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Chemical Structure| 623-04-1
Chemical Structure| 623-04-1
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Product Details of [ 623-04-1 ]

CAS No. :623-04-1 MDL No. :MFCD00014782
Formula : C7H9NO Boiling Point : -
Linear Structure Formula :- InChI Key :AXKGIPZJYUNAIW-UHFFFAOYSA-N
M.W : 123.15 Pubchem ID :69331
Synonyms :

Calculated chemistry of [ 623-04-1 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.14
Num. rotatable bonds : 1
Num. H-bond acceptors : 1.0
Num. H-bond donors : 2.0
Molar Refractivity : 36.97
TPSA : 46.25 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.21 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.28
Log Po/w (XLOGP3) : -0.22
Log Po/w (WLOGP) : 0.62
Log Po/w (MLOGP) : 0.88
Log Po/w (SILICOS-IT) : 0.98
Consensus Log Po/w : 0.71

Druglikeness

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

Water Solubility

Log S (ESOL) : -0.89
Solubility : 15.8 mg/ml ; 0.128 mol/l
Class : Very soluble
Log S (Ali) : -0.29
Solubility : 62.6 mg/ml ; 0.508 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.82
Solubility : 1.86 mg/ml ; 0.0151 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 623-04-1 ]

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

Application In Synthesis of [ 623-04-1 ]

* 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 [ 623-04-1 ]
  • Downstream synthetic route of [ 623-04-1 ]

[ 623-04-1 ] Synthesis Path-Upstream   1~14

  • 1
  • [ 623-04-1 ]
  • [ 108-24-7 ]
  • [ 16375-88-5 ]
YieldReaction ConditionsOperation in experiment
98% at 20℃; for 0.2 h; Green chemistry General procedure: In a round-bottomed flask (25 mL) equipped with a magnetic stirrer, a mixture of aniline (0.093 g, 1 mmol) and Co3O4 (0.006 g) was prepared. Acetic anhydride (0.102, 1 mmol) was then added to the reaction mixture and stirring was continued at room temperature for 3 min. The progress of the reaction was followed by TLC. After the reaction completion, the products was extracted with EtOAc and filtered to remove Co3O4. The organic solvent was then washed with H2O (2 x 10 mL) and saturated NaHCO3 solution and then dried over anhydrous Na2SO4. The solvent was removed under vacuum to afford the pure product.
91% at 20℃; for 0.1 h; General procedure: Alcohol, phenol, and/or amine (1 mmol) were added to amixture of the ZnAl2O4SiO2 nanocomposite (100 mg) andacetic anhydride (1 mmol). The mixture was stirred at 75 °C(for alcohols and phenols) or at room temperature (for amines)for a time. The progress of the reaction was monitored by TLCand/or GC‐MS. When the reaction was completed, ethyl acetate(10 mL) was added and the mixture was filtered to separate offthe catalyst. The catalyst was washed twice with 7.5 mL ethylacetate. The combined organic phases were washed with a10percent solution of NaHCO3 and then dried over MgSO4. The solventwas removed to yield the product. If further purificationwas needed, the product was passed through a short column ofsilica gel. All products were characterized on the basis ofGC‐MS, FT‐IR, and 1H‐NMR spectral data by comparing thesespectra with those of standard samples or literature data.
91% at 50℃; for 0.15 h; General procedure: In a round-bottom flask (10 mL) equipped with a magnetic stirrer, a mixture of PhNH2(1 mmol, 0.093 g) and H2O(3 mL) in oil bath (50 °C) was prepared. Magnetically recyclable nanoparticles of Fe3O4/Cu (0.05 mmol) was then added, and the mixture was stirred for 1 min under oil bath conditions. Addition of Ac2O(1 mmol, 0.102 g) to the prepared mixture was followed by stirring for 3 min at 50 °C. After completion of the reaction, the copper nanocatalyst was separated by an external magnet and the mixture was extracted with EtOAc (3 × 8 mL). Organic layers were then dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure affords the pure acetanilide in 95percent yield (0.128 g, Table 2, entry 1).
Reference: [1] Research on Chemical Intermediates, 2017, vol. 43, # 1, p. 413 - 422
[2] Chinese Journal of Catalysis, 2014, vol. 35, # 3, p. 368 - 375
[3] Journal of the Iranian Chemical Society, 2017, vol. 14, # 11, p. 2467 - 2474
[4] Applied Catalysis A: General, 2010, vol. 382, # 2, p. 293 - 302
[5] Journal of the Iranian Chemical Society, 2014, vol. 11, # 4, p. 1103 - 1112
[6] Journal of Organic Chemistry, 2001, vol. 66, # 26, p. 8815 - 8830
[7] Journal of Organic Chemistry, 2012, vol. 77, # 21, p. 9553 - 9561
[8] Journal of Organic Chemistry, 2018, vol. 83, # 5, p. 2542 - 2553
[9] Chemistry of Materials, 2011, vol. 23, # 21, p. 4844 - 4856
[10] Journal of the American Chemical Society, 2016, vol. 138, # 17, p. 5568 - 5575
  • 2
  • [ 623-04-1 ]
  • [ 10387-40-3 ]
  • [ 16375-88-5 ]
Reference: [1] ACS Catalysis, 2016, vol. 6, # 3, p. 1732 - 1736
  • 3
  • [ 78981-72-3 ]
  • [ 124-38-9 ]
  • [ 623-04-1 ]
  • [ 13734-28-6 ]
  • [ 100-01-6 ]
Reference: [1] Journal of Medicinal Chemistry, 1981, vol. 24, # 5, p. 479 - 480
  • 4
  • [ 24424-99-5 ]
  • [ 623-04-1 ]
  • [ 144072-29-7 ]
YieldReaction ConditionsOperation in experiment
100% With N-ethyl-N,N-diisopropylamine In tetrahydrofuranHeating / reflux To a solution of p-amino-benzylalcohol (1 g, 8.12 mmol, 1 eq) in 80 mL of anhydrous THF were added DIEA (1.4 mL, 8.12 mmol, 1 eq) and BoC2O (1.9 mL, 8.12 mmol, 1 eq). The mixture was heated to reflux overnight, then cooled down and evaporated under vacuum. The residue was dissolved in EtOAc. The organic layer was washed with a 0.1 N HCl solution, dried over MgSO4, filtered and evaporated under vacuum. The crude product was purified by <n="74"/>column chromatography on silica gel (Hex-EtOAc, 1:1, v/v) to give 1.85 g of product (quantitative yield): 1H NMR δ 0.1.49 (9H, s), 2.17 (IH, s), 4.53 (2H5 s), 6.83 (IH, s), 7.19 (2H, d, J = 8.5 Hz), 7.28 (2H, d, J = 8.2 Hz); 13 C NMR δ 28.28, 64.54, 80.37, 118.49, 127.59, 135.31, 137.46, 152.72.
98% for 18 h; To a 250 mL round bottom flask was added (4-amino-phenyl)-methanol (4.13 g, 33.6 mmol), dichloromethane (50 mL) followed by di-tert-butyl dicarbonate (8.5 g, 36.9 mmol). The mixture was allowed to stir for 18 h under a nitrogen atmosphere. By TLC, a small amount of starting amine remained, which reacted during concentration by rotary evaporation. The product was purified by column chromatography (ethyl acetate : hexanes, 1:1) to yield (4- hydroxymethyl-phenyl)-carbamic acid tert-butyl ester (7.36 g, 33.0 mmol, 98 percent) as a white solid.
98% at 80℃; for 0.166667 h; Green chemistry General procedure: The reactions were carried out in a 50 mL RB flask under reduced pressure for 10 min at 80°C unless reported differently. In a typical experiment, 5 mmol of amine was added to 5 mmol of BOC anhydride, and the reaction was allowed to proceed for 10 min. The desired product was obtained in a rotary evaporator under vacuum conditions.
87% With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 1.5 h; PREPARATION 15; Preparationof teri-buty\\ 4-(chloromethyl)phenylcarbamate; A. To a stirred solution of 4-aminobenzyl alcohol ( 1.50 g. 12.18 mmol) in 1.4-dioxane (30 mL) was added sodium hydroxide (0.49 g. 12.2 mmol) in water (30 mL). The mixture was cooled to 0 0C. and di-/1H NMR (300 MHz. CDCl3) δ 7.37-7.26 (m. 4H). 6.52 (br s. I H). 4.63 (s, 2H). 1.52 (s. 9H); MS (ES+) m/z 246.3 (M + 23).
83% With triethylamine In tetrahydrofuran at 20 - 50℃; A i00-mL, three-necked, round-bottomed flask, was equipped with a magnetic stimng bar, a retlux condenser, and a pressure-equalizing dropping funnel that was connected to a nitrogen flow line and charged with a solution of 97percent di-tert-butyl dicarbonate (4.04 g, 18.5 nimol) in tetralydrofuran (30 mid). Amino benzyi alcohol (2.5 g, 20.3 mmol) was placed in the flask and suspended in tetrahydrofuran (65 mL) and 99percent triethylamine (3.1 mL, 22 mmoi). The resultmg white suspension was cooled with an ice-water bath and the solution of di-tert-butyl dicarbonate was added dropwise over a period of 30 minutes. After 10 mm of additional stirring, the ice-water bath was removed and the suspension was stirred overnight at room temperature, then warmed at 50°C for a further 3 hours. T he solvent was removed tinder reduced pressure and the residue partitioned between EtOAc (50 mL) and saturated aqueous bicarbonate solution (50 mL). The aqueous phase was extracted with three 50-ni. portions of EtOAc. The combined organic phases were dried with anhydrous MgSO4 and concentrated under reduced pressure to give 3.72 g (83percent yield) of the product as a brown oil that was used without further purification. ‘H NMR (as rotamers) (400 MHz, CDCh) 6 9.26 (s, I H), 8.64 (s, iH), 7.39 (.4H), 7.20 (4H), 5,75 (s, 1H), 5.05 (2H), 4.49 —4.35 (m, 4H), i.47 (s, 9H), 1.40 (s, 1H).
82% With triethylamine In 1,4-dioxane at 20℃; Intermediate 10: tert-butyl 4-(hydroxymethyl)phenylcarbamateTo a solution of p-aminobenzyl alcohol (38,2 mmol) in 100 ml dioxane were added triethylamine (114 mmol) and di-tert-butyldicarbonate (42,0 mmol) was added in portions. The mixture was stirred overnight at room temperature. The solvent was evaporated. EtOAc was added and washed with 2N HCI, saturated NaHCO3 and brine solution. The organic layer was dried over Na2SO4 and evaporated to yield a brown oil.Yield: 82 percent, MS (ESI) m/z 224.3 [M+H]1H-NMR (ODd3, 400 MHz) 51.54 (s, 9H), 4.65 (s, 2H), 6.54 (s, 1H), 7.22-7.43 (m, 4H).
74% With acetic acid In tetrahydrofuran; water at 20℃; for 18 h; Inert atmosphere tert-Butyl (4-(hydroxymethyl)phenyl)carbamate 19. To a solution of ra-aminobenzyl alcohol (0.123 g, 0.0999 mmol) in AcOH (10percent in water, 8 mL) was added a solution of di-feri-butyl dicarbonate in THF (1 M, 1.05 mL, 1 .05 mmol), and the reaction was stirred for 18 h at ambient temperature. Water (30 mL) was added, and the mixture was basified with a NaOH solution (2 M) to pH 14. The resulting mixture was extracted with Et20 (3 χ 30 mL). The combined organic layer was washed with water (2 x 1 5 mL), dried over Na2S04, filtered, and concentrated under reduced pressure to afford boc-protected aminobenzyl alcohol 19 (0.166 g, 0.743 mmol, 74percent yield) as a light yellow solid. [000219] NMR (600 MHz, CDC13) δ 7.34 (2H, d, J = 8.0 Hz), 7.28 (2H, d, J = 8.4 Hz), 4.62 (2H, s), 1 .52 (9H, s). [000220] 13C NMR (150 MHz, CDC13) δ 152.9, 138.0, 135.6, 128.0, 1 18.7, 65.1 , 31.3, 28.5. [000221] HRMS: Obsvd 246.1 102 [M + Na]+, Calcd for C12H17NNa03: 246.1 101.
59% With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; To a solution of (4-aminophenyl)methanol (30, 8.0 g, 65.0 mmol) in THF (50 mL) were added Boc2O (21.3 g, 97.5 mmol) and DIEA (16.8 g, 130.0 mmol) at rt, and the resulting mixture was refluxed overnight. The reaction mixture was concentrated and purified by column chromatography (silica gel, eluted with 1:10 MeOH/DCM) to yield 31 (8.6 g, 59percent) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 1.53 (9H, s), 4.54 (2H, s), 7.26 (2H, d, J = 8.4 Hz), 7.38 (2H, d, J = 8.4 Hz). MS (API): m/z 206.0 (M + H - H2O)+.

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[2] Patent: WO2006/31806, 2006, A2, . Location in patent: Page/Page column 99
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[5] Journal of Medicinal Chemistry, 1992, vol. 35, # 22, p. 4150 - 4159
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[7] Patent: WO2008/127349, 2008, A2, . Location in patent: Page/Page column 103
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[9] Patent: WO2015/144933, 2015, A1, . Location in patent: Page/Page column 33; 34
[10] Patent: WO2017/66668, 2017, A1, . Location in patent: Paragraph 000218-000221
[11] Tetrahedron Letters, 2010, vol. 51, # 33, p. 4371 - 4374
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[13] Journal of Medicinal Chemistry, 2015, vol. 58, # 23, p. 9354 - 9370
[14] Journal of Medicinal Chemistry, 1989, vol. 32, # 4, p. 811 - 826
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[17] Patent: US2004/157900, 2004, A1, . Location in patent: Page 5
[18] Patent: US2003/153752, 2003, A1,
[19] Patent: US2003/153752, 2003, A1,
[20] Patent: US2004/77646, 2004, A1, . Location in patent: Page 93
[21] Chemistry of Materials, 2011, vol. 23, # 21, p. 4844 - 4856
[22] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3614 - 3622
  • 5
  • [ 34619-03-9 ]
  • [ 623-04-1 ]
  • [ 144072-29-7 ]
Reference: [1] Patent: EP2123637, 2009, A1, . Location in patent: Page/Page column 75
  • 6
  • [ 623-04-1 ]
  • [ 239074-27-2 ]
Reference: [1] Journal of Medicinal Chemistry, 1989, vol. 32, # 4, p. 811 - 826
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 23, p. 9354 - 9370
  • 7
  • [ 623-04-1 ]
  • [ 18162-48-6 ]
  • [ 131230-76-7 ]
YieldReaction ConditionsOperation in experiment
98% With dmap; triethylamine In N,N-dimethyl-formamide at 20℃; Preparation of 4-((tert-butyldimethyIsilyloxy)methyI)aniline; To a solution of (4-aminophenyl)methanol (3 g, 24.36 mmol) in DMF (85 mL) was added DMAP (0.982 g, 8.04 mmol) and triethylamine (4.07 mL, 29.2 mmol). Tertbutylchloro- dimethylsilane (4.04 g, 26.8 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was filtered to remove the salt. The filtrate was concentrated to afford 7.9 g of a red solid, which was dissolved in EtOAc (200 mL), washed with water (100 mL), saturated ammonium chloride (2 x 50 mL), water (2 x 50 mL) and brine (50 mL), the organic layer was dried over Na2SO4. Filtration and concentration afforded 4- <n="153"/>((tertbutyldimethylsilyloxy)methyl)aniline (5.66 g, 23.84 mmol, 98percent yield) as a red oil. LCMS (Table 1, Method a) R, = 3.10 min, m/z 238.19 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 6.94 (d, 2H), 6.51 (d, 2H), 4.95 (s, 2H), 4.49 (s, 2H), 0.87 (s, 9H), 0.03 (s, 6H).
96% With 1H-imidazole In dichloromethane at 20℃; for 1 h; To a solution of (4-Aminophenyl)methanol (1.50 g, 12.18 mmol) in CH2CI2 (20 ml.) was added TBDMSCI (1.84 g, 12.18 mmol) and imidazole (0.91 g, 13.40 mmol). After stirring for 1 h at room temperature, the solution was diluted with brine, and extracted with E-tOAc. The organic extract was dried (Na2SO4), filtered, and evaporated. The residue was purified by silica gel column chromatography with gradient of EtOAc (25-100percent) in Hexane to afford 67 (2.76 g, 96percent) as a light yellow oil. LRMS (ESI): (calc.) 237.4; (found) 238.2 (MH) +
82% With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 0.25 h; A- Aminobenzyl alcohol (1.5 grams, 12.18 mmol, 1 equivalent) and imidazole (830 mg, 12.18 mmol, 1 equivalent) were dissolved in DMF and cooled to 0 0C. Thereafter TBDMS-CI (1.836 grams, 12.18 mmol, 1 equivalent) was added and the reaction stirred for 15 minutes at room temperature. EtOAc was then added, the organic phase washed with saturated NH4CI and dried over MgSO4. Flash chromatography afforded the protected alcohol Compound A (2.36 grams, 82 percent yield, CAS No. 131230-76-7).
82% With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 5 h; To a solution of 4-aminobenzyl alcohol (2.0g, 16.24mmol) in dry DMF (20mL) were added tert-butyldimethylsilyl chloride (3.67g, 24.35mmol) and imidazole (2.21g, 32.46mmol), the resulting mixture was further stirred for 5hat room temperature. The reaction mixture was then diluted with saturated brine solution and extracted with CH2Cl2. The organic layer was separated and washed with brine solution for several times, then dried over anhydrous Na2SO4, evaporated under vacuum, the obtained brown residue was purified by silica gel chromatography (petroleum ether-ethyl acetate), a brown oil was obtained (3.15g, 82percent). 1H NMR (CDCl3, 400MHz) δ7.12 (d, 2H, J=8.4Hz), 6.67 (d, 2H, J=8.0Hz), 4.62 (s, 2H), 3.80 (brs, 2H), 0.91 (s, 9H), 0.08 (s, 6H).

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[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6205 - 6219
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 1, p. 280 - 290
[4] Drug Metabolism and Disposition, 2011, vol. 39, # 12, p. 2355 - 2360
[5] Patent: WO2006/102760, 2006, A1, . Location in patent: Page/Page column 71
[6] Journal of Organic Chemistry, 2001, vol. 66, # 26, p. 8815 - 8830
[7] Journal of the Chinese Chemical Society, 2012, vol. 59, # 11, p. 1449 - 1454
[8] Patent: WO2008/53479, 2008, A1, . Location in patent: Page/Page column 49-50
[9] Dyes and Pigments, 2017, vol. 136, p. 846 - 851
[10] European Journal of Medicinal Chemistry, 1995, vol. 30, # 3, p. 199 - 208
[11] Journal of Medicinal Chemistry, 2007, vol. 50, # 20, p. 4898 - 4908
[12] Chemistry - A European Journal, 2010, vol. 16, # 32, p. 9846 - 9854
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[15] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 14, p. 1921 - 1926
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[17] Patent: WO2007/72041, 2007, A1, . Location in patent: Page/Page column 71
[18] Patent: US2012/46467, 2012, A1, . Location in patent: Page/Page column 22
[19] Patent: WO2018/91633, 2018, A1, . Location in patent: Page/Page column 37; 38
  • 8
  • [ 24424-99-5 ]
  • [ 623-04-1 ]
  • [ 104060-23-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 26, p. 6627 - 6637
  • 9
  • [ 159858-21-6 ]
  • [ 623-04-1 ]
  • [ 159858-22-7 ]
YieldReaction ConditionsOperation in experiment
88% With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 48 h; Darkness DCM/MeOH=2/1 mixed solvent 60 ml was added to the reaction flask, followed by addition of Fmoc-vc2g (4.2 mmol) and1.04 g (2 eq) of PABOH was added. After stirring the dissolved portion, 2.0 g (2 eq) of EEDQ was added. The reaction system is protected from light at room temperatureStir the reaction for 2.0 days. After completion of the reaction, the mixture was concentrated under reduced pressure at 40°C to give a white solid. Collect white solids and add methyl tert-butylEthyl ether (100 ml) was stirred and filtered, and the filter cake was washed with methyl tert-butyl ether. The resulting white solid was dried at 40 °C under reduced pressure to give 2.2 g.About 88percent
85% With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 36 h; Darkness; Inert atmosphere Fmoc-Val-Cit-PABOH 2. To a solution of Fmoc-protected dipeptide 1 (0.30 g, 0.60 mmol) in CH2Cl2/MeOH (2: 1 , 9 mL) was added P-aminobenzyl alcohol (0.12 g, 0.98 mmol ) and EEDQ (0.24 g, 0.98 mmol), and the reaction mixture was stirred in the dark for 1.5 d. The solvents were evaporated, and the resultant was triturated with Et20 (25 mL). The resulting suspension was sonicated for 20 min and left to stand for 30 min. The crude product was collected by filtration and then purified by flash chromatography using a pre-packed 50 g silica column [solvent A: MeOH; solvent B: CH2C12; gradient: 0percentA / 100percentB (1 CV), 0percentA / 100percentB -→ 20percentA / 80percentB (10 CV), 20percentA / 80percentB (2 CV); flow rate: 40 mL/min; monitored at 254 and 280 nm] to afford Fmoc-protected compound 2 (0.31 g, 0.51 mmol, 85percent yield) as a brown solid. [000188] NMR (500 MHz, DMSO-d6) 6 10.00 (1 H, s), 8.13 (1 H, d, J = 7.7 Hz), 7.92 (2H, d, J = 7.5 Hz), 7.81 - 7.71 (2H, m), 7.57 (2H, d, J= 8.4 Hz), 7.49 - 7.40 (3H, m), 7.35 (2H, t, J= 7.4 Hz), 7.26 (2H, d, J = 8.3 Hz), 5.99 (1 H, t, J = 6.5 Hz), 5.43 (2H, s), 5.12 (1 H, t, J= 5.6 Hz), 4.45 (2H, d, J= 5.4 Hz), 4.32 (1H, d,J= 10.1 Hz), 4.29 - 4.19 (3H, m), 4.00 - 3.88 (1H, m), 3.12 - 2.91 (2H, m), 2.09 - 1.94 (1H, m), 1.80-1.31 (4H, m), 0.90 (3H, d, .7=6.6 Hz), 0.88 (3H, d,J=6.7 Hz). [000189] I3C NMR (125 MHz, DMSO-d6) δ 171.7, 170.9, 159.3, 156.6, 144.4, 144.2, 141.2, 138.0, 137.9, 128.1, 127.6, 127.4, 125.8, 120.6, 119.3, 66.2, 63.1, 60.6, 47.2,30.9,30.0, 27.3, 19.7, 18.8, 15.0.
82% With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol at 20℃; for 36 h; Fmoc-val-cit (1 eq),Add 2 eq of p-aminobenzyl alcohol (2 eq) to DMC / MeOH (2: 1), add EEDQ (2 eq) and shake for 1.5 days at room temperature.After completion of the reaction, the solvent is dried and precipitated with ether. Repeat after filtering with Ether. Yield: yellow solid 82percent.
77% With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 40℃; Step 3
Synthesis of (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (92)
To the suspension of compound 90 (70 g, 0.141 mol) in DCM/MeOH (1 L/500 mL) was added compound 91 (34.7 g, 0.282 mol) followed by EEDQ (69.7 g, 0.282 mol).
The mixture was stirred at 40° C. overnight.
The reaction mixture was filtered and the wet cake was suspended in EtOAc/TBME (500 mL/200 mL) and stirred for 30 min, then filtered.
The solid was washed with EtOAc/TBME to provide compound 92 as off-white solid 65 g (77percent).
1H NMR (400 MHz, DMSO-d6) δ=9.98 (s, 1H), 8.11 (d, 1H), 7.87 (d, 2H), 7.77 (m, 2H), 7.52 (d, 2H), 7.39 (m, 3H), 7.30 (m, 2H), 7.21 (d, 2H), 5.97 (m, 1H), 5.41 (s, 2H), 5.10 (m, 1H), 4.42 (m, 3H), 4.22 (m, 3H), 3.90 (m, 1H), 2.93 (m, 2H), 1.98 (m, 1H), 1.50 (m, 2H), 1.30 (m, 2H), 0.84 (m, 6H).
76% With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; A solution of compound 28 (1 g, 2.01 mmol, leq) andp-aminobenzyl alcohol (273 mg, 2.21 mmol, 1.1 eq) in a mixture of DCM/MeOH (20 mL/10 mL) was treated with EEDQ (996 mg, 4.03 mmol, 2 eq). The mixture was stirred in the dark at room temperature overnight. The solvents were removed under vacuum and the resulting solid residue was triturated with 10 mL of ethyl ether. The solid was collected by filtration and washed with ethyl ether to yield the product (925 mg, 76percent yield): 1H NMR (DMSO-5 d, J -8.5 Hz), 7.74 (2H, t, J = 6.7 Hz), 7.89 (2H, d, J = 7.6 Hz)5 8.12 (IH, d, J = 7.3 Hz); 13 C NMR (DMSO-c^) δ 18.34, 19.28, 26.84, 29.56, 30.47, 46.67, 53.05, 60.05, 62.55, 65.65, 118.71, 119.98, 125.23, 126.79, 126.94, 127.51, 137.27, 137.36, 140.55, 143.60, 143.73, 155.93, 158.69, 170.17, 171.06.
65% With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 16 h; Darkness EEDQ (840 mg, 3.4 mmol) is added to a solution containing compound [12] (870 mg, 1 .7 mmol) and p-aminobenzyl alcohol (227 mg, 1 .8 mmol) in dichloro- methane/methanol 2:1 (15 mL). The reaction is left in the dark at room temperature for 16 hours. The solvents are removed, and the resulting solid residue filtrated using diethyl ether to give product [14] as a white solid, 660 mg (65percent yield). MS: m/z 624 [M+Na]+.1H NMR (400 MHz, DMSO) δ 10.00 (bs, 1 H), 8.13 (m, 4H), 7.92 (d, J = 7.3 Hz, 2H), 7.76 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.51 - 7.10 (m, 2H), 6.02 (s, 1 H), 5.43 (m, 4H), 5.13 (s, 1 H), 4.47 (s, 3H), 4.31 (m 4H), 3.13 - 2.74 (m, 2H), 2.03 (s, 1 H), 1 .83 - 1 .55 (m, 2H), 1 .43 (s, 2H), 0.90 (d, J = 6.7 Hz, 6H).13C NMR (101 MHz, DMSO) δ 171 .2, 170.4, 158.93, 156.15, 144.6, 143.8, 140.7, 137.5, 127.6, 127.2 (2C) 125.3, 120.1 (2C), 1 18.9, 65.7, 62.6, 60.1 , 53.0, 46.7, 31 .0, 30.5, 26.7, 19.6, 18.7.

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[2] Patent: CN107789630, 2018, A, . Location in patent: Paragraph 0073; 0074; 0075
[3] Patent: WO2017/66668, 2017, A1, . Location in patent: Paragraph 000187-000189
[4] Journal of Controlled Release, 2012, vol. 160, # 3, p. 618 - 629
[5] Patent: KR2017/41562, 2017, A, . Location in patent: Paragraph 0431-0432
[6] Patent: US2016/271270, 2016, A1, . Location in patent: Paragraph 0379; 0382
[7] Patent: WO2008/34124, 2008, A2, . Location in patent: Page/Page column 79
[8] Patent: WO2018/178060, 2018, A1, . Location in patent: Page/Page column 64; 65; 67
[9] Patent: WO2014/80251, 2014, A1, . Location in patent: Sheet 16/23
[10] Bioconjugate Chemistry, 2015, vol. 26, # 11, p. 2261 - 2278
[11] Nature Communications, 2017, vol. 8, # 1,
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[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000
[3] Patent: CN107789630, 2018, A,
[4] Patent: CN108743968, 2018, A,
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Reference: [1] Patent: WO2014/80251, 2014, A1,
[2] Patent: WO2016/94505, 2016, A1,
[3] Patent: WO2016/94509, 2016, A1,
[4] Patent: WO2017/214462, 2017, A2,
[5] Patent: US2017/355769, 2017, A1,
[6] Patent: US2017/355769, 2017, A1,
[7] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000
[8] Patent: WO2017/214456, 2017, A1,
[9] Patent: CN107789630, 2018, A,
[10] Patent: WO2018/178060, 2018, A1,
[11] Patent: CN108743968, 2018, A,
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  • [ 623-04-1 ]
  • [ 159857-79-1 ]
Reference: [1] Patent: WO2016/94509, 2016, A1,
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  • [ 623-04-1 ]
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Reference: [1] Patent: US2016/271270, 2016, A1,
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