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[ CAS No. 215184-78-4 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 215184-78-4
Chemical Structure| 215184-78-4
Chemical Structure| 215184-78-4
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Product Details of [ 215184-78-4 ]

CAS No. :215184-78-4 MDL No. :MFCD08752227
Formula : C14H18BrNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :YSAAGRAKROVFRY-UHFFFAOYSA-N
M.W : 312.20 Pubchem ID :18315369
Synonyms :

Calculated chemistry of [ 215184-78-4 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 18
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.5
Num. rotatable bonds : 3
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 79.33
TPSA : 29.54 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.84 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.4
Log Po/w (XLOGP3) : 3.33
Log Po/w (WLOGP) : 3.21
Log Po/w (MLOGP) : 3.18
Log Po/w (SILICOS-IT) : 3.11
Consensus Log Po/w : 3.24

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.92
Solubility : 0.0373 mg/ml ; 0.00012 mol/l
Class : Soluble
Log S (Ali) : -3.63
Solubility : 0.0737 mg/ml ; 0.000236 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.3
Solubility : 0.0157 mg/ml ; 0.0000504 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.39

Safety of [ 215184-78-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338-P310 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 215184-78-4 ]

* 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 [ 215184-78-4 ]
  • Downstream synthetic route of [ 215184-78-4 ]

[ 215184-78-4 ] Synthesis Path-Upstream   1~8

  • 1
  • [ 24424-99-5 ]
  • [ 1258856-73-3 ]
  • [ 215184-78-4 ]
YieldReaction ConditionsOperation in experiment
99% With triethylamine In tetrahydrofuran at 20℃; for 1 h; 5-Bromo-1 ,2,3,4-tetrahydroisoquinoline hydrobromide (2.24g, 9.0 mmol, Zannan Pharma), di-tert-butyl dicarbonate (3.1 ml, 14 mmol) and triethylamine (2.8ml, 20 mmol) were dissolved in THF (40ml) and the mixture was stirred at room temperature for 1 h then concentrated in vacuo. Water (15ml) was added to the residue and the mixture extracted with ethyl acetate (2x 15ml). The combined organic phases were dried (Na2SO4) and concentrated in vacuo to give 1 ,1-dimethylethyl 5-bromo-3,4- dihydro-2(1 H)-isoquinolinecarboxylate (2.79g, 99percent) as an off-white solid which was used in the next step without further purification. LCMS (Method formate, 5min): Retention time 3.60min, MH+ = 312 / 314
Reference: [1] Patent: WO2010/146105, 2010, A1, . Location in patent: Page/Page column 86
  • 2
  • [ 24424-99-5 ]
  • [ 215184-78-4 ]
YieldReaction ConditionsOperation in experiment
75.5%
Stage #1: With potassium hydroxide In methanol for 36 h; Reflux
Stage #2: With dmap In tetrahydrofuran at 20℃; for 4 h;
Toa solution of 4a (10.0 g, 35.3 mmol)in MeOH (200 mL) was added 8M KOH solution (20 mL) and then heated to reflux.After 36 h, the reaction mixture was concentrated under reduced pressure.The mixture was diluted with H2O (100 mL), extracted with EA (75 mL×2), dried over Na2SO4 and concentrated under reducedpressure. The residue was dissolved in THF (100 mL). Di-tert-butyldicarbonate (9.0 g, 41.2 mmol) and DMAP (0.5 g, 4.0 mmol) was added and thenthe reaction mixture was stirred at room temperature for 4 h. Afterconcentration, the residue was purified by silica gel column chromatography(PET/EA = 15:1, v/v) to affordcompound 5a as colorless oil (8.3 g,75.5percent). 1H NMR (400 MHz, DMSO-d6) δ 7.40 (d, J =7.6 Hz, 1H), 7.11 (d, J = 7.6 Hz,1H), 7.07 (t, J = 7.6 Hz, 1H), 4.53(s, 2H), 3.63 (t, J = 6.0 Hz, 2H),2.74 (t, J = 6.0 Hz, 2H), 1.44 (s,9H). 13C NMR (100 MHz, DMSO-d6)δ 205.2, 154.1, 134.3, 130.3, 127.7, 125.8, 124.9, 79.2, 29.4, 27.9 (3C).
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 18, p. 3050 - 3056
  • 3
  • [ 24424-99-5 ]
  • [ 81237-69-6 ]
  • [ 215184-78-4 ]
YieldReaction ConditionsOperation in experiment
5 g With triethylamine In tetrahydrofuran at 20℃; To a solution of 5-bromo-l,2,3,4-tetrahydroisoquinoline (4.24 g, 20 mmol) and di-tert- butyl pyrocarbonate (5.2 g, 24 mmol) in THF (45 mL) was added TEA (4.0 g, 40 mmol) dropwise. The resulting mixture was stirred for 15 hrs at rt, then poured into water (50 mL) and extracted with EA (75 mL) twice. The organic layers were combined, then washed with water and brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by column (eluting with PE/EA=5/1, v:v) to provide tert-butyl 5-bromo-3,4-dihydro-lH- isoquinoline-2-carboxylate (5 g) as a white solid.
Reference: [1] Patent: WO2018/83136, 2018, A1, . Location in patent: Page/Page column 62
  • 4
  • [ 24424-99-5 ]
  • [ 923591-51-9 ]
  • [ 215184-78-4 ]
Reference: [1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 24, p. 4049 - 4056
  • 5
  • [ 19472-74-3 ]
  • [ 215184-78-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 18, p. 3050 - 3056
  • 6
  • [ 65185-58-2 ]
  • [ 215184-78-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 18, p. 3050 - 3056
  • 7
  • [ 140202-11-5 ]
  • [ 215184-78-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 18, p. 3050 - 3056
  • 8
  • [ 215184-78-4 ]
  • [ 73183-34-3 ]
  • [ 1035235-26-7 ]
YieldReaction ConditionsOperation in experiment
100% With potassium acetate In 1,4-dioxane at 80℃; for 2 h; Inert atmosphere 1 ,1-Dimethylethyl 5-bromo-3,4-dihydro-2(1 H)-isoquinolinecarboxylate (Preparation 53) (2.7g, 8.7 mmol), potassium acetate (2.55g, 26 mmol), [1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.63g, 0.87 mmol) and 4.4.4'.4'.5.5.5'.5'-octamethyl-2.2'-bi-1 .3,2-dioxaborolane (4.39g, 17 mmol) were dissolved in 1 ,4-dioxane (40ml), stirred at 800C under nitrogen for 2h and allowed to cool. Water (30ml) was added and the mixture was extracted with ethyl acetate (3x 20ml).The combined organic phases were concentrated in vacuo. Purification of the residue by flash chromatography (ethyl acetate in cyclohexane 15percent) gave 1 ,1- dimethylethyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,4-dihydro-2(1 H)- isoquinolinecarboxylate as a clear gel (3.25g, 105percent). LCMS (Method formate): Retention time 1.51 min, MH+ = 360
89% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In N,N-dimethyl-formamide at 90℃; Inert atmosphere A mixture of tert-butyl 5-bromo-3,4-dihydroisoquinoline-2(lH)-carboxylate (0.500 g, 1.60 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (0.488 g, 1.92 mmol) in DMF (8 mL) was subjected to 3 evacuate-fill cycles with nitrogen. Potassium acetate (0.472 g, 4.80 mmol) and PdCi2(dppf) DCM complex (0.117 g, 0.160 mmol) were added, the mixture was subjected to 2 more evacuate-fill cycles with nitrogen, and heated 90 °C overnight under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted with EtOAc, washed sequentially with water, 10percent aqueous LiCl and saturated brine, dried and concentrated. The residue was subjected to column chromatography on silica gel, eluting with EtOAc-hexanes, to provide tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(17i)- carboxylate as a white solid (0.514 g, 89percent yield). Mass spectrum m/z 360 (M+H)+.
57% With potassium acetate In 1,4-dioxane at 80℃; for 2 h; Inert atmosphere 1 ,1-Dimethylethyl 5-bromo-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 27) (0.281 g, 0.899 mmol), potassium acetate (0.265 g, 2.70 mmol), [1,f- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.066 g, 0.090 mmol) and 4i4i4li4Ii5,5,5',5'-octamethyl-2,2'-bi-1I3,2-dioxaborolane (0.274 g, 1.079 mmol) were dissolved in 1 ,4-dioxane (5 ml) and the resulting mixture was stirred at 800C under nitrogen for 2 hours then cooled to room temperature and diluted with water (15 ml). The aqueous phase was extracted with AcOEt (3 x 10 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (c-Hexane/AcOEt: 15percent) gave 1,1- dimethylethyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,4-dihydro-2(1 H)- isoquinolinecarboxylate 158 mg, 57percent) as a light yellow oil. LCMS: retention time 1.54 min; no mass ion detected.
15.45 g With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos In 1,4-dioxane at 120℃; for 48 h; Inert atmosphere Intermediate E: tert-Butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4- dihydroisoquinoline-2(lH)-carboxylate A solution of tert-butyl 5-bromo-3,4-dihydroisoquinoline-2(lH)-carboxylate (20.00 g, 64.1 mmol), bis(pinacolato)diboron (Boron Molecular, Research Triangle, NC, 24.40 g, 96 mmol), potassium phosphate (40.8 g, 192 mmol), Pd2(dba)3 (Sigma- Aldrich, St. Louis, MO, 0.750 g, 3.20 mmol) and X-Phos (Strem Chemicals Inc., Newburyport, MA, 7.63 g, 16.02 mmol) in 100 mL dioxane was placed under argon and was heated to 120 °C for 48 hours. LC/MS showed mostly product, so the reaction mixture was allowed to cool to room temperature, diluted with diethyl ether, and filtered through a plug of diatomaceous earth eluting with diethyl ether. The filtrate was concentrated and the resulting residue was purified by silica gel chromatography (0 to 15percent EA in heaxanes) to provide tert-butyl 5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(lH)-carboxylate (15.45 g, 43.0 mmol) as a light yellow oil.

Reference: [1] Patent: WO2010/146105, 2010, A1, . Location in patent: Page/Page column 86-87
[2] Patent: WO2016/65222, 2016, A1, . Location in patent: Page/Page column 57
[3] Patent: WO2010/145202, 2010, A1, . Location in patent: Page/Page column 38
[4] Patent: WO2013/134518, 2013, A1, . Location in patent: Page/Page column 39
[5] Patent: WO2016/44666, 2016, A1, . Location in patent: Paragraph 0589; 0591
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