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Chemical Structure| 536-25-4
Chemical Structure| 536-25-4
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Product Details of [ 536-25-4 ]

CAS No. :536-25-4 MDL No. :MFCD00017095
Formula : C8H9NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :VNQABZCSYCTZMS-UHFFFAOYSA-N
M.W : 167.16 Pubchem ID :10815
Synonyms :

Calculated chemistry of [ 536-25-4 ]

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 44.15
TPSA : 72.55 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.73 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.3
Log Po/w (XLOGP3) : 0.83
Log Po/w (WLOGP) : 0.77
Log Po/w (MLOGP) : 0.74
Log Po/w (SILICOS-IT) : 0.5
Consensus Log Po/w : 0.83

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.64
Solubility : 3.85 mg/ml ; 0.0231 mol/l
Class : Very soluble
Log S (Ali) : -1.94
Solubility : 1.94 mg/ml ; 0.0116 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.53
Solubility : 4.91 mg/ml ; 0.0294 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.26

Safety of [ 536-25-4 ]

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 [ 536-25-4 ]

* 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 [ 536-25-4 ]
  • Downstream synthetic route of [ 536-25-4 ]

[ 536-25-4 ] Synthesis Path-Upstream   1~20

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Reference: [1] Chemische Berichte, 1916, vol. 49, p. 16
  • 2
  • [ 122-51-0 ]
  • [ 536-25-4 ]
  • [ 924869-17-0 ]
Reference: [1] Organic Letters, 2010, vol. 12, # 15, p. 3567 - 3569
  • 3
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Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1915, vol. <2> 92, p. 265
  • 4
  • [ 64-18-6 ]
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  • [ 924869-17-0 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2008, vol. 45, # 4, p. 1187 - 1190
  • 5
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  • [ 134997-87-8 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1900, vol. 311, p. 168
[2] Justus Liebigs Annalen der Chemie, 1900, vol. 311, p. 168
  • 6
  • [ 99-42-3 ]
  • [ 536-25-4 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogen In methanol 4-Hydroxy-3-nitro-benzoic acid methyl ester (500 mg, 2.54 mmol) is dissolved in MEOH (10 mL), then 10percent palladium on carbon (50 mg of 50percent wet) is added, and the reaction is placed under 1 atm of H2 overnight. The mixture is filtered through CELITE# TO remove the catalyst and the filtrate is concentrated under reduced pressure to afford the sub-title compound (435 mg, >100percent) which is used without further purification. 'H NMR (300 MHz, DMSO-d6) 8 3.74 (s, 3H), 4.78 (br s, 2H), 6.70 (d, J= 8.2 Hz, 1H), 7.09 (DD, J = 2.1, 8.2 Hz, 1H), 7. 24 (d, J= 2.1 Hz, 1H),-10 (br s, 1H). APCI MS MLZ 168 [C8H9NO3 + H] +.
100% With hydrogen In ethanol for 2.75 h; Step 1. A solution of 4-hydroxy-3-nitro-benzoic acid methyl ester (5.0 g, 25.4 mmol) in ethanol (120 mL) was treated with 5percent palladium on active carbon (0.24 g, 2.3 mmol, 0.1 equiv.) and the flask was evacuated and placed under an hydrogen atmosphere. The mixture was stirred vigorously for 2 h and 45', the palladium was filtered off, washing extensively with ethanol. The solvent was removed in vacuo to yield 3-amino-4-hydroxy-benzoic acid methyl ester as a white solid, 4.2 g (100percent), MS (ISP): m/e=168.3 (M+H+.). This was used crude in the following reaction.
86% With ammonium formate In methanol; water at 20℃; for 0.666667 h; To a [2000ML] three-necked flask containing [3-NITRO-4-HYDROXY-BENZOIC] acid methyl ester [(43G,] 218mmol) in [MEOH] [(860ML] ; 20vols) was added palladium on carbon in water (2g in [10ML] of water). Ammonium formiate (68.76g, 5eq.) was added in a single portion under stirring. After 2 to 3 minutes a suspension was observed, and temperature rised from [20°C] to [30°C.] Ice bath was used to cool reaction mixture to [20°C] and the reaction was stirred at [20°C] for 40minutes until completion (no more yellow color). Reaction mixture was filtered on silica plug, rinsed with [MEOH,] and the filtrate was concentrated under vacuum to give a green oil which was taken up in ethyl acetate (400ml). The organic phase was washed twice with water, dried over [MGS04,] filtered and concentrated to give a cream solid m=31. 35g (86percent). LC-MS: M/Z ESI: 0.81 min, 168.37 [(M+1)]
74% With palladium 10% on activated carbon; hydrogen In methanolInert atmosphere; Schlenk technique A heterogeneous methanol solution (150 mL) of 10 (9.40 g, 48 mmol) and 10percent Pd/C (3.42 g) was stirred overnight under hydrogen atmosphere and the palladium catalysts were removed by Celite pad filtration. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography with hexane/ethyl acetate (2:1) to give 11 (6.31 g, 38 mmol, 74percent) as a white solid. 1H NMR data were in agreement with those reported in the literature[24]. 1H NMR (400 MHz; CDCl3): δ 7.46 (s, 1H), 7.42 (d, J = 8.2 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 3.87 (s, 3H); MS (ESI) m/z 168 [M + H]+, 190 [M + Na]+, 206 [M + K]+.

Reference: [1] Patent: WO2004/67529, 2004, A1, . Location in patent: Page 179
[2] Patent: US2007/191603, 2007, A1, . Location in patent: Page/Page column 25
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 13, p. 6201 - 6220
[4] Patent: WO2004/7491, 2004, A1, . Location in patent: Page 72-73
[5] Journal of Organometallic Chemistry, 2013, vol. 747, p. 189 - 194
[6] Patent: US6365736, 2002, B1, . Location in patent: Example 4
[7] Journal of Organic Chemistry, 2006, vol. 71, # 17, p. 6374 - 6381
[8] Letters in Drug Design and Discovery, 2012, vol. 9, # 6, p. 625 - 632
[9] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2004, vol. 43, # 10, p. 2243 - 2244
[10] Chemische Berichte, 1897, vol. 30, p. 991
[11] Patent: DE97334, , ,
[12] Die Fabrikation pharmazeutischer und chemisch-technischer Produkte <Berlin 1931>, S. 223,
[13] Justus Liebigs Annalen der Chemie, 1900, vol. 311, p. 55
[14] Journal of the Society of Chemical Industry, London, 1945, vol. 64, p. 212,214
[15] Journal of Heterocyclic Chemistry, 2008, vol. 45, # 4, p. 1187 - 1190
[16] Patent: US2008/305169, 2008, A1,
[17] Acta Poloniae Pharmaceutica - Drug Research, 2008, vol. 65, # 4, p. 449 - 455
[18] Patent: EP2172453, 2010, A1, . Location in patent: Page/Page column 15-16
[19] Patent: US2007/10670, 2007, A1, . Location in patent: Page/Page column 96
[20] ChemCatChem, 2017, vol. 9, # 19, p. 3743 - 3751
[21] Patent: WO2018/53157, 2018, A1, . Location in patent: Page/Page column 103; 104
[22] Patent: US2008/64871, 2008, A1, . Location in patent: Page/Page column 59
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  • [ 536-25-4 ]
YieldReaction ConditionsOperation in experiment
99% at 0 - 20℃; for 12 h; Heating / reflux A solution (0.2 M) of acetyl chloride (3.0 eq. ) in MeOH was prepared at 0 °C then allowed to warm to 20 °C. 3-amino-4-hydroxybenzoic acid (1.0 eq. ) was added and the mixture was heated under reflux for 12 h then cooled and concentrated in VACUO. The residue was triturated with H20 and dried to afford the title compound (99percent) as a solid. H NMR (300 MHz, DMSO-D6, 300 K) 8 3.83 (s, 3H), 7.15 (d, J 8.5 Hz, 1H), 7.79 (dd, J2. 1, 8. 5 Hz, 1H), 7.93 (d, J 2. 1 Hz, 1H), 11.65 (br s, 1H).
98% at 0 - 20℃; for 24 h; Hydrogen chloride (1.25M in Methanol, lOOmL) was placed in a reactor at 0°C. Then 3- amino-4-hydroxybenzoic acid (5g, 0.032mo1) was added in portions. The reaction mixture was stirred 5 minutes at 0°C and 24 hours at room temperature. The solvent was removed under reduced pressure and the crude was partitioned between ethyl acetate and satu-rated bicarbonate. The organics layer were combined, dried, filtered and the solvent was removed under reduced pressure to obtain the title compound as a solid (5.38g, 98percent), which was used in the next step without further purification.LRMS (m/z): 168 (M+1)+
57% at 55℃; for 48 h; 3-Amino-4-hydroxybenzoic acid (0.40 g, 2.61 mmol) was dissolved in anhydrous methanol (10 ml) and treated with TMSCl (0.75 ml, 5.94 mmol). The mixture was stirred at 55 °C for 2 days. After evaporation of the solvent, the obtained residue was purified by column chromatography on silica gel eluting with ethyl acetate (yield: 0.25 g, 1.50 mmol, 57percent, white solid). 0.20 g of the obtained methyl 3-amino-4-hydroxybenzoate, dissolved in anhydrous THF (10 ml), was mixed with TCDI (0.26 g, 1.46 mmol) under an inert atmosphere. The solution was stirred overnight at room temperature. After evaporation of the solvent the residue was treated with water (15 ml) and extracted with ethyl acetate (3 .x. 15 ml). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The remaining crude product was recrystallized from ethanol yielding 0.22 g (1.05 mmol, 88percent) of methyl 2-sulfanylbenzo[d]oxazole-5-carboxylate (21) as a brown solid. Mp: 203-205 °C.
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 5, p. 1314 - 1317
[2] Patent: WO2004/87714, 2004, A1, . Location in patent: Page 53
[3] Patent: WO2014/95920, 2014, A1, . Location in patent: Page/Page column 66
[4] European Journal of Organic Chemistry, 2011, # 1, p. 100 - 109
[5] Heterocycles, 2011, vol. 83, # 12, p. 2851 - 2856
[6] MedChemComm, 2014, vol. 5, # 4, p. 474 - 488
[7] European Journal of Medicinal Chemistry, 2004, vol. 39, # 3, p. 291 - 298
[8] European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 4419 - 4429
[9] CrystEngComm, 2011, vol. 13, # 24, p. 7207 - 7211
[10] Justus Liebigs Annalen der Chemie, 1900, vol. 311, p. 55
[11] Patent: DE97333, , ,
[12] Xenobiotica, 1995, vol. 25, # 5, p. 501 - 510
[13] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 14, p. 6724 - 6731
[14] Patent: US2009/176775, 2009, A1, . Location in patent: Page/Page column 29-30
[15] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 14, p. 4001 - 4013
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YieldReaction ConditionsOperation in experiment
95% at 20℃; for 16 h; To a solution [OF 3-AMINO-4-HYDROXYBENZOIC] acid [(100G,] 0. [65MOL)] in methanol (1. [5L)] was added [THIONYLCHLORIDE] (233g, 1. [96MOL)] drop-wise at [5-10°C] with stirring and allowed to reflux at [65°C] for 16h. Excess methanol and thionylchloride was distilled off and crude dissolved in ethylacetate [(500ML).] The organic layer was washed with 5percent aqueous [NAHC03] solution, water, brine and dried. The solvent was removed under vacuum to give methyl-3-amino-4-hydroxybenzoate [(105G,] 95percent).
Reference: [1] Patent: WO2004/7491, 2004, A1, . Location in patent: Page 75
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  • [ 536-25-4 ]
YieldReaction ConditionsOperation in experiment
99% at 0 - 20℃; for 12 h; Heating / reflux A solution (0.2 M) of acetyl chloride (3.0 eq) in MeOH was prepared at 0 °C then allowed to warm to 20 °C. 3-amino-4-hydroxybenzoic acid (1.0 eq) was added and the mixture was heated under reflux for 12 h then cooled and concentrated in vacuo. The residue was triturated with H20 and dried to afford the title compound (99 percent) as a solid. 'H NMR (300 MHz, DMSO-d6) S 3.83 (s, 3H), 7.15 (d, J 8. 5 Hz, 1H), 7.79 (dd, J 2. 1, J 8.5 Hz, 1H), 7.93 (d, J 2.1 Hz, 1H), 11.65 (br s, 1H)
Reference: [1] Patent: WO2005/34941, 2005, A1, . Location in patent: Page/Page column 19
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YieldReaction ConditionsOperation in experiment
51% for 0.5 h; 3-(dimethylamino)-4-hvdroxybenzoic acid: 3-Amino-4-hydroxybenzoic acid (459mg, 3 mmol) was dissolved in methanol (12ml) and toluene (36ml) was added. A 2.0M solution of (trimethylsilyl)diazomethane in hexanes (1.5ml, 3.0 mmol) was added dropwise and the mixture stirred for 0.5h. The reaction mixture was concentrated under vacuum and the residue purified by flash column chromatography on silica to afford methyl 3-amino-4-hydroxybenzoate as a pink solid (254mg, 51percent).A buffer solution at pH 5.5 was prepared by the addition of acetic acid to a 1M aqueous sodium acetate solution. Methyl 3-amino-4-hydroxybenzoate (254mg, 1.5 mmol) was dissolved in a mixture of buffer (1ml) and methanol (2ml). Formaldehyde solution (37percent by weight in water; 0.75ml, lOmmol) was added, the mixture stirred for 15 minutes, and then sodium cyanoborohydride (283mg, 4.5mmol) was added portionwise. The reaction mixture was stirred for an additional 0.5h and then concentrated. The residual oil was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with water, brine and dried over sodium sulfate. The solvent was removed and the crude product was purified by flash column chromatography on silica to give methyl 3-dimethylamino-4-hydroxybenzoate as a yellow gum (213mg, 73percent).To a solution of methyl 3-dimethylamino-4-hydroxybenzoate (210mg, 1.1 mmol) in 1,4-dioxane (2ml) was added 1 M LiOH (aq) (4mmol). After stirring for 4Oh, the mixture was acidified to pH 2 by addition of 1 M HCI (aq). The mixture was partitioned between water and ethyl acetate, and the aqueous layer was lyophilized to give a mixture of sodium chloride and 3-dimethylamino-4- hydroxybenzoic acid as a brown semi-solid (378mg). The crude material was used in the subsequent reaction.
51% for 0.5 h; 4.14 3-(dimethylamino)-4-hvdroxybenzoic acid; 3-Amino-4-hydroxybenzoic acid (459 mg, 3 mmol) was dissolved in methanol (12 ml) and toluene (36 ml) was added. A 2.0 M solution of (trimethylsilyl)diazomethane in hexanes (1.5 ml, 3.0 mmol) was added dropwise and the mixture stirred for 0.5h. The reaction mixture was concentrated under vacuum and the residue purified by flash column chromatography on silica to afford methyl 3-amino-4-hydroxybenzoate as a pink solid (254 mg, 51 percent).
Reference: [1] Patent: WO2006/64286, 2006, A1, . Location in patent: Page/Page column 98
[2] Patent: WO2007/144379, 2007, A1, . Location in patent: Page/Page column 43
[3] Patent: WO2007/70173, 2007, A2, . Location in patent: Page/Page column 92-93
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Reference: [1] Journal of Organic Chemistry, 2006, vol. 71, # 17, p. 6374 - 6381
[2] Journal of Organometallic Chemistry, 2013, vol. 747, p. 189 - 194
[3] Patent: US2008/64871, 2008, A1,
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Reference: [1] Heterocycles, 2004, vol. 64, p. 193 - 198
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Reference: [1] Archiv der Pharmazie, 2008, vol. 341, # 6, p. 386 - 392
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  • [ 1571-72-8 ]
Reference: [1] Journal of the Society of Chemical Industry, London, 1945, vol. 64, p. 212,214
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YieldReaction ConditionsOperation in experiment
73% With potassium carbonate In N,N-dimethyl-formamide at 70℃; Step 2. A solution of 3-amino-4-hydroxy-benzoic acid methyl ester (4.2 g, 25.4 mmol) in dimethylformamide (85 mL) was treated with K2CO3 (14.2 g, 102.9 mmol, 4 equiv.) and 1,2-dibromoethane (19.3 g, 102.9 mmol, 4 equiv.). The mixture was stirred at 70° C. overnight, then filtered to remove the solids. The filtrate was removed under vacuo, and the residue was purified by flash chromatography (heptane/ethyl acetate gradient) to yield 3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, 3.65 g (73percent) as a light yellow solid, MS (ISP): m/e=235.1 (M+CH3CN+.); δH (300 MHz; CDCl3) 7.36 (1H, dd, J=8.5, 2.0), 7.30 (1H, d, J=2.0), 6.78 (1H, d, J=8.5), 4.30 (2H, m); 3.85 (3H, s), 3.43 (2H, m).
Reference: [1] Patent: US2007/191603, 2007, A1, . Location in patent: Page/Page column 25
[2] Patent: US2009/176775, 2009, A1, . Location in patent: Page/Page column 30
[3] Patent: EP2172453, 2010, A1, . Location in patent: Page/Page column 15-16
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Reference: [1] Patent: US2008/64871, 2008, A1,
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YieldReaction ConditionsOperation in experiment
84.1%
Stage #1: With oxalyl dichloride In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 1 h;
Stage #2: With pyridine In tetrahydrofuran; N,N-dimethyl-formamide at 20℃;
Comparative Example 1
Preparation of 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester
4-Adamantan-1-yl-phenoxy acetic acid (143.2 mg, 0.5 mmol) was dissolved in 5 ml of THF and oxalyl chloride (178.5 mg, 0.11 ml, 1.5 mmol), to which DMF was added.
After reacting the mixture at room temperature for 1 hour, 3-amino-4-hydroxy-benzoic acid methyl ester (125.4 mg, 0.75 mmol) and pyridine (0.05 ml) were added thereto.
The reaction mixture was reacted at room temperature.
Upon completion of the reaction, the reaction mixture was extracted with ethylacetate and NaCl solution, thereafter the organic layer was dried over anhydrous MgSO4, and concentrated.
The residue was purified by silicagel column chromatography (N-Hexane: EtOAc:MeOH=6:3:1) to give the target compound as a white solid (183.2 mg, yield: 84.1percent).
1H-NMR (DMSO-d6, 300 Hz) 11.10 (1H, s, OH), 9.24 (1H, s, NH), 8.69 (1H, m, aromatic-H), 7.60-7.64 (1H, m, aromatic-H), 7.30 (2H, d, J=8.4 Hz, aromatic-H), 6.94-6.99 (3H, m, aromatic-H), 4.74 (2H, s, CH2), 3.79 (3H, s, CH3), 2.04 (3H, m, adamantly-H), 1.83 (6H, m, adamantly-H), 1.72 (6H, m, adamantly-H)
84.1%
Stage #1: With oxalyl dichloride In tetrahydrofuran at 20℃; for 1 h;
Stage #2: With pyridine In tetrahydrofuran at 20℃;
4-Adamantan-1-yl-phenoxy)-acetic acid (143.2 mg, 0.5-mmol) was dissolved in THF (5 mL), and oxalyl chloride (178.5 mg, 0.11 mL, 1.5 mmol) and one drop of DMF were added to the solution.
After the mixture was stirred for 1 h at room temperature, 3-amino-4-hydroxy-benzoic acid methyl ester (125.4 mg, 0.75 mmol) and pyridine (0.05 mL) were added, and the resulting.
Solution was stirred at room temperature overnight, and then partitioned between ethyl acetate and 10percent HCl.
The organic phase was washed with brine, dried (MgSO4-anh), and concentrated.
The residue was purified by (n-Hexane:Ethyl acetate:MeOH=6:3:1) to give 3-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester as a white solid (183.2 mg, 84.1percent yield).
1H-NMR (DMSO-d6, 300 Hz) 11.10 (1H, s, OH), 9.24 (1H, s, NH), 8.69 (1H, m, aromatic-H), 7.60-7.64 (1H, m, aromatic-H), 7.30 (2H, d, J=8.4 Hz, aromatic-H), 6.94-6.99 (3H, m, aromatic-H), 4.74 (2H, s, CH2), 3.79 (3H, s, CH3), 2.04 (3H, m, adamantly-H), 1.83 (6H, m, adamantly-H), 1.72 (6H, m, adamantly-H).
80% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; N,N-diethylaniline In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Schlenk technique General procedure: A mixture of 5 (846 mg, 3.0 mmol), 11 (869 mg, 5.2 mmol), EDCI (997 mg, 5.2 mmol), HOBt (796 mg, 5.2 mmol), DIPEA (0.89 mL, 5.2 mmol) was dissolved DMF (5 mL) and stirred at room temperature overnight. The reaction was quenched by 1 N of HCl solution and the reaction mixture was extracted with ethyl acetate, neutralized with saturated aqueous NaHCO3 solution, washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated. The resulting solid was washed with cold methanol to afford 6 (939 g, 2.2 mmol, 73percent) as a white solid. This solid compound was pure enough to perform the next step:
Reference: [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 7, p. 1675 - 1684
[2] Patent: US2013/237542, 2013, A1, . Location in patent: Paragraph 0216; 0217; 0218
[3] Patent: US2009/306078, 2009, A1, . Location in patent: Page/Page column 26
[4] Journal of Organometallic Chemistry, 2013, vol. 747, p. 189 - 194
[5] Journal of Medicinal Chemistry, 2014, vol. 57, # 22, p. 9522 - 9538
[6] Angewandte Chemie - International Edition, 2013, vol. 52, # 39, p. 10286 - 10289[7] Angew. Chem., 2013, vol. 125, # 39, p. 10476 - 10479
[8] Journal of Medicinal Chemistry, 2017, vol. 60, # 20, p. 8631 - 8646
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YieldReaction ConditionsOperation in experiment
84.1%
Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 20℃; for 1 h;
Stage #2: With pyridine In tetrahydrofuran at 20℃;
10 <Example 18>3-[2-(4-Adamantan-l-yl-phenoxy)-aceryl-amino]-4-hydroxy-benzoic acidmethyl ester. (4-Adamantan-l-yl-phenoxy)-acetic acid (143.2. mg,.0.5_mmol) was dissolved in THE (5 mL),.and. oxalyl chloride (178.5 mg, 0.11 mL, 1.5 mmol) and one drop of DMF were added to the solution. After the mixture was stirred for Ih at room temperature, 3-amino-4-hydroxy-benzoic acid methyl ester (125.4 mg, 0.7515 mmol) and pyridine (0.05 mL) were added, and the resulting. Solution was stirred at room temperature overnight^ and then partitioned between ethyl acetate and 10percent HCl. The organic phase was washed with brine, dried (MgSψ4 anh), and concentrated. The residue was purified by (n-Hexane:Ethyl acetatMeOH = 6:3: 1) to give 3-[2- (4-Adamantan-l-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester as a white solid (1832 mg, 84.1percent yield). ' 20 1H-NMR (DMSO-dg, 300 Hz) 11.10 (IH, s, OH), 9.24 (IH, s,NH), 8.69 (IH, m, aromatic-H), 7.60 -7.64 (IH, m, aromatic-H), 7.30 (2H, d, J = 8.4 Hz, aromatic-H), 6.94 - 6.99 (3H, m, aromatic-H), 4.74 (2H, s, CH2), 3.79 (3H, s, CH3), 2.04 (3H, m, adamantly-H), 1.83 (6H, m, adamantly-H), 1.72 (6H, m, adamantly-H).
Reference: [1] Patent: WO2008/4798, 2008, A1, . Location in patent: Page/Page column 30
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Reference: [1] Patent: WO2012/53768, 2012, A2, . Location in patent: Page/Page column 14-15
  • 20
  • [ 536-25-4 ]
  • [ 136663-38-2 ]
Reference: [1] Patent: US2015/315198, 2015, A1,
Same Skeleton Products
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Pharmaceutical Intermediates of
[ 536-25-4 ]

Afatinib Intermediates

Chemical Structure| 314771-88-5

[ 314771-88-5 ]

(S)-N-(3-Chloro-4-fluorophenyl)-6-nitro-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4-amine

Chemical Structure| 3095-95-2

[ 3095-95-2 ]

2-(Diethoxyphosphoryl)acetic acid

Chemical Structure| 162012-67-1

[ 162012-67-1 ]

N-(3-Chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine

Chemical Structure| 314771-76-1

[ 314771-76-1 ]

(S)-N4-(3-Chloro-4-fluorophenyl)-7-((tetrahydrofuran-3-yl)oxy)quinazoline-4,6-diamine

Chemical Structure| 767-00-0

[ 767-00-0 ]

4-Hydroxybenzonitrile

Related Functional Groups of
[ 536-25-4 ]

Aryls

Chemical Structure| 63435-16-5

[ 63435-16-5 ]

Methyl 4-amino-3-hydroxybenzoate

Similarity: 0.96

Chemical Structure| 24812-90-6

[ 24812-90-6 ]

Methyl 3-amino-4-methoxybenzoate

Similarity: 0.95

Chemical Structure| 2840-26-8

[ 2840-26-8 ]

3-Amino-4-methoxybenzoic acid

Similarity: 0.92

Chemical Structure| 67973-80-2

[ 67973-80-2 ]

Methyl 3-amino-5-hydroxybenzoate

Similarity: 0.91

Chemical Structure| 5121-34-6

[ 5121-34-6 ]

Methyl 2-amino-3-methoxybenzoate

Similarity: 0.90

Esters

Chemical Structure| 63435-16-5

[ 63435-16-5 ]

Methyl 4-amino-3-hydroxybenzoate

Similarity: 0.96

Chemical Structure| 24812-90-6

[ 24812-90-6 ]

Methyl 3-amino-4-methoxybenzoate

Similarity: 0.95

Chemical Structure| 67973-80-2

[ 67973-80-2 ]

Methyl 3-amino-5-hydroxybenzoate

Similarity: 0.91

Chemical Structure| 5121-34-6

[ 5121-34-6 ]

Methyl 2-amino-3-methoxybenzoate

Similarity: 0.90

Chemical Structure| 42753-75-3

[ 42753-75-3 ]

Methyl 5-amino-2-hydroxybenzoate

Similarity: 0.90

Amines

Chemical Structure| 63435-16-5

[ 63435-16-5 ]

Methyl 4-amino-3-hydroxybenzoate

Similarity: 0.96

Chemical Structure| 24812-90-6

[ 24812-90-6 ]

Methyl 3-amino-4-methoxybenzoate

Similarity: 0.95

Chemical Structure| 2840-26-8

[ 2840-26-8 ]

3-Amino-4-methoxybenzoic acid

Similarity: 0.92

Chemical Structure| 67973-80-2

[ 67973-80-2 ]

Methyl 3-amino-5-hydroxybenzoate

Similarity: 0.91

Chemical Structure| 5121-34-6

[ 5121-34-6 ]

Methyl 2-amino-3-methoxybenzoate

Similarity: 0.90