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Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
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Structure of 2417-72-3 * 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.
Reference：
[1] Russian Chemical Bulletin, 2014, vol. 63, # 11, p. 2564 - 2566[2] Izv. Akad. Nauk, Ser. Khim., 2014, # 11, p. 2564 - 2566,3
2
[ 2417-72-3 ]
[ 19158-51-1 ]
[ 35066-32-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 1, p. 262 - 266
3
[ 2417-72-3 ]
[ 18469-52-8 ]
Reference：
[1] European Journal of Pharmacology, 2018, vol. 824, p. 78 - 88
[2] Chemistry - A European Journal, 2015, vol. 21, # 28, p. 10179 - 10184
[3] Patent: WO2006/138350, 2006, A2,
4
[ 2417-72-3 ]
[ 18469-52-8 ]
[ 18153-53-2 ]
[ 70785-70-5 ]
Reference：
[1] Green Chemistry, 2018, vol. 20, # 14, p. 3339 - 3345
5
[ 2417-72-3 ]
[ 52787-14-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 1998, vol. 41, # 26, p. 5219 - 5246
[2] Patent: WO2015/100363, 2015, A1,
6
[ 2417-72-3 ]
[ 143-33-9 ]
[ 76469-88-0 ]
Yield
Reaction Conditions
Operation in experiment
55%
at 40℃; for 1.5 h;
A solution of sodium cyanide (20 g, 0.41 mol) in dimethylsulfoxide at 40° C. was treated dropwise with a solution of methyl 4-(bromomethyl)benzoate (52 g, 0.227 mol) in dimethylsulfoxide, stirred for 90 min., cooled to room temperature, quenched with saturated aqueous sodium chloride and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. Purification of the concentrate via column chromatography (silica, hexanes:ethyl acetate 0-->5percent) provided methyl 4-(cyanomethyl)benzoate (55percent). 1H NMR (400 MHz, CDCl3): 8.05 (d, J=8 Hz, 2H); 7.42 (d, J=8 Hz, 2H); 3.93 (s, 3H); 3.81 (s, 2H). [M+H] 176
55%
at 40℃; for 1.5 h;
Step 1: Methyl 4-(Cyanomethyl)benzoate A solution of sodium cyanide (20 g, 0.41 mol) in dimethylsulfoxide at 40° C. was treated dropwise with a solution of methyl 4-(bromomethyl)benzoate (52 g, 0.227 mol) in dimethylsulfoxide, stirred for 90 min., cooled to room temperature, quenched with saturated aqueous sodium chloride and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. Purification of the concentrate via column chromatography (silica, hexane:ethyl acetate 0-->5percent) provided methyl 4-(cyanomethyl)benzoate (55percent). 1H NMR (400 MHz, CDCl3): 8.05 (d, J=8 Hz, 2H); 7.42 (d, J=8 Hz, 2H); 3.93 (s, 3H); 3.81 (s, 2H). [M+H] 176
Reference：
[1] Patent: US2009/23707, 2009, A1, . Location in patent: Page/Page column 26
[2] Patent: US2007/219240, 2007, A1, . Location in patent: Page/Page column 31
[3] Journal of Medicinal Chemistry, 1998, vol. 41, # 26, p. 5219 - 5246
[4] Journal of Medicinal Chemistry, 2003, vol. 46, # 3, p. 345 - 348
7
[ 7677-24-9 ]
[ 2417-72-3 ]
[ 76469-88-0 ]
Yield
Reaction Conditions
Operation in experiment
68.7%
Stage #1: for 1 h; Stage #2: at 80℃; for 1 h;
Step A: 4-Cyanomethyl-benzoic acid methyl esterTo a solution of trimethylsilylcyanide (TMSCN, 12 mL, 96 mmol), tetra-M- butylammonium fluoride (TBAF, 25 g, 96 mmol) was added portion wise over a period of 30 minutes and stirred for another 30 minutes. 4-Bromethyl benzoic acid methyl ester (20 g, 87.3 mmol) dissolved in acetonitrile (100 mL) was added drop wise over a period of 30 minutes, the reaction temperature was increased to 80 °C and stirring continued for another 30 minutes. On completion of the reaction, solvent was distilled out under reduced pressure, the crude material obtained was purified by column chromatography to give the pure title compound (10 g, Yield 68.7 percent).
Commercially available 4- bromomethylbenzoic acid methyl ester (5.0 g) was dissolved in methanol (40 mL) . A potassium cyanide solution (5.63 g in 8 ml water) was added dropwise over 15 min. The resulting suspension was heated to reflux for 5 h. Volatiles were removed under reduced pressure and the residue dissolved in diethylether and water. The organic layer was concentrated to a dark oil which was purified by column chromatography (5percent ethyl acetate in hexane) to give the intermediate. Yield 3.82 g, 58,6percent.. [M+H] ' - 176.3 (APCI+) . FontWeight="Bold" FontSize="10" H MP. (CHClj, 400 MHz): δ 8.05 (d, J=8.1 Hz, 1H), 7.42 (d, J=8.1 , 1H) , 3.93 (s, 3H) , 3.81 (s, 2H) .
Reference：
[1] Patent: WO2015/100363, 2015, A1, . Location in patent: Page/Page column 51
[2] Angewandte Chemie - International Edition, 2010, vol. 49, # 37, p. 6633 - 6637
[3] Chemistry - A European Journal, 2012, vol. 18, # 5, p. 1383 - 1400
9
[ 773837-37-9 ]
[ 2417-72-3 ]
[ 76469-88-0 ]
Reference：
[1] Journal of Organic Chemistry, 2017, vol. 82, # 2, p. 1114 - 1126
[2] European Journal of Organic Chemistry, 2009, # 2, p. 223 - 237
[3] Patent: US4598077, 1986, A,
10
[ 2417-72-3 ]
[ 151-50-8 ]
[ 76469-88-0 ]
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 1999, vol. 42, # 4, p. 325 - 335
[2] Tetrahedron, 2003, vol. 59, # 46, p. 9083 - 9090
[3] European Journal of Organic Chemistry, 2002, # 6, p. 1037 - 1046
[4] Patent: US2006/173183, 2006, A1, . Location in patent: Page/Page column 118-119
Reference：
[1] Green Chemistry, 2018, vol. 20, # 19, p. 4418 - 4422
13
[ 2417-72-3 ]
[ 71831-21-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
With diisobutylaluminium hydride In tetrahydrofuran; dichloromethane
4-Bromomethylbenzyl alcohol To a solution of methyl 4-bromomethylbenzoate (5.73 g, 25 mmol) in dry CH2Cl2 (150 mL) cooled to -78° C. with stirring under nitrogen was added dropwise a solution of DIBAL-H (82.5 mL, 1.0 M solution in THF). Stirring was continued for 1.5 h at -78° C., and the reaction mixture was then allowed to warm to 0° C. and quenched with H2O. The organic layer was separated and the aqueous was extracted with CH2Cl2 (2*100 mL). The combined organic extracts were dried (MgSO4) and evaporated to give the desired alcohol (5.0 g, 100percent) as a white solid: 1H NMR (CDCl3) δ1.84 (br, 1H), 4.49 (s, 2H), 4.67 (s, 2H), 7.33 (d, 2H, J=8.2 Hz), 7.38 (d, 2H, J=8.2 Hz).
100%
With diisobutylaluminium hydride In tetrahydrofuran; dichloromethane
4-Bromomethylbenzyl Alcohol To a solution of methyl 4-bromomethylbenzoate (5.73 g, 25 mmol) in dry CH2Cl2 (150 mL) cooled to -78° C. with stirring under nitrogen was added dropwise a solution of DIBAL-H (82.5 mL, 1.0 M solution in THF). Stirring was continued for 1.5 h at -78° C., and the reaction mixture was then allowed to warm to 0° C. and quenched with H2O. The organic layer was separated and the aqueous was extracted with CH2Cl2 (2*100 mL). The combined organic extracts were dried (MgSO4) and evaporated to give the desired alcohol (5.0 g, 100percent) as a white solid: 1H NMR (CDCl3) δ 1.84 (br, 1H), 4.49 (s, 2H), 4.67 (s, 2H), 7.33 (d, 2H, J=8.2 Hz), 7.38 (d, 2H, J=8.2 Hz).
100%
With diisobutylaluminium hydride In tetrahydrofuran; dichloromethane at -78℃; for 1.5 h; Inert atmosphere
General procedure: 4.1.57 4-Bromomethylbenzyl alcohol (14) To a solution of methyl 4-bromomethylbenzoate 13 (3.09 g, 13 mmol) in dry CH2Cl2 (80 mL) cooled to -78 °C with stirring under nitrogen was added dropwise a solution of DIBAL-H (47 mL, 1.0 M solution in THF). Stirring was continued for 1.5 h at -78 °C, and the reaction mixture was then allowed to warm to 0 °C and quenched with H2O. The organic layer was separated and the aqueous was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4 and evaporated to yield quantitatively the desired alcohol as a white solid. CAS: 71831-21-5.
90%
Stage #1: With diisobutylaluminium hydride In toluene at -20 - 35℃; for 1 h; Stage #2: With hydrogenchloride; water In toluene at -20 - 35℃;
Example 3Preparation of intermediate (Va where n=l and R= acetyl) 4-(4-acetyl-piperazin- 1 -yl-methy lpheny Dmethano 15.5 volumes of Toluene were loaded in a glass lined vessel under N2 and cooled down to -200C +/- 2°C.In a separate vessel, 1.5 kg of methyl-4-bromo-methylbenzoate were charged portion wise while stirring under N2 at room temperature to obtain a solution (solution B).19.8 liters (3.02 eq.) of a 1 M solution DIBAL-H/Toluene under N2 were added, cooling down the solution to -200C +/- 2°C and stirring.The solution B was loaded under N2 portion wise while maintaining the temperature in the range 0-150C (< 350C) by addition over about 1 hour.Reaction was monitored by HPLC when addition was completed. The mixture was cooled down to -200C +/- 2°C under stirring.8.8 volumes (2.02 eq.) of IM acq. HCl (cooled to 5°C +/- 2°C) were added drop wise under very slow stirring and maintaining the temperature below 300C (<35°C).Stirring was stopped and phases separated at 8°C +/- 2°C. Water phase was removed.5 volumes Of H2O were then charged, maintaining the temperature at 100C +/- 2°C, very slowly stirring was done for a further 10 minutes.Stirring was stopped and phases separated at 100C +/- 2°C, then removed. Washing with water and phase separation were repeated. <n="14"/>Toluene was removed by distillation under reduced pressure maintaining solution temperature at 35°C (< 400C) to obtain a white solid with yield equal to 90percent.The above solid is dissolved in 7 volumes of dichloromethane in a vessel under N2 stirring at 25°C for about 15 minutes. In a separate vessel, 1.05 kg of N-acetyl- piperazine were dissolved in 3 volumes of dichloromethane stirring at 25°C.Sodium bicarbonate was charged portion wise to the dichloromethane solution under stirring at 23°C +/- 2°C in about 10 minutes.N-acetyl-piperazine solution was loaded to dichlorometane-bicarbonate mixture under stirring at 300C +/- 2°C. The mixture was stirred at that temperature for 15 hours, monitoring the reaction by HPLC.The reaction mixture was cooled down at 23°C +/- 2°C.2 volumes of water were added under stirring at 25°C for about 15 minutes. Stirring was stopped and the phases were separated. Organic phases were separated.Organic phases were washed with water (2 x 2 volumes) under stirring for 15 minutes at 25°C. Water phases were collected and washed (2 x 3 volumes) with dichloromethane under stirring for 15 minutes at 25°C. Organic phases were removed, collected and dried over anhydrous sodium sulfate. The solid cake was washed with 2 volumes of dichloromethaneDichloromethane solution was concentrated (about 15 volumes at 400C under vacuum), subsequently 6 volumes of ethyl acetate were added.6 volumes of solvent were removed at 65°C.The solution was cooled down to 53°C in about 1 hour under slow stirring, then to 5°C +/- 2°C in about 2.5 hours under slow stirring to obtain crystallization of the material.The mixture was filtered at 5°C and the solid cake washed with 1 volume of ethyl acetate (cooled at 5°C).A second crop of material could be obtained from mother liquors by concentration and cooling. <n="15"/>The solid was dried in vacuo in oven (30°C+/-2°C) for about 15 hours.Average yield 70percent (wt) starting from methyl-4-bromo-methylbenzoate, average purity for this step (> 97percent) on 13 batches.
81%
Stage #1: With diisobutylaluminium hydride In hexane; dichloromethane at -78 - 20℃; for 16 h; Stage #2: With water; Rochelle's salt In hexane; dichloromethane
Preparation 36[4-(Bromomethyl)phenyl]methanolTo a solution of 4-bromomethyl-benzoic acid methyl ester (5 g, 21.82 mmol) in DCM (200 mL) is added DIBAL-H (1.0 M in hexane, 54.56 mL, 54.56 mmol) drop wise at -78° C. The reaction mixture is allowed to warm to room temperature and stirred for 16 hours. The reaction mixture is quenched with sodium potassium tartrate (10percent solution, 8 mL) and diluted with DCM (100 mL). The combined organic layer is washed with water (50 mL), brine (25 mL), dried over sodium sulfate, and evaporated to give the title compound as an off white solid (3.5 g, 81percent). 1H NMR (400 MHz, CDCl3) δ 7.23-7.21 (m, 2H), 7.4-7.3 (m, 2H), 4.5-4.3 (bs, 2H), 4.68 (s, 2H).
80%
With diisobutylaluminium hydride In dichloromethane at -78℃; for 1.5 h; Inert atmosphere
To a solution of methyl 4-(bromomethyl)benzoate (2.3 g, 0.01 mol) in dry DCM (80 mL) was added DIBAL- H (22 mL, 0.03 mol) at -78 °C under N2. The mixture was stirred at -78 °C for 1.5 h. The reaction mixture was quenched by careful addition of H2O (50 mL), and then extracted with DCM (100 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford (4- (bromomethyl)phe
Reference：
[1] Patent: US6506770, 2003, B1,
[2] Patent: US6872714, 2005, B1,
[3] Journal of Medicinal Chemistry, 2010, vol. 53, # 3, p. 1250 - 1260
[4] European Journal of Medicinal Chemistry, 2015, vol. 104, p. 127 - 138
[5] Journal of Labelled Compounds and Radiopharmaceuticals, 2017, vol. 60, # 10, p. 466 - 480
[6] Patent: WO2008/125518, 2008, A2, . Location in patent: Page/Page column 12-14
[7] Patent: US2011/92531, 2011, A1, . Location in patent: Page/Page column 11
[8] Organic Letters, 2003, vol. 5, # 13, p. 2239 - 2242
[9] Patent: WO2015/103317, 2015, A1, . Location in patent: Page/Page column 196
[10] Tetrahedron, 1990, vol. 46, # 23, p. 7793 - 7802
[11] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 9, p. 3187 - 3200
[12] Patent: US2016/24063, 2016, A1, . Location in patent: Paragraph 0247-0249
[13] European Journal of Medicinal Chemistry, 2017, vol. 139, p. 290 - 304
14
[ 2417-72-3 ]
[ 71831-21-5 ]
Yield
Reaction Conditions
Operation in experiment
58.3%
With diisobutylaluminium hydride In methanol; hexane; water; ethyl acetate; toluene
Preparation of 4-(bromomethyl)benzaldehyde In a 5 lier three-neck flask under a nitrogen atmosphere methyl 4-(bromomethyl)benzoate (49.86 g, 217.7 mmol) was dissolved in 700 ml of toluene. The stirring solution was cooled via dry ice/acetone bath to an internal temperature of -78° C. before the dropwise addition of diisobutylaluminum hydride (600 ml of a 1.0M solution in toluene). The DIBAH was added at such a rate that the internal temperature never exceeded -70° C. The progress of the reaction was monitored by thin layer chromatography (silica; 10percent ethyl acetate in hexane). To the stirring reaction mixture was slowly added 250 ml of methanol. The reaction mixture was then removed from the ice bath and allowed to warm to room temperature. To this reaction mixture was then added water (500 ml), sodium potassium tartrate tetrahydrate (280 g) and ether (1.5 L) and the reaction was stirred at room temperature overnight. The phases were then separated and the aqueous fraction was extracted with ether (750 ml). The combined organic phases were washed with water (300 ml), followed by a wash with brine (300 ml) and then dried over magnesium sulfate. The solvents were removed in vacuo to yield 41.6 grams of white solid which was then dissolved in hot ether and then filtered. The ether filtrate was concentrated to about 250 ml on a steam bath and then solwly diluted with hexane to a final volume of about 350 ml. After another filtration, the filtrate was permitted to cool to room temperature. The crystals which formed during the cooling period were collected and dried to yield 25.5 g (58.3percent) of 4-bromomethylbenzyl alcohol as a crystalline solid.
Reference：
[1] Patent: US5747517, 1998, A,
[2] Patent: US5747517, 1998, A,
15
[ 2417-72-3 ]
[ 62642-62-0 ]
Reference：
[1] Patent: WO2018/29604, 2018, A1,
16
[ 2417-72-3 ]
[ 88089-94-5 ]
Reference：
[1] Tetrahedron Letters, 1999, vol. 40, # 46, p. 8049 - 8053
[2] Journal of Chemical Research, Miniprint, 1995, # 11, p. 2569 - 2583
17
[ 99-75-2 ]
[ 2417-72-3 ]
[ 104901-43-1 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1986, vol. 22, p. 24 - 32[2] Zhurnal Organicheskoi Khimii, 1986, vol. 22, # 1, p. 30 - 39
Reference：
[1] Patent: WO2006/113468, 2006, A2, . Location in patent: Page/Page column 78
[2] European Journal of Medicinal Chemistry, 2016, vol. 109, p. 124 - 133
21
[ 2417-72-3 ]
[ 142-64-3 ]
[ 142-63-2 ]
[ 86620-81-7 ]
Reference：
[1] Patent: US4616086, 1986, A,
22
[ 2417-72-3 ]
[ 86620-81-7 ]
Reference：
[1] Patent: WO2016/146220, 2016, A1,
23
[ 2417-72-3 ]
[ 333986-70-2 ]
Reference：
[1] Patent: US6562978, 2003, B1,
24
[ 2417-72-3 ]
[ 90-02-8 ]
[ 351335-29-0 ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 80℃; for 0.166667 h; Microwave irradiation
General procedure: A microwave vial was charged with bromomethylbenzene derivative (0.4 mmol, 1 equiv), appropriated phenol derivative (0.44 mmol, 1.1 equiv), K2C03 (0.8 mmol, 2equiv), few crystals of Nal and dimethylformamide (DMF) (1 .4 mL). The reaction mixture was heatedunder microwave irradiation at 80°C for 10 minutes. Then, resulted mixture was poured into water and extracted with ethyl acetate. Combined organic phases were washed with brine, dried over Mg504 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (CH2CI2/MeOH)
In tetrahydrofuran; water; N,N-dimethyl-formamide;
Part A: To a stirred solution of 7.5 g(153 mmol) sodium cyanide in 75 mL of THF was added 40 mL of DMF followed by 11.5 g(50.2 mmol) of of methyl 4-(bromomethyl)benzoate in 30 mL of DMF over 10 min. The solution was stirred 18 and treated with 100 mL water. The mixture was filtered, rinsed with water, and air-dried briefly to give 6.7 g (76%) of 4-(carbomethoxy)phenylacetonitrile as a white solid. 1H NMR (300 MHz, DMSO) delta7.95(d, 2H, J=8.4 Hz); 7.47(d, 2H, J=8.5 Hz); 4.14(s, 2H); 3.82(s, 3H).
6.7 g (76%)
In tetrahydrofuran; water; N,N-dimethyl-formamide;
Part A: To a stirred solution of 7.5 g(153 mmol) sodium cyanide in 75 mL of THF was added 40 mL of DMF followed by 11.5 g(50.2 mmol) of of methyl 4-(bromomethyl)benzoate in 30 mL of DMF over 10 min. The solution was stirred 18 and treated with 100 mL water. The mixture was filtered, rinsed with water, and air-dried briefly to give 6.7 g (76%) of 4-(carbomethoxy)phenylacetonitrile as a white solid. 1H NMR (300 MHz, DMSO) delta 7.95(d, 2H, J=8.4 Hz); 7.47(d, 2H, J=8.5 Hz); 4.14(s, 2H); 3.82(s, 3H).
With diisobutylaluminium hydride; In tetrahydrofuran; dichloromethane;
4-Bromomethylbenzyl alcohol To a solution of methyl 4-bromomethylbenzoate (5.73 g, 25 mmol) in dry CH2Cl2 (150 mL) cooled to -78° C. with stirring under nitrogen was added dropwise a solution of DIBAL-H (82.5 mL, 1.0 M solution in THF). Stirring was continued for 1.5 h at -78° C., and the reaction mixture was then allowed to warm to 0° C. and quenched with H2O. The organic layer was separated and the aqueous was extracted with CH2Cl2 (2*100 mL). The combined organic extracts were dried (MgSO4) and evaporated to give the desired alcohol (5.0 g, 100percent) as a white solid: 1H NMR (CDCl3) delta1.84 (br, 1H), 4.49 (s, 2H), 4.67 (s, 2H), 7.33 (d, 2H, J=8.2 Hz), 7.38 (d, 2H, J=8.2 Hz).
100%
With diisobutylaluminium hydride; In tetrahydrofuran; dichloromethane;
4-Bromomethylbenzyl Alcohol To a solution of methyl 4-bromomethylbenzoate (5.73 g, 25 mmol) in dry CH2Cl2 (150 mL) cooled to -78° C. with stirring under nitrogen was added dropwise a solution of DIBAL-H (82.5 mL, 1.0 M solution in THF). Stirring was continued for 1.5 h at -78° C., and the reaction mixture was then allowed to warm to 0° C. and quenched with H2O. The organic layer was separated and the aqueous was extracted with CH2Cl2 (2*100 mL). The combined organic extracts were dried (MgSO4) and evaporated to give the desired alcohol (5.0 g, 100percent) as a white solid: 1H NMR (CDCl3) delta 1.84 (br, 1H), 4.49 (s, 2H), 4.67 (s, 2H), 7.33 (d, 2H, J=8.2 Hz), 7.38 (d, 2H, J=8.2 Hz).
100%
With diisobutylaluminium hydride; In tetrahydrofuran; dichloromethane; at -78℃; for 1.5h;Inert atmosphere;
General procedure: 4.1.57 4-Bromomethylbenzyl alcohol (14) To a solution of methyl 4-bromomethylbenzoate 13 (3.09 g, 13 mmol) in dry CH2Cl2 (80 mL) cooled to -78 °C with stirring under nitrogen was added dropwise a solution of DIBAL-H (47 mL, 1.0 M solution in THF). Stirring was continued for 1.5 h at -78 °C, and the reaction mixture was then allowed to warm to 0 °C and quenched with H2O. The organic layer was separated and the aqueous was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4 and evaporated to yield quantitatively the desired alcohol as a white solid. CAS: 71831-21-5.
90%
Example 3Preparation of intermediate (Va where n=l and R= acetyl) 4-(4-acetyl-piperazin- 1 -yl-methy lpheny Dmethano 15.5 volumes of Toluene were loaded in a glass lined vessel under N2 and cooled down to -200C +/- 2°C.In a separate vessel, 1.5 kg of methyl-4-bromo-methylbenzoate were charged portion wise while stirring under N2 at room temperature to obtain a solution (solution B).19.8 liters (3.02 eq.) of a 1 M solution DIBAL-H/Toluene under N2 were added, cooling down the solution to -200C +/- 2°C and stirring.The solution B was loaded under N2 portion wise while maintaining the temperature in the range 0-150C (< 350C) by addition over about 1 hour.Reaction was monitored by HPLC when addition was completed. The mixture was cooled down to -200C +/- 2°C under stirring.8.8 volumes (2.02 eq.) of IM acq. HCl (cooled to 5°C +/- 2°C) were added drop wise under very slow stirring and maintaining the temperature below 300C (<35°C).Stirring was stopped and phases separated at 8°C +/- 2°C. Water phase was removed.5 volumes Of H2O were then charged, maintaining the temperature at 100C +/- 2°C, very slowly stirring was done for a further 10 minutes.Stirring was stopped and phases separated at 100C +/- 2°C, then removed. Washing with water and phase separation were repeated. <n="14"/>Toluene was removed by distillation under reduced pressure maintaining solution temperature at 35°C (< 400C) to obtain a white solid with yield equal to 90percent.The above solid is dissolved in 7 volumes of dichloromethane in a vessel under N2 stirring at 25°C for about 15 minutes. In a separate vessel, 1.05 kg of N-acetyl- piperazine were dissolved in 3 volumes of dichloromethane stirring at 25°C.Sodium bicarbonate was charged portion wise to the dichloromethane solution under stirring at 23°C +/- 2°C in about 10 minutes.N-acetyl-piperazine solution was loaded to dichlorometane-bicarbonate mixture under stirring at 300C +/- 2°C. The mixture was stirred at that temperature for 15 hours, monitoring the reaction by HPLC.The reaction mixture was cooled down at 23°C +/- 2°C.2 volumes of water were added under stirring at 25°C for about 15 minutes. Stirring was stopped and the phases were separated. Organic phases were separated.Organic phases were washed with water (2 x 2 volumes) under stirring for 15 minutes at 25°C. Water phases were collected and washed (2 x 3 volumes) with dichloromethane under stirring for 15 minutes at 25°C. Organic phases were removed, collected and dried over anhydrous sodium sulfate. The solid cake was washed with 2 volumes of dichloromethaneDichloromethane solution was concentrated (about 15 volumes at 400C under vacuum), subsequently 6 volumes of ethyl acetate were added.6 volumes of solvent were removed at 65°C.The solution was cooled down to 53°C in about 1 hour under slow stirring, then to 5°C +/- 2°C in about 2.5 hours under slow stirring to obtain crystallization of the material.The mixture was filtered at 5°C and the solid cake washed with 1 volume of ethyl acetate (cooled at 5°C).A second crop of material could be obtained from mother liquors by concentration and cooling. <n="15"/>The solid was dried in vacuo in oven (30°C+/-2°C) for about 15 hours.Average yield 70percent (wt) starting from methyl-4-bromo-methylbenzoate, average purity for this step (> 97percent) on 13 batches.
81%
Preparation 36[4-(Bromomethyl)phenyl]methanolTo a solution of 4-bromomethyl-benzoic acid methyl ester (5 g, 21.82 mmol) in DCM (200 mL) is added DIBAL-H (1.0 M in hexane, 54.56 mL, 54.56 mmol) drop wise at -78° C. The reaction mixture is allowed to warm to room temperature and stirred for 16 hours. The reaction mixture is quenched with sodium potassium tartrate (10percent solution, 8 mL) and diluted with DCM (100 mL). The combined organic layer is washed with water (50 mL), brine (25 mL), dried over sodium sulfate, and evaporated to give the title compound as an off white solid (3.5 g, 81percent). 1H NMR (400 MHz, CDCl3) delta 7.23-7.21 (m, 2H), 7.4-7.3 (m, 2H), 4.5-4.3 (bs, 2H), 4.68 (s, 2H).
80%
With diisobutylaluminium hydride; In dichloromethane; at -78℃; for 1.5h;Inert atmosphere;
To a solution of methyl 4-(bromomethyl)benzoate (2.3 g, 0.01 mol) in dry DCM (80 mL) was added DIBAL- H (22 mL, 0.03 mol) at -78 °C under N2. The mixture was stirred at -78 °C for 1.5 h. The reaction mixture was quenched by careful addition of H2O (50 mL), and then extracted with DCM (100 mL X 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford (4- (bromomethyl)phe
With diisobutylaluminium hydride; In dichloromethane; at -78℃; for 5h;Inert atmosphere;
Methyl 4-(bromomethyl)benzoate (5.0 g) and MC (20 ml) were loaded in a 1 L flask in nitrogen atmosphere, followed by stirring for dissolving them. Then, 70 ml of DIBAL-H was slowly added thereto at ?78° C., followed by stifling for 5 hours. Upon completion of the reaction, the mixture was cooled down to 0° C. and distilled water was slowly added thereto, followed by extraction using MC. The extracted organic layer was dried under reduced pressure to give the target compound. (0249) 1H NMR (400 MHz, CDCl3): delta 7.42 (2H, d), 7.38 (2H, d), 4.73 (2H, s), 4.52 (2H, m).
With diisobutylaluminium hydride; In dichloromethane; at 0 - 20℃; for 1h;
To a solution of methyl 4-(bromomethyl)benzoate 17(4.36 mmol) in anhydrous DCM (10 mL), DIBAL-H (10.9 mmol) wasadded at 0 °C and then the solution was stirred at ambient temperaturefor 1 h. The reaction mixture was quenched with NH4Clsolution, diluted with DCM, filtered through celite bed and then thebed was washed with DCM. The organic layer was washed withbrine solution, dried over anhydrous Na2SO4, filtered and evaporatedunder reduced pressure to afford tittle compound 17a, whichwas used for the next step without further purification. Yield 75percent;White solid; 1H NMR (300 MHz, CDCl3) delta 7.32-7.45 (m, 4H), 4.71 (d,J 5.87 Hz, 2H), 4.51 (s, 2H), 1.69 (t, J 5.91 Hz, 1H).
With caesium carbonate; In DMF (N,N-dimethyl-formamide); for 20h;
In dry N, N-dimethylformamide (15 ml), <strong>[387-46-2]2,6-dihydroxybenzaldehyde</strong> (0.293 g, 2.12 mmol) and Cs2CO3 (0.828 g, 2.54 mmol) were dissolved. Following the addition of methyl 4- (bromomethyl) benzoate (0.490 g, 2.14 mmol) the mixture was stirred at room temperature overnight. After filtration, the solvent was evaporated, the residue dissolved in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. Drying (Na2SO4) and evaporation afforded crude material that was purified by flash chromatography (ethyl acetate: heptane, 1: 3), giving methyl-4-[(2-formyl-3- hydroxyphenoxy)methyl]benzoate as a white solid (0.385 g, 63%). 1H-NMR (400 MHz, DMSO-d6): delta 10.4 (1H, s); 7.99 (2H, d); 7.65 (2H, d); 7.52 (1H, t); 6.68 (1H, d); 6.55 (1H, d); 5.35 (2H, s); 3.85 (3H, s).
Commercially available 4-bromomethylbenzoic acid methyl ester (10.0 g) was dissolved in ethanol (40 mL). A potassium cyanide solution (5.63 g in 8 mL water) was added dropwise over 15 min. The resulting suspension was heated to reflux for 3 h. Volatiles were removed under reduced pressure and the residue dissolved in diethylether and water. The organic layer was concentrated to a dark oil which was purified by column chromatography (5% ethyl ether in dichloromethane) to give the intermediate (6.0 g). [MH]+=176.
A solution of sodium cyanide (20 g, 0.41 mol) in dimethylsulfoxide at 40 C. was treated dropwise with a solution of methyl 4-(bromomethyl)benzoate (52 g, 0.227 mol) in dimethylsulfoxide, stirred for 90 min., cooled to room temperature, quenched with saturated aqueous sodium chloride and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. Purification of the concentrate via column chromatography (silica, hexanes:ethyl acetate 0?5%) provided methyl 4-(cyanomethyl)benzoate (55%). 1H NMR (400 MHz, CDCl3): 8.05 (d, J=8 Hz, 2H); 7.42 (d, J=8 Hz, 2H); 3.93 (s, 3H); 3.81 (s, 2H). [M+H] 176
55%
In dimethyl sulfoxide; at 40℃; for 1.5h;
Step 1: Methyl 4-(Cyanomethyl)benzoate A solution of sodium cyanide (20 g, 0.41 mol) in dimethylsulfoxide at 40 C. was treated dropwise with a solution of methyl 4-(bromomethyl)benzoate (52 g, 0.227 mol) in dimethylsulfoxide, stirred for 90 min., cooled to room temperature, quenched with saturated aqueous sodium chloride and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. Purification of the concentrate via column chromatography (silica, hexane:ethyl acetate 0?5%) provided methyl 4-(cyanomethyl)benzoate (55%). 1H NMR (400 MHz, CDCl3): 8.05 (d, J=8 Hz, 2H); 7.42 (d, J=8 Hz, 2H); 3.93 (s, 3H); 3.81 (s, 2H). [M+H] 176
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃;
(3d) Potassium carbonate (5.2 g, 37.7 mmol) and methyl 4-(bromomethyl)benzoate (2.8 g, 12.6 mmol) were added to a solution of (3c) (1.9 g, 12.6 mmol) in 20 mL of anhydrous DMF. The reaction mixture was heated to 80 C. overnight. After cooling to rt, the solid was filtered off and rinsed with DMF. The filtrate was concentrated in vacuo and the residue was purified on silica gel column to provide methyl 4-(2,3-dihydro-4H-1,4-benzothiazin-4-ylmethyl)benzoate (3.02 g, 80%).
37%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;
To a round bottom flask charged with compound 16-1 (151 mg, 1.0 mmol) and methyl 4-(bromomethyl)benzoate (228 mg, 1.0 mmol) in DMF (5 mL) was added K2CO3 (276 mg, 2.0 mmol). The resulting mixture was allowed to stir for 2 h at 80 C. The mixture was cooled to room temperature and after addition of water (15 mL) extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (0 - 50% EtOAc/hexanes) to afford as colorless oil (110 mg, 37%).1H NMR (CDCI3) delta 8.00, 7.33 (AlphaAlpha'ChiChi' multiplet, AX + J AX = 8.4 Hz, 4H), 7.08 (dd, / = 7.7 Hz, 1.5 Hz, 1H), 6.90 (incompletely resolved ddd approaching dt, average of two larger / = 7.8 Hz, additional / = 1.1 Hz, 1H), 6.63 (incompletely resolved ddd approaching dt, average of two larger / = 7.5 Hz, additional / = 0.8 Hz, 1H), 6.54 (dd, 7 = 8.3 Hz, 0.7 Hz, 1H), 4.57 (s, 2H), 3.90 (s, 3H), 3.69, 3.08 (AlphaAlpha'ChiChi' multiplet, AX + J AX = 10.4 Hz, 4H). 13C NMR (CDCI3) delta 166.9, 143.8, 143.4, 130.1 (2C), 129.1, 128.0, 126.6 (2C), 126.1, 118.0, 117.8, 113.2, 56.3, 52.1, 50.6, 25.9. ESI LRMS: [M+H]+, mlz 300.2.
9-fluorenyl-methoxycarbonyl-cyclohexyl alanine[ No CAS ]
[ 462-94-2 ]
[ 1458-98-6 ]
[ 78-77-3 ]
[ 1809-10-5 ]
[ 110-53-2 ]
[ 592-55-2 ]
[ 7328-91-8 ]
[ 871-76-1 ]
[ 105-83-9 ]
[ 144-48-9 ]
[ 929-59-9 ]
[ 107-59-5 ]
[ 5324-30-1 ]
[ 5428-54-6 ]
[ 27129-86-8 ]
[ 2417-72-3 ]
[ 2581-34-2 ]
[ 554-84-7 ]
[ 3385-21-5 ]
[ 126-38-5 ]
[ 636-93-1 ]
[ 88-30-2 ]
[ 620-13-3 ]
[ 823-78-9 ]
[ 5035-82-5 ]
[ 29022-11-5 ]
[ 539-48-0 ]
[ 35661-39-3 ]
[ 26759-46-6 ]
[ 20439-47-8 ]
[ 2615-25-0 ]
[ 6393-01-7 ]
[ 5372-81-6 ]
[ 35661-40-6 ]
[ 100-39-0 ]
[ 611-17-6 ]
[ 23915-07-3 ]
[ 71989-23-6 ]
[ 35737-15-6 ]
[ 2592-95-2 ]
[ 18880-00-7 ]
[ 88681-68-9 ]
[ 100063-22-7 ]
[ 75-03-6 ]
[ 106-94-5 ]
[ 104-81-4 ]
[ 589-10-6 ]
[ 107-15-3 ]
[ 109-76-2 ]
[ 110-60-1 ]
[ 7051-34-5 ]
[ 106-95-6 ]
[ 622-95-7 ]
[ 589-15-1 ]
[ 134-20-3 ]
[ 2550-36-9 ]
[ 89-92-9 ]
[ 456-41-7 ]
[ 766-80-3 ]
[ 459-46-1 ]
[ 874-98-6 ]
[ 402-49-3 ]
[ 870-63-3 ]
[ 85118-01-0 ]
[ 22115-41-9 ]
[ 3958-57-4 ]
[ 100-11-8 ]
[ 107-82-4 ]
[ 6482-24-2 ]
[ 3132-64-7 ]
[ 112883-41-7 ]
[ 3433-80-5 ]
[ 52727-57-8 ]
C18H15N2O3PolS[ No CAS ]
C20H20N3OPolS[ No CAS ]
C23H19N2O2PolS[ No CAS ]
C18H23ClN3OPolS[ No CAS ]
C22H26N3OPolS[ No CAS ]
C22H23N2O5PolS[ No CAS ]
C20H26ClN2O3PolS[ No CAS ]
C23H22ClN2O3PolS[ No CAS ]
C20H21FN3O3PolS[ No CAS ]
C22H29N2O3PolS[ No CAS ]
C21H28N3O3PolS[ No CAS ]
C19H26N3O4PolS2[ No CAS ]
C22H30N3OPolS[ No CAS ]
C21H28N3O4PolS[ No CAS ]
C26H26N3OPolS[ No CAS ]
C23H15ClF3N2O2PolS[ No CAS ]
C24H22N3O3PolS[ No CAS ]
C23H16ClF2N2O2PolS[ No CAS ]
C22H22Br2N3OPolS[ No CAS ]
C24H26FN2O5PolS[ No CAS ]
C25H22FN2O4PolS[ No CAS ]
C26H22N3O4PolS[ No CAS ]
C25H25ClN3O3PolS[ No CAS ]
C25H18ClF2N2O3PolS[ No CAS ]
C29H26N3O3PolS[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With piperidine; Carbonyldiimidazole; tin-2-ethylhexanoate dihydrate; potassium tert-butylate; water; N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; diisopropyl-carbodiimide; dibromotriphenylphosphorane; In DMF (N,N-dimethyl-formamide); dichloromethane; N,N-dimethyl acetamide; 1,2-dichloro-ethane;Combinatorial reaction / High throughput screening (HTS);
EXAMPLE 1 [0213] This example shows the synthesis of a combinatorial library of thioquinazolinone derivatives. [0214] Step 1a: Preparation of Wang Bromide Resin [0215] 40 tea bags containing 2 g each of Wang resin (80 g, 120 mmol) was taken in a 5 L PP container. A solution of triphenylphosphine dibromide (152 g, 0.15 M, 3 eq., 360 mmol) in 2000 ml DCM was added and the solution was shaken at room temperature overnight. The resin was sequentially washed with DCM (4×, 1.5 L each) and diethylether (6×, 1.5 L each) and dried under vacuum, to give the bromo wang resin. [0216] Step 1b: Loading of the Nitrophenol on Bromo Wang [0217] 20 g of the Bromo wang resin (1.5 meq/g) was taken in a 2 L wide-mouthed glass container and 1000 mL DMA was addded to it followed by the addition of the nitro phenol (10 eq., 0.3M, 300 mmol). Potasium t-butoxide (33.46 g, 10 eq., 300 mmol) was then added to it and the bottles were heated at 50 C. overnight. The bags were washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The tea bags were then dried overnight in air. The following nitrophenols were used: [0218] 2-METHYL-5-NITROPHENOL [0219] 5-HYDROXY-2-NITROBENZOTRIFLUORIDE [0220] 3-METHYL-4-NITROPHENOL [0221] 2-METHOXY-5-NITROPHENOL [0222] M-NITROPHENOL [0223] Step 1c: Reduction of the Nitro Group to Amine [0224] A 2.0 M solution of tin-2-ethylhexanoate dihydrate was prepared in DMF containing 0.5% H2O. The tea bags were added and the solution is heated at 50 C. for 40 hours. After cooling the bags are washed with DMF/10% HOAc (3×), DMF (3×), 5% DIEA/DCM (2×), DCM (2×) and MeOH (2×) and dried in air overnight. [0225] Step 1d: Coupling N-FMOC Protected Amino Acid to Wang Resin. [0226] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL plastic bottle. DMF (300 mL), DCM (300 mL), FMOC-Cyclohexyl alanine (70.82 g, 6 eq., 0.3M, 180 mmol), DIC (22.71 g, 6 eq., 180 mmol), HOBt (24.32 g, 6 eq., 180 mmol) were added sequentially. After shaking for 12 hours, the packet was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried overnight in air. The tea bags containing the amino acids were then treated with 20% piperidine/DMF for 2 h at room temperature to deblock the FMOC group. The following amino acids were used: [0227] FMOC-GLY-OH [0228] FMOC-ALA-OH [0229] FMOC-L-ISOLEUCINE [0230] FMOC-L-PHENYLALANINE [0231] FMOC-D-NLE-OH [0232] FMOC-CHA-OH [0233] FMOC-L-TRYPTOPHAN [0234] Step 1e: Coupling of the Diamines to Wang Resin [0235] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL Nalgene bottle. 600 mL of DCM was added followed by the addition of the carbonyl diimidazole (29.9 g, 6 eq., 0.3M, 180 mmol) and the flasks were shaken at room temperature for 3 hours after which they were decanted and washed with DCM (2×, 600 mL). To these Nalgene bottles were added the diamines (6 eq., 0.4M, 180 mmol) in 450 mL of DCM (0.4M) and they were shaken at room temperature overnight. The diamines used were as follows: [0236] 2,2-DIMETHYL-1,3-PROPANEDIAMINE [0237] 1,3-CYCLOHEXANEDIAMINE [0238] (1R,2R)-(-)-1,2-DIAMINOCYCLOHEXANE [0239] TRANS-1,4-DIAMINOCYCLOHEXANE [0240] P-XYLYLENEDIAMINE [0241] 1,4-BIS(3-AMINOPROPYL)PIPERAZINE [0242] ETHYLENEDIAMINE [0243] 1,3-DIAMINOPROPANE [0244] 1,8-DIAMINO-3,6-DIOXAOCTANE [0245] 1,4-DIAMINOBUTANE [0246] 1,5-DIAMINOPENTANE [0247] 1,6-HEXANEDIAMINE [0248] N,N-BIS(3-AMINOPROPYL)METHYLAMINE [0249] 2,2'-THIOBIS(ETHYLAMINE) [0250] 2,5-DIMETHYL-1,4-PHENYLENEDIAMINE [0251] After shaking overnight, the packets was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried in air. [0252] Step 2: Formation of the Isothiocyanate [0253] The o-amino benzoate ester (136 g, 10 eq., 900 mmol) was taken in a 5 L wide-mouthed glass bottle and 2.7 L of dichloroethane was added to it (0.3M). The following esters were used: [0254] METHYL ANTHRANILATE [0255] METHYL 2-AMINO-4-CHLOROBENZOATE [0256] 2-AMINO-4,5-DIMETHOXYBENZOIC ACID [0257] METHYL ESTER [0258] METHYL 3,4,5-TRIMETHOXYANTHRANILATE [0259] DIMETHYL AMINOTEREPHTHALATE [0260] METHYL 2-AMINO-5-BROMOBENZOATE [0261] METHYL 3-AMINOTHIOPHENE-2-CARBOXYLATE [0262] METHYL 3-AMINO-5-PHENYLTHIOPHENE-2-CARBOXYLATE [0263] Thiocarbonyl diimidazole (160 g, 10 eq., 900 mmol) was added to it and the solution was heated at 55 C. overnight to form the isothiocyanate. [0264] Step 3: Formation of the Thioquinazolinone [0265] The next day the tea bags containing the amino acids, diamines and the amino phenols on wang resin (90 mmol) was added to the isothiocyanate solution from reaction 2 and the glass bottles were heated at 55 C. overnight. After cooling the bags was washed alternatively with DMF (2000 mL) and DCM (2000 mL) 3 cycles followed by 6 cycles of MeOH...
In N,N-dimethyl-formamide; at 120℃; for 0.0833333h;Microwave irradiation;
293 mg of the sodium ethansulfmate was combined with 230 mg of methyl (4-bromoethyl)benzoate in 2 mL of DMF and heated to 120 C for 5 min in a microwave reactor. The reaction was then extracted with Ethyl Acetate and Brine to give 250 mg of methyl 4-(ethylsulfonylmethyl)benzoate after evaporation of the organic layer.
In N,N-dimethyl-formamide; at 120℃; for 0.0833333h;Microwave irradiation;
Ethanesulfonyl chloride was reduced to <strong>[20035-08-9]sodium ethanesulfinate</strong> according to the procedure in J. Med. Chem. 1989, vol. 32, no. 11, p 2436. Briefly, 2.5 ml of ethanesulfonyl chloride was added dropwise to a solution of 3.67 g of sodium carbonate and 5.51 g of sodium sulfate in 13 mL of water. After completion of the reaction the water was evaporated and the solids were suspended in ethanol and heated to 80 C. for 1 h prior to filtering the solids. The filtrate was then evaporated to give 2.5 grams of the <strong>[20035-08-9]sodium ethanesulfinate</strong>. 293 mg of the sodium ethansulfinate was combined with 230 mg of methyl (4-bromoethyl)benzoate in 2 mL of DMF and heated to 120 C for 5 min in a microwave reactor. The reaction was then extracted with Ethyl Acetate and Brine to give 250 mg of methyl 4-(ethylsulfonylmethyl)benzoate after evaporation of the organic layer. 200 mg of methyl 4-(ethylsulfonylmethyl)benzoate was hydrolyzed via Procedure M to give 119 mg of 4-(ethylsulfonylmethyl)benzoic acid.
With potassium iodide;chloro(1,5-cyclooctadiene)rhodium(I) dimer; at 75℃;
Example 12: 4-[l-(5-Benzo[6]thien-2-yl-2,4-dimethoxy-benzoyl)-vinyl]-benzoic acid methyl ester[0270] Ex-12 A: 4-Bromomethyl-benzoic acid methyl ester (2.5 g, 10.91 mmol), potassium iodide (91 mg, 0.55 mmol) and chloro (1,5-cyclooctadiene) rhodium (I) dimer (540 mg, 1.1 mmol) were suspended in formic acid (20 mL). The reaction was flushed with nitrogen and then heated to 75 0C under an atmosphere of carbon monoxide. After aging overnight, the reaction was concentrated to dryness, diluted with EtOAc and washed with 1 N HCl. The organic layer was extracted with saturated NaHCO3 and the resulting aqueous was acidified with HCl and then extracted with EtOAC. The organic layer was dried with MgSO4 and concentrated onto silica gel. The crude was purified by silica gel chromatography (10% MeOH in CH2Cl2) to afford 0.53 g (25% yield) of desired 4-carboxymethyl-benzoic acid methyl ester. 1H-NMR (CDCl3) delta 8.01 (d, J = 7.9 Hz, 2H), 7.36 (d, J= 7.9 Hz, 2H), 3.91 (s, 3H), 3.71 (s, 2H).
(95a) Using conditions analogous to (1f), 2-methyl-5-nitro-benzimidazole (101 mg, 0.568 mmol) was reacted with methyl 4-(bromomethyl)-benzoate to provide the desired ester (71 mg, 40%). MS found: (M+H)+=326.
REFERENCE EXAMPLE 81 Methyl 4-(4-Piperidinylmethyl)benzoate Hydrochloride By a similar manner to Reference Example 3-1, the titled compound was synthesised by using methyl 4-(bromomethyl)benzoate. 1H NMR (DMSO-d6) delta 1.28-1.84 (5H, m), 2.62 (2H, d, J=7.0Hz), 2.70-2.83 (2H, m), 3.18-3.24 (2H, m), 3.84 (3H, s), 7.34 (2H, d, J=8.2Hz), 7.90 (2H, d, J=8.2Hz), 8.95 (2H, br s).
EXAMPLE 4 Preparation of (Z)-5-[[4-[(4-acetyl-3-hydroxy-2-propylphenoxymethyl)]phenyl]methylene]-2-thioxo-4-thiazolidinone Under a nitrogen atmosphere a three-neck round bottom flask was charged with methyl (4-bromomethyl)benzoate (10.0 g, 43.6 mmol) dissolved in 100 ml of toluene. The colorless solution was cooled to -70° C. After cooling, diisobutylaluminum hydride (100 mmol dissolved in 100 ml of toluene) was added dropwise at a rate such that the internal temperature of the reaction mixture never exceeded -65° C., resulting in the production of an orange-yellow color, followed by clarification of the solution. The progress of the reaction was monitored by thin layer chromatography. The reaction was quenched by the addition of methanol and was then poured into a solution of potassium sodium tartrate tetrahydrate (Rochelle's salt). The solution was diluted with diethyl ether and stirred vigorously for about thirty minutes. After separation the organic phase was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to yield 9.0 g of 4-bromomethylbenzyl alcohol as a white crystalline solid.
25.5 g (58.3%)
With diisobutylaluminium hydride; In methanol; hexane; water; ethyl acetate; toluene;
Preparation of 4-(bromomethyl)benzaldehyde In a 5 lier three-neck flask under a nitrogen atmosphere methyl 4-(bromomethyl)benzoate (49.86 g, 217.7 mmol) was dissolved in 700 ml of toluene. The stirring solution was cooled via dry ice/acetone bath to an internal temperature of -78° C. before the dropwise addition of diisobutylaluminum hydride (600 ml of a 1.0M solution in toluene). The DIBAH was added at such a rate that the internal temperature never exceeded -70° C. The progress of the reaction was monitored by thin layer chromatography (silica; 10percent ethyl acetate in hexane). To the stirring reaction mixture was slowly added 250 ml of methanol. The reaction mixture was then removed from the ice bath and allowed to warm to room temperature. To this reaction mixture was then added water (500 ml), sodium potassium tartrate tetrahydrate (280 g) and ether (1.5 L) and the reaction was stirred at room temperature overnight. The phases were then separated and the aqueous fraction was extracted with ether (750 ml). The combined organic phases were washed with water (300 ml), followed by a wash with brine (300 ml) and then dried over magnesium sulfate. The solvents were removed in vacuo to yield 41.6 grams of white solid which was then dissolved in hot ether and then filtered. The ether filtrate was concentrated to about 250 ml on a steam bath and then solwly diluted with hexane to a final volume of about 350 ml. After another filtration, the filtrate was permitted to cool to room temperature. The crystals which formed during the cooling period were collected and dried to yield 25.5 g (58.3percent) of 4-bromomethylbenzyl alcohol as a crystalline solid.
EXAMPLE 14. Methyl 4-(piperazin-1-ylmethyl)-benzoate A mixtue of 38 g. (0.2 mole) piperazine hexahydrate, 28 g. (0.2 mole) <strong>[142-64-3]piperazine dihydrochloride</strong> and 150 ml. methanol is mixed, while stirring at ambient temperature, with 45 g. (0.2 mole) methyl 4-bromomethylbenzoate. The reaction mixture is left to stand for 2 days and suction filtered from the precipitate. The clear solution is evaporated and the residue is recrystallized from ethanol to give 39 g. (64%) of the desired compound as a monohydrochloride; m.p. 226-227 C. The desired compound can also be prepared in the following way:
Step 1: 4-(6-Methoxy-1H-benzoimidazol-2-ylsulfanylmethyl)-benzoic Acid Methyl Ester Hydrobromide (234): To a solution of methyl 4-(bromomethyl)benzoate (2.51 g, 11.0 mmol) in DMF (50 mL) was added 5-methoxy-2-benzimidazolethiol (1.98 g, 11.0 mmol). The mixture was stirred at room temperature for 24 h and the solvent was evaporated in vacuo. The residue was suspended in ethyl acetate and the hydrobromide salt was collected by filtration to afford the title compound 234 (4.10 g, 91% yield) as a colorless solid. 1H NMR: (DMSO-d6) delta (ppm): 7.90 (d, J=8.2 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.2 Hz, 1H), 7.03 (s, 1H), 6.94 (d, J=8.2 Hz, 1H), 4.65 (s, 2H), 3.82 (s, 3H), 3.79 (s, 3H).
91%
In ethyl acetate; N,N-dimethyl-formamide;
Step 1: 4-(6Methoxy-1H-benzoimidazol-2-ylsulfanylmethyl)-benzoic acid methyl ester hydrobromide (234): To a solution of methyl 4-(bromomethyl)benzoate (2.51 g, 11.0 mmol) in DMF (50 mL) was added 5-methoxy-2benzimidazolethiol (1.98 g, 11.0 mmol). The mixture was stirred at room temperature for 24 h and the solvent was evaporated in vacuo. The residue was suspended in ethyl acetate and the hydrobromide salt was collected by filtration to afford the title compound 234 (4.10 g, 91% yield) as a colorless solid. 1H NMR: (DMSO-d6) delta (ppm): 7.90 (d, J=8.2 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.2 Hz, 1H), 7.03 (s,1H), 6.94 (d, J=8.2 Hz,1H), 4.65 (s,2H), 3.82 (s,3H), 3.79 (s, 3H).
<strong>[26621-44-3]3-Nitro-1H-pyrazole</strong> (1.1 8 g, 10.44 mmol) was dissolved in anhydrous N,N-dimethylformamide (15 mL) and a 60% suspension of sodium hydride in mineral oil (500 mg, 12.53 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture stirred for an additional 25 min, the mixture was chilled to 0 C. and the 4-bromomethyl-benzoic acid methyl ester (2.63 g, 11.48 mmol) was added. The mixture continued to stir under nitrogen at 0 C. for 20 min. The solution was poured into ice water, a white precipitate formed and was collected by vacuum filtration and dried in vacuo for 16 h. Recrystallization from hexanes and ethyl acetate (~4:1) gave the desired product, 4-(3-nitro-pyrazol-1-ylmethyl)-benzoic acid methyl ester (1.2 g, 44% yield), as a white powder upon collection and drying in vacuo: H1-NMR (400 MHz, CDCl3) delta=3.93 (3H, s), 5.43 (2H, s), 6.93 (1H, d, J=2.4 Hz), 7.33 (2H, d, J=8.4 Hz), 7.42 (1H, d, J=2.8 Hz), 8.05 (2H, d, J=8.4 Hz).
10.01 g of commercially available bromomethyl benzoate methylester was dissolved in 100 ml of DMF, and then 9.70 g of potassium phthalimide was added to the solution and the whole was stirred for 1.5 hours at room temperature. On completion of the reaction, the solution was concentrated and then water was added, followed by extraction with chloroform. Subsequently, the resultant was washed with a saturated salt solution. After the resultant was dried with sodium hydrogensulfate, the solvent was distilled off. Consequently, 12.91 g of a white solid product was obtained. 7.56 g of the product was dissolved in 100 ml of methanol, and then 6.25 ml of hydrazine monohydrate was added to the solution and the whole was stirred for 1.5 hours at 60C. On completion of the reaction, a precipitated solid product was separated by filtration and then the solvent was distilled off. Water was added totheproduct, followedbyextractionwithchloroform. Theproduct was washed with a 0.3 mol/l sodium hydroxide aqueous solution and a saturated salt solution. The resultant was dried with anhydrous sodium sulfate and then a solvent was distilled off. In this, 120 ml of methanol and 2.35 g of 2-imidazole carboaldehyde were added and the whole was stirred for 2 days at room temperature. On completion of the reaction, a precipitated solid product was collected by filtration. A liquid layer was concentrated and dried so as to be solidified, followed by adding and washing with 30 ml of anhydrous methanol. A solid product was separated by filtration. Said solid product and the solid product previously-collected by filtration were suspended in 86 ml of methanol, and then 1.42 g of sodium borohydride was added to the suspension under ice cold condition. The mixture was stirred for 1 hour at room temperature and the solvent was distilled off. After water was added, the resultant was extracted with chloroform, and an organic layer was then washed with a saturated salt solution. After being dried with anhydrous sodium sulfate, the resultant was concentrated under reduced pressure and dried, and 4.32 g of a colorless viscous product was obtained. 4.28 g of the product was dissolved in 65 ml of DMF, and 8.9 ml of di-t-butyldicarbonate was added to the solution and the whole was stirred for 1 hour at room temperature. On completion of the reaction, the solvent was distilled off. Subsequently, the residue was dissolved in chloroform and washed with a saturated salt solution. After the resultant was dried with anhydrous sodium sulfate, the solvent was distilled off, and then 43 ml of THF, 43 ml of methanol, and 43 ml of a 1 mol/l sodium hydroxide aqueous solution were added thereto and the whole was stirred for 14 hours at room temperature. On completion of the reaction, the solvent was distilled off, 5 ml of water was added to the resultant, and a 1 mol/l hydrochloric acid was carefully added to the resultant. Then, an acidic-precipitated product was collected by filtration and dried, consequently 4.87 g of the above-mentioned compound was obtained as a white solid product. MS(FAB,Pos.):m/z=332[M+1]+
With N-benzyl-N,N,N-triethylammonium chloride; In dichloromethane; water;
REFERENTIAL EXAMPLE 17 To 250 ml of carbon tetrachloride, were added 25.0 g of methyl 4-methylbenzoate, 32.6 g of N-bromosuccinimide, and 2.0 g of benzoyl peroxide. The mixture was heated with stirring under reflux for one hour. The reaction mixture was freed from the insolubles by filtration and stripped of the solvent by distillation. To the residue dissolved in methylene chloride, were added 9.8 g of sodium cyanide, 3.9 g of triethylbenzylammonium chloride, and 10 ml of water. The mixture was stirred at room temperature for 30 minutes and then heated overnight under reflux. The reaction mixture was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and stripped of the solvent by distillation. The residue was fractionated and purified by silica gel column chromatography. The intended fractions (Rf=0.41) were collected and recrystallized from an ether-n-hexane mixture to yield 18.1 g of colorless needle crystals of methyl 4-cyanomethylbenzoate; m.p. 60-62 C.
Step C: Methyl 4-{3-tert-butoxy-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}benzoate. Tert-butyl[(tert-butoxycarbonyl)amino]acetate (1.01 g, 4.37 mmol) was dissolved in THF (10 mL) and cooled to -78 C. LiHMDS (6.5 mL, 1M solution in THF) was slowly added and allowed to stir for 30 minutes. Methyl 4-(bromomethyl)benzoate (1.98 g, 8.64 mmol) in THF (6 mL) was added to the mixture and allowed to stir overnight, slowly warming to room temperature. The reaction was diluted with ethyl acetate and quenched with saturated ammonium chloride. The aqueous layer was extracted three times with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography. MS: cal'd 379 (MH+), exp 402 (MH+).
With 18-crown-6 ether; potassium carbonate; In acetone; for 48h;Reflux;
A mixture of <strong>[27955-94-8]1,1,1-tris(4-hydroxyphenyl)ethane</strong> (4.60 g, 15.0 mmol), methyl 4-(bromomethyl)benzoate (10.65 g, 46.5 mmol, 3.1 equiv.), potassium carbonate (7.77 g, 56.3 mmol, 3.75 equiv.) and 18-crown-6. (1.19 g, 4.5 mmol, 0.3 equiv.) in acetone (120 mL) was heated at reflux and stirred vigorously under nitrogen for 48 h. The mixture was allowed to cool and rotary evaporated to dryness under reduced pressure. The residue was partitioned between water and methylene chloride, and the aqueous layer was extracted with methylene chloride for three times. The combined extracts were dried over sodium sulfate and evaporated. The crude product was purified by flash column chromatography eluting with methylene chloride and then with gradual increasing proportions of ethyl acetate (to 1:50 ethyl acetate/methylene chloride) to give a white solid 20 (11.22 g, 99percent).
With potassium carbonate; potassium hydrogencarbonate; In acetonitrile; for 18h;Inert atmosphere; Reflux;
(e) Synthesis of BRI7160 and BRI7161; The compounds were prepared according to Reaction Scheme 4: Compound 4 was prepared following the method of R. Guilard et al., Bull. Soc. Chim. Fr., 1996, 133, 65-73.A magnetically stirred suspension of compound 4 (430 mg, 0.86 mmol), (4-bromomethyl) methyl benzoate (217 mg, 0.95 mmol), KHCO3 (172 mg) and K2CO3 (174 mg) in dry acetonitrile (17 ml) was heated at reflux for 18 h under an atmosphere of nitrogen. The reaction mixture was cooled to room temperature then concentrated under reduced pressure to yield a straw coloured oil which was purified by flash chromatography (silica, 5% methanol/dichloromethane elution). Concentration of the appropriate fractions (RF 0.38) afforded adduct 5a as a clear, colourless oil. Mass Spectrum (APCI) m/z 649 [(M+H)+, 100%].
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃;
A suspension of compound 21 (1.59 g), commercially available (Aldrich Chemical Co., Milwaukee, WI) compound 22 (0.8 g) and K2CO3 (0.48 g) in DMF (15 ml) is stirred at 600C overnight. The reaction mixture is concentrated to a thick oil and filtered through a glass syringe filter, dissolved inCH2Cl2 and purified by column chromatography (silica) to give compound 23 (1.96 g)
Commercially available 4- bromomethylbenzoic acid methyl ester (5.0 g) was dissolved in methanol (40 mL) . A potassium cyanide solution (5.63 g in 8 ml water) was added dropwise over 15 min. The resulting suspension was heated to reflux for 5 h. Volatiles were removed under reduced pressure and the residue dissolved in diethylether and water. The organic layer was concentrated to a dark oil which was purified by column chromatography (5% ethyl acetate in hexane) to give the intermediate. Yield 3.82 g, 58,6%.. [M+H] ' - 176.3 (APCI+) . FontWeight="Bold" FontSize="10" H MP. (CHClj, 400 MHz): delta 8.05 (d, J=8.1 Hz, 1H), 7.42 (d, J=8.1 , 1H) , 3.93 (s, 3H) , 3.81 (s, 2H) .
methyl 4-[2-(3-chlorophenyl)-3-oxobutyl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step A.; Methyl 4-r2-("3-chlorophenyl)-3-oxobutyllbenzoateSodium t-butoxide (0.6Og, 6.34mmol) was added all at once to a THF solution (1OmL) of l-(3-chloro-phenyl)-propan-2-one (1.08g, 6.40mmol) stirred at -780C. After 3minutes 4-bromomethyl- benzoic acid methyl ester (1.54g, 6.72mmol) was added all at once and the reaction solution was allowed to warm to room temperature. After stirring for lhour the reaction solution was partitioned between aqueous IN HCl and ethyl acetate. The organic phase was washed with brine and dried over MgSO4. The solution was filtered, concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): delta 7.91 (d, J = 8.2 Hz, 2 H); 7.29-7.25 (m, 2H); 7.20 (s, 1 H); 7.13 (d, J = 8.2 Hz, 2 H); 7.07-7.03 (m, 1 H); 3.91 (broad s, 4 H); 3.47 (dd, J = 7.2, 13.8 Hz, 1 H); 2.96 (dd, J = 7.6, 13.8 Hz, 1 H); 2.07 (s, 3 H). LCMSl 3.66min. (M+H)=317
<strong>[4877-80-9]2,3,6,7,10,11-hexahydroxytriphenylene</strong> 1 (HHTP) was prepared according to the reported procedure [34]. To give compounds 2, 3 and 4, th e mixture of HHTP (1 mmol) and K2CO3 (8 mmol) in 50.0 mL of dry acetone was refluxed for 1 h. Then, ethyl bromoacetate, methyl 5-bromovalerate or methyl (4-bromomethyl)benzoate (8 mmol) upon this solution were added and refluxed for 24 h. The reactionwas monitored by TLC. The resulting solutionwas allowed to warm up to room temperature. At the end of the reaction, the reaction mixture was filtered and the organic layer was removed under reduced pressure. The observed solid product was dissolved in CHCl3 and washed twice with 0.2 N HCl and water. The combined organic phase was dried over Na2SO4 filtered, andconcentrated under reduced pressure to afford the desired pure product (2, 3 and 4).
General procedure: A solution of tetraethylen glycol (400 muL, 2.31 mmol) in THF (30 mL) was cooled to 0 C. After dropwise addition of KHMDS (0.5 M in toluene, 13.9 mL, 6.93 mmol) the mixture was stirred for 15 min. Subsequently, a solution of 13 (1.86 g, 6.93 mmol) in THF (8 mL) was added. After being stirred for 2 h at room temperature the mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. After evaporation the crude product was purified by flash chromatography (hexane/EtOAc 1:1) to give 18a in 46% yield (620 mg).
With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 6h;Sealed vial;
Example 7 (illustrates Method B)4-[(6-Methoxypyridin-3-yl)oxy1methyl)-N-(methylsulfonyl)benzamidePota ss i u m ca rbon ate (138 mg, 1 .0 mmol), a solution of methyl 4- (bromomethyl)benzoate in DMF (0.476 M, 1 .05 mL, 0.5 mmol) and 6-methoxypyridin-3- ol (62.5 mg, 0.5 mmol) in DMF (1 .5 mL) was added into an ArQule vial. The reaction vessel was sealed and heated at 65C for 6 hours. After cooling, the residue was partitioned between EtOAc and water (2.5 mL). The organic layer was separated and concentrated in vacuo. The resulting residue was dissolved in THF (2.5 mL) and aqueous lithium hydroxide (5 M, 0.5 mL) was added. The reaction mixture was stirred at 55C for 1 8 hours. Water (3 mL) was then added and the resulting mixture was washed with diethyl ether (1 mL), acidified with aqueous hydrochloric acid (2 M, 2 mL) and extracted with EtOAc. The organic layer was evaporated and to the remaining residue N,N-dimethylpyridin-4-amine in DCM (1 M, 1 mL), N-[3-(dimethylamino)propyl]- N'-ethylcarbodiimide hydrochloride in DCM (1 M, 1 mL) and methanesulphonamide in DCM (1 M, 1 mL) was added. The reaction vessel was sealed and stirred at room temperature for 18 hours. The resulting mixture was partitioned between DCM (2 mL) and aqueous hydrochloric acid (2 M, 2 mL). The organic layer was passed through a phase separation cartridge and evaporated to dryness. The crude residue was dissolved in DMSO (50 mg/nnL) and purified by preparative HPLC to afford the title compound (21 .4 mg, 15%).LCMS Rt = 3.00 minutes MS m/z 337 [MH]+, 335 [M-H]",Preparative Acidic conditionsColumn: SunFire C18, 5um 19 x 100 mmTemperature: AmbientDetection: ELSD - MSFractionlynx 1Injection Volume: 1000uLFlow Rate: 18 mL / minMobile Phase: A: H2O + 0.1 % formic acid, B: acetonitrile + 0.1 % formic acidGradient (Time/mins,%B) - (0-1 , 5),( 1 -7, 5-98),(7-9, 98),(9-9.1 , 98-5),(9.1 -10, 5)Acidic Analytical (QC)Column: SunFire C18, 5um 4.6 x 50mmTemperature: AmbientDetection: UV 225nm - ELSD - MSSystem/Data file: CTC - MUX1 Injection volume: 5uLFlow rate: 1 .5mL / minMobile phase: A: H2O + 0.1 %formic acid, B: acetonitrile+0.1 % formic acidGradient (Time/mins, %B) -(0,5),(3,95),(4,95),(4.1 ,5),(5,5)
Step A: 4-Cyanomethyl-benzoic acid methyl esterTo a solution of trimethylsilylcyanide (TMSCN, 12 mL, 96 mmol), tetra-M- butylammonium fluoride (TBAF, 25 g, 96 mmol) was added portion wise over a period of 30 minutes and stirred for another 30 minutes. 4-Bromethyl benzoic acid methyl ester (20 g, 87.3 mmol) dissolved in acetonitrile (100 mL) was added drop wise over a period of 30 minutes, the reaction temperature was increased to 80 C and stirring continued for another 30 minutes. On completion of the reaction, solvent was distilled out under reduced pressure, the crude material obtained was purified by column chromatography to give the pure title compound (10 g, Yield 68.7 %).
Methyl 4[te/?-butoxycarbonyl) (2-iota'ert-butoxy-2-oxoethyl)amino]methyl}benzoate. N-(tert- butoxycarbonyl)glycine (1.0063 g, 4.35 mmol) was dissolved in THF (10 ml). The solution was cooled to -78C. Lithium bis(trimethylsilyl)amide (6.5 ml, 6.48 mmol) was added. The reaction was allowed to stir for approximately 30 minutes. Methyl 4-(bromomethyl)benzoate (0.99 mg, 4.32 mmol) was added. The reaction was allowed to stir overnight, slowly warming to room temperature. The reaction was diluted with ethyl acetate and quenched with saturated aqueous <n="90"/>ammonium chloride. The aqueous layer was extracted three times with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography. MS: cal'd 402 (M+23), exp 402 (M+23).
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 80℃; for 0.166667h;Microwave irradiation;
General procedure: A microwave vial was charged with bromomethylbenzene derivative (0.4 mmol, 1 equiv), appropriated phenol derivative (0.44 mmol, 1.1 equiv), K2C03 (0.8 mmol, 2equiv), few crystals of Nal and dimethylformamide (DMF) (1 .4 mL). The reaction mixture was heatedunder microwave irradiation at 80C for 10 minutes. Then, resulted mixture was poured into water and extracted with ethyl acetate. Combined organic phases were washed with brine, dried over Mg504 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (CH2CI2/MeOH)
60%
With potassium carbonate; potassium iodide; In ethyl acetate; at 70℃; for 5.0h;
A suspension of 5, 15 or 28 (6.55mmol) and the corresponding benzaldehydes (6.55mmol) including potassium carbonate (13.10mmol), and potassium iodide (7.86mmol) was heated at 70C for 5h. The solvent was evaporated, the residue was dissolved in ethyl acetate (50mL), washed with saturated aqueous NaHCO3 solution (2×20mL), water (2×20mL), and brine (2×10mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using ethyl acetate/ petroleum ether as an eluent. 4.2.5 Methyl 4-((2-formylphenoxy)methyl)benzoate (6) (white powder, yield 60%) 1H NMR (300MHz, CDCl3): delta 10.57 (s, 1H), 8.07 (d, J=8.43Hz, 2H), 7.86 (d, J=7.50Hz, 1H), 7.53 (d, J=8.43Hz, 2H), 7.76 (t, J=7.50Hz, 1H), 7.06 (t, J=7.50Hz, 1H), 7.01 (d, J=8.44Hz, 1H), 5.25 (s, 2H), 3.92 (s, 3H) ppm. 13C NMR (75.49MHz, CDCl3): delta 189.48, 166.68, 160.64, 141.18, 135.94, 130.03, 128.73, 126.85, 125.19, 121.31, 112.90, 69.76, 52.20ppm. MS (ESI, SQ), m/z (%):293.1 [M+Na]+.
Reference Example 10 4-(5-Cyano-4-methyl pyrrolo[1, 2-b]pyridazine-7-yl)benzoic acid methyl ester To a solution of <strong>[1120-88-3]4-methyl pyridazine</strong> (1.00 g) in ethyl acetate (30 ml) was added 4-bromomethyl benzoic acid methyl ester (2.92 g) at room temperature, and the mixture was stirred at 80C overnight. The precipitated solid was collected by filtration, washed with ethyl acetate and dried under reduced pressure. To a solution of the obtained compound (4.50 g) in 1, 2-dimethoxyethane (26 mL) were added acrylonitrile (3.69 g), manganese dioxide (6.05 g) and triethylamine (4.22 g) at room temperature, and the mixture was stirred at 80C for 7 hours. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.330 g).
Sodium hydride (0.97 g, 24 mmol) was suspended in DMF (15 mL) under nitrogen at 0 C. A solution of (25',45)-l-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2- carboxylic acid (2.0 g, 8.7 mmol) in DMF (20 mL) was added dropwise. The reaction mixture was stirred at 0 C for 10 min and treated with a solution of methyl 4- (bromomethyl)benzoate (2.3 g, 10 mmol) in DMF (5 mL). The reaction mixture was stirred at 0 C for 1 h, and mixed with ethyl acetate and IN HC1 solution. The EtOAc layer was separated, washed with brine, and dried over MgS04. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (eluting with 20% EtOAc/DCM) to afford the title compound as a white solid (1.2 g, 37%). 1H NMR (CDCls) delta 7.99 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 3.5 Hz, 2H), 4.78 - 4.26 (m, 3H), 4.19 - 4.1 1 (m, 1H), 3.90 (s, 3H), 3.71 - 3.46 (m, 2H), 2.84 - 2.39 (m, 1H), 2.23 - 2.04 (m, 1H), 1.48 (br. s., 9H); MS(ESI+) m/z 324.0 (M-55)+.
methyl 4-(((di-tert-butoxyphosphoryl)oxy)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
With sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere;
Methyl4-(bromomethyl)benzoate (1200 mg, 5.24 mmol), potassium di-tertbutylphosphate (1431 mg, 5.76 mmol) and sodium iodide (785 mg, 5.24 mmol) werecombined in DMF (3.00 mL) under nitrogen. The reaction mixture was stirred at roomtemperature for 24 h. The reaction mixture was diluted with ether, washed with 10percentLiCl solution and brine, then dried (MgS04), filtered and concentrated in vacuo. The10 residue was purified by silica gel chromatography (hexane/EtOAc) to provide Preparation55A (571 mg, 1.593 mmol, 30percent): 1H NMR (400MHz, CDCb) 8 8.03 (d, J=8.4 Hz, 2H),7.53-7.37 (m, 2H), 5.05 (d, J=7.5 Hz, 2H), 3.92 (s, 3H), 1.48 (d, J=0.4 Hz, 18H).
methyl 4-[(3-oxo-8-azabicyclo[3.2.1]oct-8-yl)methyl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.66 g
With potassium carbonate; In acetonitrile; for 4h;
A slurry of <strong>[25602-68-0]8-azabicyclo[3.2.1]octan-3-one hydrochloride</strong> salt (0.52 g, 3.2 mmol) and methyl 4-(bromomethyl)benzoate (0.75 g, 3.3 mmol) in 30 ml of acetonitrile was stirred as solid potassium carbonate (1.9 g, 13.6 mmol) was added. After 4 days, the reaction was filtered. The filtrate was concentrated. Purification by chromatography on silica gel using hexane gave 0.66g of methyl 4-[(3-oxo-8-azabicyclo[3.2.1]oct-8-yl)methyl]benzoate.
methyl 4-(((2-methoxy-5-(trifluoromethyl)phenyl)amino)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40.3%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 16h;
(Formula 1-2: methyl 4-(((2-methoxy-5-(trifluoromethyl)phenyl)amino)methyl)benzoate)[1737][1738]Compound ofFormula 1-1(2-methoxy-5-(trifluoromethyl)aniline; 0.385 mL, 4.625 mmol), methyl 4-(bromomethyl)benzoate (1.271 g, 5.550 mmol) and DIPEA (1.228 mL, 6.937 mmol) were dissolved in acetonitrile (5 mL) at room temperature and stirred at the same temperature for 16 hours. Water was poured into the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=20%) to give the desired compound ofFormula 1-2(0.607 g, 40.3%) in the form of a white solid.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 17h;
(Formula 1-2: methyl 4-(((2,3-difluorophenyl)amino)methyl)benzoate)[1779][1780]Compound ofFormula 1-1(<strong>[4519-40-8]2,3-difluoroaniline</strong> (0.300 g, 2.324 mmol), methyl 4-(bromomethyl)benzoate (0.639 g, 2.788 mmol) and DIPEA (0.809 mL, 4.647 mmol) were dissolved in acetonitrile (3 mL) at room temperature and stirred at the same temperature for 17 hours. Water was poured into the reaction mixture, and the organic layer was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=10percent) to give the desired compound ofFormula 1-2(0.284 g, 44.1percent) in the form of a white solid.
methyl 4-((6-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 12h;
The compound of formula 3-1 (6-chloro- 1 H-pyrrolo[2,3-b]pyridine) (1.0 g, 6.55 mmol), methyl 4-(bromomethyl)benzoate (1.65 g, 7.21 mmol) and sodium hydride (60.00%, 0.3 15 g, 7.87 mmol) were dissolved in N,N-dimethylformamide (50 mL) at room temperature, and the solution was stirred at the same temperature for 12 hours. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Si02, 40 g cartridge; ethyl acetate / hexane = from 5% to 10%) to afford the desired compound of formula 3-2 (1.25 g, 63% as a white solid).
methyl 4-((4-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.2%
With potassium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 12h;
The compound of formula 11-i (4-chioro- I H-pyrrolo[3,2-c]pyridine) (0.300 g, 1.966mmol), methyl 4-(bromoethyl)benzoate (0.495 g, 2.163 mmol) and potassium hydroxide (0.132 g, 2.359 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, and the solution was stirred at the same temperature for 12 hours. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and water (20 mL) was added to the concentrate, followed by stirring. Then, the precipitated solid was filtered, washed with water, and dried, thereby obtaining the desired compound of formula 11-2 (0.497 g, 84.2 %) as a white solid.
methyl 4-((6-bromo-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57.1%
With potassium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 12h;
The compound of formula 11-1 (6-bromo-IH-pyrrolo[3,2-b]pyridine) (0.300 g, 1.523 mmol), methyl 4-(bromomethyl)benzoate (0.384 g, 1.675 mmol) and potassium hydroxide (0.103 g, 1.827 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, and the solution was stirred at the same temperature for 12 hours. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2, 12 g cartridge; ethyl acetate I hexane = from 20% to 30%) to afford the desired compound (0.300 g, 57.1 %) as yellow oil.
methyl 4-((5-chloro-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82.7%
With potassium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 12h;
The compound of formula 11-1 (<strong>[131084-55-4]5-chloro-1H-pyrrolo[2,3-c]pyridine</strong>) (0.300 g, 1.966 mmol), methyl 4-(bromomethyl)benzoate (0.495 g, 2.163 mmol), and potassium hydroxide (0.132 g, 2.359 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, and the solution was stirred at the same temperature for 12 hours. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and water (20 mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with water, and dried to afford the desired compound of formula 11-2 (0.488 g, 82.7 %) as a yellow solid.
(R)-methyl 4-(((1-(3-methoxyphenyl)ethyl)amino)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere;
To a solution of methyl 4-(bromomethyl)benzoate (0.50 g, 2.2 mmol) in DMF (10 mL) was added (R)-1-(3-methoxyphenyl)ethanamine (0.38 g, 2.5 mmol) and K2CO3 (0.60 g, 4.4 mmol). The reaction mixture was stirred at rt for 2 h and diluted with ethyl acetate and water. The organic layer was separated, washed with brine, and dried over MgSO4. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (eluting with 20% EtOAc/DCM) to afford the title compound as a white solid (0.52 g, 79%). 1H NMR (CDCl3) delta 7.99 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.6 Hz, 2H), 7.30-7.22 (m, 1H), 7.00-6.90 (m, 2H), 6.81 (ddd, J=8.3, 2.5, 1.1 Hz, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 3.80-3.74 (m, 1H), 3.75-3.61 (m, 2H), 1.38 (d, J=6.6 Hz, 3H); MS(ESI+) m/z 300.3 (M+H)+.
(R)-1-(2-Fluorophenyl)ethanamine, HCl salt (253 mg, 1.44 mmol) was dissolved in saturated aq. NaHCO3 solution and the resulting suspension was extracted with ethyl acetate (twice). The organic layers were combined and dried over MgSO4. The filtrate was concentrated in vacuo. To the residue was added DMF (6 mL), methyl 4-(bromomethyl)benzoate (300 mg, 1.31 mmol) and K2CO3 (452 mg, 3.27 mmol). The resulting suspension was stirred at rt for 3 h. The reaction mixture was diluted with ethyl acetate and brine. The organic layer was separated and dried over MgSO4. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (eluting with 25% EtOAc/hexanes) to afford the title compound as a colorless oil (0.30 g, 78%). 1H NMR (CDCl3) delta 8.11-7.90 (m, 2H), 7.44 (td, J=7.6, 1.8 Hz, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.27-7.20 (m, 1H), 7.18-7.11 (m, 1H), 7.04 (ddd, J=10.7, 8.0, 1.1 Hz, 1H), 4.15 (q, J=6.6 Hz, 1H), 3.91 (s, 3H), 3.78-3.62 (m, 2H), 1.67 (br. s., 1H), 1.42 (d, J=6.6 Hz, 3H); MS(ESI+) m/z 288.2 (M+H)+.
methyl 4-((4-methyl-1H-pyrazol-1-yl)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91.1%
methyl 4-((4-methyl-1H-pyrazol-1-yl)methyl)benzoateInto a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed <strong>[7554-65-6]4-methyl-1H-pyrazole</strong> (820 mg, 9.99 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL) with stirring at 0 C. This was followed by the addition of 60% sodium hydride in mineral oil (600 mg, 25.00 mmol, 1.50 equiv) in portions at 0 C. in 10 min. To this was added methyl 4-(bromomethyl)benzoate (2.29 g, 10.00 mmol, 1.00 equiv) in portions at 0 C. Then it was stirred for 2 h at 25 C. The mixture was diluted with 50 mL of water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated. This resulted in 2.10 g (91.1%) of methyl 4-[(4-methyl-1H-pyrazol-1-yl)methyl]benzoate as a yellow solid. MS (ESI) m/z 231 [M+1]+
methyl 4-[(3-formyl-1-pyrrolidinyl)methyl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.00 g
Tert-Butyl 3-formylpyrrolidine-1-carboxylate (4.75 g, 23.84 mmol) was dissolved in dichloromethane (DCM) (20 mL). Trifluoroacetic acid (15 mL, 195 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. After concentrating acetonitrile (100 mL) was added followed by methyl 4-(bromomethyl)benzoate (6.55 g, 28.6 mmol) and potassium carbonate (16.47 g, 119 mmol). The reaction was heated to reflux for 16 hours. The mixture was filtered and concentrated. Dichloromethane (75 ml) was added and the solution was washed with water, dried over MgSO4, filtered and concentrated. The residue was purified via silica gel chromotography (0% to 100% EtOAc:Hex; 50 g-HP- silica gel column). Obtained 2.00 g 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.99-2.23 (m, 2H), 2.46-2.57 (m, 1H), 2.60-2.79 (m, 2H), 2.88-2.99 (m, 2H), 3.68 (d, J=4.29 Hz, 2H), 3.92 (s, 3H), 7.40 (d, J=8.59 Hz, 2H), 7.93-8.09 (m, 2H), 9.66 (d, J=2.02 Hz, 1H);
2 g
<strong>[59379-02-1]tert-butyl 3-formylpyrrolidine-1-carboxylate</strong> (4.75 g, 23.84 mmol) was dissolved in dichloromethane (DCM) (20mL). Trifluoroacetic acid (15 mL, 195 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. After concentrating acetonitrile (100 mL) was added followed by methyl 4-(bromomethyl)benzoate (6.55 g, 28.6 mmol) and potassium carbonate (16.47 g, 119 mmol). The reaction was heated to reflux for 16 hours. The mixture was filtered and concentrated. Dichloromethane (75 ml) was added and the solution was washed with water,dried over MgSO4, filtered and concentrated. The residue was purified via silica gel chromotography
2-(4-hydroxybenzene)-2'-(4-(4-esterylbenzyloxy)hexafluoropropane)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68.5%
With potassium carbonate; In acetone; at 55℃; for 48h;
A mixture of methyl bromobenzoate (2.8 g, 12.0 mmol), anhydrous potassium carbonate (2.0 g,14.5 mmol), 2,2-bis (4-hydroxyphenyl) hexafluoropropane (4.9 g, 14.4 mmol) and acetone (50 mL) at 55 C for 48 h with vigorous stirring. The filtrate was filtered and the filtrate was evaporated. Solvent, white crude product. The crude product was purified by silica gel column chromatography three times with acetone: dichloromethane (1: 200 by volume) as eluant. After vacuum drying, 4.0 g of a white powdery solid was obtained in 68.5% yield.
General procedure: To a solution of 2a (500 mg, 2.46 mmol) in dry DMSO (8 ml) was added NaH(60%, 108 mg, 2.71 mmol) and stirred at room temperature for 1 h.4-Chlorobenzyl bromide (557 mg, 2.71 mmol) was added and stirred at room temperature for 10 h. The reaction solution was quenched with saturated NH4Cl and extracted with CH2Cl2 (150 ml× 3), and the combined organic layers dried with Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using CH2Cl2 as elunt to give 3a as a white solid
Compound 101 was prepared as a colorless solid according to the general procedure described in Scheme 2 from commercially available starting material by the specific reaction sequence in Scheme 3. Alkylation of acetic acid 8 with benzyl bromide 9 in basic condition affords product 10. Amide formation between the acid 10 and aniline 11 followed by intramolecular condensation under basic condition gives the benzimidazole compound 12. Treatment of compound 12 with taurine generates sulfonic acid intermediate 13 that is coupled with boronic acid 14 catalyzed by a palladium ion to complete Compound 101 synthesis. Calculated elemental analysis of C38H43N3O4S·0.5H2O: C, 70.56; H, 6.86; and N, 6.50; and found: C, 70.55; H, 6.89; and N, 6.73. Scheme 3
tert-butyl 6-(4-(methoxycarbonyl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a stirred solution of compound 1 (1 g, 1 eq) in dry DMF (10 mL) at 0 C, NaH (60 %, 0.123 g, 1.5 eq) was added slowly and stirred at same temperature for 30 mm. To this solution, compound 2 (0.47 g, 1 eq) was added slowly. The resulting reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion, the reaction was quenched with water and extracted with ethyl acetate. The organic layers were separated, washed with water and dried over Na2504 and concentrated. The crude residue was purified by silica gel column chromatography to provide the desired compound.
tert-butyl (3R,5S)-4-(4-(methoxycarbonyl)benzyl)-3,5-dimethylpiperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In acetonitrile; at 20℃; for 16h;
To a stirred solution of compound 1(2.1 g, 1 eq.) and compound 2 (2.3 g, 1 eq.) in ACN (20 mL), potassium carbonate (4.1 g, 3 eq.) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction completion was monitored by TLC. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous Na2504, filtered and concentrated under reduced pressure to give a crude residue which was purified by silica gel column chromatography to afford compound 3.
methyl 4-((1-methyl-5-nitro-1H-indol-3-yl)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With silver(l) oxide; In 1,4-dioxane; at 60℃; for 20h;Inert atmosphere; Microwave irradiation;
Silver (I) oxide (1 eq.) was added to a stirred solution of indole (1eq.) and benzyl bromide (1 eq.) in dioxane (1 mL/mmol of indole) ina microwave tube under nitrogen gas. The reaction was sealed andstirred at 60 C for 20 h. EtOAc (2 mL/mmol of indole) was added tothe reaction. The reaction was then filtered through celite and thefiltrate was rotovapped. Product was purified by column chromatographyto give a yellow solid; 25-45%; 1H NMR (DMSO): delta 8.42 (d,J 2.3 Hz, 1H), 8.02 (dd, J 9.1, 2.3 Hz, 1H), 7.93e7.84 (m, 2H), 7.60(d, J 9.1 Hz, 1H), 7.44 (d, J 8.3 Hz, 3H), 4.21 (s, 2H), 3.83 (d,J 4.1 Hz, 6H); 13C NMR (DMSO): delta166.59, 147.18, 140.80, 140.05,132.12, 129.82, 129.25, 127.93, 126.82, 116.99, 116.29, 116.03, 110.86,52.45, 33.30, 30.65
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h;
Compound 2 (2.1 g, 16 mmol) was dissolved in N,N-dimethylformamide.Add cesium carbonate (10.4 g, 32 mmol),Methyl 4-bromomethylbenzoate (3.7 g, 16 mmol),Stir at room temperature and continue to stir the reaction.TLC detects the progress of the reaction,The reaction was complete after 4 hours.Add appropriate amount of ethyl acetate and dilute the extract.Washed with saturated saline,The organic phase is concentrated,Separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1/3).4.0 g of a white solid compound 3 was obtained in a yield of 90%.
methyl 4-((tetrabromo-2H-benzo[d][1,2,3]triazol-2-yl)methyl)benzoate[ No CAS ]
methyl 4-((tetrabromo-1H-benzo[d][1,2,3]triazol-1-yl)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%; 18%
With potassium carbonate; In acetone; at 150℃; for 0.0166667h;Microwave irradiation;
A solution ofTBB[73] (200 mg, 0.45 mmol), K2CO3(9 eq) and methyl 4-(bromomethyl)benzoate (105 mg, 0.65 mmol) in acetone (5 mL) was irradiated under MW conditions at 150 C for one minute. The solvent was removed under vacuum and the crude was solved in EtOAc. The organic phase was washed with brine and H2O, dried over MgSO4, filtered and evaporated. The crude material was purified by column chromatography on silica gel (hexane/DCM 35:65), giving12a(215 mg, 80%) and12b(50 mg, 18%). For12a:1H-NMR (400 MHz, DMSO) delta 7.98 (d,J= 8.3 Hz, 2H), 7.51 (d,J= 8.3 Hz, 2H), 6.19 (s, 2H), 3.84 (s, 3H). For 12b:1H-NMR (400 MHz, DMSO) delta 7.84 (d,J= 8.4 Hz, 2H), 7.23 (d,J= 8.3 Hz, 2H), 6.30 (s, 2H), 3.83 (s, 3H).
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