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[ CAS No. 159857-81-5 ] {[proInfo.proName]}

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Chemical Structure| 159857-81-5
Chemical Structure| 159857-81-5
Structure of 159857-81-5 * Storage: {[proInfo.prStorage]}
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Product Details of [ 159857-81-5 ]

CAS No. :159857-81-5 MDL No. :MFCD22200431
Formula : C35H43N7O11 Boiling Point : -
Linear Structure Formula :- InChI Key :HYSPJPGXSALJRR-DHIFEGFHSA-N
M.W : 737.76 Pubchem ID :57587849
Synonyms :
Maleimidocaproyl-L-valine-L-citrulline-p-aminobenzyl alcohol p-nitrophenyl carbonate;MC-VC-PAB-PNP

Calculated chemistry of [ 159857-81-5 ]

Physicochemical Properties

Num. heavy atoms : 53
Num. arom. heavy atoms : 12
Fraction Csp3 : 0.4
Num. rotatable bonds : 25
Num. H-bond acceptors : 11.0
Num. H-bond donors : 4.0
Molar Refractivity : 195.09
TPSA : 266.35 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -9.26 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.17
Log Po/w (XLOGP3) : 2.17
Log Po/w (WLOGP) : 2.04
Log Po/w (MLOGP) : -0.08
Log Po/w (SILICOS-IT) : 0.33
Consensus Log Po/w : 1.53

Druglikeness

Lipinski : 2.0
Ghose : None
Veber : 2.0
Egan : 1.0
Muegge : 4.0
Bioavailability Score : 0.17

Water Solubility

Log S (ESOL) : -4.3
Solubility : 0.0371 mg/ml ; 0.0000503 mol/l
Class : Moderately soluble
Log S (Ali) : -7.4
Solubility : 0.0000296 mg/ml ; 0.0000000401 mol/l
Class : Poorly soluble
Log S (SILICOS-IT) : -6.06
Solubility : 0.000646 mg/ml ; 0.000000875 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 4.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 5.65

Safety of [ 159857-81-5 ]

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 [ 159857-81-5 ]

* 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 [ 159857-81-5 ]
  • Downstream synthetic route of [ 159857-81-5 ]

[ 159857-81-5 ] Synthesis Path-Upstream   1~14

  • 1
  • [ 159857-80-4 ]
  • [ 5070-13-3 ]
  • [ 159857-81-5 ]
YieldReaction ConditionsOperation in experiment
57% With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 23℃; for 20 h; To a solution of Compound 11 (500 mg, 0.87 mmol) and bis(4-nitrophenyl) carbonate (bis-PNP) (2.64 g, 8.72 mmol) in DCM:DMF (8:2, 25 mL) was added DIPEA (0.45 mL, 2.61 mmol). The reaction mixture was stirred for 20 h at 23 °C and poured onto a silica gel column (DCM:CH3OH, from 50:1 to 10:1 ) to afford pure target Compound 9 (364 mg, 57percent). Rf= 0.40 (CH2CI2:CH3OH, 9:1 ).1H NMR (400 MHz, CDCI3/CD3OD): δ 9.45 (s, 1 H), 8.23 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 6.65 (s, 2H), 5.20 (s, 2H), 4.56 (dt, J = 10.5, 5.4 Hz, 1 H), 4.15 (d, J = 7.2 Hz, 1 H), 3.46 (dd, J = 8.0, 6.4 Hz, 2H), 3.16-2.89 (m, 2H), 2.21 (dd, J = 8.3, 6.6 Hz, 2H), 2.06-1 .97 (m, 1 H), 1.90-1.83 (m, 1 H), 1.73-1.46 (m, 7H), 1.34- 1.20 (m, 2H), 0.91 (d, J = 6.7 Hz, 3H), 0.90 (d, = 6.7 Hz, 3H).13C NMR (125 MHz, CDCI3/CD3OD) δ 174.4, 172.4, 171.1 , 170.6, 160.5, 155.5, 152.5, 145.3, 138.7, 134.1 , 129.9, 129.5, 125.2, 121.8, 120.0, 70.6, 59.0, 53.2, 37.5, 35.8, 30.6, 29.6, 29.3, 28.1 , 26.2, 26.2, 25.1 , 19.1 , 18.1. ESI-MS m/z: Calcd. for CasH^N O^: 737.3. Found: 738.3 (M+H)+.
57% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 15 h; Inert atmosphere Preparation Example 1-2: Preparation of Compound (II-3) (0054) (0055) Under an argon stream, 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)hexanamide(5.0 g, 8.7 mmol, Dubowchik et al., Bioconjugate Chem., 2002, 13 (4), pp 855-869) was dissolved in 60 mL of anhydrous dimethylformamide, added with N, N-diisopropylethylamine (3.0 mL, 17.4 mmol), and then cooled to 0°C. To the mixture was added at once bis(4-nitrophenyl) carbonate (7.94 g, 26.1 mmol), followed by stirring at room temperature for 15 hrs. After completion of the reaction, the reaction mixture was concentrated in a high vacuum, and the concentrate was purified by silica gel column chromatography to obtain 4-((S)-2-((S)-2-(6-(2 ,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl (4-nitrophenyl) carbonate (3.65 g, 57 percent) as a pale yellow solid. (0056) 1H NMR (400 MHz, DMSO-d6) δ 0.83 (d, J = 6.8 Hz, 3 H), 0.86 (d, J = 6.8 Hz, 3 H), 1.09 (t, J = 7.2 Hz, 1 H), 1.19 (m, 2 H), 1.34 - 1.76 (m, 7 H), 1.96 (m, 1 H), 2.15 (m, 2 H), 2.99 (m, 2 H), 3.37 (m, 2 H), 4.19 (t, J= 7.8 Hz, 1 H), 4.39 (m, 1 H), 5.24 (s, 2 H), 5.41 (s, 2 H), 5.97 (brt, J= 5.6 Hz, 1 H), 7.00 (s, 2H), 7.41 (d, J= 8.4 Hz, 2 H), 7.57 (d, J= 7.2 Hz, 2 H), 7.65 (d, J= 8.4 Hz, 2 H), 7.80 (d, J= 8.4 Hz, 1 H), 8.09 (d, J = 7.2 Hz, 1 H), 8.31 (d, J = 7.2 Hz, 2 H), 10.05 (brs, 1 H) (0057) Under an argon stream, 4-((S)-2-((S)-2-(6-(2, 5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl (4-nitrophenyl) carbonate (3.65 g, 4.95 mmol) was dissolved in 90 mL of anhydrous dimethylformamide, and stirred, together with t-butyl (2-aminoethyl)(methyl)carbamate (0.86 g, 4.95 mmol), at 20 - 25°C for 2 hrs. After completion of the reaction, the reaction mixture was completely concentrated in a high vaccum, and the concentrate was purified by silica gel column chromatography to obtain an amino-protected derivative of compound (II-3) (3.8 g, 99percent). (0058) LC-MS m/z: 773.5 [M+H]+ (0059) To a solution of the amino-protected derivative of compound (II-3) (146 mg, 0.186 mmol) in 5 mL of dichloromethane was dropwise added 2 mL of trifluoroacetic acid, followed by stirring at 20 - 25°C for 2 hrs. After completion of the reaction, the reaction solvent was removed by vacuum concentration, and then trifluoroacetic acid was completely removed by adding 5 mL of toluene twice to obtain a concentrated TFA salt of the title compound.
46% Inert atmosphere To stirred solution of 6-maleimidocaproyl-val-cit-PAB 38 in dry DMF under nitrogen, bis-(p-nitrophenyl)carbonate was added followed by DIPEA, resulting in a colour change from colourless to bright yellow. The solution was stirred at room temperature under nitrogen for 1 h after which the DMF was removed by high vacuum to give an oily residue. This was triturated with ethyl acetate for 15 min resulting in precipitation which was completed by the addition of ether. The solid was collected and washed well with ether and air dried to give an off-white solid. TLC [silica gel: 10 percent MeOH/DCM Rf0.46].This was purified by chromatography [silica gel: 5-10percent MeOH/DCM gradient elution] to give the activated linker 39 as a white solid 0.006 g, (46percent). MS (m/z) 738..3091 (M+H), HRMS (m/z) calculated for C35H43N7O11Na M+Na 760.2918 found 760.2922
40% With pyridine In dichloromethane at 0 - 20℃; for 3.16667 h; Inert atmosphere 168.6 mg (0.294 mmol) of mc-vc-PABOH was dissolved in 5 ml of anhydrous pyridine under nitrogen protection.Cool to about 0°C. Another 179 mg (3 eq) of PNP was dissolved in 5 ml of DCM, and it was slowly added to the reaction system. And inThe ice bath was removed after keeping at 0° C. for 10 min, and the reaction was stirred at room temperature for 3 h. After the reaction is completed, add 70ml EA and 100ml 15percentAqueous citric acid, dispense organic layer. The organic layer was washed successively with citric acid, water, saturated saline and dried over anhydrous sodium sulfate.Dry and filter. The filtrate was concentrated to dryness under reduced pressure to give a pale yellow oil. Methyl tert-butyl ether was added for crystallization to give an off-white solid.86mg, yield 40percent.
40% With pyridine In dichloromethane at 0 - 20℃; for 3.16667 h; Inert atmosphere Under the protection of nitrogen, 168.6 mg (0.294 mmol) of mc-vc-PABOH was dissolved in 5 ml of anhydrous pyridine.The reaction system was cooled to about 0 °C. Further, PNP 179 mg (3 eq) was dissolved in 5 ml of DCM, and then slowly added to the reaction system.And after 10 minutes at 0 ° C, remove the ice bath.The reaction was further stirred at room temperature for 3 h. The reaction is completed,Add 70 ml EA and 100 ml 15percent aqueous citric acid solution.The organic layer was separated. The organic layer was washed successively with citric acid, water and saturated brine.Dry over anhydrous sodium sulfate and filter.The filtrate was concentrated to dryness under reduced pressure to give a pale yellow oil.Crystallization with methyl tert-butyl ether gave 86 mg of an off-white solid.The yield was 40percent.

Reference: [1] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[2] Patent: WO2017/66668, 2017, A1, . Location in patent: Paragraph 000199; 000200
[3] Patent: WO2014/191578, 2014, A1, . Location in patent: Page/Page column 137-138
[4] Patent: EP2927227, 2015, A1, . Location in patent: Paragraph 0051; 0052; 0053; 0054; 0055-0059
[5] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000
[6] Patent: WO2016/46574, 2016, A1, . Location in patent: Page/Page column 76
[7] Patent: CN107789630, 2018, A, . Location in patent: Paragraph 0082; 0083; 0084
[8] Patent: CN108743968, 2018, A, . Location in patent: Paragraph 0025; 0026; 0027
[9] Journal of Medicinal Chemistry, 2018, vol. 61, # 17, p. 7991 - 8000
[10] Patent: WO2007/8603, 2007, A1, . Location in patent: Page/Page column 137; 166; 167
[11] Patent: WO2007/8848, 2007, A2, . Location in patent: Page/Page column 108; 137
[12] Patent: EP2486933, 2015, B1, . Location in patent: Paragraph 0494; 0497
  • 2
  • [ 55750-53-3 ]
  • [ 159857-81-5 ]
Reference: [1] Patent: WO2014/191578, 2014, A1,
[2] Patent: WO2017/66668, 2017, A1,
[3] Patent: WO2017/66668, 2017, A1,
[4] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[5] Patent: CN107789630, 2018, A,
[6] Patent: CN108743968, 2018, A,
  • 3
  • [ 159858-22-7 ]
  • [ 159857-81-5 ]
Reference: [1] Patent: EP2486933, 2015, B1,
[2] Patent: WO2017/66668, 2017, A1,
[3] Patent: WO2017/66668, 2017, A1,
[4] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[5] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000
[6] Patent: CN107789630, 2018, A,
[7] Patent: CN108743968, 2018, A,
  • 4
  • [ 159857-79-1 ]
  • [ 159857-81-5 ]
Reference: [1] Patent: EP2486933, 2015, B1,
[2] Patent: WO2016/46574, 2016, A1,
[3] Patent: WO2017/66668, 2017, A1,
[4] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[5] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000
[6] Patent: CN107789630, 2018, A,
[7] Patent: CN108743968, 2018, A,
  • 5
  • [ 55750-63-5 ]
  • [ 159857-81-5 ]
Reference: [1] Patent: WO2017/66668, 2017, A1,
[2] Patent: WO2017/66668, 2017, A1,
[3] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[4] Patent: CN107789630, 2018, A,
[5] Patent: CN108743968, 2018, A,
  • 6
  • [ 159858-21-6 ]
  • [ 159857-81-5 ]
Reference: [1] Patent: WO2017/66668, 2017, A1,
[2] Patent: WO2017/66668, 2017, A1,
[3] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[4] Patent: CN107789630, 2018, A,
[5] Patent: CN108743968, 2018, A,
  • 7
  • [ 623-04-1 ]
  • [ 159857-81-5 ]
Reference: [1] Patent: WO2014/191578, 2014, A1,
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000
[3] Patent: CN107789630, 2018, A,
[4] Patent: CN108743968, 2018, A,
  • 8
  • [ 130878-68-1 ]
  • [ 159857-81-5 ]
Reference: [1] Patent: WO2017/66668, 2017, A1,
[2] Patent: WO2017/66668, 2017, A1,
[3] Patent: WO2017/66668, 2017, A1,
[4] Patent: WO2017/66668, 2017, A1,
[5] Patent: CN107789630, 2018, A,
[6] Patent: CN108743968, 2018, A,
  • 9
  • [ 159857-80-4 ]
  • [ 7693-46-1 ]
  • [ 159857-81-5 ]
Reference: [1] Patent: WO2017/66668, 2017, A1, . Location in patent: Sheet 3
  • 10
  • [ 372-75-8 ]
  • [ 159857-81-5 ]
Reference: [1] Patent: WO2017/66668, 2017, A1,
[2] Patent: WO2017/66668, 2017, A1,
[3] Patent: WO2017/66668, 2017, A1,
[4] Patent: WO2017/66668, 2017, A1,
[5] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
  • 11
  • [ 68858-20-8 ]
  • [ 159857-81-5 ]
Reference: [1] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[2] Patent: CN107789630, 2018, A,
[3] Patent: CN108743968, 2018, A,
  • 12
  • [ 60-32-2 ]
  • [ 159857-81-5 ]
Reference: [1] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[2] Patent: CN107789630, 2018, A,
[3] Patent: CN108743968, 2018, A,
  • 13
  • [ 1037794-22-1 ]
  • [ 159857-81-5 ]
Reference: [1] Patent: WO2017/66668, 2017, A1,
[2] Patent: WO2017/66668, 2017, A1,
[3] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000
  • 14
  • [ 870487-04-0 ]
  • [ 159857-81-5 ]
Reference: [1] Patent: WO2017/66668, 2017, A1,
[2] Patent: WO2017/66668, 2017, A1,
[3] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000
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