Structure of 102-09-0
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CAS No. : | 102-09-0 |
Formula : | C13H10O3 |
M.W : | 214.22 |
SMILES Code : | O=C(OC1=CC=CC=C1)OC2=CC=CC=C2 |
MDL No. : | MFCD00003037 |
InChI Key : | ROORDVPLFPIABK-UHFFFAOYSA-N |
Pubchem ID : | 7597 |
GHS Pictogram: |
![]() ![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H302-H319-H372-H410 |
Precautionary Statements: | P260-P264-P273-P301+P312-P305+P351+P338-P314 |
Class: | 9 |
UN#: | 3077 |
Packing Group: | Ⅲ |
Num. heavy atoms | 16 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 59.54 |
TPSA ? Topological Polar Surface Area: Calculated from |
35.53 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.53 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.28 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.26 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.94 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.45 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.89 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.53 |
Solubility | 0.0639 mg/ml ; 0.000298 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.7 |
Solubility | 0.0426 mg/ml ; 0.000199 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.35 |
Solubility | 0.00955 mg/ml ; 0.0000446 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
Yes |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.28 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.03 |
* 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 |
---|---|---|
85% | Part F: Preparation of (5-Acetyl-4-methyl-thiazol-2-yl)-carbamic Acid Phenyl Ester Sodium hydride (60% dispersion in mineral oil, 3.07 g, 77 mmol) was washed twice with hexane and suspended in N,N-dimethylformamide. 2-Amino-5-acetyl-4-methylthiazole (10.0 g, 64 mmol) was added with stirring and cooling on an ice bath. Stirring was continued until the sodium hydride was consumed. Diphenyl carbonate (34 g, 160 mmol) was added and the mixture was stirred for 30 minutes at room temperature. The solvent was removed under vacuum to yield a brown residue, which was dissolved in chloroform and washed successively with 0.5N aqueous hydrochloric acid, twice with water and finally with saturated aqueous sodium chloride. The aqueous phases were back extracted twice with chloroform. The combined organic fractions were dried over sodium sulfate and concentrated under vacuum to give a white solid. This was chromatographed on silica gel, eluding with 15%-70% ethyl acetate in hexane, to give a white solid (15.0 g, 85%). 1H NMR (300 MHz, CDCl3) δ 11.42 (bs, 1H), 7.47-7.40 (m, 2H), 7.33-7.27 (m, 1H), 7.22-7.18 (m, 2H), 2.72 (s, 3H), 2.50 (s, 3H). Mass spec (ES+) m/z 277.1 (M+H+). | |
With hydrogenchloride; NaH; In chloroform; water; N,N-dimethyl-formamide; mineral oil; | Example 6 (5-Acetyl-4-methyl-thiazol-2-yl)-carbamic Acid Phenyl Ester In a round-bottom flask, NaH 60% dispersion in mineral oil (3.07 g, 77 mmol) was washed 2*with hexane and suspended in DMF. Then 2-amino-5-acetyl-4-methyl-thiazole (10.0 g, 64 mmol) was added and stirred while cooling in an ice bath. Stirring continued until the NaH was consumed. Diphenyl carbonate (34 g, 160 mmol) was added while cooling and after the addition was complete the reaction mixture was stirred for an additional 30 minutes at room temperature. The DMF was removed on a rotary evaporator (high vacuum, 40 C.) to yield a brown residue. This residue was dissolved in 1 L of CHCl3 and washed successively with 2 L of 0.5N HCl, 2*1 L of water, and finally by 1 L of brine. The aqueous portions were back extracted twice with ~300 mL of CHCl3. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give a white solid. This was chromatographed on silica (15%-70% EtOAc/hexane) to give 15 g of the desired carbamate as a white solid. 1H NMR (300 MHz, CDCl3) δ 11.42 (bs, 1H), 7.47-7.40 (m, 2H), 7.33-7.27 (m, 1H), 7.22-7.18 (m, 2H), 2.72 (s, 3H), 2.50 (s, 3H). ESI MS: (M+H)+=277.1. | |
With hydrogenchloride; NaH; In chloroform; water; N,N-dimethyl-formamide; mineral oil; | Part A Preparation of (5-acetyl-4-methyl-thiazol-2-yl)-carbamic acid phenyl ester In a round-bottom flask, NaH 60% dispersion in mineral oil (3.07 g, 77 mmol) was washed 2* with hexane and suspended in DMF. Then 2-amino-5-acetyl-4-methyl-thiazole (10.0 g, 64 mmol) was added and stirred while cooling in an ice bath. Stirring continued until the NaH was consumed. Diphenyl carbonate (34 g, 160 mmol) was added while cooling and after the addition was complete the reaction mixture was stirred for an additional ~30 minutes at room temperature. The dimethylformamide was removed on a rotary evaporator (high vacuum, 40 C.) to yield a brown residue. This residue was dissolved in 1 L of chloroform and washed successively with 2 L of 0.5N aqueous hydrochloric acid, twice with 1 L of water, and finally by 1 L of brine. The aqueous portions were back extracted twice with 300 mL of chloroform. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give a white solid. This was chromatographed on silica (15%-70% EtOAc/hexane) to give 15 g of the desired carbamate as a white solid. 1H NMR (300 MHz, CDCl3) δ: 11.42 (bs, 1 H), 7.47-7.40 (m, 2 H), 7.33-7.27 (m, 1 H), 7.22-7.18 (m, 2 H), 2.72 (s, 3 H), 2.50 (s, 3 H). ESI MS: (M+H)+=277.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; potassium tert-butylate; In ice-water; ISOPROPYLAMIDE; 2,4-dichlorophenoxyacetic acid dimethylamine; | Example 2 Methyl 2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-amino]-carbonyl]-amino]-sulfonyl]-4-iodobenzoate. 2.59 g of potassium tert-butylate was added to a suspension of 2.85 g of <strong>[1668-54-8]2-amino-4-methoxy-6-methyl-1,3,5-triazine</strong> in 40 ml of dimethylacetamide (DMA) at room temperature to form a first mixture. A solution of 4.94 g of diphenyl carbonate in 20 ml of DMA was then added dropwise to the first mixture at about 5° C. to form a second mixture. The second mixture was subsequently added dropwise to a solution of 5.00 g of methyl 2-aminosulfonyl-4-iodobenzoate (92.5percent pure) in 15 ml of DMA at about 5° C., to form a third mixture. When the reaction ended, the third mixture was filtered over kieselguhr (.(R).Celite). The filtrate was introduced into a solution of 200 ml of ice-water and 10 ml of concentrated hydrochloric acid, whereby the crude urea product separated out. The crude product which separated out was then purified by stirring with methanol and diisopropyl ether and dried. The yield was 4.50 g (66percent of theory). This Example also demonstrates that the carbamate of formula (IV) can be formed and converted, without isolation, to the sulfonylurea of formula (I), in a good yield (of both (IV) and (I)), without using an alkali metal hydride or phosgene. | |
With sodium t-butanolate; In water; 2,4-dichlorophenoxyacetic acid dimethylamine; | Example 4 Methyl 2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]amino]sulfonyl]-4-iodobenzoate. 5.09 g of sodium tert-butylate was added to a suspension of 3.69 g of <strong>[1668-54-8]2-amino-4-methoxy-6-methyl-1,3,5-triazine</strong> in 100 ml of DMA at room temperature. After cooling to 3-7° C., a solution of 5.64 g of diphenyl carbonate and 50 ml of DMA was added dropwise, to form a reaction mixture. The reaction mixture was then stirred at that temperature for 15 minutes. The reaction mixture was then added dropwise to a solution of 8.85 g of methyl 2-aminosulfonyl-4-iodobenzoate and 50 ml of DMA at 3-7° C., to form a resulting mixture which was stirred at 3° C. for 1 hour and at room temperature for 2 hours. The volatile components were then distilled off under reduced pressure. The residue was dissolved in 250 ml of water and acidified with concentrated hydrochloric acid (pH=2-3) whereby the crude product separated out. The crude product which separated out was washed with methanol and diisopropyl ether. After drying, 8.4 g of the desired product (purity>92percent) was obtained. This Example additionally demonstrates that the carbamate of formula (IV) can be formed and converted, without isolation, to the sulfonylurea of formula (I), with high purity, (of both (IV) and (I)) without using an alkali metal hydride or phosgene. | |
With sodium t-butanolate; In ISOPROPYLAMIDE; 2,4-dichlorophenoxyacetic acid dimethylamine; | Example 3 Methyl 2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-amino]-carbonyl]-amino]-sulfonyl]-4-iodobenzoate. 0.96 g of sodium tert-butylate was added to a suspension of 1.05 g of <strong>[1668-54-8]2-amino-4-methoxy-6-methyl-1,3,5-triazine</strong> in 20 ml of dimethylacetamide (DMA) at room temperature, with vigorous stirring, to form a first mixture. A solution of 1.12 g of diphenyl carbonate in 10 ml of DMA was then added to the first mixture, in the course of 7 minutes, while it was cooled in an ice bath, to form a second mixture. The second mixture was subsequently stirred for another 15 minutes while cooled in the ice bath, and a solution of 1.84 g of methyl 2-aminosulfonyl-4-iodobenzoate (92.5percent pure) in DMA was then added dropwise in the course of 7 minutes. When the reaction ended, the product was worked up as described in Example 1. 1.47 g of the desired product (58percent of theory) was thus obtained. This Example further demonstrates that the carbamate of formula (IV) can be formed and converted, without isolation, to the sulfonylurea of formula (I), in a good yield (of both (IV) and (I)), without using an alkali metal hydride or phosgene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In N,N-dimethyl acetamide; | EXAMPLE 1 The Preparation of phenyl (4,6-dimethoxy-1,3,5-triazin-2-yl)carbamate Into 50 ml Erlenmeyer flask, were added <strong>[16370-63-1]2-amino-4,6-dimethoxy-1,3,5-triazine</strong> 2.00 g (0.0128 mole) and dry N,N-dimethylacetamide 18 ml and stirred in the suspended condition. To the suspended mixture, at the room temperature, was added 60% oily sodium hydride 0.51 g (0.0128 mole). The reaction mixture was homogeneous after vigorous evolution of hydrogen gas. A solution of diphenyl carbonate 2.74 g (0.0128 mole) and dry N,N-dimethylacetamide was subsequently added to the mixture under the water cooling during 10 minutes, and stirred for further 10 minutes. The reaction mixture was poured into 20 ml iced water containing 1.4 ml hydrogen chloride (35% aq soln). The precipitate was filtered off and wash with iced water and then petroleum ether. After being air-dried, the product was obtained. The obtained amount (yield of theory) and the physical property were showed hereinafter. 2.60 g (73.5% of theory) mp. 141-142 C. IR (KBr,cm-1) 3304, 1780, 1752, 1618, 1482 1390, 1360, 1290, 1192 NMR (CDCl3, delta) 4.0(6H, s, OCH3 *2)7.05-7.5(5H, m, Aromatic H) 8.28-8.7(1H, bs, NH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.7%Chromat.; 14.9%Chromat. | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 2h;Product distribution / selectivity; | Example 10Methyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- lH- benzo[ai]irnidazole-7-carboxylate of formula laA mixture of methyl 2-ethoxy- l -((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l H- benzo[ii|imidazole-7-carboxylate (of formula Va; 0.1 g, 0.22 mmol), DMSO (2 ml), the corresponding carbonate (0. 1 g; DMC = dimethyl carbonate, DEC = diethyl carbonate, DPC = diphenyl carbonate) and the corresponding base (0.05 g) was stirred in a reaction vial at the room temperature for 2 hours. The results are summarized in Table IV. Table IV - Yield and purity of the product of Example 10 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.4% | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 4h; | Example 12Methyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- lH- benzo[.pound. ]imidazole-7-carboxylate of formula laDiphenyl carbonate (DPC; 0.32 g, 1 .5 mmol) was added to a mixture of methyl 2-ethoxy-l- ((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- lH-benzo[i/]imidazole-7- carboxylate (of formula Va; 0.44 g, 1 mmol), DMSO (10 ml) and K2C03 (0.2 g, 1 .4 mmol) and the mixture was stirred at the room temperature for 2 h. The mixture contained 12.4 percent of the starting compound of formula Va, 8.3 percent of phenol and 71.8 percent of the substance of formula la according to HPLC. After stirring at the room temperature for another 2 hours the reaction mixture was poured into water (25 ml) and, after acidification with acetic acid, the separated solids were aspirated and washed with water. 0.43 g (91.4 percent) of a product containing 93.2 percent of the compound (la) according to HPLC was obtained. Crystallization from ethyl acetate yielded 0.35 g (74.4 percent) of a compound with the melting point 194-197 °C with the HPLC purity of 98.8 percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5percent by mass titanium-containing composition; at 200 - 230℃; under 22.5023 - 1050.11 Torr;Industry scale;Product distribution / selectivity; | Examples 2 to 6; Start-up operation was performed in the same manner as in the example 1 except that dialkyl carbonates of types shown in the following Table 1 were used in place of bis(3-methylbutyl)carbonate, so as to produce diphenyl carbonate (diaryl carbonate). A flow rate and a pressure were controlled depending on the type of each dialkyl carbonate in control operation.In distillation separation in a distillation column 130, a high boiling component removed from a column bottom contained about 7percent by mass, about 10percent by mass, about 8percent by mass, about 9percent by mass, and about 8percent by mass of a component having a higher boiling point than that of the diphenyl carbonate, in order of examples 2 to 6.The results of analyzing a titanium-containing high boiling component obtained from a removal line 11 are shown in Table 1. All the examples satisfied the conditions of the above-mentioned items (iv) to (vi), and could stably produce the diaryl carbonates. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 2-methyltetrahydrofuran;Reflux; | 6.1 Preparation of phenyl carbatnate In order to check the base?s melting point the phenyl carbamate base was synthesised from the 3-(1H-imidazol-4-yl)-pyridine (1) and diphenyl carbonate (9) in refluxing 2-Me TI-IF (melting point: 153-155C). Similar resultswere obtained when using toluene (1 mmol), xylene (1 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | NaH (0.960 g, 40 mmol) was added to anhyd DMF (20 mL) in aflask kept in an ice bath, and the mixture was stirred for 30 min.3-Ethyl-4-methyl-1H-pyrrol-2(5H)-one (1.252 g, 10 mmol) inanhyd DMF (10 mL) was added dropwise to the above mixture,and the resulting mixture was stirred for 1.5 h. Diphenyl carbonate(4.284 g, 20 mmol) in anhyd DMF (10 mL) was added,and stirring was continued for another 5 h at r.t. When the reactionwas complete (TLC), the solvent was removed underreduced pressure, and the residue was diluted with EtOAc (100mL), washed with brine (2 × 50 mL), and dried (Na2SO4). Theorganic layer was filtered and concentrated under reduced pressure,and the crude product was purified by column chromatography(silica gel, 12percent hexane?EtOAc) to give a viscous liquid;yield: 1.600 g, (65percent).1H NMR (400 MHz, DMSO-d6): delta = 7.45 (t, J = 7.9 Hz, 2 H), 7.29(t, J = 7.4 Hz, 1 H), 7.23 (d, J = 7.5 Hz, 2 H), 4.38 (s, 2 H), 2.22 (q,J = 7.5 Hz, 2 H), 2.05 (s, 3 H), 1.01 (t, J = 7.5 Hz, 3 H). 13C NMR(100 MHz, DMSO-d6): delta = 169.5, 152.5, 150.5, 149.0, 132.6,129.9, 126.4, 122.2, 53.0, 16.5, 13.4, 13.1. HRMS (ESI): m/z [M +Na]+ calcd for C14H15NNaO3: 268.0950; found: 268.0967. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With lithium hexamethyldisilazane; In tetrahydrofuran; at 0℃; for 2h;Inert atmosphere; | Compounds <strong>[180869-38-9]4-(dimethoxymethyl)-N-methylpyrimidin-2-amine</strong> 73 8c (0.20 g, 1.09 mmol), 25 diphenyl carbonate (0.47 g, 2.19 mmol), 26 lithium hexamethyldisilazide (1.5 mL, 1.51 mmol, 1 M solution in 27 tetrahydrofuran) and tetrahydrofuran (5 mL) were mixed and stirred for 2 h at 0 C. This mixture was quenched with 10 mL of a saturated ammonium chloride solution, extracted with ethyl acetate (20 mL×2), and the organic phase was washed with saturated brine (20 mL×2). The organic phase was dried over anhydrous sodium sulfate, and filtered to remove the drying agent. The residuals were purified through a preparative silica gel plate (dichloromethane/methanol 50:1), to obtain the target product phenyl (76 4-(dimethoxymethyl)pyrimidin-2-yl)(methyl) aminocarboxylate 8 d (40 mg, white solid), at a yield of 12%. (0178) MS m/z (ESI): 304 [M+1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium carbonate; In acetonitrile; at 20 - 120℃; for 24h;Schlenk technique; | General procedure: A mixture of indole 1 (0.50 mmol), Na2CO3 (10.6 mg, 0.10 mmol, 20 mol%) and diaryl carboxylate 2 (0.60 mmol, 1.2 equiv) in CH3CN (3 mL) was added into a Schlenk flask (25 mL) and stirred at room temperature. The mixture was stirred at 120 C until the reaction was finished. Then the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (petroleum ether/ethyl acetate 50:1 to 10:1). |