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Product Details of [ 161596-47-0 ]

CAS No. :161596-47-0 MDL No. :MFCD04973350
Formula : C11H9NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :DUILGEYLVHGSEE-ZETCQYMHSA-N
M.W : 203.19 Pubchem ID :719412
Synonyms :

Calculated chemistry of [ 161596-47-0 ]

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.27
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 55.31
TPSA : 49.91 Ų

Pharmacokinetics

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) : -6.7 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.81
Log Po/w (XLOGP3) : 1.18
Log Po/w (WLOGP) : 0.3
Log Po/w (MLOGP) : 1.31
Log Po/w (SILICOS-IT) : 1.9
Consensus Log Po/w : 1.3

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.01
Solubility : 2.0 mg/ml ; 0.00984 mol/l
Class : Soluble
Log S (Ali) : -1.82
Solubility : 3.05 mg/ml ; 0.015 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.53
Solubility : 0.596 mg/ml ; 0.00293 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.98

Safety of [ 161596-47-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P305+P351+P338 UN#:N/A
Hazard Statements:H319 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 161596-47-0 ]

* 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.

  • Upstream synthesis route of [ 161596-47-0 ]
  • Downstream synthetic route of [ 161596-47-0 ]

[ 161596-47-0 ] Synthesis Path-Upstream   1~24

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Reference: [1] Patent: EP1403267, 2004, A1, . Location in patent: Page 6
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  • [ 136918-14-4 ]
  • [ 60456-23-7 ]
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YieldReaction ConditionsOperation in experiment
91% With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; 2-Oxiranylmethyl-isoindole-1, 3-dione (D1) To a stirred solution of phthalimide (10. 36g) in THF (350ML) was added triphenylphosphine (18.46g) and (S)-glycidol (5. 4MOI). This solution was cooled using an external ice bath for the dropwise addition of diethylazodicarboxyate (11. 1ML). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated, and stirred in diethyl ether for 5h. White precipitate was filtered and liquor was evaporated. The residual yellow oil was chromatographed over silica gel, eluting with ethyl acetate/hexane (1: 1). Title compound was obtained as a white solid (13G, 91percent). Mass Spectrum (Electrospray LC/MS): Found 204 (MH+). C11HGNO3 requires 203.
91% With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; To a stirred solution of phthalimide (10.36g) in THF (350MI) was added triphenylphosphine (18. 46g) and (S)-glycidol (5. 4MOI). This solution was cooled using an external ice bath for the dropwise addition of diethylazodicarboxyate (11. 1ML). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated, and stirred in diethyl ether for 5h. White precipitate was filtered and liquor was evaporated. The residual yellow oil was chromatographed over silica gel, eluting with ethyl acetate/hexane (1: 1). Title compound was obtained as a white solid (13G, 91percent). Mass Spectrum (Electrospray LC/MS) : Found 204 (MH+). C11HGNO3 requires 203.
Reference: [1] Patent: WO2004/112787, 2004, A1, . Location in patent: Page 17-18
[2] Patent: WO2004/113301, 2004, A1, . Location in patent: Page 18
[3] Tetrahedron Asymmetry, 1996, vol. 7, # 6, p. 1641 - 1648
[4] Heterocycles, 2006, vol. 67, # 2, p. 561 - 566
[5] Chemical communications (Cambridge, England), 2003, # 4, p. 468 - 469
[6] Tetrahedron, 2004, vol. 60, # 35, p. 7679 - 7692
[7] Patent: US2005/228014, 2005, A1, . Location in patent: Page/Page column 23
[8] Patent: WO2004/101557, 2004, A1, . Location in patent: Page/Page column 37
[9] Patent: WO2005/49023, 2005, A1, . Location in patent: Page/Page column 57-58
  • 3
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YieldReaction ConditionsOperation in experiment
77.5%
Stage #1: With methylamine In isopropyl alcohol at 60℃; for 5 h;
Stage #2: With sodium methylate In methanol; isopropyl alcohol at 10 - 30℃;
To a suspension of 1H-isoindole-1,3(2H)-dione (100 g, 0.68 moles) and methylamine (10 g) in isopropanol (200 ml), S-epichlorohydrin (100 g 1.08 moles) was added and the mixture was heated to 60° C. and maintained for 5 h at the same temperature. 30percent Sodium methoxide in methanol (160 g) was added portion wise at 10-15° C. to the reaction mass, the temperature was raised to 25-30° C. and the reaction mass was stirred for 2-3 h at the same temperature. After completion of the reaction, water (600 ml) was added, the reaction mixture was stirred for 10 min, the solid was filtered off and washed with water to obtain the title compound. Weight: 107 g (77.5percent)
5 g With sodium acetate In isopropyl alcohol at 65 - 70℃; In a clean round bottom flask, 5 gm of phthalimide, 7.85 gm of S-epichlorohydrin, 6.9 gm sodium acetate and 50 ml of isopropyl alcohol were charged. The reaction mass was heated to about 65° C.-70° C. and maintained for about 24 hours to about 30 hours. The reaction mass was cooled to about 25° C. and concentrated under reduced pressure at below 40° C. then 50 ml of toluene was added and stirred for about 30 minutes and filtered. To obtained filtrate 17.76 gm of potassium carbonate was added and reaction mass was heated to about 100° C.-110° C. and maintained for about 3 hours to about 5 hours at same temperature. The reaction mass was cooled to about 25° C., filtered and concentrated and degassed. 50 ml of cyclohexane was added to reaction mass and stirred for about 30 minutes, filtered and dried under reduced pressure at about 50-55° C. to yield titled compound as oil (5 gm)
84.5 g With 1-hexylamine hydrochloride; potassium <i>tert</i>-butylate; potassium iodide In isopropyl alcohol at 28℃; for 72 h; To a 1 L single-necked flask was added 67.7 g (0. 46 mol)Phthalimide,Potassium tert-butoxide 61. 9 g,10percent (0 · 046 mol) of hexylammonium chloride,Potassium iodide 0.66 g (0.0046 mol),Isopropyl alcohol 382 · 5ml, stirring evenly,At 28 ° C,(S) epichlorohydrin (85.6 g, 0.93 mol) was added to the reaction system in the presence of stirring,System from white turbidity into pale yellow turbidity,The reaction was carried out at a temperature of 28 ° C for 72 hours,Filter,Washed,dry,The final solid was 84. 5 g,Yield 90. 5percentPurity 92percent.
Reference: [1] Patent: US9643939, 2017, B1, . Location in patent: Page/Page column 16
[2] Patent: WO2012/41263, 2012, A2, . Location in patent: Page/Page column 9-10
[3] Patent: US2016/52919, 2016, A1, . Location in patent: Paragraph 0131
[4] Patent: CN103382200, 2016, B, . Location in patent: Paragraph 0072; 0073
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YieldReaction ConditionsOperation in experiment
83% With benzyltrimethylammonium chloride In isopropyl alcohol at 10℃; for 46 h; Into a reaction vessel were put potassium phthalimide (50.0g, 0.27mol), benzyltrimethylammonium chloride 5.00g, 0.02.7mol) and isopropanol (500ml), and the mixture was cooled to 10C. Thereto was added (R)-epichlorohydrin (74.9g, 0.81mol) and the mixture was stirred for 46 hours while being cooled. The solvent was removed and to the residue was added ethyl acetate (250ml). The mixture was washed with water (250ml) and then ethyl acetate was removed to give crude (R)-glycidylphthalimide (optical purity: 97percent e.e.). The crude product was crystallized from ethyl acetate-hexane to give the object (R)-glycidylphthalimide (45.6g, yield: 83percent, optical purity: 98percente.e.) as white crystals. mp 100-102C Specific rotation [a]D?25-9.7 (c2.0. CHCl3)1HNMR (CDCl3, 270MHz) d 2.70 (dd, 1H), 2.81(dd, 1H) , 3.21-3.28 (m, 1H), 3.81 (dd, 1H), 3.97 (dd, 1H), 7.27-7.91 (m, 4H) The optical purity was calculated using HPLC and by its area ratio. Condition: Column: CHIRALPAC AD (0.46cmF x 25cm L (Daicel Co., Ltd.) Mobile phase: n-hexane/isopropanol (90/10(v/v) Velocity:1.0ml/min. Detection: UV220nm Retention: (S)isomer=17.9min., (R)isomer=25.5min.
74% With benzyltrimethylammonium chloride In tetrahydrofuran at 50℃; for 44 h; Comparative examples 2-4 were shown in the following Table 1, which were conducted by changing the solvent according to the method of Comparative example 1.[Table 1] Solvent Reaction temp/hr Yield Optical purity (percent ee) Comp. ex.2 THF 50C/44hr 74 87 Comp. ex.3 Toluene 50C/20hr n.d n.d. Comp. ex.4 Dichloroethane 30C/16hr n.d. n.d.
68% With benzyltrimethylammonium chloride In methanol at 20℃; for 15 h; Into a reaction vessel were put potassium phthalimide (5.00g, 27.0mmol), benzyltrimethylammonium chloride (0.50g, 2.70mmol) and methanol (50ml) and then thereto was added (R)-epichlorohydrin (9.99g, 81.0mmol). The mixture was stirred at 20C for 15 hours and the solvent was removed. To the residue was added ethyl acetate (30ml), the mixture was washed with water (20ml) and ethyl acetate was removed to give crude (R)-glycidylphthalimide (3.74g, yield: 68percent, optical purity: 99percente.e.) as a white solid.
Reference: [1] Patent: EP1403267, 2004, A1, . Location in patent: Page 5
[2] Patent: EP1403267, 2004, A1, . Location in patent: Page 6
[3] Patent: EP1403267, 2004, A1, . Location in patent: Page 5-6
[4] Synlett, 2006, # 13, p. 2151 - 2153
[5] Patent: EP1403267, 2004, A1, . Location in patent: Page 6
[6] Patent: EP1403267, 2004, A1, . Location in patent: Page 6
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YieldReaction ConditionsOperation in experiment
80%
Stage #1: With tetra(n-butyl)ammonium hydrogensulfate; sodium carbonate In isopropyl alcohol at 50℃; for 23 h;
Stage #2: With potassium <i>tert</i>-butylate In isopropyl alcohol at 20℃; for 1 h;
Into a reaction vessel were put phthalimide (2.00g, 13.6mmol), (R)-epichlorohydrin (2.26g, 24.5mmol), anhydrous sodium carbonate (0.72g, 6.80mmol), tetra n-butylammonium hydrogensulfate (0.46g, 1.36mmol). and isopropanol (13ml) and the mixture was reacted at room temperature at 50C for 23 hours. And then to the residue was gradually added potassium tert-butoxide (1.83g, 16.3mmol) in isopropanol and the mixture is stirred at 20C for 1 hour. After the reaction, post-treatment was carried out to give crude (R)-glycidylphthalimide (2.21g, yield 80percent, optical purity 98percente.e.) as white crystals.
78%
Stage #1: With benzyltrimethylammonium chloride; sodium carbonate In isopropyl alcohol at 20℃; for 15 h;
Stage #2: With potassium <i>tert</i>-butylate In isopropyl alcohol at 20℃; for 1 h;
a reaction vessel were put phthalimide (2.00g, 13.6mol), (R)-epichlorohydrin (2.52g, 27.2mol), anhydrous sodium carbonate (144mg, 1.36mmol), benzyltrimethylammonium chloride (252mg, 1.36mmol) and isopropanol (13ml) and the mixture was reacted at room temperature for 15 hours. After removal unreacted epichlorohydrin, to the residue was added isopropanol (13ml) and the mixture is cooled to 20C. Then thereto was gradually dropped a mixture of potassium tert-butoxide (1.83g, 16.3mmol) and isopropanol (7ml) and the mixture was stirred for 1 hour at the same temperature. The solvent was removed and to the residue was added ethyl acetate (13ml). The mixture was washed with water (7ml), and then ethyl acetate was removed to give crude (R)-glycidylphthalimide (2.16g, yield 78percent, optical purity 98percente.e.) as white crystals.
17% With potassium <i>tert</i>-butylate; benzyltrimethylammonium chloride In isopropyl alcohol at 20℃; for 26 h; Into a reaction vessel were put phthalimide (2.00g, 13.6mmol), benzyltrimethylammonium chloride (252mg, 1.36mmol) and isopropanol (25mL) and the mixture was ice cooled. Thereto were added potassium tert-butoxide (3.05g, 27.2mmol) in several divided portions and then (R)-epichlorohydrin (2.52g, 27.2mmol). The mixture was reacted at room temperature for 26 hours and then post-treatment was carried out to give crude (R)-glycidylphthalimide (0.45g, yield 17percent, optical purity 96percente.e.) as a yellow highly viscous product.
Reference: [1] Patent: EP1403267, 2004, A1, . Location in patent: Page 6-7
[2] Patent: EP1403267, 2004, A1, . Location in patent: Page 6-7
[3] Patent: EP1403267, 2004, A1, . Location in patent: Page 6-7
[4] Patent: EP1403267, 2004, A1, . Location in patent: Page 7-8
[5] Patent: EP1403267, 2004, A1, . Location in patent: Page 6
[6] Patent: EP1403267, 2004, A1, . Location in patent: Page 6-7
[7] Patent: EP1403267, 2004, A1, . Location in patent: Page 6-7
[8] Patent: EP1403267, 2004, A1, . Location in patent: Page 6-7
[9] Patent: EP1403267, 2004, A1, . Location in patent: Page 6-7
[10] Patent: EP1403267, 2004, A1, . Location in patent: Page 8
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YieldReaction ConditionsOperation in experiment
53% With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; for 4 h; To a solution of triphenylphosphine (17.7 g, 67.5 mmol), (R)-(+)-glycidol (4.0 g,54.0 mmol), and phthalamide in THF (220 mL) was added DEAD (11.7 g, 67.5 mmol). The reaction mixture was stirred under nitrogen at RT for 4 hr. After evaporating solvent, EPO <DP n="100"/>the crude product was purified by flash column chromatography to provide 5.8 g (53percent) of the desired product; LCMS: [MH]+ = 204.
Reference: [1] Patent: WO2007/30761, 2007, A2, . Location in patent: Page/Page column 37; 98-99
  • 7
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YieldReaction ConditionsOperation in experiment
94% With sodium carbonate In 5,5-dimethyl-1,3-cyclohexadiene for 4 h; Reflux; Green chemistry The compound I obtained from Example 4 (50.0 g 0.21 mol), sodium carbonate 22.0 g, and xylene 250 g were placed in a four-necked bottle with a water separator. Stirring; heating and refluxing for 4 h.The reaction was completed until the residual of the compound I in the reaction solution was ≤1.0percent.Sodium carbonate was removed by filtration, and the filtrate was washed with 2×100 g of water, concentrated,Crystallization was carried out by adding 200 g of methanol to obtain 40.0 g of S-N-glycidylphthalimide (yield 94percent; HPLC 99.62percent; ee 99.80percent).
89% With sodium carbonate In 5,5-dimethyl-1,3-cyclohexadiene for 4 h; Reflux Phthalimide (100.0g 0.68mol),Basic alumina 1.0g,TMBAC 1.0g,300 g of isopropyl alcohol and 23.0 g of S-epichlorohydrin were placed in a four-necked flask and stirred.The internal temperature was controlled at 20 to 25 ° C for 12 h, and the sample was controlled until the residue of phthalimide in the reaction solution was ≤ 1.0percent, and the reaction was completed.Concentrated to remove isopropanol, add 400g of toluene, dissolve and filter to recover alumina for use; filtrate 2 × 100g of water, wash, concentrate, add 450g of n-heptane crystallize to obtain compound I 150 g (yield 92.1percent).
99.5 % ee With potassium phosphate In 1,2-dichloro-ethane at 80℃; for 14 h; Example 1[42] 25.00 g of (S)-l-amino-3-chloro-2-propanol methanesulfonic acid salt (0.123 mol),25.34 g of phthalic anhydride (0.123 mol), 18.63 ml of triethylamine (0.134 mol) and 121 ml of toluene were added into a reaction vessel. After stirring for 2 hours at 110-120°C, the solvent was removed under reduced pressure. Subsequently, 64.51 g of potassium phosphate (0.304 mol) and 121 ml of 1,2-dichloroethane were added to the reaction vessel. The mixture was stirred for 14 hours at 80°C. The reaction mixture was cooled to 0°C. After 100 ml of water was added to dissolve potassium phosphate, the solution was extracted with 1,2-dichloroethane to obtain an organic layer. The obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 17.91 g of the targeted (S)-glycidylphthalimide (yield: 72percent, optical purity: 99.5percent ee) as a white crystal.[43] Melting point: 100-102°C[44] 1H NMR (CDCl3, 300 MHz): δ 7.70-8.00 (m, 4H), 3.95 (dd, IH, J=14.4Hz, 5.1Hz),3.79 (dd, IH), 3.22-3.26 (m, 1 H), 2.80 (dd, IH), 2.67 (dd, IH, J=7.8Hz, 2.4Hz)[45] The optical purity (percent ee) of glycidylphthalimide was confirmed from high speed liquid chromatography (HPLC). CHRALPAC AD.(TM). Column (0.46 cm x 25 cm, available from Daicel Co., Ltd) was used. The mobile phase was a mixed solvent of n - hexane/isopropanol (90/10 (Wv)) and was flown at a velocity of 1 ml/min. Detection was performed at 254 nm. The (S) isomer was detected at 14.2 minutes and the (R) isomer was detected at 19.2 minutes.[46] Example 2[47] 25.00 g of (S)-l-amino-3-chloro-2-propanol methanesulfonic acid salt (0.123 mol),25.34 g of phthalic anhydride (0.123 mol), 18.63 ml of triethylamine (0.134 mol) and 121 ml of toluene were added into a reaction vessel. After stirring for 2 hours at 110-120°C, the organic layer was washed with water at room temperature. After drying with anhydrous magnesium sulfate, the solvent was removed under reduced pressure. Subsequently, 64.51 g of potassium phosphate (0.304 mol) and 121 ml of <n="10"/>1,2-dichloroethane were added to the reaction vessel. The mixture was stirred for 14 hours at 80°C. The reaction mixture was cooled to 0°C. After 100 ml of water was added to dissolve potassium phosphate, the solution was extracted with 1,2-dichloroethane to obtain an organic layer. The obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 18.12 g of the targeted (S)-glycidylphthalimide (yield: 73percent, optical purity: 99.5percent ee) as a white crystal.[48] Example 3[49] 25.00 g of (S)-l-amino-3-chloro-2-propanol hydrochloride (0.171 mol), 25.34 g of phthalic anhydride (0.171 mol), 28.64 ml of triethylamine (0.206 mol) and 171 ml of toluene were added into a reaction vessel. After stirring for 2 hours at 110-120°C, the solvent was removed under reduced pressure. Subsequently, 90.86 g of potassium phosphate (0.342 mol) and 171 ml of 1,2-dichloroethane were added to the reaction vessel. The mixture was stirred for 14 hours at 80°C. The reaction mixture was cooled to 0°C. After 100 ml of water was added to dissolve potassium phosphate, the solution was extracted with 1,2-dichloroethane to obtain an organic layer. The obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 24.01 g of the targeted (S)-glycidylphthalimide (yield: 69percent, optical purity: 99.5percent ee) as a white crystal.; Example 5[53] 5.00 g of (S)-l-amino-3-chloro-2-propanol hydrochloride (0.034 mol), 5.069 g of phthalic anhydride (0.034 mol), 5.73 ml of triethylamine (0.041 mol) and 34 ml of toluene were added into a reaction vessel. After stirring for 2 hours at 110-120°C, 30 <n="11"/>ml of water was added into the reaction vessel. An organic layer was obtained by extracting with toluene. Then, the obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. Subsequently, 18.17 g of potassium phosphate (0.069 mol) and 34 ml of 1,2-dichloroethane were added to the reaction vessel. The mixture was stirred for 14 hours at 80°C. The reaction mixture was cooled to 0°C. After 100 ml of water was added to dissolve potassium phosphate, the solution was extracted with 1,2-dichloroethane to obtain an organic layer. The obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 4.68 g of the targeted (S)-glycidylphthalimide (yield: 67percent, optical purity: 99.5percent ee) as a white crystal.
99.5 % ee With potassium phosphate In acetonitrile at 80℃; for 14 h; Example 4[51] 25.00 g of (S)-l-amino-3-chloro-2-propanol hydrochloride (0.171 mol), 25.34 g of phthalic anhydride (0.171 mol), 28.64 ml of triethylamine (0.206 mol) and 171 ml of toluene were added into a reaction vessel. After stirring for 2 hours at 110-120°C, the solvent was removed under reduced pressure. Subsequently, 90.86 g of potassium phosphate (0.342 mol) and 171 ml of acetonitrile were added to the reaction vessel. The mixture was stirred for 14 hours at 80°C. The reaction mixture was cooled to 0°C. After 100 ml of water was added to dissolve potassium phosphate, the solution was extracted with 1,2-dichloroethane to obtain an organic layer. The obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 22.34 g of the targeted (S)-glycidylphthalimide (yield: 64percent, optical purity: 99.5percent ee) as a white crystal.
99.5 % ee
Stage #1: With potassium phosphate In N,N-dimethyl-formamide at 40℃; for 3.5 h;
Stage #2: With sulfuric acid In N,N-dimethyl-formamide
Example 6[55] 5.00 g of (S)-l-amino-3-chloro-2-propanol hydrochloride (0.034 mol), 5.069 g of phthalic anhydride (0.034 mol), 5.73 ml of triethylamine (0.041 mol) and 34 ml of toluene were added into a reaction vessel. After stirring for 2 hours at 110-120°C, the solvent was removed under reduced pressure. Subsequently, 18.17 g of potassium phosphate (0.069 mol) and 34 ml of λζN-dimethylformamide were sequentially added to the reaction vessel. The mixture was stirred for 3.5 hours at 40°C. After cooling to 0°C, potassium phosphate was filtered and pH of the resultant precipitate was adjusted to 5-6 by addition of sulfuric acid. Then, an organic layer was obtained by extracting with ethyl acetate. The obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 4.07 g of the targeted (S)-glycidylphthalimide (yield: 59percent, optical purity: 99.5percent ee) as white crystals.
107 g With sodium methylate In methanol at 10 - 30℃; Example-1: (0123) Preparation of 2-[f2S)-oxiran-2-ylmethyll-lH-isoindole-l,3f2H)-dione : (0124) To a suspension of lH-isoindole-l,3(2H)-dione (100 g, 0.68 moles) and methylamine (10 g) in isopropanol (200 ml), ^-epichlorohydrin (100 g 1.08 moles) was added and the mixture was heated to 60°C and maintained for 5 h at the same temperature. 30percent Sodium methoxide in methanol (160 g) was added portion wise at 10-15°C to the reaction mass, the temperature was raised to 25-30°C and the reaction mass was stirred for 2-3 h at the same temperature. After completion of the reaction, water (600 ml) was added, stirred forlO min, filtered the solid and washed with water to obtained titled compound. (0125) Weight: 107 g (77.5percent)

Reference: [1] Patent: CN108440382, 2018, A, . Location in patent: Paragraph 0075; 0076; 0077
[2] Patent: CN108440383, 2018, A, . Location in patent: Paragraph 0086; 0087; 0088
[3] Patent: WO2007/132990, 2007, A1, . Location in patent: Page/Page column 8-10
[4] Patent: WO2007/132990, 2007, A1, . Location in patent: Page/Page column 9
[5] Patent: WO2007/132990, 2007, A1, . Location in patent: Page/Page column 10
[6] Patent: WO2017/182853, 2017, A1, . Location in patent: Page/Page column 16
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Reference: [1] Patent: WO2013/98833, 2013, A2, . Location in patent: Page/Page column 41
[2] Patent: US2014/378682, 2014, A1, . Location in patent: Paragraph 0207; 0208
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Reference: [1] Patent: WO2006/31179, 2006, A1, . Location in patent: Page/Page column 5
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YieldReaction ConditionsOperation in experiment
88.1 g With N-benzyl-N,N,N-triethylammonium chloride; potassium iodide In isopropyl alcohol at 28℃; for 72 h; To a 1 L single-necked flask was added 85 g (0.46 mol) of potassium phthalimide,Benzyltriethylammonium chloride 10. 5 g (0.04 mol)Potassium iodide 0.76 g (0.0046 mol), isopropyl alcohol 382.5 ml,Stir evenly,At 28 ° C,(S) epichlorohydrin 85. 6 g (0.9 mol) was added to the reaction system in the presence of stirring,System from white turbidity into pale yellow turbidity,The reaction was carried out at a temperature of 28 ° C for 72 hours,Filter,Washed,dry,And finally the solid 88. lg,Yield 94. 5percentPurity 92percent.
Reference: [1] Patent: CN103382200, 2016, B, . Location in patent: Paragraph 0034; 0035
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Reference: [1] Patent: EP1403267, 2004, A1, . Location in patent: Page 6
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Reference: [1] Helvetica Chimica Acta, 2014, vol. 97, # 11, p. 1507 - 1515
[2] Patent: US5608110, 1997, A,
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Reference: [1] Green Chemistry, 2010, vol. 12, # 8, p. 1380 - 1382
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Reference: [1] Helvetica Chimica Acta, 2014, vol. 97, # 11, p. 1507 - 1515
[2] Helvetica Chimica Acta, 2014, vol. 97, # 11, p. 1507 - 1515
[3] Helvetica Chimica Acta, 2014, vol. 97, # 11, p. 1507 - 1515
[4] Helvetica Chimica Acta, 2014, vol. 97, # 11, p. 1507 - 1515
[5] Helvetica Chimica Acta, 2014, vol. 97, # 11, p. 1507 - 1515
[6] Helvetica Chimica Acta, 2014, vol. 97, # 11, p. 1507 - 1515
[7] Patent: WO2017/182853, 2017, A1,
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Reference: [1] Helvetica Chimica Acta, 2014, vol. 97, # 11, p. 1507 - 1515
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Reference: [1] Organic Process Research and Development, 2017, vol. 21, # 1, p. 18 - 22
[2] Organic Process Research and Development, 2017, vol. 21, # 1, p. 18 - 22
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Reference: [1] Organic Process Research and Development, 2017, vol. 21, # 1, p. 18 - 22
[2] Organic Process Research and Development, 2017, vol. 21, # 1, p. 18 - 22
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Reference: [1] Organic Process Research and Development, 2017, vol. 21, # 1, p. 18 - 22
[2] Organic Process Research and Development, 2017, vol. 21, # 1, p. 18 - 22
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Reference: [1] Organic Process Research and Development, 2017, vol. 21, # 1, p. 18 - 22
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YieldReaction ConditionsOperation 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

Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 19, p. 5900 - 5908
[2] Patent: WO2018/127762, 2018, A1, . Location in patent: Page/Page column 12
[3] Patent: CN108164519, 2018, A, . Location in patent: Paragraph 0014; 0015; 0016; 0017
[4] Patent: CN106588905, 2017, A, . Location in patent: Paragraph 0044; 0046-0047
[5] Patent: WO2014/102820, 2014, A2, . Location in patent: Paragraph 047
[6] Patent: WO2016/199027, 2016, A1, . Location in patent: Page/Page column 18
[7] Patent: WO2013/121436, 2013, A2, . Location in patent: Page/Page column 26
[8] Patent: US2015/11756, 2015, A1, . Location in patent: Paragraph 0117
[9] Patent: WO2015/198259, 2015, A1, . Location in patent: Page/Page column 6
[10] Patent: US2005/182055, 2005, A1, . Location in patent: Page/Page column 1; 3
[11] Patent: WO2005/68456, 2005, A1, . Location in patent: Page/Page column 7
[12] Patent: WO2013/53739, 2013, A1, . Location in patent: Page/Page column 31
[13] Patent: WO2011/12321, 2011, A1, . Location in patent: Page/Page column 31
[14] Patent: WO2013/98833, 2013, A2, . Location in patent: Page/Page column 41
[15] Patent: US2014/378682, 2014, A1, . Location in patent: Paragraph 0209; 0210
[16] Patent: WO2016/30669, 2016, A1, . Location in patent: Page/Page column 28
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YieldReaction ConditionsOperation 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.
Reference: [1] Patent: WO2012/41263, 2012, A2, . Location in patent: Page/Page column 10
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YieldReaction ConditionsOperation in experiment
95.5% at 120℃; for 4 h; ((S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (4.56g, 22.46mmol, 1.3eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77g, 17.29mmol) were dissolved in isoamyl acetate (70mL) respectively, and heated to 120°C. Then magnesium chloride (0.12g, 1.28mmol) was added, the mixture was reacted for 4h, white solid was obtained by filtration (6.97g, yield:95.5percent). ESI-MS(m/z): 422(M+H), 444(M+Na); 1HNMR(400MHz, CDCl3) δ: 3.74(m, 2H), 3.94(m, 4H), 4.10(m, 2H), 4.32(s, 2H), 4.98(m, 1H), 7.34(d, 2H), 7.56(d, 2H), 7.75(m, 2H), 7.88(m, 2H); HPLC: 98.82percent
94.09% With lithium iodide In chlorobenzene at 115℃; for 4 h; [0048] (S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (3.87 g, 19.06 mmol, 1.1 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in chlorobenzene (70 mL) respectively, then heated to 115° C. and lithium iodide (0.23 g, 1.72 mmol) was added. The mixture was reacted for 4 h, white solid was obtained by filtration (6.85 g, yield: 94.09percent). [0049] ESI-MS (m/z): 422 (M+H), 444 (M+Na); [0050] 1HNMR (400 MHz, CDCl3) δ: 3.74 (m, 2H), 3.94 (m, 4H), 4.10 (m, 2H), 4.32 (s, 2H), 4.98 (m, 1H), 7.34 (d, 2H), 7.56 (d, 2H), 7.75 (m, 2H), 7.88 (m, 2H); [0051] HPLC: 98.91percent.
Reference: [1] Patent: EP2837628, 2015, A1, . Location in patent: Paragraph 0029
[2] Patent: US2015/38704, 2015, A1, . Location in patent: Paragraph 0048-0051
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Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 19, p. 5900 - 5908
[2] Patent: WO2013/53739, 2013, A1,
[3] Patent: CN106588905, 2017, A,
  • 24
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  • [ 438056-69-0 ]
  • [ 446292-08-6 ]
Reference: [1] Patent: WO2013/98833, 2013, A2,
[2] Patent: WO2013/121436, 2013, A2,
[3] Patent: US2015/11756, 2015, A1,
[4] Patent: WO2014/102820, 2014, A2,
[5] Patent: US2014/378682, 2014, A1,
[6] Patent: WO2015/198259, 2015, A1,
[7] Patent: WO2016/199027, 2016, A1,
[8] Patent: WO2018/127762, 2018, A1,
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