| 92% |
With thionyl chloride; N,N-dimethyl-formamide; at 80℃; for 2h; |
Into a 250-mL round-bottom flask, was placed 4-bromo-2-fluorobenzoic acid (10 g, 45.66 mmol), thionyl chloride (50 mL) and N,N-dimethylformamide (0.1 mL). The resulting mixture was stirred for 2 h at 80C. After cooling to room temperature, the solution concentrated under vacuum. This resulted in 10 g (92%) of the title compound as light yellow oil. The product was used in the next step directly without further purification. |
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With oxalyl dichloride; In chloroform; for 22h;Heating / reflux; |
Oxalyl chloride (4.00 mL, 45.8 mmol) was added dropwise to 4-bromo-2- FLUOROBENZOIC acid (5.1 G, 23.3 mmol) dissolved in CHCI3 (50 mL). After refluxing for 18 h, additional oxalyl chloride (4.00 mL) was added and refluxing was continued for 4 h. The volatiles were removed under reduced pressure to afford 5.0 G of the crude acid chloride that was used without purification. AIC13 (10.0 g, 75.0 mmol) was added portionwise to the crude acid chloride (5.0 G) dissolved in ANISOLE (10 mL) at 0 C. The reaction mixture was stirred at RT for 3 days and then cooled to 0 C. Water (200 mL) was cautiously added dropwise, and the mixture was extracted with ET20 (3 x 100 mL). The combined ethereal extracts were washed with water (250 mL), brine (250 mL), and dried over MgS04. Concentration followed by flash chromatography (20: 1 to 5: 1 hexanes: EtOAc) and recrystallization from hexanes afforded 4.1 G (57% based on 4-bromo-2-fluorobenzoic acid) of 75 as a white SOLID. H NMR (400 MHz, CDCI3) : 8 3.87 (s, 3H), 6.94 (d, J = 8.8 Hz, 2H), 7.33-7. 40 (m, 3H), 7.79 (d, J = 8.2 Hz, 2H). |
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With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h; |
To a stirring solution of 4-bromo-2-fluorobenzoic acid (1.0mmol) and oxalyl chloride (2.0mmol) in dichloromethane (0.10M), add 2 drops of dimethylformamide as a catalyst. Stir at room temperature for 3 hours. After this time, ...concentrate the reaction in vacuo. Assume total conversion to the acid chloride. |
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With oxalyl dichloride;N,N-dimethyl-formamide; In tetrahydrofuran; at 0 - 20℃; for 1h;Product distribution / selectivity; |
Intermediate 30; Preparation of (E)-2-fluoro-4-(3,3,3-trifluoroprop-1-enyl)benzoic acid and (Z)-2-fluoro-4-(3,3,3-trifluoroprop-1-enyl)benzoic acid; tert-Butyl 4-bromo-2-fluorobenzoate To a stirred solution of 4-bromo-2-fluorobenzoic acid (3.0 g, 0.014 mol) in THF (50 mL) at 0 C. was added DMF (0.1 mL) and oxalyl chloride (1.5 mL, 0.018 mol). The mixture was stirred at 0 C. for 1 h and then warmed to rt. The solvent was removed under reduced pressure. The obtained acid chloride was added to a mixture of tert-butyl alcohol (5.0 g, 0.067 mol), pyridine (10 mL), and CH2Cl2 (50 mL) at 0 C. The mixture was stirred at rt for 3 h, and then at 50 C. overnight. The mixture was washed with water, 2 N NaOH, and brine, dried (MgSO4), and concentrated under vacuum. The residue was purified by column to give a colorless oil (1.5 g, 45%). |
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With thionyl chloride;N,N-dimethyl-formamide; In 1,2-dichloro-ethane; for 1h;Heating / reflux;Product distribution / selectivity; |
Intermediate 31; Preparation of 4-(3,3-dimethylbut-1-ynyl)-2-fluorobenzoic acid; 4-Bromo-2-fluoro-benzoic acid methyl ester 4-Bromo-2-fluorobenzoic acid (10 g, 0.04 mol) was suspended in 1,2-dichloroethane (60 mL, 0.8 mol) to which was added thionyl chloride (10 mL, 0.1 mol) followed by a drop of DMF. The mixture was heated to reflux for 1 hour. Excess thionyl chloride and 1,2-dichloroethane were stripped off and the crude product was treated with methanol (50 mL) and heated to reflux for an hour. The mixture was concentrated to dryness, dissolved in dichloromethane, treated with cold sat. sodium bicarbonate solution. The organic layer was dried, then concentrated under vacuum to obtain the title compound as a white solid. |
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With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; |
To a stirring solution of 2-amino-4-benzyloxy-butyric acid hydrochloride salt (1.0 mmol) (See Intermediate 34) and sodium carbonate (3.0 mmol) in 1:1 acetone / water (0.5M) in a 0 C ice bath, slowly add 4-bromo-2-fluoro-benzoyl chloride (1.2mmol) diluted in acetone (prepared from 4-bromo-2-fluoro-benzoic acid (1.0 mmol) and oxalyl chloride (1.0 mmol) in dichloromethane using catalytic dimethylformamide). Stir for 30 minutes at 0 C. After this time, wash the reaction with IN hydrochloric acid while extracting with ethyl acetate. Concentrate the organics in vacuo. Purify on an Isco CombiFlash chromatography system eluting with 1% acetic acid in ethyl acetate and hexane. MS (m/e) (79Br/81Br): 410.3/412.3 (M+l) |
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With oxalyl dichloride; In dichloromethane; at 0 - 20℃; for 15h; |
A solution of 3.8 ml (44 mmol) oxalyl chloride in 30 ml CH2CI2 is added dropwise to a iced- cooled solution of 4.88 g (21.9 mmol) 4-bromo-2-fluorobenzoic acid in 180 ml CH2CI2. After complete addition, the cooling bath is removed and stirring maintained for 15h at RT. The solvent is evaporated to dryness, the resultant colorless residue is dried under vacuum and then diluted with 80 ml CH2CI2. This solution of 2-Fluoro-4-bromobenzoyl chloride (CAS 151982-51-3) is then added dropwise to a mixture of 9.55 ml (54.7 mmol) of diisopropylethylamine, 2.01 ml (23 mmol) of morpholine in 100 ml CH2CI2. After 1h30, the reaction mixture is diluted with water and the two phases are separated. The aqueous phase is re-extracted with CH2CI2 and the combined organic extracts are washed with water, saturated brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo to afford, after drying in HV, the title compound which is used in the next step without further purification. |
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With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; for 0.5h; |
Production Example 323 N1-(2,4-Difluorophenyl)-4-bromo-2-fluorobenzamide 284 muL oxalyl chloride was added to a suspension of 356 mg 4-bromo-2-fluorobenzoic acid in dichloromethane in the presence of a catalytic amount of N,N-dimethylformamide, and the mixture was stirred for 30 minutes.. The reaction mixture was evaporated, and the resulting acid chloride was dissolved in 3 ML dichloromethane and then added dropwise to a solution mixture of 232mg 2, 4-difluoroaniline, 550mg sodium bicarbonate, 5 ML water and 5 ML dichloromethane, and the mixture was vigorously stirred at room temperature for 1 hour.. The organic layer was concentrated and purified by NH silica gel column, to give 400 mg of the title compound as colorless crystals.1H-NMR (CDCl3) delta: 6.79-6.97(m, 2H), 7.41(dd, J=11. 6, 2.0Hz, 1H), 7.49(dd, J=8.4, 2.0Hz, 1H), 8.06(dd, J=8.4, 8.4Hz, 1H), 8.37-8.44(m, 1H), 8.57(br, 1H) |
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With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h; |
To a mixture of 4-bromo-2-fluorobenzoic acid (75 mg, 0.34 mmol) and DMF (5 muL) in DCM (2 mL) is added oxalyl chloride (30 muL, 0.34 mmol). The mixture is stirred for about 1 hour at RT then is concentrated in vacuo to afford crude acid chloride 18a1 which is utilized without further purification. |
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With thionyl chloride; for 2h;Heating / reflux; |
Example A.4; a) Preparation of intermediate (10); A mixture of 4-bromo-2-fluoro- benzoic acid (24 mmol) and thionyl chloride (20 mL) was refluxed for 2 hours. The reaction mixture was concentrated in vacuo and co- evaporated twice with toluene (40 mL), yielding intermediate (10). The residue was used as such in the next step. |
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With thionyl chloride; for 4h;Heating / reflux; |
Description 50 5- (4-Bromo-2-fluorophenyl)-3-methyl-1, 2, 4-OXADIAZOLE (D50) 4-Bromo-2-fluorobenzoic acid (5.27g) was heated at reflux in thionyl chloride (50ML) for 4h and then allowed to cool. The mixture was evaporated in vacuo and the residue re- evaporated with DCM (2x) to give the acid chloride as a light brown oil. This was added dropwise to vigorously stirred, ice-cooled concentrated aqueous ammonia (50ml) and when addition was complete the mixture was stirred for 5min and then extracted (3x) with EtOAc. The combined organic extracts were washed with water and brine, dried (NA2SO4) and evaporated to give 4-bromo-2-fluorobenzamide as a white solid (4. 72G). This material and N, N-DIMETHYLACETAMIDE dimethylacetal (17ML) were heated together at 120C for 2h. The reaction was allowed to cool to rt and the liquid evaporated in vacuo to give a brown gum which was partitioned between saturated aqueous sodium hydrogen carbonate and EtOAc. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated to a gum. This was purified by chromatography (silica gel, eluant hexane/EtOAc) to give the acylamidine intermediate as a gum which solidified in vacuo (4.15g). Hydroxylamine hydrochloride (1. 32G) in 1N NAOH SOLUTION (23. 5MI) was added, followed by dioxane (23. 5MOI) then ACOH (30MOL) The reaction mixture was stirred at rt for 30min then heated at 90C for 3h. The reaction was allowed to cool to rt and poured into water. The pH was adjusted to-9 by addition of solid NAHC03 AND the precipitated product was collected by filtration, washed on the filter with water and dried at 40C IN VACUO to give the title compound (D50) as a greyish-brown solid (2. 82G). LCMS electrospray (+ve) 257 and 259 (MH+). |
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With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h; |
Example 30[4'-(Pyrrolidine-1-carbonyl)-biphenyl-4-yl]-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone The title compound is prepared starting with (4-Bromo-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-yl)methanone and 4-methoxycarbonylphenyl boronic acid perform procedures significantly analogous to those found in Procedures BB, V', W' (with pyrrolidine in place of (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine) and Q. MS (m/e): 432.4 (M+1) |
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With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; for 1h; |
Oxalyl chloride (0.65ml) was added to a solution of 4-bromo-2-fluorobenzoic acid (1.5g) in DCM (20ml), followed by DMF (catalytic amount). The mixture was stirred for Ih, then added toluene and evaporated under reduced pressure. The residue was redissolved in DCM (20ml) and pyrrolidine (1.2ml) was added and then stirred overnight. The mixture was partitioned between water and DCM, dried and the solvents evaporated to give the subtitle compound, yield 2g. |
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With thionyl chloride; for 4h;Heating / reflux; |
5-(4-Bromo-2-fluorophenyl)-3-methyl-1 ,2,4-oxadiazole (D32); 4-Bromo-2-fluorobenzoic acid (5.27g) was heated at reflux in thionyl chloride (50ml) for 4h and then allowed to cool. The mixture was evaporated in vacuo and the residue re- evaporated with DCM (2x) to give the acid chloride as a light brown oil. This was added dropwise to vigorously stirred, ice-cooled concentrated aqueous ammonia (50ml) and when addition was complete the mixture was stirred for 5min and then extracted (3x) with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated to give 4-bromo-2-fluorobenzamide as a white solid (4.72g). This material and /V,Lambda/-dimethylacetamide dimethyl acetal (17ml) were heated together at 1200C for 2h. The reaction was allowed to cool to rt and the liquid evaporated in vacuo to give a brown gum which was partitioned between saturated aqueous sodium hydrogen carbonate and EtOAc. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated to a gum. This was purified by chromatography (silica gel, eluant hexane/EtOAc) to give the acylamidine intermediate as a gum which solidified in vacuo (4.15g). Hydroxylamine hydrochloride (1.32g) in 1 N NaOH solution (23.5ml) was added, followed by dioxane (23.5ml) then AcOH (30ml). The reaction mixture was stirred at rt for 30min then heated at 900C for 3h. The reaction was allowed to cool to rt and poured into water. The pH was adjusted to ~9 by addition of solid NaHCO3 and the precipitated product was collected by filtration, washed on the filter with water and dried at 4O0C in vacuo to give the title compound (D32) as a greyish-brown solid (2.82g). LCMS electrospray (+ve) 257 and 259 (MH+). |
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With thionyl chloride;Heating / reflux; |
Description 16; 5-(4-Bromo-2-fluorophenyl)-3-methyl-1 ,2,4-oxadiazole (D16); 4-Bromo-2-fluorobenzoic acid (5.27g) was heated at reflux in thionyl chloride (50ml) for 4h and then allowed to cool. The mixture was evaporated in vacuo and the residue re- evaporated with dichloromethane (2x) to give the acid chloride as a light brown oil. This was added dropwise to vigorously stirred, ice-cooled concentrated aqueous ammonia (50ml) and when addition was complete the mixture was stirred for 5min and then extracted with ethyl acetate (3x). The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated to give 4-bromo-2-fluorobenzamide as a white solid (4.72g). This material and Lambda/,Lambda/-dimethylacetamide dimethylacetal (17ml) were heated together at 1200C for 2h. The reaction was allowed to cool to rt and the liquid evaporated in vacuo to give a brown gum which was partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated to a gum. This was purified by chromatography (silica gel, eluant hexane/ethyl acetate) to give the acylamidine intermediate as a gum which solidified in vacuo (4.15g). Hydroxylamine hydrochloride (1.32g) in 1 N sodium hydroxide solution (23.5ml) was added, followed by dioxane (23.5ml) then acetic acid (30ml). The reaction mixture was stirred at rt for 30min then heated at 900C for 3h. The reaction was allowed to cool to rt and poured into water. The pH was adjusted to ~9 by addition of solid NaHCO3 and the precipitated product was collected by filtration, washed on the filter with water and dried at 400C in vacuo to give the title compound (D16) as a greyish-brown solid (2.82g). LCMS electrospray (+ve) 257 and 259 (MH+). |
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With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 4h;Inert atmosphere; |
Example 8; 1-Ethyl-4-oxo-7-[4-(3-pyridin-3-ylmethylureido)phenyl]-2-(2-pyrrolidin-1-ylethylamino)-1,4-dihydroquinoline-3-carboxylic Acid (2-pyrrolidin-1-ylethyl)amide Hydrochloride (No. 61)8.1: 4-Bromo-2-fluorobenzoyl Chloride In a 500 ml round-bottomed flask, under a nitrogen atmosphere, 20.0 g (91.3 mmol) of 2-fluoro-4-bromobenzoic acid are dissolved in 250 ml of anhydrous dichloromethane. 10.7 ml (123.3 mmol) of oxalyl chloride are added dropwise, followed by the addition of DMF, dropwise, until evolution of gas. The solution is stirred for 4 h at ambient temperature and then the solvents are evaporated off under reduced pressure, so as to obtain 21.7 g (91.3 mmol) of crude product in the form of a yellow oil which is used directly for the next stage. |
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With thionyl chloride; In Isopropyl acetate; N,N-dimethyl-formamide; at 21 - 72℃; for 4.58333h;Inert atmosphere; Industry scale; |
To a nitrogen flushed 50 L reactor was charged the dry benzoic acid A-1 (1.8 kg, 8.22 mol) followed by isopropylacetate (IPAc) (12.6 L, 7 vol) and DMF (36 mL, 0.02 equiv). To the stirred slurry was added thionyl chloride (689 mL, 9.47 mol, 1.15 equiv) over 5 min (batch warmed from 21 C to 23 C). The batch was heated to 60 C over 2.5 h, maintained at 60-68 C for 1 h and was sampled for HPLC analysis. The batch was a thin slurry at this point. The conversion to the acid chloride was found to be 99.9% (the acid chloride intermediate was quenched with N-propylamine prior to analysis). After stirring for an additional 1 h at 70-72 C, the batch was cooled to 10 C over 1 h.To a nitrogen flushed 30 L reactor was charged aqueous MeNH2 (3.6 L, 41.1 mol, 5 equiv) which was then cooled to 2-10 C. IPAc (3.6 L, 2 vol) was added to the MeNH2 and the MeNH2/IPAc mixture was cooled to 2-10 C. The acid chloride was transferred to the MeNH2/IPAc mixture over 50 min, during which the reaction warmed to 35 C. The reactor that contained the acid chloride was rinsed with IPAc (1.8 L, 1 vol) into the 30-L reactor. The batch was allowed to stir for 15 min at 30-35 C before sampling for HPLC analysis. The conversion to the product was found to be 100%.[0112] Agitation was ceased and the phases were allowed to separate for 10 min. The green lower layer was removed. The IPAc phase was further washed with water (3 vol followed by 1 vol). The last phase separation was allowed to separate over 14 h at 30 C. After the final separation, the IPAc phase was filtered through a Celite pad which was rinsed with IPAc (3.6 L, 2 vol) to remove the dark green material. The filtrate was then reduced in volume by distillation to 9.5 L (5.3 vol) over 5 h (30-35 C, 100-200 mbar, 1.5-2.9 psi). Precipitation initiated at 8-9 volumes. n-Heptane (18 L, 10 vol) was added to the reactor and the mixture was distilled to 8 L (4.4 vol) over 6 h (30-35 C, 100-200 mbar, 1.5-2.9 psi). At this stage the IPAc/n-heptane ratio was 26:1. The resulting slurry was allowed to stir for 12 h at 25 C before cooling to 5-10 C over 1 h. The batch was stirred for 1.5 h at 5-10 C before filtering, rinsing with n-heptane (2x1 vol) and air-drying. The filter cake (1.87 kg) was vacuum dried at 55-60 C for 141 h to yield 1.72 kg (90% yield) of desired amide product A-2 with an HPLC purity of 99.5%, and 0.2% H20. |
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4.2.1 Preparation of 4-bromo-2-fluorobenzoyl chloride (2b) In a mixture of 4-bromo-2-fluorobenzoic acid (944 mg, 4.31 mmol) in CH2Cl2 (3.8 mL), oxalyl chloride (1095 mg, 8.62 mmol) in CH2Cl2 (3.7 mL) was added and the mixture was stirred at room temperature and under a nitrogen atmosphere for 1 h. Then DMF (14 muL) was added to the mixture and stirring was continued at room temperature, under a nitrogen atmosphere for 24 h. The mixture was evaporated under reduced pressure and the product [IR (neat) 1773, 1734 cm-1] was used as an acylating agent in the following reactions without further purification, considering it being 80% pure. |
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With thionyl chloride; In benzene; for 12h;Reflux; Inert atmosphere; |
To a suspension of 4-bromo-2-fluoro-benzoic acid (10 g, 45.65 mmol) in benzene (50 ml) was added thionyl chloride (7.8 ml, 12.79 g, 91.32 mmol) and the resulting mixture was heated to reflux for 12 hours. Thionyl chloride was evaporated, the reaction mixture was diluted with 1,2-dichloroethane (50 ml) and added to a slurry of aluminum chloride (5.7 g, 42.53 mmol) in 1,2 dichloroethane (50 ml) at room temperature. Ethylene was bubbled through the reaction mixture for 5 hours and the reaction mixture was stirred for another 2 hours at room temperature. It was then quenched with 2N HCl (50 ml). The layers were separated. The aqueous phase was extracted twice with 100 ml dichloromethane. The combined organic phases were washed with saturated sodium bicarbonate solution (50 ml) followed by water (50 ml). It was then dried over Na2SO4 and evaporated under reduced pressure to get the crude product, which was purified subsequently by column chromatography (silica gel, 0-5% ethyl acetate/hexane) to afford 8.6 g (71%) of the title compound as reddish solid. |
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With oxalyl dichloride; In chloroform; at 20℃; for 3h;Cooling with ice; |
Oxalyl chloride (3.2 mL) and DMF (one drop) were added to a suspension of 4-bromo-2-fluorobenzoic acid (4.0 g) in CHCl3 (40 mL) in an ice bath, followed by stirring at room temperature for 3 hours. After concentration, a mixture of THF and MeCN (1/1 (v/v), 40 mL) was added to the residue. TMSCH2N2 (2 mol/L Et2O solution, 18.3 mL) was added thereto at 0 C., followed by stirring at room temperature for 2 hours. After concentration, a mixture of 1,4-dioxane and water (1/1 (v/v), 60 mL) and then silver acetate (916 mg) were added thereto, followed by stirring at 100 C. for 2 hours. After concentration, a saturated aqueous NaHCO3 solution was added thereto, followed by stirring at room temperature for 1 hour. EtOAc was added thereto, and the solid was removed by filtration through Celite (registered trademark) to separate the organic layer. Under ice cooling, 3 mol/L HCl was added to the aqueous layer to make the system acidic. The aqueous layer was extracted from CHCl3 (50 ml*9). The combined organic layer was filtered through a phase separator, and the filtrate was concentrated under reduced pressure to yield the title compound (2.46 g, colorless powder). MS (ESI neg.) m/z: 231, 233 ([M-H]-). |
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With thionyl chloride; at 20℃; for 12h; |
Step 1 : 4-Bromo-2-fluoro-benzoyl chloride To a 100 mL flask is added 4-bromo-2-fluorobenzoic acid (5.0 g, 22.8 mmol) and sulfurous dichloride (50 mL). The reaction mixture is stirred at room temperature for 2 hrs. After removal of extra sulfurous dichloride, the residue (4.0 g, 74%) is used in the next step without further purification. ( MS: [M+l] 239) |
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With thionyl chloride; In N,N-dimethyl-formamide; toluene; at 80℃; for 1h; |
7.9 g of thionyl chloride was added to a mixture of 7.23 g of 4-bromo-2-fluorobenzoic acid, 30 mL of toluene and 0.1 ml of DMF, and the mixture was stirred at 80 C for 1 hour. The reaction mixture was concentrated under reduced pressure, and 30 ml of toluene, 6.22 g of N-methyl-4-trifluoromethylsulfanylaniline and 7.74 g of diisopropylethylamine were added, and the mixture was stirred at 80C for 1 hour. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 12.84 g of N-(4-trifluoromethylsulfanyl-phenyl)-4-bromo-2-fluoro-N-met hyl-benzamide. |
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With thionyl chloride; at 70℃; for 1h; |
Step A: 4-Bromo-2-fluorobenzoyl chloride (0179) A solution of 4-bromo-2-fluorobenzoic acid (10.8 g, 50.0 mmol) in SOCl2 (50 mL) was stirred at 70 Celsius for 1 hour. After cooling to rt, the resulting mixture was concentrated to give 4-bromo-2-fluorobenzoyl chloride as colorless oil, which was used directly in the next step without purification. |
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With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 10 - 30℃; |
N,N-Dimethylformamide (0.5 mL, 0.006 mol) was added to the suspension of 4-bromo-2- fluorobenzoic acid (10.0 g, 0.045 mol) in dichloromethane (70 mL) at 10 to 15 C. To the reaction mixture oxalyl chloride (8.0 mL, 0.093 mol) was added drop wise and stirred at 25- 30C for 2 to 3 hrs. Distill off the solvents to get residue. Methyl tertiary butyl ether (100 mL) was added to the residue and cooled to 10 to 15 C. To the obtained reaction mixture aqueous methyl amine (40%) was added drop wise at a pH around 8 to 9. The reaction mixtures was stirred at 25-30C for 30 min to 1 hr. Add DM water and stir for 30 min and separate the organic layer. The aqueous layer was extracted twice with Dichloromethane (2 x 100 ml) and combined organic layer washed with 5% citric acid solution (100 mL). The organic layer was washed with 100 ml of 5% NaHC03 solution followed by 200 ml of DM water wash. The organic layer was concentrated to obtain title product as off-white solid. Yield: 7.6gm |
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With thionyl chloride; N,N-dimethyl-formamide; In ethyl acetate; at 20℃; for 4h;Inert atmosphere; Reflux; |
200 g of 2-fluoro-4-bromobenzoic acid was dissolved in 1400 mL of ethyl acetate at room temperature and then under nitrogen,To the mixture was added 1 g of N, N-dimethylformamide and 150 g of thionyl chloride,After the addition of the starting material, the reaction was refluxed for 4 hours and concentrated to dryness to give 230 g of crude 4-bromo-2-fluorobenzoyl chloride,Add 1000mL of ethyl acetate to dissolve,The solution was slowly added dropwise to a mixture of 800 mL of methylamine and ethyl acetate (1: 1 by volume)Temperature control at 30 ~ 35 , continue to stir the reaction 15min, with TLC detection reaction is complete,Add 400 mL of saturated brine to the aqueous layer, add 500 mL of ethyl acetate, layer, combine the organic phase,Dried over anhydrous sodium sulfate, filtered, concentrated and dried to give 195 g of a white solid in 92% yield. |
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With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 3h;Inert atmosphere; |
To a suspension of compound 5-10 (12 g, 54.79 mmol) in DCM (120 mL) was added oxalyl chloride (COCl) (10.43 g, 82.19 mmol) and two drops of DMF in a catalytic quantity at 0 C. under nitrogen atmosphere, and then the reaction solution was reacted under nitrogen atmosphere at r.t. for 3 h. Then the solvent was removed, MeOH (100 mL) was added, and the resulting reaction solution was reacted at r.t. for 18 h. After TLC indicated the reaction was complete, the reaction solution was concentrated, and the residue was dissolved in EtOAc (100 mL) and washed with saturated Na2CO3 (aq., 50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give purified compound 5-11 (12 g, Yield 93.97%). |
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With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; |
In a 250 mL glass flask,2-fluoro-4-bromobenzoic acid (3.28 g, 15 mmol) was added,N,N-Dimethylformamide (0.4 mL) and dichloromethane (50 mL).The reaction solution was cooled to zero with an ice-water bath and thionyl chloride (1.32 mL, 18 mmol) was added.The reaction was warmed to room temperature and stirred overnight.After evaporation to dryness by rotary evaporation, the crude product was purified by co-evaporation with toluene (30 mL×2).The colorless liquid was directly used for the next reaction. |
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With thionyl chloride;N,N-dimethyl-formamide; at 20℃; for 18h; |
Step 13' Suspend 4-bromo-2-fluorobeozojc acid (55 mg, 0,25 mmol) m thionyl chloride (500 mul_) and add DMF (10 muL), Stir for about 18 h at RT. Evaporate the volatiles, then co- evaporate with toluene. Dissolve the residue tn pyridine (1 mL) and add solid SaS (60 mgf 0.19 mmol). Sltr at RT for aboyt 3 h. Evaporate the volatntes and dilute with EOAc, Wash with 10% citric acid |aqueoys) and saturated NaHCOj (aqueous). Pass the organic portion through a pad of EXTRELUT, concentrate, and punty the residue wilt flash chromatography (EtGAc/Hexanes) to provide Sa 14Step 14: |
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With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h; |
4-Bromo-2-fluorobenzoic acid (1.0mmol) and oxalyl chloride (2.0 mmol) are combined in dichloromethane (0.10 M), and 2 drops of dimethylf ormamide are added as a catalyst. The reaction is stirred at room temperature for 3 h. After this time, the reaction is concentrated in vacuo. Total conversion to the acid chloride is assumed. |
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With thionyl chloride; In ethyl acetate; at 80℃; |
S1:10 g of 4-bromo-2-fluorobenzoic acid was placed in a dry 100 ml three-necked flask.50 ml of anhydrous ethyl acetate was added, and the mixture was evacuated and replaced with nitrogen at 80 C.After the reaction is completed, the solvent is evaporated to dryness.4-Bromo-2-fluorobenzoyl chloride was obtained. |
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With thionyl chloride; N,N-dimethyl-formamide; In toluene; at 30 - 70℃; |
Dimethyl formamide (1 ml) was charged to the mixture of 4-Bromo-2-fluoro benzoic acid (100 g) and toluene (200 ml) with stirring at a temperature from about 30-35C. The temperature of the reaction mixture was raised to 65-70C. Thionyl chloride (100 g) was added slowly to the mass at 65-70C. The mass was stirred for 1-2 hours to get clear solution. The mass was cooled to l0-l5C. The mass was slowly added to the 40% solution of monomethylamine (281 ml) previously cooled to l 5C. The mixture was stirred for 1 hour at l0-l5C. The mass was filtered under vacuum at 50-60 torr. The reaction mass was washed with Toluene (50 ml) followed by washing with water (100 ml). The product was dried in hot air oven at a temperature from about 60 C to about 65 C to get dry weight (100 g) having a purity of 99.44%. |
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With oxalyl dichloride; In dichloromethane; at 20℃; for 2.16667h;Cooling with ice; Large scale; |
To an ice cold stirred solution of 4-bromo-2-fluorobenzoic acid (I-12) (1.25 Kg, 5.71 mol) in DCM (12.5 L, 15 vol), was added oxalyl chloride (0.98 L, 11.42 mol) in a drop wise manner. The resulting reaction mixture was stirred for 10 min at the same temperature. DMF (150 mL) was then added in a drop wise manner to the reaction mixture. The resulting reaction mass was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction (by TLC monitoring), excess oxalyl chloride was removed under reduced pressure under a nitrogen atmosphere to obtain the crude product (I-13) (1.08 Kg, 80%), which was used in the next step without further purification. |
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With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2.16667h;Cooling with ice; Large scale; |
To an ice cold stirred solution of 4-bromo-2-fluorobenzoic acid (I-12) (1.25 Kg, 5.71 mol) in DCM (12.5 L, 15 vol), was added oxalyl chloride (0.98 L, 11.42 mol) in a drop wise manner. The resulting reaction mixture was stirred for 10 min at the same temperature. DMF (150 mL) was then added in a drop wise manner to the reaction mixture. The resulting reaction mass was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction (by TLC monitoring), excess oxalyl chloride was removed under reduced pressure under a nitrogen atmosphere to obtain the crude product (I-13) (1.08 Kg, 80%), which was used in the next step without further purification. |
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