* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With iodine; potassium carbonate In acetonitrile at 80℃; for 8 h; Inert atmosphere; Schlenk technique; Sealed tube
General procedure: Arylboronic acid 1 (0.5 mmol) and K2CO3 (1 mmol, 138.0mg) were added to a 20 mL Schlenk-tube equipped with amagnetic stir bar. The tube was evacuated twice and backfilledwith N2. MeCN (2 mL) and I2 (0.75 mmol, 191 mg)were added to the tube at r.t. under a stream of N2, and thetube was sealed and placed into a pre-heated oil bath at 80 °Cfor 8–12 h. The resulting solution was cooled to r.t. and H2O(10 mL) was added. The aq layer was extracted with EtOAc (3 × 5 mL). For products 2s and 2t, HCl (1 M) was added tothe aq solution until pH 2 before extraction. The combinedorganic phase was dried over anhydrous Na2SO4, filteredand concentrated by rotary evaporation. Purification of theresidue by column chromatography on silica gel providedthe desired product 2a–v
Reference：
[1] Synlett, 2014, vol. 25, # 7, p. 995 - 1000
[2] Chemistry - A European Journal, 2011, vol. 17, # 20, p. 5652 - 5660
4
[ 585-76-2 ]
[ 618-51-9 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; 1,1,1,3,3,3-hexamethyl-disilazane; sodium iodide In 1,4-dioxane at 110℃; for 23 h; Stage #2: With hydrogenchloride; water In 1,4-dioxane at 20℃;
A Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 molpercent), 3- bromobenzoic acid (210 mg, 1.00 mmol), NaI (300 mg, 2.00 mmol), evacuated and [BACKELLEDWITHARGON. TRANS-N, NAPOS;-DIMETHYL-1,] 2-cyclohexanediamine [(16) IL,] 0. 10mmol, 10 molpercent), 1,1, 1,3, 3,3-hexamethyldisilazane [(211, UL,] 1.00 mmol), and dioxane (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at [110 °C] for 23 h. The resulting suspension was allowed to reach room temperature, poured into 10percent aq HCl (20 mL), and extracted with dichloromethane [(3X 15] mL). The combined organic phases were dried [(NA2SO4)] and concentrated. The residue was dissolved in dichloromethane (50 mL) and washed with an aqueous solution of 1percent HCl and 1percent [NA2SO3.] The aqueous phase was extracted with with dichloromethane [(2X20] mL). The organic phases were combined, dried (Na2SO4) and concentrated. The solid residue was washed with hexane [(3X15 ML)] and dried to provide 3-iodobenzoic acid (222 mg, 90percent yield) as white, fine needles.
Reference：
[1] Patent: WO2004/13094, 2004, A2, . Location in patent: Page 44
[2] Chemical Communications, 2012, vol. 48, # 33, p. 3993 - 3995
[3] Russian Chemical Bulletin, 1995, vol. 44, # 6, p. 1050 - 1055[4] Izvestiya Akademi Nauk, Seriya Khimicheskaya, 1995, # 6, p. 1090 - 1095
5
[ 201230-82-2 ]
[ 626-00-6 ]
[ 618-51-9 ]
Yield
Reaction Conditions
Operation in experiment
84%
at 20℃; for 9 h;
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 (90percent); 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.
With ethanol In water at 85℃; for 30 h; Ionic liquid
General procedure: A mixture of nitrobenzene 1 (4 mmol), KCN (20,40 or 80 mmol), EtOH (5 or 7 ml), water (5 or 7 ml) and [bmim]BF4(7 mmol, 175 molpercent) was heated on the oil bath with stirring at 85 °C (seeTables 1 and 2). Then 10 ml of water was added and the mixture wasextracted with CH2Cl2 (3×10 ml) and diethyl ether (3×20 ml). The aqueouslayer was acidified with HCl to pH 1–2 and extracted with diethyl ether(3×20 ml). Magnesium sulfate (~5 g) and absorbent carbon (~1 g) wereadded to the ether layer and this was stirred for 5 h. The solid was filteredoff, the filtrate was evaporated and the residue was crystallized from thecorresponding solvent to give product 2.
With dipotassium peroxodisulfate; choline chloride; iodine In acetonitrile at 65℃; for 3 h;
General procedure: To a solution of aromatic compound (10 mmol) in acetonitrile (5 mL) in a 100 mL round-bottomed flask with a magnetic bar was added choline chloride(10 mmol), potassium peroxodisulfate (10 mmol) and iodine (15 mmol). The reaction mixture was stirred for the appropriate time at 65 °C. The progress of the reaction was monitored by TLC. The reaction mixture was poured into aqueous sodium thiosulfate solution (1 mol/L) in order to remove unreacted iodine and extracted with ethyl acetoacetate (10 mL, 3 times). Organic layer is dried over anhydrous sodium sulphate. Evaporation of the solvent under vacuum followed by column chromatography on silica gel gave the corresponding iodinated compounds (Scheme-I).
Reference：
[1] Bulletin of the Chemical Society of Japan, 2000, vol. 73, # 4, p. 951 - 956
[2] Molecules, 2005, vol. 10, # 10, p. 1307 - 1317
[3] Journal of Organic Chemistry, 2002, vol. 67, # 24, p. 8622 - 8624
[4] European Journal of Organic Chemistry, 2017, vol. 2017, # 22, p. 3234 - 3239
[5] Bulletin of the Chemical Society of Japan, 1999, vol. 72, # 1, p. 115 - 120
[6] Journal of Organic Chemistry, 1993, vol. 58, # 8, p. 2058 - 2060
[7] Bulletin of the Chemical Society of Japan, 1997, vol. 70, # 7, p. 1665 - 1669
[8] Molecules, 2004, vol. 9, # 7, p. 595 - 601
[9] Molecules, 2005, vol. 10, # 3, p. 671 - 675
[10] Synthesis, 2006, # 7, p. 1195 - 1199
[11] Synthesis, 2004, # 3, p. 441 - 445
[12] Synthetic Communications, 2003, vol. 33, # 8, p. 1319 - 1323
[13] Tetrahedron, 2004, vol. 60, # 41, p. 9113 - 9119
[14] Organic Preparations and Procedures International, 2002, vol. 34, # 6, p. 647 - 651
[15] Chinese Chemical Letters, 2012, vol. 23, # 3, p. 261 - 264
[16] Journal of Chemical Research, 2006, # 9, p. 575 - 576
[17] Russian Journal of Organic Chemistry, 2007, vol. 43, # 9, p. 1291 - 1296
[18] Molecules, 2005, vol. 10, # 2, p. 394 - 400
[19] Synthesis, 2008, # 5, p. 690 - 692
[20] Asian Journal of Chemistry, 2018, vol. 30, # 7, p. 1659 - 1663
[21] Synthesis, 1999, # 5, p. 748 - 750
[22] Synthesis, 2011, # 5, p. 739 - 744
[23] Tetrahedron Letters, 2000, vol. 41, # 47, p. 9101 - 9104
[24] Journal of applied chemistry of the USSR, 1984, vol. 57, # 1 pt 2, p. 121 - 123
[25] Russian Journal of Organic Chemistry, 1998, vol. 34, # 7, p. 997 - 999
[26] Russian Journal of Organic Chemistry, 2007, vol. 43, # 9, p. 1278 - 1281
[27] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, # 11, p. 2623 - 2624
[28] Journal of the Indian Chemical Society, 1930, vol. 7, p. 503
[29] Justus Liebigs Annalen der Chemie, 1865, vol. 136, p. 201
[30] Journal of the Chemical Society, 1950, p. 3694
[31] Zhurnal Obshchei Khimii, 1953, vol. 23, p. 1022; engl. Ausg. S. 1071
[32] Journal of the Chemical Society, 1952, p. 993,1000
[33] Journal of Organic Chemistry, 1959, vol. 24, p. 1818
[34] Journal of the American Chemical Society, 1919, vol. 41, p. 294
[35] Russian Journal of Organic Chemistry, 2008, vol. 44, # 6, p. 935 - 936
8
[ 99-05-8 ]
[ 618-51-9 ]
Reference：
[1] Chemistry - A European Journal, 2018, vol. 24, # 55, p. 14622 - 14626
[2] Justus Liebigs Annalen der Chemie, 1865, vol. 135, p. 108
[3] Journal fuer Praktische Chemie (Leipzig), 1878, vol. <2> 18, p. 326
[4] Justus Liebigs Annalen der Chemie, 1860, vol. 113, p. 335[5] Justus Liebigs Annalen der Chemie, 1861, vol. 117, p. 13,21
9
[ 625-95-6 ]
[ 618-51-9 ]
Reference：
[1] Synthetic Communications, 2010, vol. 40, # 19, p. 2922 - 2929
[2] Journal of Chemical Education, 1938, vol. 15, p. 217
[3] Journal of the Chinese Chemical Society (Peking), 1946, vol. 14, p. 24,29
10
[ 201230-82-2 ]
[ 626-00-6 ]
[ 121-91-5 ]
[ 618-51-9 ]
Reference：
[1] Journal of Organic Chemistry, 1999, vol. 64, # 18, p. 6921 - 6923
Reference：
[1] Chemistry - An Asian Journal, 2015, vol. 10, # 6, p. 1286 - 1290
36
[ 75-16-1 ]
[ 618-51-9 ]
[ 14452-30-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 1991, vol. 34, # 8, p. 2452 - 2463
37
[ 618-51-9 ]
[ 69113-59-3 ]
Reference：
[1] Patent: US4579848, 1986, A,
38
[ 67-56-1 ]
[ 618-51-9 ]
[ 618-91-7 ]
Yield
Reaction Conditions
Operation in experiment
97%
at 80℃; for 24 h;
3-lodobenzoic acid (50 g, 0.20 mol) was mixed with 300 mL methanol followed by the addition of 1 mL of concentrated sulfuric acid. The reaction was heated at 80 °C for 24 hours. During this process, the mixture of methanol and water was replaced by methanol twice. When the reaction appeared complete by TLC, the solvents were removed. The addition of 600 mL I feO and overnight stirring led to the formation of large amount of white precipitate. The product was readily isolated by filtration and washed by water to give a white solid (51.3 g, 97 percent). NM (300 MHz, C CI3): δ 8.34 (s, br, III), 7.97 (d, J= 7.5 I Iz, I H), 7.85 (d, J= 7.2 Hz, I H), 7.151 (td, J/ - 7.8 Hz, J2 = 2.7 Hz, I II), 3.89 (s, 311). GC-MS (m/z): [M'j calcd. for C8H7l02: 262.0, found: 262.0.
96.5%
for 24 h; Reflux
To a solution of 3-iodobenzoic acid (50.0 g, 0.202 mol) in methanol (300.0 ml) was added H2SO4 (1.0 ml). The reaction mixture was heated to reflux. After reflux 24 h, heating was stopped. The reaction mixture was cooled to room temperature. Water (400.0 ml) was added, the product was extracted with ethyl acetate (2 x 300.0 ml). The organic layer was washed with 20percent OfNaHCO3 water solution and followed with water. After removal of ethyl acetate, the crude product was purified by recrystallization from ethanol/water. Final white pure product was obtained in 51.0 g (96.5percent) after dry under vacuum. 1H NMR (400 MHz, CDCl3, δ): 8.35 (t, J = 1.6 Hz, 1 H), 7.97 (dt, Ji = 8.4 Hz, J2 = 1.6 Hz, 1 H), 7.85 (dt, Jl = 8.4 Hz, J2 = 1.6 Hz, 1 H), 7.14 (t, J = 8.4 Hz, 1 H), 3.89 (s, 3 H, OCH3). 13C NMR (100 MHz, CDCl3, δ): 165.56, 141.70, 138.42, 131.93, 130.03, 128.70, 93.76, 52.38.
96%
for 21 h; Reflux
3-iodobenzoic acid (103) and (3.00 g) was dissolved in methanol (60 mL), concentrated sulfuric acid (2 mL) was added and refluxed for 21 hours. The reaction mixture was concentrated, the residue was dissolved in ethyl acetate (100 mL), the organic layer was washed with water (100 mL), saturated aqueous sodium hydrogen carbonate solution (100 mL), saturated brine (100 mL), sulfuric anhydride dried with sodium, and filtered. The filtrate was concentrated under reduced pressure to give 3-iodo-benzoic acid methyl ester (104) and (3.04 g, 96percent yield) as a pale yellow solid.
93%
at 0 - 20℃; for 16 h;
117A: Methyl 3-iodobenzoate; 3-iodobenzoic acid (7.44 g, 30 mmol) was suspended in dry MeOH (40 mL) under nitrogen at 0° C. SOCl2 (3.3 mL) was added over 5 minutes. Stirring continued at room temperature for 16 hours, after which the reaction mixture was concentrated. The residue was dissolved in EtOAc and was washed twice with NaHCO3 (conc.). The organic solution was dried over MgSO4, filtered and concentrated to yield a white crystalline solid (7.32 g, 93percent). NMR 1H (ppm, CDCl3): 8.36 (t, J4=1.6 Hz, 1H), 7.98 (d, J3=7.8 Hz, 1H), 7.86 (d, J3=7.9 Hz, 1H), 7.16 (t, J3=7.8 Hz, 1H), 3.90 (s, 3H).
78.4%
at 80℃; for 18 h;
Example 3: Synthesis of 3-trimethylstannyl-benzoic acid 2,5-dioxo- pryolidin-1-yl ester3d) Methyl 3-lodobenzoate (2)One drop of dimethylformamide was added to a stirring suspension of 3- iodobenzoic acid (1.Og, 4.03 mmol), in thionyl chloride (20 ml). The mixture was then heated at 800C for 18 hours. After cooling to ambient temperature, the solvent was completely evaporated, then methanol (20 ml) was slowly added and the mixture stirred at ambient temperature for 30 minutes. Evaporation of methanol afforded the crude product as oil which solidified on standing at ambient temperature. The crude product was purified by flash chromatography using ethyl acetate/ hexane (1 :1) and the pure product was obtained as slightly yellow crystals (824 mg, 78.4percent).1H NMR (500 MHz, CDCI3, .pound.3.95 (s, 3H, CH3), 7.20 (t, 1 H), 7.9 (d, 1 H), 8.0 (d, 1 H), 8.20 (s, 1 H)
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 7, p. 3197 - 3214
[2] Patent: WO2014/11477, 2014, A1, . Location in patent: Page/Page column 29; 30
[3] Patent: WO2010/149620, 2010, A1, . Location in patent: Page/Page column 45
[4] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 9562 - 9575
[5] Patent: JP5725475, 2015, B2, . Location in patent: Paragraph 0028; 0029
[6] Synthetic Communications, 2010, vol. 40, # 23, p. 3561 - 3568
[7] Patent: US2008/153802, 2008, A1, . Location in patent: Page/Page column 105
[8] Organic and Biomolecular Chemistry, 2008, vol. 6, # 19, p. 3497 - 3507
[9] Journal of Organic Chemistry, 2005, vol. 70, # 11, p. 4314 - 4317
[10] Patent: WO2010/86398, 2010, A1, . Location in patent: Page/Page column 25
[11] Chemical Communications, 2010, vol. 46, # 20, p. 3457 - 3459
[12] Zeitschrift fuer Physikalische Chemie, Stoechiometrie und Verwandtschaftslehre, 1897, vol. 24, p. 221
[13] Zeitschrift fuer Physikalische Chemie, Stoechiometrie und Verwandtschaftslehre, 1897, vol. 24, p. 221
[14] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 6, p. 3091 - 3107
[15] Synlett, 2016, vol. 27, # 1, p. 25 - 28
39
[ 618-51-9 ]
[ 618-91-7 ]
Yield
Reaction Conditions
Operation in experiment
100%
With chloro-trimethyl-silane In methanol
8(a) Methyl 3-iodobenzoate 3-Iodobenzoic acid (10.0 g, 40.3 mmol) was placed in dry methanol (50 mL) under an argon atmosphere and was treated with chlorotrimethylsilane (15.4 mL, 0.12 mol). After heating at 65° C. for 4 h, the mixture was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate (100 mL) and water, the organic phase was washed twice with water, was dried (Na2 SO4) and was evaporated to provide the titled compound as a white solid (10.6 g, 100percent).
Reference：
[1] Patent: US6037367, 2000, A,
[2] Journal of the Chinese Chemical Society (Peking), 1946, vol. 14, p. 24,29
40
[ 3240-34-4 ]
[ 618-51-9 ]
[ 618-91-7 ]
Reference：
[1] European Journal of Organic Chemistry, 2014, vol. 2014, # 10, p. 2027 - 2031
41
[ 186581-53-3 ]
[ 618-51-9 ]
[ 618-91-7 ]
Reference：
[1] Magnetic Resonance in Chemistry, 1989, vol. 27, # 6, p. 585 - 591
42
[ 64-17-5 ]
[ 618-51-9 ]
[ 58313-23-8 ]
Yield
Reaction Conditions
Operation in experiment
83%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃;
To a 250 mL round-bottom flask in a 0 °C ice bath was added 3-iodobenzoic acid (10 g, 40 mmol), EDCI (8.5 g, 44 mmol), DCM (80 mL) and allowed to stir for 10 min. To the stirred solution was added DMAP (500 mg, 4 mmol), ethanol (2.9 mL) and allowed to stir overnight. Disappearance of SM was monitored by HPLC and TLC. Reaction mixture was diluted with 1 N HCI, extracted with EtOAc, dried with magnesium sulfate, and concentrated in vacuo. Required column chromotography (10: 1 Hex/EtOAc) to isolate product.
83%
Stage #1: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 0.166667 h;
To a 250 mL round-bottom flask in a 0 °C ice bath was added 3-iodobenzoic acid (10 g, 40 mmol), EDCI (8.5 g, 44 mmol), DCM (80 mL) and allowed to stir for 10 min. To the stirred solution was added DMAP (500 mg, 4 mmol), ethanol (2.9 mL) and allowed to stir overnight. Disappearance of SM was monitored by HPLC and TLC. Reaction mixture was diluted with 1 N HCI, extracted with EtOAc, dried with magnisium sulfate, and concentrated in vacuo. Required column chromotography (10: 1 Hex/EtOAc) to isolate product.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 9, p. 2229 - 2241
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 24, p. 5937 - 5944
[3] Organic Letters, 2009, vol. 11, # 5, p. 1079 - 1082
[4] Patent: WO2005/70407, 2005, A1, . Location in patent: Page/Page column 201
[5] Patent: WO2005/87215, 2005, A1, . Location in patent: Page/Page column 231
[6] Justus Liebigs Annalen der Chemie, 1865, vol. 135, p. 108
[7] Phosphorus, Sulfur and Silicon and the Related Elements, 2006, vol. 181, # 9, p. 2079 - 2087
[8] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 6014 - 6024
[9] RSC Advances, 2018, vol. 8, # 12, p. 6306 - 6314
43
[ 618-51-9 ]
[ 58313-23-8 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 16, p. 1927 - 1934
With 1-hydroxy-pyrrolidine-2,5-dione; oxygen; nitric acid; at 90℃; under 1500.15 - 6000.6 Torr; for 30h;Autoclave; Green chemistry;
The m-iodotoluene (5.00 g, 22.94 mmol), 30% by mass of dilute nitric acid 12.05 g (57 mmol) and the catalyst N-hydroxysuccinimide (0.26 g, 2.26 mmol) were placed in a 100 mL autoclave, using 0.2 MPa oxygen replacement tank air 3 times, filled with oxygen pressure to 0.8MPa, turn on the stirring, warm up to 90 C, stir the reaction for 30h to stop heating (reaction processOnce the medium pressure is reduced, the oxygen is added to 0.8 MPa in time, cooling, suction filtration, the filter cake is rinsed with water to neutral, and dried to obtain a solid 5.18 g, the purity of the product is 92.65%, and the yield of the product is 84.37%. . The solid product was analyzed by liquid chromatography-mass spectrometry indicating that the product obtained was m-iodobenzoic acid.
3-lodobenzoic acid (50 g, 0.20 mol) was mixed with 300 mL methanol followed by the addition of 1 mL of concentrated sulfuric acid. The reaction was heated at 80 °C for 24 hours. During this process, the mixture of methanol and water was replaced by methanol twice. When the reaction appeared complete by TLC, the solvents were removed. The addition of 600 mL I feO and overnight stirring led to the formation of large amount of white precipitate. The product was readily isolated by filtration and washed by water to give a white solid (51.3 g, 97 percent). NM (300 MHz, C CI3): delta 8.34 (s, br, III), 7.97 (d, J= 7.5 I Iz, I H), 7.85 (d, J= 7.2 Hz, I H), 7.151 (td, J/ - 7.8 Hz, J2 = 2.7 Hz, I II), 3.89 (s, 311). GC-MS (m/z): [M'j calcd. for C8H7l02: 262.0, found: 262.0.
96.5%
sulfuric acid; for 24h;Reflux;
To a solution of 3-iodobenzoic acid (50.0 g, 0.202 mol) in methanol (300.0 ml) was added H2SO4 (1.0 ml). The reaction mixture was heated to reflux. After reflux 24 h, heating was stopped. The reaction mixture was cooled to room temperature. Water (400.0 ml) was added, the product was extracted with ethyl acetate (2 x 300.0 ml). The organic layer was washed with 20percent OfNaHCO3 water solution and followed with water. After removal of ethyl acetate, the crude product was purified by recrystallization from ethanol/water. Final white pure product was obtained in 51.0 g (96.5percent) after dry under vacuum. 1H NMR (400 MHz, CDCl3, delta): 8.35 (t, J = 1.6 Hz, 1 H), 7.97 (dt, Ji = 8.4 Hz, J2 = 1.6 Hz, 1 H), 7.85 (dt, Jl = 8.4 Hz, J2 = 1.6 Hz, 1 H), 7.14 (t, J = 8.4 Hz, 1 H), 3.89 (s, 3 H, OCH3). 13C NMR (100 MHz, CDCl3, delta): 165.56, 141.70, 138.42, 131.93, 130.03, 128.70, 93.76, 52.38.
96%
With sulfuric acid; for 21h;Reflux;
3-iodobenzoic acid (103) and (3.00 g) was dissolved in methanol (60 mL), concentrated sulfuric acid (2 mL) was added and refluxed for 21 hours. The reaction mixture was concentrated, the residue was dissolved in ethyl acetate (100 mL), the organic layer was washed with water (100 mL), saturated aqueous sodium hydrogen carbonate solution (100 mL), saturated brine (100 mL), sulfuric anhydride dried with sodium, and filtered. The filtrate was concentrated under reduced pressure to give 3-iodo-benzoic acid methyl ester (104) and (3.04 g, 96percent yield) as a pale yellow solid.
93%
With thionyl chloride; at 0 - 20℃; for 16h;
117A: Methyl 3-iodobenzoate; 3-iodobenzoic acid (7.44 g, 30 mmol) was suspended in dry MeOH (40 mL) under nitrogen at 0° C. SOCl2 (3.3 mL) was added over 5 minutes. Stirring continued at room temperature for 16 hours, after which the reaction mixture was concentrated. The residue was dissolved in EtOAc and was washed twice with NaHCO3 (conc.). The organic solution was dried over MgSO4, filtered and concentrated to yield a white crystalline solid (7.32 g, 93percent). NMR 1H (ppm, CDCl3): 8.36 (t, J4=1.6 Hz, 1H), 7.98 (d, J3=7.8 Hz, 1H), 7.86 (d, J3=7.9 Hz, 1H), 7.16 (t, J3=7.8 Hz, 1H), 3.90 (s, 3H).
78.4%
With thionyl chloride; N,N-dimethyl-formamide; at 80℃; for 18h;
Example 3: Synthesis of 3-trimethylstannyl-benzoic acid 2,5-dioxo- pryolidin-1-yl ester3d) Methyl 3-lodobenzoate (2)One drop of dimethylformamide was added to a stirring suspension of 3- iodobenzoic acid (1.Og, 4.03 mmol), in thionyl chloride (20 ml). The mixture was then heated at 800C for 18 hours. After cooling to ambient temperature, the solvent was completely evaporated, then methanol (20 ml) was slowly added and the mixture stirred at ambient temperature for 30 minutes. Evaporation of methanol afforded the crude product as oil which solidified on standing at ambient temperature. The crude product was purified by flash chromatography using ethyl acetate/ hexane (1 :1) and the pure product was obtained as slightly yellow crystals (824 mg, 78.4percent).1H NMR (500 MHz, CDCI3, .pound.3.95 (s, 3H, CH3), 7.20 (t, 1 H), 7.9 (d, 1 H), 8.0 (d, 1 H), 8.20 (s, 1 H)
With sulfuric acid; at 60℃;Inert atmosphere;
General procedure: Conc. H2SO4 (0.55 mL/mmol benzoic acid) was added cautiously to the appropriate benzoic acid (1.0 eq.), dissolved in methanol (0.18 M). under a N2 atmosphere. Reaction was heated to 60°C overnight before being cooled to room temperature and diluted with Et2O and washed with water (2x). Organic layer was further washed with aq. NaHCO3 (sat.) and brine, dried over MgSO4, filtered and solvents removed in vacuo. Further purification was not necessary unless otherwise specified.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0℃;
To a 250 mL round-bottom flask in a 0 C ice bath was added 3-iodobenzoic acid (10 g, 40 mmol), EDCI (8.5 g, 44 mmol), DCM (80 mL) and allowed to stir for 10 min. To the stirred solution was added DMAP (500 mg, 4 mmol), ethanol (2.9 mL) and allowed to stir overnight. Disappearance of SM was monitored by HPLC and TLC. Reaction mixture was diluted with 1 N HCI, extracted with EtOAc, dried with magnesium sulfate, and concentrated in vacuo. Required column chromotography (10: 1 Hex/EtOAc) to isolate product.
83%
To a 250 mL round-bottom flask in a 0 C ice bath was added 3-iodobenzoic acid (10 g, 40 mmol), EDCI (8.5 g, 44 mmol), DCM (80 mL) and allowed to stir for 10 min. To the stirred solution was added DMAP (500 mg, 4 mmol), ethanol (2.9 mL) and allowed to stir overnight. Disappearance of SM was monitored by HPLC and TLC. Reaction mixture was diluted with 1 N HCI, extracted with EtOAc, dried with magnisium sulfate, and concentrated in vacuo. Required column chromotography (10: 1 Hex/EtOAc) to isolate product.
With sulfuric acid; In water; for 6h;Reflux;
General procedure: Hydrazides (30-58) were synthesized by one pot conventionalmethod24 Benzoic acid or its derivative (10 mmol) was dissolvedin ethanol (20 mL). Sulfuric acid (3 N, 2 mL) was added and thereaction contents were refluxed for six hours. The reaction wasmonitored with TLC. After the completion of the reaction, the reactionmixture was neutralized by adding solid NaHCO3, and filteredto remove excess of NaHCO3. In the neutralized reaction mixture which contains ethyl ester, hydrazine monohydrate (1.5 mL,3 mmol) was added and refluxed for 3-6 h to complete the reaction.Ethanol and unreacted hydrazine were removed by distillationupto 1/3 volume. The reaction contents were cooled, filteredand recrystallized from methanol to obtain the desired hydrazidecrystals (see Supporting information).
[9831 Step 1: Synthesis of 3-iodobenzoyl chloride[9841 3-iodobenzoic acid (0.200 g, 0.806 mmol) was dissolved in 50C12(1.170 mL, 16. 128 mmol) and stirred at 100 C for 2 hours, and the reaction mixture was concentrated under reduced pressure. The obtained product was used without additional purification (0.215 g, 100.0 %, brown oil).
In thionyl chloride; toluene;
a) 2.21 g (0.00891 mol) of 3-iodobenzoic acid were dissolved in 25 ml of thionyl chloride under argon and boiled under reflux for 2 hrs. The excess thionyl chloride was distilled off and the residue was taken up twice with 50 ml of toluene and concentrated each time. 1.6 g (67%) of 3-iodobenzoyl chloride were obtained as a yellow solid.
In thionyl chloride;
A stirred suspension of 3-iodobenzoic acid (8.84 g) in thionyl chloride (44 mL) is heated at reflux for 30 minutes. The dark brown solution is evaporated to give 3-iodobenzoyl chloride (9.8 g) as a brown oil.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; for 18h;
To a suspension of m-iodobenzoic acid (21, [5.] 0g, 20.1 mmol) suspended in [CH2CL2] (60 mL) was added DMF (2 drops), followed by oxalyl chloride (20.1 [ML] of a 2 M solution in [CHZCLZ,] 40.2 mmol) under nitrogen atmosphere. After stirring for [18] h, the reaction mixture was nearly homogeneous. Acid chloride 22 was then concentrated, azeotroped with toluene (2 x 25 mL), and placed on a high vacuum.
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h;
Methyl 3alpha-acetoxy-6alpha-ethyl-7alpha-(3'-iodobenzoyl)oxy-5beta-cholan-24-oate (4); <strong>[618-51-9]3-Iodobenzoic acid</strong> (3.93 g, 15. mmol) was suspended in CH2Cl2 (30ml) and treated with oxalyl chloride (3.21 ml, 36.1 mmol) in the presence of 2 drops of DMF at room temperature until the mixture become dissolved (about 1 h). Volatiles were removed under reduced pressure and the acylc chloride thus obtained was dissolved in 150 ml of toluene and was added to a stirred solution of 3 (4.2 g, 8.82mmol) in toluene (150 ml). To the above solution, CaH2 (2.66 g, 63.5 mmol) and BnEt3N+Cl- (0.5 g, 2.2 mmol) were added, and the mixture was refluxed for 48 h. The reaction mixture was then cooled to room temperature, the solvent was evaporated under reduced pressure, the residue was suspended in CHCl3 (200 ml) and filtered. The organic filtrate was washed with a saturated solution of sodium bicarbonate (2x100 ml), water (100 ml), brine (100 ml), dried over anhydrous sodium sulphate and evaporated to dryness. The residue was purified by flash chromatography using from 5 to 10% of EtOAc in petroleum ether to yield 3.54 g (5.01 mmol, 57%) of 4 and 1.23g (2.58 mmol) of unreacted started material (conversion yield 80%).1H-NMR (CDCl3) delta: 0.67 (3H, s, 18-CH3), 0.88-0.92 (6Eta, m, 21-CH3, 26-CH3), 1.13-1.32 (15Eta, m), 1.7-1.74 (5H, m), 1.89-1.91 (5H, m), 2.05 (3H, s, 3-CHOC(O)CH3), 2.18-2.30 (2Eta, m), 3.63 (3H, s, COOCH3), 4.60-4.62 (1Eta, m, 3-CEta), 5.41 (1Eta, bs, 7-CEta), 7.23 (1Eta, dd, Jl = 6.5Etaz, J2= 6.7 Hz, 5'-H ), 7.94 (IH, d, J= 6.7 Hz, 4'-H), 8.04 (IH, d, J= 6.5 Hz, 6'-H); 8.37 (IH, s, 2'-H). 13C-NMR (CDCl3) delta: 11.6, 11.7, 18.2, 20.7, 21.7, 22.2, 23.1, 23.9, 26.8, 27.9, 29.6, 30.8 (x2), 34.4, 35.1 (2x), 35.5, 39.2, 39.3, 41.3, 42.9, 44.6, 50.6, 51.4, 55.3, 74.2, 74.5, 93.9, 128.9, 130.1, 132.4, 138.6, 141.6, 164.5, 170.3, 174.6.
8(a) Methyl 3-iodobenzoate 3-Iodobenzoic acid (10.0 g, 40.3 mmol) was placed in dry methanol (50 mL) under an argon atmosphere and was treated with chlorotrimethylsilane (15.4 mL, 0.12 mol). After heating at 65° C. for 4 h, the mixture was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate (100 mL) and water, the organic phase was washed twice with water, was dried (Na2 SO4) and was evaporated to provide the titled compound as a white solid (10.6 g, 100percent).
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃; for 24h;Inert atmosphere;
To a 100 ml Rb flask was added <strong>[618-51-9]3-Iodobenzoic acid</strong> (1.93g, 7.8 mmol), NHS (1g, 8.6 mmol, 1.1 eqv), DCC (1.79 g, 8.6 mmol, 1.1 eqv) in 20 mL dry THF and contents stirred overnight. The white suspension seen was filtered and the clear filterate was evaporated on a rotavapor at 40C. The white solid seen was purified by column chromatography using EtOAc/hexanes as the eluent. Yield = 2.5g, 92%. 1H-NMR delta: : 8.54 (s, 1H), 8.2 (d, 1H), 8.12 (d, 1H), 7.43 (t, 1H), 2.9 (s, 4H).
74%
With dicyclohexyl-carbodiimide; In acetonitrile; at 0 - 20℃; for 5h;
SIB-c(RGDfK) (5) and SBrBc(RGDfK) (7) were prepared by conjugation of c(RGDfK)peptide with N-succinimidyl 3-iodobenzoate (SIB) or N-succinimidyl3-bromobenzoate (SBrB).SIB was synthesized according to a previous report witha slight modification.26) Namely, 3-iodobenzoic acid (719 mg,2.90 mmol) was dissolved in 10 mL of acetonitrile. NHydroxysuccinimide(NHS) (401 mg, 3.48 mmol) was addedto the solution, and 50 mL of acetonitrile containing N,N-dicyclohexylcarbodiimide (DCC) (718 mg, 3.48 mmol) wasadded dropwise at 0C. The reaction mixture was stirred atroom temperature for 5 h. After filtration, the solvent in filtratewas removed in vacuo. The residue was purified by chromatographyon silica gel using ethyl acetate-hexane (1 : 2) as theeluent to obtain SIB (742 mg, 74%) as a white solid. 1H-NMR(CDCl3) delta: 2.92 (4H, s), 7.27 (1H, t, J=8.0 Hz), 8.01 (1H, d,J=7.6 Hz), 8.11 (1H, d, J=7.6 Hz), 8.47 (1H, s).SBrB (68 mg, 76%) was obtained as a white solid from3-bromobenzoic acid (60 mg, 300 mumol) as a starting materialinstead of 3-iodobenzoic acid in the above-mentioned method.1H-NMR (CDCl3) delta: 2.92 (4H, s), 7.41 (1H, t, J=8.0 Hz), 7.81(1H, d, J=8.0 Hz), 8.07 (1H, d, J=7.6 Hz), 8.28 (1H, s).SIB (5.4 mg, 16.0 mumol) and c(RGDfK) (2.7 mg, 4.5 mumol) were dissolved in 400 muL of DMF, then 1 muL of triethylamine(TEA). The mixture was shaken for 3 h and purified by RPHPLCon Cosmosil 5C18-AR-300 (10×150 mm) at a flow rateof 4 mL/min, the gradient mobile phase was 40% methanolin water with 0.1% TFA to 90% methanol in water with 0.1%TFA for 20 min. Chromatograms were obtained by monitoringthe UV absorption at a wavelength of 220 nm. The fractionscontaining SIB-c(RGDfK) (5) was determined by massspectrometry, and collected. The solvent was removed bylyophilization to provide SIB-c(RGDfK) (5) as a white powder(2.2 mg, 59%). ESI-MS m/z: 834 ([M+H]+)SBrB (4.7 mg, 16.0 mumol) and c(RGDfK) (2.4 mg, 4.0 mumol)were reacted and purified at the above-mentioned method toobtain SBrB-c(RGDfK) (7) (1.1 mg, 35%) as a white powder.
29%
With dicyclohexyl-carbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 6h;
Example 2: Synthesis of <strong>[618-51-9]3-iodo-benzoic acid</strong> N'-pyridin-2-yl-hvdrazide2(i) Reaction carried out with 127I<strong>[618-51-9]3-iodo-benzoic acid</strong> 2,5-dioxo-pyrrolidin-1-yl ester was prepared by reaction of 3-iodo benzoic acid (1g, 4mmol), N-hydroxysuccinimide (464mg, 4mmol) and dicyclohexylcarbodiimide (DCC) (4mls of a 1 M solution in dichloromethane, 4mmol). The reaction mixture was stirred at room temperature for 6 hours in 10ml DMF The resulting white precipitate was filtered and discarded and the resulting filtrate reduced in vacuo and purified by column chromatography giving a 29% yield.
With bis(1,1'-ethylene-3,3'-divinylimidazole-2,2'-diylidene)nickel(II) dibromide dihydrate; potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 8h;Inert atmosphere; Schlenk technique;
General procedure: The typical procedure is as follows. Oven dried Schlenk tube was equipped with stirrer bar, was charged with aryl halides (1 mmol), aryl phenylboronic acid (1.2 mmol), K2CO3 (2 mmol) and catalyst2 (3 mol %) in1:1 mixture of DMF/H2O medium. The reaction mixture was stirred in an oil bath at 100C in the presence of air. After completion of the reaction, the reaction mixture was then cooled to room temperature and diluted with Et2O/H2O (1:1, 20 mL). The organic layer was alienated and dried with anhydrous MgSO4. The product was filtered and dried under vacuum. The resulting crude compound was purified by column chromatography on silica gel to afford the corresponding products.
89%
With potassium carbonate; In ethanol; water; for 4h;Reflux;
General procedure: A solution of phenylboronic acid (11 mmol), aryl iodide (10 mmol) and K2CO3 (20 mmol) in EtOH (30 mL, EtOH: H2O = 2: 1) was treated with Ni(0)-AOFs (6 mol%) at room temperature. After the mixture was stirred and refluxed for 4 h, the catalyst was separated by filtration, washed with hot ethanol and distilled water, and dried at room temperature, and reused in a next cycle. The filtrate was cooled, and products were precipitated as white scaly crystals. The the solid product was filtered, dried, and recrystallised from EtOH-H2O to afford the pure product.
P-LODO-BENZOIC acid (4.96 g, 20 MMOL), phenyl boronic acid (2. 68 g, 22 MMOL), NA2CO3 (6.36 g, 60 MMOL) and Pd (OAc) 2 (44 mg) were dissolved in 80 mi water and heated to 50C for 1 hour. Filtered and washed EtOAc, then acidified with 1 M HCI and extracted into EtOAc, dried with NA2SO4, evaporated and recrystallised from EtOAc and heptane to yield 3.9 g of meta-phenyl benzoic acid as a white solid. 2- (3-Biphenyl-3-yl-ureido)-4-chloro-benzoic acid was then prepared according to method E (m. p. 181-183C).
With triethylamine;palladium diacetate; In N,N-dimethyl-formamide; at 140℃; for 3h;
A solution of 3-iodobenzoic acid (20.2 g, 81.4 mmol), ethyl acrylate (9.0 g, 90.2 mmol), triethylamine (24 mL) and palladium acetate (92 mg, 0.41 mmol) in DMF (130 mL) was stirred at 140C for 3 hr. The reaction mixture was cooled to room temperature, partitioned between ethyl acetate and 1N hydrochloric acid, and the ethyl acetate layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 50: 50 - 0: 100) to give the title compound (18.7 g, quant.) as an orange solid. 1H NMR (300 MHz, CDCl3) delta 8.35-8.23 (m, 1H), 8.19-8.09 (m, 1H), 7.71 (d, J=16.0Hz, 1H), 7.79-7.69 (m, 1H), 7.52 (t, J=7.7Hz, 1H), 6.54 (d, J=16.0Hz, 1H), 4.29 (q, J=7.2Hz, 2H), 1.36 (t, J=7.2Hz, 3H).
18.7 g
With palladium diacetate; triethylamine; In N,N-dimethyl-formamide; at 140℃; for 3h;Inert atmosphere;
A) (E)-3-(3-ethoxy-3-oxoprop-1-en-1-yl)benzoic acid Under an argon atmosphere, to a solution of 3-iodobenzoic acid (20.2 g) in DMF (130 mL) were added ethyl acrylate (9.00 g), triethylamine (24 mL) and palladium (II) acetate (92 mg), and the mixture was stirred at 140C for 3 hr. The reaction mixture was cooled to room temperature, and 1N hydrochloric acid was added. The reaction mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (18.7 g) as an orange amorphous solid. 1H NMR (300 MHz, CDCl3) delta 1.36 (3H, t, J = 7.2 Hz), 4.29 (2H, q, J = 7.2 Hz), 6.54 (1H, d, J = 16.0 Hz), 7.52 (1H, t, J = 7.7 Hz), 7.69-7.79 (1H, m), 7.71 (1H, d, J = 16.0 Hz), 8.09-8.19 (1H, m), 8.23-8.35 (1H, m).
With potassium carbonate; ethylene glycol;copper(l) iodide; In isopropyl alcohol; at 80℃; for 24h;
Cu [(I)] iodide (10 mg, 0.05 mmol), potassium carbonate (414 mg, 3.0 mmol) and 3- iodobenzoic acid (248 mg, 1.0 mmol) were charged into a screw-capped test tube with Teflon-lining. The tube was evacuated and backfilled with argon (3 cycles). 2-Propanol (1.0 mL, bench grade solvent without degassing and pre-drying), ethylene glycol (111 [U. L,] 2.0 mmol, bench grade solvent) and <strong>[696-63-9]4-methoxythiophenol</strong> [(123] [UL,] 1.0 mmol) were added by syringes at room temperature. The tube was heated to 80 [C] and stirred for 24 hours. The reaction mixture was then allowed to reach room temperature. Ethyl acetate (-5 mL), water (-10 [ML)] and dil. [HC1] were added to reach pH 3-4. The reaction mixture was extracted with ethyl acetate (2 x 10 mL) and [CH2C12] [(2 X 10 ML). THE] combined organic phase was passed through a short pad of silica (0.5 cm diameter x 1 cm height). Solvent was removed and the yellow residue was redissolved in minimum amount [OF CH2C12.] Hexane was added slowly and the solution was stand overnight at room temperature. White crystal was obtained as the titled product (221 mg, 85% yield). Rf= 0.2 (hexane/ethyl acetate = 2/1) (Note: same Rf value as the starting material). Melting point; 121-123 [C. LH] NMR [(CDC13,] 300 MHz) 8 10.68 (brs, 1 H), 7. 86 (s, 1 H), 7. 82 (dt, 1 H, [J=] 1. [8] Hz, 6.6 Hz), 7.42 (dt, 2 H, J= 2.1 Hz, 8.7 Hz), 7.28-7. 31 (m, 2 H), 6.90 (dt, 2 H, J= 2.1 Hz, 8.7 Hz), 3.83 (s, 3 H). [13C] NMR (CDCl3, 75 MHz) 8 172.0, 160.3, 140.3, 136.1, 132.8, 130.2, 129.2, 129.1, 127.4, 123.1, 55.7. IR (neat, [CM'')] 2964 (broad), 2943,2902, 2875, 2856, 2840, [2813,] 2360,2342, [1688.] MS [(EI)] [M/Z] (relative intensity) 260 (100). Anal. Cald. for [C14H1203S,] Cald. C: 64.60, H: 4.65 ; Found C: 64.52, H: 4.68.
3-lodobenzoic acid (2.00 g, 8.06 mmol) was dissolved in THF (20 mL) then oxalyl chloride (1.4 mL, 16 mmol) and DMF (0.05 mL) were added and the resulting mixture stirred for 2 hours. The volatiles were evaporated under reduced pressure and the residue was dissolved in THF (20 mL) and concentrated aqueous ammonia (10 mL). After 60 minutes water (200 mL) was added and after a further 30 minutes the resulting precipitate was collected by filtration and air dried to give the title compound (1142) (1.97 g, 99% yield) as a white powder; H NMR (400 MHz, cVMeOH) delta 8.23 (t, J = 1.8 Hz, 1 H), 7.90 (ddd, J = 7.9, 1.7, 1.0 Hz, 1 H), 7.86 (ddd, J = 7.8, 1.7, 1.0 Hz, H), 7.24 (t, J = 7.8 Hz, 1 H). LCMS Method C rt 5.29 min, m/z 248.1 [M+H}
99%
3-lodobenzoic acid (2.00 g, 8.06 mrnol) was dissolved in THF (20 mL) then oxalyl chloride (1.4 mL, 16 mrnol) and DMF (0.05 mL) were added and the resulting mixture stirred for 2 hours. The volatiies were evaporated under reduced pressure and the residue was dissolved in THF (20 mL) and concentrated aqueous ammonia (10 mL). After 60 minutes water (200 mL) was added and after a further 30 minutes the resulting precipitate was collected by filtration and air dried to give the title compound (1142) (1.97 g, 99% yield) as a white powder; 1H NMR (400 MHz, oVMeOH) delta 8.23 (t, J = 1.8 Hz, 1 H), 7.90 (ddd, J = 7.9, 1.7, 1.0 Hz, 1 H), 7.86 (ddd, J = 7.8, 1.7, 1.0 Hz, 1 H), 7.24 (t, J = 7.8 Hz, 1 H). LCMS Method C: rt 5.29 min, m/z 248.1 [M+Hf .
Preparation 61 3-iodobenzoic acid tert-butyl ester To a solution of 3-iodobenzoic acid (50 g, 0.2 mol) in N,N-dimethylformamide (250 mL) was added solid 1,1'-carbonyldiimidazole (32.4 g, 0.2 mol) over 15 min. The resulting mixture was heated at 40 C. for 1 hr, then was added tert-butyl alcohol (29.6 g, 0.4 mol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (30.4 g, 0.2 mol) and heated at 40 C. overnight. The reaction was cooled to room temperature, diluted with water (500 mL) and extracted with hexane (2*500 mL). The combined organic layers were washed with water (2*400 mL), brine (250 mL), dried over anhydrous magnesium sulfate (15 g), filtered and concentrated under reduced pressure to give the title compound (56 g, 92%) as an oil. NMR 60 MHz, (CDCl3), delta 8.3 (m, 1H), 7.8 (m, 2H), 7.0 (m, 1H), 1.6 (s, 9H).
92%
Preparation 61 3-iodobenzoic acid tert-butyl ester To a solution of 3-iodobenzoic acid (50 g, 0.2 mol) in N,N-dimethylformamide (250 mL) was added solid 1,1'-carbonyldiimidazole (32.4 g, 0.2 mol) over 15 min. The resulting mixture was heated at 40 C. for 1 hr, then was added tert-butyl alcohol (29.6 g, 0.4 mol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (30.4 g, 0.2 mol) and heated at 40 C. overnight. The reaction was cooled to room temperature, diluted with water (500 mL) and extracted with hexane (2*500 mL). The combined organic layers were washed with water (2*400 mL), brine (250 mL), dried over anhydrous magnesium sulfate (15 g), filtered and concentrated under reduced pressure to give the title compound (56 g, 92%) as an oil. NMR 60 MHz, (CDCl3), delta 8.3 (m, 1H), 7.8 (m, 2H), 7.0 (m, 1H), 1.6 (s, 9H).
With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃;
To a solution of methyl 3-iodobenoic acid (250.0 mg, 0.81 mmol, 1.0 equiv) in DMF (3.0 mL) were added methylamine (0.6 mL, 1.2 mmol, 1.5 equiv, 2M/THF), HATU (368 mg, 1.0 mmol, 1.2 equiv.), and DIEA (208 mg, 1.6 mmol, 2.0 equiv.). The mixture was stirred at rt overnight, diluted with water, and extracted with EA (20 mL). The organic layer was washed with brine twice, dried over Na2S04, concentrated under reduced pressure, and purified by silica gel column chromatography using PE/EA (4/1) as eluent to afford 200 mg of 3 - i o do - - m c t h y 1 b c n z a m i dc (Intermediate 55-2) as an off-white solid. LRMS (ES) m/z 262 (M+H).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
Into a 500-mL round-bottom flask, was placed a solution of 3-iodobenzoic acid (9.92 g, 40.00 mmol, 1.00 equiv) in DMF (100 mL), 1-(bromomethyl)benzene (6.84 g, 40.00 mmol, 1.00 equiv), potassium carbonate (11.04 g, 80.00 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at room temperature. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was diluted with 50 mL of water and extracted with 2*50 mL of ethyl acetate. The combined organic layers were washed with 2*50 mL of sodium chloride, dried over anhydrous sodium sulfate and concentrated under vacuum to give 13.1 g (97%) of benzyl 3-iodobenzoate as light brown oil
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 24℃; for 1.66h;
Intermediate 1 : Phenylmethyl 3-(4-amino-6-methyl-1 /-/-indazol-1-yl)benzoate; a) Preparation of phenylmethyl 3-iodobenzoate; 3-lodobenzoic acid (12.4g) was dissolved in DMF (10OmL) and potassium carbonate(7.6g) was added. Benzyl bromide (6.5ml_) was then added dropwise over approximately10 minutes causing a slight exotherm to 24C. The suspension was stirred at room temperature for 1.5 hours. The suspension was then poured into water (approximately30OmL) and was extracted with diethyl ether. The combined organic phase was back washed with water and brine and dried over sodium sulfate. The solvent was stripped to yield a crude product as a colourless oil (17.Og). The crude product was applied to a silica gel column and was eluted with cyclohexane-ethyl acetate (95:5) to give a colourless oil (13.08g).1H NMR (400MHz, CDCI3) 8.41 (1 H, t), 8.05 (1 H, dt), 7.90 (1 H, dt), 7.48-7.34 (5H, m), 7.19 (1 H1 1) and 5.37 (2H1 s)
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 24℃; for 1.66667h;
3-lodobenzoic acid (12.4g) was dissolved in DMF (10OmL) and potassium carbonate (7.6g) was added. Benzyl bromide (6.5mL) was then added dropwise over approximately IOmins causing a slight exotherm to 24C. The suspension was stirred at room temperature for 1.5hrs. The suspension was then poured into water (approximately 30OmL) and was extracted with diethyl ether. The combined organic phase was back washed with water and brine and dried over sodium sulfate. The solvent was stripped to yield a crude product as a colourless oil (17.Og). The crude <n="57"/>product was applied to a silica gel column and was eluted with cyclohexane/ethyl acetate (95:5) to give the title compound as a colourless oil (13.08g). 1H NMR (400MHz, CDCI3) 8.41 (t, 1 H), 8.05 (dt, 1 H), 7.90 (dt, 1 H), 7.48-7.34 (m, 5H), 7.19 (t, 1 H) and 5.37 (s, 2H).
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 24℃; for 1.66h;
3-lodobenzoic acid (12.4g, 50mmol) was dissolved in DMF (10OmL) and potassium carbonate (7.6g, 55mmol) was added. Benzyl bromide (6.5mL, 55mmol) was then added dropwise over approximately 10 minutes causing a slight exotherm to 24C. The suspension was stirred at room temperature for 1.5 hours. The suspension was then poured into water (approximately 30OmL) and was extracted with diethyl ether. The combined organic phase was back washed with water and brine and dried over sodium sulfate. The solvent was stripped to yield a crude product as a colourless oil (17.Og). The crude product was applied to a silica gel column and was eluted with cyclohexane-ethyl acetate (95:5) to give the title compound as a colourless oil (13.08g).1H NMR (400MHz, CDCI3) 8.41 (1 H, t), 8.05 (1 H, dt), 7.90 (1 H, dt), 7.48-7.34 (5H, m), 7.19 (1 H, t) and 5.37 (2H, s)
With dmap; In dichloromethane; at 20℃; for 64h;Inert atmosphere;
To a solution of 3-iodobenzoic acid (5.06 g, 20.4 mmol) in DCM (25 mL) was added a solution of Boc20 (4.90 g, 22.5 mmol) in dichloromethane (10 mL) and 4-DMAP (0.624 g, 5.1 mmol) in dichloromethane (5 mL). The resulting solution was stirred at room temperature under a nitrogen atmosphere for 64 hours. The resulting mixture was partitioned between water (100 mL) and dichloromethane (50 mL) and the layers separated. The organic layer was washed with water (2x 00 mL) before being concentrated under reduced pressure. The resulting residue was purifed using silica gel column chromatography (0-50% dichloromethane/petroleum benzene 40-60 C) to give the title compound (115) (65% 4.02 g) as a colourless oil; 1H NMR (400 MHz, CDCI3) 5 8.30 (dd, J = 1 .6, 1 .6 Hz, 1 H), 7.95 (ddd, J = 7.8, 1.5, 1 .1 Hz, 1 H), 7.85 (ddd, J = 7.9, 1.8, 1.1 Hz, 1H), 7.16 (ddd, J = 7.8, 7.8, 0.2 Hz, 1 H), 1.59 (s, 9H). LCMS Method C: rt 6.88 min.
65%
With dmap; In dichloromethane; at 20℃; for 64h;Inert atmosphere;
To a solution of 3-iodobenzoic acid (5.06 g, 20.4 mmol) in DCM (25 mL) was added a solution of Boc20 (4.90 g, 22.5 mmol) in dichloromethane (10 mL) and 4-DMAP (0.624 g, 5.1 1 mmol) in dichloromethane (5 mL). The resulting solution was stirred at room temperature under a nitrogen atmosphere for 64 hours. The resulting mixture was partitioned between water (100 mL) and dichloromethane (50 mL) and the layers separated. The organic layer was washed with water (2x100 mL) before being concentrated under reduced pressure. The resulting residue was purifed using silica gel column chromatography (0-50% dichloromethane/petroleum benzene 40-60 C) to give the title compound (115) (65% 4.02 g) as a colourless oil; 1H NMR (400 MHz, CDCI3) delta 8.30 (dd, J = 1.6, 1.6 Hz, 1 H), 7.95 (ddd, J = 7.8, 1.5, 1.1 Hz, 1 H), 7.85 (ddd, J = 7.9, 1.8, 1.1 Hz, 1 H), 7.16 (ddd, J = 7.8, 7.8, 0.2 Hz, 1 H), 1.59 (s, 9H). LCMS Method C: rt 6.88 min.
Commercially available 3-iodobenzoic acid (7.41 g, 29.9 mmol) was dissolved in THF (121 mL), and the mixture was stirred at room temperature for 45 minutes after adding 1,1'-carbonyldiimidazole (5.33 g, 32.9 mmol). The mixture was further stirred at room temperature for 2 hours after adding hydrazine·monohydrate (5.3 mL, 109 mmol). The mixture was then concentrated under reduced pressure, and recrystallized from methanol and water to give 3-iodobenzohydrazide (6.08 g, 78%). ESI-MS: m/z 261 [M-H]-.
With copper(I) oxide; 1D-1-O-Methyl-muco-inostol; sodium hydroxide; In water; at 100℃; for 6h;
In the l00mL hydrothermal synthesis reactor,Add sodium hydroxide (3 mmol), water (5 mL), stir and dissolve,Add m-iodobenzoic acid (0.5 mmol), cuprous oxide (0.05 mmol),White lignan (0.05 mmol), the reaction was stirred at 100 C for 6 hours.After cooling, adjust the pH to 2 with dilute hydrochloric acid, and extract with ethyl acetate.The liquid was concentrated and subjected to column chromatography to obtain m-hydroxybenzoic acid, 60.7 mg.The yield was 88%.
86%
General procedure: A typical method for preparation of phenols: A Schlenk test tube with a magnetic stirring bar was charged with CuSO4·5H2O (13 mg, 5 mol %), NaAsc (20 mg, 10 mol %), benzene halide (1.0 mmol), KOH (168-336 mg, 3.0-6.0 equiv) in DMSO/H2O (v/v=1:1, 3.0 mL) at 120 C for 24h. After cooling to room temperature, carefully acidified with dilute aqueous HCl to pH=2-3 and the mixture were stirred for half hour. Then the resultant mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. Purification via silica gel column chromatography with a mixture of ethyl acetate/petroleum ether. Details as follows:
77%
With copper(I) oxide; 2-(N,N-dimethylamino)athanol; water; potassium hydroxide; In dimethyl sulfoxide; at 110℃; for 24h;Inert atmosphere;
General procedure: To a test tube containing a magnetic bar was added aryl halide (1.0 mmol), Cu2O (14.3 mg, 0.1 mmol), KOH (169 mg, 3.0 mmol), 2-dimethylaminoethanol (0.3 mL, 3.0 mmol), and DMSO/H2O (1.5 mL/0.5 mL). After flushing with argon, the mixture was stirred in a preheated oil bath at 100 C for 24 h. After cooled to ambient temperature, the reaction mixture was distributed in aqueous HCl (5 %) and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated under vacuum. The crude product was further purified by column chromatography (EtOAc/n-Hexane) to provide the phenols.
With ammonium hydroxide; ethanol; In sulfuric acid; at 0 - 80℃;
3-Iodobenzoic acid (50 g, 0.2 mol) and N-hydroxymethylphthalimide (35.7 g, 0.2 mol) were suspended in concentrated sulfuric acid (200 ml) and heated for three hours at 80 C. The reaction mixture was poured onto ice and the product was filtered, washed with water and dilute ammonium hydroxide and then stirred in hot (70 C.) ethanol for 1.5 hours before cooling and drying to yield the title compound (24 g, 45%). 1H NMR (360 MHz, d6 DMSO) X 8.63 (1H, brs), 7.95 (1H, s), 7.92 (1H, d, J=7 and 1 Hz), 7.42 (1H, d, J=7 and 1 Hz), 4.33 (2H, s). m/z (ES+) 260 (M+).
With triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 73h;
[00176] To 26.1 mg PdCl2(dppf).CH2Cl2 in a reaction tube under nitrogen were added 4 ml dioxane, 0.43 ml (3 mmol) triethylamine, 0.37 ml (2.6 mmol) pinacolborane and 250 mg (1.0 mmol) 3-iodobenzoic acid. The reaction solution was stirred at room temperature to ensure that the carboxylic acid group had reacted with pinacolborane. The hydrogen evolved was flushed out of the reaction tube with argon. Over this period, the initial crimson coloured reaction solution turned to an orange colour. After warming to 80 C. with stirring for 73 h in an oil bath, an aliquot (0.3 ml) was removed from the reaction solution, extracted into ethyl acetate and washed with dilute sulphuric acid and then several times with water before analysing by gc (fid detector, SGE HT5 capillary column). No 3-iodobenzoic acid was found in the solution indicating that the reaction had gone to completion. Only 3 peaks were observed in the gc, other than the solvent, and these were shown by gc/ms to be due to benzoic acid and the pinacol esters of phenylboronic acid and the desired carboxylated phenylboronic acid which was present in highest concentration.
To a mixture of 3-iodobenzoic acid (11.9 g, 48 mmol), <strong>[209919-30-2]4-chloro-2-methylphenylboronic acid</strong> (9.8 g, 57.7 mmol) and sodium carbonate (6.1 g, 57.7 mmol) under nitrogen atmosphere, was added i-PrOH-water (1/1, 180 mL) followed by 10% Pd-C (2 g, 19.2 mmol) with caution. The reaction mixture was heated at 80 C. under nitrogen overnight. The catalyst was removed by filtration, and the filtered catalyst was washed with EtOH (60 mL). Most of organic solvent was removed under reduced pressure. The resulting aqueous residue was treated with 2N HCl (aq) to bring the pH <2. The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water and saturated brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Compound 9.7 was obtained as white solid (12 g), which was used directly in the next step. MS ESI (neg.) m/e: 245 (M-H).
12 g
With palladium 10% on activated carbon; sodium carbonate; In water; isopropyl alcohol; at 80℃;Inert atmosphere;
To a mixture of 3-iodobenzoic acid T1 (11.9 g, 48 mmol), <strong>[209919-30-2]4-chloro-2-methylphenylboronic acid</strong> (9.8 g, 57.7 mmol) and sodium carbonate (6.1 g, 57.7 mmol) under nitrogen atmosphere, was added i-PrOH-water (1/1, 180mL) followed by 10% Pd-C (2 g, 19.2 mmol) with caution. The reaction mixture was heated at 80 C under nitrogen overnight. The catalyst was removed by filtration, and the filtered catalyst was washed with EtOH (60 mL). Most of organic solvent was removed under reduced pressure. The resulting aqueous residue was treated with 2N HCl (aq) to bring the pH < 2. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water and saturated brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Compound T2 was obtained as white solid (12 g), which was used directly in the next step. MS ESI (neg.) m/e: 245 (M-H).
With triethylamine;palladium diacetate; In acetonitrile; at 100℃; for 12h;
Reference Example 14 A 104 mg portion of palladium acetate and 5 ml of TEA were added one by one to 50 ml of acetonitrile solution containing 7.44 g of 3-iodobenzoic acid and 3.9 ml of ethyl acrylate, and the mixture was sealed in a tube and heated at 100C for about 12 hours. After spontaneous cooling, the catalyst was removed by filtration while washing with appropriate amounts of methanol and ethyl acetate, and the filtrate was evaporated under a reduced pressure. The thus formed crude crystals were recrystallized from a small amount of ethanol to obtain 5.82 g (88%) of 3-(3-ethoxy-3-oxoprop-1-en-1-yl) benzoic acid as white crystals. FA: 221
With potassium carbonate; In ethanol; water; at 180℃; for 0.25h;Microwave heating;
The carboxylic acids 2, 4, 6, and 8 were created by the following general procedure: 3- or 4-iodobenzoic acid (1.24 g, 5 mmol), K2CO3 (2.7 g, 20 mmol) and the appropriate boronic acid (4-chlorophenyl (0.89 g, 5.5 mmol) or 2-naphthyl (0.95 g, 5.5 mmol)) were dissolved in a mixture Of H2O (7.5 ml) and ethanol (7.5 Ml) and heated to 180 C for 15 min using microwave heating. The reaction mixture was filtered through a plug of Celite, HCl (IM, 25 mL) was added to the filtrate and the resulting mixture was extracted twice with EtOAc. The organic phases were combined, washed with water (50 mL) and brine (50 mL) and concentrated to yield a crude solid, which was recrystallized from toluene to afford the desired compound as a white solid. Scheme 3 below illustrates the creation of the carboxylic acids.; [0164] 3-Iodobenzoic acid and 4-chlorophenylboronic acid yielded 1.2 g (99%) of 2. Mp 180.9 - 181.7 0C. IH NMR (DMSO-d6) delta 7.51 (d, 2H, J = 7.7 Hz), 7.58 (dd, IH, J = 7.7, 8.2 Hz), 7.71 (d, 2H, J = 7.7 Hz), 7.88 (d, IH, J = 8.2 Hz), 7.96 (d, IH, J = 7.7 Hz), 8.19 (s, IH). 13C NMR (DMSO-d6) delta 127.8, 128.8, 129.0 (2 C:s), 129.5 (2 C:s), 129.9, 131.4, 132.5, 133.3, 138.6, 139.7, 168.2.
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In N,N-dimethyl-formamide; at 60℃; for 2h;
3-[(2-aminopyrimidin-5-yl)ethynyl]benzoic acid A mixture of 5-ethynylpyrimidin-2-amine (intermediate 2) (2.00 g), 3-iodobenzoic acid (4.16 g), copper iodide (80 mg) and triethylamine (5.2 mL) in DMF (50 mL) was stirred and degassed with nitrogen. Dichlorobis(triphenylphosphine)palladium(II) (590 mg) was added and the mixture heated at 60 C. for 2 hours. The mixture was concentrated, then the residue dissolved in a 1N aqueous solution of sodium hydroxide (350 mL) and washed with ethyl acetate (200 mL). The aqueous solution was acidified with a 2N aqueous solution of hydrochloric acid. On acidification to pH 3, a yellow solid precipitated from the solution. The solid was collected by filtration and washed with water (2*50 mL) then dried under vacuum for 20 hours, to give the title compound (4.27 g, 96%). 1H NMR (DMSO-d6) 7.14 (br s, 2H), 7.53 (t, 1H), 7.71 (d, 1H), 7.91 (d, 1H), 8.00 (s, 1H), 8.45 (s, 2H), 13.12 (br s, 1H); MS m/e MH+240.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 120h;
lambda/,lambda/-Diisopropylethylamine (15.23mL, 87.4mmol) and HATU (6.99g, 18.38mmol) were added sequentially to a stirred solution of 3-iodobenzoic acid (4.34g, 17.5mmol) in anhydrous DMF (10OmL) and the mixture was stirred under nitrogen for 10 min. D- prolinamide (5g, 43.8mmol) was then added and the mixture stirred at room temperature for 3 hours and then allowed to stand for 5 days and was then partitioned between water (60OmL) and ethyl acetate (60OmL). The organic phase was separated, washed successively with aqueous sodium bicarbonate, water, 2M hydrochloric acid and brine, passed through a hydrophobic frit and evaporated to give the title compound as an orange gum (2.221 g). LCMS: tRET = 2.34 min; MH+ = 345
With sodiumsulfide nonahydrate; copper; ethane-1,2-dithiol; In dimethyl sulfoxide; at 100℃; for 20h;Inert atmosphere; Green chemistry;
General procedure: To a test tube containing a magnetic bar was added aryl iodide(1 mmol), copper powder (6.35 mg, 0.1 mmol), Na2S·9H2O(720.54 mg, 3 mmol), and DMSO (2 mL). After flushing withargon, 1,2-ethanedithiol (8.4 muL, 0.1 mmol) was added. Themixture was stirred in the oil bath at 100 C for 20 h. Aftercooled to ambient temperature, the reaction mixture was distributedin aq HCl (5%) and EtOAc. The organic layer was separated and washed with water and brine, dried, and concentratedunder vacuum. The crude product was further purifiedby column chromatography using ethyl acetate/n-hexane aseluent to provide the desired aryl thiol.
To a 125 mL round-bottom flask in a 0 C ice bath was added 3-iodobenoic acid (5.0 g, 23 mmol), EDCI (5.0 g, 26 mmol), DCM (50 mL) and allowed to stir for 10 min. To the stirred solution was added DMAP (0.3 mg, 2.3 mmol) and methanol (1.1 mL) and the reaction allowed to stir overnight. Disappearance of SM was monitored by HPLC. Reaction mixture was diluted with DCM, washed with 1 N HCI, dried with magnisium sulfate, and concentrated in vacuo. Required column chromatography (10: 1 Hex/EtOAc) to isolate product (4.56 g, 87%); LC retention time = 3.77 min.
Step 1: Preparation of 3'-(methoxycarbonyl)biphenyl-3-carboxylic acid <n="92"/>[00147] 3-Iodobenzoic acid (1.0 g, 4.03 mmol, 1 equiv.), 3- (methoxycarbonyl)phenylboronic acid (0.73 g, 4.03 mmol, 1 equiv.), and Pd(OAc)2 (27 mg, 0.12 mmol, 0.03 equiv.) were mixed in DMF (10 mL) at RT with stirring, followed by the addition of 1.5M cesium carbonate (8.06 mL, 1.16 mmol, 3 equiv.). The mixture was heated at 40 0C for 4 hours. At the conclusion of this period, the reaction was worked up by adding water and adjusting the pH to 3 with IN HCl. The aqueous mixture was extracted (3X) with EtOAc/THF. The organic layers were rinsed (3X) with water. The organic layer was dried over sodium sulfate and concentrated to give an off-white solid. The solid was stirred in hexanes (10 mL), filtered and dried under high vacuum to give 3 '-(methoxycarbonyl)biphenyl-3- carboxylic acid (860 mg, 3.36 mmol, 83% yield) as a white solid. MS (ESI+) = 257.23 (M+H)+
[0427] To a solution of Example 62e (1000 mg, 4.003 mmol) in con.H2S04 (10 mL) was added Example 62f (856 mg, 4.83 mmol). The mixture was stirred at 90C for 3h. The mixture was added into H20 (100mL)andwhite solid was separated out. The suspension was filtered, then the solid was added into NH3.H20/MeOH (15mL/15mL).The mixture was stiired at 80C for lh. The suspension was filtered to afford Example 62g (620 mg, yield: 59.2%) as a white solid.
55%
With sulfuric acid; at 55 - 90℃; for 6h;
Example 8; Part A; Compound 309A (4.96 g, 20 mmol) and compound 309B (3.72 g, 21 mmol) were suspended in concentrated sulfuric acid (20 mL) and heated at 55 0C for 3 hours, then at 90 0C for 3 hours. The reaction mixture was cooled to room temperature, poured into ice-water (150 mL), and filtered. The solid was washed with water, 3% ammonium hydroxide, dried, and heated in EtOH (30 mL) at 70 0C for 1 hour. The mixture was cooled to room temperature, filtered and a yellow solid (2.87 g, 55%) was obtained. HPLC-MS tR = 1.39 min (UV 254 nm); mass calculated for formula C8H6INO 258.95, observed LCMS m/z 260.0 (M+H).
48%
With sulfuric acid; at 80℃; for 3.5h;
A mixture of 2-(hydroxymethyl)isoindoline-1,3-dione (500 g, 202 mmol), 3-iodobenzoic acid (35 7 g, 202 mmol) and H2SO4 was heated at 80 C for 3 5 h The mixture was cooled to room temperature and then poured into ice The precipitate was filtered off, washed with H2O (1 O L), dilute NH4OH (500 mL) and recrystallized from EtOH (300 mL) to provide compound 69-1 (25 2 g, 48%) as an off white solid
To a solution of 3-iodobenzoic acid (1 g, 4.03 mmol, 1 eq) in concentrated H2SO4(10 mL) was added 2-(hydroxymethyl)isoindoline-1,3-dione (857 mg, 4.84 mmol, 1.2 eq). The reaction mixture was stirred at 90C for 3 hours. The mixture was added into H2O (100 mL) and filtered. The filter cake was added into NH3.H2O (15 mL, 25 wt.% in H2O) and MeOH (15 mL), and then the mixture was stirred at 80C for 1 hour. The mixture was filtered, and the filter cake was dried in vacuum to give the title compound (600 mg, 57.4% yield, 94.0% purity on LCMS) as a white solid.1H NMR (400 MHz, DMSO-d6) d 8.66 (s, 1H), 7.95-7.95 (m, 2H), 7.41 (d,1 H), 4.37 (s, 2H).LCMS: m/z 259.9 (M+H)+(ES+).
Intermediate 28 To a solution of 1.0 g of 3-iodobenzoic acid in 20 ml of CH2CI2 under argon atmosphere was added via cannula a solution of 1.11 g of DCC in 22 ml of CH2CI2. The resulting mixture was stirred for 1 h, then was added a solution of 0.65 g of Intermediate 1 and 0.414 ml of Et3N in 13 ml of CH2CI2. The resulting mixture was stirred overnight, diluted with Et2O, filtered off and the filter cake washed with Et2O. The filtrate was washed with 10% NaHCO3 and brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel eluting with EtOAc-Hex 10:90 to 50:50 to afford 1.063 g (91 %) of the title compound as a colourless oil. 1H NMR (delta, ppm, CDCI3): 7.79 and 7.75 (s, 1 H); 7.39 (s, 1 H); 7.23 (d, 2H); 7.21-7.1 1 (m, 2H); 4.72 and 4.49 (s, 2H); 3.02 and 2.88 (s, 3H). [ES MS] m/z: 436 (MH+).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;
3-lodobenzoic acid (248 mg, 1.0 mmol), <strong>[496-12-8]isoindoline</strong> (284 uL, 1.5 mmol), and triethylamine (420 uL, 3.0 mmol) were dissolved in 10 ml. of CH2CI2 and treated with HOBt (203 mg, 1.5 mmol) and EDC (288 mg, 1.5 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with EtOAc, and washed with water, 1N HCI, and brine. The organic layer was dried (MgSO4), filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel (CH2CI2/Et0Ac) to yield 304 mg (87%) of the product as a tan solid. MS (+ESI): m/z 349.9 [M+H]+.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; for 18h;
SM053-lodo-N,N-dimethylbenzamideEDCI (1 .3 g, 6.6 mmol) was added to a solution of dimethylamine in THF (2 M, 6 mL, 10 mmol) and 3-iodobenzoic acid (1 .5 g, 6 mmol). After 18 h stirring the reaction was transferred into water, and then extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The solvent was evaporated to afford the product as a viscous, clear oil. The product was used in the next reaction step without further purification. MS m/z: 276 [M + H]+.
General procedure: At room temperature, organic carbonyl acid 3 (R-COOH, 0.5 mmol) was added into a reaction tube equipped with a small magnet. Then a solution of tertiary amine 1 (R1CH2-NR2R3, 0.5 mmol ) in DCM (2.5 mL) was added dropwise in 2 min. After the mixture was stirred at room temperature for a few minutes, 1 equivalents of dimethyl acetylenedicarboxylate (DMAD, 2) was added. The reaction was stirred overnight at room temperature, and then monitored by TLC with silica gel coated plates. After being stirred for 14 h, the solvent was removed and the residue was purified by a flash column chromatography with silica gel with ethyl acetate/hexane (1:25-30) as eluent to give the desired products 4, 5, and 7. Most of compounds are known and confirmed by NMR, ESI-MS, IR.
[0115] Specifically, to a degassed solution of 3-iodoben- zoic acid 13 (49 mg, 0.2 mmol) inNMP (0.3 mE) were added KOAc (59 mg, 0.6 mmol) and Pd(PPh3)2C12 (7 mg, 0.01 mmol). The resulting pale orange solution was stirred for 10 mm followed by the addition of hexabutylditin 12 (290 mg, 0.5 mmol). Afier stirring at room temperature for 24 h, the dark red reaction mixture was diluted with diethyl ether (0.5 mE) and directly loaded on a silica gel column and flushed with 1:1 hexanes/ethyl acetate to afford the desired arylstannane 14 in 91% yield (75 mg, 0.182 mmol).
69.4%
With tetrakis(triphenylphosphine) palladium(0); In toluene; at 95℃; for 4h;Inert atmosphere;
A mixture of 3-iodobenzoic acid (248 mg, 1 mmol), Pd(PPh3)4 (115.8 mg, 0.1 mmol) and Bis(tributyltin) (2.9 g, 5 mmol) in 8 mL toluene was deoxygenated by purging into nitrogen for 15 min and then heated at 95 C for 4 h. The solvent was removed, and the residue was purified by FC (EtOH/hexane = 4/6) to give 48 as a colorless oil (yield: 40 mg, 69.4%): 1HNMR (400 MHz, CDC13) delta: 8.16-8.25 (m, 1H), 8.02-8.04 (m, 1H), 7.66-7.76 (m, 1H), 7.41-7.45 (m, 1H), 1.46-1.64 (m, 6H), 1.30-1.41 (m, 6H), 1.02-1.20 (m, 6H), 0.89-0.95(m, 9H).
(S)-6-[(Diphenyl-p-tolyl-methyl)-amino]-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid[ No CAS ]
[ 198544-42-2 ]
[ 147290-11-7 ]
[ 618-51-9 ]
C63H63BrF2I2N9O16P[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4%
General procedure: General Procedure A for Rink Amide Resin Activation. Rink amide resin (Advanced ChemTech) was mixed with DCM (1 mL per 100 mg resin) and then shaken for 30 minutes. After activation, resin was washed three times with DMF (1 mL per 100 mg resin). [0079] General Procedure B for the Removal of the Fmoc Group from the Rink Amide Resin. Rink amide resin was mixed with 20% piperidine in DMF (1 mL per 100 mg resin) and shaken for 30 minutes, and then washed with DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times) sequentially. The removal of the Fmoc group was confirmed by the ninhydrin test. [0080] General Procedure C for the Removal the Alloc Group from the Rink Amide Resin. The resin (200 mg) was washed with DCM (2 mL, 5 times) and shaken under 2 overnight with a solution of tetrakis(triphenylphosphine)palladium(0) (10 mg), AcOH (0.5 mL), and NMM (0.2 mL) in DCM (10 mL). The resin was then washed with DMF (2 mL, 3 times), isopropanol (2 mL, 3 times), and DCM (2 mL, 3 times). The removal of the Alloc group was confirmed by the ninhydrin test. [0081 ] General Procedure D for the Removal the Mtt Group from the Rink Amide Resin. The resin was washed with DCM (1 mL per 100 mg resin, 10 times). The resin was shaken with TFA (1% in DCM, 1 mL per 100 mg resin) for 1 minute (repeat 10 times). The resin was then washed with DCM (1 mL per 100 mg resin, 3 times), DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times). The removal of the Mtt group was confirmed by the ninhydrin test. [0082] General Procedure E for the Coupling of Carboxylic Acids to the Rink Amide Resin. Carboxylic acids (5 equiv, 0.5 M in DMF) were first mixed with HBTU (5 equiv, 0.5 M in DMF), HOBt (5 equiv, 0.5 M in DMF), and NMM (15 equiv, 1.5 M inDMF). The mixed solution was then added to the resin and shaken for 2 hours. The resin was then washed with DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times). The completion of the coupling reaction was confirmed by the ninhydrin test. [0083] General Procedure F for Peptide Cleavage from the Rink Amide Resin. The resin was washed with DCM (1 mL per 100 mg resin, 5 times) and subsequently shaken with a solution of 95% TFA, 2.5% TIS, and 2.5% H20 (1 mL per 100 mg resin) for 2 hours. The resin was removed by filtration, and the TFA was evaporated under vacuum. The crude peptide was obtained after trituration with diethyl ether (5 mL per 100 mg resin, 2 times). Compound 6a was synthesized using standard Fmoc chemistry on the Rink amide resin in a disposable syringe with a frit (Figure 16). Rink amide resin (200 mg, 0.7 mmol/g loading, 0.14 mmol) was first activated with DCM (2 mL, general procedure A). Fmoc group was removed by piperidine (20% solution in DMF, 2mL, general procedure B). The resin was the coupled with Fmoc-Lys(Mtt)-OH (general procedure E). After the deprotection of Fmoc group (general procedure B), the resin was couple with Fmoc^-Ala-OH (general procedure E). The resin was treated with piperidine (general procedure B) and coupled with Fmoc-Dpr(Boc)-OH (general procedure E). The resin was treated with piperidine (general procedure B) and coupled with Fmoc- Orn(Alloc)-OH (general procedure E). The Fmoc group was removed (general procedure B), and the resin was coupled with Fmoc-F2Pmp-OH (general procedure E). The resin was treated with piperidine (general procedure B) and coupled with BMBA (general procedure E). The Alloc group was removed (general procedure C), and resin was coupled with mlBA (general procedure E). The resin was treated with 1% TFA in DCM for the removal of Mtt group (general procedure D) and coupled with 5-FAM (general procedure E). Compound 6a was cleaved from beads (general procedure F). Crude peptide was purified by HPLC to afford Compound 6a (8.6 mg, 4% yield). MS (ESI): calculated for [M] 1477, found [M+H]+ 1478. Figure 16 depicts the synthesis of Compound 6a: (a) 30% piperidine/DMF; (b) Fmoc-Lys(Mtt)-OH/HBTU/HOBt/NMM; (c) Fmoc-p-Ala- OH/HBTU/HOBt/NMM; (d) Fmoc-Dpr(Boc)-OH/HBTU/HOBt/NMM; (e) Fmoc- Orn(Alloc)-OH/HBTU/HOBt/NMM; (f) Fmoc-F2Pmp-OH/HBTU/HOBt/NMM; (g) 3- bromo-4-methylbenzoic acid/HBTU/HOBt/NMM; (h) Pd(0)/NMM/AcOH; (i) 3- iodobenzoic acid/HBTU/HOBt/NMM; (j)l% TFA/TIS/DCM; (k) 5-Carboxyfluorescein/ HBTU/HOBt/NMM; (1) 95% TFA/H2O/TIS.
(S)-6-[(Diphenyl-p-tolyl-methyl)-amino]-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid[ No CAS ]
[ 147290-11-7 ]
[ 618-51-9 ]
C52H53F2IN7O14P[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6%
General procedure: .General Procedure A for Rink Amide Resin Activation. Rink amide resin (Advanced ChemTech) was mixed with DCM (1 mL per 100 mg resin) and then shaken for 30 minutes. After activation, resin was washed three times with DMF (1 mL per 100 mg resin). [0079] General Procedure B for the Removal of the Fmoc Group from the Rink Amide Resin. Rink amide resin was mixed with 20% piperidine in DMF (1 mL per 100 mg resin) and shaken for 30 minutes, and then washed with DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times) sequentially. The removal of the Fmoc group was confirmed by the ninhydrin test. [0080] General Procedure C for the Removal the Alloc Group from the Rink Amide Resin. The resin (200 mg) was washed with DCM (2 mL, 5 times) and shaken under 2 overnight with a solution of tetrakis(triphenylphosphine)palladium(0) (10 mg), AcOH (0.5 mL), and NMM (0.2 mL) in DCM (10 mL). The resin was then washed with DMF (2 mL, 3 times), isopropanol (2 mL, 3 times), and DCM (2 mL, 3 times). The removal of the Alloc group was confirmed by the ninhydrin test. [0081 ] General Procedure D for the Removal the Mtt Group from the Rink Amide Resin. The resin was washed with DCM (1 mL per 100 mg resin, 10 times). The resin was shaken with TFA (1% in DCM, 1 mL per 100 mg resin) for 1 minute (repeat 10 times). The resin was then washed with DCM (1 mL per 100 mg resin, 3 times), DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times). The removal of the Mtt group was confirmed by the ninhydrin test. [0082] General Procedure E for the Coupling of Carboxylic Acids to the Rink Amide Resin. Carboxylic acids (5 equiv, 0.5 M in DMF) were first mixed with HBTU (5 equiv, 0.5 M in DMF), HOBt (5 equiv, 0.5 M in DMF), and NMM (15 equiv, 1.5 M inDMF). The mixed solution was then added to the resin and shaken for 2 hours. The resin was then washed with DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times). The completion of the coupling reaction was confirmed by the ninhydrin test. [0083] General Procedure F for Peptide Cleavage from the Rink Amide Resin. The resin was washed with DCM (1 mL per 100 mg resin, 5 times) and subsequently shaken with a solution of 95% TFA, 2.5% TIS, and 2.5% H20 (1 mL per 100 mg resin) for 2 hours. The resin was removed by filtration, and the TFA was evaporated under vacuum. The crude peptide was obtained after trituration with diethyl ether (5 mL per 100 mg resin, 2 times). Compound 4a was synthesized using standard Fmoc chemistry on the Rink amide resin in a disposable syringe with a frit (Figure 14). Rink amide resin (200 mg, 0.7 mmol/g loading, 0.14 mmol) was first activated with DCM (2 mL, general procedure A). Fmoc group was removed by piperidine (20% solution in DMF, 2mL, general procedure B). The resin was the coupled with Fmoc-Lys(Mtt)-OH (general procedure E). After the deprotection of Fmoc group (general procedure B), the resin was couple with Fmoc^-Ala-OH (general procedure E). The resin was treated with piperidine (general procedure B) and coupled with <strong>[147290-11-7]<strong>[147290-11-7]Fmoc-Orn(Alloc)</strong>-OH</strong> (general procedure E). The Fmoc group was removed (general procedure B), and the resin was coupled with Fmoc- F2Pmp-OH (general procedure E). The Alloc group was removed (general procedure C), and resin was coupled with mlBA (general procedure E). The resin was treated with 1% TFA in DCM for the removal of Mtt group (general procedure D) and coupled with 5-FAM (general procedure E). The resin was treated with piperidine to remove Fmoc group. Compound 4a was cleaved from beads (general procedure F). Crude peptide was purified by HPLC to afford 4a (10.4 mg, 6%> yield). MS (ESI): calculated for [M] 1195, found [M+H]+ 1196 Figure 14 depicts the synthesis of Compound 4a: (a) 30% piperidine/DMF; (b) Fmoc-Lys(Mtt)-OH/HBTU/HOBt/NMM; (c) Fmoc-p-Ala-OH/HBTU/HOBt/NMM; (d) <strong>[147290-11-7]<strong>[147290-11-7]Fmoc-Orn(Alloc)</strong>-OH</strong>/HBTU/HOBt/NMM; (e) Fmoc-F2Pmp-OH/HBTU/HOBt/NMM; (f) Pd(0)/NMM/AcOH; (g) 3-iodobenzoic acid/HBTU/HOBt/NMM; (h) 1% TFA/TIS/DCM; (i) 5-Carboxyfluorescein/HBTU/HOBt/NMM; (j) 95% TFA/H20/TIS.
General procedure: General Procedure A for Rink Amide Resin Activation. Rink amide resin (Advanced ChemTech) was mixed with DCM (1 mL per 100 mg resin) and then shaken for 30 minutes. After activation, resin was washed three times with DMF (1 mL per 100 mg resin). [0079] General Procedure B for the Removal of the Fmoc Group from the Rink Amide Resin. Rink amide resin was mixed with 20% piperidine in DMF (1 mL per 100 mg resin) and shaken for 30 minutes, and then washed with DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times) sequentially. The removal of the Fmoc group was confirmed by the ninhydrin test.General Procedure C for the Removal the Alloc Group from the Rink Amide Resin. The resin (200 mg) was washed with DCM (2 mL, 5 times) and shaken under 2 overnight with a solution of tetrakis(triphenylphosphine)palladium(0) (10 mg), AcOH (0.5 mL), and NMM (0.2 mL) in DCM (10 mL). The resin was then washed with DMF (2 mL, 3 times), isopropanol (2 mL, 3 times), and DCM (2 mL, 3 times). The removal of the Alloc group was confirmed by the ninhydrin test.General Procedure E for the Coupling of Carboxylic Acids to the Rink Amide Resin. Carboxylic acids (5 equiv, 0.5 M in DMF) were first mixed with HBTU (5 equiv, 0.5 M in DMF), HOBt (5 equiv, 0.5 M in DMF), and NMM (15 equiv, 1.5 M inDMF). The mixed solution was then added to the resin and shaken for 2 hours. The resin was then washed with DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times). The completion of the coupling reaction was confirmed by the ninhydrin test. [0083] General Procedure F for Peptide Cleavage from the Rink Amide Resin. The resin was washed with DCM (1 mL per 100 mg resin, 5 times) and subsequently shaken with a solution of 95% TFA, 2.5% TIS, and 2.5% H20 (1 mL per 100 mg resin) for 2 hours. The resin was removed by filtration, and the TFA was evaporated under vacuum. The crude peptide was obtained after trituration with diethyl ether (5 mL per 100 mg resin, 2 times) Compound 8 was synthesized using standard Fmoc chemistry on the Rink amide resin (Figure 18). The resin (200 mg, 0.7 mmol/g loading) was first activated by DCM (General procedure A). The Fmoc group on the resin was removed by piperidine in DMF (General procedure B). The resin was then coupled with Fmoc-Dpr(Boc)-OH. The Fmoc group on the resin was removed by piperidine in DMF (General procedure B). The resin was then coupled with <strong>[147290-11-7]<strong>[147290-11-7]Fmoc-Orn(Alloc)</strong>-OH</strong>. The Fmoc group was removed (General procedure B) and Fmoc-Phe-OH was attached to resin (General procedure E). The Fmoc group was again removed (general procedure B) and the amine group on the F2Pmp residue was coupled with BMBA (general procedure E). The resin was treated with Pd(0) for the deprotection of Alloc group (general procedure C). 3- Iodobenzoic acid (mlBA) was attached to resin (general procedure E). The resin was treated with TFA (general procedure F) to give the crude peptide intermediate, which was treated with a mixture of HVA (0.5 M in DMF, 100 muGamma), HBTU (0.5 M in DMF, 100 muGamma), HOBt (0.5 M in DMF, 100 muGamma) and NMM (1.5 M in DMF, 100 muGamma) to give the crude product 8. The crude product was purified by HPLC to afford 8 (15.8 mg, 12% yield). The assignment of proton NMR utilized additional information from COSY. 1H NMR (500 MHz, DMSO-d6): S= 8.70 (d, J= 8.1 Hz, 1 H, BMBA-NH), 8.60-8.55 (m, 1 H, mlBA- NH), 8.35 (d, J= 6.9 Hz, 1 H, Phe-NH), 8.19 (s, 1 H, mlBA-ArH), 8.04-7.95 (m, 2 H, Orn-NH, BMBA-ArH), 7.91-7.83 (m, 3 H, mlBA-ArH, HVA-NH), 7.67 (d, J= 7.5 Hz, 1 H, BMBA-ArH), 7.40-7.15 (m, 9 H, BMBA-ArH, Phe-ArH, -CONH2 , mlBA-ArH), 6.77 (s, 1 H, HVA-ArH), 6.63 (d, J= 7.6 Hz, 1 H, HVA-ArH), 6.58 (d, J= 7.6 Hz, 1 H, HVA- ArH), 4.78-4.72 (m, 1 H, Phe-CaH), 4.30-4.22 (m, 2 H, Dpr-CaH, Orn-CaH), 3.70 (s, 3 H, HVA-OCH3), 3.40-3.35 (m, 1 H, Dpr-CpHH'), 3.35-3.18 (m, HVA-CH2-CO, Dpr-CpHH', Omicronpiiota-OmicrondeltaEta2, Phe-CpHH'), 3.04-2.96 (m, 1 H, Phe-CpHH'), 2.35 (s, 3 H, BMBA-Ar-CH3), I.81-1.74 (m, 1 H, Orn-CpHH'), 1.68-1.52 (m, 3 H, Orn-CpHH', Orn-CYH2). 13C MR (125 MHz, DMSO-d6 ): S= 171.79, 171.39, 171.25, 171.17, 164.70, 164.52, 147.13, 144.94, 140.65, 139.46, 138.30, 136.49, 135.51, 133.34, 130.75, 130.32, 129.00, 127.92, 126.62, 126.54, 126.10, 123.78, 121.26, 1 15.05, 1 13.13, 94.53, 55.37, 54.77, 53.01, 52.80, 41.74, 40.57, 36.68, 28.99, 25.46, 22.26. MS (ESI): calculated for [M], 954, found [M+H]+ 955. HPLC purity analysis: > 95% (UV, lambda = 254 nm). Figure 18 depicts the synthesis of Compound 8: (a) 30% piperidine/DMF; (b) Fmoc-Dpr(Boc)-OH/HBTU/HOBt/NMM; (c) <strong>[147290-11-7]Fmoc-Orn(Alloc)</strong>- OH/HBTU/HOBt/NMM; (d) Fmoc-Phe-OH/HBTU/HOBt/NMM; (e) 3-bromo-4- methylbenzoic acid/HBTU/HOBt/NMM; (f) Pd(0)/NMM/AcOH; (g) 3 -iodobenzoic acid/HBTU/HOBt/NMM; (h) 95% TFA/H2O/TIS; (i) homovanillic acid/HBTU/HOBt/NMM.
General procedure: General Procedure A for Rink Amide Resin Activation. Rink amide resin (Advanced ChemTech) was mixed with DCM (1 mL per 100 mg resin) and then shaken for 30 minutes. After activation, resin was washed three times with DMF (1 mL per 100 mg resin). [0079] General Procedure B for the Removal of the Fmoc Group from the Rink Amide Resin. Rink amide resin was mixed with 20% piperidine in DMF (1 mL per 100 mg resin) and shaken for 30 minutes, and then washed with DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times) sequentially. The removal of the Fmoc group was confirmed by the ninhydrin test.General Procedure C for the Removal the Alloc Group from the Rink Amide Resin. The resin (200 mg) was washed with DCM (2 mL, 5 times) and shaken under 2 overnight with a solution of tetrakis(triphenylphosphine)palladium(0) (10 mg), AcOH (0.5 mL), and NMM (0.2 mL) in DCM (10 mL). The resin was then washed with DMF (2 mL, 3 times), isopropanol (2 mL, 3 times), and DCM (2 mL, 3 times). The removal of the Alloc group was confirmed by the ninhydrin test.General Procedure E for the Coupling of Carboxylic Acids to the Rink Amide Resin. Carboxylic acids (5 equiv, 0.5 M in DMF) were first mixed with HBTU (5 equiv, 0.5 M in DMF), HOBt (5 equiv, 0.5 M in DMF), and NMM (15 equiv, 1.5 M inDMF). The mixed solution was then added to the resin and shaken for 2 hours. The resin was then washed with DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times). The completion of the coupling reaction was confirmed by the ninhydrin test. [0083] General Procedure F for Peptide Cleavage from the Rink Amide Resin. The resin was washed with DCM (1 mL per 100 mg resin, 5 times) and subsequently shaken with a solution of 95% TFA, 2.5% TIS, and 2.5% H20 (1 mL per 100 mg resin) for 2 hours. The resin was removed by filtration, and the TFA was evaporated under vacuum. The crude peptide was obtained after trituration with diethyl ether (5 mL per 100 mg resin, 2 times). Compound 7 was synthesized using standard Fmoc chemistry on the Rink amide resin (Figure 17). The resin (200 mg, 0.7 mmol/g loading) was first activated by DCM (General procedure A). The Fmoc group on the resin was removed by piperidine in DMF (General procedure B). The resin was then coupled with Fmoc-Dpr(Boc)-OH. The Fmoc group on the resin was removed by piperidine in DMF (General procedure B). The resin was then coupled with <strong>[147290-11-7]<strong>[147290-11-7]Fmoc-Orn(Alloc)</strong>-OH</strong>. The Fmoc group was removed (General procedure B) and Fmoc-F2Pmp-OH was attached to resin (General procedure E). The Fmoc group was again removed (general procedure B) and the amine group on the F2Pmp residue was coupled with BMBA (general procedure E). The resin was treated with Pd(0) for the deprotection of Alloc group (general procedure C). 3-Iodobenzoic acid (mlBA) was attached to resin (general procedure E). The resin was treated with TFA (general procedure F) to give the crude peptide intermediate, which was treated with a mixture of HVA (0.5 M in DMF, 100 LL), HBTU (0.5 M in DMF, 100 LL), HOBt (0.5 M in DMF, 100 LL) and NMM (1.5 M in DMF, 100 mu,) to give the crude product 7. The crude product was purified by HPLC to afford compound 7 (21.5 mg, 14% yield). The assignment of proton NMR utilized additional information from COSY. 1H NMR (500 MHz, CD3OD): delta= 8.16 (s, 1 H, mlBA-ArH), 7.92 (s, 1 H, BMBA-ArH), 7.86 (d, J= 7.9 Hz, 1 H, mlBA-ArH), 7.78 (d, J= 7.9 Hz, 1 H, mlBA-ArH) 7.64 (d, J= 8.2 Hz, 1 H, BMBA-ArH), 7.58-7.52 (m, 3 H, BMBA-ArH, F2Pmp-ArH), 7.39 (d, J= 7.9 Hz, 2 H, F2Pmp-ArH) 7.27 (d, J= 8.2 Hz, 1 H, BMBA-ArH), 7.21-7.16 (m, 1 H, mlBA-ArH), 6.81- 6.78 (m, 1 H, HVA-ArH), 6.71-6.63 (m, 2 H, HVA-ArH), 4.83-4.80 (m, 1 H, F2Pmp- CH), 4.48-4.42 (m, 1 H, Dpr- CH), 4.30-4.24 (m, 1 H, Orn- CH), 3.77 (s, 3 H, HVA- OCH3), 3.63-3.58 (m, 1 H, Dpr- CpHH'), 3.51-3.45 (m, 1 H, Dpr- CpHH'), 3.41 - 3.33 (m, 5 H, Orn-C5H2, F2Pmp-CpHH', HVA-CH2-CO-), 3.16-3.09 (m, 1 H, F2Pmp-CpHH'), 2.39 (s, 3 H, BMBA-Ar-CH3). 1.92-1.85 (m, 1 H, Orn-CpHH'), 1.75-1.62 (m, 3 H, Orn-CpHH', Orn-CYH2). 13C MR (125 MHz, CD30D): delta= 175.72, 174.20, 174.15, 168.85, 168.48, 148.97, 146.60, 143.20, 141.53, 141.41, 137.67, 137.41, 134.42, 132.45, 131.95, 131.35, 130.25, 127.83, 127.63, 127.60 127.53, 125.65, 122.83, 1 16.30, 1 13.84, 101.39, 94.73, 56.73, 56.43, 55.33, 43.37, 42.17, 4Figure 17 depicts the synthesis of Compound 7: (a) 30% piperidine/DMF; (b) Fmoc-Dpr(Boc)-OH/HBTU/HOBt/NMM; (c) <strong>[147290-11-7]Fmoc-Orn(Alloc)</strong>- OH/HBTU/HOBt/NMM; (d) Fmoc-F2Pmp-OH/HBTU/HOBt/NMM; (e) 3-bromo-4- methylbenzoic acid/HBTU/HOBt/NMM; (f) Pd(0)/NMM/AcOH; (g) 3 -iodobenzoic acid/HBTU/HOBt/NMM; (h) 95% TFA/H2O/TIS; (i) homovanillic acid/HBTU/HOBt/NMM.0.39, 37.76, 29.54, 26.96, 23.03. MS (ESI): calculated for [M], 1084, found [M+H]+ 1085. HPLC purity analysis: > 95% (UV, lambda = 254 nm).
General procedure: General Procedure A for Rink Amide Resin Activation. Rink amide resin (Advanced ChemTech) was mixed with DCM (1 mL per 100 mg resin) and then shaken for 30 minutes. After activation, resin was washed three times with DMF (1 mL per 100 mg resin). [0079] General Procedure B for the Removal of the Fmoc Group from the Rink Amide Resin. Rink amide resin was mixed with 20% piperidine in DMF (1 mL per 100 mg resin) and shaken for 30 minutes, and then washed with DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times) sequentially. The removal of the Fmoc group was confirmed by the ninhydrin test.General Procedure C for the Removal the Alloc Group from the Rink Amide Resin. The resin (200 mg) was washed with DCM (2 mL, 5 times) and shaken under 2 overnight with a solution of tetrakis(triphenylphosphine)palladium(0) (10 mg), AcOH (0.5 mL), and NMM (0.2 mL) in DCM (10 mL). The resin was then washed with DMF (2 mL, 3 times), isopropanol (2 mL, 3 times), and DCM (2 mL, 3 times). The removal of the Alloc group was confirmed by the ninhydrin test.General Procedure E for the Coupling of Carboxylic Acids to the Rink Amide Resin. Carboxylic acids (5 equiv, 0.5 M in DMF) were first mixed with HBTU (5 equiv, 0.5 M in DMF), HOBt (5 equiv, 0.5 M in DMF), and NMM (15 equiv, 1.5 M inDMF). The mixed solution was then added to the resin and shaken for 2 hours. The resin was then washed with DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times). The completion of the coupling reaction was confirmed by the ninhydrin test. [0083] General Procedure F for Peptide Cleavage from the Rink Amide Resin. The resin was washed with DCM (1 mL per 100 mg resin, 5 times) and subsequently shaken with a solution of 95% TFA, 2.5% TIS, and 2.5% H20 (1 mL per 100 mg resin) for 2 hours. The resin was removed by filtration, and the TFA was evaporated under vacuum. The crude peptide was obtained after trituration with diethyl ether (5 mL per 100 mg resin, 2 times). Compound 5 was synthesized using standard Fmoc chemistry on the Rink amide resin (Figure 15). The resin (200 mg, 0.7 mmol/g loading, 0.14 mmole) was first activated by DCM (General procedure A). The Fmoc group on the resin was removed by piperidine in DMF (General procedure B). The resin was then coupled with <strong>[147290-11-7]<strong>[147290-11-7]Fmoc-Orn(Alloc)</strong>-OH</strong> (general procedure E). The Fmoc group was removed (General procedure B) and Fmoc-F2Pmp-OH was attached to resin (General procedure E). The Fmoc group was again removed (general procedure B) and the resin was couple with BMBA (general procedure E). The resin was treated with Pd(0) for the deprotection of Alloc group (general procedure C). 3-Iodobenzoic acid (mlBA) was attached to resin (general procedure E). Compound 5 was cleaved from beads (General procedure F). Crude peptide was purified by HPLC to afford 5 (13.6 mg, 12% yield). The assignment of proton NMR utilized additional information from COSY. 1H NMR (500 MHz, CD3OD): delta= 8.14 (s, 1 H, mlBA-ArH), 7.98 (s, 1 H, BMBA-ArH), 7.84 (d, J= 7.9 Hz, 1 H, mlBA-ArH), 7.76 (d, J= 7.9 Hz, 1 H, mlBA-ArH) 7.64 (d, J= 8.2 Hz, 1 H, BMBA-ArH), 7.51 (d, J= 7.9 Hz, 2 H, F2Pmp- ArH), 7.38 (d, J= 7.9 Hz, 2 H, F2 Pmp- ArH) 7.31 (d, J= 8.2 Hz, 1 H, BMBA-ArH), 7.21-7.17 (m, 1 H, mlBA-ArH), 4.79-4.73 (m, 1 H, F2Pmp-CaH), 4.41-4.34 (m, 1 H, Orn-CaH), 3.40-3.32 (m, 2 H, Orn-C5H2 ), 3.20- 3.15 (m, 2 H, F2Pmp-CpH2), 2.41 (s, 3 H, BMBA-Ar-CH3). 1.82-1.75 (m, 1 H, Orn- CpHH'), 1.75-1.61 (m, 3 H, Orn-CpHH', Orn-CYH2). 13C NMR (125 MHz, CD3OD): delta= 173.28, 168.65, 143.18, 141.53, 137.75, 137.39, 134.53, 132.51, 131.98, 131.36, 130.35, 127.64, 127.59, 125.70, 94.75, 57.05, 40.40, 38.44, 30.44, 26.76, 23.07. MS (ESI):calculated for [M], 834, found [M+H]+ 835. HPLC purity analysis: > 95% (UV, lambda = 254 nm).Figure 15 depicts the synthesis of Compound 5: (a) 30% piperidine/DMF; (b) <strong>[147290-11-7]<strong>[147290-11-7]Fmoc-Orn(Alloc)</strong>-OH</strong>/HBTU/HOBt/NMM; (c) Fmoc-F2Pmp-OH/HBTU/HOBt/NMM; (d) 3-bromo-4-methylbenzoic acid/HBTU/HOBt/NMM; (e) Pd(0)/NMM/AcOH; (f) 3- iodobenzoic acid /HBTU/HOBt/NMM; (g) 95% TFA/H2O/TIS.
General procedure: Compound 3 was synthesized using standard Fmoc chemistry on the Rink amide resin (Figure 13). The resin (200 mg, 0.7 mmol/g loading, 0.14 mmol) was first activated by DCM (General procedure A). The Fmoc group on the resin was removed by piperidine in DMF (General procedure B). The resin was then coupled with <strong>[147290-11-7]<strong>[147290-11-7]Fmoc-Orn(Alloc)</strong>-OH</strong> (general procedure E). The Fmoc group was removed (General procedure B) and Fmoc-F2Pmp-OH was attached to resin (General procedure E). The Fmoc group was again removed (general procedure B) and the amine group on the F2Pmp residue was capped by AcOH (general procedure E). The resin was treated with Pd(0) for the deprotection of Alloc group (general procedure C). 3- Iodobenzoic acid (mlBA) was attached to resin (general procedure E). Compound 3 was cleaved from beads (General procedure F). Crude peptide was purified by HPLC to afford 3 (15.1 mg, 16% yield). The assignment of proton NMR utilized additional information from COSY. NMR (500 MHz, CD3 OD): delta= 8.17 (s, 1 H, mlBA-ArH), 7.87 (d, J= 7.9 Hz, 1 H, mlBA-ArH) 7.79 (d, J= 7.9 Hz, 1 H, mlBA-ArH) 7.50 (d, J= 7.9 Hz, 2 H, F2Pmp-ArH), 7.33 (d, J= 7.9 Hz, 2 H, F2Pmp-ArH), 7.24-7.20 (m, 1 H, mlBA-ArH), 4.59- 4.53 (m, 1 H, F2Pmp-CaH), 4.37-4.32 (m, 1 H, Orn-CaH), 3.40-3.32 (m, 2 H, Orn-C6H2 ), 3.07-3.02 (m, 2 H, F2Pmp-CpH2 ), 1.94 (s, 3 H, - COCH3). 1.80-1.71 (m, 1 H, Orn- CpHH'), 1.68-1.54 (m, 3 H, Orn-CpHH', Orn-CYH2). 13C NMR (125 MHz, CD30D): delta= 173.32, 173.16, 141.53, 140.72, 137.78, 137.35, 131.36, 130.32, 127.59, 94.68, 56.43, 40.36, 38.63, 30.40, 26.72, 22.37. MS (ESI): calculated for [M], 680, found [M+H]+ 681. HPLC purity analysis: > 95% (UV, lambda = 254 nm).Figure 13 depicts the synthesis of Compound 3: (a) 30% piperidine/DMF; (b) <strong>[147290-11-7]<strong>[147290-11-7]Fmoc-Orn(Alloc)</strong>-OH</strong>/HBTU/HOBt/NMM; (c) Fmoc-F2Pmp-OH/HBTU/HOBt/NMM; (d) AcOH/HBTU/HOBt/NMM; (e) Pd(0)/NMM/AcOH; (f) 3-iodobenzoic acid /HBTU/HOBt/NMM; (g) 95% TFA/H2O/TIS.
With di-tert-butyl peroxide; copper(II) bis(trifluoromethanesulfonate); In 1,2-dichloro-ethane; at 130℃; for 12h;Sealed tube;
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.
(R)-methyl 2-(3-iodobenzamido)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With triethylamine; HATU; In dichloromethane; at 20℃;
General procedure: To a suspension of carboxylic acid (1.0 eq.), amine or amine. HCI salt (1.05 - 1.1 eq.) and HATU (1.1 - 1.3 eq.) in dry DCM (10 mL/g) was added DIPEA or TEA (2.0 - 3.0 eq.). The reaciton was stirred at rt until complete by LCMS. The volatiles were removed in vacuo and the residue partitioned between EtOAc (20 mL/g) and sat. aq. ammonium chloride (20 mL/g). The aqueous layer was extracted with EtOAc (2 x 20 mL/g) before the combined organic extracts were washed with sat. aq. ammonium chloride (30 mL/g), water (30 mL/g) then brine (30 mL g) and dried (MgS04 or Na2S04), filtered and concentrated in vacuo. The crude material was purified by column chromatography.; Using the general procedure described for amide coupling, the reaction of 3- iodobenzoic acid (22.3 g, 90 mmol), (R)-methyl 2-aminopropanoate.HCI (13.55 g, 97 mmol), HATU (37.6 g, 99 mmol) and TEA (31.3 ml, 225 mmol) in dry DCM (200 mL) gave the title compound (R)-methyl 2-(3-iodobenzamido)propanoate (41 g, 96% yield) as a pale yellow oil. No purification required. ( H) DMSO-d6: 1.40 (3H, d, J = 7.3 Hz), 3.64 (3H, s), 4.47 (1 H, qn, J = 7.3 Hz), 7.30 (1 H, t, J = 7.8 Hz), 7.89 (1 H, ddd, J = 1.1 , 1.6, 7.8 Hz), 7.93 (1 H, ddd, J = 1.0, 1.7, 7.8 Hz), 8.25 (1 H, t, J = 1.6 Hz), 8.92 (1 H, d, J = 6.8 Hz) ppm. MS(ES+) m/z 334.0 (M+H).
96%
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃;
General procedure: General method for amide coupling:To a suspension of carboxylic acid (1.0 eq.), amine oramine.HCI salt (1.05- 1.1 eq.) and HATU(1.1 -1.3 eq.) in dry DCM (10 mL/g)was added DIPEA0rTEA(2.0-3.0 eq.). The reaciton was stirred at ii until complete by LCMS. The volatiles wereremoved in vacuo and the residue partitioned between EtOAc (20 mLg) and sat. aq. ammonium chloride (20 mLIg). The aqueous layer was extracted with EtOAc (2 x 20 mL/g) before the combined organic extracts were washed with sat. aq. ammonium chloride (30 mL/g), water (30 mL/g) then brine (30 mLIg) and dried (MgSO4 or Na2SO4), filtered and concentrated in vacuo. The crude material was purified bycolumn chromatography Using the general procedure described for amide coupling, the reaction of 3-iodobenzoic acid (22.3 g, 90 mmol), (R)-methyl 2-aminopropanoate.HCI (13.55 g, 97mmol), HATU (37.6 g, 99 mmol) and TEA (31.3 ml, 225 mmol) in dry DCM (200 mL)gave the title compound (R)-methyl 2-(3-iodobenzamido)propanoate (41 g, 96% yield)as a pale yellow oil. No purification required.(1H) DMSO-d6: 1.40 (3H, d, J- 7.3 Hz), 3.64 (3H, s), 4.47 (IH, qn, J= 7.3 Hz), 7.30(1H, t, J=7.8 Hz), 7.89 (IH, ddd, J= 1.1, 1.6, 7.8 Hz), 7.93 (IH, ddd, J- 1.0,1.7,7.8Hz), 8.25 (IH, t, J= 1.6 Hz), 8.92 (IH, d, J- 6.8 Hz) ppm.MS(ESi-) m/z 334.0 (M+H),
With water; palladium diacetate; potassium carbonate; at 20℃; under 760.051 Torr; for 9h;
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): delta = 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): delta = 165.9, 150.0, 136.4, 130.7, 123.8.
4-[3′-[4″-(3‴-iodobenzoyl)piperazine-1″-carbonyl]-4′-fluorobenzyl]-2H-phthalazin-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 20h;
EXAM PLE A.2. Compound c-1 (127l): 4-(4-fluoro-3-(4-(3-iodobenzoyl)piperazine-l-carbonyl)benzyl)- phthalazin-l(2H)-one. (0301) [0148] To a solution of 4-(4-fluoro-3-(piperazine-l-carbonyl)benzyl)phthalazin-l(2H)-one (10 mg, 0.0275 mmol), triethylamine (40 mu, 0.3 mmol) a nd H BTU (16 mg, 0.0413 mmol) in dimethyl formamide (DM F, 500 mu) was added to 3-iodobenzoic acid (6 mg, 0.0275 mmol). The mixtu re was stirred at room temperature for 20 h. The crude product was then purified by preparative HPLC and dried under vacuum, yielding a white solid (6.9 mg, 48% yield). 1H NM R (CDCIs) delta = 10.00 (s, 1H), 8.40-8.38 (m, 1H), 7.71-7.69 (m, 4H), 7.64-7.63 (m, 1H), 7.30-7.26 (m, 3H), 7.09 (m, 1H), 7.04-6.87 (m, 1H), 4.21 (s, 2H), 3.71-3.29 (m, 8H). LC-ESI-MS (+) m/z = 597.1 [M+H+]+. H RMS-ESI [M-H+]" m/z calculated for [C27H22FIN4O3]- 595.0642, found 595.0660.
General procedure: A mixture of the carboxylic acid (3-bromobenzoic acid) (14-Br) (10 g, 49.75 mmol), DMF (cat.amount), oxalyl chloride (74.62 mmol) in THF (100 mL) was stirred at room temperature for 2 hrs. Afterthe mixture was concentrated to dryness in vacuo, a solution of the amine (4a) (49.75 mmol) in DMA (80mL) was added at 0C thereto. The mixture was stirred overnight at room temperature, diluted with anaqueous NaHCO3 solution and extracted with AcOEt. The organic layer was separated, washed with water, dried over Na2SO4. After the solvent was distilled off under reduced pressure, the resulting crude productwas purified by silica gel column chromatography to afford the corresponding amide (15-Br) as a solid(11.51g, 63%).
With C10H16N2O8*Cl2Pd; potassium carbonate; In water; at 100℃; for 5h;
3-iodobenzoic acid (24) 1. 8g, 5-methyl-2-boronic acid (25) 1. 1g, potassium carbonate 2. 9g suspended in 50 ml distilled water. In its suspension, Tetrahedron Letters, vol. 49 (2005), adjusted by the method stated in 5751-5754 a 1 ml of an aqueous solution of palladium chloride (II)-EDTA complex is added, with stirring 100 °C 5 time. After the reaction is completed, 1, 2-dichloroethane by using an aqueous solution of sodium bicarbonate and filtered through sedum light. In addition to the water layer 1N hydrochloric acid, acidic, 2 times the extracted with ethyl acetate. The organic layer, washed with saturated saline, anhydrous magnesium sulfate and dry, solvent distillation under reduced pressure. The precipitated crystal Phenylbicyclohexane using filtered cleaning, 3-(5-methyl-2-yl)-benzoic acid (26) 1. 4g is obtained.
With triphenyl phosphite; chloro(1,5-cyclooctadiene)rhodium(I) dimer; caesium carbonate; In toluene;Reflux; Inert atmosphere;
In a 250 ml reaction flask, 10 g of <strong>[186663-74-1]tert-butyl N-(2-hydroxyphenyl)carbamate</strong> and 13 g of 3-iodobenzoic acid were added.0.85 g RhCl(cod) 2, 1.5 g triphenyloxyphosphine, 46 g cesium carbonate and 100 ml toluene,The reaction was refluxed under nitrogen and the reaction was monitored by TLC.Add 100 ml of water, extract with ethyl acetate, dry and concentrate to give the product(13 g, yield: 83%, HPLC purity: 97%).
General procedure: Complex 1 was prepared by the reaction of an aqueous solution of copper(II) acetate monohydrate (1mmol, 0.20g) with N-methylnicotinamide (2mmol, 0.27g) followed by addition of 4-fluorobenzoic acid (2mmol, 0.28g). The reaction mixture was stirred until a blue product was precipitated (3days). The fine blue microcrystals were filtered off, washed with a small portion of water and dried at ambient temperature. The mother liquor obtained from filtration were left to crystallize. The blue crystals suitable for X-ray structure determination were separated after several days. Yield: 0.41g (65%).
With dmap; 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 tetrahydrofuran; at 20℃; for 0.5h;
Put 3-iodobenzoic acid (750mg, 3mmol), HATU (1.4g, 3.6mmol), DMAP (440mg, 3.6mmol) and DIEA (460mg, 3.6mmol) in a 100mL eggplant-shaped bottle, add 30ml of tetrahydrofuran, stir at room temperature After 20 min, methylamine hydrochloride (240 mg, 3.6 mmol) was added, and stirring was continued at room temperature for 30 min. The reaction was monitored by TLC, the solvent was evaporated to dryness, dichloromethane was added to dissolve, and washed once with 10% hydrochloric acid solution, water, saturated sodium bicarbonate solution, water and saturated sodium chloride solution. Dry over anhydrous sodium sulfate, filter and evaporate to give a colorless oily liquid. The yield was 93%.
With 4,4'-dimethyl-2,2'-bipyridines; 1,2-bis(diphenylphosphino)ethane nickel(II) chloride; methylphenylsilane; acetic anhydride; In tetrahydrofuran; at 60℃; for 8h;Schlenk technique; Inert atmosphere;
In a dry 10mL Schlenk reaction tube, add 3-iodobenzoic acid (124mg, 0.50mmol), and then add L3 (9mg, 0.050mmol), NiCl2 (dppe) (9.6mg, 0.025mmol) in order, under the protection of argon, THF (1.0 mL) was added,Acetic anhydride (95 muL, 1 mmol), H2SiMePh (76 muL, 0.55 mmol),Reaction at 60 C for 8h.After the reaction is completed, extraction is performed, and the solvent is removed under reduced pressure.Column chromatography (petroleum ether / ethyl acetate = 13/1, volume ratio) gave the target product C.Experimental data of the compound Experimental data of the compound:White solid, isolated yield 78%,
With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;Inert atmosphere;
First, 3-adibo-3-oxopropyl-3'-iodobenzamide (3-ADIBO-3-oxopropyl-3'-iodobenzamide) represented by Formula B is 3-iodobenzoic acid ( 3-Iodobenzoic acid) (42.5 mg, 0.171 mmol), ADIBO-amine (43 mg, 0.156 mmol), TBTU (64.9 mg, 0.202 mmol) and HOBt (27.3 mg, 0.202 mmol) in Rb Anhydrous DMF (2 mL) and DIEA (40.7 uL, 0.233 mmol) were added thereto, and the mixture was stirred at room temperature for 4 hours. An organic layer was obtained by extraction with a saturated aqueous solution of ethylacetate (Ethylacetate)/NH4Cl, washed with a saturated aqueous solution of NaHCO3, and passed through anhydrous Na2SO4Pad to remove remaining moisture and then reduced pressure. Silicagel Flash Column Chromatography (60% EtOAc/Hexane) was performed to obtain 50 mg (pale yellow foamy solid, 63%).
Stage #1: 4-methoxy-2-methyl-benzaldehyde; 1-amino-4-[(tert-butyloxycarbonyl)amino]butane; dodecane-1-isonitrile; meta-carboxy iodo-benzene In methanol at 60℃; for 3.5h; Sealed tube; Irradiation;
Stage #2: With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 0.5h;
General procedure for the synthesis of compounds 8a-x
General procedure: A mixture of N-Boc-1,4-diaminobutane (1 eq.), paraformaldehyde orthe corresponding aldehyde (1 eq.), 3-iodobenzoic acid (1 eq.), thecorresponding alkyl isocyanide (1 eq.) and MeOH (0.8 M) were introducedin a microwave vial, the reaction was sealed and irradiated at60 C for 3.5 h. After this time, the solvent was evaporated, and thecrude was used in the next step. The crude was dissolved in dichloromethane(4.5 mL), trifluoroacetic acid (1.1 mL) was added dropwise at0 C, and the reaction mixture was stirred for 30 min at room temperature.After completion of the reaction, the product was concentratedunder vacuum and the crude was dissolved with ethyl acetate andwashed with an aqueous solution of NaOH (2 × 20 mL) and water (2 ×20 mL); the organic layer was dried over sodium sulphate and evaporatedunder vacuum, to obtain compound 8a-x. The crude product ofcompounds 8a-x was used in the next reactions.
Stage #1: 4-methoxy-2-methyl-benzaldehyde; 1-amino-4-[(tert-butyloxycarbonyl)amino]butane; dodecane-1-isonitrile; meta-carboxy iodo-benzene In methanol at 60℃; for 3.5h; Sealed tube; Irradiation;
Stage #2: With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 0.5h;
General procedure for the synthesis of compounds 8a-x
General procedure: A mixture of N-Boc-1,4-diaminobutane (1 eq.), paraformaldehyde orthe corresponding aldehyde (1 eq.), 3-iodobenzoic acid (1 eq.), thecorresponding alkyl isocyanide (1 eq.) and MeOH (0.8 M) were introducedin a microwave vial, the reaction was sealed and irradiated at60 C for 3.5 h. After this time, the solvent was evaporated, and thecrude was used in the next step. The crude was dissolved in dichloromethane(4.5 mL), trifluoroacetic acid (1.1 mL) was added dropwise at0 C, and the reaction mixture was stirred for 30 min at room temperature.After completion of the reaction, the product was concentratedunder vacuum and the crude was dissolved with ethyl acetate andwashed with an aqueous solution of NaOH (2 × 20 mL) and water (2 ×20 mL); the organic layer was dried over sodium sulphate and evaporatedunder vacuum, to obtain compound 8a-x. The crude product ofcompounds 8a-x was used in the next reactions.
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