Structure of 1668-54-8
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CAS No. : | 1668-54-8 |
Formula : | C5H8N4O |
M.W : | 140.14 |
SMILES Code : | COC1=NC(=NC(=N1)C)N |
MDL No. : | MFCD00052764 |
InChI Key : | NXFQWRWXEYTOTK-UHFFFAOYSA-N |
Pubchem ID : | 15466 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.4 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 35.69 |
TPSA ? Topological Polar Surface Area: Calculated from |
73.92 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.66 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.13 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.22 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-1.32 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.17 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.28 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.8 |
Solubility | 2.23 mg/ml ; 0.0159 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.28 |
Solubility | 0.742 mg/ml ; 0.0053 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.41 |
Solubility | 5.46 mg/ml ; 0.039 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.35 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.38 |
* 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 |
---|---|---|
6.1 gm. (87%) | EXAMPLE 2 2-Amino-4-methoxy-6-methyl-s-triazine To a 100 ml. flask charge 5.5 gm. acetamidine hydrochloride, 5.7 gm. dimethyl (N-cyanoimido)carbonate, 11 gm. methanol and 11 gm. toluene. Cool the mixture to 5° C. and add dropwise 11.8 gm. of 30percent sodium methoxide while maintaining the reaction temperature at 5°-10° C. When the addition is complete, warm the reaction mixture to room temperature. Filter the slurry and wash the filter cake with methanol. Reslurry the filtercake in water, filter, wash the filter cake with water. Dry the solids to give 6.1 gm. (87percent) 2-amino-4-methoxy-6-methyl-s-triazine, mp256°-258° C. | |
1,095 g (97.7%) | EXAMPLE 10 A mixture of 1,441 g (8 moles) of 30percent technical grade methanolic sodium methylate solution (BASF AG) and 2,150 ml of methanol was cooled to 0° C. 984.8 g (4 moles) of pure O-methylisourea sulfate (O-methylisourea sulfate, pure from SKW Trostberg AG) were added to this cooled solution, while stirring vigorously and with exclusion of atmospheric moisture, and the mixture was cooled at 0° C. for a further 15 minutes. 897 g (8 moles) of pure N-cyanoacetimido-ethyl ester were then added dropwise, while stirring and cooling externally (ice bath), such that the internal temperature did not rise above 6° C. When the addition of the N-cyanoacetimido-ethyl ester had ended, the mixture was stirred at an internal temperature of 0° C. for a further 2 hours. Thereafter, the reaction mixture was stirred at room temperature, without external cooling, for 22 hours and then cooled to 12° C. and centrifuged. To remove the sodium sulfate, the solid residue was suspended in 4 liters of water and the suspension was centrifuged. The residue was suspended once again in 4 liters of water, the suspension was centrifuged and the centrifugate was washed free of sodium sulfate. It was dried at 80° C. in a vacuum drying cabinet. The yield was 1,095 g (97.7percent) of 2-amino-4-methoxy-6-methyl-s-triazine having a melting point of 262°-264° C. (decomposition). | |
If Y is hydrogen in the case of the employed arylsulfonamide of the formula II, preferred amines of the formula IV according to the process of the invention are the following:2-amino-4-methyl-6-methoxy-s-triazine,2-amino-4-methyl-6-methoxypyrimidine,2-amino-4-methyl-6-difluoromethoxypyrimidine,2-amino-4,6-dimethoxypyrimidine,2-amino-4,6-dimethoxy-s-triazine,2-amino-4,6-dimethylpyrimidine,2-amino-4-methoxy-6-ethoxy-s-triazine,2-amino-4-dimethylamino-6-methoxy-s-triazine,2-amino-4-cyclopropyl-6-methoxy-s-triazine,... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.2% | In ethyl acetate; xylene; at 50℃; for 8h;Product distribution / selectivity; | Under protective gas, a 14.5percent strength solution (1465 g) of methyl 4-iodo-2-isocyanatosulfonylbenzoate in xylene is added over 4 hours at a constant rate at 50° C. to a suspension of 84.5 g of <strong>[1668-54-8]2-amino-4-methoxy-6-methyl-1,3,5-triazine</strong> in 670 g of ethyl acetate. After the addition has ended, the mixture is stirred at the same temperature for approximately 4 hours, and the ethyl acetate is then distilled off under reduced pressure (80-60 mbar, T=50° C.). The suspension that remains is filtered off with suction and the solid is washed repeatedly with dilute hydrochloric acid and dried; if appropriate, acetone can be added to the hydrochloric acid. This gives 297 g (content>98percent) of the title compound; yield 99.2percent of theory. |
81% | In toluene; at 50℃; for 24h;Product distribution / selectivity; | The process according to Example 7a is repeated correspondingly using pure toluene as solvent. After 24 hours, the reaction is still incomplete. The title compound is obtained in a yield of 81percent of theory and a purity of 89percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | Example 1 At room temperature (approximately 20° C.), 1.7 g (7.8 mmol) of 2,4-dimethyl-thien-3-yl-sulphonyl isocyanate are added with stirring to a mixture of 1.01 g (7.8 mmol) of <strong>[1668-54-8]2-amino-4-methoxy-6-methyl-1,3,5-triazine</strong> and 40 ml of acetonitrile. The reaction mixture is then heated under reflux for 12 hours and allowed to cool to room temperature. The resulting crystalline product is then isolated by filtration with suction. This gives 2.08 g (75percent of theory) of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-N'-(2,4-dimethyl-thien-3-yl-sulphonyl)-urea of melting point 189° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; potassium tert-butylate; In ice-water; ISOPROPYLAMIDE; 2,4-dichlorophenoxyacetic acid dimethylamine; | Example 2 Methyl 2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-amino]-carbonyl]-amino]-sulfonyl]-4-iodobenzoate. 2.59 g of potassium tert-butylate was added to a suspension of 2.85 g of <strong>[1668-54-8]2-amino-4-methoxy-6-methyl-1,3,5-triazine</strong> in 40 ml of dimethylacetamide (DMA) at room temperature to form a first mixture. A solution of 4.94 g of diphenyl carbonate in 20 ml of DMA was then added dropwise to the first mixture at about 5° C. to form a second mixture. The second mixture was subsequently added dropwise to a solution of 5.00 g of methyl 2-aminosulfonyl-4-iodobenzoate (92.5percent pure) in 15 ml of DMA at about 5° C., to form a third mixture. When the reaction ended, the third mixture was filtered over kieselguhr (.(R).Celite). The filtrate was introduced into a solution of 200 ml of ice-water and 10 ml of concentrated hydrochloric acid, whereby the crude urea product separated out. The crude product which separated out was then purified by stirring with methanol and diisopropyl ether and dried. The yield was 4.50 g (66percent of theory). This Example also demonstrates that the carbamate of formula (IV) can be formed and converted, without isolation, to the sulfonylurea of formula (I), in a good yield (of both (IV) and (I)), without using an alkali metal hydride or phosgene. | |
With sodium t-butanolate; In water; 2,4-dichlorophenoxyacetic acid dimethylamine; | Example 4 Methyl 2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]amino]sulfonyl]-4-iodobenzoate. 5.09 g of sodium tert-butylate was added to a suspension of 3.69 g of <strong>[1668-54-8]2-amino-4-methoxy-6-methyl-1,3,5-triazine</strong> in 100 ml of DMA at room temperature. After cooling to 3-7° C., a solution of 5.64 g of diphenyl carbonate and 50 ml of DMA was added dropwise, to form a reaction mixture. The reaction mixture was then stirred at that temperature for 15 minutes. The reaction mixture was then added dropwise to a solution of 8.85 g of methyl 2-aminosulfonyl-4-iodobenzoate and 50 ml of DMA at 3-7° C., to form a resulting mixture which was stirred at 3° C. for 1 hour and at room temperature for 2 hours. The volatile components were then distilled off under reduced pressure. The residue was dissolved in 250 ml of water and acidified with concentrated hydrochloric acid (pH=2-3) whereby the crude product separated out. The crude product which separated out was washed with methanol and diisopropyl ether. After drying, 8.4 g of the desired product (purity>92percent) was obtained. This Example additionally demonstrates that the carbamate of formula (IV) can be formed and converted, without isolation, to the sulfonylurea of formula (I), with high purity, (of both (IV) and (I)) without using an alkali metal hydride or phosgene. | |
With sodium t-butanolate; In ISOPROPYLAMIDE; 2,4-dichlorophenoxyacetic acid dimethylamine; | Example 3 Methyl 2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-amino]-carbonyl]-amino]-sulfonyl]-4-iodobenzoate. 0.96 g of sodium tert-butylate was added to a suspension of 1.05 g of <strong>[1668-54-8]2-amino-4-methoxy-6-methyl-1,3,5-triazine</strong> in 20 ml of dimethylacetamide (DMA) at room temperature, with vigorous stirring, to form a first mixture. A solution of 1.12 g of diphenyl carbonate in 10 ml of DMA was then added to the first mixture, in the course of 7 minutes, while it was cooled in an ice bath, to form a second mixture. The second mixture was subsequently stirred for another 15 minutes while cooled in the ice bath, and a solution of 1.84 g of methyl 2-aminosulfonyl-4-iodobenzoate (92.5percent pure) in DMA was then added dropwise in the course of 7 minutes. When the reaction ended, the product was worked up as described in Example 1. 1.47 g of the desired product (58percent of theory) was thus obtained. This Example further demonstrates that the carbamate of formula (IV) can be formed and converted, without isolation, to the sulfonylurea of formula (I), in a good yield (of both (IV) and (I)), without using an alkali metal hydride or phosgene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methanesulfonic acid; triethylamine; In diethyl ether; water; acetonitrile; | EXAMPLE 1 STR12 (Process (a)) 2.34 g (15 mmol) of phenyl chloroformate are added to a mixture of 3.53 g (15 mmol) of 2-ethoxycarbonyl-thiophene-3-sulphonamide, 3.03 g (30 mmol) of triethylamine and 60 ml of acetonitrile at 10° C. to 20° C. while stirring. After stirring for thirty minutes, 1.44 g (15 mmol) of methanesulphonic acid and 2.10 g (15 mmol) of 2-amino-4-methoxy-6-methyl-s-triazine are added in succession to the mixture. The reaction mixture is heated under reflux for 30 minutes. It is then evaporated down under a vacuum from a water pump, and the residue is thoroughly shaken with water/methylene chloride. The organic phase is separated off, dried with sodium sulphate and filtered. The filtrate is evaporated down, the residue is stirred with diethyl ether and the crystalline product is isolated by filtration under suction. 3.4 g (57percent of theory) of N-(4-methoxy-6-methyl-s-triazin-2-yl)-N'-(2-ethoxycarbonyl-thien-3-yl-sulphonyl)-urea of melting point 166° C. are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; | EXAMPLE 1 Preparation of N-[2-(3,3,3-trifluoropropynyl)-phenyl]aminosulfonyl-N,-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea (Compound Nr 1) 0.71 g (5 mmoles) of chlorosulfonylisocyanate are slowly added dropwise, in an atmosphere of nitrogen, to a suspension of 0.70 g (5 mmoles) of <strong>[1668-54-8]2-amino-4-methoxy-6-methyl-1,3,5-triazine</strong> in 25 ml of tetrahydrofuran cooled to -5° C. The mixture is maintained under stirring at room temperature for 8 hours. Subsequently a solution of 0.93 g (5 mmoles) of 2-(3,3,3-trifluoropropynyl)-aniline and 0.73 ml (5.2 mmoles) of triethylamine in 5 ml of tetrahydrofuran is added and the mixture is maintained under stirring for a further 3 hours at room temperature. It is poured into water (150 ml) and extracted with methylene chloride (3*30 ml). The organic phase is then washed again with water, anhydrified with sodium sulfate and concentrated. The raw product is purified by silica gel chromatography eluating with methylene chloride/acetone in a ratio of 9:1. 1.13 g of a yellow solid are obtained which is further purified by crushing with hexane/ethyl ether/ethyl acetate in a ratio of 4:1:1. 0.95 g of a solid are obtained from this purification corresponding to Compound Nr 1 having a melting point of 98° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | EXAMPLE 5 2-Methoxycarbonyl-5-isocyanato-N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]benzenesulfonamide To 27 g of 2-methoxycarbonyl-5-isocyanatobenzenesulfonylisocyanate in 250 ml of anhydrous acetonitrile is added in small portions at ambient temperatures, 14 g of <strong>[1668-54-8]2-amino-4-methoxy-6-methyl-1,3,5-triazine</strong>, the mixture is then stirred at ambient temperature for 16 hours. The resultant product, a white precipitate is removed by filtration and dried in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; | EXAMPLE 12 Ethyl 4-[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]aminosulfonyl]-2-methyl-5-thiazolecarboxylate (I; Q=Q-2, R=CH3, R2 =CO2 C2 H5, Z=N, X=OCH3, Y=CH3) A 7 ml portion of the methylene chloride solution of the sulfonyl isocyanate, prepared in Example 10, was added to a stirred suspension of 0.35 g of <strong>[1668-54-8]4-methoxy-6-methyl-1,3,5-triazin-2-amine</strong> and a crystal of diaza[2.2.2]bicyclooctane in methylene chloride. The reaction mixture was stirred overnight. The clear solution was concentrated to a yellow-brown oil. On lengthy trituration with ether, a solid was obtained which was collected, washed with ether and dried to give 0.48 g of the title compound, m.p. 126°-130°. IR: 1725 and 1720 cm-1 (2*C=O). NMR (CDCl3): delta1.35 (t, 3H, CH3), 2.6 (s, 3H, CH3), 2.75 (s, 3H, CH3), 4.15 (s, 3H, OCH3), 4.4 (q, 2H, OCH2), 8.2 (broad s, 1H, NH) and 12.6 (broad s, 1H, NH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium hydroxide; In methanol; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; | EXAMPLE 2 Acetamidine hydrochloride (9.5 g) was added to a predissolved solution of methanol (50 mL) and KOH pellets (6.8 g) at 10° C. It was then dropped into a solution of 11.4 g of dimethyl N-cyanoimidocarbonate and 40 mL of methanol at 10° C. After the addition, the reaction mixture was stirred at 25° C. for 2 hours onto 40 mL of ice water. The solid crystals were collected by filtering and washing with water and methanol. After drying at 70° C. overnight, 11.8 g (84percent yield) of 2-methyl-4-amino-6-methoxy-1,3,5-triazine was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; | EXAMPLE I Preparation of: 1-(2-methylcarbonylphenylsulfamoyl)-3-(4-methyl-6-methoxy-1,3,5-triazin-2-yl)urea To a stirred solution of 0.01 mole of chlorosulfonyl isocyanate in methylene chloride maintained at 0°-5° C. via an ice bath was added 1.4 grams (0.01 mole) of <strong>[1668-54-8]2-amino-4-methyl-6-methoxy-1,3,5-triazine</strong>. After two hours reaction time, a methylene chloride solution containing 1.35 grams (0.01 mole) of o-amino acetophenone and 1.0 gram (0.01 mole) of triethylamine is added dropwise. The reaction mixture was stirred rapidly while in the ice bath and was then removed and allowed to warm to room temperature. After standing overnight, the reaction mixture was poured into aqueous sodium carbonate. The aqueous layer was washed once with chloroform and filtered. Acidification with dilute aqueous hydrochloric acid resulted in a white precipitate which after suction filtration and vacuum drying afforded 2.4 grams of material confirmed by NMR analysis as the desired product. | |
With triethylamine; In dichloromethane; | Example I Preparation of: 1-(2-methylcarbonylphenylsulfamoyl)-3-(4-methyl-6-methoxy-1,3,5-triazin-2-yl)urea To a stirred solution of 0.01 mole of chlorosulfonyl isocyanate in methylene chloride maintained at 0-5°C. via an ice bath was added 1.4 grams (0.01 mole) of <strong>[1668-54-8]2-amino-4-methyl-6-methoxy-1,3,5-triazine</strong>. After two hours reaction time, a methylene chloride solution containing 1.35 grams (0.01 mole) of o -amino acetophenone and 1.0 gram (0.01 mole) of triethylamine is added dropwise. The reaction mixture was stirred rapidly while in the ice bath and was then removed and allowed to warm to room temperature. After standing overnight, the reaction mixture was poured into aqueous sodium carbonate. The aqueous layer was washed once with chloroform and filtered. Acidification with dilute aqueous hydrochloric acid resulted in a white precipitate which after suction filtration and vacuum drying afforded 2.4 grams of material confirmed by NMR analysis as the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; triethylamine; In dichloromethane; | EXAMPLE II Preparation of: 1-(2-methylcarbonyl-4-fluorophenylsulfamoyl)-3-(4-methyl-6-methoxy-1,3,5-triazin-2-yl)urea To 75 milliliters of methylene chloride maintained at 0°-5° C. via an ice bath were added 1.4 grams of <strong>[1668-54-8]4-methyl-6-methoxy-2-amino-1,3,5-triazine</strong> and 1.55 grams of chlorosulfonyl isocyanate. After stirring for 2 hours at ice bath temperature a methylene chloride solution containing 1.0 gram of triethylamine and 1.53 grams of 5-fluoro-2-amino-acetophenone was added dropwise. The stirred reaction mixture was permitted to warm to room temperature and was then shaken once with 2 percent aqueous hydrochloric acid then twice with water. Removal of solvent afforded a crystalline solid which was washed with a small amount of diethyl ether. Suction drying afforded light tan crystals identified by NMR analysis as the desired product. | |
With hydrogenchloride; triethylamine; In dichloromethane; | Example II Preparation of: 1-(2-methylcarbonyl-4-fluorophenylsulfamoyl)-3-(4-methyl-6-methoxy-1,3,5-triazin-2-yl)urea To 75 milliliters of methylene chloride maintained at 0-5°C via an ice bath were added 1.4 grams of <strong>[1668-54-8]4-methyl-6-methoxy-2-amino-1,3,5-triazine</strong> and 1.55 grams of chlorosulfonyl isocyanate. After stirring for 2 hours at ice bath temperature a methylene chloride solution containi ng 1.0 gram of triethylamine and 1.53 grams of 5-fluoro-2-amino-acetophenone was added dropwise. The stirred reaction mixture was permitted to warm to room temperature and was then shaken once with 2 percent aqueous hydrochloric acid then twice with water. Removal of solvent afforded a crystalline solid which was washed with a small amount of diethyl ether. Suction drying afforded light tan crystals identified by NMR analysis as the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; water; | EXAMPLE 11 900 g (5 moles) of 30percent methanolic sodium methylate solution (technical grade) and 1,350 ml of methanol were taken together, with exclusion of atmospheric moisture, and 617 g (2.5 moles) of O-methylisourea sulfate, pure from SKW Trostberg AG (corresponding to 5 moles of O-methylisourea) were introduced, while stirring and cooling externally with cold water, and stirring was continued for a further 15 minutes. 577 g (5 moles) of crude N-cyanoacetimido-ethyl ester with a content of 97.9percent were added dropwise, while stirring vigorously and cooling externally by running cold water, at a rate such that the internal temperature did not rise above 20° C. When the addition of the N-cyanoacetimido-ethyl ester had ended, the mixture was stirred for a further 2 hours, while cooling externally with cold water. The reaction mixture was then stirred for 17 hours, without cooling (room temperature: about 20° C.), 200 ml of water were subsequently added and stirring was continued at room temperature for a further 25 hours. The mixture was filtered with suction and the colorless residue was suspended twice in 2,000 ml of water each time, to remove the sodium sulfate, and then washed free from sodium sulfate on a suction filter. After drying in a vacuum drying cabinet at 80° C. (20 mbar), 694 g (99percent of theory) of 2-amino-4-methoxy-6-methyl-s-triazine having a melting point of 262° C. (decomposition) were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | EXAMPLE 7 4-Chloro-2-[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]aminosulfonyl]benzoic acid, (1-methylethyl)ester Under a nitrogen atmosphere, (1-methylethyl)-4-chloro-2-(isocyanatosulfonyl)benzoate (388.1 g) was added slowly to a stirred suspension of 143.2 g <strong>[1668-54-8]4-methoxy-6-methyl-1,3,5-triazin-2-amine</strong> in 1280 mL of dry acetonitrile; the addition caused an exotherm of 7 C. The resulting mixture was stirred at ambient temperature for 3 days. The mixture was filtered under a nitrogen atmosphere, and the filter cake was washed with methylene chloride. The methylene chloride solution was concentrated in vacuo to give 188.9 g of the title compound, m.p. 165-166 C. The original acetonitrile filtrate was concetrated in vacuo, and the resulting oil was triturated with ether to given an additional 64.7 g of the title compound, m.p. 154-159 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In 1,4-dioxane; | (c) N-(3-Chloropyridazine-6-sulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea STR9 A mixture of 14.2 g of N-(3-chloropyridazine-6-sulfonyl)phenylcarbamate and 6.3 g of <strong>[1668-54-8]2-amino-4-methoxy-6-methyl-1,3,5-triazine</strong> are refluxed for 1 hour in 120 ml of absolute dioxan. When the reaction is complete, the mixture is concentrated in vacuo and the residue is taken up in a saturated aqueous solution of sodium bicarbonate and the insoluble constituents are extracted with methylene chloride. The aqueous phase is acidified with dilute hydrochloric acid and extracted with methylene chloride. The methylene chloride solution is dried over sodium sulfate and concentrated, affording 7 g of the compound of the above formula with a melting point of 135° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; | EXAMPLE III Preparation of: 1-[2-(1-methoxyethyl)phenylsulfamoyl]-3-(4-methyl-6-methoxy-1,3,5-triazin-2-yl)urea To 75 milliliters of methylene chloride maintained at 0°-5° C. via an ice bath were added 1.4 grams of <strong>[1668-54-8]4-methyl-6-methoxy-2-amino-1,3,5-triazine</strong> and 1.55 grams of chlorosulfonyl isocyanate. After stirring for 3 hours at ice bath temperature a methylene chloride solution containing 1.0 gram of triethylamine and 1.4 grams of 2-(1-methoxyethyl)aniline was added dropwise. The reaction mixture was removed from the ice bath, allowed to stir an additional one-half hour and then extracted with aqueous sodium carbonate solution. Acidification with cold, dilute aqueous hydrochloric acid solution afforded a white precipitate which was suction filtered and vacuum dried affording 2.2 grams of material confirmed by NMR analysis as the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; triethylamine; In diethyl ether; dichloromethane; chloroform; water; | EXAMPLE I Preparation of: 1-[2-(1-hydroxyethyl)phenylsulfamoyl]-3-(4-methyl-6-methoxy-1,3,5-triazin-2-yl)urea To 75 milliliters of methylene chloride maintained at 0°-5° C. via an ice bath were added 1.4 grams of <strong>[1668-54-8]4-methyl-6-methoxy-2-amino-1,3,5-triazine</strong> and 1.55 grams of chlorosulfonyl isocyanate. After stirring for 3 hours at ice bath temperature a methylene chloride solution containing 1.0 gram of triethylamine and 1.37 grams of 2-(1-hydroxyethyl)aniline was added dropwise. The reaction mixture was removed from the ice bath, allowed to stir an additional one-half hour and then poured into 100 milliliters of 2 percent aqueous hydrochloric acid solution. After phase separation, the organic layer was washed in water and concentrated on a rotary evaporator affording a dark oil. Addition of diethyl ether to the dark oil resulted in the formation of a precipitate which was filtered-off. The filtrate was evaporated and the residue was taken-up in chloroform and again evaporated affording a powdery solid. Vacuum drying afforded 1.7 grams of light tan solid confirmed by NMR analysis as the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; | EXAMPLE 7 Methyl 4-methoxy-2-[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]aminosulfonyl]benzoate A solution of 119 g of the compound of Example 6 in 100 ml dichloromethane was added over 0.25 hours to a suspension of 57 g of <strong>[1668-54-8]4-methoxy-6-methyl-1,3,5-triazin-2-amine</strong> in 1000 ml dichloromethane. The reaction was heated at reflux for 3 to 4 hours, then stirred overnight at ambient temperature. The reaction mixture was filtered and dried. The crude product was dissolved in 2000 ml boiling dichloromethane, the solution filtered, and the filtrate evaporated in vacuo to give 75 g of the title compound, m.p. 183°-186° C. |
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