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Product Details of [ 106685-41-0 ]

CAS No. :106685-41-0 MDL No. :MFCD08063923
Formula : C29H30O3 Boiling Point : -
Linear Structure Formula :- InChI Key :PGXNMQBGOVUZNC-UHFFFAOYSA-N
M.W : 426.55 Pubchem ID :10526466
Synonyms :
Chemical Name :Methyl 6-(3-(adamantan-1-yl)-4-methoxyphenyl)-2-naphthoate

Calculated chemistry of [ 106685-41-0 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 32
Num. arom. heavy atoms : 16
Fraction Csp3 : 0.41
Num. rotatable bonds : 5
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 128.93
TPSA : 35.53 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -3.2 cm/s

Lipophilicity

Log Po/w (iLOGP) : 4.56
Log Po/w (XLOGP3) : 8.03
Log Po/w (WLOGP) : 6.77
Log Po/w (MLOGP) : 5.54
Log Po/w (SILICOS-IT) : 6.75
Consensus Log Po/w : 6.33

Druglikeness

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

Water Solubility

Log S (ESOL) : -7.58
Solubility : 0.0000111 mg/ml ; 0.0000000261 mol/l
Class : Poorly soluble
Log S (Ali) : -8.63
Solubility : 0.000001 mg/ml ; 0.0000000023 mol/l
Class : Poorly soluble
Log S (SILICOS-IT) : -8.76
Solubility : 0.000000745 mg/ml ; 0.0000000018 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 5.17

Safety of [ 106685-41-0 ]

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

Application In Synthesis of [ 106685-41-0 ]

* 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 [ 106685-41-0 ]
  • Downstream synthetic route of [ 106685-41-0 ]

[ 106685-41-0 ] Synthesis Path-Upstream   1~19

  • 1
  • [ 106685-41-0 ]
  • [ 106685-40-9 ]
YieldReaction ConditionsOperation in experiment
97%
Stage #2: With hydrogenchloride In water
Step D: Basic hydrolysis of methyl-6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthenoateExample 13; Into a 600 mL beaker is introduced 10 g of methyl-6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthenoate, 300 mL of ethylene glycol and heated almost to boiling. The obtained clear solution is added 15 g of sodium hydroxide in 3 portions and vigorously stirred for 20 min.The hot reaction mixture is slowly added with vigorous stirring to a cold 5percent solution of aqueous hydrochloric acid.The suspension thus obtained is stirred for 30 min and filtered off. The precipitate is pressed on filter, washed with 3.x.500 mL of hot water and dried at 100° C. for 16 h. 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, 9.3 g (96percent) with m.p. 320° C. and purity over 97percent is obtained.NMR (500 MHz, DMSO δ: 1.79 (s, 6H), 2.10 (s, 3H), 2.16 (s, 6H), 3.90 (s, 3H), 6.99 (d, 1H, J=8 Hz), 7.51 (s, 1H), 7.52 (d, 1H, J=8 Hz), 7.76 (d, 1H, J=9 Hz), 7.92 (d, 1H, J=9 Hz), 7.98-8.02 (m, 3H), 8.55 (s, 1H), 12.7 (s, 1H).Using 1,2-propanediol instead of ethylene glycol the concentration of the hydrolyzed methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthenoate in solution can be increased by 50percent.
96%
Stage #2: With hydrogenchloride In water
Step D: Basic hydrolysis of methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtenoate; EXAMPLE 18; Into a 600 mL beaker 10 g of methyl-6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtenoate is introduced, 300 mL of ethylene glycol added and heated almost to boiling. To the obtained clear solution 15 g of sodium hydroxide is added in 3 portions and vigorously stirred for 20 min. The hot reaction mixture is slowly added with vigorous stirring to cold 5percent solution of aqueous hydrochloric acid. The suspension thus obtained is stirred for 30 min and filtered off. The precipitate is pressed on filter, washed with 3.x.500 mL of hot water. Dried at 100° C. for 16 h. 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtoic acid, 9.3 g (96percent) with m.p. 320° C. and purity over 97percent is obtained.NMR (500 MHz, DMSO D6 δ: 1.79 (s, 6H), 2.10 (s, 3H), 2.16 (s, 6H), 3.90 (s, 3H), 6.99 (d, 1H, J=8 Hz), 7.51 (s, 1H), 7.52 (d, 1H, J=8 Hz), 7.76 (d, 1H, J=9 Hz), 7.92 (d, 1H, J=9 Hz), 7.98-8.02 (m, 3H), 8.55 (s, 1H), 12.7 (s, 1H).Using 1,2-propanediol instead of ethylene glycol the concentration of the hydrolized methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtoate in solution can be increased by 50percent.
Reference: [1] Patent: US2010/76219, 2010, A1, . Location in patent: Page/Page column 4
[2] Patent: US2010/160677, 2010, A1, . Location in patent: Page/Page column 5-6
[3] Catalysis Science and Technology, 2016, vol. 6, # 13, p. 4690 - 4694
[4] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 151 - 158
[5] Organic Process Research and Development, 2006, vol. 10, # 2, p. 285 - 288
[6] Journal of Medicinal Chemistry, 1995, vol. 38, # 26, p. 4993 - 5006
[7] Patent: WO2007/383, 2007, A1, . Location in patent: Page/Page column 19; 20
[8] European Journal of Medicinal Chemistry, 2014, vol. 79, p. 251 - 259
[9] Patent: WO2007/125542, 2007, A2,
[10] Patent: WO2007/125542, 2007, A2,
  • 2
  • [ 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
  • 3
  • [ 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
  • 4
  • [ 106685-43-2 ]
  • [ 74-88-4 ]
  • [ 106685-41-0 ]
YieldReaction ConditionsOperation in experiment
82%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1 h;
Stage #2: at 20℃; for 1.5 h;
The above compound (506 mg, 1.23 mmol) was added to an ice-cooled suspension of NaH (78.8 mg, 60percent) in dry DMF (3 mL). The mixture was stirred 1h at 0 °C, then CH3I (0.107 mL) was added and stirring was continued for 90 min. After addition of cold water, the aqueous phase was extracted with CH2Cl2. The collected organic phases were dried and evaporated. The residue was purified by flash chromatography (hexane/ethyl acetate 9: 1 v/v) to afford 300 mg (82percent) of 6-(3-Adamantan-1-yl-4-methoxyphenyl)naphthalene-2-carboxylic acid methyl ester as a white solid m.p 223 °C.
Reference: [1] European Journal of Medicinal Chemistry, 2014, vol. 79, p. 251 - 259
  • 5
  • [ 459423-32-6 ]
  • [ 366799-67-9 ]
  • [ 106685-41-0 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: for 1 h; Heating / reflux
Stage #2: With water; potassium carbonate In tetrahydrofuran at 50℃; for 24 h; Heating / reflux
A round-bottom flask is loaded with nickel (II) chloride (0.158 g; 1.2 mmol) and THF (15 ml), and tris(hydroxypropyl)phosphine (1.53 g; 7.3 mmol) is added. The mixture is refluxed for an hour, then cooled to a temperature of 50°C and added in succession with methyl 6-tosyl-naphthalene-2-carboxylate (8.7 g; 24.4 mmol), potassium carbonate (6.75 g; 48.8 mmol), 4-methoxy-3-adamantyl-phenylboronic acid (9.1 g; 31.8 mmol), water (8.11 g; 450.5 mmol) and THF (30 ml). The mixture is refluxed for 24 hours, then cooled to a temperature ranging from 50 to 55°C, added with water, and adjusted to pH lower than 7 with acetic acid. After cooling to 15°C, the resulting product is filtered, thereby obtaining adapalene methyl ester (9.37 g; 21.96 mmol) in 90percent yield.
82%
Stage #1: for 1 h; Heating / reflux
Stage #2: With potassium phosphate; water In tetrahydrofuran at 50℃; for 24 h; Heating / reflux
A round-bottom flask is loaded with nickel (II) chloride (0.158 g; 1.2 mmol) and THF (20 ml), and tris(hydroxypropyl)phosphine (1.53 g; 7.3 mmol) is added to the mixture, which is refluxed for an hour, then cooled to a temperature of 50°C and added in succession with methyl 6-tosyl-naphthalene-2-carboxylate (8.7 g; 24.4 mmol), potassium phosphate (10.38 g; 48.8 mmol), 4-methoxy-3-adamantyl-phenylboronic acid (7 g; 24.4 mmol), water (0.88 g; 48.8 mmol) and THF (50 ml). The mixture is heated under reflux for 24 hours, then cooled to a temperature ranging from 50 to 55°C and added with water, adjusting pH to a value below 7 with acetic acid. After cooling to a temperature of 15°C, the resulting product is filtered, thereby obtaining crystalline adapalene methyl ester (8.5 g; 20.08 mmol) in 82percent yield. 1H NMR: (300 MHz, DMSO), δ 8.6 (s, 1H), δ 8.3-7.8 (m, 6H), δ 7.7-7.5 (m, 2H), δ 7.1 (d, 1H), δ 3.9 (s, 3H), δ 3.85 (s, 3H), δ 2 (m, 9H), δ 1.7 (m, 6H); A round-bottom flask is loaded with nickel (II) chloride (0.158 g; 1.2 mmol) and THF (20 ml), and tris(hydroxypropyl)phosphine (1.53 g; 7.3 mmol) is added. The mixture is refluxed for an hour, then cooled to a temperature of 50°C and added in succession with methyl 6-tosyl-naphthalene-2-carboxylate (8.7 g; 24.4 mmol), potassium phosphate (10.38 g; 48.8 mmol), 4-methoxy-3-adamantyl-phenylboronic acid (9.1 g; 31.8 mmol), water (10.53 g; 585.3 mmol) and THF (50 ml). The mixture is refluxed for 24 hours, then cooled to a temperature ranging from 50 to 55°C, added with water, and adjusted to pH lower than 7 with acetic acid. After cooling to 15°C, the resulting product is filtered, thereby obtaining adapalene methyl ester (9 g; 21.2 mmol) in 86percent yield.
78% With potassium phosphate In tetrahydrofuran for 24 h; Heating / reflux A round-bottom flask is loaded with methyl 6-tosyl-naphthalene-2-carboxylate (8.7 g; 24.4 mmol), THF (70 ml), potassium phosphate (10.38 g; 48.8 mmol), 4-methoxy-3-adamantyl-phenylboronic acid (7 g; 24.4 mmol), nickel chloride complexed with tri(cyclohexyl)phosphine (0.83 g; 1.2 mmol) and tri(cyclohexyl)phosphine (1.37 g; 4.88 mmol). The mixture is refluxed for 24 hours, then cooled to a temperature ranging from 50 to 55°C and added with water, then cooled to 15°C. The resulting product is filtered, thereby obtaining adapalene methyl ester (8.1 g; 19.0 mmol) in 78percent yield.
Reference: [1] Patent: EP1707555, 2006, A1, . Location in patent: Page/Page column 5
[2] Patent: EP1707555, 2006, A1, . Location in patent: Page/Page column 4
[3] Patent: EP1707555, 2006, A1, . Location in patent: Page/Page column 5
  • 6
  • [ 106685-40-9 ]
  • [ 18107-18-1 ]
  • [ 106685-41-0 ]
YieldReaction ConditionsOperation in experiment
79% at 0 - 20℃; for 1 h; To a solution of adapalene (50 mg, 0.121 mmol) in 4: 1 THF/MeOH (0.4 mL) at 0 °C was added TMSCH2N2 (0.15 mL, 0.290 mmol) and the reaction was warmed to room temperature over 1 hour. The reaction mixture was concentrated, IN HCl was added, and was extracted with EtOAc 3x. The combined organic layers were washed with water and brine, dried over Na2S04, filtered, and concentrated; yielding the title compound as a white solid (41 mg, 79percent yield). NMR (500 MHz, CDC13) δ 8.61 (s, 1H), 8.07 (dd, J = 8.6, 1.7 Hz, 1H), 8.03 - 7.96 (m, 2H), 7.92 (d, J = 8.6 Hz, 1H), 7.80 (dd, J = 8.5, 1.8 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.55 (dd, J = 8.4, 2.4 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 3.99 (s, 3H), 3.91 (s, 3H), 2.19 (s, 6H), 2.10 (s, 3H), 1.80 (s, 6H); 13C NMR (125 MHz, CDC13) δ 167.44, 159.03, 141.51, 139.11, 136.06, 132.67, 131.35, 130.95, 129.82, 128.33, 127.02, 126.59, 126.09, 125.84, 125.68, 124.84, 112.21, 55.27, 52.31, 40.72, 37.25, 29.23; HRMS Accurate mass (ES+): Found 427.2268, C29H3i03 (M+H+) requires 427.2273.
Reference: [1] Patent: WO2018/213609, 2018, A1, . Location in patent: Page/Page column 93
  • 7
  • [ 1036766-56-9 ]
  • [ 33626-98-1 ]
  • [ 106685-41-0 ]
YieldReaction ConditionsOperation in experiment
87% With potassium phosphate In tetrahydrofuran; waterInert atmosphere; Reflux Step C. Catalytic Coupling of 3-(1-adamantyl)-4-methoxyphenyl-boronic Acid Derivatives with 6-bromo-2-naphtoic Acid Esters According to Suzuki-MiyauraEXAMPLE 12Into a 1 L flask with stirrer and reflux condenser 0.25 g (0.5 mol percent) of tris(dibenzylydeneacetone)dipalladium(0) [Pd2(dba)3] was dissolved in 500 mL of thetrahydrofuran, then 1 g (0.5 mol percent) of 2-dicyclohexyl-phosphino-2',6'-dimethoxybipheyl (Sphos) added and the resulting solution stirred under a slight stream of argon.To the reaction mixture was added 30 g (0.105 M) of 3-(1-adamantyl)-4-methoxyphenylboronic acid and 25 g (0.094 M) of methyl 6-bromo-2-naphtenoate and stirred until dissolved. The final component is a solution of 30 g (0.28 M) of sodium carbonate in 150 mL of water, prepared in advance, that is added to the reaction mixture in one portion.The process is carried on under vigorous stirring and reflux under a slight stream or argon.After the completion the reaction mixture is cooled to room temperature and filtered without separating the layers. The precipitate constitutes the main portion of the product. The rest of the product is obtained by concentrating the organic layer to 1/4, cooling and filtering off the precipitate. The raw product is dissolved in 200 mL of dimethylacetamide, filtered hot, reduced to about 150 mL and left for 16 h at room temperature for crystallization. The voluminous crystals are filtered off and dried at 150-180° C. for 2 h. Methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtenoate, 35.2-36.8 g (88-92percent) with m.p. 222-225° C. is obtained.NMR (500 MHz, DMSO D6)δ: 1.79 (s, 12H), 2.10 (s, 3H), 2.16 (s, 6H), 3.90 (s, 3H), 3.94 (s, 3H), 6.99 (d, 1H, J=8 Hz), 7.51 (s, 1H), 7.52 (d, 1H, J=8 Hz), 7.78 (d, 1H, J=9 Hz), 7.94 (d, 1H, J=9 Hz), 7.98-8.02 (m, 3H), 8.55 (s, 1H).Replacing 3-(1-adamantyl)-4-methoxyphenylboronic acid with its pinacol or ethylene glycol ester, or replacing tris(dibenzylydeneacetone)-dipalladium(0) [Pd2(dba)3] with palladium acetate (Pd(OAc)2), or using potassium carbonate or potassium phosphate as the basic agent does not substantially change the yield of methyl 6-[3-(1-adamantyl)-4-methoxy-phenyl]-2-naphtenoate.; EXAMPLE 14Reaction is performed as described in Example 12. As the boronic acid component 3-(1-adamantyl)-4-methoxyphenylboronic acid pinacol ester is used, 39 g (0.105 M), as the Pd[0] source-palladium acetate, 0.11 g (0.5 mol percent). As the basic agent the solution of 60 g (0.28 M) of potassium phosphate in 200 mL of water is used. Methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtenoate, 35 g (87percent) is obtained.A gradual increase of the quantity of catalyst up to 5 mol percent leads to the shortening of the reaction time to half-hour, but does not influence the yield of the end product. Reducing the quantity of the catalyst to 0.05 mol percent leads to the increase of reaction time to 16 hours and drops the yield of methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtenoate to 76percent.Scaling up the synthesis under the optimal reaction conditions did not lower the yield of methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtenoate.Using as a catalyst freshly prepared tetrakis(triphenyl-phosphine)palladium(0) Pd[P(Ph)3]4 under the optimal reaction conditions, the yield of the end product was lower, both with 3-(1-adamantyl)-4-methoxyphenylboronic acid and 3-(1-adamantyl)-4-methoxyphenylboronic acid pinacol ester.
85% With sodium carbonate In tetrahydrofuran; waterInert atmosphere Step C. Catalytic coupling of 3-(1-adamantyl)-4-methoxyphenylboronic acid with 6-bromo-2-naphthoic acid ester according to Suzuki-MiyauraExample 10; In a 1 L double-necked flask, equipped with a stirrer, a reflux condenser and a gas inlet adapter is introduced 0.25 g (0.5 mol percent) of tris(dibenzylydeneacetone)dipalladium(0) Pd2(dba)3 and dissolved in 500 mL of tetrahydrofuran. Then 1 g (1 mol percent) of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (Sphos) is added and the solution stirred for 30 min under a slight stream or argon.To the reaction mixture 30 g (0.105 M) 3-(1-adamantyl)-4-methoxyphenylboronic acid and 25 g (0.094 M) methyl 6-bromo-2-naphthenoate is added and stirred until all components are dissolved. A solution of 30 g (0.28 M) of sodium carbonate in 150 mL of water is added. To complete the reaction, the mixture is vigorously stirred for 4 h with boiling under a slight stream of argon.After the completion the reaction mixture is cooled to room temperature and filtered without separating the layers. The precipitate constitutes the main portion of the product. The rest of the product is obtained by concentrating the organic layer to 1/4, cooling and filtering off the precipitate and combining with the main portion.The raw product is dissolved in 200 mL of dimethylacetamide, filtered hot, reduced to about 150 mL and left for 16 h at room temperature to crystallize.The voluminous crystals are filtered off and dried at 150-180° C. for 2 h. Methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthenoate, 34 g (85percent) with m.p. 222-225° C. is obtained.1H NMR (500 MHz, DMSO δ: 1.79 (s, 6H), 2.10 (s, 3H), 2.16 (s, 6H), 3.90 (s, 3H), 3.94 (s, 3H), 6.99 (d, 1H, J=8 Hz), 7.51 (s, 1H), 7.52 (d, 1H, J=8 Hz), 7.78 (d, 1H, J=9 Hz), 7.94 (d, 1H, J=9 Hz), 7.98-8.02 (m, 3H), 8.55 (s, 1H). Increasing the concentration of the catalyst to 5 mol percent shortens the reaction time to 0.5 h, but does not influence the yield of the end product. Reducing the quantity of the catalyst to 0.05 mol percent leads to increase of reaction time to 16 hours and drops the yield of methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthenoate to 76percent.Scaling up the synthesis 5 times under the optimal reaction conditions did not lower the yield and quality of methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthenoate.Methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthenoate can be prepared without separation and purification of 3-(1-adamantyl)-4-methoxyphenylboronic acid pinacol ester.
Reference: [1] Patent: US2010/160677, 2010, A1, . Location in patent: Page/Page column 5
[2] Patent: US2010/76219, 2010, A1, . Location in patent: Page/Page column 3-4
  • 8
  • [ 459423-32-6 ]
  • [ 33626-98-1 ]
  • [ 106685-41-0 ]
YieldReaction ConditionsOperation in experiment
92% With sodium carbonate In tetrahydrofuran; waterInert atmosphere; Reflux Step C. Catalytic Coupling of 3-(1-adamantyl)-4-methoxyphenyl-boronic Acid Derivatives with 6-bromo-2-naphtoic Acid Esters According to Suzuki-MiyauraEXAMPLE 12Into a 1 L flask with stirrer and reflux condenser 0.25 g (0.5 mol percent) of tris(dibenzylydeneacetone)dipalladium(0) [Pd2(dba)3] was dissolved in 500 mL of thetrahydrofuran, then 1 g (0.5 mol percent) of 2-dicyclohexyl-phosphino-2',6'-dimethoxybipheyl (Sphos) added and the resulting solution stirred under a slight stream of argon.To the reaction mixture was added 30 g (0.105 M) of 3-(1-adamantyl)-4-methoxyphenylboronic acid and 25 g (0.094 M) of methyl 6-bromo-2-naphtenoate and stirred until dissolved. The final component is a solution of 30 g (0.28 M) of sodium carbonate in 150 mL of water, prepared in advance, that is added to the reaction mixture in one portion.The process is carried on under vigorous stirring and reflux under a slight stream or argon.After the completion the reaction mixture is cooled to room temperature and filtered without separating the layers. The precipitate constitutes the main portion of the product. The rest of the product is obtained by concentrating the organic layer to 1/4, cooling and filtering off the precipitate. The raw product is dissolved in 200 mL of dimethylacetamide, filtered hot, reduced to about 150 mL and left for 16 h at room temperature for crystallization. The voluminous crystals are filtered off and dried at 150-180° C. for 2 h. Methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtenoate, 35.2-36.8 g (88-92percent) with m.p. 222-225° C. is obtained.NMR (500 MHz, DMSO D6)δ: 1.79 (s, 12H), 2.10 (s, 3H), 2.16 (s, 6H), 3.90 (s, 3H), 3.94 (s, 3H), 6.99 (d, 1H, J=8 Hz), 7.51 (s, 1H), 7.52 (d, 1H, J=8 Hz), 7.78 (d, 1H, J=9 Hz), 7.94 (d, 1H, J=9 Hz), 7.98-8.02 (m, 3H), 8.55 (s, 1H).Replacing 3-(1-adamantyl)-4-methoxyphenylboronic acid with its pinacol or ethylene glycol ester, or replacing tris(dibenzylydeneacetone)-dipalladium(0) [Pd2(dba)3] with palladium acetate (Pd(OAc)2), or using potassium carbonate or potassium phosphate as the basic agent does not substantially change the yield of methyl 6-[3-(1-adamantyl)-4-methoxy-phenyl]-2-naphtenoate.
Reference: [1] Patent: US2010/160677, 2010, A1, . Location in patent: Page/Page column 4-5
[2] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 151 - 158
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  • [ 74-88-4 ]
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Reference: [1] Patent: WO2007/383, 2007, A1, . Location in patent: Page/Page column 19; 20
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  • [ 1036766-57-0 ]
  • [ 33626-98-1 ]
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YieldReaction ConditionsOperation in experiment
86% With potassium carbonate In tetrahydrofuran; waterInert atmosphere; Reflux Step C. Catalytic Coupling of 3-(1-adamantyl)-4-methoxyphenyl-boronic Acid Derivatives with 6-bromo-2-naphtoic Acid Esters According to Suzuki-MiyauraEXAMPLE 12Into a 1 L flask with stirrer and reflux condenser 0.25 g (0.5 mol percent) of tris(dibenzylydeneacetone)dipalladium(0) [Pd2(dba)3] was dissolved in 500 mL of thetrahydrofuran, then 1 g (0.5 mol percent) of 2-dicyclohexyl-phosphino-2',6'-dimethoxybipheyl (Sphos) added and the resulting solution stirred under a slight stream of argon.To the reaction mixture was added 30 g (0.105 M) of 3-(1-adamantyl)-4-methoxyphenylboronic acid and 25 g (0.094 M) of methyl 6-bromo-2-naphtenoate and stirred until dissolved. The final component is a solution of 30 g (0.28 M) of sodium carbonate in 150 mL of water, prepared in advance, that is added to the reaction mixture in one portion.The process is carried on under vigorous stirring and reflux under a slight stream or argon.After the completion the reaction mixture is cooled to room temperature and filtered without separating the layers. The precipitate constitutes the main portion of the product. The rest of the product is obtained by concentrating the organic layer to 1/4, cooling and filtering off the precipitate. The raw product is dissolved in 200 mL of dimethylacetamide, filtered hot, reduced to about 150 mL and left for 16 h at room temperature for crystallization. The voluminous crystals are filtered off and dried at 150-180° C. for 2 h. Methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtenoate, 35.2-36.8 g (88-92percent) with m.p. 222-225° C. is obtained.NMR (500 MHz, DMSO D6)δ: 1.79 (s, 12H), 2.10 (s, 3H), 2.16 (s, 6H), 3.90 (s, 3H), 3.94 (s, 3H), 6.99 (d, 1H, J=8 Hz), 7.51 (s, 1H), 7.52 (d, 1H, J=8 Hz), 7.78 (d, 1H, J=9 Hz), 7.94 (d, 1H, J=9 Hz), 7.98-8.02 (m, 3H), 8.55 (s, 1H).Replacing 3-(1-adamantyl)-4-methoxyphenylboronic acid with its pinacol or ethylene glycol ester, or replacing tris(dibenzylydeneacetone)-dipalladium(0) [Pd2(dba)3] with palladium acetate (Pd(OAc)2), or using potassium carbonate or potassium phosphate as the basic agent does not substantially change the yield of methyl 6-[3-(1-adamantyl)-4-methoxy-phenyl]-2-naphtenoate.; EXAMPLE 13Reaction is performed as described in Example 12. As the boronic acid component 3-(1-adamantyl)-4-methoxyphenylboronic acid ethylene glycol ester is used, 33 g (0.105 M), as the basic agent-41 g (0.3 M) of potassium carbonate solution in 200 mL of water. Methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtenoate, 34.5 g (86percent) is obtained.
Reference: [1] Patent: US2010/160677, 2010, A1, . Location in patent: Page/Page column 5
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  • [ 22635-62-7 ]
  • [ 106685-41-0 ]
Reference: [1] Patent: US5015758, 1991, A,
  • 12
  • [ 768-95-6 ]
  • [ 106685-41-0 ]
Reference: [1] Journal of Medicinal Chemistry, 1995, vol. 38, # 26, p. 4993 - 5006
[2] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 151 - 158
[3] Patent: WO2007/125542, 2007, A2,
  • 13
  • [ 1036766-54-7 ]
  • [ 33626-98-1 ]
  • [ 106685-41-0 ]
Reference: [1] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 151 - 158
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  • [ 104224-68-2 ]
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Reference: [1] Journal of Medicinal Chemistry, 1995, vol. 38, # 26, p. 4993 - 5006
[2] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 151 - 158
[3] European Journal of Medicinal Chemistry, 2014, vol. 79, p. 251 - 259
[4] Patent: WO2007/125542, 2007, A2,
  • 15
  • [ 1036766-56-9 ]
  • [ 93353-66-3 ]
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Reference: [1] Russian Journal of General Chemistry, 2010, vol. 80, # 4, p. 870 - 871
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  • [ 106-41-2 ]
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Reference: [1] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 151 - 158
[2] Patent: WO2007/125542, 2007, A2,
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Reference: [1] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 151 - 158
[2] Catalysis Science and Technology, 2016, vol. 6, # 13, p. 4690 - 4694
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Reference: [1] European Journal of Medicinal Chemistry, 2014, vol. 79, p. 251 - 259
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Reference: [1] Catalysis Science and Technology, 2016, vol. 6, # 13, p. 4690 - 4694
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