* 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.
Stage #1: With potassium carbonate In acetone at 40℃; for 0.333333 h; Inert atmosphere Stage #2: for 20 h; Reflux
22A. Methyl 4-fluoro-2-methoxy-benzoatePotassium carbonate (15.5 g, 112 mmol) was added to a stirred solution of 4-fluoro-2- hydroxy-benzoic acid (5.0 g, 32.1 mmol) in acetone (100 mL) and the mixture heated to 40°C under a nitrogen atmosphere for 20 minutes. Methyl iodide (15.8 g, 112mmol) was added dropwise and then the mixture heated to reflux for 20 hours then allowed to cool to room temperature. The mixture was filtered through celite and the filtrate concentrated under reduced pressure to give the title compound (5.9 g, 100percent) which was used without further purification.
Reference：
[1] Patent: WO2015/120390, 2015, A1, . Location in patent: Page/Page column 93; 147
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 18, p. 8473 - 8494
2
[ 67-56-1 ]
[ 395-82-4 ]
[ 204707-42-6 ]
Yield
Reaction Conditions
Operation in experiment
98%
for 23 h; Reflux
1.702 g of 4-fluoro-2-methoxybenzoic acid was dissolved in 14 ml of methanol, 0.5 ml of sulfuric acid was added, the temperature was heated to reflux, and the mixture was heated for 23 hours. The reaction mixture was concentrated and evaporated to dryness. The residue was dissolved in ethyl acetate , Washed with saturated aqueous sodium bicarbonate solution without air bubbles, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated by filtration. Column chromatography (dichloromethane: methanol = 97: 3, V / V) to give 1.805 g of a colorless oil in a yield of 98.0percent.
70%
at 0℃; for 12 h;
Methyl 4-fluoro-2-methoxybenzoate. To a solution of 4-fluoro-2-methoxybenzoic acid (1.7 g, 10 mmol) in methanol (100 mL) was added thionyl chloride (5.73 g, 48 mmol) at 0°C. The resultant mixture was stirred for 12 hours and then solvent was evaporated in vacuo. To the residue, saturated sodium bicarbonate aqueous solution (50 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was dried by sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuo to give methyl 4-fluoro-2- methoxybenzoate (1.3 g, 70percent).
70%
at 0℃; for 12 h;
To a solution of 4-fluoro-2-methoxybenzoic acid (1.7 g, 10 mmol) in methanol (100 mL) was added thionyl chloride (5.73 g, 48 mmol) at 0° C. The resultant mixture was stirred for 12 hours and then solvent was evaporated in vacuo. To the residue, saturated sodium bicarbonate aqueous solution (50 mL) was added and the mixture was extracted with ethyl acetate (100 mL×3). The organic phase was dried by sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuo to give methyl 4-fluoro-2-methoxybenzoate (1.3 g, 70percent).
Reference：
[1] Patent: CN106146493, 2016, A, . Location in patent: Paragraph 0534; 0535; 0536; 0537
[2] Patent: WO2013/75083, 2013, A1, . Location in patent: Paragraph 00254; 00255
[3] Patent: US9206128, 2015, B2, . Location in patent: Page/Page column 135; 136
With sulfuric acid; nitric acid; at -5℃; for 0.166667h;Inert atmosphere;
[000136] To a stirred solution of <strong>[204707-42-6]methyl 4-fluoro-2-methoxybenzoate</strong> 71(500 mg, 2.50 mmol) in sulfuric acid (1 mL) under inert atmosphere was added the mixture of nitric acid (0.125 mL), sulfuric acid (0.5 mL) at -5 C and stirred for 10 mm. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with CH2C12 (2 x 30 mL). The combined organic extracts were washed with 10% NaHCO3 solution (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was triturated with diethyl ether (2 x 5 mL) to afford compound 72 (200 mg, 33%) as an off-white solid. TLC: 20% EtOAc/ hexanes (R 0.4); 1H-NMR (CDC13, 400 MHz):oe 8.69 (d, J= 8.8 Hz, 1H), 6.83 (d, J= 12.8 Hz, 1H), 4.01 (s, 3H), 3.92 (s, 3H).
8.24 g
With sulfuric acid; potassium nitrate; at 0 - 20℃; for 3h;
Methyl 4-fluoro-2-methoxybenzoate (7.07 g, 38.4 mmol) was dissolved in concentrated sulfuric acid (50 mL). The reaction mixture was cooled to 0 C and KNO3 (4.26 g, 42.2 mmol) was added in small portions. The reaction was stirred was warm up to ambient temperature and after 3 h, the mixture was poured into ice water. The solid was collected by filtration and dried on vacuum affording ZYJ12 (8.24 g) as a solid. ?H NMR (400 MHz, CDC13): 8.72 (d, I = 8.79 Hz, 1H), 6.85 (d, I = 12.69 Hz, 1H), 4.03 (s, 3H), 3.95 (s, 3H).
With sodium hydride; In DMF (N,N-dimethyl-formamide); for 18h;
Step 1: Treat the ester (1.42 g, 7.7 mmol) in DMF (20 ml) with NaH (60% in oil, 0.46 g, 0.28 g NaH, 12 mmol) and CH3I (0.62 ml, 10 mmol). Stir 18 h and partition with EtOAc and 5% citric acid. Wash with 1N NaOH, then brine, dry (MgSO4) and concentrate to obtain the ether as a yellow oil
With sodium hydride; In DMF (N,N-dimethyl-formamide); for 18h;
Treat methyl 4-fluorosalicylate (1.42 g, 7.7 mmol) in DMF (20 ml) with NaH (60% in oil, 0.46 g, 0.28 g NaH, 12 mmol) and CH3l (0.62 ml, 10 mmol). Stir 18 h and partition with EtOAc and 5% citric acid. Wash with 1N NaOH, then brine, dry (MgSO4) and concentrate to obtain the ether as a yellow oil.
Step 2: Combine the product of Step 1 (1.43 g, 7.2 mmol) and iron powder (0.018 g) in CH2Cl2 (15 ml ). Add dropwise Br2 (0.44 ml, 8.7 mmol) in CH2Cl2 (5 ml). Stir 18 h and wash with water, then 1N NaOH. Dry (MgSO4) and concentrate to obtain the bromide as a yellow solid
With bromine;iron; In dichloromethane; for 18h;
Combine the product of Step 1 (1.43 g, 7.2 mmol) and iron powder (0.018 g) in CH2Cl2 (15 ml). Add dropwise Br2 (0.44 ml, 8.7 mmol) in CH2Cl2 (5 ml). Stir 18 h and wash with water, then 1N NaOH. Dry (MgSO4) and concentrate to obtain the bromide as a yellow solid.
The methyl 4-fluoro-2-methoxybenzoate used in the preparation of the precursor for Examples 18d-e was prepared from 4-fluoro-2-methoxybenzoic acid according to the procedure described in W098/13332.
1 4-floro-2-methoxybenzylalcohol To a suspension of LiAlH4 (94.6 mg, 2.49 mmol) in THF (3 ml) was added dropwise a solution of <strong>[204707-42-6]methyl 4-fluoro-2-methoxybenzoate</strong> obtained in Example 23-2) (273.3 mg, 1.48 mmol) in THF (3 ml). The mixture was stirred for 1 hour. To the mixture was added dropwise aqueous THF followed by water. The mixture was extracted three times with ethyl acetate and dried over MgSO4. The solvent was evaporated to give the crude title compound (310.8 mg; 83%). 1H-NMR(CDCl3) 7.23 (dd, 1H, J=8.6, 6.6 Hz), 6.68-6.59 (m, 2H), 4.64 (d, 2H, J=6.3 Hz), 3.86 (s, 3H), 2.13 (t, 1H, J=6.3 Hz)
With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 20h;
Example 25Preparation of methyl 2-methoxy-4-(4-methylpiperazin-l-yl)benzoate; Methyl 2-methoxy-4-fluoro-benzoate (1.6 gr, 9.7 mmol), K3CO3 (1.3 gr, 9.7 mmol) and N-methyl piperazine (1.3 mL, 11.7 mmol) were heated at 1000C in DMSO (5 mL) for 20 hours. Reaction mixture was diluted with DCM and washed with water. Organic phase was dried over sodium sulfate and evaporated to dryness. Column chromatography purification on silica gel using dichloromethane/methanol 95:5 as the eluant, afforded 1.7 g (yield 66%) of the title compound. IH-NMR (400 MHz), delta (ppm, DMSO-J6): 2.25 (s, 3H) 2.45 (br. s., 4H) 3.26 - 3.34 (m, 4H) 3.70 (s, 3H) 3.80 (s, 3H) 6.49 (d, J=2.32 Hz, IH) 6.53 (dd, J=8.84, 2.38 Hz, IH) 7.61 (d, J=8.78 Hz, IH)
66%
With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 20h;
Preparation 6; Preparation of methyl 2-methoxy-4-(4-methylpiperazin-1-yl)benzoate; Methyl 2-methoxy-4-fluoro-benzoate (1.6 gr, 9.7 mmol), K2CO3 (1.3 gr, 9.7 mmol) and N-methyl piperazine (1.3 mL, 11.7 mmol) were heated at 1000C in DMSO (5 mL) for 20 hours. Reaction mixture was diluted with DCM and washed with water. Organic phase was dried over sodium sulfate and evaporated to dryness. Column chromatography purification on silica gel using dichloromethane/methanol 95:5 as the eluant, afforded 1.7 g (yield 66%) of the title compound.1 H-NMR (400 MHz), delta (ppm, DMSO-de): 2.25 (s, 3H) 2.45 (br. s., 4H) 3.26 - 3.34 (m, 4H) 3.70 (s, 3H) 3.80 (s, 3H) 6.49 (d, J=2.32 Hz, 1 H) 6.53 (dd, J=8.84, 2.38 Hz, 1 H) 7.61 (d, J=8.78 Hz, 1 H)
59.2%
With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 18h;Inert atmosphere;
921 mg of <strong>[204707-42-6]methyl 4-fluoro-2-methoxybenzoate</strong> was dissolved in 5 ml of dimethylsulfoxide, 0.67 ml of 1-methylpiperazine and 1.040 g of potassium carbonate were added and the temperature was raised to 120 C under argon After heating for 18 hours, the reaction was quenched by adding 25 ml of water. The reaction mixture was extracted with ethyl acetate. The organic phase was combined and washed five times with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated by filtration. Column chromatography (Dichloromethane: methanol = 99: 1-98: 2, V / V) to give 783 mg of a yellow oil in a yield of 59.2%.
at 80℃; for 40h;
A mixture of <strong>[204707-42-6]methyl 4-fluoro-2-methoxybenzoate</strong> (1.84 g, 10.0 mmol, 1.0 eq) and 1- methylpiperazine (2.0 g, 20.0 mmol, 2.0 eq) was added to a 100 ml three-neck round bottomflask. The reaction was heated to 80 C and stirred for 40 hours. Then water(20 ml) was poured into the reaction solution, and the mixture was extracted with ethyl acetate (20 mlx3), and the organic layers were combined and dried over anhydrous sodium sulfate. Evaporation under vacuum at 45 C gave a yellow oil. The yellow oil was dissolved with DCM (30 ml), HC1 in isopropanol (30%, 4 ml) was added to the reaction solution, some solids appeared. The solidswere collected by filtration and the collected solids were washed with DCM (10 mlx2) to give a crude product 1.32 g.
With iodine; silver trifluoromethanesulfonate; In methanol; at 20℃; for 2h;
Methyl 4-fluoro-5-iodo-2-methoxybenzoate[00576JTo a solution of <strong>[204707-42-6]methyl 4-fluoro-2-methoxybenzoate</strong> (254 g, 13 80 mmol) and silver triilate (5 35 g, 20 82 mmol) m MeOH (4o mL) was added iodine (5 35 g, 21 07 mmol) and stirred at rt for 2 L The resulting precipitate was filtered off and the mother liquor was diluted with EtOAc (100 mL) The organic layer was washed (Na2S2O4 (100 mL), H2O (100 mL), brine (100 mL)), dried over Na2SO4 and concentrated to give the desired product as a white solid (409 g) NMR (CDC13) delta 823 (d, 1H), 675 (d, 1H), 3 92 (s, 3H), 3 91 (s, 3H)
1.702 g of 4-fluoro-2-methoxybenzoic acid was dissolved in 14 ml of methanol, 0.5 ml of sulfuric acid was added, the temperature was heated to reflux, and the mixture was heated for 23 hours. The reaction mixture was concentrated and evaporated to dryness. The residue was dissolved in ethyl acetate , Washed with saturated aqueous sodium bicarbonate solution without air bubbles, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated by filtration. Column chromatography (dichloromethane: methanol = 97: 3, V / V) to give 1.805 g of a colorless oil in a yield of 98.0%.
70%
With thionyl chloride; at 0℃; for 12h;
Methyl 4-fluoro-2-methoxybenzoate. To a solution of 4-fluoro-2-methoxybenzoic acid (1.7 g, 10 mmol) in methanol (100 mL) was added thionyl chloride (5.73 g, 48 mmol) at 0C. The resultant mixture was stirred for 12 hours and then solvent was evaporated in vacuo. To the residue, saturated sodium bicarbonate aqueous solution (50 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was dried by sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuo to give methyl 4-fluoro-2- methoxybenzoate (1.3 g, 70%).
70%
With thionyl chloride; at 0℃; for 12h;
To a solution of 4-fluoro-2-methoxybenzoic acid (1.7 g, 10 mmol) in methanol (100 mL) was added thionyl chloride (5.73 g, 48 mmol) at 0 C. The resultant mixture was stirred for 12 hours and then solvent was evaporated in vacuo. To the residue, saturated sodium bicarbonate aqueous solution (50 mL) was added and the mixture was extracted with ethyl acetate (100 mL×3). The organic phase was dried by sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuo to give methyl 4-fluoro-2-methoxybenzoate (1.3 g, 70%).
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 12h;
Methyl 2-methoxy-4-phenoxybenzoate. To a solution of methyl 4-fluoro-2- methoxybenzoate (1.84 g, 10 mmol) in N, N-dimethylformamide (100 mL) were added phenol (0.94 g, 10 mmol) and potassium carbonate (2.67 g, 20 mmol). The mixture was heated to 80C and stirred for 12 hours. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 7: 1) to give methyl 2- methoxy-4-phenoxybenzoate (2.1 g, 81%).
81%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 12h;
To a solution of <strong>[204707-42-6]methyl 4-fluoro-2-methoxybenzoate</strong> (1.84 g, 10 mmol) in N,N-dimethylformamide (100 mL) were added phenol (0.94 g, 10 mmol) and potassium carbonate (2.67 g, 20 mmol). The mixture was heated to 80 C. and stirred for 12 hours. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=7:1) to give methyl 2-methoxy-4-phenoxybenzoate (2.1 g, 81%).
1-(2-(5-cyclopropyl-4-(4,4-difluoropiperidin-1-yl)-2-methoxybenzyl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl)-4-methylpiperidine-4-carboxylic acid[ No CAS ]
ethyl 1-(2-(5-cyclopropyl-4-(4,4-difluoropiperidin-1-yl)-2-methoxybenzyl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl)-4-methylpiperidine-4-carboxylate[ No CAS ]
methyl 4-(4,4-difluoropiperidin-1-yl)-2-methoxybenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.24 g
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;
A mixture of <strong>[204707-42-6]methyl 4-fluoro-2-methoxybenzoate</strong> (2.17 g), potassium carbonate (3.25 g), 4,4-difluoropipericline hydrochloride (3.71 g) and DMF (30 mL) was stirred overnight at 120C. Water was added to the reaction mixture, and extraction thereof was performed using ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by a silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the title compound (1.24 g). ^NMR (300 MHz, CDC13) delta 1.87-2.21 (4H, m), 3.43-3.56 (4H, m), 3.84 (3H, s), 3.90 (3H, s), 6.40 (1H, d, J = 2.3 Hz), 6.48 (1H, dd, J = 8.8, 2.4 Hz), 7.81 (1H, d, J = 8.8 Hz).
22A. Methyl 4-fluoro-2-methoxy-benzoatePotassium carbonate (15.5 g, 112 mmol) was added to a stirred solution of 4-fluoro-2- hydroxy-benzoic acid (5.0 g, 32.1 mmol) in acetone (100 mL) and the mixture heated to 40C under a nitrogen atmosphere for 20 minutes. Methyl iodide (15.8 g, 112mmol) was added dropwise and then the mixture heated to reflux for 20 hours then allowed to cool to room temperature. The mixture was filtered through celite and the filtrate concentrated under reduced pressure to give the title compound (5.9 g, 100%) which was used without further purification.
22B. tert-Butyl 4-(3-methoxy-4-methoxycarbonyl-henyl)erazine-1 -carboxylatePotassium carbonate (1.49 g, 10.8 mmol) was added to a stirred solution of methyl 4- fluoro-2-methoxy-benzoate (1.0 g, 5.4 mmol) in DMSO (10 mL) and the mixture stirred at room temperature under a nitrogen atmosphere for 20 minutes. N-Boc piperazine (2.01 g, 10.8 mmol) was added and then the mixture heated to 80C for 18 hours. The cooled mixture was poured into ice-water (100 mL) and extracted with EtOAc (5 x 150mL). The combined organic extracts were washed with brine (100 mL), dried (Na2504) and evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 45% EtOAc/hexane as the eluent to give the title compound (4.6 g, 41%) as a white solid.
4-(6-((1-(4-(3-(2,6-difluoro-3-(((R)-3-fluoropyrrolidine)-1-sulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)-N-(2,6-dioxopiperidin-3-yl)-2-methoxybenzamide[ No CAS ]
tert-butyl 6-(3-methoxy-4-(methoxycarbonyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 120℃; for 2h;
To a solution of methyl 4-fluoro-2-methoxy-benzoate (500 mg, 2.71 mmol, 1 eq) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate;oxalic acid (660 mg, 1.36 mmol, 0.5 eq) in dimethylsulfoxide (10 mL) was added diisopropylethylamine (701 mg, 5.43 mmol, 945.80 uL, 2 eq). The mixture was stirred at 120 C for 2 h. Water (50 mL) was poured into the mixture and stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=10/1 to 1/1). Compound tert-butyl 6-(3- methoxy-4-methoxycarbonyl-phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (250 mg, 0.68 mmol, 25% yield) was obtained as a white solid. LC/MS (ESI) m/z: 363.2 [M+1] +.
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