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[ CAS No. 159857-79-1 ] {[proInfo.proName]}

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Chemical Structure| 159857-79-1
Chemical Structure| 159857-79-1
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Product Details of [ 159857-79-1 ]

CAS No. :159857-79-1 MDL No. :MFCD22381209
Formula : C18H29N5O4 Boiling Point : -
Linear Structure Formula :- InChI Key :VEGGTWZUZGZKHY-GJZGRUSLSA-N
M.W : 379.45 Pubchem ID :54387473
Synonyms :
Valine-Citrulline-p-Aminobenzylcarbamate;VC-PAB

Calculated chemistry of [ 159857-79-1 ]

Physicochemical Properties

Num. heavy atoms : 27
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.5
Num. rotatable bonds : 13
Num. H-bond acceptors : 5.0
Num. H-bond donors : 6.0
Molar Refractivity : 101.95
TPSA : 159.57 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -8.97 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.59
Log Po/w (XLOGP3) : -0.5
Log Po/w (WLOGP) : -0.31
Log Po/w (MLOGP) : -0.04
Log Po/w (SILICOS-IT) : 0.25
Consensus Log Po/w : 0.2

Druglikeness

Lipinski : 1.0
Ghose : None
Veber : 2.0
Egan : 1.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.18
Solubility : 24.8 mg/ml ; 0.0655 mol/l
Class : Very soluble
Log S (Ali) : -2.38
Solubility : 1.57 mg/ml ; 0.00414 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.58
Solubility : 0.0989 mg/ml ; 0.000261 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 3.32

Safety of [ 159857-79-1 ]

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 [ 159857-79-1 ]

* 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 [ 159857-79-1 ]
  • Downstream synthetic route of [ 159857-79-1 ]

[ 159857-79-1 ] Synthesis Path-Upstream   1~15

  • 1
  • [ 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,
  • 2
  • [ 159858-22-7 ]
  • [ 159857-79-1 ]
YieldReaction ConditionsOperation in experiment
96% With diethylamine In N,N-dimethyl-formamide for 2 h; [0438] Fmoc-val-cit-PAB-OH (14.61 g, 24.3 mmol, 1.0 eq.; see, e.g., U.S. Patent No. 6,214,345 to Firestone et al.) was diluted with DMF (120 mL, 0.2 M) and to this solution was added a diethylamine (60 mL). The reaction was monitored by HPLC and found to be complete in 2 h. The reaction mixture was concentrated and the resulting residue was precipitated using ethyl acetate (ca. 100 mL) under sonication over for 10 min. Ether (200 mL) was added and the precipitate was further sonicated for 5 min. The solution was allowed to stand for 30 min. without stirring and was then filtered and dried under high vacuum to provide Val-cit-P AB-OH, which was used in the next step without further purification. Yield: 8.84 g (96percent). Val-cit-PAB-OH (8.0 g, 21 mmol) was diluted with DMF (110 mL) and the resulting solution was treated with MC-OSu (Willner et at, 1993, Bioconjugate Chem. 4:521; 6.5 g, 21 mmol, 1.0 eq.). The reaction was complete according to HPLC after 2 h. The reaction mixture was concentrated and the resulting oil was precipitated using ethyl acetate (50 mL). After sonicating for 15 min, ether (400 mL) was added and the mixture was sonicated further until all large particles were broken up. The solution was then filtered and the solid dried to provide an off-white solid intermediate. Yield: 11.63 g (96percent); ES-MS m/z 757.9 [M-H]
96% With diethylamine In N,N-dimethyl-formamide for 2 h; [0454] Fmoc-val-cit-P AB-OH (14.61 g, 24.3 mmol, 1.0 eq., see, e.g., U.S. Patent No. 6,214,345 to Firestone et al.) was diluted with DMF (120 mL, 0.2 M) and to this solution was added a diethylamine (60 mL). The reaction was monitored by HPLC and found to be complete in 2 h. The reaction mixture was concentrated and the resulting residue was precipitated using ethyl acetate (ca. 100 mL) under sonication for 10 min. Ether (200 mL) was added and the precipitate was further sonicated for 5 min. The solution was allowed to stand for 30 min. without stirring and was then filtered and dried under high vacuum to provide Val-cit-P AB-OH, which was used in the next step without further purification. Yield: 8.84 g (96percent). Val-cit-P AB-OH (8.0 g, 21 mmol) was diluted with DMF (110 mL) and the resulting solution was treated with MC-OSu (Willner et al, 1993, EPO <DP n="138"/>Bioconjugate Chem. 4:521; 6.5 g, 21 mmol, 1.0 eq.). The reaction was complete according to HPLC after 2 h. The reaction mixture was concentrated and the resulting oil was precipitated using ethyl acetate (50 mL). After sonicating for 15 min, ether (400 niL) was added and the mixture was sonicated further until all large particles were broken up. The solution was then filtered and the solid dried to provide an off-white solid intermediate. Yield: 11.63 g (96percent); ES-MS m/z 757.9 [M-H]
96% With diethylamine In N,N-dimethyl-formamide for 2 h; Example 1
- Preparation of compound AB
Fmoc-val-cit-PAB-OH (14.61 g, 24.3 mmol), 1.0 eq., ) was diluted with DMF (120 mL, 0.2 M) and to this solution was added a diethylamine (60 mL).
The reaction was monitored by HPLC and found to be complete in 2 h.
The reaction mixture was concentrated and the resulting residue was precipitated using ethyl acetate (ca. 100 mL) under sonication over for 10 min.
Ether (200 mL) was added and the precipitate was further sonicated for 5 min.
The solution was allowed to stand for 30 min. without stirring and was then filtered and dried under high vacuum to provide Val-cit-PAB-OH, which was used in the next step without further purification. Yield: 8.84 g (96percent). Val-cit-PAB-OH (8.0 g, 21 mmol) was diluted with DMF (110 mL) and the resulting solution was treated with MC-OSu (Willner et al., (1993) Bioconjugate Chem. 4:521; 6.5 g, 21 mmol, 1.0 eq.).
93% With diethylamine In 1-methyl-pyrrolidin-2-one at 20℃; for 16 h; Inert atmosphere Val-Cit-PABOH 3. To a solution of Fmoc-protected compound 2 (0.31 g, 0.51 mmol) in NMP (5 mL) was added diethylamine (1 mL), and the reaction mixture was stirred for 16 h at ambient temperature. The solvent was then evaporated under reduced pressure, and the resulting oil was triturated with CH2C12, and the mixture was sonicated for 30 min. The solid was collected by filtration and washed with CH2C12 (3 x 10 mL) to afford desired compound 3 (0.19 g, 0.49 mmol, 93percent yield) as a brown solid. [000191] NMR (500 MHz, DMSO-d6) δ 10.03 (1H, s), 8.18 (1H, d, J= 6.2 Hz), 7.52 (2H, d, J= 8.4 Hz), 7.22 (2H, d,J = 8.4 Hz), 5.97 (1H, t, J = 5.8 Hz), 5.39 (2H, s), 5.08 (1H, s), 4.51 - 4.43 (3H, m), 3.13 - 2.95 (2H, m), 2.92 (1H, dd, J= 13.2, 6.3 Hz), 1.93 (2H, dd, J= 11.9, 6.5 Hz), 1.74 - 1.61 (1H, m), 1.61 - 1.49 (1H, m), 1.47-1.29 (2H,m),0.87 (3H, d, ,7=6.8 Hz), 0.78 (3H, d, .7=6.8 Hz). [000192] nC NMR (125 MHz, DMSO-d6) δ 170.9, 159.3, 137.9, 137.9, 127.4, 119.4, 63.0, 59.8, 53.0, 31.6,30.5,27.1, 19.8, 17.5.
90% at 20℃; for 24 h; 490 mg (0.815 mmol) of Fmoc-vc-PABOH was added to 10 ml of NMP, dissolved under stirring, and then diethylamine was added.2ml. The reaction was stirred at room temperature for 24 h. After completion of the reaction, the mixture was concentrated under reduced pressure at 40° C., and 20 ml of DCM was added to the resulting oil and stirred.The crystals were crystallized and filtered. The filter cake was washed with DCM and the resulting solid was dried under reduced pressure to give 277 mg in 90percent yield.
90% With diethylamine In 1-methyl-pyrrolidin-2-one at 20℃; for 24 h; Fmoc-vc-PABOH 490 mg (0.815 mmol) was added to 10 ml of NMP and stirred to dissolve, and then 2 ml of diethylamine was added.The reaction was stirred at room temperature for 24 h. After completion of the reaction, the mixture was concentrated under reduced pressure at 40 ° C.Crystallization, filtration, filter cake washed with DCM,The obtained solid was dried under reduced pressure to give 277 mg.The yield was 90percent.
72% With piperidine In N,N-dimethyl-formamide at 20℃; To a solution of compound 29 (622 mg, 1.03 mmol) in 10 mL of anhydrous DMF was added piperidine (2 mL). The mixture was stirred at room temperature overnight and then the solvents were evaporated under vacuum. The residue was triturated with DCM and the resulting solid was filtered and washed with DCM to give the product (283 mg, 72percent yield): 1H NMR (DMSO-^) δ 0.79 (3H, d, J = 6.7 Hz), 0.89 (3H, d, J = 6.7 Hz), 1.38-1.42 (2H, m), 1.52-1.68 (2H, m), 1.94 (IH, sext, J = 6.3 Hz), 2.89-3.01 (2H, m), 3.05 (IH, d, J = 4.7 Hz), 4.46 (2H, s), 5.09 (IH, brs), 5.40 (2H, s), 5.98 (IH, t, J = 5.3 Hz), 7.23 (2H, d, J - 8.2 Hz), 7.54 (2H, d, J = 8.5 Hz), 8.14 (IH, brs), 10.03 (IH, s); 13 C NMR (DMSO-
60% With piperidine In N,N-dimethyl-formamide at 20℃; for 3 h; Piperidine (2.2 mL) is added to a solution of compound [14] (660 mg, 1 .09 mmol) in anhydrous dimethylformamide (5 mL) and the reaction left at room temperature for 3 h. The solvent is removed under vacuum and the residue treated with di- chloromethane in order to obtain a solid that is filtered to give product [15], 240 mg (60percent mg). MS: m/z 380 [M+H]+.1H NMR (400 MHz, DMSO) δ 10.1 1 (s, 1 H), 8.25 (s, 1 H), 7.58 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 6.10 (s, 1 H), 5.46 (s, 2H), 4.48 (m, 3H), 3.23 - 3.09 (m, 2H), 3.1 1 - 2.88 (m, 2H), 1 .99 (dd, J = 12.2, 6.4 Hz, 2H), 1 .99 (dd, J = 12.2, 6.4 Hz, 1 H), 1 .81 - 1 .55 (m, 2H), 1 .55 - 1 .28 (m, 2H), 1 .04 - 0.68 (m, 6H).13C NMR (101 MHz, DMSO) δ 173.3, 170.4, 158.9, 137.5, 126.9 (2C), 125.3, 1 19.9 (2C), 62.6, 59.3, 52.6, 31 .1 , 29.9, 26.6, 19.3, 17.0 (2C).
597 mg With piperidine In N,N-dimethyl-formamide at 20℃; for 1 h; Step 2.
To a solution of compound 44-3 (2.14 mmol) in DMF (10 mL) was added compound 44-4 (0.6 mL, 4.5 mmol) and stirred at r.t. for 1 h. The mixture was concentrated and washed with MTBE (30 mL x 3), filtered and the filtrate was concentrated to give 44-5 (597 mg, Yield: 70 percent).

Reference: [1] Patent: WO2007/8603, 2007, A1, . Location in patent: Page/Page column 137; 165; 166
[2] Patent: WO2007/8848, 2007, A2, . Location in patent: Page/Page column 108; 136; 137
[3] Patent: EP2486933, 2015, B1, . Location in patent: Paragraph 0495
[4] Patent: WO2017/66668, 2017, A1, . Location in patent: Paragraph 000190-000192
[5] Patent: CN107789630, 2018, A, . Location in patent: Paragraph 0076; 0077; 0078
[6] Patent: CN108743968, 2018, A, . Location in patent: Paragraph 0019; 0020; 0021
[7] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[8] Patent: WO2008/34124, 2008, A2, . Location in patent: Page/Page column 79
[9] Patent: WO2018/178060, 2018, A1, . Location in patent: Page/Page column 64; 65; 67; 68
[10] Patent: WO2014/80251, 2014, A1, . Location in patent: Sheet 16/23
[11] Patent: WO2015/95227, 2015, A2, . Location in patent: Page/Page column 144; 145
[12] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000
[13] Chemical Science, 2018, vol. 9, # 31, p. 6490 - 6496
  • 3
  • [ 870487-09-5 ]
  • [ 159857-79-1 ]
Reference: [1] Patent: WO2016/94505, 2016, A1,
[2] Patent: WO2016/94509, 2016, A1, . Location in patent: Paragraph 0001029
[3] Patent: WO2017/214462, 2017, A2, . Location in patent: Page/Page column 596
[4] Patent: US2017/355769, 2017, A1, . Location in patent: Paragraph 2008
[5] Patent: WO2017/214456, 2017, A1, . Location in patent: Page/Page column 294
[6] Patent: US2018/133340, 2018, A1, . Location in patent: Paragraph 0137; 0138
  • 4
  • [ 870487-09-5 ]
  • [ 76-05-1 ]
  • [ 159857-79-1 ]
Reference: [1] Patent: WO2016/94509, 2016, A1, . Location in patent: Paragraph 0001029
[2] Patent: US2017/355769, 2017, A1, . Location in patent: Paragraph 2008
  • 5
  • [ 68858-20-8 ]
  • [ 159857-79-1 ]
Reference: [1] Patent: WO2014/80251, 2014, A1,
[2] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[3] Patent: CN107789630, 2018, A,
[4] Patent: WO2018/178060, 2018, A1,
[5] Patent: CN108743968, 2018, A,
  • 6
  • [ 130878-68-1 ]
  • [ 159857-79-1 ]
Reference: [1] Patent: WO2014/80251, 2014, A1,
[2] Patent: WO2015/95227, 2015, A2,
[3] Patent: WO2017/66668, 2017, A1,
[4] Patent: WO2017/66668, 2017, A1,
[5] Patent: CN107789630, 2018, A,
[6] Patent: WO2018/178060, 2018, A1,
[7] Patent: CN108743968, 2018, A,
  • 7
  • [ 159858-21-6 ]
  • [ 159857-79-1 ]
Reference: [1] Patent: WO2014/80251, 2014, A1,
[2] Patent: WO2017/66668, 2017, A1,
[3] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[4] Patent: CN107789630, 2018, A,
[5] Patent: WO2018/178060, 2018, A1,
[6] Patent: CN108743968, 2018, A,
  • 8
  • [ 623-04-1 ]
  • [ 159857-79-1 ]
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,
  • 9
  • [ 1037794-22-1 ]
  • [ 159857-79-1 ]
Reference: [1] Patent: WO2015/95227, 2015, A2,
[2] Patent: WO2016/94505, 2016, A1,
[3] Patent: WO2016/94509, 2016, A1,
[4] Patent: WO2017/214462, 2017, A2,
[5] Patent: WO2017/66668, 2017, A1,
[6] Patent: US2017/355769, 2017, A1,
[7] Patent: US2017/355769, 2017, A1,
[8] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000
[9] Patent: WO2017/214456, 2017, A1,
  • 10
  • [ 870487-04-0 ]
  • [ 159857-79-1 ]
Reference: [1] Patent: WO2015/95227, 2015, A2,
[2] Patent: WO2016/94509, 2016, A1,
[3] Patent: WO2017/66668, 2017, 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,
  • 11
  • [ 372-75-8 ]
  • [ 159857-79-1 ]
Reference: [1] Patent: WO2015/95227, 2015, A2,
[2] Patent: WO2017/66668, 2017, A1,
[3] Patent: WO2017/66668, 2017, A1,
[4] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
  • 12
  • [ 1037793-80-8 ]
  • [ 159857-79-1 ]
Reference: [1] Patent: WO2015/95227, 2015, A2,
  • 13
  • [ 623-04-1 ]
  • [ 159857-79-1 ]
Reference: [1] Patent: WO2016/94509, 2016, A1,
  • 14
  • [ 870487-04-0 ]
  • [ 159857-79-1 ]
Reference: [1] Patent: WO2016/94509, 2016, A1,
  • 15
  • [ 1037794-22-1 ]
  • [ 159857-79-1 ]
Reference: [1] Patent: WO2016/94509, 2016, A1,
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