There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type | HazMat fee for 500 gram (Estimated) |
Excepted Quantity | USD 0.00 |
Limited Quantity | USD 15-60 |
Inaccessible (Haz class 6.1), Domestic | USD 80+ |
Inaccessible (Haz class 6.1), International | USD 150+ |
Accessible (Haz class 3, 4, 5 or 8), Domestic | USD 100+ |
Accessible (Haz class 3, 4, 5 or 8), International | USD 200+ |
Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 459-04-1 | MDL No. : | MFCD00674181 |
Formula : | C8H6ClFO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SIOJFYRPBYGHOO-UHFFFAOYSA-N |
M.W : | 172.58 | Pubchem ID : | 3744988 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 41.17 |
TPSA : | 17.07 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.56 cm/s |
Log Po/w (iLOGP) : | 1.88 |
Log Po/w (XLOGP3) : | 2.53 |
Log Po/w (WLOGP) : | 2.55 |
Log Po/w (MLOGP) : | 2.52 |
Log Po/w (SILICOS-IT) : | 3.08 |
Consensus Log Po/w : | 2.51 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.78 |
Solubility : | 0.289 mg/ml ; 0.00168 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.54 |
Solubility : | 0.503 mg/ml ; 0.00292 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.64 |
Solubility : | 0.0394 mg/ml ; 0.000229 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.27 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 3261 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
GHS Pictogram: |
* 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 |
---|---|---|
69% | With trifluoroacetic acid 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 (10percent EtOAc in hexane) 2.43 g (36percent) 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 (10percent EtOAc in hexane) afforded the title compound in 69percent 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 |
---|---|---|
86% | With hydrazine hydrate; triethylamine In acetonitrile for 3 h; 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 0.666667 h; | 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 (5percent methanol-dichloromethane gradient elution) provided 2- (4-FLUOROPHENYL) acetic hydrazide (673 mg, 69percent) 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), |
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 |
---|---|---|
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 |
---|---|---|
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-alpha]; 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 muL, 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) delta 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) delta 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 |
---|---|---|
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 |
---|---|---|
80% | With triethylamine; | (A-70) According to the method of the reference(J. Org. Chem. 1987, 52, p2714), <strong>[100499-66-9](5-methylisoxazole-4-yl)amine hydrochloride</strong>(16.15g, 120mmol) was reacted with 4-fluorophenylacetyl chloride(20.8g, 120mmol) in the presence of triethylamine to give 2-(4-fluorophenyl)-N-(5-methylisoxazole-4-yl)acetamide(22.55g, yield:80%). NMR(CDCl3)delta: 2.28(3H, s), 3.69(3H, s), 6.71(1H, brs), 7.06-7.20(2H, m), 7.26-7.32(2H, m), 8.46(1H, s). |
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 |
---|---|---|
aluminium chloride; In dichloromethane; water; | (b) p-Fluorophenylacetyl chloride (17.25 g) in dichloromethane (100 ml) was added dropwise to aluminium chloride (26.7 g) suspended in dichloromethane (400 ml) maintained at -10 C. by cooling in a solid carbon dioxide/acetone bath. Ethylene gas was then passed through the mixture for 15 minutes while maintaining the temperature at -10 C. The mixture was then allowed to warm to room temperature and stirred for 3 hours. The mixture was then cooled to 5-10 C. and ice and water (160 ml) added cautiously with stirring over a period of 45 minutes. The dichloromethane was then separated and washed successively with dilute hydrochloric acid, (150 ml*2), sodium bicarbonate solution (150 ml*2) and brine. The dichloromethane was then dried and evaporated. The residue was distilled to give 6-fluoro-2-tetralone (12.81 g) with a boiling range of 68-76 C./0.05 Torr. The distillatte crystallized on standing. |
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) delta7.10-7.20 (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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.2% | With thionyl chloride; | (1) 46.3 g (0.389 mol) of thionyl chloride was added to 15.0 g (0.097 mmol) of <strong>[405-51-6]4-fluorophenyl acetate</strong> and stirred at 80 C. for 1 hour, then concentrated under reduced pressure to obtain 4-fluorophenylacetyl chloride. 200 ml of methylene chloride solution containing 24.2 g of thioanisole (0.195 mol) was added to the obtained compound and then 15.6 g (0.117 mol) of an aluminum chloride was added thereto, then heated under reflux for 4 hours. 300 ml of IN hydrochloric acid was added dropwise to the reaction mixture which was then extracted with 500 ml of methylene chloride. The organic layer was washed with 500 ml of saturated sodium bicarbonate aqueous solution and 500 ml of saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 18.0 g of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)ethanone as yellow powdery crystal (yield: 53.2%). Melting Point: 137-139 C. 1H-NMR(CDC13)delta: 7.90(2H,m,Ar-H), 7.26(2H,m,Ar-H), 7.21(2H,m,Ar-H), 7.00(2H,m,Ar-H), 4.21(2H,s,CH2), 2.51(3H,s,SCH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With triethylamine; In toluene; at 110℃; for 16h; | Step B; 4-(4-Benzyloxy-phenyl)-3-(4-fluoro-phenyl)-1-phenethyl-azetidin-2-one; EPO <DP n="40"/>A solution of (4-benzyloxy-benzylidene)-phenethyl-amine (20.8 g, 66.0 mmol) and 4- fluorophenylacetyl chloride (11.4 g, 66.0 mmol) in toluene (100 ml_) was heated to 110 C and Et3N (8.0 g, 79.1 mmol) was slowly added while maintaining vigorous stirring. Once the addition was complete, the reaction was stirred at 110 0C for 16 hrs and then cooled to 25 0C. The solids were removed by filtration, and the filtrate was concentrated to a yellow oil that was purified by silica gel chromatography (3 → 25% EtOAc/hexane) to afford racemic 4-(4-benzyloxy-phenyl)-3-(4-fluoro-phenyl)-1 -phenethyl-azetidin-2-one (15.5 g, 52%). H-NMR (CDCI3) δ 7.42-7.10 (m, 12 H), 6.97-6.89 (m, 6 H), 5.05 (s, 2 H), 4.08 (d, 1 H), 3.95 (d, 1 H), 3.95-3.90 (m, 1 H), 3.09-3.02 (m, 1 H), 2.89-2.86 (m, 1 H), 2.80-2.76 (m, 1 H); MS(APCI+): m/z 452.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With triethylamine; In toluene; at 110℃; for 12h; | Step B; 3-[2-(4-Benzyloxy-phenyl)-3-(4-fluoro-phenyl)-4-O-azetidin-1-yl]-propionic acid ethyl ester; A solution of 3-[(4-benzyloxy-benzylidene)-amino]-propionic acid ethyl ester (37.3 g, 120 mmol) and 4-fluorophenylacetyl chloride (20.7 g, 120 mmol) in toluene (400 mL) was heated to 110 0C and Et3N (14.5 g, 144 mmol) was slowly added while maintaining vigorous stirring. Once the addition was complete, the reaction was stirred at 110 0C for 12 hrs and then cooled to 25 C. The solids were removed by filtration, and the filtrate was concentrated to a yellow oil that was purified by silica gel chromatography (10 -→ 30% EtOAc/hexane) to afford racemic 3-[2-(4-benzyloxy-phenyl)-3-(4-fluoro-phenyl)-4-O- azetidin-1-yl]-propionic acid ethyl ester (26.5 g, 49%); MS(APCI+): m/z 448.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminum (III) chloride; In 1,2-dichloro-ethane; at 0 - 20℃; for 12h; | 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) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Synthesis Example 34 3-(4-Fluorophenylacetyl)-4-hydroxy-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one; In accordance with a process described in JP-61-246183A or J. Med. Chem., 31, 2108 (1988), 4-hydroxy-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (918 mg, 3.0 mmol) in DMF (24 mL) was added sodium hydride (purity of about 60%, 264 mg, 6.6 mmol, 2.2 eq.), and the mixture was stirred until no more hydrogen was generated. Then, 4-fluorophenylacetyl chloride (3.6 mmol, 1.2 eq.) was added thereto, and the mixture was stirred at a room temperature for 2 hours. To the mixture was added water. The resulting mixture was acidified with hydrochloric acid, and the precipitate was separated by filtration and washed with water. The precipitate was purified by a flash column chromatography to give 3-(4-fluorophenylacetyl)-4-hydroxy-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one as a form of crystal (650 mg, yield 49%). mp: 133-134C 1H NMR (CDCl3)δ: 4.58 (2H, s), 7.02 (2H, app-tt, J=8.9Hz, 2.3Hz), 7.22-7.29 (3H, m), 7.46-7.50 (1H, m), 7.55 (1H, brs), 7.72 (1H, t, J=7.6Hz), 7.76-7.79 (1H, m), 8.52 (1H, dd, J=2.0Hz, 4.0Hz) 8.54 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Synthesis Example 28 3-(4-Fluorophenylacetyl)-4-hydroxy-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one; In accordance with a process described in JP-61-246183A or J. Med. Chem., 31, 2108 (1988), 4-hydroxy-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one was synthesized. The synthesized compound (967 mg, 3.0 mmol) was suspended in DMF (24 mL). To the suspension was added sodium hydride (purity of about 60%, 264 mg, 6.6 mmol, 2.2 eq.), and the mixture was stirred until no more hydrogen was generated. Then, 4-fluorophenylacetyl chloride (3. 6 mmol, 1.2 eq.) was added thereto, and the mixture was stirred at a room temperature for 2 hours. To the mixture was added water. The resulting mixture was acidified with hydrochloric acid, and the precipitate was separated by filtration and washed with water. The precipitate was purified by a flash column chromatography to give 3-(4-fluorophenylacetyl)-4-hydroxy-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one as a form of crystal (662 mg, yield 48%). mp: 137-138C 1H NMR (CDCl3)δ: 4.58 (2H, s), 7.00 (2H, app-tt, 8.9Hz, 2.3Hz), 7.16-7.29 (5H, m), 7.37 (1H, app-quin.d, J=1.0Hz, 8.6Hz), 7. 61 (1H, t, J=7.9Hz), 8.51 (1H, dd, J=2.0Hz, 7.9Hz), 8.53 (1H, dd, J=2.0Hz, 4.6Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium carbonate; In tetrahydrofuran; at 0 - 20℃; for 2h; | Example 9.2: Preparation of 3-Benzyloxy-7-methyl-4-oxo-4/-r-pyrido[l,2- α]pyrimidine-2-carboxylic acid iV-[2-(4-fluoro-phenyl)-acetyl]-hydrazide; <n="58"/>The product from Example 9.1 (160 mg, 0.524 mmol) and sodium carbonate (106 mg, 1 mmol) were mixed with anhydrous tetrahydrofuran (25 mL) and then cooled in ice bath. To this stirred solution was added 4-fluorophenylacetyl chloride (90 mg, 0.55 mmol) dropwise. The mixture was stirred at room temperature for 2 h then concentrated in vacuo. The residue was portioned between ethyl acetate and water and the organic phase washed with water, dried (Na2SO4) and concentrated in vacuo. Short column chromatography afforded the desired compound (210 mg, yield 86%)1H NMR (300MHz, CDCl3): δ 2.45 (s, 3H), 3.67 (s, 2H), 5.40 (s, 2H), 6.95-7.10 (m, 2H), 7.30-7.42 (m, 5H), 7.50-7.60 (m, 3H), 7.64 (d, J=9.4 Hz, IH), 8.70-8.80 (m, 2H), 10.42 (brs, IH).MS (ESI+) m/z 461 (M+l), 483(M+23). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In tetrahydrofuran; dichloromethane; at 20℃; for 2h; | Example 11.4: Preparation of 3-BenzyIoxy-2-[5-(4-fluoro-benzyl)-[l,2,4]oxadiazol- 3-yl]-7-methyl-pyrido[l,2-fl]pyrimidin-4-one; The product from Example 11.3 (472 mg, 1.46 mmol) was dissolved in a mixed solvent of dichloromethane/tetrahydrofuran (120 mL: 120 mL) with stirring. Triethylamine (155mg, 1.53 mmol) was then added followed by the dropwise addition 4-fluorophenyl acetyl chloride (263 mg, 1.53 mmol). The mixture was stirred at room temperature for 2 h then concentrated in vacuo and the resulting residue dissolved in ethyl acetate and washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting solid was used without purification. The above solid (668 mg) was suspended in toluene (25 mL) and the mixture was refluxed for 24 h. The solvent concentrated in vacuo to give the desired compound quantitatively.1H NMR (300MHz, CDCl3): δ 2.46 (d, J=0.7 Hz, 3H), 4.32 (s, 2H), 5.38 (s, 2H), 7.00- 7.08 (m, 2H), 7.20-7.30 (m, 3H?), 7.32-7.37 (m, 2H), 7.44-7.52 (m, 2H), 7.55 (dd, J-9.2, 1.9 Hz, IH), 7.74 (d, J=9.1 Hz, IH), 8.81-8.85 (m, IH).MS (ESI+) m/z 443 (M+l), 465 (M+23). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; | 4-fluoro-phenylacetyl chloride (500 μL, 3.65 mmol) and diisopropylethylamine (1.30 mL, 7.30 mmol) was added to a solution of tert-butyl 2- aminoethylcarbamate (584 mg, 3.65 mmol) dissolved in anhydrous DCM (15 mL). After stirring at room temperature for 1 hour, formation of a precipitate was observed and the reaction mixture was diluted with ethyl acetate. The organic layer was separated and washed with 5% Na2CO3 (2x), H2O (2x), and brine (Ix), dried over Na2SO4, and concentrated to obtain a yellow solid (998 mg, 92 % yield). The solid was taken directly to the next step without further purification. 1H NMR (DMSO-fi? |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 3.5h;Cooling with ice; | General procedure: Appropriate phenylacetyl chloride (1equiv) was added dropwise into a solution of Meldrum's acid (1equiv) and TEA (2.4equiv) in DCM (1M) under ice bath. The reaction mixture was then allowed to warm to room temperature and stirred for 3.5h. The reaction mixture was extracted with a mixture of CH2Cl2 and 1N HCl solution. The organic layer was washed with brine, dried over MgSO4, and concentrated. To the residue was added absolute ethanol (1M), and the reaction mixture was heated at reflux for 2h. The solvent was removed in vacuo, and to the resulting ethyl-4-aryl-3-oxobutanoate ( 27) in xylene (1M) was added DMF-DMA (2.5equiv). The resulting mixture was heated at reflux for 4h and then concentrated in vacuo. To the solution of residue in MeOH (1M) was added ammonium acetate (5equiv), and the resultant mixture was heated at reflux for 4h. The crude ethyl ester of appropriate 29 was saponified by 10% (w/v) NaOH (10mL) in MeOH (20mL) at reflux for 2.5h. The mixture was then adjusted to pH 1 by titrating with 3N HCl. The precipitate was collected by filtration, washed with MeOH, water, and diethyl ether, and dried to give appropriate analogs of 29. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.8% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 3h; | A mixture of 4-fluorophenylacetyl chloride (4.91 g, 24.3 mmol), 2,2- dimethyl- l ,3-dioxane-4,6-dione (3.50 g, 24.3 mmol) and DIEA (5.84 g, 49.8 mmol) in CH2C12 (30 mL) was stirred for 1 h at 0 C and at ambient temp for 2 h. The solution was diluted with CH2C12 (40 mL) and the organic phase was washed with 0.1 N HC1 and brine, dried over Na2S04 and evaporated to dryness. The resulting orange solid was suspended in EtOH (100 mL) and refluxed for 2 hours. The solution 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). |
37% | With pyridine; In dichloromethane; at 0℃; | To a solution of 2,2-dimethyl-l,3-dioxane-4,6-dione (Meldrum's acid, 8.0 g, 56 mmol) dissolved in anhydrous methylene chloride (100 mL) and pyridine (11 mL), at 00C under nitrogen atmosphere, was slowly added 2-(4-fluorophenyl)acetyl chloride (7.6 mL, 9.6 g, 56 mmol). The red solution was stirred at 00C for 1.5 h. The reaction mixture was treated with 1 ν HCl (13 mL) and diluted with methylene chloride (200 mL). The layers were separated and the organic layer was washed with saturated aqueous sodium chloride, dried and concentrated in vacuo to give 5-(2-(4- fluorophenyl)acetyl)-2,2-dimethyl-l,3-dioxane-4,6-dione. The crude intermediate was suspended in absolute ethanol (150 mL) and the resulting mixture was refluxed for 4 hours. The solvent was then removed in vacuo and the residue was purified by flash column chromatography (SiC^, 230-400 mesh, 8: 1 hexane-ethyl acetate gradient elution) to afford the desired product (4.6 g, 37%). 1H νMR (CDCl3) δ 7.23-7.15 (m, 2 H), 7.05-6.98 (m, 2 H), 4.18 (q, 2 H, J = 7.0 Hz), 3.81 (s, 2 H), 3.46 (s, 2 H), 1.26 (t, 3 H, J = 7.0 Hz); MS(ESI+) m/z 225 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Diisopropylethylamine (98.2 μL, 0.56 mmol) was added to a room temperature solution of 70a (108.1 mg, 0.282 mmol) in dichloromethane (0.9 mL), followed by (4-Fluorophenyl)-acetyl chloride (54.5 mg, 0.310 mmol). The mixture was stirred at room temperature for 23 hours. Triethylamine (2.5 mL) and methanol (2.5 mL) were added, and stirring continued for 3 days. After evaporation to dryness, the crude product was purified by silica gel chromatography (eluting with 70% ethyl acetate in hexanes) to give 70 (38.9 mg, 30%) as a white solid. 1H NMR (dmso-d6) δ: 0.99 (q, J=7.3 Hz, 1H), 1.21 (quint, J=4.7 Hz, 1H), 1.58 (s, 6H), 1.90 (m, 1H), 2.72 (m, 1H), 3.59 (s, 2H), 4.32 (s, 2H), 6.38 (d, J=3.0 Hz, 1H), 7.11 (m, 5H), 7.23 (t, J=7.5 Hz, 2H), 7.31 (dd, J=5.7, 8.3 Hz, 2H), 10.65 (s, 1H), 12.29 (s, 1H). Anal. (C25H26FN5O2.0.55H2O) C, H, N, F. HRMS: [M+H]+ calc. 448.2143; found 448.2138; error 1.12 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | (A-126) N,N-Nitrosomethylurea(10.1g, 97.8mmol) was added to 50% potassium hydroxide aqueous solution(40ml)-diethyl ether(250ml), then the yellow ether layer was added to the above-mentioned compound A-125(8.44g, 48.9mmol) in diethyl ether(80ml) under ice cooling.. The mixture was stirred at 0C for 15 minutes and at room temperature for 15 minutes.. The solution was Cooled at -30C, to which was added 48% hydrogen bromide(50ml), then which was stirred at -30C for 30 minutes and at room temperature for 30 minutes.. To the solution was added water, then which was extracted with diethyl ether, washed, dried and evaporated under reduced pressure to give 1-bromo-3-(4-fluorophenyl)propane-2-one(6.52g, yield:58%). NMR(CDCl3)δ:3.91(2H, s), 3.94(2H, s), 7.01-7.07(2H, m), 7.18-7.22(2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | To a solution of 4-aminobutan-2-one hydrochloride (2.95 g, 24 mmol) in N, N-dimethylacetamide (50 mL) was slowly added (4-fluorophenyl) acetylchloride (4.90 g, 29 mmol) under ice- cooling, and the mixture was stirred at room temperature for 2 hr. Triethylamine (4.80 g, 48 mmol) was added to the mixture, and the mixture was stirred at room temperature for 17 hr. Ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the mixture, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (χ3) . The combined organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) to give the title compound (2.10 g, 39%) as a white solid. 1H-NMR (DMSO-d6, 300 MHz) δ 2.07 (3H, s) , 2.58 (2H, t, J = 6.7 Hz), 3.17 - 3.25 (2H, m) , 3.36 (2H, s) , 7.05 - 7.16 (2H, m) , 7.21 - 7.30 (2H, m) , 8.04 (IH, br. s.) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.8% | With sodium carbonate; In tetrahydrofuran; at 20℃; | To a mixture of the product of example 15 (807mg, 1.97mmol) and sodium carbonate (418mg, 3.95mmol) in tetrahydrofuran (25ml), 4-fluorophenylacetyl chloride (374mg, 2.17mmol) was added drop-wise. The resulting mixture was stirred overnight at room temperature. Then water (25ml) was added and the mixture was stirred for 1 hour. The resulting solids were collected by filtration, washed with water and PE successively and dried to give the titled product (697mg, 64.8%).1H NMR (300MHz, DMSO-d6) δ 2.43 (t, J=3.6 Hz, 4H), 3.55-3.63 (m, 8H), 5.16 (s, 2H), 7.12-7.20 (m, 2H), δ 7.29-7.41 (m, 5H), 7.54 (dd, J= 8.0 Hz, 1.5Hz, 2H), δ 7.71 (dd, J= 9.0Hz, 0.9 Hz, IH), δ 7.88 (dd, J= 9.0 Hz, 1.8Hz, IH), δ 8.85 (dd, J= 1.8, 0.9 Hz, IH), 10.44 (s, H), 10.52 (s, IH)MS (ESI") m/z 544 (M-I) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; | The product of example 20 (200 mg, 0.51mmol) and 4-fluorophenylacetyl chloride (0.073mL, 0.53 mmol) were dissolved in THF (5ml). To this solution was added TEA (0.14mL, 1.02 mmol) dropwise at 00C. The mixture was stirred at room temperature overnight and then poured into water (30 ml). The crude product was obtained by filtration. It was recrystallized from CH2Cl2/ PE to give the titled product (261mg, yield 97.0%)1H NMR(300MHz, DMSO) δ 8.20 (d, J= 2.6Hz, IH), 8.03 (dd, J= 2.5, 9.9 Hz, IH), 7.69 (d, J= 9.9 Hz, IH), 1.52-1 Al (m, 2H), 7.38 (dd, J= 5.6, 8.7 Hz, 2H), 7.35-7.28 (m, 3H), 7.17 (t, J= 8.8 Hz, 2H), 7.02-6.92 (brs, 2H), 5.12 (s, 2H), 3.81-3.75 (m, 6H), 3.23 (t, J= 4.8Hz, 4H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | INTERMEDIATE 127 - PREPARATION OF ethyl 5-(4-fluorobenzyl)-1 ,2,4-oxadiazole-3- carboxylate; 2-(4-fluorophenyl)acetyl chloride (0.518 ml 3.78 mmol) was added to a mixture of ethyl 2- amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 ml 6.06 mmol) in dichloromethane (15 ml.) at -15C. The reaction mixture was stirred at room temperature overnight and poured into a mixture of ice and water. The formed precipitate was filtered off, suspended in pyridine (18 mL) and refluxed in a sealed tube for 20 h and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.315 g (33%) of ethyl 5-(4-fluorobenzyl)-1 ,2,4-oxadiazole-3-carboxylate as a white solid. ESI/APCI(+): 251 (M+H), 273(M+Na). ESI/APCK-): 249 (M-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃; | To a suspension of ethyl 3-amino-1 H-pyrrole-2-carboxylate (2 g, 10.49 mmol) and triethylamine (3.21 ml_, 23.08 mmol) in DCM (20 ml.) at 0C was added drop-wise (4- fluorophenyl)acetyl chloride (1.81 1 g, 10.49 mmol). The reaction mixture was then stirred from 0C to RT for 1 h before being quenched with 1 N HCI. The organic layer was separated and washed successively with sat. NaHC03 and brine, dried over Na2S04, filtered and concentrated under reduced pressure to give ethyl 3-[(4- fluorophenyl)acetyl]amino}-1 H-pyrrole-2-carboxylate (3.52 g, 12.13 mmol, 1 16 % yield) as an orange solid. LCMS: (M+H)+ : 291 ; Rt: 2.83 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With triethylamine; In dichloromethane; at 20℃; for 2h; | To stirred solution of 3- (benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2, 1 -c] [ 1 ,4]oxazine-2- carbohydrazide (0.170 g, 0.49 mmol) and Et3N (0.14 mL, 1 mmol) in CH2C12 (10 mL) was added 2-(4-fluorophenyl)acetyl chloride (69 mL, 0.5 mmol) and the mixture stirred 2 h at room temperature. The reaction mixture was purified by preparativeHPLC on a C18 column using water/MeOH containing 0.1% TFA as eluent to afford the title compound (0.078 g, 33% yield) as a white solid. 1HNMR (500 MHz, CDCI3) δ: 9.97 (1H, d, J = 7.0 Hz), 8.42 (1H, d, J = 6.7 Hz), 7.54 (2H, d, J = 6.7 Hz), 7.35-7.27 (5H, m), 7.05 (2H, t, J = 8.6 Hz), 5.36 (2H, s), 4.04-3.98 (4H, m), 3.64 (2H, s), 1.60 (6H, s). HRMS (M + H) calcd for C25H26 4O5F: 481.1887; found: 481.1866. |
33% | With triethylamine; In dichloromethane; at 20℃; for 2h; | To stirred solution of3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbohydrazide(S9) (0.170 g, 0.49 mmol) and Et3N(0.14 mL, 1 mmol) in DCM (10 mL) was added 2-(4-fluorophenyl)acetyl chloride (0.069mL, 0.5 mmol) and the mixture stirred 2 h at room temperature. The reactionmixture was purified by preparative HPLC on a C18 column using water/MeOHcontaining 0.1 % TF A as eluent to afford the title compound (0.078 g, 33%) asa white solid.1H NMR (500 MHz, CDCl3) δ 9.97 (1H, d, J =7.0 Hz), 8.42 (1H, d, J = 6.7 Hz), 7.54 (2H, d, J = 6.7 Hz),7.35-7.27 (5H, m),7.05 (2H, t, J = 8.6 Hz), 5.36 (2H, s), 4.04-3.98 (4H, m), 3.64 (2H, s), 1.60(6H, s). HRMS (M + H) calculated for C25H26N4O5F:481.1887; found: 481.1866. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;solid phase reaction; | 100 mg of p-methylbenzhydrylamine (MBHA) (loading: 1.1 mmol/g) was sealed within a polypropylene mesh packet. Reactions were carried out in polyethylene bottles. Starting from p-methylbenzhydrylamine (MBHA) resin 1, 2-nitrobenzoic acid was tethered to the resin in the presence of DIC (6 equiv) and HOBt (6 equiv) with DMF as solvent at room temperature overnight. After washing with DMF (three times), DCM (three times) and air dried, the resin-bound nitrobenzoic amide was reduced by SnCl2 (20 equiv 2 M) in DMF at room temperature overnight. The resin was then washed with DMF (10 times), DCM (three times) and air dried. The afforded resin was reacted with phenylacetyl chloride (6 equiv 0.1 M) in the presence of DIEA (6 equiv 0.1 M) in DCM at room temperature overnight and then washed with DMF (three times) and DCM (three times). The afforded resin was reduced with BH3-THF at 65 C for 4 days, washed with THF (once), MeOH (three times) and then treated with piperidine for another 24 h at 65 C. After washing with DMF (three times), DCM (three times), MeOH (once) and air drying, the resulting diamine resin was cyclized with carbonyliimidazole (6 equiv 0.05 M) in DCM at room temperature overnight. The resin was then washed with DMF (three times), DCM (three times) and MeOH (three times). The crude product was released from the resin by HF at 0 C for 1.5 h. The crude product was purified by preparative HPLC and characterized by LC-MS under ESI condition and 1H NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;solid phase reaction; | 100 mg of p-methylbenzhydrylamine (MBHA) (loading: 1.1 mmol/g) was sealed within a polypropylene mesh packet. Reactions were carried out in polyethylene bottles. Starting from p-methylbenzhydrylamine (MBHA) resin 1, 2-nitrobenzoic acid was tethered to the resin in the presence of DIC (6 equiv) and HOBt (6 equiv) with DMF as solvent at room temperature overnight. After washing with DMF (three times), DCM (three times) and air dried, the resin-bound nitrobenzoic amide was reduced by SnCl2 (20 equiv 2 M) in DMF at room temperature overnight. The resin was then washed with DMF (10 times), DCM (three times) and air dried. The afforded resin was reacted with phenylacetyl chloride (6 equiv 0.1 M) in the presence of DIEA (6 equiv 0.1 M) in DCM at room temperature overnight and then washed with DMF (three times) and DCM (three times). The afforded resin was reduced with BH3-THF at 65 C for 4 days, washed with THF (once), MeOH (three times) and then treated with piperidine for another 24 h at 65 C. After washing with DMF (three times), DCM (three times), MeOH (once) and air drying, the resulting diamine resin was cyclized with carbonyliimidazole (6 equiv 0.05 M) in DCM at room temperature overnight. The resin was then washed with DMF (three times), DCM (three times) and MeOH (three times). The crude product was released from the resin by HF at 0 C for 1.5 h. The crude product was purified by preparative HPLC and characterized by LC-MS under ESI condition and 1H NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;solid phase reaction; | 100 mg of p-methylbenzhydrylamine (MBHA) (loading: 1.1 mmol/g) was sealed within a polypropylene mesh packet. Reactions were carried out in polyethylene bottles. Starting from p-methylbenzhydrylamine (MBHA) resin 1, 2-nitrobenzoic acid was tethered to the resin in the presence of DIC (6 equiv) and HOBt (6 equiv) with DMF as solvent at room temperature overnight. After washing with DMF (three times), DCM (three times) and air dried, the resin-bound nitrobenzoic amide was reduced by SnCl2 (20 equiv 2 M) in DMF at room temperature overnight. The resin was then washed with DMF (10 times), DCM (three times) and air dried. The afforded resin was reacted with phenylacetyl chloride (6 equiv 0.1 M) in the presence of DIEA (6 equiv 0.1 M) in DCM at room temperature overnight and then washed with DMF (three times) and DCM (three times). The afforded resin was reduced with BH3-THF at 65 C for 4 days, washed with THF (once), MeOH (three times) and then treated with piperidine for another 24 h at 65 C. After washing with DMF (three times), DCM (three times), MeOH (once) and air drying, the resulting diamine resin was cyclized with carbonyliimidazole (6 equiv 0.05 M) in DCM at room temperature overnight. The resin was then washed with DMF (three times), DCM (three times) and MeOH (three times). The crude product was released from the resin by HF at 0 C for 1.5 h. The crude product was purified by preparative HPLC and characterized by LC-MS under ESI condition and 1H NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;solid phase reaction; | 100 mg of p-methylbenzhydrylamine (MBHA) (loading: 1.1 mmol/g) was sealed within a polypropylene mesh packet. Reactions were carried out in polyethylene bottles. Starting from p-methylbenzhydrylamine (MBHA) resin 1, 2-nitrobenzoic acid was tethered to the resin in the presence of DIC (6 equiv) and HOBt (6 equiv) with DMF as solvent at room temperature overnight. After washing with DMF (three times), DCM (three times) and air dried, the resin-bound nitrobenzoic amide was reduced by SnCl2 (20 equiv 2 M) in DMF at room temperature overnight. The resin was then washed with DMF (10 times), DCM (three times) and air dried. The afforded resin was reacted with phenylacetyl chloride (6 equiv 0.1 M) in the presence of DIEA (6 equiv 0.1 M) in DCM at room temperature overnight and then washed with DMF (three times) and DCM (three times). The afforded resin was reduced with BH3-THF at 65 C for 4 days, washed with THF (once), MeOH (three times) and then treated with piperidine for another 24 h at 65 C. After washing with DMF (three times), DCM (three times), MeOH (once) and air drying, the resulting diamine resin was cyclized with carbonyliimidazole (6 equiv 0.05 M) in DCM at room temperature overnight. The resin was then washed with DMF (three times), DCM (three times) and MeOH (three times). The crude product was released from the resin by HF at 0 C for 1.5 h. The crude product was purified by preparative HPLC and characterized by LC-MS under ESI condition and 1H NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33.8% | With sodium hydrogencarbonate; In acetonitrile; at 55℃; for 0.75h;Microwave irradiation; | Example 2-(4-fluorophenyl)-/V-[2-(1 H-1 ,2,4-triazol-1 -yl)-5-(trifluoromethyl)phenyl]- acetamide[2-(1 H-1 ,2,4-triazol-1 -yl)-5-(trifluoromethyl)phenyl]amine (ENAMINE, 30 mg, 0.131 mmol) was dissolved in acetonitrile (2 ml). Sodium bicarbonate (12 mg, 0.146 mmol) was added followed by (4-fluorophenyl)acetyl chloride (ALDRICH, 0.020 mL, 0.146 mmol). Reaction was heated 45 min at 55C under MW irradiation. Solution was concentrated to dryness and crude was purified by silica chromatography using hexane/EtOAc as eluents. 2-(4- fluorophenyl)-/V-[2-(1 /-/-1 ,2,4-triazol-1-yl)-5-(trifluoromethyl)phenyl]-acetamide (18 mg, 0.049 mmol, 33.8% yield) was obtained. 1 H NMR (400 MHz, CDCI3) δ ppm: 9.62 (s, 1 H), 8.93 (s, 1 H), 8.41 (s, 1 H), 7.90 (s, 1 H), 7.45 (t, 1 H), 7.43 (t, 1 H),7.21-7.25 (m, 1 H), 7.09 (t, 2H), 7.07 (t, 1 H), 3.73 (s, 2H). [ES+ MS] m/z 365 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With pyridine; In tetrahydrofuran; at 120 - 130℃; for 4h; | Example 27 1-[2-(4-fluorophenypacetylamino]-2-(chloroacetamido)-anthraquinone (CC-24) Compound CC-05 (1.28 g, 4 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml). To the solution, pyridine (0.5 ml), and 4-fluorophenylacetyl chloride (1.7 ml, 12 mmole) were added successively at room temperature and the mixture was stirred for 5 to 10 minutes. Then, the mixture was stirred within a mini-reactor in an oil bath at temperature of 120-130 C. for 4 hours. After the completion of the reaction, the mixture was filtered, and the filtrate was concentrated by reduced pressure concentrator (such as Vacuum Evaporator). The residue was extracted with ethyl acetate for several times. The extract was dried on magnesium sulfate, and concentrated under reduced pressure. The crude product was washed with ethyl acetate/hexane. Finally, the crude product was recrystallized in hot ethanol to obtain a Clay brown compound CC-24. Mol. Wt.: 450.8462 (C24H16ClFN2O4); Rf: 0.37 (ethyl acetate:n-hexane=1:2); Yield: 37%; Mp.: 213-214 C. (EtOH); HRMS (EI) m/z: calcd [M]+, 450.0783 (C24H16ClFN2O4+); found, 450.0782; 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 3.86 (s, 2H, -CH2-), 4.37 (s, 2H, -CH2Cl), 7.17 (t, J=9.0 Hz, 1H, Ar-H), 7.42-7.47 (m, 2H, Ar-H), 7.90-7.93 (m, 2H, Ar-H), 8.11-8.23 (m, 3H, Ar-H), 8.32 (d, J=8.7 Hz, 1H, Ar-H), 9.64 (s, 1H, Ar-NH-), 10.20 (s, 1H, Ar-NH-); 13C-NMR (300 MHz, DMSO-d6) δ (ppm): 41.48, 43.03, 114.69, 114.97, 125.67, 126.26, 126.79, 127.79, 128.15, 128.28, 129.14, 130.45, 131.42, 131.53, 132.23, 134.27, 134.50, 139.18, 165.23 (NCO), 170.70 (NCO), 181.54 (CO), 183.46 (CO). |
37% | With pyridine; In tetrahydrofuran; at 70℃;Inert atmosphere; Autoclave; | General procedure: A solution of compound 5 (1.28 g, 4 mmol) was dissolved in anhydrous THF (30 mL), and acyl chloride (12 mmol), pyridine (0.5 mL) were added dropwise under nitrogen. The reaction mixture was heated and refluxed at 70 C in miniclave for 3-4 h. After removal of THF, the reaction mixture was washed with ethyl acetate/hexane and the crude product was extracted in ethyl acetate. The organic layer was collect and dried over anhydrous Na2SO4, and then the solvent was evaporated. The crude compound was washed and purified by crystallization from hot ethanol to afford desired compounds 8-28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrazine hydrate; In dichloromethane; at 0 - 20℃; for 1.5h; | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃; for 12h; | General procedure: To a solution of methyl piperidinecarboxylate hydrochloride 2 (0.02 mol) in methylene chloride (20 ml) was added in a dried round-bottom flask, to which triethylamine (0.05 mol) and solution of phenylacetyl chloride in methylene chloride (0.024 mol) was added dropwise separately in an ice bath for over 20 min, next the cold bath was removed. The reaction was stirred at room temperature for 12 h, and TLC traced the reaction to completion. After the completion of the reaction, the solution was dissolved in water (20 ml), and the aqueous solution was extracted with methylene chloride (30 ml × 2) twice. The combined organic phases were washed with 5% Na2CO3 solution (30 ml × 2) and water to neutrality and dried over anhydrous Na2SO4. After filtration and concentration, the corresponding compound 5 were received through the above methods. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.78% | With triethylamine; In dichloromethane; at 0 - 20℃; for 4h; | Intermediate 10; Benzyl (3-(benzyloxy)-2-((2-((4-fluorophenyl)acetyl)hydrazinyl)carbonyl)-4- oxo-6, 7,8,9-tetrahydro-7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl)carbamate.; To a solution of benzyl (3-(benzyloxy)-2-(hydrazinylcarbonyl)-4-oxo-6,7,8,9-tetrahydro- 7,10-ethanopyrimido[l,2-a]azepin-10(4H)-yl)carbamate, Intermediate 9 (400 mg, 0.794 mmol) in CH2C12 (15 mL) at 0 C was added triethylamine (0.221 mL, 1.589 mmol) followed by 2-(4-fluorophenyl)acetyl chloride (0.098 mL, 0.715 mmol) and the resulting mixture stirred for lh. The mixture was allowed to warm to room temp and stirred for 3h. The mixture was then concentrated and purified by preparative HPLC to afford the title compound (70 mg, 0.109 mmol, 13.78 % yield) as a white solid. XH NMR (500 MHz, CDC13) δ ppm 10.00 (1 H, br. s.), 8.35 (1 H, br. s.), 7.48 - 7.53 (2 H, m), 7.27 - 7.38 (10 H, m), 7.00 - 7.07 (2 H, m), 6.55 (1 H, br. s.), 5.39 (2 H, s), 5.05 (2 H, s), 4.10 (2 H, d, J=3.36 Hz), 3.60 (2 H, s), 2.56 - 2.70 (2 H, m), 2.47 (1 H, br. s.), 1.88 - 2.04 (4 H, m), 1.59 - 1.71 (2 H, m). LCMS (M+H) = 640.35. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 1h; | General procedure: Phosphorus ylide (1.0 equiv, 10 mmol) was dissolved in 100 mL CH2Cl2 in a 250 mL round-bottom flask with a stir bar, then Et3N (1.0 equiv, 10 mmol) was added, to the stirring mixture, a solution of acyl chloride (1.0 equiv, 10 mmol) in 20 mL CH2Cl2 was slowly added at room temperature. After the addition was finished, the reaction mixture was stirred for further 1 h at room temperature, then the solution was concentrated and treated with petroleum ether (80 mL) and EtOAc (20 mL), the solution was stirred for 0.5 h again. Finally, the mixture was filtered and the filtrate was evaporated, the crude residue was purified by column chromatography on silica gel (5% EtOAc/ petroleum ether) to afford the title allenic esters. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.78% | With triethylamine; In dichloromethane; at 20℃; for 3h; | To a solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (10.1 mg, 0.024 mmol) in CH2Cl2 (5 mL) was added Et3N (9.85 μl, 0.071 mmol) followed by 2-(4-fluorophenyl)acetyl chloride (6.10 mg, 0.035 mmol) and the resulting mixture stirred at room temperature. (Mixture became a clear, colorless solution within 30 min.) After 3 h, the solvent was removed and the residue was taken up in MeOH/DMF and purified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm). The product containing fractions were concentrated to remove the organic solvent and the resulting precipitate isolated by filtration and washed with water to give 2-tert-butoxy-2-(4-(4-fluorophenyl)-6-(2-(4-fluorophenyl)acetyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (1.6 mg, 11.78% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.13-7.53 (5H, m), 6.88-7.09 (3H, m), 4.80-4.88 (1H, m), 4.32-4.46 (0.5 H, m), 4.18-4.32 (1H, m), 3.97 (0.5 H, d, J=16.56 Hz), 3.79-3.92 (1.5 H, m), 3.55-3.68 (3H, m), 3.52 (0.5 H, d, J=13.05 Hz), 1.37 (3H, d, J=6.53 Hz), 1.32 (3H, d, J=7.53 Hz), 1.27 (3H, dd, J=6.27, 5.02 Hz), 1.15 (3H, dd, J=6.53, 4.77 Hz), 0.91-1.06 (9H, m). 19F NMR (400 MHz, CD3OD) δ ppm -114.90, -115.19, -117.98, -118.41. LCMS (M+H) calcd for C33H39F2N2O4: 565.28; found: 565.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With dmap; In dichloromethane; at 0℃; for 10h; | First, 2-amino-benzoic acid methyl ester (1.00 g, 6.61 mmol) was dissolved in purified CH2Cl2, and DMAP (0.04 g, 0.33 mmol) was added thereto at 0 C. Then, the mixture was added to the reaction vessel containing (4-fluorophenyl)-acetyl chloride produced from reaction of (4-fluoro-phenyl)-acetic acid (1.53 g, 9.90 mmol) with SOCl2, and then reacted at normal temperature for 10 hours. After adding cold sodium bicarbonate solution containing ice, the reaction mixture was extracted with CH2Cl2, and then concentrated under reduced pressure to obtain 1.50 g (79%) of the compound 2-[2-(4-fluorophenyl)-acetylamino]-benzoic acid methyl ester as the solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In tetrahydrofuran; water; at 0 - 20℃; | General procedure: To a stirred solution of 9a (200 mg, 0.85 mmol) in THF (2 mL) were added a solution of potassium carbonate (354 mg, 2.56 mmol) in water (2 mL) and 4-fluorophenylacetyl chloride (162 mg, 0.94 mmol) at 0 C, successively. The mixture was stirred at room temperature for 30 min, diluted with water, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was suspended in diisopropyl ether and the solid was collected by filtration to give 10a |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium carbonate; In tetrahydrofuran; water; at 0 - 20℃; | General procedure: To a stirred solution of 9a (200 mg, 0.85 mmol) in THF (2 mL) were added a solution of potassium carbonate (354 mg, 2.56 mmol) in water (2 mL) and 4-fluorophenylacetyl chloride (162 mg, 0.94 mmol) at 0 C, successively. The mixture was stirred at room temperature for 30 min, diluted with water, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was suspended in diisopropyl ether and the solid was collected by filtration to give 10a (240 mg, 76%). 1H NMR (300 MHz, DMSO-d6) δ 1.24 (3H, d, J = 6.8 Hz), 2.86 (3H, s), 3.61-3.67 (2H, m), 4.67 (2H, s), 5.51 (1H, q, J = 6.8 Hz), 6.93-7.15 (5H, m), 7.32-7.44 (2H, m), 10.88 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With potassium carbonate; In tetrahydrofuran; water; at 0 - 20℃; | General procedure: To a stirred solution of 9a (200 mg, 0.85 mmol) in THF (2 mL) were added a solution of potassium carbonate (354 mg, 2.56 mmol) in water (2 mL) and 4-fluorophenylacetyl chloride (162 mg, 0.94 mmol) at 0 C, successively. The mixture was stirred at room temperature for 30 min, diluted with water, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was suspended in diisopropyl ether and the solid was collected by filtration to give 10a |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In tetrahydrofuran; water; at 0 - 20℃; | General procedure: To a stirred solution of 9a (200 mg, 0.85 mmol) in THF (2 mL) were added a solution of potassium carbonate (354 mg, 2.56 mmol) in water (2 mL) and 4-fluorophenylacetyl chloride (162 mg, 0.94 mmol) at 0 C, successively. The mixture was stirred at room temperature for 30 min, diluted with water, and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was suspended in diisopropyl ether and the solid was collected by filtration to give 10a |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; | Step B - Synthesis of Intermediate Compound 2c To a solution of BocNHNH2 (102.9 g, 0.78 mol) and TEA (135.4 mL, 0.97 mol) in anhydrous DCM (800 mL) was added a solution of compound 2b (138 g) in anhydrous DCM (500 mL) at 0 C under drying tube charging with CaCl2. The mixture was warmed up to room temperature and stirred for 2 hours. The mixture was quenched with Ι0 (1 L). The reaction was done in two batches which were combined. The two phases were separated and the aqueous layer was extracted with DCM (1LX2). The organic layer was washed with water (1LX4), brine, dried over Na2S04, concentrated in vacuo to provide compound 2c as a solid. | |
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; | To a solution of BocNHNH2 (102.9 g, 0.78 mol) and triethylamine (135.4 mL, 0.97 mol) in anhydrous dichloromethane (800 mL) was added a solution of compound 2b (138 g) in anhydrous dichloromethane (500 mL) at 0 C under drying tube charging with CaC. The mixture was warmed up to room temperature and stirred for 2 hours. The mixture was quenched with water (1 L). The reaction was done in two batches which were combined. The two phases were separated and the aqueous layer was extracted with dichloromethane (1LX2). The organic layer was washed with water (1LX4), then brine, dried over Na2S04, and concentrated in vacuo to provide compound 2c | |
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; | To a solution of BocNHNH2 (102.9 g, 0.78 mol) and triethylamine (135.4 mL, 0.97 mol) in anhydrous dichioromethane (800 mL) was added a solution of compound 2b (138 g) in anhydrous dichloromethane (500 mL) at 0 C under drying tube charging with CaC12. The mixture was warmed up to room temperature and stirred for 2 hours. The mixture was quenchedwith water (1 L). The reaction was done in two batches which were combined. The two phases were separated and the aqueous layer was extracted with dichloromethane (1 L x2). The organic layer was washed with water (lLx4), then brine, dried over Na2SO4, and concentrated in vacuo to provide compound 2c as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
197 mg | With triethylamine; In dichloromethane; at 20℃; for 12h;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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 16.5h; | To a solution of compound 4-(4-aminopiperidin-1-yl)benzonitrile (500 mg, 2.48 mmol) in anhydrous THF (5 mL) was added TEA (754 mg, 7.45 mmol) followed by (4-Fluoro-phenyl)-acetyl chloride (514 mg, 2.98 mmol) at 0 C. After stirring at the temperature for 0.5 hour, the mixture was allowed to warm to 20 C and stirred for 16 hours. The reaction mixture was diluted with water (100 mL), extracted with EtOAc (50 mLx3). The extracts was washed with brine, dried over Na2SO4 and concentrated to give a residue which was purified by silica gel column (eluent: PE/EA = 4/1 to 1/2) to afford 380 mg (yield: 45%) of D1 as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With tin(IV) chloride; In nitromethane; dichloromethane; at 20℃; | General procedure: To a stirred solution of the corresponding indole derivatives (5.0 mmol) in DCM(10 mL), SnCl4 (1.0 M in DCM, 7.5 mmol) was added. The reactionmixture stirred for 30 min at rt and then, the corresponding phenyl acetylchloride (6.0 mmol) was added slowly following the addition of MeNO2(10 mL). After stirring overnight at rt, the reaction was quenched withice/water, extracted with ethyl acetate, washed by 1.0 M NaOH solution threetimes and one time by brine. The solvent was removed and the product wasgenerated and used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | General procedure: 2,7-Diazaspiro[3.5]nonane intermediate (552 μπιο) was dissolved CH2CI2 (4mL) and a chloride (552 μπιο) was added followed by DIPEA (286 mg, 386 μ, 2.21 mmol). The resulting reaction mixture was stirred at RT until completion. The volatiles were evaporated in vacuo, the residue was purified by preparative HPLC or flash chromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With triethylamine; In dichloromethane; at 0 - 20℃; | 0.5g (4.9mmol) <strong>[80-65-9]3-amino oxazolidinone</strong> (Intermediate 2) was added to a 50ml three-necked flask, 25ml dichloromethane and 0.75g (7.4mmol) triethylamine were added, and 1.0g (5.9mmol) 2-(4-fluorophenyl) acetyl chloride was slowly added dropwise at 0C in an ice bath, and then the mixture was stirred at room temperature overnight, the solvent was distilled under reduced pressure, and the residue was recrystallized in ethanol, to get 0.52g white solid (Compound 31), with a yield of 45%. 1H-NMR(400MHz,DMSO)deltappm:10.41(1H,s),7.30(2H,t,J=4.0Hz,J=8.0Hz),7.17(2H, t,J=8.0Hz,J=8.0Hz),4.35(2H,t,J=8.0Hz,J=8.0Hz),3.65(2H,t,J=8.0Hz,J=8.0Hz),3.49(2H, s);EI-MS(m/z): 239.2[M+H]+; m.p. 131-134C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.8% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; | Example 72 (S)-2-(tert-Butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5-(4-(2-(4- fluorophenyl)acetamido)phenyl)-2, 6-dimethylpyridin-3-yl)acetic acid. To a stirred solution of (S)-2-(5-(4-aminophenyl)-4-(4,4-dimethylpiperidin-l-yl)-2,6-dimethylpyridin- 3-yl)-2-(tert-butoxy)acetic acid (0.025 g, 0.057 mmol) and DIEA (0.020 ml, 0.114 mmol) in CH2CI2 (3 mL) was added 2-(4-fluorophenyl)acetyl chloride (9.36 μ, 0.068 mmol) at rt. After 1 h, concentrated and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4- (4,4-dimethylpiperidin-l-yl)-5-(4-(2-(4-fluorophenyl)acetamido)phenyl)-2,6- dimethylpyridin-3-yl)acetic acid (0.0209 g, 0.036 mmol, 63.8 % yield) as white solid. 1H NMR (500MHz, METHANOL-d4) δ 7.86 (dd, J=8.4, 2.2 Hz, IH), 7.71 (dd, J=8.2, 2.2 Hz, IH), 7.43 - 7.39 (m, 2H), 7.37 (dd, J=8.4, 2.0 Hz, IH), 7.15 (dd, J=8.4, 2.0 Hz, IH), 7.12 - 7.07 (m, 2H), 5.53 (s, IH), 3.74 (s, 2H), 2.76 (br. s., 2H), 2.70 (s, 3H), 2.30 (s, 3H), 1.38 (br. s., 4H), 1.21 (s, 9H), 0.85 (s, 6H). 2H of piperidine are missing. LCMS (M+H) = 576.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium carbonate; In tetrahydrofuran; at 20℃; for 1h;Inert atmosphere; | General procedure: The acid chlorides 25 (1 mmol) were suspended in dry THF (5 mL) under argon, 4`-aminoacetophenone (135 mg, 1 mmol) and K2CO3 (68 mg, 0.5 mmol) were added and the mixture was stirred at room temperature for one hour. The solvent was evaporated under reduced pressure. Aqueous HCl (0.5 M, 15 mL) was added, and the solution was extracted with ethyl acetate (30 mL). The crude residue obtained after evaporation of solvent was purified by silica gel flash chromatography using hexane-ethyl acetate (1:1) or by crystallization from 70% methanol to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine; In tetrahydrofuran; at 70℃; for 6h; | General procedure: To a solution of 4a or 4b (1mol equiv.) in anhydrous THF was added TEA (3mol equiv.). The mixture was added drop wise the solution of acyl chlorides (1.1mol equiv.) in anhydrous THF at 0C and stirred at 70C for 6h. The water was added to quench the reaction. The mitxure was extracted with ethyl acetate to afford the crude product that was purified by flash column chromatography on silica gel to yield the target products.4.1.6.1 3-(2-(4-Fluorophenyl)acetyl)benzo[d]oxazol-2(3H)-one (9a) (0050) White solid. Yield 86%. Mp 180-182C. 1H NMR (300MHz, DMSO-d6): δ(ppm) 7.98-7.89 (m, 1H), 7.50-7.41 (m, 1H), 7.41-7.28 (m, 4H), 7.24-7.14 (m, 2H), 4.41 (s, 2H). MS (EI): m/z 272.2 [M+H]+. IR (KBr): 3067, 1796, 1721, 1601, 1514, 1248cm-1. |
86% | With triethylamine; In tetrahydrofuran; water; at 70℃; for 6h;Cooling with ice; | A solution of 1a (0.10 g, 0.74 mmol) was dissolved in 10 mL of dry tetrahydrofuran,Triethylamine (0.22 g, 2.22 mmol) was added to the acid,No addition of p-fluorophenyl acetyl chloride to the ice bathWater tetrahydrofuran solution (0.15 g, 0.89 mmol)Drop the reaction temperature will rise to room temperature,Heated to 70 C,Reaction 6h,The reaction was quenched with 10 mL of water and extracted with ethyl acetate (3 x 7 mL). Column chromatography (Petroleum ether: ethyl acetate = 10: 1) to give 0.17 g of a white solid, 86% yield, mp 180-182 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triethylamine; In tetrahydrofuran; at 70℃; for 6h; | General procedure: To a solution of 4a or 4b (1mol equiv.) in anhydrous THF was added TEA (3mol equiv.). The mixture was added drop wise the solution of acyl chlorides (1.1mol equiv.) in anhydrous THF at 0C and stirred at 70C for 6h. The water was added to quench the reaction. The mitxure was extracted with ethyl acetate to afford the crude product that was purified by flash column chromatography on silica gel to yield the target products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.28 g | In toluene; at 90℃; | To a toluene solution (8 mL) of <strong>[697-86-9]2-bromo-4,6-dichloroaniline</strong> (1 g) (CAS registry number: 697-86-9), 4-fluorophenyl acetyl chloride (788 mg) was added, followed by stirring at 90 C. overnight. The reaction mixture was cooled to room temperature, and precipitate was filtered. The precipitate was washed with toluene and then dried under reduced pressure at 50 C. to obtain the title compound (1.28 g) having the following physical property values. TLC: Rf 0.43 (hexane:ethyl acetate=1:1); 1H-NMR (CD3OD): delta 3.72, 7.02-7.08, 7.38-7.43, 7.58, 7.69. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; 1,4-dioxane; at 20℃; for 15h;Inert atmosphere; | To a heterogeneous mixture of the TFA salt of(1-(6-fluoroquinolin-4- yl)piperidin-4-yl)methanamine (1B, 41.8 mg, 0.09 mmol) in anhydrous THF (1 mL) and dioxane (0.5 mL), under nitrogen atmosphere, was added DIPEA (0.06 mL, 0.3 mmol) followed by 2-(4- fluorophenyl)acetyl chloride (15.5 mg, 0.09 mmol). After stirring at ambient temperature for 15 hours, the mixture was diluted with DMSO, filtered through a syringe filter, then purified via preparative HPLC/MS to afford the title compound (6.1 mg; 18% yield). MS (ES): m/z = 396 [M+Hf’. tR = 1.19 mm (Method A). ‘H NMR (500MHz, DMSO-d6) ö 8.60 (d, J6.7 Hz, 1H), 8.23 - 8.19 (m, 1H), 8.02 (dd, J=9.2, 5.1 Hz, 1H), 7.90 - 7.84 (m, 1H), 7.76 (d, J9.9 Hz, 1H),7.31 - 7.26 (m, 2H), 7.15 (d, J6.7 Hz, 1H), 7.09 (t, J=8.8 Hz, 2H), 4.03 (d, J=12.4 Hz, 2H), 3.41 (s, 2H), 3.31 (t, J=12.2 Hz, 2H), 3.10 - 3.00 (m, 2H), 1.83 - 1.76 (m, 3H), 1.43 - 1.33 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Another reaction flask was charged with 15.9 g (0.077 mol) of <strong>[328-90-5]4-trifluoromethylsalicylic acid</strong>, 6.2 g (0.077 mol) of pyridine,50ml acetone, stirred for 30min, slowly added to the acid chloride solution prepared in the previous step in an ice bath, stirred at room temperature overnight.Filtration, to the filtrate was added 100ml of water, after separation and rotary evaporation to give a pale yellow solid, washed with toluene, dried,A white powder was obtained as a crude product of O- (4-fluorophenylacetyl) - (4-trifluoromethyl) salicylic acid. Yield: 75.76%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃; for 12h; | General procedure: To a solution of methyl piperidinecarboxylate hydrochloride 2 (0.02 mol) in methylene chloride (20 ml) was added in a dried round-bottom flask, to which triethylamine (0.05 mol) and solution of phenylacetyl chloride in methylene chloride (0.024 mol) was added dropwise separately in an ice bath for over 20 min, next the cold bath was removed. The reaction was stirred at room temperature for 12 h, and TLC traced the reaction to completion. After the completion of the reaction, the solution was dissolved in water (20 ml), and the aqueous solution was extracted with methylene chloride (30 ml × 2) twice. The combined organic phases were washed with 5% Na2CO3 solution (30 ml × 2) and water to neutrality and dried over anhydrous Na2SO4. After filtration and concentration, the corresponding compound 5 were received through the above methods. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | To a solution of <strong>[168297-85-6](S)-4-benzyl-5,5-dimethyloxazolidin-2-one</strong> (1 g, 4.87 mmol, 1.0 equiv) in THF (16 ml) at -78 C under argon, n-butyllithium (1.1 equiv, 2.42M in hexanes) was added dropwise. The solution was stirred for 30 min at -78 C. 4-Fluorophenylacetyl chloride (1.01 g,5.85 mmol, 1.2 equiv) was added dropwise at -78 C. After stirring at -78 C for 2 h, the reaction mixture was quenchedwith saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate (3 x 20 ml). The combinedorganic layers were washed with brine, dried with sodium sulfate, concentrated in vacuo. The resulting crude productwas purified by column chromatography (silica, 12% ethyl acetate in hexanes) to afford the title compound (1.10 g, 3.23mmol, 66%) as a white solid. |
Tags: 459-04-1 synthesis path| 459-04-1 SDS| 459-04-1 COA| 459-04-1 purity| 459-04-1 application| 459-04-1 NMR| 459-04-1 COA| 459-04-1 structure
[ 121639-61-0 ]
3,4-Difluorophenyl acetyl chloride
Similarity: 0.92
[ 451-81-0 ]
2-(2-Fluorophenyl)acetyl chloride
Similarity: 0.90
[ 116622-90-3 ]
2,6-Difluorophenylacetyl chloride
Similarity: 0.88
[ 141060-00-6 ]
2,4-Difluorophenylacetyl chloride
Similarity: 0.88
[ 157033-23-3 ]
2,5-Difluorophenylacetyl chloride
Similarity: 0.88
[ 121639-61-0 ]
3,4-Difluorophenyl acetyl chloride
Similarity: 0.92
[ 451-81-0 ]
2-(2-Fluorophenyl)acetyl chloride
Similarity: 0.90
[ 116622-90-3 ]
2,6-Difluorophenylacetyl chloride
Similarity: 0.88
[ 141060-00-6 ]
2,4-Difluorophenylacetyl chloride
Similarity: 0.88
[ 157033-23-3 ]
2,5-Difluorophenylacetyl chloride
Similarity: 0.88
[ 121639-61-0 ]
3,4-Difluorophenyl acetyl chloride
Similarity: 0.92
[ 451-81-0 ]
2-(2-Fluorophenyl)acetyl chloride
Similarity: 0.90
[ 116622-90-3 ]
2,6-Difluorophenylacetyl chloride
Similarity: 0.88
[ 141060-00-6 ]
2,4-Difluorophenylacetyl chloride
Similarity: 0.88
[ 157033-23-3 ]
2,5-Difluorophenylacetyl chloride
Similarity: 0.88
[ 121639-61-0 ]
3,4-Difluorophenyl acetyl chloride
Similarity: 0.92
[ 451-81-0 ]
2-(2-Fluorophenyl)acetyl chloride
Similarity: 0.90
[ 116622-90-3 ]
2,6-Difluorophenylacetyl chloride
Similarity: 0.88
[ 141060-00-6 ]
2,4-Difluorophenylacetyl chloride
Similarity: 0.88
[ 157033-23-3 ]
2,5-Difluorophenylacetyl chloride
Similarity: 0.88
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :