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Product Details of [ 258515-65-0 ]

CAS No. :258515-65-0 MDL No. :MFCD08752229
Formula : C14H18BrNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :PWPKRLMPHNRWHK-UHFFFAOYSA-N
M.W : 312.20 Pubchem ID :15885175
Synonyms :

Calculated chemistry of [ 258515-65-0 ]

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 : 79.32
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) : 3.43
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 : 3.25

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 : 2.33

Safety of [ 258515-65-0 ]

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 [ 258515-65-0 ]

* 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 [ 258515-65-0 ]
  • Downstream synthetic route of [ 258515-65-0 ]

[ 258515-65-0 ] Synthesis Path-Upstream   1~8

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Reference: [1] Patent: WO2018/83136, 2018, A1,
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YieldReaction ConditionsOperation in experiment
99% With triethylamine In dichloromethane at 20℃; for 18 h; A.
7-Bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester.
To a solution of 7-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (4.0 g, 16.1 mmol) and Et3N (6.7 mL, 48.3 mmol) in CH2Cl2 (500 mL) was added di-tert-butyl-dicarbonate (4.2 g, 19.2 mmol).
After 18 h at rt, the mixture was concentrated and the product was purified on SiO2 (EtOAc/hexanes) to afford a clear oil (5.00 g, 99percent).
90% With triethylamine In dichloromethane at 20℃; for 2 h; To a mixture of 7-bromo-l,2,3,4-tetrahydroisoquinoline HCl salt (37 g, 150 mmol) and TEA (30 g, 300 mmol) in DCM (400 mL), Boc20 (41 g, 180 mmol) was added. The mixture was stirred at rt for 2 h, then diluted with DCM (500 mL). The organic layer was washed with water (300 mL), brine (300 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (PE : EA = 10 : 1) to give tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(lH)-carboxylate (42 g, yield: 90percent) as a white solid. ESI-MS (M-56+H) +: 256.1. 1H NMR (400 MHz, CDC13) S: 7.28-7.25 (m, 2H), 7.01 (d, / = 8.0 Hz, 1H), 4.53 (s, 2H), 3.63 (t, J = 5.2 Hz, 2H), 2.84 (t, J = 5.2 Hz, 2H), 1.48 (s, 9H).
82% With sodium carbonate In dichloromethane; water at 20℃; for 1 h; 7 a 7-Bromo-3,4-dihydro-1 /-/-isoquinoline-2-carboxylic acid te/f-butyl ester To 10.0 g (40.2 mmol) 7-bromo-1 ,2,3,4-tetrahydro-isoquinoline hydrochloride in 250 mL DCM and 50 mL (101 mmol) 2M aqueous Na2CO3-solution is added a solution of 9.27 g (42.5 mmol) BOC-anhydride in DCM. The reaction is stirred 1 h at RT and is diluted with 100 mL water. The organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated. To the residue is added PE and the mixture is cooled to -300C. The precipitate is collected, washed with cold PE and dried. Yield: 10.3 g (82percent of theory)ESI Mass spectrum: [M+H]+ = 312/314 Rf-value: 0.5 (silica gel, mixture C).
82% With water; sodium carbonate In dichloromethane at 20℃; for 1 h; To 10.0 g (40.2 mmol) 7-bromo-1 ,2,3,4-tetrahydro-isoquinoline hydrochloride in 250 mL DCM and 50 mL (101 mmol) 2M aqueous Na2CO3-solution is added a solution of 9.27 g (42.5 mmol) BOC-anhydride in DCM. The reaction is stirred 1 h at RT and is diluted with 100 mL water. The organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated. To the residue is added PE and the mixture is cooled to -300C. The precipitate is collected, washed with cold PE and dried.Yield: 10.3 g (82percent of theory); ESI Mass spectrum: [M+H]+ = 312/314 Rf-value: 0.5 (silica gel, mixture C).

Reference: [1] Patent: US2008/200454, 2008, A1, . Location in patent: Page/Page column 53-54
[2] Patent: WO2018/140876, 2018, A1, . Location in patent: Page/Page column 45; 46
[3] Patent: WO2008/22979, 2008, A1, . Location in patent: Page/Page column 82
[4] Patent: WO2009/103478, 2009, A1, . Location in patent: Page/Page column 65
[5] Patent: US2012/289493, 2012, A1, . Location in patent: Page/Page column 115-116
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YieldReaction ConditionsOperation in experiment
100% With sodium carbonate In tetrahydrofuran; water at 20℃; To a solution of 7-bromo-l,2,3,4-tetrahydroisoquinoline (1 g, 4.71 mmol), Na2C03 (1 g, 9.4 mmol) in THF/H20 (16 mL/6 mL) was added (Boc)20 (1.51 mL, 7.06 mmol) at rt. The reaction was stirred at rt overnight, then diluted with water (50 mL), and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over a2S04, filtered and concentrated in vacuo to give the title compound as colorless oil (1.46 g, 100percent).
100% With sodium carbonate In tetrahydrofuran; water at 20℃; A solution of 7-bromo-1,2,3,4-tetrahydroisoquinoline (1 g, 4.71 mmol)Sodium carbonate (1 g, 9.4 mmol)Was dissolved in a mixture of tetrahydrofuran / water (16 mL / 6 mL)Boc anhydride (1.51 mL, 7.06 mmol) was added at room temperature.The reaction was stirred at room temperature overnight, diluted with water (50 mL) and extracted with ethyl acetate (50 mL x3). The combined organic phases were dried over anhydrous sodium sulfateFilter, and concentrated under reduced pressure,The title compound was obtained as a colorless oil (1.46 g, 100percent).
97% With triethylamine In tetrahydrofuran at 20℃; for 1 h; Step 1:
tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate
Di-tert-butyldicarbonate (0.34 g, 1.6 mmol) was added to a mixture of 7-bromo-1,2,3,4-tetrahydroisoquinoline (0.30 g, 1.4 mmol, Alfa Aesar, Cat. #: B25712) and triethylamine (0.29 g, 2.8 mmol) in THF (4.0 mL).
The mixture was stirred at room temperature (r.t.) for 1 hour (1 h.), quenched with aqueous Na2CO3, and extracted with ethyl acetate (3*20 mL).
The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford the desired product (0.43 g, yield: 97percent) which was directly used in next step reaction without further purification.
Analytic LCMS (M+Na)+: m/z=334.2/336.2; (M-But+H)+=256.1/258.1.
94% With triethylamine In tetrahydrofuran; water at 20℃; for 2 h; A solution of 7-bromo-1 ,2,3,4-tetrahydroisoquinoline (870 mg, 4.10 mmol) in THF (15 mL) and water (5 mL) was treated with EtzN (0.66 mL, 4.76 mmol) and di-te/f-butyl dicarbonate (940 mg, 4.31 mmol). The reaction was allowed to stir for 2 h at room temperature. The THF was removed in vacuo and the reaction mixture was taken up in water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with a saturated NH4CI solution (20 mL), dried over MgS04 and the solvent removed in vacuo. The resulting residue was purified by flash column flash chromatography eluting 0-20percent EtOAc in hexane to provide te/f-butyl 7-bromo-1 ,2,3,4-tetrahydroisoquinoline-2-carboxylate (1.21 g, 94percent) as a yellow oil; 1 H NMR (Method A) (CDCb): δ ppm 7.21 (s, 1 H), 7.19 (m, 1 H), 6.93 (m, 1 H), 3.57-3.53 (m, 2H), 2.72-2.69 (m, 2H), 1.51-1.48 (m, 2H), 1.42-1.41 (m, 9H); LC-MS (Method F) 212.4 [MH+]; RT 3.97 min.
75% With triethylamine In dichloromethane at 20℃; for 24.1667 h; In a 100mL three-necked flask, 7-bromo-1,2,3,4-tetrahydroisoquinoline (1g, 4.72mmol) in dichloromethane (30mL) and triethylamine (712mg, 7.04mmol) were stirred for 10 minutes. Was then added Boc2O (1.02g, 4.67mmol). The reaction mixture was stirred for 24 hours at room temperature then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to give the product (1.1g, 75percent yield).
64.6% With triethylamine In dichloromethane at 20℃; for 16 h; Intermediate 26: 7-Bromo-3,4-dihvdro-lH-isoquinoline-2-carboxylic acid tert-butyl ester; To a solution of 7-Bromo-l,2,3,4-Tetrohedro-isoquinoline (4.Og 18.9mmol, leq) in dichloromethane (20 ml) were added di-t-butyl dicarbonate (4.9g, 22.5mmol) and triethylamine (4 ml, 36.4 mmol). The reaction mixture was stirred at rt for 16 hr. Aqueous sodium bicarbonate solution (150 ml) was added and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated, then the residue was purified by silica gel chromatography (0-20percent ethyl acetate in hexanes as eluant). Intermediate 26 was obtained as a clear oil (3.8g, 64.6percent). LCMS (Method 2) m/z 211.7 [MH+], Tr = 3.18 min.
2.2 g With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 3 h; A mixture of 7-bromo-l,2,3,4-tetrahydroisoquinoline (1.5 g, 7.07 mmol), Boc20 (3.09 g, 14.1 mmol) and DIPEA (914 mg, 1.24 mL, 7.07 mmol) in THF (30 mL) was stirred at rt. 3 hrs. The resulting mixture was concentrated in vacuo and the residue was purified by column (eluting with PE/EA=5/1, v:v) to give tert-butyl 7-bromo-3,4-dihydro-lH-isoquinoline-2-carboxylate (2.2 g) as light yellow oil

Reference: [1] Patent: WO2014/89324, 2014, A1, . Location in patent: Paragraph 0240
[2] Patent: CN104016979, 2017, B, . Location in patent: Paragraph 0620; 0621
[3] Patent: US2010/240671, 2010, A1, . Location in patent: Page/Page column 58
[4] Patent: WO2017/1853, 2017, A1, . Location in patent: Page/Page column 42-43
[5] Patent: CN105524045, 2016, A, . Location in patent: Paragraph 0274; 0275; 0276
[6] Patent: WO2008/116185, 2008, A2, . Location in patent: Page/Page column 63
[7] Patent: US5977134, 1999, A,
[8] Patent: WO2010/75270, 2010, A1, . Location in patent: Page/Page column 94-95
[9] Patent: WO2018/83136, 2018, A1, . Location in patent: Page/Page column 41
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YieldReaction ConditionsOperation in experiment
79.3%
Stage #1: With potassium hydroxide In methanol for 36 h; Reflux
Stage #2: With dmap In tetrahydrofuran at 20℃; for 4 h;
General procedure: 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).
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 18, p. 3050 - 3056
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Reference: [1] Patent: US5977134, 1999, A,
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 18, p. 3050 - 3056
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 18, p. 3050 - 3056
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 18, p. 3050 - 3056
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