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Structure of 2393-23-9 * Storage: {[proInfo.prStorage]}
* 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.
at 20℃; for 0.5 h; Microwave irradiation; Sealed tube
General procedure: General procedure for the 1,4-dioxane mediated transamidation of amides with an amine under microwave. An oven-dried 10-mL microwave reaction vial containing a Teflon-coated magnetic stir bar was charged with carboxamide (1 mmol), amine (1 mmol), and dioxane (2 ml) (undried). The vessel was sealed with a plastic microwave septum, stirred at room temperature for 5 min and then placed into the MW cavity for a specified temperature and time. After the completion of reaction (TLC), the mixture was cooled to room temperature; distilled water (10 mL) was added to it and then extracted with ethyl acetate (3 10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and then concentrated using a rotary vacuum evaporator. The crude product was purified by column chromatography using a mixture of ethyl acetate/n-hexane (10–20percent of ethyl acetate depending upon the product) as an eluent
81%
With [Ru-NHC] In toluene at 110℃; for 8 h; Inert atmosphere; Schlenk technique; Sealed tube
General procedure: A mixture of amide (5mmol), amine (5mmol), [Ru–NHC] complex (0.5molpercent) and toluene (5mL) was stirred in a sealed tube under nitrogen atmosphere at 110°C for 8h. After cooling down to room temperature, the reaction solvent was removed under vacuum. After removal of the solvent, the crude reaction mixture was dissolved in CH2Cl2 and purified by column chromatography on silica gel (200–400mesh) eluting with heptane:ethanol [25:1] to give corresponding amides as a white solid. The yields are mentioned in Tables 3–5. The product was confirmed by NMR spectroscopy. Reported isolated yields are an average of two runs.
Reference：
[1] Chemical Communications (Cambridge, United Kingdom), 2012, vol. 48, # 95, p. 11626 - 11628,3
[2] Chemical Communications, 2012, vol. 48, # 95, p. 11626 - 11628
[3] Tetrahedron Letters, 2013, vol. 54, # 20, p. 2553 - 2555
[4] RSC Advances, 2016, vol. 6, # 58, p. 52724 - 52728
[5] Journal of Molecular Catalysis A: Chemical, 2015, vol. 403, p. 15 - 26
2
[ 201230-82-2 ]
[ 2393-23-9 ]
[ 17061-63-1 ]
Reference：
[1] Chemical Communications (Cambridge, United Kingdom), 2012, vol. 48, # 92, p. 11310 - 11312,3
[2] Green Chemistry, 2017, vol. 19, # 1, p. 88 - 92
[3] Patent: CN105272868, 2016, A, . Location in patent: Paragraph 0034; 0035
[4] Patent: CN106278923, 2017, A, . Location in patent: Paragraph 0027; 0028
3
[ 64-18-6 ]
[ 2393-23-9 ]
[ 17061-63-1 ]
Reference：
[1] Synlett, 2004, # 14, p. 2570 - 2572
[2] Angewandte Chemie - International Edition, 2013, vol. 52, # 48, p. 12714 - 12718[3] Angew. Chem., 2013, vol. 125, # 48, p. 12946 - 12950,5
[4] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 9, p. 2437 - 2451
4
[ 67-56-1 ]
[ 2393-23-9 ]
[ 17061-63-1 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2015, vol. 357, # 4, p. 834 - 840
[2] Organic Letters, 2013, vol. 15, # 7, p. 1776 - 1779
[3] Chemistry - A European Journal, 2013, vol. 19, # 36, p. 11832 - 11836
[4] Angewandte Chemie - International Edition, 2017, vol. 56, # 15, p. 4229 - 4233[5] Angew. Chem., 2017, vol. 129, # 15, p. 4293 - 4297,5
[6] Patent: WO2017/137984, 2017, A1, . Location in patent: Paragraph 00406; 00407
5
[ 124-38-9 ]
[ 2393-23-9 ]
[ 17061-63-1 ]
Reference：
[1] Chemical Communications, 2018, vol. 54, # 81, p. 11395 - 11398
[2] ACS Catalysis, 2017, vol. 7, # 4, p. 2500 - 2504
[3] Angewandte Chemie - International Edition, 2015, vol. 54, # 41, p. 12116 - 12120[4] Angew. Chem., 2015, vol. 127, p. 12284 - 12288,5
6
[ 50-00-0 ]
[ 2393-23-9 ]
[ 17061-63-1 ]
Reference：
[1] Angewandte Chemie - International Edition, 2015, vol. 54, # 26, p. 7564 - 7567[2] Angew. Chem., 2015, vol. 127, p. 7674 - 7677
[3] Green Chemistry, 2016, vol. 18, # 3, p. 808 - 816
[4] Tetrahedron Letters, 2010, vol. 51, # 44, p. 5804 - 5806
7
[ 2393-23-9 ]
[ 109-94-4 ]
[ 17061-63-1 ]
Yield
Reaction Conditions
Operation in experiment
88%
at 150℃; for 12 h;
To a stirred solution of 4-methoxybenzylamine (3.93 mL, 30 mmol) was added ethyl formate (2.45 mL, 24.2 mmol). The reaction mixture was stirred and heated at 150 °C for 12 h. The reaction mixture was cooled to room temperature and the precipitate was collected by filtration, dried and washed with ethyl ether to give 5b as a white solid (4.4 g). Yield: 88percent; mp 79-80 °C; IR (KBr) cm-1: 3286 (s, N-H); 3012 (m, C-H); 2943-2834 (m, C-H); 1645 (s, CO). 1H NMR (400 MHz, DMSO-d6) δ: 3.73 (s, 3H, OCH3); 4.22 (d, 2H, CH2-NH); 6.89 (d, 2H, H3 + H5, J3-2 = J5-6 = 8.5 Hz); 7.19 (d, 2H, H2 + H6); 8.1 (s, 1H, H-CO); 8.43 (s, 1H, CH2-NH); Elemental Analysis for C9H11NO2 Calcd/Found (percent): C: 65.45/65.07; H: 6.66/6.37; N: 8.48/8.29.
Reference：
[1] Chemical Communications, 2017, vol. 53, # 15, p. 2382 - 2385
[2] New Journal of Chemistry, 2017, vol. 41, # 12, p. 5075 - 5081
[3] Tetrahedron Letters, 2009, vol. 50, # 37, p. 5210 - 5214
[4] European Journal of Medicinal Chemistry, 2012, vol. 47, # 1, p. 283 - 298
[5] Journal of Medicinal Chemistry, 1983, vol. 26, # 3, p. 309 - 312
[6] Tetrahedron Letters, 1985, vol. 26, # 48, p. 5863 - 5866
[7] Pharmazie, 2015, vol. 70, # 8, p. 507 - 510
[8] Journal of Medicinal Chemistry, 2017, vol. 60, # 16, p. 7199 - 7205
[9] Chemistry - A European Journal, 2017, vol. 23, # 52, p. 12758 - 12762
8
[ 2393-23-9 ]
[ 64-18-6 ]
[ 17061-63-1 ]
Yield
Reaction Conditions
Operation in experiment
40%
at 50℃; for 1.5 h;
General procedure: Typical procedure for formylation of amines After the hydrosilylation of CO2 with 1a was completed, piperidine (4a, 1 mmol) was added to the reaction solution of dimethylphenylsilyl formate (2a) and the reaction mixture was vigorously stirred at 50 °C for 1 h. The conversion and the yield of the products were determined by GC and 1H NMR analyses. The formamides were confirmed by the comparison of their GC retention times and GC mass spectra. A typical procedure for isolation of formamides is as follows: After the hydrosilylation of CO2 with 1a was completed, acetonitrile was removed by evaporation, followed by addition of n-hexane (2 mL). Catalysts (Rh2(OAc)4 and K2CO3) were insoluble in n-hexane and separated by filtration. Then, 4e (1 mmol) was added to the filtrate, and the mixture was vigorously stirred at 50 °C for 1 h. n-Hexane was evaporated, and white precipitates obtained were washed with n-hexane and extracted with toluene. Evaporation of toluene afforded analytically pure N-benzylformamide (5e, 35percent yield).
Reference：
[1] Journal of Molecular Catalysis A: Chemical, 2013, vol. 366, p. 347 - 352
9
[ 2393-23-9 ]
[ 68-12-2 ]
[ 17061-63-1 ]
Reference：
[1] RSC Advances, 2016, vol. 6, # 58, p. 52724 - 52728
[2] Journal of Organic Chemistry, 2013, vol. 78, # 9, p. 4512 - 4523
[3] Chemical Communications, 2014, vol. 50, # 19, p. 2438 - 2441
10
[ 201230-82-2 ]
[ 2393-23-9 ]
[ 17061-63-1 ]
[ 93731-94-3 ]
Reference：
[1] Chemical Communications, 2009, # 8, p. 947 - 949
Reference：
[1] Organic and Biomolecular Chemistry, 2005, vol. 3, # 7, p. 1240 - 1244
16
[ 95062-72-9 ]
[ 2393-23-9 ]
[ 54582-35-3 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2005, vol. 3, # 7, p. 1240 - 1244
17
[ 95062-74-1 ]
[ 2393-23-9 ]
[ 54582-35-3 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2005, vol. 3, # 7, p. 1240 - 1244
18
[ 95062-75-2 ]
[ 2393-23-9 ]
[ 54582-35-3 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2005, vol. 3, # 7, p. 1240 - 1244
19
[ 105-36-2 ]
[ 2393-23-9 ]
[ 20839-78-5 ]
Reference：
[1] Journal of Medicinal and Pharmaceutical Chemistry, 1962, vol. 5, p. 861 - 865
20
[ 2393-23-9 ]
[ 696-60-6 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1911, vol. <4> 9, p. 823
[2] Journal of the American Chemical Society, 1964, vol. 86, p. 3075 - 3084
[3] Molecules, 2013, vol. 18, # 6, p. 6990 - 7003
21
[ 2393-23-9 ]
[ 75-05-8 ]
[ 22993-76-6 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 2, p. 293 - 304
22
[ 15481-55-7 ]
[ 2393-23-9 ]
[ 22993-76-6 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 1881 - 1886
[2] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 1881 - 1886
23
[ 515-46-8 ]
[ 2393-23-9 ]
[ 22993-76-6 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 1881 - 1886
24
[ 20443-71-4 ]
[ 2393-23-9 ]
[ 22993-76-6 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 1881 - 1886
25
[ 2393-23-9 ]
[ 80-40-0 ]
[ 22993-76-6 ]
[ 125833-51-4 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 1881 - 1886
26
[ 123-11-5 ]
[ 2393-23-9 ]
[ 854391-95-0 ]
Yield
Reaction Conditions
Operation in experiment
91%
Stage #1: for 4 h; Reflux Stage #2: at 0℃; for 18 h; Stage #3: With hydrogenchloride In 1,4-dioxane; diethyl ether at 0℃; for 2 h;
Pre aration of Intermediate 1-16.A mixture of p-anisaldehyde (1.8 mL, 14.8 mmol) and 4-methoxybenzylamine (1.9 mL, 14.8 mmol) in EtOH (50 mL) was refluxed for 4 h. On cooling to 0 °C, NaBH4 (562 mg, 14.8 mmol) was added and the reaction mixture was stirred for 18 h at rt. On cooling to 0 °C, water (50 mL) and DCM (250 mL) were added. The organic phase was separated and the aqueous layer was extracted with DCM (2 x 250 mL). The combined organic layers were dried (MgS04), filtered and evaporated. The residue was dissolved in Et20 (100 mL) and the mixture was cooled to 0 °C. 4N HCI in dioxane (-10 mL) was added dropwise and the mixture was stirred for 2 h at 0 °C. The resulting white solid was filtered off, washed with Et20/EtOAc to give the desired product (3.99 g, 91 percent) as a white solid.1H NMR (300 MHz, DMSO) δ 9.40 (s, 2H), 7.45 (d, J = 8.7 Hz, 4H), 6.98 (d, J = 8.7 Hz, 4H), 4.03 (s, 4H), 3.77 (s, 6H).
91%
With sodium tetrahydroborate In ethanol at 0 - 20℃; for 22 h; Reflux
Preparation of Intermediate I-16 [0278] [0279] A mixture of p-anisaldehyde (1.8 mL, 14.8 mmol) and 4-methoxybenzylamine (1.9 mL, 14.8 mmol) in EtOH (50 mL) was refluxed for 4 h. On cooling to 0° C., NaBH4 (562 mg, 14.8 mmol) was added and the reaction mixture was stirred for 18 h at rt. On cooling to 0° C., water (50 mL) and DCM (250 mL) were added. The organic phase was separated and the aqueous layer was extracted with DCM (2×250 mL). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was dissolved in Et2O (100 mL) and the mixture was cooled to 0° C. 4N HCl in dioxane (−10 mL) was added dropwise and the mixture was stirred for 2 h at 0° C. The resulting white solid was filtered off, washed with Et2O/EtOAc to give the desired product (3.99 g, 91percent) as a white solid. [0280] 1H NMR (300 MHz, DMSO) δ 9.40 (s, 2H), 7.45 (d, J=8.7 Hz, 4H), 6.98 (d, J=8.7 Hz, 4H), 4.03 (s, 4H), 3.77 (s, 6H).
With triethylamine In dichloromethane at 0 - 20℃; for 3 h;
General procedure: Ethyl bromoacetate (374 mg, 2.2 mmol, 1.0 equiv)was added dropwise to a solution of p-methoxybenzylamine(307 mg, 2.2 mmol) and triethylamine (227 mg, 2.2 mmol, 1.0 equiv)in dichloromethane (10 mL) at 0 °C. The mixture was stirred at room temperature for 3.0h and quenched with water. The organic layer was separated, washed with water,and dried over anhydrous sodium sulfate. The organic solvent was evapolated in vacuo and the residue was purified bysilica gel chromatography eluted with n-hexane/ethylacetate. The product was recovered in 42 percent yield. 1H-NMR (500 MHz, CDCl3)d 1.21(t, 3H, J=7.1 Hz, -CH2CH3), 1.87 (s, 1H, -NH-), 3.33 (s, 2H, -CH2-), 3.68 (s, 2H, -CH2-), 3.72 (s, 3H, CH3O-), 4.13 (q, 2H, J=7.1 Hz, -CH2CH3), 6.80 (d, 2H, J=8.3 Hz, Ar-H), 7.19 (d,2H, J=8.3 Hz, Ar-H).
Reference：
[1] Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 2482 - 2487
[2] Journal of the American Chemical Society, 1993, vol. 115, # 2, p. 536 - 547
[3] Monatshefte fur Chemie, 2004, vol. 135, # 8, p. 951 - 958
[4] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 16, p. 3226 - 3229
28
[ 105-36-2 ]
[ 2393-23-9 ]
[ 60857-16-1 ]
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 22, p. 3824 - 3835
[2] Synthesis, 2005, # 19, p. 3412 - 3422
Acetic acid (100 ml) was added to 4-methoxybenzylamine (100 g) at 25-30°C. Again acetic acid (750 ml) was added to the reaction mixture. Sulfiiryl chloride (87.84 ml) was added slowly to the reaction mixture at 20-25°C and stirred for 6 hours at the same temperature. Methyl tertiary butyl ether (850 ml) was added to the reaction mixture at 25-30°C. The reaction mixture was cooled to 15-20°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with methyl tertiary butyl ether and then dried to get title compound. Yield: 1 18 g
22.8 g
With sulfuryl dichloride In acetic acid at 20 - 25℃; for 27 h;
To a four-neck 500 mL flask provided with a thermometer, Dimroth condenser and stirrer, 20 g (0.146 mol) of MBA was added. In a state in which the reaction liquid was cooled to 20° C. or lower, 250 g of acetic acid was added thereto and stirring was started. Then, 29.3 g of sulfuryl chloride (theoretical molar ratio to MBA: 1.5) was dropped into the four-neck flask for 1 hour while maintaining the reaction liquid temperature at 25° C. or lower. After the dropping, the inner temperature was maintained at 20-25° C. and in this state the reaction was carried out for 26 hours and finished when the remaining amount of MBA-based substances was confirmed to be 0.5percent or less by the HPLC analysis. Then, 150 g of toluene was added to the reaction liquid, which was cooled to 5° C. and then held for 1 hour. The reaction liquid after being held was filtrated to obtain a wet cake, which was washed with 20 g of toluene cooled to 5° C. The wet crystals thus obtained were dried using a vacuum drier and a dried product of 22.8 g of white crystals was obtained as a CMBA-HCl-containing composition. The yield was 75.5 mol percent and the HPLC purity was 98.9percent. In the CMBA-HCl-containing composition, 0.50percent of MBA-based substances remained and 0.23percent of dichloro products were generated as by-products.
Reference：
[1] Journal of molecular catalysis, 1989, vol. 50, # 3, p. 333 - 341
32
[ 5909-24-0 ]
[ 2393-23-9 ]
[ 211230-35-2 ]
Yield
Reaction Conditions
Operation in experiment
88%
With triethylamine In tetrahydrofuran
Example 14 4-(4-Methoxybenzylamino)-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester To a room temperature solution of 4-chloro-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester (6.05 g, 26.07 mmol) in 60 mL of tetrahydrofuran was added triethylamine (11 mL, 79.5 mmol) followed by 3.6 mL (27.6 mmol) of 4-methoxybenzylamine. The solution was stirred for 1 hour then filtered. The white solid was washed with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was partitioned between chloroform and saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to provide 7.60 g (88percent) of 4-(4-methoxybenzylamino)-2-methanesulfanyl-pyrimidine-5-carboxylic acid ethyl ester, mp 72-74° C. Analysis calculated for C16H19N3O3S: C, 57.64; H, 5.74; N, 12.60. Found: C, 57.65; H, 5.80; N, 12.57.
5.20 g
With triethylamine In N,N-dimethyl-formamide at 0℃; for 1 h;
Ethyl 4—chloro—2—(methylthio)pyrimidine—5—carboxylate (3g, 12.9 mmol) was dissolved in DMF (10 mL) and cooled to0 °C. A solution of triethylamine (2 mL, 14.4 mmol) and(4-methoxyphenyl)methanamine (1.85 mL, 14.2 mmol) in DMF(10 mL) was added slowly. The mixture was stirred for 1 hthen poured into ice / 10percent citric acid solution. The mixture was extracted with ethyl acetate (x 2) . The combined organic layers were washed with citric acid solution then brine, then dried with Mg504, filtered andconcentrated in vacuo. The residue was azeotroped with cyclohexane / DCM to give a syrup which crystallised to yield 5.20 g of a white solid on standing. This was dissolved in ethanol (25 mL) and 2 M NaOH (25 mL) and the solution was stirred overnight. The mixture wasconcentrated in vacuo, then acidified (2 M HC1) . The precipitated solid was collected by filtration, then dried in vacuo to give the title compound as a white solid (4.1 g, quantitative) . ‘H NMR (500 MHz, DMSO—d6) : 5 13.30 (br s, 1H), 8.85 (t, 1H), 8.53 (s, 1H), 7.29 (t,2H), 6.90 (t, 2H), 4.63 (d, 2H), 3.74 (s, 3H), 2.45 (s,3H) . LCMS (Method A) : = 1.05 mm, m/z = 306 [M+H].
With triethylamine; In acetonitrile; at 20℃; for 3.58333h;Heating / reflux;
4-Methoxy-1-(4-methoxybenzyl)-1,5-dihydropyrrol-2-oneA solution of 4-methoxybenzyl amine (19.7 mL, 0.151 mol) in acetonitrile (75 mL) was heated to reflux. To this was added simultaneously a solution of <strong>[110104-60-4](E)-4-chloro-3-methoxy-but-2-enoic acid methyl ester</strong> (20 g, 0.122 mol) in acetonitrile (85 mL) and a solution of triethylamine (15.28 mL, 0.11 mol) in acetonitrile (30 mL) over 35 minutes. After 3 hours, the reaction was cooled and allowed to stand at room temperature overnight. The resulting precipitate was removed by filtration. The mother liquor was concentrated and purified by flash chromatography on silica gel eluting with a gradient of 20 to 100% ethyl acetate in hexanes to afford the desired compound (17.04 g, 60%). 1H NMR (300.132 MHz, DMSO) delta 7.12 (dt, J=8.9, 2.4 Hz, 2H), 6.89 (dt, J=8.8, 2.4 Hz, 2H), 5.16 (s, 1H), 4.38 (s, 2H), 3.78 (s, 2H), 3.75 (s, 3H), 3.73 (s, 3H). MS APCI, m/z=234 (M+H). HPLC 1.47 min.
With O-(ethoxycarbonyl)cyanomethylamino-N-N-N'-N'-tetramethyl uronium fluoroborate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃;
6.56 g (20 mmol) of TOTU and 2.6 ml (2.74 g, 20 mmol) of 4-methoxybenzylamine are added to a stirred solution of 4.2 g (18.1 mmol) of <strong>[41684-07-5]4-amino-3-methylcarboxylate-1-phenyl carboxylic acid</strong> in 150 ml of anhydrous DMF. The mixture is cooled at 0 C. and 9.5 ml (7.02 g, 54.3 mmol) of DIPEA are added. The reaction mixture is stirred overnight at room temperature and concentrated under vacuum. The residue is taken up in 150 ml of dichloromethane, washed with 100 ml of a saturated solution of NaHCO3. The organic layer is dried and concentrated under vacuum. After a chromatography over silica gel 3.5 g (yield=62%) of the desired compound are isolated. [00316] TLC: CH2Cl2/MeOH 90/10 Rf=0.80 [00317] N.M.R (DMSO-d6) 1H delta(ppm): 3.80 (s, 3H); 3.90 (s, 3H); 4.55 (d, 2H); 6.0-6.15 (bs, 2H); 6.15-6.30 (bs, 1H); 6.65 (d, 1H); 6.90 (d, 1H); 7.25-7.30 (m, 2H); 7.80 (d, 1H); 8.25 (s, 1H). [00318] PURITY: HPLC=98.5%
With sodium hydrogencarbonate; In i-Amyl alcohol; at 150℃; for 0.25h;Microwave irradiation;
Example 145 [N- {6- [4- (4-BROMO-6-TRIFLUOROMETHYL-LH-BENZOIMIDAZOL-2-YL)-PIPERAZIN-1-YL]-5-] trifluoromethyl-pyridin-2-yl}-acetamide, trifluoroacetic acid salt. (a) [(6-CHLORO-5-TRIFLUOROMETHYL-PYRIDIN-2-YL)- (4-METHOXY-BENZYL)-AMINE,] trifluoroacetic acid salt. A suspension of 2, 6-dichloro-3-trifluoromethylpyridine (1.08 gm, 5 mmol, Lancaster), 4-methoxybenzyl amine (700 mg, 5 mmol, Aldrich) and sodium bicarbonate (430 mg, 5 mmol) in isoamyl alcohol (5 mL) was heated at [150 C] in a microwave synthesizer for 15 min. The reaction mixture was allowed to cool to room temperature, diluted with MeOH (10 mL) and filtered. The filtrate was evaporated in vacuo and the residue was purified by preparative HPLC (gradient 0. [1%] trifluoroacetic acid in acetonitrile) to provide the title compound as a colorless oil. MS (ESI, pos. ion) [M/Z] : 317 [(M+1).]
methyl 5-chloro-2-((4-methoxybenzyl)amino)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
In methanol;Heating / reflux;
A solution of 2, 5-dichloro-nicotinic acid methyl ester (71) (25 g, 121 mmol) in anhydrous methanol was purged with argon and added P-METHOXYBENZYLAMINE (34.5 mL, 266 mmol) at room temperature. The solution was refluxed overnight under argon. The solution was cooled and the solvent was evaporated under reduced pressure. The residue was taken in dichloromethane, sonicated briefly and undisolved solids were filtered off. The filtrate was washed by water, dried over MGS04 and concentrated. The crude product was purified by flash chromatography eluting with hexane : CH2C12 (1: 1) to yield 16.2 g (44 %) of 5-CHLORO-2- (4-METHOXY-BENZYLAMINO)-NICOTINIC acid methyl ester (72) as a white solids. Mp 94 C. 1H-NMR (DMSO-D6) : d 3.71 (s, 3H), 3. 82 (s, 3H), 4.59 (d, J= 5.6 Hz, 2H), 6.87 (m, 2H), 7.24 (m, 2H), 8. 06 (d, J= 2.8 Hz, 1H), 8.27 (m, 1H), 8. 32 (d, J= 2. 8 Hz, 1H); EIMS m/z 307 (M+1).
28%
In ethanol; at 65℃; for 12h;
EtOH (30.0 mL) was added to <strong>[67754-03-4]methyl 2,5-dichloronicotinate</strong> (2020.0 mg, 9.79 mmol), and then 4-methoxybenzylamine (2.6 mL, 19.60 mmol) was added thereto. The mixture was stirred at 65 C. for 12 hours and then cooled to room temperature. The reaction mixture was distilled under reduced pressure and the residue was purified by column chromatography (EtOAc:n-Hex=1:9) on silica. The fractions containing the product were collected and evaporated to obtain colorless liquid compound of methyl 5-chloro-2-((4-methoxybenzyl)amino)nicotinate (840.0 mg, 28%). [1034] LCMS ESI (+): 307 (M+1)
methyl 6-Amino-N-(4-methoxy-benzyl)-isophthalate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With sodium hydrogencarbonate; N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide;
Step 1 Methyl 6-Amino-N-(4-methoxy-benzyl)-isophthalate 6.56 g (20 mmol) of TOTU and 2.6 ml (2.74 g, 20 mmol) of 4-methoxybenzylamine are added to a stirred solution of 4.2 g (18.1 mmol) of <strong>[41684-07-5]4-amino-3-methylcarboxylate-1-phenyl carboxylic acid</strong> in 150 ml of anhydrous DMF. The mixture is cooled at 0 C. and 9.5 ml (7.02 g, 54.3 mmol) of DIPEA are added. The reaction mixture is stirred overnight at room temperature and concentrated under vacuum. The residue is taken up in 150 ml of dichloromethane, washed with 100 ml of a saturated solution of NaHCO3. The organic layer is dried and concentrated under vacuum. After a chromatography over silica gel 3.5 g (yield=62%) of the desired compound are isolated. TLC: CH2Cl2/MeOH 90/10 Rf=0.80
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 70℃; for 4h;
To a solution of 6-Chloro-2-methoxy-nicotinic acid methyl ester (18.5.0 g, 0.092 mol) in 50 mL of NMP was added p-methoxybenzylamine (19.0 g, 0.14 mol) and triethylamine (10.Og, 0.1 mol). The mixture was heated to 70 0C for 4 h, cooled and diluted with water and extracted with ethyl acetate, washed with water, brine, dried with sodium sulfate, and evaporated to get an oil which was precipitated with ethylacetate/hexane mixture (1 :1). This was then filtered and dried to yield 15 g (60 %) of the target compound.
Example 3 2-[1-(4-Methoxy-benzyl)-5-oxo-4-phenyl-2,5-dihydro-1H-pyrrol-2-ylsulfanyl]-N-thiazol-2-yl-acetamide (Compound 3) A. 1-(4-Methoxy-benzyl)-4-phenyl-pyrrole-2,5-dione: Phenylmaleic anhydride (2.4 g, 13.8 mmol) and 4-methoxybenzylamine (1.8 mL, 13.8 mmol) in 10 mL glacial acetic acid were heated in a 95 C. oil bath for 2 h. The mixture was cooled to room temperature, diluted with methanol and filtered to provide the title compound as a solid (3.2 g, 79%).
4-hydroxy-N,N'-bis[(4-methoxyphenyl)methyl]-1,3-benzenedicarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
In N-methyl-acetamide; thionyl chloride; dichloromethane;
Intermediate D: 4-hydroxy-N,N'-bis[(4-methoxyphenyl)methyl]-1,3-benzenedicarboxamide A mixture of <strong>[636-46-4]4-hydroxyisophthalic acid</strong> (2.0 g; 11 mmol) in thionyl chloride (20 ml) and dimethylformamide (2 drops) was heated at reflux under stirring overnight. The excess of thionyl chloride was removed by evaporation and the residue dissolved into dichloromethane (100 ml). After cooling, 4-methoxybenzylamine (6.8 g; 50 mmol) was added in one portion and the mixture obtained was stirred at room temperature for 1 hour. The insoluble solid was separated by filtration and purified by chromatography on silica gel (CH2Cl2 95/methanol 5) to give 2.0 g of the entitled compound (yield: 43%) as a white solid pure in TLC (CH2Cl2 90/methanol 10; Rf=0.70).
With potassium carbonate; In isopropyl alcohol; for 18h;Heating / reflux;
A solution of <strong>[89284-61-7]4-chloronicotinonitrile</strong> (1.00 g, 7.22 mmol), 4- methoxybenzylamine (1.03 ml, 7.94 mmol) and potassium carbonate (1.20 g, 8.66 mmol) in propan-2-ol (20 mL) was heated under reflux for 18 hours. The solvent was concentrated in vacuo and the residue partitioned between EtOAc (150 mL) and water (50 mL). The organic phase was dried (Na2SO4), filtered and evaporated to give a brown oil. The oil was pre- adsorbed onto H-MN and purified by flash column chromatography (Si- PPC, cyclohexane: EtOAc, gradient 80:20 to 0:100) to provide the title compound as a white solid (1.61 g, 93%). IH NMR (CDCl3, 300 MHz) 8.46 (d, J = 0.7 Hz, IH), 8.30 (dd, J = 6.1 Hz, 0.7 Hz, IH), 7.24 (dd, J = 8.6 Hz, 2.1 Hz, 2H), 6.92 (dd, J = 8.6 Hz, 2.1 Hz, 2H), 6.55 (d, J = 6.1 Hz, IH), 5.35 (br t, IH), 4.40 (d, J = 5.6 Hz, 2H), 3.82 (s, 3H).
Preparation 3 : 3-bromo-1-[4-(methyloxy)phenyl]methyl}-1W-pyrrole-2,5-dione (P3) <n="53"/>A mixture of 3-bromo-2,5-furandione (6 g), 1-[4-(methyloxy)phenyl]methanamine (4.44 mL), and AcOH (80 mL) was heated at 100 0C overnight. The solution was then concentrated in vacuo. AcOH (70 mL) and AcONa (2 g) were added to the crude product and the mixture was reflux for 2 hours. Water was then added and the aqueous phase was extracted with DMC. The organic phase was dried and evaporated in vacuo. The crude was purified by flash chromatography eluting with cyclohexane/ethyl acetate from 9/1 to 7/3 to give the title compound (8.2 g). NMR (1H, CDCI3) delta 7.32 (d, 2H), 6.86 (m, 3H), 4.66 (s, 2H), 3.80 (s, 3H).
With acetic acid; triethylamine; In water; acetone;
Example 5-1b 4-(N-(4-methoxybenzyl)sulfamoyl)benzoic acid <strong>[10130-89-9]4-(Chlorosulfonyl)benzoic acid</strong> (5 g, 22.7 mmol) was added, in three portions as a solid, to a stirring solution of 4-methoxy benzylamine (6.1 g, 45 mmol) and triethylamine (2.3 g, 22.7 mmol) in acetone (100 mL) cooled to 0 C. via an ice water bath over a 10 minute period. The ice bath was removed and the reaction was stirred for an additional 4 hours. The reaction mixture was diluted with a solution of 5% acetic acid in H2O (150 mL) and extracted with ethyl acetate (3*, 100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated on the rotovap. The resulting white solid was triturated with hexanes/ethyl acetate (9/1) to afford 4-(N-(4-methoxybenzyl)sulfamoyl)benzoic acid (5.1 g, 70%) as a white solid. 1H NMR (400 MHz, DMSO d6) delta 3.68 (s, 3H), 3.91 (s, 2H), 6.79 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.8 Hz, 2H), 7.80 (d, J=8.8 Hz, 2H), 8.02 (d, J=8.4 Hz, 2H).
70%
With acetic acid; triethylamine; In water; acetone; for 4h;
<strong>[10130-89-9]4-(Chlorosulfonyl)benzoic acid</strong> (5 g, 22.7 mmol) was added, in three portions as a solid, to a stirring solution of 4-methoxy benzylamine (6.1 g, 45 mmol) and triethylamine (2.3 g, 22.7 mmol) in acetone (100 mL) cooled to 0 C. via an ice water bath over a 10 minute period. The ice bath was removed and the reaction was stirred for an additional 4 hours. The reaction mixture was diluted with a solution of 5% acetic acid in H2O (150 mL) and extracted with ethyl acetate (3*, 100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated on the rotovap. The resulting white solid was triturated with hexanes/ethyl acetate (9/1) to afford 4-(N-(4-methoxybenzyl)sulfamoyl)benzoic acid (5.1 g, 70%) as a white solid. 1H NMR (400 MHz, DMSO d6) delta 3.68 (s, 3H), 3.91 (s, 2H), 6.79 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.8 Hz, 2H), 7.80 (d, J=8.8 Hz, 2H), 8.02 (d, J=8.4 Hz, 2H).
Intermediate 7: 3-(4-Methoxybenzyl)pyridor3,2-tflpyrimidine-2,4(1 H,3H)-dione; A solution of Intermediate 6 (10.3 g; 56.9 mmol; 1 eq.) and TEA (10.25 ml; 73.9 mmol; 1.3 eq.) in dry THF (206 ml_) was cooled to -10 0C. Ethyl chloroformate (8.19 ml; 85.3 mmol; 1.5 eq.) was added dropwise over 25 min) and the reaction mixture was stirred at this temperature for 1.5 hour. A solution of sodium azide (6.28 g; 96.7 mmol; 1.7 eq.) in water (103 mL) was then added in one portion. After 1.5 hour at 0 0C, the resulting heterogenous mixture was filtered, the two liquid phases were separated and the aqueous phase was extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over magnesium sulphate and concentrated in vacuo. The residue was taken up in toluene (62 mL) and stirred at refluxed for 2 hours. After cooling to room temperature, a solution of 4- methoxybenzylamine (7.36 ml; 56.9 mmol; 1 eq.) in pyridine (103 mL) was added and the reaction mixture was stirred at refluxed for 24 hours. After concentration in vacuo, the residue was washed with ethanol to afford the title compound as a white solid. 1H NMR (300 MHz, DMSOd6) delta 1 1.54 (br s, 1 H), 8.49 (dd, J = 4.2, 1.5 Hz, 1 H), 7.69-7.57 (m, 2H), 7.30 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.02 (s, 2H), 3.71 (s, 3H). HPLC (method A): RT 2.10 min (purity 91 %).
General procedure: A mixture of 5 (5.0 mmol), the respective amine (12 mmol), equimolecular amounts of triethylamine, and ethanol (15 mL) was heated at 70 C for 5 h with stirring. The solvent was removed under vacuum and the residue was dissolved in water (30 mL); the mixture was extracted with chloroform (3 × 25 mL) and the organic extracts were dried over anhydrous sodium sulfate and the solvent was removed in vacuum. For compounds 6t-y the resulting solid was purified by recrystallization as indicated in Table 1. For compounds 6z-ai the residual material isolated after removal of the solvent was washed with 5% HCl (25 mL) and the resulting solid was isolated and purified as indicated in Table 1.
(E)-1-ethylidene-3-(4-methoxybenzyl)-7-methyl-5-(2,4,4-trimethylpentan-2-yl)-3,3a,5a,6-tetrahydropyrrolo[3',2':3,4]pyrrolo[2,3-b]indole-2,4(1H,5H)-dione[ No CAS ]
5-Methyl-2,4-dioxo-hexanoic acid ethyl ester (5.6 g, 36.4 mmol) was added to a solution of 4-methoxybenzyl amine (5 g, 36.4 mmol) in acetic acid (40 mL). The mixture was stirred for 10 min at rt. 4-Chloro-2-methylbenzaldehyde (6.77 g, 36.4 mmol) was added. The reaction mixture was heated to 120C, stirred at this temperature overnight, allowed to cool to rt and diluted with acetonitrile. The resulting precipitate was collected by vacuum filtration and dried to provide 1 1 g of the title compound. tR: 1.80 min (LC-MS 2); ESI-MS: 414 [M+H]+(LC-MS 2).
With sodium sulfate; In methanol; at 20℃;Sealed tube;
General procedure: To a solution of imidazole carbaldehyde (1a-d) (100 mg, 1 equiv) in methanol (3 mL) were added successively Na2SO4 (0.2 g), amine 2a-d (1.2 equiv), alkynoic acid 3a-c (1.2 equiv) and isonitrile 4a-c (1.2 equiv) in a screw capped vial equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 24-48 h in closed vial. After completion of the reaction, the mixture was diluted with dichloromethane (100 mL) and was extracted with water (50 mL). Organic layer was washed with brine (50 mL), dried over magnesium sulfate and evaporated under reduced pressure to obtained residue which was subjected to silica gel column chromatography (1-5 % methanol in dichloromethane) to afford the desired product 5a-r as solid.
3-N-(4-methoxybenzyl)pyridazine-3,6-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With potassium phosphate; copper(l) iodide; 4R-4-hydroxyproline; In dimethyl sulfoxide; at 50℃; for 24h;Inert atmosphere;
General procedure: A 10 mL round-bottomed flask containing a magnetic stirbar was charged with CuI (0.1 mmol) followed by L-hydroxyproline (0.2 mmol),<strong>[187973-60-0]6-iodopyridazin-3-amine</strong> (1.3 mmol) and K3PO4 (3.0 mmol). The flask wasflushed with N2 and a solution of the appropriate amine (1.0 mmol) inanhydrous DMSO (1.5 mL) was then added. The mixture was stirred under N2at 50 C for 24 h. MeOH (5 mL) and H2O (5 mL) were added and the stirredmixture was neutralised by dropwise addition of AcOH. The resultant solidswere allowed to settle out and the supernatant solution added to the top of astrong cation exchange (SCX) column. The remaining solid was washed withfurther MeOH (5 mL), and the washings also added to the SCX column. Thesolution was allowed to elute slowly through the column, which was thenflushed with further MeOH. These MeOH washings were discarded. A 1 Msolution of NH3 in MeOH was flushed through until elution of the product wascomplete and the solvent was evaporated under reduced pressure to yield acrude material. Purification was done by flash silica chromatography, elutiongradient typically 0-10% MeOH in CH2Cl2. Relevant fractions were evaporatedto dryness to afford the desired product.
3,6-dichloro-N-(4-methoxybenzyl)pyridazin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
In tetrahydrofuran; at 50℃; for 2h;Sealed tube;
<strong>[6082-66-2]3,4,6-Trichloropyridazine</strong> (500 mg, 2.73 mmol, Eq: 1) was dissolved in THF (5 ml) ina glass tube. Then (4-methoxyphenyl)methanamine (1.16 g, 1.09 ml, 8.18 mmol, Eq:3) was added resulting in an orange suspension. The tube was sealed and the mixturewas heated to 50 C for 2 hours. The mixture was diluted with ethyl acetate and waterand then extracted 4 times with ethyl acetate. The organic layers were combined,washed once with brine, dried with sodium sulfate, filtered and concentrated in vacuo. A crude brown oil was obtained and purified by silica gel chromatography (50 g prepacked silica gelcolumn eluted with heptane/ ethyl acetate 100:0 to 0:70). 3,6-Dichloro-N-(4-methoxybenzyl)pyridazin-4-amine was obtained as an orange solid (536 mg, 62%). LC-HRMS: m/z=284.0361 [(M+H)+ calcd for C12H11Cl2N3O: 284.03519; Diff 0.9 mDa]. 1H NMR(CHLOROFORM-d, 600MHz): (ppm) 7.24 (d, J=8.3 Hz, 2H), 6.93 (d, J=8.3 Hz, 2H), 6.55 (s, 1H),5.37 (br. s., 1H), 4.34 (d, J=5.1 Hz, 2H), 3.83 (s, 3H). 13C NMR (CHLOROFORM-d, 151MHz): (ppm) 159.8, 155.7, 144.2, 143.5, 128.8, 126.9, 114.7, 105.6, 55.4, 46.4.
N-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
525 mg
at 150℃; for 6h;
To <strong>[871836-51-0]4-chloro-1H-pyrazolo[4,3-c]pyridine</strong> (1.3 g, 8.46 mmol) was added (4- methoxyphenyl) methanamine (5 mL) and the resultant reaction mixture was heated in a closed reaction vessel at 150 °C for 6 h. The reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with EtOAc (500 mL). The organic layer was washed with saturated NH4C1 solution (12x50 mL), water (2x200 mL), brine (150 mL), dried over Na2SO4 and concentrated. The crude compound was purified by silica-gel (100-200) column chromatography, compound eluting at 40percent EtOAc/hexane to afford N-(4- methoxybenzyl)- 1H-pyrazolo[4,3-c]pyridin-4-amine (525 mg) as a light brown solid.
2-[6-(4-Methoxybenzylamino)-purin-9-yl]-5-(1H-tetrazol-5-yl)-tetrahydrofuran-3,4-diol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With cyfluthrin; ammonium chloride; dimethyl sulfoxide; N-ethyl-N,N-diisopropylamine; In propan-1-ol; dichloromethane; N,N-dimethyl-formamide;
2-[6-(4-Methoxybenzylamino)-purin-9-yl]-5-(1H-tetrazol-5-yl)-tetrahydrofuran-3,4-diol (16) The crude acid 18 obtained from oxidation of 17-acetonide (ca. 3.98 mmol) with PhI(OAc)2/TEMPO was treated with ammonium chloride (426 mg, 7.96 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 3.07 g, 5.97 mmol), hydroxybenzotriazole (HOBt, 807 mg, 5.97 mmol) and diisopropylethylamine (2.5 mL, 15.9 mmol) in anhydrous DMF (40 mL) at 50 C. for 14 h. The mixture was concentrated under reduced pressure. The residue was extracted with CH2Cl2 and H2O. The organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel; EtOAc/hexane (1:1 to 4:1)) to yield an amide product 20 as colorless oil. A solution of dimethyl sulfoxide (0.85 mL, 11.9 mmol) in CH2Cl2 (10 mL) was added to a solution of oxalyl chloride (0.7 mL, 7.96 mmol) in CH2Cl2 (10 mL) at -78 C. The mixture was stirred for 30 min, and a solution of amide 20 (ca. 3.98 mmol) in CH2Cl2 (20 mL) was added. The mixture was stirred at -78 C. for another 30 min, and diisopropylethylamine (2.6 mL, 15.9 mmol) was added. After 1 h stirring, formation of nitrile 21 was monitored by TLC analysis. The mixture was extracted with CH2Cl2 and H2O. The organic phase was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel; EtOAc/hexane (2:3)) to yield nitrile 21 as colorless oil (863 mg) contaminated with a small amount of HOBt. The above-prepared nitrile product (863 mg, 2.68 mmol) was treated with 4-methoxybenzylamine (1.84 g, 13.4 mmol) and diisopropylethylamine (15.5 mL) in 1-propanol (26 mL) at 70 C. for 4 h. The mixture was concentrated under reduced pressure, and the residue was extracted with CH2Cl2 and H2O. The organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel; CH2Cl2/MeOH (300:1 to 150:1)) to give compound 22 (905 mg, 54% overall yield). C21H22NO4; colorless oil; TLC (EtOAc/hexane (4:1)) Rf=0.55; [alpha]26D=+25.8 (EtOAc, c=1.0); IR numax (neat) 3373, 3282, 2990, 2925, 2853, 1679, 1618, 1.512, 1465, 1376, 1331, 1295, 1249, 1212, 1135, 1086 cm-1; 1H NMR (CDCl3, 400 MHz) delta 8.39 (1H, br s), 7.64 (1H, br s), 7.26 (2H, d, J=10.4 Hz), 6.83 (2H, d, J=10.4 Hz), 6.54 (1H, t, J=5.6 Hz), 6.13 (1H, s), 5.77 (1H, d, J=4.0 Hz), 5.68 (1H, dd, J=1.6, 4.0 Hz), 4.95 (1H, d, J=1.6 Hz), 4.75 (2H, br s), 3.79 (3H, s), 1.57 (3H, s), 1.42 (3H, s); 13C NMR (CDCl3, 100 MHz) delta 158.8, 154.5, 153.2, 148.2, 138.9, 130.2, 128.9 (2*), 119.7, 115.9, 114.5, 113.9 (2*), 91.6, 84.6, 83.9, 75.1, 55.3, 44.0, 26.6, 25.1; ESI-HRMS (negative mode) calcd for C21H22N6O4: 421.1624. found: m/z 421.1612 [M-H]-.
2-chloro-N-(4-methoxybenzyl)-6-phenylpyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
In N,N-dimethyl-formamide; at 40℃; for 18h;
General procedure: The respective dichloropyrimidine derivative 9 (between 60 mg and 120 mg) and 1.5 equivalents of the respective amine are dissolved in DMF (2.00 mL). The reaction mixture is heated to 40 C and stirred for 18 hours. Subsequently, the solvent is removed under reduced pressure and the crude product is purified via column chromatography (SiO2, dichloromethane / ethyl acetate = 20:1).
N-(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)ethanamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
Intermediate 179: N-(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)ethanamine To a stirred solution of <strong>[137052-08-5]1-(tetrahydro-2H-pyran-4-yl)ethanone</strong> (3.2 g, 24.97 mmol) in DCM) (50 mL was added (4-methoxyphenyl)methanamine (6.87 g, 50.1 mmol). The resulting yellow solution was stirred for 4.5 h and sodium triacetoxyborohydride (10 g, 48.6 mmol) added. The white suspension was stirred. The reaction mixture was partitioned between DCM and aq. sat. NaHCO3. The organic layer was removed and the aqueous extracted 3 times with DCM. The combined organic phases were passed through a hydrophobic frit and concentrated in vacuo to give a yellow oil. The oil was dissolved in DCM, purified by silica gel chromatography eluting with EtOAc:EtOH (7.5 - 25%) and evaporated in vacuo to give the title compound as a yellow oil. The total yield of the reaction was 80%. LCMS (System A): tRET = 1.27 min, MH+ = 366.
N-(4-methoxybenzyl)-6-fluoroquinazoline-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With triethylamine; In N,N-dimethyl-formamide; for 4.0h;Reflux;
General procedure: Compound 4 (1.84 g, 0.01 mol) was mixed with (1.06 g, 0.01 mol) of trimethylamine and (0.01 mol)of the appropriate aromatic amine in 5 mL of dimethylformamide (DMF). The mixture was refluxedfor 4 h, cooled, and poured on crushed ice. The crystals were collected and crystallized from ethylalcohol. The melting points for all synthesized compounds were above 300 C.
6-chloro-2-((4-methoxybenzyl)amino)nicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72.9%
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120℃;Inert atmosphere;
To a solution of <strong>[40381-90-6]2,6-dichloronicotinonitrile</strong> (2.0 g, 11.6 mmol, 1.0 eq.) in NMP (50 mL)was added PMBNH2 (2.4 g, 17.3 mmol, 1.5 eq.) and DIEA (3.0 g, 23.1 mmol, 2.0 eq.). The mixture was stirred at 120C under N2 atmosphere overnight until TLC showed that the reaction was completed, then cooled and concentrated. The residue was quenched with H20 (200 mL), extracted with EA (80 mL x 3). The combined organic layer was washed with brine (80 mL x 2), dried over anhydrous Na2SO4, concentrated. The residue was purified by column chromatography (PE/EA = 10:1) to provide 6-chloro-2-((4-methoxybenzyl) amino)nicotinonitrile (2.3 g, 72.9%) as a yellow solid.
72.9%
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120℃;Inert atmosphere;
To a solution of <strong>[40381-90-6]2,6-dichloronicotinonitrile</strong> (2.0 g, 11.6 mmol, 1.0 eq.) in NMP (50 mL) was added PMBNH2 (2.4 g, 17.3 mmol, 1.5 eq.) and DIEA (3.0 g, 23.1 mmol, 2.0 eq.). The mixture was stirred at 120C under N2 atmosphere overnight until TLC showed that the reaction was completed, then cooled and concentrated. The residue was quenched with H20 (200 mL), extracted with EA (80 mL x 3). The combined organic layer was washed with brine (80 mL x 2), dried over anhydrous Na2S04, concentrated. The resulting residue was purified by column chromatography (PE/EA = 10: 1) to provide 6-chloro-2-((4- methoxybenzyl) amino)nicotinonitrile (2.3 g, 72.9%) as yellow solid.
2-amino-5-bromo-4-fluoro-N-(4-methoxybenzyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With 1-[(1-(cyano-?2-?ethoxy-?2-?oxoethylidenaminooxy)?dimethylamino-?morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 10 - 35℃;
A mixture of <strong>[143945-65-7]2-amino-5-bromo-4-fluorobenzoic acid</strong> (10 g, 42.73 mmol), (4-methoxyphenyl)methanamine (6.45 g, 47.00 mmol), COMU (18.30 g, 42.73 mmol) and DIEA (11.05 g, 85.46 mmol) in DMF (200 mL) was stirred at room temperature overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0?50% ethyl acetate/hexane) to give 2-amino-5-bromo-4-fluoro-N-(4-methoxybenzyl)benzamide (8 g, 22.65 mmol, 53.0%) as a brown solid. 1H NMR (300 MHz, CDCl3):delta 1.38-1.49(m,2H), 3.81(s,3H), 4.51(d,J=5.29 Hz,2H), 5.77(brs,2H), 6.12(brs,1H), 6.44(d,J=10.20Hz,1H), 6.90(d,J=8.69 Hz,2H), 7.27-7.31(m,1H), 7.44(d,J=7.18 Hz,1H).
5-bromo-7-(((4-methoxybenzyl)amino)methyl)quinolin-8-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
The solution of 4-methoxybenzylamine (211 muIota_, 0.226 g, 1.65 mmol) in ethanol (4 mL) was added 37percent formaldehyde (62 muIota_, 0.049 g, 1.65 mmol). The mixture was stirred for 1 hour. Then the solution of <strong>[1198-14-7]5-bromoquinolin-8-ol</strong> (0.336 g, 1.5 mmol) in ethanol (5 mL) was added to the reaction mixture. After that the mixture was refluxed at 50°C for 72 hours. The reaction mixture was allowed to cool down and the obtained precipitate was filtered off, washed with ethanol and crystallized from ethanol to give the titled compound (0.150 g, 27percent) as yellow crystals. Mp. 129-132 °C. 1 H NMR (300 MHz, CDCI3): delta 3.81 (d, 5H), 4.12 (s, 2H), 6.87 (d, 2H), 7.28 (d, 2H), 7.46-7.51 (m, 1 H), 7.62 (s, 1 H), 8.40 (d, 1 H), 8.83 (d, 1 H). 13C NMR (75 MHz, CDCI3): delta 49.4, 52.3, 55.2, 109.4, 1 13.9, 120.9, 122.3, 127.0, 129.6, 131.2, 134.9, 135.3, 139.6, 149.0, 152.0, 158.9. LCMS RT= 4.19 min. ESI+ m/z: 375.6 [M+H+].
(2R,3R)-ethyl 3-[2,4-bis(trifluoromethyl)phenyl]-5-(4-methoxybenzyl)-6-methyl-4-oxo-2,3,4,5-tetrahydrofuro-[3,2-c]pyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
General procedure: A mixture of 4-hydroxy-6-methyl-2H-pyran-2-one (100 mg, 0.786 mmol), benzyl amine (84 mg, 0.786 mmol) in EtOH (5 mL), was stirred at room temperature for 5 min. Then benzaldehyde (83 mg, 0.147 mmol), pyridinium ylide (193 mg, 0.786 mmol), triethylamine (8 mg, 0.786 mmol) added sequentially to the mixture and it was refluxed at 80 °C for 20 min till the completion of the reaction (monitored by TLC). After completion of reaction ethanol was distilled out and in the product crushed ice (25 g) was added. To this 0.5 MHCl (1 mL) was added and the resulting aqueous with suspended solids was extracted with dichloromethane (2 × 10 mL) and concentrated. Crude product was purified through column chromatography by eluting with hexanes and EtOAc mixtures (TLC, 45 percent EtOAc in hexanes; Rf = 0.34). After recrystallization from EtOH, product obtained as light yellow colour crystalline solid;
With magnesium sulfate; In dichloromethane; at 20℃;
A mixture of <strong>[206181-90-0]3-chloropicolinaldehyde</strong> (1.5 g, 10.64 mmol), (4-methoxyphenyl)methanamine (1.5 g, 10.64 mmol) and MgSO4 (3.8 g, 31.9 mmol) in CH2C12(45 ml) was stirred at room temperature overnight. The reaction mixture was used directly in thenext step.
5-chloro-N-(4-methoxybenzyl)pyridazin-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 120℃; for 16h;
To a stirred solution of <strong>[1837-55-4]3,5-dichloropyridazine</strong> (CAS Number 1837-55-4; 1 .500 g, 10.1 mmol) and (4-methoxyphenyl)methanamine (CAS Number 2393-23-9; 1 .650 g, 12.1 mmol) in DMF (10 ml) was added K2CO3 (2.780 g, 20.1 mmol) and Kl (3.340 g, 20.13 mmol) at rt. The reaction mixture was heated at 120C for 16 h. The resulting mixture was cooled to rt, diluted with ice cold water (100 ml) and extracted with EtOAc (4 x 25 ml). The combined organic phase was washed with brine solution (50 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (53% EtOAc in hexane) yielding 5-chloro-N-(4-methoxy-benzyl)pyridazin-3-amine (3.100 g, quantitative). LCMS: Method C, 1 .646 min, MS: ES+ 250.38.
8-bromo-N-[(4-methoxyphenyl)methyl]isoquinolin-1-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N,N-dimethyl-formamide; at 120℃; for 2.0h;
S4. Take another 2L four-necked flask with 10 ml of N,N-dimethylformamide and add 2.5 g of <strong>[1233025-78-9]8-bromo-1-chloroisoquinoline</strong> with stirring.Afterwards, 10 ml of p-methoxybenzylamine was slowly added. After all the addition, the system was heated to 120 C. and reacted for at least two hours. TLC tracking was performed every 0.5 hours until the reaction was complete.The reaction mixture was poured into 80 ml of water and the product was repeatedly extracted with 80 ml of ethyl acetate until the extraction was complete by TLC. The organic phase was washed with 40 ml of water and washed with 40 ml of saturated brine.Then dried with 15g of anhydrous sodium sulfate, spin-drying, and then using 100 mesh silica gel column to give S4-step product 8-bromo-N-(4-methoxybenzyl)-1-aminoisoquinoline.
1-benzoyl-N-(4-methoxybenzyl)piperidine-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
General procedure: To a solution of compound 3 (233mg, 1.0mmol) in MeCN (4 mL), PyBroP (466mg, 1.0mmol) and Et3N (0.32mL, 2.5mmol) were added and stirred at room temperature for 10 mins. A solution of 3,4-dimethoxybenzylamine (167mg, 1.0mmol) in MeCN (3 mL) was then added and the reaction mixture stirred under microwave irradiation (80W) at 90C for 20min. The solvent was removed under reduced pressure, and the crude mixture was suspended in H2O (20mL) and extracted with dichloromethane (2*20mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 10% ethyl acetate in hexane, followed by 50% ethyl acetate in hexane as eluent to yield.
To a stirred solution of 15-1 (2.0 g, 17.6 mmol) in DCE (50.0 mL) was added 15-2 (2.29mL, 17.6 mmol) and Acetic acid (1 mL, 17.6 mmol) and the reaction mixture was stirred for 1hour. Sodium cyanoborohydride (1.65 g, 26.4 mmol) was then added and the reaction mixture wasstirred at room temperature for 16 hours. It was diluted with 20percent IP A/DCM and organic layer was5 washed with saturated aqueous NaHC03 solution, water, dried over sodium sulfate andconcentrated. Crude material was purified by column chromatography (silica, gradient, 0percent-2.5percentMethnol in DCM) to afford 15-3 as Light yellow gummy solid. Yield-61 percent; LC MS: ES+ 23 5 .2.
2-chloro-6-((4-methoxybenzyl)amino)nicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; at 90℃; for 6h;
6-amino-2-chloronicotinonitrile To a solution of <strong>[40381-90-6]2,6-dichloronicotinonitrile</strong> (6.500 g, 37.6 mmol) at room temperature were added (4-methoxyphenyl)methanamine (5.15 g, 37.6 mmol) and diisopropylethylamine (13.09 mL, 75 mmol). The reaction mixture was heated at 90 C for 6 hours. Intermediate 2-chloro-6-((4-methoxybenzyl)amino)nicotinonitrile was formed as observed by LC/MS analysis: ES [MS] m/z: 273.9 [M+H]+.
methyl 6-(4-methoxybenzylamino)pyridazine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In acetonitrile; at 80℃; for 16h;
To a solution of (4-methoxyphenyl)methanamine (19.9 g, 145 mmol) in acetonitrile (150 ml_) at room temperature was added potassium carbonate (20.0 g, 145 mmol) and <strong>[65202-50-8]methyl 6-chloropyridazine-3-carboxylate</strong> (12.5 g, 72.4 mmol). The reaction mixture was stirred at 80 C for 16 h before it was cooled to room temperature and diluted with water (300 ml_). The aqueous layer was extracted with ethyl acetate (200 ml_ c 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether =1/3) to afford methyl 6-(4-methoxybenzylamino)pyridazine-3-carboxylate (28.0 g, crude) as a light yellow oil. (LCMS (ESI) m/z: 274.1 [M+H]+. Used in the next step directly without additional purification.
N-[(4-methoxyphenyl)methyl]-5-oxotetrahydrofuran-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
To 5-oxotetrahydrofuran-2-carboxylic acid (120 g, 922 mmol) was added SOCl2 (246 g, 2.07 mol) at 0 C. slowly. The mixture was stirred at 85 C. for 3 hrs, and then the mixture was stirred at 15 C. for 6 hrs. The mixture was concentrated in vacuo. The residue was dissolved in dry DCM (1 L) at 0 C. under N2. After that a solution of Et3N (187 g, 1.84 mol) and 4-methoxybenzylamine (101 g, 738 mmol) in DCM (400 mL) was added, then the mixture was stirred at 15 C. for 3 hrs. On completion, water (600 mL) was added and the mixture was extracted with DCM (3×300 mL). The combined organic phase was washed with 0.5 M HCl (500 mL), brine (500 mL), dried over with anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash silica gel chromatography (PE:EA=1:1) to give the title compound (138 g, 60% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 7.22-7.20 (d, J=8.0, 1H), 6.89-6.87 (d, J=8.0, 1H), 4.90-4.86 (m, 1H), 4.47-4.4.36 (m, 2H) 3.81 (s, 3H), 2.67-2.64 (m, 1H), 2.59-2.54 (m, 2H), 2.40-2.38 (m, 1H); LC-MS (ESI+) m/z 272.0 (M+Na)+.
4-Methoxybenzyl amine (114.8 g, 83.728 mol) was added to a stirred solution mixture of <strong>[55583-59-0]4,6-dichloropyrimidine-2,5-diamine</strong> [55583-59-0] (100 g, 55.81 mol) and TEA (169 mL, 167.45 mol) in ethanol (1.0 L) at 0 C. and the resulting reaction mixture was stirred at reflux temperature for 18 h. The solvent was evaporated under reduced pressure, the thick mass was poured into ice cold water and stirred for 30 min. The precipitated solid was collected by filtration, washed with water and dried under vacuum to afford 6-chloro-N4-(4-methoxybenzyl)pyrimidine-2,4,5-triamine (35) (100 g, 64%) as a brown solid. ES+, m/z 280.1 [M+H]+; C12H14ClN50; 1H NMR (500 MHz, DMSO-d6): delta 8.25 (d, J=8.5 Hz, 2H), 6.92 (t, J=6.0 Hz, 1H), 7.87 (d, J=8.5 Hz, 2H), 5.63 (s, 2H), 4.47 (d, J=5.5 Hz, 2H), 3.91 (s, 2H), 3.72 (s, 3H).
6-chloro-4-[(4-methoxyphenyl)methylamino]pyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
In acetonitrile; at 65℃; for 12h;
To a solution of <strong>[166526-03-0]4,6-dichloropyridine-3-carbonitrile</strong> (5.78 mmol, 1000 mg) in MeCN (20 mL) (4-methoxyphenyl)methanamine (8.68 mmol, 1189.4 mg, 1.13 mL) was added and the mixture was stirred at 65C for 12h, a white precipitate was formed. After cooling at room temperature, water and EtAcO were added, the two phases were separated, the organic layer was washed with water and brine, dried over Na2S04, filtered and evaporated. The crude was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether gradient starting from 0: 100 to 30:70. 513 mg of the desired product were obtained as white powder (yield 32 %).
methyl 4-((4-methoxybenzylcarbamoyloxy)methyl)picolinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
150 mg
To a stirred solution of <strong>[317335-15-2]methyl 4-(hydroxymethyl)picolinate</strong> 1 (150 mg, 0.898 mmol) in DMF (2 mL) was added 1,1'-Carbonyldiimidazole (291 mg 1.796 mmol) at room temperature and stirred at RT for 2 h. To the reaction mixture (4- methoxyphenyl)methanamine (246 mg, 1.796 mmol) was added and stirred at 70 C for 16 h. After completion of the reaction, to the mixture was added ice water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The separated organic layer was washed with ice water (2 x 20 mL), brine solution (20 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain crude Methyl 4-((4-methoxybenzylcarbamoyloxy)methyl)picolinate 3 (150 mg, crude). Crude compound was used directly for next step without further purification. TLC system: 70 % Ethyl acetate / hexane; Rf: 0.3; LCMS: m/z = 331.12(M+H)+
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