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Product Details of [ 3470-53-9 ]

CAS No. :3470-53-9 MDL No. :MFCD00099462
Formula : C10H11NO Boiling Point : -
Linear Structure Formula :- InChI Key :BEVVUJBVEXJGKM-UHFFFAOYSA-N
M.W : 161.20 Pubchem ID :339537
Synonyms :

Calculated chemistry of [ 3470-53-9 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.3
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 48.7
TPSA : 43.09 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) : -6.33 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.5
Log Po/w (XLOGP3) : 1.34
Log Po/w (WLOGP) : 1.8
Log Po/w (MLOGP) : 1.35
Log Po/w (SILICOS-IT) : 2.29
Consensus Log Po/w : 1.65

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.05
Solubility : 1.42 mg/ml ; 0.00884 mol/l
Class : Soluble
Log S (Ali) : -1.85
Solubility : 2.29 mg/ml ; 0.0142 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.02
Solubility : 0.152 mg/ml ; 0.000944 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.56

Safety of [ 3470-53-9 ]

Signal Word:Warning Class:
Precautionary Statements:P280-P305+P351+P338 UN#:
Hazard Statements:H317-H319 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 3470-53-9 ]

* 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 [ 3470-53-9 ]
  • Downstream synthetic route of [ 3470-53-9 ]

[ 3470-53-9 ] Synthesis Path-Upstream   1~17

  • 1
  • [ 3470-53-9 ]
  • [ 108-24-7 ]
  • [ 88611-67-0 ]
Reference: [1] Patent: WO2008/76336, 2008, A2, . Location in patent: Page/Page column 78
[2] Patent: WO2010/78427, 2010, A1, . Location in patent: Page/Page column 221
  • 2
  • [ 3470-53-9 ]
  • [ 3470-46-0 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 1, p. 130 - 151
[2] Journal of Organic Chemistry, 1962, vol. 27, p. 70 - 76
  • 3
  • [ 3470-53-9 ]
  • [ 703-67-3 ]
Reference: [1] Chemistry - A European Journal, 2015, vol. 21, # 14, p. 5561 - 5583
[2] Organic Letters, 2011, vol. 13, # 24, p. 6488 - 6491
[3] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 17, p. 3004 - 3008
  • 4
  • [ 3470-53-9 ]
  • [ 26673-31-4 ]
YieldReaction ConditionsOperation in experiment
88% With tert.-butylnitrite; copper dichloride In acetonitrile at 60℃; for 0.75 h; CuCl2 (2.0 g, 15.0 mmol) and t-butyl nitrite (2.2 mL, 15.0 mmol) in dry CH3CN were heated at 60° C., followed by the addition of 6-aminotetralone (2.0 g, 12.0 mmol). The reaction mixture was heated for 45 min, then cooled down at room temperature, quenched with 2N HCl (200 mL) and Et2O (200 mL). The aqueous layer was extracted with Et2O and the combined organic layer was washed with water, brine, dried over anhydrous Na2SO4, concentrated by rotary evaporation, and purified by column chromatography to give 6-chloro-3,4-dihydronaphthalen-1(2H)-one (16) (88percent). 111 NMR (600 MHz, CDCl3) δ 7.96 (d, J=6.0 Hz, 1H), 7.28-7.26 (m, 2H), 2.94 (t, J=6.0 Hz, 2H), 2.65 (t, J=6.0 Hz, 2H), 2.16-2.11 (m, 2H), 7.12-7.07 (m, 2H), 6.92 (d, J=12.0 Hz, 1H), 6.85 (s, 1H), 5.67 (s, 1H). GC-MS (ES) for C10H9C10 [M]+ 180.
70% With tert.-butylnitrite; copper dichloride In acetonitrile at 60℃; for 0.5 h; Inert atmosphere 6.29. Method YPreparation of 6-Chloro-3,4-dihydronaphthalen-1(2H)-one; Under N2, t-butyl nitrite (0.954 g, 9.30 mmol) was added drop-wise at room temperature to a stirred suspension of copper (II) chloride (1.00 g, 7.44 mmol) in acetonitrile (10 mL). The suspension was heated to 60° C., aniline 82 was added and the reaction was stirred at 60° C. for 30 minutes. The reaction was cooled to room temperature, diluted with diethyl ether, washed successively with 1N HCl, H2O (3.x.), and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give crude product as brown oil. The mixture was purified by silica gel column chromatography (ethyl acetate-hexanes gradient) to give chloride 83 (0.785 g, 70percent) as a clear oil.
Reference: [1] Patent: US2015/105351, 2015, A1, . Location in patent: Paragraph 0440
[2] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 11, p. 1259 - 1262
[3] Organic Letters, 2011, vol. 13, # 24, p. 6488 - 6491
[4] Patent: US2012/302562, 2012, A1, . Location in patent: Page/Page column 21
[5] Australian Journal of Chemistry, 2010, vol. 63, # 2, p. 211 - 226
[6] Angewandte Chemie - International Edition, 2013, vol. 52, # 51, p. 13642 - 13646[7] Angew. Chem., 2013, vol. 125, # 51, p. 13887 - 13891,5
[8] Patent: WO2017/147410, 2017, A1,
[9] Tetrahedron, 2018, vol. 74, # 4, p. 433 - 440
  • 5
  • [ 3470-50-6 ]
  • [ 3470-53-9 ]
Reference: [1] Organic Letters, 2011, vol. 13, # 24, p. 6488 - 6491
[2] Chemistry - An Asian Journal, 2016, vol. 11, # 4, p. 498 - 504
[3] Organic Letters, 2005, vol. 7, # 17, p. 3629 - 3631
[4] Organic Letters, 2005, vol. 7, # 17, p. 3629 - 3631
[5] Australian Journal of Chemistry, 2010, vol. 63, # 2, p. 211 - 226
  • 6
  • [ 88611-67-0 ]
  • [ 3470-53-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 11, p. 3436 - 3440
[2] Journal of Medicinal Chemistry, 1976, vol. 19, # 4, p. 472 - 475
[3] Journal of Medicinal Chemistry, 1994, vol. 37, # 21, p. 3482 - 3491
[4] Patent: EP1650202, 2006, A1, . Location in patent: Page/Page column 18
  • 7
  • [ 22246-26-0 ]
  • [ 3470-53-9 ]
Reference: [1] ACS Catalysis, 2015, vol. 5, # 3, p. 1526 - 1529
[2] Green Chemistry, 2015, vol. 17, # 2, p. 898 - 902
  • 8
  • [ 1116358-98-5 ]
  • [ 3470-53-9 ]
Reference: [1] European Journal of Medicinal Chemistry, 2009, vol. 44, # 1, p. 322 - 331
  • 9
  • [ 418761-92-9 ]
  • [ 3470-53-9 ]
Reference: [1] Organic Letters, 2005, vol. 7, # 17, p. 3629 - 3631
[2] Australian Journal of Chemistry, 2010, vol. 63, # 2, p. 211 - 226
[3] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 4, p. 391 - 396
[4] Organic Syntheses, 2007, vol. 84, p. 325 - 333
  • 10
  • [ 50878-03-0 ]
  • [ 3470-53-9 ]
Reference: [1] Journal of Organic Chemistry, 1962, vol. 27, p. 70 - 76
[2] Journal of Medicinal Chemistry, 1976, vol. 19, # 4, p. 472 - 475
  • 11
  • [ 418761-91-8 ]
  • [ 3470-53-9 ]
Reference: [1] Organic Letters, 2005, vol. 7, # 17, p. 3629 - 3631
[2] Australian Journal of Chemistry, 2010, vol. 63, # 2, p. 211 - 226
  • 12
  • [ 1078-19-9 ]
  • [ 3470-53-9 ]
Reference: [1] Organic Letters, 2005, vol. 7, # 17, p. 3629 - 3631
[2] Organic Letters, 2005, vol. 7, # 17, p. 3629 - 3631
  • 13
  • [ 3470-53-9 ]
  • [ 151-50-8 ]
  • [ 90401-84-6 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 1, p. 130 - 151
  • 14
  • [ 3470-53-9 ]
  • [ 544-92-3 ]
  • [ 90401-84-6 ]
Reference: [1] Journal of Organic Chemistry, 1962, vol. 27, p. 70 - 76
  • 15
  • [ 3470-53-9 ]
  • [ 91270-68-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 5, p. 1284 - 1304
  • 16
  • [ 3470-53-9 ]
  • [ 66361-67-9 ]
YieldReaction ConditionsOperation in experiment
80% With hydrogen bromide; copper(I) bromide; sodium nitrite In water at 0 - 20℃; for 1 h; A solution of NaNO2 (2.35 g, 34 mmol) in water (10 mL) was added dropwise to the solution of 6-amino-1,2,3,4-tetrahydronaphthalen-1-one (5.0 g, 31 mmol) in 25percent HBr (16 mL) at 0°C. The suspension was then transferred to a stirred mixture of CuBr (8.9 g, 62 mmol) in 48percent HBr (30 mL) at 0°C. The resulting mixture was allowed to warm to room temp and stirred for 1 hr. The mixture was extracted with EtOAc, dried (Na2504), and concentrated. The residue was purified by silica gel chromatography (0percent-60percent EtOAc/Hex) to give 5.6 g (80percent) of the title compound as a light yellow oil. ‘H NMR (400 MHz, CDC13): ö 2.10-2.16 (2H, m), 2.64 (2H, t, J=6.4 Hz), 2.94 (2H, t, J=6.0 Hz), 7.42 (1H, s), 7.44 (1H, s), 7.87 (1H, d, J=8.9 Hz). [M+H1 calculated for C,oH9BrO: 225, 227; found: 225, 227.
74%
Stage #1: at 0℃;
Stage #2: With hydrogen bromide; copper(I) bromide; sodium nitrite In water at 0 - 20℃;
  6-Aminotetralone (47, 500 mg, 3.1 mmol) was dissolved in 25percent   HBr (1 mL). The mixture was cooled to 0 °C and a solution of   NaNO2 (263 mg, 3.8 mmol) in   water (1 mL) was slowly added. The reaction mixture was further added to a solution of   CuBr (458 mg, 3.2 mmol) in 48percent HBr (1 mL) and the reaction was stirred for 1.5 h while warming to rt. The solution was extracted with EtOAc (3 × 5 mL), dried over MgSO4 and the solvent was removed in vacuo. The crude material was purified by column chromatography (0–20percent   DCM in   heptane) to afford the desired   product (435 mg, 74percent). 1H NMR (CDCl3), δ: 2.08–2.19 (m, 2H, CH2), 2.65 (dd, J = 7.2, 5.9, 2H, CH2), 2.96 (t, J = 5.9, 2H, CH2), 7.42–7.47 (m, 2H, ArH), 7.89 (d, J = 8.8, 1H, ArH). LC–MS: Rf = 2.04 min; m/z 225/227 ([M+H]+, 100).
66% With hydrogen bromide; copper(I) bromide; sodium nitrite In water at 0 - 20℃; for 1.5 h; 6-aminotetralone (2.0 g, 12 mmol) was disolved in 25percent HBr (4.0 mL) at 0° C. and then, a solution of NaNO2 (1.0 g, 15 mmol) in water (4.0 mL) was added slowly. Afterwards, a solution of CuBr (1.8 g, 4.0 mmol) in 48percent HBr (4.0 mL) was added and the reaction was stirred at room temperature for 1.5 h. The solution was quenched by adding water and extracted with EtOAc (3×10 mL). The combined organic layer was dried over anhydrous Na2SO4, concentrated by rotary evaporation, and purified by column chromatography to give 6-bromo-3,4-dihydronaphthalen-1(2H)-one (19) (66percent). NMR was according to reference 5.
64% With hydrogen bromide; copper(I) bromide; sodium nitrite In water at 0℃; for 1 h; Preparation of Compound 20 ,36-bromo-3,4-dihydronaphthalen-1(2H)-one
[0032] A solution of 6-amino-1 ,2,3,4-tetrahydronaphthalen-1 -one (0.500 g, 3.10 mmol) 8 mL 25percent HBr(aq) and 1 mL 50percent HBr(aq) was cooled to 0° C before a solution of sodium nitrite (0.263 g, 3.82 mmol) in water (1 .25 mL) was added dropwise. This reaction mixture was then added dropwise to a cooled solution of copper(l) bromide (0.458 g, 3.19 mmol) in 50percent HBr(aq) (2.38 mL). The reaction mixture was stirred at 0 ° C for 1 h, then warmed to rt, diluted with a bit of water, extracted with 4:1 Et20:EtOAc (3x). The combined organic phases were dried (Na2S04), filtered and concentrated. The crude material was purified by silica gel column chromatography using 12:1 PE:EtOAc to afford the title compound (444 mg, 64percent) as a pale orange oil. 1H NMR (500 MHz, CDCI3) δ 7.89 (d, J = 9.0 Hz, 1 H), 7.46 - 7.42 (m, 2H), 2.94 (t, J = 6.1 Hz, 2H), 2.68 - 2.61 (m, 2H), 2.14 (m, 2H). HRMS (ESI+): calcd for C10H1079BrO (M + H)+, 224.9910; found 224.9910.
52% With sodium nitrite In water at -5 - 20℃; for 3.5 h; Inert atmosphere To a stirred solution of XXVI-1 (5.00 g, 0.03 mmol) in 15 mL of 40percent aqueous HBr was added a solution of NaNO2 (2.35 g, 0.034 mmol) in H2O, maintaining the temperature at −5° C. under nitrogen. After the addition, the solution was stirred for another 0.5 hour. Then the resulting solution was warmed slowly to the rt and stirred for another 3 hours. Then the solution was concentrated and the mixture was extracted with EtOAc. The organic layer was combined and washed with brine, dried over Na2SO4, concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford XXVI-2 (3.5 g, yield: 52percent).
46%
Stage #1: With hydrogen bromide; sodium nitrite In water at 5℃; for 1 h;
Stage #2: With copper(I) bromide In water at 20℃; for 3 h;
Referring to Scheme 2b, to a solution of 2b-l (20.6 g, 0.128 mol) in 45 mL of 48percent hydrobromic acid and 10 mL of water was added a solution of 9.72 g (0.141 mol) of sodium nitrite in 18 mL of water, maintaining a temperature below 5 °C. After stirring at 5 °C for 1 hr, CuBr (0.128 mol) was added and the resulting mixture was stirred at rt for 3 hrs. Subsequently, the mixture was extracted with EtOAc (2 x 200 mL). The extracts were combined, washed with brine, and dried with anhydrous Na2S04. The solvent was removed and the residue was purified by silica gel column chromatography (Hex/EtOAc= 12/1 (v/v)) to afford 2b-2 (13.3 g, 46percent yield) as a powder. 1H NMR (CDC13, 400 MHz): δ 7.90 (d, 1H), 7.44 (m, 2H), 2.96 (t, 2H), 2.64 (t, 2H), 2.15 (m, 2H) ppm.
46%
Stage #1: With hydrogen bromide; sodium nitrite In water at 5℃; for 1 h;
Stage #2: With copper(I) bromide In water at 20℃; for 3 h;
Referring to Scheme 12-1, to a solution of 1 (20.60 g, 0.128 mol) in 45 mL of 48percent hydrobromic acid and 10 mL of ]3/4Owas added a solution of 9.72 g (0.141 mol) of sodium nitrite in 18 mL of water, maintaining a temperature below 5 °C. After stirring at 5 °C for 1 h, CuBr (0.128 mol) was added and the resulting mixture was stirred at rt for 3 h. Subsequently, the mixture was extracted with EtOAc (2 x 200 mL). The extracts were combined, washed with brine, and dried with anhydrous Na2S04. The solvent was removed and the residue was purified by silica gel column chromatography (Hexane/EtOAc= 12/1 (v/v)) to afford 2 (13.3 g, 46percent yield) as a powder. NMR (CDC13, 400 MHz) δ 7.90 (d, 1H), 7.44 (m, 2H), 2.96 (t, 2H), 2.64 (t, 2H), 2.15 (m, 2H) ppm. [0408]
46%
Stage #1: With hydrogen bromide; sodium nitrite In water at 5℃; for 1 h;
Stage #2: With copper(I) bromide In water at 20℃; for 3 h;
EXAMPLE 12 - Synthesis of compounds of Formula XIVScheme 12-1[0407] Step a. Referring to Scheme 12-1, to a solution of 1 (20.60 g, 0.128 mol) in 45 mL of 48percent hydrobromic acid and 10 mL OfH2OWaS added a solution of 9.72 g (0.141 mol) of sodium nitrite in 18 mL of water, maintaining a temperature below 5 °C. After stirring at 5 °C for 1 h, CuBr (0.128 mol) was added and the resulting mixture was stirred at rt for 3 h. Subsequently, the mixture was extracted with EtOAc (2 x 200 mL). The extracts were combined, washed with brine, and dried with anhydrous Na2SO4. The solvent was removed and the residue was purified by silica gel column chromatography (Hexane/EtOAc= 12/1 (v/v)) to afford 2 (13.3 g, 46percent yield) as a powder. 1R NMR (CDCl3, 400 MHz) δ 7.90 (d, 1H), 7.44 (m, 2H), 2.96 (t, 2H), 2.64 (t, 2H), 2.15 (m, 2H) ppm.
45%
Stage #1: With hydrogen bromide; sodium nitrite In water at 0℃; for 0.25 h;
Stage #2: With hydrogen bromide; copper(I) bromide In water at 0 - 20℃; for 1 h;
6-bromo-3,4-dihydronaphthalen-l(2H)-one. To a solution of 6-amino-3,4- dihydronaphthalen-l(2H)-one (2.0 g, 12 mmol) in bromic acid (aqueous, 10 mL, 25percent) was added sodium nitrite (0.92 g, 13.3 mmol) at 0°C. The mixture was stirred at 0°C for 15 minutes, and then copper(I) bromide (2.0 g, 13.8 mmol) and bromic acid (aqueous, 20 mL, 25percent) was added at 0°C. After addition completed, the reaction mixture was stirred at room temperature for 1 hour. After the reaction, it was diluted with water (200 mL) and the product was extracted with ethyl acetate (200 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica gel, ethyl acetate/petroleum ether = 1 :20) to give the pure product 6-bromo-3,4-dihydronaphthalen-l(2H)-one (1.2 g, 45percent). 1H NMR (300 MHz, CDC13): δ 7.87 (d, J= 8.7 Hz, 1H), 7.44-7.42 (m, 2H), 2.93 (t, J= 6.0 Hz, 2H), 2.64 (t, J= 6.0 Hz, 2H), 2.15-2.11 (m, 2H).
45% With bromic acid; copper(I) bromide; sodium nitrite In water at 0 - 20℃; for 1.25 h; To a solution of 6-amino-3,4-dihydronaphthalen-1(2H)-one (2.0 g, 12 mmol) in bromic acid (aqueous, 10 mL, 25percent) was added sodium nitrite (0.92 g, 13.3 mmol) at 0° C. The mixture was stirred at 0° C. for 15 minutes, and then copper (I) bromide (2.0 g, 13.8 mmol) and bromic acid (aqueous, 20 mL, 25percent) was added at 0° C. After addition completed, the reaction mixture was stirred at room temperature for 1 hour. After the reaction, it was diluted with water (200 mL) and the product was extracted with ethyl acetate (200 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica gel, ethyl acetate/petroleum ether=1:20) to give the pure product 6-bromo-3,4-dihydronaphthalen-1(2H)-one (1.2 g, 45percent). 1H NMR (300 MHz, CDCl3): δ 7.87 (d, J=8.7 Hz, 1H), 7.44-7.42 (m, 2H), 2.93 (t, J=6.0 Hz, 2H), 2.64 (t, J=6.0 Hz, 2H), 2.15-2.11 (m, 2H).
27% With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 60℃; Inert atmosphere 6.30. Method ZPreparation of 6-Bromo-3,4-dihydronaphthalen-1(2H)-one; Under N2, t-butyl nitrite (2.05 g, 19.9 mmol) was added dropwise at room temperature to a stirred suspension of copper (II) bromide (3.56 g, 15.9 mmol) in acetonitrile (60 mL). The suspension was heated to 60° C., aniline 83 was added to the reaction then stirred at 60° C. overnight. The reaction was cooled to room temperature, quenched with 2N HCl (200 mL) then extracted thrice with diethyl ether. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give crude product as black oil. The mixture was purified by silica gel column chromatography (ethyl acetate-hexanes gradient) to give bromide 68 (0.820 g, 27percent yield) as a white solid.

Reference: [1] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 4, p. 391 - 396
[2] Chemistry - A European Journal, 2018, vol. 24, # 50, p. 13150 - 13157
[3] Patent: WO2018/183370, 2018, A2, . Location in patent: Paragraph 00136
[4] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 5, p. 1284 - 1304
[5] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 1, p. 130 - 151
[6] Organic Letters, 2011, vol. 13, # 24, p. 6488 - 6491
[7] Patent: US2015/105351, 2015, A1, . Location in patent: Paragraph 0447
[8] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 11, p. 1259 - 1262
[9] Patent: WO2015/49535, 2015, A1, . Location in patent: Paragraph 0032
[10] Patent: US2014/200215, 2014, A1, . Location in patent: Paragraph 1156; 1157
[11] Patent: WO2011/156543, 2011, A2, . Location in patent: Page/Page column 32
[12] Patent: WO2011/150243, 2011, A1, . Location in patent: Page/Page column 147
[13] Patent: WO2010/65668, 2010, A1, . Location in patent: Page/Page column 147
[14] Patent: WO2013/75083, 2013, A1, . Location in patent: Paragraph 00344; 00345
[15] Patent: US9206128, 2015, B2, . Location in patent: Page/Page column 170; 171
[16] Journal of the American Chemical Society, 1980, vol. 102, p. 7910
[17] Patent: US2012/302562, 2012, A1, . Location in patent: Page/Page column 21
[18] Journal of Medicinal Chemistry, 1994, vol. 37, # 21, p. 3482 - 3491
[19] Patent: WO2010/94242, 2010, A1, . Location in patent: Example 2.1
[20] Angewandte Chemie - International Edition, 2013, vol. 52, # 51, p. 13642 - 13646[21] Angew. Chem., 2013, vol. 125, # 51, p. 13887 - 13891,5
[22] Patent: WO2016/44770, 2016, A1, . Location in patent: Page/Page column 860
[23] Tetrahedron, 2018, vol. 74, # 4, p. 433 - 440
  • 17
  • [ 3470-53-9 ]
  • [ 340825-13-0 ]
YieldReaction ConditionsOperation in experiment
35.2%
Stage #1: With hydrogenchloride; sodium nitrite In water at 5℃; for 0.5 h;
Stage #2: With potassium iodide In water at 60℃; for 3 h; Cooling with ice
[Synthesis Example 1 - Synthesis 1 of intermediate of specific compound] <Synthesis of Compound (2)> According to the following reaction formula (scheme), Compound (2) was synthesized. 1 2 The amine compound having the above formula 1 was purchased from SIGMA Aldrich Co. and subjected to notreatments before use. A 500 mL beaker was charged with the compound having the above formula 1 (20 g, 119.0 mmol) and 15percent HC1 (96 mL). While the resultant mixture was being maintained at 5°C or lower with ice cooling, aqueous sodium nitrite solution (9.9 g, 143.0 mmol + water (42 mL)) was added dropwise thereto.After completion of dropwise addition, the mixture was stirred at the same temperature for 30 min. Then, aqueous potassium iodide solution (23.7 g, 143.0 mmol + water (77 mL)) was added to the mixture at one time. The beaker was taken out from the ice bath and the mixture was stirred for 2.5 hours. Thereafter, the mixture was heated at 60°C for 0.5 hours until generation of nitrogen was terminated. After cooled to room temperature, the reaction solution was extracted three times with diethyl ether. The organic layer was washed with 5percent aqueous sodium thiosulfate solution (100 mL x 3) and further washed with saturated brine (100 mL x 2). Moreover, the organic layer was dried with sodium sulfate, followed by filtration. The filtrate was concentrated to obtain red oil. The obtained red oil was purified through silica gel chromatography (solvent: ethyl acetate/hexane = 9/1) to obtain a pale orange solid. Further, the obtained solid wasrecrystallized from 2-propanol to obtain Compound (2) as pale orange crystals (yield amount: 11.4 g, yield rate: 35.2percent). The analysis results of Compound (2) are shown below. iH NMR (500 MHz, CDC13, TMS, δ) : 2.13 (quint, 2H, J = 5.7 Hz), 2.64 (t, 2H, J = 6.3 Hz), 2.92 (t, 2H, J = 6.0 Hz), 7.66 (d, 1H, J = 8.0 Hz), 7.67 (s, 1H), 7.72 (d, 1H, J = 8.0 Hz) Melting point: 74.0°C-75.0°C Mass spectrometry: GC-MS m/z = 272(M+) From the above analysis results, it was confirmed that a structure of the synthesized product did not contradict that of Compound (2).
35.2%
Stage #1: With hydrogenchloride; sodium nitrite In water at 5℃; for 0.5 h;
Stage #2: With potassium iodide In water at 5 - 60℃; for 3 h;
The above 6-amino-3,4-dihydro-1(2H)— naphthalenone as a raw material was purchased from SIGMA Aldrich Co. and subjected to no treatments before use. (0169) A 500 mL beaker was charged with 6-amino-3,4-dihydro-1(2H)-naphthalenone (20 g, 119.0 mmol) and 15percent HCl (96 mL). While the resultant mixture was being maintained at 5° C. or lower with ice cooling, aqueous sodium nitrite solution (9.9 g, 143.0 mmol water (42 mL)) was added dropwise thereto. After completion of dropwise addition, the mixture was stirred at the same temperature for 30 min. Then, aqueous potassium iodide solution (23.7 g, 143.0 mmol water (77 mL)) was added to the mixture at one time. The beaker was taken out from the ice bath and the mixture was stirred for 2.5 hours. Thereafter, the mixture was heated at 60° C. for 0.5 hours until generation of nitrogen was terminated. After cooled to room temperature, the reaction solution was extracted three times with diethyl ether. The organic layer was washed with 5percent aqueous sodium thiosulfate solution (100 mL×3) and further washed with saturated brine (100 mL×2). Moreover, the organic layer was dried with sodium sulfate, followed by filtration. The filtrate was concentrated to obtain red oil. (0170) The obtained red oil was purified through silica gel chromatography (solvent: ethyl acetate/hexane=9/1) to obtain a pale orange solid. Further, the obtained solid was recrystallized from 2-propanol to obtain Compound 6 as pale orange crystals (yield amount: 11.4 g, yield rate: 35.2percent). The analysis results of Compound 6 are shown below. (0172) 1H NMR (500 MHz, CDCl3, TMS, δ): 2.13 (quint, 2H, J=5.7 Hz), 2.64 (t, 2H, J=6.3 Hz), 2.92 (t, 2H, J=6.0 Hz), 7.66 (d, 1H, J=8.0 Hz), 7.67 (s, 1H), 7.72 (d, 1H, J=8.0 Hz) (0173) Melting point: 74.0° C.-75.0° C. (0174) Mass spectrometry: GC-MS m/z=272 (M) (actual measured value); 272.082 (theoretical value of molecular weight) (0175) It was confirmed that the synthesized compound is corresponding to compound 6 from the results of the analysis.
35.2%
Stage #1: With hydrogenchloride; sodium nitrate In water at 5℃; for 0.5 h; Cooling with ice
Stage #2: With potassium iodide In water at 60℃; for 3 h;
In the above formula, the starting material 6-amino-3,4-dihydro-1 (2H) -naphthalenone purchased from SIGMA Aldrich was used as it was.To a 500 mL beaker was added 6-amino-3,4-dihydro-1 (2H)- naphthalenone (20 g, 119.0 mmol) and 15percent HCl (96 mL)While maintaining 5 ° C or less under ice cooling,Aqueous sodium nitrite (9.9g, 143.0mmol + water 42 mL) was slowly added dropwise.After completion of the dropwise addition, the mixture was stirred at the same temperature for 30 minutes,Potassium iodide aqueous solution (23.7 g, 143.0 mmol + water 77 mL) was added at once, the ice bath was removed and the mixture was stirred for 2.5 hours,Thereafter, heating was carried out at 60 ° C. for 0.5 hour until the evolution of nitrogen ceased.After cooling to room temperature, the reaction solution was extracted three times with diethyl ether.The organic layer was washed with 5percent aqueous sodium thiosulfate solution (100 mL × 3 times),And further washed with saturated brine (100 mL × twice).Further, it was dried with sodium sulfate,The filtrate was concentrated to give a red oil.This was purified by silica gel column chromatography (solvent: ethyl acetate / hexane = 9/1) to obtain a pale orange solid.Further, by recrystallization from 2-propanol,Compound 6 was obtained as pale orange crystals (yield 11.4 g, yield 35.2percent).
17.3 g
Stage #1: With sulfuric acid; acetic acid; sodium nitrite In water at 0℃;
Stage #2: With sodium iodide In water at 0 - 20℃;
Intermediate 8A: 6-Iodo-3,4-dihydronaphthalen-1(2H)-one
To a stirred clear solution of 6-amino-3,4-dihydronaphthalen-1(2H)-one (15 g, 93 mmol) in acetic acid (150 mL) and water (150 mL) was added sulfuric acid (5.5 mL, 101 mmol) dropwise at 0° C. A solution of sodium nitrite (12.90 g, 187 mmol) in water (100 mL) was then added dropwise over 40 min at the same temperature.
The mixture was stirred at 0° C. for 10 min before being added to a stirred solution of sodium iodide (55.8 g, 372 mmol) in water (600 mL) slowly over 2 h at 0° C.
The resulting brown suspension was stirred at 0° C. for 30 min and at room temperature for 1 h.
The mixture was extracted with ethyl acetate (400 mL, 2*100 mL).
The combined ethyl acetate extracts were washed with water (60 mL), saturated aqueous Na2S2O3 solution until the brown color disappeared, and saturated aqueous K3PO4 (60 mL) solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
Flash chromatography purification (330 g silica gel column, gradient elution from 5 to 15percent ethyl acetate in hexanes) afforded 6-iodo-3,4-dihydronaphthalen-1(2H)-one (17.3 g, 63.6 mmol) as a solid. LC/MS M+1=273.

Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 11, p. 3436 - 3440
[2] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 9, p. 3309 - 3320
[3] European Journal of Organic Chemistry, 2015, vol. 2015, # 19, p. 4119 - 4130
[4] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 3, p. 283 - 288
[5] Patent: WO2011/158953, 2011, A1, . Location in patent: Page/Page column 144-146
[6] Patent: US9293713, 2016, B2, . Location in patent: Page/Page column 72; 73
[7] Patent: JP6146001, 2017, B2, . Location in patent: Paragraph 0108-0111
[8] Angewandte Chemie - International Edition, 2013, vol. 52, # 51, p. 13642 - 13646[9] Angew. Chem., 2013, vol. 125, # 51, p. 13887 - 13891,5
[10] Patent: US2014/235591, 2014, A1, . Location in patent: Paragraph 0396-0397
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