Structure of 446292-07-5
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CAS No. : | 446292-07-5 |
Formula : | C21H21N3O5 |
M.W : | 395.41 |
SMILES Code : | O=C1N(C[C@H](O)CNC2=CC=C(N3C(COCC3)=O)C=C2)C(C4=C1C=CC=C4)=O |
MDL No. : | MFCD11977664 |
InChI Key : | CKFVSMPWXAASIQ-MRXNPFEDSA-N |
Pubchem ID : | 11516758 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 29 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.29 |
Num. rotatable bonds | 6 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 112.25 |
TPSA ? Topological Polar Surface Area: Calculated from |
99.18 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.68 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.98 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.17 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.19 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.65 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.33 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.82 |
Solubility | 0.6 mg/ml ; 0.00152 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.65 |
Solubility | 0.883 mg/ml ; 0.00223 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.92 |
Solubility | 0.00481 mg/ml ; 0.0000122 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
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) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-8.02 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
3.04 |
* 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 |
---|---|---|
93% | at 20 - 100℃; for 3 h; | Example 3:Preparation of 2-((2R)-2-Hydroxy-3-[4-(3-oxomorpholin-4-yl)- phenyl]amino}proply)-1 /-/-isoindole-1 ,3(2H)-dione (7a): Potassium phthalimide (7.16 g, 38.632 mmoL) was added in one portion to a mechanically stirred mixture of 4-[4-(N-(3-chloro-2R-hydroxy-1-propyl)amino)phenyl]morpholin-3- one (10 g, 35.119 mmoL) in DMF (60 mL). The suspension was stirred at room temperature and was heated to 100 °C, stirred at that temperature for 3 h and then cooled to room temperature. Water (60 mL) was charged and the suspension stirred for another 15 min. The suspension was filtered through a Buchner funnel. The solid was washed with water (2 x 40 mL) and dried under vacuum at 50°C for 10 h to yield 2-((2f?)-2-Hydroxy-3-[4-(3-oxomorpholin-4- yl)-phenyl]amino}proply)-1 7-isoindole-1 ,3(2/-/)-dione (12.55 g, 93percent) as a crystalline white solid.1HNMR (400MHz, DMSO-d6) δ 2.99-3.05 (m, 1 H), 3.14-3.2 (m, 1 H), 3.59-3.69 (m, 4H), 3.91-3.94 (m, 2H), 3.97-4.05 (m, 1 H), 4.14 (s, 2H), 5.16 (d, J=5.2 Hz, 1 H), 5.66 (t, J=6.0 Hz, 1 H), 6.61 (d, J=8.7 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 7.82-7.88 (m, 4H). |
92% | Stage #1: With sodium hydroxide In dichloromethane; water at 20℃; for 8 h; Stage #2: at 100℃; for 3 h; |
The above 57.6 g of intermediate 4 and 400 mL of dichloromethane were charged into a 1 L three-necked flask,A solution of 17.8 g of Na0H and 60 mL of water was added dropwise at room temperature,After stirring at room temperature for 6 h, the organic layer was washed with 120 mL of water and then with 60 mL of saturated brine,The organic layer was dried over anhydrous sodium sulfate,Filtered, concentrated to 180mL of liquid, by adding 360mL n-hexane heated reflux 30min,System cooling to room temperature and then stirring 2h,The filter cake was washed with dichloromethane and n-hexane (1: 3)The filter cake was dried in vacuo for 12 h to give 48.2 g of white crystals.48 g (0.17 mol) of the above solid and 240 mL of the 4-dioxane were charged into a 500 mL three-necked flask,34.4 g (0.19 mol) of potassium phthalimide potassium salt was added with stirring,System gradually heated to 100 ° C, stirring 3h, cooling to room temperature, add 60mL water stirring 15min,Filter, filter cake washed with 2X1 OOmL,White crystals were obtained at 50 ° C in vacuum and dried 1 Oh to give 60.2 g of compound 6 (92percent) mp. = 211.7-211.9 ° C. |
87.8% | for 10 h; Reflux | The reaction flask, and the resulting 32.7g (0.115mol) of intermediate V with 300ml of anhydrous methanol was dissolved, followed by addition of 29.1g (0.157mol) of potassium phthalimide and heated at reflux for 9 hours, TLC in the control (ethyl acetate: methanol = 10: 1, volume ratio) to complete the reaction, filtered hot, the filtrate was lowered to room temperature (about 25 ) was stirred for 2 hours, filtered, the filter cake was rinsed with 75ml of anhydrous methanol, and drying under reduced pressure, intermediate VI to give an off-white about 39.9g (0.101mol), intermediate V molar yield intermediate VI is prepared from about 87.8percent. |
87.8% | for 9 h; Reflux | In the reaction flask, the obtained 32.7 g (0.115 mol) of the intermediate V was dissolved with 300 ml of anhydrous methanol,Then, 29.1 g (0.157 mol) of potassium phthalimide was added and the mixture was heated to reflux for 9 hours.The reaction was completed by TLC (ethyl acetate:methanol=10:1, volume ratio) and the reaction was complete. The filtrate was cooled to room temperature (about 25° C.) and stirred for 2 hours. The mixture was filtered, and the filter cake was rinsed with 75 ml of anhydrous methanol. drying,About 39.9 g (0.101 mol) of the off-white intermediate VI was obtained, and about 87.8percent of the intermediate V was produced in the molar yield of the intermediate VI. |
51.4 g | for 10 h; Reflux | In the reaction flask, the obtained 42.6 g (0.15 mol)Intermediate V was dissolved with 400 ml anhydrous methanol.Then 38.8 g (0.21 mol) of potassium phthalimide was added,The mixture was heated at reflux for 10 hours, and the reaction was completed by TLC (ethyl acetate: methanol = 10:1, volume ratio).Heat filtered, the filtrate was cooled to room temperature (about 25°C) and stirred for 2 hours, filtered,The filter cake was rinsed with 100 ml of anhydrous methanol and dried under reduced pressure to obtain about 51.4 g (0.13 mol) of the off-white intermediate VI. The intermediate V produced the intermediate VI in a molar yield of about 86.7percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | at 65 - 70℃; for 32 h; | 4-(4-aminophenyl)morpholinone 100 gm, 0.5202 moles and (S)-(+)glycidyl phthalimide 106.6 gm ( 0.5246 moles) was charged to the mixture of, methanol and water 1000 ml (9: 1) and heated to 65°C-70°C. Continued stirring for next 20 hrs at 65°C-70°C. Add second lot of S)-(+)glycidyl phthalimide 10.6 gm (0.05246 moles) and 200 ml (9: 1) methanol water mixture and stir for next 12 hrs. Cooled the reaction mass to 25°C-30°C and filter the slurry on Buckner funnel, suck dried well. Wet cake washed with 100 ml mixture of methanol and water (9: 1). The solid obtained was dried at 50°C to 55°C to get 190 gm compound of Formula-3 as dry material. Yield-92percent |
92% | for 10 h; Reflux | Add 4-(4-aminophenyl)morphin-3-one (192.2 g, 1 mol) to a 1000 ml three-necked flask,2-(2-chloroethoxy)propane(203.2 g, 1 mol), 790 ml of ethanol, stirring was started, the temperature was raised to reflux, and the TLC was detected. It was found that the starting material disappeared after 10 hours of reaction, and the reaction was completed and lowered to room temperature. After suction filtration, 100 ml of ethanol was washed three times, and the compound (4) was dried to obtain 363.78 g, the yield was 92percent, and the HPLC detection was 98.67percent. |
89.7% | for 14 h; Reflux | A mixture of 5.68 g(27.9 mmol) of compound V was added compound VI 5.35 g (27.9 mmol) was suspended in 140 ml of 1/9 water - ethanol, stirring reflux for 14 hours, cooled to 20 °C, filter, filter the filter cake with ethanol 3 times. 65-70 °C under reduced pressure, to obtain 9.9 g of the compound of the formula (I) (yield: 89.7percent ) HPLC content 98.5percent (normalization). |
87.5% | at 25℃; for 24 h; Reflux | In a four neck round bottom flask charged Isopropyl alcohol (135 ml), 4-(4-aminophenyl) morpholin-3-one (10 g), 2-[(2s)-oxiran-2yl methyl]-lH-isoindole-l,3(2H) dione ((11.6 g) and water (15 ml) at 25 to 30°C. Slowly heated the reaction mixture to reflux and maintained for 24 h at reflux temperature. Reaction mass is cooled to 25 to 30°C after completion of the reaction. Reaction mass then maintained at 25 to 30°C for 30 minutes. Finally obtained solid is filtered off and washed by isopropyl alcohol (25 ml) Yield 87.5percent |
87.5% | for 24 h; Reflux | To a 2 litre 4 neck RBF, charge Methanol (1500 ml), 4-(4-aminophenyl)-3-morpholinone Compound (VI), (100 gms), (S)-Glycidyl Phthalimide Compound (V), (127 gms). Reflux the reaction mass for 24 hrs. Cool the reaction mass at 25-30°C and filter. Wash the residue with Methanol (50 ml). Dry the solid at 45-50°C under vacuum. Dry Wt: 180 gms (Theoretical yield: 87.50percent); Purity: 98.20percent |
82.6% | Reflux | A suspension of 4-(4-aminophenyl)morpholin-3-one (100 gm) and 2-[(2S)-oxiran-2-ylmethyl}-1H-isoindole-1,3(2H)-dione (116.2 gm) in isopropyl alcohol and water mixture (l700ml :300 ml) is refluxed for 25-30 h. The precipitated solid is filtered off, washed with isopropyl alcohol (100 ml) to obtain solid, which is then dried under vacuum at 50 to 55 °C for 4 to5 hr to obtain 2-[(2R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl]-1 H-isoindole-1,3(2H)-dione. [Yield = 170 gm (82.6percent); Purity (H PLC) = 95.0 percent] |
82.6% | Reflux | A suspension of 4-(4-aminophenyl)morpholin-3-one (100 gm) and 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione (116.2 gm) in isopropyl alcohol and water mixture (1700 ml:300 ml) is refluxed for 25-30 h. The precipitated solid is filtered off, washed with isopropyl alcohol (100 ml) to obtain solid, which is then dried under vacuum at 50 to 55° C. for 4 to 5 hr to obtain 2-[(2R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl]-1H-isoindole-1,3(2H)-dione. [Yield=170 gm (82.6percent); Purity (HPLC)=95.0percent] |
82.7% | at 0 - 60℃; for 20 h; Large scale | This example relates to the preparation of 2-{(fl)-2-hydroxy-3-[4-(3-oxo- morpholine-4-yl)-phenylamino]-propyl}isoindol-1 ,3-dione, step a) of the process. 10.0 kg of 4-(4-aminophenyl)morpholine-3-one, 13.0 kg of (S)-(+)-N-(2,3- epoxypropyl)phthalimide and 170 kg of methanol are loaded into a reactor as a single solvent. The mass is heated to around 60 °C and maintained at this temperature for 20 hours, then cooled to 0-10 °C. There is precipitation of the desired product, which is filtered and washed with 30.0 kg of methanol. The product obtained is oven-dried, obtaining 17.0 kg of the desired compound (III), with a reaction yield equal to 82.7percent. |
81.4% | at 20 - 60℃; for 36 h; | 1173 g of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)dione (II) and 4-(4-aminophenyl)-3-morpholinone (III) are mixed at 20° C. with 6.7 l of water and 14.4 l of ethanol. The suspension is heated to 58 to 60° C., and the resulting solution is stirred for 36 hours. After 2 hours, 5 g of crystalline 2-((2R)-2-hydroxy-3-[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione (V) are added to the reaction mixture, after which the product starts to crystallize. After cooling to 26° C., the precipitated reaction product is filtered off with suction, washed with ethanol and then dried. Yield: 1522 g; equivalent to 81.4percent of theory. Melting point: 215° C. |
80.68% | at 80℃; for 9 h; | 238.50 g (1.174 mol) of 2-[(2S)-2-oxiranylmethyl]-1 H-isoindole-1 , 3(2H)-dione (I), 150 g (0.781 mol) of 4-(4-amino phenyl)-3-morpholinone and 3L of ethanol were charged in a 5L flask and the reaction mass was heated at 80 °C for 9 hours. Afterwards the reaction mass was cooled down to 30 °C, and the resulting solid was filtered off and dried under vacuum at 70 °C.Yield: 249 g. Molar yield: 80.68percent. HPLC purity 96.90percent. M.P.: 214 °C. Specific Optical Rotation (S.O.R.): [a ]D25 = +6.24° (c = 1 ,DMSO) |
75.4% | With water In ethanol at 60℃; for 36 h; Industry scale | A suspension of (S) -2- (oxiran-2-ylmethyl) isoindoline-1, 3-dione (4.5kg, 1.22eq) and 4- (4-aminophenyl) morpholin-3-one (3.286kg , 17.088 mol) in ethanol/water (42L/16kg), was heated at 60 0C for 36 hours. It was further cooled to room temperature, the precipitate was filtered, and dried in vacuum. An amount of 5.1 kg of the product was obtained (Yield 75,4percent). |
203 g | at 80℃; for 8 h; | To 100 gm (0.5208 moles) of 4-(4-Aminophenyl) morpholin-3-one (III) in 2500 ml purified water, 185 gm (0.9104 moles) of (S)- Glycidyl Phthalimide (IV) and 1000ml purified water0 was charged and the reaction mixture was heated to 80 °C for 8 hours. The precipitated products was filtered and washed with purified water. The product was dried under vacuum at 60°C to 65°C for 24 hours. Dried weight = 203 gm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | for 20 h; Reflux | Example 3: (2R)-2-Hydroxy-3-[4-(3-oxo-4-morpholinyl)phenyI]aminopropyl-lH-isoindol- l,3(2H)-dione, the compound of formula III(S)-2-(Phthalimidomethyl)oxirane (12.0 g; 0.06 mol) and N-(4-aminophenyl)- morpholinone (10.0 g; 0.05 mol) were charged into a flask and methanol (200 ml) and water (20 ml) were added. The mixture was heated up to boil and refluxed for 20 hours. The white suspension was cooled to the temperature of 15°C, stirred for 1 hour, aspirated and washed with methanol (20 ml) at the temperature of 15°C.The thoroughly aspirated product was dried in a vacuum drier at a temperature up to 60°C. 15.5g (75 percent of theory) of (2R)-2-hydroxy-3-[4-(3-oxo-4-morpholinyl)phenyl]aminopropyl- l H-isoindol- l ,3(2H)-dione with the isomeric purity of 99.0percent were obtained. |
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