* 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] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 5957 - 5960
2
[ 403-33-8 ]
[ 22090-24-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 9, p. 3703 - 3726
3
[ 403-33-8 ]
[ 456-06-4 ]
Yield
Reaction Conditions
Operation in experiment
83%
With hydrazine hydrate In methanol for 5 h; Reflux
General procedure: To a solution of an appropriate methyl esters17(a–j) (1.0 mmol) in 50 mL of methanol was added 99 percenthydrazine hydrate (4.0 mmol) and the mixture was refluxedfor 5 h up to reaction completed (TLC). After completionof reaction, it was allowed to cool and the obtained solidwas washed with methanol. The crude products wererecrystallized from ethanol.
80%
With hydrazine hydrate In ethanol at 40℃;
General procedure: Various methyl benzoate 8A-V (1.0 equiv) reacted with hydrazine hydrate (excess amount) in anhydrous ethanol. The reaction was stirred at 40 °C for overnight. The ethanol was removed under reduced pressure. The products were purified by recrystallization, which were washed with ethyl ether. The products were obtained as white solid.
75%
With hydrazine hydrate In ethanol for 5 h; Reflux
General procedure: Compound 12 (0.013 mol) and 80percent NH2NH2H2O (5 mL) wereadded to EtOH (10 mL), the mixturewas stirred under reflux for 5 h.After being cooled to room temperature, the precipitate was obtainedby filtration, and was dried to give the title compounds,respectively.4.1.7.1. 4-Fluorobenzohydrazide (13a). A white solid. Yield: 75percent. Mp161.9e164.4 C. 1H NMR (400 MHz, DMSO-d6) d 9.78 (s, 1H,eNHeN), 7.83e7.93 (m, 2H, ArH), 7.22e7.33 (m, 2H, ArH), 4.48 (s,2H, eNHeNH2). ESI-MS m/z: 155.1 [M H].
50%
With hydrazine hydrate In ethanol for 24 h; Reflux
General procedure: Various benzohydrazides 5-7 and 9-13 were obtained accordingto known procedures [40,65] except for benzohydrazides 4and 8 which were commercially available. A solution of the methylbenzoate (1 equiv) in ethanol was added dropwise to 65percent hydrazinemonohydrate (5 equiv). The reaction mixture was then heatedunder reflux and stirred overnight. The reaction progress was followedup by TLC. Crude product was collected by filtration aftercooling of the reaction medium and finally washed with coldethanol unless specified otherwise. The desired benzohydrazides were used without any further purification.The analysis of spectral data (1H and 13C NMR), the yields, HRMS,Mp and Rf of these precursors are presented in SupplementaryInformation.
280 mg
Reflux
General procedure: 4-fluorobenzoic acid as the raw material, methanol as a reaction solvent, a small amount of concentrated sulfuric acid catalyst, followed by stirring under heating at reflux, thin layer chromatography (TLC) to track progress of the reaction, a certain amount after the completion of the reaction NaHCO3Solution for hydrazine and the reaction liquid solution to give ester intermediate (3-1), continue to add more than the corresponding proportion of hydrazine hydrate reaction mixture was heated with stirring at reflux, thin layer chromatography (TLC) to track progress of the reaction, the reaction after completion of the reaction solution was added to a certain amount of water, then a large amount of white sink to the bottom, suction filtration to afford intermediate hydrazides (3-2)
Reference：
[1] Biomedicine and Pharmacotherapy, 2017, vol. 94, p. 499 - 513
[2] Letters in Drug Design and Discovery, 2012, vol. 9, # 3, p. 276 - 281
[3] Medicinal Chemistry Research, 2016, vol. 25, # 4, p. 627 - 643
[4] European Journal of Medicinal Chemistry, 2016, vol. 120, p. 202 - 216
[5] New Journal of Chemistry, 2016, vol. 40, # 10, p. 8846 - 8854
[6] European Journal of Medicinal Chemistry, 2015, vol. 104, p. 115 - 126
[7] Arzneimittel-Forschung/Drug Research, 2001, vol. 51, # 7, p. 569 - 573
[8] European Journal of Medicinal Chemistry, 2018, vol. 159, p. 324 - 338
[9] Journal of the Indian Chemical Society, 1982, vol. 59, # 10, p. 1174 - 1176
[10] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 8, p. 3028 - 3036
[11] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2010, vol. 65, # 2, p. 178 - 184
[12] Monatshefte fur Chemie, 2010, vol. 141, # 4, p. 479 - 484
[13] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2011, vol. 79, # 5, p. 1837 - 1842
[14] Journal of Molecular Structure, 2011, vol. 1003, # 1-3, p. 52 - 61
[15] Magnetic Resonance in Chemistry, 2011, vol. 49, # 10, p. 648 - 654
[16] Journal of Molecular Structure, 2012, vol. 1011, p. 121 - 127
[17] Journal of Agricultural and Food Chemistry, 2012, vol. 60, # 4, p. 1036 - 1041
[18] Medicinal Chemistry, 2012, vol. 8, # 6, p. 1190 - 1197,8
[19] Medicinal Chemistry, 2012, vol. 8, # 6, p. 1190 - 1197
[20] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2015, vol. 70, # 8, p. 609 - 616
[21] Medicinal Chemistry Research, 2013, vol. 22, # 3, p. 1305 - 1312
[22] Medicinal Chemistry Research, 2013, vol. 22, # 10, p. 4980 - 4991
[23] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2013, vol. 115, p. 683 - 689
[24] Chemical Biology and Drug Design, 2013, vol. 82, # 5, p. 546 - 556
[25] Comptes Rendus Chimie, 2015, vol. 18, # 12, p. 1320 - 1327
[26] Phosphorus, Sulfur and Silicon and the Related Elements, 2016, vol. 191, # 6, p. 904 - 907
[27] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 1, p. 192 - 194
[28] Medicinal Chemistry Research, 2014, vol. 23, # 4, p. 1661 - 1671
[29] Synthetic Communications, 2014, vol. 44, # 18, p. 2724 - 2737
[30] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 3, p. 481 - 484
[31] Chemical Communications, 2015, vol. 51, # 76, p. 14365 - 14368
[32] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5611 - 5617
[33] Letters in Drug Design and Discovery, 2016, vol. 13, # 9, p. 968 - 981
[34] Journal of the Chemical Society of Pakistan, 2016, vol. 38, # 5, p. 864 - 881
[35] Patent: CN104488911, 2016, B, . Location in patent: Paragraph 0019-0020
[36] Patent: CN104488908, 2016, B, . Location in patent: Paragraph 0007; 0016; 0017
[37] Patent: CN104488909, 2016, B, . Location in patent: Paragraph 0016-0017
[38] Patent: CN104522035, 2016, B, . Location in patent: Paragraph 0016; 0017
[39] Patent: CN104542624, 2016, B, . Location in patent: Paragraph 0019; 0020
[40] Patent: CN104521990, 2016, B, . Location in patent: Paragraph 0016; 0017
[41] Chemical Biology and Drug Design, 2017, vol. 90, # 2, p. 200 - 209
[42] Patent: CN104672162, 2017, B, . Location in patent: Paragraph 0111; 0112
[43] Patent: CN104488963, 2017, B, . Location in patent: Paragraph 0026-0027
[44] Patent: CN106957242, 2017, A, . Location in patent: Paragraph 0085; 0087; 0088; 0089; 0091
[45] Patent: CN106866708, 2017, A, . Location in patent: Paragraph 0080
[46] Patent: CN104488893, 2017, B, . Location in patent: Paragraph 0036; 0037
[47] Patent: CN104488900, 2017, B, . Location in patent: Paragraph 0007; 0016-0017
[48] Patent: CN104488926, 2016, B, . Location in patent: Page/Page column 0016; 0018
[49] Bulletin of the Chemical Society of Ethiopia, 2017, vol. 31, # 3, p. 481 - 489
[50] Pharmaceutical Chemistry Journal, 2018, vol. 51, # 10, p. 907 - 917
[51] Journal of Chemistry, 2017, vol. 2017,
4
[ 403-33-8 ]
[ 459-56-3 ]
[ 391-92-4 ]
[ 392-04-1 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2008, vol. 6, # 7, p. 1251 - 1259
5
[ 403-33-8 ]
[ 392-04-1 ]
Yield
Reaction Conditions
Operation in experiment
78%
With oxone; Ru(MesCO2)(4,4'-dibromobipyridine)(p-cymene); trifluoroacetic acid; trifluoroacetic anhydride In 1,2-dichloro-ethane at 110℃; for 8 h; Sealed tube; Green chemistry
General procedure: The Ru(MesCO2)(L) (p-cymene) [L- 2,2’-bypyridine or 4,4’-dibromobipyridine] (2.5 molpercent), oxidant (2.0 eq) and ester (1.0 eq) were added to a sealed tube. Following that, trifluoroacetic acid (TFA) and trifluoroacetic anhydride (TFAA) in the ratio of 0.6 ml: 0.4 were added. The reaction mixture was kept on a pre-heated bath at 110°C and stirred until its completion. It was continuously monitored by TLC. Ice water was added to quench the reaction mixture and it was extracted with dichloromethane. The organic layer was dried over Na2SO4 and rota-evaporated. Finally the residue was purified by silica gel column chromatography to give corresponding products.
Reference：
[1] Organic and Biomolecular Chemistry, 2008, vol. 6, # 7, p. 1251 - 1259
7
[ 403-33-8 ]
[ 75-05-8 ]
[ 4640-67-9 ]
Yield
Reaction Conditions
Operation in experiment
83%
With sodium hexamethyldisilazane In tetrahydrofuran; toluene at -5 - 0℃; Large scale
Methyl 4-fluorobenzoate (29.44 kg), toluene (177 L) and acetonitrile (59 L; 5.9 mol equivalents versus methyl 4-fluorobenzoate) were charged to the reactor. The mixture was cooled to a temperature of -5 / 0 ° C. A solution of sodium bis (trimethylsilyl) amide (NaHMDS 40percent in THF) (192 L; 2 mol / mol vs. methyl 4-fluorobenzoate) was added while maintaining the temperature between -5 / + 5 ° C. The addition line was washed off with toluene (9 L). The reaction mixture was quenched by adding dilute hydrochloric acid while maintaining the temperature of -5 / + 25 ° C. The addition of acid was continued until pH <5. The layers separated and the lower aqueous layer was removed. The solvent was removed by vacuum distillation to a small amount. Toluene (59 L) was added and the mixture was heated to 85/90 ° C. to give a solution. The mixture was cooled to T = 50/55 ° C. and n-heptane (29 L) was added to obtain a precipitate. The mixture was further cooled to T = 20/25 ° C. and the solid product was isolated by filtration and washed with n-heptane (59 L). The product in the moist state was dried under vacuum at T = 40/45 ° C. to give 4-fluorobenzoylacetonitrile (26 kg, yield 83percent) of purity 98.7percent Apercent GC. The amount of 4-methoxybenzoylacetonitrile as an impurity was 0.03percent (Apercent GC).
Reference：
[1] Patent: JP2018/43989, 2018, A, . Location in patent: Paragraph 0124-0131
8
[ 403-33-8 ]
[ 75-05-8 ]
[ 456-22-4 ]
[ 4640-67-9 ]
Yield
Reaction Conditions
Operation in experiment
64%
With sodium hydride In tert-butyl methyl ether; water at 90℃;
Methyl 4-fluorobenzoate (50 g)Was added to a suspension of sodium hydride in methyl-tert-butyl ether (MTBE)(2 eq.) At 90 ° C.4-fluorobenzoylacetonitrile was obtained in about 64percent yield.4-fluorobenzoic acid with a purity of 81percent, 17.5percent4-methoxybenzoylacetonitrile was about 3percent
Reference：
[1] Patent: JP2018/43989, 2018, A, . Location in patent: Paragraph 0129
9
[ 288-32-4 ]
[ 403-33-8 ]
[ 101184-08-1 ]
Yield
Reaction Conditions
Operation in experiment
59%
With potassium carbonate In dimethyl sulfoxide at 120℃; for 3 h;
A mixture of imidazole (132 g, 1.9 mol), methyl 4-fluorobenzoate (170 ml, 1.3 [0385] mol) and potassium carbonate (357 g, 2.6 mol) in DMSO (200 ml)And the mixture was stirred at 120 ° C for 3 hours. After cooling to room temperature, the mixture was added to cold water. The precipitated product was filtered and washed with water. Yield: 59percent.
Reference：
[1] Patent: KR101502187, 2015, B1, . Location in patent: Paragraph 0384; 0385
[2] Journal of Medicinal Chemistry, 1990, vol. 33, # 4, p. 1091 - 1097
[3] Patent: US4804662, 1989, A,
10
[ 403-33-8 ]
[ 18156-74-6 ]
[ 420-56-4 ]
[ 101184-08-1 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 4, p. 1151 - 1154
With potassium carbonate; In dimethyl sulfoxide; at 120.0℃; for 3h;
A mixture of imidazole (132 g, 1.9 mol), methyl 4-fluorobenzoate (170 ml, 1.3 [0385] mol) and potassium carbonate (357 g, 2.6 mol) in DMSO (200 ml)And the mixture was stirred at 120 C for 3 hours. After cooling to room temperature, the mixture was added to cold water. The precipitated product was filtered and washed with water. Yield: 59%.
With potassium carbonate; In water; dimethyl sulfoxide;
Preparation 5 4-(1H -Imidazol-1-yl)benzoic acid methyl ester Heat 101.6 g (0.65 mol) of methyl 4-fluorobenzoate, 66.65 g (0.98 mol) of imidazole, and 182.0 g (1.31 mol) of potassium carbonate in dimethylsulfoxide at ca. 120 C. for about 3 hr. Cool the solution to room temperature and pour into 500 mL of cold water. Filter to obtain crystals of the title compound. NMR (CDCl3): delta=4.00(s,3), 7.30(m1), 7.40(m1), 7.45(d,2), 7.95(m1), and 8.20(d,2) ppm.
With hydrazine hydrate; In methanol; for 0.08333330000000001h;Microwave irradiation;
General procedure: The benzoic acid hydrazides, 3a-h were prepared accordingto reported method in literature28,29 with some desirablemodifications. The ester (2a-h, 0.1 mol) dissolved inappropriate volume of methanol was transferred to a flaskwith a reflux condenser. Hydrazine hydrate (99%, 0.15 mol) was slowly added to the mixture and then kept on reflux forabout 5-6 h. The excess of solvent and hydrazine hydratewere distilled off. On addition of water the product separatedout which was washed several times with distilled water anddried. The product was recrystallized from 80% aqueous ethanoland melting points determined (Table 2).Microwave method: The same procedure as stated abovewas adopted using 100 ml methanol following the other conditionsof microwave in a microwave reactor at 350 Watt(power) for 3-5 min. Precipitation and separation of precipitatewas done as for conventional method (Table 2).
83%
With hydrazine hydrate; In methanol; for 5.0h;Reflux;
General procedure: To a solution of an appropriate methyl esters17(a-j) (1.0 mmol) in 50 mL of methanol was added 99 %hydrazine hydrate (4.0 mmol) and the mixture was refluxedfor 5 h up to reaction completed (TLC). After completionof reaction, it was allowed to cool and the obtained solidwas washed with methanol. The crude products wererecrystallized from ethanol.
80%
With hydrazine hydrate; In ethanol; at 40℃;
General procedure: Various methyl benzoate 8A-V (1.0 equiv) reacted with hydrazine hydrate (excess amount) in anhydrous ethanol. The reaction was stirred at 40 C for overnight. The ethanol was removed under reduced pressure. The products were purified by recrystallization, which were washed with ethyl ether. The products were obtained as white solid.
75%
With hydrazine hydrate; In ethanol; for 5.0h;Reflux;
General procedure: Compound 12 (0.013 mol) and 80% NH2NH2H2O (5 mL) wereadded to EtOH (10 mL), the mixturewas stirred under reflux for 5 h.After being cooled to room temperature, the precipitate was obtainedby filtration, and was dried to give the title compounds,respectively.4.1.7.1. 4-Fluorobenzohydrazide (13a). A white solid. Yield: 75%. Mp161.9e164.4 C. 1H NMR (400 MHz, DMSO-d6) d 9.78 (s, 1H,eNHeN), 7.83e7.93 (m, 2H, ArH), 7.22e7.33 (m, 2H, ArH), 4.48 (s,2H, eNHeNH2). ESI-MS m/z: 155.1 [M H].
50%
With hydrazine hydrate; In ethanol; under 760.051 Torr; for 24.0h;Reflux;
General procedure: Various benzohydrazides 5-7 and 9-13 were obtained accordingto known procedures [40,65] except for benzohydrazides 4and 8 which were commercially available. A solution of the methylbenzoate (1 equiv) in ethanol was added dropwise to 65% hydrazinemonohydrate (5 equiv). The reaction mixture was then heatedunder reflux and stirred overnight. The reaction progress was followedup by TLC. Crude product was collected by filtration aftercooling of the reaction medium and finally washed with coldethanol unless specified otherwise. The desired benzohydrazides were used without any further purification.The analysis of spectral data (1H and 13C NMR), the yields, HRMS,Mp and Rf of these precursors are presented in SupplementaryInformation.
With hydrazine hydrate; In methanol;Reflux;
General procedure: Methyl benzoates were synthesized from their respective p-substituted benzoic acids, using excess dry methanol in the presence of H2SO4. para-Substituted benzoic hydrazides (2a-i) were prepared by reaction of the corresponding methyl benzoates (10 mmol) with hydrazine hydrate 99% (50 mmol) in methanol under reflux for 4-6 h. The excess solvent was removed under vacuum and the residue was filtered under suction, washed with water, and dried. The spectral and analytical data of benzoic hydrazide (2a) [26], 4-bromobenzoic hydrazide (2b) [27], 4-chlorobenzoic hydrazide (2c) [28], 4-fluorobenzoic hydrazide (2d) [26], 4-hydroxybenzoic hydrazide (2e) [29], 4-methoxybenzoic hydrazide (2f) [30], 4-methylbenzoic hydrazide (2g) [28], 4-nitrobenzoic hydrazide (2h) [28] and 4-aminobenzoic hydrazide (2i)[28] are in good agreement with literature values.
With hydrazine hydrate; In methanol;Reflux;
General procedure: Methyl benzoates were synthesized from their respective p-substituted benzoic acids, using excess of dry methanol in presence of H2SO4. p-Substituted benzoic acid hydrazides (2a-i) were prepared by reaction of the corresponding methyl benzoates (10 mmol) with hydrazine hydrate 99% (50 mmol) in methanol under reflux for 4-6 h. The excess solvent was removed under vacuum and the residue was filtered under suction, washed with water and dried. The spectral and analytical data of benzoic hydrazide (2a) [35], 4-bromobenzoic hydrazide (2b) [36], 4-chlorobenzoic hydrazide (2c) [37], 4-fluorobenzoic hydrazide (2d) [35], 4-hydroxybenzoic hydrazide (2e) [38], 4-methoxybenzoic hydrazide (2f) [39], 4-methylbenzoic hydrazide (2g) [37], 4-nitrobenzoic hydrazide (2h) [37] and 4-aminobenzoic hydrazide (2i) [38] are in good agreement with literature values.
With hydrazine hydrate; In ethanol;Reflux;
General procedure: Different substituted carboxylic acids (20 mmol) (A) were stirred with thionyl chloride (100 mmol) in dry methanol (75 ml) or 5-6 h to synthesize corresponding methyl esters (B) (Scheme1). After extraction of esters in chloroform, solvent was evaporated and esters (66 mmol) were refluxed with hydrazine hydrate(330 mmol) in ethanol (75 ml) for 4-5 h. A solid was obtained upon removal of the solvent by rotary evaporation. The resulting solid was washed with hexane to afford hydrazide ligand (C). The spectral and analytical data are given below.
With hydrazine hydrate; In methanol; for 5.0h;Reflux;
General procedure: Compounds 6a-t were synthesized from substituted benzoic acid via six steps according to the literature method as described. Various substituted benzoic acids 1a-t were treated with SOCl2 to give compounds 2a-t, which were reacted with CH3OH and EtN3 in CH2Cl2 at 0 to afford compounds 3a-t. Compounds 4a-t were prepared by the reaction of compounds 3a-t, hydrazine hydrate in CH3OH under reflux condition about 5h. Subsequently, compounds 5a-t were obtained by reaction of compounds 4a-t with CS2 and KOH in CH3OH. Compounds 6a-t were obtained by the cyclization reaction of compounds 5a-t in the presence of HCl at 0-5C.
With hydrazine hydrate; In methanol; for 8.0h;Reflux;
General procedure: To a solution of methyl ester of aromatic carboxylic acid 2 (0.1 mol) in methanol (30 mL), hydrazine hydrate (0.2 mol) was added drop wise with stirring. The resulting mixture was allowed to reflux for 8 h. After the completion of the reaction as monitored by TLC, the excess methanol was distilled off under reduced pressure. The resulting acid hydrazide 3 was washed with cold water, dried and recrystallized from ethanol.
With hydrazine hydrate; In methanol;Reflux;
Methyl acetate dissolved in different methanol, and then slowly add 40% - 80% hydrazine hydrate, reflux reaction is complete until the precipitation of different substituted formyl hydrazide
With hydrazine hydrate; In methanol;Reflux;
General procedure: Methyl formate was dissolved in methanol,Then slowly add 40% -80% hydrazine hydrate,Reflux reaction is complete,After cooling, different substituted formylhydrazides are precipitated;
With hydrazine hydrate; In methanol; for 7.0h;Reflux;
0.05 mol of methyl p-fluorobenzoate and methanol were added50 mL was cast in a 100 mL three-necked round bottom flask,80% hydrazine hydrate (0.06 mol) was added slowly at room temperature,The temperature was refluxed for 7 hours to complete.Decompression recovery of methanol, cooling and standing after the precipitation of white crystals, pumping rate, the methanol recrystallization.
280 mg
With hydrazine hydrate;Reflux;
General procedure: 4-fluorobenzoic acid as the raw material, methanol as a reaction solvent, a small amount of concentrated sulfuric acid catalyst, followed by stirring under heating at reflux, thin layer chromatography (TLC) to track progress of the reaction, a certain amount after the completion of the reaction NaHCO3Solution for hydrazine and the reaction liquid solution to give ester intermediate (3-1), continue to add more than the corresponding proportion of hydrazine hydrate reaction mixture was heated with stirring at reflux, thin layer chromatography (TLC) to track progress of the reaction, the reaction after completion of the reaction solution was added to a certain amount of water, then a large amount of white sink to the bottom, suction filtration to afford intermediate hydrazides (3-2)
With hydrazine hydrate; at 80℃; for 5.0h;
1) In a 100 ml round bottom flask,12.32 g (80.0 mmol) of methyl p-fluorobenzoate was added,And hydrazine hydrate 30ml (excess) at 80 for 5h,After the reaction was completely cooled, the solid was precipitated at low temperature,Filter,Dried to give p-fluorobenzoyl hydrazide.
With hydrazine hydrate; In methanol;Reflux;
Methyl formate was dissolved in methanol, Then slowly add 40% -80% hydrazine hydrate, reflux reaction is complete, after cooling out of different substituted formyl hydrazide;
With hydrazine; In ethanol; water; for 10.0h;Reflux;
General procedure: The oil was thendissolved in EtOH, and NH2NH2.H2O (3 eq) was added.The mixture was refluxed for 10 h. CH2Cl2 (30 mL) was thenadded and extracted with distilled H2O (3 × 20 mL). Theorganic phase was separated, dried on anhydrous Na2SO4,and evaporated under vacuum to afford correspondinghydrazide 7a in very good yield (white solid, 1.02g, 93%)
With hydrazine hydrate; In ethanol; at 85℃; for 1.0h;
A solution of methyl 4-fluorobenzoate (3.4 g, 22.06 mmol, 1 equiv.) and hydrazine hydrate(10 mL) in EtOH (10 mL) was stirred at 85 C for 1 hour. The resulting mixture wasconcentrated under vacuum. The residue was purified by silica gel column chromatography,eluted with CH2C12 / MeOH (0 to 10:1) to afford product (2.5 g) as a white solid. ESI-MS m/z= 540.15 [M+Hj . ESI MS m/z= 154.95 [M+Hj
With hydrazine hydrate; In methanol;Reflux;
General procedure: Carboxylic acid hydrazides are synthesized following a modifiedprocedure from one already reported in the literature [22]. Hydrazinehydrate (80%, 0.06 mol) is added slowly to a solution ofcarboxylate esters (0.02 mol) in methanol (30 mL). The reactionmixture is subjected to reflux for 6-8 h. Upon completion of reaction,the mixture is cooled down to the room temperature and icewater is added. The precipitated solid product obtained wasfiltered, dried and recrystallized from methanol.
With hydrazine hydrate; In methanol; at 65℃; for 4.0h;
General procedure: To a solution of esters (2a~2t, 1.0 equiv.), furan-2-carbonyl chloride (7a, 1.0 equiv.) orthiophene-2-carbonyl chloride (7b, 1.0 equiv.) in MeOH (2 mL/1 mmol) was added hydrazine hydrate(1 mL/1 mmol), then the mixture was allowed to reach 65 C and stirred for 4 h. After completion(monitored by TLC), the organic solvent was removed and extracted three times with ethyl acetate,the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to givethe corresponding hydrazides (3a~3t, 8a, or 8b) in high yields, which were taken up for the next stepwithout any purification.
With hydrazine hydrate; In methanol;Reflux; Inert atmosphere;
General procedure: Hydrazine hydrate (5 mL, 40%) was added to a solution of requiredester (5.0 mmol) in methanol (20 mL). The solution was refluxed for12-24 h and monitored by TLC until starting material was completelyconsumed. After that, solvent was evaporated under reduced pressureand a small amount of water (5 mL) was added to precipitate the hydrazide,which was filtered and dried in vacuum to give a shiny white toyellow solid in excellent yields, without further purification.
With 2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane 2,8,9-tris(1-methylethyl); In tetrahydrofuran; at 23 - 25℃;Inert atmosphere;
General procedure: A round bottom centrifuge tube containing catalyst 4 (6.7 mol % based on the percent phosphorus determined by elemental analysis or as otherwise stated in the footnotes of the corresponding Tables) was equipped with a rubber septum and two magnetic stir bars for extra stirring efficiency. After flushing the tube with argon, it was charged via syringe with a higher ester (5 mmol) and MeOH (5 mL) for transesterifications. For amidations, the tube was similarly charged with an ester (2 mmol), amino alcohol (2 mmol), and THF (3 mL). The reaction mixture was vigorously stirred at room temperature (23-25 C) and progress of the reaction was monitored by thin layer chromatography. Upon completion of the reaction, the reaction mixture was filtered through Whatman No. 1 filter paper and washed with 3 × 10 mL of THF. The combined organics were subjected to short-path silica gel chromatography (0-20% ethyl acetate in hexanes v/v) to obtain an analytically pure product. In the case of amides, products were purified using a short-path silica gel column eluted with dichloromethane/methanol (95:5, v/v).
With sodium hydride In tetrahydrofuran; dimethyl sulfoxide
68%
Stage #1: methyl 4-flurobenzoate With sodium hydride In dimethyl sulfoxide at 20℃; for 0.666667h; Inert atmosphere;
Stage #2: 1-(4-Fluorophenyl)ethanone In dimethyl sulfoxide at 60℃; for 4h;
7 Synthesis of intermediate (216-a):
A dry 250ml bottle was repeatedly evacuated and filled with nitrogen three times, placed with sodium hydride (5eq) followed by dimethyl sulfoxide (150mL), followed by methyl p-fluorobenzoate (1eq), stirred at room temperature for 40 minutes, then 4-Fluoroacetophenone (0.7eq) was slowly added, and the reaction was completed by heating to 60°C for 4 hours.Then slowly add ice water (1000mL) to quench the remaining sodium hydride, then add petroleum ether (1000mL x 3) for extraction, concentrate to obtain a reddish-brown liquid, after distillation, a clear liquid intermediate (216-a) is obtained in a yield of 68 %.
50%
With sodium hydride In toluene Inert atmosphere; Reflux;
50%
With sodium hydride In tetrahydrofuran; mineral oil at 20℃;
3.9 g
Stage #1: 1-(4-Fluorophenyl)ethanone With 18-crown-6 ether; potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.5h;
Stage #2: methyl 4-flurobenzoate In tetrahydrofuran at 20℃; for 3h;
6.02.01.20 1,3-Bis-(4-fluoro-phenyl)-l, 3-propanedione
1,3-Bis-(4-fluoro-phenyl)-l, 3-propanedione9.27 g KOtBu was added to 109 mg 18-Krone-6 and 5 mL 4-fluoracetophenone in 150 mL THF. After 30 min at RT 10.7 g 4-fluoro-benzoic acid methyl ester was added and stirred for 3 h at RT. The reaction was decomposed with water and filtered, the filtrate was concentrated and the residue was purified by chromatography on silica gel (cyclohexane/EE: 98:2). The solvent was removed and 3.9 g of the desired compound was obtained.(M+H)+: 261
3.9 g
Stage #1: 1-(4-Fluorophenyl)ethanone With 18-crown-6 ether; potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.5h;
Stage #2: methyl 4-flurobenzoate In tetrahydrofuran at 20℃; for 3h;
6.02.01.01 6.02.01.01
6.02.01.01 1,3-Bis-(4-fluoro-phenyl)-1,3-propandione 9.27 g KOtBu was added to 109 mg 18-Krone-6 and 5 mL 4-fluoracetophenone in 150 mL THF. After 30 min at RT 10.7 g 4-fluoro-benzoic acid methyl ester was added and stirred for 3 h at RT. The reaction was decomposed with water and filtered, the filtrate was concentrated and the residue was purified by chromatography on silica gel (cyclohexane/EE: 98:2). The solvent was removed and 3.9 g of the desired compound was obtained. (M+H)+: 261. 1H-NMR, DMSO 8.30-8.23 (m, 3H, 3/CH), 8.10-8.01 (m, 1H, CH), 3.88-3.85 (s, 1H, CH2)
3.9 g
Stage #1: 1-(4-Fluorophenyl)ethanone With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.5h;
Stage #2: methyl 4-flurobenzoate In tetrahydrofuran at 20℃; for 3h;
1.20 6.02.01.20 1,3-Bis-(4-fluoro-phenyl)-1,3-propanedione
6.02.01.20 1,3-Bis-(4-fluoro-phenyl)-1,3-propanedione 9.27 g KOtBu was added to 109 mg 18-Krone-6 and 5 mL 4-fluoracetophenone in 150 mL THF. After 30 min at RT 10.7 g 4-fluoro-benzoic acid methyl ester was added and stirred for 3 h at RT. The reaction was decomposed with water and filtered, the filtrate was concentrated and the residue was purified by chromatography on silica gel (cyclohexane/EE: 98:2). The solvent was removed and 3.9 g of the desired compound was obtained.
Stage #1: 1-(4-Fluorophenyl)ethanone With sodium hydride In tetrahydrofuran at 0℃; for 1h;
Stage #2: methyl 4-flurobenzoate In tetrahydrofuran at 0 - 20℃;
With sodium hydride In tetrahydrofuran; mineral oil at 20℃;
With sodium hydride In tetrahydrofuran at 0 - 20℃;
With sodium hydride In tetrahydrofuran at 0 - 20℃; for 4h; Inert atmosphere;
With sodium hydride In tetrahydrofuran; mineral oil at 0℃; Inert atmosphere; Reflux;
With C39H53ClN2P2Ru; potassium methanolate; hydrogen; In tetrahydrofuran; at 20℃; under 38002.6 Torr; for 16.0h;Glovebox; Autoclave;
General procedure: In a glove box, add a ruthenium complex Il (0.75 mg, 0.001 mmol),Potassium methoxide (3.5 to 70 mg, 0.05 to 1 mmol), tetrahydrofuran (1 to 10 mL), and ester compounds (0.5 to 10 mmol).After sealing the autoclave, remove it from the glove box and fill it with hydrogen to the required pressure.The reaction vessel was stirred at room temperature for 16 to 24 hours.After slowly releasing excess hydrogen, the reaction solution was depressurized to remove the solvent, and the residue was purified by a short column of silica gel to obtain an alcohol compound.The results are shown in Table 7.
With potassium carbonate; In dimethyl sulfoxide; at 130℃; for 18h;
Example 37a; (S)-N-(4-Aminobiphenyl-3-yl)-4-(3-aminopyrrolidin-l-yl)benzamide (327); Scheme 37; Step 1 : (SVMethyl 4-(3-aminopyrrolidin-l-v0benzoate (323); [0940] K2CO3 (7.71 g, 55.84 mmol) was added to a solution of (S)-pyrrolidin-3 -amine (5.0 g,58.04 mmol) and methyl 4-fluorobenzoate (8.6 g, 55.81 mmol) in DMSO (20 mL). The reaction mixture was stirred for 18 h at 130 0C in a sealed tube. The reaction mixture was cooled, diluted with AcOEt and H2O, and extracted with AcOEt (3 times). The extract was washed with water,NH4Cl and brine, dried over MgSO4, filtered and concentrated to give the title compound 323(7.98 g, 65% yield) as a pink solid.[0941] 1H NMR (DMSO-de) delta (ppm): 7.75 (d, J = 9.0 Hz, 2H), 6.52 (d, J = 9.0 Hz, 2H), 3.74(s, 3H), 3.60-3.55 (m, IH), 3.45-3.41 (m, 2H), 3.32-3.25 (m, IH), 2.97-2.93 (m, IH), 2.09-2.01(m, IH), 1.72-1.68 (m, IH). LRMS calc. 220.1; found 221.1 (MH)+.
With bismuth(lll) trifluoromethanesulfonate; dichloro bis(acetonitrile) palladium(II); oxygen; potassium carbonate; at 60℃; for 3.0h;Schlenk technique;
General procedure: To a 25-mL Schlenk tube equipped with a magnetic stirrer, PdCl2(CH3CN)2 (0.05mol, 5mol%), Bi(OTf)3 (0.05mol, 5mol%), K2CO3 (1mmol) were added. Substrates 1 (1mmol) and MeOH (2mL) were added subsequently. The reaction tube was vacuumed and backfilled with oxygen (3 times). Then the reaction mixture was stirred at 60C for 3h in the presence of an oxygen balloon. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. Subsequently, the combined organic layer was concentrated under reduced pressure and the crude product was purified by column chromatography with hexane/ethyl acetate to afford the corresponding products 2.
61%
With carbon tetrabromide; oxygen; at 20℃; for 20.0h;Irradiation;
General procedure: Typical procedure: A solution of 4-tert-butylbenzyl alcohol (1a, 0.3 mmol) and CBr4 (0.09 mmol) in dry MeOH (4 mL) in a pyrex test tube, purged with an O2-balloon, was stirred and irradiated externally with four 22 W fluorescent lamps for 20 h. The reaction mixture was concentrated in vacuo. Purification of the crude product by PTLC (toluene) provided methyl 4-tert-butylbenzoate (2a) (Rf = 0.40, 54.0 mg, 94%).
29%
With palladium 10% on activated carbon; oxygen; sodium carbonate; at 120℃; under 15001.5 Torr; for 1.5h;Microwave irradiation; Green chemistry;
General procedure: Na2CO3 (2 equiv) was dissolved in MeOH (1 mL) and sonicated with a US bath for 10 sec (20.3 kHz, 60 W). The substrate (aldehyde or alcohol, 1 mmol) and 10% Pd/C (5% Pd/mol of substrate) were added to this mixture. The reaction was carried out under magnetic stirring in a MW reactor Synth-Wave. The 1 L pressure-resistant PTFE cavity (up to 200 bar) equipped with a 15 position vial rack was loaded with O2 (2.5 bar) followed by the addition of N2 up to 20 bar total pressure. The reaction was irradiated for an appropriate reaction temperature ranging from 90 to 120 C (average power 300 W), and for 1 to 2 hours (see Table 2 and Table 3). The mixture was then filtered off through celite, the catalyst washed with MeOH and the solvent evaporated under vacuum. Isolated yields for all substrates reported were obtained using these conditions.
With sulfuric acid; bromine; silver sulfate; In water; at 0 - 20℃; for 24h;
Example 7; Methyl 9-(3,5-dichloro-4-pyridylcarbamoyl)-6-methoxydibenzo[6,«f]furan-2- carboxylate; Step 1: Methyl-(4-fluoro-3-Bromo) benzoate; EPO <DP n="36"/>Methyl-(4-fluoro) benzoate (28 g, 181.81 mmoles) was added to mixture sulphuric acid (93.63 ml) and water (1.6 ml) then bromine (8.4 ml, 163.63 mmoles) was added at O0C followed by addition of silver sulphate (51.02 g, 163.63 mmoles) .Reaction was stirred for 24 h. at room temperature. Reaction mass was poured in ice cold water (250 ml) and extracted with diethyl ether ( 100 x 3 ml) , dried and concentrated under reduced pressure to yield pale yellow liquid (36 g).1H nmr (300 MHz, DMSOd6): delta 3.86 (s, 3H), 7.54 (t, IH), 7.98-8.04 (m, IH), 8.19- 8.22 (dd, IH, J= 6.6 Hz).IR(KBr) cm4: 3098, 3052, 2847, 1727, 1599, 1507, 1492, 1436, 1389, 1282, 1226, 1107, 1048, 860, 763, 608.
With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 10.0h;
General procedure: Methyl 4-fluorobenzoate (4.6 g, 29.7 mmol) was dissolved in DMSO (20 mL), followed by the addition of K2CO3 (12.3 g, 89.1 mmol) and 1-ethylpiperazine (7.6 mL, 59.4 mmol). The mixture was heated to 110 C and stirred for 10 h before being cooled to room temperature and diluted with water (50 mL) and EtOAc (200 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using CH2Cl2-MeOH (10:1) to get 4a (6.4 g, 89.2%) as a yellow solid.
With potassium carbonate; In diethyl ether; water; acetonitrile; pentane;
A. 4-(4-Methyl-piperazin-1-yl)-benzoic acid methyl ester <strong>[403-33-8]4-Fluorobenzoic acid methyl ester</strong> (34 mmol), 1-methyl-piperazine (75 mmol) and potassium carbonate (34 mmol) are suspended in acetonitrile (30 ml) and stirred under reflux for three days. After evaporation of the solvent, the residue is dissolved in water and extracted three times with ethyl acetate. The extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with (CH2Cl2/MeOH=95:5) as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A pale yellow powder with mp. 117-119 C., Rf=0.20 (CH2Cl2/MeOH=95:5) is obtained.
With potassium carbonate; In dimethyl sulfoxide; at 110℃;
Weigh the raw material 5-1 (1eq) and the raw material5-2 (2eq) in a single-mouth bottle,Was dissolved with DMSO [dimethylsulfoxide], potassium carbonate (3 eq) was added,110 C overnight.After completion of the reaction, the reaction solution was cooled, poured into water, extracted three times with ethyl acetate,The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate,DCM [dichloromethane]: MeOH [methanol](Volume ratio) = 30: 1 to obtain compound 5-3.
1
A mixture of piperazine (6Og) in acetonitrile (200ml) was heated to a temperature of 75-8O0C (internal temperature) and then further heated to a temperature of 8O0C once the piperazine was in solution. The mixture was then treated with 4-fluoro-benzoic acid-methyl ester (2Og) within a period of 15 minutes. The reaction mixture was then stirred for about 20 hours. The reaction mixture was then cooled to a temperature of 4O0C and TBME (300ml) and water (200ml) were added at this temperature. Brine (100ml) was then added to the reaction mixture and the 2-phase mixture was stirred for approximately 5 minutes. The water phase was then extracted with TBME (100ml). The combined organic layers were then washed with a further solution of brine (2 x 100ml). The resulting organic phase may be used directly in the next step. GC: 14% of (V).
In acetonitrile for 24h; Heating / reflux;
3
Piperazine (696mmol) , 4-Fluorobenzoic acid methyl ester (1 29mmol) are suspended in Acetonitrile ( 200 ml) and refluxed 24h; the reaction mixture is transferred into TBME (t-Butylmethylether) and diluted brine . The organic phase is washed with brine; a solution with 168 mmol 4-(piperazin-1 -yl) benzoic acid methylester is concentrated at vacuo and TBME replaced by 370 ml acetone ; after addition of 218 mmol K2CO3 and 218 mmol n-propyliodide the reaction mixture is stirred 3h at 50°. After partial evaporation of acetone and replacement by TBME, the organic phase is washed with water and concentrated until 4-(4-propyl-piperazin-1 -yl) benzoic acid methylester cristallised; after filtration is obtained a colourless powder.NMR (CDCI3): 7.9 (d/ 2H), 6.9 (d/ 2H), 3.9 (s/3H), 3.4 (m/4H), 2.6 (m/ 4H), 2.4 (t/2H), 1 .6 (m/2H), 0.9 (t/3H).
In acetonitrile at 75 - 80℃; for 20h;
Synthesis of Methyl 4-(piperazin-1-yl)benzoate (3)
A mixture of piperazine 2 (60.00 g, 0.70 mol) in acetonitrile (200 mL) was heated to a temperature of75-80 °C. The mixture was then treated with 4-fluoro-benzoic acid-methyl ester 1 (20.00 g, 0.13 mol).After stirring for 20 h, the reaction mixture was cooled to room temperature, and diethyl ether (300mL) and water (200 mL) were added at this temperature. The aqueous layer was extracted with diethylether (200 mL×2). The combined organic layer was washed with brine (50 mL×2), dried over Na2SO4and concentrated to give 3 as a white solid without further purification.
With 40% KF/Al2O3 ;18-crown-6 ether; In dimethyl sulfoxide; at 120℃; for 48h;
A compound wherein a methyl group was introduced into the 5-position of the pyrazole ring of XO-TT469 was synthesized. A pyrazole, XO-TT485, was prepare by condensation reaction of 1-phenyl-1,3-butanedione and hydrazine. And a 4-phenylcarboxylic acid unit was introduced (the following scheme).; XO-TT486A; XO-TT485 (300 mg, 1.90 mmol) was dissolved in dimethyl sulfoxide (10 mL), and to the solution were added 40% potassium fluoride-alumina (600 mg), methyl 4-fluorobenzoate (492 mL, 3.80 mmol) and 18-crown-6 (100 mg, 0.380 mmol). The mixture was stirred at 120C for 2 days. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The residue was purified by column chromatography on silica gel (hexane : ethyl acetate = 10 : 1 to 5 : 1) to give XO-TT486A as a white solid (64.9 mg, 12% yield).
With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 10h;
Methyl 4-fluorobenzoate (4.6 g, 29.7 mmol) was dissolved in DMSO (20 mL), followed by the addition of K2CO3 (12.3 g, 89.1 mmol) and 1-ethylpiperazine (7.6 mL, 59.4 mmol). The mixture was heated to 110 C and stirred for 10 h before being cooled to room temperature and diluted with water (50 mL) and EtOAc (200 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using CH2Cl2-MeOH (10:1) to get 4a (6.4 g, 89.2%) as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 7.94 (d, J = 9.0 Hz, 1H), 6.89 (d, J = 9.0 Hz, 1H), 3.88 (s, 3H), 3.36-3.39 (m, 4H), 2.60-2.63 (m, 4H), 2.50 (q, J = 7.2 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H). ESI-MS (m/z): [M + H]+ = 249.0.
85.8%
With potassium carbonate; In dimethyl sulfoxide; at 120℃;Inert atmosphere;
Under nitrogen protection, 4-fluorobenzoic acid methyl ester (3.0 mL, 20.69 mmol) was dissolved in 20 mL DMSO,K2CO3 (5.718 g, 41.38 mmol) was added sequentially,<strong>[5308-25-8]N-ethylpiperazin</strong>e (1.93 mL, 24.83 mmol). 120 C overnight,The reaction was cooled to room temperature, and the mixture was partitioned between ethyl acetate and saturated brine (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with saturated sodium chloride,Dried over anhydrous sodium sulfate,The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane / methanol = 10/1) to obtain 4.405 g of a white solid, yield 85.8%.
68%
In dimethyl sulfoxide; at 25 - 120℃; for 18h;
1-Ethylpiperazine (3.68 mL, 29.0 mmol) was added to methyl 4-fluorobenzoate (1.50 mL, 11.6 mmol) in dimethylsulfoxide (29.0 mL) at 25 C. The resulting solution was stirred at 120 C. for 18 h. The reaction mixture was concentrated and diluted with EtOAc (50 mL) and water (20 mL). NaOH (2N aqueous solution, 20 mL) was added and the layers were separated and washed with EtOAc (40 mL). The organic layers were combined and washed with water (40 mL) and saturated brine (40 mL). The organic layer was dried over magnesium sulphate, filtered and evaporated to afford the desired product (1.960 g, 68%). This was used without further purification. 1H NMR (399.9 MHz, CDCl3) delta 1.06 (3H, t), 2.40 (2H, q), 2.52 (4H, t), 3.29 (4H, t), 3.79 (3H, s), 6.78-6.81 (2H, m), 7.83-7.86 (2H, m). MS: m/z 249 (MH+)
With potassium carbonate; In N,N-dimethyl acetamide; at 150℃;
Reference example 64; (1); To compound (1) (20.0g) and compound (2) (32.0g) in dimethylacetamide (90ml) was added potassium carbonate powder (27.6g) and the mixture was stirred at 150C overnight. After being cooled, to the mixture was added ethyl acetate, and the mixture was washed with water and saturated brine, and dried. After removal of the solvent, the residue was purified with silica gel column chromatography (chloroform:methanol=100:0?95:5) to give a yellowish orange solid. The solid was recrystallized from diisopropyl ether/hexane to give compound (3) (25.8g) as yellow crystals. Compound (3) was dissolved in 6N hydrochloric acid (120ml), and the solution was stirred under reflux for 9 hours. The reaction mixture was cooled and allowed to stand for 2 hours. The resulting crystals were taken by filtration, washed with a small amount of cold water and dried to give compound (4) (15.9g) as a pale yellow solid. APCI-MS (m/e): 235 (M+H)+
With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 10h;
General procedure: Methyl 4-fluorobenzoate (4.6 g, 29.7 mmol) was dissolved in DMSO (20 mL), followed by the addition of K2CO3 (12.3 g, 89.1 mmol) and 1-ethylpiperazine (7.6 mL, 59.4 mmol). The mixture was heated to 110 C and stirred for 10 h before being cooled to room temperature and diluted with water (50 mL) and EtOAc (200 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using CH2Cl2-MeOH (10:1) to get 4a (6.4 g, 89.2%) as a yellow solid.
24.1%
In N,N-dimethyl acetamide; at 100℃; for 40h;
1-Methyl-1,4-diazepane (15.07 g, 132.00 mmol) was added to methyl 4-fluorobenzoate (7.76 mL, 60 mmol) in DMA (150 mL). The resulting solution was stirred at 100 C. for 40 h. The reaction mixture was evaporated and quenched with 2M sodium hydroxide (50 ml). This was extracted with DCM (3×50 ml). The combined organic extracts were washed with saturated brine (50 ml), dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford methyl 4-(4-methyl-1,4-diazepan-1-yl)benzoate (3.59 g, 24.10%) as a tan waxy solid. 1H NMR (399.9 MHz, CDCl3) delta 1.95 (2H, q), 2.31 (3H, s), 2.48 (2H, d), 2.63-2.65 (2H, m), 3.47 (2H, t), 3.54-3.56 (2H, m), 3.78 (3H, s), 6.56-6.59 (2H, m), 7.79-7.83 (2H, m).
Stage #1: 2-Methyl-1H-benzimidazole With potassium carbonate In methylsulphoxide at 20℃; for 0.5h;
Stage #2: methyl 4-flurobenzoate In methylsulphoxide at 80℃; for 72h;
1.1
Step 1: A solution of 2-methylbenzimidazole (5.00 g, 37.68 mmol) in anhydrous methylsulfoxide in a pressure vessel at room temperature was treated with potassium carbonate (20.83 g, 150.72 mmol), stirred at room temperature for 0.5 h and treated with methyl-4-fluorobenzoate (14.62 mL, 113.03 mmol). The pressure vessel was sealed, allowed to heat at 80° C. for 72 h and cooled to room temperature. The vessel was unsealed and the reaction mixture was filtered. The filtrate was partitioned between dichloromethane and 5% aqueous citric acid. The organic phase was washed sequentially with 5% aqueous citric acid, saturated aqueous sodium bicarbonate, and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by ISCO CombiFlash chromatography (silica, 2.5-3.5% methanol/dichloromethane) to provide methyl 4-(2-methylbenzimidazol-1-yl)benzoate as an off-white solid, 5.72 g (57%), mp 153-154° C.; MS (ES) m/z 267.1 [M+H]+.
With potassium carbonate In dimethyl sulfoxide at 80℃; for 72h;
With potassium carbonate; In dimethyl sulfoxide; at 120 - 130℃;Inert atmosphere;
4-Chloro-3-(trifluoromethyl)phenol (1.19 g, 6.06 mmol), methyl 4-fluorobenzoate (0.934 g, 6.06 mmol) and potassium carbonate (2.51 g, 18.2 mmol) were stirred in dimethylsulfoxide (10 mL) at 120° C. overnight under an atmosphere of nitrogen. The temperature was then increased to 130° C. and the reaction mixture stirred for a further 17 hours. The reaction mixture was cooled to room temperature. Water (100 mL) was added and the mixture extracted with ethyl acetate (3.x.50 mL). The combined organic phase was washed sequentially with water (50 mL) and brine (50 mL), dried over magnesium sulphate, filtered and concentrated in vacuo to afford the title compound as a yellow oil (1.92 g, 96percent, contains residual dimethylsulfoxide). This material was taken on crude in subsequent steps.1HNMR (d6-DMSO): delta 3.82 (s, 3H), 7.18 (m, 2H), 7.42 (m, 1H), 7.60 (m, 1H), 7.78 (m, 1H), 8.00 (m, 2H).LCMS Rt=3.71 minutes MS m/z 331 [MH]+
With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h;
To a stirred solution of methyl 4-fluorobenzoate (2.0 g, 11.9 mmol) in dimethylformamide (5 mL) was added 3,4-dichlothiophenol (1.29 g, 11.8 mmol) and caesium carbonate (3.9 g, 12.0 mmol). The reaction mixture was heated at 50 C. for 16 hours, then diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The extracts were combined, washed with water (50 mL), brine (50 mL), dried over Na2SO4 and evaporated in vacuo to give the title compound (500 mg, 14%) which was used without further purification.LCMS Rt=3.08 minutes, MS m/z 297 [M-H]-1HNMR (400 MHz, DMSO): delta 7.33-7.40 (m, 3H), 7.68-7.73 (m, 2H), 7.89-7.92 (d, 2H), 13.05 (br s, 1H).
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 18h;
To a stirred solution of methyl 4-fluorobenzoate (500 mg, 3.24 mmol) in dimethylformamide (5 mL) was added 3-trifluoromethoxythiophenol (565 mg, 2.91 mmol) and caesium carbonate (1.38 g, 4.24 mmol). The reaction mixture was heated at 80 C. for 18 hours, then diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The extracts were combined, washed with water (3×30 mL), brine (2×30 mL), dried over Na2SO4 and evaporated in vacuo. The crude product was purified by silica gel column chromatography eluting with hexane:ethyl acetate (0-20%) to afford the title compound (300 mg, 35%).LCMS Rt=3.74 minutes, MS m/z 315 [MH]+
Stage #1: methyl 4-flurobenzoate With cesium fluoride In N,N-dimethyl-formamide for 0.166667h; Inert atmosphere;
Stage #2: N-trimethylsilylpyrrolidine In N,N-dimethyl-formamide at 60℃; for 110h;
5
Under a nitrogen atmosphere, 368 mg (2.42 mmol) of CsF, previously activated with sodium hydroxide, were suspended in 5 ml of DMF and stirred for 30 min. Then, 1.25 g (8.11 mmol) of 4-fluorobenzoic acid methyl ester were added. After 10 min 1.44 ml (8.25 mmol) of N-trimethylsilylpyrrolidine were added, and the mixture was stirred at 60° C. for 110 hr. For workup, most of the DMF was removed under vacuum (oil pump), and then 15 ml of water and 25 ml of dichloromethane were added to the reaction mixture. The organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed several times with water and dried over magnesium sulfate, and the solvent was removed under vacuum.Yield: 1.19 g (5.80 mmol, 72%), appearance: colorless crystalline solid. 1H NMR (CDCl3, 25° C., 400.13 MHz): δ=2.00-2.03 (m, 4H, H-8, H-9), 3.32-3.35 (m, 4H, H-7, H-10), 6.48-6.51 (m, 2H, H-3, H-5), 7.88-7.90 (m, 2H, H-2, H-6). 13C NMR (CDCl3, 25° C., 100.62 MHz): δ=25.6 (C-8, C-9), 47.7 (C-7, C-10), 51.4 (CH3), 110.9 (C-3, C-5), 116.8 (C-1), 131.5 (C-2, C-6), 151.1 (C-4), 167.7 (CO).
Example of General Method A: 10a-(4-fluorophenyl)- 1 -r(3-methyl- 1 ,2-oxazol-4-yl)carbonyll-2,3 , 10, 10a- tetrahydroimidazo \\2.1 -g] \\ 1.7 ] naphthyridin-5 ( 1 H) -one (4)Step 1: To generate LDA: To a chilled (ice-acetone bath) solution of diisopropylamine (5.1 mL, 36 mmol) in dry THF (30 mL) was added n-BuLi (1.45 M solution in hexanes, 24 mL, 35 mmol) drop-wise and under an atmosphere of nitrogen. The solution was stirred for 15 minutes before being added to a suspension of <strong>[4021-07-2]3-methylpyridine-2-carboxylic acid</strong> (1.5 g, 11 mmol) in THF (50 mL) drop-wise, at -78 °C and under an atmosphere of nitrogen. The dark purple mixture was stirred at - 78 °C for 30 minutes and then at -5 °C for 30 minutes. After this time the mixture was re-cooled to -78 °C and a solution of methyl 4-fluorobenzoate (1.6 mL, 12 mmol) in THF (15 mL) was added. The dark brown mixture was stirred at -78 °C for 1.5 hours and then at 0 °C for 2.5 hours. The mixture was then poured into chilled water (50 mL) and washed with ethyl acetate (3 x 35 mL). The aqueous layer was acidified to pH 2 with HC1 and extracted with ethyl acetate (3 x 75 mL). The three extracts were combined and concentrated in vacuo to yield 3-[2-(4-fluorophenyl)-2- oxoethyl]pyridine-2-carboxylic acid as a pale yellow solid (1.5 g, 53percent yield). ESI- MI m/z [M+H]+ 259.95. LH NMR (400 MHz, DMSO) delta 8.61 (dd, J= 4.7, 1.6 Hz, 1H), 8.14 (dd, J= 8.9, 5.5 Hz, 2H), 7.86 (dd, J= 7.8, 1.6 Hz, 1H), 7.62 (dd, J= 7.7, 4.7 Hz, 1H), 7.40 (t, J= 8.9 Hz, 2H), 4.78 (s, 2H).
With copper(I) trifluoromethanesulfonate bis(trimethylacetonitrile) complex; 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate In ethyl acetate at 80℃; for 12h; Inert atmosphere; Glovebox;
In dimethyl sulfoxide; at 150℃; for 4h;Inert atmosphere; Microwave irradiation;
Production Example 8-1 Methyl 4-(4-(pyrrolidin-1-yl)piperidin-1-yl)benzoate Commercially available methyl 4-fluorobenzoate (1.5 g, 9.73 mmol) was added to a solution of commercially available <strong>[5004-07-9]4-(1-pyrrolidinyl)piperidine</strong> (3.0 g, 19.5 mmol) in dimethylsulfoxide (15 mL) at room temperature and then the mixture was stirred under nitrogen atmosphere and under irradiation with microwave at 150 C. for 4 hours. The reaction liquid was allowed to stand to cool to room temperature and then diluted with water and ethyl acetate. The organic layer was washed with water and then dried by a conventional method. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The residue was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=1:1) to obtain the title compound (2.06 g, 73%). 1H-NMR Spectrum (CDCl3) delta (ppm): 1.54-1.70 (2H, m), 1.74-1.88 (4H, m), 1.93-2.06 (2H, m), 2.12-2.26 (1H, m), 2.53-2.65 (4H, m), 2.90 (2H, td, J=12.4, 2.6 Hz), 3.74-3.97 (5H, m), 6.86 (2H, d, J=9.2 Hz), 7.89 (2H, d, J=9.2 Hz).
INTERMEDIATE 7 Methyl 4-(3 -iodo- 1 H-p yrazol- 1 -yPbenzoate To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (0.7 g, 3.61 mmol) in DMSO (18.0 mL) was added sodium hydride (60% disp. in oil (0.173 g, 4.33 mmol), and the resulting mixture was stirred for 0.5 h before adding methyl 4- fluoro benzoate (0.556 g, 3.61 mmol). The reaction mixture was stirred at 90 C overnight. The reaction was quenched by the addition of water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgS04 and concentrated in vacuo. The crude mixture was purified by flash chromatography (ISCO, 40 g, 0-20 % EtOAc in hexanes) to afford methyl 4-(3-iodo-lH-pyrazol-l-yl)benzoate, as a white solid. LCMS calc. - 328.97; found = 328.96 (M+H)+. NMR (500 MHz, CDC13): delta 8.12 (m, 2 H); 7.81 (d, J= 2.4 Hz, 1 H); 7.76 (m, 2 H); 6.65 (m, 1 H); 3.94 (s, 3 H).
With lithium hydroxide monohydrate; silver trifluoromethanesulfonate; Selectfluor In ethyl acetate at 55℃; Sealed tube;
16 General procedure for the silver-mediated fluorination of potassium aryl and heteroaryl trifluoroborates with Selectfluor (Table 4)
General procedure: Trifluoroborate (0.50 mmol, 1.0 equiv), LiOH·H2O (25.2 mg, 0.60 mmol, 1.2 equiv), Selectfluor (212 mg, 0.60 mmol, 1.2 equiv), AgOTf (386 mg, 1.5 mmol, 3.0 equiv) were weighed into a 20 mL microwave vial. EtOAc (5 mL) was added, and sealed with a microwave cap and the mixture was allowed to stir at 55 °C for 5-15 h. The resulting solution was cooled to room temperature. For the compounds reported with isolated yields (2a, 2b, 2c, 2d, 2e, 2g, 2h, 2j, 2k, 2l, 2m, 2o, 2p, 2t, 2u, 2x, 2v, 2y, 2ab, 2ac, and 2ag) the reaction mixture was diluted with MTBE or hexane (5 mL) and H2O (4.0 mL). Then organic phase was separated, the aqueous phase was extracted with MTBE (2*5 mL). The combined organic phases were dried over anhydrous Na2SO4. The filtrate was concentrated in rotavapor and the residue was purified by column chromatography on Combiflash with hexanes/EtOAc to afford the desired compounds. The volatile and low yielding products were not isolated and their yields were determined only by 19F NMR of the reaction mixture. For the compounds reported with 19F NMR yields, 4-fluorobenzonitrile (0.50 mmol) was added as reference to the reaction mixture, stirred for 5 min, and then diluted with MTBE or hexane (5 mL) and H2O (3.0 mL). The layers were separated and an an aliquote of the organic phase was withdrawn for the 19F NMR measurement in CDCl3.
With iodine; aluminium In acetonitrile at 80℃; for 18h;
75%
With high-silica Hβ-75 zeolite In water at 130℃; for 24h;
2.4. Catalytic tests
General procedure: The heterogeneous catalysts, stored under ambient conditions,were used for catalytic reactions without any pretreatment. Typically,ester (1 mmol), 1 mL H2O and 10 mg of catalysts and a magneticstarter bar were added to a reaction vessel (Pyrex pressuretube, 13 mL), and the mixture was heated at 130 °C under air withstirring at 300 rpm. For the catalytic tests in Table 1 and kineticstudy, conversions and yields were determined by GC-FID usingn-dodecane as an internal standard as follows. After completionof the reaction, acetone (7 mL) was added to the mixture, andthe catalyst was separated by centrifugation. Then, n-dodecane(0.2 mmol) was added to the reaction mixture, and the mixturewas analyzed by GC-FID and GC-MS. The GC-FID sensitivities ofthe products were determined using commercial carboxylic acidsor the isolated products after the reaction. For some of the productsin Tables 2 and 3, we determined isolated yields of the carboxylicacids as follows. After the filtration of the catalyst, followed bywashing the catalyst with acetone (6 mL), and by evaporation,the product was isolated by column chromatography using silicagel 60 (spherical, 63-210 μm, Kanto Chemical Co. Ltd.) with hexane/ethyl acetate (60/40-80/20) as the eluting solvent, followedby analyses by 1H NMR, 13C NMR and GC-MS equipped with thesame column as GC-FID.
methyl 4-([2-[2-(2-hydroxyethoxy)ethoxy]ethyl]amino)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 130℃; for 12h;
Into a 25-mL round-bottom flask, was placed methyl 4-fluorobenzoate (500.0 mg, 3.24 mmol, 1.00 equiv), NMP (10 mL), potassium carbonate (894.24 mg, 6.47 mmol, 2.00 equiv), 2-[2-(2-aminoethoxy)ethoxy]ethan-1-ol (580.0 mg, 3.89 mmol, 1.20 equiv). The resulting solution was stirred 12 h at 130C in an oil bath. The resulting solution was extracted with ethyl acetate (50 mL x 3) and the organic layers combined. The resulting mixture was washed with brine (50 mL x 3). The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (9/1). This resulted in 300.0 mg (33%) of methyl 4-([2-[2-(2-hydroxyethoxy)ethoxy]ethyl]amino)benzoate as light yellow oil. LC-MS (ES+): m/z 284,05[MH+]
With potassium carbonate In dimethyl sulfoxide at 110℃; for 10h;
Methyl 4-(4-ethylpiperazin-1-yl)benzoate (4a)
General procedure: Methyl 4-fluorobenzoate (4.6 g, 29.7 mmol) was dissolved in DMSO (20 mL), followed by the addition of K2CO3 (12.3 g, 89.1 mmol) and 1-ethylpiperazine (7.6 mL, 59.4 mmol). The mixture was heated to 110 °C and stirred for 10 h before being cooled to room temperature and diluted with water (50 mL) and EtOAc (200 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using CH2Cl2-MeOH (10:1) to get 4a (6.4 g, 89.2%) as a yellow solid.
With oxone; Ru(MesCO2)(4,4'-dibromobipyridine)(p-cymene); trifluoroacetic acid; trifluoroacetic anhydride; In 1,2-dichloro-ethane; at 110℃; for 8h;Sealed tube; Green chemistry;
General procedure: The Ru(MesCO2)(L) (p-cymene) [L- 2,2?-bypyridine or 4,4?-dibromobipyridine] (2.5 mol%), oxidant (2.0 eq) and ester (1.0 eq) were added to a sealed tube. Following that, trifluoroacetic acid (TFA) and trifluoroacetic anhydride (TFAA) in the ratio of 0.6 ml: 0.4 were added. The reaction mixture was kept on a pre-heated bath at 110C and stirred until its completion. It was continuously monitored by TLC. Ice water was added to quench the reaction mixture and it was extracted with dichloromethane. The organic layer was dried over Na2SO4 and rota-evaporated. Finally the residue was purified by silica gel column chromatography to give corresponding products.
With sodium hexamethyldisilazane; In tetrahydrofuran; toluene; at -5 - 0℃;Large scale;
Methyl 4-fluorobenzoate (29.44 kg), toluene (177 L) and acetonitrile (59 L; 5.9 mol equivalents versus methyl 4-fluorobenzoate) were charged to the reactor. The mixture was cooled to a temperature of -5 / 0 C. A solution of sodium bis (trimethylsilyl) amide (NaHMDS 40% in THF) (192 L; 2 mol / mol vs. methyl 4-fluorobenzoate) was added while maintaining the temperature between -5 / + 5 C. The addition line was washed off with toluene (9 L). The reaction mixture was quenched by adding dilute hydrochloric acid while maintaining the temperature of -5 / + 25 C. The addition of acid was continued until pH <5. The layers separated and the lower aqueous layer was removed. The solvent was removed by vacuum distillation to a small amount. Toluene (59 L) was added and the mixture was heated to 85/90 C. to give a solution. The mixture was cooled to T = 50/55 C. and n-heptane (29 L) was added to obtain a precipitate. The mixture was further cooled to T = 20/25 C. and the solid product was isolated by filtration and washed with n-heptane (59 L). The product in the moist state was dried under vacuum at T = 40/45 C. to give 4-fluorobenzoylacetonitrile (26 kg, yield 83%) of purity 98.7% A% GC. The amount of 4-methoxybenzoylacetonitrile as an impurity was 0.03% (A% GC).
With sodium hydride; In tert-butyl methyl ether; water; at 90℃;
Methyl 4-fluorobenzoate (50 g)Was added to a suspension of sodium hydride in methyl-tert-butyl ether (MTBE)(2 eq.) At 90 C.4-fluorobenzoylacetonitrile was obtained in about 64% yield.4-fluorobenzoic acid with a purity of 81%, 17.5%4-methoxybenzoylacetonitrile was about 3%
2-(2-chloropyridin-3-yl)-1-(4-fluorophenyl)ethan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.45 g
At -78 C., 19.6 ml of 1.9 mol/L solution of hexamethyldisilazane sodium in THF was added dropwise to 100 ml of THF solution containing 2.00 g of <strong>[61494-55-1]2-<strong>[61494-55-1](2-chloropyridin-3-yl)acetic acid</strong></strong>, and the mixture was stirred for 10 minutes. Next, 1.50 ml of methyl p-fluorobenzoate was added dropwise. The mixture was then brought from -78 C. to room temperature and was stirred for 1 hour. Saturated aqueous ammonium chloride solution was added thereto, and the mixture was stirred. Thereafter, ethyl acetate was added, and the resultant liquid mixture was separated. The obtained organic layer was washed with saturated brine and was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel column chromatography. The title compound was obtained as a colorless amorphous compound weighing 1.45 g. 1H-NMR(CDCl3)delta:8.36(1H,dd,J=4.6,1.9 Hz),8.11-8.07(2H,m),7.62(1H,dd,J=7.4,1.9 Hz),7.27-7.24(1H,m),7.21-7.17(2H,m),4.42(2H,s).
Stage #1: 2,5-Dihydroxyacetophenone With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 10℃; for 3h; Inert atmosphere;
Stage #2: methyl 4-flurobenzoate In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;
5.2 General procedure for the synthesis of 12a-e
General procedure: A solution of LiHMDS in THF (1M, 4 equiv) was added to a well-stirred solution of 2,5-dihydroxyacetophenone (9, 1 equiv) in anhydrous THF (20mL) under argon at-78°C over 15min. The reaction mixture was stirred at-78°C for 1h and at-10°C for 2h and was cooled again to-78°C, and a solution of 10a-e (1 equiv) in THF (5mL) was added in one portion. The mixture was stirred at-78°C for 1h and at room temperature overnight. The reaction mixture was poured into a mixture of ice and neutralized with conc. HCl (6.5mL) and extracted with dichloromethane. The combined organic layer was washed with brine and dried over sodium sulfate, filtered, and evaporated to give crude 11a-e. Crude 11a-e were dissolved in glacial acetic acid (20mL) and concentrated sulfuric acid (0.2mL). The reaction was stirred at room temperature for 4h. H2O (20mL) was added to the reaction mixture, and the resulting solid was filtered, washed with water, and dried to afford 12a-e.
Stage #1: di-<i>tert</i>-butyl dicarbonate; 2-(4-fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane With 4,4'-dimethyl-2,2'-bipyridines; lithium methanolate; copper(l) chloride In N,N-dimethyl acetamide at 30℃; for 6h; Inert atmosphere; Schlenk technique;
Stage #2: methyl iodide In N,N-dimethyl acetamide at 30℃; for 2h; Schlenk technique;
Methyl (Het)arylcarboxylates 3a-y, 5a-e; General Procedure
General procedure: A 15 mL Schlenk tube equipped with a stirrer bar was chargedwith CuCl (10 mol%), L7 (13 mol%), LiOMe (2.5 equiv), and theappropriate boronic ester 1 or 4 (0.375 mmol). The vessel wasthen evacuated and filled with Ar (three cycles). DMA (0.5 mL)and (Boc)2O (0.25 mmol) were added sequentially under Ar, andthe mixture was stirred at 30 for 6 h. MeI (5 equiv) was thenadded in air, and the mixture was stirred at 30 for additional2 h. The mixture was finally diluted with EtOAc and washedwith sat. aq NaCl (20 mL). The aqueous phase was furtherextracted with EtOAc (3 × 20 mL), and the combined organicphases were dried (Na2SO4) and concentrated. The residue waspurified by column chromatography [silica gel EtOAc-hexane(1:100 to 1:50)].
With potassium carbonate In N,N-dimethyl-formamide Inert atmosphere; Heating;
21
Intermediate 68 (1.0g, 1.0eq.), intermediate 20 (1.8g, 1.0eq.),Potassium carbonate (1.3g, 1.5eq) was dissolved in 10mL of anhydrous N,N-dimethylformamide, protected by argon, heated to 90°C and reacted overnight.TLC detects that the raw material has reacted completely, the reaction solution is concentrated, and purified by column chromatography (V petroleum ether/V ethyl acetate=4/1) to obtain 1.1 g of white solid with a yield of 39%.
With potassium phosphate; palladium diacetate; tricyclohexylphosphine In water; toluene at 100℃; for 12h; Inert atmosphere;
2.1 Preparation of substrates (3c-3p)
General procedure: The substrates from 3c to 3p were prepared according to the published procedures.1, 2 A flame-dried three-neck flask equipped with a stir bar and a reflux condenser was added with substituted bromobenzene (8.95 mmol), cyclopropylboronic acid (1.00 g, 11.6 mmol), and K3PO4 (6.5 g, 31.3 mmol) in toluene (30 mL) and H2O (2 mL) under N2. After the mixture was stirred, 10 wt. % solution of PCy3 in toluene (2.5 mL, 1.8 mmol) was then added via syringe, followed by Pd(OAc)2 (0.101 g, 0.45 mmol). The reaction mixture was heated to 100 oC overnight. After removing from heat, the reaction mixture was diluted with H2O and extracted into EtOAc. The combined organic layers were washed with brine, dried with NaSO4, filtered through Celite, and concentrated. Arylcyclopropane products were purified via column chromatography.
Stage #1: toluene With cesium sulfate; lithium hexamethyldisilazane In 2-methyltetrahydrofuran at 110℃; for 4h; Inert atmosphere; Sealed tube;
Stage #2: methyl 4-flurobenzoate In 2-methyltetrahydrofuran at 50℃; for 4h; Inert atmosphere; Sealed tube;
With potassium carbonate In dimethyl sulfoxide at 130℃;
8 Example 8. Preparation of 4-((2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl) amino) pyridin-3-yl) (Methyl) Amino) Ethyl) (Methyl) amino)-N-hydroxybenzamide (Compound 8)
Compound 8a (1.0 g, 6.49 mmol) and compound 8b (1.14 mg, 12.98 mmol) were dissolved in DMSO (10 mL) followed by the addition of anhydrous K2CO3 (2.69 g, 19.47 mmol). The reaction mixture was stirred at 130° C. overnight. The reaction was monitored by TLC. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by SO2 column chromatography (CH2Cl2:MeOH=20:10) to afford compound 8c (1.0 g, yield 70%) as a colorless oil. MS m/z 223.1 [M+H]+.
70%
With potassium carbonate In dimethyl sulfoxide at 130℃;
8 Example 8. Preparation of 4-((2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl) amino) pyridin-3-yl) (Methyl) Amino) Ethyl) (Methyl) amino)-N-hydroxybenzamide (Compound 8)
Compound 8a (1.0 g, 6.49 mmol) and compound 8b (1.14 mg, 12.98 mmol) were dissolved in DMSO (10 mL) followed by the addition of anhydrous K2CO3 (2.69 g, 19.47 mmol). The reaction mixture was stirred at 130° C. overnight. The reaction was monitored by TLC. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by SO2 column chromatography (CH2Cl2:MeOH=20:10) to afford compound 8c (1.0 g, yield 70%) as a colorless oil. MS m/z 223.1 [M+H]+.
70%
With potassium carbonate In dimethyl sulfoxide at 130℃;
8 Example 8. Preparation of 4-((2-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl) amino) pyridin-3-yl) (Methyl) Amino) Ethyl) (Methyl) amino)-N-hydroxybenzamide (Compound 8)
Compound 8a (1.0 g, 6.49 mmol) and compound 8b (1.14 mg, 12.98 mmol) were dissolved in DMSO (10 mL) followed by the addition of anhydrous K2CO3 (2.69 g, 19.47 mmol). The reaction mixture was stirred at 130° C. overnight. The reaction was monitored by TLC. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by SO2 column chromatography (CH2Cl2:MeOH=20:10) to afford compound 8c (1.0 g, yield 70%) as a colorless oil. MS m/z 223.1 [M+H]+.
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