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CAS No. : | 13831-31-7 | MDL No. : | MFCD00011535 |
Formula : | C4H5ClO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HZDNNJABYXNPPV-UHFFFAOYSA-N |
M.W : | 136.53 | Pubchem ID : | 26297 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 27.62 |
TPSA : | 43.37 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) : | -6.64 cm/s |
Log Po/w (iLOGP) : | 1.45 |
Log Po/w (XLOGP3) : | 0.69 |
Log Po/w (WLOGP) : | 0.31 |
Log Po/w (MLOGP) : | -0.09 |
Log Po/w (SILICOS-IT) : | 0.64 |
Consensus Log Po/w : | 0.6 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.92 |
Solubility : | 16.3 mg/ml ; 0.119 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.18 |
Solubility : | 9.06 mg/ml ; 0.0664 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.9 |
Solubility : | 17.4 mg/ml ; 0.127 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.73 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P261-P280-P305+P351+P338-P310 | UN#: | 3265 |
Hazard Statements: | H314-H335 | 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 |
---|---|---|
90.8% | With glycolic Acid; N-(tert-butoxy)-1H-pyrrole-2-carboxamide; toluene-4-sulfonic acid In 1,4-dioxane; acetonitrile at 80℃; for 10 h; | At room temperature,100 mmol of the compound of formula (I)100 mmol of the compound of formula (II)16 mmol of catalyst (mixture of 8 mmol of ruthenium tetracarbonyl diboride and 8 mmol of triphenylphosphine copper (Cu (PPh3) Br)140 mmol of acetoxyacetyl chloride,30 mmol of acidic compound p-toluenesulfonic acid and 6 mmol of additive L were added to an appropriate organic solvent (volume ratio 2: 1Of a mixture of acetonitrile and 1,4-dioxane)Then heated to 80 ° C,And the reaction was stirred at that temperature for 10 hours;After the reaction,The reaction system was filtered,And with the alkali to adjust the pH value of the filtrate is neutral,Then vacuum distillation,The residue was passed through a silica gel column,In an equal volume of a mixture of chloroform and ethyl acetate,And again under reduced pressure distillation,To give a compound of the above formula (III) having a melting point of 109 to 110 ° C (wherein Ac is acetoxy, the same applies hereinafter) in a yield of 90.8percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.6% | With di(rhodium)tetracarbonyl dichloride; triphenylphosphine copper; toluene-4-sulfonic acid In 1,4-dioxane; acetonitrile at 100℃; for 8 h; | At room temperature, 100 mmol of the compound of formula (I)150 mmol of the compound of formula (II)14 mmol of a catalyst (a mixture of 7 mmol of ruthenium tetracarbonyl diboride and 7 mmol of triphenylphosphine copper (Cu (PPh3) Br)160 mmol of acetoxyacetyl chloride and 25 mmol of acidic compound p-toluenesulfonic acid were added to an appropriate organic solvent (a mixture of acetonitrile and 1,4-dioxane in a volume ratio of 2: 1) and then heated to 100 ° C The reaction was stirred at this temperature for 8 hours;After completion of the reaction, the reaction system was filtered and the pH of the filtrate was adjusted to pH with a base, and then distilled under reduced pressure The silica gel column was eluted with an equal volume of a mixture of chloroform and ethyl acetate and distilled again under reduced pressure to give The compound of the above formula (III) having a melting point of 109 to 110 ° C has a yield of 80.6percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; | E. Preparation of Acetoxyacetyl Chloride (8) STR5 The <strong>[13831-30-6]acetoxyacetic acid</strong> (568.75 g, 4.82 mol) and thionyl chloride (759.19 g, 6.38 mol) were combined and heated with stirring at 65-70 for 1 hour. The solution was then heated 1 hour at 70-75 and lastly 1 hour at 77 (reflux). The thionyl chloride was removed under reduced pressure and the residue was vacuum distilled. The fraction boiling at 53-60 (12-15 mm) was collected giving 85.6% of 8. The ir spectrum was consistent with the assigned structure. | |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃;Inert atmosphere; | Example 5: Lambda/-(4-(4-(3-(3-terf-Butyl-1 -p-tolyl-1 H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy) pyrTo a suspension of <strong>[13831-30-6]acetoxyacetic acid</strong> (34.3 mg, 0.290 mmol) in dry DCM (1.5 ml.) under nitrogen and at 00C was added oxalyl chloride (28.6 mul, 0.339 mmol) followed by DMF (1 drop) and the mixture maintained at 00C for 20 min and then warmed to RT. After 1 hr the mixture was cooled to 00C, and a solution of Intermediate A1 (49 mg, 0.097 mmol) and DIPEA (84 mul, 0.484 mmol) were added. The reaction mixture was kept at 00C for 30 min and was then warmed to RT and after 2.75 hr was quenched by addition of a solution of 1 % NH3 in MeOH (3.0 ml_). After a further 64 hr the volatiles were evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 12 g, [5% MeOH in EtOAc] in isohexane, 0- 70%, gradient elution). The product so obtained was subjected to SCX capture and release and was then re-purified by flash column chromatography (SiC>2, 12 g, [5% MeOH in EtOAc] in isohexane, 0-70%, gradient elution) to afford the title compound, Example 5, as a white solid (1 1 mg, 20%); R1 2.25 min (Method 2); m/z 565 (M+H)+ (ES+); 1H NMR (400MHz, DMSO-d6) delta: 1.28 (9H, s), 2.40 (3H, s), 3.96 (2H, d), 5.64 (1 H, t), 6.41 (1 H, s), 6.72 (1 H, dd), 7.35 (1 H, d), 7.38 (2H, d), 7.47 (2H, m), 7.57 (1 H, m), 7.65 (2H, m), 7.83 (1 H, dd), 7.97 (1 H, d), 8.09 (1 H, d), 8.19 (1 H, d), 8.81 (1 H, br s), 9.14 (1 H, br s), 9.75 (1 H, br s). | |
With thionyl chloride; In dichloromethane; at 80℃; | 1.2 molar equivalent of thionyl chloride (12 g, 7.4 mL, 0.1 mol) was added dropwise to a solution of acetoxy acetic acid (10 g, 0.08 mol) in CH2Cl2 (100 mL), and then left to stir on reflux in oil bath at about 80oC. The evolution of SO2 gas was monitored by connecting the flask to a bubbler containing hexane. When the production of SO2 stopped, the excess thionyl chloride was distilled off. The resulting acyl chloride appears as colorless oil. |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h; | The resulting syrup was dissolved in 150 mL of dichloromethane, and the solution was transferred to a 500 mL three-necked flask, and then 150 yL, N-dimethylformamide (DMF) was added. To the resulting reaction mixture, 60.2 g of oxalyl chloride (1.2 eq) was gradually added dropwise at room temperature. After the dropwise addition was completed, the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure at 35 to 40 C to dryness to dryness. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In pyridine; water; | EXAMPLE 6 Preparation of 2-(acetoxyacetylamino)-5,6-dimethylbenzothiazole: <strong>[29927-08-0]2-Amino-5,6-dimethylbenzothiazole</strong> (4.5 g) is dissolved in pyridine (80 ml) and thereto is added dropwise acetoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting oil is solidified with addition of water. The obtained solids are filtered off and washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (5.4 g) having the following physical properties. Melting point: 214-215 C. IR (KBr) nu: 3470, 3160, 2930, 1760, 1740, 1570, 1555, 1460, 1290, 1240, 1180, 1095, 1045, 970, 860 cm-1. NMR (DMSO-d6) delta: 12.39 (1H, br.s), 7.67 (1H, s), 7.51 (1H, s), 4.78 (2H, s), 2.30 (6H, s), 2.13 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; | EXAMPLE 12 Preparation of 2-(acetoxyacetylamino)-6-methoxybenzamide: To a solution of <strong>[1591-38-4]2-amino-6-methoxybenzamide</strong> (1.7 g) in methylene chloride (20 ml) is added pyridine (1.6 ml), and thereto is added dropwise acetoxyacetyl chloride (1.1 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 2 hours, and thereafter, the solvent is distilled off under reduced pressure. The resulting crude crystals are washed with water and then are recrystallized from ethanol to give the title compound (2.1 g) having the following physical properties. Melting point: 163 -165 C. IR (KBr) υ: 3465, 3195, 1750, 1695, 1650, 1605, 1520, 1470, 1440, 1395, 1235, 1095, 1080, 925, 815, 785, 540 cm-1. NMR (DMSO-d6) δ: 11.45 (1 H, brs), 8.05-6.84 (3 H, m), 7.91 (2 H, brs), 4.60 (2 H, s), 3.82 (3 H, s), 2.20 (3 H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; | EXAMPLE 13 Preparation of 2-(acetoxyacetylamino)-6-methoxybenzonitrile: To a solution of <strong>[1591-37-3]2-amino-6-methoxybenzonitrile</strong> (3.7 g) in methylene chloride (50 ml) is added pyridine (2.4 ml), and thereto is added dropwise acetoxyacetyl chloride (2.7 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, the solvent is distilled off under reduced pressure. The resulting crude crystals are washed with water and ether and then are recrystallized from ethanol to give the title compound (5.4 g) having the following physical properties. Melting point: 131 -132 C. IR (KBr) upsilon: 3435, 3210, 3095, 3070, 2220, 1775, 1695, 1610, 1590, 1555, 1485, 1460, 1440, 1425, 1390, 1380, 1305, 1275, 1245, 1220, 1100, 970, 845, 795, 740, 725 cm-1. NMR (DMSO-d6) delta: 9.94 (1 H, brs), 7.54-6.96 (3 H, m), 4.65 (2 H, s), 3.85 (3 H, s), 2.10 (3 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine In ethyl acetate at 0 - 20℃; | 2-4 Example 2 Preparation of Compound B (acetoxy-acetic acid 2-(4-methanesulfonyl-phenyl)-1,1-dimethyl-2-oxo-ethyl ester): Compound A (40.0 g, 1.0 eq) and 400 mL of ethyl acetate were combined, and then triethylamine (33.4 g, 2.0 eq) was added, and the mixture was stirred and cooled to below 5 °C. Acetoxyacetyl chloride (40.6 g, 1.8 eq) was added dropwise, and then the temperature was controlled at 0 to 20 ° C for 1 to 2 h, and the reaction was completely monitored by HPLC. After adding 200 mL of water, the extract was separated, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated under reduced pressure to give Compound B: acetoxy-acetic acid 2-(4-methylsulfonyl-phenyl)-1 , 1-dimethyl-2-oxo-ethyl ester, (62 g, light brown solid, yield 100%, directly to the next reaction). |
99.5% | With dmap; triethylamine In dichloromethane at 0℃; | 13 Example 13 Preparation of 2-Methyl-1-[4-(methylsulfonyl)phenyl]-2-(2-acetoxyacetoxy)-1-propanone This Example provides intermediate D Preparation: Intermediate C 5.0 g,Triethylamine 4.2g,DMAP 0.5g was added to 50 mL of dichloromethane and stirred.Cool to 0°C4.2 g of acetoxyacetyl chloride are added dropwise.After the reaction is complete, add water and dry it. Evaporate the solvent under reduced pressure to obtain intermediate D, namely:2-methyl-1-[4-(methylsulfonyl)phenyl]-2-(2-acetoxyacetoxy)-1-propanone, (7.0 g, yield 99.5%,Yellow solid). |
With pyridine In acetonitrile |
207 g | With triethylamine In dichloromethane at 20℃; for 3h; | 1-3 After mixing the compound having the structure shown by Formula IV with methylene chloride (800 ml) and 150 g of triethylamine, 205 g of acetoxyacetyl chloride was added dropwise at room temperature, and after the dropwise addition was completed, the reaction was continued for 3 h. After the reaction was completed, 800 ml of water was added to the system, and the mixture was allowed to stand for 0.5 h after being stirred for 10 min. The phases were separated and the organic phase was retained. 500 ml of ethyl acetate was added to the system, and the temperature was increased to 80 ° C, and then the temperature was lowered overnight. After the temperature was lowered to 10 ° C, it was filtered to obtain a gray solid powder, which was dried under vacuum at a temperature of 55 ° C to obtain a compound having the structure represented by Formula V (207g); |
220 g | With triethylamine In dichloromethane at 20℃; for 4h; | 1-3 The compound having the structure represented by Formula V and dichloromethane (800 mL) are mixed until completely dissolved, triethylamine (100 g) is added, and acetoxyacetyl chloride (137 g) is added dropwise at room temperature over about 1 h.After the addition, the reaction was continued for 3h. After the reaction was completed, 800 mL of water was added to the system, and the mixture was allowed to stand for 0.5 h after being stirred for 10 minutes. The phases were separated, and the organic phase was retained. The organic phase was concentrated under reduced pressure until no liquid flowed out. A gray solid powder was obtained by filtration, and vacuum drying was performed under the conditions of a temperature of 55 ° C and a degree of vacuum of -0.1 MPa to obtain a compound (220 g) having a structure represented by Formula VI. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine In dichloromethane at 20℃; | 1 To a stirred solution of N-(4-METHOXYPHENYL)- (2-CHLOROPHENYL) imine 22 (17.00 g, 69.15 mmol) and triethylamine (26.8 g, 36 ml, 207.6 mmol) was added a solution of acetoxyacetyl chloride (9.76 g, 7.69 ml, 90.0 mmol) in methylene chloride (30 ml) dropwise over 10 minutes. The resultant mixture was stirred at room temperature until TLC indicated the disappearance of starting material. The solvent was removed under reduced pressure, and the crude material was purified by washing with ice-cold methanol to give 19.48 g (86%) of 23 as white solid, mp 130-132 °C. LH NMR (250 MHz) 6 7.43 (d, J= 7.8 Hz), 7.29-7. 24 (M, 5H), 6.83 (d, J= 8.3 Hz, 2H), 6.16 (d, J= 4.6 Hz, 1H), 5. 78 (d, J= 4.6 Hz, 1H), 3.76 (s, 3H), 1.76 (s, 3H). 13C NMR (63 MHz) 8 168.7, 161.4, 156.7, 133.8, 130.2, 130.0, 129.8, 128.7, 126. 8, 118.6, 114.5, 75.4, 58.2, 55.4, 19.9. |
44% | With triethylamine In dichloromethane at 20℃; for 1h; | |
With triethylamine In dichloromethane at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine In dichloromethane at 0 - 20℃; | 31.1 Step iAcetic acid-2-(4,4-difluoro-piperidin-1 -yl)-2-oxo-ethyl ester4,4-Difluoropiperidine hydrochloride (600mg, 3.8mmol) was stirred in DCM (10ml) with Et3N (11.4mmol, 1.151g, 1.59ml) and this mixture was cooled to O0C. Acetoxy acetyl chloride (5.7mmol, 778mg, 0.612ml) in DCM (5ml) was added drop-wise and the reaction mixture was stirred overnight at RT. The reaction mixture was washed sequentially with saturated NaHCO3 solution (x2) and brine(x2). The organic layer was dried (MgSO4), filtered, and the filtrate solvent was removed in vacuo. The residue was cooled and triturated with hexane to produce the title compound as a colourless oil, (773mg (92%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; | 16.a Benzylethanolamine (1.78 g, 11.8 mmol.) was weighed into a 25 mL round bottom flask and diluted with dichloromethane. N,N-Diisopropylethylamine (2.66 mL, 15.3 mmol) was added quickly via syringe and the reaction was cooled to 0° C. After stirring at 0° C. for 10 minutes, acetoxyacetyl chloride (1.26 mL, 11.8 mmol) was added dropwise via syringe. The reaction was stirred overnight and allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was separated and dried over anhydrous magnesium sulfate. The drying agent was removed via filtration and solvent was removed in vacuo to give crude title intermediate as a yellow oil. The crude material was chromatographed on silica gel using ethyl acetate as the mobile phase. Fractions were combined and solvent was removed in vacuo to give pure title intermediate as a clear oil (1.75 g, 59% yield). (m/z): [M+H]+ calcd for C13H17NO4 252.13, found 252.3. |
59% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 2h; | 77.1 Step 1: 2-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]amino}-2-oxoethyl acetate4-(4-Bromophenyl)-1,3-thiazol-2-ylamine (2.00 g, 7.84 mmol) was dissolved in methylene chloride, diisopropylethylamine (1.50 mL, 8.62 mmol) was added and the mixture was cooled to 0° C. Acetoxy acetyl chloride (0.920 mL, 8.62 mmol) was added dropwise, the mixture was stirred for 2 h and then diluted with ethyl acetate. The mixture was washed with NaHCO3, water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (20% acetone/hexane) followed by recrystallization from acetone/hexane afforded 1.16 g of 2-[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}-2-oxoethyl acetate (1.16 g, 42%) as a white solid. HRMS: calcd for C13H, BrN2O3S+H+, 354.97465; found (ESI, [M+H]+), 354.9738. Analytical HPLC: retention time 9.8 min, 210-370 nm the Xterra RP18 column, 3.5%, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In chloroform at 20℃; for 0.5h; Inert atmosphere; | 13 To a solution of 4-bromo-2-fluoroaniline (9.5 g, 50.0 mmol) in 150 ml dry CHCl3 was added drop wise acetoxyacetyl chloride (7.5 g, 55.0 mmol) under nitrogen. The mixture was stirred at room temperature for 0.5 h, then water was added and the solution was extracted several times with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4 and evaporated, affording 2-(4-bromo-2-fluorophenylamino)-2-oxoethyl acetate (15.2 g) as colorless solid in quantitative yield. |
100% | In chloroform at 20℃; Inert atmosphere; | 13 To a solution of 4-bromo-2-fluoroaniline (9.5 g, 50.0 mmol) in 150 ml dry CHCI3 was added drop wise acetoxyacetyl chloride (7.5 g, 55.0 mmol) under nitrogen. The mixture was stirred at room temperature for 0.5 h, then water was added and the solution was extracted several times with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4 and evaporated, affording 2-(4-bromo-2-fluorophenylamino)-2-oxoethyl acetate (15.2 g) as colorless solid in quantitative yield. |
75% | With potassium carbonate In chloroform |
In chloroform at 20℃; for 0.5h; Inert atmosphere; | 2-(4-Bromo-2-fluorophenylamino)-2-oxoethyl acetate (1c) Acetoxyacetyl chloride(7.5 g, 55.0 mmol) was added drop wise to a solution of 4-bromo-2-fluoroaniline (9.5 g,50.0 mmol) in 150 ml dry CHCl3 under a nitrogen atmosphere. The mixture was stirred atroom temperature for 0.5 h, water was added and the solution was extracted several timeswith CH2Cl2. The combined organic layers were washed with brine and dried overanhydrous MgSO4, affording crude product (15.2 g) as colorless solid in quantitativeyield. 1H-NMR (500 MHz, CDCl3): δ = 2.23 (s, 3H), 4.71 (s, 2H), 7.28-7.31 (m, 2H),8.03 (s, 1H), 8.22-8.26 (m, 1H). 13C-NMR (125 MHz, CDCl3): δ = 20.6, 63.2, 116.6 (d,3J = 9.7 Hz), 118.5 (d, 2J = 22.6 Hz), 122.7, 124.6 (d, 2J = 10.7 Hz), 127.9 (d, 3J = 4.3Hz), 152.1 (d, 1J = 249.3 Hz), 165.0, 169.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine In dichloromethane at 0 - 20℃; for 1h; | 1 Example 1. Preparation of 3-[3-fluoro-4-(hydroxyacetyl)piperazin-1-ylphenyl]-5-(isoxazol-3-ylaminomethyl)isoxazole To a solution of 2.0 g (5.8 mmol) of 3-(3-fluoro-4-piperazin-1 -ylphenyl)-5-(isoxazol-3-ylaminomethyl)isoxazole (Intermediate 10) in 40 mL of dichloromethane were added 1.37 mL (1.0 g, 9.9 mmol) of triethylamine at 0C. Then, 1.1 mL (1.3 g, 9.9 mmol) of acetoxyacetyl chloride were added dropwise. The mixture was stirred for 1 h while allowing to cool down at room temperature. The crude product was diluted with 600 mL of dichloromethane, and washed with a 5% sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, and filtered, and the solvent was distilled off by reduced pressure. The resulting solid was broken up with hexane. 2.22 g (yield = 88%) of 3-[3-fluoro-4-(acetoxyacetyl)piperazin-1-ylphenyl]-5-(isoxazol-3-ylaminomethyl)isoxazol were obtained. IR (KBr): 3300, 1747, 1650 cm-1. 1H-NMR (200 MHz, CDCl3/d6-DMSO, ? ppm): 8.39 (d, 1H), 7.65 (m, 1H), 7.59 (s, 1H), 7.15 (m, 1H), 6.90 (m, 2H), 6.04 (d, 1H), 4.81 (s, 2H), 4.45 (d, 2H), 3.56 (m, 4H), 3.08 (m, 4H), 2.08 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine In dichloromethane at 0 - 20℃; for 2h; | 89 Example 89; [ 5-CHLORO-2-2-T (CIS)-3- (4-FL UORO-PHENOXY)-8-AZA-BICVCLOF3. 2. 11OCT-8-VLL-2-OXO- ETHOXVE-NICOTINAMIDE]; Acetic acid 2-[(cis)-3-(4-fluoro-phenoxy)-8-aza-bicyclo[3.2.1]oct-8-yl]-2-oxo-ethyl ester To a solution of [(CIS)-3- (4-FLUORO-PHENOXY)-8-AZA-BICYCLO] [3.2. 1] octane (920 mg, 3.3 [MMOL)] in [DICHLOROMETHANE] (15 ml) at [0°C] was added triethylamine (0.69 ml, 4.95 [MMOL)] and acetic acid [CHLOROCARBONYLMETHYL] ester (0.425 ml, 3.95 [MMOL).] The reaction was allowed to warm to ambient temperature and stirred for two hours. The reaction was then diluted with [DICHLOROMETHANE] and washed with a 0.2 M aqueous hydrochloric acid solution. The organic layer was separated, dried'over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (1. 08 g, 100 % yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 19 Acetic acid 2-(4-[5-fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-2-oxo-ethyl ester 5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (100 mg, 0.251 mmol) and N,N-dimethylaminopyridine (5 mg) were dissolved in dichloromethane (3 ml) under nitrogen at room temperature and triethylamine (120 l, 0.753 mmol) was added followed by acetic acid chlorocarbonyl methyl ester (56 mg, 0.42 mmol). The reaction was allowed to stir at room temperature for 2 h and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80 mg, 0.377 mmol) followed by triethylamine (120 ml, 0.753 mmol). The reaction was stirred at room temperature for 18 h, quenched with sat. ammonium chloride solution (0.5 ml), diluted with water (3 ml) and the organic layer was removed via a separation tube. The solvent was removed under reduced pressure and the residue was by flash column chromatography on a biotage system eluding with a solvent gradient of dichloromethane methanol:concentrated aqueous ammonia (99.5:0.5:0.05 changing to 95:5:0.5, by volume) to give Acetic acid 2-(4-([5-fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-2-oxo-ethyl ester (81 mg) as an off-white solid. 1H NMR (400 MHz, CD3OD): delta=8.08-8.10 (1H, d), 7.97-8.00 (1H, dd), 7.28-7.32 (1H, t), 7.06-7.13 (1H, d), 7.03 (1H, s), 6.85-6.90 (1H, d), 4.75-4.84 (2H, quart, partially masked by solvent), 4.26-4.34 (1H, d), 4.12-4.18 (1H, m), 3.72-3.81 (1H, d), 3.18-3.29 (1H, m, partially masked by solvent), 2.90-3.00 (1H, d), 2.45 (3H, s), 2.10 (3H, s), 1.95-2.09 (2H, m), 1.46-1.63 (2H, m) ppm. LRMS (electrospray): m/z [M+Na]+ 484, [2M+Na]+ 945, [M-H]+ 460. Anal. Found C, 56.76; H, 65.26; N, 8.64. C22H24FN3O5S. 0.2 mol H2O requires C, 56.81; H, 5.29; N, 9.03%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine In dichloromethane at 20℃; | |
93% | With triethylamine In dichloromethane at 20℃; | 253.C C. Acetic acid {1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylcarbamoyl}- methyl ester. To a solution of {1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4- ylamine dihydrochloride (413 mg, 1.0 MMOL) in CH2CI2 (20 mL) at room temperature was added TEA (0.70 mL, 5.0 MMOL), followed by ACETOXYACETYL chloride (0. 16 mL, 1. 5 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was dissolved in CH2CT2 (100 mL), washed with SAT. AQ. NAHCO3 (1 x 25 mL), dried (NA2SO4) and concentrated under reduced pressure to yield the crude product as an off-white solid. The crude product was purified on SiO2 (40 G ; 0-10% CH3OH/CH2CI2) to GIVE A WHITE SOLID (410 MG, 93% YIELD). MS (ESI) : MASS CALCULATED FOR C23H25N304S, 439.2 ; M/Z FOUND, 440.4 [M+H] +. 1H NMR (400 MHZ, CDCL3) : 7.72 (d, J = 7. 8, 1 H), 7.65 (d, J = 8.1, 1 H), 7.40-7. 35 (m, 3H), 7.32-7. 23 (m, 3H), 6. 11 (d, J= 8.3, 1H), 4.53, (s, 2H), 3.93-3. 82 (m, 1H), 3.50 (s, 2H), 2.83 (d, J=11. 9,2H), 2.15 (s, 3H), 2.14 (t, J=11. 9,2H), 1.93 (d, J=12. 1,2H), 1.56-1. 45 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With dmap In dichloromethane at 20℃; for 3h; | 25.B STEP B. 2-[(4-[[2-TERT-BUTYL-1-(TETRAHYDRO-2H-PYRAN-4-YLMETHYL)-LH- BENZIMIDAZOL-5-YL] (methyl) amino] sulfonyl} phenyl) amino]-2-oxoethyl acetate; 4-AMINO-N-[2-TERT-BUTYL-1-(TETRAHYDRO-2H-PYRAN-4-YLMETHYL)-LH-BENZIMIDAZOL-5-YL]- N-methylbenzenesulfonamide (45 mg, 0.0986 mmol) and acetoxyacetyl chloride (0.013 mL, 0.118 mmol) were stirred in 2 mL of DCM containing a catalytic amount of DMAP at rt for 3h. The solution was washed with saturated aqueous NAHC03 solution, brine and dried over anhydrous MGS04. THE crude product was purified by silica gel flash chromatography using EtOAc as eluent. Yield: 45 mg (82%) ; 1H NMR (400 MHz, CHLOROFORM-D): 8 1.50-1. 55 (M, 13 H), 2.23 (s, 3 H), 2.25- 2.33 (m, 1 H), 3.18 (s, 3 H), 3.29-3. 37 (M, 2 H), 3.97 (t, J=2. 83 HZ, 1 H), 4.00 (t, J=2.64 Hz, 1 H), 4.18 (d, J=7.23 Hz, 2 H) 4.67-4. 71 (m, 2 H), 7.18-7. 24 (M, 2 H), 7.24-7. 29 (M, 1 H), 7.51 (d, J=8.79 Hz, 2 H), 7.62 (d, J=8.79 Hz, 2 H), 8.31 (s, 1 H). |
82% | In dichloromethane at 20℃; for 3h; | 83.B Step B. 2-[(4-[[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yll (methyl) amino] SULFONYL} PHENYL) AMINO]-2-OXOETHYL acetate; 4-AMINO-N-[2-TERT-BUTYL-1-(TETRAHYDRO-2H-PYRAN-4-YLMETHYL)-1 H-BENZIMIDAZOL-5-YL]- N-methylbenzenesulfonamide (45 mg, 0. 0986 mmol) and ACETOXYACETYL chloride (0.013 mL, 0. 118 MMOL) were stirred in 2 mL of DCM containing a catalytic amount of DMAP at rt for 3h. The solution was washed with saturated aqueous NAHC03 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using EtOAc as eluent. Yield: 45 mg (82%) ;'H NMR (400 MHz, CHLOROFORM-D): 8 1.50-1. 55 (m, 13 H), 2.23 (s, 3 H), 2.25- 2.33 (m, 1 H), 3. 18 (s, 3 H), 3. 29-3. 37 (m, 2 H), 3. 97 (t, J=2. 83 HZ, 1 H), 4.00 (t, J=2. 64 HZ, I H), 4. 18 (d, J=7. 23 Hz, 2 H) 4.67-4. 71 (m, 2 H), 7.18-7. 24 (m, 2 H), 7. 24-7. 29 (m, 1 H), 7.51 (d, J=8. 79 Hz, 2 H), 7.62 (d, J=8.79 Hz, 2 H), 8. 31 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine In dichloromethane at 18 - 25℃; for 1.25h; | 21 Example 21 2- 4- [4- (2-Acetoxyacetvl) piperazin-1-yl] anilino-4- (1-isopropyl-2-methyl-lH-imidazol-5- yl . pyrimidine; 2- [4- (Piperazin-1-yl) anilino]-4- (l-isopropyl-2-methyl-1H-imidazol-5-yl) pyrimidine (Example 20; 330mg 0. 88 mmol) was stirred in DCM (6ml) at room temperature. Triethylamine was added (153mg 1.51 mmol) followed by dropwise addition of acetoxyacetylchloride (143 mg 1.05 mmol). After stirring for 1.25 hours, DCM (10 ml) and brine (5 ml) were added. The reaction was stirred vigorously for 10 minutes then the organic layers were separated, dried and evaporated under reduced pressure to give the title compound as a yellow foam. Quantitative yield. The solid was triturated with ether and re- evaporated. NMR: 1.40 (d, 6H), 2.08 (s, 3H), 2. 48 (s, 3H), 3.05 (b d, 4H), 3.54 (b d, 4H), 4.81 (s, 2H), 5.70 (septuplet, 1H), 6.92 (d, 2H), 6.95 (d, 1H), 7.40 (s, 1H), 7. 48 (d, 2H), 8.31 (d, 1H), 9.18 (s, 1H) ; m/z 478. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: 6-methyl-N-[3-(4-piperidinyloxy)phenyl]-4'-(trifluoromethoxy)-[1,1'-biphenyl]-2-carboxamide In tetrahydrofuran at 20℃; for 3h; Stage #2: Acetoxyacetyl chloride In tetrahydrofuran at 20℃; Stage #3: In tetrahydrofuran at 20℃; for 3h; | T2 N- [3-(Piperidin-4-yloxy)phenyl]-6-methyl-4'-trifluoromethoxybiphenyl-2-car- boxamide (70.6 mg; 0.15 mmol) and N-methylmorpholine polystyrene resin (3.6 eq. ; 0.54 mmol) are dissolved in 3.5 ml of THF. The resin is left to swell for 3 hours at room temperature. Acetoxyacetyl chloride (1.2 eq.; 0.18 mmol; 24.6 mg) is then added. The reaction medium is stirred at room temperature overnight, 3.0 eq. of Trisamine polystyrene resin (0.45 mmol) are then added and the reac- tion medium is stirred for a further 3 hours at room temperature. After filtration, the filtrate is evaporated and the crude product is purified by flash chromatography on silica (elution: gradient of heptane to 100% ethyl acetate) to give 82.1 mg of the expected product. Yld = 96 % Mass: ES+ = 513.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium hydrogencarbonate In water; acetone at 0℃; for 0.25h; | 4.6 To a ice-cooled, stirred solution of 5(R)-[N-Isoxazol-3-yl-N-(2,2,2-trichloroethyloxycarbonyl)aminomethyl]-3-[3-fluoro-4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl]oxazolidin-2-one (102 mg, 0.18 mmol) and sodium bicarbonate (75 mg, 0.89 mmol) in acetone (10 ml)/water (5 ml), was added dropwise acetoxyacetyl chloride (49 mg, 0.36 mmol, 38.51l). After 15 minutes, complete reaction had occurred by TLC (10% MeOH/CH2Cl2, WV visualisation, Rf=0.75). Water was then added and the aqueous phase extracted with ethyl acetate, and the resulting organic phase washed with water, 2M hydrochloric acid and saturated brine, dried over sodium sulfate and concentrated by rotary evaporation to give the title compound as a crude yellow gum (105 mg, 93%). [0408] NMR: 2.10 (broad s, 3H), 2.42 (m, 2H), 3.62 (dt, 2H), 3.94 (m, 1H), 4.19 (m, 4H), 4.40 (dd, 1H), 4.84 (d, 2H), 5.05 (m, 3H), 6.01 (broad s, 1H), 6.91 (s, 1H), 7.31 (d, 1H), 7.43 (m, 2H), 8.91 (s, 1H); m/z: ES+ (M+H)=633. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydrogencarbonate In water; acetone at 0 - 20℃; for 2h; | 33.11 Reference Example 11 To a suspension of Reference Example 10, (3.00 g, 5.85 mmol) and sodium hydrogen carbonate (2.46 g, 29.3 mmol) in acetone (100 ml)/water (50 ml), stirred at 0° C., under N2, was added dropwise a solution of acetoxyacetyl chloride(879 mg, 6.44 mmol, 692 μl) in acetone (5 ml). The reaction was stirred at 0° C. for 30 min and at ambient temperature for a further 90 min, then water was added and the mixture extracted with EtOAc (2*) and the organic extracts washed with water and saturated brine, dried (sodium sulfate) and concentrated by rotary evaporation to give the title compound as a crisp white foam (3.29 g, 98%). NMR (300Mz, DMSO-d6), δ/ppm: 1.48 (s, 9H), 2.08 (s, 3H), 2.30 (m, 1H), 2.42 (m, 1H), 3.60 (dt, 2H), 3.86 (dd, 1H), 3.97 (dd, 1H), 4.10 (m, 2H), 4.22 (m, 2H), 4.82 (s, 1H), 4.87 (s, 1H), 5.03 (m, 1H), 5.89 (m, 1H), 6.89 (d, 1H), 7.33 (m, 2H), 8.81 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.56 g (75%) | In tetrahydrofuran; diethyl ether; | {N-[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]carbamoyl}methyl acetate I-31 To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added (chlorocarbonyl)methyl acetate (0.55 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.56 g (75%) of product as an off-white solid: mp 234-236 C.; 1H NMR (DMSO-d6) delta11.15 (s, 1H), 10.06 (s, 1H), 8.55 (d, J=8.3 Hz, 1H), 7.87 (t, J=8.0 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 5.17 (dd, J=5.0 and 12.4 Hz, 1H), 4.78 (s, 2H), 2.99-2.85 (m, 1H), 2.65-2.52 (m, 2H), 2.22 (s, 2H), 2.11-2.07 (m, 1H); 13C NMR (DMSO-d6) delta172.70, 169.69, 169.50, 167.99, 166.57, 136.40, 135.59, 131.35, 125.34, 118.72, 116.96, 62.60, 48.98, 30.90, 21.91, 20.41; Anal. Calcd. For C17H15N3O7: C, 54.69; H, 4.05; N, 11.26. Found: C, 54.43; H, 4.05; N, 10.97. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In chloroform; water; | EXAMPLE 18 Preparation of 2-(acetoxyacetylamino)-6-chlorobenzonitrile: To a solution of <strong>[6575-11-7]2-amino-6-chlorobenzonitrile</strong> (4.6 g) in chloroform (100 ml) is added triethylamine (4.8 ml), and thereto is added dropwise acetoxyacetyl chloride (3.8 ml). The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with chloroform. The organic layer is washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethanol-water to give the title compound (3.8 g) having the following physical properties. Melting point: 109 -110 C. IR (KBr) upsilon: 3290, 3110, 2250, 1850, 1700, 1600, 1585, 1540, 1460, 1440, 1430, 1380, 1310, 1285, 1255, 1180, 1155, 1075, 975, 905, 800, 730 cm-1. NMR (DMSO-d6) delta: 10.37 (1 H, brs), 7.80-7.49 (3 H, m), 4.72 (2 H, s), 2.13 (3 H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In pyridine; | EXAMPLE 4 Preparation of 2-(acetoxyacetylamino)-4-methoxybenzothiazole: 2-Amino-4-methoxybenzothiazole (4.5 g) is dissolved in pyridine (80 ml) and thereto is added dropwise acetoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting solids are washed with water and then with diethyl ether, dried and recrystallized from ethanol to give the title compound (4.3 g) having the following physical properties. Melting point: 161-162 C. IR (KBr) nu: 3460, 2940, 1745, 1715, 1600, 1555, 1480, 1425, 1315, 1275, 1205, 1080, 1045, 975, 775, 745 cm-1. NMR (DMSO-d6) delta: 12.63 (1H, br.s), 7.61-6.83 (3H), 4.80 (2H, s), 3.90 (3H, s), 2.15 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In ethanol; acetic acid; acetone; | EXAMPLE 5 3-(Acetoxyacetylamino)-5-(4-pyridinyl)-2(1H)-pyridinone To a stirred mixture containing 9.35 g. of <strong>[60719-84-8]3-amino-5-(4-pyridinyl)-2(1H)-pyridinone</strong> and 100 ml. of dried pyridine under an atmosphere of nitrogen (bubbled slowly through the reaction mixture) was added dropwise with stirring over a period of about 8 minutes 8.22 g. of acetoxyacetyl chloride whereupon the reaction temperature rose from 22° to 44° C. The reaction mixture was stirred for 2 and 1/2 hours and was allowed to stand at room temperature overnight under nitrogen. To the reaction mixture was added acetone (200 ml.) and the mixture stirred well. The separated solid was collected, washed with acetone, air-dried, and then dried in vacuo at 80° C. to yield 16.3 g. of the crude product as its hydrochloride salt. A 6.5 g. portion of product was dissolved in hot acetic acid to which was added a small amount of hydrogen chloride in ethanol (aided dissolution). The hot solution was treated with decolorizing charcoal, filtered to give a bright yellow filtrate from which crystals separated. The mixture was allowed to cool to room temperature and stand overnight. The crystalline precipitate was collected, washed with acetone and dried in vacuo at 90° C. for about 40 hours to yield 5.2 g. of 3-(acetoxyacetylamino)-5-(4-pyridinyl)-2(1H)-pyridinone as its monohydrochloride hemiacetate, m.p. 267°-290° C. with decomposition. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine In dichloromethane at 0℃; for 2h; | 144 Acetyloxyacetyl chloride (304 mg) was added dropwise to a stirred solution of compound 142-I (200 mg) and Et3N (0.3 mL) in CH2Cl2 (10 mL) at 0° C. for 2 hours to afford a residue. The resultant residue was purified by chromatography on silica gel (EtOAc/Hexane=1/1) to afford intermediate 144-II (200 mg) in a 90% yield. An aqueous solution of 20% LiOH (4 mL) was added to 144-II (200 mg) in THF (5 mL). After stirring for 12 hour, the mixture was acidified with 2M HCl to obtain a crude product. The crude product was purified by chromatography on silica gel (EtOAc/MeOH=20/1) afforded intermediate 144-III (98 mg) in a 51% yield. Compound 144-III (98 mg) was treated with 20% TFA/CH2Cl2 (2 mL) at room temperature for 12 hours and then concentrated. The resultant residue was purified by chromatography on silica gel (21% NH3 (aq)/MeOH=1/19) to afford compound 144 (65 mg) in a 90% yield. Compound 144 was then treated with 1 M HCl (2 mL) in CH2Cl2 (2 mL) for 0.5 hour. The solvents were evaporated and the residue was treated with ether and filtered to afford the hydrochloride salt of compound 144. CI-MS (M++1): 583.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 1-(2-{(2R)-2-(3,4-dichlorophenyl)-4-[3,5-bis(trifluoromethyl)benzoyl]morpholin-2-yl}ethyl)spiro[(2S)-2-hydroxy]indane-1,4'-piperidine; Acetoxyacetyl chloride In toluene at 20℃; for 20h; Stage #2: With hydrogenchloride In 1,4-dioxane; ethanol | 1 [Example] [Example 1] 1-(2-{(2R)-2-(3,4-Dichlorophenyl)-4-[3,5-bis(trifluoromethyl)benzoyl]morpholin-2-yl}ethyl)spiro{(2S)-2-[(acetoxy)-1,4'-piperidine hydrochloride (Exemplary compound No. 2-97 hydrochloride) 0.07 mL of acetoxyacetyl chloride was added to a solution of 150 mg (0.214 mmol) of 1-(2-{(2R)-2-(3,4-dichlorophenyl)-4-[3,5-bis(trifluoromethyl)benzoyl]morpholin-2-yl}ethyl)spiro[(2S)-2-hydroxy]indane-1,4'-piperidine and 320 mg (1.07 mmol, 3.3 mmol/g) of PS-diisopropylethylamine in toluene (3.0 mL). After the mixture was stirred at room temperature for 20 hours; the resin was removed by filtration. After the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography (eluting solvent: methylene chloride/methanol=10/1), it was dissolved in ethanol (5.0 mL) and 4N hydrochloric acid-dioxane solution (0.5 mL) was added thereto. The solvent was distilled off again under reduced pressure, followed by azeotropy with diethyl ether twice. The thus obtained residue was recrystalized from hexane to obtain 171 mg (yield: 95%) of the title compound as a white crystal. 1H-NMR spectrum (400 MHz, DMSO-d6) δ ppm: 8.45-8.01 (3H, m), 7.85-7.12 (7H, m), 5.43 (1H, bs), 4.56 (2H, bs), 4.21-1.62 (24H, m). IR spectrum ν max cm-1 (KBr): 2961, 1748, 1646, 1474, 1439, 1376, 1282, 1186, 1137, 905, 681. Mass spectrum (FAB) m/z: 801 ((M+H)+, free form) Elementary analysis (for C38H37Cl3F6N2O6) Calculated (%): C:54.46, H:4.45, N:3.34, F:13.60, C1:12.69 Found (%): C:52.13, H:4.54, N:3.43, F:12.23, C1:11.83Optical rotation: [α]D20 = +39.5 (c=1.00, methanol) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine In dichloromethane at 0 - 20℃; for 1.5h; | 1 13-Cyclohexyl-N-[(morpholin-4-yl)sulfonyl]-6-[[]-(2-acetoxyacetyl)piperazin-4-yl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxamide; Step 1; 2-Chloro-2-oxoethyl acetate (1.5 mL, 14 mmol) was added to a solution of tert-butyl piperazine-1-carboxylate (2.0 g, 10.7 mmol), triethyl amine (2.2 mL, 16 mmoL) in dichloromethane (30 mL) at 0° C. The reaction mixture was stirred for 1.5 hr at r.t. removed the solvents in vacuo. The residue was taken up with dichloromethane/hexane and washed with cold 1 NHCl (2×), 1 N NaOH (2×), brine, dried (MgSO4), removed the solvents in vacuo to afford the product as a white solid (2.8 g, 91%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.46 (s, 9 H) 3.14-3.63 (m, J=50.11 Hz, 8 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine In dichloromethane at 20℃; for 2h; | 49 E^iαple 4% reL-N-[(2:E^10]M4bR)-8-cy^^&bwzo[a^ψγdQll,2^a^phi-2-γl]^2^hyxc^^ (IO : R8 - CN, Ra =*; A stiixβd solution of & (Ra = CN; 25 tng. 0.0825 mmol) andtaetbylamiαe (14 tnL^ 0,099 rαmol) ϖiDCM (2 mL) was cooled to 0 0C. Acetαxyacetycbloride (11 mL3 0.09? K)HOD -was added and the leactjon was stuied at room teraperaturo for 2 hotirs. The reaction was quenched with a saturated NaHCO3 solution Ja H3O and the prodwt was φrtr-icted into DCM'. The organics were dded and concentrated under reduced pressure, ΗIΘ crαds produot was purified lay colviwwi chxom&togfaphy on silica to give 10 (Ra ~ CN, R2 = COCMjOC(O)CH3; 30 mg, 90 %), Data : (naΛO = 404 (M+Wf. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; | A solution of acetoxyacetyl chloride (13.8 g, 101 mmol) in dichloromethane (20 niL) was added dropwise to a stirred solution of 3-amino-4-chloroquinoline (15 g, 84 mmol) and triethylamine (27 mL, 190 mmol) in dichloromethane (150 mL), and the reaction was stirred overnight at room temperature. An analysis by LC/MS indicated the presence of starting material, and additional acetoxyacetyl chloride (11.2 g, 82.0 mmol) in dichloromethane (35 mL) was added dropwise. The reaction was stirred overnight at room temperature and then stirred for five minutes with saturated aqueous sodium bicarbonate (75 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (2 x 25 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 22.3 g of a mixture of 1 :3 2-[(4- chloroquinolin-3-yl)amino]-2-oxoethyl acetate and N-(4-chloroquinolin-3-yl)-2- hydroxyacetamide as a brown, gummy solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: N,N',N''-tris-[5-amino-3-chlorocarboxy-2,4,6-triiodophenyl]-cyanuric acid; Acetoxyacetyl chloride In N,N-dimethyl acetamide at 20℃; Stage #2: With sodium hydrogencarbonate In N,N-dimethyl acetamide; water | 4.a a. N,N',N"-Tris-r5-acetoxyacetamido-3-chlorocarboxy-2,4,6-triiodophenvn-cvanuric acid.; N,N',N"-Tris-[5-amino-3-chlorocarboxy-2,4,6-triiodophenyl]-cyanuric acid prepared in step 3g (0.36 g, 0.21 mmol) was dissolved in dry N,N-dimethylacetamide (2.0 ml), and with efficient stirring at ambient temperature acetoxyacetyl chloride (0.17 ml,1.52 mmol) was added dropwise. The mixture was stirred over night and the poured into a dilute solution of aqueous sodium hydrogencarbonate (5 %, 8.0 ml). The light brown precipitate formed was filtered off, washed with water (2x5 ml), sucked dry on filter and dried at 400C in vacuo (12 torr). Yield: 0.40 g (95 %).1H NMR (DMSOd6): 10.31 (br. s, 3H), 4.52 (s, 6H), 2.08 (s, 9H).13C NMR (DMSOd6): 170.1 , 169.9, 165.7, 157.6, 156.4, 149.7, 145.4, 141.5, 80.2,61.0, 60.7, 20.8, 20.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In N,N-dimethyl acetamide at 20℃; for 18h; | E Synthesis of acetic acid β-fallyl-methyl-carbamoylVS-chlorocarbonyl^Ae-triiodo- phenylcarbamoyll-methyl ester (3)(3)Compound (2) (15g, 23.8mmol) was dissolved in λ/,λ/-dimethylacetamide (75ml) and acetoxyacetylchloride (6.5g, 47.6mmol) added. The mixture was stirred for 18h at ambient temperature with nitrogen bubbling through the solution. . Ethyl acetate (350ml) was added and the solution washed with cold water, dried and evaporated. The product was purified by chromatography on silica gel eluting with ethyl acetate - petrol (10-100%) and isolated as a solid foam in 95% yield (16.5g). The structure was confirmed by 1H and 13C NMR and purity by LCMS. |
91% | In N,N-dimethyl acetamide at 20℃; | 5.c c) Synthesis of acetic acid rS-fallyl-methyl-carbamovD-δ-chlorocarbonyl-ςAδ- triiodo-phenylcarbamovU-methyl ester (11); 3-(Allyl-methyl-carbamoyl)-5-amino-2,4,6-triiodo-benzoyl chloride (8) (5g, 7.93mmol) was dissolved in dry DMA (20 mL) was acetoxyacetyl chloride (1.7 ml_, 15.9mmol) was added dropwise. The reaction mixture was stirred at overnight at RT, with nitrogen bubbling through the reaction mixture. The reaction was monitored by TLC on silica gel plates eluting with ethyl acetate: petrol (1 :1). (6) had an Rf of 0.62 and 0.76 whilst there were two new spots at 0.32 and 0.22. The solution was diluted with ethyl acetate (~100 mL) and washed with ice water/brine (50:50, 20ml x 5). The organics were dried over MgSO4, filtered, concentrated and dried under high vacuum to give the desired compound (5.26g, 91%). The structure was confirmed by 1H and 13C NMR, and purity by LCMS. |
91% | In ISOPROPYLAMIDE at 20℃; | I 3-(Allyl-methyl-carbamoyl)-5-amino-2,4,6-triiodo-benzoyl chloride (6) (5 g, 7.93 mmol) was dissolved in dry DMA (20 mL) was acetoxyacetyl chloride (1.7 mL, 15.9 mmol) was added dropwise. The reaction mixture was stirred at overnight at RT, with nitrogen bubbling through the reaction mixture. The reaction was monitored by TLC on silica gel plates eluting with ethyl acetate:petrol (1:1). (6) had an Rf of 0.62 and 0.76 whilst there were two new spots at 0.32 and 0.22. The solution was diluted with ethyl acetate (100 mL) and washed with ice water/brine (50:50, 20 ml×5). The organics were dried over MgSO4, filtered, concentrated and dried under high vacuum to give the desired compound (5.26 g, 91%). The structure was confirmed by 1H and 13C NMR, and purity by LCMS. |
91% | In dimethylacetamide (DMA) at 20℃; | E 3-(Allyl-methyl-carbamoyl)-5-amino-2,4,6-triiodo-benzoyl chloride (8) (5g, 7.93mmol) was dissolved in dry DMA (20 ml.) was acetoxyacetyl chloride (1.7 ml_, 15.9mmol) was added dropwise. The reaction mixture was stirred at overnight at RT, with nitrogen bubbling through the reaction mixture. The reaction was monitored by TLC on silica gel plates eluting with ethyl acetate: petrol (1 :1). (6) had an Rf of 0.62 and 0.76 whilst there were two new spots at 0.32 and 0.22. The solution was diluted with ethyl acetate (~100 ml_) and washed with ice water/brine (50:50, 20ml x 5). The organics were dried over MgSO4, filtered, concentrated and dried under high vacuum to give the desired compound (5.26g, 91%). The structure was confirmed by 1H and 13C NMR, and purity by LCMS. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In tetrahydrofuran; at 0 - 20℃; | a) Acetic acid [(2-bromo-benzyl)-methyl-carbamoyl]-methyl ester; <n="132"/>To a solution of 2-bromo-N-methyl benzylamine (CASNo. 698-19-1 , 0.57 ml_, 3.89 mmol) in THF (10 ml_)at 0 0C is added triethylamine (0.98 ml_, 1.03 mmol) followed by acetoxyacetylchloride (0.63 ml_, 5.86 mmol). The reaction is permitted to warm to room temperature and after two hours the reaction is quenched with saturated aqueous NaHCO3 and diluted with ethyl acetate. The layers are separated and the organic layer is dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-hexanes, 1 :4 to 3:2) to provide acetic acid [(2-bromo-benzyl)- methyl-carbamoyl]-methyl ester; MS: (ESI) m/z 300.1 , 302.1 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: (2S,4S)-methyl 4-fluoropyrrolidine-2-carboxylate hydrochloride With triethylamine In acetonitrile at 0℃; for 0.5h; Stage #2: Acetoxyacetyl chloride In acetonitrile at 0℃; for 1h; | 1.C Process C: Methyl (2S,4S)-4-fluoropyrrolidine-2-carboxylate hydrochloride (1.84 g) was suspended in dehydrated acetonitrile (30 mL). While the suspension was cooled in an ice bath, triethylamine (3.10mL) was added dropwise and the mixture was stirred for 30 minutes. To the reaction mixture, acetoxyacetyl chloride (1.13 mL) was added dropwise at the same temperature and the mixture was further stirred for 1 hour. The insoluble material in the reaction mixture was collected by filtration and washed with acetonitrile. The filtrate and the wash were combined and concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (150 mL) and the solution was washed successively with water (20 mL) and saturated brine (2 x 20 mL). The washes were combined and sodium chloride was added to saturation. The resulting mixture was extracted with ethyl acetate (100 mL x 2). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (30 mL) saturated with ammonia and the solution was stirred at room temperature for 2.5 hours. The resulting crystal was collected by filtration, washed with methanol, and dried under reduced pressure to give (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide as a white crystal (1.42 g, 76% yield). MS (CI+) m/z: 191 (MH+). Elemental analysis (%): calcd for C7H11FN2O3: C, 44.21; H, 5. 83; N, 14.73. found: C,43.95; H,5.73; N, 14.60 |
Yield | Reaction Conditions | Operation in experiment |
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(Reference Example 2) Synthesis of (2S)-4,4-difluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide Methyl (2S,4S)-4-fluoropyrrolidine-2-carboxylate hydrochloride (1.61 g) was suspended in dehydrated acetonitrile (25 mL). While the suspension was cooled in an ice bath, triethylamine (2.50 mL) was added dropwise and the mixture was stirred for 15 minutes. To the reaction mixture, acetoxyacetyl chloride (0.91 mL) was added dropwise at the same temperature and the mixture was further stirred for 1 hour. The insoluble material in the reaction mixture was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and the solution was washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant = ethyl acetate). The eluted pale brown tar-like material was dissolved in methanol (24 mL) saturated with ammonia and the solution was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure and the residue was purified on a silica gel column (eluant = ethyl acetate: methanol = 5:1) to give (4S)-4,4-difluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide as a white resin-like material (1.66 g, 100% yield). MS (CI+) m/z: 209 (MH+). HRMS (ESI+) for C7H11F2N2O3: calcd, 209.0738; found, 209.0736. |
Yield | Reaction Conditions | Operation in experiment |
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81% | With pyridine; In dichloromethane; at 0 - 25℃; for 12.25h; | To a solution of 5-Amino-indan-1-one (commercially available, 100 mg, 0.679 mmol, 1 eq.) in DCM (5 mL) is added pyridine (0.066 mL, 0.815 mmol, 1.2 eq.). The resulting solution is cooled to 0 C. followed by the addition of acetoxy acetyl chloride (0.073 mL, 0.679 mmol, 1 eq.). After stirring at 0 C. for 15 min., the reaction is warmed to 25 C. and stirred for 12 h. The reaction is diluted with DCM and sequentially washed with 1 N HCl (aq) and saturated aqueous NaHCO3. The resulting organic solution is dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (1:6 hexanes/EtOAc) to give Acetic acid (1-oxo-indan-5-ylcarbamoyl)-methyl ester as an off-white solid (136 mg, 81% yield). [MS: (ES+) 248.1 (M+1)+]. |
Yield | Reaction Conditions | Operation in experiment |
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96% | Step A: 5-(2-Acetoxy-acetyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester. A solution of (S,S)-Boc-[2.2.1]diazobicycloheptane (150.6 g, 0.76 mol) in CH2Cl2 (1.5 L) was cooled to 5 C. and Et3N (117 mL, 0.84 mol) was added. Over 50 min was then added acetoxy acetyl chloride (82 mL, 0.76 mol). The ice bath was removed and the heterogeneous mixture was stirred for 16 h. The reaction mixture was then poured over 9 wt % NaHCO3(aq) solution (1.5 L) and the layers were mixed and separated. The organic layer was washed with 26 wt % NaCl(aq) (1.5 L), dried (Na2SO4), filtered, and concentrated to provide the title compound as a white solid (217 g, 96%).1H NMR (600 MHz, DMSO-d6, 100 C.): 4.75-4.41 (m, 4H), 3.50-3.46 (m, 4H), 2.86 (s, 2H), 2.04 (s, 3H), 1.85-1.72 (m, 2H), 1.41 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
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With (R)-2-hydroxy-1-(6-(4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone hydrochloride; In dichloromethane; at 20℃; for 0.5h; | Step A: Preparation of 2-(6-Bromo-3,4-dihydroisoquinolin-2(lH)-yl)-2-oxoethyl Acetate. To a solution of 6-bromo-l,2,3,4-tetrahydroisoquinoline hydrochloride (0.400 g, 1.609 mmol) and triethylamine (1.122 mL, 8.05 mmol) in DCM (10 mL)was added 2-chloro-2- oxoethyl acetate (0.242 g, 1.770 mmol). The reaction was stirred at room temperature for 30 min. The mixture was diluted with DCM, washed with 1 M HCl, brine, dried over Na2SO4, and concentrated to give the title compound without further purification |
Yield | Reaction Conditions | Operation in experiment |
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60.7% | With pyridine; In dichloromethane; at -40 - 20℃;Cooling with acetone-dry ice; | Step 1 Acetic acid (2-oxo-2,3-dihydro-1H-indol-5-ylcarbamoyl)-methyl ester 5-Amino-1,3-dihydro-indol-2-one 30c (500 mg, 3.38 mmol) was dissolved in 10 ml of dichloromethane under stirring at room temperature, and pyridine (470 mul, 5 mmol) was added to the solution at -40° C. in a dry ice-acetone bath. Acetic acid chlorocarbonylmethyl ester (473 mg, 3.48 mmol) was dissolved in 10 ml of dichloromethane, the resulting solution was added dropwise to the above reaction solution. Upon completion of the addition, the dry ice-acetone was removed, and the reaction mixture was allowed to warm up to room temperature and stirred overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The filter cake was washed with water (10 ml*3) and recrystallized to obtain the title compound acetic acid (2-oxo-2,3-dihydro-1H-indol-5-ylcarbamoyl)-methyl ester 44a (510 mg, yield 60.7percent) as a yellow solid. |
60.7% | With pyridine; In dichloromethane; at -40 - 20℃; | 5-Amino-1,3-dihydro-indol-2-one 30c (500 mg, 3.38 mmol) was dissolved in 10 ml of dichloromethane under stirring at room temperature, and pyridine (470mul, 5 mmol) was added to the solution at -40°C in a dry ice-acetone bath. Acetic acid chlorocarbonylmethyl ester (473 mg, 3.48 mmol) was dissolved in 10 ml of dichloromethane, the resulting solution was added dropwise to the above reaction solution. Upon completion of the addition, the dry ice-acetone was removed, and the reaction mixture was allowed to warm up to room temperature and stirred overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The filter cake was washed with water (10 ml.x.3) and recrystallized to obtain the title compound acetic acid (2-oxo-2,3-dihydro-1H-indol-5-ylcarbamoyl)-methyl ester 44a (510 mg, yield 60.7percent) as a yellow solid. MS m/z (ESI): 247.7[M-1] |
Yield | Reaction Conditions | Operation in experiment |
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70.4% | Stage #1: 6-amino-5-fluoroindolin-2-one With pyridine In tetrahydrofuran at 20℃; Stage #2: Acetoxyacetyl chloride In tetrahydrofuran at -40 - 20℃; | 27.1 Acetic acid (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-methyl ester 6-Amino-5-fluoro-1,3-dihydro-indol-2-one 3d (500 mg, 3.0 mmol) was dissolved in 10 ml of tetrahydrofuran under stirring, and added with 0.4 ml of pyridine to the solution at room temperature. After stirring to mix well, the mixture was cooled down to -40°C in a dry ice-acetone bath. A solution of acetic acid chlorocarbonylmethyl ester (420 mg, 3.0 mmol) in 10 ml of tetrahydrofuran was added dropwise to the above reaction system. Upon completion of the addition, the dry ice-acetone bath was removed, and the reaction mixture was allowed to warm up to room temperature and stirred overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The resulting solid was washed with water for three times and dried to obtain the title compound acetic acid (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-methyl ester 27a (562 mg, yield 70.4%) as a gray solid. MS: 265.3[M-1] |
70.4% | With pyridine In tetrahydrofuran at -40 - 20℃; Cooling with acetone-dry ice; | 9.4 5-Fluoro-6-amino-indol-2-one 9d (500 mg, 3.0 mmol) was dissolved in 10 mL of tetrahydrofuran under stirring at room temperature, and 0.4 mL of pyridine was then added to the solution. After stirring to mix well, the reaction system was cooled down to -40°C in a dry ice-acetone bath. Chlorocarbonylmethyl ester (420 mg, 3.0 mmol) was dissolved in 10 mL of tetrahydrofuran, and the solution was then added dropwise to the above reaction system. Upon completion of the addition, the dry ice-acetone bath was removed. The reaction system was allowed to warm up to room temperature and stirred overnight until TLC showed the disappearance of starting materials. The reaction mixture was filtered, and the filter cake was washed with water thrice to give the title compound acetic acid (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-methyl ester 9e (562 mg, yield 70.4%) as a gray solid. MS: 265.3[M-1] |
70.4% | With pyridine In tetrahydrofuran at -40 - 20℃; Cooling with acetone-dry ice; | 9.4 Step 4 Acetic acid (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-methyl ester 5-Fluoro-6-amino-indol-2-one 9d (500 mg, 3.0 mmol) was dissolved in 10 mL of tetrahydrofuran under stirring at room temperature, and 0.4 mL of pyridine was then added to the solution. After stirring to mix well, the reaction system was cooled down to -40° C. in a dry ice-acetone bath. Chlorocarbonylmethyl ester (420 mg, 3.0 mmol) was dissolved in 10 mL of tetrahydrofuran, and the solution was then added dropwise to the above reaction system. Upon completion of the addition, the dry ice-acetone bath was removed. The reaction system was allowed to warm up to room temperature and stirred overnight until TLC showed the disappearance of starting materials. The reaction mixture was filtered, and the filter cake was washed with water thrice to give the title compound acetic acid (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-methyl ester 9e (562 mg, yield 70.4%) as a gray solid. MS: 265.3[M-1] |
Yield | Reaction Conditions | Operation in experiment |
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100% | Stage #1: 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine hydrochloride With triethylamine In dichloromethane at 20℃; for 0.5h; Stage #2: Acetoxyacetyl chloride In dichloromethane at 0 - 20℃; for 1h; | 63 General Procedure 63 To a suspension of 3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine as the HCl salt (procedure 6) (150 mg, 0.288 mmol) in CH2Cl2 (2 mL) was added NEt3 (0.121 mL, 0.863 mmol) and stirred for 30 minutes at room temperature. The reaction was cooled to 0° C. and acetic acid chlorocarbonylmethyl ester was added and stirred for 1 hour at room temperature. The reaction was monitored by LC-MS and after complete conversion to the desired product, water (2 mL) was added. |
100% | Stage #1: 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine hydrochloride With triethylamine In dichloromethane at 20℃; for 0.5h; Stage #2: Acetoxyacetyl chloride In dichloromethane at 20℃; for 1h; | 7 To a suspension of 3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine as the HCI salt (procedure 6) (150 mg, 0.288 mmol) in CH2CI2 (2 mL) was added NEta (0.121 mL, 0.863 mmol) and stirred for 30 minutes at room temperature. The reaction was cooled to 0°C and acetic acid chlorocarbonylmethyl ester was added and stirred for 1 hour at room temperature. The reaction was monitored by LC-MS and after complete conversion to the desired product, water (2 mL) was added. The reaction was extracted with EtOAc (4x10 mL), dried over Na2SO4, and concentrated togive quantitative yield of acetic acid 2-[4-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidin-1-yl]-2-oxo-ethyl ester (164 mg, quant). |
Yield | Reaction Conditions | Operation in experiment |
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74% | Stage #1: 3,5-difluorobromobenzene With isopropylmagnesium chloride In tetrahydrofuran at 20 - 30℃; for 1.16667h; Inert atmosphere; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Stage #3: Acetoxyacetyl chloride With copper(l) chloride In tetrahydrofuran at 30℃; Inert atmosphere; | |
70% | Stage #1: 3,5-difluorobromobenzene With isopropylmagnesium chloride In tetrahydrofuran at 40 - 45℃; for 3h; Inert atmosphere; Stage #2: Acetoxyacetyl chloride In tetrahydrofuran at -10℃; for 4h; Inert atmosphere; Stage #3: With hydrogenchloride; water In tetrahydrofuran; tert-butyl methyl ether at 0 - 10℃; Inert atmosphere; | 3.1 STEP 1: Synthesis of Hydroxyketone 2Materials: FW Grade Amount mmolesBromide 1 192.99 43.8 g 227THF 88 mL/-PrMgCl 102.85 2 M (THF) 113 mL 227(1 .0 eq)THF 20OmLCuCl 99.00 1.12g 11.351 [0 .05 eq)Acetoxyacetyl chloride 136.53 36.6 mL 340(1 .5 eq)MTBE 40OmLHCl 36.46 1.0 M 454 mL 454(2 .0 eq) Satd. aq. NaCl 227 mLSatd. aq. NaHCO3 227 mLThis process should be conducted under inert gas (N2) with exclusion of water/oxygen at all stages until aqueous workup (maintain exclusion of oxygen during workup).Charge THF (88 mL, KF = 50 ppm, 250 ppm BHT inhibitor is tolerated) to 0.5 L RBF equipped with overhead stirrer. Charge l-bromo-3,5-difluorobenzene (43.8 g, 0.227 mol, KF = 170 ppm). KF from resultant solution was 130 ppm. Heat the solution of 1 to 40 0C. Charge /-PrMgCl over 2 h (2 M in THF, 113 mL, 1 equiv), maintaining temperature 40-45 0C. Mg-Br Exchange is typically complete < 1 h after completion of /-PrMgCl charge to afford a homogenous solution. Monitor exchange via HPLC, quenching samples into MeOH and detect the 1,3-difluorobenzene.In a separate vessel, prepare mixture of CuCl (1.12 g, 0.05 equiv) in THF (200 mL) then add acetoxyacetyl chloride (37 mL, 1.5 equiv). Cool the CuCl/acid chloride mixture to -10 0C. Transfer (via dropping funnel) the solution of Grignard prepared above in THF - 10 0C over 4 h. No age is required after transfer of the Grignard. Proceed to next step upon complete addition.In a separate vessel, a two-phase mixture of IM HCl (227mL, 1.0 equiv) and MTBE (400 mL) is prepared and cooled to 0-10 0C. The reaction mixture is transferred into the aqueous workup mixture, maintaining < 10 0C. The resulting two-phase mixture can be allowed to warm to 20 0C for the phase cut. Wash the organic phase with a second portion of 1 M aqueous HCl (227 mL, 1.0 equiv). Wash the organic phase with saturated aqueous NaCl solution (227 mL). Wash the organic phase with saturated NaHCOβ solution (227 mL). Distill the organic phase and azeotrope with fresh MTBE until KF value was 483 ppm. Concentrate until solution is super-saturated and induce crystallization with seeding if necessary. Solvent switch to minimum 85% heptane and cool to 0-5 0C until supernatant concentration is < 3 g/L then filter. Rinse the cake with fresh heptane and then dry at 30 0C with N2 sweep. Acetoxyketone (1.1) was isolated as an off-white solid, 36 g, > 96 wt% purity for a corrected isolated yield of 70%.Charge 100.2 g of 93 wt% acetoxyketone to a 2 L flask with overhead stirring. Charge 300 mL MeOH. Charge 5 M aq. HCl (200 mL) and heat the thick slurry to 40-45 0C. After 5 h at 45 0C conversion is > 95:5 LCAP ratio of hydroxyketone: acetoxyketone. Color will change to light orange. Cool the batch to 20 0C and seed to induce crystallization if necessary. Add 1.2 L water over 1 h to cause further crystallization of 2 and then cool to 0-5 0C until supernatant concentration is < 4 g/L then filter. The hydroxyketone 2 is collected by filtration and rinsed with additional water. After 15 min suction drying the wet cake was 81 g. After 48 h under vacuum the mass was 62.5 g. The 62.5 g of off-white solid was 96 wt% purity for a corrected yield of 80% from the acetoxyketone. Overall yield from bromide 1 is 86% x 80% = 69%. This material is of sufficient quality for Step 2 but if necessary (e.g. wt% < 95%) the material can be recrystallized from EtO Ac/heptane as described below -After brief drying to remove bulk water, the hydroxyketone solid is re-dissolved in EtOAc and the resultant solution is subjected to azeotropic distillation until water content by KF titration is < 1000 ppm. The dry EtOAc solution is filtered and concentrated to approximately 5 volumes then switched with heptane at constant volume until the ratio is approx 3:1 heptane: EtOAc. The slurry of 2 is cooled to 0 0C and aged for 1 h, achieving < 10 mg/mL in the supernatant. The slurry is then filtered and rinsed with cold 3:1 heptane:EtOAc (1 bed volume) then heptane. The white solid is dried at 30-40 0C and approximately 20-25 in Hg (vacuum with N2 sweep). Isolated solid 2 has purity of > 98 LC wt% and > 98 NMR wt%. |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine; at 20℃; for 4h; | General procedure: <strong>[13831-30-6]Acetoxyacetic acid</strong> (3.8 g, 32 mmol) was dissolved in pyridine (18 ml) at room temperature, acetoxyacetyl chloride (3.3 mL, 32 mmol) was added thereto, and the mixture was stirred for 4 hours at room temperature. In addition, 2-(2-aminopyridin-4-ylmethylthio)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide compound 9e, 3.0 g, 8.1 mmol) was added thereto, and the mixture was stirred for 15 hours. Ethyl acetate (300 mL) was added to the reaction mixture, and the whole was washed with 1 N hydrochloric acid (100 mL) twice, saturated aqueous sodium hydrogen carbonate solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was filtered off with diethyl ether and ethyl acetate. Then the solid was dried under reduced pressure to give 3.3 g of the intermediate (2-(2-acetoxyacetylaminopyridin-4-ylmethylthio)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide) as a pale yellow solid. The intermediate (3.3g, 7.1 mmol) was dissolved in the mixture of methanol (10 mL) and tetrahydrofuran (50 mL), and 1M aqueous sodium hydroxide solution (10mL) was added thereto. The mixture was stirred for 5 minutes at room temperature and diluted with ethyl acetate (200 mL), and then the whole was washed with brine (100 mL). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting solid was filtered off with diethyl ether to give 2.4 g of the intermediate (2-(2-hydroxyacetylaminopyridin-4-ylmethylthio)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide) as a pale yellow solid. (Yield 69% in 2steps) The intermediate (1.8 g, 4.2 mmol) was suspended in anhydrous dichloromethane (20 mL) under ice-cooling, and thionyl chloride (1.1 mL, 9.2 mmol) was added thereto. The mixture was stirred for 2 hours at room temperature, and the solvent was evaporated under reduced pressure. The resulting solid was filtered off with diethyl ether to give 1.6 g of the title compound as a pale yellow solid. (Yield 81%) |
Yield | Reaction Conditions | Operation in experiment |
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95% | With sodium hydrogencarbonate In water; acetonitrile at 0℃; for 4h; | |
95% | With sodium hydrogencarbonate In water; acetonitrile at 0℃; for 4h; | 2 Uridine 5'-diphospho-2-hydroxyacetamido-2-deoxy-α-D-glucopyranoside (UDP-GlcNGc, F5-5) To a solution of UDP-GlcNH2 F5-2 (30 mg, 0.049 mmol) in CH3CN-H2O (30 mL, 1:1, v/v) in the presence of NaHCO3 (40 mg, 0.49 mmol), the Acetoxyacetyl chloride (6.9 μL, 0.098 mmol) in CH3CN (5 mL) was added. The reaction mixture was stirred for 4 hours at 0° C. and was neutralized with DOWEX HCR-W2 (Fr) resin, filtered, and concentrated. The residue was purified by flash column chromatography (EtOAc:MeOH:H2O=5:2:1, by volume) to afford UDP-GlcNGcAc F5-4 in 95% yield (31 mg). 1H NMR (600 MHz, D2O) δ 7.99 (d, J=7.8 Hz, 1H), 6.03-6.04 (m, 2H), 5.62 (dd, J=6.6, 3.6 Hz, 1H), 4.41-4.45 (m, 2H), 4.24-4.35 (m, 3H), 4.13 (d, J=10.2 Hz, 1H), 4.01 (d, J=7.8 Hz, 1H), 3.86-3.96 (m, 3H), 3.63 (t, J=9.6 Hz, 1H), 2.25 (s, 3H). UDP-GlcNGcAc F5-4 was dissolved in dry methanol (50 mL) containing analytic amount of sodium methoxide. The resulted mixture was stirred at r.t. for overnight. The reaction mixture was then neutralized with DOWEX HCR-W2 (H+) resin, filtered, and concentration to give product UDP-GlcNGc F5-5 in 98% yield (28 mg). 1H NMR (600 MHz, D2O) δ 7.92 (d, J=7.8 Hz, 1H), 5.93-5.95 (m, 2H), 5.52 (dd, J=7.2, 3.0 Hz, 1H), 4.31-4.35 (m, 2H), 4.09-4.25 (m, 5H), 4.02 (d, J=10.2 Hz, 1H), 3.83-3.91 (m, 3H), 3.79 (dd, J=12.6, 4.2 Hz, 1H), 3.55 (t, J=9.6 Hz, 1H). 13C NMR (150 MHz, D2O) δ 175.47, 166.37, 151.92, 141.74, 101.73, 94.36, 88.53, 83.28 (d, J=8.4 Hz), 73.86, 73.09, 70.69, 69.71, 69.54, 65.05, 61.11, 60.36, 53.46 (d, J=7.7 Hz). HRMS (ESI) m/z calcd for C17H27N3O18P2 (M+H) 624.0843, found 624.0847. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃; for 4h; | Intermediate 21 : 2-[4-cyano-3-(trifluoromethyl)phenyl]amino}-2-oxoethylacetate; To a stirred solution of 4-amino-2-(trifluoromethyl)benzonitrile (commerciallyavailable, for example from Maybridge. Cornwall, United Kingdom, 85. Og) in DCM (1 litre) at 0C was added triethylamine (92.2g, 0.913mol) and the reaction stirred for 15 minutes. Then acetoxyacetylchloride (74.5g, 0.547mol) was added at 0C and the reaction stirred for 4 hours at room temperature. The reaction mixture was diluted with DCM and washed with ice water followed by aqueous NaHC03. The organic layer was separated and washed with brine solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude product was purified bytriturating with diethyl ether (500mL) to yield 2-[4-cyano-3-(trifluoromethyl)phenyl]amino}-2-oxoethyl acetate (85. Og).MS ES-ve m/z 285 (M-H)1 H NMR (400 MHz, Chloroform-d) delta ppm 2.26 (s, 3H) 4.74 (s, 2 H) 7.8 (d, 1 H) 8.0(m, 2H), 8.33 (br.s., 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 3h; | Intermediate 46: 2-[4-cyano-2-methyl-3-(trifluoromethyl)phenyl]amino}-2- oxoethyl acetate; To a solution of <strong>[573764-86-0]4-amino-3-methyl-2-(trifluoromethyl)benzonitrile</strong> (commercially available, for example from Sunshine Chemlab, Downington, PA, USA, 500 mg, 2.50 mmol) and triethylamine (0.383 mL, 2.75 mmol) in dichloromethane (10 mL) was added 2-chloro-2-oxoethyl acetate (0.269 mL, 2.50 mmol) dropwise. The reaction mixture was stirred at room temperature for 3hours. The reaction mixture was diluted with DCM (100ml) and water (50ml) and aqueous was extracted with DCM (100ml). The organics were combined, passed through a phase separator and concentrated to afford 710mg of the title compound as a pale yellow powder.MS ES-ve m/z 299 (M-H)1H NMR (400 MHz, METHANOLS) δ ppm 2.18 (s, 3 H) 2.41 (q, J=2.12 Hz, 3 H) 4.78 (s, 2 H) 7.81 (d, J=8.33 Hz, 1 H) 7.92 (d, J=8.33 Hz, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃; for 4h; | Intermediate 38: 2-[3-Cyano-4-(trifluoromethyl)phenyl]amino}-2-oxoethyl acetate; Triethylamine (1.09 g, 10.8 mmol) was added to a stirred solution of 5-amino-2- (trifluoromethyl)benzonitrile (Intermediate 37, 1.0 g, 5.37 mmol) in DCM (40 mL), at 0C, and the mixture was stirred for 15 min. Chloro-2-oxoethyl acetate (1.10 g, 8.06 mmol) was added at 0C and the mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with DCM and washed with ice water, and saturated brine solution. The organic layer was dried over anhydrous Na2S04, and concentrated under reduced pressure to afford the crude compound. This was purified by column chromatography (100-200 mesh silica gel), eluting with 20%-40% EtOAc/pet. ether to give the title compound (1.1 g).MS ES+ve m/z 285 (M-H).1H NMR (400 MHz, Chloroform-d) delta ppm 2.26 (s, 3 H), 4.76 (s, 2 H), 7.72-7.82 (m, 1 H), 7.90-8.00 (m, 1 H), 8.08-8.18 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 22h;Cooling with ice; | Intermediate 29: 2-[3-cyano-5-(trifluoromethyl)phenyl]amino}-2-oxoethyl acetate; A solution of <strong>[49674-28-4]3-amino-5-(trifluoromethyl)benzonitrile</strong> (Intermediate 28, 2.20g, 11.82 mmol) and di-isopropylethylamine (2.27mL, 13.0mmol) in dichloromethane (40 mL) was cooled in an ice-water bath before the addition of 2-chloro-2-oxoethyl acetate (1.40mL, 13.0mmol) dropwise. The reaction was allowed to warm to room temperature and stirred for 4 hours. To the reaction was added 2-chloro-2-oxoethyl acetate (0.14mL) and the reaction stirred at room temperature for a further 18 hours. The reaction was diluted with DCM (100mL) and the solution washed with 2N HCI (75mL) and NaHC03 (75mL), collected via a hydrophobic frit and the solvent removed to yield the title compound as an orange oil (3.7g)MS ES+ve m/z 287 (M+H)1H NMR (400 MHz, CHLOROFORM-d) delta ppm 2.27 (s, 3 H) 4.74 (s, 2 H) 7.69 (s, 1 H) 8.05 (s, 1 H) 8.17 (br. s. , 1 H) 8.22 (s, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.5% | With triethylamine In dichloromethane at 0 - 20℃; for 2h; | 48-II TEA (0.29g, 0.296 mmol) and acetoxyacetyl chloride (0.323g, 0.00237 mol) are added, at 0°C, to a solution of 2-[l-phenyl-2-methyl-5-(4-methylsulphonylphenyl)-/H-pyrrol-3-yl]- ethanamine (W2008014821 ), (0.7g, 0.00197 mol), in CH2C12 (10 mL). It is stirred at RT for 2h. Then it is poured into water and extracted with CH2CI2, washed with NaHC03 s.s., and then with ¾0, dried and concentrated. The solid obtained (0.85g, 95.5%) is used as it is for the next step. |
95.5% | With triethylamine In dichloromethane at 20℃; for 2h; | 48.II 2-(Acetoxy)-N-[2-(1-phenyl-2-methyl-5-(4-methylsulphonylphenyl)-1H-pyrrol-3-yl)-ethyl]acetamide 2-(Acetoxy)-N-[2-(1-phenyl-2-methyl-5-(4-methylsulphonylphenyl)-1H-pyrrol-3-yl)-ethyl]acetamide TEA (0.29 g, 0.296 mmol) and acetoxyacetyl chloride (0.323 g, 0.00237 mol) are added, at 0° C., to a solution of 2-[1-phenyl-2-methyl-5-(4-methylsulphonylphenyl)-1H-pyrrol-3-yl]-ethanamine (W2008014821), (0.7 g, 0.00197 mol), in CH2Cl2 (10 mL). It is stirred at RT for 2 h. Then it is poured into water and extracted with CH2Cl2, washed with NaHCO3 s.s., and then with H2O, dried and concentrated. The solid obtained (0.85 g, 95.5%) is used as it is for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2.0h; | General procedure: To a mixture of <strong>[2015-19-2]5-amino-2-chlorobenzenesulfonamide</strong> (1.24 g, 6.0 mmol) and Et3N (0.67 g, 6.6 mmol) in 60 mL of THF at 0 C, was added dropwise acyl chloride (6.5 mmol). The reaction was monitored with TLC and complete after 2 h of stirring at room temperature. Then the resulting suspension was filtered, washed with THF (10 mL). The filtrate was evaporated, and 30 mL of water was added to the residue. The mixture was intensively stirred for 20 min, and the resulting suspension was filtered to give the intermediates 6a-6k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With pyridine In dichloromethane at 20 - 35℃; for 3.5h; | 5 A 3-neck round-bottom flask equipped with a mechanical stirrer, thermocouple and addition funnel with nitrogen inlet was charged with N-hydroxysuccinimide (commercially available from Sigma-Aldrich, St. Louis, Mo.) (211 g, 1.83 mol) and DCM (2.25 L) at room temperature, resulting in a suspension. Pyridine (178 mL, 2.2 mol) was added in one portion with no change in the internal temperature. A solution of acetoxyacetyl chloride (commercially available from Sigma-Aldrich, St. Louis, Mo.) (197 mL, 1.83 mol) in DCM (225 mL) was added dropwise over 60 minutes and the temperature rose to 35° C. Stirring was continued at room temperature for 2.5 hours. The reaction mixture was washed with water (1*1 L), 1N HCl (2*1 L) and brine (1*1 L). The organic layer was concentrated under vacuum and azeotroped with toluene (1*1 L) to obtain the product as a white solid (367 g, 93%). 1H NMR (400 MHz, CDCl3) δ 4.96 (2H, s), 2.86 (4H, s), 2.19 (3H, s) ppm; LCMS m/z: 238 (M+Na). |
93% | With pyridine In dichloromethane at 35℃; for 3.5h; Inert atmosphere; | |
79% | With triethylamine In 1,2-dichloro-ethane at 0 - 20℃; for 0.5h; | To a stirred cooled (0° C) solution of A-hydroxysuccinimide (992 mg, 8.62 mmol) and Et3N (1.141 mL, 8.21 mmol) in dry 1.2-dichloroetane (15 mL) a solution of acetoxyacetyl chloride ACOCH2(CO)C1 (1.121 g, 8.21 mmol) in 1.2-dichloroetane (5 mL) was added in several portions. The reaction mixture (precipitate of Et3N hydrochloride was formed) was stirred at room temperature for 30 min, then AcOH (0.47 mL) was added. The mixture was diluted with 20 mL of 1% AcOH, stirred by shaking, and organic layer was extracted with 20 mL of 1% AcOH one more time. The organic solution was evaporated, and the residue was dried in vacuum. Crystalline material was rubbed with 20 mL of Et2O/hexane (1 : 1) mixture, decanted, rubbed with 20 mL of hexane, decanted, and dried in vacuum. Yield of pure ACOCH2(CO)ONSU was 1394 mg (79%). (0339) TLC: Rf= 0.67 (chloroform/methanol 10: 1 by volume). (0340) ’H NMR (CDCL + 1% d4-AcOH, 700 MHz, 30°C) 5 7.258 (s, CHCI3), 4.943 (s, 2H; OCH2CO), 2.847 (s, 4H; CH2CH2 of succinimide), 2.175 (s, 3H; C(O)CH3) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine In 1,4-dioxane at 23℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -35 - 25℃; for 25h; | To a solution of G-i (i.00 g, 4.84 mmol) in DCM (5 mL) at -35C is added DIPEA (2.6i mL, i4.5 mmol) followed by B-2 (644 .iL, 5.8i mmol). The reaction is warmed up to ambient temperature over i h and stuffed for 24 h. The mixture is diluted with EtOAc (i 25 mL), and washed with saturated aqueous NH4C1 (i 00 mL), saturated aqueous NaHCO3 (iOO mL) and brine (40 mL). The combined aqueous layers are extracted with EtOAc (i25mL). The organic layers are pooled, dried over Na2SO4, filtered and concentrated to afford G-2, which is used in the next step without purification. | |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -35 - 25℃; for 25h;Inert atmosphere; | Intermediate S: Preparation of Acetic acid ((R)-methyl-pyrrolidin-3-yl-carbamoyl)- methyl ester (S)To a solution of S-1 (1.00 g, 4.84 mmol) in DCM (5 ml) at -35C is added DIPEA (2.61 ml, 14.5 mmol) followed by S-2 (644 mu, 5.81 mmol). The reaction is warmed up to ambient temperature over 1 h and stirred for 24 h. The mixture is diluted with EtOAc (125 ml), and washed with saturated aqueous NH4CI (100 ml), saturated aqueous NaHC03 (100 ml) and brine (40 ml). The combined aqueous layers are extracted with EtOAc (125 ml). The organic layers are pooled, dried over Na2S04, filtered and concentrated to afford S-3, which is used in the next step without purification. To a solution of S-3 (1.53 g, 4.84 mmol) in DCM (50 ml) is added HC1 in 1,4-dioxane (24.7 ml, 4 M, 98.8 mmol) at ambient temperature. The mixture is stirred at ambient temperature for 24 h, concentrated in vacuo, dissolved in a mixture of MeOH and DCM (1 mL: 100 ml), treated with PS-DIEA resin (3.5 g) and stirred for 18 h. The suspension is filtered, and the filtrate is concentrated to afford the title product (S), which is used in the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 1h; | General procedure: Compounds 20-30 were prepared followingthis general procedure unless otherwise noted. To 5 dissolved in THF was added triethylamine(1.0 eq). The mixture was cooled in an ice-bath, and to the mixture was added substituted acidchloride (1.0 eq). The mixture was stirred at room temperature and the reaction was monitoredvia LC/MS. After 1 h, the reaction solvent was evaporated. The resulting crude was purified byrecrystallization from ethanol or purified via flash column chromatography to give desiredproduct.2,2-Dimethyl-N- [4-(pyridin-2-yl)-1,3-thiazol-2-yl]propanamide (30). 14 mg, 33%yield, as off-white solid; 1H NMR: (300 MHz, CDCl3): delta 1.37 (s, 9H), 7.21-7.28 (m, 1H), 7.65(s, 1H), 7.73-7.78 (t, J = 7.7 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 8.65-8.66 (m, 1H), 9.00 (br s,1H); 13C NMR: (300 MHz, CDCl3): delta 27.2, 111.9, 120.4, 122.6, 136.8, 149.6; HRMS MS ESI m/zcalcd for C13H15N3OS (M+H)+ 262.1009, found 262.0998 (Delta 1.1 ppm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triethylamine In dichloromethane at 25℃; for 1h; | 33.4 [0409] Step 4: j IZ-hydroxyimino)(13-j(2-methylpropane-2- sulfinyl)aminoj cyclobutyll )methylj carbamoyll methyl acetate: into a 250-mL round-bottom flask, was placed a solution of(Z)-N-hydroxy-3-[(2-methylpropane-2-sulfinyl)amino]cyclobut-1-carboximidamide (3.7 g, 15.86 mmol, 1.00 eq.) in dichloromethane (mL). To the solution were added TEA (3.2 g, 31.62 mmol, 2.00 eq.) and 2-chloro-2-oxoethyl acetate (2.6 g, 19.04 mmol, 1.20 eq.). The resulting solution was stirred for 1 hour at 25 °C. The resulting solution was diluted with 300 mL of H20 and then it was extracted with ethyl acetate (2x500 mL) and the organic layers combined. The resulting mixture was washed with brine (2x500 mL), driedover anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 3.7 g (70%) of [[Z-hydroxyimino)([3 - [(2-methylpropane-2- sulfinyl)amino]cyclobutyl])methyl]carbamoyl]methyl acetate as a yellow solid. LC-MS[M+H] = 334. |
70% | With triethylamine In dichloromethane at 25℃; for 1h; | 4 Step 4: [[Z-hydroxyimino)([3-[(2-methylpropane-2- sulfinyl)amino]cyclobutyl])methyl]carbamoyl] methyl acetate Step 4: [[Z-hydroxyimino)([3-[(2-methylpropane-2- sulfinyl)amino]cyclobutyl])methyl]carbamoyl] methyl acetate: into a 250-mL round-bottom flask, was placed a solution of (Z)-N-hydroxy-3-[(2-methylpropane-2-sulfinyl)amino]cyclobut- 1 -carboximidamide (3.7 g, 15.86 mmol, 1.00 eq.) in dichloromethane ( mL). To the solution were added TEA (3.2 g, 31.62 mmol, 2.00 eq.) and 2-chloro-2-oxoethyl acetate (2.6 g, 19.04 mmol, 1.20 eq.). The resulting solution was stirred for 1 hour at 25 °C. The resulting solution was diluted with 300 mL of H20 and then it was extracted with ethyl acetate (2x500 mL) and the organic layers combined. The resulting mixture was washed with brine (2x500 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 1 ). This resulted in 3.7 g (70%) of [[Z-hydroxyimino)([3-[(2-methylpropane-2- sulfinyl)amino]cyclobutyl])methyl]carbamoyl]methyl acetate as a yellow solid. LC-MS [M+H]+ = 334. |
70% | With triethylamine In dichloromethane at 25℃; for 1h; | 33.4 Step 4: [[Z-hydroxyimino)([3-[(2-methylpropane-2- sulfinyl)amino]cyclobutyl])methyl] carbamoyl] methyl acetate: into a 250-mL round-bottom flask, was placed a solution of (Z)-N-hydroxy-3-[(2-methylpropane-2-sulfinyl)amino]cyclobut- 1 -carboximidamide (3.7 g, 15.86 mmol, 1.00 eq.) in dichloromethane ( mL). To the solution were added TEA (3.2 g, 31.62 mmol, 2.00 eq.) and 2-chloro-2-oxoethyl acetate (2.6 g, 19.04 mmol, 1.20 eq.). The resulting solution was stirred for 1 hour at 25 °C. The resulting solution was diluted with 300 mL of H20 and then it was extracted with ethyl acetate (2x500 mL) and the organic layers combined. The resulting mixture was washed with brine (2x500 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 1). This resulted in 3.7 g (70%) of [[Z-hydroxyimino)([3-[(2-methylpropane-2- sulfinyl)amino]cyclobutyl])methyl]carbamoyl]methyl acetate as a yellow solid. LC-MS [M+H]+ = 334. |
70% | With triethylamine In dichloromethane at 25℃; for 1h; | 33.4 [[(Z)-hydroxyimino([3-[(2-methylpropane-2- sulfinyl)amino]cyclobutyl])methyl]carbamoyl]methyl acetate into a 250-mL round-bottom flask, was placed a solution of (Z)-N-hydroxy-3-[(2-methylpropane-2-sulfinyl)amino]cyclobut- 1 -carboximidamide (3.7 g, 15.86 mmol, 1.00 eq.) in dichloromethane ( mL). To the solution were added TEA (3.2 g, 31.62 mmol, 2.00 eq.) and 2-chloro-2-oxoethyl acetate (2.6 g, 19.04 mmol, 1.20 eq.). The resulting solution was stirred for 1 hour at 25 °C. The resulting solution was diluted with 300 mL of H20 and then it was extracted with ethyl acetate (2x500 mL) and the organic layers combined. The resulting mixture was washed with brine (2x500 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 1). This resulted in 3.7 g (70%) of [[Z-hydroxyimino)([3-[(2-methylpropane-2- sulfinyl)amino]cyclobutyl])methyl]carbamoyl]methyl acetate as a yellow solid. LC-MS [M+H]+ = 334. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
First, Intermediate C52 was reductively alkylated with benzyl (2S)-2- [(benzyloxy)carbonyl]amino} -4- oxobutanoate analogously to C2. The secondary amino group was then acylated with 2-chloro-2- oxoethyl acetate and the two ester groups were then hydrolysed with 2M lithium hydroxide solution in methanol. The intermediate obtained in this manner was dissolved in ethanol, palladium on carbon (10%) was added and the mixture was hydrogenated at RT with hydrogen under standard pressure forh. The deprotected compound was taken up in dioxane/water 2:1 and in the last step the Fmoc protective group was introduced using 9H-fluoren-9-ylmethyl chlorocarbonate in the presence of N,Ndiisopropylethylamine.LC-MS (Method 1): R1 = 1.37 mm; MS (ESIpos): mj’z = 734 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
312 mg | First, Intermediate C52 was reductively alkylated with benzyl (2S)-2- [(benzyloxy)carbonyl]amino} -4- oxobutanoate analogously to Intermediate C2. First, Intermediate C52 was reductively alkylated with benzyl (2S)-2- { [(benzyloxy)carbonyl] amino} -4-oxobutanoate analogously to C2. The secondary amino group was then acylated with 2-chloro-2-oxoethyl acetate as described for Intermediate C27, and the two ester groups were then hydrolysed with 2M lithium hydroxide solution in methanol. Theintermediate obtained in this manner was dissolved in ethanol, palladium on carbon (10%) was added and the mixture was hydrogenated at RT with hydrogen under standard pressure for 1 h.500 mg (0.886 mmol) of this frilly deprotected intermediate were taken up in 60 ml of dioxane, and 253 mg (0.975 mmol) of 1 -( { [2-(trimethylsilyl)ethoxy]carbonyl} oxy)pyrrolidine-2,5-dione and 198 jid of triethylamine were added. After 24 h of stirring at RT, the reaction was concentrated and the residue waspurified by preparative HPLC. Combination of the appropriate fractions, concentration under reduced pressure and drying under high vacuum gave 312 mg (50% of theory) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine In dichloromethane at 20℃; for 5h; | |
79% | With triethylamine In dichloromethane at 20℃; for 20.25h; | (2S)-4-[ { (lR)-1-[1-Benzyl-4-(2,5-difluorophenyl)-1H -pyrrol-2-yl]-2,2-dimethylpropyl} (glycoloyl)amino ]-2-( [2-(trimethylsilyl)ethoxy ]carbonyl} amino )butanoic acid 2.06 g (3.36 mmol) of this intermediate were initially charged in 76 ml ofDCM and acylated with 0.81ml (7.17 mmol) of 2-chloro-2-oxoethyl acetate in the presence of 2.1 ml of triethylamine. After 20 h ofstirring at RT, 0.36 ml of 2-chlor-2-oxoethyl acetate and 0.94 ml of triethylamine were added and the10 reaction was stirred at RT for a further 15 min. The mixture was then diluted with 500 ml of ethylacetate and extracted successively twice with 300 ml of 5% strength citric acid, twice with 300 ml ofsaturated sodium bicarbonate solution and once with 100 ml of saturated sodium chloride solution andthen dried over magnesium sulphate and concentrated. Drying under high vacuum gave 2.17 g (79% oftheory) of the protected intermediate.15 LC-MS (Method 1): Rt = 1.48 min; MS (ESipos): m/z = 714 (M+Ht. |
75% | With triethylamine In dichloromethane at 20℃; | To a solution of 200 mg (0.33 mmol) methyl (2S)-4-({(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H- pyrrol-2-yl] -2,2-dimethylpropyl} amino)-2-( { [2-(trimethylsilyl)ethoxy]carbonyl} amino)butanoate 10 mE DCM were added 105 jiL triethylamine and 77 jiL (0.717 rnmol) acetoxyacetylchloride. The reaction mixture was stirred overnight at room temperature diluted with ethyl acetate and washed twice with asaturated sodium hydrogen carbonate solution and then with brine. The organic layer was dried over magnesium sulfate and evaporated to afford 213 mg (75%) of the title compound.LC-MS (Method 1): R1 = 1.46 mm; MS (ESIpos): m/z= 714 (M+H). |
75% | With triethylamine In dichloromethane at 20℃; | Intermediate C75 [0605] 200 mg (0.33 mmol) of this intermediate were dissolved in 10 ml of DCM, and 105 μl of triethylamine and 77 μl (0.717 mmol) of acetoxyacetyl chloride were then added. The mixture was stirred at RT overnight and then concentrated under reduced pressure. The residue was taken up in ethyl acetate and extracted twice with saturated sodium bicarbonate solution and then with saturated sodium chloride solution. The organic phase was dried over magnesium sulphate and then concentrated. This gave 213 mg (75%) of the title compound as a beige foam. [0606] LC-MS (Method 1): Rt=1.46 min; MS (ESIpos): m/z=714 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With triethylamine In dichloromethane at 0 - 20℃; | |
77% | With triethylamine In dichloromethane at 0 - 20℃; | M9 171.2 mg (0.32 mmol) of 2-[3-({(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}amino)propyl]-1H-isoindole-1,3(2H)-dione were initially charged in 5.0 ml of dichloromethane, and 73.6 mg (0.73 mmol) of triethylamine were added. At 0° C., 94.9 mg (0.70 mmol) of acetoxyacetyl chloride were added, and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and the organic phase was washed twice with saturated sodium hydrogencarbonate solution and once with saturated NaCl solution. After drying over magnesium sulphate, the solvent was evaporated under reduced pressure and the residue was purified using Biotage Isolera (silica gel, column 10 g SNAP, flow rate 12 ml/min, ethyl acetate/cyclohexane 1:3). The solvents were evaporated under reduced pressure and the residue was dried under high vacuum. This gave 159.0 mg (77%) of the compound 2-({(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]amino)-2-oxoethyl acetate. LC-MS (Method 1): Rt=1.35 min; MS (ESIpos): m/z=642 [M+H]+. |
77% | With triethylamine In dichloromethane at 0 - 20℃; | Example M9 [1644] 171.2 mg (0.32 mmol) of 2-[3-({(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}amino)propyl]-1H-isoindole-1,3(2H)-dione were initially charged in 5.0 ml of dichloromethane, and 73.6 mg (0.73 mmol) of triethylamine were added. At 0°C., 94.9 mg (0.70 mmol) of acetoxyacetyl chloride were added, and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and the organic phase was washed twice with saturated sodium bicarbonate solution and once with sat. NaCl solution. After drying over magnesium sulphate, the solvent was evaporated under reduced pressure and the residue was purified using Biotage Isolera (silica gel, column 10 g SNAP, flow rate 12 ml/min, ethyl acetate/cyclohexane 1:3). The solvents were evaporated under reduced pressure and the residue was dried under high vacuum. This gave 159.0 mg (77%) of the compound 2-({(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]amino)-2-oxoethyl acetate. [1645] LC-MS (Method 1): Rt=1.35 min; MS (ESIpos): m/z=642 [M+H]+. |
159 mg | With triethylamine In dichloromethane at 0 - 20℃; | 171.2 mg (0.32 mmol) of 2-[3-( {(1 R)- 1 -[1 -benzyl-4-(2,5-difluorophenyl)- 1 H-pyrrol-2-yl]-2,2- dimethylpropyl} amino)propyl] -1 H-isoindole- 1,3 (2H)-dione were initially charged in 5.0 ml of dichloromethane, and 73.6 mg (0.73 mmol) of triethylamine were added. At 0°C, 94.9 mg (0.70 mmol) of acetoxyacetyl chloride were added, and the reaction mixture was stirred at RI overnight. Ihe reactionmixture was diluted with ethyl acetate and the organic phase was washed twice with saturated sodium bicarbonate solution and once with sat. NaCl solution. After drying over magnesium sulphate, the solvent was evaporated under reduced pressure and the residue was purified using Biotage Isolera (silica gel, column 10 g SNAP, flow rate 12 mllmin, ethyl acetate/cyclohexane 1:3). Ihe solvents were evaporated under reduced pressure and the residue was dried under high vacuum. Ihis gave 159.0 mg(77%) of the compound 2-( {(1 R)- 1 -[1 -henzyl-4-(2,5-difluorophenyl)- 1 H-pyrrol-2-yl]-2,2- dimethylpropyl} [3-( 1,3 -dioxo- I ,3-dihydro-2H-isoindol-2-yl)propyl] amino)-2-oxoethyl acetate.LC-MS (Method 1): R1 = 1.35 mm; MS (ESIpos): m/z = 642 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.5% | With N-(tert-butoxy)-1H-pyrrole-2-carboxamide; toluene-4-sulfonic acid; In 1,4-dioxane; acetonitrile; at 110℃; for 7h; | At room temperature,100 mmol of the compound of formula (I)200 mmol of the compound of formula (II)10 mmol of catalyst (a mixture of 5 mmol of ruthenium tetracarbonyl diboride and 5 mmol of triphenylphosphine copper (Cu (PPh3) Br)180 mmol of acetoxyacetyl chloride,20 mmol of acidic compound p-toluenesulfonic acid and 12 mmol of additive L were added to an appropriate organic solvent (volume ratio 2:1 mixture of acetonitrile and 1,4-dioxane)Then heated to 110 C,And the reaction was stirred at that temperature for 7 hours;After the reaction,The reaction system was filtered,And with the alkali to adjust the pH value of the filtrate is neutral,Then vacuum distillation,The residue was passed through a silica gel column,Was eluted with a mixture of chloroform and ethyl acetate in an equal volume ratio and distilled again under reduced pressure to giveThe compound of the above formula (III) having a melting point of 85 to 86 C (wherein n-Bu is n-butyl) in a yield of 91.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.8% | With glycolic Acid; N-(tert-butoxy)-1H-pyrrole-2-carboxamide; toluene-4-sulfonic acid; In 1,4-dioxane; acetonitrile; at 80℃; for 10h; | At room temperature,100 mmol of the compound of formula (I)100 mmol of the compound of formula (II)16 mmol of catalyst (mixture of 8 mmol of ruthenium tetracarbonyl diboride and 8 mmol of triphenylphosphine copper (Cu (PPh3) Br)140 mmol of acetoxyacetyl chloride,30 mmol of acidic compound p-toluenesulfonic acid and 6 mmol of additive L were added to an appropriate organic solvent (volume ratio 2: 1Of a mixture of acetonitrile and 1,4-dioxane)Then heated to 80 C,And the reaction was stirred at that temperature for 10 hours;After the reaction,The reaction system was filtered,And with the alkali to adjust the pH value of the filtrate is neutral,Then vacuum distillation,The residue was passed through a silica gel column,In an equal volume of a mixture of chloroform and ethyl acetate,And again under reduced pressure distillation,To give a compound of the above formula (III) having a melting point of 109 to 110 C (wherein Ac is acetoxy, the same applies hereinafter) in a yield of 90.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-aminopyrazole-1-carboxylic acid tert-butyl ester; Acetoxyacetyl chloride With triethylamine In dichloromethane at 0 - 20℃; for 4h; Stage #2: With water; potassium carbonate In methanol at 20℃; | 91.3 Step 3: Synthesis of 2-hydroxy-N-(1H-pyrazol-3-yl)acetamide A 100-mL round-bottom flask was charged with tert-butyl 3-amino-1H-pyrazole-1- carboxylate (2.00 g, 10.9 mmol, 1.00 equiv), DCM (20 mL), and triethylamine (2.75 g, 27.2 mmol, 2.50 equiv). 2-Chloro-2-oxoethyl acetate (1.93 g, 14.1 mmol, 1.30 equiv) was added dropwise at 0 °C. The resulting solution was stirred 4 h at room temperature and concentrated under reduce pressure. Then the resulting solid was dissolved in MeOH (20 mL). Potassium carbonate (3.03 g, 21.8 mmol, 2.00 equiv) and water (5 mL) was added. The mixture was stirred for overnight at room temperature and concentrated under reduced pressure. The residue was triturated in acetonitrile (50 mL). The solids were filtered and washed with acetonitrile (3 x 20 mL). The filtrate was concentrated under reduced pressure to provide 1.38 g (crude) of 2- hydroxy-N-(1H-pyrazol-3-yl)acetamide as a brown solid. LCMS (ESI, m/z): 142 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.6% | With di(rhodium)tetracarbonyl dichloride; triphenylphosphine copper; toluene-4-sulfonic acid; In 1,4-dioxane; acetonitrile; at 100℃; for 8h; | At room temperature, 100 mmol of the compound of formula (I)150 mmol of the compound of formula (II)14 mmol of a catalyst (a mixture of 7 mmol of ruthenium tetracarbonyl diboride and 7 mmol of triphenylphosphine copper (Cu (PPh3) Br)160 mmol of acetoxyacetyl chloride and 25 mmol of acidic compound p-toluenesulfonic acid were added to an appropriate organic solvent (a mixture of acetonitrile and 1,4-dioxane in a volume ratio of 2: 1) and then heated to 100 C The reaction was stirred at this temperature for 8 hours;After completion of the reaction, the reaction system was filtered and the pH of the filtrate was adjusted to pH with a base, and then distilled under reduced pressure The silica gel column was eluted with an equal volume of a mixture of chloroform and ethyl acetate and distilled again under reduced pressure to give The compound of the above formula (III) having a melting point of 109 to 110 C has a yield of 80.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.9% | With di(rhodium)tetracarbonyl dichloride; triphenylphosphine copper; toluene-4-sulfonic acid; In 1,4-dioxane; acetonitrile; at 80℃; for 10h; | At room temperature, 100 mmol of the compound of formula (I)100 mmol of the compound of formula (II)16 mmol of catalyst (for8 mmol of ruthenium tetracarbonyl dichloride with 8 mmol of triphenylphosphine copper (Cu (PPh3) Br)),140 mmol of acetoxyacetyl chloride and 30 mmol of acidic compound p-toluenesulfonic acid were added to an appropriate organic solvent (a mixture of acetonitrile and 1,4-dioxane in a volume ratio of 2: 1) and then raised to 80 C The reaction was stirred at this temperature for 10 hours;After completion of the reaction, the reaction system was filtered and the pH of the filtrate was adjusted to pH with a base, and then distilled under reduced pressure The silica gel column was eluted with an equal volume of a mixture of chloroform and ethyl acetate and distilled again under reduced pressure to give The compound of the above formula (III) having a melting point of 106 to 107 C (wherein Ac is acetoxy, the same applies hereinafter) in a yield of 95.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.3% | With di(rhodium)tetracarbonyl dichloride; triphenylphosphine copper; toluene-4-sulfonic acid; In 1,4-dioxane; acetonitrile; at 110℃; for 7h; | At room temperature,100 mmol of the compound of formula (I)200 mmol of the compound of formula (II)10 mmol of catalyst (a mixture of 5 mmol of ruthenium tetracarbonyl diboride and 5 mmol of triphenylphosphine copper (Cu (PPh3) Br)180 mmol of acetoxyacetyl chloride and 20 mmol of acidic compound p-toluenesulfonic acid were added to a suitable organic solvent (a mixture of acetonitrile and 1,4-dioxane in a volume ratio of 2: 1) and then raised to 110 C The reaction was stirred at this temperature for 7 hours;After completion of the reaction, the reaction system was filtered and the pH of the filtrate was adjusted to pH with a base, and then distilled under reduced pressure The silica gel column was eluted with an equal volume of a mixture of chloroform and ethyl acetate and distilled again under reduced pressure to give The compound of formula (III) having a melting point of 138-139 C in a yield of 95.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine In dichloromethane at 0 - 20℃; for 16h; | 5 Example 5 Synthesis of benzene-1 ,4-d iyibis[(2-decyitetradecyi) imino]-2-oxoethane-2, 1- diyi} diacetate (4) Triethyiamine (0.70 mi, 4.99 mmoi) was added to N,N-bis(2-decyitetradecyi)benzene-1,4-di- amine (1 .77 g, 2.27 mmoi) dissoived in dry DCM (22.70 mi) at Q 00. Acetoxyacetyi chioride (0.54 mi, 4.99 mmoi) was injected into the fiask drop wise before the reaction was aiiowed to warm to room temperature and stirred for 16 hours. The reaction was quenched with NaHCO3 and EtOAc added. The phases were separated and the aqueous phase extracted three timeswith EtOAc. The combined organic phase was washed with brine dried over MgSO4, the saits fiitered and the soivent removed under pressure to give paie yeiiow soiid, 2.00 g, 96 %. 1 H NMR (400 MHz, Chioroform-d) 6 7.32 (s, 4H), 4.33 (s, 4H), 3.64 (d, J = 7.0 Hz, 4H), 2.12 (s, 6H), 1.53-1.41 (m, 2H), 1.37-1.02 (m, 80H), 0.94 -0.79 (m, 12H). 130 NMR (101 MHz, CDCi3) 6 170.61, 166.56, 141.13, 129.79, 61.79, 53.41, 36.25, 32.06, 31.23, 30.15, 29.82,29.75, 29.50, 26.39, 22.83, 20.65, 14.25. MS TOF LD+: 062H1 12N206 [M+H] found 980.9 |
With triethylamine In dichloromethane Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium carbonate In acetonitrile at 25℃; for 20h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium carbonate; In benzene; at 20℃; for 1.5h; | General procedure: Acetoxyacetyl chloride (17.6 mmol) was slowly added to a mixture of K2CO3(15.2 mmol), compound 2 (14 mmol) and benzene (34 mL) at room temperature. TLC monitored the reaction. Then the mixture was cooled, washed with water, and filtered.The filtrate was washed and dried over magnesium sulfate anhydrous. Benzene was removed under vacuum. The crude products were recrystallized with EtOAc and light petroleum. The physical and spectra data of the compounds 3a-f were as follows |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium carbonate; In benzene; at 20℃; for 1.5h; | General procedure: Acetoxyacetyl chloride (17.6 mmol) was slowly added to a mixture of K2CO3(15.2 mmol), compound 2 (14 mmol) and benzene (34 mL) at room temperature. TLC monitored the reaction. Then the mixture was cooled, washed with water, and filtered.The filtrate was washed and dried over magnesium sulfate anhydrous. Benzene was removed under vacuum. The crude products were recrystallized with EtOAc and light petroleum. The physical and spectra data of the compounds 3a-f were as follows: 3-Methyl-4-acetoxyacetyl-3,4-dihydro-2H-1,4-benzoxazine (3a) White solid; Yield 68%; mp 95-960. IR(KBr): 3019-2891(C-H), 1748-1686 (C=O),1586-1495(C=C); 1HNMR(CDCl3, 300MHz): 6.87-7.27(m, 4H, Ar-H), 5.00-5.05 (d, J=14.4 Hz, 2H, O-CH2-C=O), 4.71-4.76 (d,J=14.7 Hz, 1H, N-CH-Me), 4.13-4.22 (m, 2H, O-CH2-C), 2.14 (s, 3H, CH3-C=O), 1.17-1.19 (d, J=6.9Hz,3H, -CH3); 13C-NMR(CDCl3, 75MHz): 170.61, 165.47, 146.36, 126.82, 124.13, 122.67, 120.61, 117.28,70.03, 62.10, 44.04, 20.56, 15.14. ESI-MS m/z:250[M+H+]. [Found: C 62.68, H 6.04, N 5.56C13H15NO4requires C 62.64, H 6.07, N 5.62%]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With pyridine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | 61.1 Step 7: Preparation of 2-(7-bromo-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl acetate To a solution of 7-bromo-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine (537 mg, 2.50 mmol) in DCM (12 mL) was added pyridine (1.01 mL, 12.5 mmol). The reaction mixture was cooled to 0 °C and then dropwise added 2-chloro-2-oxoethyl acetate in DCM (6 mL). The reaction mixture was then warmed to 20 °C, stirred at 20 °C for 12 h under N2 atmosphere. The colorless solution turned to yellow gradually. LCMS (Rt = 0.560 min; MS Calcd: 313.9; MS Found: 314.8 [M+H]+). The reaction mixture was concentrated. The residue was purified by Combi Flash (l% Et3N in DCM) to afford 2-(7-bromo-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-oxoethyl acetate (630 mg, yield: 80%) as a yellow solid. (0955) NMR (400 MHz, CDCb) 2.21 (3H, s), 3.86 (2H, t, J= 4.4 Hz), 4.67 (2H, t , J= 4.8 Hz), 4.85 (2H, s), 8.08 (1H, d, J= 2.4 Hz), 8.55 (1H, brs). |
In tetrahydrofuran; ethyl acetate at 0 - 25℃; for 2h; Cooling with ice; | 89.1 Step 7: Preparation of 2-(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxoethyl acetate. [0611] A solution of 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (200 mg, 0.930 mmol) in THF (2 mL) was added EtOAc (282 mg, 2.79 mmol) and 2-chloro-2-oxoethyl acetate (508 mg, 3.72 mmol) at 0 °C. The ice bath was removed and the mixture was stirred for 2 h at 25 °C. The green solution turned to suspension. TLC showed the reaction was completed. The mixture was concentrated under reduced pressure. The residue was purified by Combi Flash (1% MeOH in DCM) to give 2-(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2- oxoethyl acetate (320 mg, crude) as a yellow solid. 'H NMR (400 MHz, DMSO-r/e) d 2.05 (3H, s), 3.86 (2H, t, J= 4.8 Hz), 4.40 (2H, t, J= 4.8 Hz), 5.01 (2H, s), 8.05 (1H, d, J= 2.4 Hz), 8.67 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | A mixture of acetoxyacetyl chloride (0.4 ml_, 3.8 mmol) and <strong>[13831-30-6]acetoxyacetic acid</strong> (457 mg, 3.9 mmol) in THF (3 ml_) was cooled to 0 C. A/,//-Diisopropylethylamine (1.8 ml_, 10.4 mmol) was added at less than 5 C. The resulting solution was warmed to room temperature and stirred for 30 min. 3-Hydroxycyclopent-1-ene-1 -carboxylic acid (HOCPCA) (Vogensen et al., 2013) (222 mg, 1.7 mmol) and 4-dimethylaminopyridine (22 mg, 0.2 mmol) were dissolved in THF (1.5 ml_). The solution was added to the re action mixture in one portion and was stirred for 3h at room temperature. Water (3 ml_) was added and the reaction was stirred for 90 minutes at room temperature. The mix ture was extracted with EtOAc. The combined organic phase was dried over Na2S04, filtered, and evaporated in vacuo. Purification by column chromatography (EtOAc/hep- tane 1 :1 + 1 % of AcOH) furnished 3-(2-acetoxyacetoxy)cyclopent-1-ene-1-carboxylic acid (35 mg, 9%) as a off-white solid. 1H NMR (600 MHz, Methanol-^) d: 6.62 (q, J = 2.1 Hz, 1 H), 5.85 - 5.82 (m, 1 H), 4.62 (s, 2H), 2.73 - 2.67 (m, 1 H), 2.57 - 2.51 (m, 1 H), 2.48 - 2.42 (m, 1 H), 2.12 (s, 3H), 1.98 - 1.92 (m, 1 H). 13C NMR (151 MHz, Methanol- d4) d 172.1 , 169.3, 167.7, 143.7, 139.0, 81.9, 61.9, 31.0, 31.0, 20.3. HPLC (254 nm): 95% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene; for 8h;Reflux; | Amidoxime 1 (3.0 g, 21 mmol) was addedwith stirring to PhMe (50 ml), then acetoxyacetyl chloride(6.7 ml, 63 mmol) was added. The reaction mixture wasbrought to a boil and heated under reflux for 8 h, thencooled to room temperature, and evaporated under reducedpressure. The residue was dissolved in MeOH (20 ml), H2O(10 ml) and HCl (1 ml) were added, and the mixture washeated under reflux for 2 h. The solvent was evaporatedunder reduced pressure, the residue was recrystallized fromMeOH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.1 g | With triethylamine In acetonitrile at 0℃; for 1h; | Description 33: 2-(allyl(benzyl)amino)-2-oxoethyl acetate (D33) A solution of 2-chloro-2-oxoethyl acetate (0.89 mL) in dry MeCN (10 mL) was added drop wise to a 0°C cooled solution of D32 (1.2 g, 8.16 mmol) and Triethylamine (2.2 mL 16.4 mmol) in dry MeCN (30 mL). The reaction was stirred at the same temperature for lhr then was diluted with EtOAc and washed with 5% citric acid solution and brine. The organic layer was dried over Na2S04, filtered and concentrated to afford D33 (2.1 g) as a colourless liquid that was used without further purification. Method 1; Rt:l.70. m/z: 248.27 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With triethylamine; In tetrahydrofuran; at 0 - 30℃; for 1h;Inert atmosphere; | To a solution of (2E)-3-(2-hydroxyphenyl)prop-2-enoic acid 18-1 (1.5 g, 9.1 mmol) in tetrahydraofuran (10 V) were added triethyalamine (2.9 mL, 22 0 mmol) and acetoxy acetyl chloride 4-1 (2.1 mL, 20 mmol) at 0 C. The reaction mixture was allowed to stir at 25-30 C over a period of 1 hour. The resulting reaction mass was concentrated under reduced pressure at 45 C. The crude product obtained upon evaporation of volatiles was purified through reverse phase column chromatography to obtain product 19- 1 as a white solid 0 75 g (31%). 1H NMR (400 MHz, D SO-dO) d 12.55 (s, 1H), 7.90 (d, 1H), 7.56 (d, IB), 7.48 (t, 1H), 7.35 (t, 1H), 7.23 (d, 1H), 6.58 (d, 1H), 5.02 (s, 2H), 2.15 (s, 3H); m/z [M+H]+ 265.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In dichloromethane at 0 - 20℃; Large scale; | 1.3 Step 3: Preparation of Roxatidine Hydrochloride Acetate Step 3: Preparation of Roxatidine Hydrochloride Acetate Add 3-[3-(1-piperidinylmethyl)phenoxy]alanine (31kg), dichloromethane (60L) into the reaction kettle, stir evenly, cool to 0, and add acetoxyacetyl chloride dropwise (18kg) dichloromethane mixed solution, drip the reaction at room temperature, monitor the completion of the reaction, add acetone to the reaction kettle, stir to crystallize, filter, and dry in a vacuum drying oven to obtain the product (40kg), yield 92%, purity 99.89% . (See Figure 4) |
92.1% | In dichloromethane at -5 - 5℃; for 1h; Inert atmosphere; | 1.4; 2.4; 3.3 4) Preparation of Roxatidine Hydrochloride Acetate Finished Product Add 40.0 g of fine N-[3-(3-aminopropoxy)-benzyl]piperidine (Ra-II) obtained in step 3) and 200.0 g of dichloromethane into the reaction flask; constant pressure dropping funnel Add 22.0 g of acetoxyacetyl chloride and 40.0 g of dichloromethane, and under the condition of nitrogen replacement and protection, the dichloromethane solution of acetoxyacetyl chloride in the constant pressure dropping funnel is controlled from -5 °C to 5 °C. It was added dropwise to the reaction flask, stirred for 1 hour after the dropwise addition, added 200.0 g of ethyl acetate, continued to stir for 1 hour, filtered, and the filter cake was rinsed with 80.0 g of ethyl acetate to obtain 57.0 g of white solid, namely rosatidine hydrochloride Acetate finished product (yield 92.1%, purity 99.86%, impurity II not detected). |
91.4% | With triethylamine In dichloromethane at -5 - 5℃; for 1h; Inert atmosphere; | 1-2; 1-5; 6.3 (2) in reaction flask, add the product that step (1) obtains,250.0 g isopropanol,Turn on stirring,150.0g isopropanol was added dropwise at a temperature of 55-60°CA solution prepared with 10.0 g of anhydrous oxalic acid,After dropping and cooling to 10°C to 20°C, filter, collect filter cake,Dissolve the filter cake in 500ml of water, and then add 15ml of industrial hydrochloric acid dropwise to dissolve it;Add 4.0 g of activated carbon to decolorize at room temperature for 1 h, filter, and collect the filtrate.Transfer the filtrate to a bottle and add dropwise a 10% sodium hydroxide solution,Adjust the pH to greater than 10,Add 150.0g of dichloromethane and stir at room temperature for 20min,The layers were separated, the dichloromethane layer was collected and concentrated to dryness,The intermediate N-[3-(3-aminopropoxy)-benzyl]piperidine (Ra-II) of roxatidine hydrochloride acetate was obtained (purity 99.89%, yield 91.4%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With triethylamine In dichloromethane at 0 - 20℃; for 19h; | General Procedure 3 (GP3) - N-acylation of piperazine: General procedure: Starting piperazine (1.0eq.) was dissolved in DCM (30mL), cooled on an ice-bath, and then Et3N (2.0eq.) and acetoxyacetyl chloride (1.2eq.) were added subsequently. The reaction mixture was stirred on ice-bath for 1h, and subsequently at room temperature for 18h. The reaction mixture was washed with H2O (2×30mL) and saturated brine (30mL), dried over Na2SO4, filtered, and the volatile components were evaporatedin vacuo. The product was purified by column chromatography. |
74% | With triethylamine In dichloromethane at 0 - 20℃; for 19h; | General Procedure 3 (GP3) - N-acylation of piperazine: General procedure: Starting piperazine (1.0eq.) was dissolved in DCM (30mL), cooled on an ice-bath, and then Et3N (2.0eq.) and acetoxyacetyl chloride (1.2eq.) were added subsequently. The reaction mixture was stirred on ice-bath for 1h, and subsequently at room temperature for 18h. The reaction mixture was washed with H2O (2×30mL) and saturated brine (30mL), dried over Na2SO4, filtered, and the volatile components were evaporatedin vacuo. The product was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With triethylamine In dichloromethane at 0 - 20℃; for 19h; | General Procedure 3 (GP3) - N-acylation of piperazine: General procedure: Starting piperazine (1.0eq.) was dissolved in DCM (30mL), cooled on an ice-bath, and then Et3N (2.0eq.) and acetoxyacetyl chloride (1.2eq.) were added subsequently. The reaction mixture was stirred on ice-bath for 1h, and subsequently at room temperature for 18h. The reaction mixture was washed with H2O (2×30mL) and saturated brine (30mL), dried over Na2SO4, filtered, and the volatile components were evaporatedin vacuo. The product was purified by column chromatography. |
60% | With triethylamine In dichloromethane at 0 - 20℃; for 19h; | General Procedure 3 (GP3) - N-acylation of piperazine: General procedure: Starting piperazine (1.0eq.) was dissolved in DCM (30mL), cooled on an ice-bath, and then Et3N (2.0eq.) and acetoxyacetyl chloride (1.2eq.) were added subsequently. The reaction mixture was stirred on ice-bath for 1h, and subsequently at room temperature for 18h. The reaction mixture was washed with H2O (2×30mL) and saturated brine (30mL), dried over Na2SO4, filtered, and the volatile components were evaporatedin vacuo. The product was purified by column chromatography. |
Tags: 13831-31-7 synthesis path| 13831-31-7 SDS| 13831-31-7 COA| 13831-31-7 purity| 13831-31-7 application| 13831-31-7 NMR| 13831-31-7 COA| 13831-31-7 structure
[ 17229-14-0 ]
Ethyl 2-(2-chloroethoxy)acetate
Similarity: 0.81
[ 83881-47-4 ]
Methyl 2-(2-chloroethoxy)acetate
Similarity: 0.78
[ 17229-14-0 ]
Ethyl 2-(2-chloroethoxy)acetate
Similarity: 0.81
[ 83881-47-4 ]
Methyl 2-(2-chloroethoxy)acetate
Similarity: 0.78
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P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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