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Structure of 76-83-5 * 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.
Synthesized in the following manner according to literature [Nucleosides Nucleotides, 8, 1529-1535 (1989)]: In a stream of nitrogen, triphenylmethyl chloride (15 g, 53.7 mmols) was added to a pyridine (40 ml) solution of thymidine (10 g, 41.3 mmols) at room temperature, and the mixture was stirred for 21.5 hours at room temperature. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the system was extracted with a methylene chloride solution. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:1)* to obtain Compound 41 (19.4 g, 97.1percent) as a colorless acicular substance.
48%
at 65℃; for 16 h; Inert atmosphere
In a 25ml round bottom flask 100mg (0.39mmol) of4was evaporated 3 times with 3mL of dry pyridine and dissolved in 3mL of dry pyridine. Trityl chloride (120.0mg, 0.43mmol) was added and the reaction mixture was heated at 65°C for 16h under argon atmosphere. After 16h, the mixture was cooled to room temperature, quenched with 3mL of MeOH and stirred for 30min. The mixture was evaporated to dryness. The obtained crude compound was purified by column chromatography to obtain 92mg (48percent) of17. TLC (CH2Cl2/MeOH, 9:1):Rf=0.70.1H NMR (500MHz, CDCl3):δ8.61 (bs, 1H), 7.56 (s, 1H), 7.42–7.26 (m, 15H), 6.42–6.40 (m, 1H, H-1′), 4.58 (s, 1H), 4.20–4.10 (m, 1H), 3.49–3.46 (m, 1H), 3.40–3.37 (m, 1H), 2.44–2.40 (m, 1H, H-2′/H-2″), 2.34–2.30 (m, 1H, H-2′/H-2″), 1.48 (s, 3H, 5-CH3).13C NMR (125MHz, CDCl3):δ163.6, 150.3, 143.3, 135.5, 128.6, 128.2, 128.0, 127.5, 111.3, 87.5, 86.0, 84.6, 72.4, 70.7, 63.7, 40.9, 11.9; HRMS (EI+): m/z for [C42H48N4O10Na]+, calcd. 507.1890; found 507.1907.
Reference：
[1] Patent: EP1486504, 2004, A1, . Location in patent: Page 27; 28; 29
[2] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 6, p. 2819 - 2828
[3] Journal of Nanoscience and Nanotechnology, 2013, vol. 13, # 7, p. 4593 - 4600
[4] Journal of Pharmaceutical Sciences, 1985, vol. 74, # 3, p. 246 - 249
[5] Organic and Biomolecular Chemistry, 2010, vol. 8, # 2, p. 391 - 397
[6] Tetrahedron Letters, 2003, vol. 44, # 2, p. 293 - 297
[7] Tetrahedron Letters, 1999, vol. 40, # 9, p. 1787 - 1790
[8] Tetrahedron Letters, 1992, vol. 33, # 19, p. 2645 - 2648
[9] European Journal of Medicinal Chemistry, 2014, vol. 76, p. 98 - 109
[10] Journal of Fluorine Chemistry, 1991, vol. 55, # 3, p. 283 - 289
[11] Nucleosides and Nucleotides, 1995, vol. 14, # 1-2, p. 209 - 218
[12] Journal of Medicinal Chemistry, 1995, vol. 38, # 14, p. 2672 - 2680
[13] Synthetic Communications, 2000, vol. 30, # 21, p. 3873 - 3882
[14] Tetrahedron Letters, 2003, vol. 44, # 47, p. 8571 - 8575
[15] Journal of the Chemical Society, 1953, p. 951,954
[16] Journal of Biological Chemistry, 1935, vol. 109, p. 623,626
[17] Journal of the American Chemical Society, 1958, vol. 80, p. 6212,6220
[18] Journal of Organic Chemistry, 2006, vol. 71, # 15, p. 5774 - 5777
[19] Patent: US4788181, 1988, A,
[20] Patent: US2004/110720, 2004, A1,
[21] Patent: US7544794, 2009, B1, . Location in patent: Page/Page column 12
[22] Journal of Medicinal Chemistry, 2010, vol. 53, # 10, p. 4130 - 4140
[23] Journal of Medicinal Chemistry, 2010, vol. 53, # 19, p. 7156 - 7166
[24] Chinese Chemical Letters, 2011, vol. 22, # 8, p. 899 - 902
[25] Heterocyclic Communications, 2015, vol. 21, # 5, p. 291 - 295
2
[ 76-83-5 ]
[ 50-89-5 ]
[ 7791-71-1 ]
[ 52417-07-9 ]
Reference：
[1] ChemistryOpen, 2016, vol. 5, # 3, p. 227 - 235
[2] European Journal of Medicinal Chemistry, 2013, vol. 65, p. 249 - 255
3
[ 76-83-5 ]
[ 16053-52-4 ]
[ 7791-71-1 ]
Reference：
[1] Journal of Organic Chemistry, 2016, vol. 81, # 22, p. 10742 - 10758
4
[ 76-83-5 ]
[ 50-89-5 ]
[ 73189-04-5 ]
[ 7791-71-1 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1992, vol. 29, # 6, p. 1405 - 1407
5
[ 288-32-4 ]
[ 76-83-5 ]
[ 15469-97-3 ]
Yield
Reaction Conditions
Operation in experiment
95.6%
Stage #1: With triethylamine In N,N-dimethyl-formamide at 0℃; for 0.5 h; Large scale Stage #2: at 0 - 15℃; for 16 h; Large scale
Compound XIII (880g, 12.9mol, 1.0eq.) In the autoclave 50L, 12L DMF were dissolved, cooled To below 0 °C, triethylamine (1308g, 12.9mol, 1.0eq. ) The reaction was kept 30min, 0 ° C solution of the following threePhenyl chloride (3605.0g, 12.9mol, 1.0eq. ) In DMF (16L), drops Bi, 15 ° C overnight with stirring 16 h. Thereaction mixture was poured into water, large amount of solid precipitated, suction filtered, the filter cake washedwith water, drained, dried to obtain compound XIV-1 White The solid 3835.1g, Yield: 95.6percent.
91%
Stage #1: With triethylamine In N,N-dimethyl-formamide at 0℃; for 0.5 h; Stage #2: at 0 - 20℃;
1-trityl-midazol (Compound 28, Scheme 19) was prepared by adding Et3N (5.1 ml, 36.7 mmol) at 0° C. to a stirred solution of the imidazole Compound 27 (2.5 grams, 36.7 mmol) dissolved in 75 ml DMF. After 30 minutes of stirring, trityl-chloride (10.3 grams, 36.7 mmol) dissolved in DMF (45 ml) was added slowly to the reaction mixture, and the reaction mixture was allowed to reach room temperature while stirred continuously for over night. Thereafter the reaction mixture was quenched with cold water (1 L) to precipitate a solid, which was collected by filtration and recrystallized from hexane/DCM to afford Compound 28 as a white solid (91percent yield).1H NMR (500 MHz, CDCl3)-δ: 7.47 (s, 1H), 7.33-7.30 (m, 9H), 7.16-7.12 (m, 6H), 7.07 (s, 1H), 6.83 (s, 1H).
90%
With ammonium chloride; triethylamine In dichloromethane
Example 22 Synthesis of 1-tritylimidazole (5) To a solution of trityl chloride (5.58 g, 20.0 mmol.) in dry methylene chloride (100 ml) cooled down to 0° C. and stirred under Ar, was added dropwise over 1.5 hours a solution of imidazole (1.36 g, 20.0 mmol.) and triethylamine (2.7 mml, 20 mmol.) in 50 ml dry methylene chloride. At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred under Ar at that temperature overnight. The reaction mixture was then washed with 20 ml of a 10percent solution of ammonium chloride, then with 20 ml of distilled water. The organic phase was dried over magnesium sulfate and evaporated in vacuo to yield quantitatively a white solid. Recrystallization from methylene chloride/hexanes yielded 5.60 g of (5) (yield=90percent after recrystallization). m.p. 214° C.; 1H NMR (200 MHz, CDCl3) δ7.43 (m, 1H, NCHN), 7.3-7.4 (m, 9H, 3*C6H5), 7.1-7.2 (m, GH, 3*C6H5), 7.0 (m, 1H, Ph3CNCH=CH), 6.81 (m, 1H, Ph3CNCH=CH); 13C NMR (50 MHz, CDCl3) δ142.3, 139.0, 129.6, 128.2, 128.3, 121.6.
90%
With ammonium chloride; triethylamine In dichloromethane
Example 22 Synthesis of 1-tritylimidazole (5) STR73 To a solution of trityl chloride (5.58 g, 20.0 mmol.) in dry methylene chloride (100 ml) cooled down to 0° C. and stirred under Ar, was added dropwise over 1.5 hours a solution of imidazole (1.36 g, 20.0 mmol.) and triethylamine (2.7 mml, 20 mmol.) in 50 ml dry methylene chloride. At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred under Ar at that temperature overnight. The reaction mixture was then washed with 20 ml of a 10percent solution of ammonium chloride, then with 20 ml of distilled water. The organic phase was dried over magnesium sulfate and evaporated in vacuo to yield quantitatively a white solid. Recrystallization from methylene chloride/hexanes yielded 5.60 g of (5) (yield=90percent after recrystallization). m.p. 214° C.; 1 H NMR (200 MHz, CDCl3) δ 7.43 (m, 1H, NCHN), 7.3-7.4 (m, 9H, 3xC6 H5), 7.1-7.2 (m, 6H, 3xC6 H5), 7.0 (m, 1H, Ph3 CNCH=CH), 6.81 (m, 1H, Ph3 CNCH=CH); 13 C NMR (50 MHz, CDCl3) δ 142.3, 139.0, 129.6, 128.2, 128.3, 121.6.
90%
With ammonium chloride; triethylamine In dichloromethane
Example 22 Synthesis of 1-tritylimidazole (5) STR70 To a solution of trityl chloride (5.58 g, 20.0 mmol.) in dry methylene chloride (100 ml) cooled down to 0° C. and stirred under Ar, was added dropwise over 1.5 hours a solution of imidazole (1.36 g, 20.0 mmol.) and triethylamine (2.7 mml, 20 mmol) in 50 ml dry methylene chloride. At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred under Ar at that temperature overnight. The reaction mixture was then washed with 20 ml of a 10percent solution of ammonium chloride, then with 20 ml of distilled water. The organic phase was dried over magnesium sulfate and evaporated in vacuo to yield quantitatively a white solid. Recrystallization from methylene chloride/hexanes yielded 5.60 g of (5) (yield=90percent after recrystallization). m.p. 214° C.; 1 H NMR (200 MHz, CDCl3) δ7.43 (m, 1H, NCHN), 7.3-7.4 (m, 9H, 3*C6 H5), 7.1-7.2 (m, 6H, 3*C6 H5), 7.0 (m, 1H, Ph3 CNCH=CH), 6.81 (m, 1H, Ph3 CNCH=CH); 13 C NMR (50 MHz, CDCl3) δ142.3, 139.0, 129.6, 128.2, 128.3, 121.6.
Reference：
[1] Patent: CN104086553, 2016, B, . Location in patent: Paragraph 0065-0068
[2] Patent: US2010/16610, 2010, A1, . Location in patent: Page/Page column 28
[3] Journal of Heterocyclic Chemistry, 1982, vol. 19, p. 253 - 256
[4] Tetrahedron, 1999, vol. 55, # 13, p. 4109 - 4122
[5] Patent: US6476216, 2002, B1,
[6] Patent: US6160109, 2000, A,
[7] Patent: US5734041, 1998, A,
[8] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 3, p. 903 - 906
[9] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 1, p. 2 - 6
[10] European Journal of Organic Chemistry, 2011, # 30, p. 6092 - 6099
[11] Heterocycles, 1985, vol. 23, # 11, p. 2895 - 2906
[12] Arzneimittel-Forschung/Drug Research, 1992, vol. 42, # 6, p. 832 - 835
[13] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 4, p. 857 - 860
[14] Patent: US5039691, 1991, A,
[15] ChemMedChem, 2010, vol. 5, # 6, p. 899 - 910
With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere
A 500 mL Schlenk flask backfilled with N2was added 4-bromo-1H-pyrazole (10.0g, 68.0 mmol) and dry THF (250 mL). The resulting solution was cooled to 0 °C understirring before 60percent NaH dispersion (3.3 g, 81.6 mmol) was added slowly. Once H2evolution had ceased, trityl chloride (20.9 g, 74.8 mmol) was added slowly, andthe resulting mixture was stirred overnight at RT before quenching with H2O(5 mL) and drying in vacuo.Theresulting residue was triturated in dichloromethane (5 mL) and methanol (200mL) for 2 hours.The resulting suspension wasfiltered and dried overnight at 50°C to give4-bromo-1-trityl-1H-pyrazole(26.0g, 66.8 mmol, 98.2percent) as a white solid.1HNMR (300 MHz, DMSO-d6)δ = 7.03 – 7.06 (m, 6 H), 7.34 – 7.40 (m, 9 H), 7.51 (s, 1 H), δ 7.76 (s, 1H).
96%
With pyridine In dichloromethane at 20℃; for 16 h;
A solution of 150 g (1.0 mol) of 4-bromo-1H-pyrazole, 334 g (1.2 mol, 1.2 eq.) of trityl chloride, 158 g (2.0 mol, 2.0 eq.) of pyridine and 6.1 g (0.05 mol, 5 mol percent) of 4-dimethylaminopyridine in 2 L of dichloromethane was stirred at room temperature for 16 h. The resulting mixture was washed with water and saturated aqueous ammonium chloride solution. The organic layer was dried over sodium sulfate and concentrated. The residue was triturated with hexanes to give 380 g (96percent) of 4-bromo-1-trityl-1H-pyrazole.
87%
With triethylamine In N,N-dimethyl-formamide at 70℃; for 3 h;
Manufacturing Example 32-1-1 4-Bromo-1-trityl-1H-pyrazole; To a solution of 4-bromopyrazole (10.0 g, 68.0 mmol) in N,N-dimethylformamide (100 mL) was added dropwise triethylamine (23.7 mL, 170 mmol) under nitrogen atmosphere at room temperature. Trityl chloride (37.9 g, 136 mmol) was added to the reaction solution on an ice bath (0° C.), and stirred for 3 hours at 70° C. Water (400 mL) was added to the reaction solution to precipitate the solids. The precipitated solids were filtered and dried under a reduced pressure. The solids were then azeotropically dried with toluene to obtain the title compound (22.9 g, 87percent).1H-NMR Spectrum (DMSO-d6) δ (ppm): 7.04-7.07 (6H, m), 7.35-7.38 (9H, m), 7.52 (1H, d, J=0.4 Hz), 7.76 (1H, d, J=0.8 Hz).
87%
With triethylamine In N,N-dimethyl-formamide at 0 - 70℃; for 3 h;
To a solution of 4-bromopyrazole (10.0 g, 68.0 mmol) in N,N-dimethylformamide (100 mL) was added dropwise triethylamine (23.7 mL, 170 mmol) under nitrogen atmosphere at room temperature. Trityl chloride (37.9 g, 136 mmol) was added to the reaction solution on an ice bath (0° C.), and stirred for 3 hours at 70° C. Water (400 mL) was added to the reaction solution to precipitate the solids. The precipitated solids were filtered and dried under a reduced pressure. The solids were then azeotropically dried with toluene to obtain the title compound (22.9 g, 87percent). 1H-NMR Spectrum (DMSO-d6) δ (ppm): 7.04-7.07 (6H, m), 7.35-7.38 (9H, m), 7.52 (1H, d, J=0.4 Hz), 7.76 (1H, d, J=0.8 Hz).
Reference：
[1] Tetrahedron Letters, 2016, vol. 57, # 8, p. 895 - 898
[2] Patent: US2008/261975, 2008, A1, . Location in patent: Page/Page column 12
[3] Journal of the American Chemical Society, 2011, vol. 133, # 31, p. 12285 - 12292
[4] Patent: US2009/82403, 2009, A1, . Location in patent: Page/Page column 81
[5] Patent: US2007/105904, 2007, A1, . Location in patent: Page/Page column 78
[6] Heterocycles, 2010, vol. 81, # 6, p. 1509 - 1516
[7] Journal of Medicinal Chemistry, 1998, vol. 41, # 13, p. 2390 - 2410
[8] Synthesis, 1997, # 5, p. 563 - 566
[9] Organic Letters, 2015, vol. 17, # 5, p. 1142 - 1145
[10] Journal of Organic Chemistry, 2018, vol. 83, # 5, p. 2954 - 2958
[11] Patent: US6492416, 2002, B1,
[12] Patent: US6200978, 2001, B1,
[13] Patent: WO2007/52943, 2007, A1, . Location in patent: Page/Page column 20-21
[14] Patent: US2008/287440, 2008, A1, . Location in patent: Page/Page column 5
[15] Patent: WO2003/104200, 2003, A1, . Location in patent: Page 20
[16] Patent: WO2003/104189, 2003, A2, . Location in patent: Page 16
8
[ 288-88-0 ]
[ 76-83-5 ]
[ 31250-99-4 ]
Yield
Reaction Conditions
Operation in experiment
93%
Stage #1: With triethylamine In N,N-dimethyl-formamide for 0.0833333 h;
j0185j Triethylamine (5.49 g, 54.30 mmol) is added to a solution of 1,2,4-triazole (3.0 g, 43.44 mmol) in DMF (50 mL) at rt. After stirring for 5 minutes, trityl chloride (12.11 g, 43.44 mmol) is added as a solid and the mixture is stirred overnight. The solvent is distilled off under reduced pressure and the crude is partitioned between dichloromethane (50 mL) and water (50 mL). The organic layer is separated and the aqueous layer is extracted with dichloromethane (3 x 50 mL). The combined organic layers are washed with water (3 x 40 mL). The organic layer is dried over Na2SO4 and concentrated under reduced pressure to afford the product 1-trytil-1H- 1,2,4-triazole (12.6 g, 93 percent). n-BuLi (4.5 mL, 11.24 mmol; 2.5 M solution in hexanes) is added to a solution of 1-trityl-1H-1,2,4-triazole (3.5 g, 11.24 mmol) in THF (120 mL) at -78°C and the solution is stirred for 45 mm. Bromine (1.76 g, 11.02 mmol) is added dropwise over a period of 5 minutes and the solution is stirred for 2 h allowed to warm to -20 °C and quenched by adding saturated NH4C1 solution (30 mL). The reaction mixture ias diluted with water (60 mL) and dichloromethane (40 mL). The organic layer is separated and the aqueous layer is extracted with CH2C12 (4 x 50 mL).The combined organic extract was dried over Na2SO4 and the solvent evaporated under reduced pressure to afford crude which is used as such for the next step (4.2 g, 95 percent). 7.09-7.16 (m, 6H), 7.27-7.40 (m, 9H), 7.86 (s, 1H).
Reference：
[1] Patent: WO2014/159248, 2014, A1, . Location in patent: Paragraph 0185
[2] European Journal of Medicinal Chemistry, 2009, vol. 44, # 7, p. 3064 - 3067
[3] Tetrahedron, 1997, vol. 53, # 30, p. 10289 - 10312
[4] MedChemComm, 2014, vol. 5, # 1, p. 72 - 81
[5] Patent: US6620841, 2003, B1,
[6] Patent: EP1219607, 2002, A1,
[7] Heterocycles, 1985, vol. 23, # 11, p. 2895 - 2906
[8] Patent: US5393732, 1995, A,
9
[ 288-88-0 ]
[ 76-83-5 ]
[ 136633-98-2 ]
[ 31250-99-4 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1991, vol. 110, # 9, p. 369 - 373
[2] Tetrahedron Letters, 2000, vol. 41, # 8, p. 1297 - 1301
10
[ 76-83-5 ]
[ 23785-21-9 ]
[ 53525-60-3 ]
Yield
Reaction Conditions
Operation in experiment
55%
With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 12 h;
To a stirred solution of XLIV, (2 g; 14 mmol) in dimethylformide (50 ml) was added trityl chloride (3.98 g; 14 mmol) and triethylamine (1.73 g, 17 mmol) at 0°C. The resulting solution was stirred for 12 h at room temperature. The reaction mixture was cooled, concentrated at reduced pressure and diluted with water. The aqueous layer was extracted with ethyl acetate.The combined organic layers were washed with brine, dried over Na2504, filtered and concentrated under vacuum to afford ethyl 1 -trityl- 1 H-imidazole-4-carboxylate as a brown solid (XLV; 3 g, 55percent yield). MS (M+1) 383.34.
Reference：
[1] Farmaco, Edizione Scientifica, 1985, vol. 40, # 8, p. 541 - 554
[2] Patent: WO2015/97122, 2015, A1, . Location in patent: Page/Page column 96; 97
[3] Journal of Heterocyclic Chemistry, 1982, vol. 19, p. 253 - 256
[4] Patent: US4935437, 1990, A,
[5] Patent: US2016/272594, 2016, A1, . Location in patent: Paragraph 0023
11
[ 76-83-5 ]
[ 79848-49-0 ]
[ 32926-43-5 ]
Reference：
[1] Chemistry of Natural Compounds, 1982, vol. 18, # 3, p. 322 - 327[2] Khimiya Prirodnykh Soedinenii, 1982, # 3, p. 349 - 354
12
[ 5400-78-2 ]
[ 76-83-5 ]
[ 519-73-3 ]
[ 121-89-1 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 12, p. 1978 - 1999
13
[ 76-83-5 ]
[ 3034-50-2 ]
[ 33016-47-6 ]
Yield
Reaction Conditions
Operation in experiment
100%
With triethylamine In N,N-dimethyl-formamide at 0 - 20℃;
Example 33: 1 -trityl-1 H-imidazole-4-carbaldehydeTo a solution of 1W-imidazole-4-carbaldehyde {30.0 g, 0.30 mol) in DMF (200 mL) was added Et3N (70 mL, 0.375 mol) under ice bath, and then Trt-CI (105 g, 0.375 mol) was added in portions and the mixture stirred at RT overnight. The mixture was evaporated in vacuo and the residue was washed with anhydrous Et2O (4 x 50 mL), and the resulting precipitate was dried to yield the title compound (100 g, 100percent) as a yellow solid.
98%
With triethylamine In dichloromethane at 0 - 20℃;
[2372] To a stirred solution of 4(5)-imidazolecarboxaldehyde (20.0 g, 0.208 mmol) in CH2Cl2 (200 mL), was added Et3N (29.0 mL, 0.208 mmol). The solution was then cooled down at 0° C., followed by addition of triphenylmethylchloride (52.8 g, 0.18 mmol) at 0° C. The resulting solution was stirred at room temperature overnight and then washed it with brine, water and concentrated to dryness to give a white solid (63.0 g, 98percent yield, MH+=339.1)
96%
With triethylamine In acetonitrile
Dry triethylamine (12.6 mL, 90.0 mmol) was added drop wise over two hours to a slurry of (l,3)-H-imidazole-4-carbaldehyde (5.0 g, 52 mmol) and trityl chloride (16.0 g, 57.0 mmol) in acetonitrile (170 mL). After complete addition of the triethylamine, the resulting solution was stirred overnight and then hexane (16.6 mL) and water (170 mL) were added. After stirring for an additional 30 minutes, the resulting solid was collected and dried overnight under vacuum to provide the title compound as a white solid (16.8 g, 96percent). 1H NMR (400 MHz, CDCl3): δ 9.81 (s, IH), EPO <DP n="24"/>7.54 (s, IH), 7.46 (s, IH), 7.29 (m, 10H), 7.04 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 186.9, 141.9, 141.2, 141.0, 130.0, 129.0, 128.9, 127.2, 76.7.
95%
With alkaline condition In acetonitrile at 20℃; for 2 h;
To a mixture of 10 (1.03 g, 10.7 mmol) and TrCl (3.29 g, 11.8 mmol, 1.1 eq) in MeCN (45 mL) was added Et3N (2.5 mL, 18.0 mmol, 1.7 eq) at rt. After stirring for 2 h, hexane (3 mL) and H2O (40 mL) were added and the mixture was filtered. The resultant cake was washed with water three times and dried in a house vacuumoven at 50 °C to afford 18 (3.42 g, 95percent) as a white powder.1H NMR (500 MHz, CDCl3) δ 7.10-7.13 (m, 5H), 7.35-7.38 (m, 10H), 7.53 (d, J = 1.1 Hz, 1H), 7.61 (d, J =1.7 Hz, 1H), 9.88 (s, 1H)
78%
With triethylamine; citric acid In <i>N</i>-methyl-acetamide; ethyl acetate
Synthesis of 1-Trityl-1H-imidazole-4-carbaldehyde STR49 To dimethylformamide (100 mL) was added imidazole-4-carboxaldehyde (10 g, 0.104 mol, Aldrich Chemical Corp.) and triethylamine (20.5 mL, 0.147 mol). A solution of trityl chloride (40 g, 0.143 mol) in dimethylformamide (300 mL) was added, followed by stirring at 25° C. for 6 hours. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate (1.5 L) and 1N citric acid (350 mL). The phases were separated, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Concentration of the solution in vacuo gave a white solid, 27.59 g, 78percent yield. NMR was consistent with structure. MS: APCI: M-1: 337.2 (M: 338.41).
67%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 18 h;
Intermediate 18:l-trityl-lH-imidazole-4-carbaldehyde[00417 ] Triethylamine (3.05 ml, 21.86 mmol) was added to a solution of lH-imidazole-4- carbaldehyde (2 g, 20.82 mmol) and triphenylmethyl chloride (5.80 g, 20.82 mmol) in N5N- dimethylformamide (20 ml). The reaction mixture was stirred at room temperature for 18 hours. The crude mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The organic phase was washed dried over sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallised from dichloromethane and hexanes to afford the title compound as a cream solid (4.7 g, 67percent yield).[00418] 1H NMR (DMSO-d6, 400 MHz) δ 7.10-7.16 (6H, m), 7.36-7.57 (9H, m), 7.63 (IH, s), 7.64 (IH, s), 9.91 (IH, s).
65%
With triethylamine In ISOPROPYLAMIDE at 25℃; for 24 h;
Reference Example 11 To 4 (5) -formylimidazole (2 g, 20.8 mmol) were added D Ac (30 mL) and triethylamine (3.5 mL, 25.0 mmol, 1.2 equivalents), and then trityl chloride (4.06 g, 14.6 mmol, 0.7 equivalents) was added thereto at room temperature. The mixture was stirred at room temperature for 24 hr, and to the reaction mixture was added water (60 mL) at room temperature, and the mixture was stirred at room temperature for 2 hr. The crystals werecollected by filtration, washed with water, and vacuum-dried(50°C) to a constant amount to give a crude compound (4.6 g) . To the crude compound (0.2 g) was added methanol (1 mL) , and the. mixture was stirred at room temperature for 2 hr. The crystals were collected by filtration, was washed withmethanol (0.2 mL) , and vacuum-dried (50°C) to a constant amount to give l-trityl-4-formyl-lH-imidazole (0.14 g) . yield 65percent.
10 g
With triethylamine In N,N-dimethyl-formamide at 0 - 35℃;
A) 1-trityl-1H-imidazol-4-carbaldehyde A mixture of 1H-imidazol-4-carbaldehyde (3.00 g), triethylamine (7.00 g) and N,N-dimethylformamide (40 mL) was cooled to 0°C, trityl chloride (10.5 g) was added thereto. The reaction mixture was stirred at room temperature for 18 hr, water was added thereto, and the solid was collected by filtration. The obtained solid was washed with water and diethyl ether to give the title compound (10.0 g). 1H NMR (400 MHz, DMSO-d6) δ 7.11-7.14 (6H, m), 7.40-7.48 (9H, m), 7.67 (1H, d, J = 0.8 Hz), 7.80 (1H, d, J = 1.2 Hz), 9.23 (1H, s).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 23, p. 7993 - 8002
[2] Patent: WO2008/4096, 2008, A1, . Location in patent: Page/Page column 79
[3] Journal of Medicinal Chemistry, 2002, vol. 45, # 1, p. 177 - 188
[4] European Journal of Organic Chemistry, 2015, vol. 2015, # 18, p. 3957 - 3962
[5] Patent: US2004/122018, 2004, A1, . Location in patent: Page 317
[6] Organic and Biomolecular Chemistry, 2011, vol. 9, # 7, p. 2274 - 2278
[7] Journal of Medicinal Chemistry, 2011, vol. 54, # 6, p. 1693 - 1703
[8] Angewandte Chemie - International Edition, 2005, vol. 44, # 31, p. 4903 - 4906
[9] Journal of Medicinal Chemistry, 2006, vol. 49, # 19, p. 5710 - 5727
[10] Patent: WO2006/102159, 2006, A2, . Location in patent: Page/Page column 21; 22
[11] Chemistry - A European Journal, 2006, vol. 12, # 16, p. 4321 - 4332
[12] Synlett, 2016, vol. 27, # 19, p. 2734 - 2736
[13] Chemical Communications, 2011, vol. 47, # 48, p. 12855 - 12857
[14] Patent: US6143766, 2000, A,
[15] Journal of Medicinal Chemistry, 2010, vol. 53, # 4, p. 1712 - 1725
[16] Patent: WO2008/94992, 2008, A2, . Location in patent: Page/Page column 188
[17] Tetrahedron Letters, 2006, vol. 47, # 8, p. 1253 - 1255
[18] Patent: WO2012/173280, 2012, A1, . Location in patent: Page/Page column 35-36
[19] Patent: US2003/199522, 2003, A1,
[20] Patent: US2002/82272, 2002, A1,
[21] Patent: WO2010/52256, 2010, A1, . Location in patent: Page/Page column 37
[22] Patent: WO2010/52255, 2010, A1, . Location in patent: Page/Page column 68
[23] Patent: WO2006/23720, 2006, A2, . Location in patent: Page/Page column 48
[24] Patent: US2007/49616, 2007, A1, . Location in patent: Page/Page column 29
[25] Patent: EP2848618, 2015, A1, . Location in patent: Paragraph 0816
[26] ChemMedChem, 2018, vol. 13, # 8, p. 842 - 851
14
[ 3034-50-2 ]
[ 76-83-5 ]
[ 33016-47-6 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 0 - 20℃;
[1815] To a stirred solution of 4(5)-imidazolecarboxaldehyde (20.0 g, 0.208 mmol) in CH2Cl2 (200 mL), was added Et3N (29.0 mL, 0.208 mmol). The solution was then cooled down at 0° C., followed by addition of triphenylmethylchloride (52.8 g, 0.18 mmol) at 0° C. The resulting solution was stirred at room temperature overnight and then washed it with brine, water and concentrated to dryness to give a white solid (63.0 g, 98percent yield, MH+=339.1)
94%
With triethylamine In acetonitrile at 20℃; for 20.3333 h;
To a 1L three-necked round-bottomed flask with an addition funnel was added 3H-imidazole-4-carbaldehyde (4, 12 g, 0.125 mol) trityl chloride (38.3 g, 0.137 mol) and acetonitrile (400 mL). The mixture was stirred at rt to give a slurry. Triethylamine (30 mL, 0.215 mol) was added drop wise over 20 min. After the addition was complete, the reaction mixture was stirred at rt for 20 h. Hexane (40 mL) and water (400mL) were added. The slurry was stirred for 30 min and filtered. The cake was washed with water (3 × 100 mL) and dried in a vacuum oven at 50 °C for 20 h to give 5 as a white solid (39.8 g, 94percent).
Reference：
[1] Patent: US2003/229099, 2003, A1, . Location in patent: Page 269
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 10, p. 3887 - 3898
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 23, p. 6492 - 6499
[4] Organic Process Research and Development, 2000, vol. 4, # 6, p. 613 - 614
[5] Journal of Medicinal Chemistry, 2007, vol. 50, # 19, p. 4585 - 4605
[6] Journal of Medicinal Chemistry, 2009, vol. 52, # 12, p. 3703 - 3715
Reference：
[1] Polymer, 2015, vol. 69, p. 274 - 282
17
[ 95383-91-8 ]
[ 76-83-5 ]
[ 75-78-5 ]
[ 35146-32-8 ]
Reference：
[1] Journal of Organic Chemistry, 1982, vol. 47, # 7, p. 1324 - 1326
18
[ 75-77-4 ]
[ 95383-91-8 ]
[ 76-83-5 ]
[ 58995-29-2 ]
[ 35146-32-8 ]
Reference：
[1] Journal of Organic Chemistry, 1982, vol. 47, # 7, p. 1324 - 1326
19
[ 76-83-5 ]
[ 31938-11-1 ]
Reference：
[1] Journal of Organic Chemistry, 2004, vol. 69, # 18, p. 5926 - 5933
[2] Angewandte Chemie - International Edition, 2014, vol. 53, # 1, p. 324 - 328[3] Angew. Chem., 2014, vol. 126, # 1, p. 337,1
[4] Tetrahedron, 2016, vol. 72, # 32, p. 4813 - 4820
20
[ 76-83-5 ]
[ 21947-98-8 ]
Reference：
[1] Organic Letters, 2005, vol. 7, # 13, p. 2615 - 2618
[2] Patent: CN106432014, 2017, A,
21
[ 76-83-5 ]
[ 107-96-0 ]
[ 27144-18-9 ]
Yield
Reaction Conditions
Operation in experiment
93%
at 20℃;
Trityl chloride (14.1 g, 50.6 mmol, 1.1 eq.) was dissolved in DCM(160 mL) and 3-mercaptopropionic acid (4 mL, 46 mmol, 1.0 eq) was added to the flask.Reaction was stirred at room temperature overnight during which the product precipitatedas a white solid. Reaction was filtered off and the white solid was washed extensively withDCM and then dried under high vacuum. The product was obtained in 93percent yield (14.8 g).1H-NMR (DMSO-d6): δ 7.18 – 7.39 (m, 15H, arom H), 2.28 (t, J = 7.2 Hz, 2H, -S-CH2-), 2.16 (t, J= 7.2 Hz, 2H, -CH2-CO2H); 13C-NMR (DMSO-d6): δ 172.7, 144.3, 129.1, 128.0, 126.7, 66.2,32.9, 26.7;
88%
at 23℃; for 17 h;
Triphenylmethyl chloride (2.7 g, 9.5 mmol, 1.0 equiv) was added to a stirred solution of 3-thiopropanoic acid (1.0 g, 9.5 mmol, 1.0 equiv) in N,N-dimethylformamide (15 mL) at 23° C. The resulting colorless solution was stirred at 23° C. for 17 h. The reaction mixture was diluted with water (300 mL) and extracted with diethyl ether (4*150 mL). The combined organic layers were diluted with dichloromethane (100 mL) and methanol (100 mL) in order to dissolve all solids, dried (MgSO4), gravity filtered, and concentrated by rotary evaporation. The residue was rinsed with dichloromethane and vacuum-filtered to afford the title compound as white crystals (2.9 g, 88percent): mp 205-208° C.; IR (KBr thin film) 3438 (w), 3024 (w), 2909 (w), 2742 (w), 2649 (w), 2565 (w), 1701 (s) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 12.24 (br s, 1H), 7.20-7.40 (m, 15H), 2.28 (t, J=7 Hz, 2H), 2.16 (t, J=7 Hz, 2H); ESIMS m/z 347 ([M-H]-).
120 g
at 25 - 30℃; for 6 h;
To a solution of trityl chloride (100 gm) in toluene (500 ml), 3-mercapto propionic acid (41.9 gms) was added at 25-30°C and stirred it for 6 hours at 25-30°C. 500 ml of water was added to the reaction mixture at 25-30°C and stirred it for 15 minutes at the same temperature. Filtered the precipitated solid, washed with water and dried to get title compound. Yield: 120 gms; Melting Range 200-205°C.
Reference：
[1] Chemistry and Physics of Lipids, 2002, vol. 115, # 1-2, p. 17 - 37
[2] Chemistry and Physics of Lipids, 2005, vol. 136, # 1, p. 23 - 46
[3] ChemMedChem, 2010, vol. 5, # 12, p. 2057 - 2064
[4] Angewandte Chemie - International Edition, 2018, vol. 57, # 24, p. 7023 - 7027[5] Angew. Chem., 2018, vol. 130, # 24, p. 7141 - 7145,5
[6] Synlett, 2018, vol. 29, # 19, p. 2582 - 2587
[7] ChemPlusChem, 2015, vol. 80, # 4, p. 704 - 714
[8] Patent: US2012/53146, 2012, A1, . Location in patent: Paragraph 0180; 0181
[9] Tetrahedron, 2009, vol. 65, # 7, p. 1257 - 1267
[10] Tetrahedron Letters, 1998, vol. 39, # 51, p. 9327 - 9330
[11] Chemical Communications, 2010, vol. 46, # 37, p. 6992 - 6994
[12] Tetrahedron, 1997, vol. 53, # 49, p. 16859 - 16866
[13] Bulletin de la Societe Chimique de France, 1924, vol. <4> 35, p. 388
[14] Helvetica Chimica Acta, 1996, vol. 79, # 7, p. 2023 - 2034
[15] Journal of Organic Chemistry, 2008, vol. 73, # 21, p. 8142 - 8153
[16] Patent: US2003/235916, 2003, A1, . Location in patent: Page 20
[17] International Journal of Pharmaceutics, 2010, vol. 396, # 1-2, p. 229 - 238
[18] Chemical Communications, 2013, vol. 49, # 45, p. 5177 - 5179
[19] Patent: WO2014/74218, 2014, A1, . Location in patent: Paragraph 00406-00408
[20] Patent: WO2017/68596, 2017, A1, . Location in patent: Page/Page column 25; 26
[21] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 11, p. 3039 - 3045
22
[ 52-89-1 ]
[ 76-83-5 ]
[ 2799-07-7 ]
Yield
Reaction Conditions
Operation in experiment
89%
at 20℃; for 48 h;
L-Cysteine hydrochloride (100 g, 0.634 mol) and trityl chloride (270 g, 0.969 mol) were stirred in DMF (400 mL) for 2 days at room temperature. A 10percent sodium acetate solution (3.5 L) was then added dropwise and the white precipitate which formed was filtered and washed with distilled water. Afterward, the residue was stirred in acetone at 50° C. for 30 min after which it was cooled to 0° C. and filtered. The precipitate was washed with a little acetone and diethyl ether and dried in vacuo. S-Trityl-L-cysteine 1b (205 g, 89percent) was obtained as a white powder. 1b: m.p. 192° C. (decomp). 1H NMR (DMSO-d6) δ 2.45 (dd, 1H, J=9 Hz, 12 Hz), 2.58 (dd, 1H, J=4.4 Hz, 12 Hz), 2.91 (m, 1H), 7.22-7.36 (m, 15H); 13C NMR (75.5 MHz, DMSO-d6): δ 33.8, 53.7, 66.4, 127.1, 127.8, 128.1, 128.4, 129.5, 144.5, 168.4. This material was directly used in the next step without further purification.
89%
With sodium acetate In N,N-dimethyl-formamide at 20℃; for 48 h;
L-Cysteine hydro-chloride (100 g, 0.634 mol) and trityl chloride (270 g, 0.969 mol) were stirred in DMF (400 mL) for 2 days at room temperature. A 10percent sodium acetate solution (3.5 L) was then added dropwise and the white precipitate which formed was filtered and washed with distilled water. Afterward, the residue was stirred in acetone at 50 0C for 30 min after which it was cooled to 00C and filtered. The precipitate was washed with a little acetone and diethyl ether and dried in vacuo. S-Trityl-L-cysteine Ic (205 g, 89percent) was obtained as a white powder. Ic: m.p. 192 °C (decomp) ; 1H NMR (300 MHz, DMSCW5) δ 2.45 (dd, IH, J= 9 Hz, 12 Hz), 2.58 (dd, IH, J= 4.4 Hz, 12 Hz), 2.91 (m, IH), 7.22-7.36 (m, 15H); 13C NMR (75.5 MHz, DMSO- d6): δ 33.8, 53.7, 66.4, 127.1, 127.8, 128.1, 128.4, 129.5, 144.5, 168.4. This material was directly used in the next step without further purification.
78%
at 20℃; for 48 h;
Preparation 75: Synthesis of (R)-3-amino-4-tritylsulfanyl-butyric acid methyl ester hydrochloride; (Step 1); L-cysteine hydrochloride (5Og, 284.7mmol) was dissolved in N,N- dimethylformamide (200ml). Trityl chloride (119g, 427.0mmol) was added thereto, and the mixture was stirred for 48 h at room temperature. After completion of the reaction, 10percent sodium acetate (1.5L) was added. The mixture was filtered to give a solid, which was then added to acetone (1.5L), and stirred for 30 min at 50 °C . The insoluble solid was filtered, and dried to give a trityl compound (80g, Yield 78percent).
77%
at 20℃; for 48 h;
Synthetic Example 1; (R)-3-Mercapto-2-(5-methyl-4-phenyl-thiazoI-2-yIamino)-propionic acid; Step 1 : S-Trityl-L-cysteine falso known as (R)-2-amino-3- (tritylsulfanyl)propanoic acid); L-Cysteine hydrochloride (5.0 g, 31.7 mmol) and trityl chloride (13.5 g, 48.4 mmol) were stirred in DMF (20 ml) for 48 h at room temperature. A 10percent NaOAc solution (175 mL) was then added, and the precipitate was filtered and washed with water. Afterward, the residue was suspended in acetone and stirred at 50 °C for 30 min, then cooled and filtered. The residue was washed with acetone (cold) and diethyl ether. After drying 8.86 g (77percent) S-trityl-L-cysteine was obtained.
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 4, p. 619 - 626
[2] Organic Letters, 2005, vol. 7, # 13, p. 2615 - 2618
[3] Patent: US7829709, 2010, B1, . Location in patent: Page/Page column 19-20
[4] Patent: WO2009/100431, 2009, A1, . Location in patent: Page/Page column 28
[5] Patent: WO2009/82152, 2009, A2, . Location in patent: Page/Page column 214
[6] Patent: WO2009/151744, 2009, A1, . Location in patent: Page/Page column 93
[7] Chemical Communications, 2009, # 4, p. 407 - 409
[8] Acta Chemica Scandinavica (1947-1973), 1959, vol. 13, p. 383
[9] Journal of the American Chemical Society, 1962, vol. 84, p. 3887 - 3897
23
[ 76-83-5 ]
[ 2799-07-7 ]
Yield
Reaction Conditions
Operation in experiment
76.15%
at 60 - 65℃; for 8 h;
The compound L-cysteine hydrochloride (10 g, 63.45 mmol)Was dissolved in N, N-dimethylformamide (120 ml)Triphenylchloromethane (19.46 g, 69.795 mmol) was added,Heated to 60-65 ° C,Reaction for 8 hours,TLC detection reaction is completed,Cooled to room temperature,A 10percent sodium acetate solution (300 ml) was added,Precipitation of white solid,filter,The residue was washed with pure water (300 ml)Then washed with acetone (200 ml)dry,The product was a white solid (17.56 g, yield: 76.15percent).
Reference：
[1] Patent: CN106432014, 2017, A, . Location in patent: Paragraph 0096; 0097; 0098; 0099; 0142; 0143; 0144; 0145
Stage #1: With sodium hydroxide In water; acetone at 40℃; for 1 h;
Dissolve compound 2 (200 g) with stirring at 40°C700mL of acetone,Aqueous sodium hydroxide solution (40.67 g sodium hydroxide dissolved in 160 mL water) is added,Continue stirring for 1h,A solution of triphenylchloromethane in acetone (270.8 g of triphenylmethyl chloride dissolved in 800 mL of acetone) was initially added dropwise.The solid was added dropwise and gradually evolved into a white turbid liquid.The reaction was monitored by TLC until it was completely filtered off and washed with water to give a solid as intermediate 3.The solid was blow dried at 50°C to give white intermediate 3 (385 g), yield: 95.2percent, HPLC: 99.44percent.
67%
With dmap; triethylamine In dichloromethane at 20℃;
General procedure: A solution of the appropriate tetrazole 1 (10.0 mmol) in CH2Cl2 (5mL) was added to a solution of TrCl (3.1 g, 11.0 mmol), Et3N (2.5mL, 17.6 mmol), and DMAP (92 mg, 0.4 mmol) in CH2Cl2 (10 mL)at r.t., and the mixture was stirred overnight. The reaction was thenquenched with H2O (5 mL) and the mixture was extracted withEtOAc (3 × 15 mL). The organic phases were combined, washedwith brine (5 mL), dried (Na2SO4), and concentrated at 15 Torr. Theresidue was purified by column chromatography (deactivated silicagel, hexane–EtOAc) to give the expected tetrazoles 1a–f and 1i–l.For the preparation of the ditritylated compound 1g, the amounts ofthe reagents and solvents used were double those indicated above.
67%
With dmap; triethylamine In dichloromethane at 20℃;
General procedure: A solution of the corresponding tetrazole (10.0 mmol) in CH2Cl2 (5 mL) was added to a solution of trityl chloride (3.1 g, 11.0 mmol),triethylamine (2.5 mL, 17.6 mmol) and 4-(dimethylamino)pyridine (92 mg, 0.4 mmol) in CH2Cl2 (10 mL) at room temperature and themixture was stirred overnight. The reaction was then quenched with water (5 mL) and extracted with ethyl acetate (3 15 mL) and thecombined organic phases were washed with brine (5 mL) and dried over sodium sulfate. After evaporation of the solvents (15 Torr),the resulting residue was purified by column chromatography (deactivated silica gel, hexane/ethyl acetate) affording the expectedtetrazoles 1a-1f and 1i-1l.For the preparation of the double tritylated compound 1g the amounts of the reagents and solvent used were double the ones indicatedabove. Compound 1g was separated by column chromatography [deactivated silica gel, hexane/ethyl acetate]. The correspondingphysical, spectroscopic and analytical data for the tritylated tetrazoles follow.
67%
With dmap; triethylamine In dichloromethane at 20℃;
General procedure: A solution of the corresponding tetrazole (10.0 mmol) in CH2Cl2 (5 mL) was added to a solution of trityl chloride (3.1 g, 11.0 mmol), triethylamine (2.5 mL, 17.6 mmol) and 4-(dimethylamino)pyridine (92 mg, 0.4 mmol) in CH2Cl2 (10 mL) at r.t. and the mixture was stirred overnight. The reaction was then quenched with H2O (5 mL) and extracted with EtOAc (3 × 15 mL) and the combined organic phases were washed with brine (5 mL) and dried over sodium sulfate. After evaporation of the solvents (15 torr), the resulting residue was purified by column chromatography (deactivated silica gel; hexane–EtOAc) to afford the expected tetrazole 1a–f,i–l. For the preparation of the double tritylated compound 1g, the amounts of the reagents and solvent used were double those indicated above. Compound 1g was separated by column chromatography [deactivated silica gel; hexane–EtOAc].
Reference：
[1] Patent: WO2013/78237, 2013, A1, . Location in patent: Page/Page column 111; 112
[2] Patent: CN107935957, 2018, A, . Location in patent: Paragraph 0020; 0040-0042
[3] Synthetic Communications, 2008, vol. 38, # 20, p. 3577 - 3581
[4] Journal of Chemical Sciences, 2011, vol. 123, # 4, p. 393 - 401
[5] Archiv der Pharmazie, 2016, vol. 349, # 12, p. 934 - 943
[6] Synthesis (Germany), 2014, vol. 46, # 15, p. 2065 - 2070
[7] Synlett, 2015, vol. 26, # 17, p. 2399 - 2402
[8] Synthesis (Germany), 2016, vol. 48, # 15, p. 2455 - 2460
[9] Journal of Chemical Sciences, 2014, vol. 126, # 1, p. 205 - 212
[10] Journal of Chemical Sciences, 2014, vol. 126, # 1, p. 205 - 212
[11] Patent: EP2162441, 2016, B1, . Location in patent: Paragraph 0219
33
[ 1461-22-9 ]
[ 76-83-5 ]
[ 124750-53-4 ]
Reference：
[1] Patent: US5254546, 1993, A,
[2] Patent: US5254546, 1993, A,
34
[ 114772-53-1 ]
[ 76-83-5 ]
[ 124750-53-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 8, p. 2370 - 2378
[2] Journal of Organic Chemistry, 1991, vol. 56, # 7, p. 2395 - 2400
[3] Farmaco, 1997, vol. 52, # 3, p. 147 - 155
With triethylamine In tetrahydrofuran; dichloromethane at 20℃; for 1 h;
To a single-necked flask was added 4-bromoimidazole (30 g, 205 mmol)Dichloromethane: tetrahydrofuran = 1: 1,And triphenylchloromethane (62 g, 226 mmol)Triethylamine (29 ml) was added with stirring at room temperature,Continue stirring for 1 h, add water and 1N hydrochloric acid,Adding methylene chloride extraction,The organic layers were combined and dried over anhydrous sodium sulfate,Spin dry dichloromethane to give compound 7 (61g, 72percent yield).
Reference：
[1] Journal of Medicinal Chemistry, 2010, vol. 53, # 4, p. 1712 - 1725
[2] Patent: CN106256830, 2016, A, . Location in patent: Paragraph 0044; 0045; 0055; 0056; 0057
40
[ 2302-25-2 ]
[ 76-83-5 ]
[ 76-84-6 ]
[ 87941-55-7 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1989, p. 95 - 99
41
[ 71759-89-2 ]
[ 76-83-5 ]
[ 96797-15-8 ]
Yield
Reaction Conditions
Operation in experiment
94%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 24 h;
To a solution of 3 (3.5 g,18.0 mmol) in DMF (70 mL) was added TEA (3.0 mL, 21.7 mmol) andtrityl chloride (5.5 g, 19.7 mmol). After stirring at 20 C for 24 h, thesolution was poured into water. The solid was filtered to yield thecrude compound that was purified by flash column chromatographyon silica gel to afford 4 as a white solid (7.4 g, 94.0percent). Mp148e150 C. 1H NMR (300 MHz, Chloroform-d) d(ppm) 6.9 (m, 1H),7.0e7.2 (m, 6H), 7.25e7.4 (m, 10H). MS (EI) m/z 437.1 [MH].
94%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 24 h;
2 (3.5 g, 18.0 mmol) was dissolved in DMF (70 mL),Triethylamine (3.0 mL, 21.6 mmol) was added dropwise,Trityl chloride (5.5 g, 19.7 mmol) was added,After 24 hours at room temperature,Poured into 200mL water,Precipitation of a large number of solids,Suction filtration,Ether filtered and washed,Drying gives a white solid,Yield 94.0percent
93%
With triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 48 h;
To a solution of 4-iodoimidazole (50 g, 258 mmoles) in DMF (500 ml) was added triethyl amine (37.7 ml, 270.6 mmoles) and than triphenylmethyl chloride (69.7 g, 250 mmoles). After stirring at room temperature for 48 hours, the solution was poured into ice water (2.5 L). The solid was filtered and pumped on for several hours to yield the crude compound. Ethyl ether (200 ml) was added to the crude compound and the solution was filtered to yield 4-IODO-1-TRITYL-LH-IMIDAZOLE (104.1, 93percent) as a white solid. ME (437)
93%
With triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 48 h;
To a solution of 4-iodoimidazole (50 g, 258 mmoles) in DMF (500 ML) was added triethyl amine (37.7 ml, 270.6 mmoles) and than triphenylmethyl chloride (69.7 g, 250 mmoles). After stirring at room temperature for 48 hours, the solution was poured into ice water (2.5 L). The solid was filtered and pumped on for several hours to yield the crude compound. Ethyl ether (200 ml) was added to the crude compound and the solution was filtered to yield 4-IODO-1-TRITYL-LH-IMIDAZOLE (104.1, 93percent) as a white solid. MH+ (437)
93%
With triethylamine In dichloromethane at 25℃; for 17 h; Cooling with ice; Inert atmosphere
After dissolving 4-iodo -1Himidazole(compound 1) (1.9g, 10mmol) in dichloromethane (40mL), under ice-cooling,triethylamine (2.1mL, 15mmol), trityl chloride (3.4g, 12mmol) It was added, under argon, andstirred for 17 hours at room temperature (25 ° C). After completion of the reaction, water wasadded, and the mixture was extracted twice with dichloromethane. The combineddichloromethane layers were dried anhydrous sodium sulfate and concentrated under reducedpressure, silica and the resulting crude product was gel column chromatography (eluent:chloroform / n-hexane = 1/1 → chloroform) at Purification, Compound 2 It was obtained (4.1g,9.3mmol, 93percent yield).
93%
With triethylamine In dichloromethane at 25℃; for 17 h; Inert atmosphere
4-Iodo-1H-imidazole (Compound 25, manufactured by Wako Pure Chemical Industries, Ltd.) (1.9 g, 10 mmol) was dissolved in dichloromethane (40 mL)Triethylamine (2.1 mL, 15 mmol) and trityl chloride (3.4 g, 12 mmol) were added and the mixture was stirred at room temperature (25 ° C.) for 17 hours under an argon gas atmosphere. After completion of the reaction, water was added and the mixture was extracted twice with dichloromethane. The combined dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: chloroform / n-hexane = 1/1 → chloroform) to obtain compound 26 (4.1 g, 9.3 mmol, yield 93percent).
93%
With triethylamine In dichloromethane at 25℃; for 17 h; Inert atmosphere
4-iodo-1H-imidazole (Compound 13, manufactured by Wako Pure Chemical Industries, Ltd.) (1.9 g, 10 mmol) was dissolved in dichloromethane (40 mL)below freezing,Triethylamine (2.1 mL, 15 mmol),Trityl chloride (3.4 g, 12 mmol) was added,Under an argon gas atmosphere,And the mixture was stirred at room temperature (25 ° C.) for 17 hours.After completion of the reaction,Add water,Extraction was carried out twice with dichloromethane.The combined dichloromethane layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure,The obtained crude product was purified by silica gel column chromatography (eluent (volume ratio): chloroform / n-hexane = 1/1 → chloroform) to obtain Compound 14 (4.1 g, 9.3 mmol, yield 93percent).
92%
at 20℃; for 24 h;
To a solution of 4-iodoimidazole (1 eq) in DMF at room temperature was added triphenylmethyl chloride (1.2 eq). After stirring at room temperature for 24 h, the solution was poured into ice water and left stirring for 30 min. The solid was filtered and pumped on for several hours to yield the crude compound. Ethyl ether was added to the crude compound and the solution was filtered to yield 4-iodo-1- TRITYL-LH-IMIDAZOLE (92percent) as a white solid. MH+ (437).
92%
Stage #1: With triethylamine In N,N-dimethyl-formamide at 0℃; for 0.166667 h; Stage #2: at 20℃; for 16 h;
At 0° C., to a solution of 4-iodo-1H-imidazole (5 g, 25.8 mmol) in DMF (100 mL) was added triethylamine (3.13 g, 30.9 mmol) slowly. After stirring for additional 10 min at 0° C., the reaction mixture was added by TrtCl (7.17 g, 25.7 mmol). The resulting solution was then stirred at room temperature for 16 h. The reaction mixture was poured into 1 L water. A white solid precipitated out and were collected by filtration. The solid was rinsed with MeOH (50 mL×2) and Et2O (50 mL×3), and then dried in vacuo to yield 4-iodo-1-(triphenylmethyl)-1H-imidazole as white solid (10.4 g, 92percent).
90%
at 0 - 20℃;
4-lodo-1tf-imidazole (2.8g, 14.6mmol) and trityl chloride (5.Og, 20.5mmol) were dissolved in λ/,λ/-dimethylacetamide (45mL). The solution was cooled to 0"C and triethylamine (4mL, 29.2mmol) added slowly. The reaction mixture was slowly warmed to room temperature. After 48 hours the solution was poured to water(15OmL). The solid was filtered, washed with water, hexane and dried to give a white solid (5.7g) with a yield of 90percent. The product was pure enough for the next step reaction without further purification.
88.9%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 48 h;
4-iodo-1H-imidazole (20 g, 103 mmoles) was dissolved in DMF (100 mL) then triethylamine (15.1 mL, 108 mmoles) and triphenylmethyl chloride (27.8 g, 100 mmoles). The reaction mixture was stirred at room temperature for 48 h, then poured into ice water (500 mL), and then evaporated to dryness, and filtered, and dried to give white crystals of 4-iodo-1-triphenylmethyl-1H-imidazole (40 g, 91.7 mmol, 88.9percent).
81%
With triethylamine In tetrahydrofuran at 70℃; for 3 h; Inert atmosphere
Triethylamine (36.0 mL, 258 mmol) was added to a mixture of 4-iodoimidazole (24.8 g, 128 mmol) and trityl chloride (39.2 g, 141 mmol) in THF (275 mL), the resulting mixture was heated at 70 °C for 3 hours under nitrogen. The reaction was cooled to 45 °C and filtered to remove thesuspended white solid (Et3N.HCI). The filtrate was concentrated in vacuo, dissolved in DCM (500 mL) and washed with 5 wtpercent aq. sodium thiosulfate solution (300 mL). The aqueous layer was extracted with DCM (150 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford an off white solid. Hot filtration was carried out with methanol (500 ml) at 90°C to afford a white solid characterised as 4-iodo-1-trityl-imidazole (45.2 g, 104 mmol, 81percentyield). 1H NMR (CDCI3, 400 MHz) O: 7.36-7.44 (m, 9H), 7.28-7.32 (m, 1H), 7.10-7.15 (m, 6H), 6.94 (5, 1 H). LCMS purity >95percent, [M+H] = 437.0, 4.47 mm (analytical long).
71%
With triethylamine In tetrahydrofuran at 80℃;
4-Iodoimidazole (0101-1) (10.0 g, 51.6 mmol, 1.0 eq.)Dissolved in 150 ml of tetrahydrofuran,Triphenylmethyl chloride (17.2 g, 61.7 mmol, 1.2 equivalents) andTriethylamine (14.5 ml, 10.4 mmol, 2.0 eq),Heat to 80°C and react overnight.Cooled to room temperature, concentrated under reduced pressure, added ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Methanol and a small amount of dichloromethane were added and stirred for half an hour. The solid was collected by suction, washed twice with methanol, and vacuum dried. ,4-Iodo-1-trityl-1H-imidazole (16 g, yield: 71percent) was obtained as a white solid.
66%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 14 h;
After dissolving 4-iodo-1H-imidazole (3.0 g, 0.015 mol) and triphenylmethyl chloride (6.0 g, 0.021 mol) in anhydrous N, N-dimethylformamide (50 mL) Deg.] C, triethylamine (7.2 mL, 0.052 mol) was added slowly, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated, and then distilled water (100 mL) was added thereto. After stirring at room temperature for 20 minutes, the solid was filtered The filtrate was washed with distilled water and diethyl ether to give the title compound 60-a (4.4 g, 66percent) as a white solid.
59%
With triethylamine In water; N,N-dimethyl-formamide
Preparation 72 4-Iodo-1-triphenylmethyl-1H-imidazole To 4-iodo-1H-imidazole (Preparation 71, 3.0 g, 15.3 mmol) in N,N-dimethylformamide (25 ml) was added triphenylmethyl chloride (4.72 g, 16.9 mmol) and then triethylamine (2.5 ml, 18.4 mmol). After stirring at room temperature for 2.5 h, water (200 ml) was added and the reaction mixture was filtered and washed with water. The crude solid was chromatographed on silica gel eluding with hexane:ethyl acetate (5:1 and then 2:1). The material was then recrystallized from hexane and dichloromethane to give the title compound as a white solid (4.0 g, 59percent). NMR (CDCl3, selected data for the free base: 6.9 (m, 1H), 7.0-7.2 (m, 6H), 7.25-7.4 (m, 10H). MS (TSP): M/Z (MH+): 436.3; C22H17129IN2+H requires 437.1.
55.57%
With triethylamine In tetrahydrofuran at 70℃; for 3 h;
4-iodoimidazole (5.38g, 27.72mmol) was dissolved in THF (86ml_). Trityl chloride, (8.5g, 30.49mmol) and triethylamine (7.73ml_, 55.44mmol) were added and the reaction was heated at 70 °C. After 3 h, TLC showed that the reaction had gone to completion. Therefore, the reaction mixture was allowed to cool to 45 C and filtered to remove the suspended white solid. The filtrate was concentrated, redissolved in DCM (300 mL) and washed with 5 wtpercent aq. sodium thiosulfate solution (300 mL), which was back-extracted with DCM (150 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated to yield the crude product. The white solid was taken up in EtOAc (300ml) and heated to reflux for 30 minutes. The mixture was cooled and the solid was obtained by vacuum filtration. The white solid was dried in the vacuum oven for 3 hours affording 4- iodo-1 -trityl-imidazole (6.721 g, 15.40mmol, 55.57percent yield). MS Method 2: RT 2.08 min, ES+ m/z 459 [M+Na]+ H NMR (400MHz, DMSO) δ/ppm: 7.35-7.40 (m, 10H), 7.06-7.1 1 (m, 7H).
Reference：
[1] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 57 - 59
[2] European Journal of Medicinal Chemistry, 2017, vol. 140, p. 293 - 304
[3] Patent: CN107501272, 2017, A, . Location in patent: Paragraph 0085; 0086; 0091; 0092
[4] Patent: WO2004/96822, 2004, A2, . Location in patent: Page 262
[5] Patent: WO2004/96823, 2004, A2, . Location in patent: Page 44; 45
[6] Patent: JP2015/93833, 2015, A, . Location in patent: Paragraph 0057; 0058
[7] Patent: JP2015/93831, 2015, A, . Location in patent: Paragraph 0016; 0100; 0101
[8] Patent: JP2015/110563, 2015, A, . Location in patent: Paragraph 0016; 0078; 0079
[9] Patent: WO2004/96822, 2004, A2, . Location in patent: Page 239; 240
[10] Patent: US2016/75711, 2016, A1, . Location in patent: Paragraph 0216-0217
[11] Patent: WO2009/93981, 2009, A1, . Location in patent: Page/Page column 96
[12] Patent: CN108203438, 2018, A, . Location in patent: Paragraph 0142; 0143; 0144; 0145
[13] Patent: WO2016/59412, 2016, A1, . Location in patent: Paragraph 00200; 00201
[14] Synthesis, 1994, # 7, p. 681 - 682
[15] Patent: CN107383024, 2017, A, . Location in patent: Paragraph 0112
[16] Patent: KR101798840, 2017, B1, . Location in patent: Paragraph 1139-1142
[17] Journal of Medicinal Chemistry, 2008, vol. 51, # 10, p. 2944 - 2953
[18] Patent: US6313312, 2001, B1,
[19] Patent: WO2016/55786, 2016, A1, . Location in patent: Paragraph 00231
[20] Journal of Medicinal Chemistry, 1996, vol. 39, # 15, p. 3001 - 3013
[21] Journal of Organic Chemistry, 2007, vol. 72, # 10, p. 3741 - 3749
[22] Patent: US5932606, 1999, A,
[23] Patent: US2002/19527, 2002, A1,
42
[ 71759-89-2 ]
[ 60-29-7 ]
[ 76-83-5 ]
[ 96797-15-8 ]
Reference：
[1] Patent: US2003/125266, 2003, A1,
43
[ 50-99-7 ]
[ 76-83-5 ]
[ 54325-28-9 ]
Yield
Reaction Conditions
Operation in experiment
88%
at 80℃; for 4 h;
To glucose (5g; 0.0277 mole) as a suspension in pyridine (50 mL) was added trityl chloride and stirred at 8O0C for about 4 hours. The completion of the reaction was checked by TLC using dichloromethane: methanol (85:15). The reaction was quenched with water (100 mL) and extracted with dichloromethane (150 ml x 2). The organic layer was washed with saturated solution of sodium bicarbonate and water, dried over anhydrous sodium sulfate and the solvent was removed by rotory evaporator. Trityl Chloride and pyridine were removed by triturating with hexane: diethyl ether mixture (10OmL) to afford the desired product (10.3 g; 88percent), LC-MS gave the M+ at 446 amu in accordance with the structure.
With dmap; triethylamine In dichloromethane at 20℃; Inert atmosphere; Cooling
Trityl protected glycidol derivative 401 was prepared as described previously (Schweizer, et al., Synthesis 2007, 3807-3814; which is incorporated herein by reference.) A solution of (/?)-glycidol (5.0 g, 61 mmol) in CH2Cl2 (30 mL) was added by syringe to a stirred solution of trityl chloride (18.6 g, 66.8 mmol) and triethylamine (16.9 mL, 122 mmol) in CH2Cl2 (67 mL) in an ice bath under argon. DMAP (742 mg, 6.08 mmol) was added to the reaction mixture following addition of the glycidol. The reaction was allowed to warm to room temperature. After 14 hours, the reaction mixture was diluted with 300 mL saturated aqueous NH4CI. The mixture was further diluted to ~ 1 L with water to dissolve precipitated salts. The product was extracted from the quenching solution with Et2O (3 x); combined ethereal layers were washed with brine, dried over MgSO4, filtered through paper, and concentrated by rotary evaporation to a white solid. The crude product was purified by recrystallization from boiling MeOH (200 mL) affording the desired product 401 (14.1 g, 73percent) as white crystals. NMR analysis of this material was consistent with that reported in the literature. (Schweizer, et al., Synthesis 2007, 3807-3814.)
Reference：
[1] Synthesis, 2007, # 24, p. 3807 - 3814
[2] Tetrahedron Letters, 2000, vol. 41, # 33, p. 6323 - 6326
[3] Journal of Organic Chemistry, 2003, vol. 68, # 8, p. 3026 - 3042
[4] Journal of Organic Chemistry, 2013, vol. 78, # 11, p. 5172 - 5183
[5] Patent: WO2010/53572, 2010, A2, . Location in patent: Page/Page column 163
[6] ACS Chemical Neuroscience, 2018,
[7] Tetrahedron Letters, 1994, vol. 35, # 20, p. 3243 - 3246
[8] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1994, # 16, p. 2229 - 2236
[9] Journal of Organic Chemistry, 1998, vol. 63, # 6, p. 1961 - 1973
[10] Tetrahedron Letters, 1999, vol. 40, # 12, p. 2371 - 2374
[11] Patent: WO2006/14429, 2006, A2, . Location in patent: Page/Page column 11; figure 3
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 6 h;
General procedure: The 4-hydroxybenzaldehyde 4 (0.8 g, 6.5 mmol) was reacted with 4-monometoxytriphenylmethyl (1.0 g, 3.2 mmol) in 10 mL of anhydrous DCM in the presence of DIEA (2.2 mL, 12.9 mmol). After 6 h at r.t., the reaction was quenched by dilution with DCM (100 mL), and the organic phase was washed three times with a solution of 0.1 M NaOH (3×100 mL). The organic phase was dried with MgSO4, and then the solvent was removed under vacuum. The crude material was then purified on a column of silica gel (70 g) suspended in hexane/EtOAc 70:30 (v/v) with 1percent of TEA, leading to product 5 (1.05 g, 82percent). 1H NMR (400 MHz, 25°C, δ, ppm in CDCl3): δ 9.76 (s, 1H), 7.57–7.25 (complex signals, 14H), 6.86 (d, J=8.5 Hz, 2H), 6.82 (d, J=8.0 Hz, 2H), 3.77 (s, 3H). 13C NMR (100 MHz, 25°C, δ, ppm in CDCl3): δ 190.7, 161.9, 158.7, 143.8, 134.9, 130.6, 130.2, 128.3, 127.8, 127.3, 120.3, 113.1, 91.1, 55.0. Product 5 (1.05 g, 2.66 mmol) was subsequently treated with 0.25 g of NaBH4 (6.60 mmol) in THF (10 mL) for 6 h at r.t. The mixture was diluted with DCM (3×100 mL), and the organic phase was washed three times with water (100 mL). The organic phase was dried with MgSO4, and then the solvent was removed under vacuum. The crude solid thus obtained was purified on a column of silica gel (70 g) suspended in hexane/EtOAc 60:40 (v/v) with 1percent of TEA. From the column was recovered 0.845 g of clean desired product 6 (2.13 mmol, 80percent). 1H NMR (400 MHz, 25°C, δ, ppm in CDCl3): δ 7.49 (d, J=6.0 Hz, 4H), 7.37–7.22 (complex signals, 8H), 6.98 (d, J=7.2 Hz, 2H), 6.79 (d, J=7.2 Hz, 2H), 6.70 (d, J=6.8 Hz, 2H), 4.45 (s, 2H), 3.75 (s, 3H). 13C NMR (100 MHz, 25°C, δ, ppm in CDCl3): δ 158.4, 155.8, 144.5, 135.6, 133.3, 130.4, 128.6, 127.6, 127.4, 126.9, 120.6, 112.8, 90.0, 64.8, 55.0. Then, 0.40 g (1.01 mmol) of product 6 was reacted with N,N-diisopropyldichlorophosphoramidite (124 μL, 0.67 mmol) in the presence of DIEA (348 μL, 2.68 mmol) in DCM (7 mL). After 1.5 h, the reaction was quenched by dilution with DCM, and the organic phase was washed three times with cold water. The organic phase was dried with MgSO4 and the solvent removed under vacuum. The material was purified with column chromatography of silica gel in hexane/EtOAc 85:15 (v/v) with 2percent of TEA. From the column was recovered 0.74 g of clean desired product (1, 87percent).
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 10, p. 2979 - 2988
[2] Tetrahedron Letters, 2017, vol. 58, # 12, p. 1227 - 1229
55
[ 269410-08-4 ]
[ 76-83-5 ]
[ 863238-73-7 ]
Reference：
[1] Journal of the American Chemical Society, 2017, vol. 139, # 1, p. 211 - 217
With triethylamine In dichloromethane at 15 - 23℃; for 3.5 h; Flow reactor; Large scale
I. Candesartan (10kg) and methylene chloride (100kg) were added to the reactor, and the temperature was lowered to 15°C. Triethylamine (4.5kg) was slowly added dropwise; after the addition was completed, the temperature of the reaction system was raised to 23°C. Triphenylchloromethane (7kg) was added in portions; after the addition, the reaction system temperature was maintained at 23°C for 3.5 hours; TLC monitoring (developer dichloromethane:methanol = 10:1 (V/V),Rf = 0.78) After the reaction is complete, add 0.1 mol/L HCl 30L (system pH = 5.4) at a time, add 5L 9mol/L HCl slowly to pH = 2.2, and separate the aqueous and organic layers by standing. 60L for the organic layer. The saturated saline solution was washed, transferred to a vacuum vessel, and the dichloromethane was recovered under reduced pressure.The residue in the kettle was added with 65 L of ethanol, and the temperature was raised to 45° C. and stirred for 3 hours until a large amount of white solid precipitated. The heating was stopped, and the temperature was lowered to room temperature. The filter cake was washed with a small amount of ethanol and dried at normal pressure at 50° C. for 12 hours to obtain three. Phenyl candesartan (white crystalline powder, 14.5 kg). Calculated according to the following formula, the yield of this step is 94.0percent.
90%
With triethylamine In acetone at 55 - 60℃; for 4 - 8 h;
Examples-l; Preparation of tritylated Candesartan acid (acetone) A mixture of Candesartan acid, triethylamine and acetone was heated to reflux temperature at 55-600C. To this trityl chloride solution in acetone was added and refluxed it for 4-8 hours. The reaction mixture was cooled at ambient temperature followed by addition of D. M. water and stirred for one hour. The reaction mixture was filtered and washed with mixture of acetone and D. M. water. To the solid, D. M water was added and stirred for 30 minutes at ambient temperature. The mixture was filtered and washed with D. M. water. The solid was dried to obtain tritylated Candesartan acid. Yield: 90 percent Purity: 99percent
90%
With triethylamine In acetone at 55 - 60℃;
A mixture of Candesartan acid, triethylamine and acetone was heated to reflux temperature at 55-60° C. To this trityl chloride solution in acetone was added and refluxed it for 4-8 hours. The reaction mixture was cooled at ambient temperature followed by addition of D. M. water and stirred for one hour. The reaction mixture was filtered and washed with mixture of acetone and D. M. water. To the solid, D. M water was added and stirred for 30 minutes at ambient temperature. The mixture was filtered and washed with D. M. water. The solid was dried to obtain tritylated Candesartan acid.Yield: 90percentPurity: 99percent
89%
With triethylamine In methyl iso-butyl ketone (MIBK) at 55 - 60℃; for 4 - 8 h;
ExampIes-2; Preparation of tritylated Candesartan acid (MIBK)A mixture of Candesartan acid, triethylamine and methyl isobutyl ketone (MIBK) was heated to reflux temperature at 55-600C. To this trityl chloride solution in MIBK was added and refluxed it for 4-8 hours. The reaction mixture was cooled at ambient temperature followed by addition of D. M. water and stirred for one hour. The reaction mixture was filtered and washed with mixture of acetone and D. M. water. To the solid, D. M water was added and stirred for 30 minutes at ambient temperature. The mixture was filtered and washed with D. M. water. The solid was dried to obtain tritylated Candesartan acid. Yield: 89 percent Purity: 98.5percent
88%
With triethylamine In butanone at 55 - 60℃; for 4 - 8 h;
Examples-3; Preparation of tritylated Candesartan acid (MEK) A mixture of Candesartan acid, triethylamine and methyl ethyl ketone (MEK) was heated to reflux temperature at 55-600C. To this trityl chloride solution in MEK was added and refluxed it for 4-8 hours. The reaction mixture was cooled at ambient temperature followed by addition of D. M. water and stirred for one hour. The reaction mixture was filtered and washed with mixture of acetone and D. M. water. To the solid, D. M water was added and stirred for 30 minutes at ambient temperature. The mixture was filtered and washed with D. M. water. The solid was dried to obtain tritylated Candesartan acid. Yield: 88 percent .bul. Purity: 98percent
83.8%
With triethylamine In dichloromethane at 25 - 30℃; for 2 h; Heating / reflux
Example-1: Preparation of Candesartan cilexetil (with isolation of cilexetil trityl candesartan); Step-I: Preparation of Trityl candesartanTo solution of Candesartan (10Og in 350 ml MDC) and triethyl amine (34.3 g) Trityl chloride (76.8g in 150 ml MDC) is added slowly at temperature of 25 - 3O0C. Temperature of the reaction mass is raised and maintained at reflux temperature for 2 hrs. Reaction mass is cooled to temperature of 30 - 350C, water (100 ml) is added, stirred for about 15 min, allowed to settle and separated the layers. Aqueous layer is extracted with MDC (2x 100 ml), combined organic layer is washed with water and MDC is removed below 5O0C from organic layer. Ethyl acetate (600 ml) is added, raised and maintained the temperature of the reaction mass at reflux temperature for 2hrs. The temperature of the mass is cooled, maintained for 1 hr at 25 - 3O0C and isolated the product by filtration. Wet cake is washed with ethyl acetate (100 ml) and dried at temperature of 45 - 5O0C to constant weight. <n="7"/>The weight of trityl candesartan is 130 g (Yield 83.8percent)
53%
With triethylamine In dichloromethane at 20℃; for 2.5 h;
To a solution of 2-ethoxy-1-[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl}-benzimidazole-7-carboxylic acid (78 mg) in methylene chloride (1ml) were added trityl chloride (63 mg) and triethylamine (0.03ml). The mixture was stirred at room temperature for two hours thirty minutes. The reaction mixture was washed with water, dried and concentrated to dryness. The residue was purified by column chromatography on silica (eluant: cyclohexane /ethyl acetate: from to 90/10 to 0/100) to give 2-ethoxy-1-[{2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]-1,1'-biphenyl-4-yl}methyl]-benzimidazole-7-carboxylic acid (60mg, 53percent yield) as a white solid. 1H-NMR (400MHz, CDCl3) δ 1.40 (t, J=7Hz, 3H), 4.62 (q, J=7Hz, 2H), 5.59 (s, 2H), 6.76 (d, J=8Hz, 2H), 6.92-6.96 (m, 8H), 7.14 (t, J=8Hz, 1 H), 7.19-7.30 (m, 10H), 7.38 (m, 2H), 7.64 (d, J=8Hz, 1 H), 7.76-7.83 (m, 2H) ppm.
125.5 g
With triethylamine In dichloromethane at 25 - 35℃; for 20 h;
250 g of tributyl tin azide was added into 600 ml of xylene. 100 g of candesartan cyclic compound (in formula II, R is ethyl) was added, heated to 140-150° C., and refluxed to react for 20 h. After the end of the reaction, the reaction mixture was cooled to 40-50° C. 600 ml of sodium hydroxide solution (48 g of sodium hydroxide dissolved in 600 ml of water) was added, and stirred under 20-35° C. (0032) The organic layer was removed. (0033) The alkaline aqueous layer was heated to 70-80° C. to completely hydrolyze candesartan ethyl ester. The temperature of the mixture was controlled at 25-35° C. 400 ml of dichloromethane was added. Glacial acetic acid was added dropwise to adjust pH of the mixture to 5-6 to precipitate candesartan. (0034) Triethylamine was added dropwise into the mixture until the candesartan solid was dissolved completely. The dichloromethane layer was separated. The aqueous layer was extracted by adding 200 ml of dichloromethane once again. The organic layers were combined. 68 g of triphenyl chloromethane was added into the organic layer. The temperature of the mixture was controlled at 25-35° C. to react until the content of candesartan was reduced to less than 1.0percent monitored by HPLC. After the end of the reaction, 100 ml of water was added for washing. The aqueous layer was removed. The organic layer was dried under reduced pressure. 600 ml of anhydrous ethanol was added to crystallize. The resulting crystals were collected by filtration, and dried to provide 125.5 g of trityl candesartan, yield 78.2percent, purity 97
WORKING EXAMPLE 6 2-Ethoxy-1-[[2'-(N-triphenylmethyltetrazol-5-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid To a solution of 2-ethoxy-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (2.07 g) in methylene chloride (10 ml) were added trityl chloride (1.59 g) and triethylamine (0.8 ml). The mixture was stirred at room temperature for one hour. The reaction mixture was washed with water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to give crystals. Recrystallization of crude crystals thus obtained from ethyl acetate-benzene gave colorless crystals (2.12 g, 66percent), m.p. 168°-170° C. 1 H-NMR(200 MHz, CDCl3) δ: 1.40(3H,t), 4.61(2H,q), 5.58(2H,s), 6.76(2H,d), 6.91-6.96(8H,m), 7.12(1H,t), 7.17-7.41(12H,m), 7.60(1H,dd), 7.73-7.82(2H,m)
Reference：
[1] Patent: US5196444, 1993, A,
59
[ 821-25-0 ]
[ 76-83-5 ]
[ 139481-59-7 ]
[ 139481-72-4 ]
Reference：
[1] Patent: US6177587, 2001, B1,
60
[ 76-83-5 ]
[ 5401-94-5 ]
[ 942189-39-1 ]
Yield
Reaction Conditions
Operation in experiment
10%
Stage #1: With bromine In methanol Stage #2: With sodium hydride In N,N-dimethyl-formamide
(S)-N-(3-(6-isopropoxypyridin-3-yl)- 1H-indazol-5-yl)- 1 -(2-(4-(4-(1 -methyl-1H- 1 ,2,4-triazol-3 -yl)phenyl)-3 , 6-dihydropyridin- 1 (2H)-yl)-2-oxoethyl)-3 -(methylthio)pyrrolidine3-carboxamide free base synthesis is a 19 step process. Compound preparation is divided into three intermediate preparations A, B and C followed by coupling of the intermediates. Allintermediates start with commercially available compounds. Compound 5 is prepared by reaction of the commercially available bromo-4-cyanobenzene with methyl hydrazine under acidic conditions to form the hydrazinoimidate 2 in modest yield. After reaction with formic acid in two steps the bromophenyl-N-methyl triazole intermediate 3 is obtained. The tetrahydropyridine ring is introduced by a Suzuki reaction of the commercially available Bocprotected tetrahydropyridine-boronate to obtain the tricyclic ring system 4. Chloroacetamide 5 is obtained in excellent yield by reaction of the deprotected 4 with chloroacetylchloride. The pyrrolidine core lOa is obtained in good yield in 5 steps starting from commercially available 6. Reaction with thionylchloride gave the thiomethyl olefin 7. Cycloaddition (2+3) gives 8 followed by removal of the benzyl protection group to give 9. L-Tartaric acid resolution of thepyrrolidine core gives the pure (5) enantiomer 9 after filtration from methanol. After protection as the Boc derivative and hydrolysis of the methyl ester, 10 is obtained in overall 50percent yield. Compound 17 is obtained from commercially available indazole 11. Bromination at the 3- position of indazole 11 proceeds in excellent yield without chromatography to obtain 12. Suzuki reaction of the bromo compound 12 with 14 gives the nitro indazole 16 after chromatography.Reduction of 16 gives aniline 17 as an oil in quantitative yield without chromatography. The final coupling of the intermediates proceeded by coupling 17 with lOa to obtain 18 in good yield. After deprotection of the Boc and Trityl groups the final coupling with 5 gave (S)-N-(3-(6- isopropoxypyridin-3-yl)- 1H-indazol-5-yl)-1 -(2-(4-(4-(1 -methyl-1H- 1 ,2,4-triazol-3-yl)phenyl)- 3 ,6-dihydropyridin- 1 (2H)-yl)-2-oxoethyl)-3 -(methylthio)pyrrolidine-3 -carboxamide afterchromatography. Final purification is carried out by crystallization from methanol/diethylether.This synthetic route has been conducted on a scale that delivered (S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)- 1 -(2-(4-(4-(1 -methyl-1H- 1 ,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1 (2H)-yl)-2-oxoethyl)-3 -(methylthio)pyrroli dine-3 -carboxamide free base (Compound I).
With triethylamine In dichloromethane at 0 - 30℃; for 15.5 h;
To BIH (100 g, 1 eq) was added methylene chloride (500 mL, 5 vol), and the mixture was dissolved. Triethylamine (32.3 mL, 1.1 eq) was added thereto, and the reaction mixture was cooled to 0°C - 5°C. A solution of trityl chloride (63.22 g, 1.08 eq) in methylene chloride (300 mL, 3 vol) was slowly added thereto at 0°C - 5°C over 30 min, and the reaction mixture was stirred at 25°C - 30°C for 12 hr. Trityl chloride (2.92 g, 0.05 eq) was added, and the reaction mixture was further stirred for 3 hr. Using TLC (thin layer chromatography) (TLC eluent: 10percent methanol/methylene chloride, detection method: UV), complete disappearance of BIH was confirmed. [0300] The reaction mixture was cooled to 0°C - 5°C, desalting water (270 mL, 2.7 vol) was added, and the mixture was stirred at 25°C - 30°C for 15 min. The mixture was left standing and partitioned. The aqueous layer was extracted with methylene chloride (200 mL, 2 vol), the extracts were combined with the organic layer, and the mixture was washed with deionized water (500 mL, 5vol). The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure at 40°C - 45°C to give BIT (135 g, 89percent).
75.4%
With triethylamine In dichloromethane at 0 - 25℃; for 4.5 h;
Example 1-3 (0323) (0324) To a mixture of BIH (0.656 g, 1.38 mmol), triethylamine (0.22 mL, 1.52 mmol) and methylene chloride (7.8 mL, 12 vol) was added a solution of trityl chloride (0.416 g, 1.49 mmol) in methylene chloride (1.5 mL) at 0-5° C., and the mixture was stirred at the same temperature for 1 hr and at 25° C. for 3.5 hr. The reaction mixture was concentrated under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (17-18percent ethyl acetate/hexane) to give BIT (746 mg, yield 75.4percent). (0325) 1H NMR (CDCl3): δ=7.88 (d, J=1.6 Hz, 1H), 7.50-7.44 (m, 2H), 7.37-7.24 (m, 6H), 7.09 (d, J=8.4 Hz, 2H), 6.96-6.94 (m, 6H), 6.72 (d, J=8.4 Hz, 2H), 5.81 (s, 1H), 5.35 (s, 2H), 4.13 (q, J=7.2 Hz, 2H), 2.51 (t, J=7.6 Hz, 2H), 1.64 (s, 6H), 1.69-1.61 (m, 2H), 1.08 (t, J=7.2 Hz, 3H), 0.88 (t, J=7.2 Hz, 3H); (0326) Mass: 717.6 [M+H]+.
L-Cysteine hydrochloride (100 g, 0.634 mol) and trityl chloride (270 g, 0.969 mol) were stirred in DMF (400 mL) for 2 days at room temperature. A 10percent sodium acetate solution (3.5 L) was then added dropwise and the white precipitate which formed was filtered and washed with distilled water. Afterward, the residue was stirred in acetone at 50° C. for 30 min after which it was cooled to 0° C. and filtered. The precipitate was washed with a little acetone and diethyl ether and dried in vacuo. S-Trityl-L-cysteine 1b (205 g, 89percent) was obtained as a white powder. 1b: m.p. 192° C. (decomp). 1H NMR (DMSO-d6) delta 2.45 (dd, 1H, J=9 Hz, 12 Hz), 2.58 (dd, 1H, J=4.4 Hz, 12 Hz), 2.91 (m, 1H), 7.22-7.36 (m, 15H); 13C NMR (75.5 MHz, DMSO-d6): delta 33.8, 53.7, 66.4, 127.1, 127.8, 128.1, 128.4, 129.5, 144.5, 168.4. This material was directly used in the next step without further purification.
89%
With sodium acetate; In N,N-dimethyl-formamide; at 20℃; for 48h;
L-Cysteine hydro-chloride (100 g, 0.634 mol) and trityl chloride (270 g, 0.969 mol) were stirred in DMF (400 mL) for 2 days at room temperature. A 10percent sodium acetate solution (3.5 L) was then added dropwise and the white precipitate which formed was filtered and washed with distilled water. Afterward, the residue was stirred in acetone at 50 0C for 30 min after which it was cooled to 00C and filtered. The precipitate was washed with a little acetone and diethyl ether and dried in vacuo. S-Trityl-L-cysteine Ic (205 g, 89percent) was obtained as a white powder. Ic: m.p. 192 °C (decomp) ; 1H NMR (300 MHz, DMSCW5) delta 2.45 (dd, IH, J= 9 Hz, 12 Hz), 2.58 (dd, IH, J= 4.4 Hz, 12 Hz), 2.91 (m, IH), 7.22-7.36 (m, 15H); 13C NMR (75.5 MHz, DMSO- d6): delta 33.8, 53.7, 66.4, 127.1, 127.8, 128.1, 128.4, 129.5, 144.5, 168.4. This material was directly used in the next step without further purification.
78%
In N,N-dimethyl-formamide; at 20℃; for 48h;
Preparation 75: Synthesis of (R)-3-amino-4-tritylsulfanyl-butyric acid methyl ester hydrochloride; (Step 1); L-cysteine hydrochloride (5Og, 284.7mmol) was dissolved in N,N- dimethylformamide (200ml). Trityl chloride (119g, 427.0mmol) was added thereto, and the mixture was stirred for 48 h at room temperature. After completion of the reaction, 10percent sodium acetate (1.5L) was added. The mixture was filtered to give a solid, which was then added to acetone (1.5L), and stirred for 30 min at 50 °C . The insoluble solid was filtered, and dried to give a trityl compound (80g, Yield 78percent).
77%
In N,N-dimethyl-formamide; at 20℃; for 48h;
Synthetic Example 1; (R)-3-Mercapto-2-(5-methyl-4-phenyl-thiazoI-2-yIamino)-propionic acid; Step 1 : S-Trityl-L-cysteine falso known as (R)-2-amino-3- (tritylsulfanyl)propanoic acid); L-Cysteine hydrochloride (5.0 g, 31.7 mmol) and trityl chloride (13.5 g, 48.4 mmol) were stirred in DMF (20 ml) for 48 h at room temperature. A 10percent NaOAc solution (175 mL) was then added, and the precipitate was filtered and washed with water. Afterward, the residue was suspended in acetone and stirred at 50 °C for 30 min, then cooled and filtered. The residue was washed with acetone (cold) and diethyl ether. After drying 8.86 g (77percent) S-trityl-L-cysteine was obtained.
Preparation of (Z)-(Tritylamino-2-thiazol-4yl)-2-Tritylxoyimino ethyl acetate (V) To a suspension of (Z) 2-(2-aminothiazol-4-yl)-2hydroxyimino ethyl acetate (80 g, 0.372 moles) in acetonitrile (840 ml) was added to triethylamine (155.6 ml, 1.11 moles) and the mixture was stirred at a temperature of between 20 C. to 25 C. for 10 minutes, under one atmosphere of nitrogen. To this was added trityl chloride (238.6 g, 0.858 moles) in one lot under gentle stirring. Thereafter, the reaction was stirred at a temperature of between 55 C. to 60 C. for 1 hour. Acetonitrile was distilled out at atmospheric pressure and to the resulting thick slurry was added water (2400 ml). A precipitate formed which was filtered, washed with water, and dried to give 259 g (99.2%) of (Z)-(Tritylamino-2-thiazol-4yl)-2-Tritylxoyimino ethyl acetate (V) as a white solid.
85%
With triethylamine; In N,N-dimethyl-formamide; at 50℃;
Example 12; (Z)-5-benzo[d]thiazol-2-yl-2-(5-chloro-2-(tritylamino)thiazol-4-yl)-2- (trityloxyimino)ethanethioate; Step 1 : To a solution of (Z)-ethyl-2-(2-aminothiazol-4-yl)-2- (hydroxyimino)acetate 1 (21.5 g, 0.1 mol) in 100 mL DMF, Et3N (30.6 mL, 0.22 mol) was added. Then, TrCl (64 g, 0.22 mol) was added during 20 minutes, the reaction solution was stirred at 5O0C for 48 h until LC-MS indicated the reaction was over. The reaction solution was slowly poured into water (600 mL). (Z)-ethyl-2-(2- (tritylamino)thiazol-4-yl)-2-(trityloxyimino)acetate 2 was obtained as a white solid in 85% yield. The resulting product was used without further purification.
85%
With triethylamine; In N,N-dimethyl-formamide; at 50℃;
Step 1: To a solution of (Z)-ethyl-2-(2-aminothiazol-4-yl)-2- (hydroxyimino)acetate 1 (21.5 g, 0.1 mol) in 100 niL DMF, Et3N (30.6 niL, 0.22 mol) was added. Then, TrCl (64 g, 0.22 mol) was added during 20 minutes, the reaction solution was stirred at 5O0C for 48 hrs until LC-MS indicated the reaction was over. The reaction solution was slowly poured into water (600 mL). (Z)-ethyl-2-(2- (tritylamino)thiazol-4-yl)-2-(trityloxyimino)acetate 2 was obtained as a white solid in 85% yield. The resulting product was used without further purification.
Example 33; (Z)-5-benzo[d]thiazol-2-yl-2-(5-(trifluoromethyl)-2-(tritylamino)thiazol-4-yl)-2-(trityloxyimino)ethanethioate; Step 1 : To a solution of 1 (43 g, 0.2 moL) in 300 mL DMF was added 63 mL TEA. The mixture was stirred for 10 min, then 123 g of trityl chloride was added and the mixture was kept at 50 0C for 72 hrs. The mixture was concentrated and extracted with acetic ether. The acetic ether was washed with 1% NaOH solution three times, the organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was dried in vacuum overnight to provide (Z)-ethyl-2-(2-(tritylamino)thiazol-4-yl)-2-(trityloxyimino)acetate 2 (120 g, yield 85%).
Compound XIII (880g, 12.9mol, 1.0eq.) In the autoclave 50L, 12L DMF were dissolved, cooled To below 0 °C, triethylamine (1308g, 12.9mol, 1.0eq. ) The reaction was kept 30min, 0 ° C solution of the following threePhenyl chloride (3605.0g, 12.9mol, 1.0eq. ) In DMF (16L), drops Bi, 15 ° C overnight with stirring 16 h. Thereaction mixture was poured into water, large amount of solid precipitated, suction filtered, the filter cake washedwith water, drained, dried to obtain compound XIV-1 White The solid 3835.1g, Yield: 95.6percent.
91%
1-trityl-midazol (Compound 28, Scheme 19) was prepared by adding Et3N (5.1 ml, 36.7 mmol) at 0° C. to a stirred solution of the imidazole Compound 27 (2.5 grams, 36.7 mmol) dissolved in 75 ml DMF. After 30 minutes of stirring, trityl-chloride (10.3 grams, 36.7 mmol) dissolved in DMF (45 ml) was added slowly to the reaction mixture, and the reaction mixture was allowed to reach room temperature while stirred continuously for over night. Thereafter the reaction mixture was quenched with cold water (1 L) to precipitate a solid, which was collected by filtration and recrystallized from hexane/DCM to afford Compound 28 as a white solid (91percent yield).1H NMR (500 MHz, CDCl3)-delta: 7.47 (s, 1H), 7.33-7.30 (m, 9H), 7.16-7.12 (m, 6H), 7.07 (s, 1H), 6.83 (s, 1H).
90%
With ammonium chloride; triethylamine; In dichloromethane;
Example 22 Synthesis of 1-tritylimidazole (5) To a solution of trityl chloride (5.58 g, 20.0 mmol.) in dry methylene chloride (100 ml) cooled down to 0° C. and stirred under Ar, was added dropwise over 1.5 hours a solution of imidazole (1.36 g, 20.0 mmol.) and triethylamine (2.7 mml, 20 mmol.) in 50 ml dry methylene chloride. At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred under Ar at that temperature overnight. The reaction mixture was then washed with 20 ml of a 10percent solution of ammonium chloride, then with 20 ml of distilled water. The organic phase was dried over magnesium sulfate and evaporated in vacuo to yield quantitatively a white solid. Recrystallization from methylene chloride/hexanes yielded 5.60 g of (5) (yield=90percent after recrystallization). m.p. 214° C.; 1H NMR (200 MHz, CDCl3) delta7.43 (m, 1H, NCHN), 7.3-7.4 (m, 9H, 3*C6H5), 7.1-7.2 (m, GH, 3*C6H5), 7.0 (m, 1H, Ph3CNCH=CH), 6.81 (m, 1H, Ph3CNCH=CH); 13C NMR (50 MHz, CDCl3) delta142.3, 139.0, 129.6, 128.2, 128.3, 121.6.
90%
With ammonium chloride; triethylamine; In dichloromethane;
Example 22 Synthesis of 1-tritylimidazole (5) STR73 To a solution of trityl chloride (5.58 g, 20.0 mmol.) in dry methylene chloride (100 ml) cooled down to 0° C. and stirred under Ar, was added dropwise over 1.5 hours a solution of imidazole (1.36 g, 20.0 mmol.) and triethylamine (2.7 mml, 20 mmol.) in 50 ml dry methylene chloride. At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred under Ar at that temperature overnight. The reaction mixture was then washed with 20 ml of a 10percent solution of ammonium chloride, then with 20 ml of distilled water. The organic phase was dried over magnesium sulfate and evaporated in vacuo to yield quantitatively a white solid. Recrystallization from methylene chloride/hexanes yielded 5.60 g of (5) (yield=90percent after recrystallization). m.p. 214° C.; 1 H NMR (200 MHz, CDCl3) delta 7.43 (m, 1H, NCHN), 7.3-7.4 (m, 9H, 3xC6 H5), 7.1-7.2 (m, 6H, 3xC6 H5), 7.0 (m, 1H, Ph3 CNCH=CH), 6.81 (m, 1H, Ph3 CNCH=CH); 13 C NMR (50 MHz, CDCl3) delta 142.3, 139.0, 129.6, 128.2, 128.3, 121.6.
90%
With ammonium chloride; triethylamine; In dichloromethane;
Example 22 Synthesis of 1-tritylimidazole (5) STR70 To a solution of trityl chloride (5.58 g, 20.0 mmol.) in dry methylene chloride (100 ml) cooled down to 0° C. and stirred under Ar, was added dropwise over 1.5 hours a solution of imidazole (1.36 g, 20.0 mmol.) and triethylamine (2.7 mml, 20 mmol) in 50 ml dry methylene chloride. At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred under Ar at that temperature overnight. The reaction mixture was then washed with 20 ml of a 10percent solution of ammonium chloride, then with 20 ml of distilled water. The organic phase was dried over magnesium sulfate and evaporated in vacuo to yield quantitatively a white solid. Recrystallization from methylene chloride/hexanes yielded 5.60 g of (5) (yield=90percent after recrystallization). m.p. 214° C.; 1 H NMR (200 MHz, CDCl3) delta7.43 (m, 1H, NCHN), 7.3-7.4 (m, 9H, 3*C6 H5), 7.1-7.2 (m, 6H, 3*C6 H5), 7.0 (m, 1H, Ph3 CNCH=CH), 6.81 (m, 1H, Ph3 CNCH=CH); 13 C NMR (50 MHz, CDCl3) delta142.3, 139.0, 129.6, 128.2, 128.3, 121.6.
In 5,5-dimethyl-1,3-cyclohexadiene; water; ethyl acetate;
EXAMPLE VII 1-TRITYLIMIDAZOLE To a stirred solution of 23.5 g (0.35 mole) of imidazole in 425 mL of ethyl acetate was added 48.0 g (0.32 mole) of triphenylmethyl chloride. The mixture was stirred for 20 hours and then 500 mL of water was added. After being stirred for an additional 2 hours, the mixture was filtered. The ethyl acetate layer was separated, dried (MgSO4) and concentrated. Recrystallization of the residue from xylene gave 41 g of white crystals, mp 222°-225° C..
Ethyl (Z)-2-(2-Aminothiazol-4-yl)-2-trityloxyiminoacetate Sodium hydride (60% dispersion in mineral oil, 13.2 g, 0.33 mol) was added portionwise to a cold (0 C.) mixture of ethyl (Z)-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate (64.5 g, 0.3 mol) in dry THF (1 L) with vigorous stirring and the mixture was stirred for 0.5 hr. at room temperature. To the mixture was added a solution of trityl chloride (92.0 g, 0.33 mol) in dry THF (0.2 L) with cooling and stirring. The mixture was stirred for 2 hr. at ambient temperature and evaporated under reduced pressure. Chloroform (1 L) was added to the residue and the mixture was washed with water. The insoluble material was filtered and the organic layer of the filtrate was separated. The insoluble material was extracted again with a mixture of chloroform (300 ml) and methanol (50 ml) by sonication for 10 min. and subsequent filtration. The extract was combined with the separated organic layer and evaporated under reduced pressure. The residue was triturated with toluene (0.3 L) to crystallize the product as colorless prisms, which were collected by filtration, washed with a small toluene and dried in vacuo. Yield, 91.2 g (66%). The filtrate was evaporated and treated with toluene to give 19.2 g of the second crop. Total yield, 110.4 g (80%). MP 181-183 C. IR numax (KBr)cm-1 3450, 1735, 1620. 1 H NMR (60 MHz, CDCl3) delta1.30 (3H, t, J=7 Hz, CH3), 4.37 (2H, q, J=7 Hz, CH2), 5.93 (2H, s, NH2), 6.42 (1H, s, thiazole-H), 7.3 (15H, s, phenyl). Anal Calcd for C26 H23 N3 O3 S 0.6 (CHCl3): C 60.38, H 4.50, N 7.94, S 6.06. Found: C: 60.68, H 4.38, N 7.95, S 6.10.
With pyridine; In N,N-dimethyl-formamide; at 50℃; for 6h;
1H-<strong>[1072-84-0]imidazole-4-carboxylic acid</strong>(5.0 g, 44.6 mmol) and triphenylchloromethane (13.8 g, 49.1 mmol)It was added to a mixture of 50 ml of DMF and 2.5 ml of pyridine. After the addition, the temperature is raised to 50 ° C for 6 h.The reaction was detected by HPLC. Post-treatment: The system is cooled, and the reaction system is slowly added to 100 ml of water.The gray solid precipitated, and the suspension was stirred for 1 hour and then filtered.The filter cake was washed with a small amount of water, dried for 30 min, and dried under vacuum at 50 ° C to obtain 15.8 g of a gray solid.Yield: 99.7percent.
95%
With pyridine; In N,N-dimethyl-formamide; at 20℃;
1-(Triphenylmethyl)-1H-<strong>[1072-84-0]imidazole-4-carboxylic acid</strong> was prepared as described in J. Med. Chem. 2001, 44, 1268. 1 H-lmidazole-4-carboxylic acid (0.50 g, 4.5 mmol) and trityl chloride (1.35 g, 4.9 mmol) were added to a solution of DMF (30 ml.) and pyridine (15 ml.) and stirred overnight. Water and EtOAc were added. The layers were separated and the aqueous layer extracted with EtOAc (2 x 50 ml_). The organic extracts were combined, washed with water and brine, dried over Na2SO4, filtered and evaporated. The oil was triturated with EtOAc to afford the title compound (1.5 g, 95percent) as a white solid. 1H NMR (400 MHz, DMSO-d6): delta ppm 12.40 (br. s., 1 H), 7.42 (t, 9 H), 7.17 - 7.35 (m, 2 H), 7.10 (d, 6 H). MS: m/z 1 11 (M-243).
79%
With pyridine; In N,N-dimethyl-formamide; at 20℃;
Example 6; To a RT solution of 1H-<strong>[1072-84-0]imidazole-4-carboxylic acid</strong> (1.12 g, 9.99 mmol) in pyridine (15 mL) and DMF (30 mL) was added triphenylmethyl chloride (3.06 g, 11.0 mmol). The reaction mixture was stirred at RT overnight, then was partitioned between EtOAc (500 mL) and H2O (50 mL). The organic phase was washed with H2O (20 mL), 10percent citric acid (20 mL) and brine (5 mL), dried (MgSO4) and concentrated in vacuo. The residue was triturated with EtOAc to afford 1-trityl-1H-<strong>[1072-84-0]imidazole-4-carboxylic acid</strong> (2.78 g, 79percent yield) as a white solid. LCMS Method A (ESI, positive ion spectrum): (M+H)/z=not observed, tR=3.27 min.
In step A, TF(4 mmol) is reacted with trityl chloride (8.8 mmol) and TEA (8 mmol) (Aldrich, 99%) in 40 ml of CHCl3 for four hours at room temperature. A clear solution is obtained. In step B, 40 ml of methanol is added into the above clear solution. The mixture is heated to 50 C. and stirred for one hour, a lot of precipitates appeared in the solution. After the reaction mixture is cooled down to room temperature, precipitates were collected by filtration. They were further purified from CHCl3/methanol. 3.4 mmol of Product B were obtained.
With triethylamine; In dichloromethane; at 20℃; for 24h;
Example 17: Synthesis of 1, 1, 1-TRIFLUORO-4- (5-FLUORO-2-METHOXYPHENYL)-2- (4-IMINO-4H- quinolin-1-ylmethyl)-4-methylpentan-2-ol A mixture of <strong>[578-68-7]4-aminoquinoline</strong> (H. SHINKAI et AL., J. Med. Chem. , 2000,43, pp. 4667-4677) (251 mg), chlorotriphenylmethane (533 mg), and triethylamine (266 pL) in methylene chloride (5 ML) was stirred at room temperature for 24 hours. The reaction mixture was then poured into saturated aqueous sodium bicarbonate solution and extracted twice with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 50% ethyl acetate-hexanes) to give quinolin-4-yltritylamine as a pale yellow foam (610 mg). To a suspension of quinolin-4-yltritylamine (428 mg) in anhydrous dimethylsulfoxide (3.4 mL) and tetrahydrofuran (0.6 mL) was added sodium hydride (60% dispersion in mineral oil, 44.3 mg) in one portion. After 30 minutes, 2- [2- (5-FLUORO-2-METHOXYPHENYL)-2-METHYLPROPYL]-2- trifluoromethyloxirane (292 mg) was added and the mixture stirred for 3 hours. The mixture was poured into half-saturated aqueous ammonium chloride and extracted twice with ethyl acetate. The combined organic phases were washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 0.2% triethylamine-ethyl acetate) to give a 2: 1 mixture of quinolin-4-yltritylamine and product, 1, 1, 1-TRIFLUORO-4- (5-FLUORO-2-METHOXYPHENYL)- 4-METHYL-2- [4- (TRITYLIMINO)-4H-QUINOLIN-1-YLMETHYL] PENTAN-2-OL (480 mg), which was used without further purification. To a solution of 1, 1, 1-TRIFLUORO-4- (5-FLUORO-2-METHOXYPHENYL)-4-METHYL-2- [4- (TRITYLIMINO)-4H- QUINOLIN-1-YLMETHYL] PENTAN-2-OL (470 mg) in methylene chloride (50 mL) was added trifluoroacetic acid (2 mL). After 2 hours, another portion of trifluoroacetic acid (1 mL) was added and the mixture was stirred for another 4 hours. The reaction was quenched by slow addition of saturated aqueous sodium bicarbonate solution and was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 8 to 10% methanol-methylene chloride) to give the title compound (84.2 mg), m. p. 137C-140C.
With triethylamine; In tetrahydrofuran; chloroform; at 23℃; for 3.25h;
To a suspension of 4R-hydroxypyrrolidine-2R-carboxylic acid methyl ester hydrochloride salt (7.94 g, 38. 2 mmol, 1 eq.; Product from Step 1 of Example 90) in [CHC13] (100 mL) at 23 [°C] was added Et3N (16.0 mL, 115 mmol, 3 eq. ) followed by trityl chloride (11.2 g, 40.1 mmol, 1.05 eq. ). After 15 min THF (15 mL) was added. The resulting mixture was stirred for 3 h, then partitioned between H20 (300 mL) and Et2O (400 mL). The layers were separated and the organic layer washed with 1.0 N [HC1] (300 mL), brine (200 mL), dried MgS04 and concentrated in vacuo. The product was purified via flash column chromatography on silica gel (40percent [ETOACHEXANES] as eluent) to give [4R-HYDROXY-1-TRITYLPYRROLIDINE-2R-CARBOXYLIC] acid methyl ester (7.37 g, 19.0 mmol, 50percent yield).
With triethylamine; In dichloromethane; at 0 - 20℃;
To a stirred suspension of 1.37 g (10.0 mmol) of <strong>[64051-79-2]3-hydroxypiperidine hydrochloride</strong> and 2.53 g (3.5 [ML)] of triethylamine in 30 mL of dichloromethane at 0 [C] was added dropwise 2.93 g (10.5 mmol) of trityl chloride. The mixture was stirred at ambient temperature overnight, diluted with 100 mL of dichloromethane, washed sequentially with water, 5% aqueous citric acid solution, saturated sodium bicarbonate solution, and brine, dried over sodium sulfate, and concentrated to give 3.85 g of the title compound as a white foam.
With triethylamine; In tetrahydrofuran; DMF (N,N-dimethyl-formamide);
Trityl chloride (59.8 g, 0.215 mol) was added to a solution of <strong>[4138-26-5]piperidine-3-carboxylic acid amide</strong> (25 g, 0.20 mol) and triethylamine (54 mL, 0.39 mol, 2equiv) in a mixture of THF and DMF (300 mL, 2:1) under N2. After stirring overnight, the reaction was quenched with methanol (15 mL) and then concentrated. The residue was dissolved in 200mL ethyl acetate and poured into 150 mL NaHCO3. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and water, dried (Na2SO4), and concentrated. Chromatography on silica gel (10percent methanol in chloroform) afforded N-1-trytylpiperidin-3-carboxylic acid amide 3a (60 g, 83percent) as a yellow solid.
With triethylamine; In methanol; N,N-dimethyl-formamide;
Step 1 Preparation of 1-trityl-<strong>[4928-88-5]1H-[1,2,4]triazole-3-carboxylic acid methyl ester</strong> A solution of <strong>[4928-88-5]1H-[1,2,4]triazole-3-carboxylic acid methyl ester</strong> (3.0 g, 0.23 mol) in N,N-dimethylformamide (76 mL) at 25° C. was treated with triphenylmethylchloride (7.2 g, 0.23 mol) and triethylamine (6.41 mL, 0.23 mol). The reaction mixture was stirred at 25° C. for 4 days and then diluted with ethyl acetate. The mixture was then washed with a dilute aqueous hydrochloric acid solution. At this time, methanol was added to the organic layer. A precipitate formed and was removed by filtration. The organics were further washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was triturated with diethyl ether. The solid was collected by filtration and washed again with diethyl ether to afford 1-trityl-<strong>[4928-88-5]1H-[1,2,4]triazole-3-carboxylic acid methyl ester</strong> as a white solid (2.45 g, 84percent) which was used without further purification: LR-FAB for C23H19N3O2 (M+) at m/z=369.
84%
With triethylamine; In N,N-dimethyl-formamide;
Step 1 Preparation of 1-trityl-<strong>[4928-88-5]1H-[1,2,4]triazole-3-carboxylic acid methyl ester</strong> A solution of <strong>[4928-88-5]1H-[1,2,4]triazole-3-carboxylic acid methyl ester</strong> (3.0 g, 0.023 mol) in N,N-dimethylformamide at 25° C. was treated with triphenylmethylchloride (7.2 g, 0.025 mol) and triethylamine (6.41 mL, 0.046 mol). The reaction was stirred at 25° C. for 4 days. At this time, the reaction was concentrated in vacuo. The residue was diluted with ethyl acetate and then washed with a dilute 1N aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solids were diluted with ether, collected by filtration, washed with ether, and dried in vacuo to afford 1-trityl-<strong>[4928-88-5]1H-[1,2,4]triazole-3-carboxylic acid methyl ester</strong> (2.45 g, 84percent) as a white solid: LR-FAB for C23H19N3O2 (M+H)+ at m/z=370.
84%
With triethylamine; In DMF (N,N-dimethyl-formamide); at 25℃; for 96h;
A solution of [LH-[1,] 2,4] triazole-3-carboxylic acid methyl ester (3.0 g, 0.23 mol) in [N, N-DIMETHYLFORMAMIDE] (76 mL) at [25 oC] was treated with triphenylmethylchloride (7.2 g, 0.23 mol) and triethylamine (6.41 mL, 0.23 mol). The reaction mixture was stirred at [25 oC] for 4 days and then diluted with ethyl acetate. The mixture was then washed with a dilute aqueous hydrochloric acid solution. At this time, methanol was added to the organic layer. A precipitate formed and was removed by filtration. The organics were further washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was triturated with diethyl ether. The solid was collected by filtration and washed again with diethyl ether to afford 1-trityl-1H-[1, 2,4] triazole-3-carboxylic acid methyl ester as a white solid (2.45 g, 84percent) which was used without further purification.A solution of 2, 2-dimethyl-propionic acid 8- (4-acetylamino-benzyl)-3-butyl-2, 6- dioxo-1, 2,3, 6-tetrahydro-purin-7-ylmethyl ester (104 mg, 0.22 mmol) in acetonitrile (2.0 mL) was treated with [1,] 8-diazabicyclo [5.4. 0] [UNDEC-7-ENE] (0.03 mL, 0.24 mmol) and [2-BROMOMETHYL-1-FLUORO-4-NITRO-BENZENE] (56.6 mg, 0.24 mmol). The resulting solution was heated to [50 oC FOR] 6 h. At this time, another portion of 1,8- diazabicyclo [5. [4 : 0] UNDEC-7-ENE] (0.03 mL, 0.24 mmol) was added. The reaction was stirred at [25 oC] for 18 h. At this time, the reaction was poured into ethyl acetate (200 mL) and was washed with a 1N aqueous hydrochloric acid solution [(1] x 50 mL) and a saturated aqueous sodium chloride solution [(1] x 50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 1: 1 ethyl acetate/petroleum ether) afforded 2,2- dimethyl-propionic acid 8- (4-acetylamino-benzyl)-3-butyl-1- (2-fluoro-5-nitro-benzyl)- 2, [6-DIOXO-1,] 2,3, 6-tetrahydro-purin-7-ylmethyl ester (45.3 mg, 33percent) as a tan solid
85 g
With pyridine; at 0℃; for 3.5h;Reflux;
To a cooled (0 oC) solution of <strong>[4928-88-5]methyl 1H-1,2,4-triazole-3-carboxylate</strong> (36 g, 283.2 mmol, 1.0 equiv) in pyridine(300mL) was added triphenylmethyl chloride (85 g, 304.9 mmol, 1.1 equiv) and the suspension was stirred for 90 min at room temperature. Then the suspension was then heated at 100 oC and refluxed for 2h. The clear solution was cooled to room temperature and concentrated under vacuum. Isopropanol (500 mL) was added to the residue and the solid was filtered and washed with 3x 300 mL H2O. The solid was dried in an oven under reduced pressure to afford 85 g of the title compound as a white solid. LCMS ES+ 243 [M+H]+ (Trityl fragment).
2-{4-[(3-O-acetyl-4,6-O-benzylidene-1deoxy-2-O-(4-methoxybenzyl)-β-D-galactopyranosyl)thio]phenoxy}acetic acid[ No CAS ]
[ 196398-47-7 ]
Yield
Reaction Conditions
Operation in experiment
171 mg (81%)
With silver trifluoromethanesulfonate; In dichloromethane;
7.30. 2-{4-[(3-O-acetyl-4,6-O-benzylidene-1deoxy-2-O-(4-methoxybenzyl)-beta-D-galactopyranosyl)thio]phenoxy}acetic acid (95) To a solution of 81, prepared as above (139 mg, 0.303 mmol) and 2,6-di-t-butyl-4-methyl pyridine (187 mg, 0.91 mmol) in 5 mL CH2 Cl2, are added chlorotriphenylmethane (101 mg, 0.364 mmol) and silver trifluoromethanesulfonate (78 mg, 0.30 mmol). The reaction mixture is stirred at room temperature for 45 min and then is filtered though celite and washed with 10 mL of aqueous NaHCO3. The aqueous solution is extracted with CH2 Cl2 (2*10 mL) and the organic layers are combined and dried over Na2 SO4, filtered and concentrated. The product is purified by flash chromatography (25percent EtOAc/hexane) to give 171 mg (81percent) of 1-deoxy-3,4-O-isopropylidene-1-{4-[2-(trimethylsilyl)ethoxymethoxy]phenylthio}-6-O-triphenylmethyl-beta-D-galactopyranose 89 as white solid: Rf 0.2 (25percent EtOAc/hexane); 1 H NMR (CDCl3, 300 MHz) delta 7.53-7.40 (m, 8H), 7.31-7.21 (m, 9H), 6.95 (d, J=8.5 Hz, 2H), 5.19 (s, 2H), 4.29 (d, J=10.2 Hz, 1H, H-1), 4.14 (dd, J=5.6, 2.0 Hz, 1H, H-4), 4.02 (dd, J=6.9, 5.6 Hz, 1H, H-3), 3.73 (m, 3H), 3.56 (dd, J=9.6, 6.9 Hz, 1H, H-6), 3.48 (ddd, J=8.9, 6.9, 2.0 Hz, 1H, H-2), 3.36 (dd, J=9.6, 5.3 Hz, 1H, H-6), 2.37 (d, J=2.0 Hz, 1H, OH), 1.37 (s,3H), 1.31 (s, 3H), 0.96 (t, J=7.2 Hz, 2H), 0.00 (s, 9H)
With hydrogenchloride; potassium hydroxide; potassium tert-butylate; In tetrahydrofuran; ice-water; ethanol; di-isopropyl ether; water; ethyl acetate;
Adduct with N,N-dimethylacetamide 148 g (1.32 mol) of potassium tert-butylate are added in one portion at +2 C. with stirring and cooling to a suspension of 258.3 g (1.2 mol) of ethyl (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate in 2 l of dry tetrahydrofuran. On warming to +4 C., the suspension changes color to red-brown. The mixture reaches room temperature without cooling after 30 minutes. It is stirred for a further hour and then cooled to 15 C., and 362.4 g (1.3 mol) of trityl chloride are added. Without external cooling, it is stirred for a further 5 hours, a maximum internal temperature of +39 C. being reached after about 2 hours. The suspension is then poured into a mixture of 1.5 l of ice-water and 1.2 l of diisopropyl ether, stirred for half an hour and left overnight at 5 C., and the precipitate is filtered off with suction and washed in portions with 1 l of water and 700 ml of diisopropyl ether. For hydrolysis, the still moist product is boiled for 3 hours with a solution of 67.4 g (1.2 mol) of potassium hydroxide in 1 l of water and 1.2 l of ethanol. After 2 hours, a clear, dark solution is present. It is cooled to 60 C., 1.2 l of ethyl acetate are added and the mixture is cooled to +10 C. and about 190 ml of 6N hydrochloric acid are added up to a pH of 4.0 with stirring in the course of 15 minutes. A crystalline precipitate is formed. After 16 hours at 5 C., it is filtered off with suction, washed with 1.5 l of water and then 1.5 l of diisopropyl ether in portions, and dried in vacuo at 80 C. The crude acid is introduced into a mixture of 600 ml of dimethylacetamide and 1.2 l of toluene, stirred at 65 C. for 10 minutes, cooled in an ice-bath for 1 hour, filtered off with suction, washed with 800 ml of toluene in portions and dried in vacuo at 80 C. Yield: 372 g of pale grey crystals (60% of theory), Dec. 179-181 C. 1 H-NMR (DMSO-d6, 270 MHz): delta=1.96 (s, 3H, CH3 CO); 2.80 (s, 3H, NCH3); 2.95 (s, 3H, NCH3); 6.69 (s, 1H, thiazole); 7.2-7.42 (m, 15H, trityl)
ethyl 3-triphenylmethyltetrazol-5-ylacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In pyridine;
a. Ethyl 1-triphenylmethyltetrazol-5-ylacetate. To a solution of <strong>[13616-37-0]ethyl 5-tetrazolylacetate</strong> (1 g) (Lofquist et al. J. Amer. Chem. Soc. (1958), 80, 3908) in pyridine (6 mL) was added triphenylmethyl chloride (2.2 g) and the resulting solution allowed to stir for 3 h. The solvent was evaporated and the product crystallized from ether/hexane to give ethyl 3-triphenylmethyltetrazol-5-ylacetate as a white solid (2 g); TLC: Rf =0.5, ether:hexane (50:50).
ethyl 5-methyl-1-triphenylmethyl-4-1H-imidazolecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
In tetrahydrofuran;
(a) Sodium hydride (900 mg, 80percent oil dispersion, 30 mmol) was added in portions over 5 minutes to a stirred solution of ethyl 4-methyl-imidazole-5-carboxylate (3.85 g, 25 mmol) in dry tetrahydrofuran (100 ml) at room temperature under nitrogen. After 10 minutes, trityl chloride (8.36 g, 30 mmol) was added in one portion. After 1 h, the mixture was diluted with ethyl acetate (500 ml) and washed with water (200 ml). The washings were extracted with ethyl acetate (2*75 ml) and the combined organic solutions were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane/ethyl acetate to give ethyl 5-methyl-1-(triphenylmethyl)imidazole-4-carboxylate (1.01 g, 10percent) as a white solid. 1 H NMR (300 MHz, CDCl3) delta=1.38 (3H,t,J 6Hz), 1.83 (3H,s), 4.36 (2H,q,J 6 Hz), 7.14 (6H,m), 7.35 (10H,m).
2-carboxy-3-methyl-8-oxo-7-tritylamino-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene[ No CAS ]
[ 108-20-3 ]
[ 76-83-5 ]
[ 26395-99-3 ]
[ 14919-01-8 ]
Yield
Reaction Conditions
Operation in experiment
60%
With triethylamine; In chloroform; ethyl acetate; N,N-dimethyl-formamide;
2-Carboxy-3-methyl-8-oxo-7-tritylamino-5-thia-1-aza-bicyclo[4.2.0]octene (40percent) and its oct-3-ene isomer (60) can be obtained in the following manner: Triethylamine (55.6 cc) is added to a suspension of <strong>[26395-99-3]7-amino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene</strong> (42.8 g) in dry N,N-dimethylformamide (250 cc), and after cooling the mixture to -20° C. a solution of chlorotriphenylmethane (55.8 g) in chloroform (250 cc) is added in the course of 2 hours. The reaction mixture is stirred for 24 hours at 25° C. and then poured into normal hydrochloric acid (400 cc). After filtration, the organic phase is separated off, concentrated to half its volume under reduced pressure (40 mm Hg) at 40° C., and taken up in ethyl acetate (400 cc). The aqueous phase is extracted with ethyl acetate (400 cc), and the combined organic phases are washed with normal hydrochloric acid (2*250 cc) and then extracted with a half-saturated sodium bicarbonate solution (4*500 cc). These combined aqueous phases are washed with ethyl acetate (300 cc), then acidified to pH 3 with 12 N hydrochloric acid and extracted with ethyl acetate (2*500 cc). The combined organic solutions are washed with a saturated sodium chloride solution (250 cc), dried over sodium sulphate and concentrated to dryness under reduced pressure (40 mm Hg) at 40° C. The residue is caused to solidify by adding isopropyl ether (250 cc). The solid is filtered off, washed with isopropyl ether (100 cc) and dried. A mixture (22.2 g) of 2-carboxy-3-methyl-8-oxo-7-tritylamino-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (40percent) and its oct-3-ene isomer (60percent) is obtained in the form of a cream-coloured solid.
60%
With triethylamine; In chloroform; ethyl acetate; N,N-dimethyl-formamide;
Triethylamine (55.6 cc) is added to a suspension of 7-amino-2-carboxy-3-methyl-8-oxo-5-thia-1aza-bicyclo[4.2.0]oct-2-ene (42.8 g) in dry N,N-dimethylformamide (250 cc), and after cooling the mixture to -20° C. a solution of chlorotriphenylmethane (55.8 g) in chloroform (250 cc) is added in the course of 2 hours. The reaction mixture is stirred for 24 hours at 25° C. and then poured into normal hydrochloric acid (400 cc). After filtration, the organic phase is separated off, concentrated to half its volume under reduced pressure (40 mm Hg) at 40° C., and taken up in ethyl acetate (400 cc). The aqueous phase is extracted with ethyl acetate (400 cc), and the combined organic phases are washed with normal hydrochloric acid (2*250 cc) and then extracted with a half-saturated sodium bicarbonate solution (4*500 cc). These combined aqueous phases are washed with ethyl acetate (300 cc), then acidified to pH 3 with 12 N hydrochloric acid and extracted with ethyl acetate (2*500 cc). The combined organic solutions are washed with a saturated sodium chloride solution (250 cc), dried over sodium sulphate and concentrated to dryness under reduced pressure (40 mm Hg) at 40° C. The residue is caused to solidify by adding isopropyl ether (250 cc). The solid is filtered off, washed with isopropyl ether (100 cc) and dried. A mixture (22.2 g) of 2-carboxy-3-methyl-8-oxo-7-tritylamino-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (40percent) and its oct-3-ene isomer (60percent) is obtained in the form of a cream-coloured solid.
With 2-(Dimethylamino)pyridine; triethylamine; In chloroform;
(a) 4-Chloromethyl-2-triphenylmethylaminothiazole A solution of 2-amino-4-chloromethylthiazole hydrochloride (3.701 g), trityl chloride (11.15 g), triethylamine (10.5 ml) and dimethylaminopyridine (10 mg) in chloroform (150 ml) was stirred at room temperature. After 23 h the reaction mixture was diluted with chloroform (150 ml) and then washed with 5percent aqueous sodium hydrogen carbonate solution (2*50 ml) and brine (50 ml), dried (MgSO4) and evaporated to an orange gum. The gum was triturated with diethyl ether to give a pale brown solid. The liquors from the trituration were diluted with ethyl acetate (250 ml) and washed with M-hydrochloric acid (3*60 ml), water (60 ml), and brine (30 ml) dried (MgSO4) and evaporated to a pale brown foam.
triethylammonium 2,2-dimethyl-6β-(triphenylmethylamino)penicillanate[ No CAS ]
[ 541-41-3 ]
[ 76-83-5 ]
[ 551-16-6 ]
[ 103-67-3 ]
2,2-dimethyl-6β-(triphenylmethylamino)-3-(N-methyl-N-benzylcarbamoyl)penam[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In hexane; chloroform; ethyl acetate; triethylamine;
EXAMPLE 19 2-Dimethyl-6beta-(triphenylmethylamino)-3-(N-methyl-N-benzylcarbamoyl)penam To a suspension of <strong>[551-16-6]6-aminopenicillanic acid</strong> (30.6 g) in chloroform (150 mL) was added triethylamine (27.8 mL). The mixture was stirred at room temperature until almost completely in solution at which time trityl chloride (21.7 g) was added in one portion. The reaction was stirred at room temperature for 60 hrs to give a solution of triethylammonium 2,2-dimethyl-6beta-(triphenylmethylamino)penicillanate. A 40 mL portion of the above solution was cooled to 0° C. in an ice bath and additional triethylamine (2.8 mL) was added. Ethyl chloroformate (2.0 mL) was then added and after 1/2 hour N-methylbenzylamine (5 mL) was added via pipette below the surface of the reaction. After 1/2 hour further stirring at room temperature, was poured into water and extracted with methylene chloride (2*). The extracts were washed with dilute hydrochloric acid, sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated. The residue was flash chromatographed using a solvent gradient of 20 to 30percent ethyl acetate/hexane to give 2.2 g of 2,2-dimethyl-6beta-(triphenylmethylamino)-3-(N-methyl-N-benzylcarbamoyl)penam NMR (CDCl3): delta 1.33(s,3H), 1.60(s,3H), 2.87(2 close s,3H), 3.33(br d,1H,10 Hz), 4.3-4.7(m,4H), 4.80(2 close s,1H), 7.0-7.8(m,20H).
Triethylamine salt of 6-triphenylmethylamino-2,2-dimethylpenam-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In chloroform;
A. Triethylamine salt of 6-triphenylmethylamino-2,2-dimethylpenam-3-carboxylic acid. Tritylchloride (61.2 g., 0.22 mole) is added to a mixture of <strong>[551-16-6]6-aminopenicillanic acid</strong> (43.3 g., 0.20 mole) and triethylamine (5.56 ml.)in chloroform (300 ml.) at about 5° C. The somewhat exothermic reaction is stirred and allowed to rise gradually to room temperature. It is stirred at room temperature for three days. Evaporation of the reactionmixture affords the title product which is used without purification.
6-(triphenylmethylamino)penicillanic acid[ No CAS ]
6-(Triphenylmethylamine)penicillanic Acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; triethylamine; In chloroform; water;
EXAMPLE 1 6-(Triphenylmethylamine)penicillanic Acid To a stirred suspension of 54 g. (0.25 mole) of <strong>[551-16-6]6-aminopenicillanic acid</strong> and 70 ml. (0.50 mole) of triethylamine in 500 ml. of chloroform (free of ethanol) at room temperature, 70 g. (0.25 mole) of chlorotriphenylmethane was added in portions over a period of a few minutes. Stirring was continued for two days. The volatile components were evaporated under reduced pressure, and the foamy residue taken up in 400 ml. of water. The aqueous mixture was washed twice with 300 ml. portions of diethyl ether, and then brought to pH 4.0 by the monitored addition of 4N hydrochloric acid. Organic matter was extracted with two 300 ml. portions of diethyl ether. The extracts were combined, washed twice with 200 ml. portions of water, once with 200 ml. of a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Evaporation of the solvent affords 6-(triphenylmethylamino)penicillanic acid as a yellow foam; yield 95 g. (83percent); 1 H-nmr (CDCl3) ppm (delta):1.4 (s,3-alpha-CH3), 1.6 (s,3,beta-CH3), 4.4 (m,3,c-3, C-5, C-6 protons), 7.4 (m,15,C6 H5).
magnesium bromide; In acetonitrile; at 40 - 50℃;Product distribution / selectivity;
Example 16: H-Cys(Tr)-OH (S-trityl cysteine) by selective S- tritylation of cysteine.Method A.; 0.20 g of cysteine (1.7 mmol) are dissolved in a solution of 0.46 g of triphenylmethyl chloride (1.7 mmol) and 0.31 g of MgBr2 (1.7 mmol) in 4 mL of MeCN, kept under stirring at 40 - 50°. The clear, yellow solution loses its colour when its temperature is lowered at room temperature. An equal volume of water containing 0.32 g (1.7 mmol) of citric acid is added to the final mixture and TEA is added until the pH is about 5. The evaporation under vacuum of MeCN gives rise to a suspension. The solid, isolated by filtration and washings with water, is thoroughly washed with Ac and the organic washings are added to a second portion of the water solution of citric acid, and treated as previously described, obtaining a second portion of the solid insoluble in Ac. The amount of solid, chromatographically pure H-Cys (Tr) -OH recovered in the two successive EPO <DP n="33"/>treatments is 0.28 g (th. 0.60 g, 46.67percent; mp 182 - 84 dec; an. C 72.63 (72.70), H 6.11 (5.87), N 3.85 (3.85), S 8.55 (8.82) .
zinc(II) chloride; In acetonitrile; at 20℃; for 0.166667h;Product distribution / selectivity;
Method B.; 0.10 g of cysteine (0.8 mmol) , on dissolving under stirring in 4 piiL of hot MeCN containing 0.11 g of ZnC12 (0.8 mmol) and 0.23 g of TrCl (0.8 mmol), gives rise to complete dissolution and loss of colour in about 5 min. After further 5 min at room temperature, the liquid becomes turbid. The reaction mixture is poured into 100 mL of water and kept under vigorous stirring after the pH is adjusted to 5, the suspension was filtered off, the solid washed with water. The dried solid is dissolved in 4 mL of Ac and mixed with an equal volume of water containing citric acid in a molar ratio 8:1. The mixture, alkalinised to pH 6 with TEA becomes clear. Ac is distilled under vacuum and 4 mL of water are added to the remaining suspension. Filtration leads to the isolation of a solid only partially soluble in Ac. After washing with this solvent, 0.23 g of chromatographically pure H-Cys (Tr) -OH are obtained. The treatment of the organic filtrate, reunited with washings, with citric acid, according to the procedure described above, produces further product (0.18 g) with analogous features (th. 0.60 g, 68.33percent; mp 183 - 84° dec; an.: C 72.65 (72.70), H 6.05 (5.82), N 3.83 (3.85), S 8.72 (8.82) .
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 10 - 20℃; for 1.08333h;
Example 2Preparation of the compound of formula VI (R = Tr)Diisopropylethylamine (8.58 ml, 49.25 mmol, 1.1 equiv.) is added to a suspension of the imine IV (9.82 g; 45.6 mmol) and tritylchloride (V; R = Tr, X = Cl) (13.73 g, 49.25 mmol; 1.08 equiv.) in dichloromethane (150 ml) under stirring and cooling to 10C within 5 minutes. The obtained solution is heated up to the laboratory temperature while the course of the reaction is monitored with TLC. After 1 hour the reaction mixture is washed with water (80 and 50 ml) <n="14"/>and saline (50 ml), the organic phase is filtered off and evaporated in a rotatory vacuum evaporator. A glassy residue is obtained that is brought to boil with isopropylalcohol (55 ml), which causes the formation of crystals. The suspension is left to cool down to it overnight. The crystals are sucked off, washed with isopropylalcohol (18 ml) and dried at 40C. Melting temp. 138-140 0C.Yield: 20.41 g, i.e. 97.8 % of the compound of formula VI (R = Tr).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 10 - 20℃;
Example 5 c To a suspension of N-(4-hydroxybenzylidene)-4-fluoroaniline (4.30 g; 20.0 mmol) and trityl chloride (5.91 g, 21.2 mmol; 1.06 equiv.) in dichloromethane (65 ml) diisopropylethylamine (10.1 ml, 59.0 mmol) is added under stirring and cooling to 10 C during 5 min. The obtained solution is left to heat up to the laboratory temperature while the course of the reaction is monitored with TLC.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 10 - 20℃;
EXAMPLE 5To a suspension of N-(4-hydroxybenzylidene)-4-fluoroaniline (4.30 g; 20.0 mmol) and trityl chloride (5.91 g, 21.2 mmol; 1.06 equiv.) in dichloromethane (65 ml) diisopropylethylamine (10.1 ml, 59.0 mmol) is added under stirring and cooling to 10 C. during 5 min. The obtained solution is left to heat up to the laboratory temperature while the course of the reaction is monitored with TLC. After completion of the reaction the solution is cooled down to -5 C., and a solution of (S)-3-[4-[2-(4-fluorophenyl)-[1.3]dioxan-2-yl]-1-oxobutyl]-4-phenyloxazolidin-2-one (6.62 g, 16.0 mmol) in dichloromethane (15 ml) is added under stirring during 5 min. Then, the mixture is cooled down to -32 C., and after stirring for 10 min a solution of TiCl3(Oi-Pr) starts to be added during 20 min, which has been prepared previously by mixing of TiCl4 (a 1M solution in CH2Cl2; 15.5 ml, 15.5 mmol) and Ti(Oi-Pr)4 (1.54 g, 5.17 mmol) in CH2Cl2 (25 ml) at 10 C., followed by stirring for 30 min. The obtained dark solution is stirred at the same temperature for 2.5 h and then acetic acid (4.5 ml) is added during 5 min and the solution is stirred at -30 C. for another 10 min. Then, to the reaction mixture a 0.46M solution of sodium dihydrogen citrate is added (120 ml, or the other way round the reaction mixture is poured onto this buffer) as well as methylene chloride (50 ml). The reaction mixture is intensively stirred for 20 min, the organic phase is separated and the aqueous phase is extracted with CH2Cl2 (50 ml). The combined organic phases are washed with water (50 ml), brine (40 ml) and evaporated in a rotational vacuum evaporator. To the evaporation residue methanol (200 ml) and 10% aqueous hydrochloric acid (4.5 ml) are added and the mixture is stirred at the temperature of 25 C. overnight. The separated product is filtered off, washed with EtOH (2×10 ml) and dried. The obtained product is recrystallized from ethyl acetate (120 ml), the crystals are sucked off, washed with ethyl acetate and dried at 45 C. Melting temp. 210-213 C.Yield: 4.69 g (51.4%) of a compound of solution IV (PG=H). HPLC: diastereoisomeric purity 98.6%.1H-NMR (250 MHz, CD3SOCD3): delta 7.95 (dd, J=8.6 Hz, J=5.7 Hz, 2H), 7.38-7.26 (m, 4H), 7.25-7.05 (m, 5H), 6.80 (t, J=8.9 Hz, 2H), 6.68 (d, J=8.5 Hz, 2H), 6.56 (m, 2H), 6.00 (d, J=9.4 Hz, 1H), 5.55 (dd, J=8.6 Hz, J=4.5 Hz, 1H), 4.76 (t, J=8.6 Hz, 1H), 4.50-4.30 (m, 2H), 4.10 (dd, J=8.7 Hz, J=4.5 Hz, 1H), 2.93 (t, J=7.3 Hz, 2H), 1.69 (m, 2H).
<strong>[952511-48-7]5-Bromo-4-methyl-1H-benzimidazole</strong> (6.62 g, 31.36 mmol) was dissolved in anhydrous tetrahydrofuran (150 ml) and cooled to 0° C. Sodium hydride oil dispersion (60percent, 1.55 g, 38.75 mmol) was slowly added. The mixture was stirred for 1 h at 0° C. Triphenylmethyl chloride and a catalytic amount of tetrabutylammonium iodide were added. The resultant mixture was heated at reflux for 12 h, cooled to room temperature, quenched with saturated ammonium chloride solution (50 ml) and partitioned between ethyl acetate and water. The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was suspended in 50 ml of 50percent ethyl acetate in hexanes, heated to reflux, cooled to room temperature and filtered to afford the title compound as a pale brown solid. The filtrate was concentrated and purified by silica gel column chromatography (5 to 20percent ethyl acetate in hexanes) to give more title compound.1H NMR (400 MHz, CDCl3) delta ppm 2.70 (s, 3H) 6.19 (d, 1H) 7.00-7.20 (m, 7H) 7.20-7.45 (m, 9H) 7.92 (s, 1H); LC-MS: (Ph3C+) 243.11, 3.27 min (LC/MS method A)
With dmap; triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
To a solution or suspension of the amine or amine hydrochloride salt (1 mmol) in dry DCMor DMF were added a solution of trityl chloride (1.1 mmol), Et3N (2 - 4 mmol) and DMAP(10 mol percent) at 0 oC and the mixture was stirred at rt until the disappearance of startingmaterials. The reaction was then quenched with H2O and extracted with EtOAc. Thecombined organic phases were washed with brine and dried (Na2SO4). After evaporation ofthe solvent at reduced pressure, the resulting residue was purified by column chromatography(deactivated silica gel, pet ether-ethyl acetate) to afford the expected tritylamine.
First step The compound (85) (2.50 g) was dissolved in pyridine (25 ml), trityl chloride (5.47 g) and dimethylaminopyridine (2.40 g) were added, the mixture was stirred at 100°C for 22 hours. Water was added, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography to afford the compound (86) (2.81 g). 1H-NMR (CDCl3), delta: 0.94 (3H, t, J = 7.1 Hz), 3.82 (2H, q, J = 7.1 Hz), 6.97 (1H, d, J = 1.0 Hz), 7.12 (7H, m), 7.28-7.30 (9H, m).
With triethylamine; In dichloromethane; for 15.0h;
Obtained in 96% yield as a white crystalline solid by treatment of <strong>[64987-16-2]methyl 2-amino-4-thiazolylacetate</strong> with trityl chloride and TEA in DCM for 15 h and successive crystallization of the crude product from diisopropyl ether; mp 177 C; 1H NMR (CDCl3) delta 7.25-7.34 (m, 15H), 6.22 (s, 1H), 3.76 (s, 3H), 3.66 (s, 2H).
With pyridine hydrochloride; In N,N-dimethyl-formamide;
197 g (684 mmol) of trityl chloride are added, over 2hrs, in three portions, to a solution of pyridinium chloride (22.6 g, 196 mmol) and 2-bromo-4- hydroxymethyl-phenol (133 g, 653 mmol) in 530 mL of dry DMF and 265 mL of dry pyridine. The mixture is stirred overnight at the same temperature. The reaction is diluted with water (1.3L) and Toluene (1.3L), let to separate and the aqueous layer is discarded. After removal of most of pyridine under reduced pressure, the remaining mixture is diluted with ethyl acetate and the organic phase is washed, in order, with 5percent aq. sodium bisulphate, 7percent aq. sodium bicarbonate and finally with water. The organic phase is treated with active charcoal and then concentrated to a solid residue, under vacuum. The product is slurried with methanol (1500 mL) at reflux and finally isolated at room temperature, affording 259 g (581 mmol) (c.y 85percent).of pure compound [(VI), (X=Tr)]. HPLC-MS (m/z): 443 (M-H+) IR (cm"1): 3328, 3079, 3059, 3020, 2936, 2881, 1815, 1723, 161 1, 1509, 1489, 1446, 1419, 1375, 1284, 1218, 1001, 769, 751, 705. m.p. (DSC, onset-peak-endset, °C): 156-159-162. NMR (CDC13). ;H-N R (ppm, 400 MHz): 4.12 (2H, s, -CH2O ); 5.51 (1H, broad, OH);: 7.02 (1H, d, J = 9 Hz, H-Q; 7.25 (1H, dd, J = 9, 2 Hz, H-5); 7.50 (1H, d, J = 2 Hz, R-A) 7.28 - 7.60 (15H, m, Ph3C-).
(1S,3S,5S)-2-[(2S)-2-triphenylmethylamino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 6 Preparation of (lS,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-l-yl)acetyl]-2- azabicyclo[3.1.0]hexane-3-carboxamide Tert-butoxycarbonylamino-(3-hydroxy-adamantan-l-yl)-acetic acid (100 g; 0.307 mole) was added to dichloromethane (500 ml) with stirring. The methanesulfonic acid salt of (1S,3S,5S)- 2-azabicyclo[3.1.0]hexane-3-carboxamide (64.8 g; 0.292 mole) was added, and the reaction mixture was stirred for 15 minutes at 25-35°C. In a separate flask, 1-hydroxybenzotriazole monohydrate (11.8 g; 0.077 mole) and triethylamine (34.2 g) were added to dichloromethane (500 ml) and stirred to form a solution. This solution was added to the reaction mixture gradually over 30 minutes at 25-30°C. The reaction mixture was then cooled to 5-15°C, 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1) (70.6 g) was added, and the mixture was stirred for 15 minutes at 5-15°C. Triethylamine (65.2 g) was added to the reaction mixture and stirred for 30 minutes. Temperature of the reaction mixture was raised to 25-35°C and stirred continuously for 12 hours. Reaction completion was confirmed by HPLC. Water (500 ml) was added, the mixture was stirred, and the organic layer was separated. The organic layer was washed with dilute hydrochloric acid solution (500 ml, prepared by adding concentrated hydrochloric acid (60 ml) to water (440 ml)), and further washed with sodium bicarbonate solution (3 times), followed by washing with sodium chloride solution. Hydrogen chloride in isopropanol (14.2percent w/w, 315.6 g) was added over 60 minutes, and the mixture was stirred for 4 hours. Completion of the reaction was confirmed by HPLC. The mixture was distilled under vacuum to remove dichloromethane. Toluene was added to the residue and distilled under vacuum. Acetonitrile (400 ml) was added to the residue followed by addition of triethylamine (79.2 g) over 15 minutes with stirring. The reaction mixture was cooled to 10- 20°C, and trityl chloride (72.7 g) was added gradually, followed by stirring for 2 hours. Completion of the reaction was confirmed by HPLC. The mixture was distilled under vacuum to remove acetonitrile. Toluene was added to the residue and distilled under vacuum. Toluene (500 ml) followed by water (500 ml) were added to the residue, the mixture was heated at 45- 55°C and filtered and dried to obtain the product. (Yield=60.3percent; HPLC purity=94percent) Mass: 576 [M+H]+ 1H-NMR (CD3OD) delta: 7.43-7.45 (5 H, d), 7.06-7.17 (10 H, m), 4.50 (1 H, s), 3.84-3.87 (1 H, dd), 3.42 (1 H, s), 3.09-3.13 (1 H, m), 2.87-2.91 (1 H, m), 2.15-2.23 (1 H, m), 2.09 (1 H, s), 1.90-1.92 (1 H, d), 1.42-1.77 (13 H, m), 1.19-1.22 (1 H, t), 0.72-0.76 (1 H, m), 0.50-0.55 (1H, m)
With triethylamine; In dichloromethane; at 20℃; for 1h;
[007101 Compound 80 was prepared in 4 steps from 1 H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> according to the following procedures: <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (2.1 mmol, 1.0 equiv) was dissolved in 20 mL methylene chloride followed by the addition of triethylamine (3.0 equiv) and trityl chloride (1.0 equiv). The reaction was stirred at RT for lh after it was quenched with water (lmL) and extrated with methylene chloride. The organic layers were concentrated and purified using flash silica gel chromatography (gradient 0-30percent methanol/methylene chloride with 0.5percent triethylamine). 1-Trity -]H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> was then converted to it?s corresponding alkyne using Method J after which it was coupled to compound B using the analogous coupling conditions in Example 1. The resulting compound was then deprotected under standard triflouroacetic acid in methylene chloride deprotection conditions after which it was concentrated and purified using flash silica gel chromatography (ISCO, gradient 0-5percent methanol/methylene chroride with 0.05percent triethylamine and then repurified using reverse-phase HPLC (Interchim Cl 8-Sunfire column, gradient of acetonitrile/water with 0.01percent formic acid) to provide compound 80. ESI-MS m/z: 515.0 [M+H]b.
With triethylamine; In dichloromethane; at 20℃; for 1h;
[001366] Compound 80 was prepared in 4 steps from lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> according to the following procedures: lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (2.1 mmol, 1.0 equiv) was dissolved in 20 mL methylene chloride followed by the addition of triethylamine (3.0 equiv) and trityl chloride (1.0 equiv). The reaction was stirred at RT for lh after it was quenched with water (ImL) and extrated with methylene chloride. The organic layers were concentrated and purified using flash silica gel chromatography (gradient 0-30percent methanol/methylene chloride with 0.5percent triethylamine). 1-Trity -/H-pyrazole-4- carbaldehyde was then converted to it's corresponding alkyne using Method J after which it was coupled to compound B using the analogous coupling conditions in Example 1. The resulting compound was then deprotected under standard triflouroacetic acid in methylene chloride deprotection conditions after which it was concentrated and purified using flash silica gel chromatography (ISCO, gradient 0-5percent methanol/methylene chroride with 0.05percent triethylamine and then repurified using reverse-phase HPLC (Interchim C18-Sunfire column, gradient of acetonitrile/water with 0.01percent formic acid) to provide compound 80. ESI-MS m/z: 515.0 [M+H]+.
[0234] A mixture of <strong>[623-57-4]3-(dimethylamino)-1,2-propanediol</strong> (3.0 g, 25 mmol) and triphenylmethyl chloride (7.75 g, 27.8mmol) in dry pyridine (100 mL) was refluxed for 30 min. Upon cooling, most of the solvent was evaporated in vacuo,and the resulting residual was re-dissolved in 400 mL of dichloromethane. The organic phase was washed with water(3 x 200 mL), brine (150 mL), and dried over anhydrous Na2SO4. Evaporation of the solvent gave 6.3 g of yellow oil asa crude product. The crude product was purified by column chromatography on silica gel (230-400 mesh, 500 mL) elutedwith 0-10percent methanol gradient in dichloromethane. This afforded 4.0 g of the product (DMAP-Tr) as yellow oil.
The compound L-cysteine hydrochloride (10 g, 63.45 mmol)Was dissolved in N, N-dimethylformamide (120 ml)Triphenylchloromethane (19.46 g, 69.795 mmol) was added,Heated to 60-65 ° C,Reaction for 8 hours,TLC detection reaction is completed,Cooled to room temperature,A 10percent sodium acetate solution (300 ml) was added,Precipitation of white solid,filter,The residue was washed with pure water (300 ml)Then washed with acetone (200 ml)dry,The product was a white solid (17.56 g, yield: 76.15percent).
General procedure: Compound 40-7 was combined with trityl chloride and TEA in DMF to give compound 40-8.Compound 40-8 was combined with vmyknagnesium bromide in THF to give compound 40-9. Compound 40-9 was combined with Mn02 in dioxane to give compound 40-10. Compound 40-10 was combined with HBr and acetic acid to give Compound 40-11. Compound 40-11 was combined with CS7CO3 in acetonitrile to give compound 40-3. Compound 40-3 was combined with NaBH4 in MeOH to produce compound 40-4. Compound 40-4 was combined with compound 1 -1, PPh3, and DIAD in THF to give compound 40-5. To compound 40-5 in MeOH was added Pd/C, and the mixture is stirred under H2 to produce compound 40-6. Compound 40-6, compound 5-5, and TsOH were combined in 1,4-dioxane to give compound D-36. MS /z ------ 379.2 [M +H]+.
2-C-methyl-D-ribono-gamma-lactone 1 (1.62 g, 10.0 mmol) was suspended in pyridine (10 mL) followed by the addition of triphenylchloromethane (2.06 g, 11 mmol) under ice bath. After the reaction was completed, the solvent was removed under reduced pressure and the residue was purified by silica-gel column chromatography (PE/EtOAc = 50/1) to give the Trt-protecting intermediate. This intermediate (400 mg, 1 mmol) was dissolved in dichloromethane (4 mL). To the solution, benzoic anhydride (226 mg, 1 mmol), triethylamine (0.2 mL, 2 mmol) and 4-dimethylaminopyridine (20 mg) were successively added under ice bath. After stirring for 3h at room temperature, the solvent was removed under reduced pressure and the residue was purified by silica-gel column chromatography to afford 2j as a white solid.
(((2-bromo-5-fluorobenzyl)oxy)methanetriyl)tribenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With dmap; triethylamine; In dichloromethane; at 40℃; for 28h;
(2) 100 g of compound II, 150 g of triphenylchloromethane, 6 g of DMAP were dissolved in 100 ml of dichloromethane, 200 ml of triethylamine was added, and the mixture was heated to 40 C for 28 h, and the plate was placed, and 100 ml of deionized water was added. The organic layer and the aqueous layer were separated by stirring, and the organic layer was taken, and then the aqueous layer was extracted twice with dichloromethane, and then 100 ml of dichloromethane, and the organic layer was combined, and the organic layer was washed once with saturated brine. Dry over sodium sulfate for 3 h, Filtration under reduced pressure to dryness of crude compound III, 400 ml of methanol was added to the crude compound III, heated to reflux temperature of the solvent and refluxed for 4 hours, stirring was continued during the reflux, cooled and filtered, washed with methanol, dried under reduced pressure. Compound III was obtained in a yield of 90%.
177 g
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 40 - 45℃; for 5h;
Trityl chloride (204 gm) was added to a stirred solution of methylene chloride (150 ml) at 25°C - 30°C. DIPEA (136 ml) was added to the reaction mixture and heated to 40° C - 45 °C. To obtained reaction mixture was added solution of (2- bromo-5-fluoro-phenyl)-methanol (100 gm) in methylene chloride (1050 ml) at 40° C - 45 °C over a 3 hour period and stirred the said mixture for 2 hours. The reaction progress was monitored by thin layer chromatography (TLC). After completion of the reaction, reaction mixture was cooled to 25°C - 30°C and water (400 ml) was added slowly to the reaction mixture and stirred for 15 to 20 minutes. The phases were separated and organic phase was distilled under vacuum at 40°C - 45°C. Methanol (500 ml) was added to the obtained reaction mass and heated up to the reflux temperature for 1 hour. The reaction mixture was cooled to 45°C - 50°C, stirred for 30 minutes and filtered. The solid was washed with methanol (100x2 ml) and dried at 65 °C under vacuum for 24 hrs to obtain crude l-bromo-4-fluoro-2-trityloxymethyl-benzene (210.5 gm). The said crude compound was added to the stirred solution of acetone (875 ml) and heated at 58°C - 60°C with stirring for 30 minutes. The reaction mixture filtered and washed with acetone (50 ml). The filtrate was distilled under vacuum at 58°C - 60°C and cooled to 15°C - 20°C. The obtained solid was filtered and washed with acetone (102 ml) and dried at 65 °C under vacuum for 24 hrs to obtain 177 gm of the compound of formula-(IV); Purity: 99.68percent.
Compound 84 (1 g) was dissolved in pyridine, triphenylchloromethane (2.0 eq) and DMAP were added and heated to 80 ° C.3h, a small amount of raw materials remained. After adding triphenylchloromethane, the raw material remains, stop the reaction, concentrate and add water to wash, BEthyl acetate was dried over anhydrous sodium sulfate. Column chromatography gave 1 g of a white solid.
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