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Structure of 459-04-1
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CAS No. : | 459-04-1 |
Formula : | C8H6ClFO |
M.W : | 172.58 |
SMILES Code : | O=C(Cl)CC1=CC=C(F)C=C1 |
MDL No. : | MFCD00674181 |
InChI Key : | SIOJFYRPBYGHOO-UHFFFAOYSA-N |
Pubchem ID : | 3744988 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H314 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Class: | 8 |
UN#: | 3261 |
Packing Group: | Ⅱ |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With aluminum (III) chloride; In dichloromethane; at 0 - 20℃; | General procedure: Anhydrous AlCl3 (172.9 mg, 1.3 mmol, 1.3 equiv) was added to a mixtureof 2-phenylacetyl chloride (154.0 mg, 1.0 mmol, 1.0 equiv) and toluene (92.0 mg, 1.0 mmol, 1.0 equiv) in anhydrous DCM (15 mL) at 0C. The reaction mixture was stirred at r.t. until the reaction was completed (detected by TLC). The mixture was poured into water and extractedwith DCM (3 × 20 mL). The combined organic layers weredried over Mg2SO4 and concentrated in vacuo. The residue was purifiedby column chromatography on silica gel [ethyl acetate/petroleumether (EA/PE), 1:50 to 1:15] to give 2-phenyl-1-(p-tolyl)ethan-1-one (3b; 130.2 mg, 62%) as a white solid. Similarly, compounds 3e, 3f, 3h-3o, 3q, 3t, and 3u were obtained using this method. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% - 99%Chromat. | With oxalyl dichloride;N,N-dimethyl-formamide; In toluene; at 20 - 35℃; for 2.7 - 7h;Product distribution / selectivity; | Into a suitable agitated reactor is charged 4-fluorophenylacetic acid (79.4 kg, 515 mol), N,N-dimethylformamide (0.5 kg, 6.8 mol), and toluene (318 kg). Oxalyl chloride (68.3 kg, 538 mol) is added at a rate as to maintain the temperature below 35C. The solution is stirred for at least 7 hours at about 25C, typically affording a 22.1 wt % solution of 4-fluorophenylacetyl chloride.1 A suitable reactor is charged with 4-(2,3-dimethoxybenzoyl)piperidine (16) (20.4 kg, 86.3 mol, ~ 20 wt % in toluene), 50 wt% sodium hydroxide solution (11.6 kg, 145 mol) and about 29 kg of water. The mixture is cooled to about 10C. The 4-fluorophenylacetyl chloride- toluene solution (17.0 kg, 90.2 mol) is added at a rate as to maintain the temperature below 25C. The addition line is flushed with about 10 kg of toluene and the mixture is held for at least 30 minutes at about 25C.2 The phases are separated and the organic phase is washed with 20 wt% sodium chloride solution (29 kg). The organic solution is concentrated by vacuum distillation to approximately 1/3 of its original volume3 and is used as a toluene solution in Example 87, Scheme I, step a. 1The solution is sampled and analyzed by HPLC assay to determine the wt % of 4-fluorophenylacetyl chloride and yield.2The mixture is sampled and analyzed by HPLC assay to confirm the formation of-[1-oxo-1-(2,3-dimethoxyphenyl)methyl]-N-2-(4-fluorophen-1-oxo-ethyl)piperidine (4).3The concentrate is sampled and weighted to determine the amount of 4-[1-oxo-1-(2,3-dimethoxyphenyl)methyl]-N-2-(4-fluorophen-1-oxo-ethyl)piperidine (4) by HPLC analysis. The water content is determined by Karl Fischer analysis if the water content is greater than 300 ppm additional toluene may be added and the distillation continued.; Example 112 Scheme M, step a: 4-[1-Hydroxy-1-(2,3-dimethoxyphenyl)methyl)methyl]-N-2-(4-fluorophen-1-oxo-ethyl)piperidine (20) Into a suitable reactor is charged 4-fluorophenylacetic acid (122.5 kg, 795 mol), N,N-dimethylformamide (0.37 kg, 5.1 mol), and toluene (490 kg). Oxalyl chloride (105.2 kg, 829 mol) is added at a rate to maintain the temperature at about 35C. The solution is stirred for at least 7 hours at about 25C, typically affording a solution of about 22.1 wt% 4-fluorophenylacetyl chloride (99% yield as determined by HPLC assay).; Example 113a Scheme M, step a: 4-[1-Hydroxy-1-(2,3-dimethoxyphenyl)methyl]-N-2-(4-fluorophen-1-oxo-ethyl)piperidine (20) Into a 1-L three-neck flask equipped with a mechanical stirrer, an addition funnel, and a nitrogen bubbler vented to a water scrubber was placed 60.0 g (0.389 mol) of 4-fluorophenylacetic acid, 0.18 g, 0.002 mol) of N,N-dimethylformamide and 250 g of toluene. The addition funnel was charged with 50.4 g (0.397 mol) of oxalyl chloride and added to the reaction mixture over a 10 minute period resulting in gas evolution (4.7C exotherm was observed). The reaction mixture was stirred at ambient temperature for 2.5 hours (gas evolution complete) and the head space of the reaction flask was sparged with nitrogen for 10 minutes before storing the material. HPLC assay of the solution indicated that 19.1 wt % of the solution was 4-fluoroacetyl chloride, thus affording a 99% yield. Purification of crude 4-fluorophenylacetyl chloride by vacuum distillation (57-58C, 0.15 mm Hg) affords 4-fluorophenylacetyl chloride as a clear liquid in 90% yield. 1H NMR (CDCl3) δ 7.25-7.21 (m, 2H, aromatic), 7.05 (t, 2H, J=8.6 Hz, aromatic), 4.11 (s, 2H, -CH2); 13C NMR (CDCl3) δ 171.6, 164.2, 160.9, 131.2, 131.1, 127.1, 127.0, 116.4, 115.7, 52.1. |
75% | With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h; | (A-125) To a methylene chloride(100ml) solution of 4-fluorophenylacetic acid(10.0g, 64.9mmol) and dimethylformamide(0.5ml), oxalyl chloride(9.06g, 71.4mmol) was added dropwise at room temperature and the mixture was stirred for 1 hour, which was evaporated under reduced pressure.. The residue was distilled to give (4-fluorophenyl)acetyl chloride(8.44g, yield:75%). Boiling point:80C/15MmHg |
With thionyl chloride; at 50 - 100℃; for 0.5 - 1h;Product distribution / selectivity; | 4-Fluorophenyl acetate (169 mg, 1.1 mmol) was dissolved in thionyl chloride (651 mg, 5.48 mmol), followed by stirring at 100 C. for 1 hr. The reaction mixture was cooled down to room temperature, and thionyl chloride was evaporated under a reduced pressure. The resultant residue was dissolved in acetonitrile (10 ml), and then potassium thiocyanate (213 mg, 2.19 mmol) was added thereto, followed by stirring at 50 C. for 1 hr. The reaction mixture was cooled down to room temperature, and then 4-(4-amino-2-fluorophenoxy)pyridin-2-ylamine (160 mg, 0.912 mmol) was then added thereto, followed by stirring at room temperature for 59.5 hrs. The reaction mixture was partitioned between water (50 ml) and ethyl acetate (100 ml). The organic layer was washed with brine, and dried over sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, hexane:ethyl acetate=1:2, ethyl acetate, and then ethyl acetate:methanol=10:1) to provide the titled compound (84.6 mg, 28%) as yellow powder. ESI-MS (m/z): 415 [M+H]+. |
150.4 g (89.5%) | With thionyl chloride; In N,N-dimethyl-formamide; toluene; | Step A 4-Fluorophenylacetyl chloride A solution of 150 g (0.974 mol) of 4-fluorophenylacetic acid an 1 mL of N,N-dimethylformamide in 500 mL of toluene at 40 C. was treated with 20 mL of thionyl chloride and heated to 400 C. An additional 61.2 mL of thionyl chloride was added dropwise over 1.5 hours. After the addition, the solution was heated at 50 C. for 1 hour, the solvent was removed in vacuo and the residual oil was distilled at reduced pressure (1.5 mmHg) to afford 150.4 g (89.5%) of the title compound, bp=68-70 C. |
150.4 g (89.5%) | With thionyl chloride; In N,N-dimethyl-formamide; toluene; | Step A' 4-Fluorophenylacetyl chloride A solution of 150 g (0.974 mol) of 4-fluorophenylacetic acid an 1 mL of N,N-dimethylformamide in 500 mL of toluene at 40 C. was treated with 20 mL of thionyl chloride and heated to 40 C. An additional 61.2 mL of thionyl chloride was added dropwise over 1.5 hours. After the addition, the solution was heated at 50 C. for 1 hour, the solvent was removed in vacuo and the residual oil was distilled at reduced pressure (1.5 mmHg) to afford 150.4 g (89.5%) of the title compound, bp=68-70 C. |
150.4 g (89.5%) | With thionyl chloride; In N,N-dimethyl-formamide; toluene; | Step A': 4-fluorophenylacetyl chloride A solution of 150 g (0.974 mol) of 4-fluorophenylacetic acid an 1 mL of N,N-dimethylformamide in 500 mL of toluene at 40 C. was treated with 20 mL of thionyl chloride and heated to 40 C. An additional 61.2 mL of thionyl chloride was added dropwise over 1.5 hours. After the addition, the solution was heated at 50 C. for 1 hour, the solvent was removed in vacuo and the residual oil was distilled at reduced pressure (1.5 mmHg) to afford 150.4 g (89.5%) of the title compound, bp=68-70 C. |
150.4 g (89.5%) | With thionyl chloride; In N,N-dimethyl-formamide; toluene; | Step A' 4-Fluorophenylacetyl chloride A solution of 150 g (0.974 mol) of 4-fluorophenylacetic acid an 1 mL of N,N-dimethylformamide in 500 mL of toluene at 40 C. was treated with 20 mL of thionyl chloride and heated to 40 C. An additional 61.2 mL of thionyl chloride was added dropwise over 1.5 hours. After the addition, the solution was heated at 50 C. for 1 hour, the solvent was removed in vacuo and the residual oil was distilled at reduced pressure (1.5 mmHg) to afford 150.4 g (89.5%) of the title compound, bp=68-70 C. |
150.4 g (89.5%) | With thionyl chloride; In N,N-dimethyl-formamide; toluene; | Step A': 4-Fluorophenylacetyl chloride A solution of 150 g (0.974 mol) of 4-fluorophenylacetic acid an 1 mL of N,N-dimethylformamide in 500 mL of toluene at 40 C. was treated with 20 mL of thionyl chloride and heated to 40 C. An additional 61.2 mL of thionyl chloride was added dropwise over 1.5 hours. After the addition, the solution was heated at 50 C. for 1 hour, the solvent was removed in vacuo and the residual oil was distilled at reduced pressure (1.5 mmHg) to afford 150.4 g (89.5%) of the title compound, bp=68-70 C. |
With thionyl chloride; In toluene; | (a) p-Fluorophenylacetic acid (20 g) was stirred with thionyl chloride (30 ml) at room temperature for 5 hours. The excess of thionyl chloride was then removed under reduced pressure. The remaining oil was dissolved in toluene, and the toluene then removed under reduced pressure. The remaining oil was distilled (b.p. 41-42/0.1 mm) to give p-fluorophenylacetyl chloride (19.74 g). | |
With thionyl chloride; N,N-dimethyl-formamide; In toluene; at 6 - 70℃; for 3.5h; | EXAMPLE 1 Process to Ketone Step 1: 2-(4-Fluorophenyl)-N-methoxy-N-methylacetamide (2) Summary: This reaction gives consistently high yield and high purity of material. No major side products have been identified. The final product is an oil (typically clear or slightly yellow) and is isolated with the above purity profile from the crude work up. Procedure: FW: Amt. Moles Equiv. 4-Fluorophenylacetic acid (1) 154 5.0 kg 32.47 mol 1.0 eq. DMF 73.1 48 mL 0.65 mol 0.02 eq. SOCl2 119 2.84 L 38.96 mol 1.2 eq. Weinreb amine-HCl 97.5 4.75 kg 48.70 mol 1.5 eq. NaOH 4.0 M 32.47 L 129.87 mol 4.0 eq. Toluene - 49.19 L - Brine - 64.92 L - A 100 L extractor equipped with a reflux condenser, and a base scrubber was charged with toluene (49.2 L, KF100 ppm) and 4-fluorophenylacetic acid (1) was added (5.0 kg). This solution was heated to 70 C. Once 70 C. was reached the DMF (48 mL, KF150 ppm) was added and thionyl chloride (2.8 L) was slowly added over 3 hours. Batch temperature will decrease while thionyl chloride is added. Typical temperature changes range from 6-10 C. When all thionyl chloride has been added and off-gassing has ceased (typically 30 min. after addition is complete) an aliquot of the batch was quenched into excess methanol for HPLC analysis as the methyl ester. Reaction is done when acid 1 is at <0.5 LCAP. Next the reaction was cooled to 5-10 C. The Weinreb amine-HCl (4.75 kg) was added to the batch at this point. Slow addition of NaOH (32.5 L) was begun at this point. This base was added at a rate that maintained the batch temperature at or below 10 C. with a typical addition time of 3 hours. Once this addition was done an aliquot of the batch was quenched into MeOH and assayed by HPLC to check for complete consumption of the acid chloride. Complete consumption of the acid chloride (in the form of the methyl ester after this quench) should be seen. Additional base can be added if the acid chloride is still present. The biphasic solution was separated at between 5 C. and room temperature and the organic phase was washed with 15 wt. % NaCl (aq) (2×32.5 L). Typical assay yield of the organic phase was 96%. The organic phase was concentrated to a 50 wt. % solution (typical KF500 ppm). | |
With thionyl chloride; In toluene; at 105℃; for 16h; | Step B: I-[(4-FluorophenyI)acetyl]piperidine4-FluorophenyIacetic acid (280g, 1.82mol) was suspended in 1.9L toluene followed by the careful addition of 185mL thionyl chloride (303g, 2.545mol). The reaction was heated to 1050C for 16hr (overnight). The reaction was allowed to cool to room temperature and the volatiles were removed in vacuo. The crude acid chloride was dissolved in 1.9L THF, cooled to 00C, and 0.72L piperidine (618g, 7.27mol) was added. The reaction vessel was allowed to warm to ambient temperature for 18hr. The mixture was quenched with a saturated solution of aq. NaHCθ3 and extracted several times withEtOAc. The combined organic extracts were washed with brine, dried over Na2SO^ and filtered on a <n="21"/>fritted funnel. The volatiles were removed in vacuo and the crude residue was purified on silica gel and eluted with a mixture of EtOAc/heptanes (0-75% gradient elution). This furnished the title compound. 1H-NMR (CDCI3): δ 1.32-1.42 (m, 2H), 1.48-1.64 (m, 4H), 3.34-3.42 (m, 2H), 3.54-3.60 (m, 2H), 3.69(s, 2H), 6.90-7.05 (m, 2H), 7.18-7.24 (m, 2H) ppm. | |
With oxalyl dichloride;N,N-dimethyl-formamide; In tetrahydrofuran; at 20℃; for 1h; | To a solution of 4-fluorophenylacetic acid (9.9 g) in THF (100 ml) was added DMF (5 drops) and then oxalyl chloride (9.0 ml) was added at room temperature, and the mixture was stirred for 1 hr. The mixture was concentrated in vacuo to give 4-fluorophenylacetyl chloride. Aluminum chloride (16.0 g) was added to a suspension of 2H-1, 4-benzoxazin-3 (4H) -one (8.0 g) in 1, 2-dichloroethane (100 ml) under ice-cooling and then 4-fluorophenylacetyl chloride obtained above was added. The reaction mixture was allowed to warm to room temperature and stirred for 12 hr, then poured into ice-cooled water (200 ml) and the resulting crystals were collected by filtration. The crystals were suspended in methanol and the mixture was refluxed for 1 hr. After cooling the mixture, the resulting crystals were collected by filtration. The title compound was obtained as crystals (5.45 g) . | |
With thionyl chloride; at 60℃; for 1h; | 4-Fluorophenylacetic acid [starting compound B] (15 g) was dissolved in thionyl chloride (15 ml) to prepare a solution which was then heated at 60C for one hr. Excess thionyl chloride was removed by evaporation under the reduced pressure to give 4-fluorophenylacetyl chloride. | |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1 - 2.1h;Product distribution / selectivity; | Scheme 1; 2-(4-Fluorophenyl)acetyl isothiocyanate (2); Method A (For the Method B see scheme 20); To a solution of 4-fluorophenylacetic acid (1) (25 g, 162 mmol) in DCM (75 mL) was added oxalyl chloride (28.4 mL, 324 mmol) and 3-4 drops of DMF. The mixture was stirred at r.t. for Ih - 2h and concentrated to produce 2-(4-fluorophenyl)acetyl chloride (Ia) (yellow oil) <n="95"/>that was re-dissolved in toluene (100 mL). To this solution was added lead(II) thiocyanate (55.0 g, 170 mmol). The mixture was heated to reflux for 1.5h - 2h, cooled down, filtered and the filtrate was concentrated. The residue was applied onto a silica gel pad (20 cm) and eluted with EtOAc / hexanes (1/9), to afford after evaporation of the solvents title compound 2 (31 g, 98% yield) as a yellow oil. MS (m/z): 228.1 (M+H+MeOH). 1H NMR (400 MHz, DMSOd6) δ (ppm): 7.26-7.22 (m, 2H), 7.09-7.07 (m, 2H), 3.84 (s, 2H).; Step 5: tert-butyl (6-(7-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)thioureido)phenoxy)thieno[3,2- ]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (14); To a solution of 4-fluorophenylacetic acid (1, scheme 1) (26.5 g, 172 mmol) in DCM (93 mL) was added oxalyl chloride (2 eq., 30.1 mL, 344 mmol) over 5 min and DMF (0.005 eq., 0.067 mL, 0.86 mmol) over 1 min. The reaction mixture was stirred at r.t for 2h then concentrated. The residual DCM was removed as an azeotrope with toluene (2x 20 mL) to afford intermediate 2-(4-fluorophenyl)acetyl chloride (Ia) (30.85 g, 179 mmol, assumed quantitative yield) as yellow oil. Part of that material was used as is in the next step. | |
With thionyl chloride; In N,N-dimethyl-formamide; toluene; at 70℃; for 3h; | A lOO L extractor equipped with a reflux condenser, and a base scrubber was charged with toluene (49.2 L, KF< 100 ppm) and 4-fluorophenylacetic acid (1) was added (5.0 kg). This solution was heated to 70 C. Once 70 "C was reached the DMF (48 mL, KF< 150ppm) was added and thionyl chloride (2.8 L) was slowly added over 3 hours. EPO <DP n="15"/>Batch temperature will decrease while thionyl chloride is added. Typical temperature changes range from 6-10 C.When all thionyl chloride has been added and off-gassing has ceased (typically 30 min. after addition is complete) an aliquot of the batch was quenched into excess methanol for HPLC analysis as the methyl ester.Reaction is done when acid 1 is at <0.5 LCAP.Next the reaction was cooled to 5-10 "C. The Weinreb amine-HCl (4.75 kg) was added to the batch at this point. Slow addition of NaOH (32.5 L) was begun at this point. This base was added at a rate that maintained the batch temperature at or below 10 "C with a typical addition time of 3 hours. Once this addition was done an aliquot of the batch was quenched into MeOH and assayed by HPLC to check for complete consumption of the acid chloride.Complete consumption of the acid chloride (in the form of the methyl ester after this quench) should be seen. Additional base can be added if the acid chloride is still present.The biphasic solution was separated at between 5 C and room temperature and the organic phase was washed with 15 wt. % NaCl (aq) (2 x 32.5 L).Typical assay yield of the organic phase was 96%.The organic phase was concentrated to a 50 wt. % solution (typical KF < 500 ppm). | |
With oxalyl dichloride;N,N-dimethyl-formamide; In tert-butyl methyl ether; at 20℃; for 0.833333h; | 4-(4-Fluoro-phenyl)-2-methyl-buta-2,3-dienoic acid ethyl ester To a solution of (4-fluoro-phenyl)-acetic acid (22.33 g, 144.9 mmol) in 100 mL of methyl tert-butyl ether and 250 μL of DMF was added 13.02 mL (146.3 mmol) of oxalyl chloride at room temperature dropwise over 30 minutes. The resulting mixture was stirred at room temperature for an additional 20 minutes (HPLC indicated completed reaction), and then the entire solution was added dropwise over 1 hour to a solution of N,N-diisopropylethylamine (50.48 mL, 289.8 mmol) and ethyl 2-(triphenylphosphoranylidene)propionate (50.0 g, 138.0 mmol) in 100 mL of methyl tert-butyl ether, while maintaining the internal temperature between 0-15 C. After the addition was complete, the reaction mixture was stirred for an additional 10 minutes at 0-10 C., when HPLC indicated a completed reaction. The reaction mixture was then diluted with 100 mL of heptane, and stirred for 30 minutes at 0-10 C. The resulting solid was filtered and washed with 2*100 mL of 1:1 methyl tert-butyl ether:heptane. | |
With oxalyl dichloride;N,N-dimethyl-formamide; In tert-butyl methyl ether; at 20℃; for 0.833333h; | To a solution of (4-fluoro-phenyl)-acetic acid (22.33 g, 144.9 mmol) in 100 ml_ of methyl terf-butyl ether and 250 μl_ of DMF was added 13.02 ml_ (146.3 mmol) of oxalyl chloride at room temperature dropwise over 30 minutes. The resulting mixture was stirred at room temperature for an additional 20 minutes (HPLC indicated completed reaction), and then the entire solution was added dropwise over 1 hour to a solution of Λ/,Λ/-diisopropylethylamine (50.48 ml_, 289.8 mmol) and ethyl 2- (thphenylphosphoranylidene)propionate (50.0 g, 138.0 mmol) in 100 ml_ of methyl terf-butyl ether, while maintaining the internal temperature between 0-15 C. After the addition was complete, the reaction mixture was stirred for an additional 10 minutes at 0-10 C, when HPLC indicated a completed reaction. The reaction mixture was then diluted with 100 mL of heptane, and stirred for 30 minutes at 0- 10 C. The resulting solid was filtered and washed with 2x 100 mL of 1 :1 methyl tert- butyl etheϖheptane. The filtrate and the washings were combined and washed with 100 mL of water, 100 mL of 1 M citric acid, 2x100 mL of water, then concentrated azeotropically at 25 C/60 mmHg to a total volume of -40 mL. The residue was diluted with 60 ml_ of methyl te/t-butyl ether. This solution was then directly used for the next step. | |
With thionyl chloride; for 4h;Heating / reflux;Product distribution / selectivity; | p-Fluorophenylacetic acid (31.4 g, 0.203 mol) is treated with SOCl2 (45 mL, 0.62 mol) and the resulting solution is heated at reflux for 4 hours. The reaction mixture is diluted with toluene and concentrated by distillation to remove remaining SOCl2. When the temperature of the distillate reaches 114C, the distillation is discontinued and the reaction mixture cooled to ambient temperature. | |
With thionyl chloride; for 2h;Reflux; | 4-Fluorophenylacetic acid (900 mg) was dissolved in thionyl chloride (5 mL), and the solution was refluxed under heating for 2 hours. The reaction system was concentrated under reduced pressure and azeotroped with toluene, to thereby yield 4-fluorophenylacetyl chloride as a crude product. This acid chloride was dissolved in acetonitrile (20 mL), and potassium thioisocyanate (851 mg) was added to the solution, followed by stirring at 70 C. for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Subsequently, the product was separated with saturated aqueous solution of sodium hydrogencarbonate (100 mL) and ethyl acetate (50 mL). The organic layer was washed with saturated brine (100 mL) and dried over sodium sulfate, followed by concentration under reduced pressure, to thereby yield 4-fluorophenylacetyl thioisocyanate. This thioisocyanate was not subjected to further purification and dissolved in tetrahydrofuran (20 mL). A solution (20 mL) of compound 1c (374 mg) in tetrahydrofuran was added to the thioisocyanate solution and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the formed solid was filtrated, to thereby yield compound 19a (452 mg, yield: 79%).1H-NMR(CDCl3)δ: 12.47(1H,s), 11.82(1H,s), 8.73(1H,s), 8.65(1H,d,J=4.4 Hz), 7.95(1H, dd,J=11.2 Hz, 2.8 Hz), 7.49(1H,s), 7.43-7.40(1H,m), 7.31-7.25(3H,m), 7.15(2H,m), 6.42(1H,dd,J=5.2 Hz, 1.2 Hz), 4.03(3H,s), 3.74(2H,s), 1.64(9H,s); ESI-MS m/z 580(MH+). | |
With thionyl chloride; In benzene; at 80℃; for 3h; | The chemicals were purchased from the commercial venders and were used without purification. The reactions were monitored and the purity of the product was checked by thin layer chromatography (TLC). Silica gel 60 F254 chromatoplates were used for TLC. The solvent systems were chloroform/methanol (15:1). Thionyl chloride (1.5 ml) and 4-fluorophenyl acetic acid (0.5 mmol) were refluxed in benzene (5 ml) at 80 for 3 h, and then excess thionyl chloride was removed in vacuo [27]. The residue was dissolved in ether (10 ml) and the solution added during 1 h to a stirred, ice-cold mixture of 2-amino-5-nitrophenol (0.5 mmol), sodiumbicarbonate (0.5 mmol), diethyl ether (10 ml), and water (10 ml). The mixture was stirred overnight at room temperature and filtered. After the precipitate was washed with water, 2 N HCl and water, respectively, and finally with ether, compound was obtained. The crude product was purified by recrystallization from ethanol. | |
With thionyl chloride; at 80℃; for 1h;Product distribution / selectivity; | Synthesis of (4-Fluoro-phenyl) -acetic acid hydrazide; (4-Fluoro-phenyl)-acetyl chloride was readily prepared from thecorresponding acid by refluxing the acid in thionyl chloride for 1 h. However, the acid chloride was too reactive. Addition of hydrazine hydrate to a solution of the acid chloride gave only the dimer. Reverse addition of acid chloride to hydrazine hydrate at 0 C gave the desired hydrazide with some dimer. The acid chloride was then transformed to the corresponding ethyl ester. Reaction of the ethyl ester with 2 equiv. of hydrazine hydrate in refluxing EtOH gave cleanly the (4-Fluoro-phenyl)-acetic acid hydrazide in 76% yield. The results are summarized below. | |
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | General procedure: Acid (1 equiv) was placed in a round bottom flask and flushed with Ar (2x). Anhydrous DCM (7 mL) was then added followed by the dropwise addition of oxalylchloride (2 M in DCM, 3.1 equiv). After a few minutes, a few drops of anhydrous DMF were added to the reaction mixture and once the fizzing stopped, the reaction was allowed to stir overnight at R.T. Solvent was then evaporated using reduced pressure and the crude residue was used right away without any further purification. | |
With thionyl chloride; at 80℃; for 3h; | General procedure: For the synthesis of compounds 4a-4h and 5a-5h was depicted in Scheme 2. Firstly, 2-phenylacetic acid (1 mmol) and SOCl2 (4-6 mL) were refluxed at 80 C for 3 h. The reaction liquid was cooled to room temperature and then evaporated to give reactive acyl chloride. The product was obtained as an oil matter, which would be dissolved in acetone (5-6 mL) in the next step. Treatment of 3a (5-phenylthiazol-2-amine) with 2-phenylacetyl chloride in acetone for 5 h at ice-bath afforded the aimed amine. Meanwhile, K2CO3 (0.8 g) was added to the mixture. Then the mixture was evaporated under reduced pressure and the resulting solid was washed with diluted NaOH liquid. The aimed amide was extracted from the NaOH liquid with ethyl acetate for column chromatography. Column chromatography was performed using silica gel (200-300 mesh) eluting with ethyl acetate and petroleum ether to give the aimed amine (4a). Compounds of 4b-4h and 5a-5h could begot with corresponding acids by the procedures above. | |
With thionyl chloride; for 3h;Reflux; | A solution of 2-(4-fluorophenyl)acetic acid (5.0 g, 32.5 mmol, 1.00 equiv) in SOCl2 (30 mL) was heated for 3 hr at reflux in a 50-mL round-bottom flask. Most of SOCl2 was removed under vacuum, and the residue was added dropwise into a solution of AlCl3 (12.8 g, 96.2 mmol, 3.00 equiv) and fluorobenzene (6.1 g, 63.54 mmol, 2.00 equiv) in DCM (20 mL) at 0 C. The resulting solution was allowed to react, with stirring, for 2 hrs at room temperature. | |
With thionyl chloride; In dichloromethane; at 0℃;Reflux; | Example 2 Preparation of Intermediate Compound 2 Step A - Synthesis of Intermediate Compound 2b To a solution of compound 2a (100 g, 0.65 mol) in anhydrous DCM (1 L) was added SOCI2 (200 mL) dropwise at 0 C under a drying tube charged with CaCl2. After the addition, the mixture was heated to reflux and stirred overnight. The reaction was done in 2 batches, which were combined and concentrated in vacuo to provide crude compound 2b as an oil. | |
With thionyl chloride; In N,N-dimethyl-formamide; toluene; at 70℃; | The method of Kuethe et al. is depicted in FIG. 1. Briefly, commercially available 4-fluorophenylacetic acid g (Sigma-Aldrich Co. LLC, St. Louis, Mo.) is reacted with thionyl chloride in DMF/toluene to yield acid chloride (2). The acid chloride (6) is then reacted with the hydrochloride salt of the Weinreb amine (CH3NHOCH3.HCl) in the presence of sodium hydroxide to give 2-(4-fluorophenyl)-N-methoxy-N-methylacetamide (4). A vinyl Grignard reaction converts (4) to 1-(4-fluorophenyl)but-3-en-2-one (5). TES dienyl ether (6) is produced from the reaction of (5) with chlorotriethylsilane (TESCl) in the presence of iPr2NEt2. | |
With trichlorophosphate; In 1,2-dichloro-ethane; for 3h;Reflux; | General procedure: Aralkanoic acid chlorides 2a-g were synthesized by the reaction of aralkanoic acid 1a-g (1 mmol) in the presence of 1,2-dichloroethane (12 mL) solvent and phosphorous oxychloride(0.4 mL) chlorinating agent under reflux for 3hours. Then, the resulting solution was cooled to room temperature, and the solvent was removed under reduced pressureto afford aralkanoic acid chloride 2a-g, which was directly used in the next step without further purification. Acid chloride 2a-g was dissolved in acetonitrile (80 mL), addeddropwise to a solution containing hydrazine hydrate(1 mmol), TEA (0.5 mL) and acetonitrile (20 mL) and allowed to reflux for 3 hours with monitoring by TLC. After consumption of the starting material, the reaction mixture was cooled to room temperature. Evaporation of the solvent under reduced pressure yielded crude acid hydrazide 3a-g as a white solid on cooling, which was purified by column chromatography and crystallized in methanol [46]. | |
With thionyl chloride; In dichloromethane; at 0℃;Reflux; | To a solution of compound 2a (100 g, 0.65 mol) in anhydrous dichloromethane (1 L) was added SOCI2 (200 mL) dropwise at 0 C under a drying tube charged with CaCl2. After the addition, the mixture was heated to reflux and stirred overnight. The reaction was done in 2 batches, which were combined and concentrated in vacuo to provide crude compound 2b as an oil that was used without further purification. | |
With thionyl chloride; In dichloromethane; at 0℃;Reflux; | To a solution of compound 2a (100 g, 0.65 mol) in anhydrous dichloromethane (1 L) was added SOC12 (200 mL) dropwise at 0 C under a drying tube charged with CaC12. Afterthe addition, the mixture was heated to reflux and stirred overnight. The reaction was done in 2 batches, which were combined and concentrated in vacuo to provide crude compound 2b as an oil that was used without flirther purification. | |
With thionyl chloride; In N,N-dimethyl-formamide; at 0℃; for 3h; | General procedure: To the carboxylic acid (10mmol) was added thionyl chloride (20 mmol) followed by a catalytic amount ofDMF (1 drop). The mixture was stirred at 0 C until completion (ca. 3 h). Thesolvent was then removed under reduced pressure to afford the crude acidchloride. Alkoxyamine hydrochloride (11 mmol) was added to a mixture of K2CO3(20 mmol) in a 2:1 mixture of EA: H2O (0.2 M). The resultingsolution was cooled to 0 C followed by dropwise addition of the crude acidchloride dissolved in EtOAc (50 mL). The reaction was allowed to stir for 4 hwhile reaching room temperature. The two layers were separated, and the aqueousphase was extracted with EA (50 mL × 2). The combined organic phase was driedover anhydrous Na2SO4,filtered, and evaporated under reduced pressure. The residue was purified by flash columnchromatography on silica gel to give the desired products. | |
With thionyl chloride; at 80℃; for 4h;Inert atmosphere; | General procedure: A dry flask containing the corresponding carboxylic acid (1 mmol) and SOCl2 (0.6 mL) was heated at 80 C for 4 h under a nitrogen atmosphere. After the reaction period, the reaction mixture was concentrated under reduced pressure to remove the volatiles and then, the resultant crude reaction mixture was diluted with anhydrous DCM (2 mL). The DCM solution of corresponding acid chloride was slowly added to another RB flask containing the corresponding amine (1 mmol), Et3N (111 mg, 1.1mmol) and DCM (4 mL) under a nitrogen atmosphere. The resulting mixture was stirred at rt for 12 h. After this period, the reaction mixture was diluted with dichloromethane and washed with water and saturated aqueous NaHCO3 solution (twice). The combined organic layers were dried over anhydrous Na2SO4 and then, the solvent was evaporated in vacuo to afford a crude reaction mixture. Purification of the crude reaction mixture by column chromatography (neutral alumina (EtOAc/hexanes=25:75) furnished the corresponding products 1f-j. | |
With oxalyl dichloride; N,N-dimethyl-formamide; In tetrahydrofuran; at 0℃; for 0.5h;Inert atmosphere; | General procedure: A carboxylic acid (0.75 mmol) was added into a dry double-neckflask, and 5 mL of dry THF was added to the flask. N,N-dimethylformamide(1.50 mmol, 0.15 mL) was added into the solutionunder nitrogen at 0 C. When the solids were completely dissolved,oxalyl chloride (3.75 mmol) was added slowly. After 30 min, thesolvent and excess oxalyl chloride were removed under reducedpressure to obtain an acyl chloride which was kept dry. 100 mg ofcompound 2-4 (0.53 mmol) was added into a dry double-neckflask, and 5 mL of dry THF was added to the flask. When thesewere completely dissolved, dry pyridine (1.06 mmol, 0.01 mL) wasadded under nitrogen at 0 C. The THF solution of an acyl chloride(0.793 mmol) was added into the mixture slowly. After 30 min,20 mL of saturated ammonium chloride solution was slowly addedinto the mixture, and the mixture was extracted with EtOAc(3 x 20 mL). The organic layer was dried over anhydrous Na2SO4,filtered and concentrated to dryness, then purified through silicagel column (EA: PE 2: 1) to give B-1~B-15. | |
With trichlorophosphate; In 1,2-dichloro-ethane; 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 thionyl chloride; In benzene; at 20℃; for 18h; | General procedure: To a stirred solution of carboxylic acid 7a-h or 9c, i (0.55 mmol)in CH2Cl2 for 7a-h or benzene for 9c, i (3 mL) was added SOCl2(0.05 mL, 0.66 mmol), and the resulting mixture was stirred atroom temperature for 18 h. The solvent was removed, and thento the residue were added CH2Cl2 (3 mL), NH4SCN (63 mg,0.82 mmol), and PEG-400 (1 drop), and the resulting mixture wasstirred at room temperature for 2 h. The solvent was removed,and the residue was chromatographed on SiO2 (Hexane:Acetone= 50:1 40:1) to give corresponding isothiocyanate 8a-hand 10c, i which were used in the next step immediately. | |
With thionyl chloride; In N,N-dimethyl-formamide; toluene; for 6h;Reflux; | 15.4 g (0.1 mol) of p-fluorophenylacetic acid, 24.0 g (0.2 mol) of thionyl chloride, 60 ml of toluene and 4 drops of DMF were placed in a reaction flask,The reaction was refluxed for 6 hours, evaporated to dryness under reduced pressure to give a light red liquid, diluted with 20ml of acetone, spare. | |
With thionyl chloride; at 65 - 70℃; for 12h; | General procedure: The substituted phenylacetic acid (3 mmol) and thionyl chloride (10 ml) were placed in a dry round-bottomed flask, and the mixture was heated to reflux at 65-70 C for 12 h, which was detected by TLC. After the completion of reaction, the solvent was removed in vacuo and the residue was washed with CH2Cl2. The above procedure was repeated twice to obtain the crude intermediates 4, which were used for the next reaction without further purification. | |
With thionyl chloride; for 2h;Heating / reflux; | Step A: Preparation of Ethyl 2-(4-fluorophenyl)acetate; [0282] A mixture of 2-(4-fluorophenyl)acetic acid (23.5 g, 152 mmol) in thionyl chloride 56 mL, 762 mmol) was refluxed for 2 hours and then concentrated in vacuo. The residue was diluted with 200 mL DCM, and stirred at O0C. The mixture was treated with EtOH (9.8 mL, 168 mmol) and TEA (26 mL) dropwise. The mixture was then stirred for 2 hours. The mixture was quenched with 20 mL H2O and extracted with DCM (3 x 50 mL). The combined organics were washed with H2O (3 x 50 mL) and brine 20 mL, dried over anhydrous Na2SO4, and concentrated in vacuo to give 24.7 g of a pale yellow oil. | |
With thionyl chloride; | Example 12.7: Preparation of l-Amino-3-(4-fluoro-phenyl)-propan-2-one hyrdrochlorideCNCH2CO2Et 1BuOKThe proecdures as described in Tetrahedron. 1994, 50 (21), 6287-6298 and Chem. Pharm. Bull 1984, 32 (7), 2536-2543 were adapted to afford l-amino-3-(4-fluoro- phenyl)-propan-2-one hydrochloride. | |
With thionyl chloride; In toluene; at 105℃; for 16h; | 4-Fluorophenylacetic acid (28Og, 1.82mol) was suspended in 1.9L toluene followed by the careful addition of 185mL thionyl chloride (303g, 2.545mol). The reaction was heated to 1050C for 16hr (overnight). The reaction was allowed to cool to room temperature and the volatiles were removed in vacuo. The crude acid chloride was dissolved in 1.9L THF, cooled to 00C, and 0.72L piperidine (618g, 7.27mol) was added. The reaction vessel was allowed to warm to ambient temperature for 18hr. The mixture was quenched with a saturated solution of aq. NaHCO3 and extracted several times withEtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and filtered on a fritted funnel. The volatiles were removed in vacuo and the crude residue was purified on silica gel and eluted with a mixture of EtO Ac/heptanes (0-75% gradient elution). This furnished the title compound. 1H-NMR (CDCI3): δ 1.32-1.42 (m, 2H), 1.48-1.64 (m, 4H), 3.34-3.42 (m, 2H)5 3.54-3.60 (m, 2H), 3.69(s, 2H), 6.90-7.05 (m, 2H), 7.18-7.24 (m, 2H) ppm. | |
With thionyl chloride; In dichloromethane; at 50℃; for 2h; | Dissolve 2- (4-fluorophenyl) acetic acid (100.0 g, 648 mmol, 1.0 eq) in dichloromethane (200 mL), add sulfoxide (193.0 g, 1622 mmol, 2.5 eq), and stir the reaction at 50 C. 2 The reaction was monitored for completion by TLC and concentrated under reduced pressure to give the product (116.0 g of crude product). | |
With thionyl chloride; In dichloromethane; at 60℃; for 3h;Inert atmosphere; | Add 2- (4-fluorophenyl) acetic acid (50.0 g, 324.380 mmol, 1.0 eq)And dichlorosulfoxide (77.18g, 648.761mmol, 2.0eq)Dissolved in dichloromethane (250.0mL),The temperature was raised to 60 C under N2 protection and refluxed for 3h. TLC showed that the reaction was complete.The reaction solution was concentrated under reduced pressure, and an appropriate amount of dichloromethane was added and concentrated.This was repeated twice to obtain a yellow oily product. | |
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; for 2h;Cooling with ice; | Add 473mg of 4-fluorophenylacetic acid and 25ml of DCM into a 100ml single-necked flask, After stirring for a while, add (2eq) 0.513ml of oxalyl chloride under ice bath, Two drops of DMF are used as a catalyst, and the reaction is very violent, releasing a lot of gas. Stir in an ice bath for 2 hours, evaporate the solvent to obtain 4-fluorophenylacetyl chloride, which is prepared for immediate use. | |
With oxalyl dichloride; N,N-dimethyl-formamide; In N,N-dimethyl-formamide; at 0 - 20℃; for 6h;Inert atmosphere; | General procedure: To a stirred solution of substituted or unsubstituted phenylaceticacid (14ae14f) (5.0 mmol, 1.0 eq) in anhydrous dichloromethane(20 mL)was successively added oxalyl chloride (6.0 mmol,1.2 eq) and DMF (0.5 mmol, 0.1 eq) at 0 C under argon atmosphere.The resulting mixture was subsequently warmed up to roomtemperature and stirred for 6 h. The reaction mixture wasconcentrated in vacuum to afford the corresponding phenylacetylchloride. The solution of the corresponding phenylacetyl chloridein anhydrous dichloromethane (10 mL) was slowly added to astirred solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (5.0 mmol,1.0 eq), pyridine (10.0 mmol, 2.0 eq) in anhydrous dichloromethane(10 mL) at 0 C under argon atmosphere. The resulting mixture wassubsequently warmed up to room temperature and stirred for 5 h.The reaction mixture was concentrated and the resulting residuewas dissolved in anhydrous ethanol (20 mL), and the mixture washeated to 80 C for additional 4 h. After cooling, the mixture wasconcentrated to dryness and distributed inwater and ethyl acetate.The organic layer was separated and washed with water and brinesuccessively, dried over anhydrous sodium sulfate and concentratedin vacuum. The resulting residue was purified by silica gelchromatography (petroleum ether/ethyl acetate, v/v, 99:1 to 90:10)to give the desired product.5.1.1.1. Ethyl 4-(4-fluorophenyl)-3-oxobutanoate (16a). The titlecompound was prepared from 15a following general procedure A.Yield: 86%. 1H NMR (300 MHz, DMSO-d6) δ7.26e7.09 (m, 4H), 4.08(q, J 7.2 Hz, 2H), 3.88 (s, 2H), 3.66 (s, 2H), 1.17 (t, J 7.2 Hz, 3H). | |
With thionyl chloride; at 0 - 80℃; for 7h; | General procedure: The starting material of phenylacetic acid analogues (20mmol) was added into SOCl2 (25mL) at 0 , then the mixture was warmed to 80 and stirred for 7h. Then, the mixture was cooled to rt, the solvent was concentrated in vacuo to afford the crude product 1a-1k which was directly for next reaction without further purification. | |
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h; | General procedure: Corresponding acid (1.0 equiv, 10 mmol) was dissolved in 25 mL CH2Cl2 in a 100 mL round-bottom flask with a stir bar, one drop of DMF was added, then SOCl2(2.0 equiv, 20 mmol) was slowly added into the mixture at room temperature, the obtained solution was stirred for 2 h at room temperature. The title acyl chloride was obtained after evaporating the solvent and used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminum (III) chloride; In dichloromethane; at 0 - 20℃; for 2h; | A solution of 2-(4-fluorophenyl)acetic acid (5.0 g, 32.5 mmol, 1.00 equiv) in SOCl2 (30 mL) was heated for 3 hr at reflux in a 50-mL round-bottom flask. Most of SOCl2 was removed under vacuum, and the residue was added dropwise into a solution of AlCl3 (12.8 g, 96.2 mmol, 3.00 equiv) and fluorobenzene (6.1 g, 63.54 mmol, 2.00 equiv) in DCM (20 mL) at 0 C. The resulting solution was allowed to react, with stirring, for 2 hrs at room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | aluminum (III) chloride; at 25 - 50℃; for 8.5h; | 2- (4-Fluoro-phenyl)-1-phenyl-ethanone To a solution of benzene (182 mL) at 0 C was added AIC13 (46.4 g, 348 mmol). A portion of 4-fluorophenyl acetyl chloride (50.0 g, 290 mmol) was then added drop- wise over 30 min. Once the addition was complete, the reaction was allowed to warm to 25 C and then heated to 50 C for 8 hr. Subsequently, the reaction mixture was cooled to 25 C and poured onto ice (400 g). To the resulting suspension in ice was added 1.0 N HCI (50 mL). The organic layer was separated and washed with 10% HCI, saturated NaHC03 and brine. The organic layer was then dried and concentrated to afford a solid that was washed twice with hexane (200 mL) and then dried under vacuum to afford 2- (4-fluoro-phenyl)-1-phenyl-ethanone (59.90 g, 97%): MS (APCI+) : Sz 215.0 (M+H); H-NMR (CDCI3) o ?. 82 (d, 2 H), 7.54-7. 41 (m, 3 H), 7.22-7. 17 (m, 2 H), 7.00-6. 96 (m, 2 H), 4.23 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium acetate; In acetone; at 20℃; for 17h; | The acid chloride was dissolved in acetone (200 ml). Ammonium acetate (112 g) was added to the solution, and the mixture was stirred at room temperature for 17 hr. An aqueous saturated sodium hydrogencarbonate solution (150 ml) was added thereto, and the mixture was stirred at room temperature for one hr. The reaction solution was then extracted with chloroform, and the solvent in the extract was removed by evaporation to give a crude crystal. The resultant crude crystal was washed with a hexane/ethyl acetate (2/1) mixed solution to give 4-fluorophenylacetamide (10.5 g, yield 70%). 1H-NMR (CDCl3, 400 MHz): δ 3.53 (s, 2H), 5.25 - 5.70 (m, 2H), 7.00 - 7.05 (m, 2H), 7. 20 - 7.26 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.70 g | With pyridine; In dichloromethane; at 0℃; for 2.5h; | Pyridine (70.35g) was added to the mixture of Maxwell acid (50.32g) in DCM ( 450ml) withstirring, followed by the addition of AlO (62.28g) at OOC. The reaction was continued at OOCfor 2.5hrs or till the reaction is completed monitored by TLC. The reaction mixture was diluted withstirring by DCM (300ml) and 750ml IN HCL The organic phase was separated and dried byvacuum to give solid, All (66.70g). |
With dmap; In dichloromethane; at 20℃; for 18h;Cooling with ice; | General procedure: A solution of an acid chloride (26 mmol) in dry CH2Cl2 (15 mL)was added dropwise with stirring over a period of 1 h to a solution of Meldrum’s acid (26 mmol) and pyridine (65 mmol) in dry CH2Cl2(50 mL) in an ice bath. The temperature was maintained for an additional 1 h, and then the reaction mixture was allowed to warmto room temperature and stirred at room temperature for 16 h. After the resulting mixture was washed with 3 mol/L HCl(3 100 mL) and water (50 mL) sequentially, the organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in methanol (50 mL) and the resulting solutionwas heated to reflux for 6 h. After the solvent was evaporated under vacuum, the residue was purified by flash columnusing PE/EA 10:1 as the eluent to afford compound 4. The yield is around 85e93%. | |
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;Inert atmosphere; | Add 2,2-dimethyl-1,3-dioxane-4,6-dione (56.10 g, 389.3 mmol, 1.2 eq)And triethylamine (78.78 g, 7798.5 mmol, 2.4 eq) in dichloromethane (250.0 mL),N2 protection drops to 0 ,The crude 2- (4-fluorophenyl) acetyl chloride obtained in the previous step was diluted with dichloromethane (100.0 mL).Slowly drip into the reaction solution, and then warm to room temperature after dripping. After 3 hours, the reaction was detected by TLC. The reaction solution was washed three times with 1 mol / L hydrochloric acid, and the pH value of the aqueous phase was 3 to 4, and then washed twice with a saturated sodium chloride aqueous solution, dried, and concentrated under reduced pressure to obtain a yellow oily product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
At -78C n-BuLi (2.5 M in hexane) (2.92 ml, 7.29 mmol) was added slowly to a solution of {R)~ (-)-4-benzyl-1 ,3-oxazolidin-2-one (1 .293 g, 7.29 mmol) in THF (10 ml), and stirring at -78 C was continued for 30min. Then 4-fluorophenylacetyl chloride (1 ml, 7.29 mmol) in THF (2 ml) was added dropwise, and the mixture stirred at -78 C for another 1 .5 h. The reaction mixture was treated with a concentrated aqueous solution of NH4CI and allowed to warm to RT before it was extracted with EtOAc. The organic phase was dried over MgS04 and the solvent was evaporated. The product was purified by chromatography (silica, flow=30ml/min, cyclohexane 100% to cyclohexane/EtOAc: 7/3). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.23 - 7.39 (7 H, m), 7.16 (2 H, t), 5.32 (1 H, dd), 4.64 - 4.72 (1 H, m), 4.24 (1 H, t), 4.14 (1 H, dd), 3.1 1 (1 H, dd), 2.95 - 3.00 (2 H, m), 2.67 (1 H, dd). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | (S)-4-Benzyl-3-(2-(4-fluorophenyl)acetyl)oxazolidin-2-one; To a cooled (-78 C.) solution of (S)-4-benzyloxazolidin-2-one (10.26 g, 58 mmol, 1.0 equiv) in 100 mL THF was added dropwise n-BuLi (40 mL, 1.6 M, 64 mmol, 1.1 equiv). After stirring for 30 minutes, 4-fluorophenylacetyl chloride (10.0 g, 0.58 mmol, 1.0 equiv) was added dropwise. After stirring for an additional 30 minutes, the reaction mixture was allowed to warm to room temperature. The reaction was quenched with sat'd. aq. NH4Cl, extracted with DCM, and washed with brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel (10-20% EtOAc/Hexanes) provided the title compound as a thick oil (14.7 g, 81%). m/z=314.3 [M+H]+. | |
81% | (S)-4-Benzyl-3-(2-(4-fluorophenyl)acetyl)oxazolidin-2-one To a cooled (-78 C.) solution of (S)-4-benzyloxazolidin-2-one (10 g, 58 mmol, 1.0 equiv) in 100 mL THF was added dropwise n-BuLi (40 mL, 1.6 M in hexanes, 64 mmol, 1.1 equiv). After stirring for 30 minutes, 4-fluorophenylacetyl chloride (10 g, 0.58 mmol, 1.0 equiv) was added dropwise. After stirring for an additional 30 minutes, the reaction mixture was allowed to warm to room temperature. The reaction was quenched with saturated aq. NH4Cl, extracted with dichloromethane, and washed with brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel (10-20% EtOAc/hexanes) provided the title compound as a thick oil (14.7 g, 81%). | |
Combine (S)-4-benzyl-2-oxazolidinone (22.9 g, 129 mmol) and tetrahydrofuran (120 mL). Cool in a dry-ice/acetone bath. Add dropwise a solution of n-butyl lithium (52 mL, 2.5 M, 130 mmol). After 15 minutes, slowly add a solution of 4-fluorophenylacetyl chloride (22.3 g, 129 mmol) in tetrahydrofuran (50 mL). Warm to ambient temperature. After 2 hours, quench the reaction mixture by the addition of a saturated aqueous sodium bicarbonate solution. Separate the layers and extract the aqueous layer with diethyl ether. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting wit 15% ethyl acetate/hexane. Combine the product containing fractions, evaporate, and recrytallize from diethyl ether/hexane to give (S)-4-benzyl-3-(4-fluorophenyl)acetyl-2-oxazolidinone. |
Alternately, combined (S)-benzyl-2-oxazolidinone(55.4 g, 313 mmol) and tetrahydrofuran (550 ml). Cool in a dry-ice/acetone bath. Add n-butyl lithium (125 ml, 1 M in hexane, 312 mmol). After 30 minutes, add dropwise 4-fluorophenylacetyl chloride (56.7 g, 328 mmol). After 30 minutes, warm to ambient temperature, add a saturated aqueous sodium bicarbonate solution, and stir. After 45 minutes, separate the layers and extract the aqueous layer three times with ethyl acetate, combine the organic layers, extract with brine, dry over MgSO4, filter, and evaporate in vacuo to give a viscous oil. Stir the viscous oil under vacuum to remove residual solvent and triturate with isopropanol to give a solid. Collect the solid by the filtration and rinse with isopropanol to give, after drying, (S)-4-benzyl-3-(4-fluorophenyl)acetyl-2-oxazolidinone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% - 95%Chromat. | With sodium hydroxide; In water; toluene; at 20 - 25℃; for 2.3h;Product distribution / selectivity; | Into a suitable reactor is charged 4-fluorophenylacetic acid (122.5 kg, 795 mol), N,N-dimethylformamide (0.37 kg, 5.1 mol), and toluene (490 kg). Oxalyl chloride (105.2 kg, 829 mol) is added at a rate to maintain the temperature at about 35C. The solution is stirred for at least 7 hours at about 25C, typically affording a solution of about 22.1 wt% 4-fluorophenylacetyl chloride (99% yield as determined by HPLC assay). A suitable inert reactor is charged with 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11) (45.6 kg, 181 mol, about 6 wt% solution in methanol) and the concentration of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11) is adjusted to about 20 wt% or higher by atmospheric distillation1. Toluene (about 550 kg) is added and distillation is continued until the temperature reaches about 110C. Toluene is added2 while at reflux to adjust the mixture to about a 9 wt% solution of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11). The reaction mixture is cooled to about 30C, causing precipitation of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)-methyl]piperidine (11)3 before 50 wt % solution of sodium hydroxide (17.4 kg, 217 mol) and about 182 kg of water are added. The 4-fluorophenylacetyl chloride/toluene solution (32.8 kg, 190 mol) is added at a rate to maintain the temperature at about 25C. The addition line is flushed with 10 kg of toluene.4 The phases are separated and the organic phase is washed with about 180 kg of water. The organic phase is concentrated and dried by atmospheric distillation5. The concentration of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]-N-2-(4-fluorophen-1-oxo-ethyl)piperidine (20) is about 18 wt % as determined by HPLC assay, affording about 67 kg of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]-N-2-(4-fluorophen-1-oxo-ethyl)piperidine (20) (95% yield).6 1The approximate wt% of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11) is arrived at by removal of approximately two-thirds of initial solvent. An exact wt% can be obtained by HPLC analysis of the solution. 2The amount of toluene back added is determined by weighing the distillate and knowing the amount of toluene initially added. 34-[1-Hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11) can be isolated at this stage is desired to increase its purity by cooling to about 20C and isolation by filtration. 4The mixture is sampled and analyzed by HPLC assay to confirm the formation of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]-N-2-(4-fluorophen-1-oxo-ethyl)piperidine (20). The reaction is complete if less than 3% of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11) (by area percent) is detected. 5The solution is sampled and the water content is determined by Karl Fischer titration. If the water content is above 500 ppm, additional toluene may be added and the distillation continued. 6The 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]-N-2-(4-fluorophen-1-oxoethyl)piperidine (20)/toluene solution is filtered through a cartridge filter and stored in drums for use in Scheme I, step c.Example 113a Scheme M, step a: 4-[1-Hydroxy-1-(2,3-dimethoxyphenyl)methyl]-N-2-(4-fluorophen-1-oxo-ethyl)piperidine (20); Into a 250-mL jacketed-bottom drain resin pot equipped with a thermowell with thermocouple and a four-joint head fitted with a mechanical stirrer, a distillation head with receiver, and two stoppers was placed 108.4 g (0.027 mol) of a 6.2 wt% solution of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)-methyl]piperidine (11) in methanol from Example 90, Scheme I. step c. The solution was heated and 81.6 g of methanol distillate was collected. To the slurry was added 80.7 g of toluene and the distillation was continued. The distillation was terminated when both the pot and distillation head temperatures stabilized at 110C (141 g of distillate was collected). To the slurry was added an additional 25.9 g of toluene, before warming to 110C to completely dissolve all of the 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11). The solution was allowed to cool and crystallize over a 30 minutes period to 28C. To the slurry was added 2.55 g (0.032 mol) of a 50 wt% solution of aqueous sodium hydroxide and 26.9 g of water. The flask was equipped with an addition funnel which was charged with 22.2 g (0.028 mol) of a 22.2 wt % solution of 4-fluorophenylacetyl chloride in toluene. After the three-phase mixture had stirred for 15 minutes, the 4-fluorophenylacetyl chloride/toluene solution was added dropwise over a 5 minute period. This resulted in formation of a two-phase solution. The mixture was allowed to stir at ambient temperature under a nitrogen atmosphere for 2 hours before monitoring by HPLC. The reaction was determined to be complete by HPLC, agitation was stopped and the phases were allowed to separate. The phases were separated and the organic phase was washed with 13.4 g of water. The toluene/4-fluorophenylacetyl chloride solution was azeotropically dried and concentrated by distillation until both the ... |
95% | With acetic acid; In water; toluene; at 20 - 60℃; for 2.25h;Product distribution / selectivity; | Into a 500-mL four-neck flask equipped with a mechanical stirrer, a thermowell with a thermocouple, a 125-mL addition funnel topped with a nitrogen bubbler, and a distillation head was placed 70.5 g (0.031 mol) of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11) as an 11.1 wt% solution in methanol (containing 2.9 wt% of acetic acid). The solution was warmed and approximately 2/3 of the methanol was removed by atmospheric distillation. To the concentrated solution was added 110 g of toluene and the distillation was continued until the distillation head temperature reached 98C. At the end of the solvent exchange the toluene unit ratio is adjusted to 10. This was accomplished by determining the weight of the distillate and knowing the amount of toluene initially added. The 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11)/toluene/acetic acid solution was allowed to cool to 60C. To the solution was added 47 g of water. The resulting slurry was allowed to stir for 15 min and the addition funnel was charged with 27.1 g (0.034 mol) of a 21.7 wt% solution of 4-fluorophenylacetyl chloride in toluene. The 4-fluorophenyl acetyl chloride/toluene solution was added in one portion to the slurry at 40C, resulting in a 4C exotherm. Within minutes of the addition, the three-phase system became a two-phase system. The reaction mixture was allowed to cool to ambient temperature and stir for 2 h. The phases were separated and the organic phase was washed with 15.7 g of a 1N hydrochloric acid solution and 15.7 g of water. The 4- [1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]-N-2-(4-fluorophen-1-oxo-ethyl)piperidine (20)/toluene solution was concentrated and azeotropically dried by rotary evaporation to afford a 95% yield of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]-N-2-(4-fluorophen-1-oxo-ethyl)piperidine (20) as an 11.5 wt% solution in toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 20℃; for 1h; | Synthesis of (4-Fluoro-phenyl) -acetic acid hydrazide; (4-Fluoro-phenyl)-acetyl chloride was readily prepared from thecorresponding acid by refluxing the acid in thionyl chloride for 1 h. However, the acid chloride was too reactive. Addition of hydrazine hydrate to a solution of the acid chloride gave only the dimer. Reverse addition of acid chloride to hydrazine hydrate at 0 C gave the desired hydrazide with some dimer. The acid chloride was then transformed to the corresponding ethyl ester. Reaction of the ethyl ester with 2 equiv. of hydrazine hydrate in refluxing EtOH gave cleanly the (4-Fluoro-phenyl)-acetic acid hydrazide in 76% yield. The results are summarized below. | |
With triethylamine; In dichloromethane; at 0℃; for 2h; | Step A: Preparation of Ethyl 2-(4-fluorophenyl)acetate; [0282] A mixture of 2-(4-fluorophenyl)acetic acid (23.5 g, 152 mmol) in thionyl chloride 56 mL, 762 mmol) was refluxed for 2 hours and then concentrated in vacuo. The residue was diluted with 200 mL DCM, and stirred at O0C. The mixture was treated with EtOH (9.8 mL, 168 mmol) and TEA (26 mL) dropwise. The mixture was then stirred for 2 hours. The mixture was quenched with 20 mL H2O and extracted with DCM (3 x 50 mL). The combined organics were washed with H2O (3 x 50 mL) and brine 20 mL, dried over anhydrous Na2SO4, and concentrated in vacuo to give 24.7 g of a pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | In carbon disulfide; | Step 1 Preparation of 1-(4-methylthiophenyl)-2-(4-fluorophenyl)ethanone; To a stirred solution of thioanisole (380 mL, 3.2 mol) and 4-fluorophenylacetyl chloride (300 g, 1.6 mol) in carbon disulfide (1.2 L), cooled to 5 C., was added anhydrous aluminum chloride portionwise at such a rate that the internal temperature did not rise above 15 C. The reaction was stirred at room temperature for 16 hours. The solution was cautiously poured into 2 L of ice and water. The aqueous solution was extracted with methylene chloride (6*150 mL), the combined extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was dissolved in 800 mL of ether and cooled to 0 C. whereupon crystals of pure product formed which were isolated by filtration on a Buchner funnel and air dried to provide the ketone (199.6 g, 48%): mp 135-138 C. 1 H NMR (CDCl3 /TMS) 300 MHz 8.00 (d, J=8.7 Hz, 2H), 7.40-7.30 (m, 4H), 7.13-7.03 (m, 2H), 4.34 (s, 2H), 2.56 (s, 3H). Mass spectrum M+ =260. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tert-butyl methyl ether; at 0 - 15℃; for 1.17h; | 4-(4-Fluoro-phenyl)-2-methyl-buta-2,3-dienoic acid ethyl ester To a solution of (4-fluoro-phenyl)-acetic acid (22.33 g, 144.9 mmol) in 100 mL of methyl tert-butyl ether and 250 μL of DMF was added 13.02 mL (146.3 mmol) of oxalyl chloride at room temperature dropwise over 30 minutes. The resulting mixture was stirred at room temperature for an additional 20 minutes (HPLC indicated completed reaction), and then the entire solution was added dropwise over 1 hour to a solution of N,N-diisopropylethylamine (50.48 mL, 289.8 mmol) and ethyl 2-(triphenylphosphoranylidene)propionate (50.0 g, 138.0 mmol) in 100 mL of methyl tert-butyl ether, while maintaining the internal temperature between 0-15 C. After the addition was complete, the reaction mixture was stirred for an additional 10 minutes at 0-10 C., when HPLC indicated a completed reaction. The reaction mixture was then diluted with 100 mL of heptane, and stirred for 30 minutes at 0-10 C. The resulting solid was filtered and washed with 2*100 mL of 1:1 methyl tert-butyl ether:heptane. | |
With N-ethyl-N,N-diisopropylamine; In tert-butyl methyl ether; at 0 - 15℃; for 1.16667h; | To a solution of (4-fluoro-phenyl)-acetic acid (22.33 g, 144.9 mmol) in 100 ml_ of methyl terf-butyl ether and 250 μl_ of DMF was added 13.02 ml_ (146.3 mmol) of oxalyl chloride at room temperature dropwise over 30 minutes. The resulting mixture was stirred at room temperature for an additional 20 minutes (HPLC indicated completed reaction), and then the entire solution was added dropwise over 1 hour to a solution of Λ/,Λ/-diisopropylethylamine (50.48 ml_, 289.8 mmol) and ethyl 2- (thphenylphosphoranylidene)propionate (50.0 g, 138.0 mmol) in 100 ml_ of methyl terf-butyl ether, while maintaining the internal temperature between 0-15 C. After the addition was complete, the reaction mixture was stirred for an additional 10 minutes at 0-10 C, when HPLC indicated a completed reaction. The reaction mixture was then diluted with 100 mL of heptane, and stirred for 30 minutes at 0- 10 C. The resulting solid was filtered and washed with 2x 100 mL of 1 :1 methyl tert- butyl etheϖheptane. The filtrate and the washings were combined and washed with 100 mL of water, 100 mL of 1 M citric acid, 2x100 mL of water, then concentrated azeotropically at 25 C/60 mmHg to a total volume of -40 mL. The residue was diluted with 60 ml_ of methyl te/t-butyl ether. This solution was then directly used for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | In dichloromethane; at -78℃; for 2h; | To a -78 C. stirred solution of methyl hydrazine (11 mL, 208.5 mmol) in CH2Cl2 (100 mL) is added dropwise a solution of commercially available 4-fluorophenyl-acetyl chloride (12 g, 69.5 mmol) in CH2Cl2 (200 mL). The reaction mixture is stirred for 2 hours at -78 C. and is then slowly warmed to room temperature. The reaction mixture is filtered and the filtrate concentrated under reduced pressure to give a pale yellow oil. Purification over silica (EtOAc) affords 7.6 g (61% yield) of the desired product: 1H NMR (300 MHz, CDCl3) δ 7.28-7.23 (m, 2H), 6.99-6.92 (m, 2H), 3.87 (s, 2H), 3.190 (s, 2H), 3.11 (s, 3H); ESI/MS: 183.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.8% | Example A7: A mixture of 4-fluorophenylacetyl chloride (4.91 g, 24.3 mmol), 2,2-dimethyl- 1,3-dioxane-4,6-dione (3.50 g, 24.3 mmol) and DIEA (5.84 g, 49.8 mmol) in DCM (30 mL)was stirred for 1 h at 0C, then warmed to RT for 2 h. The solution was diluted with DCM, washed with 0.1 N HC1 and brine, dried over Na2504 and evaporated to dryness. Theresulting orange solid was suspended in EtOH (100 mL) and refluxed for 2 hours. Thesolution was evaporated and the resulting orange oil was left in the freezer overnight to give a yellow solid. The crude solid was recrystallized from EtOH to afford ethyl 4-(4-fluorophenyl)-3 -oxobutanoate (5.3 g, 86.8% yield). | |
General procedure: To a stirred solution of substituted or unsubstituted phenylaceticacid (14ae14f) (5.0 mmol, 1.0 eq) in anhydrous dichloromethane(20 mL)was successively added oxalyl chloride (6.0 mmol,1.2 eq) and DMF (0.5 mmol, 0.1 eq) at 0 C under argon atmosphere.The resulting mixture was subsequently warmed up to roomtemperature and stirred for 6 h. The reaction mixture wasconcentrated in vacuum to afford the corresponding phenylacetylchloride. The solution of the corresponding phenylacetyl chloridein anhydrous dichloromethane (10 mL) was slowly added to astirred solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (5.0 mmol,1.0 eq), pyridine (10.0 mmol, 2.0 eq) in anhydrous dichloromethane(10 mL) at 0 C under argon atmosphere. The resulting mixture wassubsequently warmed up to room temperature and stirred for 5 h.The reaction mixture was concentrated and the resulting residuewas dissolved in anhydrous ethanol (20 mL), and the mixture washeated to 80 C for additional 4 h. After cooling, the mixture wasconcentrated to dryness and distributed inwater and ethyl acetate.The organic layer was separated and washed with water and brinesuccessively, dried over anhydrous sodium sulfate and concentratedin vacuum. The resulting residue was purified by silica gelchromatography (petroleum ether/ethyl acetate, v/v, 99:1 to 90:10)to give the desired product.5.1.1.1. Ethyl 4-(4-fluorophenyl)-3-oxobutanoate (16a). The titlecompound was prepared from 15a following general procedure A.Yield: 86%. 1H NMR (300 MHz, DMSO-d6) δ7.26e7.09 (m, 4H), 4.08(q, J 7.2 Hz, 2H), 3.88 (s, 2H), 3.66 (s, 2H), 1.17 (t, J 7.2 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In diethyl ether; water; at 20℃;Cooling with ice; | The chemicals were purchased from the commercial venders and were used without purification. The reactions were monitored and the purity of the product was checked by thin layer chromatography (TLC). Silica gel 60 F254 chromatoplates were used for TLC. The solvent systems were chloroform/methanol (15:1). Thionyl chloride (1.5 ml) and 4-fluorophenyl acetic acid (0.5 mmol) were refluxed in benzene (5 ml) at 80 for 3 h, and then excess thionyl chloride was removed in vacuo [27]. The residue was dissolved in ether (10 ml) and the solution added during 1 h to a stirred, ice-cold mixture of 2-amino-5-nitrophenol (0.5 mmol), sodiumbicarbonate (0.5 mmol), diethyl ether (10 ml), and water (10 ml). The mixture was stirred overnight at room temperature and filtered. After the precipitate was washed with water, 2 N HCl and water, respectively, and finally with ether, compound was obtained. The crude product was purified by recrystallization from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With pyridine; at 60℃; for 15h; | Step C; To a solution of 6-amino-N-((S)-1-(4-fluorophenyl)ethyl)pyrimidine-4-carboxamide hydrochloride (139 mg, 0.468 mmol) in pyridine (1 mL) was added 2-(4-fluorophenyl)acetyl chloride (242 mg). The mixture was stirred at 60 C. for 15 h and purified by silica gel chromatography (methanol/dichloromethane) to afford title compound as white solid (102.5 mg, 55%). [MH]+=397.2. |
Yield | Reaction Conditions | Operation in experiment |
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31% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 3h; | To a solution of 118AF52-95 (300 mg, 0.93 mmol) and triethylamine (0.52 mL, 3.72 mmol) in dry THF (10 mL) at [0C] a solution of 4-fluorophenylacetyl chloride (0.19 mL, 1.39 mmol) in THF (5 mL) was added dropwise and stirring was continued at rt for 3 h. The reaction mixture was filtered and the filtrate evaporated to dryness. The residue was partitioned between ethyl acetate and 1M [NAOH,] the organic layer washed with brine, dried over [NA2S04,] filtered and evaporated. Purification by silica gel column chromatography, eluting with a stepwise gradient of 0-8% methanol in dichloromethane, followed by purification of the compound by passage over an acidic ion exchange SPE cartridge, afforded the desired compound (131 mg, [31%),] which was converted to its tartrate form as described above. Rf= 0.39 (MeOH/CH2Cl2 1 : 9). LCMS m/z 459 [[M+H] +. IH-NMR] (CDC13, rotamers 0.6 : 0.4) [B] 7.25-6. 88 (m, 8H, Ar-H), 4.58-4. 52 (m, 0.6H, pip-H), 4.50 (t, 1H, [J =] 5.1, dioxane-H), 4.48 and 4.44 (2s, 2H, benzyl-H), 4.06-4. 02 (m, 2H, dioxane-H), 3.78 and 3.50 (2s, 2H, benzyl-H), 3.72-3. 64 (m, 2.4H, pip-H, dioxane-H), 2.84 (m, 2H, pip-H), 2.40-2. 35 (m, 2H, [NCH2),] 2.07-1. 99 (m, 2.2H, dioxane-H, pip-H), 1.85-1. 50 (m, 6H, pip-H, NCH2CH2), 1.30-1. 25 (m, 1. [8H,] dioxane-H, pip-H). HPLC tR = 6.9 min. |
31% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 3h; | To a solution of 118AF52-95 (300 mg, 0.93 mmol) and triethylamine (0.52 mL, 3.72 mmol) in dry THF (10 mL) at 00C a solution of 4-fluoroρhenylacetyl chloride (0.19 mL, 1.39 mmol) in THF (5 mL) was added dropwise and stirring was continued at rt for 3 h. The reaction mixture was filtered and the filtrate evaporated to dryness. The residue was partitioned between ethyl acetate and IM NaOH, the organic layer washed with brine, dried over Na2SO4, filtered and evaporated. Purification by silica gel column chromatography, eluting with a stepwise gradient of 0-8% methanol in dichloromethane, followed by purification of the compound by passage over an acidic ion exchange SPE cartridge, afforded the desired compound (131 mg, 31%), which was converted to its tartrate form as described above.[0589] R/ = 0.39 (MeOH/CH2Cl2 1 :9). LCMS m/z 459 [M+H]+. 1H-NMR (CDCl3, rotamers 0.6:0.4) δ 7.25-6.88 (m, 8H, Ar-H), 4.58-4.52 (m, 0.6H, pip-H), 4.50 (t, IH, J= 5.1, dioxane-H), 4.48 and 4.44 (2s, 2H, benzyl-H), 4.06-4.02 (m, 2H, dioxane-H), 3.78 and 3.50 (2s, 2H, benzyl-H), 3.72-3.64 (m, 2.4H, pip-H, dioxane-H), 2.84 (m, 2H5 pip-H), 2.40-2.35 (m, 2H, NCH2), 2.07-1.99 (m. 2.2H, dioxane-H, pip-H), 1.85-1.50 (m, 6H, pip-H, NCH2CH2), 1.30-1.25 (m, 1.8H, dioxane-H, pip-H). HPLC fe = 6.9 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In tetrahydrofuran; hexane; ethyl acetate; | EXAMPLE 145 N-{3-[1-((3S)-3-[(4-FLUOROPHENYL)ACETYL]AMINO}-3-PHENYLPROPYL)-4-PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE: A mixture of N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (11.0 mg, 0.0280 mmol) and (4-fluorophenyl)acetyl chloride (7.20 mg, 0.0420 mmol) in THF (5 mL) was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC using Hexane:EtOAc (2:1) to give the desired product (13 mg, 90% yield). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, 1H, J=8.4 Hz), 7.59 (s, 1H), 7.31-6.93 (m, 13H), 5.13 (q, 1H, J=6.0 Hz), 3.56 (s, 2H), 3.07 (d, 1H, J=11.7 Hz), 2.91 (d, 1H, J=11.0 Hz), 2.62-2.42 (m, 2H), 2.40-2.30 (m, 1H), 2.12-1.54 (m, 9H), 1.24 (d, 6H, J=6.7 Hz); ESMS m/e: 515.3 (M+H)+. |
90% | In tetrahydrofuran; at 20℃; for 4h; | EXAMPLE 89 N-{3-[1-((3S)-3-[(4-FLUOROPHENYL)ACETYL]AMINO}-3-PHENYLPROPYL)-4-PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE: A mixture of N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (11.0 mg, 0.0280 mmol) and (4-fluorophenyl)acetyl chloride (7.20 mg, 0.0420 mmol) in THF (5 ML) was stirred at room temperature for 4 h.. The solvent was removed under reduced pressure and the residue was purified by preparative TLC using hexane:EtOAc (2:1) to give the desired product (13 mg, 90% yield).. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, 1H, J=8.4 Hz), 7.59 (s, 1H), 7.31-6.93 (m, 13H), 5.13 (q, 1H, J=6.0 Hz), 3.56 (s, 2H), 3.07 (d, 1H, J=11.7 Hz), 2.91 (d, 1H, J=11.0 Hz), 2.62-2.42 (m, 2H), 2.40-2.30 (m, 1H), 2.12-1.54 (m, 9H), 1.24 (d, 6H, J=6.7 Hz); ESMS m/e: 515.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.9% | With sodium hydrogencarbonate; In acetonitrile; for 16.0833h;Sonicated; | To a suspension of (4-AMINO-3-NITROPHENYL)-CARBAMIC acid tert-butyl ester (1.992 g, 7.87 mmol) and NAHCO3 (5.4 g) in acetonitrile (20 mL) (4-fluorophenyl) acetyl chloride was added (1.8 mL, 1.3 eq. ). The obtained suspension was sonicated for 5 minutes and stirred at ambient temperature for 16 hrs. It was poured into water (200 mL), sonicated for 5 minutes, filtered, and washed with water and heptane. The obtained residue was dissolved in hot ethyl acetate (30 mL), saturated aqueous NAHCO3 was added (50 mL) and the obtained mixture was quenched with heptane (200 mL). The obtained suspension was sonicated for 5 minutes and filtered. The residue was washed with water and heptane and dried in vacuo to furnish 2.48 g of a brown-yellow solid. Yield 80.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With hydrazine hydrate; triethylamine; In acetonitrile; for 3h;Reflux; | General procedure: Aralkanoic acid chlorides 2a-g were synthesized by the reaction of aralkanoic acid 1a-g (1 mmol) in the presence of 1,2-dichloroethane (12 mL) solvent and phosphorous oxychloride(0.4 mL) chlorinating agent under reflux for 3hours. Then, the resulting solution was cooled to room temperature, and the solvent was removed under reduced pressureto afford aralkanoic acid chloride 2a-g, which was directly used in the next step without further purification. Acid chloride 2a-g was dissolved in acetonitrile (80 mL), addeddropwise to a solution containing hydrazine hydrate(1 mmol), TEA (0.5 mL) and acetonitrile (20 mL) and allowed to reflux for 3 hours with monitoring by TLC. After consumption of the starting material, the reaction mixture was cooled to room temperature. Evaporation of the solvent under reduced pressure yielded crude acid hydrazide 3a-g as a white solid on cooling, which was purified by column chromatography and crystallized in methanol [46]. |
69% | With hydrazine; In dichloromethane; at 0℃; for 0.666667h; | A cold (0 oC) solution of hydrazine (4. 5 ML, 144 mmol) in dichloromethane (50 mL) was treated with a dichloromethane solution of (4-fluorophenyl) acetyl chloride (1. 0 g, 5. 8 mmol). The resultant solution was stirred for 40 minutes and water was then added. The layers were separated and the aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration followed by purification by flash chromatography (5% methanol-dichloromethane gradient elution) provided 2- (4-FLUOROPHENYL) acetic hydrazide (673 mg, 69%) as a white solid. 1H NMR (DMSO-D6) : S 9. 18 (broad, 1 H), 7. 26 (dd, J= 8. 4, 5. 7 Hz, 2 H), 7. 09 (t, J= 8. 4 Hz, 2 H), 4. 21 (broad, 2 H), 3. 31 (s, 2 H) ; MS INTO 169 (M+1), |
With hydrazine; | Step 5: (7S)-3-(Benzyloxy)-N-[(4-fluorophenyl)acetyl]-5-methyl-7-phenyl-4;5,6,7- tetrahydropyrazolo[l,5-α]; A solution of (7S)-3-(benzyloxy)-5-methyl-7-phenyl-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrazine-2-carboxylic acid (148 mg, 0.39 mmol), 2-(4-fluorophenyl)acetohydrazide (99 mg, 0.59 mmol; prepared from 4-fluorophenyl acetyl chloride and hydrazine in a manner similar to that described in J. Heterocyclic Chemistry, 1977, 14, 1123), EDC (113 mg, 0.59 mmol), HOBT (79 mg, 0.59 mmol) and triethylamine (82 μL, 0.59 mmol) in DMF (1 mL) was stirred at room temperature for 1 hour. The DMF was removed in vacuo and the residue was partitioned between water and ethyl acetate, adjusting to a pH of 3 using IN HCl. The layers were then separated and the aqueous layer was extracted with more ethyl acetate (2 x 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the product as white solid. lH NMR (400 MHz, d6-DMSO) δ 10.2 (s, IH), 9.84 (s, IH), 7.98 (dd, J = 8.4 Hz, IH), 7.72 (d, J = 8.4 Hz, IH), 7.56-7.51 (m, 2H), 7.43- 7.34 (m, 6H), 7.14 (t, J = 8.9 Hz, 2H), 6.97 (d, J = 6.1 Hz, 2H), 5.79 (m, IH), 5.34 (AB quartet, J = 10.9 Hz, 2H), 4.23 (dd, J = 13, 4.7 Hz, IH), 3.84 (dd, J = 13.7, 3.7 Hz, IH), 3.52 (s, 2H), and 2.92 (s, 3H). ES MS (M+l) = 528. |
With hydrazine; In dichloromethane; for 0.75h; | To a solution of hydrazine (0.46 mL, 14.49 mmol, 2.5 equiv) in (¾(¾ (29 mL) was added slowly over 30 sec 2-(4- fluorophenyl)acetyl chloride (0.79 mL, 5.79 mmol, 1.0 equiv). Slight warming of the mixture and white precipitate were observed. After stirring 45 min, the mixture was poured into a saturated aqueous solution of NaHCC^ layered with (¾(¾ forming a thick emulsion. This emulsion was filtered through a medium glass frit to give a biphasic homogenous solution. This was extracted with CH2CI2 (x3). The combined CH2CI2 extracts were dried (Na2S04) and then concentrated in vacuo to provide the title compound (1.22 g, 124% yield) as a white solid. Source of extra mass is unclear as product is of high purity. Extra mass may reflect a measuring error of the acid chloride. XH NMR (400 MHz, CDC13) δ ppm 7.19 - 7.24 (m, 2 H), 6.99 - 7.07 (m, 2 H), 6.60 (s, 1 H), 3.85 (d, J=2.01 Hz, 2 H), 3.52 (s, 2 H); LCMS (ES+, (M+H)+) m/z 169.22. | |
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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | To a suspension of N, 8-dihydroxy [1, 6] naphthyridine-7-carboximidamide (231 mg, 1. 13 mmol) in dioxane (5 mL) was added 4-fluorophenylacetyl chloride (185, UL, 1. 35 mmol). The reaction vessel was sealed and heated at 155 oC in a microwave chamber for 10 minutes. The solids were collected on a filter. The solids were taken up in methanol (30 mL) and water (20 ML). IN aqueous sodium hydroxide solution was added until the solution was neutral. The solids were collected on a filter to provide 7- [5- (4-FLUOROBENZYL)-1, 2, 4-oxadiazol-3-yl] [1, 6] NAPHTHYRIDIN-8-OL (140 mg, 39 %) as a pale yellow SOLID. 1H NMR (DMSO-d6) : & 8. 71 (s, 1H), 8. 22 (d, J = 8. 0 Hz, 1H), 8. 06 (s, 1H), 7. 48 (dd, J = 7. 2, 4. 0 Hz, 1H), 7. 41 (t, J = 6. 4 Hz, 2H), 7. 17 (t, J = 8. 4 Hz, 2H), 4. 34 (s, 2H) ; MS m/z 323 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | To a cold (0 oC) solution OF 8-HYDROXY-1, 6-naphthyridine-7-carbohydrazide (54 mg, 0. 26 mmol) in pyridine (5 mL) was added 2- (4-fluorophenyl) acetyl chloride (0. 36 mL of a 0. 86 M stock solution in dichloromethane, 0. 31 mmol). The resultant solution was stirred at room temperature for 6 hours at which time another equivalent OF 2- (4- fluorophenyl) acetyl chloride stock solution was added. After 18 hours, the reaction mixture was concentrated in vacuo and the residue was treated with phosphorous oxychloride. This solution was heated at 105 C FOR 3 hours and worked up in a similar manner as was described in example 19 to give the title compound (6 mg, 8%) , as a yellow SOLID. 1H NMR (CDC13) : # 9. 22 (d, J= 4. 0 Hz, 1 H), 8. 93 (s, 1 H), 8. 34 (d, J= 8. 4 Hz, 1 H), 7. 69 (dd, J= 8. 4, 4. 0 Hz, 1 H), 7. 39 (dd, J= 8. 4, 5. 6 Hz, 2 H), 7. 05 (t, J= 8. 4 Hz, 2 H), 4. 36 (s, 2 H) ; MS NZLZ 323 (M+I). |
Yield | Reaction Conditions | Operation in experiment |
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59% | With pyridine; at 120℃; | A solution of the title compound of Example 116 (98 mg, 0.4 mmol) and 4- fluorophenylacetyl chloride (164 pL, 1.20 mmol) in pyridine (6 mL) was heated at 120C overnight. The solvent was removed under reduced pressure. Methylene chloride was added (20 mL) and the solution was washed with water (2x10 mL), brine (10 mL), and dried (Na2SO4). The solvent was removed under reduced pressure. Purification by column chromatography with silica gel, eluting with ethyl acetate/n-hexane (from pure to 50% of n- hexane), gave 2-(4-fluorophenyl)-N-[6-(2-furyl)-2-(1, 3-thiazol-2-yl) pyrimidin-4-yl] acetamide (62 mg, 59%) as an off-white solid. 6 (300 MHz, Ceci3) : 3.74 (s, 2H); 6.58 (dd, J1=3. 4 Hz, J2=1.8 Hz, 1H) ; 7.07 (t, J=8.6 Hz, 2H); 7. 32-7.27 (m, 2H); 7.38 (dd, J1=3. 4 Hz, J2=0.8 Hz, 1H) ; 7.52 (d, J=3.0 Hz, 1H) ; 7.61 (d, J=2.8 Hz, 1H) ; 8.00 (d, J=3.0 Hz, 1H) ; 8.22 (bs, 1H) ; 8.46 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.6% | Ethylpyrrole-2-carboxylate (2.0589 g, 14.80 mmol) in a minimal amount of dichloroethane was added to an ice cooled stirring mixture of aluminum chloride (3.9913 g, 29.93 mmol) and 4-fluorophenylacetyl chloride (5.1338 g, 29.75 mmol) in dichloroethane (22 mL, 0.66 M) under N2. The ice bath was removed, and the reaction was stirred at room temperature for 3.5 h. 20.6195 g (2.6 mMol/g) Polyamine resin HL (200-400 mesh) and dichloroethane (20 mL) were added, and the reaction was stirred for 60 min. The reaction was then filtered through a glass-fritted funnel directly into ice water. The resin was rinsed with CH2Cl2, then the organic layers were removed, dried with Na2SO4, filtered and concentrated. When 6.5 mL of 80:20 Hexanes:EtOAc were added, the organic liquid turned yellow, leaving behind a tan solid. The solid was removed by filtration, rinsed with 80:20 Hexanes:EtOAc, and dried to obtain pure 71 (2.1838 g, 53.6%). 1H (CDCl3, 400 MHz): δ 10.03 (1H, broad s), 7.54 (1H, s), 7.32 (1H, s), 7.23 (2H, dd, J=8.6, 5.3 Hz), 6.99 (2H, t, J=8.6 Hz), 4.35 (2H, q, J=7.1 Hz), 4.04 (2H, s), 1.37 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 192.81, 161.84 (d, J=244 Hz), 160.95, 130.89 (d, J=7.8 Hz), 130.37 (d, J=3.2 Hz), 126.72, 126.36, 124.30, 115.40 (d, J=21.4 Hz), 114.96, 61.02, 45.63, 14.29 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.29; CH2 carbons: 61.02, 45.63; CH carbons: 130.89 (d, J=7.8 Hz), 126.72, 115.40 (d, J=21.4 Hz), 114.96 ppm. HPLC: 9.689 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 0 - 20℃; for 18h; | Step B: I-[(4-FluorophenyI)acetyl]piperidine4-FluorophenyIacetic acid (280g, 1.82mol) was suspended in 1.9L toluene followed by the careful addition of 185mL thionyl chloride (303g, 2.545mol). The reaction was heated to 1050C for 16hr (overnight). The reaction was allowed to cool to room temperature and the volatiles were removed in vacuo. The crude acid chloride was dissolved in 1.9L THF, cooled to 00C, and 0.72L piperidine (618g, 7.27mol) was added. The reaction vessel was allowed to warm to ambient temperature for 18hr. The mixture was quenched with a saturated solution of aq. NaHCθ3 and extracted several times withEtOAc. The combined organic extracts were washed with brine, dried over Na2SO^ and filtered on a <n="21"/>fritted funnel. The volatiles were removed in vacuo and the crude residue was purified on silica gel and eluted with a mixture of EtOAc/heptanes (0-75% gradient elution). This furnished the title compound. 1H-NMR (CDCI3): δ 1.32-1.42 (m, 2H), 1.48-1.64 (m, 4H), 3.34-3.42 (m, 2H), 3.54-3.60 (m, 2H), 3.69(s, 2H), 6.90-7.05 (m, 2H), 7.18-7.24 (m, 2H) ppm. | |
4-Fluorophenylacetic acid (28Og, 1.82mol) was suspended in 1.9L toluene followed by the careful addition of 185mL thionyl chloride (303g, 2.545mol). The reaction was heated to 1050C for 16hr (overnight). The reaction was allowed to cool to room temperature and the volatiles were removed in vacuo. The crude acid chloride was dissolved in 1.9L THF, cooled to 00C, and 0.72L piperidine (618g, 7.27mol) was added. The reaction vessel was allowed to warm to ambient temperature for 18hr. The mixture was quenched with a saturated solution of aq. NaHCO3 and extracted several times withEtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and filtered on a fritted funnel. The volatiles were removed in vacuo and the crude residue was purified on silica gel and eluted with a mixture of EtO Ac/heptanes (0-75% gradient elution). This furnished the title compound. 1H-NMR (CDCI3): δ 1.32-1.42 (m, 2H), 1.48-1.64 (m, 4H), 3.34-3.42 (m, 2H)5 3.54-3.60 (m, 2H), 3.69(s, 2H), 6.90-7.05 (m, 2H), 7.18-7.24 (m, 2H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With aluminum (III) chloride; In dichloromethane; at 3 - 8℃; for 0.416667h; | Example 47: l-(5-Benzo[6]thien-2-yl-2,4-dimethoxy-phenyl)-2-(4-fluoro-phenyl)- propenone[0420] Ex-47A: l-Bromo-2,4-dimethoxybenzene (1.58 g, 7.27 mmol), 4-fluorophenyl acetyl chloride (1.00 mL, 7.42 mmol) and CH2Cl2 (20 mL) were sequentially charged into a clean reaction vessel and the resulting solution was cooled to 3 0C. AlCl3 (2.0 g, 15.0 mmol) was then added over 20 min and aged at 8 0C. After an additional 5 min, the reaction was poured into 75 mL cold H2O and extracted with EtOAc. The organic cut was washed with saturated NaHCO3, dried with MgSO4, filtered and concentracted to dryness. The crude product was dissolved in EtOAc and crystallized upon hexane addition. The product was filtered and then further purified by silica gel chromatography (20% EtOAc in hexanes) to afford 0.78 g (30% yield) of desired l-(5-bromo-2,4- dimethoxy-phenyl)-2-(4-fluoro-phenyl)-ethanone. 1H-NMR (CDCl3) δ 8.00 (s, IH), 7.13-7.18 (m, 2H), 6.95-7.01 (m, 2H), 6.44 (s, IH), 4.22 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | In dichloromethane; at 20℃; for 4h; | 47AKU-5 (218 mg, 1.0 mmol) was dissolved in 3 ml of dichloromethane in a 50 ml flask. <strong>[459-04-1]4-Fluorophenylacetyl chloride</strong> (150μl, 1.1 mmol) was added. After 4 hrs stirring at room temp, the mixture was concentrated on Rotavapor (40 C). The crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 243 mg (68%) 47AKU-14. The HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0.5. HPLC-MS (Method A): M+ =355.1 (UV/MS(%)=100/100). 1H-NMR (400 MHz, CDCl3): δ 6.92-7.33 (8H, m); 4.73 (IH, m); 4.52 (2H, s); 3.56 (2H5 2s); 3.44 (5H, m); 3.25 (2H, m); 2.52-2.67 (4H, m); 2.33 (3H, s). 13C-NMR (CDCl3): δ 172.5, 163.3, 160.9, 139.5, 134.8, 130.6, 129.8, 125.8, 115.8, 54.6, 50.8, 49.9, 46.7, 40.4. 27.2, 21.2. |
In methanol; dichloromethane; | Example 105 2-(4-Flourophenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide (47AKU-14) 47AKU-5 (218mg, 1.0 mmol) was dissolved in 3 ml of dichloromethane in a 50 ml flask. <strong>[459-04-1]4-Fluorophenylacetyl chloride</strong> (150 μl, 1.1 mmol) was added. After 4 hrs stirring at room temp. the mixture was concentrated on Rotavapor (40 C.). The crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 243 mg (68%) 47AKU-14. The HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf=0.5. HPLC-MS (Method A): M+=355.1 (UV/MS(%)=100/100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In dichloromethane; water; | Sodium hydroxide (0.12 g, 3 mmol) is dissolved in a 1:2 water/methylene chloride solution (30 mL) with rapid stirring followed by the addition of 4-methylene-pyrazolidine-1-carboxylic acid 1-benzyl ester, 2, (0.62 g, 2.8 mmol) at room temperature. (4-Fluorophenyl)acetyl chloride (0.39 mL, 4.2 mmol) is added and the reaction is allowed to stir for 18 hours after which time the reaction mixture is diluted with water (10 mL) and the layers allowed to separate. The aqueous layer is extracted with methylene chloride, the organic layers combined, dried, and filtered. Concentration in vacuo affords the crude product which is purified over silica (1:3 ethyl acetate/hexane) to provide 0.54 g (62% yield) of the desired product. Preparation of 2-[2-(4-fluorophenyl)acetyl]-4-oxo-pyrazolidine-1-carboxylic acid benzyl ester (4): | |
With sodium hydroxide; In dichloromethane; water; | Sodium hydroxide (0.12 g, 3 mmol) is dissolved in a 1:2 water/methylene chloride solution (30 mL) with rapid stirring followed by the addition of 4-methylene-pyrazolidine-1-carboxylic acid 1-benzyl ester, 9, (0.62 g, 2.8 mmol) at room temperature. (4-fluorophenyl)acetyl chloride (0.39 mL, 4.2 mmol) is added and the reaction is allowed to stir for 18 hours after which time the reaction mixture is diluted with water (10 mL) and the layers allowed to separate. The aqueous layer is extracted with methylene chloride, the organic layers combined, dried, and filtered. Concentration in vacuo affords the crude product which is purified over silica (1:3 ethyl acetate/hexane) to provide 0.54 g (62% yield) of the desired product. Preparation of 2-[2-(4-fluorophenyl)acetyl]-4-oxo-pyrazolidine-1-carboxylic acid benzyl ester (11): Ozone gas is bubbled into a solution of 2-[2-(4-fluorophenyl)-acetyl]-4-methylene-pyrazolidine-1-carboxylic acid benzyl ester, 10, (0.28 g, 0.8 mmol) in methylene chloride (15 mL) at -78 C. until the solution retains a blue color. | |
With sodium hydroxide; In dichloromethane; water; | Sodium hydroxide (0.12 g, 3 mmol) is dissolved in a 1:2 water/methylene chloride solution (30 mL) with rapid stirring followed by the addition of 4-methylene-pyrazolidine-1-carboxylic acid 1-benzyl ester, 9, (0.62 g, 2.8 mmol) at room temperature. (4-Fluorophenyl)acetyl chloride (0.39 mL, 4.2 mmol) is added and the reaction is allowed to stir for 18 hours after which time the reaction mixture is diluted with water (10 mL) and the layers allowed to separate. The aqueous layer is extracted with methylene chloride, the organic layers combined, dried, and filtered. Concentration in vacuo affords the crude product which is purified over silica (1:3 ethyl acetate/hexane) to provide 0.54 g (62% yield) of the desired product. Preparation of 2-[2-(4-fluorophenyl)acetyl]-4-oxo-pyrazolidine-1-carboxylic acid benzyl ester (11): Ozone gas is bubbled into a solution of 2-[2-(4-fluorophenyl)-acetyl]-4-methylene-pyrazolidine-1-carboxylic acid benzyl ester, 10, (0.28 g, 0.8 mmol) in methylene chloride (15 mL) at -78 C. until the solution retains a blue color. |
With sodium hydroxide; In dichloromethane; water; | Sodium hydroxide (0.12 g, 3 mmol) is dissolved in a 1:2 water/methylene chloride solution (30 mL) with rapid stirring followed by the addition of 4-methylene-pyrazolidine-1-carboxylic acid 1-benzyl ester, 9, (0.62 g, 2.8 mmol) at room temperature. (4-Fluorophenyl)acetyl chloride (0.39 mL, 4.2 mmol) is added and the reaction is allowed to stir for 18 hours after which time the reaction mixture is diluted with water (10 mL) and the layers allowed to separate. The aqueous layer is extracted with methylene chloride, the organic layers combined, dried, and filtered. Concentration in vacuo affords the crude product which is purified over silica (1:3 ethyl acetate/hexane) to provide 0.54 g (62% yield) of the desired product. Preparation of 2-[2-(4fluorophenyl)acetyl]-4-oxo-pyrazolidine-1-carboxylic acid benzyl ester (11): Ozone gas is bubbled into a solution of 2-[2-(4-fluorophenyl)-acetyl]4-methylene-pyrazolidine-1-carboxylic acid benzyl ester, 10, (0.28 g, 0.8 mmol) in methylene chloride (15 mL) at -78 C. until the solution retains a blue color. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.6% | With diisopropyl-carbodiimide; In dichloromethane; at 20℃; | Example 48; 2-(4'-Fluorophenylacetyl)-1 -pyrazolidinecarbonitrile (48)4 was prepared according to Example 4. To this was added 4-fluorophenylacetyl chloride (94.6 uL, 0.69 mmol) in one portion, and the reaction mixture was stirred overnight at room temperature. After removal of solvent by rotary evaporation, the title compound was purified by silica gel chromatography (CombiFlash, 20% ethyl acetate in hexanes to 100% ethyl acetate over 10 minutes.) The appropriate fractions were collected, combined and evaporated to dryness to yield 48 (90.1 mg, 45.6%), ESMS 234.4 (M+H+). EPO <DP n="48"/> |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
198.5 g (92%) | With bromine; In methanol; | Step B' Methyl 2-bromo-2-(4-fluoro)phenylacetate A mixture of 150.4 g (0.872 mol) of 4-fluorophenylacetyl chloride and 174.5 g (1.09 mol) of bromine was irradiated at 40-50 C. with a quartz lamp for 5 hours. The reaction mixture was added dropwise to 400 mL of methanol and the solution was stirred for 16 hours. The solvent was removed in vacuo and the residual oil was distilled at reduced pressure (1.5 mmHg) to afford 198.5 g (92%) of the title compound, bp=106-110 C. |
198.5 g (92%) | With bromine; In methanol; | Step B': Methyl 2-bromo-2-(4-fluoro)-phenylacetate A mixture of 150.4 g (0.872 mol) of 4-fluorophenylacetyl chloride (from Example 58, Step A') and 174.5 g (1.09 mol) of bromine was irradiated at 40-50 C. with a quartz lamp for 5 hours. The reaction mixture was added dropwise to 400 mL of methanol and the solution was stirred for 16 hours. The solvent was removed in vacuo and the residual oil was distilled at reduced pressure (1.5 mmHg) to afford 198.5 g (92%) of the title compound, bp=106-110 C. |
198.5 g (92%) | With bromine; In methanol; | Step B' Methyl 2-bromo-2-(4-fluoro)phenylacetate A mixture of 150.4 g (0.872 mol) of 4-fluorophenylacetyl chloride (from Example 58, Step A') and 174.5 g (1.09 mol) of bromine was irradiated at 40-50 C. with a quartz lamp for 5 hours. The reaction mixture was added dropwise to 400 mL of methanol and the solution was stirred for 16 hours. The solvent was removed in vacuo and the residual oil was distilled at reduced pressure (1.5 mmHg) to afford 198.5 g (92%) of the title compound, bp=106-110 C. |
198.5 g (92%) | With bromine; In methanol; | Step B': Methyl 2-bromo-2-(4-fluoro)phenylacetate A mixture of 150.4 g (0.872 mol) of 4-fluorophenylacetyl chloride (from Example 58, Step A') and 174.5 g (1.09 mol) of bromine was irradiated at 40-50 C. with a quartz lamp for 5 hours. The reaction mixture was added dropwise to 400 mL of methanol and the solution was stirred for 16 hours. The solvent was removed in vacuo and the residual oil was distilled at reduced pressure (1.5 mmHg) to afford 198.5 g (92%) of the title compound, bp=106-110 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | In acetonitrile; at 150℃; for 0.166667h; | lc N-(2-Bromo-4,6-dimethyl-phenyl)-2-(4-fluoro-phenyl)-acetamide.; 2-Bromo-4,6-dimethyl-aniline (600 mg) and (4-fluoro-phenyl)-acetyl chloride (543 mg) were dissolved in acetonitrile (6 mL) and heated to 150 C for 10 minutes in a sealed microwave process vial. The reaction was cooled to 0 0C, the product filtered off and washed with cold acetonitrile (50 mL) affording 665 mg (66% yield) of the title compound as a white solid. LC-MS (m/z) 337 (MH+); tR = 2.93, (UV, ELSD) 90%, 98%. 1H NMR (500 MHz, DMSOd6): 2.05 (s, 6H), 2.25 (s, 3H), 3.63 (s, 2H), 7.05 (b, IH), 7.15 (dt, 2H), 7.32 (b, IH), 7.40 (dt, 2H), 9.67 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With trifluoroacetic acid;AlCl3; In hexane; dichloromethane; ethyl acetate; | Step 3 6-Fluoro-2-naphthol A solution of 2-(4-fluorophenyl)acetyl chloride (5.0g; 29 mmol) in CH2Cl2 was added to AlCl3 (7.73g;58 mmol) in CH2Cl2 at -20 C. over 30 min. Trimethylsilyl acetylene (9.96g; 101.43 mmol) was added also over 30 min and stirred at -10 C. for 1h. The mixture was poured in ice and extracted with EtOAc. The organic phase was washed with water, NaHCO3 and brine. After purification by gel silica chromatography (10% EtOAc in hexane) 2.43 g (36%) of 3-(trimethylsilyl)-6-chloro-2-naphthol was collected. The desylilation was done with TFA in CH2Cl2 at rt overnight. Purification by gel silica chromatography (10% EtOAc in hexane) afforded the title compound in 69% yield. 1H NMR (CDCl3) δ7.10-7.20 (3H, m), 7.37 (1H, dd) and 7.65 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | EXAMPLE 1 Process to Ketone Step 1: 2-(4-Fluorophenyl)-N-methoxy-N-methylacetamide (2) Summary: This reaction gives consistently high yield and high purity of material. No major side products have been identified. The final product is an oil (typically clear or slightly yellow) and is isolated with the above purity profile from the crude work up. Procedure: FW: Amt. Moles Equiv. 4-Fluorophenylacetic acid (1) 154 5.0 kg 32.47 mol 1.0 eq. DMF 73.1 48 mL 0.65 mol 0.02 eq. SOCl2 119 2.84 L 38.96 mol 1.2 eq. Weinreb amine-HCl 97.5 4.75 kg 48.70 mol 1.5 eq. NaOH 4.0 M 32.47 L 129.87 mol 4.0 eq. Toluene - 49.19 L - Brine - 64.92 L - A 100 L extractor equipped with a reflux condenser, and a base scrubber was charged with toluene (49.2 L, KF100 ppm) and 4-fluorophenylacetic acid (1) was added (5.0 kg). This solution was heated to 70 C. Once 70 C. was reached the DMF (48 mL, KF150 ppm) was added and thionyl chloride (2.8 L) was slowly added over 3 hours. Batch temperature will decrease while thionyl chloride is added. Typical temperature changes range from 6-10 C. When all thionyl chloride has been added and off-gassing has ceased (typically 30 min. after addition is complete) an aliquot of the batch was quenched into excess methanol for HPLC analysis as the methyl ester. Reaction is done when acid 1 is at <0.5 LCAP. Next the reaction was cooled to 5-10 C. The Weinreb amine-HCl (4.75 kg) was added to the batch at this point. Slow addition of NaOH (32.5 L) was begun at this point. This base was added at a rate that maintained the batch temperature at or below 10 C. with a typical addition time of 3 hours. Once this addition was done an aliquot of the batch was quenched into MeOH and assayed by HPLC to check for complete consumption of the acid chloride. Complete consumption of the acid chloride (in the form of the methyl ester after this quench) should be seen. Additional base can be added if the acid chloride is still present. The biphasic solution was separated at between 5 C. and room temperature and the organic phase was washed with 15 wt. % NaCl (aq) (2×32.5 L). Typical assay yield of the organic phase was 96%. The organic phase was concentrated to a 50 wt. % solution (typical KF500 ppm). | |
With sodium hydroxide; In water; at 10℃; for 3h; | A lOO L extractor equipped with a reflux condenser, and a base scrubber was charged with toluene (49.2 L, KF< 100 ppm) and 4-fluorophenylacetic acid (1) was added (5.0 kg). This solution was heated to 70 C. Once 70 "C was reached the DMF (48 mL, KF< 150ppm) was added and thionyl chloride (2.8 L) was slowly added over 3 hours. EPO <DP n="15"/>Batch temperature will decrease while thionyl chloride is added. Typical temperature changes range from 6-10 C.When all thionyl chloride has been added and off-gassing has ceased (typically 30 min. after addition is complete) an aliquot of the batch was quenched into excess methanol for HPLC analysis as the methyl ester.Reaction is done when acid 1 is at <0.5 LCAP.Next the reaction was cooled to 5-10 "C. The Weinreb amine-HCl (4.75 kg) was added to the batch at this point. Slow addition of NaOH (32.5 L) was begun at this point. This base was added at a rate that maintained the batch temperature at or below 10 "C with a typical addition time of 3 hours. Once this addition was done an aliquot of the batch was quenched into MeOH and assayed by HPLC to check for complete consumption of the acid chloride.Complete consumption of the acid chloride (in the form of the methyl ester after this quench) should be seen. Additional base can be added if the acid chloride is still present.The biphasic solution was separated at between 5 C and room temperature and the organic phase was washed with 15 wt. % NaCl (aq) (2 x 32.5 L).Typical assay yield of the organic phase was 96%.The organic phase was concentrated to a 50 wt. % solution (typical KF < 500 ppm). | |
With sodium hydroxide; at 10℃; | The method of Kuethe et al. is depicted in FIG. 1. Briefly, commercially available 4-fluorophenylacetic acid g (Sigma-Aldrich Co. LLC, St. Louis, Mo.) is reacted with thionyl chloride in DMF/toluene to yield acid chloride (2). The acid chloride (6) is then reacted with the hydrochloride salt of the Weinreb amine (CH3NHOCH3.HCl) in the presence of sodium hydroxide to give 2-(4-fluorophenyl)-N-methoxy-N-methylacetamide (4). A vinyl Grignard reaction converts (4) to 1-(4-fluorophenyl)but-3-en-2-one (5). TES dienyl ether (6) is produced from the reaction of (5) with chlorotriethylsilane (TESCl) in the presence of iPr2NEt2. |
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