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CAS No. : | 118292-06-1 | MDL No. : | MFCD00902029 |
Formula : | C13H14S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KVHNVHGCQWNGLG-UHFFFAOYSA-N |
M.W : | 202.32 | Pubchem ID : | 10932539 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.38 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 0.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 63.25 |
TPSA : | 25.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -4.73 cm/s |
Log Po/w (iLOGP) : | 2.91 |
Log Po/w (XLOGP3) : | 3.95 |
Log Po/w (WLOGP) : | 3.52 |
Log Po/w (MLOGP) : | 4.19 |
Log Po/w (SILICOS-IT) : | 4.45 |
Consensus Log Po/w : | 3.8 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.9 |
Solubility : | 0.0255 mg/ml ; 0.000126 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.18 |
Solubility : | 0.0133 mg/ml ; 0.0000659 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -4.19 |
Solubility : | 0.0131 mg/ml ; 0.0000647 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 2.83 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
60% | Stage #1: With potassium carbonate; triphenylphosphine In toluene at 45 - 50℃; Stage #2: at 45 - 115℃; |
Charged ethyl 6-chloronicotinate (10.0 gm) in a R.B. Flask arranged with reflux condenser on oil bath, containing toluene (100 ml). Stirred and charged potassium carbonate (30.0 gm), triphenylphosphine (4.0 gm) and 5percent Pd/C (4.0 gm) to the reaction solution. Gradually raised the temperature to 45-50 C and maintained under stirring at 45 - 50°C for 2 hours. Charged 6-ethynyl-4,4-dimethylthiochromane (8 gm) and Copper iodide (0.05 gm) at 45-50°C. After charging, the reaction temperature was raised to 105- 115°C and maintained under stirring at 105-1150C temperature for 10 hours. After completion, the reaction mass was cooled to 25-300C and filtered the catalyst Pd/C. To the filtrate charged water (300 ml) and stirred for 30 min. Separated the organic layer and the aqueous layer was extracted with toluene (100 ml). Separated the organic layer and combined all organic layers. Concentrated the solvent under reduced pressure to get residual mass. Charged hexane (25 ml) to the residual mass and stirred at 25-300C for 1.0 hour. Cooled the reaction to -10 to 5°C and maintained for 1.0 hour. Filtered the solid Tazarotene and dried in oven till constant weight. Weight of Tazarotene = 8.3 gm percent Yield = 60.0 percent. |
9 g | Stage #1: With palladium on activated charcoal; potassium carbonate; sodium sulfate; triphenylphosphine In toluene at 50 - 55℃; for 2 h; Inert atmosphere Stage #2: With copper(l) iodide In toluene at 105 - 115℃; |
To 188 ml of toluene was added palladium on carbon (10 g) under N2 atmosphere. The mixture was heated to 105-115 °C to remove water by azeotropic distillation. Thereaction mass was cooled to 50-55 °C. To the above mixture, anhydrous sodium sulphate(12.5 g), anhydrous potassium carbonate (37.5 g), triphenylphosphine (5 g), ethyl 6-chioronicotinoate (12.5 g) and toluene (12.5 ml) were added at 50-55 °C and stirred for 2hours. To the above mixture, 4,4-dimethyl-6-ethynylthiochroman (10 g), cuprous iodide(0.06 g) and toluene (12.5 ml) were added and the reaction mixture was heated to 105-115 °C for 10-12 hours. The reaction mixture was cooled to 25-30 °C and water (125 ml)was added. The biphasi reaction mixture was filtered and from the filtrate, product enriched organic layer was separated. The organic layer was washed with water (2 X 65. ml) and brine solution (2 X 65 ml), dried over anhydrous sodium sulphate (5 g) and all the solvent was distilled off to get residual mass. The residual mass was dissolved in n20 heptane (50 ml) at 75-80 °C, which was treated with activated charcoal, neutral aluminaand filtered. The filtrate was stirred at 25-30 °C for 20 hours. The resulted solid was filtered off, washed with n-heptane (12.5 ml) and dried to yield 9 g of tazarotene. (HPLC purity of tazarotene— 97.64percent; Content of dimer impurity - 1.31percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | at -20℃; for 1 h; | EXAMPLE 4 Preparation of 4,4-dimethyl-6-ethynylthiochromane (2) from (8) Compound (8) (10.0 g, 45.87 mmol) is dissolved in N,N-dimethylformamide (150 ml), cooled to -20° C., added with phosphorous trichloride (4.0 ml, 45.87 mmol) and stirred for 1 hr, then the reaction crude is diluted with ethyl acetate (200 ml), washed with a sodium chloride saturated solution and with water. The organic phase is dried over sodium sulfate, filtered and concentrated evaporated in vacuo. The resulting solid is subjected to column chromatography (eluent:hexane/ethyl acetate=9:1) thereby obtaining 7.88 g of the desired product (yield=85percent; oil). 1H NMR (250 MHz) δ 1.35 (6H, s), 1.95 (2H, m), 3.05 (2H, m), 3.15 (1H, s), 7.13 (1H, d, J=8.6 Hz), 7.58 (1H, dd, J=8.6, 2.0 Hz), 7.99 (1H, d, J=2.0 Hz). |
85% | With phosphorus trichloride In N,N-dimethyl-formamide at -20℃; for 1 h; | Compound (8) (10.0 g, 45.87 mmol) is dissolved in N,N-dimethylformamide (150 ml), cooled to -20°C, added with phosphorous trichloride (4.0 ml, 45.87 mmol) and stirred for 1 hr, then the reaction crude is diluted with ethyl acetate (200 ml), washed with a sodium chloride saturated solution and with water. The organic phase is dried over sodium sulfate, filtered and concentrated evaporated in vacuo. The resulting solid is subjected to column chromatography (eluent: hexane/ethyl acetate = 9:1) thereby obtaining 7.88 g of the desired product (yield = 85percent; oil). 1H NMR (250 MHz) δ 1.35 (6H, s), 1.95 (2H, m), 3.05 (2H, m), 3.15 (1H, s), 7.13 (1H, d, J = 8.6 Hz), 7.58 (1H, dd, J = 8.6, 2.0 Hz), 7.99 (1H, d, J= 2.0 Hz), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With n-butyllithium In tetrahydrofuran; hexane at -5 - 35℃; | Charged 6-(l,l-dichloroethyl-4,4-dimethylthiochromane (30 gm) in R. B. Flask containing solvent tetrahydrofuran (200 ml). Stirred the reaction solution and cooled to -5°C. Charged gradually 1.6 M n-BuLi in hexane (203 ml) while maintaining reaction temperature between -5 to 50C. Raised the temperature of the reaction mass gradually to 250C and maintained under stirring at 25-35°C till completion of the reaction. Monitored the reaction on TLC. Charged ice cold water (600 ml) and stirred, charged solvent dichloromethane (600 ml) and continued stirring for 30 min. separated the organic layer and aqueous layer was again extracted with dichloromethane (100 ml). Combined the organic layer and dried over anhydrous sodium sulphate and distilled out solvent completely under reduced pressure below 400C to yield 6-ethynyl-4,4- dimethylthiochroman. Weight of oil = 20 gm. percent Yield = 90.00 percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
~ 87.68% | With sodium hydroxide; In 1,4-dioxane; water; at 80 - 90℃; for 2h; | In a 250 ml 4-necked round bottom flask fitted with a mechanical stirrer and reflux condenser, water (41.3 ml) and sodium hydroxide (5.22 g, 0.1305M) are added and heated to a temperature in the range of from about 80 C. to about 90 C. The reaction mixture is stirred, and a solution of 3-[4,4-dimethylthiochroman-6-yl]-3-chloro-2-propene-1-al (3.0 gm, 0.0113 M) is added dropwise in 1,4-dioxane (52.2 ml) under vigorous stirring. The reaction mixture is maintained at a temperature in the range of from about 80 C. to about 90 C. for about 2 hours. After completion of the reaction as determined by TLC, the solvents are distilled off and the product is extracted with ether (15 ml3). The ether layer is washed with brine (15 ml3). The organic layer is dried over sodium sulfate, and the solvent is distilled off to get an oily residue. The resulting crude oil is distilled under high vacuum and the vapors are collected at a temperature of about 126 C./0.2 mm as the main product. The main fraction appears as red viscous oil, which upon standing crystallized. Net wt of about 2.00 g, yield of about 87.68%; m.p. in the range of from about 69 C. to about 72 C., purity of about 98% (HPLC). The IR (neat) shows the following absorptions: 3200 cm-1 (CH-str), 2950 cm-1 (C=CH str), 2100 cm-1 (C=C). The 1H-NMR (CDCl3), TMS as internal standard shows the following signals ? 1.35 (6H,s), 1.92-1.98 (2H,m), 3.02-3.08 (3H,m), 7.13 (1H,d 8.6 Hz), 7.58 (1H,dd,J 8.6 Hz,2 Hz), 7.99 (1H,d,J 2 Hz). The CI/MS shows m/z 202 (M+). |
87.68% | With sodium hydroxide; In 1,4-dioxane; water; at 80 - 90℃; for 2h; | Step V: Preparation of 4,4-dimethyl-6-ethynylthiochroman; [0028] Into a 250 ml 4-necked round bottom flask fitted with a mechanical stirrer and reflux condenser, water (41.3ml) and sodium hydroxide (5.22g, 0.1305M) were added and heated to a temperature in the range of from about 80C to about 90C. The reaction mixture was stirred, and a solution of 3-[4,4-dimethylthiochroman-6-yl]-3-chloro-2- propene-1-al (3.0gm, 0.0113 M) was added dropwise in 1,4-dioxane (52.2ml) under vigorous stirring. The reaction mixture was maintained at a temperature in the range of from about 80C to about 90C for about 2 hours. After completion of the reaction as determined by TLC, the solvents were distilled off and the product was extracted with ether (15ml x 3). The ether layer was washed with brine (15ml x 3). The organic layer was dried over sodium sulfate, and the solvent was distilled off to get an oily residue. The resulting crude oil was distilled under high vacuum and the vapors were collected at a temperature of about 126C/0.2mm as the main product. The main fraction appeared as a red viscous oil, which upon standing crystallized. The product showed a net weight of about 2.00 g, a yield of about 87.68%; a m. p. in the range of from about 69C to about 72C, and a purity of about 98% (HPLC). The IR (neat) showed the following absorptions: 3200 cm-1 (C-H-str), 2950 cm-1 (-C=C-H str), 2100 cm-1 (-C=C-). The 1H- NMR (CDC13), TMS as internal standard showed the following signals 8 1.35 (6H, s), 1.92-1.98 (2H, m), 3.02-3.08 (3H, m), 7.13 (lH,d 8.6 Hz), 7.58 (lH,dd,J 8.6Hz, 2Hz), 7.99 (lH,d,J 2Hz). The CI/MS showed m/z 202 (M+). |
87.68% | With sodium hydroxide; In 1,4-dioxane; water; at 80 - 90℃; for 2h; | Into a 250 ml 4-necked round bottom flask fitted with a mechanical stirrer and reflux condenser, water (41.3 ml) and sodium hydroxide (5.22 g, 0.1305 M) were added and heated to a temperature in the range of from about 80 C. to about 90 C. The reaction mixture was stirred, and a solution of 3-[4,4-dimethylthiochroman-6-yl]-3-chloro-2-propene-1-al (3.0 gm, 0.0113 M) was added drop wise in 1,4-dioxane (52.2 ml) under vigorous stirring. The reaction mixture was maintained at a temperature in the range of from about 80 C. to about 90 C. for about 2 hours. After completion of the reaction as determined by TLC, the solvents were distilled off and the product was extracted with ether (15 ml×3). The ether layer was washed with brine (15 ml×3). The organic layer was dried over sodium sulfate, and the solvent was distilled off to get an oily residue. The resulting crude oil was distilled under high vacuum and the vapors were collected at a temperature of about 126 C./0.2 mm as the main product. The main fraction appeared as a red viscous oil, which upon standing crystallized. The product showed a net weight of about 2.00 g, a yield of about 87.68%; a m.p. in the range of from about 69 C. to about 72 C., and a purity of about 98% (HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | EXAMPLE 2; Step I: Preparation of tazarotene hydrochloride salt; [0029] Into a 2L 4-neck round bottom flask, dimethyl sulfoxide (700 ml), palladium chloride (3.83 g), and triphenyl phosphine (14.06 g) were added under stirring under a nitrogen atmosphere at room temperature and the temperature was slowly raised to about 145C. The solution became clear at a temperature of about 145C after about 10 minutes. Then the solution was slowly cooled to room temperature over about 45 minutes. In a separate 2L 4-neck round bottom flask, ethyl-6-chloro-3-nicotinate (96.40 g), 4,4- dimethy-6-ethynylthiochroman (100 g) obtained in Example 1, cuprous iodide (6.5 g), and triethanolamine (TEA) (165 g) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for about 2 to about 5 minutes and the contents from the other round bottom flask (now containing bis(triphenylphosphine) palladium (II) chloride formed in situ) were added to the reaction mixture. The temperature was slowly raised to a temperature of about 98C and maintained for about three hours. After the reaction was completed as determined by TLC, the reaction mixture was cooled to a temperature of about 20C to form tazarotene. The reaction mixture was then filtered, and the resulting cake was washed with DMSO (20 ml). All the filtrate was combined, and ethyl acetate (1 L) was added to the filtrate. The solution was washed with water (3 x 400 ml). The organic layer was separated, and the ethyl acetate was distilled out completely (KFR < 0.2%) under vacuum. An ethyl acetate HCI solution (1000 ml) was added to the residue within 15 minutes. The reaction mixture was maintained for 2 hours at room temperature to form tazarotene hydrochloride salt. The tazarotene hydrochloride solid was filtered and washed with ethyl acetate (2x150 ml). The solid was dried at room temperature for about 6 hours (to remove excess HCl gas). Tazarotene hydrochloride salt appears as a yellow solid after drying. The solid weighed about 140 g. Yield = 81 %, m. p. 112-114 C, purity 99.6 % (by HPLC). [0030] The IR (KBr) spectrum showed stretching at 2204 cm-1 and 1720 cm-1. The ¹H NMR (CDCl3) showed signals at No. 9.2(s,lH), 8.6(lH,d), 7.8 (d,2H), 7.4(d,lH), 4.4 (q,2H), 3.1(dd,2H), 2.0 (dd,2H), 1.5-1.6 (t,3H), 1.2-1.4 (s,6H). The CI Mass showed M+. m/z 352. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; potassium carbonate;tetrakis(triphenylphosphine) palladium(0); triphenylphosphine; In tetrahydrofuran; for 5h;Heating / reflux;Product distribution / selectivity; | Example 6; Preparation of ethyI-6-[2- (4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate, compound of formula 1; .25 g (0.135 mol) of ethyl-6-halonicotinoate, was mixed with 30 g ( 0.148 moles) 4,4- Dimethyl-6-ethynylthiochrornan, 23.4g( 0.020 moles) tetrakistriphenylphosphine palladium , 55.85g (0.404 mol) anhydrous K2CO3 , 10.6 g ( 0.040 moles) triphenylphosphine , 1.33 g ( 0.052 moles ) cuprous iodide in 500 ml tetrahydrofuran. EPO <DP n="22"/>The reaction mixture was heated at reflux temperature and maintained for 5 hours with | |
With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; In tetrahydrofuran; at 25 - 30℃; for 24h;Product distribution / selectivity; | Comparative Example; Preparation of ethyl-6~[2- (4,4-dimethylthiochroman-6-yi)ethynyl]nicotinate, compound of formula 1.; To 1 g (0.005 mol) Ethyl 6-halonicotinoate, compound of formula 5 in 10 ml of dry tetrahydrofuran was added 0.19 g Pd (PPh3)2Cl2 , 0.0123 g (0.000065 mol) CuI, 0.036 g (0.00013 mol )PPh3 and 1.12 ml(0.008 mol) triethylamine at 25-3O0C5 followed by gradual addition of a solution of 1.64 g (0,008 mol) of 4,4-dimethyl- 6- ethynylthiochroman, compound of formula 4, in 10 ml tetrahydrofuran at the same temperature. The above reaction mixture is stirred for 24 hours at the same temperature. Concentrate the reaction mixture to obtain a residual mass. The reaction was monitored by HPLC |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The syrupy mass was dissolved in 500 ml tetrahydrofuran. To this was added 225 ml triethylamine and 65 g ( 0.25 moles) iodine and maintained for 2 hours at room temperature with TLC control. The reaction mass was concentrated to obtain thick syrupy mass. To the reaction mixture was added 250 ml dichloromethane followed by 125 ml 2NHC1. The organic layer was separated and washed with 250 ml sodium thiosulfate EPO <DP n="21"/>solution (5% w/v) followed by Aq1NaCl wash. The organic layer was concentrated and to the residue was added 300 ml ethanol followed by 59 g ( 1.05 moles) of potassium hydroxide. The reaction mixture was refiuxed for 8 hours with TLC control. The solvent was distilled off and to the residual mass was added 250 ml hexane and washed the product enriched hexane phase with 175 ml 6N HCl followed by water wash. The product enriched hexane phase was concentrated to obtain a thick residue which was then subjected to high vacuum distillation at 1000C at < 0.5mmhg, to obtain 12.5g compound of formula 4, 4,4-Dimethyl-6-ethynylthiochroman with purity > 98% by gas chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N,N-dimethyl-formamide; phosphorus trichloride; at -20℃; for 1h; | EXAMPLE 4 Preparation of 4,4-dimethyl-6-ethynylthiochromane (2) from (8) Compound (8) (10.0 g, 45.87 mmol) is dissolved in N,N-dimethylformamide (150 ml), cooled to -20 C., added with phosphorous trichloride (4.0 ml, 45.87 mmol) and stirred for 1 hr, then the reaction crude is diluted with ethyl acetate (200 ml), washed with a sodium chloride saturated solution and with water. The organic phase is dried over sodium sulfate, filtered and concentrated evaporated in vacuo. The resulting solid is subjected to column chromatography (eluent:hexane/ethyl acetate=9:1) thereby obtaining 7.88 g of the desired product (yield=85%; oil). 1H NMR (250 MHz) delta 1.35 (6H, s), 1.95 (2H, m), 3.05 (2H, m), 3.15 (1H, s), 7.13 (1H, d, J=8.6 Hz), 7.58 (1H, dd, J=8.6, 2.0 Hz), 7.99 (1H, d, J=2.0 Hz). |
85% | With phosphorus trichloride; In N,N-dimethyl-formamide; at -20℃; for 1h; | Compound (8) (10.0 g, 45.87 mmol) is dissolved in N,N-dimethylformamide (150 ml), cooled to -20C, added with phosphorous trichloride (4.0 ml, 45.87 mmol) and stirred for 1 hr, then the reaction crude is diluted with ethyl acetate (200 ml), washed with a sodium chloride saturated solution and with water. The organic phase is dried over sodium sulfate, filtered and concentrated evaporated in vacuo. The resulting solid is subjected to column chromatography (eluent: hexane/ethyl acetate = 9:1) thereby obtaining 7.88 g of the desired product (yield = 85%; oil). 1H NMR (250 MHz) delta 1.35 (6H, s), 1.95 (2H, m), 3.05 (2H, m), 3.15 (1H, s), 7.13 (1H, d, J = 8.6 Hz), 7.58 (1H, dd, J = 8.6, 2.0 Hz), 7.99 (1H, d, J= 2.0 Hz), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; diisopropylamine; lithium diisopropyl amide; In tetrahydrofuran; hexane; water; ethyl acetate; | EXAMPLE 4 4.4-Dimethyl-6-ethynylthiochroman To a solution of 1.441 g (14.2405 mmol) of diisopropylamine in 30 ml dry tetrahydrofuran under argon at -78 C. was added dropwise 9 ml of 1.6M (14.4 mmol) n-butyllithium in hexane. After stirring this solution at -78 C. for 1 hour, it was treated dropwise with a solution of 2.95 g (13.389 mmol) of 4,4-dimethyl-6-acetylthiochroman in 5 ml of dry tetrahydrofuran. After another hour of stirring at -78 C., the solution was treated with 2.507 g (14.53 mmol) of diethyl chlorophosphate and brought to room temperature, where it was stirred for 3.75 hours. This solution was then transferred using a double ended needle to a solution of lithium diisopropylamide (prepared as above using 2,882 g (28,481 mmol) of diisopropylamine and 18 ml of 1.6M (28.8 mmol) n-butyllithium in hexane) in 60 ml dry tetrahydrofuran at -78 C. The cooling bath was removed and the solution stirred at room temperature for 15 hours, then quenched with water and acidified to pH 1 with 3N hydrogen chloride. The mixture was stirred at room temperature for 12 hours, then treated with 65 ml water and 33 ml conc. hydrogen chloride and heated at reflux for 0.5 hours. After being cooled to room temperature, the organic layer was separated and the aqueous layer extracted with 5*50 ml benzene. The recovered organic fractions were combined and washed with 5% sodium carbonate solution, water, saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) followed by kugelrohr distillation (150 C., 0.7 mm) to give the captioned compound as a pale yellow oil. PMR (CDCl3): delta 1.35 (6H, s), 1.92-1.98 (2H, m) 2.54 (3H, s), 3.02-3.08 (2H, m), 7.13 (1H, d, J~8.6 Hz), 7.58 (1H, dd, J~8.6 Hz, 2 Hz), 7.99 (1H, d, J~2 Hz). | |
With n-butyllithium; diisopropylamine; lithium diisopropyl amide; In tetrahydrofuran; hexane; water; ethyl acetate; | EXAMPLE 4 4,4-Dimethyl-6-ethynylthiochroman To a solution of 1.441 g (14.2405 mmol) of diisopropylamine in 30 ml dry tetrahydrofuran under argon at -78 C. was added dropwise 9 ml of 1.6M (14.4 mmol) n-butyllithium in hexane. After stirring this solution at -78 C. for 1 hour, it was treated dropwise with a solution of 2.95 g (13.389 mmol) of 4,4-dimethyl-6-acetylthiochroman in 5 ml of dry tetrahydrofuran. After another hour of stirring at -78 C., the solution was treated with 2.507 g (14.53 mmol) of diethyl chlorophosphate and brought to room temperature, where it was stirred for 3.75 hours. This solution was then transferred using a double ended needle to a solution of lithium diisopropylamide (prepared as above using 2.882 g (28.481 mmol) of diisopropylamine and 18 ml of 1.6M (28.8 mmol) n-butyllithium in hexane) in 60 ml dry tetrahydrofuran at -78 C. The cooling bath was removed and the solution stirred at room temperature for 15 hours, then quenched with water and acidified to pH 1 with 3N hydrogen chloride. The mixture was stirred at room temperature for 12 hours, then treated with 65 ml water and 33 ml conc. hydrogen chloride and heated at reflux for 0.5 hours. After being cooled to room temperature, the organic layer was separated and the aqueous layer extracted with 5*50 ml benzene. The recovered organic fractions were combined and washed with 5% sodium carbonate solution, water, saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) followed by kugelrohr distillation (150 C., 0.7 mm) to give the captioned compound as a pale yellow oil. PMR (CDCl3): delta1.35 (6H, s), 1.92-1.98 (2H, m) 2.54 (3H, s), 3.02-3.08 (2H, m), 7.13 (1H, d, J~8.6 Hz), 7.58 (1H, dd, J~8.6 Hz, 2 Hz), 7.99 (1H, d, J~2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium;tetrakis(triphenylphosphine)palladium (0); zinc(II) chloride; In tetrahydrofuran; hexane; ethyl acetate; | EXAMPLE 6 Ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl]nicotinate Reaction vessels used in this procedure were flame dried under vacuum and all operations carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 465.7 mg (2.3019 mmol) of <strong>[118292-06-1]4,4-dimethyl-6-ethynyl-thiochroman</strong> in 4 ml of dry tetrahydrofuran at 0 C. was added dropwise 1.5 ml of 1.6M (2.4 mmol) n-butyllithium in hexane. This was stirred at 0 C. for 10 minutes and at room temperature for 10 minutes, cooled again to 0 C. and then treated with a solution of 330 mg (2.4215 mmol) of fused ZnCl2 in 4 ml dry tetrahydrofuran using a double ended needle. Thereafter the solution was stirred at 0 C. for 30 minutes, then at room temperature for 10 minutes. A solution of 426.3 mg (2.2967 mmol) of ethyl 6-chloronicotinoate (from Example 5) in 4 ml dry tetrahydrofuran was transferred by double ended needle into a suspension of 430 mg (0.37 mmol) of tetrakistriphenylphosphine palladium in 4 ml dry tetrahydrofuran and stirred at room temperature for 10 minutes, then treated by double ended needle with the solution of the alkynylzinc prepared above. This mixture was stirred at room temperature for 18 hours, then quenched with 100 ml water. Product was recovered by extraction with 3*75 ml ether. Ether fractions were combined and washed with saturated NaCl solutions and dried (mgSO4). Solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexane) followed by HPLC (Whatman Partisil M-9 10/50; 4% ethyl acetate in hexane) to give the title compound as a white solid. PMR (CDCl3): delta 1.36 (6H, s), 1.45 (3H, t, J~7 Hz), 1.96-2.00 (2H, m), 3.05-3.09 (2H, m), 4.45 (2H, q, J~7 Hz), 7.11 (1H, d, J~8.4 Hz), 7.29 (1H, dd, J~8.4 Hz, 2.2 Hz), 7.59 (1H, d, J~7.8 Hz), 7.66 (1H, d, J~2.2 Hz), 8.30 (1H, dd, J~7.8 Hz, 2.3 Hz), 9.22 (1H, d, J~2.3 Hz). | |
With n-butyllithium;tetrakis(triphenylphosphine)palladium (0); zinc(II) chloride; In tetrahydrofuran; hexane; ethyl acetate; | EXAMPLE 6 Ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate Reaction vessels used in this procedure were flame dried under vacuum and all operations carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 465.7 mg (2.3019 mmol) of <strong>[118292-06-1]4,4-dimethyl-6-ethynyl-thiochroman</strong> in 4 ml of dry tetrahydrofuran at 0 C. was added dropwise 1.5 ml of 1.6M (2.4 mmol) n-butyllithium in hexane. This was stirred at 0 C. for 10 minutes and at room temperature for 10 minutes, cooled again to 0 C. and then treated with a solution of 330 mg (2.4215 mmol) of fused ZnCl2 in 4 ml dry tetrahydrofuran using a double ended needle. Thereafter the solution was stirred at 0 C. for 30 minutes, then at room temperature for 10 minutes. A solution of 426.3 mg (2.2967 mmol) of ethyl 6-chloronicotinoate (from Example 5) in 4 ml dry tetrahydrofuran was transferred by double ended needle into a suspension of 430 mg (0.37 mmol) of tetrakistriphenylphosphine palladium in 4 ml dry tetrahydrofuran and stirred at room temperature for 10 minutes, then treated by double ended needle with the solution of the alkynylzinc prepared above. This mixture was stirred at room temperature for 18 hours, then quenched with 100 ml water. Product was recovered by extraction with 3*75 ml ether. Ether fractions were combined and washed with saturated NaCl solutions and dried (mgSO4). Solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexane) followed by HPLC (Whatman Partisil M-9 10/50; 4% ethyl acetate in hexane) to give the title compound as a white solid. PMR (CDCl3): delta1.36 (6H, s), 1.45 (3H, t, J~7 Hz), 1.96-2.00 (2H, m), 3.05-3.09 (2H, m), 4.45 (2H, q, J~7 Hz), 7.11 (1H, d, J~8.4 Hz), 7.29 (1H, dd, J~8.4 Hz, 2.2 Hz), 7.59 (1H, d, J~7.8 Hz), 7.66 (1H, d, J~2.2 Hz), 8.30 (1H, dd, J~7.8 Hz, 2.3 Hz), 9.22 (1H, d, J~2.3 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; In tetrahydrofuran; hexane; | (b) Preparation of (4,4-dimethylthiochroman-6-yl)acetylene 7.7 g (21.2 mmol) of 2,2-dibromo-1-(4,4-dimethylthiochroman-6-yl)ethylene and 80 ml of THF were introduced into a three-necked flask under a stream of nitrogen. 17 ml (26.6 mmol) of an n-butyllithium solution (2.5M in hexane) were added dropwise at -78 C. and the mixture was permitted to heat to room temperature for one hour. The reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with heptane. 3.9 g (90%) of the expected acetylene derivative were recovered in the form of a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; triethylamine; | Alternative synthesis: The title compound of Example 6, ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate, was also prepared as follows. A solution of 15.4 g (76.2 mmol) of <strong>[118292-06-1]4,4-dimethyl-6-ethynylthiochroman</strong> and 14.0 g (75.5 mmol) of ethyl-6-chloronicotinate in 35 ml of freshly distilled triethylamine was degassed and then treated under nitrogen with a finely powdered mixture of 1 g (5.25 mmol) of high purity cuprous iodide and 2 g (2.85 mmol) of bis(triphenylphosphine) palladium (II) chloride. The mixture was heated under nitrogen at 55 C. for 20 hours and then cooled to room temperature. The triethylamine was then removed under vacuum and the residue was diluted with 200 ml of a 1:4 mixture of ethyl acetate and hexanes. This mixture was filtered through silica and the filtrate concentrated in vacuo. The resultant residue was purified by flash chromatography (silica gel; 15% ethyl acetate in hexanes) and recrystallized from a mixture of ethyl acetate and hexanes to give the title compound as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; diisopropylamine; lithium diisopropyl amide; In tetrahydrofuran; hexane; | EXAMPLE 4 4,4-Dimethyl-6-ethynylthiochroman To a solution of 1.441 g (14.2405 mmol) of diisopropylamine in 30 ml dry tetrahydrofuran under argon at -78 C. was added dropwise 9 ml of 1.6M (14.4 mmol) n-butyl lithium in hexane. After stirring this solution at -78 C. for 1 hour, it was treated dropwise with a solution of 2.95 g (13.389 mmol) of 4,4-dimethyl-6-acetylthiochroman (from Example 3) in 5 ml of dry tetrahydrofuran. After another hour of stirring at -78 C., the solution was treated with 2.507 g (14.53 mmol) of diethyl chlorophosphate and brought to room temperature, where it was stirred for 3.75 hours. This solution was then transferred using a double ended needle to a solution of lithium diisopropylamide [prepared using 2.882 g (28.481 mmol) of diisopropylamine and 18 ml of 1.6M (28.8 mmol) n-butyllithium in hexane] in 60 ml dry tetrahydrofuran at -78 C. The cooling bath was removed and the solution stirred at room temperature for 15 hours, then quenched with water and acidified to pH 1 with 3N hydrogen chloride. The mixture was extracted with 5*50 ml pentane and the combined organic fractions washed with 3N hydrogen chloride, water, saturated NaHCO3 and saturated NaCl, then dried (MgSO 4). Solvent was then removed in vacuo and the residue purified by kugelrohr distillation (100 C., 0.7 mm) to give the title compound as a pale yellow solid. PMR (CDCl3): delta 1.34 (6H,s), 1.94-1.99 (2H, m), 3.04-3.08 (3H, m), 7.06 (1H, d, J~8.4 Hz), 7.17 (1H, dd, J~8.4 Hz, 2.1 Hz), 7.51 (1H, d, J~2.1 Hz). | |
With n-butyllithium; diisopropylamine; lithium diisopropyl amide; In tetrahydrofuran; hexane; | EXAMPLE 4 4,4-Dimethyl-6-ethynylthiochroman To a solution of 1.441 g (14.2405 mmol) of diisopropylamine in 30 ml dry tetrahydrofuran under argon at -78C was added dropwise 9 ml of 1.6 M (14.4 mmol) n-butyl lithium in hexane. After stirring this solution at -78C for 1 hour, it was treated dropwise with a solution of 2.95 g (13.389 mmol) of 4,4-dimethyl-6-acetylthiochroman (from Example 3) in 5 ml of dry tetrahydrofuran. After another hour of stirring at -78C, the solution was treated with 2.507 g (14.53 mmol) of diethyl chlorophosphate and brought to room temperature, where it was stirred for 3.75 hours. This solution was then transferred using a double ended needle to a solution of lithium diisopropylamide [prepared using 2.882 g (28.481 mmol) of diisopropylamine and 18 ml of 1.6 M (28.8 mmol) n-butyllithium in hexane] in 60 ml dry tetrahydrofuran at -78C. The cooling bath was removed and the solution stirred at room temperature for 15 hours, then quenched with water and acidified to pH 1 with 3N hydrogen chloride. The mixture was extracted with 5 * 50 ml pentane and the combined organic fractions washed with 3N hydrogen chloride, water, saturated NaHCO3 and saturated NaCl, then dried (MgSO4). Solvent was then removed in vacuo and the residue purified by kugelrohr distillation (100C, 0.7 mm) to give the title compound as a pale yellow solid. PMR (CDCl3): delta 1.34 (6H,s), 1.94-1.99 (2H, m), 3.04-3.08 (3H, m), 7.06 (1H, d, J ~ 8.4 Hz), 7.17 (1H, dd, J ~ 8.4 Hz, 2.1 Hz), 7.51 (1H, d, J ~ 2.1Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; n-butyllithium;tetrakis(triphenylphosphine)palladium (0); zinc(II) chloride; In tetrahydrofuran; hexane; ethyl acetate; | EXAMPLE 6 Ethyl 4-[4,4-dimethylthiochroman-6-yl-ethynyl]benzoate Reaction vessels used in this procedure were flame dried under vacuum and all operations carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 533.9 mg (2.6389 mmol) of <strong>[118292-06-1]4,4-dimethyl-6-ethynylthiochroman</strong> (from Example 4) in 4 ml of dry tetrahydrofuran at 0C was added dropwise 1.7 ml of 1.6 M (2.72 mmol) n-butyl lithium in hexane. This was stirred at 0C for 10 minutes and at room temperature for 15 minutes, cooled again to 0C and then treated with a solution of 410 mg (3.005 mmol) of fused ZnCl2 in 4 ml dry tetrahydrofuran using a double ended needle. Thereafter, the solution was stirred at 0C for 45 minutes, then at room temperature for 20 minutes. A solution of 724.4 mg (2.6243 mmol) of ethyl 4-iodobenzoate (from Example 5) in 4 ml dry tetrahydrofuran was transferred by double ended needle into a suspension of 520 mg (0.45 mmol) of tetrakistriphenylphosphine palladium in 5 ml dry tetrahydrofuran and stirred at room temperature for 20 minutes, then treated by double ended needle with the solution of the alkynyl zinc chloride prepared above. This mixture was stirred at room temperature for 18 hours, then quenched with ice and 30 ml 3N hydrogen chloride. Product was recovered by extraction with 3 * 75 ml ether. Ether fractions were combined and washed successively with saturated NaHCO3 and saturated NaCl solutions and dried (MgSO4). Solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexane) followed by HPLC (Whatman Partisil M-9 10/50; 4% ethyl acetate in hexane) to give the title compound as a colorless oil. PMR (CDCl3): delta 1.36 (6H), 1.42 (3H, t), J ~ 7Hz), 1.93-1.99 (2H, m), 3.03-3.08 (2H, m), 4.40 (2H, q, J ~ 7Hz), 7.09 (1H, d, J ~ 8.4Hz), 7.22 (1H, dd, J ~ 8.4 Hz, 2.1 Hz), 7.56 (1H, d, J ~ 2.1Hz), 7.59 (2H, d, J ~ 7.8Hz), 8.04 (2H, d, J ~ 7.8Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Into a 500 ml 4 necked round bottom flask fitted with a mechanical stirrer and a reflux condenser was charged dimethyl sulfoxide (150 ml), PdCl2 (0.180 g), and triphenyl phosphine (0.825 g) under nitrogen atmosphere. The temperature was raised to 140 to 145 C. and maintained for 30 to 35 minutes. The reaction mixture was cooled to room temperature and added to a mixture of 6-chloronicotinonitrile (3.5 g), <strong>[118292-06-1]4,4-dimethyl-6-ethynylthiochroman</strong> (4.5 g) in dimethyl sulfoxide (50 ml). The reaction mixture was stirred for 20 to 25 minutes followed by the addition of cuprous iodide (0.325 g) and triethylamine (10 g). The temperature was slowly raised to 70 to 75 C. and maintained for 3 to 5 hours. After completion of the reaction, the reaction mass was cooled to room temperature and filtered to remove insolubles. Ethyl acetate (75 ml) was added to the filtrate and the organic layer was quenched in water (200 ml). The ethyl acetate layer was separated, washed with water and concentrated to obtain 6-[2-(4,4-Dimethylthiochroman-6-yl)ethynyl]nicotinonitrile (1.5 g). The IR (KBr) showed the following absorptions: 2955 cm-1 (C-H str), 2197 cm-1 (CN str); 1H NMR (CDCl3)-TMS as an internal standard shows the following signals delta 1.336 (6H, s), 1.995 (3H, t), 3.051 (3H, t), 7.089 (1H, d), 7.24 (1H, d), 7.6 (2H, m), 7.9(1H, dd) and 8.834 (1H, s). The CI/MS shows m/z 305 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Charged ethyl 6-chloronicotinate (10.0 gm) in a R.B. Flask arranged with reflux condenser on oil bath, containing toluene (100 ml). Stirred and charged potassium carbonate (30.0 gm), triphenylphosphine (4.0 gm) and 5% Pd/C (4.0 gm) to the reaction solution. Gradually raised the temperature to 45-50 C and maintained under stirring at 45 - 50C for 2 hours. Charged <strong>[118292-06-1]<strong>[118292-06-1]6-ethynyl-4,4-dimethylthiochroman</strong>e</strong> (8 gm) and Copper iodide (0.05 gm) at 45-50C. After charging, the reaction temperature was raised to 105- 115C and maintained under stirring at 105-1150C temperature for 10 hours. After completion, the reaction mass was cooled to 25-300C and filtered the catalyst Pd/C. To the filtrate charged water (300 ml) and stirred for 30 min. Separated the organic layer and the aqueous layer was extracted with toluene (100 ml). Separated the organic layer and combined all organic layers. Concentrated the solvent under reduced pressure to get residual mass. Charged hexane (25 ml) to the residual mass and stirred at 25-300C for 1.0 hour. Cooled the reaction to -10 to 5C and maintained for 1.0 hour. Filtered the solid Tazarotene and dried in oven till constant weight. Weight of Tazarotene = 8.3 gm % Yield = 60.0 %. | |
9 g | To 188 ml of toluene was added palladium on carbon (10 g) under N2 atmosphere. The mixture was heated to 105-115 C to remove water by azeotropic distillation. Thereaction mass was cooled to 50-55 C. To the above mixture, anhydrous sodium sulphate(12.5 g), anhydrous potassium carbonate (37.5 g), triphenylphosphine (5 g), ethyl 6-chioronicotinoate (12.5 g) and toluene (12.5 ml) were added at 50-55 C and stirred for 2hours. To the above mixture, <strong>[118292-06-1]4,4-dimethyl-6-ethynylthiochroman</strong> (10 g), cuprous iodide(0.06 g) and toluene (12.5 ml) were added and the reaction mixture was heated to 105-115 C for 10-12 hours. The reaction mixture was cooled to 25-30 C and water (125 ml)was added. The biphasi reaction mixture was filtered and from the filtrate, product enriched organic layer was separated. The organic layer was washed with water (2 X 65. ml) and brine solution (2 X 65 ml), dried over anhydrous sodium sulphate (5 g) and all the solvent was distilled off to get residual mass. The residual mass was dissolved in n20 heptane (50 ml) at 75-80 C, which was treated with activated charcoal, neutral aluminaand filtered. The filtrate was stirred at 25-30 C for 20 hours. The resulted solid was filtered off, washed with n-heptane (12.5 ml) and dried to yield 9 g of tazarotene. (HPLC purity of tazarotene- 97.64%; Content of dimer impurity - 1.31%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With n-butyllithium; In tetrahydrofuran; hexane; at -5 - 35℃;Product distribution / selectivity; | Charged 6-(l,l-dichloroethyl-4,4-dimethylthiochromane (30 gm) in R. B. Flask containing solvent tetrahydrofuran (200 ml). Stirred the reaction solution and cooled to -5C. Charged gradually 1.6 M n-BuLi in hexane (203 ml) while maintaining reaction temperature between -5 to 50C. Raised the temperature of the reaction mass gradually to 250C and maintained under stirring at 25-35C till completion of the reaction. Monitored the reaction on TLC. Charged ice cold water (600 ml) and stirred, charged solvent dichloromethane (600 ml) and continued stirring for 30 min. separated the organic layer and aqueous layer was again extracted with dichloromethane (100 ml). Combined the organic layer and dried over anhydrous sodium sulphate and distilled out solvent completely under reduced pressure below 400C to yield 6-ethynyl-4,4- dimethylthiochroman. Weight of oil = 20 gm. % Yield = 90.00 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine |
Yield | Reaction Conditions | Operation in experiment |
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73% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; for 22h;Inert atmosphere; | Embodiment 11 ethyl 2-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrimidin-5-carboxylate 4,4-Dimethyl-6-ethynylthiochroman (202.8mg, 1.0mmol) and ethyl 2-chloropyrimidin-carboxylate (156mg, 0.83mmol) used as raw material were added to a flask, followed by addition of Pd(PPh3)2Cl2 (42mg, 0.06mmol) and CuI (19mg, 0.1mmol). After the flask was purged with argon for 3 times to remove oxygen, 2mL dry DMF and 0.3mL dry Et3N were added via syringe. The reaction was continued at 80C for 22 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc = 15:1) to give WYC-203(257mg, 73%). 1H NMR (500 MHz, CDCl3) delta 9.24 (s, 2H), 7.69 (d, J = 1.7 Hz, 1H), 7.33 (dd, J = 8.2, 1.8 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 4.45 (q, J = 7.1 Hz, 1H), 3.11 - 2.99 (m, 2H), 1.99 - 1.92 (m, 2H), 1.43 (t, J = 7.1 Hz, 3H), 1.33 (s, 6H); 13C NMR (126 MHz, CDCl3) delta 163.52, 158.44, 155.85, 142.39, 136.48, 131.36, 130.15, 126.83, 121.88, 115.96, 92.65, 87.97, 62.14, 37.09, 33.14, 30.05, 23.43, 14.38. ESI(+)-MS: 353.2 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 50℃; for 22h;Inert atmosphere; | Embodiment 10 2-cyano-5-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrimidine Commercially available 4,4-dimethyl-6-ethynylthiochroman (202.8mg, 1.0mmol) and <strong>[38275-56-8]2-cyano-5-chloropyrimidine</strong> (93mg, 0.67mmol) used as raw material were added to a flask, followed by addition of Pd(PPh3)2Cl2 (23mg, 0.03mmol) and CuI (19mg, 0.1mmol). After the flask was purged with argon for 3 times to remove oxygen, 2mL dry DMF and 0.25mL dry Et3N were added via syringe. The reaction was continued at 50C for 22 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc = 30:1) to give WYC-202 (133mg, 65%). 1H NMR (400 MHz, CDCl3) delta 8.89 (s, 2H), 7.55 (d, J = 1.6 Hz, 1H), 7.21 (dd, J = 8.2, 1.7 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 3.11 - 3.03 (m, 2H), 2.01 - 1.93 (m, 2H), 1.35 (s, 6H); 13C NMR (126 MHz, CDCl3) delta 159.21, 142.59, 141.79, 136.33, 130.15, 129.31, 126.98, 122.88, 116.13, 115.70, 101.85, 81.24, 37.02, 33.15, 30.02, 23.42. ESI(+)-MS: 306.3 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; isopropylamine; In N,N-dimethyl-formamide; at 20℃; for 8h;Inert atmosphere; | Embodiment 1 methyl 4-((4,4-dimethylthiochroman-6-yl)ethynyl)-2-hydroxybenzoate Commercially available 6-ethynyl-4,4-dimethylbenzothiopyran (202.8mg, 1mmol) and methyl 2-hydroxy-4-iodobenzoate (292. 1mg, 1mmol) used as raw material were added to a flask, followed by addition of Pd(PPh3)2Cl2 (14mg, 0.02mmol) and CuI (7.6mg, 0.04mmol). After the flask was purged with argon for 3 times to remove oxygen, 2mL dry DMF and 0.2mL dry iPr2NH were added via syringe. The reaction was continued at room temperature for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution, and the mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc = 100:1 to 20:1) to give WYC-101 (296mg, 81%). 1H NMR (400 MHz, CDCl3) delta 7.79 (d, 1H), 7.53 (d, 1H), 7.18-7.20 (dd, 1H), 7.12 (d, 1H), 7.06-7.07 (d, 1H), 7.00-7.02 (dd, 1H), 3.95 (s, 3H), 3.03-3.06 (m, 2H), 1.94-1.97 (m, 1H), 1.34 (s, 6H); 13C NMR (101 MHz, CDCl3) delta 170.09, 161.38, 161.12, 153.37, 142.25, 134.10, 130.91, 130.00, 129.85, 129.24, 126.73, 122.45, 120.25, 117.90, 111.95, 93.23, 88.03, 77.48, 77.16, 76.84, 52.52, 37.27, 32.54, 29.99, 23.43; ESI(+)-MS: 353.3 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 80℃; for 6h;Inert atmosphere; | Embodiment 42 ethyl 2-fluoro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate 6-Ethynyl-4,4-dimethylbenzothiopyran (275mg, 1.36mmol) and ethyl 2-fluoro-4-iodobenzoate (200mg, 0.68mmol) were added to a flask, followed by addition of Pd(PPh3)2Cl2 (28.6mg, 0.0408mmol) and CuI (15.5mg, 0.0816mmol). After the flask was purged with argon for 3 times to remove oxygen, 3mL dry DMF and 0.3mL dry Et3N were added via syringe. The reaction was continued at 80C for 6 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA = 200:1) to give WYC-303 (215mg, 86%). 1H NMR (500 MHz, CDCl3) delta 7.90 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 1.7 Hz, 1H), 7.32 (dd, J = 8.1, 1.4 Hz, 1H), 7.28 (d, J = 1.4 Hz, 1H), 7.25 (d, J = 1.4 Hz, 1H), 7.19 (dd, J = 8.2, 1.7 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.07 - 3.03 (m, 2H), 1.98 - 1.94 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.35 (s, 6H). 13C NMR (126 MHz, CDCl3) delta 164.12, 164.09, 162.75, 160.68, 142.32, 134.45, 132.15, 132.14, 129.98, 129.20, 127.08, 127.05, 126.78, 119.79, 119.60, 117.57, 93.98, 87.00, 86.98, 61.55, 37.25, 33.12, 30.09, 23.37, 14.40. ESI(+)-MS: 369.4 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 70℃; for 8h;Inert atmosphere; | Embodiment 48 ethyl 3-fluoro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate 6-Ethynyl-4,4-dimethylbenzothiopyran (405.6mg, 2mmol) and ethyl 3-fluoro-4-iodobenzoate (294mg, 1.0mmol) were added to a flask, followed by addition of Pd(PPh3)2Cl2 (84mg, 0.12mmol) and CuI (46.0mg, 0.24mmol). After the flask was purged with argon for 3 times to remove oxygen, 5mL dry DMF and 0.5mL dry Et3N were added via syringe. The reaction was continued at 70C for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA = 500:3) to give WYC-307(250mg, 68%). 1H NMR (500 MHz, CDCl3) delta 7.81 (dd, J = 8.0, 1.3 Hz, 1H), 7.76 (dd, J = 9.8, 1.3 Hz, 1H), 7.56 (dd, J = 11.1, 4.2 Hz, 2H), 7.22 (dd, J = 8.1, 1.6 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.05 (dd, J = 7.1, 5.1 Hz, 2H), 1.98 - 1.94 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.35 (s, 6H). 13C NMR (126 MHz, CDCl3) delta 165.25, 165.23, 163.21, 161.20, 142.29, 134.42, 133.26, 133.25, 131.70, 131.64, 129.97, 129.27, 126.75, 125.15, 125.12, 117.73, 117.05, 116.92, 116.66, 116.47, 98.04, 98.02, 81.71, 61.62, 37.29, 33.13, 30.09, 23.38, 14.42. ESI(+)-MS: 369.3 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 70℃; for 8h;Inert atmosphere; | Embodiment 49 ethyl 3-nitro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate 6-Ethynyl-4,4-dimethylbenzothiopyran (405.6mg, 2mmol) and ethyl 3-nitro-4-iodobenzoate (303mg, 1.0mmol) were added to a flask, followed by addition of Pd(PPh3)2Cl2 (84mg, 0.12mmol) and CuI (46.0mg, 0.24mmol). After the flask was purged with argon for 3 times to remove oxygen, 5mL dry DMF and 0.5mL dry Et3N were added via syringe. The reaction was continued at 70C for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA = 50:1) to give WYC-308 (384mg, 97%). 1H NMR (400 MHz, CDCl3) delta 8.69 (d, J= 1.2 Hz, 1H), 8.20 (dd, J= 8.1, 1.6 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.57 (s, 1H), 7.23- 7.25 (m, 1H), 7.08 (d, J = 8.2 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 3.04 (dd, J = 7.2, 4.9 Hz, 2H), 1.98 - 1.85 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H), 1.34 (s, 6H). 13C NMR (126 MHz, CDCl3) delta 164.34, 149.33, 142.43, 135.66, 134.63, 133.24, 130.35, 130.30, 129.65, 126.86, 126.01, 123.20, 117.23, 101.65, 84.50, 62.11, 37.16, 33.12, 30.04, 23.43, 14.43. ESI(+)-MS: 396.2 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 3h; | Embodiment 21 6-ethynyl-4,4-dimethyl-1-oxothiochroman 6-Ethynyl-4,4-dimethylbenzothiopyran (2.03g, 10mmol) was added to a flask, followed by addition of 27mL dry dichloromethane. After the mixture was cooled to 0C under an ice bath, mCPBA (1.73g, 10mmol) was added. Then the reaction was continued for 1 h under the ice bath and another 2 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction was quenched with sodium thiosulfate solution, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc = 3:1) to give 1-oxo-6-ethynyl-4,4-dimethylbenzothiopyran (1.43g, 72%). 1H NMR (500 MHz, CDCl3) delta 7.41 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 7.15 (d, J = 8.0 Hz, 1H), 2.93 - 2.74 (m, 3H), 2.14 (ddd, J = 14.6, 10.5, 1.7 Hz, 1H), 1.58 (ddd, J = 15.0, 8.7, 1.8 Hz, 1H), 1.14 (s, 3H), 1.01 (s, 3H); 13C NMR (126 MHz, CDCl3) delta 144.82,138.91,131.70, 130.53, 130.17, 125.60, 82.69, 79.39, 43.23, 34.47, 31.27, 31.13, 29.67. ESI(+)-MS: 219.3 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 75℃; for 8h;Inert atmosphere; | Embodiment 55 ethyl 2,3-difluoro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate Ethyl 2,3-difluoro-4-iodobenzoate (200mg, 0.64mmol) and 6-ethynyl-4,4-dimethylbenzothiopyran (195mg, 0.96mmol) were added to a flask, followed by addition of Pd(PPh3)2Cl2 (20mg, 0.0288mmol) and CuI (11mg, 0.0576mmol). After the flask was purged with argon for 3 times to remove oxygen, 2mL dry DMF and 0.2mL dry Et3N were added via syringe. Then the reaction was continued at 75C for 8 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc = 100:1) to give WYC-313 (215mg, 82%). 1H NMR (500 MHz, CDCl3) delta 7.65 (ddd, J = 8.3, 6.5, 1.8 Hz, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.28 (ddd, J = 8.0, 4.9, 1.9 Hz, 1H), 7.21 (dd, J = 8.2, 1.8 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.07 - 3.03 (m, 2H), 1.97 - 1.93 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.34 (s, 6H). 13C NMR (126 MHz, CDCl3) delta 163.34, 152.40, 152.29, 151.69, 151.58, 150.38, 150.27, 149.60, 149.49, 142.32, 134.92, 129.98, 129.27, 127.01, 126.98, 126.76, 126.01, 125.97, 120.13, 120.07, 118.59, 118.51, 117.25, 99.26, 99.23, 80.63, 80.60, 61.87, 37.18, 33.09, 30.02, 23.35, 14.33. ESI(+)-MS: 387.2 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 70℃; for 8h;Inert atmosphere; | Embodiment 59 methyl 3-acetamido-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate Methyl 3-acetamido-4-iodobenzoate (319mg, 1mmol) and 6-ethynyl-4,4-dimethylbenzothiopyran (304mg, 1.5mmol) were added to a flask, followed by addition of Pd(PPh3)2Cl2 (47mg, 0.0675mmol) and CuI (26mg, 0.135mmol). After the flask was purged with argon for 3 times to remove oxygen, 5mL dry DMF and 0.3mL dry Et3N were added via syringe. Then the reaction was continued at 70C for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc = 10:1) to give WYC-316 (298mg, 76%). 1H NMR (500 MHz, CDCl3) delta 9.00 (s, 1H), 7.97 (s, 1H), 7.74 (dd, J = 8.1, 1.2 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.18 (dd, J = 8.1, 1.7 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 3.91 (s, 3H), 3.10 - 3.02 (m, 2H), 2.26 (s, 3H), 1.98 - 1.93 (m, 2H), 1.35 (s, 6H). 13C NMR (126 MHz, CDCl3) delta 168.23, 166.55, 142.53, 138.77, 135.02, 131.51, 130.80, 129.71, 128.90, 126.92, 124.65, 120.35, 117.03, 110.11, 99.62, 83.25, 52.42, 37.09, 33.11, 30.02, 25.03, 23.36. ESI(+)-MS: 394.2 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.5% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 80℃; for 8h;Inert atmosphere; | Embodiment 66 ethyl 5-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrazin-2-carboxylate ethyl 5-bromopyridazin-2-carboxylate (600mg, 2.61mmol) and 6-ethynyl-4,4-dimethylbenzothiopyran (635mg, 3.13mmol) were added to a flask, followed by addition of Pd(PPh3)2Cl2 (66mg, 0.094mmol) and CuI (36mg, 0.188mmol). After the flask was purged with argon for 3 times to remove oxygen, 6mL dry DMF and 0.4mL dry Et3N were added via syringe. Then the reaction was continued at 80C for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc = 50:1) to give WYC-322 (656mg, 71.5%). 1H NMR (500 MHz, CDCl3) delta 9.20 (d, J = 1.4 Hz, 1H), 8.76 (d, J = 1.4 Hz, 1H), 7.58 (d, J = 1.7 Hz, 1H), 7.23 (dd, J = 8.2, 1.8 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 3.02 - 2.97 (m, 2H), 1.92 - 1.87 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H), 1.29 (s, 6H). 13C NMR (126 MHz,CDCl3) delta 163.65, 146.68, 145.70, 143.08, 142.31, 140.30, 136.14, 130.54, 129.51, 126.74, 116.00, 97.55, 85.68, 62.37, 36.91, 32.99, 29.89, 23.27, 14.31. ESI(+)-MS: 353.5 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 80℃; for 8h;Inert atmosphere; | Embodiment 70 ethyl 2-chloro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate Ethyl 2-chloro-4-iodobenzoate (310mg, 1mmol) and 6-ethynyl-4,4-dimethylbenzothiopyran (244mg, 1.2mmol) were added to a flask, followed by addition of Pd(PPh3)2Cl2 (28mg, 0.04mmol) and CuI (11.4mg, 0.06mmol). After the flask was purged with argon for 3 times to remove oxygen, 3mL dry DMF and 0.3mL dry Et3N were added via syringe. Then the reaction was continued at 80C for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc = 50:1) to give WYC-325 (365mg, 95%). 1H NMR (500 MHz, CDCl3) delta 7.81 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 1.5 Hz, 1H), 7.52 (d, J = 1.7 Hz, 1H), 7.42 (dd, J = 8.1, 1.5 Hz, 1H), 7.18 (dd, J = 8.2, 1.8 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.06 - 3.02 (m, 2H), 1.97 - 1.93 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.34 (s, 6H). 13C NMR (126 MHz, CDCl3) delta 165.27, 142.26, 134.37, 133.89, 133.65, 131.41, 129.92, 129.38, 129.30, 129.14, 128.27, 126.72, 117.56, 93.73, 86.76, 61.71, 37.21, 33.06, 30.04, 23.32, 14.33. ESI(+)-MS: 385.2 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; isopropylamine; In N,N-dimethyl-formamide; at 20℃; for 8h;Inert atmosphere; | Embodiment 2 methyl 4-((4,4-dimethylthiochroman-6-yl)ethynyl)-2-hydroxymethylbenzoate 6-Ethynyl-4,4-dimethylbenzothiopyran (202.8mg, 1mmol) and methyl 2-hydroxymethyl-4-iodobenzoate (292mg, 1mmol) were added to a flask, followed by addition of Pd(PPh3)2Cl2 (14mg, 0.02mmol) and CuI (7.6mg, 0.04mmol). After the flask was purged with argon for 3 times to remove oxygen, 2mL dry DMF and 0.2mL dry iPr2NH were added via syringe. The reaction was continued at room temperature for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution, and the mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc = 100:1 to 50:1) to give WYC-102 (300mg, 82%). 1H NMR (400 MHz, CDCl3) delta 7.78 (d, 1H), 7.53 (d, 1H), 7.18-7.20 (dd, 1H), 7.11-7.13 (dd, 1H), 7.11 (d, 1H), 7.07 (d, 1H), 3.98 (s, 3H), 3.89 (s, 3H), 3.03-3.06 (m, 1H), 1.94-1.97 (m, 1H), 1.34 (s, 6H); 13C NMR (101 MHz, CDCl3) delta 166.25, 159.05, 142.07, 133.98, 133.58, 131.89, 129.90, 129.13, 128.85, 126.70, 123.39, 119.42, 117.88, 114.84, 92.50, 88.07, 77.48, 77.16, 76.84, 56.18, 52.18, 37.23, 33.06, 30.06, 23.31; ESI(+)-MS: 367.4 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; isopropylamine; In N,N-dimethyl-formamide; at 20℃; for 8h;Inert atmosphere; | Embodiment 3 ethyl 4-((4,4-dimethylthiochroman-6-yl)ethynyl)-2-hydroxybenzoate 6-Ethynyl-4,4-dimethylbenzothiopyran (202.8mg, 1mmol) and ethyl 2-hydroxy-4-iodobenzoate (292mg, 1mmol) were added to a flask, followed by addition of Pd(PPh3)2Cl2 (14mg, 0.02mmol) and CuI (7.6mg, 0.04mmol). After the flask was purged with argon for 3 times to remove oxygen, 2mL dry DMF and 0.2mL dry iPr2NH were added via syringe. The reaction was continued at room temperature for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution, and the mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc = 100:1 to 50:1) to give WYC-103 (300mg, 82%). 1H NMR (400 MHz, CDCl3) delta 7.80 (d, 1H), 7.52 (s, 1H), 7.18-7.20 (d, 1H), 7.12 (s, 1H), 7.06-7.07 (s, 1H), 7.00-7.02 (s, 1H), 4.39-4.44 (q, 2H), 3.04-3.06 (t, 2H), 1.95-1.97 (t, 2H), 1.44 (t, 3H), 1.35 (s, 6H); 13C NMR (101 MHz, CDCl3) 6 169.97, 161.45, 142.27, 134.07, 130.80, 130.02, 129.91, 129.26, 126.74, 122.37, 120.25, 117.94, 112.22, 93.19, 88.02, 77.48, 77.36, 77.16, 76.84, 61.71, 37.30, 33.12, 30.11, 29.85, 23.37, 14.34; ESI(+)-MS: 367.5 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; isopropylamine; In N,N-dimethyl-formamide; at 20℃; for 8h;Inert atmosphere; | Embodiment 4 ethyl 4-((4,4-dimethylthiochroman-6-yl)ethynyl)-2-hydroxymethylbenzoate 6-Ethynyl-4,4-dimethylbenzothiopyran (202.8mg, 1mmol) and ethyl 2-hydroxymethyl-4-iodobenzoate (306mg, 1mmol) were added to a flask, followed by addition of Pd(PPh3)2Cl2 (14mg, 0.02mmol) and CuI (7.6mg, 0.04mmol). After the flask was purged with argon for 3 times to remove oxygen, 2mL dry DMF and 0.2mL dry iPr2NH were added via syringe. The reaction was continued at room temperature for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution, and the mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc = 100:1 to 50:1) to give WYC-104 (293mg, 77%). 1H NMR (400 MHz, CDCl3) delta 7.77 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 1.7 Hz, 1H), 7.20 (dd, J = 8.2, 1.7 Hz, 1H), 7.14 - 7.11 (m, 1H), 7.11 - 7.05 (m, 2H), 4.36 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 3.07 - 3.04 (m, 2H), 1.95 - 1.98 (m, 2H), 1.39 (t, 3H), 1.35 (s, 6H); 13C NMR (101 MHz, CDCl3) delta 165.81,159.12,142.28,133.97,131.77,129.96,129.19,128.70,126.76,123.42,119.93, 117.98, 114.94, 92.39, 77.48, 77.37, 77.16, 76.85, 61.07, 56.25, 37.31, 33.13, 30.14, 29.85, 23.37, 14.46; ESI(+)-MS: 381.4 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; isopropylamine; In N,N-dimethyl-formamide; at 20℃; for 8h;Inert atmosphere; | Embodiment 7 methyl 4-((4,4-dimethylthiochroman-6-yl)ethynyl)-3-hydroxybenzoate 6-Ethynyl-4,4-dimethylbenzothiopyran (202.8mg, 1mmol) and methyl 3-hydroxy-4-iodobenzoate (278.1mg, 1mmol) were added to a flask, followed by addition of Pd(PPh3)2Cl2 (14mg, 0.02mmol) and CuI (7.6mg, 0.04mmol). After the flask was purged with argon for 3 times to remove oxygen, 2mL dry DMF and 0.2mL dry iPr2NH were added via syringe. The reaction was continued at room temperature for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution, and the mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc = 100:1 to 10:1) to give WYC-107 (245mg, 71%). 1H NMR (500 MHz, CDCl3) delta 7.64 (d, J = 1.5 Hz, 1H), 7.58 (dd, J = 8.0, 1.6 Hz, 1H), 7.52 (d, J = 1.7 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.19 (dd, J = 8.2, 1.7 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 6.02 (s, 1H), 3.91 (s, 3H), 3.06 -3.04 (m, 2H), 1.94 -1.97 (m, 2H), 1.34 (s, 6H); 13C NMR (101 MHz, CDCl3) delta 166.45, 156.21,142.31,134.62,131.53,131.43,129.70,128.97,126.73,121.48,117.03,115.72, 114.61, 99.27, 81.86, 77.37, 77.05, 76.74, 52.33, 37.06, 32.99, 29.94, 23.24; ESI(+)-MS: 353.4 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; isopropylamine; In N,N-dimethyl-formamide; at 20℃; for 8h;Inert atmosphere; | Embodiment 8 methyl 4-((4,4-dimethylthiochroman-6-yl)ethynyl)-3-hydroxymethylbenzoate 6-Ethynyl-4,4-dimethylbenzothiopyran (202.8mg, 1mmol) and methyl 3-hydroxymethyl-4-iodobenzoate (292.1mg, 1mmol) were added to a flask, followed by addition of Pd(PPh3)2Cl2 (14mg, 0.02mmol) and CuI (7.6mg, 0.04mmol). After the flask was purged with argon for 3 times to remove oxygen, 2mL dry DMF and 0.2mL dry iPr2NH were added via syringe. The reaction was continued at room temperature for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution, and the mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc = 100:1 to 10:1) to give WYC-108 (275mg, 75%). 1H NMR (500 MHz, CDCl3) delta 7.61-7.63 (d, 1H), 7.52-7.56 (m, 3H), 7.21-7.23 (dd, 1H), 7.05-7.07 (d, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.03-3.06 (m, 1H), 1.94-1.97 (m, 1H), 1.34 (s, 6H); 13C NMR (126 MHz, cdcl3) delta 166.59, 159.56, 141.99, 133.50, 133.19, 130.64, 129.80, 129.14, 126.49, 121.75, 118.27, 111.25, 96.82, 84.38, 77.26, 77.01, 76.76, 56.07, 52.29, 37.24, 32.97, 29.98, 23.22; ESI(+)-MS: 367.3 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 75℃; for 12h;Inert atmosphere; | Embodiment 19 2-amino-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoic acid 6-Ethynyl-4,4-dimethylbenzothiopyran (405.6mg, 2mmol) and <strong>[20776-54-9]2-amino-4-iodobenzoic acid</strong> (263mg, 1mmol) were added to a flask, followed by addition of Pd(PPh3)2Cl2 (42mg, 0.06mmol) and CuI (23mg, 0.12mmol). After the flask was purged with argon for 3 times to remove oxygen, 10mL dry DMF and 0.2mL dry Et3N were added via syringe. Then the reaction was continued at 75C for 12 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc = 5:1) to give WYC-212 (286mg, 85%). 1H NMR (500 MHz, CDCl3) delta 7.88 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 1.7 Hz, 1H), 7.18 (dd, J = 8.1, 1.8 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 1.3 Hz, 1H), 6.81 (dd, J = 8.3, 1.5 Hz, 1H), 3.08 - 3.02 (m, 3H), 1.99 - 1.94 (m, 2H), 1.35 (s, 6H); 13C NMR (126 MHz, CDCl3) delta 165.25, 165.23, 163.21, 161.20, 142.29, 134.42, 133.26, 133.25, 131.70, 131.64, 129.97, 129.27, 126.75, 125.15, 125.12, 117.73, 117.05, 116.92, 116.66, 116.47, 98.04, 98.02, 81.71, 61.62, 37.29, 33.13, 30.09, 23.38, 14.42. ESI(+)-MS: 338.3 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: bis-triphenylphosphine-palladium(II) chloride; triethylamine; copper(l) iodide / 40 °C / Schlenk technique; Inert atmosphere 2: copper(II) bis(trifluoromethanesulfonate); tricyclohexylphosphine; sodium t-butanolate / methanol; tetrahydrofuran / 12 h / 20 °C / Schlenk technique; Inert atmosphere; Sealed tube |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: bis-triphenylphosphine-palladium(II) chloride; triethylamine; copper(l) iodide / 40 °C / Schlenk technique; Inert atmosphere 2: sodium t-butanolate; copper(l) chloride / methanol; tetrahydrofuran / 12 h / 20 °C / Schlenk technique; Inert atmosphere; Sealed tube |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine at 40℃; Schlenk technique; Inert atmosphere; | 3. General Process for the Synthesis of 1a, 2a, 3a, 4a, 5a and 6a General procedure: A Schlenk flask was charged with Pd(PPh3)2Cl2 (2 mol %) and CuI (5 mol %) under N2 atmosphere.Dry triethyamine and 2-bromo-3,3,3-trifluoro-1-propene (1.2 equiv) were added subsequently followedby dropwise addition of phenylacetylene (1.0 equiv). The reaction mixture was stirred at 40 oC untilcompletion. The reaction was then quenched with saturated NH4Cl solution and extracted with pentane.Combined extracts were dried over Na2SO4 and solvent was removed under vacuum. The residue waspurified by column chromatography to afford the corresponding enyne 1a. All 1,3-enynes can beprepared in good yield by this procedure1-2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.818 % de | With (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile In acetone at 20℃; Inert atmosphere; Irradiation; Sealed tube; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: bis-triphenylphosphine-palladium(II) chloride; triethylamine; copper(l) iodide / 20 °C / Inert atmosphere 2: sodium hydrogencarbonate; copper(l) chloride / 16 h / 100 °C / Inert atmosphere; Sealed tube |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With dicarbonyl(acetylacotonato)rhodium(I); hydrogen; 2,2'-bis((bis(5-methoxy-1H-indol-1-yl)phosphaneyl)oxy)-1,1'-biphenyl In toluene; cyclohexanol at 30℃; for 8h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | Stage #1: (4,4-dimethylthiochroman-6-yl)acetylene; dimethylethylsilane With tris(pentafluorophenyl)borate In dichloromethane at -20℃; for 5h; Stage #2: phenylsilane In dichloromethane at -20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With tris(pentafluorophenyl)borate In dichloromethane at -20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In 1,2-dimethoxyethane at 25℃; for 12h; Glovebox; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: (4,4-dimethylthiochroman-6-yl)acetylene; isopropyl(phenyl)phosphine With bis(1,5-cyclooctadiene)nickel (0); dipyridamole In toluene at 20℃; Inert atmosphere; Glovebox; Stage #2: With sulfur In toluene at 20℃; for 4h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93 % ee | Stage #1: (4,4-dimethylthiochroman-6-yl)acetylene; isopropyl(phenyl)phosphine With bis(1,5-cyclooctadiene)nickel (0); diphenyl hydrogen phosphate; (2S,4S)-2,4-bis(diphenylphosphino)pentane In toluene at -10℃; for 72h; Inert atmosphere; Stage #2: With sulfur In toluene at 20℃; for 4h; Inert atmosphere; Overall yield = 97 percent; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 4,4',4''-tri-tert-butyl-2,2':6',2''-terpyridine; copper(II) bis(trifluoromethanesulfonate); potassium carbonate In methanol; acetonitrile at 25℃; for 3h; Inert atmosphere; Schlenk technique; Glovebox; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With tris(pentafluorophenyl)borate In dichloromethane at 20℃; for 0.333333h; Inert atmosphere; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: diphenylsilane With cobalt(III) acetylacetonate; triethylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In cyclohexane at 20℃; for 0.25h; Inert atmosphere; Schlenk technique; Stage #2: (4,4-dimethylthiochroman-6-yl)acetylene; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In cyclohexane at 20℃; for 24h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With bis-triphenylphosphine-palladium(II) chloride; 1,8-diazabicyclo[5.4.0]undec-7-ene; zinc(II) iodide In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 0.166667h; Glovebox; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In tetrahydrofuran at 50℃; for 5h; chemoselective reaction; |
Tags: 118292-06-1 synthesis path| 118292-06-1 SDS| 118292-06-1 COA| 118292-06-1 purity| 118292-06-1 application| 118292-06-1 NMR| 118292-06-1 COA| 118292-06-1 structure
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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.
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