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CAS No. : | 13831-03-3 | MDL No. : | MFCD00060100 |
Formula : | C7H10O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XGTPDIIFEPTULX-UHFFFAOYSA-N |
M.W : | 126.15 | Pubchem ID : | 543038 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.57 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 35.25 |
TPSA : | 26.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.95 cm/s |
Log Po/w (iLOGP) : | 2.27 |
Log Po/w (XLOGP3) : | 1.58 |
Log Po/w (WLOGP) : | 1.04 |
Log Po/w (MLOGP) : | 1.52 |
Log Po/w (SILICOS-IT) : | 1.0 |
Consensus Log Po/w : | 1.48 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.49 |
Solubility : | 4.12 mg/ml ; 0.0327 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.74 |
Solubility : | 2.28 mg/ml ; 0.0181 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.82 |
Solubility : | 19.1 mg/ml ; 0.151 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.18 |
Signal Word: | Danger | Class: | 3 |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | 3272 |
Hazard Statements: | H226-H315-H319-H335 | Packing Group: | Ⅲ |
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 |
---|---|---|
80 g | With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran for 24 h; | Approximately 60g of compound 17 (propiolic acid), N of about 100 g, N'-dicyclohexylcarbodiimide (N, N'-dicyclohexylcarbodiimide), about 10g of 4- (dimethylamino) pyridine (4- (dimethylamino ) pyridine)), and about 20g of tert- butanol (tert-butanol), it was dissolved in tetrahydrofuran and stirred for about 24 hours.After extraction with dichloromethane and water, the extracted organic layer was chemically dried and purified by column chromatography to give compound 18 of about 80 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[13831-03-3]tert-butyl 2-propynoate</strong> (50.0 g) in acetone (500 ml), silver nitrate (6.73 g) was added, and the mixture was stirred at room temperature for 1 hour. While the reaction solution was cooled in a water bath, N-bromosuccinimide (79.2 g) was added thereto, and the mixture was stirred at room temperature for 18 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. A diethyl ether/n-pentane (1:4) mixed solvent was added to the residue obtained, and the deposited insoluble matter was filtered through celite. The filtrate was concentrated under reduced pressure to obtain the title compound (81.3 g), which was used in the next reaction without being purified. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; | Example 260 Synthesis of 4-(tert-butyl) 2-ethyl 1H-imidazole-2,4-dicarboxylate. To a mixture of <strong>[10489-74-4]ethyl (Z)-2-amino-2-(hydroxyimino)acetate</strong> (660 mg, 5 mmol) and tert-butyl propiolate (694 mg, 5.5 mmol) in Xylene (10 mL) was added TEA (606 mg, 6 mmol). The mixture was stirred at 140 C. for 16 h. After cooled to RT, H2O (25 mL) was added and the mixture was extracted with EtOAc (35 mL*3). The combined organic layers were washed with brine and dried over Na2SO4, concentrated to give the crude, which was purified by silica gel chromatography (PE/EA=1/1) to give 4-(tert-butyl) 2-ethyl 1H-imidazole-2,4-dicarboxylate (400 mg, yield: 33%) as a yellow solid. ESI-MS [M+H]+: 241.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dmap In acetonitrile at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 100℃; for 0.333333h; | A DMF (17 mL) suspension of 1-(4-iodine-2-methoxyphenyl)-4-methyl-1H-imidazole (2.67 g) and tert-butyl propiolate (2.14 g), dichlorobis(triphenylphosphine)palladium(II) (300 mg), potassium carbonate (2.35 g) and iodation copper (I) (162 mg) was agitated under heating at 100 C. for 20 minutes. Ethyl acetate and a saturated ammonium chloride solution were added to the reaction solution after cooling reaction solution to room temperature, and the reaction solution was agitated for 30 minutes. After washed with a saturated saline solution, reaction solution was dried over anhydrous magnesium sulfate and the separated organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system), and 2.45 g of the title compound was obtained. 1H-NMR (CDCl3) delta (ppm): 1.56 (s, 9H), 2.29 (s, 3H), 3.87 (s, 3H), 6.93 (s, 1H), 7.21-7.24 (m, 3H), 7.78 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine;copper(l) iodide; In tetrahydrofuran; at 20℃; for 2.5h; | To a suspension of copper(I) iodide (335 mg) in tetrahydrofuran (100 mL) was added t-butyl prpiolate (3.63 mL), diisopropylethylamine (4.62 mL) and a solution of 5(R)-azidomethyl-3-[4-(1-cyanocyclopropan-1-yl)phenyl]oxazolidin-2-one (5.00 g) in tetrahydrofuran (10 mL), the mixture was stirred at room temperature for 2.5 hours, and then concentrated in vacuo. After dilution of the residue with ethyl acetate, the resulting precipitates were filtered off, and then concentrated in vacuo. Treatment of the residue with ethyl acetate gave t-butyl 1-[5(R)-3-[4-(1-cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole-4-carboxylate (6.85 g). [0423] MS (EI+) m/z: 409 (M+). [0424] HRMS (EI+) for C21H23N5O4 (M+): calcd, 409.1750; found, 409.1729. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; lithium diisopropyl amide; In tetrahydrofuran; heptane-tetrahydrofuran-ethylbenzene; water; | (a) To a solution of tert-butyl propiolate (3.54 ml, 25.81 mmole) in tetrahydrofuran (60 ml) was added at -70 C. under the argon atmosphere a solution of 2.0M lithium diisopropylamide in a heptane-tetrahydrofuran-ethylbenzene mixture (13.0 ml, 26 mmole), and the mixture was stirred for 30 minutes. The reaction mixture was then added to a solution of 4-methoxycarbonyl-2-nitrobenzaldehyde (4.5 g, 21.5 mmole) in tetrahydrofuran (100 ml), and the mixture was further stirred at -75 C. for 5 minutes. After a solution of acetic acid (3.2 ml, 53.3 mmole) in tetrahydrofuran (10 ml) and water were added, the reaction mixture was extracted with ethyl acetate (400 ml). The organic layer was washed with dilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous saline in this sequence. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give the crude product of tert-butyl 4-hydroxy-4-(4-methoxycarbonyl-6-nitrophenyl)-2-butynoate as a brown oil (7.655 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With sodium hypochlorite; In dichloromethane; water; at 20℃; for 2h; | tert-Butyl 3-(5-(tert-butoxycarbonyIamino)-2-methylpyridin-3- yI)isoxazole-5-carboxylate. In a 100 ml round-bottomed flask were placed tert-butyl 5- ((hydroxyimino)methyl)-6-methylpyridin-3-yl carbamate (77 mg, 0.28 mmol), tert-butyl propiolate (384 mul, 2.8 mmol), and DCM (5 ml). To this stirred solution was added 5% sodium hypochlorite solution (2 ml) via syringe at a rate of 25 mul/min. After the addition was complete, the reaction was stirred for 2hr at rt. The reaction was diluted with water and DCM and the aqueous layer was extracted with DCM. The organic layer was dried over Na2SO4 and the solvents removed in vacuo. The residue was purified over silica gel, eluting with 0-50% EtO Ac/Hex to afford 13 mg (12% yield) of tert-butyl 3-(5-(tert- butoxycarbonylamino)-2-methylpyridin-3~yl)isoxazole-5-carboxylate. 1H NMR (CDCl3) delta (ppm) 8.40 (d, J = 2.5Hz, IH), 8.18 (bs, IH), 7.08 (s, IH), 6.58 (bs, IH), 1.63 (s, 9H), 1.52 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; In dichloromethane; at 20℃; for 24h; | a mixture of 4-(2-methoxy ethyl) phenol (1.547g, 10.3 mmol), propiolic acid tert-butyl ester (1.367g, 10.8 mmol) and N-methyl morpholine (1.18 mL, 10.8 mmol) in CH2Cl2 (15 mL) was stirred at room temperature for 24 hours. The mixture was absorbed on SiO2 (20 g) and purified by column chromatography using a mixture of methylene chloride/hexane. The product was obtained as a two to one mixture of (E)/ (Z)-tert-butyl 3-(4-(2-methoxyethyl)phenoxy)acrylate isomers (2.0 g). | |
With 4-methyl-morpholine; In dichloromethane; at 20℃; for 24h; | CH2Cl2 (15 mL) solution of 4- (2-methoxyethyl) phenol (1.547g, 10.3mmol), propiolic acid tert- butyl ester (1.367g, 10.8mmol) and N- methylmorpholine (1 .18mL,10.8mmol) and the mixture was stirred for 24 hours at room temperature. Mixture is absorbed on SiO2 (20 g), it was purified by column chromatography using a mixture of methylene chloride / hexane. The product was obtained as a mixture of 2-one (E) / (Z) -tert- butyl 3- (4- (2-methoxyethyl) phenoxy) acrylate isomers (2.0 g). It was obtained as a mixture of 2:1. | |
With 4-methyl-morpholine; In dichloromethane; at 20℃; for 24h; | Example 1D3: Preparation of 3-(4-(2-methoxyethyl)phenoxy)propanoic acid; Step 1 : a mixture of 4-(2-methoxy ethyl) phenol (1.547g, 10.3 mmol), propiolic acid tert-butyl ester (1.367g, 10.8 mmol) and N-methyl morpholine (1.18 mL, 10.8 mmol) in CH2Cl2 (15 mL) was stirred at room temperature for 24 hours. The mixture was absorbed on SiO2 (20 g) and purified by column chromatography using a mixture of methylene chloride/hexane. The product was obtained as a two to one mixture of (E)/ (Z)-tert-butyl 3-(4-(2-methoxyethyl)phenoxy)acrylate isomers (2-0 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With triethylamine; In toluene; at 140℃; for 0.0166667h; | To ethyl cyanoformate (10 g, 101.01 mmol) was added NH2OH-HCl (8.4 g, 121.74 mmol), K2CO3 (19.9 g, 144.20 mmol), and CH2C12/H2O (100 mL). The resulting mixture was stirred for 12 hr at room temperature. The solids were filtered out and the filtrated was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :1), resulted in 6 g (45%) of (Z)-ethyl 2-amino-2- (hydroxyimino)acetate as a white solid. To a mixture of (Z)-ethyl 2-amino-2- (hydroxyimino)acetate (1 g, 7.58 mmol) and tert-butyl propiolate (940 mg, 7.46 mmol) was added Et3N (765 mg, 7.57 mmol) and toluene (50 mL). The resulting solution was stirred at 140 0C for 1 min. The resulting mixture was washed with 50 mL of H2O and then was extracted with 3 x 50 mL of dichloromethane. The organic layers were combined and washed with 20 mL of brine, then dried over anhydrous sodium sulfate. Evaporated the solvents and the residue was purified onto a silica gel column with ethyl acetate/petroleum ether (1 :1), resulted in 1.1 g (61%) of 5 -tert-butyl 2-ethyl lH-imidazole-2, 5-dicarboxylate as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium 2-(1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydro-furan-3-olate; copper(II) sulphate hydrate; In water; isopropyl alcohol; at 40 - 50℃; for 2h; | To a suspension of azide derivative 13 (1 mole eq.) in isopropanol and water (1:1) was added alkyne (2 mole eq.) followed by CuSO4H2O (0.2 mole eq.) and sodium ascorbate (0.4 mole eq.). The reaction mixture was stirred at 40-50 C for 2 h and then evaporated under reduced pressure. To the residue was added H2O and the aqueous mixture was extracted with DCM. The organic phase was washed with H2O, brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was then purified by column chromatography on silica to obtain the desired C-1 triazole derivative. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With copper(II) acetate monohydrate; 2-amino-phenol; at 20℃; for 0.25h; | General procedure: To a stirred solution of methyl propynoate (1g, 93 mg, 1.1 mmol), 4-methylbenzenesulfonyl azide (2a, 197 mg, 1 mmol), and 2-aminophenol (8a, 5.5 mg, 0.05 mmol) in EtOH (1 mL) was added Cu(OAc)2·H2O (20 mg, 0.1 mmol) at room temperature. After 2a was exhausted (ca. 15 min, monitored by TLC), the solvent was removed off in vacuum. The residue was purified by chromatography (silica gel, 10% EtOAc in PE) to give desired product 6b as a white solid (284 mg, 95%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | The methyl 5-chloro-2-(3-fluorophenyl)nicotinate (1.00 g, 3.76 mmol) was combined with freshly prepared 2-[(aminooxy)sulfonyl]-l,3,5-trimethylbenzene (0.972 g, 4.52 mmol) ether solution in acetonitrile (20.0 rnL) at room temperature. The reaction was stirred for 24 hours and became a tan colored slurry. The slurry was added portion wise to a vigorously stirring suspension of tert-butyl propiolate (1.55 mL, 1 1.3 mmol), N,N-dimethylformamide (20.0 mL, 258 mmol) and potassium carbonate (2.60 g, 18.8 mmol) open to the air. After stirring for 15 minutes, the reaction was a dark red brown suspension. This was allowed to stir for 5 hours at room temperature. The reaction was taken up in ethyl acetate and decanted from the solids. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give the crude product as a reddish brown oil. The product was purified on silica gel eluting hexane: ethyl acetate gradient to give 3-tert-butyl 6-methyl 4- chloro-7-(3-fluorophenyl)pyrazolo[l,5-a]pyridine-3,6-dicarboxylate (0.46 g, 30%) as a semisolid residue. LCMS calculated for C2oH19ClF 204 (M+H)+: m/z = 405.1 ; found: 404.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With tetrakis(triphenylphosphine) palladium(0); (TMP)2Zn.MgCl2; In tetrahydrofuran; at 25℃;Inert atmosphere; | A dry, argon-filled Schlenk tube with a magnetic stirrer bar and septum is initially charged with <strong>[13831-03-3]tert-butyl prop-2-ynoate</strong> (70 mg, 0.56 mmol) in anhydrous THF (2 ml). After adding (TMP)2Zn.MgCl2 (2.2 ml, 1.2 mmol) at 25C, the mixture is stirred for 30 min, then a solution of l -fluoro-3-iodobenzene (160 mg, 0.72 mmol), tetrakis(triphenylphosphine)palladium(0) (33 mg, 5 mol%>) in anhydrous THF (2 ml) is added dropwise and the mixture is stirred at 25C overnight. For workup, the mixture is diluted with aqueous sat. NH4CI solution (30 ml) and extracted with ethyl acetate (3 x 30 ml). After the combined organic phases have been dried over Na2S04, the solvent has been distilled off and purification has been effected by column chromatography on silica gel (heptane : ethyl acetate), the desired compound (91 mg, 75% of theory) was obtained as a colourless oil. ¾ NMR (400 MHz, CDC13): delta in ppm = 7.34 (m, 2H), 7.26 (m, 1H), 7.13 (m, 1H), 1.53 (s, 9H) Preparation of ethyl 4-(2-chloro- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With ammonium hydroxide; In ethanol; at 20℃;Inert atmosphere; | General procedure: Preparation of Copper Acetylides; Procedure 1To a solution of CuI (3.8 g, 20.0 mmol) in a mixture of NH4OH(28% NH3 solution, 50 mL) and EtOH (30 mL) was added the alkyne1 (10.0 mmol) dropwise. The deep blue reaction mixture wasstirred overnight at r.t. under argon and the yellow precipitate wascollected by filtration and successively washed with NH4OH (10%NH3 solution, 3 × 50 mL), H2O (3 × 50 mL), EtOH (3 × 50 mL), andEt2O (3 × 50 mL). The bright yellow solid was then dried under highvacuum overnight to afford the desired polymeric copper acetylide2, which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; potassium carbonate; In tetrahydrofuran; at 20 - 60℃; for 20h; | To the mixture of methyl 3-iodobenzoate (157 mg, 0.60 mmol), potassium carbonate (166 mg, 1.20 mmol), cupper(I) iodide (14 mg, 0.07 mmol) and PdCi2(Ph3P)2 (21 mg, 0.03 mmol) in tetrahydrofuran (2 mL) was added tert-butyl propiolate (330 muL, 2.40 mmol) at room temperature. After stirred for 20 h at 60°C, the mixture was evaporated to dryness. The residue was chromatographed on a silica gel (EtOAc:hexanes 0: 1~1 : 10) to give the title compound 9-1 (155 mg, 99percent yield) as a light brown oil. 1H NMR (300 MHz, CDCl3) delta 8.25 (t, J= 1.4, 1H), 8.16 - 8.05 (m, 1H), 7.80 - 7.68 (m, 1H), 7.46 (t, J= 7.8, 1H), 3.93 (s, 3H), 1.55 (s, 9H). |
99% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; potassium carbonate; In tetrahydrofuran; at 60℃; for 20h; | To the mixture of methyl 3-iodobenzoate (157 mg, 0.60 mmol), potassium carbonate (166mg, 1.20 mmol), cupper(I) iodide (14 mg, 0.07 mmol) and PdC12(Ph3P)2 (21 mg, 0.03 mmol) in tetrahydroffiran (2 mE) was added tert-butyl propiolate (330 pL, 2.40 mmol) at room temperature. Afier stirred for 20 h at 60° C., the mixture was evaporated to dryness. Theresidue was chromatographed on a silica gel (EtOAc:hex- anes=0: 1 -1 :10) to give the title compound 9-1(155 mg, 99percentyield) as a light brown oil.?H NMR (300 MHz, CDC13) oe 8.25 (t, J=1.4, 1H), 8.16- 8.05 (m, 1H), 7.80-7.68 (m, 1H), 7.46 (t, J=7.8, 1H), 3.93 (s,3H), 1.55 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | n-Butyllithium (1.6 M in hexane; 41.9 mL, 67.0 mmol) was added dropwise within 10mm at -55 to -50CC to a soln of tert-butyl propiolate (103; 8.76 mL, 63.8 mmol) in dryTHF (200 mL). The mixture was allowed to stir at -40C for 1.5 h. The mixture wascooled to -78C. A soln of 102 (7.25 g, 31 9 mmol) in THF (66 mL) was added within 10 mm with the temperature not exceeding -64C. The mixture was stirred for 0.5 h at-78C, then warmed to -40C and allowed to slowly warm to 0C over 3 h. The mixture was poured into 1 M aq. KHSO4 soln and extracted with EtOAc. The organicphase was dried (Na2SO4) and concentrated. FC (hexane/EtOAc 90:10 to 70:30) afforded the ketone 104 (8.34 g, 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With [(SPhos)AuNCMe]SbF6; In toluene; at 20℃;Inert atmosphere; | General procedure: Into an oven-dried reaction flask under Ar gas protection was added oxabicyclic alkene (0.2 mmol), Au catalyst (0.001 mmol), methyl propiolate (0.4 mmol) and toluene (1.0 mL). The reaction mixture was stirred at room temperature normally overnight. After complete consumption of the starting materials, monitored by TLC, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With [(SPhos)AuNCMe]SbF6; In toluene; at 20℃;Inert atmosphere; | General procedure: Into an oven-dried reaction flask under Ar gas protection was added oxabicyclic alkene (0.2 mmol), Au catalyst (0.001 mmol), methyl propiolate (0.4 mmol) and toluene (1.0 mL). The reaction mixture was stirred at room temperature normally overnight. After complete consumption of the starting materials, monitored by TLC, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With [(SPhos)AuNCMe]SbF6; In toluene; at 20℃;Inert atmosphere; | General procedure: Into an oven-dried reaction flask under Ar gas protection was added oxabicyclic alkene (0.2 mmol), Au catalyst (0.001 mmol), methyl propiolate (0.4 mmol) and toluene (1.0 mL). The reaction mixture was stirred at room temperature normally overnight. After complete consumption of the starting materials, monitored by TLC, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In tetrahydrofuran; at 60℃; for 20h; | To the mixture of methyl 3-iodobenzoate (157 mg, 0.60 mmol), K2CO3 (166 mg, 1.20 mmol), cupper(I) iodide (14 mg, 0.07 mmol) and PdCl2(Ph3P)2 (21 mg, 0.03 mmol) in tetrahydrofuran (2 mL) was added tert-butyl propiolate (16) (330 mL, 2.40 mmol) at room temperature. After stirred for 20 h at 60°C, the mixture was evaporated to dryness. The residue was chromatographed on a silica gel (AcOEt:hexanes=0:1~1:10) to give tert-butyl 3-(3-(methoxycarbonyl)phenyl)propiolate (17b) (155 mg, 99percent yield) as light brown oil. 1H NMR (300 MHz, CDCl3) delta 8.25 (t, J = 1.4, 1H), 8.16 ? 8.05 (m, 1H), 7.80 ? 7.68 (m, 1H), 7.46 (t, J = 7.8, 1H), 3.93 (s, 3H), 1.55 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(7S)-di-tert-butyl 7-(bis(tert-butoxycarbonyl)amino)-4-hydroxyoct-2-ynedioate (5): [0045] To a solution of tert-butyl propiolate (42.7 mg, 0.34 mmol) in a dry THF (1.5 mL) was slowly added lithium diisopropylamide (2.0 M in THF/ethyl benzene, 0.15 mL, 0.29 mmol) at -78 C. under nitrogen atmosphere. The resulting reaction mixture was continued stirring at the same temperature for 1.0 hour (to generate lithium propiolate anion), then slowly added (S)-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-oxopentanoate (0.075 g, 0.193 mmol) in 1.0 mL THF solution. The mixture was stirred at the same temperature for 90 minutes (until finished by TLC). Then, the reaction was quenched with saturated aqueous NH4Cl (0.5 mL) solution and warmed to room temperature by removing the external acetone/dry ice bath. The reaction solution was diluted with ethyl acetate (20 mL) and an aqueous saturated solution of NH4Cl (15 mL) was added with stirring. The aqueous phase was extracted with ethyl acetate (50 mL) and the combined organic layers dried and concentrated under reduced pressure. The resulting residue was purified on 12 g silica gel column (eluent, hexanes to 40% ethyl acetate in hexanes) to afford (7S)-di-tert-butyl 7-(bis(tert-butoxycarbonyl)amino)-4-hydroxyoct-2-ynedioate (diastereomeric mixture, 40 mg, 40.3% yield) as an oil. 1H NMR (CDCl3) delta ppm: 4.76 (dt, J=9.2, 5.2 Hz, 1H), 4.53 (m, 1H), 2.27 (m, 1H), 2.04 (m, 1H), 1.83 (m, 2H), 1.52 (s, 18H), 1.50 (s, 9H), 1.46 (s, 9H). 13C NMR (CDCl3) d ppm: 169.63, 169.52, 152.47, 152.40, 152.34, 84.96, 84.94, 83.63, 83.09, 83.04, 81.48, 81.46, 77.89, 77.84, 61.90, 61.37, 58.47, 58.31, 33.75, 33.70, 28.02, 27.96, 27.93, 25.13 and 24.72. MS (ESI+): 536 (M+Na)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With triethylamine; In dichloromethane; at 45℃; for 16h; | General procedure: The 2-pyrone (1 eq.), triethylamine (1 eq.) and propiolate ester (2 eq.) were stirred in CH2Cl2 (2 mL mmol) at 45 C for 16 hours. The solvent was then removed in vacuo and the product purified via flash column chromatography to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With bis-triphenylphosphine-palladium(II) chloride; In benzene; at 90℃; for 6h; | To a 5 L round bottom flask was added 1. 5 mol1,1-dimethylsilaneII,1 mol of t-butyl propiolate,10% equivalents of Pd (PPh3) 2CljP2 L benzene,Heated to 90 C, mechanical stirring reaction 6 hours.After the reaction, the silica gel column was decolorized and separated using a 10: 1 mixture of petroleum ether and ether as the eluent.(Purity & gt; 97%, colorless liquid) of pure product, 1,1-Dimethyl-3-t-butoxycarbonyl-silacyclohexeneThe isolated yield was 73%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); diethylamine; In N,N-dimethyl-formamide; at 100℃; for 0.433333h;Molecular sieve; Sealed tube; Inert atmosphere; Microwave irradiation; | (ii) Di-tert-butyl 8,8'-(((5-(2,2-dimethyl-4,20-dioxo-3,8,11,14,17-pentaoxa-5,21-diazatetracos-23-yn-24-yl)-1,3-phenylene)bis(methylene))bis(oxy))(11S,11aS,11'S, 11a'S)-bis(7-methoxy-2-methylene-5-oxo-11-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,11,11a-tetrahydro-H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate) (28) A catalytic amount of Pd(PPh3)4 (23.0 mg, 19.5 mumol) was added to a mixture of the iodoaryl compound 2a (1.02 g, 0.89 mmol), Boc-acetylene 27 (393 mg, 0.98 mmol), CuI (7.4 mg, 39.1 mumol), diethylamine (2.02 mL, 1.43 g, 19.5 mmol) and oven-dried 4 A molecular sieve pellets in dry DMF (9 mL) in an oven-dried sealable vessel. The mixture was degased and flushed with argon 3 times then heated in a microwave at 100 C. for 26 minutes at which point analysis by LC/MS revealed substantial product formation at retention time 1.89 minutes (ES+) m/z 1446 ([M+Na]+, ?100% relative intensity, 1424 ([M+H]+, ?15% relative intensity). The reaction mixture was allowed to cool to room temperature and was then filtered through a sinter to remove the sieves (washed with DMF). The filtrate was evaporated in vacuo and the resulting residue dissolved in DCM (100 mL) and washed with H2O (20 mL), brine (30 mL), dried (MgSO4), filtered and evaporated in vacuo to give the crude product. Purification by flash chromatography (gradient elution in 1% increments: 100% DCM to 97:3 v/v DCM/MeOH) provided the alkyne 28 as a yellow foam (882 mg, 70% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With copper(l) iodide; palladium diacetate; triethylamine; triphenylphosphine; at 60℃;Inert atmosphere; | A mixture of 3 (274 mg, 0.76 mmol), tert-butyl propiolate (0.314 mL, 2.28 mmol), copper (I) iodide (5.8 mg, 0.030 mmol), palladium (II) acetate (3.4 mg, 0.015 mmol) and triphenyl phosphine (12 mg, 0.046 mmol) in redistilled triethylamine (5 mL) was heated at 60 C overnight under N2 to give a dark-coloured suspension. All volatile components were pumped off. The resultant residue was stirred with DCM and the precipitate was filtered off. The filtrate was evaporated and the residue obtained was purified by silica gel column chromatography using a mixture of DCM and petroleum ether (v/v=l : 1) as eluent to give 4 (195 mg, 72 %) as an off-white solid. 1H NMR (CDC13) delta 7.48 (d, J= 7.9 Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 7.06 (s, 1H), 3.89 (s, 3H), 1.545 (s, 9H) and 1.514 (s, 9H) ppm. HRMS (ESI) found m/z 379.1510 (M + Na). C2iH24Na05 requires 379.1516. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | n-butyllithium (1.6 M in hexane; 41.9 mE, 67.0 mmol) was added dropwise within 10 mm at -55 to -50 C. to a soln of tert-butyl propiolate (103; 8.76 mE, 63.8 mmol) in dry THF (200 mE). The mixture was allowed to stir at -40 C. for 1.5 h. The mixture was cooled to -78 C. A soln of 102 (7.25 g, 31 9 mmol) in THF (66 mE) was added within 10 mm with the temperature not exceeding -64 C. The mixture was stirred for 0.5 h at -78 C., then warmed to -40 C. and allowed to slowly warm to 0 C. over 3 h. The mixture was poured into 1 M aq. KHSO4 soln and extracted with EtOAc. The organic phase was dried (Na2SO4) and concentrated. FC (hexane/EtOAc 90:10 to 70:30) afforded the ketone 104 (8.34 g, 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With copper(II) sulfate; sodium L-ascorbate; In water; dimethyl sulfoxide; tert-butyl alcohol; at 0 - 20℃; for 3h; | Step 1: (2R,3S)-3-((Z)-2-(((((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(tert-butoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid To a solution of Intermediate K (157 mg, 0.248 mmol) in a mixture of DMSO: water:tert-butanol (1:1:1, 2.0 mL) at 0 C. was added tert-butyl propiolate (68 muL, 0.496 mmol), CuSO4 (20 mg, 0.124 mmol) and sodium L-ascorbate (198 mg, 0.372 mmol). The resulting mixture was gradually brought to room temperature and stirred for 3 h, whereupon it was diluted with water (20 mL) and extracted with EtOAc (3*50 mL). The combined oganic layers were dried over Na2SO4, concentrated in vacuo dissolved in water and lyophilized, affording the title compound (180 mg, 96%) as a light yellow solid; LCMS: m/z=759.3 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triphenylphosphine; In acetonitrile; at 20℃; for 2h; | General procedure: A solution of theophylline (2 mmol) and methyl propiolate (1 mmol)in the presence of a catalytic amount of triphenyl phosphine (0.2mmol) in CH3CN (10 mL) was stirred for 2h at room temperature.After completion of the reaction (monitored by TLC), the solvent wasremoved under reduced pressure and the precipitate obtained waswashed with diethyl ether to yield a pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With copper(II) sulfate; ascorbic acid; In water; tert-butyl alcohol; at 20℃; for 12h; | A mixture of 4-azidobut- 1 -yne (20 g, 0.21 mol), tert-butyl propiolate (26.5 g, 0.210 mol), -(+)-Ascorbic acid (8.0 g, 46 mmol) and CuSC (4.0 g, 25 mmol) in t- BuOH/EkO = 1 : 1 (400 mL) was stirred at rt for 12 h. The mixture was concentrated at reduce pressure and 200 mL of water was added. The aqueous layer was extracted with EtOAc (3 x 300 mL) and the combined organic layers were concentrated at reduced pressure to give a yellow solid. The solid was washed with petroleum ether to give the title compoud as a white solid (25 g, 54%). MS (ES+) C11H15N3O2 requires: 221, found: 222 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In dichloromethane; at 20℃; | General procedure: To a stirred solution of the acetylenic ester (2 mmol) and the 1,3-diketones (2 mmol) in 10 mL of CH2Cl2 was added 0.26 g of isoquinoline (2 mmol) at r.t. After completion of the reaction (2-3 h), as indicated by TLC (AcOEt/hexane, 1:2), the solvent was removed under reduced pressure and the viscous residue was purified by column chromatography on silica gel (Merck 230-400 mesh) using hexane-AcOEt (2:1) as eluent to afford pure title compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In dichloromethane; at 20℃; | General procedure: To a stirred solution of the acetylenic ester (2 mmol) and the 1,3-diketones (2 mmol) in 10 mL of CH2Cl2 was added 0.26 g of isoquinoline (2 mmol) at r.t. After completion of the reaction (2-3 h), as indicated by TLC (AcOEt/hexane, 1:2), the solvent was removed under reduced pressure and the viscous residue was purified by column chromatography on silica gel (Merck 230-400 mesh) using hexane-AcOEt (2:1) as eluent to afford pure title compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 1,4-diaza-bicyclo[2.2.2]octane; In tetrahydrofuran; at 20℃; for 48h;Inert atmosphere; | Step A. Preparation of tert-butyl 3-(cyclohexylmethoxy)acrylate To a solution of cyclohexylmethanol (0.98 g, 8.7 mmol) and DABCO (88 mg, 0.79 mmol) in THF at room temperature under nitrogen was added tert-butyl propiolate (1.0 g, 7.9 mmol). The reaction was stirred for 2 days and then concentrated in vacuo and purified by flash column chromatography (EtOac/hexanes 0-10%) to afford the titled compound (1.4 g, 75%) as a colorless oil. [note: products were generally a mixture of E and Z alkene isomers] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Preparation of K1 Under N2, at -78 C, TiCI4 (10.8 muIota_, 98.7 mmol) was added to a solution of 1 - methoxy-2-methyl-1 -(trimethylsiloxy)propene (20 mL; 98.7 mmol) and ferf-butyl propiolate (13.5 uL, 98.7 mmol) in E (340 mL). The reaction mixture was stirred at - 78 C for 30 min. H20 (65 mL) was added at -78 C. The mixture was allowed to warm to rt and water and DCM were added. The aqueous layer was extracted with CH2CI2. The combined organic layer were washed with water, dried over MgS04, filtered and evaporated in vacuo to give K1 (79%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With oxygen; copper diacetate; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 12h;Sealed tube; | General procedure: The reaction of benzamide 1a with ethynylbenzene(2a) is representative. The dry sealed tube was charged withN-(quinolin-8-yl)benzamide (1a, 99 mg, 0.4 mmol), ethynylbenzene(2a, 82 mg, 0.8 mmol), Cu(OAc)2 (73 mg, 0.4 mmol),K2CO3 (111 mg, 0.8 mmol) and 2 mL DMF. The resulting mixturewas stirred at 80 C for 12 hours under oxygen atmosphere (O2 balloon). The mixture was diluted with dichloromethane(10 mL), filtered through a celite pad, and washed withdichloromethane (20 mL). The resulting mixture was washedwith water (3 times) and brine. The combined organic layer wasdried with Na2SO4, concentrated, and purified by column chromatographyon silica gel (DCM/MeOH 200:1-50:1) to give (Z)-3-benzylidene-2-(quinolin-8-yl)isoindolin-1-one (3a) as a paleyellow solid (81%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With tetra-n-butylphosphonium acetate; In tetrahydrofuran; at 25℃; for 12h; | General procedure: To a stirred solution of amide (1.5 mmol), propiolate (1.0mmol), and TBPA (20 mol%) in THF (3 mL), the N-heterocycle(1.0 mmol) was added slowly at 25 C (for 10 min), and theresulting mixture was stirred at ambient temperature for 12 h.After completion of the reaction (monitored by TLC), themixture was evaporated in vacuo followed by addition of H2O(10 mL), and the pH was adjusted to 2 using concentrated HCl.Afterwards, CH2Cl2 (5 mL) was added, the mixture was stirredfor an additional 30 min, and two layers were separated. Theaqueous layer was extracted with CH2Cl2 (3 × 10 mL), the combinedorganic layers were dried over MgSO4, filtered, and concentratedin vacuo to yield the crude product (purity 75-82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.0 g | With 4-methyl-morpholine; at 20℃; for 24h; | a mixture of 4-(2-methoxy ethyl) phenol (1.547 g, 10.3 mmol), propiolic acid tert-butyl ester (1.367 g, 10.8 mmol) and N-methyl morpholine (1.18 mL, 10.8 mmol) in CH2Cl2 (15 mL) was stirred at room temperature for 24 hours. The mixture was absorbed on SiO2 (20 g) and purified by column chromatography using a mixture of methylene chloride/hexane. The product was obtained as a two to one mixture of (E)/(Z)-tert-butyl 3-(4-(2-methoxyethyl)phenoxy)acrylate isomers (2.0 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-chloro-2-fluoroaniline With trifluoroacetic acid; sodium nitrite In water at 0℃; for 0.5h; Stage #2: With sodium azide In water at 20℃; Stage #3: tert-butyl prop-2-ynoate With copper diacetate; potassium carbonate; sodium L-ascorbate; <i>L</i>-proline In water; dimethyl sulfoxide at 75℃; | 23A 23 A. Preparation of 1 -(3 -chloro-2-fluorophenyl)- 1 H- 1,2,3 -triazole-4-carboxylic acid To a solution of 3-chloro-2-fluoroaniline (1.2 g, 8.24 mmol) in TFA (4m1), H20 (2m1) was added and the mixture was cooled to 0 °C. NaNO2 (1.12 g, 16.24 mmol) in H20 (2m1) was added dropwise (temperature kept <5°C). After 0.5h, NaN3 (0.5 85 g, 9.0 mmol) was added portionwise. After stirring at rt overnight, the reaction was quenchedwith H20 (lOOml), extracted with EtOAc(2x50m1), dried over Na2SO4, and concentrated to give a solid mass. To a solution of the solid dissolved in DMSO (5 ml), L-proline (0.02g), Cu(OAc)2 (0.lg) K2C03 (1.5g), sodium ascorbate (0.lg), and excess t-butyl propiolate (3 ml) were added and the mixture heated at 75°C overnight. The reaction was quenched with H20 (lOOml), extracted with EtOAc (2 x lOOml), washed with brine(50m1), dried (MgSO4), filtered, and concentrated. The crude product was purifed by normal phase chromatography to give the t-butyl ester intermediate. An aliquot of this material (0.2g) was dissolved in DCM (2m1) and treated with TFA (1 ml) at rt. After stirring overnight, the reaction was quenched with H20 (50m1), extracted with EtOAc (2 xlOOml), dried (MgSO4), filtered, and evaporated to give a brown solid mass. This material was carried forward as is without further purification. ). (ESI) m/z: 342.1 (M+H). 342.1(M+H). ‘HNMR (400MHz, CD3OD/CDC13) ö 8.20(s, 1H), 7.60-7.55(dt, 1H), 7.42-7.37(dt, 1H), 7.28-7.23(dt, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Lithium bis(trimethylsilyl)amide (4.95 mL, 4.95 mmol, 1.0 M in THF, 1.55 equiv.) was cooled to -78 C, then i-butyl propiolate (604 mg, 4.789 mmol, 1.5 equiv.) in 3 mL THF was added and the reaction mixture was stirred for 45 min. The solution was then added via cannula over 10 min to ketone (3R)-9 (953 mg, 3.193 mmol, 1 equiv.) in 5 mL THF at -78 C and stirred for 2 h. The reaction was quenched with satd aq NH4Cl (50 mL), warmed to rt, and extracted with EtOAc (4 x 50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (50%? 100% CH2Cl2 in hexanes) yielded the ester (15,3R)-10 as a clear viscous oil (1.05 g, 78%). IR (ATR): 3400, 2956, 2932, 2888, 2860, 2248, 1710, 1473, 1395, 1371, 1258, 1204, 1153, 1114, 1039, 1013, 909, 888, 838, 781, 751, 732, 695, 672, 657. 1H-NMR (500 MHz; CDCl3): delta 7.63-7.60 (m, 1H), 7.47-7.45 (m, 2H), 7.38-7.37 (m, 1H), 5.19 (dd, 7 = 8.0, 6.3 Hz, 1H), 2.96 (d, 7 = 2.3 Hz, 1H), 1.49 (s, 9H), 0.95 (s, 9H), 0.24 (s, 6H). 13C-NMR (126 MHz; CDCl3): delta 151.8, 139.5, 139.1, 130.9, 130.3, 124.9, 124.4, 124.2, 84.2, 80.6, 78.2, 74.9, 74.4, 28.0, 25.7, 18.2, -4.65, -4.84. 19F-NMR (471 MHz; CDCl3): delta delta -115.05 (d, 7 = 224.7 Hz, 1F), -128.46 (d, 7 = 224.6 Hz, 1F). HRMS (ESI) m/z calcd for C22H30O4F2SiNa ([M+Na]+) 441.1779; found 441.1785. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Lithium bis(trimethylsilyl)amide (6.5 mL, 6.492 mmol, 1.0 M in THF, 1.55 equiv.) was cooled to -78 C, then i-butyl propiolate (793 mg, 6.283 mmol, 1.5 equiv.) in 3 mL THF was added and the mixture was stirred for 45 min. The solution was then added via cannula over 10 min to ketone (3R)-9 (1.25 g, 4.189 mmol, 1 equiv.) in 5 mL THF at -78 C and stirred for 2 h. The reaction was quenched with satd aq NH4Cl (50 mL), warmed to rt, and extracted with EtOAc (4 x 50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (50%? 100% CH2Cl2 in hexanes) yielded the ester (1R,3S)-10 as a yellow tinged oil (1.778 g, 82%). IR (ATR): 3394, 2956, 2932, 2888, 2859, 2245, 1762, 1473, 1395, 1371, 1258, 1205, 1153, 1113, 1040, 1013, 909, 888, 839, 791, 751, 732, 695, 672, 657. 1H-NMR (500 MHz; CDCl3): delta 7.63-7.60 (m, 1H), 7.48-7.44 (m, 2H), 7.39-7.37 (m, 1H), 5.19 (dd, / = 8.0, 6.4 Hz, 1H), 1.49 (s, 9H), 0.95 (s, 9H), 0.24 (s, 6H). 13C-NMR (126 MHz; CDCl3): delta 151.8, 139.4, 139.1, 130.9, 130.3, 124.9, 124.4, 124.2, 84.2, 80.6, 78.2, 74.9, 74.4, 28.0, 25.7, 18.2, -4.6, -4.9. 19F-NMR (471 MHz; CDCl3): delta -115.04 (d, = 222.3 Hz, 1F), - 128.51 (d, = 223.3 Hz, 1F). HRMS (ESI) m/z calcd for C22H30O4F2SiNa ([M+Na]+) 441.1779; found 447.1774. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(ll) sulfate pentahydrate; sodium L-ascorbate; In water; tert-butyl alcohol; at 20℃; for 2h; | Step 3: 1 -[4-(tert-Butyl-dimethyl-silanyloxymethyl)-benzyl]-1 H-[1 ,2,3]triazole-4- carboxylic acid tert-butyl ester. Cupric sulfate pentahydrate (1 .03 g, 4.1 1 mmol) and sodium ascorbate (4.07 g, 20.6 mmol) are added to a stirred solution of (4-azidomethyl-benzyloxy)-tert-butyl-dimethy- silane (6.0 g, 20.6 mmol) and tert-butyl propiolate (3.10 ml, 22.6 mmol) dissolved in a mixture of 50 ml of tert-butanol and 50ml of water. The reaction mixture is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the residue is partitioned between water and DCM. The organic layer is separated and concentrated under reduced pressure to obtain the crude title compound (Yield 8.3 g). LC (Method 4): tR = 0.73 min; Mass spectrum (ES+): m/z = 404 [M+H]+. | |
With copper(ll) sulfate pentahydrate; sodium L-ascorbate; In water; tert-butyl alcohol; at 20℃; for 2h; | Oupric sulfate pentahydrate (1 .03 g, 4.11 mmol) and sodium ascorbate (4.07 g, 20.6 mmol) are added to a stirred solution of (4-Azidomethyl-benzyloxy)-tert-butyl-dimethy-silane (6.0 g, 20.6 mmol) and tert-butyl propiolate (3.10 ml, 22.6 mmol) dissolved in a mixture of 50 mL of tert-butanol and 50m1 of water. The reaction mixture is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the residue is partitioned between water and DOM. The organic layer is separated and concentrated under reduced pressure to obtain thecrude title compound (yield 8.3 g).LO (Method 4): tR = 0.73 mm; Mass spectrum (ES+): m/z = 404 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With triphenylphosphine; In dichloromethane; at 0 - 25℃; for 16h; | To a stirred solution of 1 ?-benzyl-4-chloro- 1 ,2-dihydrospiro [indole-3 ,4?-piperidine] -2-one (600 mg, 1.83 mmol, INT5c) and <strong>[13831-03-3]2-propynoic acid tert-butyl ester</strong> (0.27 mL, 2.02 mmol, CAS RN 1383 1-03-3) in DCM (70 mL) was added dropwise to a solution of PPh3 (530 mg, 2.02 mmol,CAS RN 603-35-0) in DCM (10 mL) at 0C. The reaction mixture was then allowed to warm upto 25C and stirred for 16 h. The solvent was removed under reduced pressure and the resultingcrude product was purified by column chromatography over silica gel (20-30% EtOAc/n-hexane)to yield the title product (370 mg, 44%) as a yellow solid. MS (El): mlz = 453.0 [M+H] . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | Example 9 Methyl (E)-3-[[1-(pyridin-3-yl)naphthalen-2-yl]oxy]acrylate 1-(Pyridin-3-yl)naphthalen-2-ol (80 mg, 0.26 mmol) obtained in Example 8 (1) was dissolved in dimethylformamide (2 mL), sodium hydride (16 mg, 0.4 mmol) was added thereto in an ice bath, and the solution was stirred at room temperature. After 10 minutes, methyl propiolate (91 muL, 1.1 mmol) was added to the reaction solution and the reaction solution was further stirred at 110 C. After 16 hours, water was added to the reaction solution in an ice bath, extraction was carried out using chloroform, the organic layer was dried over sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain a crude material of methyl (E)-3-[[1-(pyridin-3-yl)naphthalen-2-yl]oxy]acrylate (25 mg, yield of 22%) and methyl (Z)-3-[[1-(pyridin-3-yl)naphthalen-2-yl]oxy]acrylate. j0682] A title compound (white crystal, 24 mg, yield of41%) was obtained according to the same method as inExample 9 using 4-(2-mercaptonaphthalen- 1 -yl)benzonitrile(40 mg, 0.15 mmol) obtained in Example 48 (3) and t-butylpropiolate (63 pL, 0.46 mmol).10683] ?H NMR (CDC13, 400 MHz): oe=1.43 (s, 9H), 5.46(d, 1H, J=15 Hz), 7.32 (d, 1H, J=8 Hz), 7.4-7.5 (m, 3H),7.5-7.6 (m, 2H), 7.63 (d, 1H, J=8 Hz), 7.78 (d, 2H, J=8 Hz),7.9-8.0 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22%; 25% | With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 5h; | 4-(2-Hydroxynaphthalen-1-yl)benzonitrile (83 mg, 0.34 mmol) was dissolved in dimethylformamide (4 mL), potassium carbonate (94 mg, 0.68 mmol) and t-butyl propiolate (70 muL, 0.51 mmol) were added thereto, and the solution was stirred at 120 C. After 5 hours, the reaction solution was allowed to be cooled to room temperature, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain t-butyl (E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]acrylate (colorless oil material, 32 mg, yield of 25%) and t-butyl (Z)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]acrylate (colorless oil material, 28 mg, yield of 22%). 1H NMR (t-butyl (E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]acrylate, CDCl3, 400 MHz): delta=1.45 (s, 9H), 5.20 (d, 1H, J=12 Hz), 7.34 (d, 1H, J=9 Hz), 7.4-7.5 (m, 5H), 7.57 (d, 1H, J=12 Hz), 7.80 (d, 2H, J=8 Hz), 7.92 (d, 1H, J=8 Hz), 7.97 (d, 1H, J=9 Hz). 1H NMR (t-butyl (Z)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]acrylate, CDCl3, 400 MHz): delta=1.40 (s, 9H), 4.90 (d, 1H, J=7 Hz), 6.60 (d, 1H, J=7 Hz), 7.38 (d, 1H, J=9 Hz), 7.4-7.6 (m, 5H), 7.79 (d, 2H, J=8 Hz), 7.91 (d, 1H, J=8 Hz), 7.95 (d, 1H, J=9 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40%; 45% | With sodium hydrogencarbonate; In N,N-dimethyl acetamide; at 20℃; for 24h; | 1- (4'-tolyl) -2,2,2-trifluoroethanone (1.0 mmol),Tert-butyl propiolate (0.5 mmol),AgOOCH2CH3 (0.05 mmol),NaHCO3 (0.1 mmol) andDMA (1 mL) was added to Xu Lin grams bottle,The reaction was stirred at room temperature for 24 h and the reaction was followed by TLC.After the reaction was completed, the reaction was quenched by adding 15 mL of saturated brine and the reaction mixture was usedThe reaction product was extracted with dichloromethane (15 mL × 3). The combined organic phases were concentrated using a rotary evaporator to give the crude product. Column chromatographyThe target product was obtained. The eluant for column chromatography was petroleum ether: ethyl acetate (100: 1). The product structure was identified by NMR and high resolution mass spectrometry.1f separation yield of 40%, 2f separation yield of 45%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44%; 43% | With silver carbonate; potassium hydroxide; In N,N-dimethyl acetamide; at 20℃; for 24h; | (1.0 mmol) of 1- (4'-bromophenyl) -2,2,2-trifluoroethanone (1.0 mmol), t-butyl propiolate (1.0 mmol),t-butylpropiolateAg2CO3(0.05 mmol), KOH (0.1 mmol) and DMA (1 mL) were added to Xu Linke bottles and thereaction was stirredatroom temperature for 24 h. The reaction was followed by TLC.After completion of the reaction, 15 mL of saturated brine was added to quench the reaction, antishall reaction mixture was extracted with dichloromethane (15 mL × 3) the product, the organic phases were combined, and concentrated using a rotary evaporator to give crude productproduct column chromatography to obtain the target The product, eluting with column chromatography, was petroleum ether: ethyl acetate (100: 1) and the product structure wasidentifiedbyNMR and high resolution mass spectrometry.1l isolated yield of 44%, 2l isolated yield of 43%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39%; 44% | With silver carbonate; potassium hydroxide; In N,N-dimethyl acetamide; at 20℃; for 24h; | Sequentially 1- (4'-chlorophenyl) -2,2,2-trifluoro-ethanone (1.0mmol), tert-butyl propyne (0.5 mmol), of Ag2CO.'s. 3(0.05 mmol), of KOH ( 0.1 mmol) and DMA (1 mL) were added to Xu Linke bottle, the reaction was stirred at room temperature for 24 h, the reaction was followed byTLC.After the reaction was completed, the reaction was quenched by adding 15 mL of saturated brine and the reaction mixture was extracted with dichloromethane (15mL × 3). The combined organic phases were concentrated using a rotary evaporator to give the crude product, which was purified by column chromatography to give the title product.The eluant for column chromatography was petroleum ether: ethyl acetate (100: 1) and the product structure was identified by NMR and high resolution mass spectrometry.1iisolated yield of 39%, 2i isolated yield of 44%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With N,N,N,N,N,N-hexamethylphosphoric triamide; diisobutylaluminium hydride; In tetrahydrofuran; toluene; at 0℃; for 6h;Inert atmosphere; | Hexamethylphosphoric triamide (10.7 g, 59.9 mmol) was dissolved in tetrahydrofuran (160 mL) under nitrogen(0.5 M, 36 mL) was added at 0 C for 0.5 hour at 0 C, tert-butyl propiolate (5.04 g, 40 mmol) was added and the reaction was continued for 1 hour. Then add 2b (5.47g, 40mmol), gradually rose to room temperature, reaction 5 hours, slowly adding 1M hydrochloric acid to the reaction solution, adjust the reaction solution pH to 2 ~ 3, The organic phase was washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified. The organic phase was extracted with ethyl acetate (50 mL x 2) (Ethyl acetate: petroleum ether (v / v) = 0: 1 to 1: 9) to give the title compound 2c as a yellow oil (2.2 g, yield 21%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With N,N,N,N,N,N-hexamethylphosphoric triamide; diisobutylaluminium hydride; In tetrahydrofuran; toluene; at 0℃; for 4h;Inert atmosphere; | Hexamethylphosphoric triamide (11.5 g, 64.2 mmol) was dissolved in dry tetrahydrofuran (100 mL), nitrogen(1.5 mL of toluene solution) (36 mL, 54 mmol) was added dropwise, and the mixture was stirred at 0 C for 30 minutes, solution of t-butyl propionate (3c) (5.4 g, 43 mmol) in dry tetrahydrofuran (30 mL) was added dropwise and the mixture was stirred for 1 hour and the crude product (8 g) was added dropwise to dry tetrahydrofuran (30 mL) After the addition, the temperature was raised to room temperature for 3 hours. The mixture was extracted with ethyl acetate (30 mL x 1), and the organic layers were combined and washed with saturated sodium chloride (15 mL x 1). The aqueous layer was washed with ethyl acetate (30 mL x 1) Dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate (v: v) = 1: 0 to 20: 1) to give the title compound 3d, Yellow oil (2.6 g, yield 24%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With N,N,N,N,N,N-hexamethylphosphoric triamide; diisobutylaluminium hydride; In tetrahydrofuran; toluene; at 0℃; for 6h;Inert atmosphere; | Hexamethylphosphoric triamide (21.48 g, 119.9 mmol) was dissolved in tetrahydrofuran (320 mL) under nitrogenA toluene solution of 1.5 mol / L diisobutylaluminum hydride (108 mmol, 72 mL) was added at 0 C,0 C for 0.5 hour,Tert-Butyl propionate (10.08 g, 79.90 mmol)The reaction was continued for 1 hour,Then add 1b (10.95 g, 79.90 mmol) and gradually warmed to room temperature for 5 hours. The reaction solution was slowly added to 1 M hydrochloric acid to adjust the pH to 2 to 3, add ethyl acetate (50 mL), and extract. The aqueous phase was extracted with ethyl acetate (50 mL x 1) and the organic phases were combined. The organic phase was washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 0: 1 to 1: 9) to give the title compound 1c as a yellow oil (4.2 g, yield 20%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.5% | With triethylamine; N,N-dimethyl-formamide; at 50℃; for 4.17h; | 4 mmol of t-butyl propiolate was added to a 25 mL one-neck flask,Then 12 mL of N, N-dimethylformamide was added,Join magnetic stirrer,Then slowly dropping 12mmol of triethylamine (10 minutes drip finished),The reaction was heated with stirring in a 50 C oil bath for 4 hours.The mixture was cooled to room temperature, 15 mL of dichloromethane was added to the reaction mixture, and 30 mL of water was added thereto. The organic layer was collected by extraction and the organic phase was collected twice and extracted twice with methylene chloride. Each time 15 mL was added and the collected organic phase was washed three times with water , Adding 50 mL of water each time, and finally adding 15 g of anhydrous sodium sulfate to the organic phase to dry, filtering, collecting the filtrate, vacuum distillation and column chromatography to obtain a white solid product (eluent: petroleum ether: ethyl acetate v / v = 50: 1), yield 81.5%, 0.44g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In N,N-dimethyl-formamide; at 145℃; for 0.5h;Inert atmosphere; Sealed tube; Microwave irradiation; | General procedure: To a microwave reactor vial (5 ml) which contained the solutionof 4 or 5 or 6 or 7-bromoindoline-2,3-dione (1.0 g, 4.4 mmol) inDMF (5 ml) were added PdCl2(PPh3)2 (155 mg, 0.22 mmol),CH3COOK (0.6 g, 6.2 mmol) and ethenyl (5.3 mmol) under the atmosphereof argon. The microwave reactor vial was caped andplaced into the microwave cavity. The reaction mixture was irradiatedat high level for 30 min at 145 C. The reaction mixture wascooled to room temperature, poured onto 100 ml ice-water andthen extracted with dichloromethane (3 x 100 ml). The combinedorganic layers werewashed withwater (2 x 100 ml), brine (100 ml)and dried over anhydrous magnesium sulfate. The solvent wasremoved under vacuum to afford the crude which was purified byflash column chromatography (silica gel, petroleum ether/ethylacetate 3:1) to yield the desired (2-Carboxyethenyl) isatinderivatives. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With 1,4-diaza-bicyclo[2.2.2]octane; In dichloromethane; at 0 - 20℃;Inert atmosphere; | .,. t 0 C under argon was added DABCO (0.034 g, 0.300 mmol), followed by slow addition of tert-butyl propiolate (0.51 mL, 3.6 mmol). The mixture was stirred at this temperature for additional 20 min, then gradually warmed to rt overnight. The mixture was acidified with HOAc (34 muL). The solvent was removed under reduced pressure and the residue was purified via flash column chromatography (SiO2, hexanes/EtOAc gradient 0 to 40% EtOAc) to give E5B (0.19 g, 17% yield).1H NMR (500 MHz, chloroform-d) delta 8.03 (d, J = 0.9 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 9.6 Hz, 1H), 7.12 (d, J = 2.2 Hz, 1H), 7.03 (dd, J = 8.9, 2.2 Hz, 1H), 5.62 (d, J = 9.5 Hz, 1H), 1.47 (s, 9H), 1.03 (s, 9H), 0.23 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 1,3-bis-(diphenylphosphino)propane; copper diacetate; palladium diacetate; 3-amino propanoic acid; In N,N-dimethyl acetamide; N,N-dimethyl-formamide; at 80℃; for 0.5h;Inert atmosphere; | 0.2mmol added benzenesulfonyl hydrazide in the reactor, 0.2mmol of t-butyl propiolate, 5.0 mol% palladium acetate, 5.0 mol% dppp, 0.4 mmol copper acetate, 15 mol% beta-aminopropionic acid,2.0mL DMF and DMAc mixed solvent (volume ratio [3: 1]). In a nitrogen atmosphere, heat to 80 C and continue stirring for 0.5h to stop the reaction and cool to room temperature.Washed with saturated NaCl, then extracted with ethyl acetate, dried,The solvent was removed by distillation under reduced pressure, and the crude product was separated by column chromatography to obtain the target product with a yield of 78%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With 1,4-diaza-bicyclo[2.2.2]octane; In dichloromethane; at 20℃; | Compound 114a (1.087 ml, 7.93 mmol) and Compound 114b (1.36 g, 8.32 mmol) were dlssolved ln dlchloromethane (10 ml), And 1,4-Dlazablcyclo [2.2.2] octane (0.18 g, 1.59 mmol) was added thereto, followed by stlrrlng at room temperature overnlght.The reactlon solutlon was concentrated and subjected to slllca gel column chromatography,Eluted wlth hexane / ethyl acetate.The fractlons contalnlng the deslred compound were concentrated under reduced pressure to glve Compound 114c (1.64 g, 72%)Was obtalned. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With triethylamine; In acetonitrile; at 20℃; for 1.5h; | methyl 2-(1 H-indol-5-yl)acetate (5.60 g, 29.60 mmol) was dissolved in acetonitrile (30 mL) and triethylamine (4.54 mL, 32.55 mmol) was added to the solution followed by tert-butyl propiolate (4.46 mL, 32.55 mmol). The solution was stirred at rt for 90 mm. The mixture was concentrated to dryness. The residue was dissolved in EtOAc/H20 and, after phases separation, thecombined organic layer were washed with brine, dried over Mg504, filtered and the solution was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of Heptane/EtOAc from [100:0] to [65:35]. The fractions of the main product were concentrated to dryness to afford a pale yellow solid. This solid was triturated with heptane to obtain tert-butyl 3-[5-(2-methoxy-2-oxoethyl)-1 H-indol-1 -yl]prop_ 2-enoate Ex.57a (6.40 g, 69%) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With copper(l) iodide; In acetonitrile; at 20℃; for 3h; | General procedure: To a stirred solution of CuI (19 mg, 0.1 mmol) and ethyl alpha-diazoacetate (7a, 114 mg, 1 mmol) in MeCN (3 mL) was added a solution of but-3-yn-2-one (6a, 68 mg, 1 mmol) in MeCN (1 mL). After the resultant mixture was stirred at room temperature for 3 h (monitored by TLC), the solvent was removed by vacuum and the residue was purified by flash chromatography (silica gel, 20% EtOAc in PE) to give 110 mg (71%) of the desired product 1a as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With copper(l) iodide; In acetonitrile; at 20℃; for 3h; | General procedure: To a stirred solution of CuI (19 mg, 0.1 mmol) and ethyl alpha-diazoacetate (7a, 114 mg, 1 mmol) in MeCN (3 mL) was added a solution of but-3-yn-2-one (6a, 68 mg, 1 mmol) in MeCN (1 mL). After the resultant mixture was stirred at room temperature for 3 h (monitored by TLC), the solvent was removed by vacuum and the residue was purified by flash chromatography (silica gel, 20% EtOAc in PE) to give 110 mg (71%) of the desired product 1a as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With copper(l) iodide; In acetonitrile; at 20℃; for 3h; | General procedure: To a stirred solution of CuI (19 mg, 0.1 mmol) and ethyl alpha-diazoacetate (7a, 114 mg, 1 mmol) in MeCN (3 mL) was added a solution of but-3-yn-2-one (6a, 68 mg, 1 mmol) in MeCN (1 mL). After the resultant mixture was stirred at room temperature for 3 h (monitored by TLC), the solvent was removed by vacuum and the residue was purified by flash chromatography (silica gel, 20% EtOAc in PE) to give 110 mg (71%) of the desired product 1a as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 20℃; for 24h; | General procedure: To a stirred solution of pseudouridine (1.0mmol) in DMF (10.0 mL) at room temp., DBU (1.0 mmol) was added and the mixture was stirred for 15 mins. After 15 min. propiolate (0.8 mmol) was added to the reaction mixture and stirred for 4 h. Another portion of propiolate (0.5 mmol) was added to the reaction mixture and was further stirred at room temp. for the time specified in Table 2. Then, the reaction mixture was evaporated under rotary evaporator to give crude reaction mixture. The crude reaction mixture was purified by reverse phase column chromatography using Biotage instrument (Column: KP-C18-HS 120 g; Flow rate: 50.0 mL; Mobile phase A: Water; Mobile phase B: Acetonitrile; Gradient: 0 - 100% B). The fractions containing the pure product were evaporated and dried to give a white colored powder 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With dmap; In dichloromethane; at 0 - 20℃; for 2.5h; | To a solution of Compound IV-2 (10.0 g, 28.17 mmol) in DCM (150 mL) was added DMAP (6.8 g, 56.34 mmol). Then <strong>[13831-03-3]tert-butyl prop-2-ynoate</strong> (4.3 g, 33.80 mmol) was added dropwise to the mixture at 0 C. The resulting mixture was stirred at room temperature for 2.5 h. The reaction mixture was diluted with DCM. The resulted mixture was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with EtO Ac/petroleum ether (1 : 1, v/v) to afford the title compound (9.0 g, 66%) as a yellow oil. LCMS (ESI, m/z): [M+H]+ = 482.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | To a solution of tert-butyl propiolate Compound 1a (10 g, 79.28 mmol) in THF (600 mL) was added LDA (2.0 M in THF) (43.6 ml, 87.20 mmol) at -78 C. The reaction mixture was stirred at -78 C. for 50 minutes and then acetaldehyde (4.45 ml, 79.28 mmol) was added dropwise at the same temperature. The reaction mixture stirred at same temperature for 2 h. The progress of the reaction was monitored by TLC (25% EtOAc in petroleum ether, RF=0.2, KMnO4 active) until the starting material was consumed. The reaction mixture quenched with sat. aq. NH4Cl solution (400 ml) and stirred for 20 min. The product was then extracted in diethyl ether (2×400 ml), and dried over anhydrous sodium sulfate. The solvent removed under reduced pressure and the crude product was isolated. The product was purified by column chromatography (100-200 silica gel/eluent 20% EtOAc in petroleum ether) to give Compound 2a (7 g, 52%) as a yellow liquid. 1H NMR (400 MHz, DMSO-d6) delta =5.66 (d, J=5.7 Hz, 1H), 4.50 (quin, J=6.4 Hz, 1H), 1.43 (s, 9H), 1.32 (d, J=6.6 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With LACTIC ACID; water; at 25 - 32℃;Sonication; Green chemistry; | General procedure: In a tube was placed alkyne (0.2 mmol), KSeCN (35 mg, 0.24 mmol), water (4 mg, 0.2 mmol), lactic acid (73 mg, 0.8 mmol), then the contents were reacted under ultrasound irradiation. Upon completion, water (10 mL) was added to the reaction mixture, the aqueous solution was extracted with ethyl acetate (5 mL×3) and the combined organic layer was washed with saturated sodium bicarbonate, dried with anhydrous MgSO4, filtered, the solvent was removed to afford 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With water; potassium thioacyanate; at 50℃; for 10h;Green chemistry; | General procedure: In a vial was placed alkyne (0.3 mmol), ChCl/glycolic acid (1:2)(270 mg, 0.9 mmol), KSCN (38 mg, 0.39 mmol), water (0.3 mmol), and then the contents were reacted at 50 C. Upon completion, the reaction mixture was purified by column chromatography on silicagel (eluent: hexanes/ethyl acetate) to afford 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25 - 30℃; for 16h;Inert atmosphere; | To a stirred solution 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol hydrochloride (0.20 g, 0.64 mmol) in DMF (5 mF) were adeed tert-butyl propiolate (0.18 g, 1.29 mmol) and DIPEA (0.3 mF, 1.90 mmol) at RT and stirred for 16 h at 25-30 C under nitrogen atmosphere. Then the reaction mixture was quenched with cold water (20 mF) extracted with EtOAc (2 x 50 mF). The combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combi flash column chomatography using 50-60 % ethyl acetate in hexane as eluent to afford the title compounds, yield : 46 % FC-MS: m/z 398.2 (M+l)+ . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 1,4-diaza-bicyclo[2.2.2]octane; In tetrahydrofuran; at 20℃; for 0.25h; | To a stirred solution of 7-bromo-3,3-dibutyl-8-hydroxy-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 115; 0.1 g, 0.20 mmol) in THF (5 mL) were added DABCO (0.002 g, 0.02 mmol) and tert-butyl propiolate (0.04 g, 0.31 mmol), and the reaction mixture was stirred for 15 minutes at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc (20 mL). The organic layer was washed with water (2×10 mL) and then dried over anhydrous Na2SO4. The organic part was concentrated under vacuum to afford the crude material which was purified by Isolera column chromatography (eluent: 15% EtOAc in hexane; silica gel: 230-400 mesh) to furnish the title compound. Yield: 87% (0.11 g, brown solid). 1H NMR (400 MHz, DMSO-d6): delta 7.78 (bs, 1H), 7.65 (d, J=12.0 Hz, 1H), 7.51 (s, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.33 (d, J=6.8 Hz, 2H), 7.18 (t, J=8.0 Hz, 1H), 6.84 (s, 1H), 5.18 (d, J=12.0 Hz, 1H), 4.02 (bs, 2H), 1.51-1.35 (m, 13H), 1.26-1.01 (m, 4H), 0.90-0.80 (m, 4H), 0.80-0.60 (m, 6H). LCMS: (Method A) 605.2 (M+-2H), Rt. 3.78 min, 90.48% (max). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With 1,4-diaza-bicyclo[2.2.2]octane; In tetrahydrofuran; at 0 - 20℃; for 1h; | To a stirred solution of 3-butyl-3-ethyl-8-hydroxy-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 128, 1.0 g, 1.85 mmol) in THF (10 mL) were added DABCO (0.02 g, 0.18 mmol) and t-butyl propiolate (0.28 g, 2.22 mmol) at 0 C. and the reaction mixture was stirred for 1 hour at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc (20 mL). The organic layer was washed with water (2×15 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting crude was purified by Isolera column chromatography (eluent: 15% EtOAc in hexane; silica gel: 230-400 mesh) to afford the title compound. Yield: 49% (0.6 g, white solid). 1H NMR (400 MHz, DMSO-d6): delta 7.66 (d, J=12.3 Hz, 1H), 7.43 (s, 1H), 7.37 (t, J=7.6 Hz, 2H), 7.26 (d, J=8.6 Hz, 2H), 7.20-7.14 (m, 3H), 6.87 (d, J=8.6 Hz, 2H), 6.48-6.25 (m, 1H), 5.27 (d, J=12.1 Hz, 1H), 4.51 (s, 2H), 4.30-4.10 (m, 2H), 3.73 (s, 3H), 2.08 (s, 3H), 1.50-1.36 (m, 13H), 1.18-0.84 (m, 4H), 0.72-0.48 (m, 6H). LCMS: (Method A) 611.2 (M+-tBu+H), Rt. 3.94 min, 98.16% (max). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 1,4-diaza-bicyclo[2.2.2]octane; In tetrahydrofuran; at 20℃; for 0.5h; | To a stirred solution of 3,3-dibutyl-8-hydroxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carbonitrile 1,1-dioxide (Intermediate 143; 0.21 g, 0.49 mmol) in THF (2 mL), DABCO (5.50 mg, 0.05 mmol) and tert-butyl propiolate (81 mg, 0.69 mmol) were added and the reaction mixture was stirred for 30 minutes at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum and the obtained residue was partitioned between water (5 mL) and EtOAc (5 mL). The aqueous layer was extracted with EtOAc (2×5 mL). The combined organic layer was washed with ice-cold water (5 mL) and brine (5 mL) and dried over anhydrous Na2SO4. The organic part was concentrated under vacuum and the resulting crude material was purified by Isolera column chromatography (eluent: 25% EtOAc/PE; silica gel: 230-400 mesh) to afford the title compound. Yield: 81% (220 mg, yellow solid). 1H NMR (400 MHz, DMSO-d6): delta 7.80 (d, J=12.0 Hz, 1H), 7.75 (s, 1H), 7.37 (t, J=7.6 Hz, 3H), 7.29 (d, J=6.8 Hz, 2H), 7.11 (t, J=7.6 Hz, 1H), 5.57 (d, J=12.0 Hz, 1H), 3.82 (s, 2H), 3.53 (s, 2H), 1.46-1.27 (m, 13H), 1.21-0.85 (m, 8H), 0.74 (t, J=6.4 Hz, 6H). LCMS: (Method E) 497.2 (M+-tBu+H), Rt. 3.09 min, 80.74% (max). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With 1,4-diaza-bicyclo[2.2.2]octane; In tetrahydrofuran; at 20℃; for 1h; | To a stirred solution of 7-bromo-3-butyl-3-ethyl-8-hydroxy-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 149; 0.5 g, 1.10 mmol)) in THF (5 mL), DABCO (12.3 mg, 0.1 mmol) and tert-butyl propiolate (0.22 mL, 1.60 mmol) were added and the reaction mixture was stirred for 1 hour at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc (25 mL). The organic layer was washed with water (2×15 mL). The organic part was dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 8% EtOAc in hexane; silica gel: 230-400 mesh) to afford the title compound. Yield: 73% (0.46 g, white solid). 1H NMR (400 MHz, DMSO-d6): delta 7.75 (bs, 1H), 7.65 (d, J=16.4 Hz, 1H), 7.54 (s, 1H), 7.45-7.42 (m, 2H), 7.33-7.31 (m, 2H), 7.19-7.15 (m, 1H), 6.84 (s, 1H), 5.19 (d, J=16.4 Hz, 1H), 4.02 (bs, 2H), 1.60-1.51 (m, 2H), 1.42 (s, 9H), 1.28-0.75 (m, 6H), 0.72-0.47 (m, 6H). LCMS: (Method A) 577.2 (M+-2H), Rt. 3.41 min, 94.96%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 1,4-diaza-bicyclo[2.2.2]octane; In tetrahydrofuran; at 20℃; for 1h; | To a stirred solution of 3-butyl-3-ethyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 152; 200 mg, 0.46 mmol) in dry THF (3 mL), DABCO (5.10 mg, 0.05 mmol) and tert butyl propiolate (0.1 mL, 0.7 mmol) were added at room temperature, and the reaction mixture was stirred for 1 hour at room temperature. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with ice-cold water (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 6% EtOAc in hexane; silica gel: 230-400 mesh) to afford the title compound. Yield: 75% (190 mg, white solid). H NMR (400 MHz, DMSO-d6): delta 7.61 (d, J=12.4 Hz, 1H), 7.38 (t, J=8.0 Hz, 3H), 7.30 (d, J=7.6 Hz, 2H), 7.12 (t, J=7.2 Hz, 1H), 6.46 (s, 1H), 5.31 (d, J=12.4 Hz, 1H), 4.12 (s, 2H), 2.88 (s, 3H), 2.08 (s, 3H), 1.92-1.86 (m, 1H), 1.82-1.76 (m, 1H), 1.55-1.43 (m, 10H), 1.19-1.08 (m, 5H), 0.83-0.62 (m, 6H). LCMS: (Method A) 505.2 (M+-tBu+H), Rt. 3.65 min, 97.40%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With 1,4-diaza-bicyclo[2.2.2]octane; In tetrahydrofuran; at 20℃; for 2h; | To a stirred solution of 3-butyl-3-ethyl-7-fluoro-8-hydroxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (Intermediate 166; 500 mg, 1.28 mmol) in THF (5 mL) at room temperature, DABCO (14 mg, 0.13 mmol) and tert-butyl propiolate (161 mg, 1.28 mmol) were added and the reaction mixture was stirred for 2 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum and the obtained residue was partitioned between ice-cold water (5 mL) and EtOAc (5 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layer was washed with ice-cold water (10 mL) and brine (10 mL) and dried over anhydrous Na2SO4. The organic part was concentrated under vacuum and the resulting crude was purified by Isolera column chromatography (eluent: 5% EtOAc/PE; silica gel: 230-400 mesh) to afford the title compound. Yield: 76% (500 mg, off-white solid). 1H NMR (400 MHz, DMSO-d6): delta 7.70-7.72 (m, 2H), 7.27-7.29 (m, 4H), 7.10 (t, J=7.16 Hz, 1H), 6.69 (d, J=12.16 Hz, 1H), 5.37 (d, J=12.20 Hz, 1H), 3.83 (s, 2H), 3.45 (s, 2H), 1.53-1.54 (m, 2H), 1.43 (s, 9H), 1.27-1.30 (m, 2H), 0.96-0.98 (m, 4H), 0.69-0.70 (m, 6H). LCMS: (Method E) 462.1 (M+-tBu+H), Rt. 3.04 min, 98.65% (Max). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | General procedure: A Schlenk tube (25 cm3) equipped with a magnetic stir barwas charged with terminal alkyne (1.2 mmol), (i-Pr)2EtN(1.5 mmol), CuBr·SMe2 (0.1 mmol), TBPAc (0.3 mmol),oxirane (2.0 mmol), and 2.0 cm3 MeCN. After the mixturewas stirred at 25 C for 1 h, propiolate (1.0 mmol) wasadded under an inert atmosphere. The tube was evacuatedand backfilled with argon (three times). Subsequently, themixture was stirred for 16 h at appropriate temperature (seeTables 2, 3). After cooling to room temperature, the mixturewas passed through silica gel pad and concentrated underreduced pressure. The resulting residue was purified with column chromatography on silica gel (eluent gradient ofEtOAc/hexane, see spectroscopic analysis section) to givethe corresponding products 4 in the yields listed in Tables 2and 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: tert-butyl prop-2-ynoate With dimethyl amine In water Stage #2: 3-(4-nitrophenyl)-2-propenal With acetic acid In water at 80℃; for 12h; |
Tags: 13831-03-3 synthesis path| 13831-03-3 SDS| 13831-03-3 COA| 13831-03-3 purity| 13831-03-3 application| 13831-03-3 NMR| 13831-03-3 COA| 13831-03-3 structure
[ 762-21-0 ]
Diethyl acetylenedicarboxylate
Similarity: 0.72
[ 762-21-0 ]
Diethyl acetylenedicarboxylate
Similarity: 0.72
[ 762-21-0 ]
Diethyl acetylenedicarboxylate
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[ 169751-72-8 ]
tert-Butyl 14-hydroxy-3,6,9,12-tetraoxatetradecan-1-oate
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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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