| 77% |
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane Heating / reflux; |
2
A mixture of 2,6-difluorobenzoic acid (10 g, 63.3 mmol) and DMF (3 drops) in dichloromethane (150 ml) was treated with thionyl chloride (23 ml, 316.5 mmol). The mixture was heated at reflux overnight. The solvent was removed in vacuo and the residue azeotroped (toluene 3×50 ml) to give 2,6-difluorobenzoyl chloride as an oil (8.59 g, 77%). N Boc-L4-aminophenylalanine methyl ester (100.92 g, 40.6 mmol) and NMM (5.3 ml, 48.7 mmol) were added to a solution of the above acid chloride in DMF (50 nm). The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and aqueous. The aqueous layer was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried (MgSO4) and evaporated in vacuo to give a pale brown oily solid. Trituration with ether gave the title compound as a white solid (6.93 g). δH(d6 DMSO) 7.67-7.53 (3H, m), 7.27-7.20 (5H, m), 4.19-4.11 (1H, m), 3.62 (3H, s), 3.00-2.73 (2H, m), 1.33 (9H, s); m/z (ESI, 70V) 457 (M++Na). |
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With thionyl chloride for 2h; Heating; |
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With thionyl chloride for 3h; Heating; |
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With thionyl chloride for 12h; Heating; |
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With oxalyl dichloride; N-ethyl-N,N-diisopropylamine; N,N-dimethyl-formamide In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h; |
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With thionyl chloride |
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With thionyl chloride In N,N-dimethyl-formamide |
1.B B.
B. 2,6-Difluorobenzoyl chloride A solution of 2,6-difluorobenzoic acid (1.58 g, 10.0 mmol) and SOCl2 (1.1 ml, 15 mmol) were refluxed at 80° C. for 1 hr. Two drops of DMF were added and reflux continued for 15 min. to dissolve any remaining solid. Excess SOCl2 was evaporated in vacuo to give 2,6-difluorobenzoyl chloride as a light yellow oil. |
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With chloroformic acid ethyl ester; triethylamine In dichloromethane at 0℃; for 0.5h; |
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With thionyl chloride |
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With thionyl chloride |
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With thionyl chloride for 8h; Reflux; |
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With thionyl chloride In N,N-dimethyl-formamide; toluene at 20℃; Inert atmosphere; |
4.2. General procedure for the preparation of a solution of acid chlorides in CH2Cl2
General procedure: To a solution of carboxylic acids (1.7 mmol) in dry DMF (100 μL) and dry toluene (15 mL) under nitrogen atmosphere, freshly distillated thionyl chloride (3.4 mmol) was added and the solution was stirred at room temperature overnight. The solvent and thionyl chloride were removed under vacuum. The acid chloride was dissolved with dichloromethane (15 mL) under nitrogen atmosphere and directly used for the synthesis of the boronic acid. |
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With thionyl chloride for 5h; Reflux; Sealed tube; |
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With thionyl chloride; N,N-dimethyl-formamide at 70℃; for 2.5h; |
Preparation of 2,6-difluorobenzoyl chloride (iv) S2)
The mixture of 2,6-difluorobenzoic acid (iii) (500 mg, 3.17 mmol), thionyl chloride (11.5mL, 159 mmol) and DMF (19 μL) was heated at 70 C for 2.5 h. After cooling, the volatile materials were removed under the reduced pressure to give benzoyl chloride iv S2) as a yellow oil, which was used to the next reaction without purification. |
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With thionyl chloride In toluene for 3h; Reflux; |
General synthetic procedure for compounds 3a-3t
General procedure: A solution of thionyl chloride (25 mmol) was addeddropwisely to 1 (20 mmol) in toluene(15 mL). The mixture was heated to reflux for 3 h. Excess thionyl chloride wasremoved in vacuo. The remained mixture was added dropwise to ammonia waterbelow 10 °C, then stirred at 10 °C for 1 h. The intermediate 3 was obtained as white solid by filtration. |
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With oxalyl dichloride |
4. General Procedure for Preparation of substituent benzoyl isocyanates M6
General procedure: The reaction of substituted benzoic acid M4 (10 mmol) with oxalyl chloride (2.52 g, 20 mmol) gavesubstituted benzoyl chloride. A solution of the substituted benzoyl chloridewas added dropwise to the solution of ammonium hydroxide (5 mL) indichloromethane (10 mL) at 0 oC. Then the reaction mixture wasstirred for 3.5 h at room temperature. Dichloromethane (10 mL) was added to themixture and the mixture was washed with water, a solution of sodium hydroxide(1 M), a solution of diluted hydrochloric acid (1 M) and brine, dried oversodiumsulfate and ltered. The solvent was evaporated under reduced pressure toget crude products. The crude products were recrystallized with dichloromethaneto give the pure compounds M5, whichwere used directly for preparation of isocyanates M6. The key intermediates isocyanates M6wereprepared by the usual method. Substituted benzamides M5 (5mmol), and to this 10mmol of oxalyl chloride was addeddropwisefor 10 min at ice-bath. After addition, the resulting clearsolution was heatedat about 75 oC for 6-8 h, and then the excessive oxalyl chloride wasremoved under reduced pressure to givea clear solution of substituted benzoylisocyanate M6, which was usedfor thenext step reaction without further purication. |
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With thionyl chloride for 2h; Reflux; |
General procedure for the synthesis of the target compounds 8a-8e:
(i) A solution of 2,6-difluorobenzoic acid (0.32 mol) in thionyl chloride (100 mL) was heated to reflux for 2 h. The resulting solution was concentrated and acid chloride intermediate was used in the next step without additional purification. To a solution of the acid chloride in anhydrous THF (100 mL) was added ammonium hydroxide (79 mL) at 0 °C. After stirring at room temperature for 0.5 h, the reaction mixture was concentrated under reduced pressure. Then the reaction mixture was poured into cooled water (50 mL), extracted with ethyl acetate (100 mL x 3), and washed with brine (150 mL x 2). The organic layer was dried and concentrated to give the intermediate 2 in 90% yield which used in next step without purification. (ii) To a solution of 2,6-difluorobenzamide (0.28 mol) in concentrated sulfuric acid (90 mL) was added fuming nitric acid (12 mL) by dropwise under 0 °C. The mixture was stirred for 2 h at room temperature. The pH was adjusted to 6 with 30% sodium hydroxide solution, then filtered and the filtrate was extracted with ethyl acetate (100 mL x 3),and washed with brine (150 mL x 2). The organic layer was dried and concentrated in vacuo to give the intermediate 3 as yellow solid in 91.40%yield. (iii) To a solution of 2,6-difluoro-3-nitrobenzamide (0.25 mol) in ethanol (300 mL) was added ammonium hydroxide (25 mL). The reaction mixture was stirred at room temperature overnight and the precipitate was collected by filtration, washed with isopropanol and dried in vacuum to give 4 31.5 g as yellow solid, yield 77.6%. (iv) A suspension of 2-amino-6-fluoro-3-nitrobenzamide (0.05 mol) in ethanol (100 mL) was reduced by hydrogen in the presence of palladium on carbon (10%, 1.00 g). After stirring at room temperature for 12 h, the reaction mixture was filtered. Solvent was removed under reduced pressure and the residue was subjected to silica gel column chromatography using dichloromethane/methanol (3:1) as eluent to give 55.00 g as light yellow solid, yield 58.9%. (v) To a solution of 3-pipecolinic acid (0.06 mol) and 2,3-diamino-6-fluorobenzamide (0.06 mol) in DMF (100 mL) was treated with PyBOP (0.06 mol) and N,N-diisopropylethylamine (0.18 mol).The reaction mixture was stirred at room temperature overnight. The solvent was removed using high vacuum. The residue was subjected to flash column chromatography using methylene chloride/methanol (30:1) to give the intermediate 6 as a white solid. The intermediate 6 was dissolved in glacial acetic acid (30 mL) and refluxed for 4 h until the reaction was complete (monitoring by TLC). The solvent was removed and the solid residue was purified by column chromatography using methylene chloride/methanol(80:1) as eluent to give pure 7a-7e in 50-72% yield. (vi) A solution of 7a-7e (25 mmol) in methanol (100 mL) was reduced with hydrogen in the presence of palladium on carbon (10%, 1.00 g). After stirring at room temperature for 12 h, the reaction mixture was filtered, and the filtrate was concentrated to give pure target compounds 8a-8e in 52-80% yield. |
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With thionyl chloride; N,N-dimethyl-formamide for 5h; Reflux; |
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With thionyl chloride; N,N-dimethyl-formamide at 20℃; for 2.5h; Reflux; |
11.1 1. Step A: Synthesis of 2,6-difluorobenzoylchloride
Equipped with a reflux condenser, a 50mL two-necked flask was added 1.58g 2,6-difluorobenzoic acid and 10mL thionyl chloride. Simultaneously, 2-3 drops of DMF as a catalyst was added dropwise. It was stirred at room temperature for 30min. The reaction temperature was slowly heated to reflux for 2h. The remaining distilled thionyl chloride. The product obtained was used directly in the next reaction. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 0.5h; |
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With thionyl chloride In water monomer at 20℃; |
1.3 preparation of compound IV
To the 250 ml flask is added in three 17.2g (0.1 µM) 2, 6 - difluoro-benzamide, normal temperature next adds by drops 20% NaOH (0.2 µM) thionyl chloride aqueous solution, stirring and heating to reflux, the reaction 1 - 2h. Thin layer chromatography tracking response, the raw materials point disappears, stopping the reaction. Building material acidification, filtering and drying to obtain white solid 15g. The above-mentioned product 15g added to the 250 ml three flasks, normal temperature next adds by drops 0.15 µM asian maple tree chloride, stirring and heating to reflux, the reaction 2 - 3h. Thin layer chromatography tracking response, the raw materials point disappears, stopping the reaction. Reduced pressure distillation to remove the solvent, to obtain the product 16.75g, yield 100%. |
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With thionyl chloride |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 3h; Inert atmosphere; |
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| 77.8 g |
With thionyl chloride In N,N-dimethyl-formamide for 8h; Inert atmosphere; Reflux; |
1.1 Synthesis of 3- [4- (2,6-difluorobenzoyl) phenyl] propionic acid monomer
The first step, under an argon atmosphere,In a 1000 mL three-necked flask equipped with a mechanical stirrer, 100 g (0.63 mol) of 2,6-difluorobenzoic acid,400mL thionyl chloride, dripped 2mL Ν, N- dimethylformamide, after the addition was stirred,Heated to reflux of thionyl chloride, the reaction 8 hours, after the completion of the reaction to remove atmospheric pressure distillation thionyl chloride,Vacuum distillation gave a colorless, clear liquid A, 2,6-difluorobenzoyl chloride. After weighing 77.8g; |
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With thionyl chloride Reflux; |
4.1 1) Synthesis of 2,6-difluorobenzoyl chloride:
Add 1.58g (10.0mmol) benzoic acid to a 100ml single-mouth reaction flask.15 ml of dichlorosulfoxide was slowly added dropwise with stirring, and then the reaction was heated to reflux until the solid disappeared completely.Continue refluxing for 2-3 hours and dry the solvent on a rotary evaporator.Add a small amount of toluene to dissolve and spin dry.Try to keep the excess of thionyl chloride clean.Then a certain amount of dichloromethane was added for dissolution and used for the next step. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; Inert atmosphere; |
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With thionyl chloride Reflux; |
1.5 Synthesis of intermediate 6
General procedure: The corresponding acid compound 5 (10 mmol) was completely dissolved in 30 mL of SOCl2. The reaction was stirred at reflux temperature for 12 h. The mixture was evaporated under vacuum, the residue was dissolved in 10 mL of dry DCM and used in next step without purification. |
| 22.3 g |
With thionyl chloride at 50℃; for 4h; |
2.1 Step 1: Preparation of Intermediate 3
A mixture of 2,6-difluoro-benzoic acid (20.0 g) and thionylchloride (75 mL) was stirred at 50 °C for 4 hours before thionylchloride was evaporated under reduced pressure. Traces of thionychloride were removed from the mixture by means of co-evaporation with benzene to afford 22.3 g of the title compound intermediate. |
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With thionyl chloride at 75℃; for 4h; |
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With thionyl chloride In toluene Reflux; |
1.1 (1) Synthesis of 2,6-difluorobenzoyl chloride
In a 250mL three-necked flask,Add 0.2mol (31.62g) of 2,6-difluorobenzoic acid,Add 50 mL of toluene solvent.Put 0.3mol (35.69g) thionyl chloride in a constant pressure funnel,And add 50mL of toluene to dilute it.Was heated to reflux with stirring was slowly added dropwise thionyl chloride diluent.During the reaction, the TLC method was used for tracking detection.After the reaction, the reaction mixture was rotovaped under reduced pressure to remove the solvent,The product 2,6-difluorobenzoyl chloride was obtained and used in the next reaction. |
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With thionyl chloride In 1,2-dichloro-ethane at 20℃; Reflux; |
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With thionyl chloride In toluene for 2h; Reflux; |
General method for the preparation of the substitutedbenzoyl chloride precursors
The respective substituted benzoic acid was dissolved intoluene (ca. 20 mL per mmol) and two equivalents ofthionyl chloride were added. After heating to reflux for 2 h,the solvent and excess thionyl chloride were removed in vacuum and the substituted benzoyl chloride thus obtainedwas used in the next synthetic step without purification. |
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With thionyl chloride at 80℃; for 2h; Inert atmosphere; |
24.1 Step 1: Synthesis of 2,6-difluorobenzoyl chloride
A solution of 2,6-difluorobenzoic acid (3 g, 18.98 mmol, 1 eq.) in SOCl2 (30 mL) was stirred at 80° C. for two hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The crude product was used for next step directly without purification. 2,6-difluorobenzoyl chloride (3 g, 21.79 mmol, 99.27% yield, 86.03% purity) was obtained as light yellow oil. |
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With thionyl chloride; N,N-dimethyl-formamide In tetrahydrofuran at 65℃; for 1h; |
11.2; 22.2 (2) Synthesis of 2-(2,6-difluoro)benzamide-4,5,6,7-tetrahydrobenzo(b)thiophene-3-carboxylic acid ethyl ester derivatives
Weigh 1.5 eq of 2,6-difluorobenzoic acid, add tetrahydrofuran, 10 eq of thionyl chloride and 1 drop of N,N-dimethylformamide, and stir at room temperature. The solution is colorless and transparent. The temperature was raised to 65°C, and the mixture was stirred for 1 hour until the reaction was completed as detected by TLC. The reaction solution was concentrated under reduced pressure to obtain the benzoyl chloride derivative, which was used for later use. |
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With thionyl chloride Reflux; |
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With thionyl chloride Reflux; |
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