* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 30℃; for 0.25 h; Stage #2: at 30℃; for 16 h;
[0171] To a stirred mixture of 4-bromobenzoic acid (2.00 g,10.0 mol) and Et3N (3.03 g, 30.0 mmol) in DCM (30 mL) wasadded HATU (4.18 g, 11.0 mmol) at 30° C. After 15 mins,pyrrolidine (972 mg, 12.0 mmol) was added into the mixture,which was stirred at 30° C. for 16 hrs. After LCMS and TLC(PE:Et0Ac=2: 1) showed the reaction was complete, the mixturewas concentrated and purified by colunm chromatographyon silica gel (PE:EtOAc=l:0-20:1-10:1-5:1-3:1) to givethe title compound (2.20 g, yield: 86.9percent) as a white solid.
With dmap In <i>tert</i>-butyl alcohol at 20℃; for 12 h;
Tert-butyl 4-bromobenzoate. To a solution of 4-dimethylamiopryidine (1.5 g, 12.5 mmol) in tert-butanol (20 mL) were added 4-bromobenzoic acid (5 g, 25 mmol) and di-tert-butyl dicarbonate (10.95 g, 0.05 mol). The mixture was stirred at 20°C for 12 hours. The resultant mixture was concentrated in vacuo to give a residue and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 30: 1) to give tert-butyl 4- bromobenzoate (4 g, 62percent>).
62%
With dmap In <i>tert</i>-butyl alcohol at 20℃; for 12 h;
To a solution of 4-dimethylamiopryidine (1.5 g, 12.5 mmol) in tert-butanol (20 mL) were added 4-bromobenzoic acid (5 g, 25 mmol) and di-tert-butyl dicarbonate (10.95 g, 0.05 mol). The mixture was stirred at 20° C. for 12 hours. The resultant mixture was concentrated in vacuo to give a residue and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=30:1) to give tert-butyl 4-bromobenzoate (4 g, 62percent).
21%
With dmap In <i>tert</i>-butyl alcohol at 50℃;
To a 1000-mL round-bottom flask was added 4-bromobenzoic acid 52a (20 g, 99.495 mmol, 1.0 equiv.), tert-butano (200 mL), 4-dimethylaminopyridine (1.22 g, 9.99 mmol, 0.10equiv.), and Boc20 (32 7 g, 149.83 mmoL 150 equiv) and the resulting mixture ·was stirredat 50 °C ovemight. The mixture was diluted vvith 200 mL of H20 and extracted with ethylacetate (300 mL x 2). "fl1e combined organic extracts were washed with brine (300 mL x 2),dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thel 0 crude product was purified by Flash-Prep-HPLC using the following conditions: Column,silica gel; mobile phase, PE:EA = 100:0 increasing to 90:10 over 5 min; Detector, UV 254nm, to provide 5.43 g (21 percent) oftert-butyl4-bromobenzoate 52b as a colorless oil.
tert-Butyl 4-bromobenzoate. To a solution of 4-dimethylaminopyridine (1.5 g, 12.5 mmol) in tert-butanol(20 mL) were added 4-bromobenzoic acid (5.0 g, 25 mmol) and di-tert-butyldicarbonate (10.95 g, 50 mmol). The mixture was stirred at 20 °C for 12 h. The resultant mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (petroleumether/ethyl acetate = 30:1) to provide tert-butyl 4-bromobenzoate (4.0 g, 62percent).
55%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In chloroform at 20℃; for 18 h;
To a solution of 4-bromobenzoic acid (lOg, 49.7 mmol) in Chlorofonri (150 ml), 2- methylpropan-2-ol (18.44g, 249 mmol), EDC.HC1 (23.84g, 124 mmol), followed by DMAP (15.19g, 124 mmol) was added and stined for 18h at room temperature. After completion of reaction as indicated by TLC, the mixture was poured into water and extracted with DCM. The organic layer was collected and dried over sodium sulphate,finally evaporated and purified by column chromatography (7g, 55 percent). 1H NMR (400MHz, Chloroform-d) 7.87 (d, 2H), 7.57 (d, 2H), 1.61 (s, 9H).
49 g
With dmap; diisopropyl-carbodiimide In dichloromethane at 35℃; for 5 h;
In dichloromethane, 4-bromobenzoic acid (50 g), tert-butyl alcohol (20.3 g), and dimethylaminopyridine (12.2 g) were dissolved. The resulting solution was added drop- wise to diisopropylcarbodiimide (DIC, 37.7 g) at 35° C. The resulting mixture was stirred for 5 hours. Subsequently, the reaction liquid was filtered, and the filtrate was concentrated. The resulting solid was purified by column chromatography. Hereby, the compound M- 1 (49 g) was prepared
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 17, p. 3644 - 3649
[2] Patent: WO2017/37682, 2017, A1, . Location in patent: Page/Page column 91
[3] Patent: US2017/260150, 2017, A1, . Location in patent: Paragraph 0169; 0170
16
[ 586-76-5 ]
[ 865-47-4 ]
[ 59247-47-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8564 - 8572
17
[ 586-76-5 ]
[ 59247-47-1 ]
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 35, p. 14042 - 14053
[2] Journal of Materials Chemistry, 2012, vol. 22, # 15, p. 7366 - 7379
[3] Journal of Organic Chemistry, 2013, vol. 78, # 17, p. 8705 - 8711
18
[ 586-76-5 ]
[ 6319-40-0 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 0 - 20℃; for 5 h;
p-Brombenzoic acid (8, 5.00 g, 24.9 mmol) was slowly added in portions to a cold mixture (0 °C) of conc. nitric acid (6.2 mL, 0.15 mmol) and conc. sulfuric acid (15.2 mL, 300 mmol). The addition was performed in such a way that the temperature did not exceed 5 °C. After stirring for 3 h at 0 °C and 2 h at room temp., the mixture was poured on ice-containing water. The resulting colourless solid was filtered off and washed extensively with water. Yield: 6.00 g (24.4 mmol, 98percent) (ref.[2]: 96percent), m. p. 202 °C. 1H NMR (200 MHz, DMSO-d6): δ = 8.46 – 8.42 (m, 1H, Ar-H-2), 8.09–8.05 (m, 2H, Ar-H-5,6) ppm. 13C NMR (50 MHz, DMSO-d6): δ = 165.0 (s, CO2H), 149.7 (s, Ar-C-3), 135.4 (d, Ar-C-6), 132.4 (d, Ar-C-5), 131.7 (s, ArC-1), 125.9 (d, Ar-C-2), 118.0 (Ar-C-4) ppm. MS (EI, 70 eV): m/z = 245/247 (95/100) [M]+·. MS (CI, isobutane): m/z = 246/248 (100/99) [M + H]+. IR (ATR): ν = 3082 (arylH), 2820 (br., OH), 1684 (C=O), 1595 (arom. C=C), 1530, 1303 (NO2), 1034 (aryl-Br), 907, 809 (1,2,4-trisubst. aryl) cm-1
96%
at 0 - 20℃; for 2 h;
Example 65; 4-Bromo-3-nitrobenzoic acid (43) (Scheme 9); Fuming nitric acid (12.4 mL, 0.3 mol) was slowly added to conc. sulfuric acid (30.1 mL, 0.6 mol) at 0-5° C. The cooled nitrating mixture was taken in a beaker equipped with a mechanical stirrer and addition funnel. 4-Bromotoluic acid 42 (40 g, 0.2 mol) was added to this mixture in small portions over 5 hours at such a rate to maintain the temperature at 0-5° C. The reaction mixture was stirred further for additional 2 h at room temperature and then poured over ice. The solid that separated was filtered, washed with water till it was free of acid and then air dried to constant weight to give the pure compound 43. White solid (47.2 g, 96percent). 1H NMR (300 MHz, CDCl3): δ 7.85 (d, J=12.0 Hz, 1H); 8.09 (d, J=12.0 Hz, 1H); 8.48 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 124.2, 132.1, 135.2, 138.0, 139.8, 159.8, 171.0.
90%
Reflux
A 200 mL flask was charged with 4-bromobenzoic acid (9.84 g, 49.0 mmol), nitric acid (70percent, 90 mL) and fuming nitric acid (90percent, 70 mL), fitted with a reflux condenser and the resulting suspension was stirred under reflux overnight. The homogeneous yellow solution obtained was cooled to 0 °C, filtered and the solid washed with cold water (100 mL) to yield a white powder. Recrystallization from methanol/water afforded the product (10.82 g, 44.0 mmol, 90percent) as a microcrystalline white powder. ‘H NMR (400 MHz, DMSO-d6) 13.74 (bs, 1H), 8.39 (s, 1H), 8.09—7.94 (m, 2H). ‘3C NMR (100 MHz, DMSO-d6) 165.0,149.6, 135.4, 133.8, 131.7, 126.0, 118.2.
88%
With nitric acid In water for 24 h; Heating / reflux
4-bromo-3-nitrobenzoic acid (1): IN AS 1 L flask, 4-bromobenzoic acid (50.0 g, 0.25 mol, Aldrich Co. ), nitric acid (450 mL) and fuming nitric acid (100 mL) were mixed and refluxed for 24 h. The mixture was cooled at 0°C and the white precipitate filtered through a Buecher funnel, washed thoroughly with water and dried under reduced pressure to provide 53.9 g of the title product as a white solid. M. P.: 202-204°C (Yield : 88percent). 1H NMR (300 MHz, Acetone-d6, ppm): 11.37 (s, 1H) ; 8.47 (d, 1H, J= 1. 9 HZ) ; 8.16 (dd, 1H, J= 6.6 and 1.6 Hz); 8.04 (d, 1H, J= 8.3 Hz). 13C NMR (75 MHz, Acetone-d6, ppm): 206.35 ; 165.07 ; 136.29 ; 134.55 ; 132.26 ; 126.90 ; 119.08.
Reference：
[1] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 2267 - 2273
[2] Patent: US2008/293736, 2008, A1, . Location in patent: Page/Page column 32
[3] Patent: WO2017/7634, 2017, A1, . Location in patent: Paragraph 0730; 0731; 0732
[4] Patent: WO2005/16882, 2005, A1, . Location in patent: Page/Page column 13
[5] Justus Liebigs Annalen der Chemie, 1884, vol. 222, p. 178 Anm. 1
[6] Justus Liebigs Annalen der Chemie, 1867, vol. 143, p. 241
[7] Patent: WO2015/143653, 2015, A1, . Location in patent: Page/Page column 56
[8] Patent: WO2015/148344, 2015, A2, . Location in patent: Page/Page column 104
[9] Patent: WO2015/143652, 2015, A1, . Location in patent: Page/Page column 46
[10] Patent: WO2016/161572, 2016, A1, . Location in patent: Page/Page column 74
[11] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 11, p. 1148 - 1152
19
[ 586-76-5 ]
[ 593-51-1 ]
[ 27466-83-7 ]
Yield
Reaction Conditions
Operation in experiment
90%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane
To stirred solution of 4-bromobenzoic acid (6.00 g, 29.8 mmol) in methylene chloride (80 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (6.30 g, 32.9 mmol), 4-(dimethylamino)pyridine (7.70 g, 63.0 mmol) and methylamine hydrochloride (2.23 g, 33.0 mmol). The mixture was stirred overnight and then washed with 1.0 N hydrochloric acid, dried (Na2S04) and concentrated. The crude material was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford 4-bromo-N-methylbenzamide as a white solid (5.80 g, 90percent). To a stirred solution of this compound (4.00 g, 18.9 mmol) in 1,4-dioxane (10 mL) was added bis(pinacolato)diboron (11.9 g, 46.8 mmol), potassium acetate (5.50 g, 56.1 mmol) and [Ι, - bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (0.410 g, 0.560 mmol). The mixture was heated at 90 °C overnight, filtered and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford N-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide as a white solid (4.50 g, 91percent). This compound and ethyl 2-(4-bromophenyl)-2-methylpropanoate were reacted according to General Procedure F to generate ethyl 2-methyl-2-(4'- (methylcarbamoyl)-[l,l'-biphenyl]-4-yl)propanoate as an off-white solid. To a stirred solution of this intermediate (1.00 g, 3.07 mmol) in a mixture of tetrahydrofuran (4 mL), methanol (8 mL) and water (3 mL) was added solid sodium hydroxide (0.640 g, 16.0 mmol). After stirring at room temperature overnight, the reaction was concentrated and taken up in water. The solution was made acidic (pH ~6) with 1 N hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2S04) and concentrated to afford 2-methyl-2-(4'-(methylcarbamoyl)-[l,l'-biphenyl]-4- yl)propanoic acid as a white solid (0.950 g, 100percent). This compound was used without purification and reacted with quinuclidin-3-ol according to General Procedure I to generate the title compound as an off-white solid. 1H NMR (500 MHz, DMSO- 6) δ 8.47 (q, J = 4.5 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 6.5 Hz, 2H), 7.67-7.65 (d, J = 8.5 Hz, 2H), 7.60 (s, 1H), 7.44 (d, J= 6.5 Hz, 2H), 4.43 (m, 1H), 3.76 (m, 1H), 2.81-2.63 (m, 7H), 2.47-2.36 (m, 1H), 1.85 (m, 2H), 1.56-1.34 (m, 9H) ppm. 13C NMR (125 MHz, CD3OD) δ 170.4, 156.9, 149.1, 145.3, 139.2, 134.1, 128.8, 127.9, 126.7, 71.4, 56.1, 55.9, 48.0, 47.0, 30.0, 29.9, 27.0, 26.5, 24.6, 20.0 ppm. Purity: 100percent (214 & 254 nm) LCMS; retention time: 1.72 min; (M+H+) 422.3.
42%
Stage #1: With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.0833333 h; Stage #2: at 20℃;
15-D-2 To a solution of 4-bromobenzoic acid (402.0mg, 2mmol) in DMF (10 mL), was added HATU(836.5mg, 2.2 mmol) and DIEA (697.0μL, 4mmol). After stirring for 5 minutes at room temperature, methylamine hydrochloride salt (135.0mg, 2mmol) was added. The solution was stirred at rt overnight. EPO <DP n="131"/>The reaction mixture was diluted with water and extracted two times with ethyl acetate. The combined extract was washed with saturated sodium bicarbonate, IM HCl and brine, dried over magnesium sulfate, filtered and concentrated to dryness to provide 15-D-l (181. lmg, 42.0percent) as white crystals.
Reference：
[1] Patent: WO2014/43068, 2014, A1, . Location in patent: Page/Page column 267; 268
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 7, p. 3094 - 3116
[3] Patent: WO2006/44497, 2006, A2, . Location in patent: Page/Page column 129-130
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 4, p. 1501 - 1504
25
[ 586-76-5 ]
[ 10602-00-3 ]
Reference：
[1] Revue Roumaine de Chimie, 2010, vol. 55, # 11-12, p. 989 - 994
[2] Patent: US2013/65248, 2013, A1,
[3] Journal of Materials Chemistry B, 2015, vol. 3, # 3, p. 491 - 497
[4] Patent: US9290791, 2016, B2,
26
[ 586-76-5 ]
[ 74-88-4 ]
[ 7697-28-1 ]
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 4, p. 1501 - 1504
27
[ 586-76-5 ]
[ 5720-07-0 ]
[ 725-14-4 ]
Yield
Reaction Conditions
Operation in experiment
99%
With potassium carbonate; palladium dichloride In PEG400; water at 20℃; for 0.133333 h; Air atmosphere
General procedure: A mixture of arylboronic acid (0.5 mmol), aryl bromides/iodides (0.6 mmol), PdCl2 (0.0025 mmol), K2CO3 (1.75 mmol), PEG400 1.5 mL, and H2O 1.5 mL were added to a 50 mL round-flask, and stirred at room temperature for the desired time until complete consumption of starting material as judged by TLC. Then, the reaction mixture was extracted with ether (10 mL.x.4) and the combined organic layers were dried over anhydrous MgSO4 (acidification was needed for carboxyl substituted substrates before extraction). The solvent was removed by evaporation under reduced pressure to afford the crude products, which were further purified by column chromatography on silica gel using petroleum ether and ethyl acetate as the eluent.
Reference：
[1] Tetrahedron, 2011, vol. 67, # 26, p. 4914 - 4918
[2] Asian Journal of Chemistry, 2014, vol. 26, # 7, p. 2077 - 2082
[3] Organic and Biomolecular Chemistry, 2014, vol. 12, # 25, p. 4511 - 4516
[4] Applied Organometallic Chemistry, 2014, vol. 28, # 12, p. 861 - 867
[5] Green Chemistry, 2010, vol. 12, # 1, p. 150 - 158
[6] Journal of the American Chemical Society, 2009, vol. 131, # 23, p. 8262 - 8270
[7] Green Chemistry, 2009, vol. 11, # 12, p. 1929 - 1932
[8] Journal of Medicinal Chemistry, 1997, vol. 40, # 20, p. 3144 - 3150
[9] Tetrahedron Letters, 2004, vol. 45, # 29, p. 5661 - 5663
28
[ 586-76-5 ]
[ 97302-05-1 ]
[ 725-14-4 ]
Reference：
[1] Chemistry - A European Journal, 2010, vol. 16, # 36, p. 11072 - 11081
Reference：
[1] Journal of Polymer Science, Part A: Polymer Chemistry, 2011, vol. 49, # 1, p. 211 - 224
[2] Molecular Crystals and Liquid Crystals, 2017, vol. 647, # 1, p. 395 - 404
39
[ 30752-18-2 ]
[ 586-76-5 ]
[ 99770-93-1 ]
[ 158938-08-0 ]
Yield
Reaction Conditions
Operation in experiment
95.8%
Stage #1: With palladium diacetate; caesium carbonate In water; N,N-dimethyl-formamide at 75℃; for 7 h; Inert atmosphere; Large scale Stage #2: for 10 h; Large scale
Add N,N-dimethylformamide to a prepared lanthanum carbonate solution (8600 g cesium carbonate + 20 L water) at room temperature20 L, 1000 g of 4-bromobenzoic acid, 1800 g of 1,4-benzenediboronic acid frenquol ester were added under stirring. System replaced with nitrogen The system was 3 times, and palladium acetate 40g was added as a catalyst. Under nitrogen protection, slowly warm up to 75°C and stir for 7h, keep the temperature constant and slow Slowly add 1220 g of 4-n-pentyloxy bromobenzene and 3 l of dimethylformamide solution, and continue the reaction for 8 h after the addition is completed in 2 h. After the reaction After being used, it is cooled to 6°C with a water bath, and 0.5M dilute aqueous hydrochloric acid solution is added dropwise to the system until the pH is 5 with stirring. Stir 2h. The filter cake and the filter cake were washed with water twice and ethanol was rinsed once to obtain the target product anidifene net intermediate—p-oxyl Triple benzoic acid. The white solid was dried at 60°C for 30 hours to obtain 1725 g of white solid, yield 95.8percent, HPLC: 99.99percent.
Reference：
[1] Patent: CN107759461, 2018, A, . Location in patent: Paragraph 0031-0042
40
[ 586-76-5 ]
[ 73183-34-3 ]
[ 180516-87-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 13, p. 4036 - 4040
The title compound was made as described in general procedure D using 4-bromo benzoic acid [(10G,] 49.4 mmol), 4-trifluoromethyl phenylboronic acid [(14.] 17g, 74.61 mmol), palladium tetrakis-triphenylphosphine (5.7g, 4.974 [MMOL)] and [2N NA2C03 AQ. SOLUTION] (150 mL, 149.2 [MMOL)] in 500 ml of Toluene. After the reaction is complete, the reaction mixture was neutralized with 2N HCI then filtered. The resulting solid was dissolved in ethyl acetate then passed through a short column of silica gel giving 9.7 g (75percent) of the compound as a white solid.
Reference：
[1] Tetrahedron Letters, 2005, vol. 46, # 34, p. 5751 - 5754
[2] Green Chemistry, 2010, vol. 12, # 1, p. 150 - 158
[3] Patent: WO2004/14844, 2004, A2, . Location in patent: Page 179; 181
[4] Journal of Medicinal Chemistry, 2007, vol. 50, # 20, p. 4939 - 4952
[5] Journal of Medicinal Chemistry, 1997, vol. 40, # 20, p. 3144 - 3150
[6] Tetrahedron Letters, 2004, vol. 45, # 29, p. 5661 - 5663
[7] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 2, p. 750 - 758
43
[ 586-76-5 ]
[ 1423-26-3 ]
[ 195457-70-6 ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; ethanol at 80℃; for 2 h; Stage #2: With hydrogenchloride In water; ethyl acetate
A portion of Pd(dppf)Cl2 (1.49 mmol, 1.09 g) was added to a suspension of 4-bromobenzoic acid 4a (14.9 mmol, 3.0 g), 3-trifluoromethylboronic acid 4b (17.9 mmol, 3.4 g), and Cs2CO3 (37.3 mmol, 12.2 g) in 30 mL of dioxane and 7.5 mL of EtOH. The mixture was stirred at 80° C. for 2 h. After cooling, the solid was collected by filtration and washed with MeOH. The filtrate was concentrated and partitioned between EtOAc and 1N aqueous HCl. The organic layer was washed with brine, dried over MgSO4, and concentrated. CH2Cl2 was added to the residue and the resulting solid was collected by filtration, washed with CH2Cl2, and dried to give 3.58 g (86percent yield) of compound 4c, which was used in the next step without further purification.
Reference：
[1] Patent: US2013/102584, 2013, A1, . Location in patent: Paragraph 0307; 0308
[2] Journal of Medicinal Chemistry, 1997, vol. 40, # 20, p. 3144 - 3150
44
[ 586-76-5 ]
[ 6638-79-5 ]
[ 192436-83-2 ]
Yield
Reaction Conditions
Operation in experiment
92%
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 18 h;
To a solution of 4-bromobenzoic acid, 5 g (586-76-5, 24.87 minol) in N,N-dimethylformamide, 30 mL, was added triethylamine, 13.9 mL (99.49 minol), N,O-dimethylhydroxylamine hydrochloride, 3.64 g (37.31 minol), 1-hydroxy-7-azabenzotriazole, 5.08 g (37.31 minol) and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 9.54 g (49.75 minol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was diluted with saturatedsolution of sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layers were washed with a saturated solution of sodium hydrogen carbonate, brine dried over solid sodium sulfate, filtered and concentrated under vacuum to give Intermediate 84, 5.6 g (92percent) as a colourless solid.1H NMR (400 MHz, CDCI3): 6 [ppm] = 3.34 (s, 3H), 3.52 (s, 3H), 7.50-7.65 (m, 4H).U PLC-MS (Method 3): R = 0.71 min., 93percent. MS (ESIpos): mz = [M÷H] 244, 246.
81%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 12 h;
A solution of 4-bromobenzoic acid (1.0 mg, 5.0 mmol), N,O-dimethylhydroxylamine hydrochloride (536 mg, 5.5 mmol), EDC·HCl (1.05 g, 5.5 mmol), and NEt3 (556 mg, 5.5 mmol) in DCM (30 mL) was allowed to stir at rt for 12 h. The reaction mixture was diluted with EtOAc (100 mL), and the organic phase was washed with water and dried over anhydrous Na2SO4. After removal of the solvent, the residue was purified by flash column chromatography (0-30percent EtOAc/hexanes) to afford 11 as a colorless oil (1.0 g, 81percent). 1H NMR (CDCl3, 600 MHz) δ 7.59 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 3.54 (s, 3H), 3.36 (s, 3H). HRMS (ESI+) calcd for C9H11BrNO2 (M+H)+ 243.9968, found 243.9970.
68%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 3 h;
General procedure: To a solution of 3-cyanobenzoic acid 8a (3.0 g, 19.7 mmol) in DMF was added N,O-dimethylhydroxylamine hydrochloride (2.0 g, 20.7 mmol), Et3N (2.88 mL, d = 0.73, 20.7 mmol) and EDC*HCl (4.0 g, 20.7 mmol). After the mixture was stirred for 3 h at room temperature, the solvent was removed in vacuo and the residue was dissolved in EtOAc, washed with 10percent citric acid, 10percent NaHCO3 and saturated NaCl, and dried over Na2SO4. Then, the solvent was removed to give a colorless oil of compound 9a (3.0 g, 79percent).
Reference：
[1] Patent: WO2018/86703, 2018, A1, . Location in patent: Page/Page column 252
[2] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 4, p. 686 - 692
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8564 - 8572
[4] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 14, p. 4279 - 4289
[5] MedChemComm, 2013, vol. 4, # 2, p. 443 - 449
[6] Patent: US2013/158031, 2013, A1, . Location in patent: Paragraph 0303; 0304
[7] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1098 - 1103
[8] Patent: WO2016/22448, 2016, A1, . Location in patent: Page/Page column 90
[9] Patent: US2018/305346, 2018, A1, . Location in patent: Paragraph 0099; 0100; 0101
45
[ 586-76-5 ]
[ 192436-83-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 9, p. 4189 - 4204
[2] Journal of Organic Chemistry, 2017, vol. 82, # 2, p. 1114 - 1126
46
[ 586-76-5 ]
[ 1117-97-1 ]
[ 192436-83-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 18, p. 5567 - 5571
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 20, p. 6088 - 6092
49
[ 586-76-5 ]
[ 252017-04-2 ]
Reference：
[1] Organic Process Research and Development, 2008, vol. 12, # 6, p. 1044 - 1059
[2] Organic Process Research and Development, 2008, vol. 12, # 6, p. 1044 - 1059
50
[ 586-76-5 ]
[ 179117-44-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 13, p. 4036 - 4040
A portion of Pd(dppf)Cl2 (1.49 mmol, 1.09 g) was added to a suspension of 4-bromobenzoic acid 4a (14.9 mmol, 3.0 g), 3-trifluoromethylboronic acid 4b (17.9 mmol, 3.4 g), and Cs2CO3 (37.3 mmol, 12.2 g) in 30 mL of dioxane and 7.5 mL of EtOH. The mixture was stirred at 80 C. for 2 h. After cooling, the solid was collected by filtration and washed with MeOH. The filtrate was concentrated and partitioned between EtOAc and 1N aqueous HCl. The organic layer was washed with brine, dried over MgSO4, and concentrated. CH2Cl2 was added to the residue and the resulting solid was collected by filtration, washed with CH2Cl2, and dried to give 3.58 g (86% yield) of compound 4c, which was used in the next step without further purification.
Unless otherwise specified, carboxylic acid (0.542 mmol), TCT (0.0400 g, 0.216 mmol) and K2CO3 (0.2247 g, 1.626 mmol) were mixed together and hand ground for one minute using porcelain mortar and pestle. After addition of ammonium thiocyanate (0.0495 g, 0.650 mmol), the mixture was ground manually for further five minute. During the grinding, THF (calculated to be less than 1 L/mg of solids) was added to aid homogeneous mixing. The crude material was then purified by short column chromatography (column diameter 1.5 cm, packed with 3-4 g silica gel ) using 40-50percent ethyl acetate/hexane as an eluent.
79%
In a round-bottomed two-neck flask 812 mg 4-bromobenzoic acid (4.0 mmol) were suspended in 14 mL of a 6: 1 DCM/MeCN mixture under argon and 600 mg HOBt (4.44 mmol) and 861 mg EDC*HCI (4.4 mmol) were added under stirring. After 10 min the mixture became clear and was cooled to 0°C in an ice bath. In a round-bottomed flask 1.64 g NaOH (40 mmol) were added to 2.8 mL of a 28 percent NH4OH solution (20 mmol) and the resulting gaseous NH3 was bubbled into the reaction vessel after passing through a NaOH trap. After NH3-bubbling had ceased the mixture was concentrated under reduced pressure, taken-up in AcOEt (60 mL), washed with 5 percent KHSO4 (2x30 mL), H20 (20 mL), 5 percent NaHCO3 (3x20 mL) and brine (20 mL), dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. 636 mg 4-bromobenzamide were obtained (79 percent yield).
75%
With pyridine; potassium cyanate; 2-chloro-1-methyl-pyridinium iodide; water; In acetonitrile; for 4h;Reflux; Green chemistry;
General procedure: A suspension of Mukaiyama reagent (0.511 g, 2 mmol),potassium isocyanate (0.242 g, 3 mmol), benzoic acid (0.122g, 1 mmol) and pyridine (0.16 g, 2 mmol) in 1percent aqueousacetonitrile (7 mL) was magnetically stirred at reflux conditions.After completion of the reaction (10 min) and evaporationof acetonitrile, aqueous HCl (5percent, 10 mL) was addedand the organic layer extracted with CH2Cl2 (3 × 5 mL). Thecombined organic extracts were dried over Na2SO4, filtered,and concentrated. Purification of the crude product by shortcolumn chromatography on silica gel (hexane/EtOAc 5:3)provided benzamide (0.107 g, 88percent) as a white solid: mp127-129oC (lit. [18] 127oC); 1H NMR (DMSO-d6, 250 MHz)8.11 (brs, 2H), 7.65 (d, J = 8.0 Hz, 2H, H-2',6'), 7.32 (t, J =7.8 Hz, 2H, H-3',5'), 7.05 (t, J = 7.4 Hz, 1H, H-4').
4-(3-EthoxyphenyI)benzoic acid (B.I). Commercially available 3- ethoxyphenyl boronic acid (15.O g, 90.4 mmol) and 4-bromobenzoic acid (15.O g, 75.3 mmol) were suspended in 2-propanol: water (1 :1, 200 mL). 10% Pd/C (1.5g) was added followed by Na2CO3 (9.60 g, 90.4 mmol). The resulting mixture was heated at 80 0C for 24 hours. The mixture was filtered through Celite and rinsed with water. The filtrate was acidified to a pH of about 2. The white solid was filtered and dried in vacuo. The crude material (B.I) (18.0 g) was used in the next step without further purification.
Step 4: Preparation of 4-bromo-N,N-dimethylbenzamide. [0605] A mixture of 4-bromobenzoic acid (21.0 g, 105 mmol) in SOCh (35 mL) was heated at 80 C for 2 h under N2 atmosphere. After cooling, the reaction mixture was concentrated under reduced pressure. Then to the mixture was added DCM (100 mL), Me2NH (11.1 g, 136 mmol) and TEA (87 mL), and stirred at 25 C for 16 h under N2. TLC showed the reaction was completed. The residue was poured into water (50 mL) and extracted with DCM (50 mL x3). The combined organic layer was washed with water (100 mL), dried over anhydrous NaiSOr. filtered and concentrated in vacuum. The residue was purified by Combi Flash (10% EtOAc in pentane) to afford 4-bromo-N,N-dimethylbenzamide (23.7 g, yield: 99%) as a white solid. NMR (400 MHz, DMSO-rie) d 2.89 (3H, s), 2.97 (3H, s), 7.36 (2H, d, J= 8.8 Hz), 7.63 (2H, d, J= 8.4 Hz).
55%
To a solution mixture of 4-bromobenzoic acid (1, 5.0 g, 24.9 mmol), DMF (1 mL) and CH2Cl2 (125 mL) was slowly added oxalyl chloride (6.3 mL, 75 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for 2 hours before being concentrated to dryness under reduced pressure. The residue was then taken up in CH2Cl2 (125 mL) and treated with dimethyl amine (2M in THF, 125 mL, 250 mmol) at room temperature. The solution was allowed to stir for 16 h at room temperature followed by addition of water (50 mL). The organic layer was dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with 0-5% MeOH in CH2Cl2 to provide the title compound (3.1 g, 55%): 1H NMR (300 MHz, CDCl3) delta 7.58-7.44 (m, 2H), 7.33-7.24 (m, 2H), 3.11 (s, 3H), 2.97 (s, 3H)
With 4-methyl-morpholine; HATU; In N,N-dimethyl-formamide; for 3h;
To 2- aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g, 4.97 mmol) and 4-bromo- benzoic acid (996 mg, 4.97 mmol) in DMF (25 mL) was added N-methylmorpholine (655 mul, 5.96 mmol) and HATLJ (1.89 g, 4.97 mmol). After stirring for 3 hours the reaction was concentrated then diluted with EtOAc and washed with IN HCl, saturated NuaHC03, and brine. The organic phase was then dried over Na2Stheta4 and concentrated. The crude material was purified by silica gel chromatography (20-50% EtOAc-hexanes gradient) to afford 2-[(4-bromo- benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.91g, 4.97 mmol, quantitative yield). LCMS-ESl+: CaIcM fOr CnH24BrN2O3: 383.1 (M+H+); Found: 383.6 (M+H+).
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.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 8h;
General procedure: The intermediate (3) (0.5 g, 0.00217 mol), EDCl (0.622 g, 0.00325 mol), DMAP (0.345 g, 0.0028 mol) were stirred in dichloromethane (6 mL) at 0 C, and the substituted acid (0.00217 mol) were dissolved in (4 mL) of dichloromethane and charged to the reaction mixture and stirred at room temperature for 8 h. The reaction completion was monitored by TLC. Reaction was completed. The reaction mixture was diluted with (10 mL) of dichloromethane, and was washed with 10% NaHCO3 (10 mL). Separated the organic layer and was washed with saturated brine solution (10 mL). The organic layer was dried over sodium sulfate and concentrated the organic layer under reduced pressure to afford compounds 4a-t. The spectral data of compounds 4(a-t) are given below.
) 1,1 -dimethylethyl (35)-3 -( { [(4-bromophenyl)carbonyl] amino } methyl)- 1 - pyrrolidinecarboxylateTo a suspension of 4-bromobenzoic acid (3.01 g, 14.97 mmol) in CH2C12 (100 mL) was added oxalyl chloride (6.55 mL, 74.9 mmol) and 1 drop of DMF and the reaction mixture was stirred at 25 C for 2 h, at which time carbon dioxide evolution had ceased and a solution had been obtained. The reaction mixture was concentrated in vacuo under high vacuum to remove residual oxalyl chloride. The crystalline residue was dissolved in CH2C12 (100 mL), cooled in an ice bath, and treated successively with 1,1 -dimethylethyl (3S)-3-(aminomethyl)-l -pyrrolidinecarboxylate (3.00 g, 14.97 mmol) and DIPEA (7.85 mL, 44.9 mmol). The reaction mixture was stirred for 1 h at ice-bath temperature and then allowed to warm to ambient temperature and was stirred overnight. The reaction mixture was concentrated to dryness, dissolved in Et20 and a fine white solid was filtered off. The filtrate was concentrated to dryness and purified on silica gel eluted with 20 to 70%EtOAc/hexanes to give the title compound (4.63 g, 81%) as a white foam. 1H NMR (400 MHz, DMSO-de) delta ppm 8.64 (d, J=2.84 Hz, 1 H), 7.73 - 7.81 (m, 2 H), 7.63 - 7.69 (m, 2 H), 3.06 - 3.44 (m, 5 H), 2.87 - 3.04 (m, 1 H), 2.30 - 2.46 (m, 1 H), 1.78 - 1.95 (m, 1 H), 1.47 - 1.69 (m, 1 H), 1.36 (s, 9 H). LCMS (ES+) m/z 382.93, 384.94 [M+H]+.
With dmap; In tert-butyl alcohol; at 20℃; for 12h;
Tert-butyl 4-bromobenzoate. To a solution of 4-dimethylamiopryidine (1.5 g, 12.5 mmol) in tert-butanol (20 mL) were added 4-bromobenzoic acid (5 g, 25 mmol) and di-tert-butyl dicarbonate (10.95 g, 0.05 mol). The mixture was stirred at 20°C for 12 hours. The resultant mixture was concentrated in vacuo to give a residue and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 30: 1) to give tert-butyl 4- bromobenzoate (4 g, 62percent>).
62%
With dmap; In tert-butyl alcohol; at 20℃; for 12h;
To a solution of 4-dimethylamiopryidine (1.5 g, 12.5 mmol) in tert-butanol (20 mL) were added 4-bromobenzoic acid (5 g, 25 mmol) and di-tert-butyl dicarbonate (10.95 g, 0.05 mol). The mixture was stirred at 20° C. for 12 hours. The resultant mixture was concentrated in vacuo to give a residue and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=30:1) to give tert-butyl 4-bromobenzoate (4 g, 62percent).
21%
With dmap; In tert-butyl alcohol; at 50℃;
To a 1000-mL round-bottom flask was added 4-bromobenzoic acid 52a (20 g, 99.495 mmol, 1.0 equiv.), tert-butano (200 mL), 4-dimethylaminopyridine (1.22 g, 9.99 mmol, 0.10equiv.), and Boc20 (32 7 g, 149.83 mmoL 150 equiv) and the resulting mixture ·was stirredat 50 °C ovemight. The mixture was diluted vvith 200 mL of H20 and extracted with ethylacetate (300 mL x 2). "fl1e combined organic extracts were washed with brine (300 mL x 2),dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thel 0 crude product was purified by Flash-Prep-HPLC using the following conditions: Column,silica gel; mobile phase, PE:EA = 100:0 increasing to 90:10 over 5 min; Detector, UV 254nm, to provide 5.43 g (21 percent) oftert-butyl4-bromobenzoate 52b as a colorless oil.
With tert.-butylhydroperoxide; potassium tert-butylate; In water; at 80℃; for 8h;
General procedure: In a 25mL round-bottom flask, t-BuOK (1.5mmol) was dissolved in water (0.5mL), and diol (0.5mmol) was added. Subsequently, aq 70% TBHP (2mmol) was slowly added to this flask. The resulting suspension was then heated at 80C (using oil bath) for 8h. After completion of reaction this slurry was cooled to room temperature. The slurry was then acidified with 2M hydrochloric acid until the aqueous layer was strongly acidic by pH paper. This on simple filtration resulted in pure carboxylic acids. Note: alternate work-up procedure: The reaction mixture was then cooled to room temperature and then extracted with ethyl acetate (2×10mL) and combined organic phase was washed with saturated brine solution and dried over anhydrous Na2SO4. After removal of the solvent under reduced pressure to afford carboxylic acids.
General procedure: EDCI (1.7 mmol) was added in small batches to a solution of the carboxylic acid (1.4 mmol) and HOBt (1.7 mmol) in dry DCM or DMF (5 ml), and the reaction mixture was stirred for 10 minutes at room temperature. A solution of the appropriate amine (1.1 mmol) in 5 ml of dry DCM or DMF was added in small portions and the reaction mixture left to stir for 24 hr at room temperature (monitored by TLC until completion). The reaction mixture was then washed with saturated aqueous sodium bicarbonate (3 x 10ml), saturated aqueous sodium chloride (2 x 10ml), dried with anhydrous Na2SO4 and concentrated under reduced pressure. Purification by column silica gel chromatography (EtOAc/Hexane, 40:60) afforded the products as solids
General procedure: EDCI (1.7 mmol) was added in small batches to a solution of the carboxylic acid (1.4 mmol) and HOBt (1.7 mmol) in dry DCM or DMF (5 ml), and the reaction mixture was stirred for 10 minutes at room temperature. A solution of the appropriate amine (1.1 mmol) in 5 ml of dry DCM or DMF was added in small portions and the reaction mixture left to stir for 24 hr at room temperature (monitored by TLC until completion). The reaction mixture was then washed with saturated aqueous sodium bicarbonate (3 x 10ml), saturated aqueous sodium chloride (2 x 10ml), dried with anhydrous Na2SO4 and concentrated under reduced pressure. Purification by column silica gel chromatography (EtOAc/Hexane, 40:60) afforded the products as solids
[0171] To a stirred mixture of 4-bromobenzoic acid (2.00 g,10.0 mol) and Et3N (3.03 g, 30.0 mmol) in DCM (30 mL) wasadded HATU (4.18 g, 11.0 mmol) at 30 C. After 15 mins,pyrrolidine (972 mg, 12.0 mmol) was added into the mixture,which was stirred at 30 C. for 16 hrs. After LCMS and TLC(PE:Et0Ac=2: 1) showed the reaction was complete, the mixturewas concentrated and purified by colunm chromatographyon silica gel (PE:EtOAc=l:0-20:1-10:1-5:1-3:1) to givethe title compound (2.20 g, yield: 86.9%) as a white solid.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 15 - 25℃;Inert atmosphere;
To a suspension of 4-bromobenzoic acid (150 mg, 0.75 mmol) in DCM (7.5 mL) were added pyrrolidine (53 mg, 0.75 mmol), HOBT (110 mg, 0.78 mmol), and Et3N (190 mg, 1.9 mmol) successively at room temperature, then to the mixture was added EDCI (150 mg, 0.78 mmol) in portions. The resulting mixture was stirred overnight, then was poured into water and washed with dilute aq. HC1 (5 mL), sat.aq. NaHC03 (15 mL) and brine (10 mL). The organic layer was dried over Na2S04, filtered then concentrated in vacuo to afford the crude product which was purified by preparative TLC (petroleum ether / EtOAc: 3: 1) to afford the title compound. LRMS (ESI) calc'd. for CnHi3BrNO [M+H]+: 254, found: 254. 1HNMR (400 MHz, CDC13): delta 7.46 (d, / = 8.4 Hz, 2H), 7.33 (d, / = 8.4 Hz, 2H), 3.55 (t, / = 6.8 Hz, 2H), 3.33 (t, J = 6.4 Hz, 2H), 1.92-1.77 (m, 4H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;Inert atmosphere;
To a suspension of 4-bromobenzoic acid (150 mg, 0.75 mmol) in DCM (7.5 mL) were added pyrrolidine (53 mg, 0.75 mmol), HOBT (110 mg, 0.78 mmol), and Et3N (190 mg, 1.9 mmol)successively at room temperature, then to the mixture was added EDCI (150 mg, 0.78 mmol) in portions. The resulting mixture was stirred overnight, then was poured into water and washed with dilute aq. HC1 (5 mL), sat. aq. NaHCO3 (15 mL) and brine (10 mL). The organic layer was dried over Na2504, filtered then concentrated in vacuo to afford the crude product which was purified by preparative TLC (petroleum ether / EtOAc: 3:1) to afford comound 1-37. LRMS ESIcalcd. for C11H13BrNO [M+H]: 254, found: 254. ?HNMR (400 MHz, CDC13): oe 7.46 (d, J = 8.4 Hz, 2 H), 7.33 (d, J= 8.4 Hz, 2 H), 3.55 (t, J=6.8 Hz, 2 H), 3.33 (t, J =6.4 Hz, 2 H), 1.92-1.77 (m, 4H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 4h;
Synthesis of 4-bromo-A, -(pyrazin-2-yl)benzohydrazide (15): 4-Bromohcnzoic acid (0.5 g, 2.4 mmol) was dissolved in dichloromethane (20 mL) and cooled to 0 C. 2- Hydrazinylpyrazine (0.32 g, 2.9 mmol), EDCI (0.55 g, 2.9 mmol), HOBt (0.39 g, 2.9 mmol) and DIPEA (0.96 g, 7.4 mmol) were added at 0 C. The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction mixture was transferred into water (100 mL) and extracted with CH2C12 (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (0-5% MeOH in CH2C12) to obtain 4-bromo-N'-(pyrazin-2-yl)benzohydrazide (15). (Yield: 0.15 g, 20%). LCMS: m/z 295. 18 [M+2], = 1.8 min.
4-bromo-N-(4-cyanopyridin-2-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
a. Preparation of4-bromo-N-(?4-cyanopyridin-2-yl)benzamide (626-1) [00560j 4-Bromo-N-4-cyanopyridin-2-yl)benzamide (626-1) (11.5 g, 77percent) was obtained as a white solid from 4-bromobenzoic acid (10 g, 49.75 mmol) and <strong>[42182-27-4]4-cyanopyridin-2-amine</strong> (5.9 g, 49.75 mmol). LC-MS (ESI): m/z (M/M+2) 302.1/304.1.
General procedure: 5.1.5 1-[3-(Trifluoromethyl)benzoyl]piperazine (8a) A solution of 3-(trifluoromethyl)benzoic acid (9.5 g, 0.05 mol) and CDI (8.90 g, 0.055 mol) was stirred in 30 ml anhydrous THF at room temperature for 30 min. In a separate round bottom flask added piperazine (10.76 g, 0.125 mol) and <strong>[142-64-3]piperazine dihydrochloride</strong> (20 g, 0.125 mol) in 60 ml of water. The reaction mixture was stirred for 5 min and added 14 g NaCl. Then add the brine solution to the round bottom flask containing acyl imidazole and stir the reaction mixture for 5 h. The mixture was filtered and the filtrate distilled by rotary evaporation to remove THF. The aqueous layer was washed with ethyl acetate (3 * 10 ml) to remove diacylated product. The pH of the aqueous layer was adjusted to about 9 using saturated solution of NaOH and washed with ethyl acetate (4 * 30 ml). The organic layer was washed with water (4 * 25 ml), dried over anhydrous Na2SO4 for overnight, concentrated by rotary evaporation and purified by flash chromatography to afford 1-[3-(trifluoromethyl) benzoyl]piperazine as colorless solid (6.5 g, 50%). The intermediate compounds 1-(3-fluorobenzoyl)piperazine (8b), 1-(3-methoxybenzoyl)piperazine (8c), 1-(4-tert-butylbenzoyl)piperazine (8d), N,N-dimethyl-3-(piperazin-1-ylcarbonyl)aniline (8e), 1-(4-bromobenzoyl) piperazine (8f) and 1-(2,4-dichlorobenzoyl) piperazine (8g) were prepared by commercially available materials 3-fluorobenzoic acid, 3-methoxybenzoic acid, 4-tert-butylbenzoic acid, 3-(dimethylamino) benzoic acid, 4-bromobenzoic acid and 2,4-dichlorobenzoic acid respectively using the similar procedure of 1-[3-(trifluoromethyl)benzoyl]piperazine (8a) described above.
With dmap; di-tert-butyl dicarbonate; at 20℃; for 12h;
tert-Butyl 4-bromobenzoate. To a solution of 4-dimethylaminopyridine (1.5 g, 12.5 mmol) in tert-butanol(20 mL) were added 4-bromobenzoic acid (5.0 g, 25 mmol) and di-tert-butyldicarbonate (10.95 g, 50 mmol). The mixture was stirred at 20 °C for 12 h. The resultant mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (petroleumether/ethyl acetate = 30:1) to provide tert-butyl 4-bromobenzoate (4.0 g, 62percent).
55%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 20℃; for 18h;
To a solution of 4-bromobenzoic acid (lOg, 49.7 mmol) in Chlorofonri (150 ml), 2- methylpropan-2-ol (18.44g, 249 mmol), EDC.HC1 (23.84g, 124 mmol), followed by DMAP (15.19g, 124 mmol) was added and stined for 18h at room temperature. After completion of reaction as indicated by TLC, the mixture was poured into water and extracted with DCM. The organic layer was collected and dried over sodium sulphate,finally evaporated and purified by column chromatography (7g, 55 percent). 1H NMR (400MHz, Chloroform-d) 7.87 (d, 2H), 7.57 (d, 2H), 1.61 (s, 9H).
49 g
With dmap; diisopropyl-carbodiimide; In dichloromethane; at 35℃; for 5h;
In dichloromethane, 4-bromobenzoic acid (50 g), tert-butyl alcohol (20.3 g), and dimethylaminopyridine (12.2 g) were dissolved. The resulting solution was added drop- wise to diisopropylcarbodiimide (DIC, 37.7 g) at 35° C. The resulting mixture was stirred for 5 hours. Subsequently, the reaction liquid was filtered, and the filtrate was concentrated. The resulting solid was purified by column chromatography. Hereby, the compound M- 1 (49 g) was prepared
tert-Butyl 4-(4-(4-bromobenzamido)benzyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide;
Step 1. Preparation of tert-Butyl 4-(4-(4-bromobenzamido)benzyl)piperazine-1-carboxylate (3) 4-Bromobenzoic acid (1, 685.0 mg, 3.4 mmol) and HATU (1298.1 mg, 3.4 mmol) are partially dissolved in DMF (10 mL) at rt. DIEA (560 muL, 3.4 mmol) is added to this mixture to give a pale yellow solution. After stirring at rt for 30 min, <strong>[304897-49-2]tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate</strong> (2, 992.9 mg, 3.4 mmol) is added and the resulting reaction mixture is heated at 60 C. for 20 h, allowed to cool to rt, and poured into water (100 mL). This mixture is extracted with Et2O (3*150 mL). The combined organic extracts are evaporated to dryness to give a white solid, which is washed with water (50 mL) and dried in vacuo. This material is used in the next synthetic step without further purification. HPLC: tR 1.67 min (method 1). LC-MS m/z calcd for C23H2879BrN3O3 ([M]+), 473. found, 474 ([M+H]+). 1H NMR (CD3OD): delta 1.46 (s, 9H), 2.96 (m, 4H), 3.59 (m, 4H), 4.05 (br s, 2H), 7.46 (m, 2H), 7.69 (m, 2H), 7.78 (m, 2H), 7.85 (m, 2H).
2,6-bis(4-bromophenyl)benzo[1,2-d:5,4-d′]bis(oxazole)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With polyphosphoric acid; at 100℃; for 24h;
1.5 g (7.0 mmol) of 4,6-diaminoresorcinol dihydrochloride, 3.3 g (16.4 mmol) of 4-bromobenzoic acid and 20 mL of polyphosphoric acid were placed in a 100 mL two-necked flask, and the mixture was heated and stirred at 100 C. for 24 hours. After terminating the heating operation and cooling to room temperature, the reaction product was placed in a mixed solution of 300 mL of water and 300 mL of chloroform, and then the organic layer and the aqueous layer were separated with a separating funnel. The organic layer was dried and concentrated, to which 100 mL of methanol was then added to deposit a solid matter. The solid matter was filtered and dried to provide 3.0 g of a dibrominated compound as a reaction intermediate in the form of white powder (yield: 88%).
(4-bromophenyl)-(4-isopropylpiperazin-1-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
To a stirred solution of 4-bromobenzoic acid 1-12 at 0°C (2 g, 9.94 mmol) in a mixture of MeC : DMF (4:1, 20 mL) were added HATU (4.53 g, 11.93 mmol) and <strong>[4318-42-7]1-isopropylpiperazine</strong> (1.91 g, 14.92 mmol). The reaction mixture was allowed to stir for 30 minutes, and then diisopropylethylamine (3.85 g, 5.2 mL, 29.84 mmol) was added thereto. The resulting reaction mixture was stirred for 16 hours at room temperature. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (25 mL x 3) . The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel '(60-120 mesh size) column chromatography using 0-5 percent methanol in dichloromethane as eluent to give the desired product 1-13 (3.0 g, 97percent) as brown solid; LCMS: m/z 312.00 (M+l) .
97%
Step I: (4-bromophenyl)-(4-isopropylpiperazin-1-yl)methanone (1-13) To a stirred solution of 4-bromobenzoic acid 1-12 at 0° C. (2 g, 9.94 mmol) in a mixture of MeCN:DMF (4:1, 20 mL) were added HATU (4.53 g, 11.93 mmol) and <strong>[4318-42-7]1-isopropylpiperazine</strong> (1.91 g, 14.92 mmol). The reaction mixture was allowed to stir for 30 minutes, and then diisopropylethylamine (3.85 g, 5.2 mL, 29.84 mmol) was added thereto. The resulting reaction mixture was stirred for 16 hours at room temperature. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (25 mL*3). The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel (60-120 mesh size) column chromatography using 0-5percent methanol in dichloromethane as eluent to give the desired product 1-13 (3.0 g, 97percent) as brown solid; LCMS: m/z 312.00 (M++1).
(4-(bis(2-methoxy-2-oxoethyl)carbamoyl)phenyl)boronic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66.4%
To a mixture of 4-boronobenzoic acid (0.10 g, 0.603 mmol) and DMF (1.21 ml) at 0 C. was added HATU (0.25 g, 0.66 mmol) and DIPEA (0.316 ml, 1.81 mmol). The mixture stirred for 30 min, then dimethyl 2,2'-azanediyldiacetate, hydrochloride (0.155 g, 0.78 mmol) was added. The reaction stirred for 72 hours. The reaction was diluted with 1N HCl and extracted with EtOAc (4*). The organic layers were combined, passed through a phase separator, concentrated, and purified via flash chromatography (ISCO, 12 g silica column, 0-40% MeOH:EtOAc) to give the title compound (0.143 g, 66.4% yield). MS (m/z) 310.0 (M+H+).
With dipotassium peroxodisulfate; silver nitrate; trifluoroacetic acid; In dichloromethane; at 90℃; for 8h;
Was added quinoline (0.5mmol, 64.5mg) in a 50mL round bottom flask and 4-bromo benzoic acid (1.0mmol, 200mg), then the catalyst was added AgNO3(0.05mmol, 8.5mg), an oxidizing agent K2S2O8(1.5mmol, 405mg), trifluoroacetic acid (0.5mmol, 72mg), supplemented auxiliaries and 5.0mL 1,2- dichloroethane as solvent, the reaction was refluxed for 8.0h at 90 deg.] C; After completion of the reaction, then filtered to remove the insoluble was added to the filtrate a saturated NaHCO3Solution to neutral, extracted twice with 15mL ethyl acetate extract was washed twice with saturated aqueous sodium chloride; the extract was dried over anhydrous Na2SO4Dried, and concentrated under reduced pressure and purified by column chromatography (eluent: ethyl acetate / petroleum ether = 1/10) separation and purification, to give 0.105 g of yellow viscous liquid, a yield of 74.0%.
Add N,N-dimethylformamide to a prepared lanthanum carbonate solution (8600 g cesium carbonate + 20 L water) at room temperature20 L, 1000 g of 4-bromobenzoic acid, 1800 g of 1,4-benzenediboronic acid frenquol ester were added under stirring. System replaced with nitrogen The system was 3 times, and palladium acetate 40g was added as a catalyst. Under nitrogen protection, slowly warm up to 75C and stir for 7h, keep the temperature constant and slow Slowly add 1220 g of 4-n-pentyloxy bromobenzene and 3 l of dimethylformamide solution, and continue the reaction for 8 h after the addition is completed in 2 h. After the reaction After being used, it is cooled to 6C with a water bath, and 0.5M dilute aqueous hydrochloric acid solution is added dropwise to the system until the pH is 5 with stirring. Stir 2h. The filter cake and the filter cake were washed with water twice and ethanol was rinsed once to obtain the target product anidifene net intermediate-p-oxyl Triple benzoic acid. The white solid was dried at 60C for 30 hours to obtain 1725 g of white solid, yield 95.8%, HPLC: 99.99%.
With copper; In water; N,N-dimethyl-formamide; at 130℃; for 25h;Autoclave;
Into a 200 ml autoclavereactor was added bromobenzoic acid 20.1g (1.0eq), 50 ml of water, NN- dimethylformamide5 ml, n-butylamine 21.9g (3.0eq), copper powder 0.3g (0.05eq), added after the reactiontemperature was raised to 130 degrees for 25 hours was cooled to 25 degrees, with 10%sodium hydroxide to adjust PH = 10-12, filtered and the filtrate was added conc.hydrochloric acid to adjust pH = 1-2, collected by filtration cake was dried in vacuo togive 4-amino-n-butyric acid 18g.
tert-butyl (R)-4-(4-bromobenzoyl)-2-(hydroxymethyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With 4-methyl-morpholine; HATU; In N,N-dimethyl-formamide; at 20℃; for 12.0h;
Step 1: Preparation of tert-butyl (R)-4-(4-bromobenzoyl)-2-(hydroxymethyl)piperazine-1-carboxylate 4-Bromobenzoic acid (541 mg, 2.69 mmol), HATU (1.2 g, 3.23 mmol) and <strong>[169448-87-7](R)-tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate</strong> (582 mg, 2.69 mmol) were dissolved in DMF (8.9 mL) in a 40 mL vial. NMM (0.59 mL, 5.38 mmol) was added and the reaction was stirred at RT for 12 h then diluted with water (20 mL) and EtOAc (20 mL). The layers were separated and the organic layer was washed with water (2*10 mL) and brine (1*10 mL), then dried over sodium sulfate, filtered and concentrated. The crude mixture was purified by FCC (0-7% MeOH in DCM) to afford tert-butyl (R)-4-(4-bromobenzoyl)-2-(hydroxymethyl)piperazine-1-carboxylate (961 mg, 89%). LC-MS Rt=1.99 min (Condition C), MS (M-54)=345.1.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;
Compound 4-1 (1.0 g, 4.97 mmol), <strong>[3970-68-1]4-methyl-4-hydroxypiperidine</strong> (0.82 g, 7.12 mmol), TBTU (2.10 g, 6.54 mmol) was placed in a bottle, and 30 m LDCM, DIPEA (3.0) mL, 17.22 mmol),Was stirred overnight at room temperature, the reaction solvent was distilled off, the residue was purified by column chromatography to give 1.9g of product.
Step 7: Preparation of 4-bromo-N,N-dimethylbenzamide. [0663] A mixture of 4-bromobenzoic acid (50.0 g, 249 mmol) in SOCh (220 mL) was heated at 80 C for 12 h under N2 atmosphere. A yellow solution was formed. After cooling, the reaction mixture was concentrated under reduced pressure. Then to the mixture was added DCM (500 mL), dimethylamine hydrochloride (36.0 g, 444 mmol) and TEA (207 mL), and stirred at 25 C for 24 h under N2. A yellow suspension was formed. TLC showed the reaction was completed. The residue was poured into water (20 mL) and extracted with DCM (20 mL x3). The combined organic layer was washed with water (100 mL), dried over anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was recrystallization by MTBE to afford 4-bromo-N,N-dimethylbenzamide (50 g, yield: 88%) as a light red solid. NMR (400 MHz, CDCh) d 2.96 (3H, s), 3.09 (3H, s), 7.29 (2H, d, J= 8.4 Hz), 7.53 (2H, d, J= 8.4 Hz).
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;
General procedure: A mixture of 2 or 3 (0.50 mmol), the corresponding acids RCOOH (0.60 mmol),DCC (0.60 mmol), DMAP (0.1 mmol) in dry dichloromethane (15 mL) was stirred atroom temperature. When the reaction was completed, and checked by TLC, the mixturewas filtered to remove urea from the reaction, and the filtrate was diluted bydichloromethane (45 mL). Subsequently, the diluted organic phase was washed bysaturated aqueous NaHCO3 (30 mL), and brine (30 mL), dried over anhydrousNa2SO4, concentrated in vacuo, and purified by CC to give the pure 9R/S-acyloxyderivatives of cinchonidine and cinchonine 5a-j,l-o and 6a,c,e-o [17-19]. The dataof target compounds are shown as follows.
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