 1 .100 mmol) in DMF (50 ml) was added HATU (5.48 g, 14.430 mmol) and diisopropylethylamine (5.60 ml, 33.300 mmol) at 0°C and the resulting reaction mixture was stirred at room temperature for 1 h. The resulting reaction mixture was poured onto crushed ice and extracted with ethyl acetate (2 x 100 ml). The combined organic layer was brine washed and dried over Na2S04, filtered and concentrated under reduced pressure yielding methyl 4-(morpholin-4-ylcarbonyl)benzoate (2.76 g, 1 1 .070 mmol). LCMS: Method A, 1 .585 min, MS: ES+ 250.1 1 (M+1 ).
Stage #1: Monomethyl terephthalate With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 3h;
Stage #2: morpholine With triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 12h;
3-oxa-8-azabicyclo[3.2.1]octane hydrochloride[ No CAS ]
methyl 4-(3-oxa-8-azabicyclo [3.2.1]octane-8-carbonyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;
xvi.a Methyl 4-(3-oxa-8-azabicyclo[3.2. 1 ]octane-8-carbonyl)benzoate (137)
To a solution of 4-(methoxycarbonyl)benzoic acid (0.66 g, 3.7 mmol) in DCM (20 mL) was added, 3-oxa-8-azabicyclo[3.2.1 ]octane hydrochloride (0.50 g, 3.4 mmol), DIPEA (0.87 g, (0673) 6.7 mmol), HOBt (45 mg, 0.3 mmol) and EDCI (0.77 g, 4.0 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was partitioned against saturated aqueous NaHC03 (20 mL 2) and the aqueous layer extracted with DCM (5 mL 2). The combined organic layers were washed with brine (20 mL 2), dried ( a2S04) and concentrated. The crude residue obtained was purified by column chromatography (1 % methanol /DCM) to give the desired compound (0.79 g, 85% yield) as a white solid. LCMS- C: RT 0.61 min; m/z 276.1 [M+H]+
85%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;
ii.a (a) Methyl 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzoate I5
To a solution of 4-(methoxycarbonyl)benzoic acid (664 mg, 3.7 mmol) in CH2Cl2 (20 mL) was added, 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (500 mg, 3.4 mmol), DIPEA (865.9 mg, 6.7 mmol), HOBt (45 mg, 0.3 mmol) and EDCI (771.4 mg, 4.0 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was partitioned against with aqueous NaHCO3 (20 mL x 2) and the aqueous layer extracted with CH2Cl2 (5 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried (Na2SO4) and concentrated. The crude residue obtained was purified by column chromatography (1% methanol in CH2Cl2) to give the desired compound as a white solid (786.9 mg, 85%): LCMS: RT 0.61 min; m/z 276.1 [M+H]+.
Stage #1: Monomethyl terephthalate With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 25℃; for 0.0833333h;
Stage #2: 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride In dichloromethane at 25℃; for 0.166667h;
1 Step 1:
To a solution of 4-(methoxycarbonyl)benzoic acid (10 g, 55.5 mmol) and HATU (25.3 g, 66.6 mmol) in DCM (150 ml) was added DIEA (29.1 ml, 167 mmol). The mixture was stirred at 25 °C for 5 min. To the mixture was added 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (8.72 g, 58.3 mmol) at 25 °C. The mixture was stirred at 25 °C for 10 min and concentrated under reduced pressure. The residue was purified by column chromatography on silica (50% ethyl acetate/pet. ether) to give methyl 4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)benzoate as a solid. MS: 276 (M + 1). 1H NMR (400 MHz, CDCb) d 8.06 (d, J= 8.41 Hz, 2H), 7.52 (d, J = 8.41 Hz, 2H), 4.71 (br s, 1H), 3.91 (s, 3H), 3.86 - 3.83 (m, 2H), 3.76 - 3.51 (m, 3H), 2.09 - 2.02 (m, 2H), 2.00 - 1.81 (m, 2H)
2-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine[ No CAS ]
4-((1-(4-((3,4-dimethoxyphenyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-3-yl)aminoformyl)benzoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With dmap; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 26h;
5 Example 5. Preparation of 4 - ((1- (4 - ((3,4-dimethoxyphenyl) amino) -6,7-dihydro-5H-cyclopentadienyl[D]pyrimidin-2-yl)Pyrrolidin-3-yl)Formyl)Benzoic acid methyl ester (IA-I):
178 mg of intermediate V was dissolved in 10 ml of N,N-dimethylformamide,90 mg of monomethyl terephthalate was added,247 mg2- (7-azobenzotriazole) -N, N, N ', N'-tetramethyluronium hexafluorophosphate and 248 l ofN, N-diisopropylethylamine,After 2 hours of reaction,96 mg was added1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 61 mg of 4-dimethylaminopyridine.At room temperature for 24 hours.After completion of the reaction,Water and ethyl acetate were added to the system to separate and extract,The organic layer was washed with saturated brine,Dried over sodium sulfate,The solvent was removed under reduced pressure,The residue was purified by silica gel column chromatography (eluent: ethyl acetate)To give the title compound,200 mg of white solid in 77% yield.
Stage #1: Monomethyl terephthalate; 2-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 2h;
Stage #2: With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide
5 5.1.4 6-((1-(4-((3,4-Dimethoxyphenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)pyrrolidin -3-yl)carbamoyl)nicotinic acid (10)
General procedure: A solution of compound 6 (0.21g, 0.58mmol) in DMF (5 mL) was added intermediate 8 (0.15g, 0.58mmol), DIPEA (0.20mL, 1.16mmol), HATU (0.21g, 1.16mmol). After stirring for 2h, EDCI (0.22g, 1.16mmol) and DMAP (0.14g, 1.16mmol) were added into the solution and the resulting mixture was stirred overnight. The solution was poured into water and extracted by EtOAc and the organic layer was washed by brine, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product 9 (0.22g, yield 63%) without further purification. Then compound 9 was dissolved in MeOH (20mL) followed by the addition of 10% Pd/C (0.001mmol). The mixture was stirred under the H2 atmosphere overnight. The catalyst was filtered off and the combined organic solution was concentrated under reduced pressure to afford target compound 10 (0.046g, yield 44%) as an off-white solid. 1H NMR (400MHz, DMSO) δ: 9.15 (s, 1H), 8.94 (s, 1H), 8.59 (s, 1H), 8.42 (s, 1H), 8.09 (s, 1H), 7.62 (s, 1H), 7.21 (s, 1H), 6.89 (s, 1H), 4.89 (s, 2H), 4.68 (s, 2H), 4.51 (s, 1H), 4.37 (s, 1H), 3.71 (s, 6H), 3.41 (d, J=20.6Hz, 2H), 2.87 (d, J=64.1Hz, 1H), 2.20 (s, 1H), 1.99 (s, 1H); HRMS (ESI) m/z calcd C25H27N6O6 [M+H]+ 507.1992, found 507.1992.
methyl 4-[(3,5-dimethyl-1,2-oxazol-4-yl)carbamoyl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
Example 45A Methyl 4-[(3,5-dimethyl-1,2-oxazol-4-yl)carbamoyl]benzoate 300 mg (1.67 mmol) of monomethyl terephthalate were dissolved in 3 ml of DMF, and 377 mg (1.97 mol) of EDC and 266 mg (1.97 mmol) of HOBT were added. The mixture was left to stir at RT for 20 min and then 170 mg (1.51 mmol) of 4-amino-3,5-dimethylisoxazole were added. The mixture was stirred at RT overnight. After dilution with water, the mixture was extracted three times with in each case 10 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 16]. This gave 342 mg (75% of theory) of the target compound. LC-MS [Method 8]: Rt=0.88 min; MS (ESI+): m/z=275 (M+H)+.
With aluminum (III) chloride; thionyl chloride; In dichloromethane; at 20℃; for 4h;Reflux;
120.0 g (0.666 mol) of terephthalic acid monomethyl ester,58.0 ml (0.799 mol) of thionyl chloride,Dichloromethane 1500 ml and 134.5 g (0.666 mol)Intermediate 4 was added to the reaction flask, stirred uniformly,Then, 239.6 g (1.798 mol) of aluminum trichloride was added,After stirring, the reaction was stirred at room temperature (20 C) for 1 hour.Then heated to reflux for 3 hours,The reaction solution was concentrated under reduced pressure and then cooled and slowly added with ice water to stir,Ethyl acetate was added to extract, the organic layer was separated, washed twice,Dried over anhydrous sodium sulfate.The organic layer was evaporated under reduced pressure and recrystallized from methanol.Dried to give a white crystalline powder, 231.0 g, melting point: 141-143 C, yield 95.3%
methyl 4-(quinolin-3-ylcarbamoyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With dmap; In dichloromethane; at 20℃; for 12h;
The title compound was obtained from <strong>[580-17-6]3-aminoquinoline</strong> (0.3 g, 2.04 mmol) and 4-dimethylaminopyridine (50 mg, 0.41 mmol) according to Method B of Procedure B (0.5 g, 80 %). H NMR (300 MHz, DMSO-cfe): delta 3.90 (s, 3H, OCH , 7.56-7.62 (m, 1Eta, ArH), 7.64- 7.71 (m, 1Eta, ArH), 7.95-8.00 (m, 2Eta, ArH), 8.10-8.18 (m, 4Eta, ArH), 8.85 (d, 1Eta, / = 2.1 Hz, ArH), 9.14 (d, 1Eta, / = 2.4 Hz, ArH), 10.89 (s, 1Eta, NH). Method B: A solution of aminoquinoline (1 equiv.), 4-dimethylaminopyridine, and monomethyl terephthalate or (£")-methyl 3-(4-formylphenyl)acrylate 1.2 equiv.) in DCM (0.1 M) was stirred at room temperature for 12 hours. Water was added to the solution and the crude reaction mixture was extracted with DCM. The collected organic layer was concentrated and purified via chromatography eluted with ethyl acetare and hexane to provide the desired product.
Stage #1: Monomethyl terephthalate With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.25h;
Stage #2: 1-Adamantanamine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide
Preparation of the 1 -adamantyl containing amide intermediate
Mono-methyl terephthalate (4.7 g, 26.1 mmol) and PyBOP (15 g, 28.9 mmol) were dissolved in DMF and stirred at room temperature. After 15 min, 1 - adamantylamine (4.0 g, 26.44) and DIPEA (3.8 g, 29.5 mmol) were added and stirring was continued overnight. The addition of water to the reaction mixture resulted in the formation of a white precipitate, which was filtered off, washed with copious amounts of water and dried to get the amide intermediate. Yield: 98%. 1H NMR: δ ppm (DMSO-d6) 1 .65 (6H, t, CH2), 2.07 (9H, m, 3xCH2 and 3xCH), 3.87 (1 H, s, CH3), 7.83 (1 H, s, NH), 7.87 (2H, d, J = 8.0 Hz, CH), 7.98 (2H, d, J = 8.0 Hz, CH).
98%
Stage #1: Monomethyl terephthalate With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.25h;
Stage #2: 1-Adamantanamine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;
Stage #1: methyl 4-acetylbenzoate With iodine; dimethyl sulfoxide In chlorobenzene at 130℃; for 3h;
Stage #2: With tert.-butylhydroperoxide In chlorobenzene at 20 - 130℃; for 3h;
23 Example 23: Preparation of p-methyl ester benzoic acid (formula (2-10))
Add 1 mmol of p-methyl ester acetophenone (formula (1-10)), 6 mmol of DMSO, 0.1 mmol of I2, 2 mL of chlorobenzene solvent to a 10 mL two-neck round bottom flask equipped with a magnetic stirrer.The reaction flask was then placed in an oil bath preheated to 130 ° C, and the magnetic stirrer was turned on for 3 h.The reaction flask was taken out, cooled to room temperature, 2 mmol of TBHP was added, and the reaction was continued at a temperature of 130 ° C for 3 hours.The reaction solution was quenched by the addition of water, and then the pH was adjusted to about 11 with a sodium hydroxide solution having a concentration of 0.1 mol/L, and the aqueous phase was taken and washed three times with diethyl ether.Then, the pH was adjusted to about 2 with a hydrochloric acid solution having a concentration of 0.1 mol/L, and then extracted three times with diethyl ether. The three ether extracts were combined, and the ether was evaporated under reduced pressure.The column chromatography was further carried out, and the eluate containing the target compound was collected by using a mixture of ethyl acetate/petroleum ether volume ratio of 1:25 as an eluent.Evaporation of the solvent gave the product to p-methyl ester benzoic acid with an isolated yield of 89%.
79%
With Iron(III) nitrate nonahydrate; iodine; oxygen In dimethyl sulfoxide at 130℃; for 12h; Sealed tube;
23 Example 23: Preparation of monomethyl terephthalate (formula (2-10))
Add 1 mmol of methyl p-acetylbenzoate (formula (1-10)), 0.1 mmol of I to a 25 mL glass tube equipped with a magnetic stir bar.2, 0.1 mmol of Fe (NO3)3·9H2O, 2mL of DMSO, replace the air in the glass tube with oxygen, seal the glass tube, then put the sealed glass tube into the oil bath preheated to 130 ° C, and turn on the magnetic stirrer, after 12h reaction, remove the sealing glass Tube, wait until it is cooled to room temperature, add water to the reaction solution to quench the reaction, then adjust the pH to about 11 with sodium hydroxide solution at a concentration of 0.1 mol / L, wash three times with ethyl acetate, the concentration of the aqueous phase is 0.1 mol /L hydrochloric acid solution to adjust the pH to about 2, and then extracted three times with diethyl ether, the three ether extracts were combined, the ether was evaporated under reduced pressure, and then separated by column chromatography to ethyl acetate / petroleum ether volume ratio 1 The mixture of 25 was used as an eluent, and the eluate containing the target compound was collected, and the solvent was evaporated to give the product monomethyl terephthalate, and the isolated yield was 79%.
Multi-step reaction with 2 steps
1: iodine; dimethyl sulfoxide / chlorobenzene / 120 °C
2: tert.-butylhydroperoxide / 6 h
With Iron(III) nitrate nonahydrate; iodine; oxygen; dimethyl sulfoxide at 130℃; for 12h; Sealed tube; Green chemistry;
Typical Procedure for the Synthesis of carboxylic acid (2a) from acetophenone (1a)
General procedure: To a 20-mL tube equipped with a magnetic stirring bar was added acetophenone 1a (120 mg, 1 mmol), 2 mL of DMSO, iodine (25 mg, 0.1 mmol) and Fe(NO3)3·9H2O (40 mg, 0.1 mmol). Then the tube was sealed after being charged with oxygen to replace the air in it. The tube was placed into a preheated oil bath (130°C), and the reaction solution was stirred for 12h. Then the reaction was quenched with water, and the pH of the aqueous phase was adjusted to 11 with 0.1 mol/L NaOH. After being washed with ethyl acetate (3 x 3 mL), the pH of the aqueous phase was adjusted to 2 with 0.1mol/L HCl and extracted with ether (3 x 6 mL). The combined ether phase was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography on silica gel using ethyl acetate/petroleum ether as eluent to afford 2a as a white solid (104 mg, 85% yield). 1H NMR(600 MHz, DMSO-d6) δ 12.88 (s, 1H), 7.95 (d, J = 7.9 Hz, 2H), 7.62-7.59 (m, 1H), 7.50-7.48 (m, 2H); 13C NMR (125MHz, DMSO-d6) δ 167.3, 132.7, 130.8, 129.2, 128.5.
With N-iodo-succinimide; [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate; iodine; caesium carbonate In 1,2-dichloro-ethane at 50℃; for 24h; Inert atmosphere; Irradiation; Sealed tube;
General procedure A.
General procedure: To a 15 mL test tube with septum Cs2CO3 (0.6 mmol, 195 mg), aromaticcarboxylic acid (1) (0.3 mmol), [Ir(dF(CF3)ppy)2dtbbpy]PF6 (D) (6 μmmol, 6.7 mg), NIS (1.5mmol, 337.5 mg) and I2 (60 μmol, 20 mol%) were added. The tube was evacuated and backfilledwith argon for three times, and then 3 mL of dry DCE was added through a syringer under argon.The tube was sealed with Parafilm Mr and placed in an oil bath with a contact thermometer, andthe reaction was carried out at 50 °C under irradiation with 6 × 5 W blue LEDs (λmax = 455 nm).After 24 h or 36 h, the resulting mixture was filtered through a 2 cm thick pad of silica, and thesilica was washed with DCM) (50 mL). The filtrate was collected and the solvent was removed invacuo. The crude residue was purified by silica gel flash column chromatography to provide thetarget product (2). (Note: The reaction was very sensitive to moisture, and the yields sharplydecreased to less than 5% when 0.01 equivalent of H2O was added to the reaction system).
63%
With tris-(dibenzylideneacetone)dipalladium(0); 1-iodo-butane; N,N,N',N'-tetramethyl-1,8-diaminonaphthalene; chloro-N,N,N',N'-bis(tetramethylene)formamidinium hexafluorophosphate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 120℃; for 16h; Sealed tube; Inert atmosphere;
With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide at 100℃; for 2h;
6.1.2. Preparation of 3-oxopropanenitrile derivatives 2a, b
General procedure: 6.1.2.1. General procedure. A three-necked, round bottomed flask(500-ml), equipped with a magnetic stirrer, thermometer, decanter and condenser was charged with the proper ester 1a or 1b (10g),acetonitrile (10 ml, 10 mmol), in dry THF and stirred well, then an equivalent weight of NaH and DMF were added then refluxed to100 °C for 2 h then left to cool, and filtered washed with petroleum ether. The formed salt was dissolve in ice-cold water and acidified HCl to afford the corresponding 3-oxo-propanenitrile derivatives 2a and 2b; respectively.
75%
With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide; benzene at 100℃; for 2h;
5.1.4. Synthesis of 4-(2-cyanoacetyl) benzoic acid (6)
A three-necked, round bottomed flask (500-ml), equipped witha magnetic stirrer, thermometer, decanter and condenser wascharged with the 4-(methoxycarbonyl)benzoic acid (6) (10 g),acetonitrile (10 ml, 10 mmol), in dry THF. The mixture was stirred well then an equivalent weight of NaH and DMF were added and the mixture was then heated to 100 °C for 2 h then left to cool. The formed solid was filtered off and washed with petroleum ether [1].The formed salt was dissolve in ice-cold water and then acidified HCl to afford the corresponding 4-(2-cyanoacetyl)benzoic acid (7)as white crystals (EtOH), m.p: 170-172 °C, yield: 75%, C10H7NO3 IR (KBr, cm-1) ν 3374 (OH), 2237 (C≡N), 1715 (C]O), 1689 (C]O); 1H NMR (DMSO-d6): 3.480 (s, 2H, H2C), 7.93-8.00 (d, 2H, HC),8.01-8.15 (d, 2H, HC), 12.30 (s, 1H, HOOC D2O exchangeable); 13C NMR (DMSO-d6): δ 29.77 (CH2), 129-130 (CH), 134 (CN), 135(CH),139 (CH), 165 (C]O), 170(C]O); MS (m/z): 149 (M+, 100.0%),189 (94.3%),179 (83.8%), 120 (70.4%); Anal calcd C10H7NO3 (189.17)C, 63.49; H, 3.73; N, 7.40%; Found C, 63.53%; H, 3.77%; N, 7.45%;
2-chloro-4-[(1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile[ No CAS ]
methyl 4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h;
80%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.5h;
80%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.5h;
2; 3 General Procedure for Synthesis of Compound 39.
DIPEA (5 eq.) and HATU (1.2 eq.) were added to a solution of compounds 87 (0498) (27.8 mg, 0.1 mmol) and 106 (1.1 eq.) in DMF (2 mL). After 30 min at rt, the mixture was subject to HPLC purification to afford compound 107 in 80% yield.
With N-ethyl-N,N-diisopropylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In N,N-dimethyl-formamide at 20℃; for 1h;
5.1 Step 1: Synthesis of methyl 4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)carbamoyl)benzoate.
4-((1r,3r)-3-Amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile and 4-(methoxycarbonyl)benzoic acid were dissolved in DMF. To the solution was added DIPEA (5 eq.) and HATU (1.2 eq.), and the reaction mixture was stirred at r.t. for 1 hour. The reaction mixture was extracted by EA, washed by water, and the organic phase was dried by Na2SO4. Methyl 4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)carbamoyl)benzoate was obtained by removing the solvent under vacuum and purifing by flash column chromatography on silica gel. ESI-MS: 440.15.
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h;
1.2 Step 2 Synthesis of methyl 4-(((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2, 2,4,4- tetramethylcyclobutyl)carbamoyl)benzoate.
4-((lr,3r)-3-Amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile and 4-(methoxycarbonyl)benzoic acid were dissolved in DMF. The solution was added DIPEA (5 eq.) and HATU (1.2 eq.), the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was extracted by EA, washed by water and organic phase was dried by Na2SC>4. Methyl 4-(((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2, 2,4,4-- Il l - tetramethylcyclobutyl)carbamoyl)benzoate was obtained by removing the solvent under vacuum and flash column chromatography on silica gel. ESI-MS: 440.15.
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h;
1.2 Step 2 Synthesis of methyl 4-(((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2, 2,4,4- tetramethylcyclobutyl)carbamoyl)benzoate.
4-((lr,3r)-3-Amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile and 4-(methoxycarbonyl)benzoic acid were dissolved in DMF. The solution was added DIPEA (5 eq.) and HATU (1.2 eq.), the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was extracted by EA, washed by water and organic phase was dried by Na2SC>4. Methyl 4-(((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2, 2,4,4-- Il l - tetramethylcyclobutyl)carbamoyl)benzoate was obtained by removing the solvent under vacuum and flash column chromatography on silica gel. ESI-MS: 440.15.
To a solution (15 ml) of monomethyl terephthalate B1 (5 mmol, 900.8 mg) in tetrahydrofuran, HATU (7.5 mmol, 2851.8 mg) and triethylamine (15 mmol, 1517.9 mg) were added.After the mixture was stirred at room temperature for 30 minutes, 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide A (5 mmol, 1338.7 mg) was further added.The mixture was continuously stirred at room temperature overnight, the solvent was distilled off under reduced pressure, and recrystallized from methanol to obtain 1827 mg (85%) of product C1.
Stage #1: Monomethyl terephthalate With dichlorotriphenylphosphorane In chloroform at 20℃; for 0.25h; Inert atmosphere;
Stage #2: 4-tert-Butylaniline In chloroform at 100℃; Inert atmosphere; Irradiation;
4.1.4 Synthetic procedure (c): Amide coupling using carboxylic acids I
General procedure: The appropriate carboxylic acid (1.2 equiv.) and dichlorotriphenylphosphorane (1.5-2.4 equiv.) were suspended in chloroform (0.1-0.2M) and stirred for 15minat RT before addition of the appropriate aniline (1.0 equiv.), and the mixture was irradiated at 100°C for 1-2h. Removal of the solvent in vacuo followed by column chromatography isolated the target compound.
N-(3-aminopropyl)methacrylamide hydrochloride[ No CAS ]
C16H20N2O4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79.6%
Stage #1: Monomethyl terephthalate With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.166667h;
Stage #2: N-(3-aminopropyl)methacrylamide hydrochloride With benzotriazol-1-ol; triethylamine for 5h;
N-(3-aminopropyl)methacrylamide hydrochloride
Mono-methyl terephthalate (2.16 g,12 mmol) and N,N′-dicyclohexylcarbodiimide (DCC, 2.67 g, 13 mmol)were dissolved in dichloromethane (DCM, 20 mL, anhydrous). Underconstant stirring, the solution was kept at room temperature for 10 min.N-(3-Aminopropyl) methacrylamide hydrochloride (1.78 g, 10 mmol),hydroxybenzotriazole (HOBt, 3.06 g, 20 mmol) and triethylamine(Et3N, 3.03 g, 30 mmol) were then added. After stirring for 5 h, thesolution was filtered, concentrated and purified by flash column chromatographyto yield the product (2.42 g, yield: 79.6%).1H NMR (500 MHz, CDCl3): δ (ppm)=8.08 (d, J=8.4 Hz, 2H),7.94 (d, J=8.4 Hz, 2H), 7.81 (t, J=6.0 Hz, 1H), 6.87 (s, 1H), 5.79 (s,1H), 5.37 (s, 1H), 3.94 (s, 3H), 3.50 (m, 2H), 3.41 (m, 2H), 2.00 (s, 3H),1.76 (m, 2H), .13C NMR (125 MHz, CDCl3): δ (ppm)=169.4, 166.9, 166.3, 139.6,138.2, 132.5, 129.7, 127.1, 120.1, 52.3, 36.1, 36.0, 29.6, 18.6.MS (ESI): m/z=327.1 (M+Na+), calculated: 304.1.
Methyl 1,2,3,4-tetraphenyl-6-naphthalenecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; 1,2,3,4-tetraphenylcyclopentadiene; copper diacetate In o-xylene at 160℃; for 3h; Inert atmosphere;
Decarboxylative Coupling of 1 with 2; General Procedure
General procedure: A mixture of benzoic acid 1 (0.38 mmol), alkyne 2 (0.5 mmol),[Rh(cod)Cl2]2 (2.5 mg, 0.005 mmol), C5H2Ph4 (7.4 mg, 0.02 mmol),Cu(OAc)2 (181.6 mg, 1.0 mmol) and 1-methylnaphthalene (ca. 50 mg)as an internal standard in o-xylene (2.5 mL) was stirred at 160 °C under Ar (1 atm) for 3-24 h. After the reaction was complete, the mixturewas diluted with dichloromethane (100 mL). The organic layerwas washed with water (2 × 100 mL) and brine (100 mL), and thendried over Na2SO4. After evaporation of the solvents under vacuum,products 3 (and 3′) were isolated by column chromatography on silicagel using hexane-ethyl acetate as eluent. Further purification by GPC(gel permeation chromatography) was performed, if needed.
N-4-methoxycarbonylbenzoyl-N’-picolinoylhydrazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: Monomethyl terephthalate With thionyl chloride In chloroform; N,N-dimethyl-formamide at 60℃; for 16h; Inert atmosphere;
Stage #2: picolinic acid hydrazide With triethylamine In chloroform at 60℃; for 16h;
N-4-acetoxybenzoyl-N’-picolinoylhydrazine (IIb) and N-4-methoxycarbonylbenzoyl-N’-picolinoylhydrazine (IIIa).
General procedure: A suspensionof Ib (5.0 g, 27.7 mmol) in 20 mL of CHCl3, 6 mL of SOCl2 and threedrops of DMF under nitrogen atmosphere dissolved rapidly when heatedto 60 C. Evaporation of the solution after 16 h of stirring under nitrogenyielded a white solid which was re-dissolved in 20 mL of CHCl3 and solidpicolinic hydrazide (3.8 g, 27.7 mmol) was added. A voluminous precipitatethat formed disappeared with dropwise addition of TEA (3.1 g,30.5 mmol) and the clear solution was heated to 60 C for 16 h. The solidproduct, which was obtained after evaporating CHCl3 was treated with100 mL of water and stirred for 4 h, and then was filtrated and washedseveral times with water. Recrystallization of the crude white powder inethyl acetate:acetone (1:1, v/v) yielded colourless elongated crystals ofIIb.The reaction yielding IIIa was performed analogically, using IIa (3.2g, 17.7 mmol) as a starting material. Recrystallization from toluene:MeOH (1:1, v/v) yielded colourless crystals of IIIa.
80%
Stage #1: Monomethyl terephthalate With thionyl chloride; N,N-dimethyl-formamide In chloroform at 60℃; for 16h; Inert atmosphere;
Stage #2: picolinic acid hydrazide With triethylamine In chloroform at 60℃; for 16h;
N-4-acetoxybenzoyl-N’-picolinoylhydrazine (IIb) and N-4-methoxycarbonylbenzoyl-N’-picolinoylhydrazine (IIIa).
General procedure: A suspensionof Ib (5.0 g, 27.7 mmol) in 20 mL of CHCl3, 6 mL of SOCl2 and threedrops of DMF under nitrogen atmosphere dissolved rapidly when heatedto 60 C. Evaporation of the solution after 16 h of stirring under nitrogenyielded a white solid which was re-dissolved in 20 mL of CHCl3 and solidpicolinic hydrazide (3.8 g, 27.7 mmol) was added. A voluminous precipitatethat formed disappeared with dropwise addition of TEA (3.1 g,30.5 mmol) and the clear solution was heated to 60 C for 16 h. The solidproduct, which was obtained after evaporating CHCl3 was treated with100 mL of water and stirred for 4 h, and then was filtrated and washedseveral times with water. Recrystallization of the crude white powder inethyl acetate:acetone (1:1, v/v) yielded colourless elongated crystals ofIIb.The reaction yielding IIIa was performed analogically, using IIa (3.2g, 17.7 mmol) as a starting material. Recrystallization from toluene:MeOH (1:1, v/v) yielded colourless crystals of IIIa.
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