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Structure of 31576-51-9 * 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.
With hydrazine hydrate In ethanol at 100℃; for 3 h; Reflux
2.2.1.3 Synthesis of 2-(2-methoxyethoxy)ethylamine (2d) A mixture of N-[2-(2-methoxyethoxy)ethyl]phthalimide (2c) (27 mmol) and hydrazine monohydrate (43 mmol) in EtOH (30 mL) was refluxed at 100 °C for 3 h. After cooling down to room temperature, the mixture was filtered and the filtrate was evaporated. Acetone (50 mL) was added to the residue and the precipitate was filtered. Subsequently, the filtrate was concentrated under reduced pressure.2d was obtained as an orange oil. Yield: 62percent. 1H NMR (500 MHz, CDCl3): δ 1.83 (s, 1H), 2.00 (s, 1H), 2.15 (s, 1H), 2.87 (t, J = 5.3 Hz, 1H), 3.35-3.39 (m, 2H), 3.41 (t, J = 6.4 Hz, 1H), 3.50 (t, J = 5.3 Hz, 1H), 3.52-3.55 (m, 2H), 3.60 (dd, J = 5.7, 3.3 Hz, 1H), 3.64 (dd, J = 5.6, 3.8 Hz, 1H), 3.73 (t, J = 6.5 Hz, 1H) ppm; HR ESI-MS (in MeOH): m/z [M+H]+ Calc. 120.0973, found 120.1047.
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 6, p. 1683 - 1691
[2] Journal of Organic Chemistry, 2010, vol. 75, # 3, p. 598 - 610
[3] Inorganica Chimica Acta, 2016, vol. 452, p. 159 - 169
[4] Patent: WO2009/109035, 2009, A1, . Location in patent: Page/Page column 57-58
2
[ 111-77-3 ]
[ 31576-51-9 ]
Yield
Reaction Conditions
Operation in experiment
44%
Stage #1: With phthalimide; triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at 20℃; Stage #2: With hydrazine hydrate In ethanolReflux
Diethylene glycol monomethyl ether (3.9 mL, 33.3 mmol) and diethyl azodicarboxylate (2.2 mol/L toluenesolution) (15.5 mL, 34.1 mmol) were added to a solution of phthalimide (4.90 g, 34.2 mmol) and triphenylphosphine(9.00 g, 34.2 mmol) in tetrahydrofuran (180 mL) at room temperature, and stirred overnight. To the resulting solution,ethanol (60 mL) was further added, stirred at room temperature for 30 minutes, and then the solvent was distilled awayunder a reduced pressure. Ethyl acetate (50 mL) and hexane (50 mL) were added to the residue, and insolubles werefiltered off. After the filtrate was concentrated under a reduced pressure, ethanol (120 mL) and hydrazine monohydrate(2.4 mL, 68.6 mmol) were added, and stirred under heat reflux overnight. After this solution was cooled to room temperature,concentrated hydrochloric acid (15 mL) was added, and stirred under heat reflux for 1 hour. After this solutionwas cooled to room temperature, insolubles were filtered off, and the filtrate was concentrated under a reduced pressure.Water was added to the residue, which was washed with diethyl ether. The aqueous layer was adjusted to pH = 13 witha 3N sodium hydroxide aqueous solution, and extraction was carried out with dichloromethane. The organic layer wasdried with anhydrous sodium sulfate, the solvent was distilled away under a reduced pressure to obtain the title compound(1.74 g, 44percent) as a pale yellow oily matter.1H NMR (400 MHz, CDCl3) δ 3.64-3.61 (2H, m), 3.57-3.55 (2H, m), 3.51 (2H, t, J = 5.2 Hz), 3.39 (3H, s), 2.89-2.87 (2H, m).
Reference：
[1] Patent: EP3127900, 2017, A1, . Location in patent: Paragraph 0142; 0143
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 7, p. 1381 - 1384
[3] Journal of the American Oil Chemists' Society, 1996, vol. 73, # 1, p. 79 - 86
[4] Journal of Medicinal Chemistry, 1995, vol. 38, # 7, p. 1067 - 1083
[5] Journal of the American Chemical Society, 1994, vol. 116, # 12, p. 5057 - 5062
[6] J. Gen. Chem. USSR (Engl. Transl.), 1970, vol. 40, p. 1598 - 1602[7] Zhurnal Obshchei Khimii, 1970, vol. 40, # 7, p. 1611 - 1616
[8] Chemische Berichte, 1979, vol. 112, p. 1392 - 1399
[9] Journal of Organic Chemistry, 2011, vol. 76, # 6, p. 1683 - 1691
[10] Angewandte Chemie - International Edition, 2012, vol. 51, # 5, p. 1152 - 1155
[11] Patent: EP2439204, 2012, A1,
[12] Macromolecules, 2012, vol. 45, # 12, p. 5151 - 5156
[13] Inorganica Chimica Acta, 2016, vol. 452, p. 159 - 169
[14] Journal of the American Chemical Society, 2017, vol. 139, # 17, p. 6234 - 6241
[15] MedChemComm, 2017, vol. 8, # 3, p. 662 - 672
[16] Patent: WO2009/109035, 2009, A1,
3
[ 215181-61-6 ]
[ 31576-51-9 ]
Reference：
[1] Journal of the American Oil Chemists' Society, 1996, vol. 73, # 1, p. 79 - 86
[2] Macromolecules, 2012, vol. 45, # 12, p. 5151 - 5156
[3] MedChemComm, 2017, vol. 8, # 3, p. 662 - 672
[4] Journal of the American Chemical Society, 1994, vol. 116, # 12, p. 5057 - 5062
[5] Journal of Medicinal Chemistry, 1995, vol. 38, # 7, p. 1067 - 1083
[6] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 7, p. 1381 - 1384
[7] Patent: EP2439204, 2012, A1, . Location in patent: Page/Page column 52
[8] Macromolecules, 2012, vol. 45, # 3, p. 1362 - 1374
4
[ 50586-80-6 ]
[ 31576-51-9 ]
Reference：
[1] European Journal of Organic Chemistry, 2010, # 21, p. 3991 - 4003
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 7, p. 1381 - 1384
[3] Journal of the American Oil Chemists' Society, 1996, vol. 73, # 1, p. 79 - 86
[4] Journal of the American Chemical Society, 1994, vol. 116, # 12, p. 5057 - 5062
[5] Journal of Organic Chemistry, 2011, vol. 76, # 6, p. 1683 - 1691
[6] Angewandte Chemie - International Edition, 2012, vol. 51, # 5, p. 1152 - 1155
[7] Patent: EP2439204, 2012, A1,
[8] Macromolecules, 2012, vol. 45, # 3, p. 1362 - 1374
[9] Macromolecules, 2012, vol. 45, # 12, p. 5151 - 5156
[10] Inorganica Chimica Acta, 2016, vol. 452, p. 159 - 169
3) Synthesis of AD25-04 1.0 g of (6.9 mmol) of AD25-03 in 60 mL of tetrahydrofuran (THF) was heated with 0.5 mL of water and 9 g (10 mmol) of triphenylphosphine polystyrene for 2.5 hours with reflux. The reaction solution was allowed to cool, and the resin was filtered off and washed with 100 mL of ethyl acetate. After combined with the washings, the filtrate was concentrated under reduced pressure to obtain 896 mg of AD25-04.
N-(2-[4-(2-{6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl}ethyl)phenyl]carbamoyl}-4-{2-[2-methoxyethoxy]ethylamino}phenyl)quinoline-3-carboxamide[ No CAS ]
10-[2-(2-methoxyethoxy)ethyl]-7,8-dimethyl-3-[2-oxo-2-(1,4,7,10-tetraazacyclododec-1-yl)-ethyl]-10H-benzo[g]pteridine-2,4-dione trifluoroacetic acid salt (1:3)[ No CAS ]
Diethylene glycol monomethyl ether (3.9 mL, 33.3 mmol) and diethyl azodicarboxylate (2.2 mol/L toluenesolution) (15.5 mL, 34.1 mmol) were added to a solution of phthalimide (4.90 g, 34.2 mmol) and triphenylphosphine(9.00 g, 34.2 mmol) in tetrahydrofuran (180 mL) at room temperature, and stirred overnight. To the resulting solution,ethanol (60 mL) was further added, stirred at room temperature for 30 minutes, and then the solvent was distilled awayunder a reduced pressure. Ethyl acetate (50 mL) and hexane (50 mL) were added to the residue, and insolubles werefiltered off. After the filtrate was concentrated under a reduced pressure, ethanol (120 mL) and hydrazine monohydrate(2.4 mL, 68.6 mmol) were added, and stirred under heat reflux overnight. After this solution was cooled to room temperature,concentrated hydrochloric acid (15 mL) was added, and stirred under heat reflux for 1 hour. After this solutionwas cooled to room temperature, insolubles were filtered off, and the filtrate was concentrated under a reduced pressure.Water was added to the residue, which was washed with diethyl ether. The aqueous layer was adjusted to pH = 13 witha 3N sodium hydroxide aqueous solution, and extraction was carried out with dichloromethane. The organic layer wasdried with anhydrous sodium sulfate, the solvent was distilled away under a reduced pressure to obtain the title compound(1.74 g, 44%) as a pale yellow oily matter.1H NMR (400 MHz, CDCl3) delta 3.64-3.61 (2H, m), 3.57-3.55 (2H, m), 3.51 (2H, t, J = 5.2 Hz), 3.39 (3H, s), 2.89-2.87 (2H, m).
With trifluoroacetic acid; In dichloromethane; for 0.5h;
Di-tert-butyl dicarbonate (11 g) was added to a solution of 2-(2-hydroxy-ethoxy)-ethylamine (5.3 g) in methylene chloride (200 mL). After 1 hour, the solvents were evaporated to provide the N-tert-butoxycarbonyl derivative (10.5 g). The Boc-protected intermediate (1.0 g) was dissolved in 50 mL THF, cooled to 0 C., and treated with NaH (60% w/w in mineral oil, 0.6 g) followed by iodomethane (0.3 mL). The mixture was stirred for 3 hours at 0 C., then quenched by the addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl ether (2×100 mL) and the extracts washed with brine (1×100 mL). The crude residue isolated from the extracts was chromatographed on silica gel (30% ethyl acetate in hexanes) to provide 0.4 g of N-(tert-butyloxycarbonyl)-2-(2-methoxyethoxy) ethylamine. The Boc group was removed by dissolving the compound in 1:1 methylene chloride/TFA and stirring for 0.5 h, then evaporating the solvent to give 2-(2-methoxyethoxy) ethylamine.
N-[2-(2-Methoxyethoxy)ethyl]-1H-imidazole-1-carboxamide[ No CAS ]
2-(4-Morpholinyl)ethyl 1H-imidazole-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
Preparation U N-[2-(2-Methoxyethoxy)ethyl]-1H-imidazole-1-carboxamide The title compound was prepared in 40% yield according to the procedure described in Preparation S above, using <strong>[31576-51-9]2-(2-methoxyethoxy)ethylamine</strong> in place of 2-(4-morpholinyl)-1-ethanol.
PRODUCTION EXAMPLE 7 2-(2-methoxyethoxy)ethylguanidine 5.96 g (50.0 mmol) of <strong>[31576-51-9]2-(2-methoxyethoxy)ethylamine</strong> and 3.00 g (50.0 mmol) of acetic acid were placed in a 30 ml two neck flask. While heating the flask in a 90 C. oil bath, 3.10 g (73.7 mmol) of cyanamide was added. After 5 hours of the reaction, the product was purified by a silica gel column chromatography (eluent, chloroform/ethanol=2/1 containing 0.5% acetic acid) to obtain 3.15 g of the title compound (wax-like, 14.2 mmol, 28.5% in yield) in the form of acetate. Results of the analysis of this compound are as follows. 1 H-NMR (200 MHz, D2 O, TSP standard): delta 3.8 - 3.6 (m, 6 H), 3.45 - 3.30 (m, 5 H), 1.92 (s, 3 H) 13 C-NMR (50 MHz, D2 O, TSP standard) delta: 183.70, 160.06, 73.72, 72.24, 71.54, 60.77, 43.92, 26.06 IR (KBr, cm-1): 3348, 3104, 3084, 1686, 1650, 1554, 1456, 1406, 1356, 1304, 1246, 1202, 1100, 1018, 920, 846, 800, 760, 648
2.55 g (20 mmol) of oxalyl chloride are added to 10 g (16.5 mmol) of the title compound from Example 1a in 100 ml of dichloromethane and the mixture is stirred at room temperature for 14 h. It is evaporated to dryness in vacuo, the residue is dissolved in 100 ml of dichloromethane, 3.93 g (33 mmol) of 2-(methoxyethoxy)ethylamine (Whitesides et al., JACS, 1994, 5057-5062) are added and the mixture is subsequently stirred at room temperature for 4 h. The reaction solution is treated with 100 ml of 1 N hydrochloric acid, and thoroughly stirred for 15 min. The organic phase is separated off, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (eluent: ethyl acetate/hexane 1:1). Yield: 11.2 g (96% of theory) of a colourless wax
A suspension of carbaldehyde 325 (0.50 g, 1 3 mmol), amine 326 (0 30 g, 2 5 mmol) and acetic acid (0 14 ml, 2 5 mmol) in dichloromethane (20 ml) was stirred for 1 h at room <n="60"/>temperature. Then sodium triacetoxyborohydride (0.80 g, 3.8 mmol) was added and stirred at r.t. for 16 h. A further amount of sodium triacetoxyborohydride (1.0 g) was then added, and stirring continued for 2 h. The reaction mixture was partitioned between dichloromethane and IN NaOH. The yellow suspension was removed by filtration and rinsed with dichloromethane and IN NaOH. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; Snap lOOg column) to yield 327 (280 mg, 0.562 mmol, 44 %) as a yellow solid. LRMS (M+H): 499.4
With hydrazine hydrate; In ethanol; at 100℃; for 3h;Reflux;
2.2.1.3 Synthesis of 2-(2-methoxyethoxy)ethylamine (2d) A mixture of N-[2-(2-methoxyethoxy)ethyl]phthalimide (2c) (27 mmol) and hydrazine monohydrate (43 mmol) in EtOH (30 mL) was refluxed at 100 C for 3 h. After cooling down to room temperature, the mixture was filtered and the filtrate was evaporated. Acetone (50 mL) was added to the residue and the precipitate was filtered. Subsequently, the filtrate was concentrated under reduced pressure.2d was obtained as an orange oil. Yield: 62%. 1H NMR (500 MHz, CDCl3): delta 1.83 (s, 1H), 2.00 (s, 1H), 2.15 (s, 1H), 2.87 (t, J = 5.3 Hz, 1H), 3.35-3.39 (m, 2H), 3.41 (t, J = 6.4 Hz, 1H), 3.50 (t, J = 5.3 Hz, 1H), 3.52-3.55 (m, 2H), 3.60 (dd, J = 5.7, 3.3 Hz, 1H), 3.64 (dd, J = 5.6, 3.8 Hz, 1H), 3.73 (t, J = 6.5 Hz, 1H) ppm; HR ESI-MS (in MeOH): m/z [M+H]+ Calc. 120.0973, found 120.1047.
Diethyl ene glycol monomethyl ether (9 8 mL, 83 mmol), phthalimide (14 7 g, 100 mmol), and t?phenylphosphine (26.2 g, 100 mmol) were suspended in dry tetrahydrofuran (200 mL) to give a colorless suspension (see scheme 18, step 3). Diethyl azodicarboxylate (15.8 mL, 100 mmol) was added dropwise by syringe, and the mixture was stirred at r t for 18 h. Then ethanol (50 mL) was added, the mixture was stirred for a further 30 mm and then concentrated under reduced pressure The residue was dissolved in 1.1 ethyl acetate/hexanes (100 mL), stirred at 00C for 2h, and the resulting white precipitate was removed by suction filtration The filtrate was concentrated and used in the next step without further purification.The above crude product was dissolved in ethanol (200 mL) to give a colorless solution. Hydrazine hydrate (5 1 mL, 104 mmol) was added and the mixture was heated to reflux for 4 h It was then cooled, concentrated HCl (16 mL) was added, and the mixture reflux ed for 1 hour more It was then was cooled to r t , the white precipitate removed by suction filtration, and the filtrate concentrated. The residue was partitioned between water and ethyl acetate The aqueous phase was extracted with ethyl acetate (organic phase, containing mostly PPI13O byMS, was discarded), then basified with 3M NaOH (50 mL) to pH=13 The aqueous phase was saturated with sodium chloride and extracted repeatedly with dichloromethane (~10 x 50 mL. The organic extract was dried (MgSC^) and concentrated to yield 326 (6 6 g, 56 mmol, 67 % yield over 2 steps). This was used without further purification in subsequent reaction.. MS (m+l) = 120.2
Compound 1 (SylA-OCH3, 10 mg, 20 mumol, 1 eq.) was dissolved in ethylmethyl sulfite (500 muL) and trichloro aluminium (13 mg, 100 mumol, 5 eq.) was added in one portion. The mixture was stirred for 10 h and quenched with some drops of water. After concentration, a solution of <strong>[31576-51-9]2-(2-methoxyethoxy)ethanamine</strong> (4.8 mg, 40 mumol, 2 eq.), PyBOP (26 mg, 50 mumol, 2.5 eq.), HOAt (7 mg, 50 mumol, 2.5 eq.) and DIEA (14 muL, 80 mumol, 4 eq.) in DMF (500 muL) was added. The resulting mixture was stirred overnight and concentrated to be purified by preparative HPLC to yield 2.8 mg (4.7 mumol, 24%) of compound 3 (SylA-PEG1) as a colorless solid.
3) O-(2-Aminoethyl)-O'-methylpolyethylene glycol 1100 4.3 g of O-(2-azidoethyl)-O'-methylpolyethylene glycol 1100 and 0.4 g of Pd/C (5%) in solution in 100 ml of ethanol are introduced into an autoclave. The reaction is carried out under a hydrogen pressure of 2.5 bar, at 25 C., for 4 hours. The catalyst is removed by filtration over celite. After evaporation, 3.5 g are thus isolated with a yield of 85%. TLC: Merck SiO2 eluent: dichloromethane/methanol: 9/1. Detection: "Primary amine" specific ninhydrin Infrared: 3390 cm-1 (v NH2)
39
[ 885524-15-2 ]
[ 31576-51-9 ]
[ 1175086-32-4 ]
Yield
Reaction Conditions
Operation in experiment
56.8%
In ethanol; at 25 - 30℃;Reflux;
Example-6 Preparation of [1-(3,5-Dimethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl]-[2-(2-methoxy-ethoxy)-ethyl]-amine (Compound No. 51) 60.0 ml of ethanol and 10.0 g (0.038 mol) of 4-chloro-1-(3,5-dimethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound No. 79) were charged into a 250 ml of 4 necked round bottom flask connected to a mechanical stirrer, thermometer socket, condenser and addition funnel. 22.40 g (0.18 mol) of 2-(2-Methoxy-ethoxy)-ethyl amine was charged at 25-30 C. under stirring. Reaction mass temperature was raised to reflux. Maintained the mass temperature at reflux for 5 hours. Reaction mass temperature was cooled to 25-30 C. Maintained the mass temperature at 25-30 C. for 60 min. Reaction mass temperature cooled to 0-5 C. Maintained the mass temperature at 0-5 C. for 60 min. Solid does not formed. Distilled off Ethanol completely under vacuum. Crude oily mass was obtained. Oily mass was dissolved in 45 ml of acetonitrile. 300.0 ml of isopropyl ether was added. Solid was formed. Solid was filtered and solid was washed with 50.0 ml of isopropyl ether. Compound was dried under vacuum at 60-65 C. Dry weight of the compound: 7.50 g (yield-56.80%). Melting point: 90.4 C.Purity by HPLC is 99.76%.Spectral data:FT-IR (K Br) (cm-1): 3537, 3362, 3265, 3132, 3050, 3012, 2915, 2883, 2872, 1627, 1602, 1568, 1528, 1479, 1389, 1201, 1166, 1134, 980, 929, 886, 684400 MHz NMR (DMSO-d6) delta value (ppm): 2.35 s (2CH3),3.22 s (O-CH3),3.31 d(O-CH2-CH2),3.43-3.56 t (NH-CH2),3.61-3.69 t (O-CH2),6.96 s (Ar-Ha,Hb),7.80 s (Ar-Hc),8.37 s (Hd), 8.38 t (NH),8.54 d (He).13C NMR: delta value (ppm): 21.03(2C),40.01(1C), 57.99(1C)68.79(1C),69.48(1C),71.21(1C), 101.76(1C), 118.29(2C), 127.44(1C), 133.40(1C), 138.21(2C), 138.87(1C), 152.72(1C), 156.33(1C), 156.54(1C).MS: 342[M+1]
With ammonia; In methanol; at 120 - 130℃; for 4h;Sealed tube;
Example-10 Preparation of 2-(2-Methoxy-ethoxy)-ethyl amine (Compound No: 84) 180.0 g (0.69 mol) of benzene sulfonic acid 2-(2-methoxy-ethoxy)-ethyl ester (Compound No. 79) and 600.0 ml of methanolic ammonia were charged into 1.0 L pressure sealed kettle. Reaction mass was heated to 120-130 C. under sealed conditions. Reaction mass temperature was maintained at 120-130 C. for 4 hours. Reaction mass temperature was cooled to 25-30 C. and methanol was completely distilled under vacuum. Remaining mass was diluted with 75.0 ml of water and mass pH was adjusted to 1 to 2 with 5.0 ml of conc. hydrochloric acid. Reaction mass was washed with 200.0 ml of methylene chloride. Again aqueous layer pH was adjusted to 9-10 with 130.0 ml of aqueous ammonia solution. Compound was extracted with 300.0 ml of methylene chloride and organic layer was dried with sodiumsuiphate. Methylenechloride was completely distilled and finally applied vacuum at below 50 C. Crude oil weight was 39.60 g (yield: 48.1%). Spectral data: FT-IR (neat) (cm-1): 3369.7, 2876.4, 1584.8, 1457.2, 1354.2, 1304.3, 1245.3, 1029.7, 849.3, 578.2 MS: 120.1 [M+1]
With potassium carbonate; In ISOPROPYLAMIDE; at 120℃; for 72h;Inert atmosphere;
A mixture of 5-chloro-2-mtroaniline (1.6 g, 9.3 mmol), 2-(2-methoxy-ethoxy)- ethylamine (2.0 g, 16.8 mmol) and anhydrous potassium carbonate (1.38 g, 10 mmol) in .YN-dimemylacetarnide (3 ml) was stirred at 120 C under nitrogen for 3 days. Sample NMR analysis showed 80% conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water (30 ml) and extracted with ethyl acetate. The organic extract was washed with brine, dried and evaporated. The resulting orange yellow oil was subjected to a silica gel filtration on a 5 cm x 6cm silica gel plug, eluting first with 50% ethyl acetate / petroleum spirits (40-60C), followed by 100% ethyl acetate. Evaporation yielded an orange-red liquid, 1.1 g (45.8% yields). NMR (400 MHz, CDC13) delta 3.2, q (J=5.28 Hz), 2H; 3.34, s, 3H; 3.5, m, 2H;3.6, m, 2H; 3.65 , t (J=5.1 Hz), 2H; 5.6, d (J=2.54 Hz), 1H; 5.9, dd (J=2.35, 7.03 Hz), 1H, 6.20 broad s , 2H; 7.87, d (J=9.4 Hz), 1H
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 5h;
4) Synthesis of AD25-05 896 mg of AD25-04 in 35 mL of methylene chloride was stirred with 2.08 g (8.28 mmol) of separately synthesized AD14-02 and 1.59 g (8.28 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) at room temperature for 5 hours. The reaction solution was diluted with 70 mL of methylene chloride, washed with 20 mL of 1 mol/L hydrochloric acid, 20 mL of water, 20 mL of saturated aqueous sodium hydrogen carbonate, 20 mL of water and 20 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by intermediate pressure silica gel chromatography (silica gel 100 g, hexane : ethyl acetate = 50:50 to 0:100) to obtain 1.33 g (3.8 mmol, overall yield over two steps 55%) of AD25-05.
To a solution of 4-thioxo-l, 3-thiazolidin-2-one (2.24 g) in ethanol (20 mL) was added 2- (2-methoxyethoxy) ethanamine (2.5 g), and the mixture was stirred at room temperature for 5 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(ethyl acetate) to give the title compound (3.1 g) .XH NMR (300 MHz , CDC13) delta 3.43 (3H, s) , 3.48-3.63 (2H, m) , 3.63-3.83 (6H, m) , 4.13 (2H, s) , 6.83 (1H, brs) .MS (ESI+) : [M+H]+ 219.1.
With N-ethyl-N,N-diisopropylamine; In dichloromethane;Inert atmosphere;
In a round bottom flask under nitrogen 150 mg (0.35 mmol) of intermediate Awas dissolved in 5 mL ofCH2Ch and 0.18g of DIPEA (1.4 mmol) was added followed by 125 mg (1.05 mmol) of2-(2-Methoxy-ethoxy)-ethylamine. The mixture was allowed to stirovernight and then condensed in vacuo. The residue was dissolved in 20 mL of EtOAc andwashed with 2x 20 mL of water, 20 mL of brine, dried over Na2S04 and condensed in vacuo.Purification by biotage flash chromatography (Si02, MeOH/CH2Ch/Et3N gradient) affords 99mg of the title compound as a clear oil
3-((4-((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-ethynylbenzoic acid[ No CAS ]
tert-butyl (4-((2-((3-ethynyl-5-((2-(2-methoxyethoxy)ethyl)carbamoyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
530 mg
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 3h;
HATU (422 mg, 1.110 mmol) was added to a stirred solution of the product from step (iii) (500 mg, 1.009 mmol), <strong>[31576-51-9]2-(2-methoxyethoxy)ethanamine</strong> (180 mg, 1.514 mmol) and Huenig's Base (529 muL, 3.03 mmol) in DMF (10 mL) at rt. The mixture was stirred for 3 h then partitioned between EtOAc (100 mL) and aq sat NaHCO3 soln (50 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (40 g column, 20-100% EtOAc/isohexane) to afford the sub-title compound (530 mg) as a foam. 1H NMR (CDCl3) 400 MHz, delta: 8.06 (d, 1H), 7.96-7.93 (m, 2H), 7.80-7.76 (m, 2H), 7.70 (s, 1H), 7.60-7.48 (m, 2H), 7.41 (s, 1H), 7.18 (d, 1H), 6.89 (s, 1H), 6.83-6.76 (m, 2H), 6.42 (dd, 1H), 6.20 (d, 1H), 3.67-3.53 (m, 8H), 3.36 (s, 3H), 3.07 (s, 1H), 1.57 (s, 9H). LCMS m/z 597 (M+H)+ (ES+); 595 (M-H)- (ES-)
530 mg
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 3h;
HATU (422 mg, 1.110 mmol) was added to a stirred solution of the product from step (iii) (500 mg, 1.009 mmol), <strong>[31576-51-9]2-(2-methoxyethoxy)ethanamine</strong> (180 mg, 1.514 mmol) and Hunig?s Base (529 pL, 3.03 mmol) in DMF (lOmL) at rt. The mixture was stirred for 3h then partitioned between EtOAc (lOOmL) and aq sat NaHCO3 soln (5OmL). The organic layer was washed with brine (5OmL), dried (MgSO4), filtered and evaporated under reduced pressure.The residue was purified by chromatography on silica gel (40 g column, 20-100%EtOAc/isohexane) to afford the sub-title compound (530 mg) as a foam.1H NMR (ODd3) 400 MHz, O: 8.06 (d, 1H), 7.96-7.93 (m, 2H), 7.80-7.76 (m, 2H), 7.70 (5,1H), 7.60-7.48 (m, 2H), 7.41 (5, 1H), 7.18 (d, 1H), 6.89 (5, 1H), 6.83-6.76 (m, 2H), 6.42 (dd,1H), 6.20 (d, 1H), 3.67-3.53 (m, 8H), 3.36 (5, 3H), 3.07 (5, 1H), 1.57 (5, 9H).LCMS mlz 597 (M+H) (ES); 595 (M-H (ES)
3-amino-5-bromo-N-(2-(2-methoxyethoxy)ethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
880 mg
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; N,N-dimethyl-formamide; at 20℃;Cooling with ice;
(i) 3-Ami no-5-bromo-N-(2-(2-methoxyethoxy)ethyl)benzamideA stirred mixture of <strong>[42237-85-4]3-amino-5-bromobenzoic acid</strong> (800 mg, 3.59 mmol), 2-(2- methoxyethoxy)ethanamine (856 mg, 7.18 mmol) and Et3N (1.5 mL, 10.76 mmol) in DCM (13mL) was cooled in an ice bath. T3P (50 w/w in EtOAc, 3.2 mL, 5.38 mmol) was added dropwise, the ice bath was removed and the reaction mixture allowed to warm to room temperature. DMF (2 mL) was added to aid solubility and the reaction stirred at room temperature overnight. The reaction mixture was partitioned between sat. aq. NaHCO3 (50 mL) and DCM (50 mL). The aqueous phase was back extracted with fresh DCM (50 mL).The combined organic extracts were washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to afford an orange oil. The crude product was purified by chromatography on silica gel (40 g column, 0-5% MeOH) to afford the sub-title compound (880 mg) as an orange oil.1H NMR (DMSO-d6) 400 MHz, O: 8.36 (t, 1H), 7.07 (t, 1H), 7.00-6.99 (m, 1H), 6.84 (t, 1H),5.57 (s, 2H), 3.53-3.48 (m, 4H), 3.44-3.42 (m, 2H), 3.35 (q, 2H), 3.23 (s, 3H). LCMS m/z 317/319 (M÷H) (ES)
3-((4-((4-(3-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)-pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-methoxyethoxy)ethyl)benzamide[ No CAS ]
To a 10 mL MeOH:water (10:1, v/v) solution of compound 20 (1.0 g, 1.75 mmol) was added LiOH.H20 (0.147 g, 3.50 mmol) and stirred for 2 h at RT. After thedisappearance of the starting material 20 (TLC analysis), the mixture was neutralized with acidic resin. Resin was filtered off and removal of MeOH yielded crude acid. The crude acid (0.900 g) was dissolved in DMF (10 mL) and NH2CH2CH2OCH2CH2OCH3 (0.571 g, 4.85 mmol), benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (1.68 g, 3.23 mmol), DIPEA (0.86 mL, 4.85 mmol) were added successively at 0C. The mixture was stined for 16 h at RT under nitrogen atmosphere. The mixture was diluted with cold water (50 mL), extracted with 10% butanol in ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel) usingDCM/MeOH. Compound 24 was obtained in 46% yield (0.49 g) with 90% UPLC purity; ?HNMR (300 MHz, DMSO-d6): oe 10.00 (s, 1H), 8.05 (d, J = 7.40 Hz, 1H), 7.95-7.85 (m, 1H),7.51-7.59 (m, 1H), 7.38-7.25 (m, 7H), 6.11 (d, J= 1.80 Hz, 1H), 6.09-6. 10 (m, 1H), 5.38 (d,J= 12.60 Hz, 2H), 5.02 (s, 2H), 4.83 (d, J= 4.50 Hz, 1H), 4.34-4.45 (m, 1H), 4.16-4.27 (m,1H), 3.81-3.90 (m, 1H), 3.55 (t, J = 1.80 Hz, 2H), 3.46 (t, J = 3.30 Hz, 2H), 3.41-3.24 (m,4H), 3.23 (s, 3H), 3.01-2.91 (m, 2H), 2.01-1.90 (m, 2H), 1.69-1.31 (m, 4H), 0.82-0.87 (m,6H); MS calcd. for C321-L16N609: 658.3, Found: 659.7 (M + 1).
With sodium tris(acetoxy)borohydride; acetic acid; In tetrahydrofuran; methanol; at 20℃; for 48h;Inert atmosphere;
General procedure: Pyridine-2-aldehyde and acetic acid were added to a solution ofthe respective amino ether (1a, 2d, 3e, 4b, 5c) in dry THF/MeOHunder argon atmosphere. Subsequently sodium triacetoxy borohydridewas added to the mixture. The reaction mixture was stirredat room temperature for 48 h. The solvent was removed underreduced pressure. The residue was dissolved in DCM and washedwith a saturated aqueous NaHCO3 solution (2 100 mL). Theorganic phase was dried over Na2SO4, filtered and evaporatedunder reduced pressure.
To a solution of 2-(2-methoxyethoxy)ethan-1-amine (1.04 g, 8.72mmol, 1.10 eq) was added N,N-di-CBZ-1H-pyrazole-1-carbamidine (3.00 g, 7.93 mmol, 1.00eq) at 15 C. The mixture was stirred at 15C for 16 hrs. The reaction mixture wasconcentrated in vacuo. The residue was purified by silica gel column to give Compound 61(2.2 g) as colorless oil.?H NMR 400 MHz CDC13: oe 11.74 (s, 1H), 8.65 (s, 1H), 7.42-7.28 (m, 1OH), 5.20 (s, 2H), 5.14 (s, 2H), 3.68-3.64 (m, 6H), 3.59-3.58 (m, 2H), 3.41 (s, 3H).
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