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Chemical Structure| 104224-63-7
Chemical Structure| 104224-63-7
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Product Details of [ 104224-63-7 ]

CAS No. :104224-63-7 MDL No. :MFCD03855308
Formula : C17H21BrO Boiling Point : -
Linear Structure Formula :C10H15C6H3(OCH3)Br InChI Key :QQAMHHZQONQBFZ-UHFFFAOYSA-N
M.W : 321.25 Pubchem ID :3285024
Synonyms :

Calculated chemistry of [ 104224-63-7 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 19
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.65
Num. rotatable bonds : 2
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 82.4
TPSA : 9.23 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -4.01 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.54
Log Po/w (XLOGP3) : 5.99
Log Po/w (WLOGP) : 4.93
Log Po/w (MLOGP) : 4.85
Log Po/w (SILICOS-IT) : 4.85
Consensus Log Po/w : 4.83

Druglikeness

Lipinski : 1.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -5.71
Solubility : 0.000631 mg/ml ; 0.00000196 mol/l
Class : Moderately soluble
Log S (Ali) : -5.96
Solubility : 0.000352 mg/ml ; 0.00000109 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -5.42
Solubility : 0.00122 mg/ml ; 0.00000379 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 4.46

Safety of [ 104224-63-7 ]

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

Application In Synthesis of [ 104224-63-7 ]

* 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 [ 104224-63-7 ]
  • Downstream synthetic route of [ 104224-63-7 ]

[ 104224-63-7 ] Synthesis Path-Upstream   1~12

  • 1
  • [ 104224-63-7 ]
  • [ 106685-40-9 ]
Reference: [1] Journal of Medicinal Chemistry, 1995, vol. 38, # 26, p. 4993 - 5006
[2] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 151 - 158
[3] Catalysis Science and Technology, 2016, vol. 6, # 13, p. 4690 - 4694
[4] Patent: WO2007/125542, 2007, A2,
[5] Patent: WO2007/125542, 2007, A2,
  • 2
  • [ 104224-68-2 ]
  • [ 74-88-4 ]
  • [ 104224-63-7 ]
YieldReaction ConditionsOperation in experiment
94% With potassium carbonate In N,N-dimethyl-formamide for 2 h; To a stirred mixture of the product of Step A (0.5 g; 1.62 mmol) and K2CO3 (0.335 g; 2.42 mmol) in danhydrous DMF (5 ml) CH3I (1 ml) was added. The reaction mixture was stirred for 2 h and then diluted to 100 ml with H2O and extracted with EtOAc (100 ml). The organic layer was dried over MgSO4 and filtered. The filtrate was passed through silica gel bead. The filtrate was evaporated to dryness to give the title compound (0.49 g, 94percent), as light yellow green solid. 1H-NMR (CDCI3) 7.27 - 7.22 (m, 2H); 6.31 (d, 1 H, J = 6.5 Hz); 3.78 (s, 3H); 2.04 (s, 10H); 1.74 (b, 5H).
78%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1 h;
Stage #2: at 20℃; for 2 h;
To a suspension of sodium hydride (60percent in mineral oil, 0.402g, 10.1 mmol) in 11 mL of DMF, 2-(1-adamantyl)-4-bromophenol 2 (2.75 g, 8.38 mmol) was slowly added, while maintaining the temperature at 20°C. The mixture was stirred at room temperature for 1 h, then methyl iodide (0.73 mL, 11.7 mmol) was added. After having stirred for additional 2 h at 20°C, the solution was poured into water and extracted with diethyl ether. The organic phase was dried and evaporated. The residue was purified by flash chromatography (hexane) to give 2.1 g (78percent) of 4-bromo-1-methoxy-2-(adamantan-1-yl)-benzene, mp 136°C. 1H NMR (300 MHz, CDCl3) : 1.75 (6H, s, 6Ad), 2.05 (9H, s, 9Ad), 3.80 (3H, s, OMe), 6.72 (1H, d, 1Ar, J = 8.0 Hz), 7.24 (1H, dd, 1Ar, J = 8.0, 2.2 Hz), 7.28 (1H, d, 1Ar, J = 2.2 Hz).
Reference: [1] Patent: WO2010/43000, 2010, A1, . Location in patent: Page/Page column 80
[2] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 14, p. 4863 - 4875
[3] European Journal of Medicinal Chemistry, 2014, vol. 79, p. 251 - 259
[4] Journal of Medicinal Chemistry, 1995, vol. 38, # 26, p. 4993 - 5006
[5] Patent: US4717720, 1988, A,
  • 3
  • [ 104-92-7 ]
  • [ 768-95-6 ]
  • [ 104224-63-7 ]
YieldReaction ConditionsOperation in experiment
75% With sulfuric acid In dichloromethane at 20℃; for 20 h; 1-(5-Bromo-2-methoxyphenyl)-adamantane [0145] [0146] Reagent grade concentrated H2S04 (11 mL) was added dropwise to a solution of 1- adamantol (30.25 g, 200 mmol) and 4-bromoanisole (37.21g, 200 mmol) in 130 mL of CH2Cl2. The light pink solution was stirred at ambient temperature for 20 hours. The solvent was decanted, water (100 mL) and hexane (100 mL) were added and the solid was filtered and washed with hexane and dried to give 31 g of the product as a white powder. The supernatant was diluted with hexane, washed with water and brine, dried over MgS04 and filtered thru a silica gel pad. The solvent was removed and the solid was recrystallized from hexane to yield 17 g of the product as a white powder. [0147] Yield: 65 g (75percent) ; white solid; Rf= 0.9 in 25percent EtOAc-hexane. 1H NMR (CDC13, 300 MHz) No. 1.78 (s, 6H), 2.08 (s, 9H), 3.81 (s, 3H), 6.72 (d, 1H), 7.24 (dd, 1H), 7.28 (m, 1H)
75% With sulfuric acid In dichloromethane at 20℃; for 20 h; Reagent grade concentrated H2SO4 (11 mL) was added dropwise to a solution of 1- adamantol (30.25 g, 200 mmol) and 4-bromoanisole (37.21g, 200 mmol) in 130 mL of CH2Cl2. The light pink solution was stirred at ambient temperature for 20 hours. The solvent was decanted, water (100 mL) and hexane (100 mL) were added and the solid was filtered and washed with hexane and dried to give 31 g of the product as a white powder. The supernatant was diluted with hexane, washed with water and brine, dried over MgSO4 and filtered thru a silica gel pad. The solvent was removed and the solid was recrystallized from hexane to yield 17 g of the product as a white powder.[0157] Yield: 48 g (75percent); white solid; Rf= 0.9 in 25percent EtOAc-hexane. IH NMR (CDC13, 300 MHz) D 1.78 (s, 6H)3 2.08 (s, 9H), 3.81 (s, 3H), 6.72 (d, IH)5 7.24 (dd, IH)5 7.28 (m, IH).
72% With sulfuric acid In dichloromethane for 5 h; Step A. 2-(1-adamantyl)-4-bromoanisoleExample 1; In a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel, a mixture of 50 g (0.33 M) 1-adamantanol, 68 g (45.5 mL, 0.36 M) 4-bromoanisole and 500 mL of methylene chloride is prepared. The mixture is stirred until dissolved and then 35 g (19 mL, 0.36 M) sulfuric acid added during one hour. The reaction mixture is stirred for 4 hours, 200 mL of water added, stirred for another 10 min, transferred to separating funnel and the organic layer collected, which is neutralized by two portions of 100 mL 10percent sodium carbonate solution. Methylene chloride is distilled off completely, the residue dissolved in 300 mL of ethyl acetate, filtered, concentrated to 200 mL and left to crystallize at 0° C. for 16 h. The crystals are filtered off, washed by 50 mL of cold ethyl acetate and dried at 100° C. for one hour. 2-adamantyl-4-bromoanisole, 76 g (72percent) with m.p. 140-141° C. is obtained.NMR (500 MHz, DMSO D6) δ: 1.75 (s, 6H), 2.03 (s, 9H), 3.81 (s, 3H), 6.82 (d, 1H, J=8 Hz), 7.17 (s, 1H), 7.23 (d, 1H, J=8 Hz).Scaling the synthesis up 10 times did not change either the yield or quality of the 2-(1-adamantyl)-4-bromoanisole.
72% With sulfuric acid In dichloromethane for 5 h; Step A. 2-(1-adamantyl)-4-bromoanisole; EXAMPLE 1In a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel, a mixture of 50 g (0.33 M) 1-adamantanol, 68 g (45.5 mL, 0.36 M) 4-bromoanisole and 500 mL of methylene chloride is prepared. The mixture is stirred until dissolved and then 35 g (19 mL, 0.36 M) of sulfuric acid added during one hour. The reaction mixture is stirred for 4 hours, 200 mL of water added, stirred for another 10 min, transferred to a separating funnel and the organic layer collected. It is neutralized by two portions of 100 mL 10percent sodium carbonate solution. Methylene chloride is distilled off completely, the residue dissolved in 300 mL of ethyl acetate, filtered, concentrated to 200 mL and left to crystallize at about 0° C. for 16 h. The crystals are filtered off, washed by 50 mL of cold ethyl acetate and dried at 100° C. for one hour. 2-adamantyl-4-bromoanisole, 76 g (72percent) with m.p. 140-141° C. is obtained.NMR (500 MHz, DMSO D6)δ: 1.75 (s, 6H), 2.03 (s, 9H), 3.81 (s, 3H), 6.82 (d, 1H, J=8 Hz), 7.17 (s, 1H), 7.23 (d, 1H, J=8 Hz).Scaling the synthesis up 10 times did not change either the yield or quality of the 2-(1-adamantyl)-4-bromoanisole

Reference: [1] Beilstein Journal of Organic Chemistry, 2012, vol. 8, p. 227 - 233
[2] Patent: WO2005/108338, 2005, A1, . Location in patent: Page/Page column 47
[3] Patent: WO2007/28104, 2007, A2, . Location in patent: Page/Page column 50-51
[4] Patent: US2010/76219, 2010, A1, . Location in patent: Page/Page column 2
[5] Patent: US2010/160677, 2010, A1, . Location in patent: Page/Page column 3
  • 4
  • [ 77-78-1 ]
  • [ 104224-68-2 ]
  • [ 104224-63-7 ]
YieldReaction ConditionsOperation in experiment
58% With potassium carbonate In acetone at 20℃; for 4.25 - 6.25 h; Heating / reflux Example 4; Preparation of 2-(l-adamantyl)-4-bromoanisole (IV): A mixture of 2-(l-adamantyl)-4-bromophenol (III) (50 g, 162 mmol) and potassium carbonate (33.7 g, 216 mmol) in acetone (250 ml) was stirred at room temperature. Then dimethylsulphate (20.16 ml, 240 mmol) was added drop wise for 15 min at room temperature. The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with water, acidified with dilute HCl. The solid separated was filtered and washed with water. The solid was dissolved in dichloromethane (200 ml) and washed with water. The organic layer was dried over sodium sulphate, evaporated and the solid obtain was purified with ethyl acetate (200ml).[Yield: 30 g, 58 percent]; Example 5; Preparation of 2-(l-adamantyl)-4-bromoanisole (IV): To a solution of 2-(l-adamantyl)-4-Bromophenol (III) (50 g, 162 mmol) in acetone 200 ml, Potassium carbonate (33.7 g, 216 mmol) was added and stirred at RT. Dimethyl sulphate (20.53 ml, 244 mmol) was added dropwise for 15 min at RT. The reaction mixture was then refluxed for 4 hrs. The reaction mixture was further cooled to RT5 water was added, and the solid separated, was filtered and washed with acetone. The solid was then treated with 3N HCl till pH is about 5 to 6, filtered and washed with water and acetone and then finally dried to obtain compound (IV).[Yield: 38g, 73percent] [44 g, 84percent]
Reference: [1] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 151 - 158
[2] Organic Process Research and Development, 2006, vol. 10, # 2, p. 285 - 288
[3] Patent: WO2007/125542, 2007, A2, . Location in patent: Page/Page column 15
  • 5
  • [ 768-95-6 ]
  • [ 104224-63-7 ]
Reference: [1] Journal of Medicinal Chemistry, 1995, vol. 38, # 26, p. 4993 - 5006
[2] Patent: WO2007/125542, 2007, A2,
  • 6
  • [ 106-41-2 ]
  • [ 104224-63-7 ]
Reference: [1] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 151 - 158
[2] Patent: WO2007/125542, 2007, A2,
  • 7
  • [ 33626-98-1 ]
  • [ 104224-63-7 ]
  • [ 106685-41-0 ]
YieldReaction ConditionsOperation in experiment
50%
Stage #1: With magnesium; ethylene dibromide In tetrahydrofuran at 20 - 40℃; for 0.5 h; Heating / reflux
Stage #2: With zinc(II) chloride In tetrahydrofuran for 1.25 h; Heating / reflux
Stage #3: for 2.16667 h;
Example 6; Preparation of methyl ester of 6-[3-(l-adamantyl)-4methoxy phenyl]-2 naphthoate (V): A mixture of magnesium turnings (1.26 g, 51.85 mmol) in THF (10 ml) was stirred at room temperature and 2-(l-adamantyl)-4-bromoanisole (IV) (1.4 g, 4.36 mmol) and 1,2- dibromoethane (0.56 ml) were added under nitrogen atmosphere. The reaction mixture was heated at 40°C for initiation, and then 2-(l-adamantyl)-4-bromoanisole (12.6 g, 39.25 mmol) in tetrahydrofuran (40 ml) was added in a drop wise manner for 30 min at reflux temperature. Purified Zinc chloride (8.4 g, 61 mmol) in tetrahydrofuran (30 ml) was added in a drop wise manner for 15 min at reflux temperature. The reaction mixture was refluxed for 1 hr. Methyl 6-bromo-2-naphthoate (8.0 g, 30mmol) was added, stirred for 10 min, followed by the addition of NiCl2ZDPPE catalyst (0.21 g). The reaction mixture was stirred at same temperature for 2 hrs and concentrated to obtain a residue, which was treated with dichloromethane (100 ml) and 1 N HCl (100 ml). The dichloromethane layer washed with 10 percent EDTA disodium salt, water, dried over anhydrous sodium sulfate and distilled to obtained crude compound. The crude compound was stirred in ethyl acetate (140 ml) for 1 hr at 7O0C, cool at 15 0C for l*h and the solid obtained was filtered and dried. [Yield: 9.45 g, 50percent]
Reference: [1] Organic Process Research and Development, 2006, vol. 10, # 2, p. 285 - 288
[2] Patent: WO2007/125542, 2007, A2, . Location in patent: Page/Page column 16
[3] Journal of Medicinal Chemistry, 1995, vol. 38, # 26, p. 4993 - 5006
  • 8
  • [ 33626-98-1 ]
  • [ 104224-63-7 ]
  • [ 932033-57-3 ]
  • [ 106685-41-0 ]
YieldReaction ConditionsOperation in experiment
88.83%
Stage #1: With magnesium; ethylene dibromide In tetrahydrofuran at 45 - 55℃; for 1.5 h;
Stage #2: With zinc(II) chloride In tetrahydrofuran at 20 - 25℃; for 1 h;
Stage #3: at 20℃; for 2 h;
To a 2 L, five-necked cylindrical reaction vessel equipped with a reflux condenser, heat-transfer jacket, compensated-pressure addition funnel, anchor impeller and purged with nitrogen, were added 1.13 g of 1-(5-bromo-2-methoxyphenyl) adamantane (3.52.x.10-3 mol), 3.75 g of magnesium granules (1.54.x.10-1 mol) and 90 mL of tetrahydrofuran. Into the compensated-pressure addition funnel was added a previously prepared solution of 36.37 g of 1-(5-bromo-2-methoxyphenyl)adamantane (1.13.x.10-1 mol) and 270 mL of tetrahydrofuran. The reaction mixture was then heated to approximately 45° C., at which point 2.50 g of 1,2-dibromoethane (1.33.x.10-2 mol) was charged to the mixture. During the addition, the internal temperature increased and bubbling was observed, indicating initiation of the reaction.At approximately 50° C., addition of the solution in the compensated-pressure addition funnel was initiated and continued over approximately 45 minutes during which time the internal temperature of the solution was maintained between approximately 50 and 55° C. Following the addition, the reaction mixture was stirred for approximately 45 minutes at approximately 50° C. and then cooled to approximately 20-25° C. To the cooled suspension was added 18.18 g of anhydrous zinc chloride (1.33.x.10-1 mol) and an increase in temperature was observed within a few seconds. The mixture was permitted to cool and was stirred for approximately 1 hour at approximately 20-25° C. Thereafter, 1.05 g of 1,2-[bis(diphenylphosphino)ethane] dichloronickel(II) (2.20.x.10-3 mol) was charged to the reaction mixture followed by the addition of 24.00 g of methyl 6-bromo-2-naphtoate (9.05.x.10-2 mol). The mixture was permitted cool and was stirred for approximately two hours at room temperature.Next, 50 mL of water was slowly added and the mixture was stirred for approximately 15 minutes, at which point 200 mL of 1N HCl was slowly added. The mixture was then stirred overnight at room temperature or until the excess of magnesium pellets were dissolved. The mixture was then filtered, and the cake was washed with methyl ethyl ketone ("MEK"). The resulting solid was next suspended in 500 mL of 1N HCl and 125 mL of MEK. The resulting suspension was then stirred at room temperature for approximately 1 hour. The mixture was then filtered, and the cake was washed with MEK. The resulting solid was next suspended in 270 mL of MEK and the mixture was heated to reflux for approximately 30 minutes, cooled and filtered. The resulting cake was then washed with MEK.The wet solid obtained was suspended in 184 mL of tetrahydrofuran and was heated to approximately 50-60° C. for approximately 30 minutes, cooled and precipitated by addition of 300 mL of methanol. The precipitate was then filtered and dried at approximately 60° C. in a vacuum oven to yield 34.31 g of adapalene methyl ester (8.044.x.10-2 mol; yield: 88.83percent) as an off-white powder. Analytical data: HPLC Purity (HPLC at 272 nm): 97.32percent; Impurity (i.e., 3,3'-diadamantyl-4,4'-dimethoxybiphenyl) area percent (HPLC at 272 nm): 2.05percent.The product may also contain a small amount of an unidentified impurity, which is more polar than the final product. This unidentified impurity, when observed, as well as the 3,3'-diadamantyl-4,4'-dimethoxybiphenyl impurity, are eliminated from the synthetic pathway during the work-up described in the Example/Step 2 (below).
Reference: [1] Patent: US2009/131713, 2009, A1, . Location in patent: Page/Page column 3; 5
  • 9
  • [ 104224-63-7 ]
  • [ 106685-41-0 ]
Reference: [1] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 151 - 158
[2] Catalysis Science and Technology, 2016, vol. 6, # 13, p. 4690 - 4694
  • 10
  • [ 104224-63-7 ]
  • [ 459423-32-6 ]
YieldReaction ConditionsOperation in experiment
12%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.0833333 h;
Stage #2: With triethyl borate In tetrahydrofuran; hexane at -78℃; for 0.5 h;
Stage #3: With hydrogenchloride In tetrahydrofuran; hexane; water at 20℃;
1-(5-Boronic acid-2-methoxyphenyl)-adamantane [0149] To a solution of 1-(5-bromo-2-methoxyphenyl)-adamantane (4 g, 12.5 mmol) in 40 mL of THF was added a 2.5M solution of n-BuLi in hexane (5 mL, 12.5 mmol) at-78°C, under nitrogen. The mixture was stirred for 5 minutes at-78°C, triethylborate (1.88g, 12.9 mmol) was added and the mixture was stirred for an additional 30 minutes at -78°C. The reaction was allowed to slowly warm to room temperature and was quenched by addition of IN HCl (30 mL). The mixture was diluted with Et20, washed with water and brine, dried over Na2S04, filtered thru a pad of silica gel and the solvent was removed to yield the crude product which was recrystallized from chloroform. [0150] Yield: 0.45 g (12percent); solid; 1H NMR (CDCl3-MeOD 10:1, 300 MHz) 8 1.74 (s, 6H), 2.08 (m, 9H), 2.9 (s, 2H), 3.81 (s, 3H), 6.82 (d, 1H), 7.52 (m, 2H)
12%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.0833333 h;
Stage #2: With triethyl borate In tetrahydrofuran; hexane; water at -78℃; for 0.5 h;
Stage #3: With hydrogenchloride In tetrahydrofuran; hexane; water
To a solution of l-(5-bromo-2-methoxyphenyl)-adamantane (4 g, 12.5 mmol) in 40 mL of THF was added a 2.5M solution of n-BuLi in hexane (5 mL, 12.5 mmol) at -780C, under nitrogen. The mixture was stirred for 5 minutes at -780C, triethylborate (1.88g, 12.9 mmol) was added and the mixture was stirred for an additional 30 minutes at -780C. The reaction was allowed to slowly warm to room temperature and was quenched by addition of IN HCl (30 mL). The mixture was diluted with Et2O, washed with water and brine, dried over Na2SO4, filtered thru a pad of silica gel and the solvent was removed to yield the crude product which was recrystallized from chloroform.[0159] Yield: 0.45 g (12percent); white solid; IH NMR (CDC13-MeOD 10:1, 300 MHz) D 1.74 (s, 6H), 2.08 (m, 9H), 2.9 (s, 2H)5 3.81 (s, 3H), 6.82 (d, IH), 7.52 (m, 2H)
Reference: [1] Patent: WO2005/108338, 2005, A1, . Location in patent: Page/Page column 48
[2] Patent: WO2007/28104, 2007, A2, . Location in patent: Page/Page column 51
[3] Patent: WO2007/63522, 2007, A1, . Location in patent: Page/Page column 11-12
  • 11
  • [ 121-43-7 ]
  • [ 104224-63-7 ]
  • [ 459423-32-6 ]
  • [ 43109-77-9 ]
YieldReaction ConditionsOperation in experiment
5.7%
Stage #1: With magnesium; ethylene dibromide In tetrahydrofuranReflux; Inert atmosphere
Stage #2: at -50 - -40℃; for 0.5 h; Inert atmosphere
Stage #3: With hydrogenchloride; water In tetrahydrofuran
EXAMPLE 1
Into a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel 8 g (0.33 M) of magnesium filings are introduced and 200 mL of dry tetrahydrofuran added.
The air in the flask is displaced by argon and all further operations conducted under a slight stream of the inert gas.
Under vigorous stirring 11 g (5 mL, 0.06 M) of 1,2-dibromoethane is added.
After the vigorous reaction had subsided, the hot reaction mixture is treated with a solution of 50 g (0.16 M) 2-(1-adamantyl)-4-bromoanisole in 400 mL of dry tetrahydrofuran with such speed that a slight reflux is supported.
After the adding of all solution of 2-(1-adamantyl)-4-bromoanisole, the reaction mixture is refluxed for another 30 min.
Stirring is discontinued and the solution of the prepared Grignard's reagent decanted from the residual magnesium into a conical flask with ground stopper flushed in advance with argon.
For further functionalization reactions trimethylborate, a standard reactant for preparing phenylboronic acids was used.
In a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel a solution of 33 g (36 mL, 0.35 M) of trimethylborate in 100 mL of dry tetrahydrofuran is prepared, the solution cooled to -50° C. and under vigorous stirring the solution of the Grignard's reagent is added within 30 min at -40to -50° C.
The reaction mixture is decomposed with a solution of 50 mL of hydrochloric acid in 50 mL water with vigorous stirring without external cooling.
The mixture is transferred to separating funnel and the water and organic layers separated.
To the water layer 200 mL of water is added and then extracted twice with 100 mL of diethylether.
The pooled organic solutions are dried on anhydrous sodium sulfate, the solvents removed in vacuo at about 50° C. in the water bath.
The residue is treated with 200 mL of hexane and left in the freezer overnight.
The precipitate is filtered off, washed with cold ethyl acetate and is dried at 100° C. 3-(1-adamantyl)-4-methoxyphenylboronic acid with m.p. ~300° C. is obtained, yield 2.5 g (5.7percent).
The gas chromatographic analysis of the reaction mixture showed one main product.
The yield, according to gas chromatography data is 78percent.
The compound was isolated and identified as 2-(1-adamantyl)anisole.
The preparative yield is 67percent, m.p. 100-102° C.
Reference: [1] Patent: US2010/113816, 2010, A1, . Location in patent: Page/Page column 3
  • 12
  • [ 121-43-7 ]
  • [ 104224-63-7 ]
  • [ 459423-32-6 ]
YieldReaction ConditionsOperation in experiment
69%
Stage #1: With magnesium; ethylene dibromide; lithium chloride In tetrahydrofuran at 0℃; Inert atmosphere; Reflux
Stage #2: at -70℃; Inert atmosphere
Stage #3: With hydrogenchloride; water In tetrahydrofuran
Step B. 3-(1-adamantyl)-4-methoxyphenylboronic acidEXAMPLE 2In a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel, a mixture of 8 g (0.33 M) magnesium filings and 200 mL of dry tetrahydrofuran is stirred. 8 g (0.19 M) of pulverised anhydrous lithium chloride is added. The air in the flask is displaced by argon and all further operations performed under a slight stream of this inert gas. Under intense stirring 11 g (5 mL, 0.06 M) of 1,2-dibromoethane is added in one portion. After the vigorous reaction had subsided, the hot reaction mixture is treated with a solution of 50 g (0.16 M) 2-(1-adamantyl)-4-bromoanisole in 400 mL tetrahydrofuran with such speed that a slight reflux is supported. After adding the solution of 2-(1-adamantyl)-4-bromoanisole the reaction mixture is stirred and heated to slow reflux for another 30 min. The stirring is discontinued and the Grignard's reagent thus obtained is decanted from is the residual magnesium into a conical flask, flushed in advance with argon, closed with a ground stopper and kept at 0° C. for 2 h.In a 1 L flask equipped with a stirrer, a reflux condener and a dropping funnel a mixture of 33 g (36 mL, 0.35 M) of trimethylborate and 100 mL of dry tetrahydrofuran is prepared. The solution thus obtained is cooled to 0-+5° C. (by ice water) and under vigorous stirring treated with the previously prepared Grignard's reagent within 10 min. The reaction mixture is left overnight (16 h) in the refrigerator at 0-+5° C. The reaction mixture is decomposed with a solution of 50 mL of hydrochloric acid in 50 mL of water with vigorous stirring without external cooling. The mixture is transferred to a separating funnel and the layers separated. To the water layer 200 mL of water is added and extracted twice with 100 mL of diethyl ether. The pooled organic solutions are dried on anhydrous sodium sulfate, the solvents removed under vacuo at about 50° C. in the water bath. The residue is treated with 200 mL of ethyl acetate and left in the refrigerator overnight. The precipitate is filtered off and dried at 100° C. 3-(1-adamantyl)-4-methoxyphenylboronic acid, 30 g (68percent) with m.p.300° C. is obtained.; EXAMPLE 10Reaction is performed as described in Example 2. The interaction of 3-(1-adamantyl)-4-methoxyphenylmagnesium bromide solution with trimethylborate is performed at -70° C. 3-(1-Adamantyl)-4-methoxyphenylboronic acid, 30.6 g (69percent) is obtained.
Reference: [1] Russian Journal of General Chemistry, 2010, vol. 80, # 4, p. 868 - 869
[2] Russian Journal of General Chemistry, 2010, vol. 80, # 4, p. 868 - 869
[3] Patent: US2010/160677, 2010, A1, . Location in patent: Page/Page column 3-4
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