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. : | 34328-61-5 | MDL No. : | MFCD00011735 |
Formula : | C7H4ClFO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GVORVQPNNSASDM-UHFFFAOYSA-N |
M.W : | 158.56 | Pubchem ID : | 593866 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 36.8 |
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) : | -5.71 cm/s |
Log Po/w (iLOGP) : | 1.55 |
Log Po/w (XLOGP3) : | 2.2 |
Log Po/w (WLOGP) : | 2.71 |
Log Po/w (MLOGP) : | 2.48 |
Log Po/w (SILICOS-IT) : | 3.04 |
Consensus Log Po/w : | 2.4 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.59 |
Solubility : | 0.41 mg/ml ; 0.00259 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.19 |
Solubility : | 1.02 mg/ml ; 0.00642 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.23 |
Solubility : | 0.0938 mg/ml ; 0.000592 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.24 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
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 |
---|---|---|
96% | for 4 h; Reflux | General procedure: The suitable aldehyde (10 mmol), malonic acid (30 mmol, 3.12 g) and piperidine (0.5 mL) were dissolved in pyridine (20 mL) and the mixture was heated under reflux for 4 h. The solution was cooled to room temperature and poured in ice-cold aqueous HCl (100 mL,3 M). The white solid precipitate was filtered, washed with water (350 mL), aqueous NaHCO3 (20 mL, 5percent w/v), then again with water (250 mL) and dried in an oven (60 C). If required, the crude solid was recrystallysed from EtOH/H2O. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With potassium fluoride; | EXAMPLE 19 The reaction was conducted at 230 C. for one hour by using 8.8 g (50 mmol) of 3,4-dichlorobenzaldehyde instead of 4-chlorobenzaldehyde in Example 8, 4.36 g (75 mmol) of spray-dried potassium fluoride and the same amount of the catalyst as used in Example 8. The reaction mixture was subjected to the same post-treatment as in Example 1, and by the distillation under reduced pressure, 5.2 g of 3-chloro-4-fluorobenzaldehyde haivng a boiling point of 106-119 C./22 Torr was obtained. The yield was 66%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With piperidine; for 4.0h;Reflux; | General procedure: The suitable aldehyde (10 mmol), malonic acid (30 mmol, 3.12 g) and piperidine (0.5 mL) were dissolved in pyridine (20 mL) and the mixture was heated under reflux for 4 h. The solution was cooled to room temperature and poured in ice-cold aqueous HCl (100 mL,3 M). The white solid precipitate was filtered, washed with water (350 mL), aqueous NaHCO3 (20 mL, 5% w/v), then again with water (250 mL) and dried in an oven (60 C). If required, the crude solid was recrystallysed from EtOH/H2O. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; | To a DMF (20 mL) solution of <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (500 mg), potassium carbonate (1.20 g) and imidazole (275 mg) were added one by one, and the reaction solution was agitated at 80 C. overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (elution solvent:ethyl acetate?ethyl acetate:methanol=10:1), and 548 mg of the title compound was obtained. The physical properties of the compound are as follows. 1H-NMR (CDCl3) delta (ppm): 10.0 (s, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.91 (dd, J=2.0, 8.0 Hz, 1H), 7.80 (s, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.24-7.27 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium cyanoborohydride; In methanol; acetic acid; at 25℃; for 18h; | Sodium cyanoborohydride (1.11 g, 16.8 mmol) was added to a solution of 1- amino-lH-pyrrole-2-carboxylic acid allyl ester (Example Ib, 1.12 g, 6.74 mmol), 3- <n="121"/>chloro-4-fluorobenzaldehyde (1.32 g, 8.08 mmol) and acetic acid (1.2 niL), in methanol (50 mL) at 25 0C. The reaction mixture was stirred at 25 0C for 18 h, quenched with saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate (2 x 50 mL). The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (Teledyne Isco RediSep 40 g, 0?40% ethyl acetate in hexanes) afforded the desired product, l-(3-chloro-4-fluoro-benzylamino)-lH-pyrrole-2- carboxylic acid allyl ester (1.36 g, 4.41 mmol, 65% yield) as an off-white oil. 1H NMR (400 MHz, CDCl3) delta 4.06 (2H, d, J= 5.5 Hz), 4.76 (2H, d, J= 5.3 Hz), 5.29 (IH, d, J= 11.0 Hz), 5.40 (IH, d, J= 16.4 Hz), 5.96-6.05 (2H, m), 6.58 (IH, t, J= 5.5 Hz), 6.76 IH, (t, J= 1.9 Hz), 6.91 (IH, dd, J1 = 4.3 Hz, J2 = 1.8 Hz), 7.06 (IH, t, J= 8.6 Hz), 7.10-7.14 (IH, m), 7.33 (IH, dd, J1 = 7.1 Hz, J2 = 1.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | 4-{4-Amino-3-[(isopropylcarbamoylmethyl)carbamoyl]phenyl}-2-methylperhydro-1 ,4- diazepine-1-carboxylic acid tert-butyl ester (INTERMEDIATE V.53) (94 mg, 0.201 mmol), 3- chloro-4-fluorobenzaldehyde (40 mg, 0.252 mmol) and acetic acid (3 mul_, catalytic) were dissolved in ethanol (3 ml_) in a microwave vial and the vial sealed. The reaction mixture was stirred at 90 C for 16 h. The reaction mixture was evaporated to dryness, crude material dissolved in DCM (3 ml_) and manganese dioxide (80 mg, 0.840 mmol) was added. The reaction mixture was stirred in a sealed vial at 60 C for 3h. TLC showed incomplete reaction so additional manganese dioxide (80 mg, 0.840 mmol) was added and the reaction mixture heated at 60 C for a further 2h. Solvent was evaporated under reduced pressure and crude product purified by chromatography on silica gel with DCM:MeOH (9:1 , v/v) as eluent. This afforded A-P-beta-chloro^-fluorophenyiyS-Osopropylcarbamoylmethyl^-oxo-SA- dihydroquinazolin-beta-ylJ^-methylperhydro-IA-diazepine-i-carboxylic acid tert-butyl ester (INTERMEDIATE VII.18) ( 65 mg, 0.1 1 1 mmol, 53%).Data for 4-[2-(3-chloro-4-fluorophenyl)-3-(isopropylcarbamoylmethyl)-4-oxo-3, 4- dihydroquinazolin-6-yl]-2-methylperhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (INTERMEDIATE VII.18): MS (ESI) m/z: 586/588 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | 2-Amino-5-(3-ethylperhydro-1 ,4-diazepin-1-yl)-lambda/-(isopropylcarbamoylmethyl)benzamide (INTERMEDIATE V.26) (100 mg, 0.277 mmol), <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (51 mg, 0.332 mmol) and acetic acid (4 drops, catalytic) (0.33 mmol) were dissolved in ethanol (4 mL) in a microwave vial and the vial sealed. The reaction mixture was stirred at 90 C for 16 h. The reaction mixture was evaporated to dryness, re-dissolved in DCM and manganese dioxide (105 mg, 1.1 1 mmol) was added. The reaction mixture was stirred in a sealed vial at <n="96"/>60 C for 3 h. Solvent was evaporated under reduced pressure and crude product purified by chromatography on silica gel with a gradient of DCM to MeOH:DCM (1 :4, v/v) as eluent. This afforded 2-[2-(3-chloro-4-fluorophenyl)-6-(3-ethylperhydro-1,4-diazepin-1-yl)-4-oxo-4H- quinazolin-3-yl]-N-isopropylacetamide (EXAMPLE 6a) ( 95 mg, 0.192 mmol, 69%). Data for 2-[2-(3-chloro-4-fluorophenyl)-6-(3-ethylperhydro-1,4-diazepin-1-yl)-4-oxo-4H- quinazolin-3-yl]-N-isopropylacetamide (EXAMPLE 6a): MS (ESI) m/z: 500/502 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2-Amino-5-(4-isopropyl-1 ,4-diazepan-1-yl)-lambda/-(2-(isopropylamino)-2-oxoethyl)benzamide (INTERMEDIATE V.31 ) (400 mg, 1.07 mmol), <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (253 mg, 1.60 mmol) and acteic acid (0.01 ml_) were dissolved in ethanol (12 ml_). The reaction mixture was heated at 90 C overnight. The reaction mixture was filtered, the residue washed with EtOAc, and the filtrate evaporated under reduced pressure. Crude product was purified by SCX eluting with 2N NH3/MeOH to give a purple solid.This solid was dissolved in toluene (12.00 ml_) and potassium hexacyanoferrate (III) (3.51 g, 10.65 mmol) added followed by water (12 ml_) and 10M KOH (aq.) (4 ml_). The reaction mixture was stirred at room temperature overnight. The reaction mixture was acidified with cone. HCI, diluted with MeOH (10 ml_) and filtered. The residue was washed with MeOH and the filtrate purified by SCX, eluting with 2N NH3/MeOH. Crude product was purified by chromatography on silica gel with a gradient of DCM to DCM:MeOH:NH3 (94:5:1 , v/v) as eluent to afford 2-[2-(3-chloro-4-fluorophenyl)-6-(4-isopropylperhydro-1,4-diazepin-1-yl)-4- oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (EXAMPLE 6k) (155 mg, 0.302 mmol, 28%). Data for 2-[2-(3-chloro-4-fluorophenyl)-6-(4-isopropylperhydro-1,4-diazepin-1-yl)-4-oxo-4H- quinazolin-3-yl]-N-isopropylacetamide (EXAMPLE 6k): MS (ESI) m/z: 515/517 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | cesium fluoride; In DMF (N,N-dimethyl-formamide); at 20℃; | To a stirred solution of thiolsilyl ether (1.0 g, 3.13 mmol) in 5 ML of DMF with <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (500 mg, 3.13 mmol) at ambient temperature was added CsF (5.7 mg, 0.38 mmol).The mixture was stirred over night before it was poured in water and extracted with Et2O (2*25 ML).The combined organic layer was washed with water and brine, dried over Na2SO4, concentrated in vacuo.The residue was purified on a SiO2 flash column chromatography eluding with 5-10% EtOAc/hexanes to give 650 mg (71%) of the title compound as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate; In tetrahydrofuran; methanol; at 0℃; for 0.0333333h; | [00202] A solution of <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (3 g) in THF (40 ml) was added over 2 minutes to a stirred suspension of sodium borohydride (1.07 g) in methanol (40 ml) at 0 C. The mixture was allowed to warm to room temperature and then quenched with water. The resulting suspension was partitioned between water and diethyl ether and the combined organic extracts were dried and concentrated in vacuo. The residue was dissolved in dichloromethane (90 ml) and triphenylphosphine (4.62 g) and tetrabromomethane (6.64 g) were added at 0 C. The mixture was allowed to warm to room temperature overnight then concentrated in vacuo and the residue purified by column chromatography using iso-hexane as eluent to yield the desired product (3.57 g, 85%). NMR: delta 4.7 (s, 2H), 7.4 (m, 2H), 7.7 (m, 1H). | |
With sodium tetrahydroborate; In methanol; at 20℃; for 2h; | To a stirred solution of <strong>[34328-61-5]3-chloro-4-fluoro-benzaldehyde</strong> (31.5 mmol) in MeOH (350 ml) was slowly added sodium borohydride (31.5 mmol). The reaction mixture was stirred at room temperature for 2 hours. Methanol was evaporated. The residue was solubilised in water and AcOEt. Organic phase was washed with brine, dried over Na2SO4, filtered and evaporated to yield Intermediate 50, which was a colourless oil. Intermediate 50 was characterized by the following spectroscopic data: 1H NMR (DMSO-d6, 400 MHz) (ppm) 0.46 (d, J=5.45 Hz, 2H), 5.31-5.34 (t, J=5.45 Hz, 1H), 7.29-7.34 (m, 2H), 7.47 (d, J=6.78 Hz, 1H). | |
General procedure: To a solution of benzaldehyde (3.18 g, 30.0 mmol) inmethanol (20 mL) was added sodium borohydride (1.37g, 36.0 mmol) in portions inice-water bath. The mixture was stirred at room temperature, and after 2.0 hquenched with diluted HCl (1M). The resulting aqueous solution was then extracted with CH2Cl2 (10 mL×3).The organic phase was combined, dried over anhydrous MgSO4, filteredand concentrated reduced pressure by a rotary evaporator to provide the crude product. The crude product was purified by column chromatography on silica gelusing EtOAc-petroleumether (1:20, v/v) as eluentto give the corresponding phenylmethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In tetrahydrofuran; at 90℃; for 36h; | Example 109A 3-Chloro-4-dimethylamino-benzaldehyde A solution of 3-chloro-4-fluorobenzalde- hyde (1.00 g, 6.31 mmol) in dimethylamine (5 mL, 2 M solution in THF) was heated in a sealed tube at 90C for 18 h. A partial reaction was observed. There- fore, solvent was removed, residue treated with fresh solution of dimethylamine (5 mL, 2 M solution in THF) and heated in a sealed tube at 90C for 18 h. The solvent was removed to provide Example 109A (1.15 g, 99%) as a bright yellow SOLID. 1H NMR (400 MHz, DMSO-D6) 5 9.78 (s, 1H), 7.82 (d, J=1. 95 Hz, 1H), 7. 74 (d, JL=1. 95 Hz, J2=8. 59 Hz, 1H), 7.2 (d, J=8.2 Hz, 1H), 2.88 (s, 6H). LCMS (APCI+; Method F) m/z 184 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In dimethyl sulfoxide; at 80℃; | To a stirred solution of <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (634 mg, 4.00 mmol) in DMSO (4 mL) at rt was added sodium methanesulfinate (480 mg, 4.00 mmol) and the resulting solution was heated at 80 C overnight. The reaction was allowed to cool, quenched by the addition of water (50 mL) and extracted with ethyl acetate (45 mL). The organic layer was then washed (water, brine x 3), dried over MgS04, and concentrated in vacuo to afford 3-chloro-4- (methylsulfonyl)benzaldehyde (749 mg, 86%) as a yellow oil. -NMR (300 MHz; CDC13) delta ppm: 3.33 (3H, s), 7.98 (1H, dd, J 8.0, 1.5 Hz), 8.07 (1H, d, J 1.5 Hz), 8.37 (1H, d, J 8.0 Hz), 10.10 (1H, s). |
In dimethyl sulfoxide; at 90℃; for 6h; | To a solution containing 1.0 g of <strong>[34328-61-5]4-fluoro-3-chlorobenzaldehyde</strong> in 45 ml of DMSO was added 1.93 g of methanesulfinicacid sodiumsalt with stirring at 90 C. The solution was stirred for 6 hours at 90 C and poured into water. Sodiumhydrogencarbonate was added and the product was extracted with ethyl acetate. The extract was evaporated to dryness in vacuo. The residue was triturated with 2-propanol, yield 1.06 g. 1H NMR (DMSO-d6, 400 MHz): 3.45 (s, 3 H, CH3), 8.09-8.27 (m, 3 H, Ar), 10.01 (d, 1 H, CHO) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 34 2-[3-Chloro-4-(4-fluoro-3-methyl-phenoxy)-phenyl]-1H-benzoimidazole-5-carboxylic Acid Amide. This compound was prepared according to the methods described in Example 2 and Scheme 1, substituting <strong>[452-70-0]4-fluoro-3-methylphenol</strong> for 3-chloro-4-methylphenol and 3-chloro-4-fluorobenzaldehyde for 4-fluorobenzaldehyde. HPLC: Rt=7.73. MS (ESI+): mass calculated for C21H15ClFN3O2, 395.08; m/z found 396.09 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.41 (d, J=2.2 Hz, 1H), 8.18 (d, J=1.0 Hz, 1H), 8.14 (dd, J=8.6 Hz, J=2.2 Hz, 1H), 8.06 (br s, 1H), 7.84 (dd, J=8.5 Hz, J=1.6 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.37 (br s, 1H), 7.24 (t, J=9.1 Hz, 1H), 7.16 (d, J=8.6 Hz, 1H), 7.12 (m, 1H), 7.0 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With toluene-4-sulfonic acid; In methanol; cyclohexane; water; | EXAMPLE 6 Preparation of Bis(3-chloro-4-fluorobenzylidene)sorbitol A one liter four-necked cylindrical shaped reaction flask equipped with a Dean-Stark trap, condenser, thermometer, nitrogen inlet, and a mechanical stirrer was charged with 34.30 g of sorbitol (0.1883 mole), 600 mL of cyclohexane, 59.70 g of <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (0.3765 moles), 2.50 g of p-toluenesulfonic acid, 2.1 mL of water, and 210 mL of methanol. The reaction was stirred and heated under reflux with removal of water through the Dean Stark trap. The reaction becomes very thick and additional solvent is added as needed. After about six hours, the reaction is cooled, neutralized with potassium hydroxide, and filtered. The wet cake is washed thoroughly with water and cyclohexane, dried in a vacuum oven at 110 C. to give 39.13 g of Bis(3-chloro-4-fluorobenzylidene)sorbitol (as determined through standard analyses). The purity was about 95% as judged by GC. The compound showed melting transitions (DSCa20 C./min) at 204.8 and 220.0 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; | EXAMPLE 44 10-(3-chloro-4-fluorophenyl)-3,4,6,10-tetrahydro-2H-pyrano [3,4-b][1,6]naphthyridine-1,9(5H,8H)-dione A mixture of the product from Example 11C (0.023 g, 0.2 mmol), <strong>[50607-30-2]piperidine-2,4-dione</strong> (Nakagawa, S., Heterocycles (1979), 13, 477-495) (0.23 g, 0.2 mmol), 3-chloro-4-fluorobenzaldehyde (0.032 g, 0.2 mmol) and ethanol (2 mL) was heated to 80° C. for 60 hours and cooled to ambient temperature. The resulting solid was collected by filtration, washed with ethanol and dried under vacuum to provide the title compound. MS (APCI(+)) m/z 349 (M+H)+; MS (APCI(-)) m/z 347 (M-H)-; 1H NMR (DMSO-d6) delta 2.34-2.57 (m, 2H), 3.13-3.28 (m, 2H), 4.00 (s, 2H), 4.45 (AB q, 2H), 4.96 (s, 1H), 7.08 (d, 1H), 7.17 (ddd, 1H), 7.26 (t, 1H), 7.28 (dd, 1H), 9.55 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 20h; | 1 ,1 -dimethylethyl 1-piperazinecarboxylate (6.5g) was added in one portion to a stirred solution of <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (5g) in anhydrous DMF (80ml) under argon. Potassium carbonate (6.6g) was added and the mixture heated at 1000C for 2Oh, cooled and evaporated in vacuo. The residue was partitioned between ethyl acetate (300ml) and water (300ml) and the organic layer washed with water (300ml), dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica gel eluting with 0 - 25% ethyl acetate in pentane gradient to afford the title compound (5.67g, 56%). LC/MS (ESI) Found 325 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of N2-(c-4-aminocyclohexyl)-N4,N4,5-trimethylpyridine-2,4-diamine obtained in step F of example 4 (160 mg) in CHCl3 (2 mL) were added AcOH (38.0 mg) and 3-chloro-4- fluorobenzaldehyde (101 mg). The mixture was stirred at ambient temperature for 1 h and , EPO <DP n="72"/>NaBH(OAc)3 (163 mg) was added. The mixture was stirred at ambient temperature for 14 h and poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 three times. The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (NH-silica gel, 20% to 50% EtOAc in hexane). To a solution of the above purified material in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.5 mL). The mixture was stirred at ambient temperature for 1 h and concentrated under reduced pressure. A suspension of the residue in Et2theta (10 mL) was stirred at ambient temperature for 4 h. The precipitate was collected by filtration, washed with Et2O, and dried at 80 0C under reduced pressure to give N2-{c-4-[(3-chloro-4-fluorobenzyl)amino]cyclohexyl}-NJ,N4,5- trimethylpyridine-2,4-diamine dihydrochloride (161 mg) as a white solid.1HNMR (300 MHz, DMSO-J6, delta): 1.58-2.02 (m, 8H), 2.19 (s, 3H), 3.00 (s, 6H), 3.07-3.21 (m, IH), 3.78-3.88 (m, IH), 4.14-4.25 (m, 2H), 6.12 (brs, IH), 7.46-7.55 (m, 2H), 7.64-7.71 (m, IH), 7.87-7.99 (m, 2H), 9.36-9.60 (m, 2H), 12.51-12.79 (m, IH); ESI MS m/z 391 [M (free)++l, 100%]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; malonic acid; In pyridine; | C. 3-Chloro-4-fluorocinnamic acid A stirred mixture of 3-chloro-4-fluorobenzaldehyde (55 g, 0.35 mole), malonic acid (47 g, 0.45 mole) and 3.5 ml of piperidine in 138 ml of pyridine was heated on a steam bath for 2 hours. The reaction solution was poured into a mixture of 200 ml of concentrated hydrochloric acid and 320 g of ice to give after filtration and water wash 44 g (63%). The crude intermediate was used without further purification in part D. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With sodium; In methanol; at -15℃; for 4h; | To a stirred solution of methanol (25 mL), sodium metal (1.09 g, 47.46 mmol) was added at room temperature and allowed to stir at room temperature for 10 min. Methyl-2-azidoacetate (2a, 2.50 g, 15.80 mmol) and <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (2b, 6.10 g, 53.70 mmol) solution in methanol (5.0 mL) were added at -15 C. The reaction mixture was stirred at -15 C for 4 h. After completion of reaction, the reaction mixture was neutralized with 1 N Hydrogen chloride at 0 C up to pH ~7. The precipitated solid was filtered, washed with water (10 mL x 2). The compound obtained was dried under vacuum to afford methyl (Z)-2-azido-3-(3-chloro-4-fluorophenyl)acrylate (3a) as light yellow solid. Yield: 1.8 g (45%). MS (ESI): 255.02, m/z found 256.25 [M+H]+1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | step 10; - To a solution of O(t-Bu)-t-butylglycine HCl ( 17b, 2.0 g, 8.9 mmol) in DCM (90 mL) containing HOAc (10 mL) was added 3-chloro-4-fluoro-benzaldehyde (2.10 g, 13.4 mmol). This mixture stirred at RT for 18 h. The DCM was removed under reduced pressure. The residue was dissolved in EtOAc ( 100 mL) and was washed with IN NaOH and brine. The organics were dried (MgSO4) and removed under reduced pressure to afford 2.2 g (75%) of 17b: LCMS RT 3.13 min, M+H. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | (lR,2S)-2-Amino-cyclopentanecarboxylic acid methyl ester hydrochloride (prepared as described in Example 11a, 0.2 g, 1.27 mmol) was dissolved in methanol (5.5 mL), followed by addition of <strong>[34328-61-5]4-fluoro-3-chlorobenzaldehyde</strong> (0.201 g, 1.27 mmol) and stirred at 25 0C for 10 min. After this time, 5.2 M acetic acid (0.245 mL) was added, stirred at 25 0C for 5 min before placing in an ice-bath. Once at 0 0C, sodium borohydride (0.203 mg, 3.2 mmol) was added portionwise after which time the mixture was allowed to warm to 25 0C and continued to stir for 17 h. The reaction mixture was quenched by pouring into saturated aqueous sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was concentrated in vacuo and purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-80% ethyl acetate in hexanes) to afford the desired product, (lR,25)-2-(3-chloro-4-fluoro-benzylamino)-cyclopentanecarboxylic acid methyl ester (256 mg, 0.898 mmol, 70% as a yellow oil, containing residual ethyl acetate. 1H NMR (400 MHz, CDCl3) delta: 1.55 - 1.97 (m, 6H), 2.86 (dd, IH, J1 = 14.2 Hz, J2 = 7.0 Hz), 3.19 (dd, IH, J1 = 13.1 Hz, J2 = 6.9 Hz), 3.62 (s, 3H), 3.64 (d, 2H, / = 6.2 Hz), 6.96 (t, IH, / = 8.5 Hz), 7.04 - 7.08 (m, IH), 7.26 - 7.28 (m, IH). LC-MS (ESI) calcd for Ci4H17ClFNO2 285.09, found 286.0 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10O g (0.63 mol) of <strong>[34328-61-5]3-chloro-4-fluoro-benzaldehyde</strong> were dissolved in 300 ml of toluene and 66.3 g (0.63 mol) of aminoacetaldehyd-dimethylacetal were added at room temperature. After adding 12.0 g (0.06 mol) p-toluenesulfonic acid monohydrate, the reaction was heated in a Dean-Stark apparatus for 3 h. The solution was than cooled to room temperature and washed twice with saturated NaHCO3-solution and water. The aqueous solutions are extracted with toluene. The combined organic layers are dried with MgSO4 and evaporated. The obtained imine-intermediate is dissolved directly in 300 ml_ of ethanol and 11.93 g (0.32 mol) of sodium borohydride were added in small portions. After stirring overnight, 10 ml_ of acetic acid were added and the solvent was removed i. vac. The residue was dissolved in dichloromethane and washed twice with water. After drying with MgSO4 and evaporation of the solvent, 147.0 g of crude product were obtained as a yellow oil, which was used without further purification. Rt = 0.81 min (Method C). Detected mass: 248.2 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis of 2-(3-chloro-4-fluoro-benzylamino)-3,3-dimethyl-butyric acid methyl ester (127) To a stirring mixture of 2-amino-3,3-dimethyl-butyric acid methyl ester (126) (0.5 g, 2.75 mmol) in THF (5.5 mL, 0.5 M), cooled to 0 C. in an ice-bath, was added triethyl amine (TEA) (0.382 mL, 2.75 mmol), MgSO4 (0.331 g, 2.75 mmol) and finally <strong>[34328-61-5]3-chloro-4-fluoro-benzaldehyde</strong> (0.872 g, 5.5 mmol). The mixture was slowly warmed up to room temperature and continued stirring at room temperature for 12 h. The reaction mixture was then centrifuged and the supernatant was decanted and concentrated to dryness. The residual was resuspended in methanol (9.8 mL, 0.28 M). NaBH4 (0.208 g, 5.5 mmol) was added portionwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 h before quenching in 1N HCl (100 mL). Product was extracted with EtOAc (100 mL), washed with brine and water and concentrated to dryness to afford crude 2-(3-chloro-4-fluoro-benzylamino)-3,3-dimethyl-butyric acid methyl ester (127) (0.856 g). 1H NMR (400 MHz, CDCl3) delta: 1.20 (s, 9H), 3.21 (s, 1H), 3.79 (s, 3H), 4.08-4.17 (m, 1H), 4.66 (s, 2H), 7.31 (t, 1H, J=8.6 Hz), 7.78-7.81 (m, 1H), 7.96 (d, 1H, J=7.0 Hz), 9.92 (s, 1H). LC-MS (ESI+): m/e 288.1 [M+1]+ (exact ms: 287.7). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl acetamide; at 110℃; for 10h; | A variation of a literature procedure was employed [48]. A mixture of 4-hydroxybenzonitrile (5.00g, 0.042mol), <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (6.433g, 0.0406mol), and anhydrous K2CO3 (5.805g, 0.042mol) were heated to 110C in DMA (30mL) for 10h. The reaction mixture was poured into 10% NaOH (6mL) containing 25g of ice. The residual material was transferred with water giving a solution volume of 75mL. A solid formed while the mixture was stirred. Suction filtration produced a dull yellow crude solid (9.369g, 91%). mp 83.0-85.0C (lit 85.1-87.3C). The spectra matched the literature and the compound was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | In N,N-dimethyl-formamide; at -10 - 20℃; | Reference Example 83 3-chloro-4-(methylsulfanyl)benzaldehyde [Show Image] A solution of <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (50.0 g) in N,N-dimethylformamide (350 mL) was cooled to -10C, and sodium methanethiolate (25 g) was added. The reaction solution was warmed to room temperature, and stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (33.6 g, yield 59%) as colorless crystals. The mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 5:95 - 30:70, volume ratio) and recrystallized from hexane-ethyl acetate to give the title compound (12.3 g, yield 21%) as colorless crystals. melting point 58-59C. |
36% | In N,N-dimethyl-formamide; at -5 - 20℃; | To a solution of <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (24.0 g, 0.15 mol, 1.0 eq) in DMF ( 120 mL) was added sodium methanethiolatc (79.4 g, 0.23 mol, 1.5 eq) at -5 C. The mixture was stirred at r.t. overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether/EtOAc, 20: 1) silica gel to give 3 - chloro-4-(methylthio)benzaldehyde ( 10.3 g, 36%) as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With piperidine; In methanol; at 50℃; for 3h; | To the mixture of 6-chloro-2-oxindole (5.3 g, 32 mmol) (Crescent) and <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (5 g, 32 mmol) (Aldrich) in methanol (200 mL) was added piperidine (2.7 g, 32 mmol) (Aldrich) dropwise. The mixture was then heated at 50 C. for 3 h. After cooled to 4 C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-4-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 8 g, 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With toluene-4-sulfonic acid; In toluene; for 12h;Reflux; | Example 113 2- (3 -Chloro-4-fluoro-phenyl)-3 ,3 -dimethyl- 1 ,2,3 ,4-tetrahydro-quinoline-6-carboxylic acid A mixture solution of 4-amino-benzoic acid ethyl ester (16.5 g, 100 mmol), 3-chloro-4- fiuoro-benzaldehyde (16.1 g, 100 mmol) and -toluenesulfonic acid (384 mg, 2.0 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4- [ (3 -chloro-4-fiuoro-benzylidene) -amino] -benzoic acid ethyl ester (30.8g, quant.) as a pale-white solid: MS calcd. for Ci6Hi3ClFN02 306.74, obsd. (ESP) [(M+H)+] 306.1. |
100% | toluene-4-sulfonic acid; In toluene; for 12h;Reflux; | A mixture solution of 4-amino-benzoic acid ethyl ester (16.5 g, 100 mmol), <strong>[34328-61-5]3-chloro-4-fluoro-benzaldehyde</strong> (16.1 g, 100 mmol) and p-toluenesulfonic acid (384 mg, 2.0 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[(3-chloro-4-fluoro-benzylidene)-amino]-benzoic acid ethyl ester (30.8 g, quant.) as a pale-white solid: MS calcd. for C16H13ClFNO2 306.74, obsd. (ESI+) [(M+H)+] 306.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In tetrahydrofuran; at 20℃; for 24h;Inert atmosphere; | Preparation of ethyl (2E)-3-(3-chloro-4-fluorophenyl)acrylateA solution of 3-chloro-4-fiuorobenzaldehyde (1.0 g, 6.3 mmol) and (carbethoxymethylidene)triphenylphosphorane (2.42 g, 6.94 mmol) in dry tetrahydrofuran (25 mL, 310 mmol) is stirred at rt under nitrogen for 24 h. The mixture is concentrated and the residue is subjected to silica gel chromatography (230-400 mesh, 150 g, elution with 20% ethyl acetate/hexane) to give 1.35 g (94%) of desired product as a white solid. NMR (400 MHz, CDC13) delta 7.54 - 7.64 (m, 2 H), 7.41 (m, 1 H), 7.18 (t, 1 H), 6.39 (d, 1 H), 4.29 (q, 2 H), 1.36 (t, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.6% | With toluene-4-sulfonic acid; In toluene; for 12h;Reflux; | A mixture of 5-amino-2-cyanopyridine (2.86 g, 24 mmol), <strong>[34328-61-5]3-chloro-4-fluoro-benzaldehyde</strong> (3.79 g, 24 mmol) and p-toluenesulfonic acid (92 mg, 0.5 mmol) in toluene (150 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 5-[(3-chloro-4-fluoro-benzylidene)-amino]-pyridine-2-carbonitrile (5.8 g, 93.6%) as a light yellow solid. MS (ESI+) [(M+H)+] 260.1. |
93.6% | With toluene-4-sulfonic acid; In toluene; for 12h;Reflux; | Example 256-(3-Chloro-4-fluoro^henyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro-[l,5]naphthyridine- 2-carboxylic acid5- [(3-Chloro-4-fluoro-benzylidene)-amino]-pyridine-2-carbonitrile A mixture of 5-amino-2-cyanopyridine (2.86 g, 24 mmol), <strong>[34328-61-5]3-chloro-4-fluoro-benzaldehyde</strong> (3.79 g, 24 mmol) and p-toluenesulfonic acid (92 mg, 0.5 mmol) in toluene (150 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 5-[(3- chloro-4-fluoro-benzylidene)-amino]-pyridine-2-carbonitrile (5.8 g, 93.6%) as a light yellow solid. MS (ESI+) [(M+H)+] 260.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,4-diaza-bicyclo[2.2.2]octane; In acetonitrile; at 10 - 35℃; for 120h; | Example 10[(6RS,7SR)-7-(3-chloro-4-fluorophenyl)-1,4-oxazepan-6-yl]methanol monohydrochlorideA) methyl 2-[(3-chloro-4-fluorophenyl)(hydroxy)methyl]prop-2-enoateTo a solution of <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (10.0 g) and methyl acrylate (8.5 mL) in acetonitrile (63 mL) was added 1,4-diazabicyclo[2.2.2]octane (1.41 g), and the mixture was stirred at room temperature for 5 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (11.5 g).1H NMR (300 MHz, CDCl3) delta 3.11 (1H, d, J=6.0 Hz), 3.75 (3H, s), 5.51 (1H, d, J=5.7 Hz), 5.85 (1H, t, J=0.9 Hz), 6.37 (1H, s), 7.06-7.17 (1H, m), 7.20-7.28 (1H, m), 7.44 (1H, dd, J=7.2, 2.3 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(actonitrile)copper(I) hexafluorophosphate; 2,6-bis[5',5'-diphenyl-4'-(S)-sec-butyloxazolin-2'-yl]pyridine; In chloroform; at 20℃; for 0.25h;Inert atmosphere; | General procedure: A dry and argon-flushed 10 mL flask equipped with a magnetic stirrer and a septum was charged with Cu(I)(MeCN)4PF6 (0.01 mmol, 5 mol %) and ligand 2b or 2c (0.012 mmol, 6 mol %). Anhydrous chloroform (2 mL) was added and the mixture was stirred at rt for 30 min. After that aldehyde (0.2 mmol) and aromatic amine (0.2 mmol) were added and stirred for addition 15 min at rt. The reaction was cooled to 0 C and terminal alkyne was added (0.3 mmol) and then the reaction mixture was allowed to warm to 25 C. After the reaction was completed (monitoring by TLC) it was concentrated in vacuo and purified by chromatography on silica gel (2-10% EtOAc in hexane) yielding the pure propargylamines. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | With ytterbium(III) triflate; In acetonitrile; at 85℃; for 18h;sealed tube; | To a stirred solution of 5-amino-pyridine-2-carbonitrile (9.3 g, 78.4 mmol) and <strong>[34328-61-5]3-chloro-4-fluoro-benzaldehyde</strong> (12.3 g, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85 C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-[1,7]naphthyridine-6-carbonitrile (1.2 g, 5.0%) as a light yellow solid: MS (ESI) M+1=316.0. |
5% | ytterbium(III) triflate; In acetonitrile; at 85℃; for 18h;Sealed tube; | Example 77Cyclopropanesulfonic acid [2-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl-l,2,3,4- tetrahydro-[l,7]naphthyridine-6-carbonyl]-amideTo a stirred solution of 5-amino-pyridine-2-carbonitrile (9.3 g, 78.4 mmol) and 3-chloro-4- fluoro-benzaldehyde (12.3 g, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85 C for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL x 2) and brine (100 mL x 2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10 - 50% ethyl acetate in petroleum ether) to afford 2-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl- l,2,3,4-tetrahydro-[l,7]naphthyridine-6-carbonitrile (1.2 g, 5.0%) as a light yellow solid: MS(ESI) M+l = 316.0.To a stirred mixture solution of 2-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl-l,2,3,4- tetrahydro-[l,7]naphthyridine-6-carbonitrile (315.0 mg, 1.0 mmol) in ethanol (10.0 mL) was added 50% sodium hydroxide in water (3.5 mL). The reaction mixture was stirred at 90C for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2 x 100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-chloro-4-fluoro-phenyl)-4,4- dimethyl-l,2,3,4-tetrahydro-[l,7]naphthyridine-6-carboxylic acid (317.9 mg, 95%) as a light white solid which was used for next step without further purification: MS(ESI) M+l = 335.1. To a suspension of 60% sodium hydride (267.5 mg, 6.9 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (0.83 g, 6.9 mmol) at room temperature. The resulting mixture was stirred at 25C for 1 h to afford Solution A77. A solution of 2- (3-chloro-4-fluoro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-[l,7]naphthyridine-6- carboxylic acid (233.8 mg, 0.7 mmol) and Iota,Gamma-carbonyldiimidazole (221.0 mg, 1.4 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70C for 1 h and cooled to room temperature to afford Solution B77. Solution B77 was added to Solution A77 and the resulting mixture was stirred at 25C for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm xlOO mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [2-(3-chloro-4-fluoro- phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-[l,7]naphthyridine-6-carbonyl]-amide (72.2 mg, 23.6%) as a white solid: MS(ESI) M+l = 438.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With ytterbium(III) triflate; In acetonitrile; at 85℃; for 18h;sealed tube; | To a stirred solution of 4-amino-benzoic acid methyl ester (11.3 g, 78.4 mmol) and <strong>[34328-61-5]3-chloro-4-fluoro-benzaldehyde</strong> (12.3 g, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85 C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL), and washed with water (100 mL×2) and brine (100 mL×2), and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (8.4 g, 31.0%) as a light yellow solid: MS (ESI) M+1=348.3. |
31% | ytterbium(III) triflate; In acetonitrile; at 85℃; for 18h;Sealed tube; | Example 8Propane- 1 -sulfonic acid [2-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl-l,2,3,4- tetrahydro-quinoline-6-carbonyl]-amideTo a stirred solution of 4-amino-benzoic acid methyl ester (11.3 g, 78.4 mmol) and 3- chloro-4-fluoro-benzaldehyde (12.3 g, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85 C for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL), and washed with water (100 mL x 2) and brine (100 mL x 2), and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10 - 50% ethyl acetate in petroleum ether) to afford 2-(3-chloro-4-fluoro- phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (8.4 g, 31.0%) as a light yellow solid: MS(ESI) M+l = 348.3.To a stirred mixture solution of 2-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl-l,2,3,4- tetrahydro-quinoline-6-carboxylic acid methyl ester (348.0 mg, 1.0 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (1.5 mL). The reaction mixture was stirred at 70C for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2 x 100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid (316.4 mg, 95%) as a light white solid which was used for next step without further purification: MS(ESI) M+l = 334.1.To a suspension of 60% sodium hydride (535 mg, 13.7 mmol) in N,N-dimethylformamide (2.5 mL) was added propane- 1 -sulfonic acid amide (1.01 g, 8.2 mmol) at roomtemperature. The resulting mixture was stirred at 25C for 1 h to afford Solution A8. A solution of 2-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid (273.0 mg, 0.82 mmol) and Iota,Gamma-carbonyldiimidazole (442 mg, 2.76 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70C for 1 h and cooled to room temperature to afford Solution B8. Solution B8 was added to Solution A8 and the resulting mixture was stirred at 25C for 1 h To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm x 100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded propane- 1- sulfonic acid [2-(3-chloro-4-fluoro-phenyl)-4,4- dimethyl- 1, 2,3, 4-tetrahydro-quinoline-6-carbonyl] -amide (84.7 mg, 23.6%) as a white solid: MS(ESI) M+l = 439.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With ytterbium(III) triflate; In acetonitrile; at 90℃; for 16h;sealed tube; | To a stirred solution of 4-amino-benzoic acid methyl ester (0.825 g, 5 mmol) and <strong>[34328-61-5]3-chloro-4-fluoro-benzaldehyde</strong> (869 mg, 5.5 mmol) in acetonitrile (50 mL) were added isopropenyl-benzene (2.36 g, 20 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (465 mg, 0.75 mmol). The resulting mixture was stirred at 90 C. for 16 h in sealed tube. The mixture was diluted with ethyl acetate (50 mL) and washed with water (30 mL×2) and brine (30 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(3-chloro-4-fluoro-phenyl)-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (850 mg, 40%) as a light yellow solid: MS (ESI) M+1=424.2. |
40% | ytterbium(III) triflate; In acetonitrile; at 90℃; for 16h;Sealed tube; | Example 7 N-[2-(3-chloro-4-fluoro-phenyl)-4-methyl-4-phenyl-l,2,3,4-tetrahydro-quinoline-6- carbonyl] -methanesulf onamideTo a stirred solution of 4-amino-benzoic acid methyl ester (0.825 g, 5 mmol) and 3-chloro- 4-fluoro-benzaldehyde (869 mg, 5.5 mmol) in acetonitrile (50 mL) were addedisopropenyl-benzene (2.36 g, 20 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (465 mg, 0.75 mmol). The resulting mixture was stirred at 90C for 16 h in sealed tube. The mixture was diluted with ethyl acetate (50 mL) and washed with water (30 mL x 2) and brine (30 mL x 2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10 - 50% ethyl acetate in petroleum ether) to afford 2-(3-chloro-4-fluoro- phenyl)-4-methyl-4-phenyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (850 mg, 40%) as a light yellow solid: MS(ESI) M+l = 424.2.To a stirred mixture solution of 2-(3-chloro-4-fluoro-phenyl)-4-methyl-4-phenyl-l,2,3,4- tetrahydro-quinoline-6-carboxylic acid ethyl ester (423 mg, 1 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL) was added 30% sodium hydroxide in water (10 mL). The reaction mixture was stirred at 60C for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2 x 100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-chloro-4-fluoro-phenyl)-4-methyl-4-phenyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid (380 mg, 95%) as a light white solid which was used for next step without further purification: MS(ESI) M+l = 396.1.To a suspension of 60% sodium hydride (76 mg, 1.88 mmol) in N, N-dimethylformamide (1.5 mL) was added methanesulfonamide (181 mg, 1.9 mmol) at room temperature. The resulting mixture was stirred at 25C for 1 h to afford Solution A7. A solution of 2-(3- chloro-4-fluoro-phenyl)-4-methyl-4-phenyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid (150 mg, 0.38 mmol) and Iota,Gamma-carbonyldiimidazole (123 mg, 0.76 mmol) in N,N- dimethylformamide (1 mL) was stirred at 70C for 1 h and cooled to room temperature to afford Solution B7. Solution B7 was added to Solution A7 and the resulting mixture was stirred at 25C for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm x 100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[2-(3-chloro-4-fluoro-phenyl)-4-methyl-4-phenyl- 1,2,3,4- tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (22 mg, 12%) as a white solid: MS(ESI) M+l = 473.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.5% | ytterbium(III) triflate; In acetonitrile; at 85℃; for 18h;Sealed tube; | Example 78Cyclopropanesulfonic acid [6-(3-chloro-4-fluoro-phenyl)-8,8-dimethyl-5,6,7,8- tetrahydro-[l,5]naphthyridine-2-carbonyl]-amideTo a stirred solution of 5-amino-pyridine-2-carbonitrile (9.3 g, 78.4 mmol) and 3-chloro-4- fluoro-benzaldehyde (12.3 g, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85 C for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL x 2) and brine (100 mL x 2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10 - 50% ethyl acetate in petroleum ether) to afford 6-(3-chloro-4-fluoro-phenyl)-8,8-dimethyl- 5,6,7, 8-tetrahydro-[l,5]naphthyridine-2-carbonitrile (3.2 g, 13.5%) as a light yellow solid: MS(ESI) M+1 = 316.0.To a stirred mixture solution of 6-(3-chloro-4-fluoro-phenyl)-8,8-dimethyl-5, 6,7,8- tetrahydro-[l,5]naphthyridine-2-carbonitrile (630.0 mg, 2.0 mmol) in ethanol (10.0 mL) was added 50% sodium hydroxide in water (8.5 mL). The reaction mixture was stirred at 90C for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2 x 100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 6-(3-chloro-4-fluoro-phenyl)-8,8- dimethyl-5,6,7,8-tetrahydro-[l,5]naphthyridine-2-carboxylic acid (635.9 mg, 95%) as a light white solid which was used for next step without further purification: MS(ESI) M+l = 335.1.To a suspension of 60% sodium hydride (267.5 mg, 6.9 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (0.83 g, 6.9 mmol) at room temperature. The resulting mixture was stirred at 25C for 1 h to afford Solution A78. A solution of 6- (3-chloro-4-fluoro-phenyl)-8,8-dimethyl-5,6,7,8-tetrahydro-[l,5]naphthyridine-2- carboxylic acid (233.8 mg, 0.7 mmol) and Iota,Gamma-carbonyldiimidazole (221.0 mg, 1.4 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70C for 1 h and cooled to room temperature to afford Solution B78. Solution B78 was added to Solution A78 and the resulting mixture was stirred at 25C for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm x 100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [6-(3-chloro-4-fluoro- phenyl)-8,8-dimethyl-5,6,7,8-tetrahydro-[l,5]naphthyridine-2-carbonyl]-amide (122.4 mg, 40%) as a white solid: MS(ESI) M+l = 438.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydroxylamine; In ethanol; water; at 20℃; for 3h; | A stirred solution of <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (6 g) in ethanol (80 ml) at room temperature was treated with 50% aqueous hydroxylamine (3.7 g) and the resulting solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the resulting oily residue was dissolved in ethyl acetate, washed with water, brine then dried over sodium sulphate. The solvent was removed under reduced pressure to afford the crude title compound (6.33g), which was used as such for the next step. LCMS (Method A) RT 1.49 min, [M+H]+ 174/176. | |
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In methanol; water; at 20℃; for 2h; | <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (1 mmol) was dissolved in methanol (10 mL),NaHCO3 (1.1 mmol) and NH2OH.HCl (1.1 mmoL) in water (10 mL) were added,Stir at room temperature for 2h, add water until white solid precipitates, and filter.Drying gave the compound <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> oxime. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | a) (15',2R,35r,4R)-3-(3-Chloro-4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2- carboxylic acid ethyl ester[00459] 3-Chloro-4-fluoro-benzaldehyde (0.710 mL, 4.48 mmol) and 10 drops glacial acetic acid were added sequentially to a solution of (lS,2/?,3S,4/?)-3-amino- bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 0.82 g, 4.47 mmol) in methanol (15 mL) at 25 0C. Sodium cyanoborohydride (0.709 g, 11.3 mmol) was added, and the reaction mixture was stirred at 25 0C for 2 h, and then was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2 x 150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0 to 35% ethyl acetate in hexanes) to afford the desired product, (S,2R,3S,4R)-3-(3 -chloro-4-fluoro-benzylamino)- bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (1.12 g, 3.44 mmol, 77%), as a clear oil. 1H NMR (400 MHz, CDCl3) delta: 1.04 - 1.16 (2H, m), 1.18 - 1.24 (2H, m), 1.29 (3H, t, J= 7.4 Hz), 1.44 - 1.61 (2H, m), 1.91 - 1.94 (IH, m), 2.27 - 2.28 (IH, m), 2.42 - 2.43 (IH, m), 2.60 (IH, d, J= 7.7 Hz), 2.91 (IH, d, J= 8.8 Hz), 3.64 (IH, d, J = 13.9 Hz), 3.79 (IH, d, J= 14.2 Hz), 4.14 (2H, q, J= 7.0 Hz), 7.02 - 7.06 (IH, m), 7.13 - 7.17 (IH, m), 7.36 - 7.38 (IH, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With caesium carbonate; In N,N-dimethyl-formamide; at 95℃; for 16h;Inert atmosphere; | To a stirred solution of 4-hydroxy-3-methoxybenzonitrile (1.79 g, 12.0 mmol) in dry DMF (24 mL) was added <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (1.90 g, 12.0 mmol, 1.0 eq) followed by the addition of Cs2CO3 (6.92 g, 21.2 mmol, 1.77 eq). The reaction mixture was stirred at 95 C for 16 h under Ar atmosphere before cooling to room temperature. The mixture was diluted with EtOAc and poured onto water. The product was extracted with EtOAc (3 ? 100 mL), and the combined organic phases washed with water (3 ? 100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was subsequently purified by flash chromatography on silica with Hex-EtOAc (Hex, then Hex-EtOAc 4:1 to 3:2) to give the desired product as pale-yellow solid (2.50 g, 72%). 1H NMR (DMSO) delta 9.92 (s, 1H), 8.10 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.76 (s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 3.82 (s, 3H); 13C NMR (DMSO) delta 190.8, 156.5, 151.0, 146.3, 132.5, 131.8, 130.0, 126.2, 123.1, 122.1, 118.4, 117.4, 117.3, 108.9, 56.5; HPLC purity 97.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | General procedure: To each reaction tube in a 24-position Bohdan MiniBlock XT was added the appropriate aldehyde (5.0 equiv, 1.15 mmol), which was dissolved in MeCN (1 mL). A solution of 2-(benzo[d][1,3]dioxol-5- yl)pyrimidin-4-amine (8) in MeCN (0.13 M, 1.8 mL, 0.23 mmol, 1.0 equiv) was then dispensed into each tube. ClTi(Oi-Pr)3 (95%, 0.35 mL, 1.38 mmol, 6.0 equiv) was added to each tube, followed by AcOH (3 drops). The reactions were shaken at 450 rpm for 5 minutes, and then solid NaBH(OAc)3 (95%, 257 mg, 1.15 mmol, 5.0 equiv) was added to each tube. The reactions were shaken at 450 rpm for an additional 1.5 hours, and then a solution of 15% aqueous NH4OH (2 mL) and CH2Cl2 (2 mL) were added to each tube causing white solids to precipitate. Shaking was continued for 30 minutes at 450 rpm. Using stackable 24-position Bohdan MiniBlock XTs, the liquid portions of the crude reaction mixtures were passed into phase separators, to which H2O (2 mL) was added. The biphasic mixtures were mixed by hand using pipettes, and then the heavier organic layers were passed from the phase separators into new reaction tubes. The white solids in the original reaction tubes were washed with CH2Cl2 (2 mL) and the washings were passed into the closed phase separators. The biphasic mixtures were again mixed by hand using pipettes and the heavier organic layers were passed into the reaction tubes containing the organic layers from the first separation. The crude reaction mixtures were then placed on a sample concentrator to remove the solvents. TFA/MeOH (1:19, 3 mL) was added to each crude reaction mixture, and the samples were then shaken at 450 rpm for 1 hour. The solutions were then passed onto columns of Dowex 50WX4-400 ion exchange resin (2.0 g, pre-washed with TFA/MeOH (1:99, 5 mL)). Each reaction tube was washed with MeOH (2 mL) and the washings were allowed to pass onto the Dowex columns. The columns were washed with MeOH (3 mL) and the washings discarded. The products were then eluted into collection tubes using a mixture of Et3N/MeOH (1:9, 10 mL). Solvents were removed using a sample concentrator and the products were subjected to reverse-phase preparative HPLC purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3- Chloro-4-(2-hydroxy-5-methylphenoxy)benzoic Acid (18p) was prepared according to General Procedure D from 2-methoxy-5-methylphenol and <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong>. General Procedure D.1 The appropriate phenol (1.4 mmol) and KOH (1.1 mmol) were dissolved in DMF (1.5 mL) before the appropriate 4-fluorobenzaldehyde (1 mmol) was added. The solution was heated in a sealed tube to 175 C for 20 min, poured into H20 (25 mL) and extracted with Et20 (75 mL). The organic layer was washed with H20 (25 mL), brine (10 mL) and dried (Na2S04). The crude residue was dissolved in 5: 1 acetonitrile: water (6 mL) along with NaH2P04 (36 mg) and H202 (150 mu, 30%). In an ice bath, a solution of NaC102 (158 mg) in water (1.5 mL) is slowly added. After 12 h at r.t., the reaction was quenched with Na2S2C"3, diluted with brine and extracted with EtOAc. The desired benzoic acid was isolated by extracting into aqueous base, acidification, and extraction into EtOAc. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.05% | With sodium hydroxide; In ethanol; at 0℃; for 1h; | Preparation of Intermediate 2-Chloro-1-fluoro-4-(2-nitro-vinyl)-benzene (I-34a) Using the same reaction procedure and workup as described in Example 1, <strong>[34328-61-5]3-chloro-4-fluoro-benzaldehyde</strong> (2 g, 12.6135 mmol) in ethanol (63 mL) was reacted with nitro methane (0.68 mL, 12.6135 mmol), 10N NaOH solution (529.7 mL, 13.2441 mmol) at 0 C. for 1 hr to afford 1.7 g of the product (67.05% yield). 1H NMR (300 MHz, CDCl3): delta 7.95-7.90 (d, 1H), 7.65-7.40 (m, 3H), 7.3-7.2 (m, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With trifluoroacetic acid; In dichloromethane; at 20℃; for 3.33h;Inert atmosphere; Reflux; | Preparation of 1-(3-chloro-4-fluorophenyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole (12). [0093] <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (295 mg, 1.86 mmol) in dry dichloromethane (10 mL) was added a solution of 3-(2-hydroxyethyl)indole (300 mg, 1.86 mmol) in dry dichloromethane (4 mL). This solution was placed under argon. Then a solution of trifluoroacetic acid (42.7 muL, 0.56 mmol) in dry dichloromethane (1 mL) was slowly added. The resulting mixture was stirred for 20 min at room temperature and further refluxed for 3 h. Solvent evaporation under reduced pressure followed by chromatography on silica gel (cHex/AcOEt 94/6) afforded 12 as a yellow solid (90 mg, 16%). [0095] 1H RMN (400 MHz, CDCl3) delta 2.84-2.89 (m, 1H), 3.07-3.15 (m, 1H), 3.96-4.02 (m, 1H), 4.27-4.32 (m, 1H), 5.75 (s, 1H), 7.13-7.23 (m, 3H), 7.24-7.28 (m, 2H), 7.44 (dd, J= 7.2, 2.0 Hz, 1H), 7.57 (bs, 1H), 7.60 (d, J= 7.6 Hz). [0096] 13C RMN (100 MHz, CDCl3) delta 22.4, 65.0, 75.1, 109.5, 111.3, 117.1 (d, J= 21.1 Hz), 118.7, 120.1, 121.7 (d, J = 17.8 Hz), 122.5, 127.1, 128.4 (d, J = 7.6 Hz, 130.9, 132.8, 136.4, 137.0 (d, J= 3.6 Hz), 158.5 (d, J= 249.1 Hz). [0097] 19F RMN (160 MHz, CDCl3) delta -114.80. [0098] HPLC: tR = 9.80 min. [0099] MS : m/z 302 ([M+H]+). [0100] HRMS-ESI-TOF: m/z calculated 300.0591, found 300.0597 ([M-H]-) |
16% | With trifluoroacetic acid; In dichloromethane; at 20℃; for 3.33333h;Inert atmosphere; Reflux; | To a solution of <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (295 mg, 1.86 mmol) in dry dichloromethane (10 mL) was added a solution of 3-(2-hydroxyethyl)indole (300 mg, 1.86 mmol) in dry dichloromethane (4 mL). This solution was placed under argon. Then a solution of trifluoroacetic acid (42.7 0.56 mmol) in dry dichloromethane (1 mL) was slowly added. The resulting mixture was stirred for 20 min at room temperature and further refluxed for 3 h. Solvent evaporation under reduced pressure followed by chromatography on silica gel (cHex/AcOEt 94/6) afforded 12 as a yellow solid (90 mg, 16%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With sodium hydroxide; In methanol; at 20℃; | General procedure: A mixture of 2-acetyl-5-chlorothiophene (0.01 mol) and a halogen-substituted benzaldehyde (0.01 mol)was dissolved in methanol (20 mL). Catalytic amount of NaOH was added to the solution drop-wisewith vigorous stirring. The reaction mixture was stirred for about 5-6 h at room temperature. Theresultant crude products were filtered, washed successively with distilled water and recrystallized fromethanol to get corresponding chalcones. Crystals suitable for X-ray diffraction studies were obtainedby the slow evaporation technique using a suitable solvent .(2E)-1-(5-Chlorothiophen-2-yl)-3-(3-chloro-4-fluorophenyl)prop-2-en-1-one (3d): Solvent for growingcrystals: Mixture of acetone, ethanol and acetonitrile (1:1:1 v/v); Yield: 63%; M.P. 167-169 C;LCMS: m/z = 302 (M++1); Elemental analysis: Calculated for C13H7Cl2FOS: C, 51.85%; H, 2.34%;Found: C, 51.79%; H, 2.48%. CCDC No.: 942741. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium hydroxide; In ethanol;Reflux; | General procedure: The 2-thioxo-4-thiazolidinone (1mmol), benzaldehydes (1 mmol) and NaOH (1.0 mmol) were added to ethanol withtotal volume of 15 mL. The reaction mixture was heated to reflux and stirredfor 2-24 h. After cooling to room temperature, the mixture was concentrated under reduced pressure, neutralized to pH 7.0 with dilute hydrochloric, and then extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The resulting residue was recrystallization from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A flame-dried, two-necked, round-bottomed flask was charged with compound 5 (synthesized according to ref. 1-2) (0.4 g, 2 mmol) and 10 mL of anhydrous THF, the mixture was cooled to -70 C, n-BuLi (1 mL, 2.2 M in hexane, 2.2 mmol) was added dropwise within 2 minutes. After addition, the solution was stirred for 1 hour at the same temperature. Commercial available aldehyde (2.1 mmol) was diluted with 2 mLof anhydrous THF and added into the solution. The reaction was slowly up to room temperature after stirring for 1 hour, and quenched with 10 mL of saturated NH4Cl .The mixture was extracted with EtOAc (3 × 20 mL), the combined organic phase was washed with brine, dried over Na2SO4 and chromatographed on a silica gel to give 6 as yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Step 1 : 2-(3-chloro-4-fluorophenyl) tetrahydro-2H-pyran-4-ol 3-buten-1 -ol (3.95 mL, 45.48 mmol) was added to a solution of <strong>[34328-61-5]3-chloro-4-fluoro benzaldehyde</strong> (6 g, 38.21 mmol) in DCE (120 mL), followed by TFA (48 mL) and the RM was stirred for 72 h at RT. After completion of reaction, the solvent was removed under reduced pressure. The residue was diluted with H20 (100 mL) and basified using 6 N NaOH solution, the aq layer was extracted with DCM (500 mL). The organic layer was washed with H20 (100 mL), brine (100 mL) and concentrated under reduced pressure to get the crude compound. The crude compound was dissolved in MeOH (70 mL), added LiOH (4.5 g, 107 mmol) and stirred for 5 h at RT. The RM was concentrated under reduced pressure and the residue was diluted with DCM (300 mL); and was subsequently washed with H20 (100 mL) and brine (100 mL), dried (Na2S04) and concentrated in vacuo to get crude. Purification by CC (silica gel, 0-18% EtOAc in PE) gave 2-(3-chloro-4-fluorophenyl) tetrahydro-2H-pyran-4-ol (5.5 g; 64%) as thick liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With piperidine; In ethanol; at 20℃; for 3h; | General procedure: A mixture of 4-bromobenzaldehyde (4-tertbutylbenzaldehyde or 4-methoxybenzaldehyde) (10 mmol) and 4-hydroxycoumarin (20 mmol) was dissolved in 100 mL of EtOH. A few drops of piperidine were added, and the mixture was stirred for 3 h at room temperature. After reaction completion as determined by TLC, water was added until precipitation occurred. After filtering the precipitates, they were sequentially washed with ice-cooled water and ethanol and then dried in a vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A solution of the requisite aldehyde 3 (0.12 mmol), diethyl 2-aminomalonate(2; 17.5 mg, 0.1 mmol) and AcOH (0.17 mul, 0.03 mmol) intoluene (0.5 mL) was stirred at r.t. for 20 min. To this resultant mixturewas added the appropriate unsaturated pyrazolone 1 (0.12mmol) and an additional 0.5 mL of toluene. The reaction mixture wasstirred at r.t. for 12 h. The resultant solution was evaporated underthe reduced pressure and the residue was purified by flash columnchromatography on silica gel (eluent: PE-EtOAc, 15:1 ? 5:1) to affordthe respective pure product 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A solution of the requisite aldehyde 3 (0.12 mmol), diethyl 2-aminomalonate(2; 17.5 mg, 0.1 mmol) and AcOH (0.17 mul, 0.03 mmol) intoluene (0.5 mL) was stirred at r.t. for 20 min. To this resultant mixturewas added the appropriate unsaturated pyrazolone 1 (0.12mmol) and an additional 0.5 mL of toluene. The reaction mixture wasstirred at r.t. for 12 h. The resultant solution was evaporated underthe reduced pressure and the residue was purified by flash columnchromatography on silica gel (eluent: PE-EtOAc, 15:1 ? 5:1) to affordthe respective pure product 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A solution of the requisite aldehyde 3 (0.12 mmol), diethyl 2-aminomalonate(2; 17.5 mg, 0.1 mmol) and AcOH (0.17 mul, 0.03 mmol) intoluene (0.5 mL) was stirred at r.t. for 20 min. To this resultant mixturewas added the appropriate unsaturated pyrazolone 1 (0.12mmol) and an additional 0.5 mL of toluene. The reaction mixture wasstirred at r.t. for 12 h. The resultant solution was evaporated underthe reduced pressure and the residue was purified by flash columnchromatography on silica gel (eluent: PE-EtOAc, 15:1 ? 5:1) to affordthe respective pure product 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | General procedure: A solution of acyl hydrazine 6 (1mmol) and aromatic aldehydes 7a-s (1mmol) in i-PrOH (10mL) was refluxed until the reaction was completed (monitored by TLC, 3-5h), and then the solvent was evaporated under reduced pressure. To the resulting residue dissolved in DMSO (5mL), potassium carbonate (3mmol) and iodine (1.2mmol) were added in sequence. Then the reaction mixture was heated to 80C and stirred until the completion of reaction. After being cooled to room temperature, it was treated with 5% Na2S2O3 (20mL), extracted with ethyl acetate the combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum to obtain crude products. The crude obtained was purified by column chromatography using ethyl acetate and hexane as eluent to afford pure products (8a-s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.6% | With chloro-trimethyl-silane; In toluene; acetonitrile; at 50℃; for 16h; | To a solution of <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (7.0 mL, 59.6 mmol) in toluene (27.4 mL) and acetonitrile (27.4 mL) were added formamide (5.93 mL, 149 mmol), TMS-Cl (8.38 mL, 65.6 mmol) and intermediate 32A? (12.66 g, 81 mmol). The reaction mixture was heated in an oil-bath at 50 C. for 16 h, cooled to RT and quenched by adding water (20 mL) to generate a precipitate. To the mixture was then added MTBE (15 mL) and the mixture was stirred for a few min. before being filtered off. The filter-cake was washed with water and then air-dried. It was purified by silica gel chromatography (220 g RediSep column, eluting with a gradient of 5-90% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford intermediate 32B? (12.9 g, 63.3% yield) as a white solid. MS (ES): m/z=341.9 [M+H]+; 1H NMR (400 MHz, DMSO-d6) delta ppm 9.75 (d, J=10.8 Hz, 1H), 7.98 (d, J=1.0 Hz, 1H), 7.91-7.81 (m, 1H), 7.79-7.69 (m, 2H), 7.67-7.58 (m, 1H), 7.53-7.41 (m, 3H), 6.55 (d, J=10.5 Hz, 1H), 2.46-2.39 (m, 3H). |
701 mg | With chloro-trimethyl-silane; In toluene; acetonitrile; at 50℃; for 12h; | To a solution of 4-methylbenzenesulfmic acid (1005 mg, 6.44 mmol) in toluene/acetonitrile (1.5 + 1.5 mL) were added formamide (427pL, 10.7 mmol), <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (680 mg, 4.29 mmol) and chlorotrimethylsilane (598 pL, 4.72 mmol) and the mixture was stirred at 50 C for 12 hours. Then, water (3 mL) and 2-methoxy-2-methylpropane (4 mL) were added and the mixture was stirred at 0 C (ice bath) for 15 minutes. The precipitate was collected by filtration, washed with water (10 mL) and dried in vacuo. The product was obtained as a white solid (701 mg, 48 %). (1001) NMR shifts for major rotamer: (1002) NMR (500 MHz, DMSO-de) d (ppm) 9.75 (d, / = 10.6 Hz, 1H), 7.97 (s, 1H), 7.87 - 7.83 (m, 1H), (1003) 7.76 - 7.70 (m, 2H), 7.63 - 7.59 (m, 1H), 7.49 - 7.42 (m, 3H), 6.54 (d, / = 10.5 Hz, 1H), 2.42 (s, 3H). 19F NMR (471 MHz, DMSO-de) d (ppm) -114.98. (1004) NMR is in agreement with the published data, (patent: US2016/0257690 Al) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In toluene; at 100℃; for 2h; | tert-Butyl ((3R 4R 5S)- 1 -(3-aminopyridin-4-yl)-4- { [fert-butyl(dimethyl)silyl] oxy } -5- methylpiperidin-3-yl)carbamate (Prepared in Intermediate 1, Step 11; 30.0 mg, 0.0687 mmol) and <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (from Aldrich, 14 mg, 0.089 mmol) were added to toluene (3.0 mL). Then catalytic amount of acetic acid was added to the reaction mixture and the reaction mixture was heated at 100 C for 2 h. After this time, the reaction mixture was cooled to room temperature and toluene was evaporated under reduced pressure. The resulting intermediate imine was dissolved in methanol (5.0 mL) and the solution was cooled to 0 C. Then sodium tetrahydroborate (6.5 mg, 0.17 mmol) was slowly added to the reaction mixture and the reaction mixture was stirred at room temperature for 30 min. After this time, water was added to the reaction mixture and product was extracted with EtOAc. Combined organic fractions were washed with brine, dried over Na2S04 and solvents were evaporated under reduced pressure. The crude product was purified by Biotage Isolera to give the desired compound (40 mg, 99%). LCMS calc. for C29H45CIFN4O3S1 (M+H)+ m/z = 579.3; found: 579.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With pyridinium p-toluenesulfonate; In dichloromethane; at 20℃; for 0.123333h;Flow reactor; | General procedure: General procedure for the continuous-flow hydrazone synthesis (products 3a-j) Following initiation of the control script, using the apparatus shown in Figure 3, the system was primed with dichloromethane and the aqueous extraction solvent for several minutes until there were no air gaps in the flow path. The aldehyde (0.20 M) and pyridinium paratoluenesulfonate (PPTS) (0.10 M) in dichloromethane (7.5 mL) were loaded in to the corresponding 7.5 mL injection loop. tert-Butyl carbazate (0.4 M) in dichloromethane (10.0 mL) was loaded into the 10.0 mL injection loop. The tert-butyl carbazate loop was injected into the system 30 seconds prior to the substrate loop. Organic solution exiting the system was collected for 40 minutes. The solvent was then removed under reduced pressure to afford a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With piperidine; In ethanol; for 8h;Reflux; | General procedure: A mixture of 0.21 g 28 (0.90 mmol) and aldehyde(0.90 mmol) in 27 cm3 absolute ethanol in the presenceof few drops of piperidine was refluxed for 8 h. The formedsolid was filtered off and dried. The obtained compoundswere further purified by crystallized from ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; In dimethyl sulfoxide; at 90℃;Inert atmosphere; | A 50-mL round-bottom flask was charged with <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (1.00 g, 6.31 mmol, 1.00 equiv), DMSO (10 mL), potassium carbonate (2.62 g, 19.0 mmol, 3.00 equiv), and pyrrolidine (0.674 g, 9.48 mmol, 1.50 equiv) under nitrogen. The resulting solution was stirred overnight at 90 C and quenched with water (50 mL). The resulting solution was extracted with EtOAc (2 x 80 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 1.10 g (83% yield) of 3-chloro-4-(pyrrolidin- l-yl)benzaldehyde as a yellow oil. LCMS (ESI, m/z): 210 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 1h;Inert atmosphere; | To amine 34b (56 mg; 0.25 mmol) in DCM (5 mL) added aldehyde (42 mg g; 0.26 mmol)BzOH (152 mg; 1.24 mmol), NaBH(OAc)3 (64 mg; 0.29 mmol) and stirred for 1 h. SaturatedNaHCO3 (~3 mL) was added for 15 min. Layers were separated and the aqueous layer wasextracted twice with DCM. The combined DCM extracts were washed with water, brine,dried over anhydrous Na2SO4, concentrated to afford pure product 35. 1H NMR (400 MHz,CD3OD) delta 7.49 - 7.00 (m, 3H), 3.69 (d, J = 9.0 Hz, 2H), 2.95 (d, J = 6.8 Hz, 2H), 2.78 - 2.48(m, 5H), 2.45 - 2.23 (m, 2H), 1.84 - 1.29 (m, 8H), 0.93 (ddd, J = 17.9, 9.2, 3.7 Hz, 9H). 13CNMR (101 MHz, CD3OD) delta 159.3, 156.8, 140.8, 130.3, 125.5, 118.9, 116.9, 114.6, 112.5,59.6, 52.3, 48.9, 39.7, 37.7, 34.8, 29.5, 28.3, 22.3, 19.9, 19.4, 10.9.; HR-MS (ESI) m/z calcd.for C21H33N2ClF [M+H]+ = 367.2319; Found: 367.2310.Rf = 0.4 (DCM/MeOH (9:1; MeOH:aq. NH3) 9:1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium carbonate; In dimethyl sulfoxide; at 90℃;Inert atmosphere; | A 50-mL round-bottom flask was charged with <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (1.00 g, 6.31 mmol, 1.00 equiv), DMSO (10 mL), morpholine (0.827 g, 9.49 mmol, 1.50 equiv), andpotassium carbonate (2.62 g, 19.0 mmol, 3.00 equiv) under nitrogen. The resulting solution was stirred overnight at 90 C and quenched with water (50 mL). The resulting solution wasextracted with EtOAc (2 x 80 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue waschromatographed on a silica gel column to provide 1.04 g (73% yield) of 3-chloro-4- morpholinobenzaldehyde as a light yellow solid. LCMS (ESI, m/z): 260 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol;Reflux; Dean-Stark; | General procedure: 2-Amino-5-methylthiazole-4-carboxylic acid (0.01 M) (1) and substituted benzaldehyde (0.01 M) was taken in 100 mL round bottom flask fitted with Dean-Stark apparatus. In a compound mixture in R.B. to add 50 mL of methanol and refluxed for 7-8 h. Reaction was monitored with TLC, after completion of reaction, solvent was removed and Schiff base was filtered dried and recrystallized from ethanol to give (3a), Yield: 80-84%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With aminosulfonic acid; at 70℃; for 6h; | A round bottom flask was charged with 1 mmol (0.103 mL) of <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong>, 2 mL of 2-methylfuran, 0.1 mmol of sulfamic acid and heated in an oil bath to 70 C with magnetic stirring. Reaction 6 hour.The oil bath was removed and the temperature was lowered to room temperature. The catalyst was filtered off and the mother liquor was concentrated by rotary evaporator. The residue was extracted with petroleum ether as eluent and chromatographed on silica gel.Pure triarylmethane was obtained in 89% isolated yield. The NMR data of the compound are as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With C23H3BF16N2O; In toluene; at 25℃; for 3h;Green chemistry; | A 0.03 mol% Lewis acid-base bifunctional catalyst I (where Rf = CF3; R1, R2, R3, R4, R5, R6 = F) was added to a 100 mL single-mouth flask.0.2 mol of <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (R7=4-F-3-Cl-C6H3), 0.1 mol of o-phenylenediamine (R8, R9, R10, R11=H), 15 mL of toluene, will react at 3 hours at 25 C TLC followed the reaction until the reaction was complete. The reaction yield was: the yield of product II (R7=4-F-3-Cl-C6H3; R8, R9, R10, R11=H) was 93%; after repeated use of the catalyst system for 10 times, the catalytic performance did not decrease. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With C23H3BF16N2O; In toluene; at 25℃; for 3h;Green chemistry; | A 0.03 mol% Lewis acid-base bifunctional catalyst I (where Rf = CF3; R1, R2, R3, R4, R5, R6 = F) was added to a 100 mL single-mouth flask.0.2 mol of 3-chloro-4-fluorobenzaldehyde (R7=4-F-3-Cl-C6H3), 0.1 mol of o-fluoro-o-phenylenediamine(R8=F; R9, R10, R11=H), 15 mL of toluene, and the reaction was stirred at 25 C. for 3 hours.TLC followed the reaction until the reaction was complete. The results showed that the yield of product II (R7=4-F-3-Cl-C6H3; R8=F; R9, R10, R11=H) was 100%; after 10 times of catalyst system was reused, its catalytic performance was not. See decline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With nano-BF3/SiO2; In neat (no solvent); at 20℃; for 0.233333h;Sonication; Green chemistry; | General procedure: The mixture of benzaldehyde (3a) (1 mL, 0.010 mol), 2 (2.45 g,0.010 mol) and triethyl phosphite (4) (3.4 mL, 0.020 mol) was placed in a round bottomed flask. To this mixture, 37% nano-BF3*SiO2 (0.30g) was added and the mixture was irradiated in the ultrasonicator at ambient temperature for about 10 minutes. The progress of the reaction was monitored by TLC (EtOAc/nhexane7:3). After completion of the reaction as checked byTLC, the reaction mixture was cooled to room temperature. CH2Cl2 (15 mL) was added to the reaction content and stirred for 10 min. The catalyst nano-BF3*SiO2 was separated by filtrationas residue, washed with CH2Cl2 (2 × 10 mL) and the residue was dried under vacuum at 100C to be utilized in further studies. The combined organic layer was washed with water (15 mL), dried over anhydrous Na2SO4 and concentrated under vacuum at 50C to obtain crude 5a. Pure 5a was obtained by column chromatography (EtOAc/n-hexane 7:3). The same procedure was used for the preparation of the remaining compounds 5b-k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84%; 84% | General procedure: Synthetic procedure was based on this elaborated earlier byOleksyszyn and Soroka [34-36]. Thus, acetamide 1.18 g (0.02 mol)was dissolved in glacial acetic acid (4 mL, 4.20 g, 0.07 mol). Thesolution was cooled in an ice-bath at 0 C and acetyl chloride(0.71 mL, 0.78 g, 0.01 mol) was added observing the formation of acrystalline by-product. After a few minutes appropriate aldehyde(0.01 mol) was added, and the mixture was kept in ice-bath for30 min and then left for 1 day at room temperature with constantstirring. Then the mixturewas cooled again to 0 C and phosphorustrichloride was added dropwise (0.87 mL, 1.37 g, 0.01 mol). Afterstirring for 30 min the mixture was allowed to warm to roomtemperature, and finally heated for 1-1.5 h at 75-80 C. Evaporationof the volatile components of the reaction mixture resulted inan oily product, which was refluxed for 8 h in concentrated hydrochloricacid (50 mL). After the removal of volatile components ofthe reaction mixture oily product was dissolved in ethanol (10 mL)and left for crystallization. Resulting aminobenzylphosphonic acidwas then recrystallized from ethanol or ethanol-water. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sodium hydroxide; In ethanol; water; at 0 - 20℃; | General procedure: A mixture of 1-(4-(quinazolin-4-ylamino)phenyl)ethanone (263 mg, 1 mmol) and 4-fluorobenzaldehyde 12a (124 mg, 1 mmol) was dissolved in 10 mL ethanol. To this mixture, sodium hydroxide (100 mg, 2.5 mmol) dissolved in 1.0 mL of water was added at 0-5C. The reaction mixture was stirred at room temperature for 45 min. Then, this reaction mixture was poured over crushed ice and acidified with dilute HCl. The light yellow solid thus obtained was filtered, washed with water and dried. The residue was purified on column chromatography (silica gel with 30% ethyl acetate in hexane) affording compound 13a as a yellow solid, Yield: 81% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium hydroxide; In ethanol; water; at 0 - 20℃; | A mixture of 1-(4-(quinazolin-4-ylamino)phenyl)ethanone (263 mg, 1 mmol) and 4-fluorobenzaldehyde 12a (124 mg, 1 mmol) was dissolved in 10 mL ethanol. To this mixture, sodium hydroxide (100 mg, 2.5 mmol) dissolved in 1.0 mL of water was added at 0-5C. The reaction mixture was stirred at room temperature for 45 min. Then, this reaction mixture was poured over crushed ice and acidified with dilute HCl. The light yellow solid thus obtained was filtered, washed with water and dried. The residue was purified on column chromatography (silica gel with 30% ethyl acetate in hexane) affording compound 13a as a yellow solid, Yield: 81%; MR; 132-134C; DIPMS: m/z=400.1 (M+H), Elemental analysis: analysis calculated for C23H18FN3O2: C-72.17, H-4.54, and N-10.52; found C-72.23, H-4.41, and N-10.73; 1H NMR (CDCl3, 300 MHz): delta 9.14 (s, NH), 8.80 (s, 1H), 8.12-8.00 (m, 4H), 7.95 (d, 1H, J= 6.0 Hz), 7.88 (d, 1H, J= 6.0 Hz), 7.64 (d, 1H, J= 4.6 Hz), 7.55-7.60 (m, 4H), 7.56-7.59 (m, 2H), 7.48 (d, 1H, J= 14.5 Hz), 7.46-7.40 (m, 1H), 7.09 (m, 1H); 13C NMR (CDCl3, 75 MHz): delta 175.1, 160.6, 159.0, 158.8, 154.4, 153.8, 153.7, 152.3, 147.1, 146.2, 145.7, 142.9, 139.3, 137.2, 136.1, 135.8, 133.6, 132.7, 130.6, 130.4, 128.9, 126.5, 124.2. Following the same procedure as depicted for 13a, the other quinazoline-chalcone derivatives13b-r were prepared by the Claisen-Schmidt condensation of corresponding benzaldehydes with substituted 1-(4-(3,4-dihydroquinazolin-4-ylamino)phenyl)ethanones. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In dimethyl sulfoxide; at 70℃; | General procedure: A mixture of compound 1[3](376 mg, 2.0 mmol) and the correspounding aldehyde (2.2 mmol) were stirred in dimethylsulfoxide (DMSO, 5.0 mL) under an air atmosphere at 70 C. After the reaction wascompleted (monitoring by thin layer chromatography (TLC) using 254 nm ultraviolet ray),the precipitate obtained was filtered under vacuum from the reaction mixture and washedwith cold ethanol and water to give pure products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.7% | 0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.20 g (1.26 mmol)3-chloro-4-fluorobenzaldehyde was added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto.Stir at room temperature overnight. Then, 0.10 g (2.63 mmol) of sodium borohydride was slowly added thereto, and stirred at room temperature for 20 minutes.The reaction was stopped, a colorless clear solution was obtained, and the solvent was concentrated under reduced pressure.45 mL of water was added to the residue, followed by extraction with dichloromethane (15 mL × 3), and organic solvent was collected.Concentrated under reduced pressure1-(6-chloropyridin-3-yl)-N-(3-chloro-4-fluorobenzyl)methylamine 0.29 g, yield 96.7percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid; | Step A: To a stirred solution of <strong>[39745-40-9]3-amino-2-chloro-6-methylpyridine</strong> (1 g, 7 mmol), 4-fluoro-3-chlorobenzaldehyde (0.98 mL, 8.4 mmol) and EtOAc (11 mL) at RT under argon was added TFA (1.1 mL, 14 mmol). The solution was stirred 5 min, then NaBH(OAc)3 (1.93 g, 9.1 mmol) was added in two portions. LC/MS indicates the reaction is complete after about 60 min. The reaction was diluted with EtOAc and treated with aqueous 10% NaOH (about 14 mL), until the pH was about 8. The aqueous layer was separated and extracted with EtOAc (2*). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the crude product as a dark thick oil. The material was triturated with MeOH and the solid dried under vacuum to give 2-chloro-N-(3-chloro-4-fluorobenzyl)pyridin-3-amine, 863 mg (43%) of the product as a light tan solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With N-Bromosuccinimide; 4-chloro-2-(trifluoromethyl)aniline; palladium diacetate; In 1,2-dichloro-ethane; trifluoroacetic acid; at 60℃; for 24h; | General procedure: Compound 1 (0.4 mol), N-bromosuccinimide (NBS) (0.48 mol, 85.4 mg), and Pd(OAc)2(10 mol%, 8.9 mg), 2-Amino-5-chlorobenzotrifluoride (20 mol%, 15.6 mg) were mixed withDCE (2.5 mL) and TFA (0.5 mL) solvent. The reaction mixture was stirred 24 h at 60 C. Aftercompletion of the reaction, the solution was concentrated in vacuo and purified by columnchromatography on silica gel using PE/DCM/EtOAc as eluent to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.5% | With sodium tetrahydroborate; acetic acid; In dichloromethane; at 20℃; | To a solution of compound 19 (111 mg, 0.5 mmol) in DCM (4 mL) was added<strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (79 mg, 0.5 mmol), glacial acetic acid (0.06 mL, 1.0mmol), sodium borohydride (113 mg, 3.0 mmol) and stirred at room temperatureovernight. The produced precipitate was filtered and the filtrate was purified bycolumn chromatography (P/E = 20:1) to give the title compound (121 mg, 66.5%) as awhite solid, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In chloroform; ethyl acetate; for 1h;Reflux; | General procedure: o-Phenylenediamine (1) (1.0 mmol) was dissolved in CHCl3(10 ml), then the corresponding aldehyde 3a-o (1.1 mmol),dimedone (2) (1.0 mmol), and T3P (Aldrich 50% solutionin EtOAc, 2.0 mmol) were added. The reaction mixturewas heated at reflux. After completion of the reaction(1-2 h), the mixture was cooled to room temperature andwashed with 10% NaHCO3 solution (10 ml) and H2O(10 ml). The organic phase was dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. Thecrude residue was purified by flash column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With potassium carbonate; In N,N-dimethyl acetamide; at 111 - 115℃; for 10h;Inert atmosphere; | To 21 4-thiobenzonitrile (1.054g, 7.80mmol) in DMA (7mL) was added 1b (1.23g, 7.98mmol) and K2CO3 (1.24g, 8.81mmol). The mixture was heated at 10h at 111-115C under nitrogen then poured into 25g of ice and NaOH (10%, 6mL). The mixture was extracted with EtOAc (3×20mL), dried on MgSO4, filtered and then the solvent removed by rotary evaporation to give a white solid which was recrystallized from acetonitrile to give the product (1.452g, 66%). IR (neat, cm-1) 3367, 3085, 3034, 2827, 2794, 2725, 2231, 1697, 1697, 1583, 1548, 905, 895, 852, 809. 1H NMR (400MHz, CHCl3-d1) delta 7.19 (1H, d, J=8.13), 7.53 (AA?, 2H), 7.66 (dd, J=8.11, 1.71, 1H), 7.69 (BB?, 2H), 7.93 (d, J=1.7, 1H), 9.94 (s, 1H). 13C NMR (100MHz, CHCl3-d1) delta 112.3, 118.0, 128.1, 130.7, 132.8, 134.7, 136.0, 138.6, 142.1, 198.8. Anal. Calcd for C14H8ClNOS: C, 61.43; H, 2.95; N, 5.12; Found: C, 61.60; H, 3.12; N, 5.05. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With potassium carbonate; In N,N-dimethyl acetamide; at 100℃; for 12h; | <strong>[34328-61-5]3-Chloro-4-fluorobenzaldehyde</strong> (2.0g, 0.012mol, Oakwood Chemical), 4-cyanophenol (1.73g, 0.0126mol, Oakwood Chemical) and anhydrous K2CO3 (1.65g, 0.012mol) were mixed in DMA (9.0mL) and heated to 100C (oil bath temperature). After 12h of stirring, the reaction mixture was cooled producing a dark red-brown viscous oil. NaOH (2M, 4mL) and 25g ice were added at rt. The reaction mixture was refrigerated for over 24h. A dark red-brown solid precipitated. This was then filtered and purified via Kugelrohr distillation (73.1-76.9C at 0.04mm Hg) followed by recrystallization from diethyl ether/hexane to give a white powder (1.004g, 29%). mp 76.6-78.2C. IR (cm-1) 3090, 3059, 2852, 2745, 2237, 1690, 1508, 1236, 1205, 963, 844, 736, 646. 1H NMR (400MHz, DMSO-d6): delta 7.07 (m, 2H), 7.48 (dt, J=1.6, 8.8Hz, 1H), 7.55 (dd, J=1.6, 9.6Hz, 1H), 7.79 (dd, J=2, 8.4Hz, 1H), 7.92 (d, J=9.3Hz, 1H), 9.96 (s, 1H). 13C NMR (100MHz, DMSO-d6): delta 108.9, 117.0, 119.3, 121.2, 126.3, 129.59, 129.63, 129.77, 132.3, 133.8, 146.97, 151.7, 154.2, 155.8, 189.3. Anal. Calcd for C14H7ClFNO2: C, 61.00; H, 2.56; N, 5.08. Found: C, 61.18; H, 2.75; N, 4.92. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate; In N,N-dimethyl acetamide; at 115℃; for 15h; | To <strong>[34328-61-5]3-chloro-4-fluorobenzaldehyde</strong> (6.433g, 0.0406mol) was added 4-hydroxybenzaldehyde (5.13g, 0.0420mol) and K2CO3. The mixture was heated in DMA for 15h at 115C and then poured onto ice (30g) and NaOH (10%, 3.5mL). The gummy solid was taken up into DCM (75mL) and then extracted with water (3×75mL). The DCM phase was dried over MgSO4 and the solvent was removed by rotary evaporation giving a viscous oil (13.1g). The oil was distilled by Kugelrohr (57 C at 0.2torr) to remove volatile materials. The residue (10.2g) was then distilled (177-211C at 0.05torr) to give a colorless viscous oil (8.95g, 86%) which gradually became a camphor-like solid. mp 50-52C. IR (neat, cm-1) 3067, 2839, 2730, 1694, 1605, 1583, 1502, 1485, 1246, 1210, 1189, 1156, 1054, 923, 906, 806, 820. 1H NMR (400MHz, CHCl3-d1) delta 7.13 (AA', 2H), 7.18 (d, J=8.4Hz, 1H), 7.81 (dd, J=8.4, 2.0Hz, 1H), 7.93 (BB', 2H), 8.04 (d, J=2.0Hz, 1H), 9.96 (s, 1H), 9.98 (s, 1H). 13C NMR (50MHz, CHCl3-d1) delta 116.6, 118.3, 121.0, 127.2, 129.7, 132.2, 132.6, 133.7, 156.1, 160.7, 189.4, 190.5. HRMS TOF MS ES+ (m/z): [M+] calcd for C14H9ClO3 260.0240; found 260.0239. The compound was carried on without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium carbonate; In N,N-dimethyl acetamide; at 115℃; for 22h;Inert atmosphere; | To 1b (0.634g, 4mmol) in DMA (4mL) was added 4-(1H-imidazol-1-yl)phenol (0.646g, 4mmol) and anhydrous K2CO3 (0.608g, 4.4mmol). The mixture was then heated at 115C for 22h under nitrogen. EtOAc (30mL) was added and the mixture was extracted with water (4×30mL), and then dried over MgSO4 to give an oil (0.780g, 65%). 1H NMR (400MHz, CHCl3-d1) delta 7.05 (d, J=8.4Hz, 1H), 7.18 (AA?, 2H), 7.23 (s, 1H), 7.27 (s, 1H), 7.44 (BB?, 2H), 7.75 (dd, J=8.4, 2.0Hz, 1H), 7.80 (s, 1H), 8.03 (d, J=2.0Hz, 1H), 9.93 (s, 1H). 13C NMR (100MHz, CHCl3-d1) delta 118.4, 118.8, 120.7, 123.5, 126.0, 129.7, 130.6, 132.2, 132.8, 134.2, 135.7, 154.4, 157.6, 189.5. The product was carried on without further purification. |
Tags: 34328-61-5 synthesis path| 34328-61-5 SDS| 34328-61-5 COA| 34328-61-5 purity| 34328-61-5 application| 34328-61-5 NMR| 34328-61-5 COA| 34328-61-5 structure
[ 117820-80-1 ]
3,5-Dichloro-4-fluorobenzaldehyde
Similarity: 0.97
[ 1160573-20-5 ]
4-Chloro-3,5-difluorobenzaldehyde
Similarity: 0.94
[ 718628-28-5 ]
4-(3-Chloro-4-fluorophenyl)benzaldehyde
Similarity: 0.92
[ 1181381-74-7 ]
3-(3-Chloro-4-fluorophenyl)benzaldehyde
Similarity: 0.92
[ 117820-80-1 ]
3,5-Dichloro-4-fluorobenzaldehyde
Similarity: 0.97
[ 1160573-20-5 ]
4-Chloro-3,5-difluorobenzaldehyde
Similarity: 0.94
[ 718628-28-5 ]
4-(3-Chloro-4-fluorophenyl)benzaldehyde
Similarity: 0.92
[ 1181381-74-7 ]
3-(3-Chloro-4-fluorophenyl)benzaldehyde
Similarity: 0.92
[ 117820-80-1 ]
3,5-Dichloro-4-fluorobenzaldehyde
Similarity: 0.97
[ 1160573-20-5 ]
4-Chloro-3,5-difluorobenzaldehyde
Similarity: 0.94
[ 718628-28-5 ]
4-(3-Chloro-4-fluorophenyl)benzaldehyde
Similarity: 0.92
[ 1181381-74-7 ]
3-(3-Chloro-4-fluorophenyl)benzaldehyde
Similarity: 0.92
[ 117820-80-1 ]
3,5-Dichloro-4-fluorobenzaldehyde
Similarity: 0.97
[ 1160573-20-5 ]
4-Chloro-3,5-difluorobenzaldehyde
Similarity: 0.94
[ 718628-28-5 ]
4-(3-Chloro-4-fluorophenyl)benzaldehyde
Similarity: 0.92
[ 1181381-74-7 ]
3-(3-Chloro-4-fluorophenyl)benzaldehyde
Similarity: 0.92
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 :