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Structure of 589-15-1 * Storage: {[proInfo.prStorage]}
Abstract: Supramolecular polymer networks are non-covalently crosslinked soft materials that exhibit unique mechanical features such as self-healing, high toughness and stretchability. Previous studies have focused on optimizing such properties using fast-dissociative crosslinks (that is, for an aqueous system, dissociation rate constant kd > 10 s−1). Herein, we describe non-covalent crosslinkers with slow, tuneable dissociation kinetics (kd < 1 s−1) that enable high compressibility to supramolecular polymer networks. The resultant glass-like supramolecular networks have compressive strengths up to 100 MPa with no fracture, even when compressed at 93% strain over 12 cycles of compression and relaxation. Notably, these networks show a fast, room-temperature self-recovery (< 120 s), which may be useful for the design of high-performance soft materials. Retarding the dissociation kinetics of non-covalent crosslinks through structural control enables access of such glass-like supramolecular materials, holding substantial promise in applications including soft robotics, tissue engineering and wearable bioelectronics.
Abstract: Interest in development of potent, selective inhibitors of the phosphatase from the receptor type protein tyrosine phosphatase PTPRD as antiaddiction agents is supported by human genetics, mouse models and studies of our lead compound PTPRD phosphatase inhibitor, 7-butoxy illudalic acid analog 1 (7-BIA). We now report structure-activity relationships for almost 70 7-BIA-related compounds and results that nominate a 7- cyclopentyl methoxy analog as a candidate for further development. While efforts to design 7-BIA analogs with substitutions for other parts failed to yield potent inhibitors of PTPRDs phosphatase, ten 7-position substituted analogs displayed greater potency at PTPRD than 7-BIA. Several were more selective for PTPRD vs the receptor type protein tyrosine phosphatases S, F and J or the nonreceptor type protein tyrosine phosphatase N1 (PTPRS, PTPRF, PTPRJ or PTPN1/PTP1B), phosphatases at which 7-BIA displays activity. In silico studies aided design of novel analogs. A 7-position cyclopentyl methoxy substituted 7-BIA analog termed NHB1109 displayed 600-700 nM potencies in inhibiting PTPRD and PTPRS, improved selectivity vs PTPRS, PTPRF, PTPRJ or PTPN1/PTP1B phosphatases, no substantial potency at other protein tyrosine phosphatases screened, no significant potency at any of the targets of clin.-useful drugs identified in EUROFINS screens and significant oral bioavailability. Oral doses up to 200 mg/kg were well tolerated by mice, though higher doses resulted in reduced weight and apparent ileus without clear organ histopathol. NHB1109 provides a good candidate to advance to in vivo studies in addiction paradigms and toward human use to reduce reward from addictive substances.
Keywords:
Receptor type protein tyrosine phosphatase ; Cell adhesion molecule ; Addiction ; Drug reward ; Opiates ; Stimulants
1-Bromo-4-(bromomethyl)benzene (CAS: 589-15-1) is an analytical reagent employed in the detection of cancer cells. It is also utilized to hydrolyze malonic acid and interact with chlorides, which act as allosteric modulators to inhibit bacterial growth.
Application In Synthesis of [ 589-15-1 ]
* 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.
Morpholine (13, 1.4 mL, 1.39 g, 16 mmol) was added to a solution of 4-bromobenzyl bromide (12, 1.0 g, 4 mmol) in acetonitrile (50 mL) and the mixture was heated to reflux for 4 h. Then water was added and the mixture was extracted with CH2Cl2 (3×). The combined organic layers were dried (Na2SO4), filtered, and the solvent was removed in vacuo. The residue was purified by flash column chromatography (6 cm, 50 mL, n-hexane/ethyl acetate = 8/2, Rf = 0.19) to give 14 as colorless solid (1.0 g, 3.9 mmol, 98percent). Mp: 85 °C; 1H NMR (CDCl3): δ (ppm) = 2.41-2.45 (m, 4H, NCH2CH2O), 3.45 (s, 2H, NCH2Ar), 3.69-3.72 (m, 4H, NCH2CH2O), 7.19-7.23 (m, 2H, 2'-H4-bromophenyl, 6'-H4-bromophenyl), 7.42-7.46 (m, 2H, 3'-H4-bromophenyl, 5'-H4-bromophenyl); 13C NMR (CDCl3): δ (ppm) = 53.7 (2C, NCH2CH2O), 62.8 (1C, NCH2Ar), 67.1 (2C, NCH2CH2O), 121.1 (1C, C-4'4-bromophenyl), 131.0 (2C, C-2'4-bromophenyl, C-6'4-bromophenyl), 131.5 (2C, C-3'4-bromophenyl, C-5'4-bromophenyl), 136.7 (1C, C-1'4-bromophenyl); IR (neat): ν (cm-1) = 2966, 2927, 2862, 2815, 1487, 1449, 1351, 1110, 1065, 1007, 910, 863, 848, 789; MS (ESI): m/z = 256 (M(79Br)+H+, 100), 258 (M(81Br)+Na+, 94); HRMS (m/z): [M+H]+ calcd for C11H14BrNOH, 256.0332; found, 256.0327; HPLC (method 1): tR = 11.4 min, purity 99.9percent.
89%
With potassium carbonate In acetonitrile at 60℃;
To a stirred suspension of morpholine (8.37 g, 96 mmol) and 1-bromo-4- (bromomethyl)benzene (20.00 g, 80 mmol) in acetonitrile and potassium carbonate (27.65 g, 200 mmol) was added at room temperature and the mixture was stirred at 60°C overnight. After allowing to reach room temperature, the suspension was filtered and the filtrate was absorbed on silica gel. The crude filtrate was purified by column chromatography using a 120 g silica gel cartridge. Solvent A: Hexane. Solvent B: Ethyl Acetate (EtOAc). Gradient: 2 min hold 100percent A followed by a 27 min ramp to 40percent B and then 3 min hold 40percent B. The desired fractions were pooled together and concentrated under reduced pressure to obtain 1 as a white solid (19.5 g, 76 mmol, Yield 89percent). 1H NMR (500 MHz; CDCl3) 5 2.43-2.45 (m, 4H), 3.46 (s, 2H), 3.71-3.73 (m, 4H), 7.22- 7.24 (m, 2H), 7.44-7.47 (m, 2H) ppm. Purity by LCMS (UV Chromatogram, 190-450nm) 94percent, rt = 5.0 min, m/z 256 (M+H)+
89%
With potassium carbonate In acetonitrile at 60℃;
Preparation 1 4-[(4-Bromophenyl)methyl]morpholine To a stirred suspension of morpholine (8.37 g, 96 mmol) and 1-bromo-4-(bromomethyl)benzene (20.00 g, 80 mmol) in acetonitrile and potassium carbonate (27.65 g, 200 mmol) was added at room temperature and the mixture was stirred at 60° C. overnight. After allowing to reach room temperature, the suspension was filtered and the filtrate was absorbed on silica gel. The crude filtrate was purified by column chromatography using a 120 g silica gel cartridge. Solvent A: Hexane. Solvent B: Ethyl Acetate (EtOAc). Gradient: 2 min hold 100percent A followed by a 27 min ramp to 40percent B and then 3 min hold 40percent B. The desired fractions were pooled together and concentrated under reduced pressure to obtain 1 as a white solid (19.5 g, 76 mmol, Yield 89percent). 1H NMR (500 MHz; CDCl3) δ 2.43-2.45 (m, 4H), 3.46 (s, 2H), 3.71-3.73 (m, 4H), 7.22-7.24 (m, 2H), 7.44-7.47 (m, 2H) ppm. Purity by LCMS (UV Chromatogram, 190-450 nm) 94percent, rt=5.0 min, m/z 256 (M+H)+
87%
at 20℃; for 0.5 h;
Synthesis of 4-(4-bromo-benzyl)-morpholine (1). To a solution of morpholine (2.61 ml, 30 mmol) in DMSO (25 ml) was added 4-bromobenzylbromide (2.5 g, 10 mmol). Reaction mixture was stirred at ambient temperature for 30 min. Solvents were evaporated in vacuum. Residue was dissolved in EtOAc (150 ml) and extracted with 5percent aq. NaHCO3 (50 ml x 2) and brine (50 ml). The organic layer was dried over anh. MgSO4 and evaporated in vacuum. Residue was dried in vacuum overnight at ambient temperature to provide target material (1) (2.27 g, 87percent) as a white solid.
13 g
With potassium carbonate In ethanol for 5 h; Reflux
To a solution of 4-bromobenzyl bromide (15 g, 60 mmol) in EtOH (200 mL) was added morpholine (6 mL, 66 mmol) and K2C03 (33 g, 238 mmol) and the mixture was stirred at ref lux for 5 hours. The mixture was filtered and the solvent was evaporated under reduced pressure.The crude material was treated with Et20 and the mixture was filtered. The solvent was evaporated under reduced pressure to afford the title compound (13 g). LCMS method: Method 1, RT: 1.20 mi Ml: 256/258 [M+l]
Reference：
[1] Carbohydrate Research, 2012, vol. 359, p. 59 - 64,6
[2] Carbohydrate Research, 2012, vol. 359, p. 59 - 64
[3] Patent: WO2013/153357, 2013, A1, . Location in patent: Page/Page column 18; 39
[4] Patent: US2015/45354, 2015, A1, . Location in patent: Paragraph 0233-0236
[5] Patent: WO2008/154642, 2008, A2, . Location in patent: Page/Page column 188-189
[6] Patent: US6235771, 2001, B1,
[7] Patent: WO2007/70760, 2007, A2, . Location in patent: Page/Page column 28
[8] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 5, p. 1724 - 1727
[9] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 684 - 701
[10] Patent: WO2016/124938, 2016, A1, . Location in patent: Paragraph 00502; 00503
[11] Journal of Enzyme Inhibition and Medicinal Chemistry, 2017, vol. 32, # 1, p. 992 - 1001
[12] Patent: EP1714961, 2006, A1, . Location in patent: Page/Page column 16
(a) The reaction mixture of p-bromobenzyl bromide (corresponding to 50) (4.00g, 16.004mmol) and phthalimide potassium salt (3.26g, 17.61mmol) in DMF (10ml) was stirred for 6h at 100°C with a CaCl2 tube. After cooling, H2O (100ml) was added, and the resulting mixture was extracted with AcOEt (100ml×3). The combined organic layer was washed with H2O (100ml×1) and then brine (100ml×1), dried over Na2SO4 (anhyd), filtered, and concentrated under reduced pressure to afford 2-(4-bromobenzyl)isoindole-1,3-dione (5.28g, quant. y.) as a colorless solid. Colorless cotton-like crystal (n-hexane/AcOEt). Mp 126–129°C. 1H NMR (300MHz/CDCl3) δ 4.80 (2H, s, CH2), 7.32 (2H, d, J=7.8Hz, ArH), 7.44 (2H, d, J=8.1Hz, ArH), 7.71–7.73 (2H, m, ArH), 7.84–7.85 (2H, m, ArH).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 14, p. 3720 - 3731
[2] Chemistry - A European Journal, 2010, vol. 16, # 33, p. 10171 - 10177
[3] Journal of the Chemical Society, 1931, p. 1225,1232
[4] Tetrahedron, 1993, vol. 49, # 43, p. 9855 - 9866
[5] Patent: WO2015/103317, 2015, A1, . Location in patent: Page/Page column 271
4
[ 136918-14-4 ]
[ 589-15-1 ]
[ 153171-22-3 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: for 1 h; Milling Stage #2: for 1 h; Milling
General procedure: A mixture of 50 mg of imide and the required amount of K2CO3 were placed in a 10 mL stainlesssteel grinding jar and milled for 1 hour at 30 Hz. Upon completion, the required amount of alkylhalide was added and milling was continued for 1 hour in the presence of 100 µL of dry DMF(LAG experiment, η = 2 µL mg-1). The obtained mixture was suspended in dichloromethane andwashed with water. The organic layers were collected and the solvent was evaporated. Where itwas necessary, the products were separated by using column chromatography
Reference：
[1] Beilstein Journal of Organic Chemistry, 2017, vol. 13, p. 1745 - 1752
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 2940
10
[ 589-15-1 ]
[ 105-53-3 ]
[ 70146-78-0 ]
Yield
Reaction Conditions
Operation in experiment
85%
Reflux
To a solution Of CH3CH2OH (240 mL) was added Na (5.82 g, 0.25 mol), the mixture was stirred until Na was disappeared, then l-bromo-4-bromomethyl-benzenein (37.35 g, 0.15 mol), malonic acid diethyl ester(78 g, 0.49 mol) was added slowly, the mixture was refluxed overnight. The solvent was removed in vacuo, the residue was dissolved with H2O, extracted with ether, the organic layer was washed with 0.5N HCl aqueous, then washed with brine, dried over Na2SO4, concentrated to give diethyl 2-(4- bromobenzyl)malonate (40 g, 85percent).
33%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: at 20℃; for 14 h;
To a slurry of 60percent NaH (699 mg, 17.5 mmol) in TI-IF (20 ml) was added diethyl malonate (2.0 g, 13 mmol) dropwise and the reaction mixture was stirred at RT for 1 hr. The reaction mixture cooled to 0°C and a solution of l-bromo-4-(bromomethyl)benzene (3.13 g, 12.5 mmol) in THF (5 mL) was added dropwise. The reaction mixture was allowed to warm and stir for 14h at RT. The reaction mixture was quenched by the addition of EtOH, filteredthrough celite and the celite cake was washed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 0 to 70percent EtOAc in hexane to give Compound 95f (1 .35 g, 33 percent yield) as a colorless oil. MS m/z = 329.0 (M+H). ‘H NIVLR (CHLOROFORM-d) 6: 7.38-7.52 (m, 2H), 7.07-7.20 (m, 21-1), 4.09-4.37 (m, 4H), 3.59 (t, J=7.8 Hz, 11-1), 3.16 (d, J=7.9 Hz, 2H), 1.56 (s, 1H), 1.22 (t,J7.2 Hz, 6H), -0.01-0.05 (m, 1H)
Reference：
[1] Patent: WO2010/105179, 2010, A2, . Location in patent: Page/Page column 76
[2] Journal of Organic Chemistry, 1984, vol. 49, # 22, p. 4226 - 4237
[3] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1994, vol. 30, # 8, p. 905 - 915[4] Khimiya Geterotsiklicheskikh Soedinenii, 1993, # 8, p. 1052 - 1062
[5] Tetrahedron Asymmetry, 2001, vol. 12, # 4, p. 585 - 596
[6] Patent: WO2017/96130, 2017, A1, . Location in patent: Page/Page column 116; 119
[7] Patent: US6342622, 2002, B1, . Location in patent: Example II
[8] Patent: US2013/324464, 2013, A1, . Location in patent: Paragraph 0164
[9] Patent: EP2676965, 2013, A1, . Location in patent: Paragraph 0046; 0109
[10] Journal of Medicinal Chemistry, 2014, vol. 57, # 9, p. 3874 - 3883
11
[ 589-15-1 ]
[ 105-53-3 ]
[ 70146-78-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 3, p. 399 - 408
[2] Chemische Berichte, 1933, vol. 66, p. 1464,1467
[3] Chemische Berichte, 1933, vol. 66, p. 1464,1467
12
[ 589-15-1 ]
[ 70146-78-0 ]
Reference：
[1] Polymer, 2016, vol. 97, p. 550 - 558
13
[ 75-36-5 ]
[ 589-15-1 ]
[ 6186-22-7 ]
Reference：
[1] Journal of Organic Chemistry, 1985, vol. 50, # 9, p. 1373 - 1381
14
[ 589-15-1 ]
[ 4654-39-1 ]
Reference：
[1] Journal of Organic Chemistry, 1964, vol. 29, # 8, p. 2109 - 2116
15
[ 589-15-1 ]
[ 90562-10-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 9, p. 3874 - 3883
16
[ 589-15-1 ]
[ 75-05-8 ]
[ 57775-08-3 ]
Reference：
[1] Journal of Organic Chemistry, 1997, vol. 62, # 24, p. 8575 - 8576
[2] Journal of Agricultural and Food Chemistry, 2015, vol. 63, # 13, p. 3377 - 3386
17
[ 589-15-1 ]
[ 590-17-0 ]
[ 57775-08-3 ]
Reference：
[1] Synthesis, 1984, # 10, p. 842 - 844
18
[ 589-15-1 ]
[ 98-80-6 ]
[ 2567-29-5 ]
Yield
Reaction Conditions
Operation in experiment
82.4%
With sodium tetrahydroborate; tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; water; toluene at 100℃;
To a dry 250 mL three-necked flask was added phenylboronic acid (2.44 g, 0.02 mol), p-bromobenzyl bromide (4.99 g, 0.02 mol), tetrakis(triphenylphosphine)palladium (0.23 g, 0.2 mmol).Add anhydrous potassium carbonate (8.28 g, 0.06 mol), and 50 mL of toluene, 30 mL of absolute ethanol,10 mL of deionized water was further added with sodium borohydride (0.57 g, 15 mmol), and the mixture was heated to 100 ° C in an oil bath. After the reaction was confirmed by thin-plate chromatography, silica gel column chromatography was performed with ethyl acetate and n-hexane system to collect the product, 4.07. g, yield 82.4percent.
73%
With C24H20Cl2NPPdS; potassium carbonate; palladium In toluene at 100℃; for 24 h;
General procedure: A 100 ml round bottom flask was fitted with a reflux condenser and a magnetic stirrer bar. The flask was charged with toluene (15 ml) and the appropriate amount of catalyst reagents and the internal standard (n-Decane: 2.59 mmol). The contents were thoroughly mixed and an initial sample (t0) was then taken. The reaction flask was placed in an oil bath at the desired temperature and the reaction mixture allowed to heat/reflux with stirring. A sample was taken and analyzed every 10 min for the first hour and every 30 min thereafter until t3h. In cases where conversionwas not complete after 3 h, the reaction mixturewas then allowed to stir for a total of 24 h. The reaction at 140 °C was performed in a sealed tube. All catalytic reactions were done under aerobic conditions. Percentage conversions were determined by GC with n-decane as the internal standard and the coupling products were characterized by mass spectrometry (Table 4) as well as 1H NMR spectroscopy (Entry 5, Table 4 only).
Reference：
[1] Tetrahedron Letters, 2004, vol. 45, # 37, p. 6959 - 6962
[2] Patent: CN107522643, 2017, A, . Location in patent: Paragraph 0101-0103; 0107; 0108
[3] Journal of Organometallic Chemistry, 2012, vol. 703, p. 34 - 42
Reference：
[1] Patent: WO2005/95387, 2005, A1, . Location in patent: Page/Page column 54-55
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 9, p. 3874 - 3883
21
[ 119-61-9 ]
[ 589-15-1 ]
[ 18648-66-3 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: at 150℃; for 24 h; Inert atmosphere Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran for 24 h;
40.00 g of p-bromobenzyl bromide (0.16 mol) and 83.6 mL of triethyl phosphite (0.48 mol) were added to a solution of 500 mlThree bottles,Magnetic stirring and argon, oil bath heated at 150 ° C for 24 hours, cooled to room temperature,Get Ye Lide reagent.To the three-necked flask was added 450 ml of tetrahydrofuran (THF), 21.87 g of benzophenone (0.12 mol) and 40.39 g of potassium tert-butoxide (t-BuOK, 0.36 mol) were added and the mixture was stirred for 24 h. After the reaction was stopped, The solution was poured into water and extracted with a large amount of white precipitate. The precipitate was collected by extraction with a funnel, washed three times with ethanol and dried in a vacuum at 60C for 24 h to give Tri-Br as a white intermediate.
Reference：
[1] Patent: CN104341311, 2016, B, . Location in patent: Paragraph 0028; 0029; 0030
[2] Chinese Journal of Chemistry, 2015, vol. 33, # 8, p. 939 - 947
22
[ 589-15-1 ]
[ 122-52-1 ]
[ 38186-51-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 100℃; for 24 h;
A solution of 25 g (0.1 mol) of 4-bromobenzyl bromide and 19 ml (0.11 mol) of triethylphosphite is heated at 100° C. for 24 hours. At room temperature, the residue is purified on a silica column (dichloromethane and then ethyl acetate). [00400] Yellow oil. m=31 g. Y=100percent. 1H NMR (CDCl3): 1.22-1.28 (6H, t), 3.05-3.13 (2H, d), 3.96-4.08 (4H, q), 7.15-7.19 (2H, dd, J=6 Hz, J'=2.4 Hz), 7.42-7.45 (2H, d, J=8 Hz).
99%
at 150℃; for 12 h; Inert atmosphere
Preparing Example 2 Preparation Of Diethyl 4-Bromobenzyl-Phosphonate (Compound A) 1-bromo-4-(bromomethyl)benzene (5.00 g, 20.0 mmol) was in a two-neck bottle. after introducing nitrogen gas by vacuum pumping, anhydrous toluene (80.0 mL) and triethyl phosphite (10.4 mL, 60.0 mmol) were added and heated to 150° C. for twelve hours. After the reaction finished, the solvent was removed by the rotary concentrator to obtain yellow liquid of 6.08 g (compound A) with a yield of 99percent. 1H NMR (400 MHz, CDCl3, δ): 7.39-7.37 (m, 2H), 7.12 (dd, J=8.4 Hz, J=2.4 Hz, 2H), 3.99-3.94 (m, 4H), 3.04 (d, J=21.6 Hz, 2H), 1.21-1.18 (m, 6H)13C NMR (100 MHz, CDCl3, 5): 131.5, 131.5, 131.4, 131.3, 130.7, 130.6, 120.8, 120.8, 62.2, 62.1, 33.8, 32.4, 16.3, 16.2.
98%
at 90℃; for 19 h;
Example lj. Diethyl 4-bromobenzylphosphonate (16).; l-bromo-4-(bromomethyl) benzene (5.0 g, 20 mmol) and triethyl phosphite (51 mL, 300 mmol) were mixed in a round bottom flask and refluxed at 90 °C for 19 hours. Excess triethyl phosphite was removed under reduced pressure and the product purified by flash chromatography (1 : 1 Hexane/ EtOAc) to give compound 16. 16: 98 percent yield ; colorless liquid; 1H NMR (400 MHz, CDC13) δ 7.30 (d, 2H, J= 7.5 Hz), 7.05 (d, 2H, J= 7.6 Hz), 3.99- 3.88 (m, 4H), 2.99 (s, IH), 2.94 (s, IH), 1.12 (t, 6H, J= 6.9 Hz); 13C NMR (100 MHz, CDC13) δ 131.7, 131.6, 131.5, 121.0, 62.3, 34.0, 32.0, 16.5; HRMS Calc for CnHi6Br03P ( M+H)+ 307.0097 found 307.0093.
98%
at 160 - 170℃; Inert atmosphere
General procedure: Organohalogen compound and anhydrous NiBr2(5–10 molpercent) as catalyst were charged into a two-necked round bottom flask equipped with a dropping funnel and short distillation column (no catalyst was used in the cases of benzyl derivatives). The mixture was degassed by bubbling the solution with dry N2gas for 30 min and then heated at 160–170°C. P(OEt)3(1.2 equiv. relative to the organohalogen compound) was slowly added through the dropping funnel. The mixture was stirred and heated at 160–170°Covernight. The crude product was purified by silica gel column chromatography using dichloromethane as an eluent. The product was dried at 70°Cunder reduced pressure for 2 h.Benzyl derivatives were purified by distillation under reduced pressure without column chromatography. Diethyl organophosphonate (ArP(O)(OEt)2) was obtained as colorless liquid.
92%
at 160℃; for 2 h;
A mixture of triethyl phosphite (2.54 g, 15.3 mmol) and 4-bromobenzyl bromide (2.00 g, 10.2 mmol) was stirred at 160° C. for 2 h. During this period ethyl bromide was distilled from the reaction mixture. Subsequently, the mixture was cooled to 70° C. and the excess of triethyl phosphite was removed by distillation under reduced pressure. The product was used without further purification, yielded 92percent product. 1H NMR (400 MHz, CDCl3): δ 1.25 (t, 6H, J=7.2 Hz), 3.06, 3.11 (s, 2H), 4.01 (m, 4H), 7.16 (d, 2H, J=8.4 Hz), 7.42 (d, 2H, I=8.4 Hz).
92.5%
at 140℃; for 2 h;
General procedure: Diethyl benzylphosphonate as the basis compound for thesynthesis of the t-APE isomers was prepared according to literature[18,19]. Benzyl bromide (1.50 g, 8.8 mmol) was suspended in 5 mLof toluene, containing triethylphosphite (6.00 g, 35 mmol). The mixture was refluxed at 140 °C for 2 h. Excess triethylphosphite and toluene were removed by distillation to give the required product as a yellow oil (1.80 g, 89.9percent).
91%
at 150℃; for 3 h;
Intermediate 1 Diethyl 4-bromobenzylphosphonate 4-Bromoben2yl bromide (22.5g, 90mmol) and triethylphosphite (16.45g, 99mmol) were heated to 150°C for 3 h. The mixture was purifed by flash chromatography (1/4 EtOAc/hexane) to give diethyl 4-bromobenzylphosphonate (25.2g, 91percent). Ή NMR (300 MHz, CDCI3) δ ?7.45 (m, 2H), 7.15 (m, 2H), 4.00 (m, 4H), 3.05 (m, 2H), 1.25 (m, 6H)
81%
for 24 h; Heating / reflux
4-bromobenzylbromide (10. Og, 40.0mmol) was dissolved in triethylphosphite (8.4mL, 48.0mmol) under a nitrogen atmosphere, and the reaction solution was refluxed and stirred for 24 hours. The reaction solution was passed through a silica gel column by using hexane-ethylacetate 7:3 as an eluant. After the solvent was removed, the residue material was dried in vacuum to thereby obtain pale yellow oil (10. Og, yield: 81percent) .
Reference：
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[19] Journal of Organic Chemistry, 2004, vol. 69, # 3, p. 719 - 726
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[21] Journal of Physical Organic Chemistry, 2000, vol. 13, # 10, p. 587 - 590
[22] Organic Letters, 2005, vol. 7, # 15, p. 3199 - 3202
[23] New Journal of Chemistry, 2006, vol. 30, # 11, p. 1606 - 1613
[24] Journal of the American Chemical Society, 2002, vol. 124, # 11, p. 2518 - 2527
[25] Patent: WO2008/99986, 2008, A1, . Location in patent: Page/Page column 27; 30
[26] Patent: EP1182183, 2002, A1, . Location in patent: Page 35
[27] Patent: EP1182183, 2002, A1, . Location in patent: Page 38
[28] Patent: WO2009/51390, 2009, A2, . Location in patent: Page/Page column 64-65; 70-72
[29] Patent: WO2009/128559, 2009, A1, . Location in patent: Page/Page column 40
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[31] Patent: WO2007/87441, 2007, A2, . Location in patent: Page/Page column 76
[32] Central European Journal of Chemistry, 2011, vol. 9, # 4, p. 610 - 618
[33] Reactive and Functional Polymers, 2013, vol. 73, # 9, p. 1207 - 1212
[34] European Journal of Organic Chemistry, 2015, vol. 2015, # 27, p. 5987 - 5994
[35] Chemistry of Materials, 2015, vol. 27, # 19, p. 6543 - 6549
[36] Patent: CN103450883, 2016, B, . Location in patent: Paragraph 0051; 0055
[37] Patent: CN106905169, 2017, A, . Location in patent: Paragraph 0092
[38] Journal of Organic Chemistry, 2017, vol. 82, # 18, p. 9435 - 9451
[39] Journal of Materials Chemistry B, 2018, vol. 6, # 37, p. 5986 - 5991
23
[ 78-40-0 ]
[ 589-15-1 ]
[ 38186-51-5 ]
Reference：
[1] Advanced Materials, 2013, vol. 25, # 20, p. 2837 - 2843
[2] Journal of Polymer Science, Part A: Polymer Chemistry, 2016, vol. 54, # 17, p. 2722 - 2730
[3] Patent: CN105712917, 2016, A, . Location in patent: Paragraph 0021
24
[ 762-04-9 ]
[ 589-15-1 ]
[ 38186-51-5 ]
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[2] Journal of the American Chemical Society, 1994, vol. 116, # 15, p. 6631 - 6635
25
[ 124-40-3 ]
[ 589-15-1 ]
[ 6274-57-3 ]
Yield
Reaction Conditions
Operation in experiment
99%
With potassium carbonate In tetrahydrofuran; water at 60℃; for 24 h; Inert atmosphere
To a flask containing aq dimethylamine (50percent, 500 mmol) and K2CO3 (50 mmol) was added dropwise a solution of 4-bromobenzyl bromide (50 mmol) in THF (90 mL). The obtained mixture was stirred for 24 h at 60 °C under Ar atmosphere. Then, water (60 mL) was added to the reaction mixture and the solution was extracted with CHCl3 (100 mL×3). The organic layer was dried over Na2SO4. After filtration and removal of the solvent, 4-bromobenzyldimethylamine was obtained in 99percent yield (bp 55 °C/1 mmHg). Mg (40 mmol) was dried by a vacuum pump for 20 min at 70 °C. To the flask containing Mg was added a solution of 4-bromobenzyldimethylamine (30 mmol) in dry THF (70 mL), and the obtained mixture was stirred for 1 h at room temperature under Ar atmosphere. Then, chlorodiphenylphosphine (30 mmol) in dry THF (30 mL) was added to the mixture at 0 °C and the obtained mixture was stirred for 2 h at room temperature under Ar atmosphere. After the reaction, the mixture was filtered and washed with dichloromethane. Then, aq H2O2 (30percent, 60 mmol) was added to the obtained filtrate at 0 °C and the obtained mixture was stirred for 1 h at room temperature. After the reaction, the reaction mixture was quenched with water (100 mL) and extracted with chloroform (50 mL×3). The organic layer was washed with brine and dried over Na2SO4. After filtration and removal of the solvent, diethyl ether (300 mL) was added to the residue and the mixture was stirred for 0.5 h to dissolve the product. Then, the organic solution was filtered and removal of the solvent from the filtrate gave 4-(diphenylphosphono)benzyldimethylamine in 95percent yield. Dimethyl sulfate (120 mmol) was added to a flask containing 4-(diphenylphosphono)benzyl-dimethylamine (60 mmol) in dry 1,2-dimethoxyethane (200 mL) at 0 °C. The obtained mixture was stirred for 1 h at 50 °C under Ar atmosphere. Then, LiAlH4 (180 mmol) was added to the solution at 0 °C and the obtained mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with ice and then with aq HBr solution (1 M, 200 mL), and the obtained solution was washed with diethyl ether (200 mL×2). Then, the aqueous solution was extracted with dichloromethane (100 mL×3) and the combined organic layer was dried over Na2SO4. After filtration and removal of the solvent, diethyl ether (300 mL) was added to the residue and the mixture was stirred for 0.5 h under Ar atmosphere. Then, the mixture was filtered to give 4-(diphenylphosphino)benzyltrimethyl-ammonium bromide in 79percent yield.
58%
With potassium carbonate In ethanol at 50℃;
A solution of l-bromo-4-(bromomethyl)benzene (20 g, 80.65 mmol, 1.00 equiv), dimethylamine (13.20 g, 96.80 mmol, 1.20 equiv, 33percent) and potassium carbonate (13.36 g, 96.81 mmol, 1.20 equiv) in ethanol (200 mL) was stirred overnight at 50°C. The solid material was removed by filtration and the filtrate was concentrated under vacuum. The residue was dissolved in 200 mL of water and extracted with 3x200 mL of dichloromethane. The combined organic layer was washed with 3x200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (20: 1) to give 10 g (58percent) of (4-bromophenyl)-N,N-dimethylmethanamine as a yellow oil. LC-MS: (ES, m/z): 255 [M+CH3CN+H]+, 214 [M+H]+, 169.
58%
With potassium carbonate In ethanol at 50℃;
A solution of 1-bromo-4-(bromomethyl)benzene (20 g, 80.65 mmol, 1.00 equiv), dimethylamine (13.20 g, 96.80 mmol, 1.20 equiv, 33percent) and potassium carbonate (13.36 g, 96.81 mmol, 1.20 equiv) in ethanol (200 mL) was stirred overnight at 50° C. The solid material was removed by filtration and the filtrate was concentrated under vacuum. The residue was dissolved in 200 mL of water and extracted with 3*200 mL of dichloromethane. The combined organic layer was washed with 3*200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (20:1) to give 10 g (58percent) of (4-bromophenyl)-N,N-dimethylmethanamine as a yellow oil. LC-MS: (ES, m/z): 255 [M+CH3CN+H]+, 214 [M+H]+, 169.
Reference：
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[2] Tetrahedron, 2013, vol. 69, # 19, p. 3971 - 3977
[3] Chemical Communications, 2012, vol. 48, # 63, p. 7823 - 7825
[4] Journal of Organic Chemistry, 2016, vol. 81, # 18, p. 8520 - 8529
[5] Journal of Medicinal Chemistry, 2005, vol. 48, # 7, p. 2667 - 2677
[6] Journal of the American Chemical Society, 2017, vol. 139, # 28, p. 9519 - 9522
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[10] Journal of Heterocyclic Chemistry, 1989, vol. 26, p. 1325 - 1330
[11] Patent: WO2013/155338, 2013, A2, . Location in patent: Page/Page column 163
[12] Patent: US2015/329503, 2015, A1, . Location in patent: Paragraph 0685; 0686
[13] Chemistry - A European Journal, 2007, vol. 13, # 33, p. 9372 - 9383
[14] Journal of pharmaceutical sciences, 1962, vol. 51, p. 881 - 884
[15] Archiv der Pharmazie, 1962, vol. 295 /67, p. 690 - 697
[16] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 15, p. 3993 - 3997
[17] Patent: WO2004/63186, 2004, A1, . Location in patent: Page 26
[18] Patent: WO2009/112565, 2009, A1, . Location in patent: Page/Page column 39
[19] Journal of the American Chemical Society, 2009, vol. 131, # 41, p. 14679 - 14687
[20] Patent: WO2011/60228, 2011, A1, . Location in patent: Page/Page column 63
[21] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 684 - 701
26
[ 589-15-1 ]
[ 6274-57-3 ]
Reference：
[1] Patent: US4496567, 1985, A,
27
[ 3853-06-3 ]
[ 589-15-1 ]
[ 6274-57-3 ]
[ 196394-91-9 ]
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2009, vol. 52, # 1, p. 23 - 28
28
[ 589-15-1 ]
[ 74-89-5 ]
[ 699-03-6 ]
Yield
Reaction Conditions
Operation in experiment
87%
at 20℃; for 18 h;
To a solution of i-bromo-4-(bromoinethyl)benzene (5.00 g, 20.0 mrnol) in TI-IF (30 rnL) was added 2M methylamine in THF (100 mL, 200.0 mmol) and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture WaS diluted with 1.5 N HCI solution (50 rnL) extracted with ethyl acetate (3 x 30 mL). The aqueousextract was basified with NaFICOs and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain Intermediate 17A (3.50 g. 870percent). ‘H NMR (400 MHz, DMSO-d6) S ppm 2.26 (s, 3 H), 363 (s, 2 H), 7.24 - 7.32 (m, 2 H), 7.47 7.54 (m. 2 H), (Exchangeable proton not observed) LCMS (Method—i):retention time 0.68 mm, (M+H) 201.0.
85%
at 20℃;
Step (vii) of Reference Example 2: 1-(4-Bromophenyl)-N-methylmethanamine 4-Bromobenzyl bromide (200 mg, 0.800 mmol) was added slowly to a 2 M solution (4 ml) of methanamine in tetrahydrofuran, and the solution was stirred at room temperature for 24 hr. The reaction solution was adjusted to pH 3 by the addition of 1 N hydrochloric acid and was then washed twice with diethyl ether. A saturated aqueous sodium hydrogencarbonate solution was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure to give 136.1 mg (yield 85percent) of the title compound. 1H-NMR (400 MHz, CD3OD) δ: 2.35 (3H, s), 3.78 (2H, s), 7.24 (2H, d, J = 8.4 Hz), 7.47 (2H, d, J = 8.4 Hz).
Reference：
[1] Patent: WO2018/93569, 2018, A1, . Location in patent: Page/Page column 55; 56
[2] Patent: EP2151447, 2010, A1, . Location in patent: Page/Page column 41
[3] Journal of Medicinal Chemistry, 1986, vol. 29, # 1, p. 40 - 44
Reference：
[1] Journal of Organic Chemistry, 1984, vol. 49, # 22, p. 4226 - 4237
33
[ 589-15-1 ]
[ 68819-84-1 ]
Reference：
[1] Patent: WO2013/90696, 2013, A1,
[2] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 14, p. 3720 - 3731
34
[ 66389-77-3 ]
[ 589-15-1 ]
[ 68819-84-1 ]
Reference：
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35
[ 589-15-1 ]
[ 26177-44-6 ]
Reference：
[1] Patent: WO2013/90696, 2013, A1,
36
[ 589-15-1 ]
[ 603-35-0 ]
[ 51044-13-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
for 4 h; Heating / reflux
4-Bromobenzyl bromide (50 g, 200 mmol, 1.0 equiv), triphenylphosphine (57 g, 220mmol, 1.1 equiv), in CHC13 (400 mL, 0.5 M) was heated under reflux 4 h. The solution was cooled to room temperature and the phosphonium was crunched with Et20 (1.5 L). The crude product was diluted with CH2C12 (300 mL) and was crunched with Et20 (1.5 L) was filtered under Buchner and washed with Et20 (500 mL) to afford target compound (44) as a white solid (123 g, quant. yield).
99%
at 20℃; for 12 h;
Multi function cap round bottom 1-bromo-4-(bromomethyl) Benzene to 500 ml (14.0 g, 0.056 mol), Triphenylphosphine (16.162 g, 0.062 mol) has added. Herein, as a solvent at room temperature of 58 ml Acetone adaptation stirring time doesn't have any error frames, 12. 28.4 g is obtained complete after title compound. (99.0percent yield).
99%
at 20℃; for 12 h; Inert atmosphere
In a two-necked round bottom fask a mixture of 1-bromo-4-(bromomethyl)benzene (10g, 40mmol), triphenylphosphine (11.5g, 44mmol,1.1 eq) inacetone (42mL) was stirred atroom temperature under N2 atmospherefor 12h. The reactionmixturewasthen ltered andthewhitesolidswerecollectedwashedwithacetonebeforedrying invacuo(20.3g,99percent).
98%
at 20℃; for 23 h;
(i) Synthesis of 4-bromobenzyltriphenylphosphonium bromide 25.2 g (101 mmol) of 4-bromobenzylbromide and 100 mL of acetone were put into a 200 mL conical flask, and then 29.1 g (111 mmol) of triphenylphosphine was added thereto. Thereafter, this mixture was stirred at room temperature for 23 hours to be reacted. After the reaction, a precipitate in the reaction mixture was collected by suction filtration. Then, 50.5 g of objective 4-bromobenzyltriphenylphosphonium bromide was obtained as a white powdered solid in a yield of 98percent. Synthetic scheme of 4-bromobenzyltriphenylphosphonium bromide is illustrated below (synthetic scheme a-1).
97.6%
at 20℃; for 23 h;
[Step 1; Synthesis of 4-bromobenzyl triphenylphosphonium bromide] First, 25.2 g (101 mmol) of 4-bromobenzyl bromide and 100 mL of acetone were placed in a 200 mL conical flask, and 29.1 g (111 mmol) of triphenylphosphine was added thereto. This reaction mixture was stirred at room temperature for 23 hours. After the completion of the reaction, the precipitate in the reaction mixture was collected by suction filtration. 50.5 g of a white powdered solid, 4-bromobenzyl triphenylphosphonium bromide, which was the target substance, was obtained in a yield of 97.6percent. A synthetic scheme (a-1) of 4-bromobenzyl triphenylphosphonium bromide is shown below.
97.6%
at 20℃; for 23 h;
First, 25.2 g (101 mmol) of 4-bromobenzyl bromide and 100 mL of acetone were put into a 200 mL conical flask, and 29.1 g (111 mmol) of triphenylphosphine was added thereto. The mixture was stirred for 23 hours at room temperature. After the reaction, a precipitate in the reaction mixture was collected by suction filtration to give 50.5 g of a white powdered solid of (4-bromobenzyl)triphenylphosphoniumbromide (yield: 97.6percent).
96%
at 20℃; for 24 h;
First, 25.36 g (101.5 mmol) of 4-bromobenzylbromide and 100 mL of acetone were put in a 100 mL conical flask, and 29.28 g (111.6 mmol) of triphenylphosphine was added thereto. The mixture was stirred for 24 hours at room temperature. After the reaction, a precipitate in the reaction mixture was collected by suction filtration, and 50 g of a white powdered solid of 4-bromobenzyltriphenylphosphoniumbromide was obtained in a yield of 96percent.
96%
at 20℃; for 24 h;
A 200 mL conical flask was charged with 25.36 g (101.5 mmol) of 4-bromobenzyl bromide and 100 mL of acetone. 29.28 g (111.6 mmol) of triphenylphosphine was added thereto to be stirred for about 24 hours at room temperature. After the reaction, precipitate in the reaction mixture was collected by suction filtration to obtain 50 g of white powder of 4-bromobenzyl triphenylphosphonium bromide in a yield of 96percent. A synthesis scheme of 4-bromobenzyl triphenylphosphonium bromide is shown below.
95%
for 12 h; Reflux
A solution of 4-bromo benzyl bromide (10.0 g, 40.0 mmol) and PPh3 (10.5 g, 40.0 mmol) in toluene (100 mL) was heated to reflux for 12 hours. After cooled to room temperature, the mixture was filtrated and the filter cake was washed with toluene (200 mL), dried over high vacuum to give compound N1 19.5 g, yield: 95percent) as a white powder which was used to next step directly.
94%
for 6 h; Reflux
General procedure: Triphenylphosphine (5 mmol) was added to a solution of 4-substituted-benzyl halide (5 mmol) in toluene (50 mL). The mixture was heated to reflux for 6 h and then cooled to room temperature. The precipitate was collected, recrystallized from ethanol to give the products.
93%
for 10 h; Inert atmosphere; Reflux
General procedure: To a solution of benzylbromide (33 mmol) in toluene (20 mL) was added a solution of triphenylphosphine (36.3 mmol) in toluene (25 mL). After being heated at reflux for 5 h, the reaction mixture was cooled at room temperature and a first crop of product was collected by filtration. The filtrate was then refluxed for additional 5 h and a second crop of product precipitated (10-20percent). The collected crops were crystallized from ethanol to give pure phosphonium bromide in high yield.
93%
Reflux
4-Bromobenzyl bromide (7.07 g, 28.30 mmol) and triphenylphosphine (7.42 g, 28.30 mmol) weresuspended in 50 mL toluene and the solution was refluxed overnight. During reaction, a whiteprecipitate formed. It was filtered off, washed several times with ether and dried under vacuum(13.42 g, 93percent yield).
89%
at 120℃; for 17 h; Inert atmosphere
Intermediate 2 (4^Bromobenzyl)(triphenyl)phosphonium bromide To a stirred solution of 1 -bromo-4-(bromomethyl)benzene (8g, 32mmol) in toluene (160 ml) was added triphenylphosphine (8.4g, 32mmol). The reaction was stirred at 120°C under an atmoshpere of nitrogen for 17 hours after which time a white precipitate had formed. The reaction was then cooled to room temperature and the solid was collected by filtration, washing with a minimum amount of cold toluene to give (4- bromobenzyl)(triphenyl)phosphonium bromide as a white solid (15.4 g, 89 percent) lH NMR (400 MHz, DMSO-c/6) δ 7.85 - 8.01 (m, 2 H), 7.57 - 7.84 (m, 8 H), 7.33 - 7.55 (m, 1 H), 6.79 - 7.02 (m, 1 H), 5.04 - 5.28 (m, 2 H) MS ES+ 433, 435
Reference：
[1] Patent: WO2005/97812, 2005, A1, . Location in patent: Page/Page column 64
[2] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 8, p. 902 - 907
[3] Patent: KR2015/103967, 2015, A, . Location in patent: Paragraph 0100
[4] Dyes and Pigments, 2019, vol. 162, p. 959 - 966
[5] Patent: US2008/81934, 2008, A1, . Location in patent: Page/Page column 34
[6] Patent: US7732619, 2010, B2, . Location in patent: Page/Page column 80
[7] Patent: US7758972, 2010, B2, . Location in patent: Page/Page column 77
[8] Patent: US2007/80630, 2007, A1, . Location in patent: Page/Page column 62; 64; 66
[9] Patent: US2007/100180, 2007, A1, . Location in patent: Page/Page column 15
[10] Macromolecules, 2002, vol. 35, # 13, p. 4849 - 4851
[11] European Journal of Organic Chemistry, 2007, # 12, p. 1891 - 1904
[12] Journal of the American Chemical Society, 2012, vol. 134, # 40, p. 16671 - 16692
[13] Patent: WO2015/14993, 2015, A2, . Location in patent: Page/Page column 40
[14] European Journal of Medicinal Chemistry, 2011, vol. 46, # 7, p. 2908 - 2916
[15] Tetrahedron, 2012, vol. 68, # 20, p. 3899 - 3907
[16] Molecules, 2017, vol. 22, # 12,
[17] Journal of Fluorine Chemistry, 1996, vol. 79, # 2, p. 173 - 178
[18] Patent: WO2013/27001, 2013, A1, . Location in patent: Page/Page column 34
[19] Journal of Materials Chemistry, 2002, vol. 12, # 12, p. 3431 - 3437
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[28] Patent: US2007/78267, 2007, A1, . Location in patent: Page/Page column 18
[29] Patent: WO2008/23336, 2008, A2, . Location in patent: Page/Page column 53
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[31] Patent: US2013/338120, 2013, A1, . Location in patent: Paragraph 0196
[32] Chemical Communications, 2014, vol. 50, # 81, p. 12076 - 12079
[33] New Journal of Chemistry, 2015, vol. 39, # 9, p. 7472 - 7480
[34] Journal of Medicinal Chemistry, 2015, vol. 58, # 16, p. 6494 - 6506
[35] Journal of Fluorine Chemistry, 2015, vol. 179, p. 116 - 120
37
[ 589-15-1 ]
[ 75476-78-7 ]
Reference：
[1] Journal of Organic Chemistry, 1984, vol. 49, # 22, p. 4226 - 4237
38
[ 589-15-1 ]
[ 80382-23-6 ]
Reference：
[1] Patent: CN107176942, 2017, A,
39
[ 83857-96-9 ]
[ 589-15-1 ]
[ 143722-29-6 ]
Yield
Reaction Conditions
Operation in experiment
89.9%
With potassium carbonate In N,N-dimethyl acetamide; water; toluene
EXAMPLE 14 2-n-Butyl-4-chloro-1-p-bromobenzyl-1H-imidazole-5-carboxaldehyde A mixture of 2-n-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (0.6 m=111.9 g), p-bromobenzylbromide (0.6 m=153.02 g), anhydrous potassium carbonate (0.75 m=103.5 g), and dry N,N-dimethylacetamide (900 mL) was stirred at room temperature for 4 hours. The mixture was diluted with 1.2L of toluene and 1.8L of water. After mixing for half an hour, the layers were separated. The organic layer was washed two more times with 900 mL portions of water, then dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated. The residual oil was pumped overnight to a weight of 191.71 g (89.9percent yield).
89.9%
With potassium carbonate In N,N-dimethyl acetamide; water; toluene
EXAMPLE 14 2-n-Butyl-4-chloro-1-p-bromobenzyl-1H-imidazole-5-carboxaldehyde A mixture of 2-n-butyl-4-chloro-1H-imidazole 5-carboxaldehyde (0.6 m=111.9 g), p-bromobenzylbromide (0.6 m=153.02 g), anhydrous potassium carbonate (0.75 m=103.5 g), and dry N,N-dimethylacetamide (900 mL) was stirred at room temperature for 4 hours. The mixture was diluted with 1.2 L of toluene and 1.8 L of water. After mixing for half an hour, the layers were separated. The organic layer was washed two more times with 900 mL portions of water, then dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated. The residual oil was pumped overnight to a weight of 191.71 g (89.9percent yield).
Reference：
[1] Patent: US5310928, 1994, A,
[2] Patent: US5130439, 1992, A,
40
[ 83857-96-9 ]
[ 589-15-1 ]
[ 143722-29-6 ]
Reference：
[1] Journal of Organic Chemistry, 1994, vol. 59, # 21, p. 6391 - 6394
41
[ 589-15-1 ]
[ 364794-79-6 ]
Reference：
[1] Patent: WO2013/153357, 2013, A1,
[2] Patent: US2015/45354, 2015, A1,
[3] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 684 - 701
42
[ 589-15-1 ]
[ 481054-89-1 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 9, p. 1463 - 1467
[2] Organic and Biomolecular Chemistry, 2013, vol. 11, # 9, p. 1463 - 1467
43
[ 589-15-1 ]
[ 938043-30-2 ]
Reference：
[1] Patent: WO2012/119941, 2012, A1,
[2] Patent: WO2015/32945, 2015, A1,
[3] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 684 - 701
[4] Patent: US2018/44328, 2018, A1,
44
[ 589-15-1 ]
[ 859833-22-0 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 684 - 701
[2] Journal of the American Chemical Society, 2017, vol. 139, # 24, p. 8267 - 8276
(a) The reaction mixture of p-bromobenzyl bromide (corresponding to 50) (4.00g, 16.004mmol) and phthalimide potassium salt (3.26g, 17.61mmol) in DMF (10ml) was stirred for 6h at 100C with a CaCl2 tube. After cooling, H2O (100ml) was added, and the resulting mixture was extracted with AcOEt (100ml×3). The combined organic layer was washed with H2O (100ml×1) and then brine (100ml×1), dried over Na2SO4 (anhyd), filtered, and concentrated under reduced pressure to afford 2-(4-bromobenzyl)isoindole-1,3-dione (5.28g, quant. y.) as a colorless solid. Colorless cotton-like crystal (n-hexane/AcOEt). Mp 126-129C. 1H NMR (300MHz/CDCl3) delta 4.80 (2H, s, CH2), 7.32 (2H, d, J=7.8Hz, ArH), 7.44 (2H, d, J=8.1Hz, ArH), 7.71-7.73 (2H, m, ArH), 7.84-7.85 (2H, m, ArH).
In N,N-dimethyl-formamide; at 20℃; for 1h;
To a solution of 1 -bromo-4-bromomethyl-benzene (3.0 g, 12.0 mmol, 1.0 eq) in DMF (40 mL) was added phthalimide potassium (4.4 g, 24.0 mmol, 2.0 eq). The reaction mixture was stirred for 1 h at rt Water was added, and the mixture was extracted with EtOAc. The organic layer was dried over Na2S04 and evaporated to give 2-(4-bromo-benzyl)-isoindole-l,3-dione which was used as a white solid (4.0 g, quant)without further purification.
With potassium carbonate; In tetrahydrofuran; water; at 60℃; for 24h;Inert atmosphere;
To a flask containing aq dimethylamine (50%, 500 mmol) and K2CO3 (50 mmol) was added dropwise a solution of 4-bromobenzyl bromide (50 mmol) in THF (90 mL). The obtained mixture was stirred for 24 h at 60 C under Ar atmosphere. Then, water (60 mL) was added to the reaction mixture and the solution was extracted with CHCl3 (100 mL×3). The organic layer was dried over Na2SO4. After filtration and removal of the solvent, 4-bromobenzyldimethylamine was obtained in 99% yield (bp 55 C/1 mmHg). Mg (40 mmol) was dried by a vacuum pump for 20 min at 70 C. To the flask containing Mg was added a solution of 4-bromobenzyldimethylamine (30 mmol) in dry THF (70 mL), and the obtained mixture was stirred for 1 h at room temperature under Ar atmosphere. Then, chlorodiphenylphosphine (30 mmol) in dry THF (30 mL) was added to the mixture at 0 C and the obtained mixture was stirred for 2 h at room temperature under Ar atmosphere. After the reaction, the mixture was filtered and washed with dichloromethane. Then, aq H2O2 (30%, 60 mmol) was added to the obtained filtrate at 0 C and the obtained mixture was stirred for 1 h at room temperature. After the reaction, the reaction mixture was quenched with water (100 mL) and extracted with chloroform (50 mL×3). The organic layer was washed with brine and dried over Na2SO4. After filtration and removal of the solvent, diethyl ether (300 mL) was added to the residue and the mixture was stirred for 0.5 h to dissolve the product. Then, the organic solution was filtered and removal of the solvent from the filtrate gave 4-(diphenylphosphono)benzyldimethylamine in 95% yield. Dimethyl sulfate (120 mmol) was added to a flask containing 4-(diphenylphosphono)benzyl-dimethylamine (60 mmol) in dry 1,2-dimethoxyethane (200 mL) at 0 C. The obtained mixture was stirred for 1 h at 50 C under Ar atmosphere. Then, LiAlH4 (180 mmol) was added to the solution at 0 C and the obtained mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with ice and then with aq HBr solution (1 M, 200 mL), and the obtained solution was washed with diethyl ether (200 mL×2). Then, the aqueous solution was extracted with dichloromethane (100 mL×3) and the combined organic layer was dried over Na2SO4. After filtration and removal of the solvent, diethyl ether (300 mL) was added to the residue and the mixture was stirred for 0.5 h under Ar atmosphere. Then, the mixture was filtered to give 4-(diphenylphosphino)benzyltrimethyl-ammonium bromide in 79% yield.
58%
With potassium carbonate; In ethanol; at 50℃;
A solution of l-bromo-4-(bromomethyl)benzene (20 g, 80.65 mmol, 1.00 equiv), dimethylamine (13.20 g, 96.80 mmol, 1.20 equiv, 33%) and potassium carbonate (13.36 g, 96.81 mmol, 1.20 equiv) in ethanol (200 mL) was stirred overnight at 50C. The solid material was removed by filtration and the filtrate was concentrated under vacuum. The residue was dissolved in 200 mL of water and extracted with 3x200 mL of dichloromethane. The combined organic layer was washed with 3x200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (20: 1) to give 10 g (58%) of (4-bromophenyl)-N,N-dimethylmethanamine as a yellow oil. LC-MS: (ES, m/z): 255 [M+CH3CN+H]+, 214 [M+H]+, 169.
58%
With potassium carbonate; In ethanol; at 50℃;
A solution of 1-bromo-4-(bromomethyl)benzene (20 g, 80.65 mmol, 1.00 equiv), dimethylamine (13.20 g, 96.80 mmol, 1.20 equiv, 33%) and potassium carbonate (13.36 g, 96.81 mmol, 1.20 equiv) in ethanol (200 mL) was stirred overnight at 50 C. The solid material was removed by filtration and the filtrate was concentrated under vacuum. The residue was dissolved in 200 mL of water and extracted with 3*200 mL of dichloromethane. The combined organic layer was washed with 3*200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (20:1) to give 10 g (58%) of (4-bromophenyl)-N,N-dimethylmethanamine as a yellow oil. LC-MS: (ES, m/z): 255 [M+CH3CN+H]+, 214 [M+H]+, 169.
In DMF (N,N-dimethyl-formamide); ethanol; at 20℃; for 18h;
2M Ethanolic DIMETHYLAMINE solution (30 ml) was added to a solution of 4-bromobenzyl bromide (5 g) in DMF (20 ml). The mixture was stirred at ambient temperature for 18 h and was then partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried, evaporated and purified by column chromatography, eluting with a gradient of 0 to 5% methanol in DCM to yield the product as a clear oil. MS (M+H) + 214. 'H NMR (CDC13) 2.21 (s, 6H), 3.35 (s, 2H), 7.18 (d, 2H), 7.43 (d, 2H).
In water; N,N-dimethyl-formamide; at 5 - 20℃;
At 5 0C 4-bromobenzylbromide (100 g, 402 mmol) in 100 mL DMF is added to a mixture of dimethylamine (40 % in water, 150 mL, 1.33 mol). After 0.5 h stirring at RT, 6 M aqueous HCl is added and the reaction mixture is extracted with diethyl ether. The combined organic phases are washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue is purified by vacuum distillation (bp 58 0C at 2 mbar). Yield: 77.6 g.
In tetrahydrofuran; at 20℃; for 72h;
a) Compound 10a[0258] A solution of 4-bromobenzylbromide (2 g, 8 mmoles) in anhydrous tetrahydrofuran (10 mL) was treated with a 2.0 M solution of dimethylamine (20 mL) mL) in tetrahydrofuran. The reaction was stirred at room temperature for 3 days. The reaction mixture was then diluted with ethyl acetate (75 mL) and washed with 100 mL of saturated aqueous sodium bicarbonate solution. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. TLC analysis on silica using 15% ethyl acetate in hexanes showed no starting material and the formation of a polar product of Rf = 0.1. The ethyl acetate solution was concentrated under reduced pressure to afford a light yellow oil. Yield = 1.63 g.
With potassium carbonate; In water; acetonitrile; at 20℃; for 2h;
General procedure: To a stirred solution of 10 (1.00g, 4.00mmol) and K2CO3 (1.66g, 12.00mmol) in acetonitrile (20mL) was added dropwise diethylamine solution (1.20g, 16.00mmol) at room temperature for 2h. The solvent was evaporated in vacuo and the residue was then dissolved in EtOAc (50mL) and washed with water (20mL×3), the organic layers were washed with brine, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to provide the 11a (0.83g, 84.7% yield) as an off-white liquid. (0041) Then, a mixture of 11a (0.83g, 3.43mmol), bis(pinacolato)diboron (0.96g, 3.77mmol), PdCl2(dppf)-CH2Cl2 (0.084g, 0.103mmol) and potassium acetate (0.67g, 6.86mmol) in anhydrous 1,4-dioxane (15mL) was purged with argon and heated at 100C for 2.5h. The reaction was then treated with 6 (1.20g, 3.60mmol), 2.0M aqueous Na2CO3 (5mL) and another portion of PdCl2(dppf)-CH2Cl2 (0.084g, 0.103mmol), then heated at 110C for 12h under argon. The reaction mixture was cooled to room temperature, filtered, and concentrated. The final compound was purified by MPLC (ISCO CombiFlash purification system) (MeOH/DCM, eluted from 0% to 10%), The fractions were collected, concentrated to afford 12a (0.72g, 57.2% yield).
With sodium tetrahydroborate; tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 100℃;
To a dry 250 mL three-necked flask was added phenylboronic acid (2.44 g, 0.02 mol), p-bromobenzyl bromide (4.99 g, 0.02 mol), tetrakis(triphenylphosphine)palladium (0.23 g, 0.2 mmol).Add anhydrous potassium carbonate (8.28 g, 0.06 mol), and 50 mL of toluene, 30 mL of absolute ethanol,10 mL of deionized water was further added with sodium borohydride (0.57 g, 15 mmol), and the mixture was heated to 100 C in an oil bath. After the reaction was confirmed by thin-plate chromatography, silica gel column chromatography was performed with ethyl acetate and n-hexane system to collect the product, 4.07. g, yield 82.4%.
73%
With C24H20Cl2NPPdS; potassium carbonate; palladium; In toluene; at 100℃; for 24h;
General procedure: A 100 ml round bottom flask was fitted with a reflux condenser and a magnetic stirrer bar. The flask was charged with toluene (15 ml) and the appropriate amount of catalyst reagents and the internal standard (n-Decane: 2.59 mmol). The contents were thoroughly mixed and an initial sample (t0) was then taken. The reaction flask was placed in an oil bath at the desired temperature and the reaction mixture allowed to heat/reflux with stirring. A sample was taken and analyzed every 10 min for the first hour and every 30 min thereafter until t3h. In cases where conversionwas not complete after 3 h, the reaction mixturewas then allowed to stir for a total of 24 h. The reaction at 140 C was performed in a sealed tube. All catalytic reactions were done under aerobic conditions. Percentage conversions were determined by GC with n-decane as the internal standard and the coupling products were characterized by mass spectrometry (Table 4) as well as 1H NMR spectroscopy (Entry 5, Table 4 only).
80%Chromat.
With sodium carbonate; triphenylphosphine; In water; at 80℃; for 18h;Schlenk technique;
General procedure: A mixture of aryl halide (0.25 mmol), phenylboronicacid (0.3 mmol), Na2CO3 (0.25 mmol), PPh3 (0.025 mmol)and Pd(at)PAAs-CD (0.5 mg, 0.2 mol% Pd per mol of arylhalide) were placed into a 10 mL Schlenck tube with1 mL H2O. The reaction mixture was reacted at 80 C for18 h, and the reaction progress was monitored via gaschromatography mass spectrometry (GC-MS). The reactionmixture was allowed to cool to room temperature, andthen 3 mL water was added, and the product was extractedwith ethyl acetate (3 mL × 3). The organic layers werecombined and dried over anhydrous Na2SO4 and solventswere evaporated via rotary evaporator. The crude productwas purified by column chromatography (200-300 meshsilica) using a mixture of petroleum ether/ethyl acetate(10:1, v:v) as eluent. The structures of the products wereconfirmed by 1H NMR and 13C NMR spectroscopies.
With N,N,N',N'-tetramethylguanidine; In tetrahydrofuran; at 20℃;
A solution of 1.50 g (6 mmol) of 4-bromobenzyl bromide and 0.73 g (7.2 mmol) of 1,3-<strong>[2346-26-1]oxazolidine-2,4-dione</strong> in 6 ml of tetrahydrofuran is admixed dropwise with a solution of 1.39 g (12 mmol) of 1,1,3,3-tetramethylguanidine in 6 ml of tetrahydrofuran. The mixture is stirred at ambient temperature overnight. 50 ml of ice-cold aqueous hydrochloric acid (1N) and 100 ml of ethyl acetate are added. The organic phase is separated after settling out and washed successively with 25 ml of water and 25 ml of saturated aqueous sodium chloride solution. It is dried over sodium sulphate and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica gel, eluting with an 80/20 mixture of cyclohexane and ethyl acetate. 1.14 g of product are obtained in the form of white crystals. m.p. ( C.): 88-90 C.
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 40℃; for 3h;
Piperazine-1, 2-dicarboxylic acid, 1-TERT-BUTYL ester, 2- methyl ester (250 mg, 1.03 mmol) was added dropwise to a stirred suspension of 4-bromobenzyl bromide (283 mg, 1.14 mmol) and cesium carbonate (1.0 g, 3.09 mmol) in anhydrous DMF (10 mL) at room temperature. The reaction mixture was stirred at 40C for 3 hrs (TLC control) and then poured into water (25 mL) and extracted with diethyl ether (3 x 25 mL). The combined extract was washed with water (2 x 10 mL), brine (3 x 10 mL), dried over anhydrous MGSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 40 % ethyl acetate/hexane as eluent, afforded the title compound as a white foam (270 mg, 64 %).
64%
With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 40℃; for 3h;
Piperazine-1,2-dicarboxylic acid, 1-tert-butyl ester, 2-methyl ester (250 mg, 1.03 mmol) was added dropwise to a stirred suspension of 4-bromobenzyl bromide (283 mg, 1.14 mmol) and cesium carbonate (1.0 g, 3.09 mmol) in anhydrous DMF (10 mL) at room temperature. The reaction mixture was stirred at 40 C. for 3 hrs (TLC control) and then poured into water (25 mL) and extracted with diethyl ether (3×25 mL). The combined extract was washed with water (2×10 mL), brine (3×10 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 40% ethyl acetate/hexane as eluent, afforded the title compound as a white foam (270 mg, 64%)
9-fluorenyl-methoxycarbonyl-cyclohexyl alanine[ No CAS ]
[ 462-94-2 ]
[ 1458-98-6 ]
[ 78-77-3 ]
[ 1809-10-5 ]
[ 110-53-2 ]
[ 592-55-2 ]
[ 7328-91-8 ]
[ 871-76-1 ]
[ 105-83-9 ]
[ 144-48-9 ]
[ 929-59-9 ]
[ 107-59-5 ]
[ 5324-30-1 ]
[ 5428-54-6 ]
[ 27129-86-8 ]
[ 2417-72-3 ]
[ 2581-34-2 ]
[ 554-84-7 ]
[ 3385-21-5 ]
[ 126-38-5 ]
[ 636-93-1 ]
[ 88-30-2 ]
[ 620-13-3 ]
[ 823-78-9 ]
[ 5035-82-5 ]
[ 29022-11-5 ]
[ 539-48-0 ]
[ 35661-39-3 ]
[ 26759-46-6 ]
[ 20439-47-8 ]
[ 2615-25-0 ]
[ 6393-01-7 ]
[ 5372-81-6 ]
[ 35661-40-6 ]
[ 100-39-0 ]
[ 611-17-6 ]
[ 23915-07-3 ]
[ 71989-23-6 ]
[ 35737-15-6 ]
[ 2592-95-2 ]
[ 18880-00-7 ]
[ 88681-68-9 ]
[ 100063-22-7 ]
[ 75-03-6 ]
[ 106-94-5 ]
[ 104-81-4 ]
[ 589-10-6 ]
[ 107-15-3 ]
[ 109-76-2 ]
[ 110-60-1 ]
[ 7051-34-5 ]
[ 106-95-6 ]
[ 622-95-7 ]
[ 589-15-1 ]
[ 134-20-3 ]
[ 2550-36-9 ]
[ 89-92-9 ]
[ 456-41-7 ]
[ 766-80-3 ]
[ 459-46-1 ]
[ 874-98-6 ]
[ 402-49-3 ]
[ 870-63-3 ]
[ 85118-01-0 ]
[ 22115-41-9 ]
[ 3958-57-4 ]
[ 100-11-8 ]
[ 107-82-4 ]
[ 6482-24-2 ]
[ 3132-64-7 ]
[ 112883-41-7 ]
[ 3433-80-5 ]
[ 52727-57-8 ]
C18H15N2O3PolS[ No CAS ]
C20H20N3OPolS[ No CAS ]
C23H19N2O2PolS[ No CAS ]
C18H23ClN3OPolS[ No CAS ]
C22H26N3OPolS[ No CAS ]
C22H23N2O5PolS[ No CAS ]
C20H26ClN2O3PolS[ No CAS ]
C23H22ClN2O3PolS[ No CAS ]
C20H21FN3O3PolS[ No CAS ]
C22H29N2O3PolS[ No CAS ]
C21H28N3O3PolS[ No CAS ]
C19H26N3O4PolS2[ No CAS ]
C22H30N3OPolS[ No CAS ]
C21H28N3O4PolS[ No CAS ]
C26H26N3OPolS[ No CAS ]
C23H15ClF3N2O2PolS[ No CAS ]
C24H22N3O3PolS[ No CAS ]
C23H16ClF2N2O2PolS[ No CAS ]
C22H22Br2N3OPolS[ No CAS ]
C24H26FN2O5PolS[ No CAS ]
C25H22FN2O4PolS[ No CAS ]
C26H22N3O4PolS[ No CAS ]
C25H25ClN3O3PolS[ No CAS ]
C25H18ClF2N2O3PolS[ No CAS ]
C29H26N3O3PolS[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With piperidine; Carbonyldiimidazole; tin-2-ethylhexanoate dihydrate; potassium tert-butylate; water; N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; diisopropyl-carbodiimide; dibromotriphenylphosphorane; In DMF (N,N-dimethyl-formamide); dichloromethane; N,N-dimethyl acetamide; 1,2-dichloro-ethane;Combinatorial reaction / High throughput screening (HTS);
EXAMPLE 1 [0213] This example shows the synthesis of a combinatorial library of thioquinazolinone derivatives. [0214] Step 1a: Preparation of Wang Bromide Resin [0215] 40 tea bags containing 2 g each of Wang resin (80 g, 120 mmol) was taken in a 5 L PP container. A solution of triphenylphosphine dibromide (152 g, 0.15 M, 3 eq., 360 mmol) in 2000 ml DCM was added and the solution was shaken at room temperature overnight. The resin was sequentially washed with DCM (4×, 1.5 L each) and diethylether (6×, 1.5 L each) and dried under vacuum, to give the bromo wang resin. [0216] Step 1b: Loading of the Nitrophenol on Bromo Wang [0217] 20 g of the Bromo wang resin (1.5 meq/g) was taken in a 2 L wide-mouthed glass container and 1000 mL DMA was addded to it followed by the addition of the nitro phenol (10 eq., 0.3M, 300 mmol). Potasium t-butoxide (33.46 g, 10 eq., 300 mmol) was then added to it and the bottles were heated at 50 C. overnight. The bags were washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The tea bags were then dried overnight in air. The following nitrophenols were used: [0218] 2-METHYL-5-NITROPHENOL [0219] 5-HYDROXY-2-NITROBENZOTRIFLUORIDE [0220] 3-METHYL-4-NITROPHENOL [0221] 2-METHOXY-5-NITROPHENOL [0222] M-NITROPHENOL [0223] Step 1c: Reduction of the Nitro Group to Amine [0224] A 2.0 M solution of tin-2-ethylhexanoate dihydrate was prepared in DMF containing 0.5% H2O. The tea bags were added and the solution is heated at 50 C. for 40 hours. After cooling the bags are washed with DMF/10% HOAc (3×), DMF (3×), 5% DIEA/DCM (2×), DCM (2×) and MeOH (2×) and dried in air overnight. [0225] Step 1d: Coupling N-FMOC Protected Amino Acid to Wang Resin. [0226] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL plastic bottle. DMF (300 mL), DCM (300 mL), FMOC-Cyclohexyl alanine (70.82 g, 6 eq., 0.3M, 180 mmol), DIC (22.71 g, 6 eq., 180 mmol), HOBt (24.32 g, 6 eq., 180 mmol) were added sequentially. After shaking for 12 hours, the packet was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried overnight in air. The tea bags containing the amino acids were then treated with 20% piperidine/DMF for 2 h at room temperature to deblock the FMOC group. The following amino acids were used: [0227] FMOC-GLY-OH [0228] FMOC-ALA-OH [0229] FMOC-L-ISOLEUCINE [0230] FMOC-L-PHENYLALANINE [0231] FMOC-D-NLE-OH [0232] FMOC-CHA-OH [0233] FMOC-L-TRYPTOPHAN [0234] Step 1e: Coupling of the Diamines to Wang Resin [0235] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL Nalgene bottle. 600 mL of DCM was added followed by the addition of the carbonyl diimidazole (29.9 g, 6 eq., 0.3M, 180 mmol) and the flasks were shaken at room temperature for 3 hours after which they were decanted and washed with DCM (2×, 600 mL). To these Nalgene bottles were added the diamines (6 eq., 0.4M, 180 mmol) in 450 mL of DCM (0.4M) and they were shaken at room temperature overnight. The diamines used were as follows: [0236] 2,2-DIMETHYL-1,3-PROPANEDIAMINE [0237] 1,3-CYCLOHEXANEDIAMINE [0238] (1R,2R)-(-)-1,2-DIAMINOCYCLOHEXANE [0239] TRANS-1,4-DIAMINOCYCLOHEXANE [0240] P-XYLYLENEDIAMINE [0241] 1,4-BIS(3-AMINOPROPYL)PIPERAZINE [0242] ETHYLENEDIAMINE [0243] 1,3-DIAMINOPROPANE [0244] 1,8-DIAMINO-3,6-DIOXAOCTANE [0245] 1,4-DIAMINOBUTANE [0246] 1,5-DIAMINOPENTANE [0247] 1,6-HEXANEDIAMINE [0248] N,N-BIS(3-AMINOPROPYL)METHYLAMINE [0249] 2,2'-THIOBIS(ETHYLAMINE) [0250] 2,5-DIMETHYL-1,4-PHENYLENEDIAMINE [0251] After shaking overnight, the packets was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried in air. [0252] Step 2: Formation of the Isothiocyanate [0253] The o-amino benzoate ester (136 g, 10 eq., 900 mmol) was taken in a 5 L wide-mouthed glass bottle and 2.7 L of dichloroethane was added to it (0.3M). The following esters were used: [0254] METHYL ANTHRANILATE [0255] METHYL 2-AMINO-4-CHLOROBENZOATE [0256] 2-AMINO-4,5-DIMETHOXYBENZOIC ACID [0257] METHYL ESTER [0258] METHYL 3,4,5-TRIMETHOXYANTHRANILATE [0259] DIMETHYL AMINOTEREPHTHALATE [0260] METHYL 2-AMINO-5-BROMOBENZOATE [0261] METHYL 3-AMINOTHIOPHENE-2-CARBOXYLATE [0262] METHYL 3-AMINO-5-PHENYLTHIOPHENE-2-CARBOXYLATE [0263] Thiocarbonyl diimidazole (160 g, 10 eq., 900 mmol) was added to it and the solution was heated at 55 C. overnight to form the isothiocyanate. [0264] Step 3: Formation of the Thioquinazolinone [0265] The next day the tea bags containing the amino acids, diamines and the amino phenols on wang resin (90 mmol) was added to the isothiocyanate solution from reaction 2 and the glass bottles were heated at 55 C. overnight. After cooling the bags was washed alternatively with DMF (2000 mL) and DCM (2000 mL) 3 cycles followed by 6 cycles of MeOH...
A mixture of a 60% suspension of sodium hydride in mineral oil (4.8 g, 120 mmol) in N, N-dimethylformamide (50 mL) at about 5 C was treated with diethyl malonate (36.4 mL, 240 mmol). The mixture was stirred for about 5 minutes, slowly treated with a solution of 4- bromobenzyl bromide (20.0 g, 80 mmol) in N, N-dimethylformamide (20 mL), stirred at room temperature overnight, diluted with water, and extracted with ethyl acetate. The combined organic extracts were dried (MgS04), filtered, and concentrated under high vacuum. The residue was dissolved in a mixture of acetic acid (46 mL), water (30 mL), and concentrated sulfuric acid (13 mL) and was heated to reflux for 18 hours. The reaction mixture was cooled, concentrated under high vacuum, and diluted with water. The formed crystalline solid was collected by filtration, washed with water and diethyl ether, and was dried under high vacuum to provide the desired product. MS (DCI-NH3) : m/z 246,248 (M+NH4) +.
EXAMPLE 3 3-(4-Bromobenzyloxy)benzamide (Compound NU1014) To <strong>[618-49-5]3-hydroxybenzamide</strong> (2.0 mM) under nitrogen was added anhydrous acetonitrile (20 ml), potassium carbonate (2.0 mM), and p-bromobenzyl bromide (2.0 mM). The mixture was refluxed for 3 hours, and the progress of the reaction monitored by TLC. The excess solvent was removed under vacuum, until dry, and the title compound was recrystallized from hot dichloromethane (minimum amount). A white crystalline solid was isolated and dried. Melting point: 160-161 C. Infrared data: cm-1: KBr disc: 3323; 3146; 1670; 1622. 1 H NMR: d6 DMSO: delta=5.26 (s; 2H; CH2); 7.3 (dd; 1H: H4); 7.49-7.75 (m, 9H; PhBr; NH2; PhO) 13 C NMR: d6 DMSO: delta=114.031; 118.123; 120.402; 121.295; 129.704; 130.107; 131.690; 136.094; 136.723; 158.371; 167.843. Mass spectra: m/z: EI: 307 (M+1); 262; 212; 169 (100%) 101;90. Elemental analysis: Expect C: 55.26%; H: 3.29%; N: 4.61% Found C: 54.61%; H: 3.66%; N: 4.47%.
Morpholine (13, 1.4 mL, 1.39 g, 16 mmol) was added to a solution of 4-bromobenzyl bromide (12, 1.0 g, 4 mmol) in acetonitrile (50 mL) and the mixture was heated to reflux for 4 h. Then water was added and the mixture was extracted with CH2Cl2 (3×). The combined organic layers were dried (Na2SO4), filtered, and the solvent was removed in vacuo. The residue was purified by flash column chromatography (6 cm, 50 mL, n-hexane/ethyl acetate = 8/2, Rf = 0.19) to give 14 as colorless solid (1.0 g, 3.9 mmol, 98%). Mp: 85 C; 1H NMR (CDCl3): delta (ppm) = 2.41-2.45 (m, 4H, NCH2CH2O), 3.45 (s, 2H, NCH2Ar), 3.69-3.72 (m, 4H, NCH2CH2O), 7.19-7.23 (m, 2H, 2'-H4-bromophenyl, 6'-H4-bromophenyl), 7.42-7.46 (m, 2H, 3'-H4-bromophenyl, 5'-H4-bromophenyl); 13C NMR (CDCl3): delta (ppm) = 53.7 (2C, NCH2CH2O), 62.8 (1C, NCH2Ar), 67.1 (2C, NCH2CH2O), 121.1 (1C, C-4'4-bromophenyl), 131.0 (2C, C-2'4-bromophenyl, C-6'4-bromophenyl), 131.5 (2C, C-3'4-bromophenyl, C-5'4-bromophenyl), 136.7 (1C, C-1'4-bromophenyl); IR (neat): nu (cm-1) = 2966, 2927, 2862, 2815, 1487, 1449, 1351, 1110, 1065, 1007, 910, 863, 848, 789; MS (ESI): m/z = 256 (M(79Br)+H+, 100), 258 (M(81Br)+Na+, 94); HRMS (m/z): [M+H]+ calcd for C11H14BrNOH, 256.0332; found, 256.0327; HPLC (method 1): tR = 11.4 min, purity 99.9%.
89%
With potassium carbonate; In acetonitrile; at 60℃;
To a stirred suspension of morpholine (8.37 g, 96 mmol) and 1-bromo-4- (bromomethyl)benzene (20.00 g, 80 mmol) in acetonitrile and potassium carbonate (27.65 g, 200 mmol) was added at room temperature and the mixture was stirred at 60C overnight. After allowing to reach room temperature, the suspension was filtered and the filtrate was absorbed on silica gel. The crude filtrate was purified by column chromatography using a 120 g silica gel cartridge. Solvent A: Hexane. Solvent B: Ethyl Acetate (EtOAc). Gradient: 2 min hold 100% A followed by a 27 min ramp to 40% B and then 3 min hold 40% B. The desired fractions were pooled together and concentrated under reduced pressure to obtain 1 as a white solid (19.5 g, 76 mmol, Yield 89%). 1H NMR (500 MHz; CDCl3) 5 2.43-2.45 (m, 4H), 3.46 (s, 2H), 3.71-3.73 (m, 4H), 7.22- 7.24 (m, 2H), 7.44-7.47 (m, 2H) ppm. Purity by LCMS (UV Chromatogram, 190-450nm) 94%, rt = 5.0 min, m/z 256 (M+H)+
89%
With potassium carbonate; In acetonitrile; at 60℃;
Preparation 1 4-[(4-Bromophenyl)methyl]morpholine To a stirred suspension of morpholine (8.37 g, 96 mmol) and 1-bromo-4-(bromomethyl)benzene (20.00 g, 80 mmol) in acetonitrile and potassium carbonate (27.65 g, 200 mmol) was added at room temperature and the mixture was stirred at 60 C. overnight. After allowing to reach room temperature, the suspension was filtered and the filtrate was absorbed on silica gel. The crude filtrate was purified by column chromatography using a 120 g silica gel cartridge. Solvent A: Hexane. Solvent B: Ethyl Acetate (EtOAc). Gradient: 2 min hold 100% A followed by a 27 min ramp to 40% B and then 3 min hold 40% B. The desired fractions were pooled together and concentrated under reduced pressure to obtain 1 as a white solid (19.5 g, 76 mmol, Yield 89%). 1H NMR (500 MHz; CDCl3) delta 2.43-2.45 (m, 4H), 3.46 (s, 2H), 3.71-3.73 (m, 4H), 7.22-7.24 (m, 2H), 7.44-7.47 (m, 2H) ppm. Purity by LCMS (UV Chromatogram, 190-450 nm) 94%, rt=5.0 min, m/z 256 (M+H)+
87%
In dimethyl sulfoxide; at 20℃; for 0.5h;
Synthesis of 4-(4-bromo-benzyl)-morpholine (1). To a solution of morpholine (2.61 ml, 30 mmol) in DMSO (25 ml) was added 4-bromobenzylbromide (2.5 g, 10 mmol). Reaction mixture was stirred at ambient temperature for 30 min. Solvents were evaporated in vacuum. Residue was dissolved in EtOAc (150 ml) and extracted with 5% aq. NaHCO3 (50 ml x 2) and brine (50 ml). The organic layer was dried over anh. MgSO4 and evaporated in vacuum. Residue was dried in vacuum overnight at ambient temperature to provide target material (1) (2.27 g, 87%) as a white solid.
With triethylamine; In water; N,N-dimethyl-formamide;
Reference Example 114 In DMF (108 ml) was dissolved morpholine (9.0 g). To the mixture were added at room temperature triethylamine (24 ml) and 4-bromobenzyl bromide (21.5 g), and the mixture was stirred at 80 C. for 16 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give 4-(4-bromobenzyl)morpholine (17.2 g). 1H-NMR (200 MHz, CDCl3) delta 2.38-2.45 (4H, m), 3.44 (2H, s), 3.67-3.73 (4H, m), 7.21 (2H, d, J=8.4 Hz), 7.44 (2H, d, J=8.4 Hz).
With potassium carbonate; In acetonitrile; at 20℃;
Example 18: 4-(2'-Trifluoromethyl-biphenyl-4-ylmethyl)-morpholine; 4-(4-Bromo- benzyl)-morplioline; 2g of 4-Bromobenzyl bromide and 0.7mL morpholine in 24mL of acetonitrile were stirred at room temperature and 1. Ig of potassium carbonate was added. The reaction was stirred at room temperature overnight. The solution was filtered through Celite and concentrated in vacuo to afford a brown solid. Purification was done by flash chromatography using a methylene chloride/methanol gradient to afford 1.9g of product as a white solid. ES MS (+) m/z 257 mp=72C
With potassium carbonate; In acetonitrile; at 20℃; for 2h;
General procedure: To a stirred solution of 10 (1.00g, 4.00mmol) and K2CO3 (1.66g, 12.00mmol) in acetonitrile (20mL) was added dropwise diethylamine solution (1.20g, 16.00mmol) at room temperature for 2h. The solvent was evaporated in vacuo and the residue was then dissolved in EtOAc (50mL) and washed with water (20mL×3), the organic layers were washed with brine, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to provide the 11a (0.83g, 84.7% yield) as an off-white liquid. (0041) Then, a mixture of 11a (0.83g, 3.43mmol), bis(pinacolato)diboron (0.96g, 3.77mmol), PdCl2(dppf)-CH2Cl2 (0.084g, 0.103mmol) and potassium acetate (0.67g, 6.86mmol) in anhydrous 1,4-dioxane (15mL) was purged with argon and heated at 100C for 2.5h. The reaction was then treated with 6 (1.20g, 3.60mmol), 2.0M aqueous Na2CO3 (5mL) and another portion of PdCl2(dppf)-CH2Cl2 (0.084g, 0.103mmol), then heated at 110C for 12h under argon. The reaction mixture was cooled to room temperature, filtered, and concentrated. The final compound was purified by MPLC (ISCO CombiFlash purification system) (MeOH/DCM, eluted from 0% to 10%), The fractions were collected, concentrated to afford 12a (0.72g, 57.2% yield).
13 g
With potassium carbonate; In ethanol; for 5h;Reflux;
To a solution of 4-bromobenzyl bromide (15 g, 60 mmol) in EtOH (200 mL) was added morpholine (6 mL, 66 mmol) and K2C03 (33 g, 238 mmol) and the mixture was stirred at ref lux for 5 hours. The mixture was filtered and the solvent was evaporated under reduced pressure.The crude material was treated with Et20 and the mixture was filtered. The solvent was evaporated under reduced pressure to afford the title compound (13 g). LCMS method: Method 1, RT: 1.20 mi Ml: 256/258 [M+l]
With potassium carbonate; In acetonitrile; for 4h;Heating / reflux;
4-Bromobenzyl bromide (Aldrich Co., 2.0 g) and morpholine (0.73 ml) were dissolved in acetonitrile (15 ml), potassium carbonate (1.3 g) was added, and the mixture was heated under reflux for 4 hr. The insoluble material was filtered off, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (5:1)) to give 4-(4-bromobenzyl)morpholine (1.55 g). 4-(4-Bromobenzyl)morpholine (1.55 g), 1-(tert-butoxycarbonyl)piperazine (1.27 g), 2-(di-tert-butylphosphino)biphenyl (37 mg), tris(dibenzylideneacetone)dipalladium (57 mg) and sodium tert-butoxide (1.2 g) were added to toluene (13 ml), and the mixture was heated under reflux for 5 hr. The insoluble material was filtered through a Celite (trademark) filter, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography. The obtained 4-[4-(morpholine-4-ylmethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester was dissolved in dichloromethane, trifluoroacetic acid was added and the mixture was stirred overnight at room temperature. The mixture was neutralized with an aqueous sodium hydroxide solution, and extracted with dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-(4-piperazin-1-ylbenzyl)morpholine (1.06 g, yield 51%). 1H-NMR(300MHz,DMSO-d6)delta(ppm): 2.28(4H,t,J=4.2Hz), 2.76-2.84(4H,m), 2.95-3.02(4H,m), 3.05(1H,brs), 3.52(4H,t,J=4.5Hz), 6.83(2H,d,J=8.4Hz), 7.09(2H,d,J=8.4Hz).
3'-(4-bromobenzyl)-1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-bibenzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In ISOPROPYLAMIDE; at 20℃; for 8h;
EXAMPLE 1 1-(4-Bromobenzyl)-5-(1'-methylbenzimidazol-2'-yl)-4-methyl-2-propyl benzimidazole (II) 2-(5'-Methyl-2-propyl-1H-benzimidazol-6-yl)-1-methyl benzimidazole (2.80 g, 9.2 mmol), dimethylacetamide (14 ml), potassium carbonate (1.27 g, 9.2 mmol) and 4-bromobenzyl bromide (2.30 g, 9.2 mmol) are loaded into a round-bottom flask equipped with mechanical stirrer and thermometer. After stirring at room temperature for 8 hours, the mixture is poured into a 2:1 toluene-water (150 ml) and stirred for 15 minutes at room temperature. After two washings with water, the aqueous phase is separated and the organic phase is filtered through paper, then evaporated to a residue, which is triturated with 15 ml of hexane, to obtain 3 g of product. 1H NMR (300 MHz, CDCl3): delta (7.76-7.79 (m, 1H), 7.38-7.41 (m, 4H), 7.33-7.35 (m, 1H), 7.26-7.29 (m, 2H), 5.32 (s, 2H), 3.77 (s, 3H), 2.85 (t, J=8.0 Hz, 2H), 2.75 (s, 3H), 1.85 (sext., J=7.5 Hz, 2H), 1.01 (t, J=7.5 Hz, 3H)
2-[4-(dimethylaminomethyl)benzylthio]ethylamine[ No CAS ]
[ 6274-57-3 ]
Yield
Reaction Conditions
Operation in experiment
With dimethyl amine; In benzene;
(i) Reaction of dimethylamine with 4-bromobenzyl bromide in cold benzene gave 4-bromo-N,N-dimethylbenzylamine which was successively reacted with magnesium, formaldehyde, and cysteamine (in a similar procedure to Example 7) to give 2-[4-(dimethylaminomethyl)benzylthio]ethylamine as an oil.
ethyl 5-[(4-bromobenzyl)oxy]-1H-indole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In ethyl acetate; acetonitrile;
1) A solution of <strong>[24985-85-1]ethyl 5-hydroxy-1H-indole-2-carboxylate</strong> (508 mg, 2.48 mmol), 1-bromo-4-(bromomethyl)benzene (681 mg, 2.72 mmol) and potassium carbonate (684 mg, 4.95 mmol) in acetonitrile (12 ml) was stirred at 80C for 3 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the resulting oil, the mixture was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, the resulting residue was purified by alumina column chromatography (developing solvent: ethyl acetate), and converted into powders with isopropyl ether to obtain ethyl 5-[(4-bromobenzyl)oxy]-1H-indole-2-carboxylate (565 mg). 1H-NMR (DMSO-d6) delta: 1.33 (3H, t, J = 6.9 Hz), 4.32 (2H, t, J = 6.9 Hz), 5.08 (2H, s), 6.98-7.04 (2H, m), 7.18 (1H, d, J = 2.4 Hz), 7.36 (1H, d, J = 8.7 Hz), 7.43 (2H, d, J = 8.4 Hz), 7.59 (2H, d, J = 8.4 Hz), 11.77 (1H, s).
N-[1-(4-bromobenzyl)-4-piperidyl]-N-(1H-5-imidazolyl)amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52.4%
With potassium carbonate; acetic acid; In methanol; acetonitrile;
Example 22 N-[1-(4-Bromobenzyl)-4-piperidyl]-N-(1H-5-imidazolyl)amine Potassium carbonate (180 mg, 1.30, 2.0 eq) was added to a solution of <strong>[40064-34-4]4-piperidone monohydrate hydrochloride</strong> (100 mg, 0.65 mmol) and 4-bromobenzyl bromide (162.7 mg, 0.65 mmol, 1.0 eq) in acetonitrile, and the mixture was stirred at room temperature for 17 hr. After the completion of the reaction, the reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine and was dried over sodium sulfate. The solvent was then removed by distillation under the reduced pressure. 5-Aminoindazole (69.33 mg, 0.52 mmol, 0.8 eq) was added to a solution of the resultant oil in methanol. Acetic acid (one drop) was added thereto, and the mixture was stirred at room temperature for 5 min. A borane-pyridine complex (0.8 ml, 0.78 mmol, 1.2 eq) was added to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 4 hr. After the completion of the reaction, the reaction solution was poured into an aqueous sodium hydrogencarbonate solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and saturated brine and was dried over sodium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography [silica gel, chloroform/methanol] to give the title compound (131.2 mg, 52.4%). MS m/z: 385 1H-NMR delta: 1.43 - 1.46 (2H, m), 2.02 (2H, d, J = 12.0H), 2.12 (2H, t, J = 9.0H), 2.79 (1H, d, J = 9.0 Hz), 2.82 (1H, s), 3.23 - 3.28 (1H, m), 3.43 (2H, s), 6.73 (2H, dd, J = 2.2, 7.8 Hz), 7.15 (1H, d, J = 8.3 Hz), 7.19 (1H, d, J = 1.0 Hz), 7.22 (1H, dd, J = 1.0, 9.5 Hz), 7.38 (2H, dd, J = 1.8, 6.6 Hz), 7.80 (1H, d, J = 1.0 Hz)
With potassium carbonate; In acetonitrile; at 20℃;
Example 47: 3-Phenyl-l-(2'-trifluoromethyl-biphenyl-4-ylmethyl)-pyrrolidine; l-(4-Bromo-benzyl)-<strong>[936-44-7]3-phenyl-pyrrolidine</strong> <n="43"/>5.632g of 4-Bromobenzyl bromide and 2.211 of 3-Phenylpyrrolidine (Array) in 5OmL of acetonitrile were stirred at room temperature and 6.229g of potassium carbonate was added. The reaction was stirred at room temperature overnight. The solution was filtered through Celite and concentrated in vacuo to afford a brown solid. Purification was done by flash chromatography to afford product. Wt: 33mg, 2% yield, ES MS m/z 316/318
(S)-4-(4-bromo-benzyl)-2-phenyl-morpholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With potassium carbonate; In acetonitrile; at 20℃;
(S)- 4-(4-Bromo-benzyl)-2-phenyl-morpholine; <n="21"/>1.417g of 4-Bromobenzyl bromide and 0.617g of (S)-2-Phenyl-morpholine in HmL of acetonitrile were stirred at room temperature and 1.567g of potassium carbonate was added. The reaction was stirred at room temperature overnight. The solution was filtered through Celite and concentrated in vacuo to afford a brown solid. Purification by flash chromatography afforded 0.851g of product. 68percent yield ES MS m/z331.
Step C: Lithium hexamethyldisilazide (0.3 mL, 0.30 mmol) was added slowly to a -78C solution of 1-tert-butyl 2-methyl (25)-4,4-difluoropyrrolidine-l,2-dicarboxylate (71 mg, 0.27 mmol), hexamethylphosphoramide (0.05 mL, 0.30 mmol), and tetrabutylammonium iodide (10 mg, 0.027 mmol) in tetrahydrofuran (5 mL). After stirring at -78 0C for 15 min, a solution of bromobenzyl bromide (74 mg, 0.30 mmol) in tetrahydrofuran (5 mL) was added. After stirring at -78 C for a further 2 h, the reaction mixture was quenched with saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 1-tert-butyl 2- methyl 2-(4-bromobenzyl)-4,4-difluoropyrrolidine- 1 ,2-dicarboxylate.
Potassium tert-butoxide (0.282 g, 2.51 mmol) was added to a stirred solution of 1-METHYLIMIDAZOLIDONE (0.21 g, 2.09 mmol; Acros Organics) in THF (5 ML) at room temperature. After 30 minutes, 4- bromobenzylbromide (0.63 g, 2.51 mmol) in THF (3 mL) was added slowly and the mixture was stirred for 3 hours. The reaction was quenched with aqueous NH4C1 (satd. ) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine, dried over MgS04 and evaporated under reduced pressure. The crude product was purified by flash chromatography using acetone : petroleum ether (1 : 4) as eluent to afford 0.493 g of the sub-title compound in 87% yield. MS (ESI+) m/z: 270 (M++1) IH NMR (CDC13,270 MHz): No. 7.43 (d, J= 8.3 Hz, 2H), 7.14 (d, J= 8.3 Hz, 2H), 4.30 (s, 2H), 3.27 (m, 2H), 3.13 (m, 2H), 2.81 (s, 3H) 13C NMR (CDC13, 67.5 MHz): 8 161.3, 136.3, 131.6, 129.8, 121.2 IR (neat): 2981,2934, 1701,1450, 1156 CM'
(1) To a solution of N-(tert-butoxycarbonyl)proline methyl ester (1.30 g) in THF (20 mL) at -78 C was added a solution of KHMDS (1.25 g) in THF (20 mL). After 45 minutes, a solution of 4-bromobenzyl bromide (1.59 g) in THF (20 mL) was added at -78 C. The reaction mixture was warmed to room temperature over 3 hours and stirred for an additional 3 hours. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered and concentrated. Purification by flash column chromatography (silica gel; EtOAc/hexane 1:2) afforded N-(tert-butoxycarbonyl)-2-(4-bromobenzyl)proline methyl ester (0.474g). MS (m/z) 398 (MH+).
With potassium carbonate; In acetonitrile; at 85℃; for 20h;
A mixture of 4-bromobenzyl bromide (1.5 g, 6.0 mmol), <strong>[147688-58-2]2,2-<strong>[147688-58-2]dimethylmorpholine</strong></strong>(0.69 g, 6.0 mmol) and potassium carbonate (0.99 g, 7.2 mmol) in acetonitrile (60 mL) was heated at 85 C for 20 h. The mixture was allowed to cool to ambient temperature and the solid was removed by filtration and the filtrate evaporated. The resultant residue was dissolved in DCM/ methanol and loaded onto a 20 g SCX-2 cartridge which was washed with methanol then 2N ammonia in methanol. Concentration of the combined basic fractions afforded the title compound (1.65 g, 97%) as an orange oil. 1H NMR (CDCl3, 300MHz): 7.44 (d, J = 8.0Hz, 2H), 7.22 (d, J = 8.0Hz, 2H), 3.75 (t, J = 4.8Hz, 2H), 3.39 (s, 2H), 2.37 (t, J = 4.6Hz, 2H), 2.16 (s, 2H), 1.23 (s, 6H).
5) Preparation of benzyl 4-(4-bromobenzyl)-3-oxopiperazine-1-carboxylate 1.5; 1.117 g of sodium hydride (85% in silicone oil) were suspended in 50 ml of dry tetrahydrofuran and admixed while stirring with 5 g of benzyl 3-oxopiperazine-1-carboxylate 1.4 in portions. The mixture was stirred further until the evolution of hydrogen had ended and then cooled to 5 C. Then 6.4 g of 4-bromobenzyl bromide (dissolved in 20 ml of dry tetrahydrofuran) were added dropwise with stirring. After the addition had ended, the mixture was stirred at room temperature overnight. For workup, the reaction mixture was admixed cautiously with 25 ml of water and stirred at room temperature for 30 min. The reaction mixture was subsequently extracted by shaking 3 times with 70 ml of ethyl acetate, and the organic phase removed was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel; 80/20 to 50/50 n-heptane/ethyl acetate). This afforded benzyl 4-(4-bromobenzyl)-3-oxo-piperazine-1-carboxylate 1.5. Molecular weight 402.05 (C19H19BrN2O3); retention time Rt=1.83 min. [B]; MS (ESI): 403.08 (MH+).
[623] Example 158 - 3-ri-Methyl-5-(4-methyl-cvclohexyl)-l,2,3,6-tetrahydro-pyridin-4-yl1-5-r4-; [624] A mixture of 4-bromobenzyl bromide (1.00 g, 4.00 mmol) and triphenylphosphine (1.70 g, 6.00 mmol) in toluene (10 mL) was stirred at 80 °C overnight. The reaction mixture wasconcentrated, followed by sonication in hexane, filtration, and a subsequent hexane wash gave a white solid, which was dried in vacuo. This white solid (906 mg, 1.77 mmol) was dissolved in THF (10 mL), cooled to 0 °C, and lithium hexamethyl disilazide (1 M) in THF (1.95 mL, 1.95 mmol) was added. After 0.5 hr, thiazole-4-carboxaldehyde (200 mg, 1.77 mmol) was added, the ice bath was removed, and the mixture stirred for 0.5 hr. The reaction mixture was quenched by the addition of water, extracted with EtOAc (2x30 mL), the organic layer was washed with brine, dried over MgS04, concentrated and filtered through a silica plug using 30percent -100percent EtOAc/hexane to give 158A as a clear oil. MS calcd: M+H)+ = 267. + = 267.
With sodium hydrogencarbonate; dimethyl sulfoxide; potassium iodide; at 140℃; for 40h;Inert atmosphere;
General procedure: 4-Bromo stilbenes (11): In a two-necked round bottom flask a mixture of benzyl triphenylphosphonium chloride (0.389 g, 1.0 mmol), 4-bromobenzyl bromide (0.25 g, 1.0 mmol), NaHCO3 (0.252 g, 3.0 mmol), and potassium iodide (0.033 g, 0.2 mmol) in dimethylsulfoxide (7 mL) was stirred at 140 C under N2 atmosphere for 40 h. The cooled mixture was then poured in water (100 mL) and extracted with dichloromethane (3 × 50 mL). The organic layer was washed with water (2 × 20 mL), brine, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to obtain a viscous liquid, which was purified by column chromatography on silica gel and petroleum ether as eluent to give 4-bromo stilbenes (11) (0.193 g, 75%).
With sodium hydrogencarbonate; dimethyl sulfoxide; triphenylphosphine; potassium iodide; at 140℃; for 40h;Inert atmosphere;
General procedure: Stilbene (3): In a two-necked round bottom flask a mixture of benzyl chloride (0.241 g, 1.906 mmol), triphenylphosphine (0.250 g, 0.953 mmol), NaHCO3 (0.480 g, 5.71 mmol), and potassium iodide (0.032 g, 0.192 mmol) in dimethylsulfoxide (7 mL) was stirred at 140 C under N2 atmosphere for 40 h. The cooled mixture was then poured in water (100 mL) and extracted with dichloromethane (3 × 50 mL). The organic layer was washed with water (2 × 20 mL), brine, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to obtain a viscous liquid, which was purified by column chromatography on silica gel and petroleum ether as eluent to give pure stilbene (0.148 g, 87%) (The ratio of Z:E isomers was determined to be 45:55 by H NMR).
With FeCl(THF)L1; In diethyl ether; at 20℃; for 0.5h;Schlenk technique; Inert atmosphere;Catalytic behavior;
General procedure: [00283] Catalyst 20 (0.10 mmol) in CH2C12 (3 mL) was added to a 30 mL Schlenk flask and the solvent removed in vacuo. Et20 (5 mL) and the alkyl halide (2.0 mmol) were added to the catalyst under dry nitrogen. A solution of Grignard reagent (4.0 mmol) was added dropwise under vigorous stirring. The resulting mixture was stirred at roomtemperature for 30 min and the reaction was quenched with HC1 (2.0 M, 5 mL). The organic phase was extracted with Et20 (5 mL) and dried over MgSC>4. The organic phase was then passed through a plug of silica and the diethyl ether was removed in vacuo. The resulting products were then analyzed by GC-MS (using dodecane as internal standard) and NMR spectroscopy (using acetophenone as internal standard).
With tetrabutylammomium bromide; sodium hydroxide; In water; at 70℃; for 6h;Inert atmosphere;
3-Ethyl-3-hydroxymethyloxetane (50 mmol), 4-bromobenzyl bromide (50 mmol), n-hexane (200 mL), tetrabutylammonium bromide (2.5 mmol), and a 50 mass percent aqueous solution of sodium hydroxide (36 g) were introduced into a round-bottom flask, and the mixture was heated under stirring for 6 hours at 70° C. under nitrogen. The mixture was cooled to room temperature (25° C.), and then 200 mL of water was added thereto. The mixture was extracted with n-hexane. The solvent was distilled off, and then the residue was purified by silica gel column chromatography and distillation under reduced pressure. Thus, 9.51 g of a monomer A having a polymerizable substituent was obtained as a colorless oily substance. Yield: 67percent. The reaction scheme of this Synthesis Example is shown below. 1H-NMR (300 MHz, CDCl3, delta ppm); 0.86 (t, J=7.5 Hz, 3H), 1.76 (t, J=7.5 Hz, 2H), 3.57 (s, 2H), 4.39 (d, J=5.7 Hz, 2H), 4.45 (d, J=5.7 Hz, 2H), 4.51 (s, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H)
(R)-N-(4-bromobenzyl)-N-methyl-1-(naphthalen-1-yl)ethanamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 2h;Reflux; Inert atmosphere;
General procedure: N-Methyl-1-(naphthalen-1-yl)ethanamine (8) (0.37g, 2.00mmol), N,N-diisopropylethylamine (0.39g, 3.02mmol), 1-(bromomethyl)-4-tert-butylbenzene (0.50g, 2.20mmol) and acetonitrile (5mL) were mixed and stirred at reflux under an N2-atmosphere for 2h. The solvent was then removed at reduced pressure and CH2Cl2 (5mL) was added. The dichloromethane phase was washed with water (5mL) and the water phase was back extracted with CH2Cl2 (3×5mL). The combined organic fractions were dried over Na2SO4, and concentrated in vacuum. The crude product was purified by silica-gel column chromatography. Alternatively, the purification was done by filtration through a short silica-gel column (pentane:EtOAc, 9:1), followed by precipitation as it hydrochloride salt by addition of HCl saturated ether. The solid material was washed with cold pentane. Alternatively, using 8·HCl the reaction was run similarly, but employing a 3-fold excess of N,N-diisopropylethylamine.
(2R,4R)-1-Boc-4-((4-bromobenzyl)oxy)-2-methylpyrrolidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tetra-(n-butyl)ammonium iodide; sodium hydride; In tetrahydrofuran;
As illustrated in FIG. 3j, synthesis of compound 13 is a multistep process. For compound 13, several precursors can be used. Known precursors include compounds 13b-f. For these, compounds and spectral data is in agreement with the proposed structures and matches those reported in the literature. (See Gauchot, V. et al., J. Org. Chem. 2012, 77, 4917-4923; Watts, J.et al., Adv. Synth. Catal. 2012, 354, 1035-1042; Rosen, T et al., J. Med. Chem. 1988, 31 , 1598-161 1 ; Mitsumori, S. et al., J. Am. Chem. Soc. 2006, 128, 1040-1041 , the disclosure of which is incorporated herein by reference.) Starting with compound 13f, compound 13g is obtained as a colorless oil. Next, compound 13h is obtained as a colorless oil over two steps from 13g. Finally, compound 13 is synthesized by dissolving compound 13h (100 mg, 0.25 mmol) in 4 M HCI in dioxane (6 ml_) and stirring overnight. TLC analysis of the crude mixture should show only the desired compound. The solvent is evaporated and the residue is dissolved in pure dioxane and the solvent evaporated again. The residue was purified by flash chromatography (EtOH:DCM, 1 :9) to give compound 13 (62 mg, 73%) as a slightly yellow solid.
1-tert-butyl 3-methyl 2-(4-bromobenzyl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
A 100 mL round-bottom flask equipped with a stirring bar was charged with compound 7 (1000 mg, 5.8 mmol) and DMF (20 mL). To the solution, sodium hydride (60percent oil suspension, 233 mg, 5.8 mmol) was added. The reaction was allowed to stir at 0 °C for 1 h. To the mixture, 4-bromobenzyl bromide (1437 mg, 5.8 mmol) was added at 0 °C and the mixture was stirred at room temperature for 20 h. To the reaction mixture, H2O was added, and the mixture was extracted with CH2Cl2 (3x), dried over MgSO4, and concentrated in vacuo. The remaining residue was purified by silica gel column chromatography (hexanes/AcOEt = 90:10) to afford the desired product 4 (1551 mg, 79percent) as a colorless oil. 1H NMR (400 MHz, CDCl3) delta 7.39 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 8.3 Hz, 2H), 3.70 (s, 3H), 3.53 (t, J = 7.8 Hz, 1H), 3.13 (d, J = 7.8 Hz, 2H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) delta 169.4, 167.5, 137.0, 131.5, 130.6, 120.5, 83.2, 54.3, 52.4, 34.0, 27.8; HR-FAB MS calcd for C15H20BrO4 [M+H]+ 343.0545, found 343.0558.
1-(4-bromobenzyl)-1H-pyrazole-3-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With potassium carbonate; In acetonitrile; at 20℃;
General procedure: A mixture of 1H-imidazole-2-carbaldehyde 40 (200 mg, 2.08 mmol), potassium carbonate (0.8630 g, 6.24 mmol) and 3-(bromomethyl)-1,1'-biphenyl 38 (0.7716 g, 3.12 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature, then the solvent was removed, diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 44 as a pale yellow solid (527 mg, 97percent).
40.00 g of p-bromobenzyl bromide (0.16 mol) and 83.6 mL of triethyl phosphite (0.48 mol) were added to a solution of 500 mlThree bottles,Magnetic stirring and argon, oil bath heated at 150 C for 24 hours, cooled to room temperature,Get Ye Lide reagent.To the three-necked flask was added 450 ml of tetrahydrofuran (THF), 21.87 g of benzophenone (0.12 mol) and 40.39 g of potassium tert-butoxide (t-BuOK, 0.36 mol) were added and the mixture was stirred for 24 h. After the reaction was stopped, The solution was poured into water and extracted with a large amount of white precipitate. The precipitate was collected by extraction with a funnel, washed three times with ethanol and dried in a vacuum at 60C for 24 h to give Tri-Br as a white intermediate.
tert-butyl (3-((4-bromobenzyl)oxy)cyclohexyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
Step 1. tert-Butyl (3-((4- bromobenzyl)oxy)cyclohexyl)carbamate. To a stirring solution of tert-butyl (3- hydroxycyclohexyl)carbamate (220 mg, 1.02 mmol) in THF (3 mL) at 0 C was added NaH (41 mg, 1.02 mmol) and stirred at 0 C for 30 mins, then 4-bromobenzyl bromide (255 mg, 1.02 mmol) was added and the reaction mixture was warmed to rt and stirred for 3h. The reaction mixture was cooled to 0 C, and quenched by the dropwise addition of sat. ammonium chloride, extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using 10 - 25% EtOAc/Hexanes gradient elution to afford tert-butyl (3-((4- bromobenzyl)oxy)cyclohexyl)carbamate as a white solid (184 mg, 48%): NMR (500MHz, CDCk) delta ppm 7.45 (d, J= 8.3 Hz, 2H), 7.21 (d, J= 2H), 4.92 (bs, 1H), 4.48 (s, 2H), 3.55 (m, 1H), 3.45 (bs, 1H), 2.19 (d, 11.72 Hz, 1H), 1.70 - 1.95 (m, 3H)1.44 (s, 9H), 1.15 - 1.37 (m, 4H).
tert-butyl 3-((4-bromobenzyl)oxy)-3-methylazetidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90.5%
With tetrabutylammomium bromide; sodium hydroxide; In dichloromethane; for 16h;Reflux;
Step b. tert-Butyl 3-((4-bromobenzyl)oxy)-3-methylazetidine-l-carboxylate. Into a mixture of tert-butyl 3-hydroxy-3-methylazetidine-l-carboxylate (480 mg, 2.56 mmol), 1 -bromo-4-(bromomethyl)benzene and dichloromethane (5 mL) were added NaOH (4N, 6 mL) and tetra-n-butylammonium bromide (82.6 mg, 0.256 mmol). The mixture was refluxed for 16 hours, cooled to room temperature and extracted with ethyl ether. The organic extracts were washed with water and brine and dried over anhydrous MgS04. The solvents were removed under vacuum and the residue was purified on silica gel (Biotage; eluting solvents hexanes: EtOAc 3/1 ratio) to afford tert-butyl 3-((4-bromobenzyl)oxy)-3-methylazetidine-l- carboxylate as oil (826 mg, 90.5% yield): XH NMR (500MHz, CDCl3) delta ppm 7.48 (d, J= 8.5 Hz, 2H), 7.22 (d, J= 8.5 Hz, 2H), 4.38 (s, 2H), 3.98 (d, J= 9.5 Hz, 2H), 3.74 (d, J= 9.5 Hz, 2H), 1.55 (s, 3H), 1.44 (s, 9H).
90.5%
With tetrabutylammomium bromide; sodium hydroxide; In dichloromethane; for 16h;Reflux;
Into a mixture of <strong>[1104083-23-9]tert-butyl 3-hydroxy-3-methylazetidine-1-carboxylate</strong> (480 mg, 2.56 mmol), 1-bromo-4-(bromomethyl)benzene and dichloromethane (5 mL) were added NaOH (4N, 6 mL) and tetra-n-butylammonium bromide (82.6 mg, 0.256 mmol). The mixture was refluxed for 16 hours, cooled to room temperature and extracted with ethyl ether. The organic extracts were washed with water and brine and dried over anhydrous MgSO4. The solvents were removed under vacuum and the residue was purified on silica gel (Biotage; eluting solvents hexanes: EtOAc 3/1 ratio) to afford tert-butyl 3-((4-bromobenzyl)oxy)-3-methylazetidine-1-carboxylate as oil (826 mg, 90.5% yield): 1H NMR (500MHz, CDCl3) delta ppm 7.48 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 4.38 (s, 2H), 3.98 (d, J = 9.5 Hz, 2H), 3.74 (d, J = 9.5 Hz, 2H), 1.55 (s, 3H), 1.44 (s, 9H).
4-Bromobenzylbromide(4.50 g, 18mmol) and triphenylphosphine(4.72 g, 18mmol) were added to 10mL of toluene in a 100mL eggplant flask, and the mixture was heated at 100 C for3 h. The resulting precipitate was collected by filtration and washed with hexane, and 4-bromobenzyl triphenylphosphoniumbromide was obtained (8.18 g, 88%). 4-Bromobenzyltriphenylphosphoniumbromide(0.51 g, 1.0mmol) thus obtained was added, together with 4-bromobenzaldehyde (0.37 g, 2.0mmol) and potassium tert-butoxide (0.11 g, 1.0mmol), to 9mL of chloroform in a 100mL eggplant flask, and the mixture was stirred for 44 h at room temperature to obtain 4,4-dibromotrans-stilbene 5. The resulting precipitate was collected byfiltration and washed with cooled methanol. The NMR data was as follows.4,4-Dibromo-trans-stilbene 5 (Isolated Yield 38%):1HNMR (400 MHz, CDCl3): delta 7.02 (2H, s), 7.37 (4H, d, J =8.8 Hz), 7.48 (4H, d, J = 8.8 Hz).13CNMR (100 MHz, CDCl3): delta 121.62, 127.99, 128.07,131.84, 135.84.
General procedure: To a solution of alanine methyl ester hydrochloride (3.00 g, 21.6 mmol) in CH2Cl2(120 mL) was added NMM (6.19 mL, 45.5 mmol) and methanesulphonyl chloride (1.67mL, 21.6 mmol). The reaction was stirred at room temperature for 20h. Thereaction was quenched upon addition of 1 N HCl (120 mL) and extracted with CH2Cl2(2 x 100 mL). The combined organic extracts were dried over Na2SO4and concentrated under vacuum. The residue was dissolved in DMF (100 mL) andadded K2CO3 (5.94 g, 44.0 mmol) and 4-bromobenzyl bromide(6.00 g, 24.0 mmol). The reaction was stirred at 40 C for 6h. The reaction wascooled to room temperature, diluted with water (400 mL) and extracted withEtOAc (2 x 200 mL). The combined organic extracts were washed with 5% LiCl (aq.Solution., 2 x 300 mL) and brine (300 mL), dried over Na2SO4and concentrated under vacuum. The residue was purified by columnchromatography (silica gel) using 0 to 70% EtOAc/hexanes to afford 2 a clear yellow oil (5.56 g, 73%); 1H-NMR(400 MHz, CDCl3) delta 7.45 (dt, J= 8.5, 2.0 Hz, 2H), 7.29 (dt, J =8.5, 2.0 Hz, 2H), 4.68 (q, J = 8.0Hz, 1H), 4.59 (d, J = 16.0 Hz, 1H), 4.25 (d, J= 16.0 Hz, 1H), 3.73 (s, 3H), 2.95 (s, 3H), 1.32 (d, J = 8.0 Hz, 3H); 13C-NMR (100 MHz, CDCl3) delta 172.1,136.8, 131.6, 129.5, 121.6, 56.2, 52.5, 48.8, 39.8, 17.5.
General procedure: To a solution of alanine methyl ester hydrochloride (3.00 g, 21.6 mmol) in CH2Cl2(120 mL) was added NMM (6.19 mL, 45.5 mmol) and methanesulphonyl chloride (1.67mL, 21.6 mmol). The reaction was stirred at room temperature for 20h. Thereaction was quenched upon addition of 1 N HCl (120 mL) and extracted with CH2Cl2(2 x 100 mL). The combined organic extracts were dried over Na2SO4and concentrated under vacuum. The residue was dissolved in DMF (100 mL) andadded K2CO3 (5.94 g, 44.0 mmol) and 4-bromobenzyl bromide(6.00 g, 24.0 mmol). The reaction was stirred at 40 C for 6h. The reaction wascooled to room temperature, diluted with water (400 mL) and extracted withEtOAc (2 x 200 mL). The combined organic extracts were washed with 5% LiCl (aq.Solution., 2 x 300 mL) and brine (300 mL), dried over Na2SO4and concentrated under vacuum. The residue was purified by columnchromatography (silica gel) using 0 to 70% EtOAc/hexanes to afford 2 a clear yellow oil (5.56 g, 73%); 1H-NMR(400 MHz, CDCl3) delta 7.45 (dt, J= 8.5, 2.0 Hz, 2H), 7.29 (dt, J =8.5, 2.0 Hz, 2H), 4.68 (q, J = 8.0Hz, 1H), 4.59 (d, J = 16.0 Hz, 1H), 4.25 (d, J= 16.0 Hz, 1H), 3.73 (s, 3H), 2.95 (s, 3H), 1.32 (d, J = 8.0 Hz, 3H); 13C-NMR (100 MHz, CDCl3) delta 172.1,136.8, 131.6, 129.5, 121.6, 56.2, 52.5, 48.8, 39.8, 17.5.
1-((4-bromophenyl)methyl)-3-nitro-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tetrabutylammomium bromide; potassium carbonate; In acetone; at 20℃;
According to general procedure 4 from K2CO3 (3.46 g, 25.0 mmol), 4- bromobenzyl bromide (2.50 g, 10.0 mmol), 5-nitro-1 H-pyrazole (1.13 g, 10.0 mmol), and Bu4NBr (658 mg 2.00 mmol) in acetone (50 mL). The reaction is complete overnight. Purification of the crude by automated FC (Biotage, 100 g silicagel, EtOAc / heptane 20:80? 80:20) yields the desired product. LC-MS: tR = 0.86 min, (conditions 3). General procedure 4 for the N-alkylation of 5-nitro-1H-pyrazole. K2CO3 or NaH is added to a sol. of 5-nitro-1 H- pyrazole in acetone or DMF or THF. The mixture is stirred for 15-30 min. The desired electrophile and Bu4NBr are added. The mixture is stirred efficiently at rt until the reaction is complete. The mixture is optionally filtered (if K2CO3 is used) or quenched with water (if NaH is used), and the filtrate is evaporated under reduced pressure. The residue is partitioned between water and EtOAc. The org. layer is dried over MgS04, filtered, and the solvents are removed under reduced pressure. Purification of the crude by automated FC or by HPLC yields the desired product.
7-[(4-bromobenzyl)oxy]-4-(trifluoromethyl)-2H-chromen-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With potassium carbonate; In ethanol; at 60 - 80℃;
General procedure: The appropriate commercially available 7-hydroxylcoumarin (1 mmol, 1a-5a) and K2CO3 (1.1 mmol) were dissolved in 10 ml ethanol. To the mixture, benzyl bromide (1 mmol for compounds 1-4) or the appropriate bromobenzyl derivative (1 mmol for compounds 5-13) was added depending on the compound to be synthesised. The mixture was stirred under reflux conditions until the reaction reached completion (monitored by TLC, mobile phase = EtOAc). Once the reaction was complete, 20 ml of distilled water was added and the mixture was allowed to cool to room temperature. This resulted in the formation of a precipitate that was filtered of and allowed to dry overnight in a fume cupboard rendering the pure 7-(benzyloxy)coumarin derivatives (1-13) asoff-white amorphous solids.
7-[(4-bromobenzyl)oxy]-3-chloro-4-methyl-2H-chromen-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With potassium carbonate; In ethanol; at 60 - 80℃;
General procedure: The appropriate commercially available 7-hydroxylcoumarin (1 mmol, 1a-5a) and K2CO3 (1.1 mmol) were dissolved in 10 ml ethanol. To the mixture, benzyl bromide (1 mmol for compounds 1-4) or the appropriate bromobenzyl derivative (1 mmol for compounds 5-13) was added depending on the compound to be synthesised. The mixture was stirred under reflux conditions until the reaction reached completion (monitored by TLC, mobile phase = EtOAc). Once the reaction was complete, 20 ml of distilled water was added and the mixture was allowed to cool to room temperature. This resulted in the formation of a precipitate that was filtered of and allowed to dry overnight in a fume cupboard rendering the pure 7-(benzyloxy)coumarin derivatives (1-13) asoff-white amorphous solids.
General procedure: A mixture of 50 mg of imide and the required amount of K2CO3 were placed in a 10 mL stainlesssteel grinding jar and milled for 1 hour at 30 Hz. Upon completion, the required amount of alkylhalide was added and milling was continued for 1 hour in the presence of 100 muL of dry DMF(LAG experiment, eta = 2 muL mg-1). The obtained mixture was suspended in dichloromethane andwashed with water. The organic layers were collected and the solvent was evaporated. Where itwas necessary, the products were separated by using column chromatography
With triethylamine; In dichloromethane; for 4.0h;Reflux;
General procedure: To a solution of 7 (400 mg) in dry CH2Cl2 (8 mL), Et3N (849 mg, 8.39 mmol) and 4-substitutedbenzyl or benzoyl derivative (3.36mmol)were added at roomtemperature. Afterwards, themixturewasrefluxed for 4 h and then evaporated in vacuo. The residue was purified by column chromatographyon silica gel (10-20% EtOAc in CH2Cl2) to give 8 or 10 (about 80% yield).
1-(4-bromobenzyl)-3,5-dimethyl-1H-1,2,4-triazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
In a 50 mL round-bottomed flask under N2 at 0 °C, sodium hydride (60percent in mineral oil, 0.184 g, 4.60 mmol) was added to a solution of 3,5-dimethyl-lH-l,2,4-triazole (0.311 g, 3.20 mmol) in DMF (12 mL) and the mixture was stirred for 20 min. 4-Bromobenzyl bromide (0.960 g, 3.84 mmol) was then added to the mixture and stirring was continued at RT for 2.5 h. The reaction mixture was then poured into H20 and the product was extracted with EtOAc (x3). The combined organic extract was washed with 0 (x3) and brine, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified on ISCO using a 40 g column (0-20percent MeOH-DCM) to afford the title compound (0.382 g, 1.44 mmol, 45percent yield) as an off-white solid. LC (Method B): 1.538 min. MS (APCI): calcd for C11H13BrN3 [M + H]+ m/z 266.0, found 266.1. 1H NMR (400 MHz, CDCI3) delta ppm 7.43 - 7.52 (m, 2H), 7.00 - 7.08 (m, J = 8.22 Hz, 2H), 5.16 (s, 2H), 2.37 (s, 3H), 2.35 (s, 3H).
To a 50 mL pressure vessel containing methyl 2-ethoxy-lH-benzo[d]imidazole-7- carboxylate (1.00 g, 4.54 mmol) was added 2-propanol (15 mL) and potassium carbonate (1.25 g, 9.08 mmol) and the mixture was stirred at 30°C for 5 min. To this mixture was added l-bromo-4-(bromomethyl)benzene (1.19 g, 4.77 mmol) and tetrabutylammonium iodide (0.084 g, 0.23 mmol) and the temperature of the reaction was raised to 45 °C. After 60 min an additional 15 mL of 2-propanol was added and the reaction was stirred at the same temperature for another 90 min. The cooled reaction mixture was diluted with EtOAc (200 mL) and 0 (50 mL), the layers were separated and the organic phase was washed (brine), dried (anhydrous sodium sulfate), filtered and evaporated. The residue was dry-packed onto silica gel (15 g) and purified on a 40 gram column (ISCO/ 0-60percent EtOAc-hexane) to provide the title compound as a pale yellow solid (1.50 g, 3.86 mmol, 85percent yield). LC-MS (Method H): 1.38 min, [M + H]+= 389.0; H NMR (400 MHz, CDC13) delta ppm 7.73 (dd, J= 7.8, 1.2 Hz, 1H), 7.58 (dd, /= 7.8, 1.2 Hz, 1H), 7.33 - 7.39 (: 2H), 7.18 (t, /= 8.0 Hz, 1H), 6.87 (m, /= 8.6 Hz, 2H), 5.58 (s, 2H), 4.65 (q, /= 7.2 Hz, 2H), 3.76 (s, 3H), 1.47 (t, /= 7.0 Hz, 3H).
72%
To an eggplant flask, <strong>[150058-27-8]2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester</strong> (10 g, 45.4 mmol: "imidazole derivative (compound of formula (4a)"), potassium carbonate (12.5 g, 90.8 mmol: "Base"), and isopropyl alcohol (100 mL: first reaction solvent / branched alcohol), and the mixture was stirred at room temperature for 5 minutes. To this reaction solution, 4-bromobenzyl bromide (12 g, 47.9 mmol: "dihalogen compound") and tetra-n-butylammonium iodide (0.839 g, 2.27 mmol: "iodine catalyst") were added. Followed by stirring at 45 ° C. for 15 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (100 mL) was added to the concentrated residue, washed three times with water (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 1- (4-bromobenzyl) -1H-benzimidazole-7-carboxylic acid methyl ester ("halogenated benzimidazole derivative") as a solid in a yield of 17.1 g (44.0 mmol, yield 98percent). This product was recrystallized from ethyl acetate to obtain 12.8 g (yield 72percent) of the objective product ("halogenated benzimidazole derivative") as a pure product.
4-[(4-bromophenyl)methyl]-1,4-oxazepan-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
To a solution of 1 ,4-oxazepan-5-one (400 mg, 3.47 mmol) in A/./V-dimethylformamide (5 ml_) at 0C was added sodium hydride (60% in oil) (181 mg, 4.52 mmol) portionwise and the mixture was left stirring at 0C for 30 minutes. 4-Bromobenzyl bromide (1) (912 mg, 3.65 mmol) was then added portionwise and the reaction mixture allowed to warm to room temperature where it was stirred for 16 hours. The reaction mixture was quenched with water (2 ml_) and concentrated to dryness. The residue was taken up in EtOAc (50 ml_) and this was washed with water (2 x 50 ml_) then saturated brine solution (1 x 50 ml_). The organic phase was dried (MgS04), filtered and concentrated to dryness under reduced pressure to afford the title compound as a white oily solid (1.12 g, 96%); 1 H NMR (500 MHz, Chloroform-d) d 7.46 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 4.55 (s, 2H), 3.84 - 3.75 (m, 2H), 3.63 - 3.54 (m, 2H), 3.44 - 3.37 (m, 2H), 2.86 - 2.79 (m, 2H); LCMS (4 minute method) product at Rt = 1.50 min and ES+ m/z 284.04, 286.01 [M+H]+ (Br isotope)
tert-butyl 2-[(4-bromophenyl)methoxymethyl]morpholine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With tetra-(n-butyl)ammonium iodide; sodium hydride; sodium iodide; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 12h;
To a mixture of 1-bromo-4-(bromomethyl)benzene (1.15 g, 4.60 mmol, CAS3433-80-5), <strong>[135065-69-9]tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate</strong> (0.50 g, 2.30 mmol, CAS157634-00-9) and TBAI (85.0 mg, 0.23 mmol) in DMF (10 mL) was added NaH (184 mg, 4.60 mmol, 60% oil dispersion) at 0 C. The mixture was stirred at rt for 12 hrs. On completion, the reaction mixture was concentrated in vacuo. The mixture was poured into a solution of saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic phase was washed with brine (2×30 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo at 45 C. The residue was purified by silica gel chromatography to give the title compound (554 mg, 62% yield) as brown oil. 1H NMR (400 MHz, CDCl3) delta 7.39 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 4.43 (s, 2H), 3.96-3.63 (m, 3H), 3.41 (dd, J=4.8, 8.0 Hz, 4H), 2.94-2.59 (m, 2H), 1.39 (s, 9H).
61%
With tetra-(n-butyl)ammonium iodide; sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 12h;
To a mixture of 1-bromo-4-(bromomethyl)benzene (10.3 g, 41.4 mmol, CAS3433-80-5), <strong>[135065-69-9]tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate</strong> (4.50 g, 20.7 mmol, CAS135065-69-9), TBAI (0.80 g, 2.07 mmol) in DMF (80 mL) was added NaH (1.70 g, 41.4 mmol, 60% oil dispersion) at 0 C. The mixture was then stirred at rt for 12 hrs. On completion, the mixture was concentrated in vacuo. The mixture was poured into a solution of saturated sodium bicarbonate (60 mL) and extracted with ethyl acetate (2×80 mL). The combined organic phase was washed with brine (2×80 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo at 45 C. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=20:1) to give the title compound (4.80 g, 61% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) delta 7.47 (d, J=8.4 Hz, 2H), 7.23-7.18 (m, 1H), 7.21 (d, J=8.4 Hz, 1H), 4.51 (s, 2H), 3.90 (d, J=10.4 Hz, 3H), 3.64-3.43 (m, 4H), 2.94 (s, 1H), 2.74 (s, 1H), 1.47 (s, 9H).
1-(4-bromobenzyl)-4-[(5,6-dimethoxy-1-indanone-2-ylidene)methyl]pyridinium bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
In acetonitrile; at 80℃; for 48h;
General procedure: 5,6-Dimethoxy-2-[(pyridin-4-yl)methylene)-1-indanone (0.35 mmol) was dissolved in 4 cc acetone (for synthesis of 5a) or acetonitrile (for synthesis of 5b-o) under refux temperature, and then 1.05 mmol of appropriate alkyl halides was added. The reaction mixture was stirred for 48 h under refux condition. The precipitate was fltered and washed with appropriate solvent. The obtained solid was dried under reduced pressure to aford related compounds.
With potassium tert-butylate; iodine; In ethanol; at 80℃; for 20.0h;
In a reaction tube, p-bromobenzyl bromide (136 muL, 1 mmol), 2- (methylthio) -4,5-dihydrothiazole (56 muL, 0.5 mmol), potassium tert-butoxide (56 mg, 0.5 mmol), Iodine (256 mg, 1.0 mmol) and ethanol (1 ml) were reacted by electromagnetic stirring at a reaction temperature of 80 C. The reaction time was 20 hours.After the reaction was completed, the solvent was removed by rotary evaporation, and the mixture was separated by column chromatography. The eluent was ethyl acetate and petroleum ether (volume ratio of 1: 9). After the separation, a colorless liquid (96 mg, 71%) was obtained.
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