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Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
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Structure of 393-52-2 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Heterocyclic Chemistry, 1989, vol. 26, p. 257 - 264
2
[ 445-29-4 ]
[ 393-52-2 ]
Yield
Reaction Conditions
Operation in experiment
70%
With thionyl chloride In toluene at 50℃; for 7 h; Reflux
Step I 2-fluorobenzoyl chloride (Intermediate a) To 100mL of toluene were added 0.714 mol of 2-fluorobenzoic acid (100 g) then the mixture was heated to 50°C and added 5.7 mol (414mL) sulfoxide chloride .The reaction mixture was refluxed for 7 h. After completion of the reaction, sulfoxide chloride was evaporated to give 2-fluorobenzoyl chloride 79 g. Yield: 70percent.
70%
With thionyl chloride In toluene at 50℃; for 7 h;
To 100 mL of toluene were added 0.714 mol of 2-fluorobenzoic acid (100 g) then the mixture was heated to 50° C. and added 5.7 mol (414 mL) sulfoxide chloride. The reaction mixture was refluxed for 7 h. After completion of the reaction, sulfoxide chloride was evaporated to give 2-fluorobenzoyl chloride 79 g. Yield: 70percent.
Reference：
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[41] Medicinal Chemistry, 2010, vol. 6, # 4, p. 211 - 218
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[50] Chemistry--A European Journal, 2015, vol. 21, # 1, p. 205 - 209
[51] Archiv der Pharmazie, 2013, vol. 346, # 7, p. 521 - 533
[52] Patent: EP2647622, 2013, A1, . Location in patent: Paragraph 0124
[53] Patent: US2013/317110, 2013, A1, . Location in patent: Paragraph 0139
[54] Bioorganic Chemistry, 2014, vol. 52, p. 1 - 7
[55] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 1, p. 192 - 194
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[58] Letters in Drug Design and Discovery, 2015, vol. 12, # 6, p. 488 - 494
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[60] Patent: WO2014/125506, 2014, A2, . Location in patent: Page/Page column 21
[61] Journal of the Chemical Society of Pakistan, 2013, vol. 35, # 2, p. 449 - 455
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[80] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 14, p. 3263 - 3270
[81] Chemical Communications, 2016, vol. 52, # 70, p. 10676 - 10679
[82] Chinese Chemical Letters, 2016, vol. 27, # 9, p. 1547 - 1550
[83] Pharmacological Research, 2016, vol. 113, p. 610 - 625
[84] Chemical Biology and Drug Design, 2016, p. 664 - 676
[85] Tetrahedron Letters, 2016, vol. 57, # 48, p. 5372 - 5376
[86] Molecules, 2016, vol. 21, # 11,
[87] Organic Letters, 2016, vol. 18, # 21, p. 5536 - 5539
[88] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 3, p. 393 - 397
[89] Tetrahedron, 2017, vol. 73, # 12, p. 1576 - 1582
[90] Journal of Organic Chemistry, 2017, vol. 82, # 6, p. 3245 - 3251
[91] Chemistry - A European Journal, 2017, vol. 23, # 15, p. 3577 - 3582
[92] Patent: WO2017/37672, 2017, A1, . Location in patent: Page/Page column 49; 50
[93] Journal of Molecular Structure, 2017, vol. 1138, p. 177 - 191
[94] Journal of Organic Chemistry, 2017, vol. 82, # 1, p. 420 - 430
[95] Chemical Communications, 2017, vol. 53, # 33, p. 4601 - 4604
[96] Organic Letters, 2017, vol. 19, # 10, p. 2746 - 2749
[97] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 11, p. 2641 - 2644
[98] Synthesis (Germany), 2017, vol. 49, # 13, p. 2865 - 2872
[99] Journal of Medicinal Chemistry, 2017, vol. 60, # 15, p. 6622 - 6637
[100] Synthesis (Germany), 2017, vol. 49, # 17, p. 3937 - 3944
[101] Chemistry - A European Journal, 2018, vol. 24, # 10, p. 2360 - 2364
[102] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 1740 - 1750
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[107] Chemical Communications, 2018, vol. 54, # 77, p. 10859 - 10862
[108] Patent: US4022900, 1977, A,
3
[ 320-11-6 ]
[ 393-52-2 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 125 - 130℃; for 1 h;
(2) taking 2.97 mol of o-chlorotrichlorobenzene obtained in step (1)Stirring up to 125 ~ 130 ,Keep micro negative pressure,The micro-negative pressure is 0 to 0.5 cm water column,Began to slowly drop 0.5percent zinc chloride aqueous solution,3 hours drop finished,Maintaining the reaction temperature 125 to 130 ° C,Insulation for 1 hour,GC tracking reaction process,If the o-fluoro-trichloro Bian complement the incomplete conversion zinc chloride solution dropwise until complete conversion of o-fluoro-trichloro Bian,Using vacuum distillation method of purification,Collecting 100 to 105 ° C fractions,The product was o-fluorobenzoyl chloride 416.6 g,Purity 99.5percent yield 98percent.
Reference：
[1] Patent: CN106008197, 2016, A, . Location in patent: Paragraph 00119; 0020
4
[ 445-29-4 ]
[ 393-52-2 ]
Reference：
[1] Patent: US4999356, 1991, A,
5
[ 445-29-4 ]
[ 393-52-2 ]
Reference：
[1] Patent: US4999356, 1991, A,
6
[ 445-29-4 ]
[ 393-52-2 ]
Reference：
[1] Patent: US4195023, 1980, A,
7
[ 10026-13-8 ]
[ 108-95-2 ]
[ 445-29-4 ]
[ 393-52-2 ]
Reference：
[1] Patent: US4999356, 1991, A,
8
[ 10026-13-8 ]
[ 108-95-2 ]
[ 445-29-4 ]
[ 393-52-2 ]
Reference：
[1] Patent: US4999356, 1991, A,
9
[ 69038-73-9 ]
[ 393-52-2 ]
Reference：
[1] Journal of Organic Chemistry, 2017, vol. 82, # 6, p. 3245 - 3251
10
[ 3416-93-1 ]
[ 445-29-4 ]
[ 393-52-2 ]
Reference：
[1] Journal of the American Chemical Society, 2014, vol. 136, # 9, p. 3354 - 3357
11
[ 79-37-8 ]
[ 445-29-4 ]
[ 393-52-2 ]
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 50, p. 12149 - 12152
12
[ 106-47-8 ]
[ 393-52-2 ]
[ 784-38-3 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2001, vol. 38, # 3, p. 663 - 669
[2] Synthetic Communications, 2012, vol. 42, # 1, p. 46 - 54
13
[ 393-52-2 ]
[ 2886-65-9 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2001, vol. 38, # 3, p. 663 - 669
14
[ 696-62-8 ]
[ 393-52-2 ]
[ 348-52-7 ]
[ 100-07-2 ]
Reference：
[1] Journal of the American Chemical Society, 2018, vol. 140, # 32, p. 10140 - 10144
15
[ 393-52-2 ]
[ 446-24-2 ]
Reference：
[1] Chemistry of Heterocyclic Compounds, 2005, vol. 41, # 12, p. 1511 - 1520
[2] Journal of Heterocyclic Chemistry, 1989, vol. 26, p. 257 - 264
[3] Chemische Berichte, 1937, vol. 70, p. 1416,1419
[4] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 1, p. 192 - 194
[5] Journal of Fluorescence, 2014, vol. 24, # 4, p. 995 - 1001
[6] Journal of Molecular Structure, 2016, vol. 1117, p. 8 - 16
[7] Journal of Molecular Structure, 2017, vol. 1138, p. 177 - 191
16
[ 393-52-2 ]
[ 443-26-5 ]
Reference：
[1] Patent: US4801717, 1989, A,
17
[ 64-17-5 ]
[ 393-52-2 ]
[ 443-26-5 ]
Reference：
[1] Tetrahedron, 1997, vol. 53, # 22, p. 7557 - 7576
[2] Journal of Organic Chemistry, 2008, vol. 73, # 24, p. 9781 - 9783
18
[ 393-52-2 ]
[ 80277-41-4 ]
Yield
Reaction Conditions
Operation in experiment
66%
With sodium iodide In dichloromethane; acetonitrile
STR22 The reaction was carried out under Argon. Cuprous cyanide (4.67 g, 52.2 mmol) and anhydrous sodium iodide (14.61 g, 97 mmol) were stirred for 2 minutes in anhydrous acetonitrile (100 ml). The resulting solution was mixed with o-fluoro benzoyl chloride (7.73 g, 48.7 mmol) whereupon an orange precipitate formed. The mixture was stirred for 30 minutes at room temperature, filtered and concentrated in vacuo. The residue was taken up in dichloromethane and the resultant precipitate was filtered off. Concentration of the filtrate under reduced pressure gave an orange oil. Distillation in Kugelror apparatus gave o-fluorobenzoyl cyanide as a yellow liquid (5.07 g, 66percent). NMR (60 MHz, CDCl3): δ 7.2-8.2 (4H, complex). IR (liquid film): 2225 (medium), 1680 (strong), 1610 (strong), 1580 (medium), 750 (strong) cm-1.
Reference：
[1] Patent: US4912262, 1990, A,
[2] Journal of Organic Chemistry, 2017, vol. 82, # 1, p. 680 - 687
Reference：
[1] Chemische Berichte, 1937, vol. 70, p. 1416,1419
[2] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 10, p. 2544 - 2546
[3] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 14, p. 3263 - 3270
22
[ 393-52-2 ]
[ 399-31-5 ]
Reference：
[1] Chemische Berichte, 1937, vol. 70, p. 1416,1419
23
[ 6148-64-7 ]
[ 393-52-2 ]
[ 1479-24-9 ]
Yield
Reaction Conditions
Operation in experiment
92%
Stage #1: With triethylamine; magnesium chloride In acetonitrile at 20℃; for 0.5 h; Stage #2: With triethylamine In acetonitrile at 20℃;
Experimental operation: Take malonate potassium salt 1.00 g (about 5.47mmol) of anhydrous magnesium chloride and 0.65 g (About 6.84mmol) in 25 mLround bottom flask was added dropwise 0.55 g of triethylamine was added after 6mL of acetonitrile was dissolved, stirred 30 min at room temperature. Thendropped by 2 mL of acetonitrile was dissolved 0.48 g (2.5 mmol) o-fluorobenzoyl chloride ld, supplemented triethylamine 0.06 mL, stirred atroom temperature overnight. After treatment: 30 mL of water was added to dilutethe reaction solution, and then were added 30,20,20 mL ethyl acetate, and theethyl acetate layer was collected. After 30 mL with saturated brine ethylacetate layer was dried over anhydrous sodium sulfate, and spin dry columnchromatography (PE: EA = 15: 1) to give the product isolated 2d, in 92percent yield.
13.5 g
Stage #1: With triethylamine; magnesium chloride In tetrahydrofuran at 10 - 35℃; for 8.5 h; Stage #2: at 15 - 35℃; for 16 h;
Example-12: Preparation of compound of Formula Xlla. 2-fluorobenzoic acid (lOg) toluene (80ml) and dimethyl formamide (0.1ml) were charged into a round bottom flask at 25-35°C. To the reaction mass thionyl chloride (12.7g) was added slowly over a period of 30min at same temperature. Reaction mass was heated to reflux and stirred for 3-4hr. After completion of the reaction, reaction mass was cooled to 55-65°C and distilled completely under vacuum at 55-65°C and co-distilled with toluene (2x20ml) to obtain residue and the residue was dissolved in tetrahydrofuran (50ml). Tetrahydrofuran (150ml) and magnesium chloride (24.5g) was added in another round bottom flask at 25-35°C. Reaction mass was cooled to 10-15°C and was added potassium salt of monoethylmalonate (36.4g) at same temperature. To the reaction mass was added triethyl amine (21.6g) slowly over a period of 30min and reaction mass was heated to 25- 35 °C and stirred for 8hr at same temperature. To the reaction mass was added above pre dissolved tetrahydrofuran solution of 2-fluorobenzoyl chloride at 15-25°C and stirred for 16hr at 25-35°C. After completion of the reaction, reaction mass was distilled completely under vacuum at below 50°C and cooled to 25-35°C. To the resultant reaction mass was added water (400ml) and stirred for 3hr at same temperature. Filtered the precipitated solids and washed with water (10ml). The obtained solids were stirred with water (200ml), and a mixture of water (100ml) and sodium bicarbonate (50g), a mixture of water (100ml) and hydrochloric acid (10ml) sequentially at 25-35°C and filtered the solid and washed with water (10ml). The obtained solid was stirred with methanol (20ml) for 40min at 25-35°C. Filtered the solids and washed with methanol (10ml) and dryed the material to obtain title compound. Yield: 13.5 g.
Reference：
[1] Patent: CN105663112, 2016, A, . Location in patent: Page/Page column 15
[2] Patent: WO2017/37672, 2017, A1, . Location in patent: Page/Page column 49; 50
24
[ 1071-46-1 ]
[ 393-52-2 ]
[ 1479-24-9 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2011, vol. 48, # 3, p. 620 - 625
25
[ 393-52-2 ]
[ 1479-24-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 11, p. 2843 - 2855
[2] Archiv der Pharmazie, 2013, vol. 346, # 7, p. 521 - 533
[3] Patent: EP2799437, 2014, A1,
[4] Patent: US2014/364431, 2014, A1,
26
[ 35227-78-2 ]
[ 393-52-2 ]
[ 1479-24-9 ]
Reference：
[1] Synthesis, 1983, # 1, p. 52 - 53
27
[ 352-13-6 ]
[ 393-52-2 ]
[ 342-25-6 ]
Yield
Reaction Conditions
Operation in experiment
72%
at 25℃; for 1 h;
General procedure: 2-Fluorobenzoyl chloride (6 mmol, 1.0 eq) in 2-methyltetrahydrofuran (15 mL) and Compound 2 (9 mmol,1.5 eq) of 2-methyltetrahydrofuran solution (15 mL) passed through material channels A and B, respectively, via metering pumps P1, P2.Mixing into a mixing module M having a preset temperature of 25 ° C at a flow rate of 1 mL/min,After staying in the reaction module L for 1 h,The reaction solution flows out from the outlet D.The reaction liquid flowing out from the outlet D was collected in a 1 mol/L hydrochloric acid solution.Quenched by stirring,Saturated saline solution,Dry over anhydrous sodium sulfate,Post-treatment by concentration, column chromatography, etc.Compound 5 was obtained.
Reference：
[1] Patent: CN108409516, 2018, A, . Location in patent: Paragraph 0049-0052
[2] Journal of the American Chemical Society, 1947, vol. 69, p. 662
28
[ 462-06-6 ]
[ 393-52-2 ]
[ 342-25-6 ]
Reference：
[1] Tetrahedron Letters, 2009, vol. 50, # 4, p. 446 - 447
[2] Journal of the American Chemical Society, 1947, vol. 69, p. 662
[3] Russian Chemical Bulletin, 2001, vol. 50, # 7, p. 1208 - 1213
29
[ 74-85-1 ]
[ 393-52-2 ]
[ 651735-59-0 ]
Yield
Reaction Conditions
Operation in experiment
2.5 g
With aluminum (III) chloride; sodium chloride In dichloromethane for 2 h; Cooling with ice
As presented in the following reaction formula, a crude product of Compound 2 was dissolved in methylene chloride (50 mL). Under cooling with ice, aluminum chloride (AlCl3; 13 g, 9.7 mmol) and sodium chloride (NaCl; 6 g, 10 mmol) were added to the resulting solution, and ethylene gas was introduced for 2 hours to the mixture under stirring. Then, 100 g of ice was added to the reaction mixture, followed by filtrating. The filtrate was extracted three times with 30 mL of ether and then washed with 100 mL of saturated brine. The filtrate was dried and concentrated with anhydrous sodium sulfate, and purified with a silica gel column of 100 g using n-hexane and ethyl acetate, to thereby give Compound 3 of interest (2.5 g, yield: 23percent).
2.5 g
With aluminum (III) chloride; sodium chloride In dichloromethane for 2 h; Cooling with ice
As presented in the following reaction formula, a crude product of Compound 2 was dissolved in methylene chloride (50 mL). Under cooling with ice, aluminum chloride (AlCl3; 13 g, 9.7 mmol) and sodium chloride (NaCl; 6 g, 10 mmol) were added to the resulting solution, and ethylene gas was introduced for 2 hours to the mixture under stirring. Then, 100 g of ice was added to the reaction mixture, followed by filtrating. The filtrate was extracted three times with 30 mL of ether and then washed with 100 mL of saturated brine. The filtrate was dried and concentrated with anhydrous sodium sulfate, and purified with a silica gel column of 100 g using n-hexane and ethyl acetate, to thereby give Compound 3 of interest (2.5 g, yield: 23percent).
Reference：
[1] Journal of Organic Chemistry, 2003, vol. 68, # 26, p. 10195 - 10198
31
[ 393-52-2 ]
[ 775304-57-9 ]
Yield
Reaction Conditions
Operation in experiment
76%
Stage #1: With hydroxylamine In water; <i>tert</i>-butyl alcohol at 38 - 41℃; for 21 h; Stage #2: With triethylamine In water; <i>tert</i>-butyl alcohol at 27 - 40℃; for 7 h;
3-[5-(2-fluorophenylHl,2,41oxad-azol-3-vπ-benzoic acid: One pot process; Reflux <n="25"/>[0188] A reactor vessel was charged with 3-Cyanobenzoic acid (7.35 g) and molten ter/-butanol (100 raL). The vessel was sealed and the batch temperature was set to 600C and the agitator was started. The suspension was stirred for Ih and then the batch temperature was set to 400C. 50percent aqueous hydroxylamine (3.63 g) was charged to the reactor in an inert atmosphere over 3 hours. The batch temperature was maintained at 38- 410C during the addition. The reaction was completed after stirring for 18 hours at 400C. [0189] The batch was cooled to 27°C and charged with triethylamine (5.56 g) over 2 minutes. 2-Fluorobenzoyl chloride (7.82 g) was added over 3 hours. The batch temperature was maintained at 24-27°C during the addition. The batch was stirred for further 4 hours at 400C.[0190] The batch was heated to 790C over 30 minutes and stirred for 16 hours at about 79°C. To the white suspension was added water (100 mL) over 3 hours while the batch temperature was maintained at 700C. The batch was charged with 37percent aqueous hydrochloric acid over 20 minutes. The pH of the batch was determined to be about 2.2, by a pH meter and stirring at about 700C was continued for about an additional 1 hour. [0191] The batch was cooled in a linear fashion from 700C to 300C over 3 hours and the slurry was transferred into a filter. Filtration was complete after 5 minutes. The filter cakes were washed with fer/-butanol (50 mL, 40 0C) over 5 minutes. Purified water (100 mL, 600C) was applied to the cakes as the final wash. The cakes were dried in a vacuum oven at 70 0C for 18 hour and then discharged. Purity was determined to be about 98.68percent. The overall yield of isolated product was about 76percent (10.8 g).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 11, p. 2473 - 2476
33
[ 1141475-82-2 ]
[ 393-52-2 ]
[ 775304-60-4 ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium carbonate In acetone at 20℃; for 24 h;
General procedure: 2 mmol of either amidoxime 1 [30] or 2 [26] were dissolved in acetone (200 mL) in a round-bottomed flask; then, K2CO3 (0.35 g; 2.5 mmol) and the corresponding aroyl chloride (2.5 mmol), were added to the reaction mixture and stirred for 24 h at room temperature. The solvent was removed under vacuum and the residue treated with water and refluxed for 30 min 1,2,4-Oxadiazoles products were obtained by filtration and further purified by chromatography.
Reference：
[1] European Journal of Medicinal Chemistry, 2015, vol. 101, p. 236 - 244
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 11, p. 2473 - 2476
34
[ 6638-79-5 ]
[ 393-52-2 ]
[ 198967-24-7 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: With triethylamine In dichloromethane at 0℃; for 0.166667 h; Stage #2: at 0 - 20℃;
Triethylamine (5.32 mL, 37.84 mmol) was added dropwise to a solution of Ν,Ο-dimethylhydroxylamine hydrochloride (2.768 g, 28.38 mmol) in anhydrous dichloromethane (45 mL) at 0 °C. After stirring for 10 min, 2-fluorobenzoyl chloride (0.303 mL, 2.52 mmol) in anhydrous dichloromethane (15 mL) was added dropwise. The reaction mixture was returned to room temperature and stirred for 5 h. The reaction mixture was quenched with water (60 mL) and the products were extracted with dichloromethane (2 x 60 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification using flash chromatography (silica gel, hexanes:ethyl acetate, gradient 93:7 to 60:40) afforded 2-Fluoro-N-methoxy-N-methyl-benzamide (3.1 16, 17 mmol) in a 90percent yield. [0
90%
Stage #1: With triethylamine In dichloromethane at 0℃; for 0.166667 h; Inert atmosphere Stage #2: at 0 - 20℃; for 5 h; Inert atmosphere
Triethylamine (5.32 mL, 37.8 mmol) was added dropwise to a solution of N,O-dimethylhydroxylamine hydrochloride (2.77 g, 28.4 mmol) in anhydrous dichloromethane (45 mL) at 0 °C. After stirring for 10 min, 2-flurobenzoyl chloride (0.303 mL, 2.52 mmol) in anhydrous dichloromethane (15 mL) was added dropwise. The reaction mixture was returned to room temperature and stirred for 5 h. The reaction mixture was quenched with water (60 mL) and the products were extracted with dichloromethane (2 * 60 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification using flash chromatography (silica gel, hexanes/ethyl acetate, gradient 93:7 to 60:40) afforded 2-Fluoro-N-methoxy-N-methyl-benzamide (3.12 g, 17.0 mmol, 90percent yield). 1H NMR (500 MHz, CDCl3): δ 7.44-7.38 (2H, m), 7.19 (1H, t, J = 7.5 Hz), 7.10 (1H, t, J = 8.9 Hz), 3.55 (3H, br s), 3.35 (3H, br s). 13C NMR (125 MHz, CDCl3): δ 166.40, 158.66, (d, J = 249 Hz), 131.50, 128.90, 124.11, 123.52 (d, J = 17 Hz), 115.69 (d, J = 21 Hz), 61.21, 32.31. 19F NMR (470 MHz, CDCl3): δ -114.04 (1F, s). HRMS (ESI) calculated for C9H10FNO2H+ (M+H)+ 184.07683, found 184.07702.
62%
With pyridine In tetrahydrofuran at 0 - 20℃; for 2.25 h;
N,O-Dimethylhydroxylamine hydrochloride (23.4 g, 240 mmol) was suspended inTHF (100 ml) and cooled to 0 °C under nitrogen. Pyridine (32 ml, 400 mmol) was addedslowly. A solution of 2-fluorobenzoyl chloride (9.5 ml, 80 mmol) in THF (50 ml) was addedover 15 min. The reaction was removed from the ice bath and stirred at rt for 2 h. Water (100ml) and AcOEt (100 ml) were added, and the phases were separated. The aq. phase wasextracted with AcOEt (100 ml). The organic phases were pooled and washed with 1 N HCI (2x 100 ml) and 1 N NaOH (100 ml). After drying over MgSO4, the sample was concentrated toyield a yellow oil (10.7 g). The oil was purified by vacuum distillation, and a colorless oil wascollected (0.22 torr, 57-59 °C, 9.1 g, 62percent yield)2-fluoro-N-methoxy-N-methylbenzamide1H-NMR (300MHz, CDCI3) 53.34 (s, 3H), 3.54 (br, 3H), 7.10 (m, 1H), 7.19 (m, 1H),7.42 (m, 2H)
Reference：
[1] RSC Advances, 2013, vol. 3, # 26, p. 10158 - 10162
[2] Patent: WO2013/142038, 2013, A2, . Location in patent: Paragraph 0130
[3] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 21, p. 6974 - 6992
[4] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 4, p. 1415 - 1419
[5] Patent: WO2006/3096, 2006, A1, . Location in patent: Page/Page column 73
[6] Chemical Communications, 2012, vol. 48, # 71, p. 8976 - 8978
35
[ 393-52-2 ]
[ 1117-97-1 ]
[ 198967-24-7 ]
Yield
Reaction Conditions
Operation in experiment
84.6%
With triethylamine In dichloromethane at 0 - 20℃;
To a solution of 2-fluorobenzoyl chloride (50 g, 0.31 mol) in CH2Cl2 (200 mL) was added N,O-dimethylhydroxylamine (46 g, 0.47 mol), and a solution of triethylamine (127 g, 1.26 mol) in CH2Cl2 (100 mL) at 0° C. The reaction mixture was warmed slowly to rt, and stirred for 3 h. The mixture was quenched with iced water and extracted with CH2Cl2 (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford 2-fluoro-N-methoxy-N-methylbenzamide (48 g, yield: 84.6percent).
General procedure: 2-Fluorobenzoyl chloride (6 mmol, 1.0 eq) in 2-methyltetrahydrofuran (15 mL) and Compound 2 (9 mmol,1.5 eq) of 2-methyltetrahydrofuran solution (15 mL) passed through material channels A and B, respectively, via metering pumps P1, P2.Mixing into a mixing module M having a preset temperature of 25 ° C at a flow rate of 1 mL/min,After staying in the reaction module L for 1 h,The reaction solution flows out from the outlet D.The reaction liquid flowing out from the outlet D was collected in a 1 mol/L hydrochloric acid solution.Quenched by stirring,Saturated saline solution,Dry over anhydrous sodium sulfate,Post-treatment by concentration, column chromatography, etc.Compound 5 was obtained.
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.
With ammonium hydroxide; In dichloromethane; at 0 - 20℃; for 3.5h;
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.
General procedure: Substituted benzoyl chloride (1.1 equiv) was added dropwise toa solution of the 2.6-dichloro-pyridin-3-amine (1 equiv) in acetonitrileat 0 C. The resulting mixture was stirred for 6 h at 80 C. Aftercooling down to room temperature, the solvent was removed underreduced pressure. The crude compound was dissolved in methanol,and then white solid was recrystallized from methanol to givedesired product.
5,8-Dichloro-2-(2-fluoro-phenyl)-4H-3,1-benzoxazin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In n-heptane; ethyl acetate;
Example 1 5,8-Dichloro-2-(2-fluoro-phenyl)-4H-3,1-benzoxazin-4-one (1). <strong>[3032-32-4]2-Amino-3,6-dichlorobenzoic acid</strong> (0.5 g) and triethyl amine (20 ml) were mixed. 2-Fluorobenzoyl chloride (0.77 g) was added dropwise under cooling and stirring. The mixture was subsequently heated to RT and stirred until disappearance of starting material was seen on TLC (silicagel) using heptane/ethyl acetate (4/1) as eluent. After cooling on ice the precipitate was filtered off and the filtrate evaporated to dryness. The residue was partitioned between methylene chloride and potassium carbonate (2N), the organic layers separated, dried over magnesium sulfate and evaporated to dryness. The raw product was purified by column chromatography on silicagel using heptane/ethyl acetate as eluent. Yield 0.31 g. m.p. 140 C.
2-Fluoro-N-(4-nitro-2-trifluoromethyl-phenyl)-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In tetrahydrofuran; at 20℃; for 12h;
General procedure: To a solution of 4 (1 mmol) and triethylamine (0.1 mL, 1 mmol) in dry THF (10 mL), substituted benzoyl chloride was added dropwise. The reaction mixture was stirred at room temperature for 12h. Then water was added to the mixture which was extracted with dichloromethane. The organic phase was washed with water and brine, dried (Na2SO4), and concentrated. The obtained crude product was purified by column chromatography to give amide 6.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;
Description 9: Methyl 2-fluoro-4-[(2-fluorophenyl)carbonyl]amino}benzoate; To a suspension of <strong>[73792-08-2]methyl 4-amino-2-fluorobenzoate</strong> <n="26"/>(5.10 g, 30.2 mmol) in dichloromethane (40 ml.) at 0 0C under a flush of argon was added N, N- diisopropylethylamine (3.90 g, 30.2 mmol) followed by 2-fluorobenzoyl chloride (5.27 g, 33.2 mmol). The reaction was stirred at room temperature over a weekend. Some of the title compound formed a precipitate as this stage, which was filtered off. The filtrate was washed with aqueous HCI (2M, 35 + 15 ml.) and further dichloromethane was added to aid dissolution. The organic phase was then isolated and dried (phase separator), concentrated in vacuo and combined with the first batch of solid to give the title compound as an orange/yellow solid (8.92 g, 30.2 mmol).LC/MS (ES +ve): [M+H]+ at m/z 292 (C15H11F2NO3 requires [M+H]+ at m/z 292).
With triethylamine; In dichloromethane; at 20℃; for 12h;
Description 22: Methyl 2-fluo onyl]amino}benzoate; Methyl 4-amino-2-fluorobenzoate (3.83 g, 22.7 mmol) and triethylamine (3.81 ml_, 27.4 mmol) were dissolved in dichloromethane (40 ml_) and treated dropwise with 2- fluorobenzoyl chloride (3.25 mL, 27.4 mmol). The mixture was stirred for 1 hour at room temperature. The solution was washed with water, dried (magnesium sulphate) and evaporated. The resulting solid was triturated with ether to give the title compound (6.13g). as a whitish solid. LC/MS (ES+ve): [M+H]+ at m/z 292 (C15H11F2NO3 requires [M+H]+ at m/z 292).
With triethylamine; In dichloromethane; at 0 - 20℃; for 2.0h;
Description 23: (Methyl and Ethyl) 2-ethyl-4-[(2- fluorophenyl)carbonyl]amino}benzoate; (Methyl and ethyl) 4-amino-2-ethylbenzoate (as 1 :1 mixture of methyl and ethyl esters 0.735g, assumed 4.1 mmol) and triethylamine (0.626ml_, 4.5 mmol) were dissolved in dichloromethane (8 mL), cooled in an ice bath and treated with 2-fluorobenzoyl chloride <n="40"/>(0.54 ml_, 4.5 mmol). The mixture was allowed to warm to room temperature and stirred for 2 hours. The solution was washed with water, dried (magnesium sulphate) and evaporated. The resulting solid was triturated with ether to give the title compound (1.2g) as a 1:1 mixture of methyl and ethyl esters. LC/MS (ES+ve): [M+H]+ at m/z 302, 316 (C17H16FNO3 requires [M+H]+ at m/z 302), (C18H18FNO3 requires [M+H]+ at m/z 316).
3-[5-(2-fluorophenylHl,2,41oxad-azol-3-v?-benzoic acid: One pot process; Reflux <n="25"/>[0188] A reactor vessel was charged with 3-Cyanobenzoic acid (7.35 g) and molten ter/-butanol (100 raL). The vessel was sealed and the batch temperature was set to 600C and the agitator was started. The suspension was stirred for Ih and then the batch temperature was set to 400C. 50% aqueous hydroxylamine (3.63 g) was charged to the reactor in an inert atmosphere over 3 hours. The batch temperature was maintained at 38- 410C during the addition. The reaction was completed after stirring for 18 hours at 400C. [0189] The batch was cooled to 27C and charged with triethylamine (5.56 g) over 2 minutes. 2-Fluorobenzoyl chloride (7.82 g) was added over 3 hours. The batch temperature was maintained at 24-27C during the addition. The batch was stirred for further 4 hours at 400C.[0190] The batch was heated to 790C over 30 minutes and stirred for 16 hours at about 79C. To the white suspension was added water (100 mL) over 3 hours while the batch temperature was maintained at 700C. The batch was charged with 37% aqueous hydrochloric acid over 20 minutes. The pH of the batch was determined to be about 2.2, by a pH meter and stirring at about 700C was continued for about an additional 1 hour. [0191] The batch was cooled in a linear fashion from 700C to 300C over 3 hours and the slurry was transferred into a filter. Filtration was complete after 5 minutes. The filter cakes were washed with fer/-butanol (50 mL, 40 0C) over 5 minutes. Purified water (100 mL, 600C) was applied to the cakes as the final wash. The cakes were dried in a vacuum oven at 70 0C for 18 hour and then discharged. Purity was determined to be about 98.68%. The overall yield of isolated product was about 76% (10.8 g).
With hydrazine hydrate; triethylamine; In acetonitrile; for 3h;Reflux;
General procedure: Aralkanoic acid chlorides 2 were synthesized by the reaction ofaralkanoic acids 1 (1 mmol) in the presence of 1,2edichloroethane(12 mL) solvent and phosphorous oxychloride (0.4 mL) as chlorinatingagent under reflux for 3 h. Then, the resulting solution wascooled to room temperature, and the solvent was removed underreduced pressure to afford aralkanoic acid chlorides 2, which wasdirectly used in the next step without further purification. Aralkanoicacid chlorides 2 was dissolved in acetonitrile (80 mL), addeddrop wise to a solution containing hydrazine hydrate (1 mmol), TEA(0.5 mL) and acetonitrile (20 mL) and allowed to reflux for 3 h withmonitoring by TLC. After consumption of the starting material, thereaction mixture was cooled to room temperature. Evaporation ofthe solvent under reduced pressure yielded crude substituted aromaticacid hydrazides 3 as a white solid on cooling, which waspurified by column chromatography and crystallized on methanol.
With hydrazine hydrate; triethylamine; In acetonitrile; for 3h;Reflux;
General procedure: The obtained aralkanoic acid chloride (2) was dissolved in 80 ml of acetonitrile, and then added dropwise to a solution containing 1 mmol of hydrazine hydrate, 0.5 ml of TEA, and 20 ml of acetonitrile,It was refluxed for 3 hours monitoring by thin layer chromatography (TLC).After all the starting material had been consumed, the reaction mixture was cooled to room temperature and then the solvent was evaporated under reduced pressure to give crude substituted aromatic acid hydrazide 3 as a white solid. It was purified by column chromatography and crystallized from methanol.
Triethylamine (5.32 mL, 37.84 mmol) was added dropwise to a solution of Nu,Omicron-dimethylhydroxylamine hydrochloride (2.768 g, 28.38 mmol) in anhydrous dichloromethane (45 mL) at 0 C. After stirring for 10 min, 2-fluorobenzoyl chloride (0.303 mL, 2.52 mmol) in anhydrous dichloromethane (15 mL) was added dropwise. The reaction mixture was returned to room temperature and stirred for 5 h. The reaction mixture was quenched with water (60 mL) and the products were extracted with dichloromethane (2 x 60 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification using flash chromatography (silica gel, hexanes:ethyl acetate, gradient 93:7 to 60:40) afforded 2-Fluoro-N-methoxy-N-methyl-benzamide (3.1 16, 17 mmol) in a 90% yield. [0
90%
Triethylamine (5.32 mL, 37.8 mmol) was added dropwise to a solution of N,O-dimethylhydroxylamine hydrochloride (2.77 g, 28.4 mmol) in anhydrous dichloromethane (45 mL) at 0 C. After stirring for 10 min, 2-flurobenzoyl chloride (0.303 mL, 2.52 mmol) in anhydrous dichloromethane (15 mL) was added dropwise. The reaction mixture was returned to room temperature and stirred for 5 h. The reaction mixture was quenched with water (60 mL) and the products were extracted with dichloromethane (2 * 60 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification using flash chromatography (silica gel, hexanes/ethyl acetate, gradient 93:7 to 60:40) afforded 2-Fluoro-N-methoxy-N-methyl-benzamide (3.12 g, 17.0 mmol, 90% yield). 1H NMR (500 MHz, CDCl3): delta 7.44-7.38 (2H, m), 7.19 (1H, t, J = 7.5 Hz), 7.10 (1H, t, J = 8.9 Hz), 3.55 (3H, br s), 3.35 (3H, br s). 13C NMR (125 MHz, CDCl3): delta 166.40, 158.66, (d, J = 249 Hz), 131.50, 128.90, 124.11, 123.52 (d, J = 17 Hz), 115.69 (d, J = 21 Hz), 61.21, 32.31. 19F NMR (470 MHz, CDCl3): delta -114.04 (1F, s). HRMS (ESI) calculated for C9H10FNO2H+ (M+H)+ 184.07683, found 184.07702.
62%
With pyridine; In tetrahydrofuran; at 0 - 20℃; for 2.25h;
N,O-Dimethylhydroxylamine hydrochloride (23.4 g, 240 mmol) was suspended inTHF (100 ml) and cooled to 0 C under nitrogen. Pyridine (32 ml, 400 mmol) was addedslowly. A solution of 2-fluorobenzoyl chloride (9.5 ml, 80 mmol) in THF (50 ml) was addedover 15 min. The reaction was removed from the ice bath and stirred at rt for 2 h. Water (100ml) and AcOEt (100 ml) were added, and the phases were separated. The aq. phase wasextracted with AcOEt (100 ml). The organic phases were pooled and washed with 1 N HCI (2x 100 ml) and 1 N NaOH (100 ml). After drying over MgSO4, the sample was concentrated toyield a yellow oil (10.7 g). The oil was purified by vacuum distillation, and a colorless oil wascollected (0.22 torr, 57-59 C, 9.1 g, 62% yield)2-fluoro-N-methoxy-N-methylbenzamide1H-NMR (300MHz, CDCI3) 53.34 (s, 3H), 3.54 (br, 3H), 7.10 (m, 1H), 7.19 (m, 1H),7.42 (m, 2H)
2-(2-Fluoro-benzoylamino)-thiophene-3-carboxylic acid amide: 2-Amino-thiophene-3-carboxylic acid amide (8.73 g, 61.4 mmole) was dissolved in pyridine (100 ml), cooled to 0C, and 2-fluorobenzoyl chloride was added dropwise over 20min, then the reaction was allowed to warm to room temperature with stirring overnight. The pyridine was removed under vacuum, dichloromethane and water were added. The product was precipitated as a grey solid and was washed with diluted hydrochloric acid, water and air dried. The dichloromethane layer was separated, washed with diluted hydrochloric acid, and water, dried over sodium sulfate (anh.) and the solvent was removed to give a total of 12.45g product (77% yield)
With hydrogenchloride; carbon disulfide;aluminium trichloride; In water;
a. To a mixture of 12.5 g of aluminum chloride and 45 ml of carbon disulfide there is added dropwise 7.1 g of 2-fluorobenzoyl chloride while maintaining the temperature below 0 C. This low temperature is maintained for 1.5 hours. While maintaining this same low temperature, 5 g of <strong>[2976-74-1]2,3-dichlorophenoxyacetic acid</strong> is added incrementally. After addition is complete, the reaction mixture is maintained at low temperature for 30 minutes and then permitted to reach ambient temperature after which it is refluxed for 28 hours. The carbon disulfide is decanted from the refluxed solution leaving a dark orange residue which is poured onto a mixture of 500 ml of ice/water and 100 ml of concentrated hydrochloric acid. The resulting pink precipitate is collected by filtration, rinsed with 300 ml of warm water (50 C.) and dried in vacuum oven. The dried product is recrystallized twice from aqueous ethyl alcohol to form the product 2,3-dichloro-4-(2-fluorobenzoyl)phenoxyacetic acid having a melting point of 153 to 156 C.
3-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone[ No CAS ]
5-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In aluminium trichloride;
[c] AlCl3 <strong>[16932-45-9]2-bromo-1,3-dimethoxybenzene</strong> (217 g; 1.0 mole) and 2-fluorobenzoyl chloride (158 g; 1.0 mole) are dissolved in 1,2-dichlorothane and aluminum chloride (133 g; 1.0 mole) is added slowly. The reaction mixture is refluxed for 2 hours and then worked up with 5% hydrochloric acid. In this way a 1:2 mixture of 5-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone and 3-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone is obtained, as indicated by nuclear magnetic resonance (NMR). A quantity of this mixture is separated by preparative high pressure liquid chromatography into its two components, 5-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone, m.p. 127-129 C. and 3-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone, m.p. 137-139 C.
With hydrogenchloride; In aluminium trichloride;
[c] AlCl3 <strong>[16932-45-9]2-bromo-1,3-dimethoxybenzene</strong> (217 g; 1.0 mole) and 2-fluorobenzoyl chloride (158 g; 1.0 mole) are dissolved in 1,2-dichorothane and aluminum chloride (133 g; 1,0 mole) is added slowly. The reaction mixture is refluxed for 2 hours and then worked up with 5% hydrochloric acid. In this way a 1:2 mixture of 5-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone and 3-bromo-2'fluoro-2-hydroxy-4-methoxybenzophenone is obtained, as indicated by nuclear magnetic resonance (NMR). A quantity of this mixture is separated by preparative high pressure liquid chromatography into its two components, 5-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone, m.p. 127-129 C. and 3-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone, m.p. 137-139 C.
EXAMPLE 15 0-(4-nitro-2-ethoxycarbonyl-phenyl)-hydroxylamine A mixture of 35 g of 2-fluoro-benzoyl chloride and 400 ml of ethanol was stirred for three hours and was allowed to stand overnight. The mixture was distilled to dryness at 50 C. and 30-40 mm Hg and the residue was taken up in methylene chloride The solution was washed with 5% aqueous sodium bicarbonate and then with water, dried and evaporated to dryness under reduced pressure. The product was rectified at 14 mm Hg to obtain 34 g of ethyl 2-fluoro-benzoate with a boiling point of 90-91 C. at 14 mm Hg.
Step A Preparation of 3-(2-fluorobenzoylamino)-2-pyridone To a solution of 3.3 g. (0.03 mole) of <strong>[33630-99-8]3-amino-2-pyridone</strong> in 75 ml. of pyridine cooled in ice was added portionwise 6.3 g. (0.04 mole) of 2-fluorobenzoyl chloride over 5 minutes. After stirring for 15 hours at ambient temperature, the mixture was poured into ice-water. The resultant precipitate was collected by filtration, washed with water and recrystallized from ethanol to give 3-(2-fluorobenzoylamino)-2-pyridone, m.p. 223 C.
2,5-bis-(2-fluorophenylcarbonyloxy)-3-undecyl-1,4-benzoquinone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52.7%
With pyridine; In dichloromethane; at 15 - 30℃; for 3h;
Example 4: 2,5-Di-0-(2-fluorophenylcarbonyl)-3-undecyl-l,4-benzoquinone; Synthesis of Structure No. 4; 2,5-w-(2-fluorophenylcarbonyl oxy)-3-undecyl-l,4- benzoquinone.To a stirred solution of 2,5-dihydroxy-3-undecyl-l,4-benzoquinone (1.0 gm, 3.4 mmole) in dichloromethane (20 mL) was added pyridine (1.1 mL, 13.6 mmole). To this, was added 2-fluoro benzoylchloride (1.35 gm, 8.5 mmole) at 15-20 C and stirred, allowed to attain 30 0C and stirring was continued for 3 h (TLC). The organic layer was extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to crude which was purified by SiO2 column chromatography (10-20% EtOAc in hexane) to a pure mass (0.96 g, 52.7%).1H NMR (300 MHz, CDCl3) delta: 0.87 (t, 3H, J = 6.9 Hz), 1.1 - 1.7 (m, 18H), 2.5 (t, 2H, J = 8.0 Hz), 6.8 (s, IH), 7.2 - 8.2 (m, 8H). TOF MS ES: 539 (M + H). Mp. 66.2 - 68 C.
52.7%
With pyridine; In dichloromethane; at 15 - 30℃; for 3h;
Synthesis of Structure # 4; 2,5-bis-(2-fluorophenylcarbonyl oxy)-3-undecyl-1,4-benzoquinone To a stirred solution of <strong>[550-24-3]2,5-dihydroxy-3-undecyl-1,4-benzoquinone</strong> (1.0 gm, 3.4 mmole) in dichloromethane (20 mL) was added pyridine (1.1 mL, 13.6 mmole). To this, was added 2-fluoro benzoylchloride (1.35 gm, 8.5 mmole) at 15-20 C. and stirred, allowed to attain 30 C. and stirring was continued for 3 h (TLC). The organic layer was extracted with dichloromethane, washed (water, brine), dried (Na2SO4), concentrated to crude which was purified by SiO2 column chromatography (10-20% EtOAc in hexane) to a pure mass (0.96 g, 52.7%). 1H NMR (300 MHz, CDCl3) delta: 0.87 (t, 3H, J=6.9 Hz), 1.1-1.7 (m, 18H), 2.5 (t, 2H, J=8.0 Hz), 6.8 (s, 1H), 7.2-8.2 (m, 8H). TOF MS ES: 539 (M+H). Mp. 66.2-68 C.
(A) To a homogeneous solution of L-alanine(5 g, 56.1 mmol) in acetone (90 ml) and 1N NaOH (90 ml) was added 2-fluorobenzoyl chloride (8.9 g, 56.1 mmol) dropwise. Basicity of the reaction was maintained by adding 1N NaOH periodically. After the addition of 2-fluorobenzoyl chloride was completed, the reaction mixture was acidified to pH 2 using 1N HCl. The oil that precipitated out was extracted into EtOAc, which was dried over MgSO4, filtered, and concentrated to yield 2-(2-fluorobenzoylamino)propionic acid (intermediate XXIa, 3.92 g). Upon standing, more crystals of intermediate XXIa (2.3 g) precipitated from the acidic aqueous solution and were collected.
With triethylamine; In acetonitrile; at 0 - 20℃; for 16h;
A solution of the acyl chloride (1.0 mmol) in MeCN (10 mL) was added dropwise to a solution of the amine (1.0 mmol) and NEt3 (0.10 g, 1.0 mmol) in MeCN (10 mL) at 0 0C. After stirring for 16 h at room temperature, the reaction mixture was concentrated under reduced pressure. H2O (35 mL) was added, followed by extraction with CH2Ch (3 x 35 mL). The organic layers were washed sequentially with NaHCOj (40 mL) and H?O (40 mL), dried (Na2SO4), and concentrated in vacuo to give the crude amide, ? which was then purified by flash chromatography (80:20 v/v cyclohexane.EtOAc). Following the general procedure, the crude benzamide 1 (275 rag, 96%) was obtained as a colourless solid; m.p. 121-125 0C, Rr 0.44 (80:20 v/v hexane: EtOAc); IR (thin film) 3394, 2924, 2899, 2847, 1647 (C-O), 1537, 1450, 617, 509 cm"1; 1H NMR (300 MHz, CD3OD) delta 7.70-7.65 (1 H, overlapping dd, 6-CH), 7.55-7.47 (IH, m, 4-CH), 7.29-7.17 (2H, m, 3-CH, 5-CH), 3.10 (2H, s, CH2-NH), 1.99 (3H, s),1.80-1.67 (6H1 m), 1.61-1.60 (6H, m); 13C NMR (75.5 MHz, CD3OD) delta 167.5, 161.5 (1Jc-P = 248.7 Hz), 134.0 (CH, 3Jc-F = 8.7 Hz), 131.6 (CH, VC-F = 2.5 Hz), 125.9 (CH, <n="63"/>3J = 3.5 Hz), 125.3 (CH, 2Jc-F = 14.2 Hz), 1 17.4 (2Jc-F = 23.0 Hz), 52.7 (CH2), 41.7 (CH2), 38.4 (CH2), 35.9, 30.1 (CH); HRMS (+ESI) CaIc. for C18H22ONF [M + H]+: 288.1758, found: 288.1749; m/z (+ESI) 288 ([M + H]+, 100), 242 (12); Anal. (Ci8H22ONF): calc, C 75.23, H 7.72, N 4.87; found, C 74.91, H 7.59, N 4.85.
With pyridine; In tetrahydrofuran; at 20℃;Cooling with ice;
After dissolving 8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine (CAS87571-88-8) (2.00 g) and pyridine (1.62 ml) in tetrahydrofuran (30 ml), 2-fluorobenzoyl chloride (2.24 ml) was added dropwise while stirring on ice. The mixture was stirred at room temperature for 9 hours, and then an aqueous solution of potassium carbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain the title compound (2.77 g).1H-NMR (400 MHz, CDCl3); delta 1.72-1.92 (m, 4H), 2.12-2.21 (m, 2H), 2.26-2.34 (m, 2H), 2.31 (s, 3H), 3.14-3.25 (m, 2H), 4.29-4.36 (m, 1H), 7.09-7.16 (m, 1H), 7.24-7.35 (m, 2H), 7.44-7.51 (m, 1H), 8.09-8.15 (m, 1H).
With triethylamine; In tetrahydrofuran; at 10 - 30℃; for 1h;
To a solution of <strong>[301673-16-5]tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate</strong> (500 mg, 2.31 mmol) and triethylamine (0.483 ml, 3.47 mmol) in tetrahydrofuran (10 ml) was added 2-fluorobenzoyl chloride (440 mg, 2.77 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the object product (590 mg, 75.4percent) as an oil. 1H-NMR (CDCl3) delta; 1.48 (9H, s), 3.00-3.33 (4H, m), 3.65-3.79 (3H, m), 4.20 (2H, br s), 4.52-4.87 (1H, m), 7.07-7.13 (1H, m), 7.18-7.26 (1H, m), 7.36-7.45 (2H, m).
With triethylamine; In dichloromethane; at 0 - 20℃;
To a solution of 2-fluorobenzoyl chloride (50 g, 0.31 mol) in CH2Cl2 (200 mL) was added N,O-dimethylhydroxylamine (46 g, 0.47 mol), and a solution of triethylamine (127 g, 1.26 mol) in CH2Cl2 (100 mL) at 0 C. The reaction mixture was warmed slowly to rt, and stirred for 3 h. The mixture was quenched with iced water and extracted with CH2Cl2 (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford 2-fluoro-N-methoxy-N-methylbenzamide (48 g, yield: 84.6%).
With triethylamine; In tetrahydrofuran; dichloromethane; at -78 - 20℃; for 4.16667h;
Preparation of N-(6-amino-5-bromo(2-pyridyl))(2-fluorophenyl)carboxamide (61): A solution of <strong>[54903-86-5]3-bromo-2,6-diaminopyridine</strong> (60) (564 mg, 3 mmol), triethyl amine (0.54 ml) in DCM (6 ml)/THF (4 ml) was cooled down to -78 C. A solution of 2-fluorobenzoyl chloride (362 mul, 3.03 mmol) in 2 ml DCM was added dropwise within 10 min. The resulting reaction mixture was stirred at -78 C. for 1 h before slowly warm up to r.t. After stirred at r.t. for 3 h, the reaction quenched with aq NaHCO3 solution. 200 ml EA were added. Org. phase was washed with brine, dried over sodium sulfate, concentrated. The light yellow solid residue was triturated with DCM (ca. 15 ml), filtered and dried to give 530 mg N-(6-amino-5-bromo(2-pyridyl))(2-fluorophenyl)carboxamide (61) as white solid. (purity>95%, yield: 57%).
With aluminum (III) chloride; sodium chloride; In dichloromethane; for 2.0h;Cooling with ice;
As presented in the following reaction formula, a crude product of Compound 2 was dissolved in methylene chloride (50 mL). Under cooling with ice, aluminum chloride (AlCl3; 13 g, 9.7 mmol) and sodium chloride (NaCl; 6 g, 10 mmol) were added to the resulting solution, and ethylene gas was introduced for 2 hours to the mixture under stirring. Then, 100 g of ice was added to the reaction mixture, followed by filtrating. The filtrate was extracted three times with 30 mL of ether and then washed with 100 mL of saturated brine. The filtrate was dried and concentrated with anhydrous sodium sulfate, and purified with a silica gel column of 100 g using n-hexane and ethyl acetate, to thereby give Compound 3 of interest (2.5 g, yield: 23%).
2.5 g
With aluminum (III) chloride; sodium chloride; In dichloromethane; for 2.0h;Cooling with ice;
As presented in the following reaction formula, a crude product of Compound 2 was dissolved in methylene chloride (50 mL). Under cooling with ice, aluminum chloride (AlCl3; 13 g, 9.7 mmol) and sodium chloride (NaCl; 6 g, 10 mmol) were added to the resulting solution, and ethylene gas was introduced for 2 hours to the mixture under stirring. Then, 100 g of ice was added to the reaction mixture, followed by filtrating. The filtrate was extracted three times with 30 mL of ether and then washed with 100 mL of saturated brine. The filtrate was dried and concentrated with anhydrous sodium sulfate, and purified with a silica gel column of 100 g using n-hexane and ethyl acetate, to thereby give Compound 3 of interest (2.5 g, yield: 23%).
2-fluoro-N-(2-(pyridin-2-yl)propan-2-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane; at 0 - 20℃; for 6h;
General procedure: A solution of acid (5 mmol) in SOCl2 (5 mL) was refluxedfor 2 h and cooled to r.t.. The excess of SOCl2 wasremoved under vacuum to give the corresponding acid chloride.The acid chloride was then re-dissolved in 5 mL anhydrousCH2Cl2 and added dropwise to a 20 mL anhydrousCH2Cl2 solution containing PIP-NH2 (5 mmol) and Et3N (10mmol) at 0 C. After stirring for 6 h at r.t., the resultingmixture was washed with brine, dried over MgSO4, filteredand concentrated under reduced pressure. The residue waspurified by flash chromatography to give the desired product.
With potassium carbonate; In N,N-dimethyl-formamide; at -10 - 20℃;
General procedure: To a cooled (-10 C) mixture containing 5-amino-1H-pyrazole (0.65 mmol) and potassium carbonate (1.00 mmol) in 3.0 mL of anhydrous DMF was added dropwise a solution of the acid chloride (0.50 mmol) in 2.0 mL of DMF. The reaction was stirred at -10C for 15 minutes, and then gradually warmed to room temperature. After stirring at room temperature for 15minutes, TLC indicated that acylation of the amino group was complete. The reaction was then immersed in a preheated oil bath at 140-145 Cuntil the ring closure was complete (30 min-1h). The reaction mass was cooled to room temperature and concentrated to dryness under vacuum. The crude product was slurried in deionized water, filtered, and the resulting solid was washed with methanol:ether (2:1). Alternatively, some cases required column chromatography, which was done on silica using methanol:dichloromethane (1:9) as the eluent [ethanol:dichloromethane (1:9) was used for the product having the ethyl ester].
Experimental operation: Take malonate potassium salt 1.00 g (about 5.47mmol) of anhydrous magnesium chloride and 0.65 g (About 6.84mmol) in 25 mLround bottom flask was added dropwise 0.55 g of triethylamine was added after 6mL of acetonitrile was dissolved, stirred 30 min at room temperature. Thendropped by 2 mL of acetonitrile was dissolved 0.48 g (2.5 mmol) o-fluorobenzoyl chloride ld, supplemented triethylamine 0.06 mL, stirred atroom temperature overnight. After treatment: 30 mL of water was added to dilutethe reaction solution, and then were added 30,20,20 mL ethyl acetate, and theethyl acetate layer was collected. After 30 mL with saturated brine ethylacetate layer was dried over anhydrous sodium sulfate, and spin dry columnchromatography (PE: EA = 15: 1) to give the product isolated 2d, in 92% yield.
13.5 g
Example-12: Preparation of compound of Formula Xlla. 2-fluorobenzoic acid (lOg) toluene (80ml) and dimethyl formamide (0.1ml) were charged into a round bottom flask at 25-35C. To the reaction mass thionyl chloride (12.7g) was added slowly over a period of 30min at same temperature. Reaction mass was heated to reflux and stirred for 3-4hr. After completion of the reaction, reaction mass was cooled to 55-65C and distilled completely under vacuum at 55-65C and co-distilled with toluene (2x20ml) to obtain residue and the residue was dissolved in tetrahydrofuran (50ml). Tetrahydrofuran (150ml) and magnesium chloride (24.5g) was added in another round bottom flask at 25-35C. Reaction mass was cooled to 10-15C and was added potassium salt of monoethylmalonate (36.4g) at same temperature. To the reaction mass was added triethyl amine (21.6g) slowly over a period of 30min and reaction mass was heated to 25- 35 C and stirred for 8hr at same temperature. To the reaction mass was added above pre dissolved tetrahydrofuran solution of 2-fluorobenzoyl chloride at 15-25C and stirred for 16hr at 25-35C. After completion of the reaction, reaction mass was distilled completely under vacuum at below 50C and cooled to 25-35C. To the resultant reaction mass was added water (400ml) and stirred for 3hr at same temperature. Filtered the precipitated solids and washed with water (10ml). The obtained solids were stirred with water (200ml), and a mixture of water (100ml) and sodium bicarbonate (50g), a mixture of water (100ml) and hydrochloric acid (10ml) sequentially at 25-35C and filtered the solid and washed with water (10ml). The obtained solid was stirred with methanol (20ml) for 40min at 25-35C. Filtered the solids and washed with methanol (10ml) and dryed the material to obtain title compound. Yield: 13.5 g.
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;
TEA (1.2 mmol) and the commercially available benzoyl chloride (1.1 mmol) wereadded at 000 to a solution of the corresponding aniline (1 mmol) in DCM (0.16M). The reaction mixture was left stirring at room temperature for 2h. Sat. solution of NaHCO3 (500m1) was added. The phases were separated and the aqueous layer was extracted with DCM (3 times). The combined organic layers were evaporated and purified by flash chromatography eluting with DCM/EtOAc to obtain the compounds of examples16-18,20,21 reported in Table 4.
3-(N'-((2-fluorobenzoyl)oxy)carbamimidoyl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89.1%
Example 8 Synthesis of 3-(N'-((2-fluorobenzoyl)oxy)carbamimidoyl)benzoic acid (VIII) <strong>[199447-10-4]3-(N'-hydroxycarbamimidoyl)benzoic acid</strong> (VII) (2.0 g, 11.1 mmol, 1.0 equiv.) potassium carbonate (2.61 g, 18.9 mmol, 1.7 equiv.) and PPW (20 mL, 10 vol) were added to a suitable reactor equipped with a stir bar and a thermometer at 20-30 C. and stirred for about 5 min. The reaction mixture was cooled to 0-10 C. After reaching the appropriate temperature a solution of 2-Fluorobenzoyl chloride (IIIa) (2.13 g, 1.2 equiv.) in toluene (10 mL, 5 vol) was added to the reaction mixture. Then the reaction mixture was stirred at this temperature for 1 hr. After the reaction was completed as determined by TLC analysis, 2N HCl(aq) (12 mL, 2.16 equiv.) was subsequently added adjusting pH value to about 1-2 while maintaining internal temperature NMT 10 C. The mixture was filtered and the filtered cake was washed with toluene (10 mL, 5 vol). The wet cake was suction dried at NMT 40 C. with N2 purge for NLT 18 hr to give 3-(N'-((2-fluorobenzoyl)oxy)carbamimidoyl)benzoic acid (VIII) as white solid (2.99 g, 89.1% yield based on VII).
2-fluoro-N-(3-nitropyridin-4-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 60℃; for 2.5h;
Under ice bath, intermediate B (5.0 g, 40.0 mmol) and DIPEA(9.3 g, 80.0 mmol) were solubilized in DMF (50 mL), then 2-fluorobenzoylchloride (6.3 g, 40.0 mmol) was added drop-wise. Afterstirring for 30 min at rt, the mixture was then heated to 60 C for2 h. The mixture was poured into ice-water, the resulting precipitatewas filtered, washed with water and dried under reducedpressure to yield the title compound as a yellow solid (9.4 g,90%). MS [M+H]+ m/z: 262.05.
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