Structure of Anticancer agent 209
CAS No.: 545445-44-1
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CAS No. : | 545445-44-1 |
Formula : | C20H25N3O3 |
M.W : | 355.43 |
SMILES Code : | O=C1C(N2CCOCC2)=CCCN1C3=CC=C(N4C(CCCC4)=O)C=C3 |
MDL No. : | MFCD19440881 |
InChI Key : | SCVWQFDPLBFZAP-UHFFFAOYSA-N |
Pubchem ID : | 22352226 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 26 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.5 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 110.28 |
TPSA ? Topological Polar Surface Area: Calculated from |
53.09 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
3.21 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.59 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.01 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.44 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.89 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.83 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.02 |
Solubility | 0.341 mg/ml ; 0.000959 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.32 |
Solubility | 1.72 mg/ml ; 0.00483 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.52 |
Solubility | 0.108 mg/ml ; 0.000304 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
Yes |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
Yes |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.34 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
3.44 |
* 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 |
---|---|---|
With ammonium hydroxide; caesium carbonate; In ethyl acetate; toluene; | Part B. Soluble copper(I)-catalyzed Ullmann coupling reaction. A suspension of 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (10, 2.2 g, 5.73 mmol), piperidin-2-one (42, 851 mg, 8.59 mmol, 1.5 equiv), and Cs2CO3 (3.73 g, 11.46 mmol, 2.0 equiv) in toluene (15 mL) was treated with Cu(PPh3)3Br (1.065 g, 1.146 mmol, 20% equiv) at room temperature under N2, and the resulting reaction mixture was degassed three times under a steady stream of nitrogen. The reaction mixture was warmed up to reflux for 6 h. When HPLC showed the Ullmann coupling reaction was complete, the reaction mixture was cooled down to 5-10 C. before being quenched with 14% of ammonium hydroxide aqueous solution (20 mL) and EtOAc (30 mL) at 5-10 C. The mixture was stirred for an additional 4 h at 25 C. The two layers were then separated, and the aqueous layer, was extracted with EtOAc (3*20 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was directly purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution) to afford the desired 3-morpholin-4-yl-1-[4-(2-oxo-piperidin-1-yl)-phenyl]-5,6-dihydro-1H-pyridin-2-one (63, 1.568 g, 2.036 g theoretical, 77%) as a pale-yellow oil, which solidified upon standing at room temperature in vacuo. For 63, CIMS m/z 356 (M++H, C2OH25N3O3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; triethylamine; In ethyl acetate; | Example 55 1-(4-Methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (65). A solution of chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester (34, 470 mg, 1.3 mmol) in EtOAc (4 mL) was treated with 3-morpholin-4-yl-1-[4-(2-oxo-piperidin-1-yl)-phenyl]-5,6-dihydro-1H-pyridin-2-one (63, 334 mg, 1.3 mmol, 1.0 equiv) at 0-5 C. under N2, and the resulting reaction mixture was treated with triethylamine (TEA, 263 mg, 0.33 mL, 2.6 mmol, 2.0 equiv) at 0-5 C. under N2. The reaction mixture was then warmed up to room temperature for 30 min before being warmed up to reflux for an additional 6 h. When HPLC and TLC showed that the reaction was complete, the reaction mixture was cooled down to 5-10 C. before being treated dropwise with a 4.0 N aqueous HCl solution (1.7 mL, 6.5 mmol, 5.0 equiv) at 0-5 C. The resulting mixture was stirred at 5-20 C. for 4 h. The resulting slurry was then treated with water (10 mL) and EtOAc (10 mL) before the two layers were separated. The aqueous layer was extracted with EtOAc (2*10 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL), dried over MgSO4, and concentrated in vacuo. The residue was directly purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution) to afford the desired 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (65, 423 mg, 635 mg theoretical, 67% for two steps) as pale-yellow solids, which solidified upon standing in vacuo at room temperature. For 65, CIMS m/z 489 (M++H, C27H28N4O5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.5% | With sodium hydride; In tetrahydrofuran; at 10 - 25℃;Inert atmosphere; | The 1f (12.8g, 32.7mmol) was dissolved in tetrahydrofuran (250ml) in an ice bath was added portionwise sodium hydride (1.73g, 72.1mmol) to obtain a reaction mixture, said reaction mixture at room temperature overnight. Tracking progress of the reaction by TLC, the reaction was completed, the reaction mixture was added to ice water and quenched with sodium hydride, tetrahydrofuran was removed by distillation under reduced pressure, dichloromethane was added and extracted two times the combined organic phases were dried over anhydrous magnesium sulfate, filtered, after the solvent was distilled off under reduced pressure, the residue was purified by column chromatography to give 1g (9.8g, yellow solid), yield: 84.5%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine; potassium iodide; In dichloromethane; at 42 - 45℃; | Product of example-VA (14.2 g, 0.04 mol), TEA (17 mL, 0.12 mol), and KI (0.64 g, 0.004 mol) were added to a solution of the product of example-VI (11.3 g, 0.044 mol) in MDC (80 mL) at room temperature. The mixture was stirred at 42-45 C. for 12-15 hrs and then cooled to 0 C. To the resulting mixture was added 4.0N hydrochloric acid (50 mL, 0.02 mol) drop wise and stirred at room temperature for 2-4 hrs. Thereafter water (100 mL) was added to the mixture to separate the organic layer. The aqueous layer was extracted with MDC, 50 mL and then the combined organic extracts were washed with brine (2*100 mL), and concentrated to dryness. Recrystallization of the residue from EtOAc and drying in vacuum afforded product as cream colored solid. Yield: 16.58 g, 85%. Purity: 99.5+% |
35 g | Example-10 Preparation of ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (Formula-11) A mixture of 3-morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridin-2(1H)-one compound of formula-8 (30 g), sodium carbonate (26.83 g) and acetone (150 ml) was heated to 45-50 C. (Z)-ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate compound of formula-9 (32.5 g) was added to the reaction mixture at 45-50 C. and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 25-30 C. and aqueous hydrochloric acid (50 ml) in 50 ml of water was added to it at 25-30 C. Stirred the reaction mixture for 2 hours at 25-30 C. Water was slowly added to the reaction mixture and stirred for 45 minutes at 25-30 C. Filtered the obtained solid and washed with water. The obtained solid was recrystallized from toluene (150 ml) to get the title compound. Yield: 35 gm; MR: 155-160 C.; HPLC purity: 97%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 4 Preparation of {5-hydroxy-6-oxo-l-[4-(2-oxopiperidin-l-yl)phenyl]-l,2,3,6-tetrahydropyridin-4- yl}(oxo)acetic acid. 5,6-Dihydro-3-(4-mophiholinyl)-l-[4-(2-oxo-l-piperidinyl)phenyl]-2(lH)-pyridinone (100 gm) is stirred with sodium monoethyl oxalate (45.3 gm) in Ethanol (800 ml. After the reaction completion ethanol is distilled completely and Ethyl acetate (100 ml) is added. To this 10 % HCl solution (500 ml) is added and stirred for 1 hr. The solid is filtered and dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | EXAMPLE 1 Preparation of ethyl {5-hydroxy-6-oxo-l-[4-(2-oxopiperidin-l-yl)phenyl] -1,2,3,6- tetrahydropyridin-4-yl}(oxo)acetate. 5,6-Dihydro-3-(4-mophiholinyl)-l-[4-(2-oxo-l-piperidinyl)phenyl]-2(lH)-pyridinone (100 gm) is stirred with Ethyl oxalyl chloride (42.24 gm) in dichloromethane (800 ml) in the presence of Pyridine (26.7 gm) at 25-30C for 3 hrs. After the reaction completion dichloromethane is distilled completely and Ethyl acetate (100 ml) is added. To this 10 % HCI solution (500 ml) is added and stirred for 1 nr. The solid is filtered and dried. Yield 90% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54 mg | With triethylamine; potassium iodide; In ethyl acetate; at 25 - 80℃; | In a clean round bottomed flask ethyl acetate (525ml), ethyl (2Z)-[4-(benzyloxy)phenyl]hydrazono}(chloro)acetate (35gm), potassium iodide (1.73 g), 3-morpholino-1-[4-(2-oxopiperidin-1-yl)phenyl]-5,6-dihydropyridin-2(1H)-one (31.82g) and triethylamine (42.63g) were added at about 25-30C . The reaction mass was heated to about 75-80C for about 10-15 hrs. After completion, the reaction, mass was cooled to about 0 - 5C and dilute hydrochloric acid was added slowly to the reaction mass. The temperature of the reaction mass was raised to about 25-30C and stirred for 5-7 hrs. Ethyl acetate and water were added to the reaction mass and stirred for 15 min. The layers were separated and the organic layer was washed with aq. sodium carbonate solution followed by water and brine solution. The organic layer was concentrated under vacuum and cooled to about 25-30C. Di isopropyl ether was added to the reaction mass and stirred for 1 hr. The precipitated solid was filtered and washed with di isopropyl ether. The solid was dried under vacuum at 45-50C for 12hrs to obtain 54gm of 1-(4-benzyloxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1- yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.9% | With triethylamine; potassium iodide; In ethyl acetate; for 24h;Reflux; | (14 mmol) of the compound of the formula (IV) and 4. 0 g (16 mmol)The compound of structure (V) was added to 150 mL of ethyl acetate,0.35 g (2 mmol) of KI, 6.8 ml (49 mmol) of triethylamine was added and refluxed for 24 h, Cooled to 0C degrees, dropping 4M dilute hydrochloric acid 20mL, stirring at room temperature 2h, filtration, a small amount of cold ethyl acetate washing, water hit the public, about 50 C blast drying,To obtain crude product 6. 5g, yield 94. 6%, and then recrystallized from ethyl acetate, To obtain 5.8 g of a solid, powdery product,The yield was 89% and the purity was 99.8%. |
76% | With triethylamine; In ethyl acetate; toluene; at 85℃; for 7h; | Toluene (25 mL) was added to the reaction flask.Triethylamine (2.60 g, 25.7 mmol) and ethyl acetate (25 mL),Starting material A (2.80 g, 10.9 mmol) and starting material B (3.00 g, 8.4 mmol),The temperature was raised to 85 ° C by heating and stirred for 7 hours.The reaction solution was cooled to 25 °C. Adding a hydrochloric acid solution to the reaction solution,The dropping time is controlled at 25 minutes and the temperature is controlled at 30 °C.After the dropwise addition was completed, the reaction was stirred at 30 ° C for 1 hour.15 mL of purified water was added and stirred for 30 minutes. Filter the filter cake,Add 20 mL of isopropanol for washing.Drying apixaban intermediate 1 13.12g,The molar yield was 76.0percent. |
54 mg | With triethylamine; potassium iodide; In ethyl acetate; at 25 - 80℃; for 24h; | In 3 lit four neck equipped round bottomed flask (RBF) equipped, ethyl acetate (2.5L), 3- morpholino-l-[4-(2-oxopiperidin-l-yl)phenyl]-5,6-dihydropyridin-2(1H)-one (50gm,), acetic acid 2-chloro-2-[-(4-methoxyphenyl)hydrazinylidene]ethyl ester (36.1 gm) , ethyl amine (57 gm) and potassium iodide (2.4 gm) were added sequentially at about 25-30C . The reaction mass was heated to about 75-80C for about 24 hrs. After completion, the reaction mass was cooled to about 0 - 5C and dilute hydrochloric acid was added slowly to the reaction mass at about 0- 5C. The temperature of the reaction mass was raised to about 25-30C and stirred for 2 hrs. Water was added to the reaction mass and stirred for 15 min. The layers were separated and the organic layer was washed with aq. sodium carbonate solution followed by water. The organic layer was partially concentrated under vacuum and cooled to about 25-30C. Isopropyl ether was added to the reaction mass and stirred for 1 hr. The precipitated solid was filtered and washed with isopropyl ether. The solid was dried under vacuum at 45-50C for 12hrs to afford 54 gm of 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H- pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (HPLC purity>99%) |
The compound of formula (VIII) was prepared according to the method disclosed in the Journal Synthetic Communication, 2013, vol. 43, pag. 72-79, in particular, the paragraph entitled "Ethyl 1 -(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (2)" at pag.78, starting from the compound of formula (IX) prepared according to the example 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With bromotris(triphenylphosphine)copper(I); In 5,5-dimethyl-1,3-cyclohexadiene;Dean-Stark; Reflux; | Example-5 Preparation of 3-morpholin-4-yl-1-[4-(2-oxo-piperidin-1-yl)-phenyl]-5,6-dihydro-1H-pyridin-2-one A suspension of 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (75 g, 0.194 moles), 2-piperidone (48 g, 0.485 moles) and tripotassium phosphate (103 g, 0.485 moles) in xylene (750 ml) was treated with Cu(PPh3)3Br (54.5 g, 0.058 moles) at room temperature and heated to reflux by using a dean stark water separator for 8-10 hrs. After completion, the reaction mass was cooled to 0-5 C. Aqueous ammonia (750 ml) and ethyl acetate (1125 ml) were added to the reaction mixture and stirred for 2-3 hrs. The resultant solid was filtered and washed with ethyl acetate (20 ml) to get a solid, which was dissolved in methylene dichloride (375 ml) at 35-40 C. and treated with activated carbon. The resultant solution was filtered through a hyflow bed and distilled under vacuum to get an residue; followed by addition of methanol (90 ml) and the reaction mass was cooled to 0-5 C., stirred for 1 hr at the same temperature and filtered to get a solid material. The obtained solid was washed with methanol to get 59 g (84%) of the title compound with >99% purity. |
84% | With potassium phosphate; bromotris(triphenylphosphine)copper(I); In 5,5-dimethyl-1,3-cyclohexadiene;Reflux; Dean-Stark; | A suspension of l-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-lH-pyridin-2-one (75 g, 0.194 moles), 2-piperidone (48 g, 0.485 moles) and tripotassium phosphate (103 g, 0.485 moles) in xylene (750 ml) was treated with Cu(PPh3)3Br (54.5 g , 0.058 moles) at room temperature and heated to reflux by using a dean stark water separator for 8-10 hrs. After completion, the reaction mass was cooled to 0-5C. Aqueous ammonia (750 ml) and ethyl acetate (1125 ml) were added to the reaction mixture and stirred for 2-3 hrs. The resultant solid was filtered and washed with ethyl acetate (20 ml) to get a solid, which was dissolved in methylene dichloride (375 ml) at 35-40C and treated with activated carbon. The resultant solution was filtered through a hyflow bed and distilled under vacuum to get an residue; followed by addition of methanol (90 ml) and the reaction mass was cooled to 0-5C, stirred for 1 hr at the same temperature and filtered to get a solid material. The obtained solid was washed with methanol to get 59 g (84%) of the title compound with > 99% purity. |
35 g | Example-8 Preparation of 3-morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydro pyridin-2(1H)-one (Formula-8) A mixture of 1-(4-iodophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one compound of formula-7 (50 g), piperidin-2-one (32.25 g) and o-xylene (75 ml) was stirred for 10 minutes at 25-30 C. Potassium carbonate (27.0 g), followed by copper iodide (7.43 g) were added to the reaction mixture. The reaction mixture was heated to 140-145 C. under azeotropic distillation condition and stirred for 6 hours at the same temperature. Cooled the reaction mixture to 35-40 C., water (175 ml) was slowly added to the reaction mixture at 35-40 C. Cooled the reaction mixture to 10-15 C. and ammonia (125 ml) was added to the reaction mixture at 10-15 C. The temperature of the reaction mixture was raised to 25-30 C. and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and then dried to get title compound. Yield: 35 gm; MR: 195-200 C.; HPLC purity: 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.3% | With triethylamine; In ethyl acetate; at 80℃;Inert atmosphere; | The lg (280mg, 0. 79mmol) was dissolved in ethyl acetate (10ml), and added at room temperature [(4-methylphenyl)hydrazono]chloroacetic acid ethyl ester (246mg, 1.02mmol), triethylamine (242mg , 2. 4mmol) to give a reaction mixture, and the reaction mixture was refluxed overnight at 80 C under. Tracking progress of the reaction by TLC, the reaction was completed, slowly added dropwise 4Nu HC1 (1.6ml) at room temperature to obtain a reaction mixture, said reaction mixture at room temperature overnight. TLC withTrack progress of the reaction, the reaction was complete, was purified by column chromatography lh (295mg, yellow solid), yield: 79.3% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.8% | With triethylamine; In ethyl acetate; at 80℃;Inert atmosphere; | The 1g (280mg, 0.79mmol) was dissolved in ethyl acetate (10ml), and at room temperature was added [(4-methylthio-phenyl) hydrazono]chloroacetic acid ethyl ester (280mg, 1.03mmol), triethylamine (242mg , 2.4 mmol) to obtain a reaction mixture, and the reaction mixture was refluxed overnight at 80 C . Tracking progress of the reaction by TLC, the reaction was completed, slowly added dropwise 4N HCl (1.6ml) at room temperature to obtain a reaction mixture, said reaction mixture at room temperature overnight. TLC tracking progress of the reaction, the reaction was complete, was purified by column chromatography 2h (205mg, yellow solid), yield: 50.8% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.9% | With triethylamine; In ethyl acetate; at 80℃;Inert atmosphere; | The 1g (280mg, 0.79mmol) was dissolved in ethyl acetate (10ml), and at room temperature was added [(2-fluorophenyl)hydrazono]chloroacetic acid ethyl ester(255mg, 1.04mmol), triethylamine (242mg, 2.4 mmol) to give a reaction mixture, and the reaction mixture was refluxed overnight at 80 C . Tracking progress of the reaction by TLC, after completion of the reaction, at room temperature was slowly added dropwise 4N HCl (1.6ml) to give a reaction mixture, said reaction mixture at room temperature overnight. Thin-layer chromatography to track progress of the reaction, the reaction was complete, was purified by column chromatography 3h (255mg, yellow solid), yield: 67.9% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.2% | With triethylamine; In ethyl acetate; at 80℃;Inert atmosphere; | The 1g (280mg, 0.79mmol) was dissolved in ethyl acetate (10ml), and at room temperature was added [(3-fluoro-4-methoxyphenyl)hydrazono]chloroacetic acid ethyl ester (286mg, 1.04mmol), triethylamine (242mg, 2.4mmol) to give a reaction mixture, and the reaction mixture was refluxed overnight at 80 C . Tracking progress of the reaction by TLC, the reaction was completed, slowly added dropwise 4N HCl (1.6ml) at room temperature to obtain a reaction mixture, and the mixture was reacted at room temperature overnight. TLC tracking progress of the reaction, the reaction was complete, was purified by column chromatography 4h (344mg, yellow solid), yield: 86.2% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.27% | A solution of 5-chlorovaleroyl chloride (CVC, 82 gm, 0.5273 mol) in MDC (100 ml) was added to the suspension of product of example-IV (125 gm, 0.4573 mol), sodium hydroxide (22 gm, 0.55 mol), TBAB (3.75 gm) in MDC (1150 ml) and Water (49 ml) at 0-5 C. over 1 hr. The mixture was slowly brought to 25 to 30 C., and then the aq. solution of KOH (187 gm, 3.33 mol in 311 ml water) was added slowly in 10-15 min and stirred for 8-10 hrs at room temperature. 300 ml water was added to the reaction mass and stirred for 10 min. Organic layer was separated, washed with water (300 ml) and distilled at 50 C. to get a solid product. Recrystallization of the solid from EtOAc afforded the desired product as a buff colored solid. Yield: 153 gm, 94.27% Purity: 98+%; MP 204-206 C. | |
89% | Compound 3 (27 · 3 g, 0.1 mol), 546 mL of dichloroethane was added to a three-necked flask, cooled to 0 C in an ice bath, tetraethylammonium hydroxide (103 g, 0.7 mol) was added, and stirred for 10 min in an ice bath. Then, 5-chlorovaleryl chloride (18.6 g, 0.12 mol) was added dropwise, and the temperature was controlled at 0 to 5 C. After the completion of the dropwise addition, the ice bath was heated to reflux (80 to 85 C), and the reaction was carried out for 5 hours. The reaction materials and the intermediate state were monitored. The synthesis solution was cooled to room temperature, washed with 500 mL of water, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from acetonitrile to give 31.6 g of Compound 1 as a yellow solid.Its yield: 89%. | |
87.5% | 2 g compound C (compound Ib) and 50 ml acetonitrile were added into a three-necked flask to obtain a turbid solution. The turbid solution was stirred and cooled to 0 C. in an ice bath. 1.75 g (6 eq) sodium hydroxide was added and stirred in the ice bath for 10 min. Then 1.9 ml of 5-chloro-valeryl chloride (2 eq) (diluted with 2 ml acetonitrile) was dropwise added while controlling the temperature to 0-5 C. After completing the addition, the ice bath was removed and the temperature was naturally raised to 30 C. The reaction was performed for 5 hours. After observing the absence of the starting material and the intermediate state of the reaction, the reaction solution was cooled to 0 C. in an ice bath, and adjusted to a neutral pH with 6 N of hydrochloric acid. The reaction solution was concentrated to dryness, pulpifying for 1 hour after adding 8 ml saturated sodium bicarbonate solution, and filtered to obtain 2.29 g yellow solid. Yield: 87.5%. Purity: 95.3% (HPLC). EI-MS (m/z): 355.2. HNMR (400 MHz, DMSO, ppm) delta7.32 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 5.71 (t, J=4.8 Hz, 1H), 3.72-3.69 (m, 2H), 3.65-3.63 (m, 4H), 3.60-3.57 (m, 2H), 2.79-2.77 (m, 4H), 2.44-2.41 (m, 2H), 2.40-2.39 (m, 2H), 1.88-1.82 (m, 4H). |
86.8% | A 4-neck round bottom flask was charged with 80 g of said compound of formula (X) (1.0 eq.) (prepared as said above and containing the impurities of formula (VI) and (VII)), then with 68,3 g of triethylamine (TEA) (2.3 equiv.) and 800 mL of tetrahydrofuran (THF). A solution of 68.3 g of chlorovaleryl chloride (1 ,5 equiv.) in 160 mL of THF was dosed within 1 -2 hours at T=0/5C. The mixture is stirred at T=0/5C for additional 30 minutes, thereafter maintaining the same temperature, a solution of 98,1 g of potassium tert- butoxide (3.0 eq.) in 400mL of THF is dosed over 30-45 minutes. After 30 minutes stirring at T=0/5C, the mixture is warmed to T=20/25C for additional 2 hours. Once checked for reaction completion, the batch is distilled at reduced pressure and Tmax=35C to residual 6 volumes (480 mL) and then stripped with 560 mL of ethanol under the same conditions, again to residual 6 volumes (480 mL). The resulting mixture is diluted with 720 mL of ethanol and 880 mL of water, then the opalescent solution obtained is heated to T=40/45C and filtered on dicalite, washing with 80 mL of pre-heated ethanol (this solid cake is the starting material of the example 3). The filtered solution is distilled under reduced pressure to residual 6 volumes (480 mL). The mixture is cooled down to T=20/25C and stirred at this temperature for at least 1 hour. The slurry is finally filtered washing the wet cake with water (2 x 80 mL). Upon drying at reduced pressure and T=65C for at least 8 hours, 90.3 g of the compound of formula (IX)are obtained, (molar yield 86.8%). This solid contained the following dimer impurities: - 0,04% (HPLC A/A%) dimer impurity of formula (VI), - 0,09% (HPLC A/A%) dimer impurity of formula (VII). | |
72% | Room temperature, Compound 7 (5.8 g, 0.322 mmol), triethylamine 10. 6ml, tetrahydrofuran 176ml added to the reaction flask, stirring, cooling to 0 C, 5-chloropentanoyl chloride (5. 9g) Reaction lh; 0 C conditions, Sodium hydride (2 g, 0.083 mol) was added, Warm to Room temperature reaction 3h, The organic phase was washed with saturated brine once, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated to give a pale yellow solid. 15.3 g, nil Water ethanol recrystallization was a white solid, after drying 8. 2g, 0.023mol. Yield 72%, m.p. 202-204 C. HPLC: 99. 47% (instrument: Waters high performance liquid chromatography, column: C18, column length: 25 cm, mobile phase: water: Flow rate: l.Oml / min, wavelength: 254nm, column temperature: 30 C, injection volume: 10mu1) | |
5.2 g | Add 150 mL of dichloromethane to a 250 mL four-neck reaction flask.1.6 g of triethylamine and 3.5 g of starting material SM-1.Add 2.4g of SM-2 raw material under ice bath,After the dropwise addition, control the internal temperature to 10-30 C for 1 hour.4.5g of sodium ethoxide was subsequently solid,Add to reaction flask.The temperature was raised to 10-30 C, and the reaction was stirred for 2 hours.After the reaction was completed, 100 mL of drinking water was added.Stir for 30 minutes and pour into the separatory funnel for layering.The upper aqueous solution was extracted once with 100 mL of dichloromethane.The lower organic phases were combined and concentrated to give 5.2 g of APSB-1 solid. |