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CAS No. : | 6674-22-2 | MDL No. : | MFCD00006930 |
Formula : | C9H16N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GQHTUMJGOHRCHB-UHFFFAOYSA-N |
M.W : | 152.24 | Pubchem ID : | 81184 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.89 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 54.97 |
TPSA : | 15.6 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.25 cm/s |
Log Po/w (iLOGP) : | 2.14 |
Log Po/w (XLOGP3) : | 1.38 |
Log Po/w (WLOGP) : | 0.9 |
Log Po/w (MLOGP) : | 1.88 |
Log Po/w (SILICOS-IT) : | 2.41 |
Consensus Log Po/w : | 1.74 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.65 |
Solubility : | 3.38 mg/ml ; 0.0222 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.31 |
Solubility : | 7.44 mg/ml ; 0.0489 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.73 |
Solubility : | 2.84 mg/ml ; 0.0187 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.95 |
Signal Word: | Danger | Class: | 8,6.1 |
Precautionary Statements: | P234-P273-P280-P303+P361+P353-P304+P340+P310-P305+P351+P338 | UN#: | 2922 |
Hazard Statements: | H290-H301-H314-H412 | Packing Group: | Ⅱ |
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 |
---|---|---|
23.5% | With hydrogenchloride; N-ethyl-N,N-diisopropylamine; benzyl alcohol; In water; ethyl acetate; N,N-dimethyl-formamide; acetonitrile; | Synthesis of 5R-({5S-[(9H-fluoren-9-ylmethoxycarbonylamino)-methyl]-2,2-dimethyl-[1,3]dioxolan-4R-ylmethyl}-carbamoyl)-2,2-dimethyl-[1,3]dioxolan-4S-carboxylic acid benzyl ester (Compound 11) 2,2-Dimethyl-[1,3]dioxolan-4R,5R-dicarboxylic acid (740 mg, 3.89 mmol) was dissolved in 50 ml of acetonitrile, 1,1'-carbonyldiimidazole (CDI; 1.26 g, 7.78 mmol) was added, and this was followed by stirring at room temperature for 30 minutes. To the reaction system, benzyl alcohol (BnOH; 420 mg, 3.89 mmol) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU; 887 mg, 5.84 mmol) were added; this was followed by stirring at room temperature for 17 hours. After completion of the reaction, water was added to the reaction solution, and the solution was rendered weakly acidic by further adding 1N hydrochloric acid. The reaction solution was extracted with ethyl acetate, and the organic phase extracted was washed with saturated brine, after which it was dried with anhydrous magnesium sulfate. The organic phase obtained was concentrated under reduced pressure to yield the desired monobenzyl ester compound. The monobenzyl ester compound obtained, without purification, was dissolved in 100 ml of DMF, and the Compound 10 obtained in Production Example 19 (1.2 g, 3.14 mmol) was dissolved in 10 ml of DMF and added to the reaction system. Benzotriazol-1-yl-oxy-tris-pyrolidino-phosphonium hexafluorophosphate (PyBOP; 3.37 g, 6.48 mmol) and diisopropylethylamine (i-Pr2NEt; 1.25 g, 9.74 mmol) were added, and this was followed by stirring at room temperature for 17 hours. To the reaction solution, 100 ml of water was added; extraction with 100 ml of ethyl acetate was conducted three times. The organic phase extracted was washed with saturated brine, and the organic phase obtained was dried with anhydrous magnesium sulfate, after which it was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield the desired Compound 11 (0.49 g) at a percent yield of 23.5%. MS (m/z): 645 (MH+), 1H-NMR(CDCl3) delta: 1.33-1.39 (m, 6H), 1.43 (s, 3H), 1.50 (m, 3H), 3.42 (b, 2H), 3.53 (b, 2H), 3.75 (m, 1H), 4.21 (m, 1H), 4.37-4.48 (m, 2H), 4.76-4.82 (m, 2H), 5.25 (s, 2H), 5.29 (m, 1H), 6.93 (m, 1H), 7.28-7.41 (m, 9H), 7.59 (d, 2H, J=7.5 Hz), 7.75 (d, 2H, J=7.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 4. Preparation of novel crystalline form III of anhydrous moxifloxacin hydrochloride 1-CYCLOPROPYL-6, 7-DIFLUORO-L, 4-dihydro-4-oxo-8-methoxy quinolone-3- carboxylic acid (50 KGS), (S, S) diazabicyclo nonane (1.49 equivalents) and 1,8- diazabicyclo [5.4. 0. ] undec-7-ene (DBU) (5KGS) were added to N-METHYLPYROLIDINONE (125L) in SS Reactor and the reaction mixture was slowly heated to the 60-65 C temperature and stirred till the reaction was substantially completed. 500L of 5% aqueous isopropyl alcohol was added to the reaction mass, and pH was adjusted to 5.0-6. 0 and the product is isolated at 20-25 C. Wet cake is recrystallised in aqueous methanol at pHl. 5- 2. 0, and is made slurry in 5% aqueous methanol. Then wet cake was dissolved in aqueous methanol and the reaction mass was filtered through clarifying filter, washed with aqueous methanol. Combined total filtrate pH was adjusted to 1.5-2. 0 with Aqueous Hcl. Finally, wet cake is taken with methyl isobutylketone (800ML) and heated to reflux while collecting the low boilers and refluxed azeotropically between 115-120 C and then reaction mass is cooled to 25-35 C and product is filtered and dried at 80-90C under vacuum to afford the novel crystalline form III of anhydrous moxifloxacin hydrochloride. (Weight: 31. 3Kgs, M. C. by KF is 0.60% ; Purity by HPLC : 99.94%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With triethylamine; In ethanol; water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; | Step b. 2-(2,6-Dichloro-phenyl)-5-phenoxymethyl-2H-[1,2,3]triazole-4-carboxylic acid ethyl ester Triethylamine (2.09 mL, 15.0 mmol) was added to a stirred suspension of the product from step a (10.0 mmol) and <strong>[50709-36-9]2,6-dichlorophenylhydrazine-hydrochloride</strong> (3.20 g, 10.0 mmol) in ethanol (30 mL). The resultant solution was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and was washed sequentially with 2M HCl and brine. The organic phase was dried (MgSO4) and the filtrate was evaporated at reduced pressure. The residue was dissolved in DCM (100 mL) and the solution was cooled in ice/water. 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.84 mL, 12.3 mmol) and p-toluenesulfonyl chloride (2.14 g, 11.2 mmol) were added sequentially, the coolant removed and the reaction mixture was stirred at room temperature for 40 minutes. The reaction mixture was re-cooled in ice/water and further 1,8-diazabicyclo[5.4.0]undec-7-ene (1.84 mL, 12.3 mmol) was added. The coolant was removed and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was washed sequentially with 2M HCl, saturated aqueous sodium hydrogen carbonate and brine. The organic phase was dried (MgSO4) and the filtrate evaporated at reduced pressure. The residue was purified by flash column chromatography (2:1 hexane:ethyl acetate) to recover the title compound (1.44 g, 37%). 1H NMR (CDCl3) 7.48-7.44 (3H, m), 7.32-7.27 (2H, m), 7.08-6.98 (3H, m), 5.52 (2H, s), 4.49 (2H, q, J=7.2 Hz), 1.41 (3H, t, J=7.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile; | 5-Amino-2-dimethylaminocarbonyl-N-[(4,6-dimethoxypyrimidin-2-yl)-aminocarbonyl]benzenesulfonamide 0.6 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is added with stirring at 0 C. to a suspension of 1.0 g of 5-amino-2-dimethylaminocarbonylbenzene-sulfonamide and 1.1 g of 4,6-dimethoxy-2-(phenoxycarbonylamino)-pyrimidine in 10 ml of acetonitrile. The mixture is stirred again until complete reaction has taken place. Following the distillative removal of the volatile components, the residue is taken up in a little water and washed with diethyl ether. The aqueous phase is subsequently acidified with concentrated hydrochloric acid (pH=2-3). The deposited solid is washed with diisopropyl ether and then dried, to give 1.4 g of a solid which comprises the two compounds 5-amino-2-dimethylaminocarbonyl-N-[(4,6-dimethoxypyrimidin-2-yl)-aminocarbonyl]-benzenesulfonamide and 5-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonylamino]-2-dimethylaminocarbonyl-N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]benzenesulfonamide in a ratio of about 2:1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; | (5) 320 mg of 1-(n-propyl)-3-aminosulfonyl-2(1H)-pyridone, 330 mg of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate and 10 ml of anhydrous dimethylformamide were mixed, and 218 mg of 1,8-diazabicyclo[5.4.0]-7-undecene was added thereto. The mixture was then reacted at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was put into water, and insoluble matters were separated off, and the solution was adjusted to be weakly acidic by concentrated hydrochloric acid. The crystals thereby precipitated were collected by filtration and dried to obtain 312 mg of the desired product having a melting point of from 180 to 183 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; acetonitrile; | (5) 226 mg of 1-methyl-3-aminosulfonyl-4(1H)-pyridone, 360 mg of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate and 3 ml of anhydrous acetonitrile were mixed, and 200 mg of 1,8-diazabicyclo[5.4.0]-7-undecene was added thereto. Then, the mixture was reacted at room temperature for 1.5 hours. After completion of the reaction, water was added to the reaction mixture. Then, concentrated hydrochloric acid was added thereto until the mixture became acidic. Precipitated crystals were collected by filtration, washed with water, dried and then washed with ethyl acetate to obtain 237 mg of the desired product having a melting point of 161 C. (decomposed). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In acetonitrile; | Example A5 Methyl 4-cyclopentylidenehydrazino-2-[3-(4,6-dimethoxypyrimidin-2-yl)ureidosulfonyl]-benzoate (cf. Table 1, Example no. 40) 1.5 g (4.8 mmol) of methyl 4-cyclopentylidenehydrazino-2-sulfamoylbenzoate and 1.6 g (5.8 mmol) of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate are initially introduced into 20 ml of acetonitrile. 1.6 g (10.6 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are added dropwise at 0 C. and the mixture is stirred at this temperature for 2 hours. It is poured into water and the pH is brought to 2-3 with 2 N hydrochloric acid. The aqueous phase is extracted three times with CH2 Cl2. After the methylene chloride phase has been washed with 2 N hydrochloric acid and water, it is dried and evaporated. The residue is triturated with diisopropyl ether. After filtering off with suction and drying, 1.55 g (65% of theory) of methyl 4-cyclopentylidenehydrazino-2-[3-(4,6-dimethoxypyrimidin-2-yl)-ureidosulfonyl]benzoate of melting point 168-170 C. (decomposition) are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With diphenylphosphoranyl azide; In toluene; | Preparation HH1 2-azidomethyl-thiazole Diphenylphosphoryl azide (3.25 mL, 0.015 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.25 mL, 0.025 mol) were added to a solution of <strong>[14542-12-2]thiazol-2-yl-methanol</strong> (1.44 g, 0.013 mol) in toluene (20 mL) at 0 C. After 1 h the reaction was warmed to room temperature and stirred overnight. The mixture was diluted with toluene (20 mL) and washed with H2 O (3*) brine (1*), dried (Na2 SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (30% ethyl acetate/hexanes) to afford the azide as a tan oil (1.1 g, 63%). IR 2098 cm. 1 H NMR (250 MHz, CDCl3) delta 7.8 (d, 1H, J=2.0 Hz); 7.4 (d, 1H, J=2.0 Hz); 4.7 (s, 2H). |
63% | With diphenylphosphoranyl azide; In toluene; | 2-azidomethyl thiazole Diphenylphosphoryl azide (3.25 mL, 0.015 mol) and 1,8-diazabicyclo[5.4.0] undec-7-ene (2.25 mL, 0.025 mol) were added to a solution of <strong>[14542-12-2]thiazol-2-yl-methanol</strong> (1.44 g, 0.013 mol) in toluene (20 mL) at 0 C. After 1 hour, the reaction was warmed to room temperature and stirred overnight. The mixture was diluted with toluene (20 mL) and washed with H2 O (3*) brine (1*), dried (Na2 SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (30% ethyl acetate/hexanes) to afford the azide as a tan oil (1.1 g, 63%). IR: 2098 cm-1. 1 H NMR (250 MHz, CDCl3) delta7.8 (d, 1H, J=2.0 Hz); 7.4 (d, 1H, J=2.0 Hz); 4.7 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | b 3-(4,6-Dimethoxypyrimidin-2-yl)-1-(1-pyrrolidinosulfonylethylsulfonyl)urea To 3.6 g (0.015 mol) of 1-pyrrolidinosulfonylethanesulfonamide (Example 1a) and 4.0 g (0.019 mol) of phenyl 4,6-dimethoxypyrimidin-2-ylcarbamate in 40 ml of acetonitrile there are added 2.9 g (0.019 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). After the mixture has been stirred for five hours at room temperature, it is treated with 250 ml of ice/water and acidified with HCl to pH 2. Extraction with dichloromethane, drying and evaporation give crude 3-(4,6-dimethoxypyrimidin-2-yl)-1-(1-pyrrolidinosulfonylethylsulfonyl)urea, which is purified by trituration with diisopropyl ether (yield: 4.6 g; 73% of theory; melting point 145-146 C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.03 g (54%) | In acetonitrile; | EXAMPLE 6 Preparation of methyl 2-[[[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]amino]sulfonyl]-6-(trifluoromethyl)-3-pyridinecarboxylate (I) To a stirred solution of 0.05 g (0.176 mmol) of the product from Example 5 and 0.06 g (0.211 mmol) of phenyl (4,6-dimethoxypyrimidin-2-yl) carbamate in 0.5 mL acetonitrile was added dropwise 0.028 g (0.185 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and was stirred 15 minutes. The solution was diluted with water, acidified with 1 normal hydrochloric acid and extracted with methylene chloride. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to an oil which was triturated with ether to afford 0.03 g (54%) of a solid. m.p. 130-137 C. 1 H NMR (CDCl3) delta3.96 (6H, s), 4.05 (3H, s), 5.82 (1H, s), 7.3 (NH), 7.93 (1H, d, J=approximately 8 Hz), 8.4 (1H, d, J=approximately 8 Hz), 13.1 (NH); IR (mineral oil) 3180, 1745, 1715, 1370, 1140 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dimethyl sulfoxide; | f. 1-Cyclopropyl-6-fluoro-8-methoxy-7- [(1S:4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid A mixture of <strong>[112811-72-0]1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid</strong> (400 mg, 1.4 mmol), (1S:4S)-2-methyl-2,5-diazabicyclo-[2.2.1]heptane dihydrochloride (300 mg, 1.63 mmol, 1.2 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (710 mL, 4.75 mmol, 3.4 equiv) in anhydrous dimethyl sulfoxide (25 mL) was heated to 75 C. for 18 hours. The reaction mixture was cooled to room temperature and poured into distilled water adjusted to pH=7.4 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted several times with chloroform. The chloroform layer was then extracted with 1N HCl and the acidic aqueous phase was back extracted with chloroform. The aqueous layer was adjusted to pH=7.4 with saturated aqueous sodium bicarbonate and extracted with chloroform. The chloroform extracts were dried over sodium sulfate, filtered and concentrated in vacuo to a dark oil which was purified by flash chromatography (chloroform/methanol 10:1 v/v) to give 65 mg, 12% yield of a white solid, m.p. 190-212 C with decomposition. Anal.: Calcd. for C20 H22 FN3 O4. 0.5H2 O: C, 60.60; H, 5.80; N, 10.60. Found: C, 60.57; H, 5.70; N, 10.59. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | 5) 0.20 g of 6-[(N-ethyl-N-methylsulfonyl)amino]-2-pyridinesulfonamide obtained in the above step 4) was mixed with 0.20 g of phenyl (4,6-dimethoxypyrimidin-2-yl)carbamate and 7 ml of acetonitrile. The resulting mixture was further admixed and reacted with 0.11 g of 1,8-diazabicyclo[5.4.0]-7-undecene at room temperature for one hour. After completion of the reaction, the reaction mixture was poured into water and weakly acidified with hydrochloric acid. The resulting solid substance was filtered off, washed with water, and dried to obtain 0.25 g of the desired product (Compound No. alpha-2) having a melting point of 145 to 147 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | 4) 0.21 g of 6-[(N-ethyl-N-ethylsulfonyl)amino]-2-pyridinesulfonamide obtained in the above step 3) was mixed with 0.20 g of phenyl (4,6-dimethoxypyrimidin-2-yl)carbamate and 7 ml of acetonitrile. The resulting mixture was further admixed and reacted with 0.11 g of 1,8-diazabicyclo[5.4.0]-7-undecene at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured into water and weakly acidified with hydrochloric acid. The resulting solid substance was filtered off, washed with water, and dried to obtain 0.25 g of the desired product (Compound No. alpha-18) having a melting point of 165 to 170 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | 4) 0.12 g of 6-[(N-ethyl-N-isopropylsulfonyl)amino]-2-pyridinesulfonamide obtained in the above step 3) was mixed with 0.11 g of phenyl (4,6-dimethoxypyrimidin-2-yl)carbamate and 7 ml of acetonitrile and further admixed with 59 mg of 1,8-diazabicyclo[5.4.0]-7undecene to effect a reaction at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured into water, weakly acidified with hydrochloric acid, and subjected to extraction with methylene chloride. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography with a developing solvent (ethyl acetate:hexane=4:1) to obtain 0.11 g of the desired product (Compound No. alpha-22) having a melting point of 163 to 166 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | Following a procedure similar to that described in the first part of Preparation 3, the whole of the <strong>[33538-83-9]3-(2-methoxyphenyl)propanal</strong> prepared as described above, 1.65 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) and 1.01 g of 1,8-diazabicyclo[5,4,0]undec-7-ene were reacted in 30 ml of acetonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; acetonitrile; | Example 5 3-(4,6-Dimethoxypyrimidin-2-yl)-1-(3-dimethylsulfamoyloxy-2-pyridylsulfonyl) urea 1.9 g (12.7 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are added to a suspension of 3.0 [lacuna] (10.6 mmol) of 3-dimethylsulfamoyloxy-2-pyridinesulfonamide and 3.4 g (12.7 mmol) of N-(4,6-dimethoxypyrimidin-2-yl) phenyl carbamate in 40 ml of acetonitrile. The resulting solution is stirred at room temperature for 1 h and 30 ml o f water are then added. The mixture is acidified to pH 4 using hydrochloric acid and the precipitated product is filtered off with suction. After triturating with diethyl ether, 2.1 g (42% of theory) of 3-(4,6-dimethoxypyrimidin-2-yl)-1-(3-dimethylsulfamoyloxy-2-pyridylsulfonyl) urea of melting point 155-157 C. are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With hydrogenchloride; In acetonitrile; | EXAMPLE 1 7-([1alpha,5alpha,6beta]-6-Amino-1-methyl-3-azabicyclo[3.2.0]heptane-3-yl)1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid,hydrochloride To a suspension of 150 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in 5 ml of acetonitrile were added 200 mg of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) and 200 mg of [1alpha,5alpha,6beta]-6-amino-1-methyl-3-azabicyclo[3.2.0]heptane. The reaction mixture was heated under reflux for an hour. The solvent was evaporated out under reduced pressure. To the residue was added 5 ml of an aqueous 5percent hydrochloric acid solution. The resulting mixture was stirred at room temperature for 3 hours. The solids were collected by filtration, washed with water and then ethanol, and dried to give 140 mg of the titled compound as pale-yellow solids (yield: 61percent). m.p.: 285°-290° C. 1 H-NMR(DMSO-d6 +TFA-d) delta: 8.55(1H, s), 8.00(1H, d, J=17 Hz), 7.24(1H, d, J=7.4 Hz), 4.3-3.5 (4H, m), 3.5-3.3(1H, m), 3.0-2.6(2H, m), 2.3-2.0(2H, m), 1.31(3H, s), 1.4-1.0(4H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In chloroform; water; | a solution of 3.65 g of 1,8-diazabicyclo[5.4.0]undec-7-ene in 10 ml of chloroform is added dropwise over 20 minutes at a temperature close to 20° C. to a solution of 2.8 g of <strong>[33543-78-1]ethyl imidazole-2-carboxylate</strong> and 6.1 g of 2-bromo-5-chloro-1-indanone. After stirring for 2 hours and adding 100 ml of distilled water, the mixture is extracted 3 times with a total of 75 ml of chloroform and the organic extracts are pooled, dried over anhydrous magnesium sulphate and concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 50° C. After silica gel chromatography with a dichloromethane-ethyl acetate mixture (70-30 by volume), 1 g of ethyl 1-(5-chloro-1-oxo-2-indanyl)imidazole-2-carboxylate is obtained in the form of a thick yellow oil Rf=0.3, thin-layer chromatography on silica gel; solvent: dichloromethane-ethyl acetate (70-30 by[volume)]. The 2-bromo-5-chloro-1-indanone can be prepared as described in German Patent 2,640,358. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In acetonitrile; | A6. Methyl 2-[3-(4,6-dimethoxypyrimidin-2-yl)ureidosulfonyl]-4-(2-isobutyrylhydrazino)benzoate 0.8 g (2.5 mmol) of methyl 4-(2-isobutyrylhydrazino)-2-sulfamoylbenzoate and 0.77 g (2.8 mmol) of phenyl-N-(4,6-dimethoxypyrimidin-2-yl)carbamate are initially introduced into 25 ml of acetonitrile. 0.83 g (5.6 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is added dropwise at 0 C. and the mixture is stirred at this temperature for 2 hours. It is poured into water and the pH is brought to 2-3 with 2N HCl. The aqueous phase is extracted three times with CH2 Cl2. After the CH2 Cl2 phase has been washed with 2N HCl and water, it is dried and evaporated. The residue is triturated with diethyl ether. Filtration with suction and drying gives 0.8 g (64% of theory) of methyl 2-[3-(4,6-dimethoxypyrimidin-2-yl)-ureidosulfonyl]-4-(2-isobutyrylhydrazino)benzoate of melting point 169-171 C. (decomposition). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,1'-carbonyldiimidazole; In tetrahydrofuran; | Example 5 A solution of 1 g of 2-(1,3-benzodioxol-5-yl)-2-(1,3-dihydro-1,3-dioxoisoindol-5-yloxy)acetic acid and 0.71 g of carbonyldiimidazole in 100 ml of THF is heated at 60° for 2 hours. 0.93 g of <strong>[6292-59-7]4-tert-butylbenzenesulfonamide</strong> and 0.67 g of 1,8-diaza-bicyclo[5.4.0]-undec-7-ene are then added and the mixture is stirred for a further 1 hour at this temperature. After customary working up, 2-(1,3-benzodioxol-5-yl)-2-(1,3-dihydro-1,3-dioxo-isoindol-5-yloxy)-N-(4-tert-butylphenylsulfonyl)acetamide, m.p. 215°, is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.9 g (57%) | In dichloromethane; | e. 3-Bromoanthranilonitrile A suspension of the oxime described in Example 31d in 2.9 liters of methylene chloride was treated with 2,6-lutidine (78.1 ml) then cooled to 0 and 112 ml of trifluormethanesulfonic anhydride added. The cooling bath was removed and the mixture heated to vigorous reflux. After heating for 3 hours, complete dissolution had occurred and a dark brown solution remained. The solution was cooled to ambient temperature with a water bath and 174 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) added slowly. The internal temperature was maintained below 30 during the addition of the DBU. After stirring for 1 hour at ambient temperature, the mixture was poured slowly with vigorous stirring into excess dilute aqueous sodium bicarbonate. After stirring for several minutes the mixture was extracted with methylene chloride. The extracts were dried (MgSO4) and concentrated. The crude product was purified by column chromatography over silica gel using methylene chloride as the eluent. The product was triturated with hexane, filtered and dried under vacuum to afford 64.9 g (57%) of the 3-bromoanthranilonitrile: tlc, Rf =0.68, silica gel, ethyl acetate:hexane (2:3); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile; | Step D 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-6-(methylamino)pyridine To a suspension of 0.20 g (1.0 mmol) of 6-(methylamino)pyridine-2-sulfonamide and 0.28 g (1.0 mmol) of 4,6-dimethoxypyrimidin-2-yl phenyl carbamate in 1.0 ml of acetonitrile waa added 0.20 ml (0.20 g, 1.3 mmol) of 1,8-diazabicyclo[5,4,0]undec-7-ene. The mixture was stirred at room temperature for 1 hr, then 3 ml of water was added. Dropwise addition of 1N hydrochloric acid precipitated a solid which was filtered and washed with water to afford 0.21 g of the title compound as a white powder, m.p. 166 C. to 168 C. NMR(CDCl3 +CF3 CO2 D): delta 3.09 (s, 3H), 4.01 (s, 6H), 5.88 (s, 1H), 7.10 (d, 1H), 7.51 (d, 1H), 7.94 (dd, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; acetonitrile; | EXAMPLE 9 2-Chloro-N-[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]-6-[(2-oxo-3-oxazolidinyl)methyl]benzenesulfonamide To a suspension of 0.15 g of the product of Example 8 in 5 mL of acetonitrile, containing 0.15 g of phenyl (4,6-dimethoxypyrimidin-2-yl)carbamate, was added 0.15 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The resultant solution was stirred at 25 C. for 2 hours, diluted with 10 mL of cold water and acidified with 5 mL of 5% aqueous hydrochloric acid. The resulting precipitate was filtered. The collected white solid was washed with water, diethyl ether and suction-dried and finally dried in vacuo overnight to afford 0.14 g of the title compound as a white solid; m.p. 135-136 C. When the solid was dried in methylene chloride over magnesium sulfate and the solvent removed under reduced pressure, the title compound, as a white solid, now had m.p. 227-229 C. Spectra (IR and NMR) for both solids appeared identical. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile; | EXAMPLE 6 2-Chloro-N-[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]-6-[(1H-1,2,4-triazol-1-yl)methyl]benzenesulfonamide To a suspension of 0.14 g of the product of Example 5 in 5 mL of acetonitrile, containing 0.17 g of phenyl (4,6-dimethoxypyrimidin-2-yl)carbamate, was added 0.10 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The resultant solution was stirred at 25 C. for 2 hours, diluted with 10 mL of cold water and acidified with 5 mL 5% aqueous hydrochloric acid. The resulting solid was filtered. The collected white solid was washed with water, diethyl ether and suction-dried and finally dried in vacuo overnight to afford 0.17 g of the title compound as a white solid; m.p. 220-221 C. NMR (DMSO-d6) ppm delta 13.15, (bs, 1H, NH), 10.85, (bs, 1H, NH), 8.64, (s, 1H, triazole-H), 8.0, (s, 1H, triazole-H), 7.70, (m, 2H, Ph-H), 6.75, (m, 1H, Ph-H), 6.021, (m, 3H, CH2 & Py-H), 3.91; (s, 6H, OCH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; | EXAMPLE 7 1-Cyclopropyl-7-(6,8-diazabicyclo[3.2.2]non-6-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid A solution of 0.53 g (2.0 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.44 g (2.2 mmol) of 6,8-diazabicyclo[3.2.2]nonane, dihydrochloride, 0.90 ml (6.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 10 ml of pyridine was heated under reflux for 4 hr. The reaction mixture was cooled to room temperature and the solid was filtered and washed with ethanol to yield 0.39 g of the title compound, mp 273°-276° dec. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | EXAMPLE 6 2-(Azidomethyl)-6-[((4,6-dimethoxypyrimidin-2-yl)aminocarbonyl)aminosulfonyl]benzoic acid, ethyl ester To a suspension of 0.21 g of the compound from Example 5 and 0.23 g of 4,6-dimethoxy-2-pyrimidinylcarbamic acid, phenyl ester in 4.0 mL of dry acetonitrile was added 0.12 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). After being stirred at room temperature for 2 hours, the resulting reaction mixture was diluted with 4.0 mL of water, acidified with 1N hydrochloric acid to pH 2 and the solids collected by vacuum filtration. The solids were further washed with ether and then air dried to give 0.21 g of a white solid, m.p. 158-160 C. 1 H-NMR (200 MHz, CDCl3): 1.41 (t, CH3, 3H); 3.98 (s, OCH3, 6H); 4.43 (q, CH2, 2H); 4.44 (s, CH2, 2H); 5.78 (s, Het-H, 1H); 7.22 (br s, NH, 1H); 7.60-7.80 (m, ArH, 2H); 8.36 (dd, ArH, 1H); and 12.52 (br s, NH, 1H). | |
In acetonitrile; | Example 6 2-(Azidomethyl)-6-[((4,6-dimethoxypyrimidin-2-yl)-aminocarbonyl)aminosulfonyl]benzoic acid, ethyl ester To a suspension of 0.21 g of the compound from Example 5 and 0.23 g of 4,6-dimethoxy-2-pyrimidinylcarbamic acid, phenyl ester in 4.0 mL of dry acetonitrile was added 0.12 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). After being stirred at room temperature for 2 hours, the resulting reaction mixture was diluted with 4.0 mL of water, acidified with 1N hydrochloric acid to pH 2 and the solids collected by vacuum filtration. The solids were further washed with ether and then air dried to give 0.21 g of a white solid, m.p. 158-160C. 1H-NMR (200 MHz, CDCl3): 1.41 (t, CH3, 3H); 3.98 (s, OCH3, 6H); 4.43 (q, CH2, 2H); 4.44 (s, CH2, 2H); 5.78 (s, Het-H, 1H); 7.22 (br s, NH, 1H); 7.60-7.80 (m, ArH, 2H); 8.36 (dd, ArH, 1H); and 12.52 (br s, NH, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile; | EXAMPLE 9 2-Acetoxymethyl-6-[((4,6-dimethoxypyrimidin-2-yl)aminocarbonyl)aminosulfonyl]benzoic acid, ethyl ester To a suspension of 0.25 g of the compound from Example 8 and 0.23 g of 4,6-dimethoxy-2-pyrimidinylcarbamic acid, phenyl ester in 4.0 mL of dry acetonitrile was added 0.12 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). After being stirred at room temperature for 2 hours, the reaction mixture was diluted with 4.0 mL of water and then acidified with 1N hydrochloric acid to pH 2. The solids were collected by vacuum filtration and washed with ether to yield 0.28 g of a white solid, m.p. 162-163 C. 1 H-NMR (200 MHz, DMSO-d6): 1.22 (t, CH3, 3H); 2.00 (s, CH3, 3H); 3.90 (s, OCH3, 6H); 4.28 (q, CH2, 2H); 5.08 (s, CH2, 2H); 5.60 (s, Het-H, 1H); 7.70-7.90 (m, ArH, 2H); and 8.03-8.10 (m, ArH, 1H). | |
In water; acetonitrile; | Example 9 2-Acetoxymethyl-6-[((4,6-dimethoxypyrimidin-2-yl)aminocarbonyl)aminosulfonyl]benzoic acid, ethyl ester To a suspension of 0.25 g of the compound from Example 8 and 0.23 g of 4.6-dimethoxy-2-pyrimidinylcarbamic acid, phenyl ester in 4.0 mL of dry acetonitrile was added 0.12 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). After being stirred at room temperature for 2 hours, the reaction mixture was diluted with 4.0 mL of water and then acidified with 1N hydrochloric acid to pH 2. The solids were collected by vacuum filtration and washed with ether to yield 0.28 g of a white solid, m.p. 162-163C. 1H-NMR (200 MHz, DMSO-d6): 1.22 (t, CH3, 3H); 2.00 (s, CH3, 3H); 3.90 (s, OCH3, 6H); 4.28 (q, CH2, 2H); 5.08 (s, CH2, 2H); 5.60 (s, Het-H, 1H); 7.70-7.90 (m, ArH, 2H); and 8.03-8.10 (m, ArH, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | EXAMPLE VI (R,S)-1-(3-Cyanopropyl)-2-(3-pyridyl)pyrrolidine STR15 A solution of 5.0 g (33.8 mmole) of (R,S)-<strong>[5746-86-1]nornicotine</strong> and 6.41 g (42.25 mmole) of 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) in 50 ml of acetonitrile is cooled to 0 C., and treated with 6.26 g (42.25 mmole) of 4-bromobutyronitrile. The solution is stirred at 0 C., and treated with 6.26 g (42.25 mmole) of 4-bromobutyronitrile. The solution is stirred at 0 C. for 2 hours and at room temperature for 72 hours. The solution is acidified with 6N HCl, and washed with ether. The aqueous phase is basified (50% KOH), extracted with ether, and the ether extract is dried (Na2 SO4) and concentrated. The residual oil is distilled bulb to bulb, and the fraction distilling at an oven temperature of 135-150 C. (0.025 torr) is 3,83 g (52.6%) of product as a light yellow oil. 1 H NMR (CD2 Cl2) delta 1.44-2.0 (m, 5H), 2.0-2.63 (m, 6H), 3.10-3.35 (m, 2H), 7.20 (ddd, 1H, J=0.8, 5.0, 8.0 Hz), 7.63 (dt, 1H, J=2.0, 5.0 Hz), 8.33-8.23 (m, 2H). Anal. Calc. for C13 H17 N3: C,72.52; H,7.96; N,19.52 Found: C,72.24; H,7.88; N,19.30 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.45 g (67%) | In acetonitrile; | EXAMPLE 5 Preparation of N-[(4,6-Dimethoxypyrimidin-2-yl)aminocarbonyl]-3-(propylsulfonyl)-2-pyridinesulfonamide To a stirred suspension of 0.4 g (0.0015 mol) of the product from Example 4 and 0.63 g (0.0023 mol) of phenyl (4,6-dimethoxypyrimidin-2-yl)carbamate in 4 mls acetonitrile was added 0.35 g (0.0023 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and stirred for 30 minutes. The solution was diluted with water and acidified with 1 normal hydrochloric acid. The resulting precipitate was collected and washed with water and ether to afford 0.45 g (67%) white solid: m.p. 168-170; NMR (CDCl3, 200 MHz), 1.07 (3H, t, J=7 Hz), 1.85 (2H, m), 3.7 (2H, m), 3.97 (6H, s), 5.8 (1H, s), 7.26 (NH), 7.8 (1H, m), 8.6 (1H, m), 8.9 (1H, m), 12.9 (NH); IR (nujol) 3320, 1740, 1610, 1580, 1375, 1195, 1170 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
162 mg (64%) | With hydrogenchloride; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl acetamide; | Synthesis Example 1 Synthesis of methyl 2-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonylaminosulfonyl]-4-[(2,2,2-trifluoroethylidene)hydrazino]benzoate (Compound No. I-7) At room temperature, 166 mg (0.5 mmol) of methyl 2-(aminosulfonyl)-4-[(2,2,2-trifluoroethlidene)hydrazino]-benzoate and 137.5 mg (0.5 mmol) of phenyl (4,6-dimethoxy-pyrimidin-2-yl)carbamate were dissolved in 1.5 ml of N,N-dimethylacetamide. Then, 86.1 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene were added, followed by stirring for 5 minutes. The resultant mixture was allowed to stand for 15 hours. Thereafter, 0.2 ml of 35% hydrochloric acid was added to 20 ml of ice water, followed by the addition of the reaction mixture in 0.2 ml portions under stirring. After the reaction mixture was stirred for 20 minutes, the resulting precipitate was collected by filtration and dried in air. Using dichloromethane as an eluent, the crude product was purified by chromatography on a column of silica gel ("WAKO GEL C-300", trade name; product of Wako Pure Chemical Industries, Ltd.). The title compound was obtained as a white solid. Yield: 162 mg (64%). Melting point: 201-202 C. Its physicochemical properties are shown in Table 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | Example 4 3-(4,6-Dimethoxypyrimidin-2-yl)-1-[2-(2-methoxyethoxy)phenoxysulfonyl]urea 1.74 g (0.0063 mol) of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate are dissolved in 80 ml of acetonitrile, and 1.48 g (0.006 mol) of 2-(2-methoxyethoxy)phenyl sulfamate are added at room temperature. 1.0 g (0.0066 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are added and the reaction mixture is then stirred at room temperature for 18 hours, concentrated, diluted with H2 O and acidified with 2N hydrochloric acid to give a pH of 3-4. After the solids have been filtered off with suction and dried, 2.4 g (93% of theory) of 3-(4,6-dimethoxypyrimidin-2-yl)-1-[2-(2-methoxyethoxy)phenoxysulfonyl]urea of melting point 106-108 C. are obtained. The compounds of the Tables which follow are prepared in an analogous manner as described in Examples 1-4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In acetonitrile; | EXAMPLE 3 3-(4,6-dimethoxypyrimidin-2-yl)-1-(2-propoxyphenoxysulfonyl)urea 1.74 g (0.008 mol) of 2-propoxyphenyl sulfamate are added at room temperature to 2.32 g (0.0084 mol) of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate, dissolved in 100 ml of acetonitrile. After 1.33 g (0.0088 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) have been added, the reaction mixture is stirred at room temperature for 18 hours, concentrated, diluted with H2 O and acidified using 2N hydrochloric acid to give a pH of 3-4. After the solids have been filtered off with suction and dried, 2.85 g (86% of theory) of 3-(4,6-dimethoxypyrimidin-2-yl)- 1-(2-propoxyphenoxysulfonyl)urea of melting point 108-109 C. are obtained. The compounds of the Tables which follow are prepared as described in Examples 1-3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | In methanol; acetonitrile; | EXAMPLE 18 1-Cyclopropyl-7-[3,7-diazabicyclo[3.3.0] oct-1(5)-en-3-yl]-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (KR-10787) <strong>[93107-30-3]1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid</strong> (1.07 g), 3,7-diazabicyclo[3.3.0] oct-1(5)-ene dihydrobromide (1.08 g) and 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU, 2 ml) were suspended in acetonitrile (20 ml) and refluxed for 3 hours. After cooling the reaction mixture, the produced precipitate was collected by filtration and washed with acetonitrile and methanol. The solid was dissolved in methanol (5 ml) and conc-hydrochloric acid (5 ml) and then insoluble portion was filtered off. The filtrate was concentrated under vacuum, washed with ethanol to give the title compound (0.95 g, yield 60percent) mp: 260°-263° C. 1 H-NMR(CDCl3 +CD3 COOD, delta ppm): 9.36 (1H, s), 7.87 (1H, d, J =12.2 Hz), 6.85 (1H, d, J=7.4 Hz), 4.50 (4H, s), 4.27 (4H, s), 3.53 (1H, m), 1.40 (2H, m), 1.27 (2H, m). |
60% | In methanol; acetonitrile; | Example 18 1-Cyclopropyl-7-[3,7-diazabicyclo[3.3.0]oct-1(5)-en-3-yl]-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (KR-10787) <strong>[93107-30-3]1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid</strong> (1.07 g), 3,7-diazabicyclo[3.3.0]oct-1(5)-ene dihydrobromide (1.08 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2 ml) were suspended in acetonitrile (20 ml) and refluxed for 3 hours. After cooling the reaction mixture, the produced precipitate was collected by filtration and washed with acetonitrile and methanol. The solid was dissolved in methanol (5 ml) and conc-hydrochloric acid (5 ml) and then insoluble portion was filtered off. The filtrate was concentrated under vacuum, washed with ethanol to give the title compound (0.95 g, yield 60percent) mp: 260 - 263°C 1H-NMR (CDCl3 + CD3COOD, delta ppm): 9.36 (1H, s), 7.87 (1H, d, J = 12.2 Hz), 6.85 (1H, d, J = 7.4 Hz), 4.50 (4H, s), 4.27 (4H, s), 3.53 (1H, m), 1.40 (2H, m), 1.27 (2H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In pyridine; chloroform; | EXAMPLE 27 1-Cyclopropyl-6-fluoro-1,4-dihydro-7-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-4-oxo-3-quinoline carboxylic acid (R1 =H; Y=cyclopropyl; A=CH; R2 =a; m=1; n=2; Q=methyl) A stirred suspension of 6,7-difluoro-1-cyclopropyl-4-oxo-1,4-dihydro-3-quinoline carboxylic acid (1.5 g, 5.66 mmol) and 8-methyl-3,8-diazabicyclo-[3.2.1]octane dihydrochloride (1.45 g, 7.32 mmol) in 10.0 ml of pyridine was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (2.26 g, 14.9 mmol). The reaction mixture was heated to 80° C. for 4 hours, cooled to room temperature and poured into 250 ml of chloroform. The chloroform layer was washed with water (twice 200 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The crude off white solid was dissolved in 1N hydrochloride with warming and this solution was washed with chloroform/methanol (9:1 v/v). The aqueous solution as then basified with saturated aqueous sodium bicarbonate and extracted with chloroform (three times 200 ml). The chloroform layer was dried with sodium sulfate, filtered, concentrated in vacuo, and washed with diethyl ether to give 1.80 g (86percent yield) of an off white solid, m.p. 278°-279° C. with decomposition. |
86% | In pyridine; chloroform; | EXAMPLE 27 1-Cyclopropyl-6-fluoro-1,4-dihydro-7-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-4-oxo-3-quinoline carboxylic acid (R1 =H; Y=cyclopropyl; A=CH; R2 =a; m=1; n=2; Q=methyl) A stirred suspension of 6,7-difluoro-1-cyclopropyl-4-oxo-1,4-dihydro-3-quinoline carboxylic acid (1.5 g, 5.66 mmol) and 8-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (1.45 g, 7.32 mmol) in 10.0 ml of pyridine was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (2.26 g, 14.9 mmol). The reaction mixture was heated to 80° C. for 4 hours, cooled to room temperature and poured into 250 ml of chloroform. The chloroform layer was washed with water (twice 200 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The crude off white solid was dissolved in 1N hydrochloride with warming and this solution was washed with chloroform/methanol (9:1 v/v). The aqueous solution as then basified with saturated aqueous sodium bicarbonate and extracted with chloroform (three times 200 ml). The chloroform layer was dried with sodium sulfate, filtered, concentrated in vacuo, and washed with diethyl ether to give 1.80 g (86percent yield) of an off white solid, m.p. 278°-279° C. with decomposition. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | EXAMPLE 5 10-(2,5-Diazabicyclo[2.2.2]oct-2-yl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid A solution of 0.56 g (2.0 mmol) of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid</strong>, 0.41 g (2.2 mmol) of 2,5-diazabicyclo[2.2.2]octane dihydrochloride, 0.90 ml (6.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 25 ml of acetonitrile was heated under reflux for 18 hours. The solution was evaporated to dryness and the residue was triturated with methanol and filtered to give 0.20 g of the title compound, 260-265 C. | |
In acetonitrile; | REFERENCE EXAMPLE 5 10-(2,5-Diazabicyclo[2.2.2]oct-2-yl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid A solution of 0.56 g (2.0 mmol) of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid</strong>, 0.41 g (2.2 mmol) of 2,5-diazabicyclo[2.2.2]octane dihydrochloride, 0.90 ml (6.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 25 ml of acetonitrile was heated under reflux for 18 hours. The solution was evaporated to dryness and the residue was triturated with methanol and filtered to give 0.20 g of the title compound, 260-265C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile; | EXAMPLE 4 Ethyl 5-[[[[4,6-dimethoxypyrimidin-2-yl]aminocarbonyl]aminosulfonyl]methyl]-1,3-dimethyl-1H-pyrazole-4-carboxylate In a dry flask under nitrogen was stirred 0.33 g of the sulfonamide from Example 3 and 0.35 g of phenyl (4,6-dimethoxypyrimidin-2-yl)carbamate and 30 ml of dry acetonitrile. Then 0.19 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene was added via syringe and the solution stirred overnight. Then 50 ml of water was added, followed by a dropwise addition of 1 NHCl until a precipitate formed. The suspension was filtered. The filtrant, after being triturated with diethyl ether, gave 0.4 g of solid, m.p. 190 C.; 1R (Nujol) 1711 and 1680 (C=O) cm-1; 1 H NMR (200 MHz, CDCl3): delta 1.25 (t, CH3, 3H); 2.38 (s, CH3, 3H); 3.80 (s, OCH3, 6H); 3.94 (s, NCH3, 3H); 4.15 (q, OCH2, 2H); 5.23 (s, CH2 SO2, 2H); 5.71 (s, bs, CH, 1H); 7.35 (bs, NH, 1H) and 12.4 (bs, NH, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | EXAMPLE 3 N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-(tetrahydro-2-oxo-3-furanyl)benzenesulfonamide A solution of 240 mg of the product from Example 2 and 270 mg of (4,6-dimethoxy-2-pyrimidinyl)carbamic acid, phenyl ester in 5 mL dry acetonitrile was treated at room temperature under an atmosphere of nitrogen with 0.15 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction mixture was stirred at room temperature for one hour, diluted with 3 mL water and acidified with 5% aqueous hydrochloric acid. The resulting precipitate was collected by filtration, and washed with water and ether. The yield of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-(tetrahydro-2-oxo-3-furanyl)benzenesulfonamide was 290 mg as a white powder, m.p. 163.5-166.5 C. IR (KBr): 1775 (lactone C=O), 1710 cm-1; NMR (CDCl3): delta 12.74 (1H, br s, NH), 8.24 (1H, br d, J=8 Hz), 7.65 (1H, br t, J=8 Hz), 7.49 (1H, br t, J= 8 Hz), 7.36 (1H, br d, J=8 Hz), 7.24 (1H, br s, NH), 5.78 (1H, s), 5.13 (1H, dd, J=8, 10 Hz), 4.29-4.56 (2H, m), 3.94 (6H, s), 2.86-3.02 (1H, m) and 2.26-2.48 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In dichloromethane; acetonitrile; | EXAMPLE 6 2-Bromo-N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-N'-methylbenzenesulfonimidamide 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.15 mL, 1.0 mmol) was added dropwise over one minute to a stirred solution of 2-bromo-N'-methylbenzenesulfonimidamide (0.25 g, 1.0 mmol) and phenyl (4.6-dimethoxypyrimidin-2-yl)carbamate (0.28 g, 1.0 mmol) in dry acetonitrile (5 mL) at room temperature. The solvent was evaporated, and the residue was dissolved in dichloromethane. Evaporation of this solvent left a pale yellow viscous oil (0.65 g). This was dissolved in CH2 Cl2, and acetic acid (57 muL, 1.0 mol) was added. This solution was chromatographed on a column of silica gel using 1:1 dichloromethane-ether as eluant. Fractions containing the product were diluted with toluene. The solvent was evaporated leaving an oil. This was dissolved in dichloromethane, and the solvent was evaporated leaving 2-bromo-N-(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl-N'-methylbenzenesulfonimidamide as a hard amorphous foam (0.45 g) melting at 120-125 C. PMR (CDCl3, 200 MHz) delta ca. 7-15 (extremely broad s exchanging with H2 O, 1H, S(O)(NCH3)NHCO); 8.26 (dd, 1H, Ar-H ortho to S(O)(NCH3)NHCO); 7.78 (broad s, 1H, CONH-Het); 7.76 (dd, 1H, Ar-H ortho to Br); 7.51 (td, 1H, Ar-H); 7.43 (td, 1H, Ar-H); 5.68 (s, 1H, Het 5-H); 3.88 (s, 6H, Het-OCH3); 2.66 (s, 3H, NCH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.2 g (83%) | In acetonitrile; | EXAMPLE 8 3-Chloro-N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-[(2-oxotetrahydro-3-furanylidene)methyl]benzenesulfonamide To a stirred suspension of 0.15 g (0.0005 mol) of the product of Example 7 and 0.21 g (0.0008 mol) of (4,6-dimethoxy-2-pyrimidinyl)carbamic acid, phenyl ester in 1 mL dry acetonitrile under nitrogen was added dropwise 0.12 mL (0.12 g, 0.0008 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture was stirred at room temperature for 1 hour and was then diluted with water and acidified with 1N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and washed well with water and ether to yield 0.2 g (83%) of the title compound: m.p. 212-216 (dec); IR (nujol) 3410, 1765, 1730, 1605, 1365, 1340, 1155 cm-1; NMR (CDCl3, 200 MHz) delta 2.7-2.8 (2H, m), 3.94 (6H, s), 4.1-4.2 (2H, m), 5.84 (1H, s), 7.2-7.8 (3H, m), 8.25 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In benzene; | 1-(Ethoxycarbonyl)ethyl Cinnoline-4-carboxylate (32) A solution of 0.75 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 20 ml of benzene was added to a stirred suspension of 0.87 g of 1 in 30 ml of benzene at room temperature. After one hour of stirring, 1.36 g of ethyl 2-bromopropionate was added and the mixture was heated at reflux for 6 hours. The mixture was cooled, diluted with 25 ml of benzene, washed with water, 1 N aqueous sodium bicarbonate, and brine. It then was dried (MgSO4), the solvent was evaporated and the residue was chromatographed on silica gel, using a 1:1 v:v mixture of cyclohexane and ethyl acetate as eluent, to give 32, as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In acetonitrile; | EXAMPLE 2 N-[(4,6-Dimethoxypyrimidin-2-yl)aminocarbonyl]-3-(methoxymethyl)thiophene-2-sulfonamide To 0.41 g of 3-(methoxymethyl)thiophene-2-sulfonamide and 0.55 g of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate in 20 mL of acetonitrile is added 0.3 mL of 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU). After being stirred for 2 hours at ambient temperature and pressure, the reaction mass is poured onto 25-50 g of ice and the resultant mixture acidified to pH 3 by the addition of hydrochloric acid. The desired solid product can be isolated by filtration. Alternatively, it can be extracted into methylene chloride which is then dried over magnesium sulfate, filtered and evaporated to dryness to yield the desired product is sufficiently pure form for the purposes of this invention. | |
With hydrogenchloride; In acetonitrile; | EXAMPLE 2 N-[(4,6-Dimethoxypyrimidin-2-yl)aminocarbonyl]-3-(methoxymethyl)thiophene-2-sulfonamide To 0.41 g of 3-(methoxymethyl)thiophene-2-sulfonamide and 0.55 g of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate in 20 mL of acetonitrile is added 0.3 mL of 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU). After being stirred for 2 hours at ambient temperature and pressure, the reaction mass is poured onto 25-50 g of ice and the resultant mixture acidified to pH 3 by the addition of hydrochloric acid. The desired solid product can be isolated by filtration. Alternatively, it can be extracted into methylene chloride which is then dried over magnesium sulfate, filtered and evaporated to dryness to yield the desired product in sufficiently pure form for the purposes of this invention. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | EXAMPLE 7 N-[(4,6-Dimethoxypyrimidin-2-yl)aminocarbonyl]-3-(2-methoxyethyl)-2-thiophenesulfonamide To a mixture of 0.33 g of 3-(2-methoxyethyl)thiophene-2-sulfonamide and 0.41 g of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate in 20 mL of acetonitrile was added 0.23 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at ambient temperature with stirring. After 2 hours the mixture was poured onto ice and acidified with 12N hydrochloric acid. The resultant precipitate was removed by filtration, washed with water and dried to yield 0.42 g, m.p. 173-176. NMR (CDCl3): 3.268 delta, s, CH3 O; 3.27 delta, t, CH2; 3.64 delta, t, CH2; 3.98 delta, s, 2 X CH3 O of pyrimidine; 5.78 delta, s, CH of pyrimidine; and 7.2, 7.6 delta, d, 2 X CH of thiophene. | |
In acetonitrile; | EXAMPLE 7 N-[(4,6-Dimethoxypyrimidin-2-yl)aminocarbonyl]-3-(2-methoxyethyl)-2-thiophenesulfonamide To a mixture of 0.33 g of 3-(2-methoxyethyl)thiophene-2-sulfonamide and 0.41 of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate in 20 mL of acetonitrile was added 0.23 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at ambient temperature with stirring. After 2 hours the mixture was poured onto ice and acidified with 12N hydrochloric acid. The resultant precipitate was removed by filtration, washed with water and dried to yield 0.42 g, m.p. 173-176 C. NMR (CDCl3): 3.268 delta, s, CH3 O; 3.27 delta, t, CH2; 3.64 delta, t, CH2; 3.98 delta, s, 2 X CH3 O of pyrimidine; 5.78 delta, s, CH of pyrimidine; and 7.2, 7.6 delta, d, 2 X CH of thiophene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; acetonitrile; | EXAMPLE 5 N-[(4,6-Dimethoxypyrimidin-2-yl)aminocarbonyl]-5-methoxy-1,2,3-benzothiadiazole-4-sulfonamide A solution of 5-methoxy-1,2,3-benzothiadiazole-4-sulfonamide (0.20 g) and of O-phenyl-N-(4,6-dimethoxypyrimidin-2-yl)carbamate (0.24 g) in 7 mL of acetonitrile was treated with 0.12 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene. The solution was stirred for 2 hours. After diluting the reaction with water (10 mL) and acidifying it with 1N hydrochloric acid, the resulting precipitate was filtered, washed with water and ether, and air dried to give 0.24 g of the title compound as a beige solid, m.p. 120-129 C. with decomposition. 200 MHz NMR (DMSO-d6)delta: 3.94 (s, 6H, OCH3); 3.99 (s, 3H, NCH3); 6.04 (s, 1H, CH); 7.92 (d, 1H, arom.); 8.74 (d, 1H, arom.); 10.57 (s, 1H, NH); and 13.09 (s, 1H, NH). IR (nujol) 1700 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane; water; | EXAMPLE 9 N-[(4,6-Dimethoxypyrimidin-2-yl)aminocarbonyl]-2,3-dihydro-2-methyl-6-trimethylsilylbenzo[b]thiophene-7-sulfonamide-1,1-dioxide A solution of 2,3-dihydro-2-methyl-6-trimethylsilylbenzo[b]thiophene-7-sulfonamide-1,1-dioxide (0.23 g) and of O-phenyl-N-(4,6-dimethoxypyrimidin-2-yl)carbamate (0.21 g) in 10 ml of dry p-dioxane was treated with 0.11 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene. The solution was stirred for 4 hours, was diluted with 25 ml of water, and was acidified with concentrated hydrochloric acid. The resulting precipitate was filtered, was washed with water and ether, and was air dried to give 0.25 g of the title compound as a white solid, m.p. 188-190 C. 200 MHz NMR (CDCl3)delta: 0.49 (s, 9H, SiCH3); 1.48 (d, 3H, CH3); 2.88-3.6 (m, 3H, CH, CH2); 4.02 (s, 6H, OCH3); 5.78 (s, 1H, CH); 7.25 (s, 1H, NH); 7.75 (d of d, 2H, arom); and 13.08 (s, 1H, NH). IR(nujol) 1730 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 16e 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-4-(difluoromethoxy)benzoic acid, ethyl ester A mixture of ethyl 2-(aminosulfonyl)-4-(difluoromethoxy)benzoate (0.15 g, 0.51 mmol) and phenyl (4,6-dimethoxy-2-pyrimidinyl)carbamate (0.14 g, 0.51 mmol) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (76 muL, 0.6 mmol). The mixture was stirred at 25 C. for 1 hour and then diluted with ice water (10 mL) and acidified with aqueous HCl (1N). Filtration of the precipitate provided 0.19 g of product, m.p. 146-149 C. PMR (D6 -Acetone, 90 MHz) delta 9.4 (bs, 1H), 8.1 (d, 1H), 7.9 (d, 1H), 7.6 (dd, 1H), 7.3 (t, 1H), 5.9 (s, 1H), 4.4 (q, 2H), 4.0 (s, 6H), 1.4 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile; | EXAMPLE 3 N,N-Dimethyl-2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-3-pyridinecarboxamide To a suspension of 0.50 g (2.2 mmol) N,N-dimethyl-2-(aminosulfonyl)-3-pyridinecarboxamide and 0.60 g (2.2 mmol) of 4,6-dimethoxypyrimidin-2-yl phenyl carbamate in 3 ml acetonitrile was added 0.32 ml (2.2 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The resulting solution was stirred at room temperature for 7 minutes. The addition of 6 ml of water followed by the dropwise addition of 10% hydrochloric acid produced a white precipitate which was collected by filtration to provide 0.75 g of the subject compound, m.p. 142-159 C.(d). IR (Nujol) 1720 (CO), 1609, 1365, 1162 cm-1. NMR (DMSO): delta2.80 (s, 3H, NCH3); 2.93 (s, 3H, NCH3); 3.89 (s, 6H, OCH3); 6.02 (s, 1H); 7.70-7.80 (m, 1H); 8.00 (m, 1H); 8.72 (m, 1H); 10.62 (s, 1H, NH); and 12.75 (s, 1H, NH). | |
In water; acetonitrile; | EXAMPLE 3 N,N-Dimethyl-2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-3-pyridinecarboxamide To a suspension of 0.50 g (2.2 mmol) N,N-dimethyl-2-(aminosulfonyl)-3-pyridinecarboxamide and 0.60 g (2.2 mmol) of 4,6-dimethoxypyrimidin-2-yl phenyl carbamate in 3 ml acetonitrile was added 0.32 ml (2.2 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The resulting solution was stirred at room temperature for 7 minutes. The addition of 6 ml of water followed by the dropwise addition of 10% hydrochloric acid produced a white precipitate which was collected by filtration to provide 0.75 g of the subject compound, m.p. 142-159 C.(d). IR (Nujol) 1720 (CO), 1609, 1365, 1162 cm-1. NMR (DMSO): delta 2.80 (s, 3H, NCH3); 2.93 (s, 3H, NCH3); 3.89 (s, 6H, OCH3); 6.02 (s, 1H); 7.70-7.80 (m, 1H); 8.00 (m, 1H); 8.72 (m, 1H); 10.62 (s, 1H, NH); and 12.75 (s, 1H, NH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | EXAMPLE 27 9-Fluoro-2,3-dihydro-3-methyl-10-(7-methyl-2,7-diazaspiro[4.4]non-2-yl)-7-oxo-7H-pyrido[1,2,3-de]1,4-benzoxazine-6-carboxylic acid A suspension of 0.42 g (1.97 mmol) 2-methyl-2,7-diazaspiro[4.4]nonane dihydrochloride in 25 ml acetonitrile was treated with 0.85 g (5.80 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene and 0.52 g (1.85 mmol) 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]1,4-benzoxazine-6-carboxylic acid was added. The mixture was stirred two hours at room temperature and then refluxed overnight. The product which crystallized on cooling was filtered, washed with acetonitrile and recrystallized from acetonitrile to afford 0.45 g of the title compound, mp 227-230 C. (dec). Analysis calculated for C21 H22 N3 FO4: C, 63.15; H, 5.55; N, 10.52; Found: C, 63.13; H, 5.73; N, 10.51. | |
In acetonitrile; | EXAMPLE 27 9-Fluoro-2,3-dihydro-3-methyl-10-(7-methyl-2,7-diazaspiro[4.4]non-2-yl)-7-oxo-7H-pyrido[1,2,3-de]1,4-benzoxazine-6-carboxylic acid A suspension of 0.42 g (1.97 mmol) 2-methyl-2,7-diazaspiro[4.4]nonane dihydrochloride in 25 ml acetonitrile was treated with 0.85 g (5.80 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene and 0.52 g (1.85 mmol) 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]1,4-benzoxazine-6-carboxylic acid was added. The mixture was stirred carboxylic acid was added. The mixture was stirred two hours at room temperature and then refluxed overnight. The product which crystallized on cooling was filtered, washed with acetonitrile and recrystallized from acetonitrile to afford 0.45 g of the title compound, mp 227-230 C. (dec). Analysis calculated for C21 H22 N3 FO4: C, 63.15; H, 5.55; N, 10.52; Found: C, 63.13; H, 5.73; N, 10.51. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.1 g (64%) | In acetonitrile; | EXAMPLE 4 N-[(4,6-Dimethoxypyrimidin-2-yl)-aminocarbonyl]-2-[(2-oxotetrahydro-3-furanylidene)methyl]benzenesulfonamide To a stirred suspension of 0.09 g (0.0004 mol) of the product of Example 3 and 0.15 g (0.0005 mol) of (4,6-dimethoxy-2-pyrimidinyl)carbamic acid, phenyl ester in 1 mL dry acetonitrile under nitrogen was added dropwise 0.08 mL (0.08 g, 0.0005 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture was stirred at room temperature for 30 min and was then diluted with water and acidified with 1N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and washed well with water and ether to yield 0.1 g (64%) of the title compound: m.p. 185-190 (gas evolution); IR (nujol) 3180 (br), 1755, 1740, 1710, 1700, 1610, 1560, 1355, 1165 cm-1; NMR (CDCl3, 200 MHz) delta 3.05 (2H, m), 4.29 (2H, t, J=7 Hz), 3.99 (6H, s), 5.83 (1H, s), 7.2 (NH, s), 7.4-7.8 (3H, m), 8.1 (1H, m), 8.12 (NH, s), 8.14 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methanesulfonic acid; In water; acetonitrile; | EXAMPLE 1 Preparation of N-[2-(5-acetylfuran-2-yl)phenylsulfonyl]-N'-(4,6-dimethoxypyrimidin-2-yl)urea STR14 2.15 g (0.008.mol) of 2-(5-acetylfuranyl-2-yl)phenylsulfonamide and 2.20 g of 4,6-dimethoxy-2-phenoxycarbonylaminopyrimidine are suspended in 40 ml of acetonitrile. 1.25 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene in 5 ml of acetonitrile are then slowly added dropwise to the suspension, whereupon a solution gradually forms. The reaction mixture is stirred for 3 hours at room temperature and then poured into ice/water and 0.5 ml of methanesulfonic acid is added. The mixture is stirred for 30 minutes, the resultant precipitate is filtered off, washed with water and diethyl ether and dried, affording 3.5 g (98% of theory) of the above urea with a melting point of 199-200 C. The following ureas are prepared in a manner analogous to that of this Example. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile; | EXAMPLE 7 4-(Cyanomethyl)-2-[((4,6-dimethoxypyrimidin-2-yl)aminocarbonyl)aminosulfonyl]benzoic acid, methyl ester To a suspension of 0.12 g of the compound from Example 6 and 0.143 g of 4,6-dimethoxy-2-pyrimidinylcarbamic acid, phenyl ester in 15 ml of dry acetonitrile was added 72.7 mul of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). After being stirred at room temperature for one hour, the reaction mixture was diluted with 50 ml of water, acidified with 1N hydrochloric acid to pH 2 and extracted with ethyl acetate. The organic solution was dried (MgSO4), filtered and concentrated to an oil. Trituration of the residue with 3:1 (ethyl ether:acetonitrile) gave 0.16 g of a white solid, m.p. 177-179 C. IR (nujol) 1725 cm-1. NMR (DMSO-d6, 200 MHz)delta: 3.78 (s, OCH3, 3H), 3.92 (s, OCH3, 6H), 4.31 (s, CH2, 2H), 6.01 (S, Het-H, 1H), 7.7-8.2 (m, ArH, 3H), 10.6 and 12.7 (two s, NH, 2*1H). | |
In water; acetonitrile; | EXAMPLE 7 4-(Cyanomethyl)-2-[((4,6-dimethoxypyrimidin-2-yl)aminocarbonyl)aminosulfonyl]benzoic acid, methyl ester To a suspension of 0.12 g of the compound from Example 6 and 0.143 g of 4,6-dimethoxy-2-pyrimidinylcarbamic acid, phenyl ester in 15 ml of dry acetonitrile was added 72.7 mul of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). After being stirred at room temperature for one hour, the reaction mixture was diluted with 50 ml of water, acidified with 1N hydrochloric acid to pH 2 and extracted with ethyl acetate. The organic solution was dried (MgSO4), filtered and concentrated to an oil. Trituration of the residue with 3:1 (ethyl ether:acetontrile) gave 0.16 g of a white solid, m.p. 177-179 C.; IR (nujol) 1725 cm-1; NMR (DMSO-d6, 200 MHz)delta3.78 (s, OCH3, 3H), 3.92 (s, OCH3, 6H), 4.31 (s, CH2, 2H), 6.01 (S, Het-H, 1H), 7.7-8.2 (m, ArH, 3H), 10.6 and 12.7 (two s, NH, 2X1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | EXAMPLE 19 2-[[[(4,6-Dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]methyl]-N,N-dimethylbenzamide To a solution of 0.48 g of the compound of Example 18 and 0.54 g of N-(4,6-dimethoxypyrimidin-2-yl)carbamic acid, phenyl ester in 25 ml of acetonitrile was added 0.3 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene, and the mixture was stirred overnight at room temperature. Ice (25.0 g) was added; the aqueous mixture acidified with concentrated hydrochloric acid and then extracted with two 75 ml portions of methylene chloride. The organic solution was washed with water, brine, dried (magnesium sulfate), filtered and concentrated in vacuo. Trituration of the oily residue with 1-chlorobutane gave 0.42 g of 2-[[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]methyl]-N,N-dimethylbenzamide, m.p. 141-143; IR (nujol): 1700 and 1600 cm-1; NMR (CDCl3): delta 2.93-3.13 (6H, N(CH3)2, 2 singlets), 3.83 (6H, OCH3, s), 5.0 (2H, CH2, s) and 5.76 (1H, CH, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile; | EXAMPLE 4 2-[[(4,6-Dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]benzoic acid, 2-azidoethyl ester A solution of 0.3 g of the product from Example 3 and 0.3 g of 4,6-dimethoxypyrimidin-2-ylcarbamic acid, phenyl ester in 6 mL of dry acetonitrile was mixed with 0.16 mL 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The mixture was stirred at room temperature for 15 minutes, and then 6 mL water was added followed by 10% aqueous hydrochloric acid until a pH of 1-2 was obtained. The precipitate was collected by filtration, washed with water and ether, and was dried to give 0.36 g of the title sulfonylurea as a white powder, m.p. 162.5-164 C.; IR (nujol): 1730, 2100 cm-1; NMR (CDCl3): delta 3.65 (t, 2H, J=6 Hz), 3.99 (6H, s), 4.46 (t, 2H, J=6 Hz), 5.79 (s, 1H), 7.25 (br s, 1H), 7.7-7.8 (m, 3H), 8.42 (dd, 1H), 12.55 (br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In 1,4-dioxane; | Synthesis Example 2: Synthesis of 2-(p-aminophenyl)-5-amino-7-methoxybenzo[b]furan 5.0g (1.0 equivalent) of 3-methoxy-5-nitrosalicylaldehyde and 6.03g (1.1 equivalents) of p-nitrobenzyl bromide were dissolved in 15ml of 1,4-dioxane, and then 13.5g (3.5 equivalents) of 1,8-diazabicyclo[5.4.0]undeca-7-ene was added thereto. The resulting mixture was heated at about 100C for three hours with stirring, and then cooled to room temperature. Thereafter, the resulting solid substance was filtered off and sufficiently washed with ethanol. Thus, 4.65g of 2-(p-nitrophenyl)-5-nitro-7-methoxybenzo[b]furan was obtained (yield: 70%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile; | Step E. 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-3-methylthiomethyl-pyridine To a suspension of 0.18 g (0.82 mmole) 3-(methylthiomethyl)-2-aminosulfonylpyridine and 0.227 g (0.82 mmole) of 4,6-dimethoxypyrimidin-2-yl phenyl carbamate in 3 mls acetonitrile was added 0.126 mls (0.82 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The resulting solution was stirred at room temperature for 5 minutes. The addition of 2 mls of water, followed by the dropwise addition of 10% hydrochloric acid produced a white precipitate which was collected by filtration to provide 0.270 g of the subject compound, m.p. 145-147. Using these methods and those described in Equations 1-5, the compounds of Tables 1-14 can be prepared. | |
In water; acetonitrile; | Step E. 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-3-methylthiomethyl-pyridine To a suspension of 0.18 g (0.82 mmole) 3-(methylthiomethyl)-2-aminosulfonylpyridine and 0.227 g (0.82 mmole) of 4,6-dimethoxypyrimidin-2-yl phenyl carbamate in 3 mls acetonitrile was added 0.126 mls (0.82 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The resulting solution was stirred at room temperature for 5 minutes. The addition of 2 mls of water, followed by the dropwise addition of 10% hydrochloric acid produced a white precipitate which was collected by filtration to provide 0.270 g of the subject compound, m.p. 145-147. NMR (CDCl3) 2.09 (s, 3H, SCH3) 3.50 (s, 6H, OCH3) 4.27 (s, 2H, SCH2) 5.80 (s, 1H) 7.33 (s, 1H) 7.49 (dd, 1H) 8.10 (d, 1H) 8.50 (d, 1H) 12.83 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile; | Example 3 N-[((4,6-dimethoxypyrimidin-2 yl)aminocarbonyl)-2- (2-oxo-1-pyrrolidinylmethyl]-benzenesulfonamide To a suspension of 254 mg of the product of Example 2 in 10 mL of acetonitrile, containing 275 mg of phenyl (4,6-dimethoxypyrimidin-2-yl)carbamate, was added 0.15 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The resultant solution was stirred for 2 hours, diluted with 20 mL of water and acidified with 5 drops of concentrated hydrochloric acid. n -Butylchloride (10 mL) was added, stirred, and the white precipitate was filtered. The collected white solid was washed with a little water, suction dried and finally dried in vacuo a 70C overnight to afford 200 mg of a white solid, m.p. 185-187C Using the techniques described in Equations 1-4 and the synthetic routes summarized in Table 2, which makes use of 10 literature based synthetic procedures and the conversion procedures in Table 1, the following compounds in Tables A, J and Q may be prepared by one skilled in the art. |
Yield | Reaction Conditions | Operation in experiment |
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In N,N-dimethyl-formamide; | Example 2 N-[(4,6-Dimethoxypyrimidin-2-yl)aminocarbonyl]-4-methyl-2H-1,4-benzoxazin-3(4H)-one-5-sulfonamide (7) 4-Methyl-5-sulfonamido-2H-1,4-benzoxazin-3(4 H)-one [0.72g, from Example 1(v)] in dry N,N -dimethylformamide (5 ml) at 10oC was treated dropwise with 1,8-diazabicyclo[5.4.0]undec-7-ene(0.67 ml) and the resultant solution stirred at 0oC for 5 min before the addition of phenyl (4,6-dimethoxypyrimidinyl)carbamate (0.70 g). Stirring was continued at 0-10oC for 1 h, then at ambient temperature for 1 hr, whereupon the reaction mixture was poured into ice-cold aqueous citric acid (10%, 50 ml). This mixture was filtered, and the precipitated solid rinsed successively with aqueous citric acid (twice) and water, then drained and dried over phosphorus pentoxide to give the title sulfonylurea as a fawn powder (1.21 g). 1H NMR (d6DMSO); 3.92(s, 6H); 4.76(s, 2H); 6.00(s, 1H); 7.1-7.7(m, 3H); 9.65(s, 1H); 10.72(s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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71.8% | In acetonitrile; | Example 5 Preparation of 7-(1-amino-5-azaspiro[2,4]heptane-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 0.31g(1.17mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.26g(1.40mmol) of 1-amino-5-azaspiro[2,4]heptane hydrochloride and 0. 53g(3.48mmol) of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 5m of acetonitrile; and the resulting solution was refluxed for 3 hours and cooled to room temperature. The solid produced was filtered, washed with chilled acetonitrile, water and ethylether in turn and dried under a reduced pressure to obtain 0.30g of the desired compound(yield: 71.8percent). m.p.: 222~224°C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | In acetonitrile; | Example 11 Preparation of 7-(1-methylamino-5-azaspiro[2,4]heptane-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 0.19g(0.72mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.17g(0.86mmol) of 1-methylamino-5-azaspiro[2,4]heptane hydrochloride and 0.37g(2.43mmol) of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 3m of acetonitrile; and the resulting solution was refluxed for 3 hours and cooled to room temperature. The solid produced was filtered, washed with chilled acetonitrile, water and ethylether in turn and dried under a reduced pressure to obtain 0.15g of the desired compound(yield: 56percent). m.p.: 230~233°C |
Yield | Reaction Conditions | Operation in experiment |
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70% | In acetonitrile; | Example 5 Preparation of (-)-9-fluoro-3(S)-methyl-10-[7-methyl-3,7-diazabicyclo[3.3.0]oct-1(5)-en-3-yl]-7-oxo-2,3-dihydro-7H-pyrido[1.2.3-de]-1,4-benzoxazine-6-carboxylic acid (-)-9,10-Difluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido[1.2.3-de]-1,4-benzoxazine-6-carboxylic acid (0.562g), 3-methyl-3,7-diazabicyclo[3.3.0]oct-1(5)-ene dihydrobromide (0.68g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.55g) were dissolved in acetonitrile (20 ml) and refluxed for 7 hours. The reaction mixture was kept at room temperature overnight. The produced precipitate was collected by filtration, washed with acetonitrile and methanol and dried in vacuo to give the title compound 0.54g (yield 70%). Melting point: 264~268C(dec.) 1H-NMR (CDCl3 + CD3COOD, delta ppm): 8.22 (1H, s), 7.84 (1H, d, J = 14.1 Hz), 4.85 (2H, br. s), 4.70 (4H, s), 4.50 (1H, m), 4.40 (2H, br. s), 4.31 (2H, br. s), 3.21 (3H, s), 1.65 (3H, d, J = 6.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | In acetonitrile; | Example 13 Preparation of 10-(1-amino-5-azaspiro[2,4]heptane-5-yl)-3-(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido-[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid 760mg of 9,10-difluoro-3-(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido-[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid and 543mg of 1-amino-5-azaspiro[2,4]heptane hydrochloride and 1.35ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 10ml of acetonitrile; and the resulting solution was refluxed for 5 hours, cooled and filtered. The residue was washed with acetonitrile to obtain 500mg of the desired compound(yield: 50%). m.p.: 195~198C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | In chloroform; acetonitrile; | Example 19 Preparation of 7-(1-amino-5-azaspiro[2,4]heptane-5-yl)-1-cyclopropyl-8-methoxy-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 530mg of 1-cyclopropyl-8-methoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 520mg of 1-amino-5-azaspiro[2,4] heptane hydrobromide and 878mul of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 10ml of acetonitrile; and the resulting solution was refluxed for 4 hours and concentrated under a reduced pressure. The resultant was dissolved in 30ml of chloroform and washed with water several time. The organic layer was dried over magnesium sulfate and concentrated under a reduced pressure. The resulting material thus obtained was fractionated on silica gel column chromatography(chloroform methanol: water=15:3:1) to obtain 300mg of the desired compound(yield 50%). m.p. 183~185C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With citric acid; In dichloromethane; acetonitrile; | Example 33 Synthesis of 7-[3(S)-amino- 4(R)-methyl-l-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid hydrochloride To 30 ml of anhydrous acetonitrile were added 3.69 g of <strong>[112811-72-0]1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid</strong>, 3.02 g of 3(S)-[(t-butoxycarbonyl) amino]-4(R)-methylpyrrolidine and 1.90 g of 1,8-diazabicyclo-[5,4,0]-7-undecene (DBU), and the mixture was refluxed for 8 hours at 100C. The reaction liquor was concentrated and the residue was dissolved into 150 ml of methylene chloride, which was washed with 10 % aqueous solution of citric acid and then with saturated saline solution, dried over magnesium sulfate, and then concentrated. The residue was purified through silica gel column (elution solvent, chloroform:methanol: concentrated aqueous ammonia=50:10:1) to obtain 5.05 g of 7-[3(S)-[(t-butoxycarbonyl)amino]-4(R)-methyl-l-pyrrolidinyl]-l-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | Example A8 Methyl 2-[3-(4,6-dimethoxypyrimidin-2-yl)ureidosulfonyl]-4-isopropyl-carbamoylbenzoate 2.6 g (8.6 mmol) of methyl 4-isopropylcarbamoyl-2-sulfamoylbenzoate and 2.8 g (10.3 mmol) of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate were initially charged in 50 ml of acetonitrile. At room temperature, 2.9 g (19 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were added dropwise, and the mixture was stirred at this temperature for 3 h. The mixture was poured into ice-water and the pH was adjusted to 1 using 2N hydrochloric acid. The precipitated solid was filtered off with suction and washed with water. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In dichloromethane; | EXAMPLE 5 (compound No. 52) 6-Methyl-3-[(morpholin-4-ylsulphonyl)amino]-2-oxo-4-(phenylmethyl)-1,2-dihydropyridine-1-acetic Acid 1 ml (6.8 mmol) of morpholin-4-ylsulphonyl chloride and 1.1 ml (7.35 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene are added every three days for 15 days to 1.75 g (6.1 mmol) of methyl 3-amino-6-methyl-2-oxo-4-(phenylmethyl)-1,2-dihydropyridine-1-acetate in solution in 10 ml of dichloromethane. 100 ml of dichloromethane are then added to the reaction medium and the medium is washed successively with 20 ml of water, 100 ml of an aqueous hydrochloric acid solution and 20 ml of a saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a silica gel column, eluding with a dichloromethane:methanol (98:2) mixture and the product is recrystallized from ethanol. 1.4 g of product are obtained in the form of a white powder. Yield=52%; Melting point=160-162 C. The product obtained is hydrolyzed according to the procedure of Example 3 using 4.8 ml of a 1 N aqueous sodium hydroxide solution. 1.1 g of product are obtained. Melting point=158 C. (melting with decomposition). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | EXAMPLE 57 3-Methyl-2,4-dioxo-6-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile In analogy to the procedure described in example 17 the Z and/or E 2-cyano-3-methylsulfanyl-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-acrylic acid ethyl ester [example 13 a)] was treated with <strong>[52328-05-9]O-methylisourea hemisulfate</strong> and 1,8-diazabicyclo[5.4.0]undec-7-en in N,N-dimethylformamide at 100 C. to yield the 3-methyl-2,4-dioxo-6-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile as light yellow solid; m.p. >200 C.; MS: [M+H]+=297. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | EXAMPLE 126 4-Oxo-2-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-3-carbonitrile In analogy to the procedure described in example 17 the Z and/or E 2-cyano-3-methylsulfanyl-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-acrylic acid ethyl ester [example 13 a)] was treated with <strong>[7544-75-4]2-iminopyrrolidine hydrochloride</strong> [J. Med. Chem. (1996), 39, 669-672] and 1,8-diazabicyclo[5.4.0]undec-7-en in N,N-dimethylformamide at 100 C. to yield the 4-oxo-2-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-4,6,7,8-tetrahydro-pyrrolo [1,2-a]pyrimidine-3-carbonitrile as colorless solid; m.p. 184.5-190.5 C.; MS: [M+H]+=307. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; dimethyl sulfoxide; | Example 12 Ethyl 1-(5-iodo-2-isopropylthio-6-trifluoromethylpyrimidin-4-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylate 4-Chloro-5-iodo-2-isopropylthio-6-trifluoromethylpyrimidine (0.30 g) was dissolved in dimethylsulfoxide (3.0 ml) and <strong>[155377-19-8]ethyl 3-trifluoromethyl-1H-pyrazole-4-carboxylate</strong> (0.16 g) and 1,8-diazabicyclo-[5,4,0]-undec-7-ene (0.12 g) was added at room temperature with stirring. The mixture was heated to 80 C. and stirred for 2 hr. After cooling to room temperature, the mixture was added water and extracted with benzene. The benzene layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give ethyl 1-(5-iodo-2-isopropylthio-6-trifluoromethylpyrimidin-4-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylate (0.30 g) as colorless crystalline solid, mp 107-108 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | In methanol; | To a solution of <strong>[4016-63-1]8-bromoguanosine</strong> (50 mg, 0.138 mmol) in methanol (10 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (10.6 muL, 0.069 mmol, 97percent) was added. After 6 days and selection of single crystals suitable for X-ray diffraction experiments, the remaining crystals were filtered off and dried in vacuum yielding 38 mg (62percent) of the adduct [8-BrG][8-BrG]-[DBU-H]+: IR (KBr) lambdamax/cm-1: 3467, 3331, 3304, 3194, 3130, 2981, 2946, 2929, 2916, 2859, 1697, 1675, 1650, 1621, 1589, 1571, 1525, 1468, 1406, 1322, 1314, 1121, 1082, 1074, 1049. The integrals of protons are expressed in the ratio 1:0.5; for 2 equiv of nucleoside and 1 equiv of DBU. 1H NMR (DMSO-d6) delta/ppm: 6.80 (br s, 2H, NH2), 6.60-4.8 (br s, 3H, OH-2', OH-3', OH-5'), 5.68 (d, 1H, J=6.8 Hz, H-1'), 5.02 (t, 1H, J=6.0 Hz, H-2'), 4.13 (m, 1H, H-3'), 3.91 (m, 1H, H-4'), 3.67 (dd, 1H, J=3.6, 12.1 Hz, H-5'a), 3.50-3.55 (m, 2H, H-5'b, CH2-6), 3.44 (t, 1H, J=5.7 Hz, CH2-2), 3.24 (t, 1H, J=5.7 Hz, CH2-4), 2.62 (m, 1H, CH2-10), 1.89 (m, 1H, CH2-3), 1.62 (m, 3H, CH2-7, CH2-8, CH2-9) (see Supplementary data for details, Fig. S1); 13C NMR (DMSO-d6) delta/ppm: 164.91 (s, C-5a), 161.25 (s, C-6), 157.15 (s, C-2), 151.98 (s, C-4), 119.65 (s, C-8), 118.03 (s, C-5), 89.82 (d, C-1'), 86.35 (d, C-4'), 70.96 (d, C-3'), 70.59 (d, C-2'), 62.30 (t, C-5'), 53.20 (t, C-6), 47.81 (t, C-2), 38.09 (t, C-4), 32.01 (t, C-10), 28.25 (t, C-7), 26.06 (t, C-9), 23.50 (t, C-8), 19.14 (t, C-3) (see Supplementary data for details, Fig. S2). The assignments of the protons and C-atoms were confirmed by 2D NMR spectra; see Supplementary data for details: COSY spectrum (Fig. S3), NOESY spectrum (Fig. S4) and 1H-13C HMQC spectrum (Fig. S5). Anal. Calcd for C29H40Br2N12O10 (Mr=876.51): C, 39.74; H, 4.60; N, 19.18. Found: C, 39.85; H, 4.50; N, 19.26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In methanol; at 20℃; for 1h; | To a suspension of <strong>[4016-63-1]8-bromoguanosine</strong> (200 mg, 0.552 mmol) in dry methanol (10 mL), DBU (85 muL, 0.552 mmol, 97percent) was added dropwise. The resulting solution was stirred at room temperature for 1 h, evaporated to half of its volume and left in the fridge for 16 h. The resulting solid precipitate was filtered off, washed with ether and dried in a vacuum desiccator over solid NaOH, yielding 250 mg (88percent) of salt [8-BrG]-[DBU-H]+: IR (KBr) lambdamax/cm-1: 3466, 3424, 3336, 3202, 2924, 1653, 1616, 1580, 1560, 1458, 1437, 1306, 1275, 1128, 1084, 1065, 1005; 1H NMR (DMSO-d6) delta/ppm: 6.31 (br s, 2H, NH2), 5.67 (d, 1H, J=6.9 Hz, H-1'), 5.00 (t, 1H, J=6.0 Hz, H-2'), 4.12-3.2(br s, 3H, OH-2', OH-3', OH-5'), 4.12 (m, 1H, H-3'), 3.92 (m, 1H, H-4'), 3.66 (dd, 1H, J=3.3, 12.2 Hz, H-5'a), 3.52 (dd, 2H, J=3.6, 12.2 Hz, H-5'b), 3.40 (m, 2H, CH2-6), 3.36 (t, 2H, J=5.7 Hz, CH2-2), 3.19 (pt, 2H, J=5.7 Hz, CH2-4), 2.53 (m, 2H, CH2-10), 1.82 (m, 2H, CH2-3), 1.59 (m, 6H, CH2-7, CH2-8, CH2-9) (see Supplementary data for details Fig. S7); 13C NMR (DMSO-d6) delta/ppm: 163.44 (s, C-5a), 162.10 (s, C-6), 157.73 (s, C-2), 151.71 (s, C-4), 119.12 (s, C-8), 118.49 (s, C-5), 89.95 (d, C-1'), 86.51 (d, C-4'), 71.10 (d, C-2'(C-3')), 70.67 (d, C-3' (C-2')), 62.39 (t, C-5'), 52.80 (t, C-6), 47.72 (t, C-2), 39.59 (t, C-4), 33.20 (t, C-10), 28.48 (t, C-7), 26.64 (t, C-9), 24.15 (t, C-8), 20.04 (t, C-3) (see Supplementary data for details, Fig. S8). Anal. Calcd for C19H28BrN7O5 (Mr=514.38): C, 44.37; H, 5.49; N, 19.06. Found: C, 44.50; H, 5.31; N, 19.22. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With hydrogenchloride; In N,N-dimethyl-formamide; | Step 4 To a solution of <strong>[159622-10-3](1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid</strong> (7.5 g, 33 mmol) in DMF (50 mL) was added 1,1'-carbonyldiimidazole ("CDI", 10.7 g, 66.0 mmol) and the reaction mass was heated at 55° C. for 4 h. To this reaction mass was added 1-fluoromethylcyclopropane-1-sulfonamide (6.5 g, 42.9 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene ("DBU", 6.0 mL, 43 mmol). The reaction mixture was stirred at 55° C. for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH ?2 by using aq. 1.5 N HCl solution. The precipitated solid was isolated via filtration and washed with water to afford tert-butyl (1R,2S)-1-(1-(fluoromethyl)cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamate as off-white solid (11.5 g, 96percent). MS: MS m/z 361.4 (M+-1). |
96% | With hydrogenchloride; In N,N-dimethyl-formamide; | Step 4: Preparation of tert-butyl (1R,2S)-1-(1-(fluoromethyl)cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamate To a solution of <strong>[159622-10-3](1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid</strong> (7.5 g, 33 mmol) in DMF (50 mL) was added 1,1'-carbonyldiimidazole ("CDI", 10.7 g, 66.0 mmol) and the reaction mass was heated at 55° C. for 4 h. To this reaction mass was added 1-fluoromethylcyclopropane-1-sulfonamide (6.5 g, 42.9 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene ("DBU", 6.0 mL, 43 mmol). The reaction mixture was stirred at 55° C. for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH ?2 by using aq. 1.5 N HCl solutions. The precipitated solid was isolated via filtration and washed with water to afford tert-butyl (1R,2S)-1-(1-(fluoromethyl)cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamate as off-white solid (11.5 g, 96percent). MS:MS m/z 361.4 (M+-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; carbon monoxide; 1,3-bis-(diphenylphosphino)propane; water; In water; toluene; at 140℃; under 7500.75 Torr; for 16h;Inert atmosphere; Autoclave; | General procedure: A 12 mL vial was charged with [Pd(cinnamyl)Cl]2(1,5 mol%), dppp (3 mol%). and a stirring bar. Then, 1,2-dibromo-benzene(0.5 mmol), DBU (4.0 eq) and toluene (3 mL) were injected by syringe underargon. The vial (or several vials) was placed in an alloy plate, which wastransferred into a 300 mL autoclave of the 4560 series from Parr Instrumentsunder argon atmosphere. After flushing the autoclave three times with CO, apressure of 10 bar of CO was adjusted at ambient temperature. Then, thereaction was performed for 16-24 h at 140 oC. After the reactioncompleted, the autoclave was cooled down with ice water to room temperature andthe pressure was released carefully. After evaporation of the organic solventthe residue was adsorbed on silica gel and the crude product was purified bycolumn chromatography using EA/pentane(1:1) for phthalimides and MeOH/EA (1:40) for the amides as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | In i-Amyl alcohol; for 4h;Heating; | 2.2.1.1. Method A. Tetrachlorophthalonitrile (213.0 mg,0.80 mmol), Tb(OAc)3 x 3H2O (81.6 mg, 0.20 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (119 muL, 0.80 mmol) were stirred in3 mL of boiling isoamyl alcohol for 4 h (TLC-control: SiO2, F254,toluene). The reaction mixture was cooled to room temperatureand a MeOH:H2O (4:1 v/v) mixture was added. The precipitatewas filtered, washed with a MeOH:H2O (4:1 v/v) mixture and driedat 70 °C to give compound 1 (163.0 mg, 64percent). UV?Vis (THF) lambdamax(nm): 370 (lgepsilon 4.28); 704 (4.43). IR (vaseline oil) nu (cm-1): 1049?1140 (st C-Cl); 1329?1543 (gamma-pyrrole); 1385?1423 (C-O);1454?1543 (C=O). MS (MALDI-TOF) m/z: 1197 [M-OAc+OH-Cl]?,1214 [M-OAc]-, 1331 [M-OAc+OH-H]-. MS (MALDI-TOF/TOF) m/z: Found: 1214.4830 [M-OAc]; molecular formula C32Cl16N8Tbrequires 1214.4516 [M-OAc]. |
Tags: 6674-22-2 synthesis path| 6674-22-2 SDS| 6674-22-2 COA| 6674-22-2 purity| 6674-22-2 application| 6674-22-2 NMR| 6674-22-2 COA| 6674-22-2 structure
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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 |
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