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Chemical Structure| 4456-77-3
Chemical Structure| 4456-77-3
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Product Details of [ 4456-77-3 ]

CAS No. :4456-77-3 MDL No. :MFCD00234966
Formula : C9H7NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :QGNQEODJYRGEJX-UHFFFAOYSA-N
M.W : 161.16 Pubchem ID :349435
Synonyms :

Calculated chemistry of [ 4456-77-3 ]

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.11
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 46.41
TPSA : 46.17 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) : -6.82 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.26
Log Po/w (XLOGP3) : 0.65
Log Po/w (WLOGP) : 0.12
Log Po/w (MLOGP) : 0.89
Log Po/w (SILICOS-IT) : 1.78
Consensus Log Po/w : 0.94

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.62
Solubility : 3.88 mg/ml ; 0.0241 mol/l
Class : Very soluble
Log S (Ali) : -1.2
Solubility : 10.3 mg/ml ; 0.0638 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.04
Solubility : 0.145 mg/ml ; 0.000902 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.49

Safety of [ 4456-77-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 4456-77-3 ]

* 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 [ 4456-77-3 ]
  • Downstream synthetic route of [ 4456-77-3 ]

[ 4456-77-3 ] Synthesis Path-Upstream   1~27

  • 1
  • [ 4456-77-3 ]
  • [ 19493-45-9 ]
Reference: [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3651 - 3660
  • 2
  • [ 4456-77-3 ]
  • [ 34784-02-6 ]
  • [ 53987-60-3 ]
YieldReaction ConditionsOperation in experiment
14% for 16 h; Reflux PBr3 (10 mL) was added slowly to 33 (1.41 g, 8.7 mmol)and the mixture was heated at reflux for 16 h. The evaporation residue wasquenched (sat. aq. NaHCO3) and extracted thrice with CHCl3.Chromatography (EtOAc / petroleum ether 3:17), followed by chromatography(EtOAc / petroleum ether 1:49) gave 34 (358 mg, 14percent) aswhite crystals: mp 148-150°C (lit.4mp 147-147.5°C); 1H NMR ((CD3)2SO) d 7.93 (1 H, td, J = 6.9, 1.3 Hz, 6-H), 8.00 (1 H, td, J = 6.9, 1.2 Hz, 7-H), 8.10 (1 H, dt, J = 8.1, 0.6 Hz, 5-H), 8.27 (1 H, d, J = 8.4 Hz, 8-H), 8.38 (1 H, s, 4-H); 13C NMR((CD3)2SO) (HSQC / HMBC) d 124.66 (4-C), 126.85(5-C), 127.13 (8a-C), 127.68 (4a-C), 127.89 (8-C), 130.69 (6-C), 132.69 (7-C),138.74 (3-C), 143.18 (1-C). Further elution gave 35 (66 mg, 4percent) as whitecrystals: mp 61-63°C (lit.4mp 63-64°C; 1H NMR ((CD3)2SO)(NOE) d 7.80 (1 H, td, J= 8.0, 1.2 Hz, 6-H), 7.90 (1 H, dt, J= 8.3, 1.2 Hz, 7-H), 8.03 (1 H, d, J= 8.3 Hz, 5-H), 8.23 (1 H, d, J = 8.3Hz, 8-H), 8.27 (1 H, s, 4-H), 9.24 (1 H, s, 1-H); 13C NMR((CD3)2SO) (HSQC / HMBC) d 123.53 (4-C), 125.76(5-C), 127.25 (4a-C), 127.80 (8-C), 128.13 (6-C), 131.68 (7-C), 135.19 (3-C),137.46 (8a-C), 153.19 (1-C).
Reference: [1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5891 - 5908
  • 3
  • [ 4456-77-3 ]
  • [ 7742-73-6 ]
YieldReaction ConditionsOperation in experiment
74% With P,P-dichlorophenylphosphine oxide In tetrahydrofuran; water at 20 - 160℃; EXAMPLE 60B
1,3-dichloroisoquinoline
The product from Example 60A (6.5 g, 40.4 mmol) was treated with phenylphosphonic dichloride (11.5 mL, 81.1 mmol) and heated at 160° C. for 3 hours.
The reaction was allowed to cool to room temperature and stand overnight.
The resulting waxy orange material was dissolved in tetrahydrofuran (200 mL), treated with water (60 mL), and then concentrated under reduced to remove the tetrahydrofuran.
The remaining aqueous material was neutralized with concentrated NH4OH and extracted with ethyl acetate.
The ethyl acetate phases were combined, washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure to provide the title compound as yellow flakes (6.92 g, 74percent).
Reference: [1] Patent: US2005/113576, 2005, A1, . Location in patent: Page/Page column 30
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3651 - 3660
[3] Patent: US6340759, 2002, B1, . Location in patent: Example 17
[4] Patent: WO2010/127855, 2010, A1, . Location in patent: Page/Page column 136; 137
  • 4
  • [ 824-72-6 ]
  • [ 4456-77-3 ]
  • [ 7742-73-6 ]
Reference: [1] Patent: US6933311, 2005, B2,
[2] Patent: US2004/157849, 2004, A1,
  • 5
  • [ 4456-77-3 ]
  • [ 53987-60-3 ]
YieldReaction ConditionsOperation in experiment
56%
Stage #1: at 180℃; for 2 h;
Stage #2: With potassium hydroxide In waterCooling with ice
b) 1,3-Dibromoisoquinoline; A mixture of isoquinoline-1 ,3(2H,4/-/)-dione (preparation 20a, 0.65 g, 4.02 mmol), phosphorous tribromide (1.51 mL, 16.05 mmol) and phosphoric tribromide (1.04 g, 3.61 mmol) was stirred at 180 °C. After 2 hours, the mixture was cooled, poured onto ice- water and 2N aqueous potassium hydroxide was added until the pH was 8-9. The aqueous layer was extracted with toluene, and the organic layer was filtered through neutral alumina and the filtrate was evaporated to give the title compound (0.58 g, 56percent) as a white solid.LRMS (m/z): 286/288/290 (M+1)+.1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.67 - 7.76 (m, 3 H) 7.84 (s, 1 H) 8.24 (d, J=8.40 Hz, 1 H)
56% at 180℃; for 2 h; A mixture of   isoquinoline-1,3(2H,4H)-dione (preparation 20a, 0.65 g, 4.02 mmol), phosphorous tribromide (1.51 mL, 16.05 mmol) and phosphoric tribromide (1.04 g, 3.61 mmol) was stirred at 180   title compound (0.58 g, 56percent) as a white solid.LRMS (m/z): 286/288/290 (M+1)+.1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.67 - 7.76 (m, 3 H) 7.84 (s, 1 H) 8.24 (d, J=8.40 Hz, 1 H)
35% With phosphorus(V) oxybromide In 1,4-dioxane for 22 h; Reflux Isoquinoline-1,3-dione 33 (3.00 g, 18.6 mmol) was heated under reflux withPOBr3 (10.7 g, 37 mmol) in 1,4-dioxane (20 mL) for 22 h.The mixture was quenched with MeOH, then water. The mixture, in water, wasextracted thrice with CH2Cl2. Drying, evaporation andrecrystallisation (PhMe) gave 34 (1.87 g, 35percent) as an off-white solid, withproperties as above
Reference: [1] Patent: US6340759, 2002, B1, . Location in patent: Example 28
[2] Patent: WO2012/41476, 2012, A1, . Location in patent: Page/Page column 56-57
[3] Patent: EP2441755, 2012, A1, . Location in patent: Paragraph 0172
[4] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5891 - 5908
  • 6
  • [ 4456-77-3 ]
  • [ 34784-02-6 ]
  • [ 53987-60-3 ]
YieldReaction ConditionsOperation in experiment
14% for 16 h; Reflux PBr3 (10 mL) was added slowly to 33 (1.41 g, 8.7 mmol)and the mixture was heated at reflux for 16 h. The evaporation residue wasquenched (sat. aq. NaHCO3) and extracted thrice with CHCl3.Chromatography (EtOAc / petroleum ether 3:17), followed by chromatography(EtOAc / petroleum ether 1:49) gave 34 (358 mg, 14percent) aswhite crystals: mp 148-150°C (lit.4mp 147-147.5°C); 1H NMR ((CD3)2SO) d 7.93 (1 H, td, J = 6.9, 1.3 Hz, 6-H), 8.00 (1 H, td, J = 6.9, 1.2 Hz, 7-H), 8.10 (1 H, dt, J = 8.1, 0.6 Hz, 5-H), 8.27 (1 H, d, J = 8.4 Hz, 8-H), 8.38 (1 H, s, 4-H); 13C NMR((CD3)2SO) (HSQC / HMBC) d 124.66 (4-C), 126.85(5-C), 127.13 (8a-C), 127.68 (4a-C), 127.89 (8-C), 130.69 (6-C), 132.69 (7-C),138.74 (3-C), 143.18 (1-C). Further elution gave 35 (66 mg, 4percent) as whitecrystals: mp 61-63°C (lit.4mp 63-64°C; 1H NMR ((CD3)2SO)(NOE) d 7.80 (1 H, td, J= 8.0, 1.2 Hz, 6-H), 7.90 (1 H, dt, J= 8.3, 1.2 Hz, 7-H), 8.03 (1 H, d, J= 8.3 Hz, 5-H), 8.23 (1 H, d, J = 8.3Hz, 8-H), 8.27 (1 H, s, 4-H), 9.24 (1 H, s, 1-H); 13C NMR((CD3)2SO) (HSQC / HMBC) d 123.53 (4-C), 125.76(5-C), 127.25 (4a-C), 127.80 (8-C), 128.13 (6-C), 131.68 (7-C), 135.19 (3-C),137.46 (8a-C), 153.19 (1-C).
Reference: [1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5891 - 5908
  • 7
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  • [ 58142-49-7 ]
Reference: [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3651 - 3660
  • 8
  • [ 89-51-0 ]
  • [ 4456-77-3 ]
YieldReaction ConditionsOperation in experiment
67% With urea In neat (no solvent) at 175 - 185℃; for 2 h; 2-Carboxyphenylaceticacid 32 (20.0 g, 111 mmol) washeated with finely ground urea (7.33 g, 122 mmol) at 175-185°C for 2 h. Cooling and recrystallisation(MeOH) gave 33 (12.0 g, 67percentpercent) as anoff-white solid: mp 220-222°C (lit.3mp 236-238°C); 1HNMR ((CD3)2SO) d 4.09 (3 H, s, CH2), 7.44 (1 H,d, J = 7.6 Hz, 5-H), 7.51 (1 H, t, J = 7.6 Hz, 7-H), 7.70 (1 H, td, J = 7.6, 1.2 Hz, 6-H), 8.07 (1 H, dd, J = 7.8, 1.1 Hz, 8-H), 11.36 (1 H, s,N-H); 13C NMR ((CD3)2SO) (HSQC /HMBC) d 35.92 (4-C), 124.95 (8a-C), 127.16 (7-C), 127.41 (8-C), 127.87 (5-C),133.47 (6-C), 136.66 (4a-C), 165.34 (1-C), 170.99 (3-C).
47% With urea In 1,2-dimethoxyethane at 175℃; Sealed tube A solution of   2-(carboxymethyl)benzoic acid (1.00 g, 5.55 mmol) and   urea (0.37 g, 6.10 mmol) in   ethylene glycol anhydrous (20 mL) was heated in a sealed tube at 175   solid.LRMS (m/z): 162 (M+1)+.
34% With urea In methanol Step 1
A mixture of homophthalic acid (200 g, 1.09 mol) and urea (80 g, 1.31 mol) was ground to a fine powder then heated at 175-185° C. until it had melted then resolidified.
The mixture was cooled to ambient temperature, methanol (500 ml) was added, then the mixture was heated under reflux for 20 minutes, filtered, and allowed to cool to ambient temperature.
The resulting solid was collected by filtration, washed with methanol and dried in vacuo to give homophthalimide (60 g, 34percent) as a solid; m.pt. 235-240° C.; δH 4.0 (2H, s), 7.3-7.75 (3H, m), 8.10 (1H, d), 11.20 (1H, br s).
Reference: [1] Liebigs Annalen der Chemie, 1981, # 5, p. 811 - 818
[2] Synthetic Communications, 1998, vol. 28, # 17, p. 3195 - 3200
[3] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5891 - 5908
[4] Synthetic Communications, 1981, vol. 11, # 6, p. 447 - 454
[5] Patent: EP2441755, 2012, A1, . Location in patent: Paragraph 0172
[6] Patent: US2003/8896, 2003, A1,
[7] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3651 - 3660
[8] Journal of Medicinal Chemistry, 2008, vol. 51, # 12, p. 3507 - 3525
[9] Patent: WO2010/127855, 2010, A1, . Location in patent: Page/Page column 136; 137
  • 9
  • [ 89-51-0 ]
  • [ 95-50-1 ]
  • [ 4456-77-3 ]
YieldReaction ConditionsOperation in experiment
74%
Stage #1: With ammonia In water
Stage #2: at 200℃;
EXAMPLE 60A
isoquinoline-1,3(2H,4H)-dione
2-(Carboxymethyl)benzoic acid (10 g, 55.6 mmol) was dissolved in concentrated NH4OH (15 mL) and then was evaporated to dryness under reduced pressure.
The process was repeated with additional NH4OH (5 mL).
The resulting residue was treated with 1,2-dichlorobenzene (20 mL) and heated with stirring at 200° C. without a condenser allowing the solvent to evaporate.
The concentrated mixture was allowed to cool to room temperature, diluted with methanol (20 mL), and allowed to stand overnight.
The precipitate was collected by filtration, washed with methanol, and dried under reduced pressure to provide the title compound as tan needles (6.6 g, 74percent).
Reference: [1] Patent: US6933311, 2005, B2,
[2] Patent: US2005/113576, 2005, A1, . Location in patent: Page/Page column 29-30
[3] Patent: US2004/157849, 2004, A1,
  • 10
  • [ 703-59-3 ]
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Reference: [1] Patent: US5587385, 1996, A,
[2] Tetrahedron Letters, 2011, vol. 52, # 13, p. 1495 - 1497
[3] Tetrahedron, 1999, vol. 55, # 30, p. 9185 - 9204
[4] Tetrahedron Letters, 1987, vol. 28, # 49, p. 6187 - 6190
[5] Heterocycles, 1994, vol. 39, # 2, p. 729 - 740
[6] Patent: US6340759, 2002, B1, . Location in patent: Example 17
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YieldReaction ConditionsOperation in experiment
47% at 175℃; sealed tube PREPARATION 20; a) lsoquinoline-1,3(2H,4H)-dione; A solution of 2-(carboxymethyl)benzoic acid (1.00 g, 5.55 mmol) and urea (0.37 g, 6.10 mmol) in ethylene glycol anhydrous (20 mL) was heated in a sealed tube at 175 °C with stirring. After stirring overnight the mixture was cooled, poured onto water and 1 N aqueous hydrochloric acid was added until the pH was 4-5. The aqueous layer was extracted with ethyl acetate, dried (Na2S04) and evaporated. Methanol and few drops of hexanes were added to the crude and the precipitate was filtered, washed whith hexanes and dried to give the desired compound (0.43 g, 47percent) as a solid. LRMS (m/z): 162 (M+1)+.
Reference: [1] Patent: WO2012/41476, 2012, A1, . Location in patent: Page/Page column 56-57
[2] Patent: WO2014/164667, 2014, A1, . Location in patent: Page/Page column 36
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Reference: [1] Tetrahedron Letters, 2004, vol. 45, # 24, p. 4759 - 4762
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  • [ 512787-37-0 ]
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Reference: [1] Tetrahedron, 2002, vol. 58, # 50, p. 9925 - 9932
  • 14
  • [ 201230-82-2 ]
  • [ 195456-43-0 ]
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Reference: [1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 16, p. 2692 - 2700
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  • [ 201230-82-2 ]
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Reference: [1] Organometallics, 2011, vol. 30, # 5, p. 1079 - 1093
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  • [ 3759-28-2 ]
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Reference: [1] Green Chemistry, 2017, vol. 19, # 7, p. 1740 - 1750
  • 17
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Reference: [1] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 4, p. 793 - 796
  • 18
  • [ 29241-85-8 ]
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Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1983, # 8, p. 1813 - 1818
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Reference: [1] Tetrahedron, 2002, vol. 58, # 50, p. 9925 - 9932
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Reference: [1] Tetrahedron, 2002, vol. 58, # 50, p. 9925 - 9932
  • 21
  • [ 2848-28-4 ]
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Reference: [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1980, vol. 19, # 8, p. 641 - 643
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1980, vol. 19, # 8, p. 641 - 643
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  • [ 25113-15-9 ]
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Reference: [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1980, vol. 19, # 8, p. 641 - 643
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1980, vol. 19, # 8, p. 641 - 643
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Reference: [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1980, vol. 19, # 8, p. 641 - 643
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1980, vol. 19, # 8, p. 641 - 643
  • 24
  • [ 4476-30-6 ]
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Reference: [1] Chemische Berichte, 1887, vol. 20, p. 1204
[2] Chemische Berichte, 1907, vol. 40, p. 240
[3] Journal of the Chemical Society, 1925, vol. 127, p. 1370
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Reference: [1] Chemische Berichte, 1887, vol. 20, p. 2504
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  • [ 7664-93-9 ]
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Reference: [1] Chemische Berichte, 1887, vol. 20, p. 2504
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Reference: [1] Chemische Berichte, 1887, vol. 20, p. 1204
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