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CAS No. : | 7487-88-9 | MDL No. : | MFCD00011110 |
Formula : | MgO4S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CSNNHWWHGAXBCP-UHFFFAOYSA-L |
M.W : | 120.37 | Pubchem ID : | 24083 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P501-P260-P270-P264-P308+P311-P405 | UN#: | N/A |
Hazard Statements: | H371 | 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 |
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Stage #1: omeprazole sodium; magnesium sulfate In methanol at 29 - 30℃; for 3h; Stage #2: In methanol; acetone for 6h; | 7 EXAMPLE 7Preparation of Crystalline Esomeprazole Magnesium50 g of esomeprazole sodium obtained according to the process described in Example 3 was taken into a round bottom flask and 400 ml of methanol was added. The mixture was stirred for 30 minutes at 29° C. for clear dissolution. After a clear dissolution was obtained, 30.2 g of magnesium sulfate was added and stirred for 3 hours at 30° C. The reaction mixture was filtered through a perlite bed and then treated with carbon. The carbon treated solution was distilled at a temperature of 40° C. and a pressure of 300 mm Hg to remove 90% of the solvent. 500 ml of acetone was added to the residue and stirred for 6 hours. The separated solid was filtered and washed with 100 ml of acetone. The wet solid was dried at 34° C. for 12 hours to yield 28 g of the title compound.Purity by HPLC: 99.89R-isomer impurity: 0.02%. | |
In water at 29℃; for 2h; | 11 EXAMPLE 11Preparation of Amorphous Esomeprazole Magnesium40 g of esomeprazole sodium obtained according to the process described in Example 3 was taken into a round bottom flask and 400 ml of water was added. The mixture was stirred for 20 minutes at 29° C. for clear dissolution. After a clear solution was obtained, 20 g of magnesium sulfate dissolved in 200 ml of water was added to the reaction solution for about 1 hour and stirring continued for one more hour at 29° C. The separated solid was filtered and washed with 200 ml of water. The wet solid was dried at 64° C. for 6 hours to yield 70 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium hydroxide In water at 50 - 60℃; | EXAMPLE; 1000 g of swine bile are refluxed for 20 hours with 100 g of sodium hydroxide. The mixture is cooled to a temperature of 70° C. and added with 240 g of ethyl acetate and 6 g of hydrogen peroxide. The formed pale green mixture is acidified to pH 4-5 with 130 g of 37% hydrochloric acid. The two phases are separated. The organic phase is added with 140 g of water and the solution is alkalinised to pH 11 with 67 g of 35% sodium hydroxide.The aqueous phase is separated from the organic phase by means of a separatory funnel. The aqueous phase containing the salified cholanic acids is eluted on a DIAION HP 20SS resin, using a solvent gradient to afford the separation (water-water¥methanol-methanol).Elution on resin provides the complete separation of chenodeoxycholic acid sodium salt from a mixture containing hyocholic and hyodeoxycholic acids sodium salts.The fractions containing chenodeoxycholic acid salt are combined, treated with an amount of acetic acid sufficient to liberate the sodium salt and evaporated to a residue. The resulting solid is then dissolved in an ethyl acetate/toluene 1:5 mixture. The residue insoluble while hot is filtered off and the resulting solution is cooled to promote crystallization of the product. The formed precipitate is filtered and dried under vacuum. 20 g of chenodeoxycholic acid are obtained, having 99.9% HPLC purity.The fractions containing the mixture of hyodeoxycholic and hyocholic acids sodium salts are evaporated under reduced pressure, the residue is taken up in 500 g of water, mechanically stirred and heated to inner temperature of 50° C. A solution of 90% potassium hydroxide is added to pH 12. After that, a magnesium sulphate aqueous solution is dropped therein. The solution is cooled, the formed precipitate is filtered and dried at 50-60° C. under vacuum. The precipitate consists of hyodeoxycholic acid magnesium salt, which is placed in a reactor together with 200 g of water and 600 g of ethyl acetate; the mixture is heated to inner temperature of 55° C. and added with 35% sulfuric acid to pH 2. The phases are separated, and the organic phase is cooled to 0/-5° C. The formed white precipitate is filtered and dried under vacuum at 50° C. 24 g acid hyodeoxycholic are obtained, with 99.9% HPLC purity. |
Yield | Reaction Conditions | Operation in experiment |
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With lithium aluminium tetrahydride In tetrahydrofuran; potassium hydrogensulfate; dichloromethane | 1.3 1.3 1.3 A solution of 2.09 g (55 mmol) LAH in 250 ml THF was cooled (-50° C.) and treated during 25 min with a solution of 15.02 g (50 mmol) of trans-[4-(Methoxy-methyl-carbamoyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 250 ml THF. The reaction was warmed up to +15° C. for 3.5 h, cooled (-78° C.) and hydrolyzed with a suspension of 15 g MgSO4.7H2O, 15 g silicagel in 50 ml aqueous 10% KHSO4. The cooling bath was removed, THF was added, the mixture was stirred for 30 min and filtered. After evaporation, the residue was dissolved in CH2Cl2, dried over Na2SO4 and evaporated to yield 12.83 (quantitative) of trans-(4-Formyl-cyclohexyl)-methyl-carbamic acid tert-butyl ester, MS: 241 (M). | |
With lithium aluminium tetrahydride In tetrahydrofuran; potassium hydrogensulfate; dichloromethane | 26.3 Example 26.3 Example 26.3 A solution of 2.09 g (55 mmol) LAH in 250 ml THF was cooled (-50° C.) and treated during 25 min with a solution of 15.02 g (50 mmol) of trans-[4-(Methoxy-methyl-carbamoyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 250 ml THF. The reaction was warmed up to +15° C. for 3.5 h, cooled (-78° C.) and hydrolyzed with a suspension of 15 g MgSO4.7H2O, 15 g silicagel in 50 ml aqueous 10% KHSO4. The cooling bath was removed, THF was added, the mixture was stirred for 30 min and filtered. After evaporation, the residue was dissolved in CH2Cl2, dried over Na2SO4 and evaporated to yield 12.83 (quantitative) trans-(4-Formyl-cyclohexyl)-methyl-carbamic acid tert-butyl ester, MS: 241 (M). |
Yield | Reaction Conditions | Operation in experiment |
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With lithium aluminium tetrahydride In tetrahydrofuran; potassium hydrogensulfate; dichloromethane | 15.3 15.3 15.3 A solution of 12.25 g (313.11 mmol) LAH in 1.3 l THF was cooled (-50° C.) and treated during 30 min with a solution of 89.5 g (284.64 mmol) of trans-[4-(Methoxy-methyl-carbamoyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester in 1.3 l THF. After 20 min at this temperature, the reaction was warmed up to 0° C., cooled (-78° C.) and hydrolyzed with a suspension of 90 g MgSO4.7H2O, 90 g silicagel in 292 ml aqueous 10% KHSO4. The cooling bath was removed, THF was added, the mixture was stirred for 30 min and filtered. After evaporation, the residue was dissolved in CH2Cl2, dried over Na2SO4 and evaporated to yield 90.4 (quantitative) of trans-(4-Formyl-cyclohexylmethyl)-methyl-carbamic acid tert-butyl ester, MS: 255 (M). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium borohydrid; methylamine; In tetrahydrofuran; methanol; sodium hydroxide; dichloromethane; | Preparation 20 4-[(Methylamino)methyl]benzonitrile 4-Cyanobenzaldehyde (12.0 g, 92.0 mmol), methylamine (69 ml of a 2.0M solution in tetrahydrofuran, 137 mmol) and magnesium sulphate (45 g) were stirred in dichloromethane (300 ml) at room temperature for 5 days. The mixture was filtered and the filtrate was concentrated under reduced pressure to leave a yellow oil. The oil was dissolved in methanol (200 ml) and sodium borohydride (4.10 g, 109 mmol) was added cautiously with vigorous stirring. Once the addition was complete the reaction was stirred for 1 hour and the mixture was concentrated under reduced pressure. The residue was dissolved in 1M aqueous sodium hydroxide solution (200 ml) and the mixture was stirred at room temperature for 1 hour. The resulting solution was extracted with dichloromethane (2*200 ml) and the combined organic phases were dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide the title compound (13.4 g) as a pale yellow oil. 1H-NMR (300 MHz, CDCl3): delta=1.46 (s, 1H), 2.46 (s, 3H), 3.82 (s, 2H), 7.47 (d, 2H), 7.64 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide In water | 9 EXAMPLE 9 EXAMPLE 9 1.0M Sodium hydroxide solution (26.3 ml) was added to a stirred solution of methylammonium (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoate (15 g) in water (106 ml) at ambient temperature. A solution of magnesium sulphate (4.3 g) in water (26 ml) was added over 20 minutes and a solid precipitated. The solid was collected by filtration, washed with water (20 ml) and dried under vacuum at 40° C. (7.7 g). A mixture of the solid (5.8 g) and water (50 ml) was heated to 38° C. and diluted with water (35 ml). The mixture was stirred at ambient temperature for 4 hours and then allowed to stand for 66 hours. The solid was collected by filtration after diluting with water (30 ml). The product was dried at 35° C. under vacuum to give magnesium (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoate (4.68 g) as white crystals. The X-ray powder diffraction spectra for a typical sample of the crystalline magnesium salt is shown in hereinafter. The ten most prominent peaks in the XRD occur at about 2-theta=11.5, 14.5, 16.3, 16.8, 18.0, 19.1, 19.8, 21.8, 22.6 and 23.0°. |
Yield | Reaction Conditions | Operation in experiment |
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With hydroxylamine hydrochloride; In 5,5-dimethyl-1,3-cyclohexadiene; | REFERENCE EXAMPLE 12 4-Hydroxy-3-Iodo-Benzonitrile To a solution of 4-hydroxy-3-iodo-benzaldehyde (7.9 g, 31.8 mmol) (prepared by the method of Barnes at al.; J. Chem. Soc., 1950, 2824) in xylene (120 mL) was added hydroxylamine hydrochloride (2.34 g, 33.4 mmol), magnesium sulphate (12.7 g) and p-toluene sulphonic acid monohydrate (1.27 g, 6.4 mmol). The resulting mixture was heated to reflux and stirred at this temperature for 90 min. The reaction mixture was then allowed to cool to room temperature and filtered. The solid was washed with ethyl acetate then the combined filtrates concentrated. The residue was purified by flash chromatography (eluding with 30% ethyl acetate in hexanes) to give 6.57 g of the title compound. 1H NMR (CDCl3) d 6.1 (bs, 1H), 7.05 (d, J=8 Hz, 1H), 7.55 (dd, J=8, 1 Hz, 1H), 7.99 (d, J=1 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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In tetrahydrofuran; methanol; n-heptane; ethyl acetate | 42.2 Step 2 Step 2 2-Phenoxybenzylalcohol A 1.0 M solution of lithium aluminum hydride in THF (25 ml, 25 mmol) was added to a solution of crude 2-phenoxybenzoic acid methyl ester (5.23 g, 22.9 mmol) in THF. The reaction mixture was stirred for 2.5 hours at room temperature. Methanol (10 ml) was added carefully. THF (50 ml) was added. Magnesium sulphate was added. The solids were filtered off. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using ethyl acetate/heptane (1:1) as eluent, to give 4.08 g of 2-phenoxybenzylalcohol. 1H NMR (CDCl3) δ 4.70 (m, 2 H); 6.85 (d, 1 H); 6.97 (d, 2 H); 7.10 (m, 2 H); 7.25 (t, 1 H); 7.35 (t, 2 H); 7.45 (d, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
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1.2 g (98%) | With lithium aluminium tetrahydride In tetrahydrofuran; potassium hydrogensulfate; dichloromethane | 1.h Further Starting Compounds: A solution of 1.5 g (3.5 mmol) (2S,4R)-4-(4-methoxy-benzylsulfanyl)-2-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester dissolved in 15 ml was added to 4.2 ml (4.2 mmol, 1M THF solution) of LAH in 50 ml THF at -78° C. The reaction was was warmed up to -30° C., cooled to -78° C. and quenched with a suspension of 1.2 g silica gel/1.2 g MgSO4.7H2O in 5 ml aqueous 10% KHSO4. The suspension was stirred for 15 min at room temperature, filtered and washed with THF. After evaporation of the THF, the residue was taken up in CH2Cl2, dried over Na2SO4 and evaporated to give 1.2 g (98%) of (2S,4R)-2-formyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 351 (M+). |
Yield | Reaction Conditions | Operation in experiment |
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49% | With hydrogenchloride; sodium hydroxide In tetrahydrofuran; water; ethyl acetate; toluene | 3 EXAMPLE 3 EXAMPLE 3 In an argon atmosphere 11.2 g of (R,S)-(1-cyclopropyl-2-oxo-3-pyrrolidinyl)-triphenylphosphonium bromide are dissolved in 60 ml of toluene and 30 ml of water and cooled to 0° C. (crystallizes again). 24 ml of 1N aqueous sodium hydroxide are added dropwise within 20 min; the toluene phase colors yellow and the aqueous phase white (suspension). After stirring for 10 min at 0° C. the toluene phase is cooled to -10° C. and the aqueous phase extracted with 20 ml of toluene which is added to the toluene phase. A solution of 10.4 g of diphenylmethyl (6R,7R)-7-(1-tert-butoxyformamido)-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate in 35 ml of THF is added dropwise within 1 hour; the resulting brown suspension is stirred for 10 min. After stirring at 0° C. for 45 min, a mixture of 25 ml of 1N aqueous hydrochloric acid and 25 ml of water is added and stirring is continued for 10 min without cooling (room temperature) to yield two clear phases; the toluene phase is red and the water phase pale yellow. After separation of the phases the water phase is extracted twice with each 50 ml of toluene, the combined organic phases are washed with 50 ml of 5% aqueous sodium bicarbonate solution and afterwards with 50 ml of water. The combined toluene phases are dried over 25 g of magnesium sulphate and evaporated. 20.47 g of red-orange crude product result, which are dissolved in 50 ml of toluene/ethyl acetate (30 min) and subsequently flash-chromatographed (50-75 ml fractions) on 200 g of silica gel (Merck 60; 0.040-0.063 mm) with 4 l of toluene:ethyl acetate 4:1 as eluent. Yield: 9.5 g [6R-[3(E)-6R,7R]]-3-[(1-cyclopropyl-2-oxo-3-pyrrolidinylidene)methyl]-7-[[(1,1-dimethylethoxy)carbonyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester as yellow crystals (49% based on converted aldehyde). |
Yield | Reaction Conditions | Operation in experiment |
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With manganese dioxide In dichloromethane | 39 1-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pent-1-yn-3-one 1-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pent-1-yn-3-one A solution of 1-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pent-1-yn-3-ol (1.3 g) in dichloromethane (100 ml) was added to a stirred suspension of manganese dioxide (60 g) in dichloromethane at 0° C. The mixture was stirred at 0° C. for 3 h, filtered through magnesium sulphate (50 g) and the solvent removed in vacuo to give the title compound as a colourless oil (550 mg). NMR δ(CDCl3) 5.07 (1H,s,CH); 4.97 (1H,d,CH); 4.93 (1H,s,CH); 4.68 (1H,d,CH); 3.41 (3H,s,OMe); 2.58 (2H,q,CH2); 1.47 (3H,s,Me); 1.31 (3H,s,Me); 1.14 (3H,t,Me). |
Yield | Reaction Conditions | Operation in experiment |
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76.6% | With conc. sulphuric acid In CH2; hexane; dichloromethane; water | 6.b Preparation of 2-(p-chiorophenyl)-3-methylcrotonic acid b) 2-(p-Chlorophenyl)-3-methylcrotonic acid. -- The 120.9 g of crude 2-(p-chlorophenyl)-3-hydroxy-3-methylbutyric acid obtained above were dissolved in 200 ml of CH2 Cl2 in a 1 l round flask fitted with a magnetic stirrer, thermometer and dropping funnel. The solution was treated with 240 g of conc. sulphuric acid while cooling with an ice bath, with the reaction temperature not exceeding 20°. The CH2 CL2 was then removed at 20° on a rotary evaporator. The residual dark oil was stirred at 50° for a further 30 minutes and then poured on to 1 kg of ice while stirring well. The pink colored precipitate was filtered off under suction, washed 3 times with 100 ml of water each time and taken up in 400 ml of CH2 CL2. The solution was stirred with 20 g of magnesium sulphate and 1 g of decolorizing charcoal and filtered over 200 g of Speedex, with rinsing being carried out with 100 ml of CH2 CL2. The filtrate was concentrated on a rotary evaporator. After distilling off about 250 ml of solvent the residue was treated with 250 ml of hexane. This procedure was repeated twice, with crystallization occurring. The crystals were filtered off under suction, rinsed with 100 ml of hexane and dried at 0.1 mbar. There were obtained 76.3 g of 2-(p-chlorophenyl)-3-methylcrotonic acid as white crystals of m.p. 144-145°; yield 76.6% based on p-chlorophenylacetic acid. |
Yield | Reaction Conditions | Operation in experiment |
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With sulfuric acid; In dichloromethane; | Preparation 162 Tert-butyl 6-bromohexanoate To a solution of 6-bromohexanoic acid (9 g; 0.046 mol.) in dichloromethane (50 ml) at -78 C. was added fuming sulphuric acid (0.5 ml). To this solution was added liquid isobutylene (50 ml), dropwise. The reaction was allowed to warm to room temperature and stirred for 18 hours. The mixture was poured into ice-cooled saturated aqueous sodium carbonate solution. The mixture was extracted with dichloromethane (2*40 ml), and the combined extracts washed with brine (40 ml). The organic layer was dried using magnesium sulphate. The mixture was filtered and the solvent removed from the filtrate under reduced pressure to provide the title compound as a yellow oil which was used with further purification. TLC Rf=0.25 (silica, methanol: dichloromethane, 1:9, by volume). LRMS m/z=267.8(m+18)+. 1 H-NMR (CDCl3):delta=1.3-1.45(m,11H), 1.45-1.6(m,2H), 1.7-1.85(m,2H), 2.15(t,2H), 3.35(t,2H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
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90% | In (2-hydroxyethyl)(methyl)amine; ethyl acetate; | The starting material was prepared as follows: A solution of <strong>[3512-75-2]4-chloro-2,6-dimethylpyridine</strong> (849 mg, 6 mmol), (J. Het. Chem. 1990, 1841), in 2-(methylamino)ethanol (1.35 g, 18 mmol) and 3M ethereal hydrogen chloride (3 drops) was heated at 140° C. for 1 hour. The reaction mixture was allowed to cool and was diluted with water. The insolubles were removed by filtration and the aqueous filtrate was poured onto a suspension of magnesium sulphate (50 g) in ethyl acetate (100 ml). The insolubles were removed by filtration and the filtrate dried (MgSO4) and the solvent removed by evaporation. The solid residue was triturated with ether, collected by filtration and dried under vacuum at 50° C. to give 2-(N-(2,6-dimethyl-4-pyridyl)-N-methylamino)ethanol (960 mg, 90percent). m.p. 139-144° C. 1 H NMR Spectrum: (CDCl3) 2.4(s, 6H); 3.0(s, 3H); 3.51 (t, 2H); 3.81 (t, 2H); 6.26(s, 2H) MS - ESI: 181 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
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In dichloromethane; | (c) Preparation of N-(6-chloro-3-pyridylmethyl) phthalimide 2-Chloro-5-chloromethylpyridine (8.1 g, 0.05 mol) and potassium phthalimide (10.2 g, 0.055 mol) were mixed together at ambient temperature (20 C.) and the resulting mixture was then heated with stirring at 160 C. for 12 hours. The reaction mixture was then cooled to ambient temperature (20 C.) and dichloromethane was added until most of the solid residue had dissolved. The dichloromethane extract was then washed with water (2*150 ml) and brine (1*200 ml), dried using magnesium sulphate, and evaporated under reduced pressure to give a light-brown solid. The title product, N-(6-chloro-3-pyridylmethyl) phthalimide, was isolated from this solid by flash chromatography using silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm), with 10% v/v ether/ dichloromethane as eluent, as a buff solid (10.70 g, 78.5%), mp 140 to 142 C. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium permanganate In water | 3.c EXAMPLE 3 c) A suspension of 10 g of 4-acetylamino-2-nitrotoluene, 8 g of magnesium sulphate and 500 g of water was heated to reflux and then treated portionwise with 24 g of potassium permanganate and 8 g of magnesium sulphate within 20 minutes. The reaction mixture was heated to reflux for 1.5 hours and then filtered while hot in order to remove residues of educt. The cooled reaction mixture was made slightly acid and the separated solid was filtered off and dried. This gave 5.6 g of 4-acetylamino-2-nitrobenzoic acid of melting point 217-220° C. |
Yield | Reaction Conditions | Operation in experiment |
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44% | With bromine In tetrahydrofuran; ethanol; acetic acid; N,N-dimethyl-formamide | 15 Preparation of 2,4-Bis(p-chlorophenyl)-3-bromo-5-cyanopyrrole STR19 EXAMPLE 15 Preparation of 2,4-Bis(p-chlorophenyl)-3-bromo-5-cyanopyrrole STR19 Condensation of the β-aminoenone of 1,3-di-(p-chlorophenyl)-1,3-propanedione with aminoaceto-nitrile in refluxing ethanol followed by evaporation of the solvent, slurrying of the residue in tetrahydrofuran and filtering to remove inorganic salts and evaporation gives the glycinonitrile derivative A. Treatment of A with a base such as sodium ethoxide or pyridine or by refluxing in DMF induces cyclization to 2,4-bis(p-chlorophenyl)-5-cyanopyrrole. Bromination of 2,4-bis(p-chlorophenyl)-5-cyanopyrrole is accomplished by treatment with 1 equivalent of bromine in acetic acid in the presence of anhydrous sodium acetate yields the desired product (0.47 g, yellow solid, 44% yield, mp 98°-100° C. |
Yield | Reaction Conditions | Operation in experiment |
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3.55 g (73%) | With sodium hydroxide; methylamine In ethanol; dichloromethane | 3 N-(2-chloro-5-thiazolylmethyl)-N-methylamine EXAMPLE 3 N-(2-chloro-5-thiazolylmethyl)-N-methylamine 2-Chloro-5-thiazolylmethylchloride (5.0 g, 0.03 mol) and methylamine (4.6 g, 0.15 mol) were dissolved in ethanol (50 ml). The resulting solution was heated under reflux for 2 hours. The resulting mixture was allowed to cool to ambient temperature (20° C.) and the solvent was removed by evaporation under reduced pressure. The residue was added to a mixture of dichloromethane (150 ml) and aqueous sodium hydroxide (2N, 50 ml) and the mixture agitated. The two phases were allowed to separate and the aqueous phase was removed. Further aqueous sodium hydroxide (2N, 50 ml) was added to the organic phase and the step repeated. The aqueous phases were combined and washed with dichloromethane (50 ml). The dichloromethane product so obtained was combined with the original organic phase, washed with saturated brine (100 ml) and dried using magnesium sulphate. The solvent was evaporated to give N-(2-chloro-5-thiazolylmethyl)-N-methylamine as a yellow oil in a yield of 3.55 g (73%). NMR (CDCl3), delta (ppm):1.30 (broad,1H), 2.39 (s,3H) 3.84 (s,2H), 7.30 (s,1H) |
Yield | Reaction Conditions | Operation in experiment |
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77% | With hydrogenchloride; sodium periodate; sodium chloride; sodium hydrogencarbonate;RuCl3; In tetrachloromethane; dichloromethane; water; acetonitrile; | EXAMPLE 4 A solution of 251 mg (0.75 mmol) of 1-phenyl-1-t-butoxycarbonylamino-2-(1-ethoxyethoxy)but-3-ene, syn form, in 1.5 cm3 of acetonitrile is introduced into a 15 cm3 single-necked flask placed under an argon atmosphere and equipped with a magnetic stirring system. 1.5 cm3 of carbon tetrachloride, 2.25 cm3 of distilled water and, with thorough stirring, 409.5 mg (4.875 mmol) of sodium bicarbonate are then added successively. 882 mg (4.125 mmol) of sodium periodate are then added in small portions. The reaction medium is left to react for 5 minutes, with stirring (evolution of gas), and 25.1 mg (10% by weight) of RuCl3 are then added all at once. The reaction mixture, which has turned black and become highly heterogeneous, is left to react for 48 hours at a temperature of about 20 C., with vigorous stirring. The reaction mixture is diluted with water to give a total volume of 12 cm3. The black basic aqueous phase is extracted 3 times with 20 cm3 of ether. The basic phase is then cooled to 0 C., after which it is treated dropwise with 3 cm3 of a 2M aqueous solution of hydrochloric acid, in the presence of 30 cm3 of methylene chloride, with vigorous stirring. The resulting acidic aqueous phase is extracted 8 times with 35 cm3 of methyl chloride. The organic phases are combined and washed with 3 times 8 cm3 of water and 1 times 10 cm3 of a saturated aqueous solution of sodium chloride. They are dried over a 1/1 (w/w) mixture of <strong>[7757-82-6]sodium sulphate</strong> and magnesium sulphate and filtered under reduced pressure on Celite. The solvents are driven off under reduced pressure to a volume of 5 to 8 cm3. The residue is dried over a 4 molecular sieve. The organic phase is separated from the molecular sieve and the remaining solvent is then driven off on a rotary evaporator. 205 mg (0.58 mmol) of pure 3-phenyl-3-t-butoxycarbonylamino-2-(1-ethoxyethoxy)propionic acid, syn form, are obtained with a yield of 77% in the form of a pale yellow oil having the following characteristics: infrared spectrum (film): characteristic absorption bands at 3700-2200, 3060, 2980, 2930, 2850, 1720, 1660, 1602, 1590, 1500, 1450, 1400, 1370, 1280, 1250, 1170, 1080, 1050, 1030, 955, 930, 890 and 700 cm-1 proton nuclear magnetic resonance spectrum (300 MHz; CDCl3; chemical shifts in ppm; coupling constants J in Hz); 0.81 and 1.04 (2t, J=7, 3H); 1.18 and 1.20 (2d, J=5.4, 3H); 1.42 (s, 9H); 2.60-2.88 and 3.15-3.52 (m, 2H); 4.35-4.50 and 4.65-4.80 (m, 2H); 5.29 (s broad, 1H); 5.72 (s broad, 1H); 7.13-7.38 (m, 5H); 8.52 (s broad, 1H). Although the invention has been described in conjunction with specific embodiments, it is evident that many alternatives and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, the invention is intended to embrace all of the alternatives and variations that fall within the spirit and scope of the appended claims. The above references are hereby incorporated by reference. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide In 1,4-dioxane; water; ethyl acetate | I 2-tert.Butyloxycarbonyl-5-isoindoline carboxylic acid Example I 2-tert.Butyloxycarbonyl-5-isoindoline carboxylic acid 6.64 g of 5-isoindoline carboxylic acid hydrochloride in 80 ml of dioxane/water (2:1) are mixed with 70 ml of 1N sodium hydroxide solution and then with 8.72 g of di-tert.butylpyrocarbonate and the mixture is stirred for 31/2 hours at ambient temperature. The reaction mixture is evaporated down to some extent, adjusted to pH 2 with saturated aqueous potassium hydrogen sulphate solution and extracted several times with ethyl acetate. The combined organic phases are washed with saturated saline solution, dried and concentrated by rotary evaporation. The crude product is dissolved in 400 ml of ethyl acetate and washed three times with 20 ml of water. The organic phase is stirred with magnesium sulphate and activated charcoal, then filtered and evaporated down. Yield: 6.0 g (71% of theory), Melting point: 175°-177° C. (decomp.) Rf value: 0.48 (silica gel; ethyl acetate) |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; oxalic acid In tetrahydrofuran; dichloromethane; water | 51.e EXAMPLE 51: e) To a solution of aluminium chloride (0.29 g) in tetrahydrofuran (10 ml), lithium aluminium hydride (2.2 ml) was carefully added dropwise. After the reaction mixture had been stirred for 1 h, a solution of 3-((3,5-dimethylphenyl)methyloxy)-1-methyl-4-phenyl azetidin-2-one (0.66 g) in tetrahydrofuran (5 ml) was added via syringe. After a further hour water (1 ml) was carefully added dropwise followed by dropwise addition of 2N sodium hydroxide (1 ml). Dichloromethane (75 ml) was added followed by magnesium sulphate. After stirring for 30 minutes the solution was filtered. The organic phase was dried (MgSO4), filtered and evaporated. The crude material was chromatographed on flash silica and eluted with ethyl acetate:petrol 1:1. The resulting compound was dissolved in ether and an ethereal solution of oxalic acid was added dropwise to give the title compound as a white solid, m.p.=147°-149° C. 1 H NMR (360 MHz, DMSO) δ7.57 (2H, m), 7.43 (3H, m), 6.86 (1H, s), 6.62 (1H, s), 5.02 (m), 4.55 (m), 4.17 (1H, d, J=11 Hz), 3.94 (1H, d. J=11 Hz), 3.83 (1H, s), 2.61 (1H, s), 2.19 (1H, s); m/z (CI+) 282 (MH). Found: C, 67.75; H, 7.00; N, 3.78. Calcd for C19 H23 O1 N1. [COOH]2: C, 67.91; H, 6.78; N, 3.77%. |
Yield | Reaction Conditions | Operation in experiment |
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With sulfuric acid In tetrahydrofuran | 11 2-{2-[4-(2-Butyl-4-chloro-5-formyl-imidazol-1-yl-methyl)phenyl]-2-cyclopentyl}-acetamido-2-(2-hydroxyphenyl)acetamide STR27 Example 11 2-{2-[4-(2-Butyl-4-chloro-5-formyl-imidazol-1-yl-methyl)phenyl]-2-cyclopentyl}-acetamido-2-(2-hydroxyphenyl)acetamide STR27 60 mg (0.11 mmol) of the compound from Example VI are dissolved in 2 ml of anhydrous tetrahydrofuran and reacted with 1 ml of 25% strength aqueous ammonia solution (6 hours at 50° C.). The mixture is then adjusted to pH=7 using 0.1M sulphuric acid and extracted several times with ether. The organic phase is dried using magnesium sulphate and evaporated. After removal of the residual solvent in a high vacuum, 40 mg (0.07 mmol) of product are obtained. Rf =0.21 (petroleum ether:acetic acid=1:1) |
Yield | Reaction Conditions | Operation in experiment |
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With trifluoroacetic acid In dichloromethane; water | 9 4'-[(2-Hydroxybenzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid EXAMPLE 9 4'-[(2-Hydroxybenzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid 0.9 g (2.25 mmol) of tert.butyl 4'-[(2-hydroxybenzimidazol-1-yl)-methyl]biphenyl-2-carboxylate are dissolved in 10 ml of methylene chloride and treated with 10 ml of trifluoroacetic acid. The solution is stirred for 2 hours at ambient temperature and then evaporated to dryness on a rotary evaporator. The oily residue is dissolved in 50 ml of methylene chloride and extracted by shaking twice using water. The organic phase is dried using magnesium sulphate and evaporated to dryness. The crystalline residue thus obtained is mixed with a small amount of diethylether, filtered under suction and dried in vacuum at 50° C. Yield: 0.75 g (97.4% of theoretical), Melting point: 303°-304° C. C21 H16 N2 O3 (344.37) Calculated: C 73.24 H 4.68 N 8.13 Found: 73.07 4.81 7.95 |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; sodium methylate In methanol; water; ethyl acetate | 6 EXAMPLE 6 STR14 EXAMPLE 6 STR14 25 g (123 mmol) of ethyl N'-(α-methylamino-α-propoxy-methylene)-hydrazine-N-carboxylate are introduced into 200 ml of methanol, and 23.2 g of a solution of sodium methanolate (127 mmol of NaOCH3) in methanol are added dropwise at 5° C. to 10° C. The mixture is stirred for 6 hours at 50° C. and then concentrated under a water pump vacuum. The residue is taken up in 100 ml of water and acidified using concentrated hydrochloric acid, with ice-cooling. After the solution has been saturated with sodium chloride, it is extracted five times using ethyl acetate. The combined extraction solutions are dried using magnesium sulphate and filtered. The solvent is carefully removed from the filtrate by distillation under reduced pressure. 17.75 g (88.5% of theory) of 4-methyl-5-propoxy-2,4-dihydro-3H-1,2,4-triazol-3-one are obtained as a waxy product. Melting point: 74° C. (from acetone). |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine In tetrahydrofuran; ethyl acetate | VIII.1 Example (VIII-1) STR727 0.8 g (2.36 mmol) of α-methoximino-α-[2-(2,4-dimethylphenoxy-methyl)-phenyl]-acetyl chloride is dissolved in 10 ml of tetrahydrofuran and 0.26 g (2.6 mmol) of triethylamine is added. 0.25 g (2.6 mmol) of 0-(2-hydroxyethyl)-hydroxylamine, dissolved in 10 ml of tetrahydrofuran, is then added dropwise at 0° C. The reaction mixture is stirred for 2 hours at 20° C. and then poured into water and extracted using ethyl acetate. The extraction solution is dried using magnesium sulphate, concentrated and chromatographed (silica gel; toluene/acetone, 10:1). 0.4 g (50% of theory) of N-(2-hydroxy-ethoxy)-α-methoximino-α-[2-(2,4-dimethyl-phenoxy-methyl)-phenyl]-acetamide is obtained. 1 H NMR (CDCl3, δ): 3.65; 3.90; 9.15 ppm. |
Yield | Reaction Conditions | Operation in experiment |
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36% | With sodium hydroxide In tetrahydrofuran; methanol; dichloromethane; water | 16.b 4-Hydroxymethyl-5-methyl-1 -(triphenylmethyl)imidazole STR79 (b) A solution of lithium aluminium hydride (7.65 ml, 1M in tetrahydrofuran, 7.65 mmol) was added dropwise to a stirred suspension of ethyl 5-methyl-1 -(triphenylmethyl) imidazole-4-carboxylate (1.01 g, 2.55 mmol) in anhydrous tetrahydrofuran (50 ml) under nitrogen at 0° C. over 1 minute. After 30 minutes, water (300 μl) was added cautiously, followed by aqueous sodium hydroxide (1M, 300 μl) and water (900 μl). The suspension was filtered using Arbocel filter aid and the filter cake was washed with tetrahydrofuran (2*30 ml). The filtrate was concentrated under reduced pressure, and the residue was dissolved in boiling methanol (50 ml). Dichloromethane (200 ml) and anhydrous magnesium sulphate were added, and the mixture was filtered through Arbocel filter aid. The filtrate was concentrated under reduced pressure to give a white solid (325 mg, 36%). 1 H NMR (300 MHz, CDCl3) δ=1.47 (3H,s), 4.05 (2H,s), 7.14 (6H,m), 7.35 (10H,m). |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogen fluoride; sodium fluoride In water | 3 EXAMPLE 3 EXAMPLE 3 4.9 g 1,1,1,4-Tetrachlorobutane (25 mmoles) was charged to a 25 ml Monel autoclave, which was then purged. Hydrogen fluoride 10.7 g (535 mmoles) was added as a liquified gas, the stirrer started and the vessel heated to 65° C. at a ramp rate of 1 deg/min. The initial pressure at this temperature was ca. 70 psi, this rose to 184 psi over the next 23 hours. After allowing the temperature to drop to ca. 20° C. the vessel was cooled in an ice/IMS bath and the excess pressure (120 psi at room temperature) vented via a stirred water trap (no indication of carry over into this trap) keeping the internal temperature <0° C. to reduce the loss of entrained volatile products (the weight of the vessel dropped by approx. 1 gm during this process). On completion of the venting the vessel was opened and the dark red reaction mixture was poured carefully onto ice (ca 50 gms) and the organic phase separated, small amounts of sodium fluoride and magnesium sulphate were added to the straw coloured liquid to absorb any hydrogen fluoride and water. Damp weight of material was ca. 1 gm. The aqueous liquors were extracted with dichlorobenzene (2*30 mls) and the extracts backwashed with water and dried over magnesium sulphate. GC analysis indicated the presence of the desired product, 1,1-difluoro- 1,4-dichlorobutane. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium permanganate In acetone | 3 1-(Hex-5-ynyl)-4-n-propyl-2,6,7-trithiabicyclo[2.2.2]octane-2,2-dioxide EXAMPLE 3 1-(Hex-5-ynyl)-4-n-propyl-2,6,7-trithiabicyclo[2.2.2]octane-2,2-dioxide To a stirred solution of 1-(hex-5-ynyl)-4-n-propyl-2,6,7-trithiabicyclo[2.2.2]octane-2-oxide (0.302 g.) in dry acetone (120 ml) containing anhydrous magnesium sulphate (0.75 g) at -20° C. was added a solution of potassium permanganate (0.24 g) in dry acetone (25 ml). The mixture was allowed to warm to 20° and stirred for 72 hours. The colourless mixture was filtered through kieselguhr and the solid residue was washed with acetone. The filtrates were evaporated in vacuo and a colourless solid residue was obtained. The residue was purified by chromatography on silica eluding with dichloromethane. 1-(Hex-5-ynyl)-4-n-propyl-2,6,7-trithiabicyclo[2.2.2]octane-2,2-dioxide was obtained as a colourless solid (100 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; | (Process (a)) A mixture of 7.2 g (0.03 mol) of 4-amino-2-(4,6-dimethoxypyrimidin-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one, 21.0 g (0.09 mol) of 2-methoxycarbonyl-benzenesulphonyl chloride and 50 ml of pyridine is stirred at 20 C. for 12 hours. The mixture is subsequently concentrated under a waterpump vacuum, and the residue is taken up in methylene chloride and washed with 2N hydrochloric acid. The mixture is dried using magnesium sulphate and then filtered, and the solvent is carefully distilled off from the filtrate under a waterpump vacuum. 12.0 g (63% of theory) of 4-[bis-(2-methoxycarbonylphenylsulphonyl)-amino]-2-(4,6-dimethoxy-pyrimidin-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one are obtained as a crystalline residue of melting point 176 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; hydrogenchloride; | (Process (a)) A mixture of 4.2 g (0.016 mol) of 4-amino-5-methyl-2-(4,6-dimethoxy-pyrimidin-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one, 11.7 g (0.05 mol) of 2-methoxycarbonylbenzenesulphonyl chloride and 50 ml of pyridine is stirred at 20 C. for 12 hours, then diluted with ice-water and acidified using 2N hydrochloric acid, and the mixture is shaken with methylene chloride. The organic phase is separated off, dried using magnesium sulphate and filtered. The solvent is carefully distilled off from the filtrate under a waterpump vacuum. 3.8 g (50% of theory) of 4-(2-methoxycarbonyl-phenylsulphonylamino)-5-methyl-2-(4,6-dimethoxy-pyrimidin-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one are obtained as a crystalline residue of melting point 174 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; hydrogenchloride; In methanol; dichloromethane; | (Process (a)) A mixture of 5.7 g (0.02 mol) of 4-amino-5-methylthio-2-(4,6-dimethoxy-pyrimidin-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one, 14.0 g (0.06 mol) of 2-methoxycarbonylbenzenesulphonyl chloride and 50 ml of pyridine is stirred at 20 C. for 48 hours. The mixture is subsequently concentrated under a waterpump vacuum, the residue is taken up in methylene chloride, and the mixture is washed using 2N hydrochloric acid, dried using magnesium sulphate and filtered. The filtrate is concentrated and the residue is purified by column chromatography on silica gel using methylene chloride/methanol (vol. 10:1). 3.0 g (31% of theory) of 4-(2-methoxycarbonyl-phenylsulphonylamino)-5-methylthio-2-(4,6-dimethoxy-pyrimidin-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one of melting point 179 C. are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane | 7.a EXAMPLE 7 (a) To a solution, stirred at room temperature, of 0.9 g (5.4 mmol) of 2,4-dimethoxybenzylamine in 100 ml of methylene chloride are added 3 g of molecular sieve 4 Å and after 20 minutes 0.7 (5.4 mmol) of isopropylidene-L-glyceraldehyde and 5 g of anhydrous magnesium sulphate. The mixture is subsequently stirred at room temperature for a further 1 hour. The resulting organic solution of isopropylidene-L-glyceraldehyde (2,4-dimethoxybenzyl)imine is cooled to -20° under argon and treated while stirring with 0.88 ml (5.4 mmol) of triethylamine. Then, a solution of 1.25 g (5.6 mmol) of phthaloylglycyl chloride in 20 ml of dry methylene chloride is added dropwise within 1 hour and the mixture is subsequently stirred at room temperature overnight. The mixture is worked-up as described in Example 1 and there are obtained after chromatography 1.77 g (70%) of N-[(3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3 -dioxolan-4-yl]-2-oxo-3-azetidinyl]phthalimide as a foam; [α]D =+41° (c=0.8 in chloroform); MS: 466 (M+). After recrystallization from ethyl acetate, there is obtained a crystalline product with [α]D =+48° (c=0.6 in chloroform). | |
With sodium chloride; triethylamine In dichloromethane; water | 15.a EXAMPLE 15 (a) To a solution, stirred at room temperature, of 0.9 g (5.4 mmol) of 2,4-dimethoxybenzylamine in 100 ml of methylene chloride are added 3 g of molecular sieve 4 Å and after 20 minutes 0.7 g (5.4 mmol) of isopropylidene-L-glyceraldehyde and 5 g of anhydrous magnesium sulphate. The mixture is subsequently stirred at room temperature for 1 hour. The resulting organic solution of isopropylidene-L-glyceraldehyde(2,4-dimethoxybenzyl)imine is cooled to -20° under argon and treated while stirring with 0.88 ml (5.4 mmol) of triethylamine. Then, a solution of 1.25 g (5.6 mmol) of phthaloylglycyl chloride in 20 ml of dry methylene chloride is added dropwise thereto within 1 hour and subsequently the mixture is stirred at room temperature overnight. The mixture is washed three times with 100 ml of water each time and with 100 ml of sodium chloride solution and dried over sodium sulphate. The solution is evaporated and the residue is chromatographed on silica gel (230-400 mesh) while eluding with hexane/ethyl acetate (1:1). There are obtained 1.77 g (70%) of N-[(3S,4S)-cis-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-3-azetidinyl]phthalimide as a foam; [α]D =+41° (c=0.8 in chloroform); MS: 466 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane | 12 EXAMPLE 12 EXAMPLE 12 To a solution, stirred at room temperature, of 670 mg (4 mmol) of 3,4-dimethoxybenzylamine in 70 ml of methylene chloride are added 2.5 g of molecular sieve 4 Å and after 20 minutes 660 mg (4 mmol) of (S)-2-benzyloxypropionaldehyde and 3.7 g of anhydrous magnesium sulphate. The mixture is subsequently stirred at room temperature for 1 hour. The resulting solution is cooled to -20° in an argon atmosphere and treated while stirring with 0.65 ml (4 mmol) of triethylamine. Then, a solution of 930 mg (4.15 mmol) of phthaloylglycyl chloride is added dropwise thereto within 1 hour and the mixture is subsequently stirred at room temperature for 12 hours. The mixture is worked-up as described in Example 1 and there are obtained after chromatography 990 mg (50%) of N-[(3S,4S)-4-[(S)-1-(benzyloxy)ethyl]-1-(2,4-dimethylbenzyl)-2-oxo-3-azetidinyl]phthalimide as a foam; [α]D =+44.6° (c= 1 in chloroform); MS: =500 (M+). Elemental analysis for C29 H28 N2 O6: Calculated: C 69.59, H 5.64, N 5.60%. Found: C 69.06, H 5.80, N 5.36%. IR (KBr) cm-1: 1766, 1721, 1613, 1589, 1508. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane | 11 EXAMPLE 11 EXAMPLE 11 To a solution, stirred at room temperature, of 0.9 g (5.4 mmol) of 3,4-dimethoxybenzylamine in 100 ml of methylene chloride are added 3 g of molecular sieve 4 Å and after 20 minutes 0.7 g (5.4 mmol) of isopropylidene-L-glyceraldehyde and 5 g of anhydrous magnesium sulphate. The mixture is subsequently stirred at room temperature for 1 hour. The resulting organic solution of isopropylidene-L-glyceraldehyde (3,4-dimethoxybenzyl)imine is cooled to -20° under argon and treated while stirring with 0.88 ml (5.4 mmol) of triethylamine. Then, a solution of 1.25 g (5.6 mmol) of phthaloylglycyl chloride in 20 ml of dry methylene chloride is added dropwise thereto within 1 hour and the mixture is subsequently stirred overnight at room temperature. The mixture is worked-up as described in Example 1 and there are obtained after chromatography 1.56 g (62%) of N-[(3S,4S)-cis-1-(3,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxo-3-azetidinyl]phthalimide as a foam; [ α]D =+16.2° (c=1.0 in methanol); MS: 466 (M+). Elemental analysis for C25 H26 N2 O7: Calculated: C 64.37, H 5.62, N 6.01%. Found: C 63.53, H 5.72, N 5.96%. IR (KBr cm-1): 3430, 1766, 1721, 1609, 1517. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; sodium hydrogencarbonate; In diethyl ether; water; ethyl acetate; | A. Synthesis of the starting material STR25 6-Benzyloxycarbonylamino-penicillanic acid-1-oxide 108 g (0.5 mol) of <strong>[551-16-6]6-aminopenicillanic acid</strong> are dissolved in 1500 ml of water together with 185 g (2.2 mol) of sodium hydrogencarbonate. A solution of 81 ml (0.54 mol) of benzyloxycarbonyl chloride in 300 ml of diethyl ether is then added dropwise at 20° C. with vigorous stirring in the course of 15 min. After completion of the dropwise addition, 10 g (0.095 mol) of sodium hydrogencarbonate dissolved in 250 ml of water are added once more and the mixture is subsequently stirred at 20° C. for 2 h. It is then extracted three times with 300 ml portions of diethyl ether, and the aqueous phase is covered with 500 ml of ethyl acetate and brought to pH=4 with 2N sulphuric acid while stirring vigorously. The aqueous phase is extracted twice more with 1000 ml portions of ethyl acetate, and the combined organic phases are dried using magnesium sulphate and evaporated in vacuo. 165.2 g of solid white foam are thus obtained, which is dissolved in 2000 ml of water and 450 ml of ethanol together with 40.1 g (0.48 mol) of sodium hydrogencarbonate. 3.6 g (0.011 mol) of sodium tungstate dihydrate are then added at 0° C. and 50 ml (0.49 mol) of 30percent hydrogen peroxide are added dropwise. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; paraformaldehyde In formic acid | 22.b b) b) 4'-Acetamino-2,4-bis-(N,N-dimethyl-amino)-diphenylsulfone Paraformaldehyde (1.2 g) is dissolved in 95% formic acid (30 ml) with heating and 4'-acetamino-4-amino-2-(N,N-dimethyl-amino)-diphenylsulfone (2.3 g) is added. The reaction mixture is kept at 90° C. for 12 hours and then concentrated by evaporation in vacuo. A 2N sodium hydroxide solution (11 ml) and Na2 SO3 (2.7 g) are then added. The mixture is extracted with ethylacetate, the extract is treated with active charcoal and magnesium sulphate, concentrated to dryness in vacuo and the residue is purified over a column filled with silica gel. (eluant: dichloromethane/methanol=30:1). Colorless oil which is immediately reacted further. | |
With sodium hydroxide; paraformaldehyde In formic acid | 22.b (b) (b) 4'-Acetamino-2,4-bis-(N,N-dimethyl-amino)diphenylsulfone Paraformaldehyde (1.2 g) is dissolved in 95% formic acid (30 ml) with heating and 4'-acetamino-4-amino-2-(N,N-dimethyl-amino)-diphenylsulfone (2.3 g) is added. The reaction mixture is kept at 90° C. for 12 hours and then concentrated by evaporation in vacuo. A 2N sodium hydroxide solution (11 ml) and Na2 SO3 (2.7 g) are then added. The mixture is extracted with ethylacetate, the extract is treated with active charcoal and magnesium sulphate, concentrated to dryness in vacuo and the residue is purified over a column filled with silica gel. (eluant: dichloromethane/methanol=30:1). Colorless oil which is immediately reacted further. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In hydrogenchloride | 22.c c) c) 4'-Amino-2,4-bis-(N,N-dimethyl-amino)-diphenylsulfone The 4'-acetamino-2,4-bis-(N,N-dimethylamino)-diphenylsulfone (1 g) is dissolved in 2N hydrochloric acid (50 ml) and heated for about 45 minutes over a steam bath. Then the mixture is cooled, made basic with 2N NaOH and extracted with methylene chloride. The organic phase is treated with active charcoal and magnesium sulphate, concentrated to dryness in vacuo and the residue is purified over a column filled with silica gel (eluant: dichloromethane/methanol=50:1). The residue of the desired fraction is triturated with ether. Yellowish crystals; m.p.: 166°-168° C. | |
With sodium hydroxide In hydrogenchloride | 22.c (c) (c) 4'-Amino-2,4-bis-(N,N-dimethyl-amino)-diphenylsulfone The 4'-acetamino-2,4-bis-(N,N-dimethyl-amino)-diphenylsulfone (1 g) is dissolved in 2N hydrochloric acid (50 ml) and heated for about 45 minutes over a steam bath. Then the mixture is cooled, made basic with 2N NaOH and extracted with methylene chloride. The organic phase is treated with active charcoal and magnesium sulphate, concentrated to dryness in vacuo and the residue is purified over a column filled with silica gel (eluant: dichloromethane/methanol=50:1). The residue of the desired fraction is triturated with ether. Yellowish crystals; m.p.: 166°-168° C. |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride In thiophene; water; nitrobenzene | B.a a) a) Preparation of Compounds of the General Formula D 42.07 g (0.5 mol) of thiophene and 71.07 g (0.55 mol) of 3,3-dimethylglutaric anhydride are dissolved in 1500 ml of nitrobenzene. The reaction mixture is cooled to 0°-2° C. with a brine bath and 166.67 g (1.25 mol) of aluminium chloride are added in portions while stirring vigorously and maintaining the temperature of the reaction mixture at a value lower than 5° C. The reaction is continued for 30 minutes at a temperature of 0°-5° C. and is then completed at room temperature over a period of 10 hours. The reaction mixture is hydrolyzed with 3 l of a water/ice mixture. After the addition of 217 ml of concentrated HCl, the organic phase is decanted off, the nitrobenzene is steam distilled off and the residual aqueous phase is extracted 3 times with 200 ml of ethyl ether each time. The combined ethereal phases are washed with a normal aqueous solution of HCl and then with water. After treating with magnesium sulphate and animal black, the solvents are distilled off leaving 106.5 g of a pale-yellow oil which slowly crystallises (yield: 94%). The product can be recrystallized in water to yield, after filtration and drying, 2-(3,3-dimethylglutaryl)-thiophene in the form of a white solid, M.p.: 70° C. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine In tetrahydrofuran; dichloromethane; water | 1 EXAMPLE 1 128 g of the 5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester are dissolved in 70 ml of tetrahydrofuran, and 27.4 g of water and 3.5 g of triethylamine are added. The reaction mixture is stirred for 62 hours at 65°-70° and, having been cooled, is taken up in 200 ml of dichloromethane. The solution is dried over 200 g of magnesium sulphate, filtered and concentrated by evaporation in vacuo. Purification by column chromatography (silica gel;hexane/ethyl acetate 3:2) of the viscous oil that remains yields 2-formylamino-3-hydroxy-4-pentenoic acid ethyl ester in the form of a diastereoisomeric mixture, m.p. 50°-51°. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine In tetrahydrofuran; dichloromethane; water | 23.b E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester b) E-2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester (2) 139 g of 5-(2-propenyl)-2-oxazoline-4-carboxylic acid ethyl ester are dissolved in 70 ml of tetrahydrofuran, and 27.4 g of water and 3.5 g of triethylamine are added thereto. The reaction mixture is stirred at 65°-70° for 62 hours and, after cooling, is taken up in 200 ml of dichloromethane. The solution is dried over 200 g of magnesium sulphate, filtered and concentrated by evaporation in vacuo. Purification of the viscous oil which remains by column chromatography (silica gel; hexane/ ethyl acetate 3:2) yields 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester in the form of a diastereoisomeric mixture having a melting point of 67°. |
Yield | Reaction Conditions | Operation in experiment |
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100% | With hydrogenchloride; carbon monoxide In tetrahydrofuran; sodium hydroxide; water | 23 EXAMPLE 23 EXAMPLE 23 Carbon monoxide was bubbled through a solution containing tetrahydrofuran (30 ml) and water (1 ml). Palladium (II) chloride (0.140 g, 0.78 mmol) was added, followed by concentrated hydrochloric acid (1.0 ml), copper (II) chloride (0.84 g, 6.24 mmol), and then oxygen was bubbled through the mixture. 1-Decene (7.8 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The product was worked-up by adding distilled water (50 ml) and extracting three times with hexane (in total 250 ml). The extract was dried using magnesium sulphate and then concentrated. Further purification was carried out by dissolving the acid in 1M NaOH, extracting with ether, acidifying, and extracting again with ether. 2-Methyldecanoic acid was obtained in 100% yield. |
Yield | Reaction Conditions | Operation in experiment |
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In tetrahydrofuran; dichloromethane; water; | B. A solution of dry methyl methylthiomethyl sulphoxide (7.0 g., 0.056 mole) in dry tetrahydrofuran (25 ml.) was added dropwise to a stirred suspension of 50% sodium hydride in oil dispersion (3.0 g., 0.62 mole) in dry tetrahydrofuran (50 ml.) under nitrogen at ambient temperature. This mixture was stirred for 0.5 hours and a solution of <strong>[79002-39-4]5-cyanobenzo(b)furan</strong> (8.0 g., 0.056 mole) in dry tetrahydrofuran (25 ml.) added dropwise. The now reddish suspension was stirred at 50-60 C. overnight, and the resulting thick suspension cooled and treated dropwise with water (5 ml.). Methylene chloride (100 ml.) was next added, followed by magnesium sulphate, and the mixture filtered. Evaporation of the filtrate in vacuo furnished a brown solid (15 g.), which was triturated with ethyl acetate, collected, washed with ethyl acetate and then hexane and dried, in vacuo, to give 1-amino-1[5-benzo(b)furanyl]-2-methylsulphinyl-2-methylthio-ethylene (12.7 g.) as a cream solid, m.p. 157- 159 C. (decomp.). Analysis %: Found: C, 53.9; H, 4.9; N, 5.55; C12 H13 NO2 S2 requires: C, 53.9; H, 4.9; N, 5.2. |
Yield | Reaction Conditions | Operation in experiment |
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With trichlorophosphate In benzene | 1.a (a) (a) Ethyl 6-chloro-8-methoxycarbonyl-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2-carboxylate To a stirred solution of ethyl 4,6-dioxo-8-methoxycarbonyl-10-propyl-4H,6H-pyrano[3,2-g]quinoline-2-carboxylate (1 g) in dry benzene (20 mls) was added dropwise with stirring phosphoryl chloride (1.32 mls). The whole was then stirred at ambient temperature for twenty-four hours. The reaction mixture was poured into water, extracted into ethyl acetate, washed with water, dried using magnesium sulphate, filtered and volatiles removed in vacuo, affording a light brown solid which was purified by column chromatography; yielding the sub-title compound (0.62 g) as a light brown crystalline solid. M.P. 176°-178° C. Analysis: Found: C, 59.4; H, 4.8; N, 3.4; Cl, 8.5%. C20 H18 ClNO6 Requires: C, 59.5; H, 4.5; N, 3.5; Cl, 8.8%. |
Yield | Reaction Conditions | Operation in experiment |
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With acetic anhydride; acetic acid In water | 10.a (a) (a) N-(3-Acetyl-2-hydroxy-4-methoxyphenyl)acetamide 1-(3-Amino-2-hydroxy-6-methoxy-phenyl)ethanone (12.9 g) was added to a mixture of acetic acid (3 mls) and water (20 mls) and heated to 60° C. Acetic anhydride (9.5 mls) was then added and the whole heated on a steam bath for thirty minutes. The reaction mixture was poured into water and extracted into ether, which was dried using magnesium sulphate, and after filtration the volatiles were removed in vacuo, affording a golden brown solid which was triturated with chloroform and dried under reduced pressure, yielding 3.7 g of the sub title compound, mp 160°-162° C. |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine In dichloromethane | 1.e (e) (e) 3-(3-Cyanophenyl)propanal Solid chromium trioxide (12.7 g) was added to a stirred solution of pyridine (20.1 ml) in dichloromethane (500 ml) at 5° C. The mixture was stirred at 5° C. for 30 minutes then Celite-Hyflo Supercel (12 g) was added, the cooling bath was removed and a solution of 3-(3-cyanophenyl)propanol (4.1 g) in dichloromethane (40 ml) was added. After stirring for a further 2 hours the dark mixture was filtered through a mixture of Fluorosil and magnesium sulphate and the filtrate was evaporated to give the product as a pale oil. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; phenylhydrazine In dichloromethane; benzene | 61 3,3-Ethylenedioxy-1,2,3,4-tetrahydrocarbazole STR77 Example 61 3,3-Ethylenedioxy-1,2,3,4-tetrahydrocarbazole STR77 77.2 g (0.5 mol) of 1,4-cyclohexanedione monoethylene ketal are dissolved together with 48.4 ml (0.5 mol) of phenylhydrazine in 2 l of methylene chloride, and 300 g of magnesium sulphate are added, and the mixture is stirred for 30 min. The magnesium sulphate is then filtered off with suction, washed with methylene chloride, and the filtrate is evaporated. The residue is taken up in 1.5 l of benzene, and 62.1 g (0.46 mol) of anhydrous zinc chloride are added and the mixture is heated under reflux with a water separator for 3 h. The reaction solution is then concentrated, 2N sodium hydroxide solution is added, and the mixture is extracted 3 times with ethyl acetate. The combined ethyl acetate phases are dried with sodium sulphate and evaporated. The residue crystallizes from a little ether. In this way 3.5 g (72.9% of theory) of the product are obtained. Melting point: 145°-146° C. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium permanganate; hydroquinone In water; acetone | 1 Preparation 1 STR62 A solution of potassium permanganate (10.6 g) and magnesium sulphate (4.0 g) in water (250 cm3) was added at 0° to a mechanically stirred solution of 4-isopropenyl pyridine (14.8 g) in acetone (150 cm3) over 0.5 hours. After a further 0.5 hours at 0°, the mixture was warmed to room temperature over 1 hour, hydroquinone (0.01 g) was added and the mixture was filtered through "Avicel" (Trademark) to remove manganese dioxide. Solvents were removed in vacuo yielding a viscous oil which was chromatographed on silica ("Merck" 60.9385) eluding with methanol:chloroform, 1:19, to give 2-(4-pyridyl)propan-1,2-diol as an oil (6.0 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.5% | With hydrogenchloride; hydroxylamine hydrochloride In water; 1,2-dichloro-ethane | 9 Syn-2-Hydroxyimino-2-(thien-2-yl)acetic acid EXAMPLE 9 Syn-2-Hydroxyimino-2-(thien-2-yl)acetic acid A mixture of thien-2ylglyoxylic acid (937g) and water (9.0 liters) was stirred for 20 minutes. Magnesium hydroxide (700g) was added portionwise over 10 minutes. The mixture was stirred for a further 20 minutes whereafter a solution of hydroxylamine hydrochloride (500g) in water (1.5 liters) was added over 40 minutes. The reaction mixture was stirred for 16 hours at room temperature and then cooled to 0°. Hydrochloric acid (5N; ca 2.4 liters) was added over 45 minutes until a steady pH of 1.2 was obtained. The mixture was filtered through a Kieselguhr bed and washed by displacement with hydrochloric acid (2N:1.2 liters). The combined filtrate and wash were covered with isopropyl ether (5 liters) and stirred whilst hydrochloric acid (5N:ca 480 ml) was added. The two phases were allowed to separate and the aqueous phase re-extracted with isopropyl ether (1 * 3 liters: 2 * 1.5 liters). The first three isopropyl ether extracts were combined and washed with saturated sodium chloride solution (3 * 3 liters), each wash itself being extracted with a fourth isopropyl ether extract. The combined organic extracts were stirred with anhydrous magnesium sulphate (250g) and charcoal (50g) for 10 minutes, filtered through a Kieselguhr bed and washed by displacement with isopropyl ether (1.5 liters). With stirring the extract was concentrated in vacuo in a hot water bath (50°) to a low bulk then reconcentrated twice (2 * 2 liters) from 1,2-dichloroethane. The concentrate was slurried at 0° with 1,2-dichloroethane (2 liters), filtered, and the bed washed with 1,2-dichloroethane (1 liter). The product was dried in vacuo at 40° to give the title compound (870g:84.5%) m.p. 129° (dec), estimated to contain <5% of the anti-isomer by p.m.r. analysis as described in Example 1. |
Yield | Reaction Conditions | Operation in experiment |
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67% | With sulfuric acid; sodium In diethyl ether; ammonia; water | 1 EXAMPLE 1 EXAMPLE 1 Sodium (80 g.) was dissolved in liquid ammonia (1,500 ml.) and acetylene was passed through the solution until the blue color was discharged. While the passage of acetylene was continued anhydrous magnesium sulfate powder (100 g.) was added and the mixture was stirred for 2 hours. Diethyl ether (200 ml.) was added to the mixture followed by a solution, at -15°C. to -19°C., of methyl vinyl ketone (189 g.) in diethyl ether (600 ml.) the addition taking 12 minutes. The acetylene flow was stopped, the ammonia was evaporated and when the residue reached -20°C. it was dropped into a solution of 98% by weight aqueous sulfuric acid (200 ml.) in water (1,250 ml.) which was maintained at -5°C. to +5°C. The etheral layer was separated and the aqueous phase was extracted with diethyl ether (2 * 200 ml.). The combined etheral solutions were washed with saturated brine (80 ml.) and saturated sodium bicarbonate solution (20 ml.), then the ether was removed by distillation at atmospheric pressure. Distillation of the residue gave 3-methyl-pent-1-en-4-yn-3-ol (174 g.) b.p. 31°-37°C./18 mmHg (yield 67%). |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; lithium In 1,4-dioxane; methanol; ammonia; water; ethyl acetate; acetone | 196 13β-Ethyl-17β-acetylgon-4-en-3-one EXAMPLE 196 13β-Ethyl-17β-acetylgon-4-en-3-one Add 13β-ethyl-3-methoxy-17α-acetyl-17β-acetoxy-gona-1,3,5(10)triene (0.24 g.) in dioxan (5 cc.) to a stirred solution of lithium (0.15 g.) in liquid ammonia (100 cc.). After 30 minutes add methanol (8 cc.) followed by lithium (0.5 g.) in small pieces. Add water, extract with ether and work up to a gum (0.218 g.). Reflux this product with 4N hydrochloric acid (5 cc.) and methanol (8 cc.) for 15 minutes. Add water, extract with ether, work up and dissolve the resulting gum in acetone (30 cc.) containing anhydrous magnesium sulphate (0.5 g.) and add 8N-chromic acid dropwise with swirling until the solution assumes a permanent yellowish-orange color. Add excess isopropanol and evaporate the solution almost to dryness. Add water, extract with ether, wash, dry and evaporate the organic solution, filter the product through alumina with benzene-ether and recrystallize the product from ethyl acetate to obtain the title product (0.072 g.), m.p. 138°-142°; infrared absorption peaks at 5.9, 6 μ. This compound has progestational activity and is useful as an intermediate for preparing the hormonal compounds of this invention. | |
With hydrogenchloride; lithium In 1,4-dioxane; methanol; ammonia; water; ethyl acetate; acetone | 196 13β-Ethyl-17β-acetylgon-4-en-3-one EXAMPLE 196 13β-Ethyl-17β-acetylgon-4-en-3-one Add 13β-ethyl-3-methoxy-17α-acetyl-17β-acetoxy-gona-1,3,5(10)-triene (0.24 g.) in dioxan (5 cc.) to a stirred solution of lithium (0.15 g.) in liquid ammonia (100 cc.). After 30 minutes and methanol (8 cc.) followed by lithium (0.5 g.) in small pieces. Add water, extract with ether and work up to a gum (0.218 g.). Reflux this product with 4N hydrochloric acid (5 cc.) and methanol (8 cc.) for 15 minutes. Add water, extract with ether, work up and dissolve the resulting gum in acetone (30 cc.) containing anhydrous magnesium sulphate (0.5 g.) and add 8N-chromic acid dropwise with swirling until the solution assumes a permanent yellowish-orange color. Add excess isopropanol and evaporate the solution almost to dryness. Add water, extract with ether, wash, dry and evaporate the organic solution, filter the product through alumina with benzene-ether and recrystallize the product from ethyl acetate to obtain the title product (0.072 g.), m.p. 138°-142°; infrared absorption peaks at 5.9, 6 μ. This compound has progestational activity and is useful as an intermediate for preparing the hormonal compounds of the invention. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In benzene | N-Benzylidene-7-aminocephalosporanic acid, t-butyl ester N-Benzylidene-7-aminocephalosporanic acid, t-butyl ester 15.5 milli-equivalents 7-aminocephalosporanic acid, t-butyl ester were dissolved in 100 ml. benzene. This was followed by the addition of 15.5 milli-equivalents benzaldehyde and 10 grams magnesium sulphate. The reaction was allowed to proceed at room temperature overnight. The magnesium sulphate was removed by filtration and the filtrate was evaporated to dryness in vacuo to leave the desired product as a yellow oil in 82% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzaldehyde In dichloromethane | 1 Example 1 Example 1 Preparation of (S)-2-(benzylidene-amino)-3-(1H-indol-3-yl)-propionic acid methyl ester (Schiffs base). 245 g (S)-Tryptophan methyl ester and 118 g benzaldehyde are dissolved in 1837 ml dichloromethane and mixed with 245 g dry magnesium sulphate. The reaction mixture is stirred for 4 hours at ambient temperature. After filtering off the magnesium sulphate, the solvent is distilled off on a rotary evaporator. The very viscous mass remaining behind (364 g) can be used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In ethanol; water | 4 Magnesium α-(3-pentadecylphenoxy)-isobutyrate EXAMPLE 4 Magnesium α-(3-pentadecylphenoxy)-isobutyrate 100 g α-(3-pentadecylphenoxy)-isobutyric acid were dissolved in 250ml ethanol. To this solution, 10g aqueous sodium hydroxide in 60ml water were added until the pH of the reaction mixture was 8.0. A solution of 65g magnesium sulphate in 500 ml water was added dropwise with stirring and the gummy white solid which separated out was filtered, washed with water and dried. The yield of the gummy product identified as magnesium α-(3-pentadecylphenoxy)-isobutyrate was 94%. It could not be purified. In the further Examples which follow, the hypolipidemic activity of different doses of the calcium salt of α-(3-pentadecylphenoxy)-isobutyric acid when administered over varying periods of time is compared with the activity of a known hypolipidemic agent, viz. clofibrate, administered over similar periods. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; sodium carbonate In dichloromethane; <i>tert</i>-butyl alcohol | R.8 Reference Example 8 Reference Example 8 2-Hydroxy-6-phenylthiobenzoic acid (3.8 g) then tert-butanol (5.8 g) were added to a stirred mixture of magnesium sulphate (7.6 g) and sulphuric acid (0.8 ml) in dichloromethane. After 4 days sodium carbonate solution was added and the organic phase washed with brine, dried (magnesium sulphate) and evaporated to give tert-butyl 2-hydroxy-6-phenylthiobenzoate (3.09). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium permanganate; In water; | Potassium permanganate (68 g) was added portionwise to a solution of <strong>[196194-97-5]N-(4-methoxy-2-methyl-5-nitrophenyl)acetamide</strong> (35 g, 0.156 mol) and magnesium sulphate (38.5 g) in water (2.31) at 75 C. The mixture was maintained at 75 C. for 3.5 hours, further magnesium sulphate (4 g) and potassium permanganate (12 g) were added and stirring continued for 30 minutes at 75 C. The insolubles were removed from the hot reaction mixture by filtration through diatomaceous earth, the filtrate cooled and was acidified to pH 1 with concentrated hydrochloric acid. The precipitated solid was collected by filtration, washed with water and the aqueous filtrate extracted with ethyl acetate. The solid product and the ethyl acetate extract were combined and extracted with 2M aqueous sodium hydroxide solution. The basic aqueous layer was separated, washed with ethyl acetate, acidified with concentrated hydrochloric acid and re-extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried (MgSO4) and the solvent removed by evaporation to give 2-acetamido-5-methoxy4-nitrobenzoic acid (21.6 g, 54%) as a yellow solid. 1H NMR Spectrum: (DMSOd6) 2.12(s, 3H); 3.93(s, 3H); 7.74(s, 1H); 8.75(s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic anhydride In pyridine; cyclohexane; ethyl acetate | 1 Example 1 Preparation of the starting material A solution of 2.8 g (0.007 mol) of E-2-methoximino-2-{2-[1-(3-trifluoro-methyl-phenyl)-ethylideneiminooxymethyl]-phenyl}-acetamide in 5 ml of pyridine is cooled to 0° C., 2.2 g (0.0105 mol) of trifluoroacetic anhydride are added, and the mixture is stirred at 0° C. for 2 hours and room temperature for 18 hours. The solution is concentrated, the residue is taken in ethyl acetate, and the mixture is washed with water and highly dilute hydrochloric acid, dried using magnesium sulphate and concentrated. The residue is chromatographed on silica gel using cyclohexane/ethyl acetate (3:1). 1.8 g (69%) of E-2-methoximino-2-{2-[1-(3-trifluoro-methylphenyl)-ethylideneiminooxymethyl]-phenyl}-acetonitrile are obtained as a yellow oil (IR spectrum: 2200 cm--1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water reaction of aq. solutions of MgSO4 and Na2HPO4 below 36 °C;; formation of an amorphous precipitate; crystallization after 24 h;; | ||
With carbon dioxide In water precipitation by addition of Na2HPO4 solution to MgSO4 solution; dissolving the precipitate by inlet of CO2; crystallization;; | ||
With sodium hydroxide; sulfuric acid In water reaction of equivalent solutions of MgSO4 and Na2HPO4; dissolving the precipitate in a small amount of H2SO4; precipitation with aq. NaOH;; washing with water, alcohol, ether;; |
In water formation of a precipitate by addition of diluted MgSO4 solution to aq. Na2HPO4 solution; dissolving the precipitate by further addition of MgSO4; crystallization;; | ||
In water reaction of aq. solutions of MgSO4 and Na2HPO4 below 36 °C;; formation of an amorphous precipitate; crystallization after 24 h;; | ||
With CO2 In water precipitation by addition of Na2HPO4 solution to MgSO4 solution; dissolving the precipitate by inlet of CO2; crystallization;; | ||
With H2SO4; NaOH In water reaction of equivalent solutions of MgSO4 and Na2HPO4; dissolving the precipitate in a small amount of H2SO4; precipitation with aq. NaOH;; washing with water, alcohol, ether;; | ||
In water formation of a precipitate by addition of diluted MgSO4 solution to aq. Na2HPO4 solution; dissolving the precipitate by further addition of MgSO4; crystallization;; | ||
In water Mg : P = 1 : 1 ( 1.1 M soln. of Mg-salt, 0.25 - 0.33 M soln. of anion; pptn.), ppt. recrystn. on standing (24 h); collection, drying (between two paper filters); elem. anal.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: {(4R,6S)-6-[(E)-2-{4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl}vinyl]-2,2-dimethyl-1,3-dioxan-4-yl}acetic acid With sodium hydroxide In water Stage #2: magnesium sulfate In water at 20℃; | 6 Example 6; (6-{(E)-2-[4-(4-fluorophenyl-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-(4R,6S)-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid)-magnesium salt; A (6-{(E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-(4R,6S)-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid was prepared according to the method described in example 2. A solution of (6-{(E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-(4R,6S)-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid (4.9 g, 9.4 mmol) and acetonitrile was concentrated and the residue was dissolved in water (80 ml). Sodium hydroxide (10 ml, 1 M) was added to the solution and a solution of magnesium sulfate dehydrate (1,4 g, 12 mmol) in water (5 ml) was added dropwise to the reaction mixture. It was stirred for 10-16 hours at room temperature, filtered, washed twice with icy water (2x30 ml) and dried. Yield: 4.8 g (90%). Melting point: 175-182 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3α,6α,7α-trihydroxy-5β-cholan-24-oic acid; sodium 3α,6α-dihydroxy-5β-cholan-24-oate With potassium hydroxide In water at 50℃; Stage #2: magnesium sulfate In water | Example; 1000 g of swine bile are refluxed for 20 hours with 100 g of sodium hydroxide. The mixture is cooled to a temperature of 70°C and added with 240 g of ethyl acetate and 6 g of hydrogen peroxide. The formed pale green mixture is acidified to pH 4-5 with 130 g of 37% hydrochloric acid. The two phases are separated. The organic phase is added with 140 g of water and the solution is alkalinised to pH 11 with 67 g of 35% sodium hydroxide. The aqueous phase is separated from the organic phase by means of a separatory funnel. The aqueous phase containing the salified cholanic acids is eluted on a DIAION HP 20SS resin, using a solvent gradient to afford the separation (water - watermethanol - methanol). Elution on resin provides the complete separation of chenodeoxycholic acid sodium salt from a mixture containing hyocholic and hyodeoxycholic acids sodium salts. The fractions containing chenodeoxycholic acid salt are combined, treated with an amount of acetic acid sufficient to liberate the sodium salt and evaporated to a residue. The resulting solid is then dissolved in an ethyl acetate / toluene 1 : 5 mixture. The residue insoluble while hot is filtered off and the resulting solution is cooled to promote crystallization of the product. The formed precipitate is filtered and dried under vacuum. 20 g of chenodeoxycholic acid are obtained, having 99.9% HPLC purity. The fractions containing the mixture of hyodeoxycholic and hyocholic acids sodium salts are evaporated under reduced pressure, the residue is taken up in 500 g of water, mechanically stirred and heated to inner temperature of 50°C. A solution of 90% potassium hydroxide is added to pH 12. After that, a magnesium sulphate aqueous solution is dropped therein. The solution is cooled, the formed precipitate is filtered and dried at 50-60°C under vacuum. The precipitate consists of hyodeoxycholic acid magnesium salt, which is placed in a reactor together with 200 g of water and 600 g of ethyl acetate; the mixture is heated to inner temperature of 55°C and added with 35% sulfuric acid to pH 2. The phases are separated, and the organic phase is cooled to 0/-5°C. The formed white precipitate is filtered and dried under vacuum at 50°C. 24 g acid hyodeoxycholic are obtained, with 99.9% HPLC purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In 1,4-dioxane; water | 2.2 2. 2. Preparation of Phosphonic Acid Intermediates: Amine I (9.0 g, 41.1 mmol) was dissolved in 1,4-dioxane (100 mL). A solution of Na2CO3 (13.1 g, 123.3 mmol) in H2O (50 mL) was added to the reaction mixture and stirred for 5 minutes at room temperature. After benzyl chloroformate (8.4 g, 49.3 mmol) was added, the reaction solution was stirred at room temperature overnight. The organic phase was diluted with EtOAc and extracted with H2O and brine. The organic phase was dried over MgSO4. Concentration of the filtrate from vacuum filtration removal of the MgSO4 yielded an oil from which II was isolated by column chromatography (SiO2, 20% EtOAc in hexane) as a clear oil (11.6 g, 80%). 1H NMR (300 MHz, CDCl3) δ 7.33 (s, 5H), 6.05 (dt, J=9.9, 17.1 Hz, 1H), 5.65 (d, J=23.7 Hz, 1H), 5. (d, J=17.1 Hz, 1H), 5.06 (m, 3H), 4.06 (m, 4H), 2.09 (m, 1H), 1.73 (m, 2H), 1.15 (dt, J=8.1, 26.4 Hz, 6H). 31P NMR (121.4 MHz, CDCl3) δ 23.7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With p-toluenesulfonic acid monohydrate; In dichloromethane; | Step 7 The product of Step 6 (4.8 g), was dissolved in dichloromethane (150 mL) in a 3-necked 100 mL round bottom flask, followed by addition of p-toluenesulfonic acid monohydrate (0.4 g). 1,1-Bis(4-methoxyphenyl)-2-propyn-1-ol (3.8 g) was added to the reaction mixture slowly. The mixture was stirred at room temperature. After one hour, more <strong>[101597-25-5]1,1-bis(4-methoxyphenyl)-2-propyn-1-ol</strong>, (0.4 g) was added to the reaction mixture. After stirring for two hours, the reaction was worked up with the addition of saturated aqueous NaHCO3 (100 mL). The resulting organic layer was collected and dried over anhydrous MgSO4. The organic layer was concentrated under vacuum to provide product (8.7 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water at 20℃; for 480h; Saturated solution; | General procedure: The saturated homogeneous solution of pure ZTS was taken in two different beakers and then 1 mol% and 2 mol% of MgSO4 solution was added to the ZTS solution for doping and the same procedure was followed as in the case of pure ZTS crystal. After 20 days, optical quality transparent colourless crystals of size of 8 × 7 × 6 mm3 and 7 × 6 × 5 mm3 was harvested. The photograph of the as grown crystals of pure and MgSO4 doped ZTS are shown in Fig. 1a-c. The morphological changes and the variation of growth rate of doped ZTS crystals were observed from the photographs of as grown crystals. This is due to the partial substitution of MgSO4 in the ZTS. Grown crystals were characterised by various methods, such as Powder X-ray diffraction studies |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water at 20℃; for 480h; Saturated solution; | General procedure: The saturated homogeneous solution of pure ZTS was taken in two different beakers and then 1 mol% and 2 mol% of MgSO4 solution was added to the ZTS solution for doping and the same procedure was followed as in the case of pure ZTS crystal. After 20 days, optical quality transparent colourless crystals of size of 8 × 7 × 6 mm3 and 7 × 6 × 5 mm3 was harvested. The photograph of the as grown crystals of pure and MgSO4 doped ZTS are shown in Fig. 1a-c. The morphological changes and the variation of growth rate of doped ZTS crystals were observed from the photographs of as grown crystals. This is due to the partial substitution of MgSO4 in the ZTS. Grown crystals were characterised by various methods, such as Powder X-ray diffraction studies |
Yield | Reaction Conditions | Operation in experiment |
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85% | In propan-1-ol; ethanol at 30℃; Reflux; | 36 Preparation of gossypolone-Alanine-Magnesium complex The dissolved with 2 equivalent of magnesium sulphate (302 mg, 2mmol) of the tetrabutylorthotitanate solution (15 ml), in 30 °C to the dripping 1 equivalent embodiment 9 preparation of potassium cotton and kapok alkone -L-alanine (764 mg, 1mmol) ligand of ethanol solution (15 ml), in 40 °C constant temperature reaction 1-5 hours, heating to reflux reaction to continue, to be reaction 1-3 hours later, the suspension is cooled to the room temperature, vacuum filtration, washing of the filter cake in order to cool, to obtain the product, yield 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In water at 160℃; for 72h; Autoclave; High pressure; | 3.1 2.3.1 Synthesis of Mg(H2L)3 (1) A 0.073 g portion (0.25 mmol) of H4L was mixed with 0.043 g of MgSO4(0.375 mmol) in 10 mL of deionized distilled water, adjust pH to 0.5 with 1 mol/L hydrochloric acid, and then the solution was transferred into a 25 mL Teflon-lined stainless autoclave and heated at 160 °C for three days under autogenous pressure. The vessel was cooled to room temperature in cooling rate 2 °C/h to obtain the colorless hexagonal flaky crystal. IR (KBr pellet, cm-1): 3423.27(m), 2918.38(m), 2267.40(m), 1511.53(m), 1407.98(m), 1261.85(m), 1200.90(m), 1091.40(m), 1047.53(s), 991.32(s), 950.62(m), 901.39(w), 763.72(m), 608.07(m), 500.42(w), 470.88(w), 453.92(m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ferrous(II) sulfate heptahydrate In neat (no solvent, solid phase) at 180℃; for 2h; Stage #2: ferrous sulfide; magnesium sulfate In neat (no solvent, solid phase) Calcination; | The MF micro-size particles were synthesized by solid-phase reaction using ferrous sulfate as the main iron source. The reduction reaction under nitrogen was given as the process of reaction Equation (1). Ferrous sulfate heptahydrate was dried at 180°C for 2h and then mixed with anhydrous magnesium sulfate and ferrous sulfide at a specific ratio (δ). Subsequently, the mixture was grinded for 60min for mixing homogeneity, and then calcined in a tube furnace (SK-G06123K-R, China) at different temperatures. The samples after calcination were naturally cooled to room temperature under nitrogen protection. Finally, 5g of the as-obtained MF micro-size particles were dissolved in 1L of different solvent for 2h and repeatedly washed with deionized water to remove impurities. The undissolved MF was filtered and dried under vacuum at 120°C for 360min. |
Yield | Reaction Conditions | Operation in experiment |
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85% | Stage #1: levodopa; glycine With barium(II) hydroxide In water at 20℃; for 0.25h; Stage #2: magnesium sulfate In water at 20℃; for 2.5h; Reflux; | Synthesis of Mg(dopa)(gly): To a two-necked 200-mL round-bottomed flask equipped with a magnetic stirrer, heating mantle, reflux condenser, and 5 N2 inlet were added 6 levodopa (500 mg, 2.54 mmol) and 18 L-glycine (190 mg, 2.54 mmol). 19 Water (100 mL) was added and the mixture was heated until the solids dissolved. 20 Barium hydroxide (478 mg, 2.54 mmol) was added in one portion. The orange solution was stirred for 15 min at room temperature, and 21 MgSO4 (335 mg, 2.54 mmol) was added in one portion. A precipitate of BaSO4 formed immediately. The light gray suspension was stirred an additional 1 hour, and heated at reflux for 1.5 hours. The mixture was cooled and vacuum filtered using medium porosity filter paper. Solvent was removed under reduced pressure leaving a light tan 22 solid (638 mg, 2.17 mmol, 85%). 1H NMR (D2O): δ 6.68 (br d; J=7.2 Hz; 1 H), 6.61 (br s; 1 H), 6.51 (br d; J=5.6 Hz; 1 H), 3.81 (dd; J=8.2 Hz, J=5.0 Hz; 1 H), 3.49 (s, 2 H), 3.07 (dd; J=14.3 Hz, 5.0 Hz; 1 H), 2.86 (dd; J=14.3 Hz, 8.2 Hz; 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: Iron(III) nitrate nonahydrate; magnesium sulfate With tragacanth gum In water at 75℃; for 12h; Green chemistry; Stage #2: air at 600℃; Calcination; Green chemistry; | Green procedure for the synthesis of MgFe2O4 nanoparticles For the synthesis of MgFe2O4nanoparticles, 0.2 g tragacanthgum was dissolved in 40 mL of double distilled waterand stirred at 70 °C for 80 min. Then, 1 mmol of MgSO4 and 2 mmol Fe(NO3)3*9H2O were added to the above-mentioned tragacanth clear solution and the resulting mixture was heated in 75 °C for 12 h to obtain a brown resin. Finally, the mixture was calcined at 600 °C in air to obtain MgFe2O4 nanoparticles. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium chloride In neat (no solvent, solid phase) for 0.5h; Milling; | Synthesis of MgFe2O4 MgFe2O4 was synthesized as per the procedure applied by Jeseentharani and coworkers [28] and Das and Dhar [29]. The solid-state reaction of inorganic precursors was involved in the synthesis of MgFe2O4. Analytical grade MgSO4, Fe(NO3)2, NaOH and NaCl were mixed in a molar ratio (1:2:8:2) and ground together in an agate mortar for about 30min. This mixture was than washed with double distilled water several times to removed sodium chloride completely. After filtration, the product was dried at 90°C for 2h. |
Tags: 7487-88-9 synthesis path| 7487-88-9 SDS| 7487-88-9 COA| 7487-88-9 purity| 7487-88-9 application| 7487-88-9 NMR| 7487-88-9 COA| 7487-88-9 structure
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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