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Product Details of [ 20924-56-5 ]

CAS No. :20924-56-5 MDL No. :MFCD09744058
Formula : C9H8O2 Boiling Point : -
Linear Structure Formula :- InChI Key :OYXTZAZUFUWSIR-UHFFFAOYSA-N
M.W : 148.16 Pubchem ID :12339648
Synonyms :

Calculated chemistry of [ 20924-56-5 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.22
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 40.57
TPSA : 26.3 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.39 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.68
Log Po/w (XLOGP3) : 1.15
Log Po/w (WLOGP) : 1.25
Log Po/w (MLOGP) : 0.78
Log Po/w (SILICOS-IT) : 2.46
Consensus Log Po/w : 1.46

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.89
Solubility : 1.92 mg/ml ; 0.013 mol/l
Class : Very soluble
Log S (Ali) : -1.3
Solubility : 7.48 mg/ml ; 0.0505 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.84
Solubility : 0.216 mg/ml ; 0.00146 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.9

Safety of [ 20924-56-5 ]

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 [ 20924-56-5 ]

* 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.

  • Downstream synthetic route of [ 20924-56-5 ]

[ 20924-56-5 ] Synthesis Path-Downstream   1~84

  • 1
  • [ 20924-56-5 ]
  • [ 74096-70-1 ]
YieldReaction ConditionsOperation in experiment
74% With deuteriated sodium hydroxide In tetrahydrofuran for 0.333333h; Ambient temperature;
  • 2
  • [ 20924-54-3 ]
  • [ 20924-56-5 ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide; potassium acetate 1.) acetic anhydride, reflux, 1 h, 2.) ethanol, RT, 2 h; Yield given. Multistep reaction;
Stage #1: <(2-carboxybenxyl)oxy>acetic acid With potassium acetate; acetic anhydride for 2h; Heating / reflux; Stage #2: With sodium hydroxide; ethanol; water at 20℃; for 2h; 63.2 Step Two; lH-isochromen-4 (3H) -one; A mixture of the product of step one (8.2 g, 39.0 mmol), KOAc (16.5 g, 167.8 mmol) and Ac2O (117 ml) was heated to reflux for 2 h. The mixture was cooled to room temperature then poured onto ice. The mixture was extracted with Et20 (3 x 100 ml) and the combined organic layers dried over Mg SO4 and concentrated in vacuo. The resulting residue was dissolved in 40 ml of EtOH followed by the addition of 15 ml of 2 N NaOH. Stirring was continued at room temperature for 2h then the EtOH was removed in vacuo. The resulting aqueous layer was extracted with Et20 (3 x 75 ml) and the combined organic layers dried over MgSO4, concentrated in vacuo to yield 2.7 g of lH-isochromen-4 (3H) -one as a slight yellow oil after flash chromatography (10% EtOAc/Hexanes)
Stage #1: <(2-carboxybenxyl)oxy>acetic acid With potassium acetate; acetic anhydride at 138℃; for 2h; Stage #2: With sodium hydroxide In ethanol; water at 20℃; for 2h; 3; 5 2-[(Carboxymethoxy)methyl]benzoic acid (37.6 mmol) and potassium acetate (169.2 mmol) are combined and diluted with acetic anhydride (1 12 ml_). The reaction mixture is heated at 138 0C for 2 h and is concentrated. The residue is diluted with ice water (25 g), extracted with ether (3 x 900 ml_) and the combined organic layers are dried (magnesium sulfate), and concentrated. The residue is diluted with ethanol (150 ml_) and 4 N sodium hydroxide (20 ml_) and the reaction mixture is maintained for 2 h at rt. The reaction mixture is extracted with ether (3 x 900 ml_) and the combined organic layers are dried (magnesium sulfate), and concentrated. The residue is purified by chromatography (100/1 to 30/1 hexane/ethyl acetate) to provide 1 H-isochromen-4(3/-/)- one in 47% yield as a yellow oil.
Stage #1: <(2-carboxybenxyl)oxy>acetic acid With potassium acetate; acetic anhydride for 2h; Heating / reflux; Stage #2: With sodium hydroxide In ethanol; water at 20℃; for 2h; 74.2 A mixture of the product of step 1 (8.2 g, 39.0 mmol), KOAc (16.5 g, 167.8 mmol) and Ac20 (117 mL) was heated to reflux for 2 h. The mixture was cooled to room temperature then poured onto ice. The mixture was extracted with Et20, dried (MgS04), filtered, and concentrated in vacuo. The resulting residue was dissolved in 40 mL of EtOH, then 2 N NaOH (15 mL) was added. Stirring was continued at room temperature for 2 h then the EtOH was removed in vacuo. The resulting aqueous layer was extracted with Et20 and the combined organic layers dried (magnesium sulfate), and concentrated in vacuo to yield 2.7 g of 1H-isochromen-4 (3H) -one as a pale yellow oil after flash chromatography (10% EtOAc/Hexanes) Rf = 0. 25.'H NMR (400 MHz, CDC13) 8 8.05 (d, J= 7.88 Hz, 1 H), 7.59 (m, 1 H), 7.43 (appt, J= 7.36 Hz, 1 H), 7.24 (d, J= 7.67 Hz, 1 H), 4.91 (s, 2 H), 4.39 (s, 2 H). Anal calc'd for C9H8O2 ; C, 72.96 ; H, 5.44 ; found C, 72.50 ; H, 5.29. MS (ESI+) for CgH802 m/z 148. 8 [M+H] +.

  • 3
  • [ 20924-56-5 ]
  • [ 95-92-1 ]
  • [ 130747-46-5 ]
YieldReaction ConditionsOperation in experiment
76% With ethanol; sodium hydride In toluene at 25℃; for 12h;
  • 4
  • [ 493-05-0 ]
  • [ 4702-34-5 ]
  • [ 20924-56-5 ]
YieldReaction ConditionsOperation in experiment
72% With carbon monoxide; oxygen; copper dichloride; palladium dichloride In <i>tert</i>-butyl alcohol for 72h;
Stage #1: isochromane In aq. phosphate buffer; acetonitrile at 4℃; for 0.25h; Inert atmosphere; Stage #2: With peracetic acid In aq. phosphate buffer; water; acetonitrile at 4℃; Inert atmosphere; 4.5. General procedure for biocatalysis General procedure: A solution of Nb-C96-3 (500 μL, 100 μM), 500 μL NaPi buffer (100 μM, pH 7.0 with 10% ACN), and 12.5 μL substrate (80 mM stock in ACN) were added to 1.5 mL microcentrifuge tube, and incubated at 4 °C for 15 min. 5 μL of peracetic acid aqueous solution (1 M) was added to the mixture. The resulting solution was shaken at 4 °C overnight. The final concentrations were: 1 mM substrate, 2.5 mM AcOOH, and 50 μM hybrid. The reaction was quenched by adding 350 μL DCM. pH was adjusted to 2 for ibuprofen case. The closed vials were agitated using a vortexer for 30 s and centrifuged at 15,000 rpm for 3 min. The organic layer was isolated. 10 μL sample was injected on HPLC.
  • 5
  • [ 75-77-4 ]
  • [ 20924-56-5 ]
  • isochroman-4-one trimethylsilyl enol ether [ No CAS ]
YieldReaction ConditionsOperation in experiment
79% With triethylamine; sodium iodide In acetonitrile at 20℃; for 3h;
  • 6
  • [ 20924-56-5 ]
  • isochroman-4-one enol potassium salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide In water at 25℃;
  • 7
  • [ 387335-31-1 ]
  • [ 20924-56-5 ]
YieldReaction ConditionsOperation in experiment
With water at 25℃;
  • 8
  • 1-iodo-2-(((3-phenylprop-2-yn-1-yl)oxy)methyl)benzene [ No CAS ]
  • [ 20924-56-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 67 percent / Pd(OAc)2, PPh3, TlOAc / acetonitrile / 48 h / Heating 2: 1.) O3, 2.) Me2S / 1.) DCM, -78 deg C, 15 min, 2.) -78 deg C to rt, 15 h
  • 9
  • [ 96259-61-9 ]
  • [ 20924-56-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 42 percent / NaOH, H2O / bis-(2-hydroxy-ethyl) ether / 12 h / Heating 2: 1.) potassium acetate, 2.) 5percent KOH / 1.) acetic anhydride, reflux, 1 h, 2.) ethanol, RT, 2 h
  • 10
  • [ 20924-56-5 ]
  • [ 32521-19-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 76 percent / NaH, EtOH / toluene / 12 h / 25 °C 2: 2) iron powder / 1) EtOH, 36h reflux, 2) 3h, 40 mmHg, heating
  • 11
  • [ 20924-56-5 ]
  • [ 92614-38-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 76 percent / NaH, EtOH / toluene / 12 h / 25 °C 2: 2) iron powder / 1) EtOH, 36h reflux, 2) 3h, 40 mmHg, heating 3: 76 percent / 50percent N2H4*H2O, 5percent NaOH / 4.5 h / 75 °C
Multi-step reaction with 2 steps 1: 76 percent / NaH, EtOH / toluene / 12 h / 25 °C 2: 76 percent / 50percent N2H4*H2O, 5percent NaOH / 4.5 h / 75 °C
  • 12
  • [ 20924-56-5 ]
  • [ 130747-50-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 76 percent / NaH, EtOH / toluene / 12 h / 25 °C 2: 2) iron powder / 1) EtOH, 36h reflux, 2) 3h, 40 mmHg, heating 3: 80 percent / BuONa / butan-1-ol / 4.5 h / 110 °C
  • 13
  • [ 20924-56-5 ]
  • [ 130747-48-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 76 percent / NaH, EtOH / toluene / 12 h / 25 °C 2: 2) iron powder / 1) EtOH, 36h reflux, 2) 3h, 40 mmHg, heating 3: 65 percent / ethanol / 10 h / Heating
  • 14
  • [ 20924-56-5 ]
  • [ 130747-47-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 76 percent / NaH, EtOH / toluene / 12 h / 25 °C 2: 72 percent / 98percent N2H4*H2O, AcOH / 3 h / Heating
  • 15
  • [ 20924-56-5 ]
  • [ 130747-58-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 76 percent / NaH, EtOH / toluene / 12 h / 25 °C 2: 2) iron powder / 1) EtOH, 36h reflux, 2) 3h, 40 mmHg, heating 3: 82 percent / BuONa / butan-1-ol / 4.5 h / 110 °C
  • 16
  • [ 20924-56-5 ]
  • [ 130747-51-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 76 percent / NaH, EtOH / toluene / 12 h / 25 °C 2: 2) iron powder / 1) EtOH, 36h reflux, 2) 3h, 40 mmHg, heating 3: 73 percent / ethanol / 10 h / Heating
  • 17
  • [ 20924-56-5 ]
  • [ 130747-52-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 76 percent / NaH, EtOH / toluene / 12 h / 25 °C 2: 2) iron powder / 1) EtOH, 36h reflux, 2) 3h, 40 mmHg, heating 3: 80 percent / ethanol / 10 h / Heating
  • 18
  • [ 20924-56-5 ]
  • [ 130747-59-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 76 percent / NaH, EtOH / toluene / 12 h / 25 °C 2: 2) iron powder / 1) EtOH, 36h reflux, 2) 3h, 40 mmHg, heating 3: 69 percent / BuONa / butan-1-ol / 4.5 h / 110 °C
  • 19
  • [ 20924-56-5 ]
  • [ 130747-49-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 76 percent / NaH, EtOH / toluene / 12 h / 25 °C 2: 2) iron powder / 1) EtOH, 36h reflux, 2) 3h, 40 mmHg, heating 3: 86 percent / ethanol / 27 h / Heating
Multi-step reaction with 2 steps 1: 76 percent / NaH, EtOH / toluene / 12 h / 25 °C 2: 86 percent / ethanol / 27 h / Heating
  • 20
  • [ 20924-56-5 ]
  • [ 130747-54-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 76 percent / NaH, EtOH / toluene / 12 h / 25 °C 2: 2) iron powder / 1) EtOH, 36h reflux, 2) 3h, 40 mmHg, heating 3: 77 percent / ethanol / 27 h / Heating
  • 21
  • [ 20924-56-5 ]
  • [ 130747-53-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 76 percent / NaH, EtOH / toluene / 12 h / 25 °C 2: 2) iron powder / 1) EtOH, 36h reflux, 2) 3h, 40 mmHg, heating 3: 64 percent / ethanol / 27 h / Heating
  • 22
  • [ 20924-56-5 ]
  • [ 130747-57-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 76 percent / NaH, EtOH / toluene / 12 h / 25 °C 2: 2) iron powder / 1) EtOH, 36h reflux, 2) 3h, 40 mmHg, heating 3: 52 percent / ethanol / 27 h / Heating
  • 23
  • [ 20924-56-5 ]
  • [ 130747-56-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 76 percent / NaH, EtOH / toluene / 12 h / 25 °C 2: 2) iron powder / 1) EtOH, 36h reflux, 2) 3h, 40 mmHg, heating 3: 59 percent / ethanol / 27 h / Heating
  • 24
  • [ 20924-56-5 ]
  • [ 130747-55-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 76 percent / NaH, EtOH / toluene / 12 h / 25 °C 2: 2) iron powder / 1) EtOH, 36h reflux, 2) 3h, 40 mmHg, heating 3: 70 percent / ethanol / 27 h / Heating
  • 25
  • [ 87280-13-5 ]
  • [ 20924-56-5 ]
YieldReaction ConditionsOperation in experiment
54% With oxygen; Mn(dtbpy)<SUB>2</SUB>(OTf)<SUB>2</SUB> In methanol; 2,2,2-trifluoroethanol at 20℃; for 12h; Schlenk technique; Irradiation; chemoselective reaction;
Stage #1: 4-methyleneisochromane With pyridine; ozone In methanol; dichloromethane at -78℃; for 1h; Stage #2: With dimethylsulfide In methanol; dichloromethane at -78 - 20℃; for 3h; 63.2A Step 2 A; lH-isochromen-4 (3H) -one; l-[(allyloxy) methyl]-2-iodobenzene (23 g, 83.9 mmol) was dissolved in 100 ml of CH3CN and 58 ml of Et3N. The solution was vacuum degassed (3 cycles) followed by the addition of Pd (OAc) 2 (0. 9 g, 4.2 mmol) and PPh3 (2.2 g, 8.4 mmol). The mixture was heated to 80°C until HPLC indicated complete reaction. The mixture was cooled to room temperature and diluted with Et20 (200 ml). The mixture was washed with 1N HC1 (2x 50 ml); NaHCO3 (2 x 50 ml); brine (1 x 50 ml); dried over Na2SO4 and concentrated in vacuo to yield 4-methylene-3,4- dihydro-lH-isochromene (Heterocycles 1994,39, 497) as an oil. HRMS (ESI+) calcd for CloHloO m/z 146.0732 (M+H) +. Found 146.0728. The crude oil was dissolved in 1: 1 CH3OH/CH2Cl2 (500 ml) and 5 ml of pyridine added. The mixture was chilled to-78°C and ozone was bubbled through the mixture for 1 h, at which time TLC indicated complete reaction. The mixture was purged with N2 at-78°C and treated with Me2S, then allowed to warm to room temperature and stir for 3h. The reaction was then diluted with CH2Cl2 and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield 5.1 g of lH-isochromen-4 (3H) -one as a slight yellow oil after flash chromatography (10% EtOAc/Hexanes) Rf = 0. 25
Stage #1: 4-methyleneisochromane With pyridine; ozone In methanol; dichloromethane at -78℃; for 1h; Stage #2: With dimethylsulfide In methanol; dichloromethane at 20℃; for 3h; 75.2 1-[(Allyloxy) methyl]-2-iodobenzene (23 g, 83.9 mmol) was dissolved in 100 mL of CH3CN and 58 mL of Et3N. The solution was vacuum degassed, then Pd (OAc) 2 (0.9 g, 4.2 mmol) and PPh3 (2.2 g, 8.4 mmol) were added. The mixture was heated to 80 °C until HPLC indicated complete reaction. The mixture was cooled to room temperature and diluted with Et20 (200 mL), washed with 1 N HCI, NaHCO3, and brine (1 x 50 mL), dried (sodium sulfate), filtered, and concentrated in vacuo to yield 4-methylene-3, 4-dihydro-1 H- isochromene (Heterocycles 1994,39, 497) as an oil. HRMS (ESI+) calc'd for C10H1oO m/z 146.0732 [M+H] + ; found 146.0728. The crude oil was dissolved in 1: 1 CH30H/CH2CI2 (500 mL) and 5 mL of pyridine added. The mixture was chilled to-78 °C and ozone was bubbled through the mixture for 1 h. The mixture was purged with N2 (g) at-78 °C and treated with Me2S, then allowed to warm to room temperature and stir for 3 h. The reaction was then diluted with CH2CI2, washed with H20 and brine, dried (sodium sulfate), filtered, and concentrated in vacuo to yield 1H-isochromen-4 (3H) -one (5.1 g) as a pale yellow oil after flash chromatography (10% EtOAc/Hexanes) Rf = 0. 25.'H NMR (400 MHz, CDC13) 8 8.05 (d, J= 7.88 Hz, 1 H), 7.59 (m, 1 H), 7.43 (appt, J = 7.36 Hz, 1 H), 7.24 (d, J = 7.67 Hz, 1 H), 4.91 (s, 2 H), 4.39 (s, 2 H. Anal calc'd for C9H8O2 ; C, 72.96 ; H, 5.44 ; found C, 72.50 ; H, 5.29. MS (ESI+) for C9H802 m/z 148. 8 [M+H] +.
Stage #1: 4-methyleneisochromane With pyridine; ozone In methanol; dichloromethane at -78℃; for 5.5h; Stage #2: With dimethylsulfide In methanol; dichloromethane at -78℃; for 0.0833333h; 22.C 1H-ISOCHROMEN-4(3H)-ONE Step 22C The alkene 22b was dissolved in 1:1 DCM/MeOH (5 L) containing pyridine (42 mL). The mixture was ozonized in three batches at -78° C., until all starting material was consumed (TLC, about 5 hours per batch). The reaction mixture was then purged thoroughly with nitrogen for half an hour at -78° C. Dimethylsulfide (3 eq.) was added with stirring via an addition funnel over 5 minutes and the cold bath was removed. After warming up to room temperature, the reaction mix was washed twice with water and once with brine. The organic layer was dried over magnesium sulfate and evaporated. Chromatography on a Biotage 150 column using 5% ethyl acetate in hexanes, gave 22c as a yellow oil (49.5 g, 39% over two steps). 1H NMR (300 MHz, CDCl3) δ 8.05 (dd, J=8.1, 0.9 Hz, 1H), 7.58 (dt, J=7.5, 1.5 Hz, 1H), 7.43 (dt, J=7.5, 0.9 Hz, 1H), 7.23 (dd, J=7.5, 0.6 Hz, 1H), 4.91 (s, 2H), 4.39 (s, 2H).
With sodium periodate; osmium(VIII) oxide In <i>tert</i>-butyl alcohol at 0 - 20℃; D.3 Step 3: To a mixture of D3 (3.0 g, 20.55 mmol) in dioxane-water (1 :1, 40 mL) at 0°C was added NaI04 (13.1 g, 61.5 mmol). The reaction mixture was stirred for 10 min. After that time, a solution of Os04 (2.5 % in t-butanol, 0.104 g, 0.41 mmol) was added dropwise. The reaction was allowed to warm to RT and stirred overnight. After that time, water was added to the reaction flask and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over Na2S04, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography over silica gel eluting with 10% ethyl acetate in petroleum ether to afford D4. 1H-NMR (CDC13, 400 MHz): δ 8.06 (d, J = 7.7 Hz, 1H), 7.61-7.56 (m, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 4.91 (s, 2H), 4.39 (s, 2H).

  • 26
  • [ 50-00-0 ]
  • [ 20924-56-5 ]
  • [ 506-59-2 ]
  • [ 92614-25-0 ]
YieldReaction ConditionsOperation in experiment
75% With hydrogenchloride In ethanol; water Heating / reflux; 12.A; 13.A To the solution of 1H-isochromen-4(3H)-one 22c (24.0 g, 0.16 mol) in ethanol (500 mL), dimethylamine hydrochloride (66.2 g, 0.81 mole), paraformaldehyde (14.6 g, 0.49 mole) and aqueous hydrochloric acid (12N, 13.5 mL) were added. The cloudy suspension was heated at reflux overnight. After cooling, excess solvent was removed and the residue recrystalized from isopropyl alcohol twice. The resulting off-white precipitate was filtered and dried to give 12a (29.5 g, 76%). 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J=7.8 Hz, 1H), 7.62 (dt, J=7.8, 1.5 Hz, 1H), 7.44 (t, J=7.5 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 5.24-5.28 (m, 1H), 5.21 (d, J=15.3 Hz, 1H), 4.99 (d, J=15.3 Hz, 1H), 4.03 (dd, J=14.4, 2.4 Hz, 1H), 3.17-3.25 (m, 1H), 3.02 (s, 3H), 2.97 (s, 3H). ESI MS m/e: 206.0 ([M+H]+) EXAMPLE 13 DIMETHYL-(4-O-TOLYLOXY-ISOCHROMAN-3-YLMETHYL)-AMINE Step 13A: To the solution of the 1H-isochromen-4(3H)-one 22a (49.5 g, 334 mmol) in ethanol (1 L), dimethylamine hydrochloride (136 g, 1.67 mole), paraformaldehyde (30 g, 1.00 mole) and aqueous hydrochloric acid (12N, 21 mL) were added. The cloudy suspension was heated at reflux overnight. After cooling, the solution was concentrated to half original volume under reduced pressure. The resulting off-white precipitate (40 g, 50%) was filtered and washed with ether to give 12a. A second batch of product (20 g, 25%) was obtained from the mother liquor by treatment with ether. 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J=7.8 Hz, 1H), 7.62 (dt, J=7.8, 1.5 Hz, 1H), 7.44 (t, J=7.5 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 5.24-5.28 (m, 1H), 5.21 (d, J=15.3 Hz, 1H), 4.99 (d, J=15.3 Hz, 1H), 4.03 (dd, J=14.4, 2.4 Hz, 1H), 3.17-3.25 (m, 1H), 3.02 (s, 3H), 2.97 (s, 3H). ESI MS m/e: 206.0 ([M+H]+)
  • 27
  • [ 253-35-0 ]
  • [ 20924-56-5 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 1H-isochromene With pyridine; ozone In methanol; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran at -78℃; for 5h; Stage #2: With dimethylsulfide at 20℃; for 3h;
  • 31
  • [ 20924-56-5 ]
  • [ 1372452-73-7 ]
YieldReaction ConditionsOperation in experiment
78% With Almag CRED A131; NADP; glucose dehydrogenase In water; dimethyl sulfoxide at 30℃; Enzymatic reaction; 4.4 General procedure: Almac CRED (200 mg),NADP or NAD (10 mg), GDH (20 mg) and glucose (1.5 equiv) weremeasured into a 100 mL round bottomed flask then dissolved in0.1 M potassium phosphate buffer (pH 7, ca. 50 mL) and stirredat 30 C. Next, a solution of ketone (900-1700 mg) in DMSO(2.5-5 mL, depending on solubility) was added to the reactionand this was allowed to stir overnight under pH-stat control (pH7.0, adjusted with 1 M NaOH solution). The following day, reactionprogress was checked by 1H NMR. If not complete, additional CRED(100-200 mg), NADP or NAD (10 mg) and GDH (10 mg) wereadded and stirring was continued. This was repeated until the reactionreached completion or had stalled and would not go any further.
  • 32
  • [ 20924-56-5 ]
  • [ 1372452-79-3 ]
YieldReaction ConditionsOperation in experiment
93% With Almag CRED A231; NADP; glucose dehydrogenase In water; dimethyl sulfoxide at 30℃; Enzymatic reaction; 4.4 General procedure: Almac CRED (200 mg),NADP or NAD (10 mg), GDH (20 mg) and glucose (1.5 equiv) weremeasured into a 100 mL round bottomed flask then dissolved in0.1 M potassium phosphate buffer (pH 7, ca. 50 mL) and stirredat 30 C. Next, a solution of ketone (900-1700 mg) in DMSO(2.5-5 mL, depending on solubility) was added to the reactionand this was allowed to stir overnight under pH-stat control (pH7.0, adjusted with 1 M NaOH solution). The following day, reactionprogress was checked by 1H NMR. If not complete, additional CRED(100-200 mg), NADP or NAD (10 mg) and GDH (10 mg) wereadded and stirring was continued. This was repeated until the reactionreached completion or had stalled and would not go any further.
  • 33
  • [ 5159-41-1 ]
  • [ 20924-56-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: sodium hydride / tetrahydrofuran / 0 °C 1.2: 20 °C 2.1: triethylamine; palladium diacetate; triphenylphosphine / acetonitrile / 2 h / 80 °C 3.1: sodium periodate; osmium(VIII) oxide / <i>tert</i>-butyl alcohol / 0 - 20 °C
  • 34
  • [ 57056-92-5 ]
  • [ 20924-56-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triethylamine; palladium diacetate; triphenylphosphine / acetonitrile / 2 h / 80 °C 2: sodium periodate; osmium(VIII) oxide / <i>tert</i>-butyl alcohol / 0 - 20 °C
  • 35
  • [ 20924-56-5 ]
  • 6-Nitroisochroman-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With nitric acid at -30℃; for 5.5h;
  • 36
  • [ 20924-56-5 ]
  • C13H16N2O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: nitric acid / 5.5 h / -30 °C 2: titanium(IV) tetraethanolate / tetrahydrofuran / 1 h / Reflux
  • 37
  • [ 20924-56-5 ]
  • C18H25N3O6S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: nitric acid / 5.5 h / -30 °C 2.1: titanium(IV) tetraethanolate / tetrahydrofuran / 1 h / Reflux 3.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C / Inert atmosphere 3.2: 4 h / -78 °C
  • 38
  • [ 20924-56-5 ]
  • C14H17N3O5S*ClH [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: nitric acid / 5.5 h / -30 °C 2.1: titanium(IV) tetraethanolate / tetrahydrofuran / 1 h / Reflux 3.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C / Inert atmosphere 3.2: 4 h / -78 °C 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 2 h / 0 °C
  • 39
  • [ 20924-56-5 ]
  • C14H17N3O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: nitric acid / 5.5 h / -30 °C 2.1: titanium(IV) tetraethanolate / tetrahydrofuran / 1 h / Reflux 3.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C / Inert atmosphere 3.2: 4 h / -78 °C 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 2 h / 0 °C 5.1: copper(l) chloride / ethanol / Reflux
  • 40
  • [ 20924-56-5 ]
  • C19H25N3O7S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: nitric acid / 5.5 h / -30 °C 2.1: titanium(IV) tetraethanolate / tetrahydrofuran / 1 h / Reflux 3.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C / Inert atmosphere 3.2: 4 h / -78 °C 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 2 h / 0 °C 5.1: copper(l) chloride / ethanol / Reflux 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 20 °C
  • 41
  • [ 20924-56-5 ]
  • (S)-tert-butyl (6-amino-6,6'-dimethyl-1',1'-dioxidospiro[isochroman-4,3'-thiomorpholin]-5'-ylidene)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: nitric acid / 5.5 h / -30 °C 2.1: titanium(IV) tetraethanolate / tetrahydrofuran / 1 h / Reflux 3.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C / Inert atmosphere 3.2: 4 h / -78 °C 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 2 h / 0 °C 5.1: copper(l) chloride / ethanol / Reflux 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 20 °C 7.1: palladium 10% on activated carbon; hydrogen / ethanol; methanol / 2 h / 20 °C / Inert atmosphere
  • 42
  • [ 20924-56-5 ]
  • C25H29ClN4O6S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1.1: nitric acid / 5.5 h / -30 °C 2.1: titanium(IV) tetraethanolate / tetrahydrofuran / 1 h / Reflux 3.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C / Inert atmosphere 3.2: 4 h / -78 °C 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 2 h / 0 °C 5.1: copper(l) chloride / ethanol / Reflux 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 20 °C 7.1: palladium 10% on activated carbon; hydrogen / ethanol; methanol / 2 h / 20 °C / Inert atmosphere 8.1: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / tetrahydrofuran; ethyl acetate / 3 h / 20 °C
  • 43
  • [ 20924-56-5 ]
  • C20H21ClN4O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1.1: nitric acid / 5.5 h / -30 °C 2.1: titanium(IV) tetraethanolate / tetrahydrofuran / 1 h / Reflux 3.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C / Inert atmosphere 3.2: 4 h / -78 °C 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 2 h / 0 °C 5.1: copper(l) chloride / ethanol / Reflux 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 20 °C 7.1: palladium 10% on activated carbon; hydrogen / ethanol; methanol / 2 h / 20 °C / Inert atmosphere 8.1: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / tetrahydrofuran; ethyl acetate / 3 h / 20 °C 9.1: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C
  • 44
  • [ 20924-56-5 ]
  • C20H20F3N5O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1.1: nitric acid / 5.5 h / -30 °C 2.1: titanium(IV) tetraethanolate / tetrahydrofuran / 1 h / Reflux 3.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C / Inert atmosphere 3.2: 4 h / -78 °C 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 2 h / 0 °C 5.1: copper(l) chloride / ethanol / Reflux 6.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 20 °C 7.1: palladium 10% on activated carbon; hydrogen / ethanol; methanol / 2 h / 20 °C / Inert atmosphere 8.1: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / tetrahydrofuran; ethyl acetate / 20 °C 8.2: 3 h / 20 °C
  • 45
  • [ 20924-56-5 ]
  • [ 106-54-7 ]
  • C15H11ClO2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
30% With di-tert-butyl peroxide at 120℃; for 6h; General Procedure for the Oxidative C-S Formation General procedure: A sealed tube was charged with isochroman (or benzylic ether;1 mmol), DTBP (1.5 mmol), thiol (or thiophenol; 1.5 mmol). Thereaction mixture was stirred at 120 °C for 6 h. The reactionmixture was then cooled to obtain a brown liquid. The organicsolutions could be purified directly by column chromatographyon silica gel to give the pure product (hexane-EtOAc, 20:1).
  • 46
  • [ 20924-56-5 ]
  • (4-phenyl-1H-isochromen-3-yl)methanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: trichlorophosphate / dichloromethane / 20 °C / Inert atmosphere; Reflux 2: chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II); potassium phosphate monohydrate / water; tetrahydrofuran / 20 °C / Sealed tube; Inert atmosphere 3: sodium tetrahydroborate; methanol / 20 °C
Multi-step reaction with 3 steps 1: trichlorophosphate / N,N-dimethyl-formamide; water / 20 °C / Inert atmosphere 2: chloro(2-dicyclohexylphosphino-2’,6’-dimethoxy-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II); potassium phosphate / water; tetrahydrofuran / 20 °C / Inert atmosphere; Sealed tube 3: methanol; sodium tetrahydroborate / 20 °C
  • 47
  • [ 20924-56-5 ]
  • 4-phenyl-1H-isochromene-3-carbaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: trichlorophosphate / dichloromethane / 20 °C / Inert atmosphere; Reflux 2: chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II); potassium phosphate monohydrate / water; tetrahydrofuran / 20 °C / Sealed tube; Inert atmosphere
Multi-step reaction with 2 steps 1: trichlorophosphate / N,N-dimethyl-formamide; water / 20 °C / Inert atmosphere 2: chloro(2-dicyclohexylphosphino-2’,6’-dimethoxy-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II); potassium phosphate / water; tetrahydrofuran / 20 °C / Inert atmosphere; Sealed tube
  • 48
  • [ 20924-56-5 ]
  • [ 33513-42-7 ]
  • 4-chloro-1H-isochromene-3-carbaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
60.6% With trichlorophosphate In dichloromethane at 20℃; Inert atmosphere; Reflux; 1 Step. 4-chloro- 1 H-isochromene-3 -carbaldehyde (Intermediate G20. 1) To commercially available isochroman-4-one (900 mg, 6.07 mmol) in DCM (18 ml), DMF (0.706 ml) and POC13 (1.699 ml, 18.23 mmol) were added in sequence under Nitrogen at r.t. The mixture was refluxed for 6h and kept at r.t overnight.The reaction mixture was diluted with DCM (15 ml), washed with water and sat NaC1, then dried over Na2504 and evaporated in vacuo. The resulting crude was purified via reverse phase chromatography with a Biotage C18 SNAP 30g column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give 4-chloro-1H-isochromene-3-carbaldehyde (Intermediate G20.1, 716 mg, 60,6 %yield)1H NMR (400 MHz, DMSO-d6) d ppm 10.02 (s, 1 H), 7.61 - 7.81 (m, 1 H), 7.42 -7.58 (m, 2 H), 7.20 - 7.40 (m, 1 H), 5.21 (s, 2 H). UPLC-MS: 0.94 mm, 195 [M+H]+,method 9
60.6% With trichlorophosphate In water; N,N-dimethyl-formamide at 20℃; Inert atmosphere; G20.1 4-chloro-1H-isochromene-3-carbaldehyde (Intermediate G20.1) To commercially available isochroman-4-one (900 mg, 6.07 mmol) in DCM (18 ml), DMF (0.706 ml) and POCl3 (1.699 ml, 18.23 mmol) were added in sequence under Nitrogen at r.t. The mixture was refluxed for 6 h and kept at r.t overnight. The reaction mixture was diluted with DCM (15 ml), washed with water and sat NaCl, then anhydrified over Na2SO4 and evaporated in vacuo. The resulting crude was purified via reverse phase chromatography with a Biotage C18 SNAP 30 g column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give 4-chloro-1H-isochromene-3-carbaldehyde (Intermediate G20.1, 716 mg, 60.6% yield)1H NMR (400 MHz, DMSO-d6) d ppm 10.02 (s, 1H), 7.61-7.81 (m, 1H), 7.42-7.58 (m, 2H), 7.20-7.40 (m, 1H), 5.21 (s, 2H). UPLC-MS: 0.94 min, 195 [M+H]+, method 9
  • 49
  • [ 493-05-0 ]
  • [ 20924-56-5 ]
YieldReaction ConditionsOperation in experiment
61% With iron(III) chloride; thymidyl acetic acid; dihydrogen peroxide In water; acetonitrile at 60℃; for 6h;
  • 50
  • potassium cyanide [ No CAS ]
  • [ 20924-56-5 ]
  • [ 506-87-6 ]
  • spiro[imidazolidine-4,4'-isochroman]-2,5-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% In ethanol; water at 65℃; for 48h; 103.1 Step 1: Spiro[imidazolidine-4,4'-isochroman]-2,5-dione To a solution of isochroman-4-one_l (20 g, 135 mmol) in EtOH (150 mL) and water ( 150 mL) was added (NH4)2C03 (51.9 g, 540 mmol) and KCN ( 13.18 g, 202 mmol) at about 20 °C. The resulting mixture was heated to about 65 °C for about 48 h. The mixture was concentrated under reduced pressure to 150 mL and filtered. The solid was dried under reduced pressure to give the title compound (20 g, 68%); NMR (400 MHz, DMSO- 6): δ 10.96 (br. s., 1H), 8.68 (s, 1H), 7.34 - 7.28 (m, 2H), 7.16 - 7.14 (m, 2H), 4.79 - 4.71 (m, 2H), 4.02 - 3.95 (m, 2H).
  • 51
  • [ 20924-56-5 ]
  • 4-((tert-butoxycarbonyl)amino)isochromane-4-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: ethanol; water / 48 h / 65 °C 2: potassium hydroxide; water / 72 h / 120 °C 3: water / 12 h / 30 °C
  • 52
  • [ 20924-56-5 ]
  • C10H11NO3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: ethanol; water / 48 h / 65 °C 2: potassium hydroxide; water / 72 h / 120 °C
  • 53
  • [ 20924-56-5 ]
  • tert-butyl (4-(hydroxymethyl)isochroman-4-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: ethanol; water / 48 h / 65 °C 2: potassium hydroxide; water / 72 h / 120 °C 3: water / 12 h / 30 °C 4: lithium aluminium tetrahydride / tetrahydrofuran / -5 - 35 °C
  • 54
  • [ 20924-56-5 ]
  • (4-aminoisochroman-4-yl)methanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: ethanol; water / 48 h / 65 °C 2: potassium hydroxide; water / 72 h / 120 °C 3: water / 12 h / 30 °C 4: lithium aluminium tetrahydride / tetrahydrofuran / -5 - 35 °C 5: acetyl chloride; methanol / tert-butyl methyl ether / 12 h / 0 - 20 °C
  • 55
  • [ 20924-56-5 ]
  • 2-chloro-N-(4-(hydroxymethyl)isochroman-4-yl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: ethanol; water / 48 h / 65 °C 2: potassium hydroxide; water / 72 h / 120 °C 3: water / 12 h / 30 °C 4: lithium aluminium tetrahydride / tetrahydrofuran / -5 - 35 °C 5: acetyl chloride; methanol / tert-butyl methyl ether / 12 h / 0 - 20 °C 6: triethylamine / tetrahydrofuran / 2 h / -5 - 25 °C
  • 56
  • [ 20924-56-5 ]
  • spiro[isochromane-4,3'-morpholin]-5'-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1: ethanol; water / 48 h / 65 °C 2: potassium hydroxide; water / 72 h / 120 °C 3: water / 12 h / 30 °C 4: lithium aluminium tetrahydride / tetrahydrofuran / -5 - 35 °C 5: acetyl chloride; methanol / tert-butyl methyl ether / 12 h / 0 - 20 °C 6: triethylamine / tetrahydrofuran / 2 h / -5 - 25 °C 7: potassium <i>tert</i>-butylate / 0.33 h / 25 °C
  • 57
  • [ 20924-56-5 ]
  • (E)-N-(2,6-dibromopyridin-3-yl)spiro[isochromane-4,3'-morpholin]-5'-imine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1.1: ethanol; water / 48 h / 65 °C 2.1: potassium hydroxide; water / 72 h / 120 °C 3.1: water / 12 h / 30 °C 4.1: lithium aluminium tetrahydride / tetrahydrofuran / -5 - 35 °C 5.1: acetyl chloride; methanol / tert-butyl methyl ether / 12 h / 0 - 20 °C 6.1: triethylamine / tetrahydrofuran / 2 h / -5 - 25 °C 7.1: potassium <i>tert</i>-butylate / 0.33 h / 25 °C 8.1: trichlorophosphate / 1,2-dichloro-ethane / 0.08 h / 20 °C 8.2: 2 h / 70 °C
  • 58
  • [ 20924-56-5 ]
  • 2'-bromo-6'H,8'H-spiro[isochromane-4,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine] [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1.1: ethanol; water / 48 h / 65 °C 2.1: potassium hydroxide; water / 72 h / 120 °C 3.1: water / 12 h / 30 °C 4.1: lithium aluminium tetrahydride / tetrahydrofuran / -5 - 35 °C 5.1: acetyl chloride; methanol / tert-butyl methyl ether / 12 h / 0 - 20 °C 6.1: triethylamine / tetrahydrofuran / 2 h / -5 - 25 °C 7.1: potassium <i>tert</i>-butylate / 0.33 h / 25 °C 8.1: trichlorophosphate / 1,2-dichloro-ethane / 0.08 h / 20 °C 8.2: 2 h / 70 °C 9.1: N,N,N,N,-tetramethylethylenediamine; copper(l) iodide; potassium carbonate / dimethyl sulfoxide; acetonitrile / 12 h / 75 °C / Inert atmosphere
  • 59
  • [ 20924-56-5 ]
  • [ 147663-00-1 ]
YieldReaction ConditionsOperation in experiment
89.5% With ammonia; hydrogen; In ethanol; at 95.0℃; under 3750.38 - 30003 Torr; for 9.0h;Autoclave; Inert atmosphere; 1000ml autoclave, was added 74g isochroman-4-one, 700ml of anhydrous ethanol 11g catalyst SN-600P, the reactor was sealed, vacuum pumping with vacuum pump autoclave the air, and then filled with nitrogen to 0.5MPa, and then with Vacuum pumping vacuum; vacuum conditions filled with 44g ammonia, charge ammonia is completed, the autoclave filled with hydrogen to 4. 0MPa, and heated to 95 C for reaction. After 9 hours reaction, hydrogen pressure was found no longer decline, then stop the reaction. After the temperature of the system was lowered to room temperature, the reaction solution was filtered and concentrated to give crude isochroman-4-amine. The crude product is stirred under the circumstances, was added to the dilute hydrochloric acid solution, allowed to react to produce isochroman-4-amine hydrochloride, and dissolved in aqueous solution, and ethyl acetate to take an aqueous solution to remove organic impurities, after liquid separation , Retaining the aqueous phase, the aqueous phase was extracted twice with ethyl acetate, the pH value was adjusted to basic with sodium hydroxide, and then extracted three times with ethyl acetate, at this time the ethyl acetate phase was collected, dried and concentrated , To give isochroman-4-amine pure product 66.7g, the yield was 89.5%, and HPLC purity of 99.2%.
  • 60
  • [ 20924-56-5 ]
  • C11H13NO2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: ammonia; hydrogen / ethanol / 9 h / 95 °C / 3750.38 - 30003 Torr / Autoclave; Inert atmosphere 2: hydrogen; porcine pancreatic lipase / toluene / 12 h / 45 °C / 3750.38 Torr / Autoclave; Inert atmosphere; Enzymatic reaction
  • 61
  • [ 20924-56-5 ]
  • R-isochroman-4-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: ammonia; hydrogen / ethanol / 9 h / 95 °C / 3750.38 - 30003 Torr / Autoclave; Inert atmosphere 2: hydrogen; porcine pancreatic lipase / toluene / 12 h / 45 °C / 3750.38 Torr / Autoclave; Inert atmosphere; Enzymatic reaction 3: hydrogenchloride / methanol / Reflux
  • 62
  • [ 816417-94-4 ]
  • [ 20924-56-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: oxalyl dichloride 2: tert.-butyl lithium / tetrahydrofuran / -78 °C
  • 63
  • C11H14BrNO3 [ No CAS ]
  • [ 20924-56-5 ]
YieldReaction ConditionsOperation in experiment
With tert.-butyl lithium In tetrahydrofuran at -78℃;
  • 64
  • [ 20924-56-5 ]
  • C22H18NO2(1+)*Br(1-) [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / methanol / 4 h / 20 °C 2: acetonitrile / 1 h / 80 °C
  • 65
  • [ 20924-56-5 ]
  • C22H17FNO2(1+)*Br(1-) [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / methanol / 4 h / 20 °C 2: acetonitrile / 1 h / 80 °C
  • 66
  • [ 20924-56-5 ]
  • C22H17FNO2(1+)*Br(1-) [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / methanol / 4 h / 20 °C 2: acetonitrile / 1 h / 80 °C
  • 67
  • [ 20924-56-5 ]
  • C22H17FNO2(1+)*Br(1-) [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / methanol / 4 h / 20 °C 2: acetonitrile / 1 h / 80 °C
  • 68
  • [ 872-85-5 ]
  • [ 20924-56-5 ]
  • C15H11NO2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In methanol at 20℃; for 4h;
  • 69
  • [ 18982-54-2 ]
  • [ 20924-56-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: potassium carbonate / toluene; water / 0.5 h / 20 °C 2: sodium methylate; methanol / 20 °C 3: oxalyl dichloride 4: tert.-butyl lithium / tetrahydrofuran / -78 °C
  • 70
  • C13H17BrO3 [ No CAS ]
  • [ 20924-56-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: sodium methylate; methanol / 20 °C 2: oxalyl dichloride 3: tert.-butyl lithium / tetrahydrofuran / -78 °C
  • 71
  • [ 20924-56-5 ]
  • N-methylisochroman-4-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% With titanium(IV) isopropylate; ammonia; sodium cyanoborohydride In methanol; ethanol for 6h; Reflux; 54.1 Step 1. Isochroman-4-one (200 mg, 1.35 mmol) was dissolved in EtOH (10 mL) and treated sequentially with 2MNH3 in MeOH (3.4 mol, 6.8 mmol), Ti(Oi-Pr)4 (0.38 g, 1.35 mmol) and NaCNBH3 (0.34 g, 5.4 mmol). The reaction mixture was heated with stirring to reflux for 6 h and then cooled to room temperature and stirred for an additional 16 h. The reaction mixture was partitioned between EtOAc (40 mL) and saturated aqueous Na2CO3 (30 mL). The aqueous layer was extracted with EtOAc (2xl5mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford Nmethylisochroman-4-amine (100 mg, 45%) as a colorless oil, which was converted to the compound of Example 54 as previously described in Example 1. MS (ESI): m/z 164 [M+H] 1HNMR (300 NMR, DMSO-d6) (59.37 (brs, 1H), 9.20 (brs, 1H), 7.57 (d, J= 7.5 Hz, 1H), 7.45-7.32 (m, 2H), 7.21 (d, J 7.5 Hz, 1H), 4.87 (d, J= 15.6 Hz, 1H), 4.73 (d, J= 15.6 Hz, 1H), 4.42 (d, J= 13.2 Hz, 1H), 4.30 (brs, 1H), 3.87 (dd, J, = 12.9, 2.1 Hz, 1H), 2.56-2.50 (m, 3H).
  • 72
  • [ 20924-56-5 ]
  • [ 2181-42-2 ]
  • spiro[isochroman-4,2’-oxirane] [ No CAS ]
YieldReaction ConditionsOperation in experiment
350 mg Stage #1: trimethylsulphonium iodide With sodium hydride In dimethyl sulfoxide for 0.333333h; Stage #2: isochroman-4-one In dimethyl sulfoxide at 25℃; for 1h; T-30 Example T-30: Epoxide formation from a ketone by Corey-Chaykovsky epoxidation To a solution of trimethylsulfonium iodide (1.3774 g, 6.7496 mmol) in DMSO (10 mL) was added sodium hydride (0.243 g, 10.1244 mmol). After 20 min later isochroman-4-one (500 mg, 3.3748 mmol) was added. The reaction was stirred at 25 °C for 1 h. The reaction mixture was treated with H2O (30 mL). The aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil was purified by column chromatography (EtOAc: Hexanes=1: 10) to provide the desired product (350 mg, 1.9422 mmol) as an oil.
  • 73
  • [ 20924-56-5 ]
  • 1-(2-(isochroman-4-yl)ethyl)-4-phenoxypiperidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 20 °C 1.2: 4 h / 20 °C 2.1: palladium on activated charcoal; hydrogen / ethanol / 3 h / 20 °C 3.1: sodium hydroxide / methanol / 2 h / 65 °C 4.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 5 h / 20 °C 5.1: lithium aluminium tetrahydride / tetrahydrofuran / 0.5 h / 20 °C
  • 74
  • [ 20924-56-5 ]
  • 2-(isochroman-4-yl)acetic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 20 °C 1.2: 4 h / 20 °C 2.1: palladium on activated charcoal; hydrogen / ethanol / 3 h / 20 °C 3.1: sodium hydroxide / methanol / 2 h / 65 °C
  • 75
  • [ 20924-56-5 ]
  • 2-(isochroman-4-yl)-1-(4-phenoxypiperidin-1-yl)ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 20 °C 1.2: 4 h / 20 °C 2.1: palladium on activated charcoal; hydrogen / ethanol / 3 h / 20 °C 3.1: sodium hydroxide / methanol / 2 h / 65 °C 4.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 5 h / 20 °C
  • 76
  • [ 20924-56-5 ]
  • 4-((4-(4-fluorophenoxy)piperidin-1-yl)methyl)isochroman-4-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: sodium hydride / dimethyl sulfoxide / 0.33 h 1.2: 1 h / 25 °C 2.1: methanol / 8 h / 60 °C
  • 77
  • [ 20924-56-5 ]
  • isochroman-4-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: zinc(II) chloride / dichloromethane / 12 h / 20 °C 2: hydrogenchloride; acetic acid / water / 2 h / 130 °C
  • 78
  • [ 20924-56-5 ]
  • 4-((4-(2,3-dimethylphenyl)piperazin-1-yl)methyl)isochroman-4-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: sodium hydride / dimethyl sulfoxide / 0.33 h 1.2: 1 h / 25 °C 2.1: aluminium(III) triflate / toluene / 12 h / 80 °C
  • 79
  • [ 20924-56-5 ]
  • 4-((4-(2,3-dimethylphenyl)piperazin-1-yl)methyl)isochroman-4-yl methanesulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: sodium hydride / dimethyl sulfoxide / 0.33 h 1.2: 1 h / 25 °C 2.1: aluminium(III) triflate / toluene / 12 h / 80 °C 3.1: triethylamine / dichloromethane / 4 h / 25 °C
  • 80
  • [ 20924-56-5 ]
  • 1-((1H-isochromen-4-yl)methyl)-4-(2,3-dimethylphenyl)piperazine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: sodium hydride / dimethyl sulfoxide / 0.33 h 1.2: 1 h / 25 °C 2.1: aluminium(III) triflate / toluene / 12 h / 80 °C 3.1: triethylamine / dichloromethane / 4 h / 25 °C 4.1: acetic acid / dichloromethane / 8 h / 50 °C
  • 81
  • [ 20924-56-5 ]
  • 1-(2,3-dimethylphenyl)-4-(isochroman-4-ylmethyl)piperazine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: sodium hydride / dimethyl sulfoxide / 0.33 h 1.2: 1 h / 25 °C 2.1: aluminium(III) triflate / toluene / 12 h / 80 °C 3.1: triethylamine / dichloromethane / 4 h / 25 °C 4.1: acetic acid / dichloromethane / 8 h / 50 °C 5.1: hydrogen / methanol / 48 h / 50 °C
  • 82
  • [ 20924-56-5 ]
  • ethyl 2-(isochroman-4-yl)acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 20 °C 1.2: 4 h / 20 °C 2.1: palladium on activated charcoal; hydrogen / ethanol / 3 h / 20 °C
  • 83
  • [ 20924-56-5 ]
  • [ 867-13-0 ]
  • (Z)-ethyl 2-(isochroman-4-ylidene)acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
600 mg Stage #1: diethoxyphosphoryl-acetic acid ethyl ester With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Stage #2: isochroman-4-one In tetrahydrofuran at 20℃; for 4h; T-31 Example T-31: Olefination of ketone to α,β-unsaturated ester To a solution of sodium hydride (0.16 g, 6.74 mmol) in THF (30 mL) was added ethyl 2- (diethoxyphosphoryl)acetate (1.89 g, 8.43 mmol). The reaction was stirred at room temperature for 30 min. Isochroman-4-one (500 mg, 3.37 mmol) was added. The reaction was stirred at room temperature for 4 h. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc (5%) and hexanes(95%) to provide (Z)- ethyl 2-(isochroman-4-ylidene)acetate (600 mg) as a yellow oil.
  • 84
  • [ 20924-56-5 ]
  • [ 7677-24-9 ]
  • 4-((trimethylsilyl)oxy)isochroman-4-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.4 g With zinc(II) chloride In dichloromethane at 20℃; for 12h; T-32 Example T-32: Homologation: Ketone to acid To a solution of isochroman-4-one (500 mg, 3.37 mmol) in DCM (20 mL) was added zinc(II) iodide (0.11 g, 0.34 mmol) and trimethylsilanecarbonitrile (1 g, 10.11 mmol). The reaction was stirred at ambient temperature for 12 h. The reaction mixture was concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of hexane (100%) to hexane (90%) and EtOAc (10%) to provide 4-((trimethylsilyl)oxy)isochroman-4-carbonitrile (0.4 g, 1.62 mmol) as a colorless oil.
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