Structure of 71675-87-1
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CAS No. : | 71675-87-1 |
Formula : | C10H13NO5S |
M.W : | 259.28 |
SMILES Code : | O=C(O)C1=CC(S(=O)(CC)=O)=C(N)C=C1OC |
MDL No. : | MFCD04973619 |
InChI Key : | OJVNCXHGGYYOPH-UHFFFAOYSA-N |
Pubchem ID : | 3018232 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 17 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.3 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 62.2 |
TPSA ? Topological Polar Surface Area: Calculated from |
115.07 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.25 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.18 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.86 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.48 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.26 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.81 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.19 |
Solubility | 1.68 mg/ml ; 0.00648 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.19 |
Solubility | 0.167 mg/ml ; 0.000642 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.26 |
Solubility | 1.42 mg/ml ; 0.00548 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.04 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 |
0.56 |
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<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.35 |
* 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 |
---|---|---|
66.5% | With triethylamine; In tetrahydrofuran; water; | N-(1-cyclopropyl-methyl-2-pyrrolidinyl-methyl)-2-methoxy-4-amino-5-ethylsulphonyl-benzamide 31.3 g (0.31 mole) of triethylamine, 400 ml of tetrahydrofuran and 80.3 g (0.31 mole) of <strong>[71675-87-1]2-methoxy-4-amino-5-ethylsulphonyl benzoic acid</strong> are placed in a 1 liter flask fitted with an agitator, a thermometer, a condenser and a dropping funnel. A rubbery precipitate is formed which gradually crumbles. After 30 minutes at room temperature it is cooled to 0° C. and 33.6 g (0.31 mole) of ethyl chloroformate is added drop by drop. This is kept under agitation for 1 hour between 0° and 5° C. and 62 g (0.40 mole) of 1-(cyclopropylmethyl)-2-amino-methyl-pyrrolidine is added drop by drop while the temperature is kept at the same level. A thick precipitate is formed. The reaction medium is agitated for a further 2 hours at room temperature then left to stand overnight. The crystals obtained are filtered, washed twice with 100 ml of tetrahydrofuran and dried in an oven at 50° C. 137 g of product is obtained and is dissolved with boiling water. After filtering and drying, 91 g (74.3percent) of crystals is obtained; these are re-crystallized in 600 ml of 90percent alcohol. They are filtered, washed twice with 50 ml of alcohol and dried in an oven at 40° C. 81.5 g (yield 66.5percent) of N-(1-cyclopropylmethyl-2-pyrrolidinyl-methyl)-2-methoxy-4-amino-5-ethylsulphonyl benzamide is obtained, melting at 181° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In water; ethyl acetate; acetone; | EXAMPLE 47 N-(1-cyclohexylmethyl-3-pyrrolidinyl)-2-methoxy-4-amino-5-ethyl-sulphonyl-benzamide 7.8 g of <strong>[71675-87-1]2-methoxy-4-amino-5-ethylsulphonyl benzoic acid</strong>, 70 ml of acetone, 10 ml of water and 3 g of triethylamine are placed in a 250 ml flask fitted with an agitator, a thermometer and a dropping funnel. The mixture is cooled to 0° C. and 4.1 g of isobutyl chloroformate is poured in drop by drop. It is agitated for 45 minutes at 0° C. and 6 g of 1-cyclohexylmethyl-3-amino-pyrrolidine is dripped in. The reaction is continued for 2 hours at room temperature, 80 ml of water and 5 ml of soda lye are added, then the acetone is evaporated under vacuum. An oil is decanted; it is washed twice with 100 ml of water than dissolved hot in 50 ml ethyl acetate. It is chilled in a refrigerator. The crystals are filtered off, washed with a little ethyl acetate then dried in an oven at 50° C. 9.4 of benzamide is obtained with a melting point of 146° C. (74percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In water; acetone; Diethyl carbonate; | EXAMPLE 46 N-(1-cyclopropylmethyl-3-pyrrolidinyl)-2-methoxy-4-amino-5-ethyl-sulphonyl-benzamide 64.8 g of <strong>[71675-87-1]2-methoxy-4-amino-5-ethylsulphonyl benzoic acid</strong>, 650 ml of acetone and 25.2 g of triethylamine are placed in a liter flask fitted with an agitator, a thermometer and a dropping funnel. The solids dissolve completely then the triethylamine salt is precipitated rapidly. The reaction medium is cooled to 0° C. and 35 g of isobutyl chloroformate is poured in drop by drop. The medium is agitated for 45 minutes between 0° and 5° C., after which 37 g of 1-cyclopropylmethyl-3-aminopyrrolidine is added drop by drop. The reaction is continued for 2 hours at room temperature, after which 500 ml of water is added and the acetone evaporated under vacuum. An oil is decanted and is extracted with methylene chloride. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness under vacuum. The residue is dissolved hot in 500 ml of diethylcarbonate and the product is put in an ice chamber to crystallise. The crystals are filtered, washed with a little ether and dried in an oven at 40°. 78 g of product is obtained with a melting point of 71°-72° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In acetone; | EXAMPLE 25 N-(1-cyclohexyl-2-pyrrolidinyl-methyl)-2-methoxy-4-amino-5-ethylsulphonyl-benzamide Using a 1 liter flask fitted with an agitator, a thermometer and a dropping funnel, 98 g of 2-methoxy-4-amino-5-ethylsulphonyl-benzoic acid (0.378 mole) is dissolved in 392 ml of acetone, then 38 g of triethyl amine (0.378 mole) is added. The triethyl amine salt of the organic acid crystallises immediately. The suspension is cooled to 0° C. then 41 g of ethyl chlorofomate (0.378 mole) is added drop by drop between 0° and 5° C. The salt is dissolved gradually and the triethylamine hydrochloride is precipitated in fine white crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With triethylamine; In water; acetone; | N-(1-ethyl 2-pyrrolidylmethyl) 2-methoxy 4-amino 5-ethylsulphonyl benzamide 81 g of <strong>[71675-87-1]2-methoxy 4-amino 5-ethylsulphonyl benzoic acid</strong> and 297 cm3 of acetone are placed in a flask fitted with an agitator, a thermometer and a dropping funnel, followed by 33 g of triethylamine. The solution is cooled to 0° C., then 30 g of ethyl chloroformate is added drop by drop between 0° and 5° C. When the mixture has been agitated 51 g of 1-ethyl 2-amino methyl pyrrolidine is added drop by drop between 5° and 10° C. The mixture is agitated at 10° C. then at ambient temperature. The triethylamine hydrochloride which precipitates is drained, then the acetone is distilled. The residue is dissolved in 600 cm3 of water in the presence of caustic soda solution. The base crystallises after seeding and is drained, washed with water and dried. When the crystals have been purified by passing them through hydrochloride and re-crystallising them in acetone, 66 g of N-[1-ethyl 2-pyrrolidylmethyl] 2-methoxy 4-amino 5-ethylsulphonyl benzamide is obtained (yield 61percent-M.P.=126° to 127° C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In water; acetone; | EXAMPLE II N-[1-methyl 2-pyrrolidylmethyl] 2-methoxy 4-amino 5-ethylsulphonyl benzamide 144 g of <strong>[71675-87-1]2-methoxy 4-amino 5-ethylsulphonyl benzoic acid</strong>, 440 cm3 of acetone and 44.5 g of triethylamine are placed in a flask fitted with an agitator, a thermometer and a dropping funnel. The solution is cooled to 0° C., then 48 g of ethyl chloroformate is added drop by drop between 0° and 15° C. The mixture is agitated for 30 minutes between 0° and 5° C., then 67 g of 1-methyl 2-aminomethylpyrrolidine is added drop by drop between 5° and 10° C. The mixture is then agitated firstly at 10° C. then at room temperature. The product obtained is drained, washed with acetone, treated with 500 cm3 of water, then drained, washed with water and dried. The substance obtained is re-crystallized in absolute alcohol and purified by passing it through hydrochloride. After further re-crystallisation in absolute alcohol, 101 g of N-[1-methyl 2-pyrrolidylmethyl] 2-methoxy 4-amino 5-ethylsulphonyl benzamide is obtained (yield=157°-158° C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With hydrogenchloride; triethylamine; In water; acetone; | EXAMPLE III N-[1-allyl 2-pyrrolidylmethyl] 2-methoxy 4-amino 5-ethylsulphonyl benzamide 132 g of <strong>[71675-87-1]2-methoxy 4-amino 5-ethylsulphonyl benzoic acid</strong>, 510 cm3 acetone and 51.5 g of triethylamine are placed in a flask fitted with an agitator, a thermometer and a dropping funnel. The solution obtained is cooled to 0° C., then 55.5 g of ethyl chloroformate is added drop by drop, between 0° and 5° C. The mixture is agitated for 30 minutes at 5° C., then 96 g of 1-allyl 2-aminoethylpyrrolidine is added drop by drop, between 5° and 10° C. The mixture is agitated at 10° C. then at room temperature. The triethylamine hydrochloride which is precipitated is drained and washed with acetone, then the acetone is distilled. The residue is dissolved in water and 60 cm3 of concentrated hydrochloric acid, then the solution obtained is filtered and treated with the 30percent caustic soda solution. The oil formed is extracted with methylene chloride, then the organic solution is dried over potassium carbonate and the methylene chloride is distilled. After purification 131 g of N-[1-allyl 2-pyrrolidyl methyl] 2-methoxy 4-amino 5-ethylsulphonyl benzamide is obtained (yield=67percent-M.P.111°-112° C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | The precipitate formed by adding 70 cm3 of concentrated hydrochloric acid is cooled, drained, washed with water and dried. 61,5 g of 2-methoxy-4-amino-5-ethylsulphonylbenzoic acid hydrate is obtained (yield=42percent); Melting point: 95-100° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In acetone; | (S)-(-)-4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide 95 g of 2-methoxy-4-amino-5-ethylsulphonylbenzoic acid dissolved in 370 ml of acetone, in the presence of 37 g of trielthylamine, is treated with 40 g of ethyl chloroformate with 57 g of (S)-(-)-1-ethyl-2-aminomethylpyrrolidine. 115 g of (S)-(-)-N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-amino-5-ethylsulphonylbenzamide is obtained (yield=84%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With boron tribromide; In dichloromethane; at -50 - 20℃; | EXAMPLE 3; 4-Amino-N-((1-d5-ethylpyrrolidin-2-yl)methyl)-5-(ethylsulfonyl)-2-d3-methoxybenzamide; Step 1 4-Amino-5-(ethylsulfonyl)-2-hydroxybenzoic acid: At about -50° C., boron tribromide (7.31 mL, 77.2 mmol) was slowly added over a period of about 30 minutes to a suspension of 4-amino-5-(ethylsulfonyl)-2-methoxy benzoic acid (5.0 g, 19.3 mmol) and dry dichloromethane (100 mL). The resulting mixture was stirred at ambient temperature for about 4 hours and then poured into ice-cold water (150 mL). The resulting precipitate was collected by filtration and washed with cold water. The wet-cake was dissolved in ethyl acetate (200 mL), washed with water, washed with brine, dried over anhydrous sodium sulphate, and then concentrated in vacuo to give the title compound as an off-white solid (3.1 g, yield=65percent). 1H NMR (400 MHz, DMSO-d6) delta 1.08 (t, J=7.2 Hz, 3H), 3.16 (q, J=7.3 Hz, 2H), 6.25 (s, 1H), 6.64 (br s, exchangeable with D2O, 2H), 7.96 (s, 1H), 11.6 (br, exchangeable with D20, 1H); IR (KBr) upsilon 3449, 3357, 3225, 2974, 1678, 1633, 1275, 1230, 1118, 802, 545 cm-1; MS 244 (M-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29.7% | Step 5 4-amino-N-((1-ethylpyrrolidin-2-yl) methyl) methoxybenzamide: At about 0° C., 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (847 mg, 4.45 mmol) and hydroxybenzotriazole (451 mg, 2.95 mmol) was added to a suspension of <strong>[71675-87-1]4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid</strong> (639 mg, 2.46 mmol) and dry dichloromethane. The resulting mixture was stirred at about 0° C. for about 30 minutes, and then a solution of (1-ethylpyrrolidin-2-yl) methanamine hydrochloride (450 mg, 2.74 mmol) and dry dichloromethane was added. After slowly adding triethylamine (840 muL, 6.15 mmol), the mixture was stirred at ambient temperature for about 30 minutes. Standard extractive work up provided a crude residue (1.0 g) which was then purified by Preparative HPLC on a XTERRA RP -8(20*250 mm) column (eluding with methanol/0.01M ammonium bicarbonate (gradient) at a flow rate of 20 mL/min (UV 210 nm)). The title compound eluted at 9.4 minutes. The acetonitrile was removed by distillation and the remaining aqueous phase was then extracted with ethyl acetate and concentrated to obtain the title compound as a pale yellow powder (300 mg, 29.7percent, highly hygroscopic in nature). 1H NMR (400 MHz, Pyridine-d5) delta 1.06 (t, J=7.2 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H), 1.52-1.75 (m, 4H), 2.04-2.14 (m, 2H), 2.54-2.58 (m, 1H), 2.77-2.82 (m, 1H), 3.02-3.30 (m, 1H), 3.27 (q, 7.4 Hz, 2H), 3.41-3.44 (m, 1H), 3.71-3.72 (m, 3H), 3.91-3.97 (m, 1H), 6.54-6.55 (m, 1H), 7.14 (br, exchangeable with D2O, 2H), 8.34 (br, exchangeable with D20, 1H), 9.2 (s, 1H); IR (KBr) upsilon 3450, 3362, 3208, 3068, 2964, 2875, 2801, 1641, 1597, 1533, 1297, 1270, 1220, 1120, 1053, 992, 939, 777 cm-1; MS 370 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With chloroformic acid ethyl ester; triethylamine; In acetone; at 0 - 30℃; | To a stirring mixture of 4-amino-2-methoxy-5 -ethyl sulphonyl benzoic acid (IV) and acetone (5.0 L) at 0-5°C, triethyl amine (0.405 Kg) was added and stirred followed by addition of ethyl chloroformate (0.368 Kg). N-ethyl-2-amino methyl pyrrolidine (0.627 Kg) was added to the reaction mass at 5-10°C. Temperature of reaction mass was raised to 25-30°C and stirred for 120 min. To the same reaction mass triethyl amine (0.405 Kg) and ethyl chloroformate (0.368 Kg) was added with maintaining the temperature. Reaction mass was stirred for 120 min. After completion of reaction, water (4.0 L) was added. Reaction mass was filtered and washed with water (2.0 L). Filtrate was collected and water was added (9.0 L). pH of the reaction mass was adjusted to 10.8-1 1.2 by using 20percent NaOH solution. Reaction mass was stirred for 240-300 min, filtered and washed with water. Solid was dried under vacuumYield : 70percentPurity: 98percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dihydrogen peroxide;sodium tungstate; In methanol; water; at 20 - 30℃; for 5h;Product distribution / selectivity; | Sodium tungstate (0.726 g) was dissolved in water (100 ml) and hydrogen peroxide 30percent (250 ml) was added to the mixture. In another flask 2-methoxy-4-amino 5 ethyl thio benzoic acid (100 g) was dissolved in hot methanol (400 ml) at 40-45°C. The solution was cooled to room temperature and slowly added to the above oxidizing mixture below 25-30°C. The reaction mass was stirred for about 5 hours. The reaction mass was poured in pre cooled sodium thiosulphate solution at 5-15°C. The mixture was cooled, stirred, solid was filtered and dried.Yield: 80percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | 30percent Hydrogen peroxide was slowly added to a solution of the 4-amino-2-methoxy-5- ethylthio methyl benzoate (X) (1.21 Kg) in isopropyl alcohol (4.84 Lit.) containing sodium tungstate (0.0082 Kg) as a catalytic amount at ambient temperature. The mixture was stirred at 40-45°C for 3-4 hrs then cooled to 5-10°C. 5percent sodium thiosulphate solution (0.06 Kg in 18.15 lit. water) was added to reaction mixture. Reaction mass was stirred for 60 min and 2- methoxy-4-amino-5-ethyl-sulfonyl methyl benzoate (XI) was obtained in situ. To the reaction mixture was added sodium hydroxide (1.00 Kg, in 10 lit. water). The temperature was raised up to 60-65 °C and stirred the reaction mixture for 2-3 hrs. The reaction mass was cooled and adjusted pH 4.0 - 4.5 by using diluted hydrochloric acid (1 : 10). The product was isolated by filtration under suction.Yield : 82percentPurity: 99percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Dissolve 10 g of Amimic acid and 4.96 g of triethylamine in 50 ml of acetone, cool down to 5 C., slowly add 5.6 g of isopropyl chloroformate, and then dropwise, incubate at agitation for 0.5 h, and slowly add dropwise Example 1 A 25 mL solution of 6.42 g of R-2-aminomethyl-N-ethylpyrrolidine in acetone was prepared, and the mixture was stirred at 0° C. for 0.5 h and then stirred at room temperature for 1 h. The mixture was vortexed, water was added and extracted with dichloromethane (25 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give a yellow-brown oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Under nitrogen protection, acetone 400 ml, <strong>[71675-87-1]4-amino-2-methoxyl-5-ethylsulfonylbenzoic acid</strong> 100g is added into a 1000ml four-necked bottle, stirring, cool down at 0 ~ 10 °C, add drop-wise triethylamine 43g, after adding the drops, stir for 15 minutes, after that the reaction solution is cooled at -5 ~ 0 °C, and the temperature is controlled at -5 ~ 5 °C, added the drops of a solution of 55.8 g of pivaloyl chloride and 100 ml of acetone, dropping has been completed, the reaction is stirred for 1.5 hours. The reaction solution is used directly for the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49 g | 50 g of 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid, and 280 g of acetone were placed in a flask equipped with a stir bar, a thermocouple and a nitrogen line. Then 24 g of ethyl chloroformate was added to the reactor. The solution was cooled to -10 C., and then 28 g of 4-methyl morpholine was added slowly. The mixture was agitated at -10 C. for 1 h and then 27 g of (S)-(1-ethylpyrrolidin-2-yl)methanamine was added dropwise. The mixture was agitated at -10 C. then warmed to ambient. The reaction was concentrated and 300 mL of water and 200 mL of ethyl acetate were added. The mixture was agitated and the organic layer removed. 300 mL of ethyl acetate and 100 mL of 20 wt % aqueous potassium carbonate were added. The mixture was agitated, the phases are allowed to separate and the aqueous layer removed. The ethyl acetate layer was then washed with 200 mL of water two times. The organic layer was transferred to a flask with a mechanical stirrer, a thermocouple and distillation head. The organic layer was concentrated to dryness and 120 g of ethyl acetate added. The mixture was stirred then cooled to -10 C. and agitated until a slurry formed. The mixture was warmed to 10 C. and stirred at 10 C. for 1 h. The slurry was then filtered, washed with 30 g of ethyl acetate and dried at ambient temperature. 49 g of (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide ethyl acetate was obtained. XRPD analysis showed a pattern in accordance with Form B? and that of FIG. 8. An NMR spectrum of the S-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide ethyl acetate solvate obtained in Example 7 is illustrated in FIG. 7, having the following characteristics: 1H NMR (400 MHz, CHLOROFORM-d) delta ppm -0.02-0.00 (m, 1H) 1.11 (t, J=7.24 Hz, 3H) 1.22-1.28 (m, 4H) 1.55-1.74 (m, 4H) 1.82-1.92 (m, 1H) 2.03 (s, 1H) 2.13-2.27 (m, 2H) 2.58-2.64 (m, 1H) 2.84 (dq, J=12.08, 7.32 Hz, 1H) 3.07-3.28 (m, 4H) 3.66-3.74 (m, 1H) 3.93 (s, 3H) 5.48 (s, 2H) 6.19 (s, 1H) 8.03 (br d, J=4.30 Hz, 1H) 8.52 (s, 1H). | |
153 g of 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid and 789 g of acetone were placed in a flask fitted with a stir bar, a thermocouple and a nitrogen line. The solution was cooled to -8 C., and then 70.4 g of ethyl chloroformate was added to the flask. An addition funnel was fitted to the flask and 79.3 g of 4-methyl morpholine was added drop wise, maintaining the temperature below 0 C. The mixture was agitated at -8 C. and then 55 g of (S)-(1-ethylpyrrolidin-2-yl)methanamine was added drop wise. The mixture was agitated at 0 C. for 1 hour, warmed to ambient temperature and then further agitated at ambient temperature to provide S-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide starting material. The reaction was then concentrated to minimum volume and 822 g of water, followed by 311 g of ethyl acetate, was added. The mixture was agitated and the organic layer removed. The solution was heated to 35 C. and 755 g of ethyl acetate and 326 g of 40 wt % potassium carbonate (aq) were added. The mixture was agitated, the phases allowed to separate, and the aqueous layer removed. Then 296 g of water of water was added, the mixture agitated, the phases allowed to separate and the aqueous layer removed. 302 g of water was added, the mixture agitated, the phases allowed to separate and the aqueous layer removed. The organic layer was transferred to a flask with a mechanical stirrer, a thermocouple and a nitrogen line. The organic layer was concentrated to dryness and 531 g of ethyl acetate was added. After agitation, the solution was concentrated to 400 mL. Then 305 g of ethyl acetate was added and the solution was concentrated to 400 mL and was 0.35 wt % water by Karl Fischer titration. The solution was then cooled to 30 C. and seeded with 300 mg of S-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide and a slurry formed. The solution was then cooled to 20 C. and agitated, and 495 g of methyl t-butyl ether was added. The slurry was then filtered, washed with 3:1 wt/wt methyl t-butyl ether:ethyl acetate and dried. 160.7 g of S-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide was obtained as a crystalline solid, representing a yield of about 74%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7 g | With 4-methyl-morpholine; chloroformic acid ethyl ester; In acetone; at -10 - 20℃;Inert atmosphere; | 10 g of <strong>[71675-87-1]4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid</strong>, 100 mL of acetone and 5.3 mL of 4-methyl morpholine were placed in a flask equipped with a stir bar, a thermocouple and a nitrogen line. The solution was cooled to 0 C., and then 4.4 mL of ethyl chloroformate was added to the reactor. The mixture was agitated at -10 C. and then 5.42 g of (R)-(1-ethylpyrrolidin-2-yl)methanamine was added dropwise. The mixture was agitated at -10 C. for 1 hour then warmed to ambient. The reaction was concentrated and 100 mL of water and 100 mL of ethyl acetate were added. The mixture was agitated and the organic layer removed. 100 mL of ethyl acetate and 40 mL of 10 wt % aqueous potassium carbonate were then added. The mixture was agitated and the phases were allowed to separate and the aqueous layer was removed. The ethyl acetate layer was then washed with 50 mL of water two times. The organic layer was transferred to a flask with a mechanical stirrer, a thermocouple and distillation head. The organic layer was concentrated to dryness and 10 g of ethyl acetate was added. The mixture was stirred then cooled to -10 C. and agitated until a slurry formed. The mixture was warmed to 0 C. and stirred at 0 C. for 2 h. The slurry was then filtered, washed with ethyl acetate and dried at ambient temperature. 7 g of (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide ethyl acetate solvate, having greater than 99% chiral purity, and greater than 99% chemical purity, was obtained. An NMR spectrum of the (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide ethyl acetate solvate obtained in Example 4A is illustrated in , having the following characteristics: 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.11 (t, J=7.24 Hz, 3H) 1.23-1.27 (m, 3H), 1.25 (t, J=7.17 Hz, 0.91H) 1.55-1.77 (m, 3H) 1.82-1.92 (m, 1H), 2.04 (s, 0.93H), 2.14-2.27 (m, 2H) 2.58-2.64 (m, 1H) 2.84 (dd, J=12.13, 7.43 Hz, 1H) 3.07-3.28 (m, 4H) 3.69 (ddd, J=13.50, 7.24, 2.74 Hz, 1H) 3.93 (s, 3H) 4.11 (q, J=7.17 Hz, 0.64H) 5.52 (s, 2H) 6.21 (s, 1H) 7.26 (s, 1H) 8.04 (br d, J=5.09 Hz, 1H) 8.52 (s, 1H). |
150 g of <strong>[71675-87-1]4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid</strong> and 2000 g of acetone were placed in a flask. The solution was cooled to -9 C., and 74.3 mL of ethyl chloroformate was added to the flask. Then 88.9 mL of 4-methyl morpholine was added over 1 hour. 81.4 g of (R)-(1-ethylpyrrolidin-2-yl)methanamine was added and the mixture stirred for 16 h. The reaction was then concentrated and 800 g of water and 300 g of ethyl acetate were added. The mixture was agitated and the organic layer removed, which contained the R-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide starting material. The solution containing the starting material was basified by the addition of aqueous 20 wt % potassium carbonate and 2.5 L of ethyl acetate was added. The aqueous layer was removed. The organic layer was washed twice with water and concentrated to dryness. Then 800 g of ethyl acetate was added and the mixture was concentrated. This was repeated once. The resulting oil was dissolved into 800 g of ethyl acetate and concentrated to 600 mL. The solution was stirred at 30 C. and a slurry formed. The resulting slurry was cooled to 20 C. and agitated. 600 g of methyl t-butyl ether was added and the mixture stirred. The slurry was then filtered, washed with 3:1 wt/wt methyl t-butyl ether:ethyl acetate and dried. 165 g of R-4-Amino-N-[(1-ethyl -2-pyrrolidinyi)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide was obtained as a crystalline solid. |
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