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Chemical Structure| 33626-98-1
Chemical Structure| 33626-98-1
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Product Details of [ 33626-98-1 ]

CAS No. :33626-98-1 MDL No. :MFCD00100408
Formula : C12H9BrO2 Boiling Point : -
Linear Structure Formula :- InChI Key :JEUBRLPXJZOGPX-UHFFFAOYSA-N
M.W :265.10 Pubchem ID :854134
Synonyms :

Calculated chemistry of [ 33626-98-1 ]

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 10
Fraction Csp3 : 0.08
Num. rotatable bonds : 2
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 62.93
TPSA : 26.3 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.28 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.75
Log Po/w (XLOGP3) : 3.72
Log Po/w (WLOGP) : 3.39
Log Po/w (MLOGP) : 3.59
Log Po/w (SILICOS-IT) : 3.5
Consensus Log Po/w : 3.39

Druglikeness

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

Water Solubility

Log S (ESOL) : -4.19
Solubility : 0.0172 mg/ml ; 0.0000648 mol/l
Class : Moderately soluble
Log S (Ali) : -3.96
Solubility : 0.0288 mg/ml ; 0.000109 mol/l
Class : Soluble
Log S (SILICOS-IT) : -5.0
Solubility : 0.00263 mg/ml ; 0.00000993 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.33

Safety of [ 33626-98-1 ]

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 [ 33626-98-1 ]

* 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 [ 33626-98-1 ]
  • Downstream synthetic route of [ 33626-98-1 ]

[ 33626-98-1 ] Synthesis Path-Upstream   1~18

  • 1
  • [ 33626-98-1 ]
  • [ 5773-80-8 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: With lithium hydroxide monohydrate In tetrahydrofuran; water
Stage #2: With hydrogenchloride In tetrahydrofuran; water
General procedure: Compound 14 (4.58 g, 20 mmol) in 1:1 THF/H2O (200 mL) was treated with LiOH.H2O (4.2 g, 100 mmol), stirred overnight, and concentrated to a thick slurry and then treated with 2M HCl to pH = 3 and the precipitate was filtered, washed with water and dried under vacuum to provide 3.8 g (88percent) of 15 as a white powder
84% With potassium hydroxide In methanol at 50℃; for 8 h; A suspension of methyl 6-bromo-2-naphthoate (3b) (2.7 g, 10.0 mmol) and potassium hydroxide (1.1 g, 20.0 mmol) in methanol (50 mL) was vigorously stirred at 50 °C. The reaction mixture becomes homogeneous after the consumption of the initial compound 3b. After 8 h, the solvent was evaporated under reduced pressure (ca 2/3 vol.), water (1500 mL) was added and the unreacted ester extracted with ethyl acetate. The aqueous solution was acidified with 10percent H2SO4 to pH 3 and, after extraction with ethyl acetate (3 .x. 200 mL) and drying on anhydrous sodium sulfate, removal of the solvent afforded the pure acid 3a (2.1 g, 8.4 mmol, 84percent yield). Mp 290-294 °C (decomp.); HRMS (ESI+): m/z [M+1]+ Calcd for C11H8BrO2: 252.08591. Found: 252.08582. 1H NMR (DMSO-d6) δ = 7.72 (1 H, dd, J = 8.5 and 1.8 Hz, 7-naphthyl H), 7.99 (1 H, d, J = 8.6 Hz, 4-naphthyl H), 8.02 (1 H, dd, J = 8.6 and 1.4 Hz, 8-naphthyl H), 8.09 (1 H, d, J = 8.8 Hz, 3-naphthyl H), 8.30 (1 H, d, J = 1.6 Hz, 5-naphthyl H), 8.62 (1 H, s, 1-naphthyl H), 13.15 (1H, br. s, COOH); 13C NMR (125.76 MHz, DMSO-d6) δ = 121.93, 126.50, 127.61, 128.81, 129.83, 130.01, 130.64, 130.90, 131.63, 136.11, 167.30.
80%
Stage #1: With water; lithium hydroxide In tetrahydrofuran; ethanol at 50℃; for 16 h;
Stage #2: With hydrogenchloride In water
Example 176-BROMONAPHTHALENE-2-CARBOXYLIC ACID [(R)-1-(4-METHANESULFONYLAMINO-3-METHYLPHENYL)ETHYL]AMIDE 17A) 6-BROMONAPHTHALENE-2-CARBOXYLIC ACID To a stirred solution of 6-bromonaphthalene-2-carboxylic acid methyl ester (2 g, 8 mmol) in tetrahydrofuran (66 mL) and ethanol (22 mL) was added a solution of lithium hydroxide (542 mg, 22 mmol) in water (22 mL). The reaction was stirred at 50° C. for 16 hours. After cooling, the organic solvents were removed by evaporation, and the aqueous residue was diluted with water (100 mL) then washed with EtOAc (2.x.50 mL). The aqueous layer was acidified using 1N HCl and the products were extracted with EtOAc (3.x.50 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered and concentrated. Trituration with DCM gave the title compound (1.594 g, 80percent) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 7.74 (dd, 1H, J=8.7 Hz, 1.9 Hz), 7.99-8.04 (m, 2H), 8.10 (d, 1H, J=8.8 Hz), 8.32 (s, 1H), 8.64 (s, 1H).
70%
Stage #1: With lithium hydroxide; water In tetrahydrofuran at 20℃; for 48 h;
Stage #2: With hydrogenchloride; water In tetrahydrofuran at 0℃;
Part A. Preparation of 6-bromo-2 -naphthoic acid.; [00746] A solution of methyl 6-bromo-2-naphthoate (7.7Og, 29.0mmol) in 2:1 THF:water (15OmL) was treated with lithium hydroxide hydrate (2.44g, 58.1mmol) followed by stirring at room temperature for 48h. Concentrated under vacuum, diluted with water and cooled to O0C. Acidified to pH3 with 4N HCl. Solids were collected by filtration, dissolved in toluene-EtOAc (ca. 2L) and washed with brine. Dried over Na2SO4, filtered and concentrated under vacuum. Brown solid was triturated with ether, collected by filtration, and dried under vacuum to give the title compound as a nearly white solid (5.07g, 70percent).
70%
Stage #1: With lithium hydroxide; water In tetrahydrofuran at 20℃; for 48 h;
Stage #2: With hydrogenchloride In water at 0℃;
[00487] Example 1. Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IA-LO-2.9).; [00488] Part A. Preparation of 6-bromo-2 -naphthoic acid.; [00489] A solution of methyl 6-bromo-2-naphthoate (7.7Og, 29.0mmol) in 2:1 THF:water (15OmL) was treated with lithium hydroxide hydrate (2.44g, 58.1mmol) followed by stirring at room temperature for 48h. Concentrated under vacuum, diluted with water and cooled to O0C. Acidified to pH3 with 4N HCl. Solids were collected by filtration, dissolved in toluene-EtOAc (ca. 2L) and washed with brine. Dried over Na2SC^, filtered and concentrated under vacuum. Brown solid was triturated with ether, collected by filtration, and dried under vacuum to give the title compound as a nearly white solid (5.07g, 70percent).
70%
Stage #1: With lithium hydroxide monohydrate In tetrahydrofuran; water at 20℃; for 48 h;
Stage #2: With hydrogenchloride In tetrahydrofuran; water
Part H. Preparation of 6-bromo-2 -naphthoic acid.[00326] A solution of methyl 6-bromo-2-naphthoate (7.7Og, 29.0mmol) in 2: 1 tetrahydrofuran: water(150 mL) was treated with lithium hydroxide hydrate (2.44 g, 58.1 mmol) followed by stirring at room temperature for 48 hours. The mixture was concentrated under vacuum, diluted with water and cooled to 0 0C. The mixture was acidified to pH3 with 4 N HCl. Solids were collected by filtration, dissolved in toluene-ethyl acetate (ca. 2 L) and washed with brine. The organic layer was dried overNa2SO+, filtered and concentrated under vacuum. The brown solid was triturated with ether, collected by filtration, and dried under vacuum to give the title compound as a nearly white solid (5.07g, 70percent).
56% With potassium hydroxide In methanol at 50℃; for 48 h; Potassium hydroxide (127 mg, 2.26 mmol) was added to a suspension of methyl 6-bromo-2-naphthoate (200 mg, 0.75 mmol) in methanol (50 mL) and the mixture heated at 50 °C for 48 h. The solvent was evaporated and the residue diluted with water (30 mL), acidified with HCl (1 M) and the extracted with ethyl acetate (30 mL * 2). The combined organic layers were dried with anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The crude product was purified via recrystallization using ethyl acetate to give the product as white crystals (105 mg, yield 56percent). 1H NMR matched that previously reported. 1H NMR (400 MHz, CD3OD): δ 8.58 (s, 1H; Ar-H), 8.14 (s, 1H; Ar-H), 8.06 (dd, J = 1.8, 8.7 Hz, 1H; Ar-H), 7.92 (d, J = 8.7 Hz, 1H; Ar-H), 7.87 (d, J = 8.7 Hz, 1H; Ar-H), 7.64 (dd, J = 1.8, 8.7 Hz, 1H; Ar-H).

Reference: [1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 27, p. 7477 - 7486
[2] Organic and Biomolecular Chemistry, 2015, vol. 13, # 27, p. 7477 - 7486
[3] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 4, p. 1557 - 1568
[4] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 151 - 158
[5] Patent: US2012/88746, 2012, A1, . Location in patent: Page/Page column 47-48
[6] Patent: WO2009/39127, 2009, A1, . Location in patent: Page/Page column 174
[7] Patent: WO2009/39134, 2009, A1, . Location in patent: Page/Page column 103
[8] Patent: WO2010/111437, 2010, A1, . Location in patent: Page/Page column 73-74
[9] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 16, p. 4355 - 4367
  • 2
  • [ 67-56-1 ]
  • [ 5773-80-8 ]
  • [ 33626-98-1 ]
YieldReaction ConditionsOperation in experiment
100% Reflux 6-Bromo-2-naphthalenecarboxylic acid (2.4996 g, 10.0 mmol) was added50mL dried egg-shaped flask, add 20mL of anhydrous methanol to dissolve,Then 1 mL of concentrated sulfuric acid was slowly added dropwise and the system was refluxed overnight.TLC tracking until the conversion of raw materials is completed, stop heating,After cooling to room temperature, saturated aqueous sodium carbonate solution was added to quench the reaction.The reaction system was adjusted to neutrality, extracted with ethyl acetate,The organic phase is washed three times with anhydrous sodium sulfate.Concentration under reduced pressure afforded S7 (2.63 g, 100percent yield) as a white solid.
93% Reflux To a solution of 6-bromo-2-naphthoic acid (2.65 g, 10 mmol) in methanol 30 mL,concentrated sulfuric acid 1 mL was added drop wise. The reaction mixture was refluxed for 2 h, then added water 150 mL. The foliated crystal was collected thought filtration. Yield: 93percent;
26.4 g for 7 h; Reflux Reactor to 6-bromo-2-naphthalene carboxylic acid (T-1, manufactured by Tokyo Kasei Kogyo (Ltd.)) (25g, 99.6mmol), concentrated sulfuric acid (5.4ml, 99.6mmol), and methanol (80ml) It was placed. The mixture was stirred with heating under reflux for 7 hours. After cooling to room temperature, water was added to the reaction mixture and extracted with dichloromethane. Aqueous organic layers were washed with sodium carbonate, washed with water, then saturated brine, and dried over anhydrous magnesium sulfate. By concentrating the solution under reduced pressure to give compound (T-2) (26.4g, 99.6mmol) and. Compound (T-2) was used in the next reaction without purification.
Reference: [1] Tetrahedron, 2009, vol. 65, # 7, p. 1349 - 1360
[2] Journal of the American Chemical Society, 2008, vol. 130, # 50, p. 16836 - 16837
[3] Patent: CN107286150, 2017, A, . Location in patent: Paragraph 0153; 0154; 0155; 0156; 0157
[4] European Journal of Medicinal Chemistry, 2015, vol. 102, p. 277 - 287
[5] Patent: JP2016/37458, 2016, A, . Location in patent: Paragraph 0172; 0173
  • 3
  • [ 51934-38-4 ]
  • [ 74-88-4 ]
  • [ 33626-98-1 ]
Reference: [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 37, p. 12102 - 12105[2] Angew. Chem., 2018, vol. 130, p. 12278 - 12281,4
  • 4
  • [ 15231-91-1 ]
  • [ 33626-98-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 23, p. 2865 - 2870
  • 5
  • [ 67-56-1 ]
  • [ 201230-82-2 ]
  • [ 151600-02-1 ]
  • [ 33626-98-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 23, p. 2865 - 2870
  • 6
  • [ 123207-11-4 ]
  • [ 33626-98-1 ]
Reference: [1] Journal of Organic Chemistry, 1990, vol. 55, # 1, p. 319 - 324
  • 7
  • [ 33626-98-1 ]
  • [ 100751-63-1 ]
YieldReaction ConditionsOperation in experiment
99% With lithium aluminium tetrahydride In tetrahydrofuran at -10 - -5℃; for 1.33333 h; To a stirred 1.0 M solution of lithium aluminum hydride (108 ML, 108 mmol) was added dropwise over 20 min a solution of methyl 6-bromo-2-naphthoate (18.9 g, 71.3 mmol) in THF (180 ML), while maintaining the reaction temperature below -5° C.
When the addition was complete, the reaction mixture was stirred at -10° C. for 1 hr, then quenched by the sequential dropwise addition of distilled water (4 ML), 2 N aqueous Na2CO3 (4 ML), and distilled water (12 ML).After stirring for 15 min at room temperature, the reaction mixture was filtered.The filter cake was washed with ethyl acetate (3*100 ML) and the combined filtrates were dried (MgSO4) and filtered.This filtrate was concentrated under reduced pressure to give a white solid.Drying under vacuum overnight at 40° C. provided the product (16.84 g, 99percent yield). M.p. 149.9151.6° C. 1H NMR (CDCl3, 300 MHz) δ 7.99 (d, J=2 Hz, 1H), 7.79-7.67 (m, 3H), 7.55 (dd, J=2, 12 Hz, 1H), 7.52 (dd, J=2, 12 Hz, 1H), 4.85 (s, 2H). MS (DCl-NH3) [M+H]+ at 236.
95% With diisobutylaluminium hydride In tetrahydrofuran; hexane at 0 - 20℃; for 3 h; Methyl 6-bromo-2-naphthoate (5g, 18.9mmol) was dissolved in purified THF (10OmL) under a nitrogen atmosphere, the reaction solution was cooled down to 0°C, and then diisobutyl aluminum hydride (18.9mL, 1.0M hexane solution) was added thereto. The reaction mixture solution was stirred at room temperature for 3 hours. Sodium bicarbonate (2OmL) was added to the reaction mixture solution, and then the solvent was <n="14"/>removed by extraction with water and dichloromethane. The extracted material was dried in vacuum to thereby obtain a white solid (4.3g, yield: 95percent).
94.5%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 67℃; for 2 h;
Stage #2: With water In tetrahydrofuran at 0℃;
First, 200 g of 6-bromo-2-methyl naphthoate and 1500 ml of tetrahydrofuran were mixed in a reacting flask given a cool bath in a nitrogen atmosphere. In the cool bath, 21.5 g of lithium aluminium hydride was slowly added to the reacting flask to compose a mixture. The mixture was heated to 67° C., refluxed and stirred for two hours. Then, the mixture was bathed in cool water, and 100 g of water was added to the reacting flask to generate a white precipitation. The white precipitation was filtered out of the mixture and dried to obtain a white solid. The white solid was further mixed with water, stirred at room temperature, filtered and dried at 100° C. to obtain (6-bromo-2-naphthyl) methanol in a solid form. 169 g of the white solid was obtained (yield: 94.5percent).
90% With diisobutylaluminium hydride In tetrahydrofuran at -40 - 25℃; for 8 h; Inert atmosphere Methyl 6-bromo-2-naphthoate (12) (1.5 g, 5.66 mmol) was dissolved in anhydrous THF and cooled to -40 °C in CH3CN/dry ice bath. DIBAL-H (17 mL, 17 mmol) was added drop wise and the mixture left stirring at ambient temperature for 8 h. The mixture was then quenched using a saturated solution of NH4Cl (15 mL) followed by extraction with CH3Cl (100 mL * 2). The organic layers were combined, extracted with H2O (100 mL * 1), dried using anhydrous Na2SO4 and the solvent evaporated. Yield (1.194 g, 90percent). 1H NMR matched that previously reported. 40 1H NMR (500 MHz, acetone-d6) δ 8.07 (d, J = 1.7 Hz, 1H; Ar-H), 7.84-7.79 (m, 3H; Ar-H), 7.57-7.52 (m, 2H; Ar-H), 4.77 (s, 2H; O-CH2), 4.85 (bs, 1H; O-H).
88.3%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 1.5 h;
Stage #2: With water; sodium hydroxide In tetrahydrofuran
To a solution of LAH (22.8g, 0.6 mol) in THF (1000 mL) was added compound LXI-1 (53.2g, 0.2 mol in THF 1000 mL) dropwise at 0°C. The mixture was stirred for 1.5 h at room temperature, the mixture was quenched with water (22.8 mL) and aq. NaOH (10percent in water, 22.8 mL), then MgS04 (40 g ) was added. The resulting mixture was stirred for 1 h, filtered and concentrated to get compound LXI-2 (41.5g, yield: 88.3percent).
70.8% With lithium aluminium tetrahydride In tetrahydrofuran (6-Bromo-naphthalen-2-yl)-methanol (intermediate)
Methyl-6-bromo-2-naphtoate (25 g, 94.3 mmol) was reduced with lithiumaluminiumhydride (5.36 g, 141.4 mmol) in tetrahydrofuran (200 ml). The crystalline product was recrystalized from ethanol (96percent). Yield 15.84 g (70.8percent).
23.6 g With lithium aluminium tetrahydride In tetrahydrofuran at -10 - 0℃; for 2 h; Inert atmosphere Under a nitrogen atmosphere were placed lithium aluminum hydride to the reactor (5.67g, 149.4mmol) and THF with (100 ml), cooled with ice. There, it was obtained in the first step (T-2) (26.4g, 99.6mmol) and THF (100ml) solution then was dropped in the temperature range of -10 from 0 , and while returning to room temperature It was further stirred for 2 hours. The reaction mixture was ice-cooled, after which ethyl acetate (50ml) was added dropwise thereto in the temperature range of -10 from 0 ° C., 2N-poured into hydrochloric acid (300 ml), stirred for 15 minutes. After the layers were separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were washed with water, saturated aqueous sodium bicarbonate solution, washed sequentially with water, and saturated brine, and dried with anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to give compound (T-3) (23.6g, 99.6mmol). Compound (T-3) was used in the next reaction without purification.

Reference: [1] Patent: US2004/92521, 2004, A1, . Location in patent: Page/Page column 30
[2] Tetrahedron, 2009, vol. 65, # 7, p. 1349 - 1360
[3] Organic Process Research and Development, 2007, vol. 11, # 6, p. 1004 - 1009
[4] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1443 - 1446
[5] Patent: WO2008/91130, 2008, A1, . Location in patent: Page/Page column 11-12
[6] Angewandte Chemie - International Edition, 2014, vol. 53, # 13, p. 3436 - 3441[7] Angew. Chem., 2014, vol. 126, # 13, p. 3504 - 3509,6
[8] Patent: US2006/159953, 2006, A1, . Location in patent: Page/Page column 4
[9] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 16, p. 4355 - 4367
[10] Patent: WO2013/25733, 2013, A1, . Location in patent: Paragraph 0633
[11] Patent: WO2007/90886, 2007, A1, . Location in patent: Page/Page column 17
[12] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 5, p. 694 - 707
[13] Patent: WO2011/72257, 2011, A2, . Location in patent: Page/Page column 44-45
[14] Journal of the American Chemical Society, 2012, vol. 134, # 42, p. 17338 - 17341,4
[15] Journal of the American Chemical Society, 2012, vol. 134, # 42, p. 17338 - 17341
[16] Chemical Communications, 2015, vol. 51, # 1, p. 125 - 128
[17] Patent: JP2016/37458, 2016, A, . Location in patent: Paragraph 0172; 0174
  • 8
  • [ 33626-98-1 ]
  • [ 100751-63-1 ]
  • [ 170737-46-9 ]
YieldReaction ConditionsOperation in experiment
57% With diisobutylaluminium hydride In toluene at -78℃; Inert atmosphere Following related reports,24,25 solutions of methyl 6-bromo-2-naphthoate in toluene (12; 0.1M) and DIBAL-H in toluene (0.3M) were added via in-house built syringe pumps43 into 0.04in. internal diameter tubing at a rate of 25mL/min. Each solution was precooled to −78°C before mixing by submerging 1.6 feet of steel tubing into a dry ice/acetone bath. The solutions were mixed by meeting at a T-joint and the reactor length was 1.5in. long (0.04in. internal diameter PFA tubing) before being mixed at a different T-joint with saturated aqueous ammonium chloride. The retention time between mixing of the reagents and quenching of the reaction for the combined flow rate of 50mL/min was 37ms. The solutions were washed with diethyl ether to extract the organic material and concentrated under reduced pressure. The conversion of ester 12 and yields of alcohol 13 and aldehyde 14 were determined by both NMR and GC/MS. A variety of flow rates, reactor lengths, temperatures, and concentrations were screened, with the optimal conditions described above giving 93percent conversion of ester 12, 35percent yield of alcohol 12, and 57percent yield of aldehyde 14 (average of six experiments). The NMR data for the compounds matched those described earlier in this experimental section.
Reference: [1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 16, p. 4355 - 4367
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  • [ 106685-40-9 ]
Reference: [1] Patent: WO2008/126104, 2008, A2, . Location in patent: Page/Page column 10
  • 10
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Reference: [1] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 151 - 158
[2] European Journal of Medicinal Chemistry, 2014, vol. 79, p. 251 - 259
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Reference: [1] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 151 - 158
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  • [ 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
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  • [ 932033-57-3 ]
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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
  • 14
  • [ 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
  • 15
  • [ 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
  • 16
  • [ 1036766-57-0 ]
  • [ 33626-98-1 ]
  • [ 106685-41-0 ]
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
  • 17
  • [ 1036766-54-7 ]
  • [ 33626-98-1 ]
  • [ 106685-41-0 ]
Reference: [1] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 151 - 158
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  • [ 33626-98-1 ]
  • [ 106685-41-0 ]
Reference: [1] European Journal of Medicinal Chemistry, 2014, vol. 79, p. 251 - 259
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