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CAS No. :1255099-13-8 MDL No. :MFCD17926442
Formula : C11H10O2 Boiling Point : -
Linear Structure Formula :- InChI Key :IJWDCLWLOGCXOQ-UHFFFAOYSA-N
M.W : 174.20 Pubchem ID :53403239
Synonyms :

Safety of [ 1255099-13-8 ]

Signal Word:Warning Class:
Precautionary Statements:P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501 UN#:
Hazard Statements:H302-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 1255099-13-8 ]

* 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.

  • Downstream synthetic route of [ 1255099-13-8 ]

[ 1255099-13-8 ] Synthesis Path-Downstream   1~51

  • 1
  • [ 90347-66-3 ]
  • [ 1066-54-2 ]
  • methyl 3-ethynyl-4-methylbenzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; at 20℃; Under protective gas A-Ia (0.2 g, 0.724 mmol) together with bis-triphenylphosphine- palladium dichloride (25.4 mg, 0.036 mmol) and copper(I)iodide is added to abs. THF (3 mL) and triethylamine (1 mL). Trimethylsilyl-ethyne is added at RT to this reaction mixture and stirred overnight. For working up it is diluted with EE, poured onto 0.5 M ammonia solution and the aqueous phase is again extracted with EE. The combined organic phases are washed with 0.5 M hydrochloric acid and saturated NaCl solution, extracted again with EE, dried on sodium sulphate, filtered and evaporated down under reduced pressure.The residue is combined with methanolic KOH (1 mL) and stirred for 2 h at RT. The reaction mixture is diluted with EE, poured onto 5 % NaHCO3 solution and extracted twice <n="32"/>with EE. The combined organic phases are washed with saturated sodium chloride solution, dried on sodium sulphate, filtered and evaporated down under reduced pressure. Chromatographic purification through a short silica gel frit yields A-2a (HPLC-MS: tRet. = 3.65 min; MS (M+H)+ = 175).
With copper(l) iodide; bis(triphenylphosphine)palladium(II) chloride; triethylamine; In tetrahydrofuran; at 20℃;Inert atmosphere; <strong>[90347-66-3]Methyl 3-iodo-4-methylbenzoate</strong> (0.2 g. 0.724 mmol) was added with bis-triphenylphosphine-palladium dichloride (25.424 mg, 0.036 mmol) and copper (1) iodide in absolute THF (3 mL) and triethylamine (1 mL) under inert gas. Thereafter, trimethylsilyl-ethyne was added at RT and the mixture was stirred overnight. For working up, the mixture was diluted with ethyl acetate, poured onto 0.5M ammonia solution and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with 0.5M hydrochloric acid and saturated sodium chloride solution, again extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was added with methanolic KOH (1 mL) and stirred for 2 hours at RT. The reaction mixture was diluted with ethyl acetate, poured onto 5% NaHCO3 solution and extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 3-ethynyl-4-methylbenzoic acid.
  • 2
  • [ 1255099-13-8 ]
  • [ 1001203-03-7 ]
YieldReaction ConditionsOperation in experiment
98.87% With water; lithium hydroxide In tetrahydrofuran; methanol at 60℃; for 2h; 12.4 Step 4. Synthesis 3-ethynyl-4-methylbenzoic acid (8D) To a stirred solution of methyl 3-ethynyl-4-methylbenzoate(3.30 g, 18.944 mmol, 1.00 equiv), CH3OH(10.00 mL, 246.989 mmol, 13.04 equiv), H2O(30.00 mL, 1665.251 mmol, 87.90 equiv) in THF(40.00 mL, 493.720 mmol, 26.06 equiv) was added LiOH(2.27 g, 94.719 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred for 2h at 60 C. The resulting mixture was extracted with EtOAc (3 x100 mL). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3-ethynyl-4-methylbenzoic acid (8D) (3g,98.87%) as a Brown yellow solid.
87.2% With sodium hydroxide In methanol; water at 20℃; 20.4 Preparation of 3-ethynyl-4-methylbenzoic acid Step 4: Preparation of 3-ethynyl-4-methylbenzoic acid The product obtained in the previous step was dissolved in methanol, and to the solution 10 mL saturated sodium hydroxide aqueous solution was added, and the solution afforded was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, and to the solution about 20 mL water was added. The pH was adjusted to about 3 with hydrochloric acid. Then a large amount of white solid was precipitated and the solution was extracted with DCM 3 times. The DCM layer combined was washed with water once, dried anhydrous sodium sulfate, and the product was evaporated to dryness to afford the product 3-ethynyl-4-methylbenzoic acid as a light yellow solid (8.0 g, total yield 87.2%). 1H NMR (400 MHz, DMSO-d6) δ 13.04 (br.s, 1H), 7.93 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 4.48 (s, 1H), 2.45 (s, 3H). MS m/z (ESI): 159.0 [M-H].
29% With lithium hydroxide In tetrahydrofuran; water at 20℃; for 2h; INTERMEDIATE 39 3-ethynyl-4-methylbenzoic acid Intermediate 39 (700 mg, 4.0 mmol) and LiOH monohydrate (512 mg, 11.9 mmol) were dissolved in THF:H2O (10 mL, 1:1) and the reaction stirred at rt for 2 h. A further portion of LiOH monohydrate (512 mg, 11.9 mmol) was added and the reaction stirred at room temperature for 3d. The THF was removed in vacuo and the residue acidified with 1M HCl. The product was extracted with EtOAc (4 x 50 mL), dried (MgSO4) and concentrated in vacuo to give 3-ethynyl-4-methylbenzoic acid (200 mg, 29 %) as a light brown solid. LC- MS (Method I) 2.27 min, no ionisation observed.
29% With lithium hydroxide monohydrate; water In tetrahydrofuran at 20℃; 3-Ethynyl-4-methyl-benzoic acid Intermediate 50 (700mg, 4.0mmol) and LiOH monohydrate (512mg, 11.9mmol) were dissolved in THF:H2O (10mL, 1 :1) and the reaction stirred at rt for 2h. A further portion of LiOH monohydrate (512mg, 11.9mmol) was added and the reaction stirred at rt for 3d. The THF was removed in vacuo and the residue acidified with 1 M HCI. The product was extracted with EtOAc (4x50mL), dried (MgSO4) and concentrated in vacuo to give the title compound (200mg, 29%) as a light brown solid. LC-MS (Method F) 2.27 min, no ionisation observed.
29% With lithium hydroxide monohydrate; water In tetrahydrofuran at 20℃; 3-Ethynyl-4-methyl-benzoic acid Intermediate 50 (700mg, 4.0mmol) and LiOH monohydrate (512mg, 11.9mmol) were dissolved in THF:H2O (10mL, 1 :1) and the reaction stirred at rt for 2h. A further portion of LiOH monohydrate (512mg, 11.9mmol) was added and the reaction stirred at rt for 3d. The THF was removed in vacuo and the residue acidified with 1 M HCI. The product was extracted with EtOAc (4x50mL), dried (MgSO4) and concentrated in vacuo to give the title compound (200mg, 29%) as a light brown solid. LC-MS (Method F) 2.27 min, no ionisation observed.
With methanol; potassium hydroxide at 20℃; for 2h; A-2a Under protective gas A-Ia (0.2 g, 0.724 mmol) together with bis-triphenylphosphine- palladium dichloride (25.4 mg, 0.036 mmol) and copper(I)iodide is added to abs. THF (3 mL) and triethylamine (1 mL). Trimethylsilyl-ethyne is added at RT to this reaction mixture and stirred overnight. For working up it is diluted with EE, poured onto 0.5 M ammonia solution and the aqueous phase is again extracted with EE. The combined organic phases are washed with 0.5 M hydrochloric acid and saturated NaCl solution, extracted again with EE, dried on sodium sulphate, filtered and evaporated down under reduced pressure.The residue is combined with methanolic KOH (1 mL) and stirred for 2 h at RT. The reaction mixture is diluted with EE, poured onto 5 % NaHCO3 solution and extracted twice with EE. The combined organic phases are washed with saturated sodium chloride solution, dried on sodium sulphate, filtered and evaporated down under reduced pressure. Chromatographic purification through a short silica gel frit yields A-2a (HPLC-MS: tRet. = 3.65 min; MS (M+H)+ = 175).
With potassium hydroxide In methanol at 20℃; for 2h; 3-ethynyl-4-methylbenzoic acid Methyl 3-iodo-4-methylbenzoate (0.2 g. 0.724 mmol) was added with bis-triphenylphosphine-palladium dichloride (25.424 mg, 0.036 mmol) and copper (1) iodide in absolute THF (3 mL) and triethylamine (1 mL) under inert gas. Thereafter, trimethylsilyl-ethyne was added at RT and the mixture was stirred overnight. For working up, the mixture was diluted with ethyl acetate, poured onto 0.5M ammonia solution and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with 0.5M hydrochloric acid and saturated sodium chloride solution, again extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was added with methanolic KOH (1 mL) and stirred for 2 hours at RT. The reaction mixture was diluted with ethyl acetate, poured onto 5% NaHCO3 solution and extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 3-ethynyl-4-methylbenzoic acid.
96 % With lithium hydroxide In tetrahydrofuran; methanol; water at 60℃; 3 Step 3: Preparation of 3-ethynyl-4-methylbenzoic acid (compound 4) 400mg (2.29mmol) of compound 3 was dissolved in a mixed solvent of tetrahydrofuran, methanol and water with a volume ratio of 10:1:5, then 482mg (11.4mmol) of lithium hydroxide hydrate was added, and stirred at 60°C for 1 hour. Filter and spin dry the reaction system, then add 4M hydrochloric acid solution until the system is acidic, at this time a white solid precipitates, the white solid is collected by filtration and dried to obtain 350 mg of white solid (yield 96%).
96 % With lithium hydroxide monohydrate; water In tetrahydrofuran; methanol at 60℃; 3 Step 3: Preparation of 3-ethynyl-4-methylbenzoic acid (compound 4) 400mg (2.29mmol) of compound 3 was dissolved in a mixed solvent of tetrahydrofuran, methanol and water with a volume ratio of 10:1:5, then 482mg (11.4mmol) of lithium hydroxide hydrate was added, and stirred at 60°C for 1 hour. Filter and spin dry the reaction system, then add 4M hydrochloric acid solution until the system is acidic, at this time a white solid precipitates, the white solid is collected by filtration and dried to obtain 350 mg of white solid (yield 96%).

  • 3
  • [ 79476-07-6 ]
  • [ 1255099-13-8 ]
  • [ 1388805-30-8 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; 2 Reference Example 24-Methyl-3-[(quinolin-3-yl)ethynyl]benzoic acidA mixture of methyl 3-ethynyl-4-methylbenzoate (0.341 g, 2mmol), 3-iodoquinoline (0.5g, 2mmol), Pd(PPh3)4 (0.1 lg, O.Olmmol), Cul (0.179g, O.lmmol) and diisopropylethylamine (0.5ml, 3mmol) in DMF (15ml) was stirred at ambient temperature for 12hrs under an atmosphere of nitrogen. The reaction mixture was concentrated and the crude product was purified by flash chromatography on silica gel (elution with 10% ethyl acetate in n- hexane) to provide methyl 4-methyl-3-[(quinolin-3-yl)ethynyl]benzoate.Sodium hydroxide (0.15g, 3.71mmol) was added to a solution of the above methyl ester in methanol (20ml) and water (3ml) and stirred at 50°C for 3hrs and then concentrated in vacuo. Water (10ml) was added to the residue, adjusted pH to 4.0-4.5 with citric acid. The solid obtained was filtered, washed successively with water and diethyl ether and dried at ambient temperature to obtain 4-methyl-3-[(quinolin-3-yl)ethynyl]benzoic acid. ¾ NMR (500 MHz in DMSO-de), δ 2.66 (s, 3H), 7.56 (d, J = 8.0 Hz, 1H), 7.75 (t, J; = 15.1 Hz, J2 = 8.2 Hz, 1H), 7.89 (t, J} = 13.7 Hz, J2 = 8.5 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 8.17 (s, 1H), 8.75 (s, 1H), 9.1 1 (s, 1H), 12.84 (s, 1H).
  • 5
  • [ 1388805-29-5 ]
  • [ 1255099-13-8 ]
YieldReaction ConditionsOperation in experiment
98% With water; potassium hydroxide In methanol at 20℃; for 0.5h;
97.24% With potassium carbonate In methanol at 20℃; for 2h; 12.3 Step 3. Synthesis of Methyl 3-ethynyl-4-methylbenzoate (8C) To a stirred solution of methyl 4-methyl-3-[2- (trimethylsilyl)ethynyl]benzoate(4.80 g, 19.482 mmol, 1.00 equiv) in MeOH (40.00 mL) was added K2CO3(13.41 g, 97.020 mmol, 4.98 equiv) at room temperature. The resulting mixture was stirred for 2h. The resulting mixture was filtered; the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure.This resulted in methyl 3- ethynyl-4-methylbenzoate (8C) (3.3g,97.24%) as a yellow solid.
90% With methanol; potassium carbonate at 20℃; for 0.0833333h;
87% With lithium hydroxide In tetrahydrofuran; methanol; water at 20℃; for 10h; 2 Step 2: 4-Methyl-3-((trimethylsilyl)ethynyl)benzoic acid methyl ester (2.3g) in tetrahydrofuran (10mL), methanol (10mL) and water (2mL) are added to a mixed solution of hydration Lithium hydroxide (0.6g, 15mmol), stirred at room temperature for 10 hours, extracted with ethyl acetate, adjusted the pH of the aqueous phase to 2-3, a large amount of solids precipitated out, filtered to obtain 1.3g of white solid product, the yield was 87%.
76.1% With potassium fluoride In methanol at 20℃; 1 Methyl 3-ethynyl 4-methylbenzoate Methyl 4-methyl-3- ((trimethylsilyl) ethynyl) benzoate (95 g, 0.386 mol) and potassium fluoride(67.2g, 1.158mol) was dissolved in 1000mL of methanol with stirring, stirred at room temperature overnight. Concentration to dryness, purification of the crude by column chromatography (ethyl acetate / petroleum ether = 1: 50) afforded the title compound (51 g, 76.1%) as a yellow solid.
With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 0.25h; 1 Reference Example 1Methyl 3-ethynyl-4-methylbenzoateA mixture of methyl 3-iodo-4-methylbenzoate (2.0g, 7mmol), trimethylsilylacetylene (1.2ml, 8mmol), Pd(PPh3)4 (0.42g, 0.3mmol), Cul (0.137g, 0.7mmol) and diisopropylethylamine (2.5ml, 1 1.4mmol) in THF (20ml) was heated at 50°C for 12hrs under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and filtered through a Celite bed. The clear filtrate was concentrated and the residue purified by flash chromatography on silica gel (elution with 2% ethyl acetate in n-hexane) to provide methyl 4-methyl-3-[(trimethylsilyl)ethynyl]benzoate.To the solution of methyl 4-methyl-3-[(trimethylsilyl)ethynyl]benzoate (2.3g) in THF (40ml) was added tetrabutylammonium fluoride (1.0M in THF, 3.2ml, 1 lmmol) at ambient temperature and stirred for 15 minutes, concentrated and the residue purified by flash chromatography on silica gel (elution with 2% ethyl acetate in «-hexane) to provide methyl 3 - ethynyl- 4-methylbenzo at e .¾ NMR (500 MHz in DMSO-de), δ 2.50 (s, 3H), 3.90 (s, 3H), 4.57 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.99 (s, 1H).
With potassium carbonate In methanol at 20℃; for 0.166667h; 20.3 Preparation of 3-ethynyl-4-methylbenzoate To the oil in the previous step methanol, potassium carbonate (3.95 g, 28.57 mmol, 0.5 eq) was added. The reaction was carried out after stirred at room temperature for 10 min. The solvent was evaporated to dryness under reduced pressure. To the residue DCM was added, and the solution was washed with aqueous sodium bicarbonate, saturated sodium chloride aqueous solution, and water once. The DCM layer was dried over anhydrous sodium sulfate and separated by column chromatography to give the title product as a light yellow oil.
With potassium carbonate In methanol at 20℃; for 1h;
With methanol; tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; 2 Step 2: Preparation of methyl 3-ethynyl-4-methylbenzoate (compound 3) Dissolve the crude product from the previous step in methanol, add about 2 mL of 1 mol/L tetrabutylammonium fluoride in tetrahydrofuran, and stir at room temperature for 2 hours. The reaction system was spin-dried, and 470 mg of a yellow-brown oil was obtained by column chromatography (the total yield of the two steps was 75%).
470 mg With methanol; tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; 2 Step 2: Preparation of methyl 3-ethynyl-4-methylbenzoate (compound 3) Dissolve the crude product from the previous step in methanol, add about 2 mL of 1 mol/L tetrabutylammonium fluoride in tetrahydrofuran, and stir at room temperature for 2 hours. The reaction system was spin-dried, and 470 mg of a yellow-brown oil was obtained by column chromatography (the total yield of the two steps was 75%).

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[2]Current Patent Assignee: MONTEFIORE MEDICAL CENTER - WO2020/176501, 2020, A1 Location in patent: Paragraph 0182; 0184
[3]Gao, Mingshan; Duan, Lei; Luo, Jinfeng; Zhang, Lianwen; Lu, Xiaoyun; Zhang, Yan; Zhang, Zhang; Tu, Zhengchao; Xu, Yong; Ren, Xiaomei; Ding, Ke [Journal of Medicinal Chemistry, 2013, vol. 56, # 8, p. 3281 - 3295]
[4]Current Patent Assignee: BEIJING SCITECH MQ PHARMACEUTICALS; BEIJING SAITE MINGQIANG PHARMACEUTICAL TECH - CN111484482, 2020, A Location in patent: Paragraph 0119; 0120; 0122
[5]Current Patent Assignee: NAT INSTITUTE OF BIOLOGICAL SCIENCES BEIJING - CN107353286, 2017, A Location in patent: Paragraph 0048; 0049
[6]Current Patent Assignee: SUN PHARMA ADVANCED RESEARCH COMPANY LIMITED - WO2012/98416, 2012, A1 Location in patent: Page/Page column 40-41
[7]Current Patent Assignee: SICHUAN UNIVERSITY; ST CHUAN UNIV - US2017/305920, 2017, A1 Location in patent: Paragraph 0203
[8]Wang, Zhen; Zhang, Yali; Pinkas, Daniel M.; Fox, Alice E.; Luo, Jinfeng; Huang, Huocong; Cui, Shengyang; Xiang, Qiuping; Xu, Tingting; Xun, Qiuju; Zhu, Dongsheng; Tu, Zhengchao; Ren, Xiaomei; Brekken, Rolf A.; Bullock, Alex N.; Liang, Guang; Ding, Ke; Lu, Xiaoyun [Journal of Medicinal Chemistry, 2018, vol. 61, # 17, p. 7977 - 7990]
[9]Current Patent Assignee: SHENZHEN NEWDEL BIOTECH; JINAN UNIVERSITY (GUANGZHOU) - WO2022/217821, 2022, A1 Location in patent: Page/Page column 34-35
[10]Current Patent Assignee: SHENZHEN NEWDEL BIOTECH; JINAN UNIVERSITY (GUANGZHOU) - WO2022/217821, 2022, A1 Location in patent: Page/Page column 34-35
  • 6
  • [ 1255099-13-8 ]
  • [ 1388804-97-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrakis(triphenylphosphine) palladium(0); copper(l) iodide / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere 2.1: sodium hydroxide; water / methanol / 3 h / 50 °C 2.2: pH 4 - 4.5 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 1 h / 20 °C 3.2: 3 h
  • 7
  • [ 1255099-13-8 ]
  • [ 1388806-05-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrakis(triphenylphosphine) palladium(0); copper(l) iodide / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere 2.1: sodium hydroxide; water / methanol / 3 h / 50 °C 2.2: pH 4 - 4.5 3.1: Lawessons reagent / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere
  • 8
  • [ 1255099-13-8 ]
  • [ 1388804-86-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrakis(triphenylphosphine) palladium(0); copper(l) iodide / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere 2.1: sodium hydroxide; water / methanol / 3 h / 50 °C 2.2: pH 4 - 4.5 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 1 h / 20 °C 3.2: 3 h 4.1: 4-methyl-morpholine / chloroform / 12 h / 20 °C
  • 9
  • [ 1255099-13-8 ]
  • [ 1388806-07-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrakis(triphenylphosphine) palladium(0); copper(l) iodide / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere 2.1: sodium hydroxide; water / methanol / 3 h / 50 °C 2.2: pH 4 - 4.5 3.1: Lawessons reagent / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 1 h / 20 °C 4.2: 12 h / 20 °C
  • 10
  • [ 1255099-13-8 ]
  • [ 1388803-89-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrakis(triphenylphosphine) palladium(0); copper(l) iodide / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere 2.1: sodium hydroxide; water / methanol / 3 h / 50 °C 2.2: pH 4 - 4.5 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 1 h / 20 °C 3.2: 12 h / 20 °C
  • 11
  • [ 1255099-13-8 ]
  • [ 1388804-95-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrakis(triphenylphosphine) palladium(0); copper(l) iodide / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere 2.1: sodium hydroxide; water / methanol / 3 h / 50 °C 2.2: pH 4 - 4.5
  • 12
  • [ 705263-10-1 ]
  • methyl 3-ethynyl-4-methylbenzoate [ No CAS ]
  • [ 1429617-97-9 ]
  • 13
  • [ 1255099-13-8 ]
  • [ 1429617-57-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 80 °C / Inert atmosphere 2.1: sodium hydroxide / methanol / 6 h / 50 °C 2.2: pH 4 3.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / dichloromethane / 6 h / 20 °C
  • 14
  • [ 1255099-13-8 ]
  • [ 1429617-58-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 80 °C / Inert atmosphere 2.1: sodium hydroxide / methanol / 6 h / 50 °C 2.2: pH 4 3.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / dichloromethane
  • 15
  • [ 1255099-13-8 ]
  • [ 1429617-59-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 80 °C / Inert atmosphere 2.1: sodium hydroxide / methanol / 6 h / 50 °C 2.2: pH 4 3.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / dichloromethane
  • 16
  • [ 1255099-13-8 ]
  • [ 957147-18-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: potassium hydroxide / methanol / 2 h / 20 °C 2: thionyl chloride / 1 h / Reflux 3: triethylamine / dichloromethane / 1 h / 0 - 20 °C 4: triethylamine; sodium tris(acetoxy)borohydride / dichloromethane / 20 °C
Multi-step reaction with 5 steps 1: potassium hydroxide / methanol / 2 h / 20 °C 2: thionyl chloride / 1 h / Reflux 3: triethylamine / dichloromethane / 1 h / 0 - 20 °C 4: hydrogen / methanol; water / 3 h / 2585.81 Torr / Autoclave; Inert atmosphere; High pressure 5: sodium iodide; potassium carbonate / diethylene glycol dimethyl ether / 8 h / 130 °C
Multi-step reaction with 2 steps 1.1: sodium hydroxide / methanol; water / 20 °C 2.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 0.5 h / 20 °C 2.2: 20 h / 45 °C
  • 17
  • [ 875781-43-4 ]
  • [ 1255099-13-8 ]
  • [ 2097539-17-6 ]
YieldReaction ConditionsOperation in experiment
88% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In N,N-dimethyl acetamide at 50 - 80℃; for 24h; Inert atmosphere; 3 Example 3 Preparation of Methyl 3- (2-pyrrolo [2,3-b] pyrazine-3-ethynyl) -4-methylbenzoate Weigh 50g of 3-ethynyl-4-methyl benzoic acid methyl ester,56.9 g of 5-bromopyrrolo [2,3-b] pyrazine and 58 g of triethylamine in a reaction vessel,Add 500mL of N, N-dimethylacetamide dissolved,50 ° C,Under argon atmosphere, 8.0 g of PdCl2 (PPh3) 2 and 2.2 g of CuI were added,The reaction was heated to 80 for 24h.After the reaction,The reaction solution was slowly poured into aqueous ammonium chloride (35g of ammonium chloride dissolved in 700mL of purified water)After stirring 0.5h centrifugation,Drying gave the title compound,Yield 88%.
  • 18
  • [ 82998-57-0 ]
  • [ 1255099-13-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: sulfuric acid / 48 h / 70 °C 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine / tetrahydrofuran / 24 h / 20 °C / Inert atmosphere 3: potassium carbonate / methanol / 0.17 h / 20 °C
Multi-step reaction with 3 steps 1: sulfuric acid / 60 °C 2: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine / tetrahydrofuran / 4 h / 20 °C / Inert atmosphere 3: potassium carbonate / methanol / 2 h / 20 °C
Multi-step reaction with 3 steps 1: sulfuric acid / 24 h / Reflux; Inert atmosphere 2: triethylamine; copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / tetrahydrofuran / 22 h / 60 °C / Inert atmosphere 3: potassium hydroxide; water / methanol / 0.5 h / 20 °C
  • 19
  • [ 1255099-13-8 ]
  • [ 2097674-17-2 ]
YieldReaction ConditionsOperation in experiment
With piperidine; copper(l) iodide In dichloromethane at 20℃; for 72h; 13 Example 13,3 '- (1,3-butadiyne-1,4-yl) -Bis (4-methylbenzamide) Weigh 3-ethynyl-4-methyl benzoate 5.22g in the reaction flask, was added 30mL dichloromethaneSolution, were added CuI 0.76, piperidine 1.28g, the reaction was stopped at room temperature for 72h, the reaction solution was droppedThe mixture was warmed to zero and filtered, and the filter cake was dissolved in ethyl acetate and subjected to flash column chromatography to give the title compound.
  • 20
  • [ 1255099-13-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium(0); copper(l) iodide; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 4 h / 80 °C / Inert atmosphere 2: lithium hydroxide; water / tetrahydrofuran; methanol / 20 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap / N,N-dimethyl-formamide
Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium(0); copper(l) iodide; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 4 h / 80 °C / Inert atmosphere 2: lithium hydroxide; water / tetrahydrofuran; methanol / 20 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap / N,N-dimethyl-formamide
  • 21
  • [ 1255099-13-8 ]
  • [ 1300690-48-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0); copper(l) iodide; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 4 h / 80 °C / Inert atmosphere 2: lithium hydroxide; water / tetrahydrofuran; methanol / 20 °C
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / N,N-dimethyl-formamide / 5 h / 80 °C / Inert atmosphere 2: sodium hydroxide / methanol; water / 3 h / 60 °C
  • 22
  • [ 1255099-13-8 ]
  • [ 1233690-88-4 ]
  • [ 1356385-96-0 ]
YieldReaction ConditionsOperation in experiment
91% With  di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine; bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; triethylamine In water at 45℃; for 47h; Inert atmosphere;
84.7% With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 80℃; for 4h; Inert atmosphere; 1 Methyl 3- (imidazo [1,2-b] pyridazine-3-ethynyl) -4-methylbenzoate To a 100 mL bottle were added 3-iodoimidazo [1,2-b] pyridazine (10 g, 0.041 mol), 3-ethynyl 4- methylbenzoate(7.14 g, 0.041 mol), tetrakis (triphenylphosphine) palladium (1.42 g, 0.0021 mol), cuprous iodide (0.778 g,0.0041 mol), diisopropylethylamine (6.35 g, 0.049 mol) and N'-dimethylformamide (50 mL). The mixture was replaced with nitrogen three times and heated at 80 ° C for 4 hours, then cooled. The reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (3x100 mL). The organic phase is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1: 5) to give the title compound (10 g, 84.7%) as a white solid.
84% With tetrahydrofuran; iron(III) chloride; TPGS-750-M; methylmagnesium bromide; palladium diacetate; triethylamine; XPhos In water at 50℃; for 43h; Inert atmosphere;
  • 23
  • methyl 3-ethynyl-4-methylbenzoate [ No CAS ]
  • [ 57948-41-1 ]
  • methyl 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-4-methylbenzoate [ No CAS ]
  • 24
  • [ CAS Unavailable ]
  • [ 1255099-13-8 ]
YieldReaction ConditionsOperation in experiment
With methanol; potassium carbonate In tetrahydrofuran at 45℃; for 5h;
  • 25
  • [ 104901-43-1 ]
  • [ 1255099-13-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tetrahydrofuran; iron(III) chloride; XPhos; palladium diacetate; methylmagnesium bromide; triethylamine; TPGS-750-M / water / 50 °C / Inert atmosphere 2: potassium carbonate; methanol / tetrahydrofuran / 5 h / 45 °C
Multi-step reaction with 2 steps 1: bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)];  di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine; triethylamine / water / 45 h / 45 °C / Inert atmosphere 2: potassium carbonate; methanol / tetrahydrofuran / 5 h / 45 °C
  • 26
  • [ 2285377-14-0 ]
  • [ 1255099-13-8 ]
YieldReaction ConditionsOperation in experiment
90% With methanol; potassium carbonate In tetrahydrofuran at 45℃; for 5h;
  • 27
  • [ 1255099-13-8 ]
  • [ 1233690-88-4 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)];  di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine; triethylamine / water / 47 h / 45 °C / Inert atmosphere 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 12 h / 20 °C / Inert atmosphere
  • 28
  • [ 1255099-13-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: sodium L-ascorbate; copper(ll) sulfate pentahydrate / water; <i>tert</i>-butyl alcohol / 0.5 h / 90 °C / Microwave irradiation 2: water; lithium hydroxide / tetrahydrofuran / 24 h / 20 °C 3: dicyclohexyl-carbodiimide; dmap / dichloromethane / 2.08 h / 0 - 20 °C / Inert atmosphere
  • 29
  • [ 1255099-13-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium L-ascorbate; copper(ll) sulfate pentahydrate / water; <i>tert</i>-butyl alcohol / 0.5 h / 90 °C / Microwave irradiation 2: water; lithium hydroxide / tetrahydrofuran / 24 h / 20 °C
  • 30
  • [ 1255099-13-8 ]
  • [ 63534-36-1 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
91% With copper(ll) sulfate pentahydrate; sodium L-ascorbate In water; <i>tert</i>-butyl alcohol at 90℃; for 0.5h; Microwave irradiation;
  • 31
  • [ 1255099-13-8 ]
  • [ 2189716-66-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: lithium hydroxide monohydrate / tetrahydrofuran; lithium hydroxide monohydrate / 2 h / 20 °C 2: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 18 h / 20 °C 3: triethylamine; copper (I) iodide; [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) / acetonitrile / 3 h / 82 °C
Multi-step reaction with 3 steps 1: lithium hydroxide monohydrate; lithium hydroxyde monohydrate / tetrahydrofuran / 20 °C 2: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 18 h / 20 °C 3: triethylamine; [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide / acetonitrile / 3 h / 82 °C
  • 32
  • [ 1255099-13-8 ]
  • [ 2574594-59-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: lithium hydroxide monohydrate / tetrahydrofuran; lithium hydroxide monohydrate / 2 h / 20 °C 2: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 18 h / 20 °C
Multi-step reaction with 2 steps 1: lithium hydroxide monohydrate; lithium hydroxyde monohydrate / tetrahydrofuran / 20 °C 2: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 18 h / 20 °C
  • 33
  • [ 1299607-55-8 ]
  • [ 1255099-13-8 ]
  • [ 2699128-63-5 ]
YieldReaction ConditionsOperation in experiment
85.97% With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine In 1-methyl-pyrrolidin-2-one at 30 - 75℃; for 2h; Inert atmosphere;
85.97% With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine In 1-methyl-pyrrolidin-2-one at 30 - 75℃; for 2h; Inert atmosphere; 1.1; 2 Step 1 Under the protection of nitrogen, N-methylpyrrolidone (137.6g) was heated to 30 to 35 , and acompoundof formula 1 (14.4g, 1.3eq) , acompoundof formula 2 (19.14g, 1eq) , bis (triphenylphosphate) palladium dichloride (0.46g, 0.01eq) and cuprous iodide (0.113g, 0.01eq) were added sequentially thereto, and then triethylamine (9.45g, 1.5eq) was added thereto under the protection of nitrogen. The reaction mixture was heated to 65 to 75 and kept at this temperaturefor2 hours. In-processcontrol of the reaction was performed by liquid phase detection . When the content of thecompoundof formula 2 was ≤ 0.1%, the reaction was terminated. After the reaction was terminated, the reaction solution was cooled to 35 to 45, and N-acetyl-L-cysteine (1g, 0.1eq) was added thereto directly. The reaction was performed under stirringfor4 to 5h. The resultant product was cooled to room temperature, precipitated by adding water, centrifuged, and washed with purified water to obtain a crude filter cake. After the crude filter cake was dried under vacuum, a mixture of ethyl acetate and n-heptane (wherein the volume ratio of ethyl acetate to n-heptane was 1: 1, and 5 mL of the mixed solvent of ethyl acetate and n-heptane was used per gram of the crude filter cake) was added to the crude filter cake and slurried. The obtained slurry was dried under vacuum to give acompoundof formula 3 with a yield of 85.97%and a purity of 98.2%. The NMR data of thecompoundof formula 3 is1HNMR (400MHz, d-DMSO) : δ ppm: 8.93 (1H, d, J=2.0 Hz) ; 8.63 (1H, d, J=2.0 Hz) ; 8.49 (1H, s) ; 8.11 (1H, d, J=2.0 Hz) ; 7.92 (1H, dd, J1=1.6 Hz; J2=8.0 Hz) ; 7.52 (1H, d, J=8.0 Hz) ; 3.88 (3H, s) ; 2.59 (3H, s) ; 1.65 (9H, s) .
  • 34
  • [ 1255099-13-8 ]
  • [ 2699128-62-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine / 1-methyl-pyrrolidin-2-one / 2 h / 30 - 75 °C / Inert atmosphere 2: methanol; water monomer / 18 h / Inert atmosphere; Reflux
Multi-step reaction with 2 steps 1: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine / 1-methyl-pyrrolidin-2-one / 2 h / 30 - 75 °C / Inert atmosphere 2: water monomer / methanol / 18 h / Reflux
  • 35
  • [ 1255099-13-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine / 1-methyl-pyrrolidin-2-one / 2 h / 30 - 75 °C / Inert atmosphere 2: methanol; water monomer / 18 h / Inert atmosphere; Reflux 3: triethylamine / tetrahydrofuran / 2 h / -60 - -40 °C / Inert atmosphere
Multi-step reaction with 3 steps 1: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine / 1-methyl-pyrrolidin-2-one / 2 h / 30 - 75 °C / Inert atmosphere 2: water monomer / methanol / 18 h / Reflux 3: potassium-t-butoxide / tetrahydrofuran / 2 h / -65 - -60 °C / Inert atmosphere
  • 36
  • methyl 3-ethynyl-4-methylbenzoate [ No CAS ]
  • [ 18087-73-5 ]
  • methyl 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
99% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 80℃; for 5h; Inert atmosphere;
  • 37
  • [ 875781-17-2 ]
  • [ 1255099-13-8 ]
  • [ 2699128-62-4 ]
YieldReaction ConditionsOperation in experiment
75% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 80℃; for 5h; Inert atmosphere;
  • 38
  • [ 1255099-13-8 ]
  • [ 2552882-04-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide / N,N-dimethyl-formamide / 5 h / 80 °C / Inert atmosphere 2: sodium hydroxide / methanol; water monomer / 3 h / 60 °C
Multi-step reaction with 2 steps 1: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine / 1-methyl-pyrrolidin-2-one / 2 h / 30 - 75 °C / Inert atmosphere 2: water monomer; sodium hydroxide / tetrahydrofuran / 41 h / 20 °C
  • 39
  • [ 1255099-13-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / N,N-dimethyl-formamide / 5 h / 80 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 3 h / 45 °C
  • 40
  • [ 1255099-13-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / N,N-dimethyl-formamide / 5 h / 80 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 3 h / 45 °C 3: hydrogenchloride; sodium dihydrogen phosphate; disodium hydrogen phosphate; tris(2-carboxyethyl)phosphine / water; acetonitrile / 24 h / 40 °C / pH 7.2 / Inert atmosphere
  • 41
  • [ 1255099-13-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / N,N-dimethyl-formamide / 5 h / 80 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 3 h / 45 °C 3: hydrogenchloride; sodium dihydrogen phosphate; disodium hydrogen phosphate; tris(2-carboxyethyl)phosphine / water; acetonitrile / 24 h / 40 °C / pH 7.2 / Inert atmosphere
  • 42
  • [ 1255099-13-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / N,N-dimethyl-formamide / 5 h / 80 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 3 h / 45 °C 3: hydrogenchloride; sodium dihydrogen phosphate; disodium hydrogen phosphate; tris(2-carboxyethyl)phosphine / water; acetonitrile / 24 h / 40 °C / pH 7.2 / Inert atmosphere 4: Acidic conditions
  • 43
  • [ 1255099-13-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / N,N-dimethyl-formamide / 5 h / 80 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 3 h / 45 °C 3: hydrogenchloride; sodium dihydrogen phosphate; disodium hydrogen phosphate; tris(2-carboxyethyl)phosphine / water; acetonitrile / 24 h / 40 °C / pH 7.2 / Inert atmosphere 4: Acidic conditions
  • 44
  • [ 1255099-13-8 ]
  • [ 2764831-74-3 ]
YieldReaction ConditionsOperation in experiment
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine In acetonitrile at 60 - 70℃; for 20h; Inert atmosphere; 11 Example 11: Preparation of Compound 33 and Compound 34 Under nitrogen, to a mixture of the compound 33-1 (10 g) and acetonitrile (76 g) , bis (triphenylphosphine) palladium dichloride (0.31 g) , cuprous iodide (84 mg) , and triethylamine (6.71 g) were added. The reaction mixture was controlled at 60-70 and stirred for 20 hours, then filtered directly through silica gel to provide the dark green liquid. The dark green liquid was concentrated, beat with n-heptane for 20 hours, and filtered to provide compound 33. Compound 33:1H NMR (400 MHz, DMSO-d6) : δ7.92 (d, J=9.2, 2H) , 7.86 (d, J=7.6, 2H) , 7.45 (m, 2H) , 6.06 (s, 1H) , 5.78 (s, 1H) , 3.84 (s, J=6.0, 1H) , 2.42 (s, 3H) . MS: M+H+=349.20.
  • 45
  • [ 20511-12-0 ]
  • [ 1255099-13-8 ]
  • [ 2602852-47-9 ]
YieldReaction ConditionsOperation in experiment
51% With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 2h; Methyl 3-[2-(6-aminopyridin-3-yl)ethynyl]-4-methylbenzoate To a degassed solution of methyl 3-ethynyl-4-methyl-benzoate (375mg, 2.15mmol), 5-iodopyridin-2-amine (497mg, 2.26mmol) and DIPEA (1.12mL, 6.46mmol) in MeCN (10mL) was added Pd2(PPhs)2Cl2 (75.8mg, O.H mmol) and Cui (20.5mg, 0.11 mmol) and the reaction stirred at rt for 2h. The product was isolated by filtration and purified by SPE using a strong cation exchange resin. Trituration from TBME:heptane afforded the title compound (295mg, 51 %) as a beige solid. UPLC (Method C): 2.30 min, 99.7%, [M+H]+ = 267.0.
51% With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 2h; Methyl 3-[2-(6-aminopyridin-3-yl)ethynyl]-4-methylbenzoate To a degassed solution of methyl 3-ethynyl-4-methyl-benzoate (375mg, 2.15mmol), 5-iodopyridin-2-amine (497mg, 2.26mmol) and DIPEA (1.12mL, 6.46mmol) in MeCN (10mL) was added Pd2(PPhs)2Cl2 (75.8mg, O.H mmol) and Cui (20.5mg, 0.11 mmol) and the reaction stirred at rt for 2h. The product was isolated by filtration and purified by SPE using a strong cation exchange resin. Trituration from TBME:heptane afforded the title compound (295mg, 51 %) as a beige solid. UPLC (Method C): 2.30 min, 99.7%, [M+H]+ = 267.0.
  • 46
  • [ 3430-16-8 ]
  • [ 1255099-13-8 ]
  • [ 2583803-61-4 ]
YieldReaction ConditionsOperation in experiment
73% With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; N-ethyl-N,N-diisopropylamine In acetonitrile at 100℃; for 1h; Sealed tube; Microwave irradiation; Methyl 4-methyl-3-[2-(5-methyl-3-pyridyl)ethynyl]benzoate A solution of methyl 3-ethynyl-4-methyl-benzoate (170mg, 0.98mmol), 3-bromo- 5-methyl-pyridine (0.11 mL, 0.98mmol), DIPEA (0.51 mL, 2.93mmol) in degassed MeCN (4.0mL) was prepared in a microwave vial. Then Pd(PPhs)2Cl2 (34.4mg, 0.05mmol) and Cui (9.3mg, 0.05mmol) were added to the solution and the reaction mixture was sealed in the vial and heated to 100°C for 1 h under microwave irradiation. The reaction mixture was filtered through celite and then concentrated in vacuo. The residue was purified on silica (Biotage Isolera, normal phase, 100% heptane to EtOAc: Heptane, 1 :1) to give the title compound (572mg, 73%) as a yellow solid. UPLC (Method A) 3.64 min, 99.5 %, [M+H]+ = 266.1 .
73% With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; N-ethyl-N,N-diisopropylamine In acetonitrile at 100℃; for 1h; Sealed tube; Microwave irradiation; Methyl 4-methyl-3-[2-(5-methyl-3-pyridyl)ethynyl]benzoate A solution of methyl 3-ethynyl-4-methyl-benzoate (170mg, 0.98mmol), 3-bromo- 5-methyl-pyridine (0.11 mL, 0.98mmol), DIPEA (0.51 mL, 2.93mmol) in degassed MeCN (4.0mL) was prepared in a microwave vial. Then Pd(PPhs)2Cl2 (34.4mg, 0.05mmol) and Cui (9.3mg, 0.05mmol) were added to the solution and the reaction mixture was sealed in the vial and heated to 100°C for 1 h under microwave irradiation. The reaction mixture was filtered through celite and then concentrated in vacuo. The residue was purified on silica (Biotage Isolera, normal phase, 100% heptane to EtOAc: Heptane, 1 :1) to give the title compound (572mg, 73%) as a yellow solid. UPLC (Method A) 3.64 min, 99.5 %, [M+H]+ = 266.1 .
  • 47
  • [ 1255099-13-8 ]
  • [ 31402-54-7 ]
  • [ 2784626-53-3 ]
YieldReaction ConditionsOperation in experiment
62% With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; N-ethyl-N,N-diisopropylamine In acetonitrile at 100℃; for 1h; Microwave irradiation; Inert atmosphere; Methyl 4-methyl-3-[2-[2-(methylamino)pyrimidin-5-yl]ethynyl]benzoate To a MW vial was added methyl 3-ethynyl-4-methyl-benzoate (300mg, 1.72mmol), 5-bromo-N-methylpyrimidin-2-amine (389mg, 2.07mmol), MeCN (5.0mL) and DIPEA (0.90mL, 5.17mmol). The reaction mixture was degassed using nitrogen, Cui (16.4mg, 0.09mmol) and PdCl2(PPhs)2 (60.6mg, 0.09mmol) were added and the reaction was heated under MW irradiation for 60min at 100°C. The reaction was concentrated in vacuo. The residue was purified on silica (EtOAc:heptane, 1 :9 to 1 :1) to provide the title compound (302mg, 62%) as a beige solid. UPLC (Method A) 3.33 min, 100 %, [M+H]+ = 282.2.
62% With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; N-ethyl-N,N-diisopropylamine In acetonitrile at 100℃; for 1h; Microwave irradiation; Inert atmosphere; Methyl 4-methyl-3-[2-[2-(methylamino)pyrimidin-5-yl]ethynyl]benzoate To a MW vial was added methyl 3-ethynyl-4-methyl-benzoate (300mg, 1.72mmol), 5-bromo-N-methylpyrimidin-2-amine (389mg, 2.07mmol), MeCN (5.0mL) and DIPEA (0.90mL, 5.17mmol). The reaction mixture was degassed using nitrogen, Cui (16.4mg, 0.09mmol) and PdCl2(PPhs)2 (60.6mg, 0.09mmol) were added and the reaction was heated under MW irradiation for 60min at 100°C. The reaction was concentrated in vacuo. The residue was purified on silica (EtOAc:heptane, 1 :9 to 1 :1) to provide the title compound (302mg, 62%) as a beige solid. UPLC (Method A) 3.33 min, 100 %, [M+H]+ = 282.2.
  • 48
  • [ 1255099-13-8 ]
  • [ 1388711-59-8 ]
  • [ 2784626-55-5 ]
YieldReaction ConditionsOperation in experiment
49% With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; N-ethyl-N,N-diisopropylamine In acetonitrile at 100℃; for 1h; Inert atmosphere; Microwave irradiation; Methyl 4-methyl-3-[2-[3-methyl-2-(methylcarbamoyl)imidazol-4- yl]ethynyl]benzoate To a MW vial was added methyl 3-ethynyl-4-methyl-benzoate (90mg, 0.52mmol), 5-bromo-N,1-dimethyl-imidazole-2-carboxamide (118mg, 0.54mmol), MeCN (3.0mL) and DIPEA (0.27mL, 1 .55mmol). The reaction mixture was degassed using nitrogen, Cui (4.9mg, 0.03mmol) and PdCl2(PPhs)2 (18.2mg, 0.03mmol) were added and reaction was heated under MW irradiation for 60min at 100°C. The reaction was concentrated in vacuo. The residue was purified on silica (acetone :DCM, 1 :19 to 1 :9) to provide the title compound (78.0mg, 49%) as beige solid. UPLC (Method A) 3.22 min, 100.0 %, [M+H]+ = 312.2.
49% With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; N-ethyl-N,N-diisopropylamine In acetonitrile at 100℃; for 1h; Inert atmosphere; Microwave irradiation; Methyl 4-methyl-3-[2-[3-methyl-2-(methylcarbamoyl)imidazol-4- yl]ethynyl]benzoate To a MW vial was added methyl 3-ethynyl-4-methyl-benzoate (90mg, 0.52mmol), 5-bromo-N,1-dimethyl-imidazole-2-carboxamide (118mg, 0.54mmol), MeCN (3.0mL) and DIPEA (0.27mL, 1 .55mmol). The reaction mixture was degassed using nitrogen, Cui (4.9mg, 0.03mmol) and PdCl2(PPhs)2 (18.2mg, 0.03mmol) were added and reaction was heated under MW irradiation for 60min at 100°C. The reaction was concentrated in vacuo. The residue was purified on silica (acetone :DCM, 1 :19 to 1 :9) to provide the title compound (78.0mg, 49%) as beige solid. UPLC (Method A) 3.22 min, 100.0 %, [M+H]+ = 312.2.
49% With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; N-ethyl-N,N-diisopropylamine In acetonitrile at 100℃; for 1h; Inert atmosphere; Microwave irradiation; INTERMEDIATE 24 Methyl 4-methyl-3-{2-[1-methyl-2-(methylcarbamoyl)-1 H-imidazol-5-yl]ethynyl}benzoate Methyl 3-ethynyl-4-methyl-benzoate (90mg, 0.52mmol), Intermediate 23 (118mg, 0.54mmol), and DIPEA (0.27mL, 1.55mmol) were added to MeCN (3.0mL), and degassed using N2. Cui (4.9mg, 0.03mmol) and PdCl2(PPh3)2 (18.2mg, 0.03mmol) were added and the mixture heated using a microwave reactor at 100°C for I h. The mixture was concentrated in vacuo and purified by normal phase chromatography to give the title compound (78.0mg, 49%) as a beige solid. UPLC (Method A) 3.22min, 100%, [M+H]+ = 312.2.
49% With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; N-ethyl-N,N-diisopropylamine In acetonitrile at 100℃; for 1h; Inert atmosphere; Microwave irradiation; INTERMEDIATE 24 Methyl 4-methyl-3-{2-[1-methyl-2-(methylcarbamoyl)-1 H-imidazol-5-yl]ethynyl}benzoate Methyl 3-ethynyl-4-methyl-benzoate (90mg, 0.52mmol), Intermediate 23 (118mg, 0.54mmol), and DIPEA (0.27mL, 1.55mmol) were added to MeCN (3.0mL), and degassed using N2. Cui (4.9mg, 0.03mmol) and PdCl2(PPh3)2 (18.2mg, 0.03mmol) were added and the mixture heated using a microwave reactor at 100°C for I h. The mixture was concentrated in vacuo and purified by normal phase chromatography to give the title compound (78.0mg, 49%) as a beige solid. UPLC (Method A) 3.22min, 100%, [M+H]+ = 312.2.

  • 49
  • [ 1255099-13-8 ]
  • [ 1565458-06-1 ]
  • [ 2784626-57-7 ]
YieldReaction ConditionsOperation in experiment
54% With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; N-ethyl-N,N-diisopropylamine In acetonitrile at 100℃; for 2h; Microwave irradiation; Methyl 3-[2-[5-[3-(dimethylamino)pyrrolidin-1-yl]-3-pyridyl]ethynyl]-4- methyl-benzoate To methyl 3-ethynyl-4-methyl-benzoate (110mg, 0.63mmol) and 1-(5-bromo-3- pyridyl)-N,N-dimethyl-pyrrolidin-3-amine (209mg, 0.76mmol) in MeCN (5.0mL) was added DIPEA (0.33mL, 1.89mmol) and the reaction mixture degassed. Pd(PPhs)2Cl2 (22.2mg, 0.03mmol) and Cui (6.0mg, 0.03mmol) were added and the reaction heated to 100°C in the MW for 2h. The solvent was removed under reduced pressure and the residue dissolved in DCM (5.0mL) and filtered. The solvent was removed under reduced pressure and the residue was purified on silica (MeOH:DCM, 1 :99 to 1 :9). The material was then further purified by cationic exchange resin SCX-2 to afford the desired product (159mg, 54%) as a brown film. UPLC (Method A) 3.55 min, 78.3 %, [M+H]+ = 364.3.
54% With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; N-ethyl-N,N-diisopropylamine In acetonitrile at 100℃; for 2h; Microwave irradiation; Methyl 3-[2-[5-[3-(dimethylamino)pyrrolidin-1-yl]-3-pyridyl]ethynyl]-4- methyl-benzoate To methyl 3-ethynyl-4-methyl-benzoate (110mg, 0.63mmol) and 1-(5-bromo-3- pyridyl)-N,N-dimethyl-pyrrolidin-3-amine (209mg, 0.76mmol) in MeCN (5.0mL) was added DIPEA (0.33mL, 1.89mmol) and the reaction mixture degassed. Pd(PPhs)2Cl2 (22.2mg, 0.03mmol) and Cui (6.0mg, 0.03mmol) were added and the reaction heated to 100°C in the MW for 2h. The solvent was removed under reduced pressure and the residue dissolved in DCM (5.0mL) and filtered. The solvent was removed under reduced pressure and the residue was purified on silica (MeOH:DCM, 1 :99 to 1 :9). The material was then further purified by cationic exchange resin SCX-2 to afford the desired product (159mg, 54%) as a brown film. UPLC (Method A) 3.55 min, 78.3 %, [M+H]+ = 364.3.
  • 50
  • [ 1255099-13-8 ]
  • [ 2756810-02-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: lithium hydroxide / water; tetrahydrofuran; methanol / 1 h / 60 °C 2: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 70 °C 3: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 80 °C
Multi-step reaction with 3 steps 1: lithium hydroxide monohydrate; water / methanol; tetrahydrofuran / 1 h / 60 °C 2: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 70 °C 3: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 80 °C / Sealed tube; Inert atmosphere
  • 51
  • [ 1255099-13-8 ]
  • [ 2756810-03-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: lithium hydroxide / water; tetrahydrofuran; methanol / 1 h / 60 °C 2: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 70 °C
Multi-step reaction with 2 steps 1: lithium hydroxide monohydrate; water / methanol; tetrahydrofuran / 1 h / 60 °C 2: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 70 °C
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