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Structure of 446-52-6 * 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] Journal of Medicinal Chemistry, 2006, vol. 49, # 21, p. 6197 - 6208
[2] Organic and Biomolecular Chemistry, 2016, vol. 14, # 39, p. 9306 - 9311
9
[ 446-52-6 ]
[ 446-48-0 ]
Reference：
[1] Tetrahedron Letters, 2000, vol. 41, # 27, p. 5161 - 5164
[2] European Journal of Organic Chemistry, 2017, vol. 2017, # 5, p. 996 - 1003
10
[ 95-52-3 ]
[ 7726-95-6 ]
[ 446-48-0 ]
[ 446-51-5 ]
[ 446-52-6 ]
[ 445-29-4 ]
Reference：
[1] Journal of the Chemical Society, 1926, p. 220
11
[ 110-91-8 ]
[ 446-52-6 ]
[ 58028-76-5 ]
Yield
Reaction Conditions
Operation in experiment
63%
at 125℃; for 2.5 h; Microwave irradiation
Example 180: N-(l-Methyl-1H-pyrazol-4-yl)-1-(2-morpholinobenzyl)-1H-pyrazolo[3,4- d]pyrimidin-6-amine Step (i)A mixture of 2-fluorobenzaldehyde (0.5mL, 4.8mmol), morpholine (0.6mL, 1.5eq) and potassium carbonate (1.3g, 2eq) was heated in the microwave at 125°C for 2.5h. After evaporation, the residue was partitioned between water and DCM, the aqueous phase extracted with DCM. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford 2-morpholinobenzaldehyde (0.57g, 63percent).
50.6%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 85℃; for 4 h; Cooling with ice
To an ice-cooled and stirred solution of 9 (500 mg,1 mmol) in acetonitrile (2.5 mL), DIPEA (1 mmol) was added followed by morpholine (for 10a) (1 mmol) and heated at 85 °C for 4 h. It was cooled to room temperature and then concentrated. The residue was dissolved in ethyl acetate, washed with water followed by brine and then dried over anhydrous sodium sulphate. The solvent was removed under vacuum to get crude compound. The obtained crude material was purified over silica gel column (60–120 mesh) using gradient ethyl acetate/pet ether to give title compound as pale yellow solid. Compounds 10(b–e) were similarly synthesized. 2-Morpholinobenzaldehyde (10a) Pale yellow solid (0.39 g, 50.6 percent); mp: 84–86 °C. 1H-NMR (400 MHz, CDCl3): δ 2.85 (t, J = 10.00 Hz, 4H), 3.35 (t,J = 10.00 Hz, 4H), 7.12–7.17 (m, 2H), 7.52-7.56 (m, 1H),7.80–7.83 (m, 1H), 10.33 (s, 1H). IR (KBr, cm-1) 3067.2 (C–H, aromatic), 2960.2 (C–H, alkane), 2827.1 (C=O, aldehyde), 1332.6 (C–N, aromatic).
Reference：
[1] Russian Chemical Bulletin, 2004, vol. 53, # 6, p. 1240 - 1247
[2] Synthesis, 2010, # 24, p. 4287 - 4299
[3] Patent: WO2011/48082, 2011, A1, . Location in patent: Page/Page column 160; 161
[4] Medicinal Chemistry Research, 2015, vol. 24, # 9, p. 3516 - 3528
[5] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1975, p. 1679 - 1682
[6] Chemical Communications, 2010, vol. 46, # 35, p. 6593 - 6595
[7] Patent: EP1688138, 2006, A1, . Location in patent: Page/Page column 86
[8] Tetrahedron, 2013, vol. 69, # 34, p. 7019 - 7025
[9] Dalton Transactions, 2014, vol. 43, # 24, p. 9098 - 9110
[10] Journal of Organic Chemistry, 2014, vol. 79, # 21, p. 10434 - 10446
12
[ 446-52-6 ]
[ 699-99-0 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1973, p. 3092 - 3095
13
[ 446-52-6 ]
[ 61034-86-4 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 47, p. 9716 - 9719
14
[ 446-52-6 ]
[ 271-44-3 ]
[ 95-52-3 ]
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 21, p. 8166 - 8172
Reference：
[1] Journal of Medicinal and Pharmaceutical Chemistry, 1961, vol. 3, p. 567 - 582
24
[ 17696-73-0 ]
[ 446-52-6 ]
[ 5395-89-1 ]
Yield
Reaction Conditions
Operation in experiment
50%
at 100℃; for 16 h;
2-fluorobenzaldehyde (12.4 g, 0.1 mol, 1 eq) and methanesulphinic acid (11.2 g, 0.11 mol, 1.1 EQ) were dissolved in DMSO (75 ml) and heated to 100°C for 16 h. The reaction mixture was cooled to room temperature and poured onto crushed ice (100 g). The product was collected by filtration and dried in a vacuum oven at 45°C for 16 h to give 2- (methylsulphonyl) benzaldehyde (9.2 g, 50percent) as a yellow SOLID. 8H (300 MHz, CDC13) 10.77 (1H, s, CHO), 8.18-8. 16 (1H, m, ArH), 8.10-8. 08 (1H, m, ArH), 7.83-7. 80 (2H, m, ArH) and 3.28 (3H, S, S02CH3) ; LCMS 6 min, Rt = 1. 93 min, (M++1) = 185. 1.
Stage #1: at -33℃; for 1 h; Inert atmosphere Stage #2: at -33℃; for 1 h; Inert atmosphere; Reflux
General procedure: Under an argon atmosphere, liquid NH3 (25 mL) was condensedin a two-neck round-bottom flask immersed in a dry ice coolingbath and equipped with a dry ice reflux condenser. Aldehyde(7.34 mmol) was added, and the resulting solution (or suspension)was stirred for 1 h. KMnO4 (7.34 mmol, 1.16 g) was added,the cooling bath was removed, and the reaction mixture wasstirred for another hour with gentle reflux of NH3. Na2SO3 (22.0mmol, 2.78 g) was added, the reflux condenser was removed,and the NH3 was allowed to evaporate spontaneously. The darkbrownresidue was treated with 6 M HCl (30 mL), and theresulting precipitate was filtered, washed with H2O (100 mL)and sat. aq NaHCO3 (20 mL). All products were recrystallizedfrom EtOH.
24%
Stage #1: at -33℃; for 1 h; Inert atmosphere Stage #2: for 1 h; Inert atmosphere; Reflux
General procedure: Under an argon atmosphere, liquid NH3 (25 mL) was condensedin a two-neck round-bottom flask immersed in a dry ice coolingbath and equipped with a dry ice reflux condenser. Aldehyde (7.34 mmol) was added, and the resulting solution (or suspension)was stirred for 1 h. KMnO4 (7.34 mmol, 1.16 g) was added,the cooling bath was removed, and the reaction mixture wasstirred for another hour with gentle reflux of NH3. Na2SO3 (22.0mmol, 2.78 g) was added, the reflux condenser was removed,and the NH3 was allowed to evaporate spontaneously. The darkbrownresidue was treated with 6 M HCl (30 mL), and theresulting precipitate was filtered, washed with H2O (100 mL)and sat. aq NaHCO3 (20 mL). All products were recrystallizedfrom EtOH.
Reference：
[1] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 1999, vol. 54, # 12, p. 1532 - 1542
35
[ 593-51-1 ]
[ 446-52-6 ]
[ 399-30-4 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 16, p. 2527 - 2531
[2] Patent: WO2016/101885, 2016, A1, . Location in patent: Paragraph 0227; 0228; 0229; 0230; 0231; 0232
36
[ 1765-93-1 ]
[ 446-52-6 ]
[ 342-25-6 ]
Yield
Reaction Conditions
Operation in experiment
98%
With potassium phosphate; palladium diacetate In water; methyl cyclohexane for 8 h; Reflux
Method of the present embodiment provides a 2,4 ′-difluorobenzophenone and preparation method thereof, as follows: in a 1000 ml round bottom flask The bottle was added sequentially o-fluoro benzaldehyde 124 g of 4-fluorophenylboronic acid and 140 g of potassium phosphate, 106 grams, 1.12 g of palladium acetate, then adding 500 ml of methyl cyclohexane and 100 ml of water and heated to reflux for 8 hours., sequentially passes through filtering, layering, washing with water, removing the solvent to obtain the product., 2,4 '-difluorobenzophenone 214 g, 98percent yield.
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 130℃; for 3 h;
To a solution of the aldehyde 3a (20 g, 161.1 mmol) in dry DMF (160 ml), piperidine(19.1 ml, 193.4 mmol, 1.2 eq) and potassium carbonate (26.73 g, 193.4 mmol, 1.2eq) were successively added. The suspension was heated at 130°C for 3 h. Thereaction mixture was then poured into cold water and. acidified with citric acid up to ,pH 5. The aqueous layer was extracted 3X with EtOAc and the combined organicextract was successively washed with water, saturated NaHCO3 and brine. Afterdrying the organic extract over MgSO4, filtration and concentration, the desired 2-piperidinobenzaldehyde 3b was isolated as a red oil (28.23 g, 92percent yield).
90.5%
With potassium carbonate In DMF (N,N-dimethyl-formamide) for 6 h; Heating / reflux
EXAMPLE 1 Preparation of o-piperidino benzaldehyde (8) [0033] A mixture of o-fluorobenzaldehyde (1.24 gm, 10 mmol), potassium carbonate (2.76 gm, 20 mmol), and piperidine (1.7 gm, 20 mmol) was refluxed in dry DMF for 6 hrs. After the completion of reaction DMF was distilled out at vaccum and 5 ml of water was added to the residue and extracted the product with ethyl acetate (10 ml.x.2). Organic layer was dried over sodium sulphate and evaporated the solvent to afford 1.8 gm of product (8) (90.5percent) [0034] 1HNMR CDCl3 (Spectrum 9): 1.68(m, 6H), 3.05(m, 4H), 7.05(m, 2H), 7.45(dd, 1H), 7.75(dd, 1H).
1.72 g
With potassium carbonate In N,N-dimethyl-formamide at 110 - 150℃; for 23 h;
(1) A suspension of the Compound 1 (1.05 mE), the Compound 2 (1.09 mE), and potassium carbonate (2.76 g) in N,N-dimethylformamide (10 mE) was stirred at 1100 C. for 5 hours, and stirred at 1500 C. for 18 hours. The reaction mixture was allowed to cool to room temperature, and then water and ethyl acetate were added thereto, and the resulting mixture was stirred, and extracted with ethyl acetate. The resulting organic layers were washed with water and saturated brine, dried, and concentrated under reduced pressure. The resulting residues were purified by silica gel column chromatography (hexane:ethyl acetate=99: 1 to 88:12) to give the Compound 3 (1.72 g) as a yellow liquid. MS (APCI): mlz 190 [M+H]
Reference：
[1] Angewandte Chemie - International Edition, 2012, vol. 51, # 8, p. 1950 - 1953
[2] Heterocycles, 2008, vol. 75, # 4, p. 799 - 838
[3] Patent: WO2004/108673, 2004, A2, . Location in patent: Page 38-39
[4] Patent: US2004/192921, 2004, A1, . Location in patent: Page 4
[5] Russian Chemical Bulletin, 2004, vol. 53, # 6, p. 1240 - 1247
[6] Chemistry of Heterocyclic Compounds, 2007, vol. 43, # 1, p. 76 - 81
[7] Synthesis, 2010, # 24, p. 4287 - 4299
[8] Journal of Organic Chemistry, 1989, vol. 54, # 1, p. 199 - 209
[9] Patent: WO2004/101540, 2004, A2, . Location in patent: Page/Page column 11-13
[10] Journal of Organic Chemistry, 2009, vol. 74, # 19, p. 7464 - 7469
[11] Journal of Organic Chemistry, 2010, vol. 75, # 9, p. 2893 - 2902
[12] Organic and Biomolecular Chemistry, 2010, vol. 8, # 18, p. 4077 - 4079
[13] Chemical Communications, 2010, vol. 46, # 35, p. 6593 - 6595
[14] Journal of Organic Chemistry, 2011, vol. 76, # 1, p. 342 - 345
[15] Chinese Chemical Letters, 2012, vol. 23, # 4, p. 395 - 398
[16] Tetrahedron, 2013, vol. 69, # 34, p. 7019 - 7025
[17] Dalton Transactions, 2014, vol. 43, # 24, p. 9098 - 9110
[18] Chemistry - A European Journal, 2015, vol. 21, # 4, p. 1632 - 1636
[19] Journal of Organic Chemistry, 2014, vol. 79, # 21, p. 10434 - 10446
[20] Organic Letters, 2017, vol. 19, # 7, p. 1566 - 1569
[21] Patent: US2018/258076, 2018, A1, . Location in patent: Paragraph 0496
38
[ 288-13-1 ]
[ 446-52-6 ]
[ 138479-47-7 ]
Reference：
[1] Australian Journal of Chemistry, 1991, vol. 44, # 8, p. 1097 - 1114
[2] Journal of the American Chemical Society, 2011, vol. 133, # 39, p. 15244 - 15247
[3] Angewandte Chemie - International Edition, 2012, vol. 51, # 11, p. 2690 - 2694
39
[ 288-88-0 ]
[ 446-52-6 ]
[ 138479-53-5 ]
Reference：
[1] Australian Journal of Chemistry, 1991, vol. 44, # 8, p. 1097 - 1114
40
[ 109-01-3 ]
[ 446-52-6 ]
[ 85803-62-9 ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium carbonate In water for 18 h; Heating / reflux
PREPARATION 57; 2-(4-Methylpiperazin-1-v0benzaldehyde.2-Fluorobenzaldehyde (20.0 mL, 189.9 mmol), 1-methylpiperazine (33.0 mL, 297.7 mmol) and potassium carbonate (40.0 g, 289.4 mmol) in water (200 mL) were refluxed for 18h. After cooling, the mixture was extracted with EtOAc (2X 150 mL). These extracts were washed with brine, dried over MgSO4 and concentrated to give PP57 (38.6 g, 100percent) as an orange oil which had: NMR (CDCI3) δ 10.10 (s, 1 H), 7.77 (dd, J = 7.9, 1.7 Hz, 1 H), 7.51-7.48 (sym. mult., 1 H), 7.10-7.06 (m, 2H), 3.11 (t, J = 4.6 Hz, 4H), 2.63 (br s, 4H), 2.36 (s, 3H).
96%
With potassium carbonate In water
Example 1 2-(4-Methyl-1-piperazinyl)benzaldehyde Potassium carbonate (8.3 g, 60 mmol) and 1-methylpiperazine (7.2 g, 72 mmol) were dissolved in 40 mL of water and then 2-fluorobenzaldehyde (5.0 g, 40 mmol) was added. The mixture was heated at reflux (100-104° C.) under a nitrogen atmosphere for 22.5 hours when HPLC showed that the reaction was complete. The solution was cooled to 20-25° C. and then extracted with methylene chloride (2*40 mL). The methylene chloride extracts were combined, washed with water (2*50 mL), and then concentrated at reduced pressure to a yellow oil (7.8 g, 96percent yield). 1H NMR (CDCl3) showed that the yellow oil was essentially pure title compound and the 1H NMR spectrum was consistent with literature values (Walters et al., Synthesis, 1987: 641). 13C NMR (CDCl3) δ 191.70, 135.25, 129.94, 128.84, 122.84, 119.23, 55.34, 54.20, and 46.33.
54.8%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 85℃; for 4 h; Cooling with ice
General procedure: To an ice-cooled and stirred solution of 9 (500 mg,1 mmol) in acetonitrile (2.5 mL), DIPEA (1 mmol) was added followed by morpholine (for 10a) (1 mmol) and heated at 85 °C for 4 h. It was cooled to room temperature and then concentrated. The residue was dissolved in ethyl acetate, washed with water followed by brine and then dried over anhydrous sodium sulphate. The solvent was removed under vacuum to get crude compound. The obtained crude material was purified over silica gel column (60–120 mesh) using gradient ethyl acetate/pet ether to give title compound as pale yellow solid. Compounds 10(b–e) were similarly synthesized.
Reference：
[1] Patent: WO2006/48727, 2006, A1, . Location in patent: Page/Page column 83
[2] Patent: US2003/87914, 2003, A1,
[3] Russian Chemical Bulletin, 2004, vol. 53, # 6, p. 1240 - 1247
[4] Chemical Communications, 2017, vol. 53, # 75, p. 10448 - 10451
[5] Synthesis, 1987, # 7, p. 641 - 645
[6] Medicinal Chemistry Research, 2015, vol. 24, # 9, p. 3516 - 3528
[7] Journal of medicinal chemistry, 1983, vol. 26, # 8, p. 1116 - 1122
[8] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 8, p. 2498 - 2506
[9] Patent: US2004/254196, 2004, A1, . Location in patent: Page 9
[10] Patent: WO2005/90300, 2005, A1, . Location in patent: Page/Page column 30
41
[ 2759-28-6 ]
[ 446-52-6 ]
[ 112253-26-6 ]
Yield
Reaction Conditions
Operation in experiment
89%
With potassium carbonate In 1,4-dioxane; water for 24 h; Heating / reflux
Example 3: Synthesis of 1-[4-(1-methoxy-1-methyl-ethyl)-phenvn-3-(2-piperazin- 1-yl-bertzvD-pyrrolidin-2-one (compound 12): EPO <DP n="24"/>12A mixture of 25 g of benzylpiperazine (1) and 10 g of 2-fluorobenzaldehyde (2) were allowed to react in refluxing dioxane/water (1 :2, 90 mL total volume) for 24 hours in the presence of 17 g K2CO3. The resultant reaction mixture was allowed to cool to room temperature, was extracted with methylene chloride and the organic layer was then washed with water, 5percent hydrochloric acid, brine, and was then dried over magnesium sulfate, was filtered, and the solvent was removed in vacuo. Purification by silica gel chromatography (5:1 hexanes-ethyl acetate) afforded 20 g of the benzaldehyde 3 in 89percent yield; MS (AP/CI) observed: 281.1 (M+H)+ (100percent). The benzaldehyde 3 (8 g) was subsequently allowed to react with 7.3 g of 1-acetyl-pyrrolidin-2-one (4) in the presence of 4.6 g of NaH (60percent in mineral oil) at O0C for 1 hour followed by warming to room temperature and stirring for 2 hours. After quenching carefully with methanol at 0 0C, the solvent was removed in vacuo, the residue was diluted with water, was extracted with methylene chloride and the organic extracts were washed with brine and were dried over magnesium sulfate and were filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (40:1 chloroform-methanol) to provide 7.9g of 3-[2-(4-benzyl-piperazin-1-yl)-benzylidene]- pyrrolidin-2-one (5) in 80percent yield; MS (AP/CI) observed: 348.1 (M+H)+, 100percent. Hydrogenation of 6.3 g of 5 with 1.5 g of Pd/C in 100 mL of methanol under 50 p.s.i. of pressure at 600C provided 3.8 g (82percent yield) of 3-(2-piperazin-1-yl-benzyl)-pyrrolidin-2-one (6) following filtration, removal of solvent in vacuo, and purification by silica gel chromatography (30:1 :0.3 chloroform-methanol-ammonium hydroxide); MS (AP/CI) observed: 260.1 (M+H)+, 100percent.3-(2-Piperazin-1-yl-benzyl)-pyrrolidin-2-one (6) (1.2 grams) was subsequently allowed to react with 1.27 g of 1-bromo-4-(1-methoxy-1-methyl-ethyl)-benzene (11) in the presence of 0.041 grams of N,N'-dimethylethylenediamine, 0.088 g of CuI and 0.96 grams of K2CO3 in toluene (6 mL) at 110 °C for 17 hours to provide 1.2 grams of the racemate 1-[4-(1-methoxy- 1-methyl-ethyl)-phenyl]-3-(2-piperazin-1-yl-benzyl)-pyrrolidin-2-one (12) (64percent yield) following silica gel chromatography (40:1 :0.5 chloroform-methanol-ammonium hydroxide); MS (AP/CI) observed: 408.2 (M+H)+.
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 16, p. 2970 - 2978
43
[ 446-52-6 ]
[ 117752-04-2 ]
Reference：
[1] Journal of the American Chemical Society, 2018, vol. 140, # 8, p. 2789 - 2792
44
[ 446-52-6 ]
[ 96516-29-9 ]
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 22, p. 7348 - 7350
45
[ 141-82-2 ]
[ 446-52-6 ]
[ 117391-49-8 ]
Yield
Reaction Conditions
Operation in experiment
76%
With ammonium formate In ethanol for 7 h; Reflux
General procedure: To a solution of malonic acid (1.04g, 10mmol), ammonium formate (1.26g, 20mmol) in ethanol (50ml) was added aromatic aldehyde (10mmol). The resulting mixture was then refluxed for 7h. The reaction mixture was allowed to cool to room temperature and filtrated to yield the crude product. The crude product was further purified by recrystallization (95percent ethanol) to provide the product as a white solid.
Reference：
[1] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 402 - 418
[2] Advanced Synthesis and Catalysis, 2010, vol. 352, # 2-3, p. 395 - 406
[3] Advanced Synthesis and Catalysis, 2017, vol. 359, # 9, p. 1570 - 1576
[4] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 11, p. 1207 - 1212
[5] Journal of Organic Chemistry, 2009, vol. 74, # 23, p. 9152 - 9157
[6] Bulletin de la Societe Chimique de France, 1987, # 6, p. 1079 - 1083
[7] Tetrahedron Letters, 2005, vol. 46, # 3, p. 427 - 430
[8] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 16, p. 3685 - 3690
46
[ 67-56-1 ]
[ 1816-92-8 ]
[ 446-52-6 ]
[ 113162-36-0 ]
Reference：
[1] Canadian Journal of Chemistry, 2007, vol. 85, # 4, p. 283 - 292
47
[ 1816-92-8 ]
[ 446-52-6 ]
[ 113162-36-0 ]
Reference：
[1] Nucleosides, Nucleotides and Nucleic Acids, 2007, vol. 26, # 8-9, p. 869 - 871
48
[ 75-24-1 ]
[ 446-52-6 ]
[ 171032-87-4 ]
[ 162427-79-4 ]
Reference：
[1] Angewandte Chemie - International Edition, 2005, vol. 44, # 15, p. 2232 - 2234
With potassium bromate; sulfuric acid In water at 90℃;
Example three: equipped with electric stirring, thermometer, Dropping funnel and condenser tube reactor was added 65percent aqueous sulfuric acid 500ml, Potassium bromate 167 g (1 mol), 124.1 g (1 mol) of o-fluorobenzaldehyde was added dropwise thereto, 90 ° C for 2-3 hours, to the system by adding water 1000ml, Extraction with methyl tert-butyl ether, The organic phase was washed with aqueous sodium sulfite, dried over anhydrous sodium sulfate and concentrated by filtration to remove methyl tert-butyl ether to give a brown-red oil. Vacuum distillation collected 63-65 ° C / 3mmHg fraction 178g, Yield 88percent, content 97percent.
Reference：
[1] Patent: CN105884591, 2016, A, . Location in patent: Paragraph 0008; 0009; 0010; 0011
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 21, p. 3793 - 3796
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 17, p. 4417 - 4423
[3] Journal of Medicinal Chemistry, 2004, vol. 47, # 27, p. 6821 - 6830
[4] Journal of Organic Chemistry, 2005, vol. 70, # 22, p. 8924 - 8931
[5] Synthesis, 2010, # 24, p. 4287 - 4299
[6] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 22, p. 5605 - 5609
[7] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 17, p. 4817 - 4822
[8] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4599 - 4604
55
[ 110-85-0 ]
[ 446-52-6 ]
[ 736991-52-9 ]
Yield
Reaction Conditions
Operation in experiment
49.4%
With potassium carbonate In N,N-dimethyl-formamide at 130℃; for 6 h; Inert atmosphere
50 ml round-bottom flask by adding 55A (1.0g, 8 . 1mmol), N, N-dimethylformamide (15 ml) to dissolve, then adding piperazine (836 mg, 9 . 7mmol) and K2CO3(1.68g, 12 . 2mmol), 130 °C reaction under 6h. After cooling to room temperature, diluted with water, ethyl acetate extraction, the combined organic phase dried with anhydrous sodium sulfate, concentrated after the silica gel column chromatography (petroleum ether: ethyl acetate = 5:1; dichloromethane: methanol =10:1) separation to obtain compound 55B (760 mg, yield 49.4percent).
Reference：
[1] Patent: CN105777632, 2016, A, . Location in patent: Paragraph 0481; 0482; 0483
56
[ 446-52-6 ]
[ 1323140-60-8 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2015, vol. 99, # 1, p. 82 - 91
With potassium carbonate; at 125℃; for 2.5h;Microwave irradiation;
Example 180: N-(l-Methyl-1H-pyrazol-4-yl)-1-(2-morpholinobenzyl)-1H-pyrazolo[3,4- d]pyrimidin-6-amine Step (i)A mixture of 2-fluorobenzaldehyde (0.5mL, 4.8mmol), morpholine (0.6mL, 1.5eq) and potassium carbonate (1.3g, 2eq) was heated in the microwave at 125C for 2.5h. After evaporation, the residue was partitioned between water and DCM, the aqueous phase extracted with DCM. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford 2-morpholinobenzaldehyde (0.57g, 63%).
50.6%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 85℃; for 4h;Cooling with ice;
To an ice-cooled and stirred solution of 9 (500 mg,1 mmol) in acetonitrile (2.5 mL), DIPEA (1 mmol) was added followed by morpholine (for 10a) (1 mmol) and heated at 85 C for 4 h. It was cooled to room temperature and then concentrated. The residue was dissolved in ethyl acetate, washed with water followed by brine and then dried over anhydrous sodium sulphate. The solvent was removed under vacuum to get crude compound. The obtained crude material was purified over silica gel column (60-120 mesh) using gradient ethyl acetate/pet ether to give title compound as pale yellow solid. Compounds 10(b-e) were similarly synthesized. 2-Morpholinobenzaldehyde (10a) Pale yellow solid (0.39 g, 50.6 %); mp: 84-86 C. 1H-NMR (400 MHz, CDCl3): delta 2.85 (t, J = 10.00 Hz, 4H), 3.35 (t,J = 10.00 Hz, 4H), 7.12-7.17 (m, 2H), 7.52-7.56 (m, 1H),7.80-7.83 (m, 1H), 10.33 (s, 1H). IR (KBr, cm-1) 3067.2 (C-H, aromatic), 2960.2 (C-H, alkane), 2827.1 (C=O, aldehyde), 1332.6 (C-N, aromatic).
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 48h;
Reference Example 51 (2-Morpholin-4-ylphenyl)methanol 2-Fluorobenzaldehyde (1.0 g, 8.1 mmol) was dissolved in DMF (20 mL), morpholine (2.0 mL) and potassium carbonate (1.1 g, 8.1 mmol) were added thereto, and then the mixture was stirred at 80C for 2 days. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate = 98: 2 to 60: 40) to give an oily matter. The resulting oily matter was dissolved in methanol (20 mL), sodium borohydride (613 mg, 16.2 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure to give the title compound (474 mg, yield 30%).
With potassium carbonate; In N,N-dimethyl-formamide;Reflux;
General procedure: To a solution of 2-fluorobenzaldehyde (4.96 g, 40 mmol) and K2CO3 (6.36 g, 46 mmol) in DMF (40 mL) was added piperidine (4.56 mL, 46 mmol). The resulting reaction mixture was heated under reflux until complete consumption of 2-fluorobenzaldehyde. The reaction mixture was allowed to cool to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic extracts were washed with a saturated NH4C1 solution and concentrated under reduced pressure. The product 2-(piperidin-1-yl)benzaldehyde was utilized for next step without purification.
With potassium carbonate; In water; for 18h;Heating / reflux;
PREPARATION 57; 2-(4-Methylpiperazin-1-v0benzaldehyde.2-Fluorobenzaldehyde (20.0 mL, 189.9 mmol), 1-methylpiperazine (33.0 mL, 297.7 mmol) and potassium carbonate (40.0 g, 289.4 mmol) in water (200 mL) were refluxed for 18h. After cooling, the mixture was extracted with EtOAc (2X 150 mL). These extracts were washed with brine, dried over MgSO4 and concentrated to give PP57 (38.6 g, 100percent) as an orange oil which had: NMR (CDCI3) delta 10.10 (s, 1 H), 7.77 (dd, J = 7.9, 1.7 Hz, 1 H), 7.51-7.48 (sym. mult., 1 H), 7.10-7.06 (m, 2H), 3.11 (t, J = 4.6 Hz, 4H), 2.63 (br s, 4H), 2.36 (s, 3H).
96%
With potassium carbonate; In water;
Example 1 2-(4-Methyl-1-piperazinyl)benzaldehyde Potassium carbonate (8.3 g, 60 mmol) and 1-methylpiperazine (7.2 g, 72 mmol) were dissolved in 40 mL of water and then 2-fluorobenzaldehyde (5.0 g, 40 mmol) was added. The mixture was heated at reflux (100-104° C.) under a nitrogen atmosphere for 22.5 hours when HPLC showed that the reaction was complete. The solution was cooled to 20-25° C. and then extracted with methylene chloride (2*40 mL). The methylene chloride extracts were combined, washed with water (2*50 mL), and then concentrated at reduced pressure to a yellow oil (7.8 g, 96percent yield). 1H NMR (CDCl3) showed that the yellow oil was essentially pure title compound and the 1H NMR spectrum was consistent with literature values (Walters et al., Synthesis, 1987: 641). 13C NMR (CDCl3) delta 191.70, 135.25, 129.94, 128.84, 122.84, 119.23, 55.34, 54.20, and 46.33.
54.8%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 85℃; for 4h;Cooling with ice;
General procedure: To an ice-cooled and stirred solution of 9 (500 mg,1 mmol) in acetonitrile (2.5 mL), DIPEA (1 mmol) was added followed by morpholine (for 10a) (1 mmol) and heated at 85 °C for 4 h. It was cooled to room temperature and then concentrated. The residue was dissolved in ethyl acetate, washed with water followed by brine and then dried over anhydrous sodium sulphate. The solvent was removed under vacuum to get crude compound. The obtained crude material was purified over silica gel column (60?120 mesh) using gradient ethyl acetate/pet ether to give title compound as pale yellow solid. Compounds 10(b?e) were similarly synthesized.
With potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 10h;Heating / reflux;
42.16 ml of 2-fluorobenzaldehyde (400 mmol) was added to the 250 ml round-bottomed flask, 100 ml of dimethylformamide(DMF) was further added therein. Thereafter, 8.28 g of potassium carbonate (60 mmol) and 44.4 ml of N-methylpiperazine (400 mmol) were added therein. The reaction mixture was refluxed at 150° C. for 10 hours. [0142] After the reaction was terminated, the reaction mixture-was cooled to the room temperature. Thereafter, 400 ml of water was added to the reaction mixture. The reaction mixture was extracted with 200 ml of ethyl acetate for three times. The ethyl acetate layers were collected, washed with water for three times and dried with anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure. The resulting residue was purified with column chromatography, to give 2-(N-methylpiperazine)benzaldehyde.
With potassium carbonate; In water; for 18h;Heating / reflux;
Preparation 1; 2-(4-methvlPiperazinvl)-benzaldehvde; A solution of 1-methylpiperazine (139.5 mL, 1.26 moles), potassium carbonate (145 g, 1.05 moles), and 2-fluorobenzaldehyde (73.7 mL, 0.7 moles) in water (700 mL) was heated at reflux for 18 hours. The solution was cooled to room temperature, extracted with methylene chloride (2 x 700 mL), and the combined organic layers were washed with water (2 x 700 mL). The organic layer was dried (MgS04), filtered, and the solvent was removed in vacuo to afford 140 g of a dark oil. 1 H NMR (400 MHz, CDC13) 7.79 (dd, J = 1. 2, 7.9 Hz, 1 H), 7.52 (td, J = 1.5, 7.5 Hz, 1H), 7.11 (m, 2H), 3.12 (t, J = 4.8 Hz, 4H), 2.63 (brs, 4H), 2.39 (s, 3H); 13C NMR (100 MHz, CDC13) 191. 6, 155.8, 135.2, 130.0, 128.9, 122.8, 119.2, 55. 3, 54.1, 46.3
7-bromo-2-(2-fluorophenyl)[1,2,4]triazolo[1,5-a]pyridin-5-ylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; mesitylenesulfonylhydroxylamine;
EXAMPLE 89 7-Bromo-2-(2-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine The title compound, MS m/e (%): 290 (M+, 100), was prepared in accordance with the general method of example 63 from <strong>[329974-09-6]4-bromo-pyridine-2,6-diamine</strong>, O-mesitylene-sulfonyl-hydroxylamine, and 2-fluoro-benzaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(2-fluoro-phenyl)-acrylamide[ No CAS ]
3-(2-chloro-phenyl)-2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(4-hydroxy-phenyl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(2-iodo-phenyl)-acrylamide[ No CAS ]
3-(3-chloro-2-fluoro-phenyl)-2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-naphthalen-2-yl-acrylamide[ No CAS ]
3-(5-bromo-2-fluoro-phenyl)-2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acrylamide[ No CAS ]
2-cyano-3-(3,4-dimethoxy-phenyl)-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(1-methyl-1H-indol-3-yl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(4-imidazol-1-yl-phenyl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(2-fluoro-4-iodo-phenyl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(2,4,6-trimethyl-phenyl)-acrylamide[ No CAS ]
2-cyano-3-(2-difluoromethoxy-phenyl)-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-acrylamide[ No CAS ]
3-(2-chloro-6-fluoro-3-methyl-phenyl)-2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(2,3,6-trichloro-phenyl)-acrylamide[ No CAS ]
2-cyano-3-(3-ethoxy-2-hydroxy-phenyl)-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acrylamide[ No CAS ]
{2-[2-cyano-2-(5-ethyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-vinyl]-phenoxy}-acetic acid[ No CAS ]
2-cyano-3-(3,4-dihydroxy-5-methoxy-phenyl)-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(4-hydroxy-3,5-dimethoxy-phenyl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(2-hydroxy-4,6-dimethoxy-phenyl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(3-p-tolyloxy-phenyl)-acrylamide[ No CAS ]
3-(4-benzyloxy-phenyl)-2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-acrylamide[ No CAS ]
2-cyano-N-(5-ethyl-[1,3,4]thiadiazol-2-yl)-3-(4-hexyloxy-phenyl)-acrylamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A 0.25 M stock solution of 2-cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2- yl)-acetamide was prepared in 1.0 M diisopropylethylamine in DMF. Benzaldehyde and other heterocyclic aldehydes were individually weighed and were dissolved to 0.25 M using a Tecan Genesis workstation. The Tecan was used to dispense 200 muL of template 1 to each reaction vessel then was used to dispense 400 L of aldehyde stock solutions to individual reaction vessels. The reaction vessels were sealed and were heated at 45-50 C, with agitation, for 18 hours. The reaction vessels were then cooled, unsealed, and 50 L of aminopropyl-functionalized silica gel (Aldrich) was dispensed to each reaction vessel. Activated 4 angstrom molecular sieves (powdered, 50 L) were then dispensed to each reaction. Reaction vessels were then sealed and were heated at 45-50 C with agitation for 3 h. Reactions were then unsealed and were filtered to remove solids. B. Sample solutions were dried in vacuo using a Genevac. Samples were dissolved in 500 pL of DMSO and 500 pL of methanol and purity was determined by LC-MS with using a combination of UV254, UV220, and ELSD detection [purity = (UV254+UV220/2)]. The HPLC conditions were: 4.6 mm x 50 mm C18 column, 10-90% acetonitrile gradient over 5 minutes (mobile phases were H20 with 0.05 % TFA and acetonitrile with 0.035 % TFA), with a flow rate of 3.5 ml/min. Samples which were <80% pure were purified using a mass directed LC-MS purification. Purified samples were concentrated in vacuo then were dissolved in DMSO and were reformatted into 96 well microtiter plates. Samples were tested for purity using LC-MS and quantity was estimated by correlating ELSD response to a standard concentration-ELSD response curve. Samples were then concentrated to dryness and were dissolved in DMSO to a final concentration of 10 uM based on ELSD quantitation. C. The following compounds were prepared in the manner described above in Steps A and B using the appropriate aldehyde in place of benzaldehyde: 2-Cyano-3- (3, 4-dimethoxy-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 345 (MH+) ; 3- (4-Benzyloxy-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES) : 391 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4-hydroxy-phenyl)- acrylamide ; MS (ES): 301 (MH+) ; Acetic acid 4- [2-cyano-2- (5-ethyl- [1, 3,4] thiadiazol-2-ylcarbamoyl)-vinyl]- phenyl ester; MS (ES): 343 (MH+); 2-Cyano-3- (2, 4-dichloro-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 353 (MH+) ; 3- (2-Bromo-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 363 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (2-fluoro-phenyl)- acrylamide ; MS (ES): 303 (MH+) ; 3- (4-tert-Butyl-phenyl)-2-cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)- acrylamide ; MS (ES): 341 (MH+) ; 3- (2-Chloro-4-fluoro-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 337 (MH+) ; 2-Cyano-3- (2, 5-dimethyl-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 313 (MH+) ; 2-Cyano-5- (4-methoxy-phenyl)-penta-2, 4-dienoic acid (5-ethyl- [1,3, 4] thiadiazol-2-yl)-amide ; MS (ES): 341 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-(4-hydroxy-3, 5-dimethoxy- phenyl)-acrylamide ; MS (ES): 361 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4-hydroxy-3-iodo-5- methoxy-phenyl)-acrylamide ; MS (ES): 457 (MH+) ; 2-Cyano-3- (3, 4-dihydroxy-phenyl)-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)- acrylamide ; MS (ES): 317 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4-hydroxy-3-methoxy-5- nitro-phenyl)-acrylamide ; MS (ES): 376 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yi)-3- (4-hydroxy-3-methoxy-5- nitro-phenyl)-acrylamide ; MS (ES): 376 (MH+) ; 3-(4-Benzyloxy-3,5-dimethyl-phenyl)-2-cyano-N-(5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 419 (MH+) ; 2-Cyano-3- (3, 5-dibromo-2-methoxy-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES) : 471 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-3- (4-hexyloxy-phenyl)- acrylamide ; MS (ES): 385 (MH+) ; Acetic acid 4- [2-cyano-2- (5-ethyl- [1, 3,4] thiadiazol-2-ylcarbamoyl)-vinyl]- 2, 6-dimethoxy-phenyl ester; MS (ES): 403 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yi)-3- (4-imidazol-1-yi-phenyl)- acrylamide ; MS (ES): 351 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-(2-trifluoromethyl-phenyl)- acrylamide ; MS (ES): 353 (MH+) ; 3- (2-Chloro-3, 4-dimethoxy-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES): 379 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-3- ( 1-methyl-1 H-indol-3-yl)- acrylamide ; MS (ES): 338 (MH+) ; 2-Cyano-3- (2, 6-dichloro-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 353 (MH+) ; 2-Cyano-3-(4-dimethylamino-2-nitro-phenyl)-N-(5-ethyl-[1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES): 373 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- (2-iodo-phe...
With potassium carbonate; In N,N-dimethyl-formamide; at 135℃; for 2h;
Potassium carbonate (1.02 g) was added to a solution of 2-fluorobenzaldehyde (765 mg) and <strong>[166272-81-7]methyl 4-chloro-3-hydroxybenzoate</strong> (1.15g) in dimethylformamide (6 mL) and stirred at 135C for 2 hours. The reaction mixture was cooled down to room temperature, water was added thereto and the mixture was extracted with a mixed solvent (hexane : ethyl acetate = 1:2) for two times. The organic layer was successively washed with water and a saturated saline solution, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by a silica gel column chromatography (hexane : ethyl acetate = 20:1) to give the title compound (609 mg) having the following properties. TLC: Rf 0.49 (hexane:ethyl acetate = 4:1); NMR(CDCl3) delta 10.57, 7.98, 7.86, 7.73, 7.59, 7.52, 7.24, 6.76, 3.90.
With n-butyllithium; hydroxylamine hydrochloride; In tetrahydrofuran; formic acid;
EXAMPLE C 2-Fluoro-6-methylbenzonitrile n-Butyllithium (1.45M, 44.0 mmol, 30.3 ml) was added dropwise to a stirred solution of tetramethyleneethylenediamine (48 mmol, 6.2 ml) in tetrahydrofuran (THF) at -22 C. After 15 min., a further portion of n-butyllithium (120 mmol, 82.8 ml) was added dropwise, and after a further 15 min. 2-Fluorobenzaldehyde (40.0 mmol. 4.21 ml) in THF (16 ml) was added dropwise. The mixture was stirred at -22 C. for 16 h. Methyl iodide (12.5 ml) was added dropwise and the mixture was warmed to room temperature over 30 min., poured into 2N hydrochloric acid and ice, extracted twice with diethyl ether, dried over magnesium sulphate and evaporated to give a brown oil. This was dissolved in formic acid (50 ml) and treated with hydroxylamine hydrochloride (52 mmol, 3.6 g). The mixture was heated at reflux for 16 h, cooled to room temperature and poured into ice water, basified with 10% aqueous sodium hydroxide, extracted twice with diethyl ether, dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica gel, eluding with dichloromethane, to give a yellow solid (2.50 g).
p-toluenesulfonic acid monohydrate; In dichloromethane; toluene;
EXAMPLE 47 Preparation of 2-(2-fluorophenyl)-5-nitro-1,3-benzodioxole <strong>[3316-09-4]4-nitrocatechol</strong> (3.1 g) and 2-fluorobenzaldehyde (5.0 g) were heated under reflux for 18 hours in toluene (70 ml) containing a catalytic amount (0.2 g) of p-toluenesulphonic acid monohydrate. The water produced in the reaction was separated by means of a Dean-Stark apparatus. The reaction mixture was cooled and some solid material (unreacted catechol) filtered off, washing briefly with methylene chloride. The filtrate was evaporated under reduced pressure and the residue purified by chromatography on silica gel using methylene chloride as eluant. The material thus obtained contained traces of aldehyde which were removed by dissolving in ether and shaking the solution successively with 20% aqueous soldium bisulphite solution, saturated sodium bicarbonate solution and finally with water. The resulting ether solution was dried over anhydrous sodium sulphate and evaporated to yield the pure benzodioxole as pale yellow crystals (4.1 g, 79%), mp 86-88 C.
With n-butyllithium; In tetrahydrofuran; hexane; dichloromethane; water; ethyl acetate;
EXAMPLE 4 alpha-(2-Fluorophenyl)-4-(2,2-dimethylpropionamido)-3-pyridinylmethanol To a cooled solution of 2,2-dimethyl-N-(4-pyridinyl)propanamide (15g) in 250 ml tetrahydrofuran was slowly added n-butyllithium (2.5 M in hexane, 108 ml) at such a rate that the internal temperature was maintained between -10° and -5°. After one hour a solution of 2-fluorobenzaldehyde (21 g) in 25 ml tetrahydrofuran was slowly added. After one hour the reaction mixture was stirred with water and extracted with ether. The organic extract was washed with water and a saturated sodium chloride solution, dried (anhy. MgSO4), filtered and evaporated to 30 g of an oil. This was purified by flash chromatography (silica, 20percent ethyl acetate in dichloromethane) to yield 11 g of the product as a solid, mp 178-180°. Four grams were recrystallized from acetonitrile to yield 3.7 g crystals, mp 180-182°.
With potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 1.5h;Schlenk technique; Inert atmosphere;
The benzaldehyde intermediates are synthesized following literature procedures with modifications. Into a dry Schlenk flask under argon atmosphere the corresponding phenol (17.7 mmol), 2-fluorobenzaldehyde (2.0 g, 16.1 mmol), potas- sium carbonate (5.6 g, 40.3 mmol) and anhydrous DMF (40 ml_) are added at room temperature. The mixture is warmed in a sealed flask to 170°C and stirred at this temperature for 2 h (for preparing 2-phenoxy-benzaldehyde and 2-(4- chlorophenoxy)benzaldehyde) or at 150°C for 1 .5 h (for preparing 2-(4- (dimethylamino)phenoxy)benzaldehyde). Then the mixture is allowed to cool to room temperature and is treated with water (200 ml_) and the product is extracted with diethyl ether (3^50 ml_). The combined organic layers are washed with NaOH (1 M, 50 ml_), brine (150 ml_), dried over anhydrous MgSO4 and evaporated in vacuum. The residue is purified by column chromatography (cyclohex- ane/ethyl acetate 10:1 , v/v (for preparing 2-phenoxy-benzaldehyde and 2-(4- chlorophenoxy)benzaldehyde) or used in next reaction without purification (in case of 2-(4-(dimethylamino)phenoxy)-benzaldehyde).
79%
With potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 1.5h;Schlenk technique; Inert atmosphere; Sealed tube;
The benzaldehyde intermediates are synthesized following literature procedures with modifications. Into a dry Schlenk flask under argon atmosphere the corresponding phenol (17.7 mmol), 2-fluorobenzaldehyde (2.0 g, 16.1 mmol), potassium carbonate (5.6 g, 40.3 mmol) and anhydrous DMF (40 mL) are added at room temperature. The mixture is warmed in a sealed flask to 170°C and stirred at this temperature for 2 h (for preparing 2-phenoxy-benzaldehyde and 2-(4-chlorophenoxy)benzaldehyde) or at 150°C for 1.5 h (for preparing 2-(4-(dimethylamino)phenoxy)benzaldehyde). Then the mixture is allowed to cool to room temperature and is treated with water (200 mL) and the product is extracted with diethyl ether (3×50 mL). The combined organic layers are washed with NaOH (1 M, 50 mL), brine (150 mL), dried over anhydrous MgS04 and evaporated in vacuum. The residue is purified by column chromatography (cyclohexane/ethyl acetate 10:1, v/v (for preparing 2-phenoxy-benzaldehyde and 2-(4-chlorophenoxy)benzaldehyde) or used in next reaction without purification (in case of 2-(4-(dimethylamino)phenoxy)-benzaldehyde). [0076] 2-(4-(dimethylamino)phenoxy)benzaldehyde is obtained as a white solid (3.07 g, 79percent yield). 1H NMR (300 MHz, CDCl3) delta 10.59 (d, J = 0.8 Hz, 1 H), 7.90 (dd, J = 7.8, 1.8 Hz, 1 H), 7.44 (ddd, J = 8.5, 7.3, 1.8 Hz, 1 H), 7.12 - 7.05 (m, 1 H), 7.03 - 6.97 (m, 2H), 6.84 - 6.74 (m, 3H), 2.96 (s, 6H). [0077] 13C NMR (75 MHz, CDCl3) delta 189.85, 161.75, 148.14, 145.47, 135.76, 128.33, 126.05, 122.23, 121.25, 116.90, 114.18, 41.34.
With potassium carbonate; In dimethyl sulfoxide; at 20 - 100℃;
To a solution of 2-fluorobenzaldehyde (400 mg, 3.22 mmol) in DMSO (10 mL) are added 3-methyl-lH-l,2,4-triazole (321 mg, 3.87 mmol) and K2C03 (890 mg, 6.45 mmol) at room temperature. The solution is heated to 100 C for 2 hours. The solution is cooled down and extracted with H20 (10 mL) and EtOAc (3 x 10 mL). The combined organic layer is dried (MgS04), filtered and concentrated. The residue is purified by silica gel chromatography eluting with 50% EtOAc in heptane as the eluent to afford 2-(3-methyl- l,2,4-triazol- l-yl)-benzaldehyde (55 mg, 8%) as a white solid.
NaH (55-65%; 44 mg; 1.09 mmol; 1.2 eq.) was added to a solution of 3-fluoro-4-hydroxy- piperidine-1 -carboxylic acid tert-butyl ester (200 mg; 0.91 mmol; 1 eq.) in THF (15 mL) and the resulting mixture was stirred at room temperature for 15 minutes whereupon 2- fluoro-benzaldehyde (113 mg; 0.91 mmol; 1 eq.) was added dropwise. The reaction mixture was stirred at room temperature for 15 hours then at 60C for a further 4 hours. NaH (44 mg; 1.09 mmol; 1.2 eq.) was added and the resulting mixture was stirred at 60C for 2 hours. The solution was diluted with brine extracted with EA (2x). The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (DCM then EtOAc) afforded the title compound (196 mg, 66%) as a yellow oil. H NMR (DMSO-d6) delta 10.38 (s, 1H), 7.74-7.62 (m, 1 H), 7.38 (d, J = 8.5 Hz, 1 H), 7.12 (t, J = 7.6 Hz, 1H), 5.08-4.80 (m, 2H), 4.16-3.98 (m, 1 H), 3.94-3.78 (m, 1 H), 3.42-2.95 (m, 2H), 1.96-1.83 (m, 2H), 1.40 (s, 9H).
tBuOK (136 mg; 1.2 mmol; 1.5 eq.) was added at 10C to a solution of 3-hydroxy-3- trifluoromethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (247 mg; 0.97 mmol; 1.2 eq.) in 1 ,4-dioxane (10 mL) and the reaction mixture was stirred at room temperature for 15 minutes whereupon 2-fluoro-benzaldehyde (100 mg; 0.81 mmol; 1 eq.) was added. The reaction mixture was stirred at 100C for 3 hours then diluted with sat. aq. NH4CI and extracted with EA (2x). The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (DCM) afforded the title compound (95 mg, 33%) as a colourless oil. HPLC (max plot) 98.2%, Rt .87 min.
General procedure: A mixture of appropriate heterocyclic amine (1.0 mmol) (3) and aromatic aldehyde (1.2 mmol) (4) were stirred in tetrahydrofuran under ice-cold condition for 5 min, followed by addition of the thioglycolic acid (2.0 mmol). After 5 min, dicyclohexylcarbodiimide(1.2 mmol) was added to the reaction mixture at 0 C and the reaction mixture was stirred for an additional 3-5 h at room temperature to complete the reaction. Progresses of the reactions were monitored by TLC using acetone:chloroform (7:3) as mobile phase. The precipitated dicyclohexylurea was filtered off; the filtrate was concentrated to drynessunder reduced pressure. Deionized water was added to the residueand extracted with ethylacetate. The organic layer was successively washed with 5% aqueous sodium hydrogen carbonate and sodium chloride. Finally organic layer was dried over anhydrous sodium sulfate. The crude solid obtained on evaporation of the solvent under reduced pressure was subjected for column chromatography using silica gel 100-200 mesh using n-hexane:ethyl acetate (7:3) as the solvent system and further recrystallized in acetone to yield white/yellowish-white products[42].
General procedure: A 10 mL glass tube containing the 4-carboxyphenylboronic acid ester (248 mg, 1.00 mmol), benzaldehyde (0.10 mL, 1.00 mmol), and D.I. H2O (1 mL) was first microwave irradiated for 6 min (45 C, 150 W) under medium speed magnetic stirring. Cyclohexyl isocyanide (3, 0.124 mL, 1.00 mmol) was then added to the reaction mixture. The additional microwave irradiation was applied for 120 min (45 C, 150 W) under medium speed magnetic stirring. After being diluted in dichloromethane, the resulted reaction mixture was washed twice with a saturated aqueous solution of NaHCO3 and with brine. The resulted organic layer was collected and dried over MgSO4 and concentrated in vacuo. The crude product was then dissolved in ethyl acetate (3 mL) prior the slow addition of n-hexane. The resulting precipitate was formed and collected by filtration affording the desired product in 88% yield.
With sodium methylate; In methanol; dimethyl sulfoxide; at 20℃;
General procedure: To a solution of the <strong>[3366-95-8]1-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ol</strong> (12 mmol) in DMSO (6 mL) at room temperature were added aromatic aldehydes 1-21 (16mmol) and sodium methoxide in methanol (12.8 mmol). The reaction mixture was stirred at room temperature until TLC (VEtOAc/Vhexanes 1:2) indicated reaction completion(generally4-5h) and poured into ice-water (250mL). Theprecipitate formed was collected, washed three times with distilled water, and dried under vacuum. The crude products were purified by recrystallization with ethanol, ethyl acetate and acetone (1:1:0.05) washed by ice-water (25mL) for three times to give a pure product.
Example 66A N5-(2-Fluorobenzyl)-<strong>[428854-24-4]2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5,6-triamine</strong> 500 mg (1.43 mmol) of the compound from example 1A were added to a solution of methanol (20.0 ml) and 180 mul of acetic acid, then 333 mul (3.14 mmol) of 2-fluorobenzaldehyde were added and the mixture was stirred at RT for 15 min. Subsequently, 251 mg (4.00 mmol) of sodium cyanoborohydride were added and the reaction mixture was stirred at RT overnight. Thereafter, saturated aqueous sodium hydrogencarbonate solution was added and the mixture was stirred for a further 30 min. Subsequently, the mixture was concentrated and the residue was taken up in ethyl acetate. The organic phase was washed twice with water and once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was stirred with cyclohexane/ethyl acetate, and the solids were filtered off, washed with ethyl acetate and then dried under high vacuum. This gave 267 mg (82% purity, 34% of theory) of the title compound in solid form. Concentration of the mother liquor gave a further 490 mg (53% purity, 40% of theory) of the title compound. The crude product (82% purity) was converted without further purification. LC-MS (method 2): Rt=0.90 min MS (EIpos): m/z=459 (M+H)+.
tert-butyl-{5-[hydroxyl(2-fluorophenyl)methyl]thiazol-2-yl}carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With n-butyllithium; In tetrahydrofuran; at -78℃; for 2h;Inert atmosphere;
General procedure: n-BuLi (2.5M in THF, 1.4equiv) was added drop wise to a mixture of compound 1a or 1b (1equiv) and aldehyde (1.2equiv) in THF (?20mL) at -78C for 2h. The reaction was quenched by adding a saturated aqueous solution of NH4Cl, extracted with EtOAc, washed with water and then brine. The organic phase was dried over anhydrous Na2SO4, evaporated, and the residue was purified by silica gel column chromatography
2-(2-fluorophenyl)-7-methylquinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃;
General procedure: Sodium hydrogen sulfite (4 mmol) was added to a solution of anthranilamide 1 (2 mmol) and benzaldehyde 2 (2 mmol) in N,N- dimethylacetamide (5 mL). The mixture was heated under continuous stirring at 150 o C for 2-3 h and poured into ice water. The precipitate was then filtered, washed with water followed byethanol, and dried to yield the 2-arylquinazolinones 3-31.#10;#10;
(2E)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(2-fluorophenyl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With potassium hydroxide; In ethanol; for 10h;
General procedure: Equimolar quantities of substituted benzaldehyde and 1-(2H-1,3-benzodioxol-5-yl)ethan-1-one or <strong>[2879-20-1]1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethan-1-one</strong> were dissolved in 40% KOH and ethanol. The reactionmixture was then stirred for 10 h and poured into ice-cold water. Theprecipitated product was washed with water, dried, and recrystallizedfrom ethanol.
With sodium hydroxide; In ethanol; at 20℃;
General procedure: To <strong>[2879-20-1]1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one</strong>(A) (1 mmol) alcohol solution (5 mL) was added substituted benzaldehyde(1 mmol). After dissolution, 50% NaOH (0.5 mL) was added. After confirming the completion of the reaction by thin layer chromatography, the sediment was filtered, washed with ethanol and dried to obtain chalcone
With potassium phosphate; palladium diacetate; In water; methyl cyclohexane; for 8h;Reflux;
Method of the present embodiment provides a 2,4 ?-difluorobenzophenone and preparation method thereof, as follows: in a 1000 ml round bottom flask The bottle was added sequentially o-fluoro benzaldehyde 124 g of 4-fluorophenylboronic acid and 140 g of potassium phosphate, 106 grams, 1.12 g of palladium acetate, then adding 500 ml of methyl cyclohexane and 100 ml of water and heated to reflux for 8 hours., sequentially passes through filtering, layering, washing with water, removing the solvent to obtain the product., 2,4 '-difluorobenzophenone 214 g, 98percent yield.
General procedure: 2-Amino-5-methylthiazole-4-carboxylic acid (0.01 M) (1) and substituted benzaldehyde (0.01 M) was taken in 100 mL round bottom flask fitted with Dean-Stark apparatus. In a compound mixture in R.B. to add 50 mL of methanol and refluxed for 7-8 h. Reaction was monitored with TLC, after completion of reaction, solvent was removed and Schiff base was filtered dried and recrystallized from ethanol to give (3a), Yield: 80-84%.
With caesium carbonate; In N,N-dimethyl-formamide; at 140℃; for 5h;Inert atmosphere;
General procedure: To a suspension of 2-methylindole-3-carboxaldehyde (7a) (200 mg, 1.26 mmol) and Cs2CO3 (1.34 g, 3.80 mmol) in N,N-dimethylformamide (4 mL) was added 2-fluorobenzaldehyde (210 muL, 1.99 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 140 C until the indole substrate was all consumed (monitored by TLC), and then allowed to cool down to room temperature. The resulting mixture was filtered and washed with ethyl acetate (80 mL). The filtrate was washed with water (3 X 80 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/hexanes = 1:3) to afford the desired indolo[1,2-a]quinoline.
With 3-ethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium bromide; triethylamine; In ethanol; at 75℃;Inert atmosphere; Enzymatic reaction;
Compound 3 (20.0 g), o-fluorobenzaldehyde (12.7 g) was added to ethanol (5 mL), 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (1.03 g) And triethylamine (6.88g), heated to 75 C under nitrogen to react overnight. TLC displayThe reaction was completed, dissolved in ethyl acetate (400 mL), washed twice with water (100 mL) and brine (100 mL)2 times, dry, spin dry, purified by column to obtain crude compound 5 (5.0 g), further purified by prep-HPLC, decompression at 45 CMost of the organic phase was evaporated and lyophilized to give the pure compound 4 (700 mg)
With potassium carbonate; In dimethyl sulfoxide; at 100℃;Inert atmosphere;
(1) 3 g of o-fluorobenzaldehyde (24.2 mmol, 1.0 eq), 5.6 g of sodium ethyl sulfinate (48.3 mol, 2.0 eq) were added to a 100 mL three-necked flask.1.84 g of potassium carbonate (48.3 mmol, 2.0 eq), 30 mL of dimethyl sulfoxide, stirred under nitrogen for ten minutes.Then, the reaction was carried out at 100 C overnight, and the reaction was completely detected by TLC, and the temperature was lowered, poured into 200 mL of ice water, and extracted with 100 mL of ethyl acetate twice.The organic phase was combined, washed with 100 mL of saturated brine for 3 times, dried, and then subjected to column chromatography ( petroleum ether: ethyl acetate = 10:1 to petroleum ether: ethyl acetate = 3:1)4.5 g of a yellow solid 13 was obtained in a yield of 94.0%.
94%
With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 16h;
This example produces 3-hydroxy-2,3-dihydroarylcyclothiophene-1,1-dioxide by the following reaction,Wherein n in the formula I is a benzene ring, X is F, R1 is hydrogen, and R2 is a methyl group, and the reaction formula is as follows: Add 100 g of o-fluorobenzaldehyde (24.2 mmol, 1 eq) to a 100 mL single-mouth bottle.Sodium ethyl sulfinate 5.6 g (48.3 mol, 2 eq),Potassium carbonate 1.84 g (48.3 mmol, 2 eq),Then add 30 mL of dimethyl sulfoxide.Then, the mixture was stirred for 10 minutes, heated, and reacted at 100 C for 16 hours. The reaction was completely detected by TLC.Cool down, pour 200mL of ice water, extract 100mL of ethyl acetate twice,The combined organic phases were washed three times with 50 mL of saturated brine and dried.Mixing silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to petroleum ether:Ethyl acetate = 3:1) gave a pale yellow solid 7 mass of 4.5 g, yield 94.0%.
94%
With potassium carbonate; In dimethyl sulfoxide; at 100℃;Inert atmosphere;
3 g of o-fluorobenzaldehyde (24.2 mmol, 1.0 eq) and 5.6 g of sodium ethyl sulfinate were added to a 100 mL three-necked flask.(48.3 mol, 2.0 eq), 1.84 g of potassium carbonate (48.3 mmol, 2.0 eq), 30 mL of dimethyl sulfoxide, stirring under nitrogenThe clock was then reacted at an internal temperature of 100 C overnight. The reaction was complete by TLC, cooled, poured into 200 mL of ice water and extracted with ethyl acetate (100 mL).2 times, the organic phase was combined, 100 mL of saturated brine was washed 3 times, dried, and subjected to column chromatography (petroleum ether: ethyl acetate = 10:1 toPetroleum ether: ethyl acetate = 3:1) yielded 4.5 g of a yellow solid 11 yield 94.0%.
With sodium cyanoborohydride; acetic acid; In methanol; at 20 - 50℃;pH 6-7;
General procedure: To a stirring solution of 8 (0.3 mmol) in MeOH (5 mL) was added the corresponding aldehyde (0.4 mmol) and NaCNBH3 (0.5 mmol)at room temperature. The mixture was adjusted to pH 6-7 by acetic acid, stirred overnight at room temperature, and quenched by 1M NaOH solution (5 mL). The mixture was diluted by H2O (15 mL), and extracted by DCM (10mL x 3). The combined organic layer waswashed by brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified over silica gel column(DCM: MeOH = 20 : 1) to yield oils 9b-s (70-93%).
With potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 1h;
General procedure: A mixture of 2-fluorobenzaldehyde (1.24 g, 10 mmol), phenol (1.12 g, 11.9 mmol), K2CO3 (3.45 g, 25 mmol) in DMF (20 mL) was placed in a pre-heated oil bath at 150 C. The reaction mixturewas stirred at 150 C until the reaction was complete by TLC analysis (ca. 1 h). The reaction mixture was then cooled to room temperature, diluted with water (150 mL) and extracted withethyl acetate (3 x 60 mL). Combined ethyl acetate layer was back washed with water (2 x 50 mL), brine (1 x 50 mL), dried over Na2SO4 and evaporated. The crude reaction mixture waspurified by short silica gel column chromatography using 5 % ethyl acetate in hexane as eluent to obtain 2-phenoxy benzaldehyde 1a (1.62 g, 82 % yield) as a clear oil. The following 2-aryloxybenzaldehydes and 2-(arylthio)benzaldehydes were generated from commercially and 2-fluorobenzaldehydes and phenols and thiophenols
General procedure: A mixture of compound A (5 mmol) and corresponding benzaldehyde (5 mmol) in 10 mL ethanol was refluxed for 24 hours in a reaction flask wrapped up by silver paper. Upon the reactions completed (monitored by TLC), tawny solids were obtained through suction filtration. The precipitates were washed with ethanol (5 mLx3) and recrystallized from ethanol with 50-84% yields.
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